C-18 but the lengths are not predominantly longer than C-30.The branched and ring structures are located near the end of the chain for those waxes that are predominantly normal-alkanic.","The viscosity of normal-alkanic waxes is <10 mm2/s (at 100° C.) and the combined number average molecular weight is <600 g/mole.","The iso-alkanic waxes typically have carbon lengths that are predominantly greater than C-30.The branched chains and ring structures are located randomly along the carbon chain in those waxes that are predominantly iso-alkanic.","The viscosity of iso-alkanic waxes is greater than 10 mm2/s (at 100° C.) and the combined number average molecular weight is >600 g/mole.","Synthetic waxes are produced by means that are atypical for petroleum wax production and are thus not considered petroleum wax.","The synthetic waxes may include waxes containing branched alkanes and copolymerized with monomers such as, but not limited to propylene, polyethylene, and Fischer Tropsch type waxes.","Polyethylene wax is a synthetic wax containing alkane units of varying lengths having attached thereto ethylene monomers.","Waxes and fats are conventionally used for the adjustment of the texture and for softening of the chewing gum base when preparing chewing gum bases.","Any conventionally used and suitable type of natural and synthetic wax and fat may be used, such as for instance rice bran wax, polyethylene wax, petroleum wax (refined paraffin and microcrystalline wax), sorbitan monostearate, tallow, propylene glycol, paraffin, beeswax, carnauba wax, candelilla wax, cocoa butter, degreased cocoa powder and any suitable oil or fat, such as completely or partially hydrogenated vegetable oils or completely or partially hydrogenated animal fats.","Antioxidants prolong shelf life and storage of gum base, finished gum or their respective components including fats and flavor oils.","Antioxidants suitable for use in gum base include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), betacarotenes, tocopherols, acidulants such as Vitamin C, propyl gallate, other synthetic and natural types or mixtures thereof.","A chewing gum may include other conventional components such as sweeteners, including bulk sweeteners, sugar sweeteners, sugar-substitute sweeteners, artificial sweeteners, high-intensity sweeteners, or a combination thereof.","Bulk sweeteners may constitute from about 5 to about 95% by weight of the chewing gum, more typically about 20 to about 80% by weight, about 30 to 70%, or about 30 to 60% by weight of the gum.","Useful sugar sweeteners are saccharide-containing components commonly known in the chewing gum art including, but not limited to, sucrose, dextrose, maltose, dextrins, trehalose, D-tagatose, dried invert sugar, fructose, levulose, galactose, corn syrup solids, and the like, alone or in combination.","Sorbitol can be used as a non-sugar sweetener.","Other useful non-sugar sweeteners include, but are not limited to, other sugar alcohols such as mannitol, xylitol, hydrogenated starch hydrolysates, maltitol, isomalt, erythritol, lactitol and the like, alone or in combination.","High intensity artificial sweetening agents can also be used alone or in combination with the above sweeteners.","Non-limiting examples of high intensity sweeteners include sucralose, aspartame, salts of acesulfame, alitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, sterioside and the like, alone or in combination.","In order to provide longer lasting sweetness and flavor perception, it may be desirable to encapsulate or otherwise control the release of at least a portion of the artificial sweeteners.","Techniques such as wet granulation, wax granulation, spray drying, spray chilling, fluid bed coating, conservation, encapsulation in yeast cells and fiber extrusion may be used to achieve desired release characteristics.","Encapsulation of sweetening agents can also be provided using another chewing gum component such as a resinous compound.","Usage level of the artificial sweetener will vary considerably and will depend on factors such as potency of the sweetener, rate of release, desired sweetness of the product, level and type of flavor used and cost considerations.","The active level of artificial sweetener may vary from about 0.001 to about 8% by weight, and often ranges from about 0.02 to about 8% by weight.","When carriers used for encapsulation are included, the usage level of the encapsulated sweetener will be proportionately higher.","Combinations of sugar and/or non-sugar sweeteners may be used if desired.","A chewing gum and/or gum base may include one or more fillers/texturizers, such as magnesium and calcium carbonate, sodium sulfate, ground limestone, silicate compounds such as magnesium and aluminum silicate, kaolin and clay, aluminum oxide, silicium oxide, talc, titanium oxide, mono-, di- and tri-calcium phosphates, cellulose polymers, such as wood, and combinations thereof.","A number of other well-known chewing gum components may be present, including but not limited to waxes, fats, softeners, fillers, flavors, anti-oxidants, emulsifiers, coloring agents, binding agents and acidulates.","The chewing gum may be provided with an outer coating, such as a hard coating, soft coating, edible film-coating, or any combination thereof.","In some aspects, nicotine is compounded along with other components of the gum base such that nicotine is substantially uniformly contained in the gum base.","Nicotine or a nicotine complex may be provided on an adsorbent such as finely divided silicic acid, amorphous silica, magnesium silicate, calcium silicate, kaolin, clays, crystalline aluminosilicates, macaloid bentonite, activated carbon, alumina, hydroxylapatite, microcrystalline cellulose, or any combination thereof.","Nicotine may be encapsulated to provide a desired controlled or sustained release thereof.","An example of a chewing gum that provides for sustained release of nicotine is described in U.S. 2007/0014887, the disclosure of which is hereby incorporated by reference.","Alternatively, isomyosmine may be infused into an outer portion of a chewing gum than contains nicotine.","A similar release profile may be achieved via an oral dosage form such as a tablet, capsule, or the like.","For example, a tablet may have a core layer containing nicotine to provide a sustained release thereof, and an outer layer containing isomyosmine to provide an immediate release thereof.","Other combinations are possible.","For example, one or both of the layers may contain both isomyosmine and nicotine so that the respective active component(s) is released in both an immediate- and a sustained release manner.","In other aspects, volatile delivery vehicles may be used for administering the active component(s) including isomyosmine, such as an inhaler or e-cigarette.","In still other aspects, the active component(s) are administered transmucosally such as via a nasal spray, or transdermally such as via a transdermal patch.","A therapeutically effective amount of a therapeutic compound disclosed herein generally is in the range of about 0.001 mg/kg/day to about 100 mg/kg/day.","In aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may be, e.g., at least 0.001 mg/kg/day, at least 0.01 mg/kg/day, at least 0.1 mg/kg/day, at least 1.0 mg/kg/day, at least 5.0 mg/kg/day, at least 10 mg/kg/day, at least 15 mg/kg/day, at least 20 mg/kg/day, at least 25 mg/kg/day, at least 30 mg/kg/day, at least 35 mg/kg/day, at least 40 mg/kg/day, at least 45 mg/kg/day, or at least 50 mg/kg/day.","In other aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may be in the range of, e.g., about 0.001 mg/kg/day to about 10 mg/kg/day, about 0.001 mg/kg/day to about 15 mg/kg/day, about 0.001 mg/kg/day to about 20 mg/kg/day, about 0.001 mg/kg/day to about 25 mg/kg/day, about 0.001 mg/kg/day to about 30 mg/kg/day, about 0.001 mg/kg/day to about 35 mg/kg/day, about 0.001 mg/kg/day to about 40 mg/kg/day, about 0.001 mg/kg/day to about 45 mg/kg/day, about 0.001 mg/kg/day to about 50 mg/kg/day, about 0.001 mg/kg/day to about 75 mg/kg/day, or about 0.001 mg/kg/day to about 100 mg/kg/day.","In yet other aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may be in the range of, e.g., about 0.01 mg/kg/day to about 10 mg/kg/day, about 0.01 mg/kg/day to about 15 mg/kg/day, about 0.01 mg/kg/day to about 20 mg/kg/day, about 0.01 mg/kg/day to about 25 mg/kg/day, about 0.01 mg/kg/day to about 30 mg/kg/day, about 0.01 mg/kg/day to about 35 mg/kg/day, about 0.01 mg/kg/day to about 40 mg/kg/day, about 0.01 mg/kg/day to about 45 mg/kg/day, about 0.01 mg/kg/day to about 50 mg/kg/day, about 0.01 mg/kg/day to about 75 mg/kg/day, or about 0.01 mg/kg/day to about 100 mg/kg/day.","In still other aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may be in the range of, e.g., about 0.1 mg/kg/day to about 10 mg/kg/day, about 0.1 mg/kg/day to about 15 mg/kg/day, about 0.1 mg/kg/day to about 20 mg/kg/day, about 0.1 mg/kg/day to about 25 mg/kg/day, about 0.1 mg/kg/day to about 30 mg/kg/day, about 0.1 mg/kg/day to about 35 mg/kg/day, about 0.1 mg/kg/day to about 40 mg/kg/day, about 0.1 mg/kg/day to about 45 mg/kg/day, about 0.1 mg/kg/day to about 50 mg/kg/day, about 0.1 mg/kg/day to about 75 mg/kg/day, or about 0.1 mg/kg/day to about 100 mg/kg/day.","In other aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may be in the range of, e.g., about 1 mg/kg/day to about 10 mg/kg/day, about 1 mg/kg/day to about 15 mg/kg/day, about 1 mg/kg/day to about 20 mg/kg/day, about 1 mg/kg/day to about 25 mg/kg/day, about 1 mg/kg/day to about 30 mg/kg/day, about 1 mg/kg/day to about 35 mg/kg/day, about 1 mg/kg/day to about 40 mg/kg/day, about 1 mg/kg/day to about 45 mg/kg/day, about 1 mg/kg/day to about 50 mg/kg/day, about 1 mg/kg/day to about 75 mg/kg/day, or about 1 mg/kg/day to about 100 mg/kg/day.","In yet other aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may be in the range of, e.g., about 5 mg/kg/day to about 10 mg/kg/day, about 5 mg/kg/day to about 15 mg/kg/day, about 5 mg/kg/day to about 20 mg/kg/day, about 5 mg/kg/day to about 25 mg/kg/day, about 5 mg/kg/day to about 30 mg/kg/day, about 5 mg/kg/day to about 35 mg/kg/day, about 5 mg/kg/day to about 40 mg/kg/day, about 5 mg/kg/day to about 45 mg/kg/day, about 5 mg/kg/day to about 50 mg/kg/day, about 5 mg/kg/day to about 75 mg/kg/day, or about 5 mg/kg/day to about 100 mg/kg/day.","Dosing can be single dosage or cumulative (serial dosing), and can be readily determined by one skilled in the art.","For instance, treatment of a substance addiction may comprise a one-time administration of an effective dose of a pharmaceutical composition disclosed herein.","Alternatively, treatment may comprise multiple administrations of an effective dose of a pharmaceutical composition carried out over a range of time periods, such as, e.g., once daily, twice daily, trice daily, once every few days, or once weekly.","The timing of administration can vary from individual to individual, depending upon such factors as the severity of an individual's symptoms.","For example, an effective dose of a pharmaceutical composition disclosed herein can be administered to an individual once daily for an indefinite period of time, or until the individual no longer requires therapy.","A person of ordinary skill in the art will recognize that the condition of the individual can be monitored throughout the course of treatment and that the effective amount of a pharmaceutical composition disclosed herein that is administered can be adjusted accordingly.","A pharmaceutical composition disclosed herein can also be administered to an individual in combination with other therapeutic compounds to increase the overall therapeutic effect of the treatment.","The use of multiple compounds to treat an indication can increase the beneficial effects while reducing the presence of side effects.","The following example illustrates but does not limit the scope of the disclosure set forth above.","Example 1 This example describes experiments for determining monoamine oxidase (MAO) inhibition for isomyosmine and other alkaloids.","MAOs are enzymes located on the outer membrane of mitochondria and are involved in the catabolism of monoamine neurotransmitters.","There are two well-characterized isoenzymes: MAO-A, which predominantly catabolizes serotonin and norepinephrine, and MAO-B, which preferentially catabolizes benzylamine and phenylethylamine.","Dopamine and tyramine are metabolized by both isoforms.","To detect the activity of MAO, a luminescent method (MAO-Glo Assay kit, from Promega, Cat # V1401) was used.","In this method, a MAO substrate (a derivative of beetle luciferin provided in the kit) is mixed with the compound to be tested (in this case, myosmine and control compounds).","Then, the MAO enzymes (either A or B, purchased separately) are added to the mixture and incubated with the reaction for 1 hour at room temperature.","The MAO enzymes, if not inhibited by the test compound, will convert the substrate into methyl ester luciferin.","Finally, a luciferin detection reagent (provided by the kit) is added (20 minutes at room temperature) to stop the MAO reaction and convert methyl ester luciferin into D-luciferin.","D-luciferin reacts with luciferase to produce a luminescent signal, which is directly proportional to the D-luciferin concentration and thus the MAO activity: the greater the amount of light produced the higher the activity of MAO.","The luminescent signal is measured and recorded using a luminometer.","The following materials were obtained from Toronto Research Chemicals, North York, ON: isomyosmine, catalog #1821350; myosmine, catalog # M835000; anabasine, catalog # A637175; and nornicotine, catalog # N756995.Anatabine was obtained from Emerson Resources, Norristown, Pa. As positive controls for the experiment, clorgyline (a well-characterized potent inhibitor of MAO-A) and deprenyl (a well-characterized potent inhibitor of MAO-B) were used.","Results for MAO-A Activity When the pure alkaloids isomyosmine, myosmine, anatabine, anabasine, and nornicotine were compared, isomyosmine was the most potent of the five in inhibiting the enzymatic activity of MAO-A (FIG.","1).","The way to read this line graph is the following: a 100% activity means that the test compound has no effect on the enzyme; a 0% activity means that the test compound completely kills the enzyme.","The more the curve is shifted to the left, the greater the inhibition the test compound exerts on the enzyme.","As can be seen in FIG.","1, the curve for isomyosmine is more shifted to the left among the five alkaloids tested.","A 2 mM concentration (2,000 micromolar) gives an inhibition of about 50%.","The curve for clorgyline, the positive control for the experiment, is greatly shifted leftward.","Results for MAO-B Activity Similar results were obtained when testing the five pure alkaloids isomyosmine, myosmine, anatabine, anabasine, and nornicotine for the inhibition of MAO-B.","Isomyosmine was the most potent among the five alkaloids tested at inhibiting the activity of MAO-B, followed by myosmine (FIG.","2).","Example 2 This example shows that isomyosmine is effective to increase oxygen saturation (%) levels.","As shown in FIG.","3, oxygen saturation (%) was found to dramatically increase in fourteen individuals when measured one hour after oral administration of isomyosmine at a dose of 100-300 mg depending on body weight.","Increasing oxygen saturation levels is believed to make isomyosmine particularly effective for treating substance addictions, including tobacco/nicotine addictions, as well as addictions to heroin, cocaine, opioids, methadone, d-methamphetamine, barbiturates, alcohol, benzodiazepines, amphetamines, or buprenorphine.","For example, substances such as cocaine are known to cause blood vessels to constrict, resulting in increased heartrate and blood pressure and increased stress on the heart's ability to circulate blood and oxygen through the body.","Increasing oxygen saturation levels may, among other things, counteract these types of effects associated with substance abuse by increasing blood oxygen levels, aiding in the treatment of the underlying addiction.","While the invention has been described with respect to specific examples, those skilled in the art will appreciate that there are numerous variations and permutations of the above described systems and techniques that fall within the spirit and scope of the invention as set forth in the appended claims."]],"string":"[\n [\n \"Method of Treating Substance Addictions\",\n \"A pharmaceutical composition containing isomyosmine or a pharmaceutically acceptable salt thereof is administered to an individual in need thereof for treating a substance addiction, inclusive of addiction to heroin (diacetylmorphine), cocaine, opioids, methadone, d-methamphetamine, barbiturates, alcohol, benzodiazepines, amphetamines, or buprenorphine.\",\n \"The isomyosmine, along with optional additional therapeutic agent(s), may be administered in a capsule, tablet, or lozenge.\"\n ],\n [\n \"1.A method of treating a substance addiction comprising administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of isomyosmine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle therefor.\",\n \"2.The method of claim 1, wherein the substance addiction is an addiction to heroin.\",\n \"3.The method of claim 1, wherein the substance addiction is an addiction to cocaine.\",\n \"4.The method of claim 1, wherein the substance addiction is an addiction to opioids.\",\n \"5.The method of claim 1, wherein the substance addiction is an addiction to methadone.\",\n \"6.The method of claim 1, wherein the substance addiction is an addiction to d-methamphetamine.\",\n \"7.The method of claim 1, wherein the substance addiction is an addiction to barbiturates.\",\n \"8.The method of claim 1, wherein the substance addiction is an addiction to alcohol.\",\n \"9.The method of claim 1, wherein the substance addiction is an addiction to benzodiazepines.\",\n \"10.The method of claim 1, wherein the substance addiction is an addiction to amphetamines.\",\n \"11.The method of claim 1, wherein the substance addiction is an addiction to buprenorphine.\",\n \"12.The method of claim 1, wherein the pharmaceutical composition is administered via a capsule, tablet, or lozenge.\",\n \"13.The method of claim 1, wherein the pharmaceutical composition contains isomyosmine or a pharmaceutically acceptable salt thereof in an amount from about 5 mg to about 1,500 mg. 14.The method of claim 1, wherein the pharmaceutical composition contains isomyosmine or a pharmaceutically acceptable salt thereof in an amount from about 10 mg to about 1,200 mg. 15.The method of claim 1, wherein the pharmaceutical composition contains isomyosmine or a pharmaceutically acceptable salt thereof in an amount from about 50 mg to about 1,000 mg. 16.The method of claim 1, wherein the pharmaceutical composition contains isomyosmine or a pharmaceutically acceptable salt thereof in an amount from about 100 mg to about 850 mg. 17.The method of claim 1, wherein the pharmaceutical composition further comprises a second therapeutic agent.\",\n \"18.The method of claim 15, wherein the second therapeutic agent comprises an anti-inflammatory compound.\",\n \"19.The method of claim 15, wherein the pharmaceutical composition contains the second therapeutic agent in an amount from about 5 mg to about 1,500 mg. 20.The method of claim 1, wherein the pharmaceutical composition contains the second therapeutic agent in an amount from about 10 mg to about 1,200 mg.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>Monoamine oxidase (MAO) inhibitors can regulate the level of monoamines and their neurotransmitter release in different brain regions and in the body (including dopamine, norepinephrine, and serotonin).\",\n \"MAO inhibitors (MAOI) can thereby affect the modulation of neuroendocrine function, respiration, mood, motor control and function, focus and attention, concentration, memory and cognition, and the mechanisms of substance abuse.\",\n \"MAOI have been demonstrated to have effects on attention, cognition, appetite, substance abuse, memory, cardiovascular function, extrapyramidal function, pain and gastrointestinal motility and function.\",\n \"The distribution of MAO in the brain is widespread and includes the basal ganglia, cerebral cortex, limbic system, and mid and hind brain nuclei.\",\n \"In the peripheral tissue, the distribution includes muscle, the gastrointestinal tract, the cardiovascular system, autonomic ganglia, the liver, and the endocrinic system.\",\n \"Regulation of monoamine levels in the body has been shown to be effective in numerous disease states including depression, anxiety, stress disorders, and withdrawal symptoms, among others.\",\n \"It has been suggested that cigarette smoke may have irreversible inhibitory effect towards monoamine oxidase (MAO).\",\n \"A.\",\n \"A. Boulton et al., “Biogenic Amine Adducts, Monoamine Oxidase Inhibitors, and Smoking,” Lancet, 1 (8577):114-155 (1988), reported that the MAO inhibiting properties of cigarette smoke may help to explain the protective action of smoking against Parkinson's disease and also observed that patients with mental disorders who smoke heavily do not experience unusual rates of smoking induced disorders.\",\n \"It was suggested that smoking, as an MAOI, may protect against dopaminergic neurotoxicity that leads to Parkinson's disease and that the MAO inhibiting properties of smoking may result in an anti-depressive effect in mental patients.\",\n \"L. A. Carr et al., “Effects of Tobacco Smoke Constituents on MPTP-Induced Toxicity and Monoamine Oxidase Activity in the Mouse Brain,” Life Sciences, 48:1173 1177 (1991), found that nicotine, 4-phenylpyridine and hydrazine prevented the decrease in dopamine metabolite levels induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice, but there was no significant effect on dopamine levels.\",\n \"Because tobacco smoke particulate matter caused a marked inhibition of MAO-A and MAO-B activity when added in vitro, it was suggested that one or more unidentified substances in tobacco smoke are capable of inhibiting brain MAO and perhaps altering the formation of the active metabolite of MPTP.\",\n \"J. S. Fowler et al., “Inhibition of Monoamine Oxidase B in the Brain of Smokers,” Nature (Lond), 379(6567): 733 736 (1996), found that the brains of living smokers showed a 40% decrease in the level of MAO-B relative to nonsmokers or former smokers.\",\n \"MAO inhibition was also reported as being associated with decreased production of hydrogen peroxide.\",\n \"It has also been suggested that nicotine may not be the only constituent of tobacco responsible for tobacco addiction.\",\n \"J. Stephenson, “Clues Found to Tobacco Addiction,” Journal of the American Medical Association, 275(16): 1217 1218 (1996), discussing the work of Fowler, et al., pointed out that the brains of living smokers had less MAO-B compared with the brains of nonsmokers or former smokers.\",\n \"MAO-B is an enzyme involved in the breakdown of dopamine, which is a pleasure-enhancing neurotransmitter.\",\n \"The results suggested that the inhibition of MAO-B in the brains of smokers may make nicotine more addictive by slowing down the breakdown of dopamine, thereby boosting its levels.\",\n \"The findings provided an explanation as to why cigarette smokers were less susceptible to developing Parkinson's disease.\",\n \"Further, the findings suggested that MAOI could be used for smoking cessation.\",\n \"Williams et al.\",\n \"U.S. Pat.\",\n \"No.\",\n \"6,350,479 reported that the minor tobacco alkaloids anabasine, anatabine, and nornicotine exhibited MAO inhibitory effects against MAO-A and MAO-B.\",\n \"There remains a need for alternative therapies for treating substance addictions and for assisting individuals in reducing or eliminating cravings for nicotine or dependence on nicotine.\"\n ],\n [\n \"<SOH> SUMMARY <EOH>In accordance with aspects disclosed herein, compositions containing isomyosmine or a pharmaceutically acceptable salt thereof may be administered to an individual in need thereof for treating substance addiction, such as tobacco- or other substance addiction, including smoking addiction, smokeless tobacco addiction, and other forms of nicotine dependence.\",\n \"A substance addiction may be, example, an addiction to heroin (diacetylmorphine), cocaine, opioids, methadone, d-methamphetamine, barbiturates, alcohol, benzodiazepines, amphetamines, or buprenorphine.\",\n \"In some examples, isomyosmine or a pharmaceutically acceptable salt thereof is administered, with or without other active agent(s), in a capsule, tablet, or lozenge.\",\n \"In other examples, isomyosmine or a pharmaceutically acceptable salt thereof is administered, with or without other active agent(s), via a chewing gum, inhalation spray, e-cigarette, or transdermal patch.\",\n \"The present inventor found that isomyosmine is a potent inhibitor of monoamine oxidase (MAO), including both MAO-A and MAO-B.\",\n \"Through these and/or other mechanisms (e.g., anti-inflammatory properties), isomyosmine may be particularly effective for treating substance addiction, inclusive of affecting smoking substitution and/or assisting individuals in reducing or eliminating cravings for nicotine or dependence on nicotine.\"\n ],\n [\n \"CROSS REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of U.S. application Ser.\",\n \"No.\",\n \"15/670,012, filed Aug. 7, 2017, now U.S. Pat.\",\n \"No.\",\n \"9,884,055, which is a continuation-in-part of International Application PCT/US2016/018047, filed Feb. 16, 2016, which claims priority under 35 U.S.C.\",\n \"§ 119(e) to U.S.\",\n \"Provisional Application No.\",\n \"62/118,136, filed Feb. 19, 2015, the disclosures of which are hereby incorporated by reference in their entireties.\",\n \"BACKGROUND Monoamine oxidase (MAO) inhibitors can regulate the level of monoamines and their neurotransmitter release in different brain regions and in the body (including dopamine, norepinephrine, and serotonin).\",\n \"MAO inhibitors (MAOI) can thereby affect the modulation of neuroendocrine function, respiration, mood, motor control and function, focus and attention, concentration, memory and cognition, and the mechanisms of substance abuse.\",\n \"MAOI have been demonstrated to have effects on attention, cognition, appetite, substance abuse, memory, cardiovascular function, extrapyramidal function, pain and gastrointestinal motility and function.\",\n \"The distribution of MAO in the brain is widespread and includes the basal ganglia, cerebral cortex, limbic system, and mid and hind brain nuclei.\",\n \"In the peripheral tissue, the distribution includes muscle, the gastrointestinal tract, the cardiovascular system, autonomic ganglia, the liver, and the endocrinic system.\",\n \"Regulation of monoamine levels in the body has been shown to be effective in numerous disease states including depression, anxiety, stress disorders, and withdrawal symptoms, among others.\",\n \"It has been suggested that cigarette smoke may have irreversible inhibitory effect towards monoamine oxidase (MAO).\",\n \"A.\",\n \"A. Boulton et al., “Biogenic Amine Adducts, Monoamine Oxidase Inhibitors, and Smoking,” Lancet, 1 (8577):114-155 (1988), reported that the MAO inhibiting properties of cigarette smoke may help to explain the protective action of smoking against Parkinson's disease and also observed that patients with mental disorders who smoke heavily do not experience unusual rates of smoking induced disorders.\",\n \"It was suggested that smoking, as an MAOI, may protect against dopaminergic neurotoxicity that leads to Parkinson's disease and that the MAO inhibiting properties of smoking may result in an anti-depressive effect in mental patients.\",\n \"L. A. Carr et al., “Effects of Tobacco Smoke Constituents on MPTP-Induced Toxicity and Monoamine Oxidase Activity in the Mouse Brain,” Life Sciences, 48:1173 1177 (1991), found that nicotine, 4-phenylpyridine and hydrazine prevented the decrease in dopamine metabolite levels induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice, but there was no significant effect on dopamine levels.\",\n \"Because tobacco smoke particulate matter caused a marked inhibition of MAO-A and MAO-B activity when added in vitro, it was suggested that one or more unidentified substances in tobacco smoke are capable of inhibiting brain MAO and perhaps altering the formation of the active metabolite of MPTP.\",\n \"J. S. Fowler et al., “Inhibition of Monoamine Oxidase B in the Brain of Smokers,” Nature (Lond), 379(6567): 733 736 (1996), found that the brains of living smokers showed a 40% decrease in the level of MAO-B relative to nonsmokers or former smokers.\",\n \"MAO inhibition was also reported as being associated with decreased production of hydrogen peroxide.\",\n \"It has also been suggested that nicotine may not be the only constituent of tobacco responsible for tobacco addiction.\",\n \"J. Stephenson, “Clues Found to Tobacco Addiction,” Journal of the American Medical Association, 275(16): 1217 1218 (1996), discussing the work of Fowler, et al., pointed out that the brains of living smokers had less MAO-B compared with the brains of nonsmokers or former smokers.\",\n \"MAO-B is an enzyme involved in the breakdown of dopamine, which is a pleasure-enhancing neurotransmitter.\",\n \"The results suggested that the inhibition of MAO-B in the brains of smokers may make nicotine more addictive by slowing down the breakdown of dopamine, thereby boosting its levels.\",\n \"The findings provided an explanation as to why cigarette smokers were less susceptible to developing Parkinson's disease.\",\n \"Further, the findings suggested that MAOI could be used for smoking cessation.\",\n \"Williams et al.\",\n \"U.S. Pat.\",\n \"No.\",\n \"6,350,479 reported that the minor tobacco alkaloids anabasine, anatabine, and nornicotine exhibited MAO inhibitory effects against MAO-A and MAO-B.\",\n \"There remains a need for alternative therapies for treating substance addictions and for assisting individuals in reducing or eliminating cravings for nicotine or dependence on nicotine.\",\n \"SUMMARY In accordance with aspects disclosed herein, compositions containing isomyosmine or a pharmaceutically acceptable salt thereof may be administered to an individual in need thereof for treating substance addiction, such as tobacco- or other substance addiction, including smoking addiction, smokeless tobacco addiction, and other forms of nicotine dependence.\",\n \"A substance addiction may be, example, an addiction to heroin (diacetylmorphine), cocaine, opioids, methadone, d-methamphetamine, barbiturates, alcohol, benzodiazepines, amphetamines, or buprenorphine.\",\n \"In some examples, isomyosmine or a pharmaceutically acceptable salt thereof is administered, with or without other active agent(s), in a capsule, tablet, or lozenge.\",\n \"In other examples, isomyosmine or a pharmaceutically acceptable salt thereof is administered, with or without other active agent(s), via a chewing gum, inhalation spray, e-cigarette, or transdermal patch.\",\n \"The present inventor found that isomyosmine is a potent inhibitor of monoamine oxidase (MAO), including both MAO-A and MAO-B.\",\n \"Through these and/or other mechanisms (e.g., anti-inflammatory properties), isomyosmine may be particularly effective for treating substance addiction, inclusive of affecting smoking substitution and/or assisting individuals in reducing or eliminating cravings for nicotine or dependence on nicotine.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS A more complete understanding of the present invention and certain advantages thereof may be acquired by referring to the following detailed description in consideration with the accompanying drawings, in which: FIG.\",\n \"1 is a graph showing the ability of isomyosmine, myosmine, anatabine, anabasine, and nornicotine to inhibit the enzymatic activity of MAO-A.\",\n \"FIG.\",\n \"2 is a graph showing the ability of isomyosmine, myosmine, anatabine, anabasine, and nornicotine to inhibit the activity of MAO-B.\",\n \"FIG.\",\n \"3 is a graph showing oxygen saturation (%) in individuals before and one hour after oral administration of isomyosmine.\",\n \"DETAILED DESCRIPTION Aspects of the present specification disclose, in part, a pharmaceutical composition.\",\n \"As used herein, the term “pharmaceutically acceptable” means any molecular entity or composition that does not produce an adverse, allergic or other untoward or unwanted reaction when administered to an individual.\",\n \"As used herein, the term “pharmaceutically acceptable composition” is synonymous with “pharmaceutical composition” and means a therapeutically effective concentration of an active ingredient, such as any of the therapeutic compounds disclosed herein.\",\n \"A pharmaceutical composition may be administered to an individual alone, or in combination with other supplementary active ingredients, agents, drugs or hormones.\",\n \"A pharmaceutical composition disclosed herein may include a pharmaceutically acceptable carrier that facilitates processing of an active ingredient into pharmaceutically acceptable compositions.\",\n \"As used herein, the term “pharmacologically acceptable carrier” is synonymous with “pharmacological carrier” and means any carrier that has substantially no long term or permanent detrimental effect when administered and encompasses terms such as “pharmacologically acceptable vehicle,” “stabilizer,” “diluent,” “additive,” “auxiliary” or “excipient.” Such a carrier generally is mixed with an active compound or permitted to dilute or enclose the active compound and can be a solid, semi-solid, or liquid agent.\",\n \"It is understood that the active ingredients can be soluble or can be delivered as a suspension in the desired carrier or diluent.\",\n \"Any of a variety of pharmaceutically acceptable carriers can be used including, without limitation, aqueous media such as, e.g., water, saline, glycine, hyaluronic acid and the like; solid carriers such as, e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like; solvents; dispersion media; coatings; antibacterial and antifungal agents; isotonic and absorption delaying agents; or any other inactive ingredient.\",\n \"Selection of a pharmacologically acceptable carrier can depend on the mode of administration.\",\n \"Except insofar as any pharmacologically acceptable carrier is incompatible with the active ingredient, its use in pharmaceutically acceptable compositions is contemplated.\",\n \"Non-limiting examples of specific uses of such pharmaceutical carriers can be found in Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams & Wilkins Publishers, 7th ed.\",\n \"1999); REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 20th ed.\",\n \"2000); Goodman & Gilman's The Pharmacological Basis of Therapeutics (Joel G. Hardman et al., eds., McGraw-Hill Professional, 10th ed.\",\n \"2001); and Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, 4th edition 2003).\",\n \"These protocols are routine procedures and any modifications are well within the scope of one skilled in the art and from the teaching herein.\",\n \"Unless otherwise clear from context, all percentages referred to herein are expressed as percent by weight based on the total weight of the composition.\",\n \"Percentages expressed herein as “w/v” refer to mass, in grams, of the component per 100 ml of solvent.\",\n \"For example, a 1% (w/v) composition of isomyosmine contains 1 g (1000 mg) of isomyosmine per 100 ml of solvent, which is equivalent to 10 mg/ml.\",\n \"Isomyosmine (3-(3,4-dihydro-2H-pyrrol-2-yl)-pyridine) is a nicotine related alkaloid present in solanecea plants containing nicotine.\",\n \"Isomyosmine may be prepared synthetically using known techniques, and also is commercially available from several chemical suppliers.\",\n \"Isomyosmine has two optical isomers (+/−) owing to an asymmetric carbon atom within its pyrrole ring that joins to the pyridine ring.\",\n \"Unless otherwise clear from context, the term “isomyosmine,” as used herein, is inclusive of enantiomeric mixtures (+/−) including racemic mixtures, as well as isolated forms of one or the other enantiomer.\",\n \"In some embodiments, isomyosmine may be adsorbed on a cation exchange resin such as polymethacrilic acid (Amberlite IRP64 or Purolite C115HMR), as described in U.S. Pat.\",\n \"No.\",\n \"3,901,248, the disclosure of which is hereby incorporated by reference in its entirety.\",\n \"Such cation exchange resins have been used commercially, for example, in nicotine replacement therapy, e.g., nicotine polacrilex.\",\n \"Unless otherwise clear from context, “isomyosmine” as used herein refers to both salt and non-salt forms of isomyosmine.\",\n \"Non-limiting examples of possible salts are described in P. H. Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zürich:Wiley-VCH/VHCA, 2002, including salts of 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (−L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid (−L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), and undecylenic acid.\",\n \"As an alternative to synthetic preparation, isomyosmine may be obtained by extraction from tobacco or other materials in which it occurs naturally.\",\n \"For example, tobacco material may extracted with a solvent, such as water, ethanol, steam, and/or carbon dioxide.\",\n \"The resulting solution contains the soluble components of the tobacco, including alkaloids such as nicotine, isomyosmine, and myosmine.\",\n \"Isomyosmine (as well as other extracted components, such as nicotine, if desired) may be purified using known techniques such as liquid chromatography.\",\n \"Nicotine and/or other alkaloid components, when used, likewise may be prepared synthetically or extracted from appropriate natural materials.\",\n \"In pharmaceutical applications, an isolated form of isomyosmine generally is used.\",\n \"An “isolated form of isomyosmine,” as used herein, refers to isomyosmine that either has been prepared synthetically or has been substantially separated from natural materials in which it occurs.\",\n \"The isolated form of isomyosmine should have a very high purity (including enantiomeric purity in the case where an enantiomer is used).\",\n \"In the case of synthetic isomyosmine, for example, purity refers to the ratio of the weight of isomyosmine to the weight of the end reaction product.\",\n \"In the case of isolating isomyosmine from native material, for example, purity refers to the ratio of the weight of isomyosmine to the total weight of the isomyosmine-containing extract.\",\n \"Usually, the level of purity is at least about 95%, more usually at least about 96%, about 97%, about 98%, or higher.\",\n \"For example, the level of purity may be about 98.5%, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher.\",\n \"A pharmaceutical composition disclosed herein can optionally include, without limitation, other pharmaceutically acceptable components (or pharmaceutical components), including, without limitation, buffers, preservatives, tonicity adjusters, salts, antioxidants, osmolality adjusting agents, physiological substances, pharmacological substances, bulking agents, emulsifying agents, wetting agents, sweetening or flavoring agents, and the like.\",\n \"Various buffers and means for adjusting pH can be used to prepare a pharmaceutical composition disclosed herein, provided that the resulting preparation is pharmaceutically acceptable.\",\n \"Such buffers include, without limitation, acetate buffers, citrate buffers, phosphate buffers, neutral buffered saline, phosphate buffered saline and borate buffers.\",\n \"It is understood that acids or bases can be used to adjust the pH of a composition as needed.\",\n \"Pharmaceutically acceptable antioxidants include, without limitation, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.\",\n \"Useful preservatives include, without limitation, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, a stabilized oxy chloro composition and chelants, such as, e.g., DTPA or DTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide.\",\n \"Tonicity adjustors useful in a pharmaceutical composition include, without limitation, salts such as, e.g., sodium chloride, potassium chloride, mannitol or glycerin and other pharmaceutically acceptable tonicity adjustor.\",\n \"The pharmaceutical composition may be provided as a salt and can be formed with many acids, including but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.\",\n \"Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms.\",\n \"It is understood that these and other substances known in the art of pharmacology can be included in a pharmaceutical composition.\",\n \"Compositions may contain isomyosmine, alone or with other therapeutic compound(s).\",\n \"A therapeutic compound is a compound that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or animals.\",\n \"A therapeutic compound disclosed herein may be used in the form of a pharmaceutically acceptable salt, solvate, or solvate of a salt, e.g., a hydrochloride.\",\n \"Additionally, therapeutic compound disclosed herein may be provided as racemates, or as individual enantiomers, including the R- or S-enantiomer.\",\n \"Thus, the therapeutic compound disclosed herein may comprise a R-enantiomer only, a S-enantiomer only, or a combination of both a R-enantiomer and a S-enantiomer of a therapeutic compound.\",\n \"In some aspects, the therapeutic compound may have anti-inflammatory activity, such as a non-steroidal anti-inflammatory drug (NSAID).\",\n \"NSAIDs are a large group of therapeutic compounds with analgesic, anti-inflammatory, and anti-pyretic properties.\",\n \"NSAIDs reduce inflammation by blocking cyclooxygenase.\",\n \"NSAIDs include, without limitation, aceclofenac, acemetacin, actarit, alcofenac, alminoprofen, amfenac, aloxipirin, aminophenazone, antraphenine, aspirin, azapropazone, benorilate, benoxaprofen, benzydamine, butibufen, celecoxib, chlorthenoxacin, choline salicylate, clometacin, dexketoprofen, diclofenac, diflunisal, emorfazone, epirizole; etodolac, etoricoxib, feclobuzone, felbinac, fenbufen, fenclofenac, flurbiprofen, glafenine, hydroxylethyl salicylate, ibuprofen, indometacin, indoprofen, ketoprofen, ketorolac, lactyl phenetidin, loxoprofen, lumiracoxib, mefenamic acid, meloxicam, metamizole, metiazinic acid, mofebutazone, mofezolac, nabumetone, naproxen, nifenazone, niflumic acid, oxametacin, phenacetin, pipebuzone, pranoprofen, propyphenazone, proquazone, protizinic acid, rofecoxib, salicylamide, salsalate, sulindac, suprofen, tiaramide, tinoridine, tolfenamic acid, valdecoxib, and zomepirac.\",\n \"NSAIDs may be classified based on their chemical structure or mechanism of action.\",\n \"Non-limiting examples of NSAIDs include a salicylate derivative NSAID, a p-amino phenol derivative NSAID, a propionic acid derivative NSAID, an acetic acid derivative NSAID, an enolic acid derivative NSAID, a fenamic acid derivative NSAID, a non-selective cyclooxygenase (COX) inhibitor, a selective cyclooxygenase-1 (COX-1) inhibitor, and a selective cyclooxygenase-2 (COX-2) inhibitor.\",\n \"An NSAID may be a profen.\",\n \"Examples of a suitable salicylate derivative NSAID include, without limitation, acetylsalicylic acid (aspirin), diflunisal, and salsalate.\",\n \"Examples of a suitable p-amino phenol derivative NSAID include, without limitation, paracetamol and phenacetin.\",\n \"Examples of a suitable propionic acid derivative NSAID include, without limitation, alminoprofen, benoxaprofen, dexketoprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, pranoprofen, and suprofen.\",\n \"Examples of a suitable acetic acid derivative NSAID include, without limitation, aceclofenac, acemetacin, actarit, alcofenac, amfenac, clometacin, diclofenac, etodolac, felbinac, fenclofenac, indometacin, ketorolac, metiazinic acid, mofezolac, nabumetone, naproxen, oxametacin, sulindac, and zomepirac.\",\n \"Examples of a suitable enolic acid (oxicam) derivative NSAID include, without limitation, droxicam, isoxicam, lornoxicam, meloxicam, piroxicam, and tenoxicam.\",\n \"Examples of a suitable fenamic acid derivative NSAID include, without limitation, flufenamic acid, mefenamic acid, meclofenamic acid, and tolfenamic acid.\",\n \"Examples of a suitable selective COX-2 inhibitors include, without limitation, celecoxib, etoricoxib, firocoxib, lumiracoxib, meloxicam, parecoxib, rofecoxib, and valdecoxib.\",\n \"Isomyosmine may be administered for treating tobacco or other substance addiction, including promoting smoking cessation or otherwise assisting individuals in reducing or eliminating cravings for nicotine or dependence on nicotine.\",\n \"Isomyosmine was found to be a potent inhibitor of monoamine oxidase (MAO), including both MAO-A and MAO-B.\",\n \"Through these and/or other mechanisms, pharmaceutical compositions containing isomyosmine may be particularly effective for treating tobacco addiction and/or for assisting individuals in reducing or eliminating cravings for nicotine or dependence on nicotine.\",\n \"A therapeutic compound disclosed herein may be an ester of a therapeutic compound.\",\n \"In general, an ester of a therapeutic compound increases the log P value relative to the same therapeutic compound without the ester modification.\",\n \"An ester group may be attached to a therapeutic compound by, e.g., a carboxylic acid or hydroxyl functional group present of the therapeutic compound.\",\n \"An ester of a therapeutic compound may have an increased hydrophobicity, and as such, may be dissolved in a reduced volume of solvent disclosed herein.\",\n \"In some instances, an ester of a therapeutic compound may be combined directly with an adjuvant disclosed herein, thereby eliminating the need of a solvent.\",\n \"An ester of a therapeutic compound may enable the making of a pharmaceutical composition disclosed herein, in situations where a non-esterified form of the same therapeutic compound is otherwise immiscible in a solvent disclosed herein.\",\n \"An ester of a therapeutic compound may still be delivered in a manner that more effectively inhibits a pro-inflammatory response as long as the compound is combined with an adjuvant disclosed herein.\",\n \"In one embodiment, a therapeutic compound may be reacted with ethyl ester in order to form an ethyl ester of the therapeutic compound.\",\n \"A pharmaceutical composition may comprise a therapeutic compound in an amount sufficient to allow customary administration to an individual.\",\n \"In aspects of this embodiment, a pharmaceutical composition disclosed herein may be, e.g., at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of a therapeutic compound.\",\n \"In other aspects of this embodiment, a pharmaceutical composition disclosed herein may be, e.g., at least 5 mg, at least 10 mg, at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1,000 mg, at least 1,100 mg, at least 1,200 mg, at least 1,300 mg, at least 1,400 mg, or at least 1,500 mg of a therapeutic compound.\",\n \"In yet other aspects of this embodiment, a pharmaceutical composition disclosed herein may be in the range of, e.g., about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mg to about 1,000 mg, about 850 mg to about 1,200 mg, or about 1,000 mg to about 1,500 mg.\",\n \"In still other aspects of this embodiment, a pharmaceutical composition disclosed herein may be in the range of, e.g., about 10 mg to about 250 mg, about 10 mg to about 500 mg, about 10 mg to about 750 mg, about 10 mg to about 1,000 mg, about 10 mg to about 1,500 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50 mg to about 1,000 mg, about 50 mg to about 1,500 mg, about 100 mg to about 250 mg, about 100 mg to about 500 mg, about 100 mg to about 750 mg, about 100 mg to about 1,000 mg, about 100 mg to about 1,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mg to about 1,000 mg, about 200 mg to about 1,500 mg, about 5 mg to about 1,500 mg, about 5 mg to about 1,000 mg, or about 5 mg to about 250 mg. Pharmaceutical compositions as described herein may include a pharmaceutically acceptable solvent.\",\n \"A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gaseous (the solute), resulting in a solution.\",\n \"Solvents useful in the pharmaceutical compositions include, without limitation, a pharmaceutically acceptable polar aprotic solvent, a pharmaceutically acceptable polar protic solvent and a pharmaceutically acceptable non-polar solvent.\",\n \"A pharmaceutically acceptable polar aprotic solvent includes, without limitation, dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate, acetone, dimethylformamide (DMF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO).\",\n \"A pharmaceutically acceptable polar protic solvent includes, without limitation, acetic acid, formic acid, ethanol, n-butanol, 1-butanol, 2-butanol, isobutanol, sec-butanol, tert-butanol, n-propanol, isopropanol, 1,2 propan-diol, methanol, glycerol, and water.\",\n \"A pharmaceutically acceptable non-polar solvent includes, without limitation, pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, chloroform, n-methyl-pyrrilidone (NMP), and diethyl ether.\",\n \"A pharmaceutical composition disclosed herein may comprise a solvent in an amount sufficient to dissolve a therapeutic compound disclosed herein.\",\n \"In other aspects of this embodiment, a pharmaceutical composition disclosed herein may comprise a solvent in an amount of, e.g., less than about 90% (v/v), less than about 80% (v/v), less than about 70% (v/v), less than about 65% (v/v), less than about 60% (v/v), less than about 55% (v/v), less than about 50% (v/v), less than about 45% (v/v), less than about 40% (v/v), less than about 35% (v/v), less than about 30% (v/v), less than about 25% (v/v), less than about 20% (v/v), less than about 15% (v/v), less than about 10% (v/v), less than about 5% (v/v), or less than about 1% (v/v).\",\n \"In other aspects of this embodiment, a pharmaceutical composition disclosed herein may comprise a solvent in an amount in a range of, e.g., about 1% (v/v) to 90% (v/v), about 1% (v/v) to 70% (v/v), about 1% (v/v) to 60% (v/v), about 1% (v/v) to 50% (v/v), about 1% (v/v) to 40% (v/v), about 1% (v/v) to 30% (v/v), about 1% (v/v) to 20% (v/v), about 1% (v/v) to 10% (v/v), about 2% (v/v) to 50% (v/v), about 2% (v/v) to 40% (v/v), about 2% (v/v) to 30% (v/v), about 2% (v/v) to 20% (v/v), about 2% (v/v) to 10% (v/v), about 4% (v/v) to 50% (v/v), about 4% (v/v) to 40% (v/v), about 4% (v/v) to 30% (v/v), about 4% (v/v) to 20% (v/v), about 4% (v/v) to 10% (v/v), about 6% (v/v) to 50% (v/v), about 6% (v/v) to 40% (v/v), about 6% (v/v) to 30% (v/v), about 6% (v/v) to 20% (v/v), about 6% (v/v) to 10% (v/v), about 8% (v/v) to 50% (v/v), about 8% (v/v) to 40% (v/v), about 8% (v/v) to 30% (v/v), about 8% (v/v) to 20% (v/v), about 8% (v/v) to 15% (v/v), or about 8% (v/v) to 12% (v/v).\",\n \"In one embodiment, a solvent may comprise a pharmaceutically acceptable alcohol.\",\n \"As used herein, the term “alcohol” refers to an organic molecule comprising a hydroxyl functional group (—OH) bonded to a carbon atom, where the carbon atom is saturated.\",\n \"In aspects of this embodiment, the alcohol may be, e.g., a C1-4 alcohol, a C2-4 alcohol, a C1-5 alcohol, a C1-7 alcohol, a C1-10 alcohol, a C1-15 alcohol, or a C1-20 alcohol.\",\n \"In other aspects of this embodiment, an alcohol may be, e.g., a primary alcohol, a secondary alcohol, or a tertiary alcohol.\",\n \"In other aspects of this embodiment, an alcohol may be, e.g., an acyclic alcohol, a monohydric alcohol, a polyhydric alcohol (also known as a polyol or sugar alcohol), an unsaturated aliphatic alcohol, an alicyclic alcohol, or a combination thereof.\",\n \"Examples of a monohydric alcohol include, without limitation, methanol, ethanol, propanol, butanol, pentanol, and 1-hexadecanol.\",\n \"Examples of a polyhydric alcohol include, without limitation, glycol, glycerol, arabitol, erythritol, xylitol, maltitol, sorbitol (gluctiol), mannitol, inositol, lactitol, galactitol (iditol), and isomalt.\",\n \"Examples of an unsaturated aliphatic alcohol include, without limitation, prop-2-ene-1-ol, 3,7-dimethylocta-2,6-dien-1-ol, and prop-2-in-1-ol.\",\n \"Examples of an alicyclic alcohol include, without limitation, cyclohexane-1,2,3,4,5,6-hexyl and 2-(2-propyl)-5-methyl-cyclohexane-1-ol.\",\n \"In another embodiment, a solvent may comprise an ester of pharmaceutically acceptable alcohol and an acid.\",\n \"Suitable pharmaceutically acceptable alcohols include the ones disclosed herein.\",\n \"Suitable acids include, without limitation, acetic acid, butaric acid, and formic acid.\",\n \"An ester of an alcohol and an acid include, without limitation, methyl acetate, methyl buterate, methyl formate, ethyl acetate, ethyl buterate, ethyl formate, propyl acetate, propyl buterate, propyl formate, butyl acetate, butyl buterate, butyl formate, isobutyl acetate, isobutyl buterate, isobutyl formate, pentyl acetate, pentyl buterate, pentyl formate, and 1-hexadecyl acetate, 1-hexadecyl buterate, and 1-hexadecyl formate.\",\n \"In another embodiment, a solvent may comprise a pharmaceutically acceptable polyethylene glycol (PEG) polymer.\",\n \"PEG polymers, also known as polyethylene oxide (PEO) polymers or polyoxyethylene (POE) polymers, are prepared by polymerization of ethylene oxide and are commercially available over a wide range of molecular weights from 100 g/mol to 10,000,000 g/mol.\",\n \"PEG polymers with a low molecular mass are liquids or low-melting solids, whereas PEG polymers of a higher molecular mass are solids.\",\n \"A PEG polymer include, without limitation, PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1100, PEG 1200, PEG 1300, PEG 1400, PEG 1500, PEG 1600, PEG 1700, PEG 1800, PEG 1900, PEG 2000, PEG 2100, PEG 2200, PEG 2300, PEG 2400, PEG 2500, PEG 2600, PEG 2700, PEG 2800, PEG 2900, PEG 3000, PEG 3250, PEG 3350, PEG 3500, PEG 3750, PEG 4000, PEG 4250, PEG 4500, PEG 4750, PEG 5000, PEG 5500, PEG 6000, PEG 6500, PEG 7000, PEG 7500, PEG 8000, PEG 8500, PEG 9000, PEG 9500, PEG 10,000, PEG 11,000, PEG 12,000, PEG 13,000, PEG 14,000, PEG 15,000, PEG 16,000, PEG 17,000, PEG 18,000, PEG 19,000, or PEG 20,000.In another embodiment, a solvent may comprise a pharmaceutically acceptable glyceride.\",\n \"Glycerides comprise a substituted glycerol, where one, two, or all three hydroxyl groups of the glycerol are each esterified using a fatty acid to produce monoglycerides, diglycerides, and triglycerides, respectively.\",\n \"In these compounds, each hydroxyl groups of glycerol may be esterified by different fatty acids.\",\n \"Additionally, glycerides may be acetylated to produce acetylated monoglycerides, acetylated diglycerides, and acetylated triglycerides.\",\n \"In one embodiment, a solvent may comprise a pharmaceutically acceptable solid solvent.\",\n \"Solid solvents may be useful in the manufacture of a solid dose formulation of a pharmaceutical composition disclosed herein.\",\n \"Typically, a solid solvent is melted in order to dissolve a therapeutic compound.\",\n \"A pharmaceutically acceptable solid solvent includes, without limitation, menthol and PEG polymers described above.\",\n \"Aspects of the present specification disclose, in part, a pharmaceutically acceptable adjuvant.\",\n \"An adjuvant is a pharmacological agent that modifies the effect of other agents, such as one or more therapeutic compounds disclosed herein.\",\n \"In addition, an adjuvant disclosed herein may be used as a solvent that dissolves a therapeutic compound disclosed herein, forming an adjuvant solution.\",\n \"An adjuvant may facilitate delivery of a therapeutic compound in a manner that more effectively inhibits a pro-inflammatory response.\",\n \"In one embodiment, an adjuvant facilitates the delivery of a therapeutic compound into macrophages.\",\n \"A pharmaceutical composition may comprise a pharmaceutically acceptable adjuvant in an amount sufficient to mix with a solution or an emulsion.\",\n \"In other aspects of this embodiment, a pharmaceutical composition may comprise an adjuvant in an amount of, e.g., at least 10% (v/v), at least 20% (v/v), at least 30% (v/v), at least 35% (v/v), at least 40% (v/v), at least 45% (v/v), at least 50% (v/v), at least 55% (v/v), at least 60% (v/v), at least 65% (v/v), at least 70% (v/v), at least 75% (v/v), at least 80% (v/v), at least 85% (v/v), at least 90% (v/v), at least 95% (v/v), or at least 99% (v/v).\",\n \"In other aspects of this embodiment, a pharmaceutical composition may comprise an adjuvant in an amount in a range of, e.g., about 30% (v/v) to about 99% (v/v), about 35% (v/v) to about 99% (v/v), about 40% (v/v) to about 99% (v/v), about 45% (v/v) to about 99% (v/v), about 50% (v/v) to about 99% (v/v), about 30% (v/v) to about 98% (v/v), about 35% (v/v) to about 98% (v/v), about 40% (v/v) to about 98% (v/v), about 45% (v/v) to about 98% (v/v), about 50% (v/v) to about 98% (v/v), about 30% (v/v) to about 95% (v/v), about 35% (v/v) to about 95% (v/v), about 40% (v/v) to about 95% (v/v), about 45% (v/v) to about 95% (v/v), or about 50% (v/v) to about 95% (v/v).\",\n \"In yet other aspects of this embodiment, a pharmaceutical composition may comprise an adjuvant in an amount in a range of, e.g., about 70% (v/v) to about 97% (v/v), about 75% (v/v) to about 97% (v/v), about 80% (v/v) to about 97% (v/v), about 85% (v/v) to about 97% (v/v), about 88% (v/v) to about 97% (v/v), about 89% (v/v) to about 97% (v/v), about 90% (v/v) to about 97% (v/v), about 75% (v/v) to about 96% (v/v), about 80% (v/v) to about 96% (v/v), about 85% (v/v) to about 96% (v/v), about 88% (v/v) to about 96% (v/v), about 89% (v/v) to about 96% (v/v), about 90% (v/v) to about 96% (v/v), about 75% (v/v) to about 93% (v/v), about 80% (v/v) to about 93% (v/v), about 85% (v/v) to about 93% (v/v), about 88% (v/v) to about 93% (v/v), about 89% (v/v) to about 93% (v/v), or about 90% (v/v) to about 93% (v/v).\",\n \"In one embodiment, an adjuvant may be a pharmaceutically acceptable lipid.\",\n \"A lipid may be broadly defined as a hydrophobic or amphiphilic small molecule.\",\n \"The amphiphilic nature of some lipids allows them to form structures such as vesicles, liposomes, or membranes in an aqueous environment.\",\n \"Non-limiting examples, of lipids include fatty acids, glycerolipids (like monoglycerides, diglycerides, and triglycerides), phospholipids, sphingolipids, sterol lipids, prenol lipids, saccharolipids, and polyketides.\",\n \"A pharmaceutical composition disclosed herein may comprise a lipid such as, e.g.\",\n \"an oil, an oil-based liquid, a fat, a fatty acid, a wax, a fatty acid ester, a fatty acid salt, a fatty alcohol, a glyceride (mono-, di- or tri-glyceride), a phospholipids, a glycol ester, a sucrose ester, a glycerol oleate derivative, a medium chain triglyceride, or a mixture thereof.\",\n \"A lipid useful in the pharmaceutical compositions may be a pharmaceutically acceptable fatty acid.\",\n \"A fatty acid comprises a carboxylic acid with a long unbranched hydrocarbon chain which may be either saturated or unsaturated.\",\n \"Thus arrangement confers a fatty acid with a polar, hydrophilic end, and a nonpolar, hydrophobic end that is insoluble in water.\",\n \"Most naturally occurring fatty acids have a hydrocarbon chain of an even number of carbon atoms, typically between 4 and 24 carbons, and may be attached to functional groups containing oxygen, halogens, nitrogen, and sulfur.\",\n \"Synthetic or non-natural fatty acids may have a hydrocarbon chain of any number of carbon atoms from between 3 and 40 carbons.\",\n \"Where a double bond exists, there is the possibility of either a cis or a trans geometric isomerism, which significantly affects the molecule's molecular configuration.\",\n \"Cis-double bonds cause the fatty acid chain to bend, an effect that is more pronounced the more double bonds there are in a chain.\",\n \"Most naturally occurring fatty acids are of the cis configuration, although the trans form does exist in some natural and partially hydrogenated fats and oils.\",\n \"Examples of fatty acids include, without limitation, capryllic acid (8:0), pelargonic acid (9:0), capric acid (10:0), undecylic acid (11:0), lauric acid (12:0), tridecylic acid (13:0), myristic acid (14:0), myristoleic acid (14:1), pentadecyclic acid (15:0), palmitic acid (16:0), palmitoleic acid (16:1), sapienic acid (16:1), margaric acid (17:0), stearic acid (18:0), oleic acid (18:1), elaidic acid (18:1), vaccenic acid (18:1), linoleic acid (18:2), linoelaidic acid (18:2), α-linolenic acid (18:3), γ-linolenic acid (18:3), stearidonic acid (18:4), nonadecylic acid (19:0), arachidic acid (20:0), eicosenoic acid (20:1), dihomo-γ-linolenic acid (20:3), mead acid (20:3), arachidonic acid (20:4), eicosapentaenoic acid (20:5), heneicosylic acid (21:0), behenic acid (22:0), erucic acid (22:1), docosahexaenoic acid (22:6), tricosylic acid (23:0), lignoceric acid (24:0), nervonic acid (24:1), pentacosylic acid (25:0), cerotic acid (26:0), heptacosylic acid (27:0), montanic acid (28:0), nonacosylic acid (29:0), melissic acid (30:0), henatriacontylic acid (31:0), lacceroic acid (32:0), psyllic acid (33:0), geddic acid (34:0), ceroplastic acid (35:0), and hexatriacontylic acid (36:0).\",\n \"An adjuvant may be a pharmaceutically acceptable saturated or unsaturated fatty acid.\",\n \"A saturated or unsaturated fatty acid may comprise, e.g., at least 8, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 22, at least 24, at least 26, at least 28, or at least 30 carbon atoms.\",\n \"In some instances, a saturated or unsaturated fatty acid comprises, e.g., between 4 and 24 carbon atoms, between 6 and 24 carbon atoms, between 8 and 24 carbon atoms, between 10 and 24 carbon atoms, between 12 and 24 carbon atoms, between 14 and 24 carbon atoms, or between 16 and 24 carbon atoms, between 4 and 22 carbon atoms, between 6 and 22 carbon atoms, between 8 and 22 carbon atoms, between 10 and 22 carbon atoms, between 12 and 22 carbon atoms, between 14 and 22 carbon atoms, or between 16 and 22 carbon atoms, between 4 and 20 carbon atoms, between 6 and 20 carbon atoms, between 8 and 20 carbon atoms, between 10 and 20 carbon atoms, between 12 and 20 carbon atoms, between 14 and 20 carbon atoms, or between 16 and 20 carbon atoms.\",\n \"If unsaturated, the fatty acid may have, e.g., 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, or 6 or more double bonds.\",\n \"A pharmaceutically acceptable saturated or unsaturated fatty acid may be liquid at room temperature.\",\n \"The melting point of a fatty acid is largely determined by the degree of saturation/unsaturation of the hydrocarbon chain.\",\n \"In aspects of this embodiment, a saturated or unsaturated fatty acid has a melting point temperature of, e.g., 20° C. or below, 15° C. or below, 10° C. or below, 5° C. or below, 0° C. or below, −5° C. or below, −10° C. or below, −15° C. or below, or −20° C. or below.\",\n \"In other aspects of this embodiment, a saturated or unsaturated fatty acid has a melting point temperature in the range of, e.g., about −20° C. to about 20° C., about −20° C. to about 18° C., about −20° C. to about 16° C., about −20° C. to about 12° C., about −20° C. to about 8° C., about −20° C. to about 4° C., about −20° C. to about 0° C., about −15° C. to about 20° C., about −15° C. to about 18° C., about −15° C. to about 16° C., about −15° C. to about 12° C., about −15° C. to about 8° C., about −15° C. to about 4° C., or about −15° C. to about 0° C. An adjuvant may comprise one kind of pharmaceutically acceptable fatty acid.\",\n \"An adjuvant may comprise, for example, only palmitic acid, only stearic acid, only oleic acid, only linoleic acid, or only linolenic acid.\",\n \"Alternatively, an adjuvant may comprise a plurality of different pharmaceutically acceptable fatty acids.\",\n \"An adjuvant may comprise, e.g., two or more different fatty acids, three or more different fatty acids, four or more different fatty acids, five or more different fatty acids, or six or more different fatty acids.\",\n \"An adjuvant may comprise two or more different pharmaceutically acceptable fatty acids including at least palmitic acid, stearic acid, oleic acid, linoleic acid and/or linolenic acid, and any combination thereof.\",\n \"An adjuvant may comprise a ratio of palmitic acid and/or stearic acid and/or oleic acid:linolenic acid and/or linoleic acid of, e.g., at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 6:1, at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 15:1, or at least 20:1.In some examples, an adjuvant may comprise a ratio of palmitic acid and/or stearic acid and/or oleic acid:linolenic acid and/or linoleic acid in a range of, e.g., about 1:1 to about 20:1, about 2:1 to about 15:1, about 4:1 to about 12:1, or about 6:1 to about 10:1.An adjuvant may comprise four or more different pharmaceutically acceptable fatty acids including at least palmitic acid, stearic acid, oleic acid, linoleic acid and/or linolenic acid, and any combination thereof.\",\n \"In other aspects of this embodiment, an adjuvant may comprise a ratio of palmitic acid:stearic acid:linolenic acid:linoleic acid of, e.g., 10:10:1:1, 9:9:1:1, 8:8:1:1, 7:7:1:1, 6:6:1:1, 5:5:1:1, 4:4:1:1, 3:3:1:1, 2:2:1:1, or 1:1:1:1.In other aspects of this embodiment, an adjuvant may comprise a ratio of palmitic acid:stearic acid:linolenic acid:linoleic acid in a range of, e.g., about 10:10:1:1 to about 6:6:1:1, about 8:8:1:1 to about 4:4:1:1, or about 5:5:1:1 to about 1:1:1:1.A lipid useful in the pharmaceutical compositions may be a pharmaceutically acceptable omega fatty acid.\",\n \"Non-limiting examples of an omega fatty acid include omega-3, omega-6, and omega-9.Omega-3 fatty acids (also known as n-3 fatty acids or ω-3 fatty acids) are a family of essential unsaturated fatty acids that have in common a final carbon-carbon double bond in the n-3 position, that is, the third bond, counting from the methyl end of the fatty acid.\",\n \"The omega-3 fatty acids are “essential” fatty acids because they are vital for normal metabolism and cannot be synthesized by the human body.\",\n \"An omega-3 fatty acid includes, without limitation, hexadecatrienoic acid (16:3), α-linolenic acid (18:3), stearidonic acid (18:4), eicosatrienoic acid (20:3), eicosatetraenoic acid (20:4), eicosapentaenoic acid (20:5), heneicosapentaenoic acid (21:5), docosapentaenoic acid (22:5), clupanodonic acid (22:5), docosahexaenoic acid (22:6), tetracosapentaenoic acid (24:5), and tetracosahexaenoic acid (nisinic acid) (24:6).\",\n \"Omega-6 fatty acids (also known as n-6 fatty acids or ω-6 fatty acids) are a family of unsaturated fatty acids that have in common a final carbon-carbon double bond in the n-6 position, that is, the sixth bond, counting from the methyl end of the fatty acid.\",\n \"An omega-6 fatty acid includes, without limitation, linoleic acid (18:2), gamma-linolenic acid (18:3), calendic acid (18:3), eicosadienoic acid (20:2), dihomo-gamma-linolenic acid (20:3), arachidonic acid (20:4), docosadienoic acid (22:2), adrenic acid (22:4), docosapentaenoic acid (22:5), tetracosatetraenoic acid (24:4), and tetracosapentaenoic acid (24:5).\",\n \"Omega-9 fatty acids (also known as n-9 fatty acids or ω-9 fatty acids) are a family of unsaturated fatty acids that have in common a final carbon-carbon double bond in the n-9 position, that is, the ninth bond, counting from the methyl end of the fatty acid.\",\n \"An omega-9 fatty acid includes, without limitation, oleic acid (18:1), elaidic acid (18:1), eicosenoic acid (20:1), mead acid (20:3), erucic acid (22:1), and nervonic acid (24:1).\",\n \"A lipid useful in the pharmaceutical compositions disclosed herein may be a pharmaceutically acceptable oil.\",\n \"An oil includes any fatty acid that is liquid at normal room temperature, such as, e.g.\",\n \"about 20° C. In contrast, a fat includes any fatty acid that is solid at normal room temperature, such as, e.g.\",\n \"about 20° C. An oil suitable as a lipid useful in the pharmaceutical compositions disclosed herein, may be a natural oil or a vegetable oil.\",\n \"Examples of suitable natural oils include, without limitation, mineral oil, triacetin, ethyl oleate, a hydrogenated natural oil, or a mixture thereof.\",\n \"Examples of suitable vegetable oils include, without limitation, almond oil, arachis oil, avocado oil, canola oil, castor oil, coconut oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, linseed oil (flax seed oil), olive oil, palm oil, peanut oil, rapeseed oil, rice bran oil, safflower oil, sesame oil, soybean oil, soya oil, sunflower oil, walnut oil, wheat germ oil, or a mixture thereof.\",\n \"Each of these oils is commercially available from a number of sources well recognized by those skilled in the art.\",\n \"An oil is typically a mixture of various fatty acids.\",\n \"For example, rapeseed oil, obtained from the seeds of brassica napus, includes both omega-6 and omega-3 fatty acids in a ratio of about 2:1.As another example, linseed oil, obtained from the seeds of linum usitatissimum, includes about 7% palmitic acid, about 3.4-4.6% stearic acid, about 18.5-22.6% oleic acid, about 14.2-17% linoleic acid, and about 51.9-55.2% α-linolenic acid.\",\n \"In some instances, a pharmaceutical composition comprises an oil including at least two different fatty acids, at least three different fatty acids, at least four different fatty acids, at least five different fatty acids, or at least six different fatty acids.\",\n \"A lipid useful in the pharmaceutical compositions may be a pharmaceutically acceptable glycerolipid.\",\n \"Glycerolipids are composed mainly of mono-, di-, and tri-substituted glycerols.\",\n \"One group of glycerolipids is the glycerides, where one, two, or all three hydroxyl groups of glycerol are each esterified using a fatty acid to produce monoglycerides, diglycerides, and triglycerides, respectively.\",\n \"In these compounds, each hydroxyl groups of glycerol may be esterified by different fatty acids.\",\n \"Additionally, glycerides may be acetylated to produce acetylated monoglycerides, acetylated diglycerides, and acetylated triglycerides.\",\n \"One group of glycerolipids is the glycerides, where one, two, or all three hydroxyl groups of glycerol have sugar residues attached via a glycosidic linkage.\",\n \"In some instances, compositions may include one or more pharmaceutically acceptable stabilizing agents.\",\n \"A stabilizing agent reduces or eliminates formation of esters of a therapeutic compound that may result as a unwanted reaction with the particular solvent used.\",\n \"A stabilizing agent include, without limitation, water, a sacrificial acid comprising a fatty acid component and acetic acid, ethyl acetate, a sodium acetate/acetic acid (E262), a monoglyceride, an acetylated monoglyceride, a diglyceride, an acetylated monoglyceride, an acetylated diglyceride, a fatty acid, and a fatty acid salt.\",\n \"In one embodiment, a pharmaceutically acceptable stabilizing agent may comprise a pharmaceutically acceptable emulsifying agent.\",\n \"An emulsifying agent (also known as an emulgent) is a substance that stabilizes an emulsion comprising a liquid dispersed phase and a liquid continuous phase by increasing its kinetic stability.\",\n \"Thus, in situations where the solvent and adjuvant used to make a pharmaceutical composition disclosed herein are normally immiscible, an emulsifying agent disclosed herein is used to create a homogenous and stable emulsion.\",\n \"An emulsifying agent includes, without limitation, a surfactant, a polysaccharide, a lectin, and a phospholipid.\",\n \"An emulsifying agent may comprise a surfactant.\",\n \"As used hereon, the term “surfactant” refers to a natural or synthetic amphiphilic compound.\",\n \"A surfactant can be non-ionic, zwitterionic, or ionic.\",\n \"Non-limiting examples of surfactants include polysorbates like polysorbate 20 (TWEEN® 20), polysorbate 40 (TWEEN® 40), polysorbate 60 (TWEEN® 60), polysorbate 61 (TWEEN® 61), polysorbate 65 (TWEEN® 65), polysorbate 80 (TWEEN® 80), and polysorbate 81 (TWEEN® 81); poloxamers (polyethylene-polypropylene copolymers), such as Poloxamer 124 (PLURONIC® L44), Poloxamer 181 (PLURONIC® L61), Poloxamer 182 (PLURONIC® L62), Poloxamer 184 (PLURONIC® L64), Poloxamer 188 (PLURONIC® F68), Poloxamer 237 (PLURONIC® F87), Poloxamer 338 (PLURONIC® L108), Poloxamer 407 (PLURONIC® F127), polyoxyethyleneglycol dodecyl ethers, such as BRIJ® 30, and BRIJ® 35; 2-dodecoxyethanol (LUBROL®-PX); polyoxyethylene octyl phenyl ether (TRITON® X-100); sodium dodecyl sulfate (SDS); 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS); 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate (CHAPSO); sucrose monolaurate; and sodium cholate.\",\n \"Other non-limiting examples of surfactant excipients can be found in, e.g., Ansel, supra, (1999); Gennaro, supra, (2000); Hardman, supra, (2001); and Rowe, supra, (2003), each of which is hereby incorporated by reference in its entirety.\",\n \"An emulsifying agent may comprise a polysaccharide.\",\n \"Non-limiting examples of polysaccharides include guar gum, agar, alginate, calgene, a dextran (like dextran 1K, dextran 4K, dextran 40K, dextran 60K, and dextran 70K), dextrin, glycogen, inulin, starch, a starch derivative (like hydroxymethyl starch, hydroxyethyl starch, hydroxypropyl starch, hydroxybutyl starch, and hydroxypentyl starch), hetastarch, cellulose, FICOLL, methyl cellulose (MC), carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxyethyl methyl cellulose (NEMC), hydroxypropyl methyl cellulose (HPMC); polyvinyl acetates (PVA); polyvinyl pyrrolidones (PVP), also known as povidones, having a K-value of less than or equal to 18, a K-value greater than 18 or less than or equal to 95, or a K-value greater than 95, like PVP 12 (KOLLIDON® 12), PVP 17 (KOLLIDON® 17), PVP 25 (KOLLIDON® 25), PVP 30 (KOLLIDON® 30), PVP 90 (KOLLIDON® 90); and polyethylene imines (PEI).\",\n \"An emulsifying agent may comprise a lectin.\",\n \"Lectins are sugar-binding proteins that are highly specific for their sugar moieties.\",\n \"Lectins may be classified according to the sugar moiety that they bind to, and include, without limitation, mannose-binding lectins, galactose/N-acetylgalactosamine-binding lectins, N-acetylgluxosamine-binding lectins, N-acetylneuramine-binding lectins, N-acetylneuraminic acid-binding lectins, and fucose-binding lectins.\",\n \"Non-limiting examples of surfactants include concanavain A, lentil lectin, snowdrop lectin, Roin, peanut agglutinin, jacain, hairy vetch lectin, wheat germ agglutinin, elderberry lectin, Maackia anurensis leukoagglutinin, Maackia anurensis hemoagglutinin, Ulex europaeus agglutinin, and Aleuria aurantia lectin.\",\n \"An emulsifying agent may comprise a phospholipid.\",\n \"The structure of the phospholipid generally comprises a hydrophobic tail and a hydrophilic head and is amphipathic in nature.\",\n \"Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from sphingosine instead of glycerol.\",\n \"Phospholipids include, without limitation, diacylglycerides and phosphosphingolipids.\",\n \"Non-limiting examples of diacylglycerides include a phosphatidic acid (phosphatidate) (PA), a phosphatidylethanolamine (cephalin) (PE), a phosphatidylcholine (lecithin) (PC), a phosphatidylserine (PS), and a phosphoinositide including phosphatidylinositol (PI), phosphatidylinositol phosphate (PIP), phosphatidylinositol bisphosphate (PIP2), and phosphatidylinositol triphosphate (PIP3).\",\n \"Non-limiting examples of phosphosphingolipids include a ceramide phosphorylcholine (sphingomyelin) (SPH), ceramide phosphorylethanolamine (sphingomyelin) (Cer-PE), and ceramide phosphorylglycerol.\",\n \"The final concentration of a therapeutic compound in a pharmaceutical composition disclosed herein may vary over a wide range and generally may be characterized as a therapeutically effective amount.\",\n \"In some aspects, the final concentration of a therapeutic compound in a pharmaceutical composition may be, e.g., at least 0.00001 mg/mL, at least 0.0001 mg/mL, at least 0.001 mg/mL, at least 0.01 mg/mL, at least 0.1 mg/mL, at least 1 mg/mL, at least 10 mg/mL, at least 25 mg/mL, at least 50 mg/mL, at least 100 mg/mL, at least 200 mg/mL, at least 500 mg/mL, at least 700 mg/mL, at least 1,000 mg/mL, or at least 1,200 mg/mL.\",\n \"In other aspects of this embodiment, the concentration of a therapeutic compound disclosed herein in the solution may be, e.g., at most 1,000 mg/mL, at most 1,100 mg/mL, at most 1,200 mg/mL, at most 1,300 mg/mL, at most 1,400 mg/mL, at most 1,500 mg/mL, at most 2,000 mg/mL, at most 2,000 mg/mL, or at most 3,000 mg/mL.\",\n \"In other aspects of this embodiment, the final concentration of a therapeutic compound in a pharmaceutical composition may be in a range of, e.g., about 0.00001 mg/mL to about 3,000 mg/mL, about 0.0001 mg/mL to about 3,000 mg/mL, about 0.01 mg/mL to about 3,000 mg/mL, about 0.1 mg/mL to about 3,000 mg/mL, about 1 mg/mL to about 3,000 mg/mL, about 250 mg/mL to about 3,000 mg/mL, about 500 mg/mL to about 3,000 mg/mL, about 750 mg/mL to about 3,000 mg/mL, about 1,000 mg/mL to about 3,000 mg/mL, about 100 mg/mL to about 2,000 mg/mL, about 250 mg/mL to about 2,000 mg/mL, about 500 mg/mL to about 2,000 mg/mL, about 750 mg/mL to about 2,000 mg/mL, about 1,000 mg/mL to about 2,000 mg/mL, about 100 mg/mL to about 1,500 mg/mL, about 250 mg/mL to about 1,500 mg/mL, about 500 mg/mL to about 1,500 mg/mL, about 750 mg/mL to about 1,500 mg/mL, about 1,000 mg/mL to about 1,500 mg/mL, about 100 mg/mL to about 1,200 mg/mL, about 250 mg/mL to about 1,200 mg/mL, about 500 mg/mL to about 1,200 mg/mL, about 750 mg/mL to about 1,200 mg/mL, about 1,000 mg/mL to about 1,200 mg/mL, about 100 mg/mL to about 1,000 mg/mL, about 250 mg/mL to about 1,000 mg/mL, about 500 mg/mL to about 1,000 mg/mL, about 750 mg/mL to about 1,000 mg/mL, about 100 mg/mL to about 750 mg/mL, about 250 mg/mL to about 750 mg/mL, about 500 mg/mL to about 750 mg/mL, about 100 mg/mL to about 500 mg/mL, about 250 mg/mL to about 500 mg/mL, about 0.00001 mg/mL to about 0.0001 mg/mL, about 0.00001 mg/mL to about 0.001 mg/mL, about 0.00001 mg/mL to about 0.01 mg/mL, about 0.00001 mg/mL to about 0.1 mg/mL, about 0.00001 mg/mL to about 1 mg/mL, about 0.001 mg/mL to about 0.01 mg/mL, about 0.001 mg/mL to about 0.1 mg/mL, about 0.001 mg/mL to about 1 mg/mL, about 0.001 mg/mL to about 10 mg/mL, or about 0.001 mg/mL to about 100 mg/mL.\",\n \"A pharmaceutical composition produced using the methods disclosed herein may be a liquid formulation or a solid or semi-solid formulation.\",\n \"A liquid formulation can be formed by using various lipids like oils of other fatty acids that remain as liquids in the temperature range desired.\",\n \"In an embodiment, a pharmaceutical composition disclosed herein is liquid at room temperature.\",\n \"In aspects of this embodiment, a pharmaceutical composition disclosed herein may be formulated to be a liquid at a temperature of, e.g., about 25° C. or higher, about 23° C. or higher, about 21° C. or higher, about 19° C. or higher, about 17° C. or higher, about 15° C. or higher, about 12° C. or higher, about 10° C. or higher, about 8° C. or higher, about 6° C. or higher, about 4° C. or higher, or about 0° C. or higher.\",\n \"A solid or semi-solid formulation may take advantage of the different melting point temperatures of the various adjuvants like fatty acids.\",\n \"Formation of a solid or semi-solid dosage form can be by modifying the respective concentrations of the fatty acids comprising a pharmaceutical composition disclosed herein.\",\n \"For example, linolenic acid has a melting point temperature (Tm) of about −11° C., linoleic acid has a Tm of about −5° C., oleic acid has a Tm of about 16° C., palmitic acid has a Tm of about 61-62° C., and Stearic acid has a Tm of about 67-72° C. Increasing the proportion(s) of palmitic, stearic or oleic acid would increase the overall melting temperature of a composition, while, conversely, increasing the proportion(s) of linoleic and linolenic acid would decrease the melting temperature of a composition.\",\n \"Thus, by controlling the types and amounts of the adjuvant components added, a pharmaceutical composition disclosed herein can be made that is substantially solid or semi-solid at room temperature, but melts when it is ingested, and reaches body temperature.\",\n \"The resulting melted composition readily forms micelles which are absorbed by the intestine, assembled into chylomicrons, and ultimately absorbed by macrophages.\",\n \"The solid dosage form may be a powder, granule, tablet, capsule or suppository.\",\n \"In some aspects, a pharmaceutical composition may be formulated as a chewing gum.\",\n \"The formulation of gum bases can vary substantially depending on the particular product to be prepared and on the desired masticatory and other sensory characteristics of the final product.\",\n \"By way of example, typical ranges of the gum base components include 5-80 wt.\",\n \"% elastomeric compounds, 5-80 wt.\",\n \"% natural and/or synthetic resins (elastomer plasticizers), 0-40 wt.\",\n \"% waxes, 5-35 wt.\",\n \"% softener other than waxes, 0-50 wt.\",\n \"% filler, and 0-5 wt.\",\n \"% of other ingredients such as antioxidants, colorants, and the like.\",\n \"The gum base may comprise about 5-95 wt.\",\n \"% of the total weight of the chewing gum, often from about 10-60 wt.\",\n \"% or from about 40-50 wt.\",\n \"%.\",\n \"Often a buffer is used.\",\n \"Examples of buffers that may be used include tris buffers, amino acid buffers, carbonate, including monocarbonate, bicarbonate or sesquicarbonate, glycerinate, phosphate, glycerophosphate, acetate, glyconate or citrate of an alkali metal, such as potassium and sodium, e.g.\",\n \"trisodium and tripotassium citrate, or ammonium, and mixtures thereof.\",\n \"Other examples of buffers include acetic acid, adipic acid, citric acid, fumaric acid, glucono-δ-lactone, gluconic acid, lactic acid, malic acid, maleic acid, tartaric acid, succinic acid, propionic acid, ascorbic acid, phosphoric acid, sodium orthophosphate, potassium orthophosphate, calcium orthophosphate, sodium diphosphate, potassium diphosphate, calcium diphosphate, pentasodium triphosphate, pentapotassium triphosphate, sodium polyphosphate, potassium polyphosphate, carbonic acid, sodium carbonate, sodium bicarbonate, potassium carbonate, calcium carbonate, magnesium carbonate, magnesium oxide, or any combination thereof.\",\n \"The buffer may to some extent be microencapsulated or otherwise coated as granules with polymers and/or lipids being less soluble in saliva than is the one or more buffering agents.\",\n \"Such microencapsulation controls the dissolution rate whereby is extended the time frame of the buffering effect.\",\n \"The amount of buffer may range from 0 to about 15% and often ranges from about 0.5 to about 10% based on the total weight of the chewing gum.\",\n \"Elastomers may be used to provide a rubbery, cohesive nature to the gum.\",\n \"Elastomers suitable for use in the gum base and gum may include natural or synthetic types.\",\n \"Elastomer plasticizers may be used to vary the firmness of the gum base.\",\n \"Their specificity on elastomer inter-molecular chain interaction (plasticizing) along with their varying softening points cause varying degrees of finished gum firmness and compatibility when used in base.\",\n \"This may provide more elastomeric chain exposure to the alkane chains of the waxes.\",\n \"The elastomers employed in the gum base may vary depending upon various factors such as the type of gum base desired, the texture of gum formulation desired and the other components used in the formulation to make the final chewing gum product.\",\n \"The elastomer may be any water-insoluble polymer known in the art, and includes those gum polymers utilized for chewing gums and bubble gums.\",\n \"For example, polymers suitable for use in gum bases include, without limitation, natural substances (of vegetable origin) such as chicle gum, natural rubber, crown gum, nispero, rosidinha, jelutong, perillo, niger gutta, tunu, balata, guttapercha, lechi capsi, sorva, gutta kay, and the like, and mixtures thereof.\",\n \"Examples of synthetic elastomers include, without limitation, styrene-butadiene copolymers (SBR), polyisobutylene, isobutylene-isoprene copolymers, polyethylene, polyvinyl acetate and the like, and mixtures thereof.\",\n \"Natural resins may be used according to the invention and may be natural rosin esters, often referred to as ester gums including as examples glycerol esters of partially hydrogenated rosins, glycerol esters of polymerized rosins, glycerol esters of partially dimerized rosins, glycerol esters of tally oil rosins, pentaerythritol esters of partially hydrogenated rosins, methyl esters of rosins, partially hydrogenated methyl esters of rosins, pentaerythritol esters of rosins, synthetic resins such as terpene resins derived from alpha-pinene, beta-pinene, and/or d-limonene, and natural terpene resins.\",\n \"Resins may be selected from terpene resins, such as those derived from alpha-pinene, beta-pinene, and/or d-limonene, natural terpene resins, glycerol esters of gum rosins, tall oil rosins, wood rosins or other derivatives thereof such as glycerol esters of partially hydrogenated rosins, glycerol esters of polymerized rosins, glycerol esters of partially dimerized rosins, pentaerythritol esters of partially hydrogenated rosins, methyl esters of rosins, partially hydrogenated methyl esters of rosins or pentaerythritol esters of rosins and combinations thereof.\",\n \"Other chewing gum ingredients may be selected from bulk sweeteners, flavors, dry-binders, tableting aids, anti-caking agents, emulsifiers, antioxidants, enhancers, absorption enhancers, buffers, high intensity sweeteners, softeners, colors, and combinations thereof.\",\n \"Non-limiting examples of emulsifiers include cyclodextrins, polyoxyethylene castor oil derivatives, polyoxyethylene alkyl ethers, macrogol alkyl ethers, block copolymers of ethylene and propylene oxides, polyoxyethylene alkyl ethers, polyoxyethylene glycols, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene (20) sorbitan monostearates, polyoxyethylene (20) sorbitan monooleates, polyoxyethylene stearates, sobitan esters, diacetyl tartaric ester of monoglycerides, lactylated monoglycerides, and combinations thereof.\",\n \"The amount of emulsifiers often ranges from about 0.1% to about 25 wt.\",\n \"% based on the total weight of the chewing gum.\",\n \"Petroleum waxes aid in the curing of the finished gum made from the gum base as well as improve shelf life and texture.\",\n \"Wax crystal size influences the release of flavor.\",\n \"Those waxes high in iso-alkanes have a smaller crystal size than those waxes high in normal-alkanes, especially those with normal-alkanes of carbon numbers less than 30.The smaller crystal size allows slower release of flavor since there is more hindrance of the flavor's escape from this wax versus a wax having larger crystal sizes.\",\n \"The compatibility of gum bases made using normal-alkanic waxes is less when compared to gum bases made with iso-alkanic waxes.\",\n \"Petroleum wax (refined paraffin and microcrystalline wax) and paraffin wax are composed of mainly straight-chained normal-alkanes and branched iso-alkanes.\",\n \"The ratio of normal-alkanes to iso-alkanes varies.\",\n \"The normal-alkanic waxes typically have carbon chain lengths >C-18 but the lengths are not predominantly longer than C-30.The branched and ring structures are located near the end of the chain for those waxes that are predominantly normal-alkanic.\",\n \"The viscosity of normal-alkanic waxes is <10 mm2/s (at 100° C.) and the combined number average molecular weight is <600 g/mole.\",\n \"The iso-alkanic waxes typically have carbon lengths that are predominantly greater than C-30.The branched chains and ring structures are located randomly along the carbon chain in those waxes that are predominantly iso-alkanic.\",\n \"The viscosity of iso-alkanic waxes is greater than 10 mm2/s (at 100° C.) and the combined number average molecular weight is >600 g/mole.\",\n \"Synthetic waxes are produced by means that are atypical for petroleum wax production and are thus not considered petroleum wax.\",\n \"The synthetic waxes may include waxes containing branched alkanes and copolymerized with monomers such as, but not limited to propylene, polyethylene, and Fischer Tropsch type waxes.\",\n \"Polyethylene wax is a synthetic wax containing alkane units of varying lengths having attached thereto ethylene monomers.\",\n \"Waxes and fats are conventionally used for the adjustment of the texture and for softening of the chewing gum base when preparing chewing gum bases.\",\n \"Any conventionally used and suitable type of natural and synthetic wax and fat may be used, such as for instance rice bran wax, polyethylene wax, petroleum wax (refined paraffin and microcrystalline wax), sorbitan monostearate, tallow, propylene glycol, paraffin, beeswax, carnauba wax, candelilla wax, cocoa butter, degreased cocoa powder and any suitable oil or fat, such as completely or partially hydrogenated vegetable oils or completely or partially hydrogenated animal fats.\",\n \"Antioxidants prolong shelf life and storage of gum base, finished gum or their respective components including fats and flavor oils.\",\n \"Antioxidants suitable for use in gum base include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), betacarotenes, tocopherols, acidulants such as Vitamin C, propyl gallate, other synthetic and natural types or mixtures thereof.\",\n \"A chewing gum may include other conventional components such as sweeteners, including bulk sweeteners, sugar sweeteners, sugar-substitute sweeteners, artificial sweeteners, high-intensity sweeteners, or a combination thereof.\",\n \"Bulk sweeteners may constitute from about 5 to about 95% by weight of the chewing gum, more typically about 20 to about 80% by weight, about 30 to 70%, or about 30 to 60% by weight of the gum.\",\n \"Useful sugar sweeteners are saccharide-containing components commonly known in the chewing gum art including, but not limited to, sucrose, dextrose, maltose, dextrins, trehalose, D-tagatose, dried invert sugar, fructose, levulose, galactose, corn syrup solids, and the like, alone or in combination.\",\n \"Sorbitol can be used as a non-sugar sweetener.\",\n \"Other useful non-sugar sweeteners include, but are not limited to, other sugar alcohols such as mannitol, xylitol, hydrogenated starch hydrolysates, maltitol, isomalt, erythritol, lactitol and the like, alone or in combination.\",\n \"High intensity artificial sweetening agents can also be used alone or in combination with the above sweeteners.\",\n \"Non-limiting examples of high intensity sweeteners include sucralose, aspartame, salts of acesulfame, alitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, sterioside and the like, alone or in combination.\",\n \"In order to provide longer lasting sweetness and flavor perception, it may be desirable to encapsulate or otherwise control the release of at least a portion of the artificial sweeteners.\",\n \"Techniques such as wet granulation, wax granulation, spray drying, spray chilling, fluid bed coating, conservation, encapsulation in yeast cells and fiber extrusion may be used to achieve desired release characteristics.\",\n \"Encapsulation of sweetening agents can also be provided using another chewing gum component such as a resinous compound.\",\n \"Usage level of the artificial sweetener will vary considerably and will depend on factors such as potency of the sweetener, rate of release, desired sweetness of the product, level and type of flavor used and cost considerations.\",\n \"The active level of artificial sweetener may vary from about 0.001 to about 8% by weight, and often ranges from about 0.02 to about 8% by weight.\",\n \"When carriers used for encapsulation are included, the usage level of the encapsulated sweetener will be proportionately higher.\",\n \"Combinations of sugar and/or non-sugar sweeteners may be used if desired.\",\n \"A chewing gum and/or gum base may include one or more fillers/texturizers, such as magnesium and calcium carbonate, sodium sulfate, ground limestone, silicate compounds such as magnesium and aluminum silicate, kaolin and clay, aluminum oxide, silicium oxide, talc, titanium oxide, mono-, di- and tri-calcium phosphates, cellulose polymers, such as wood, and combinations thereof.\",\n \"A number of other well-known chewing gum components may be present, including but not limited to waxes, fats, softeners, fillers, flavors, anti-oxidants, emulsifiers, coloring agents, binding agents and acidulates.\",\n \"The chewing gum may be provided with an outer coating, such as a hard coating, soft coating, edible film-coating, or any combination thereof.\",\n \"In some aspects, nicotine is compounded along with other components of the gum base such that nicotine is substantially uniformly contained in the gum base.\",\n \"Nicotine or a nicotine complex may be provided on an adsorbent such as finely divided silicic acid, amorphous silica, magnesium silicate, calcium silicate, kaolin, clays, crystalline aluminosilicates, macaloid bentonite, activated carbon, alumina, hydroxylapatite, microcrystalline cellulose, or any combination thereof.\",\n \"Nicotine may be encapsulated to provide a desired controlled or sustained release thereof.\",\n \"An example of a chewing gum that provides for sustained release of nicotine is described in U.S. 2007/0014887, the disclosure of which is hereby incorporated by reference.\",\n \"Alternatively, isomyosmine may be infused into an outer portion of a chewing gum than contains nicotine.\",\n \"A similar release profile may be achieved via an oral dosage form such as a tablet, capsule, or the like.\",\n \"For example, a tablet may have a core layer containing nicotine to provide a sustained release thereof, and an outer layer containing isomyosmine to provide an immediate release thereof.\",\n \"Other combinations are possible.\",\n \"For example, one or both of the layers may contain both isomyosmine and nicotine so that the respective active component(s) is released in both an immediate- and a sustained release manner.\",\n \"In other aspects, volatile delivery vehicles may be used for administering the active component(s) including isomyosmine, such as an inhaler or e-cigarette.\",\n \"In still other aspects, the active component(s) are administered transmucosally such as via a nasal spray, or transdermally such as via a transdermal patch.\",\n \"A therapeutically effective amount of a therapeutic compound disclosed herein generally is in the range of about 0.001 mg/kg/day to about 100 mg/kg/day.\",\n \"In aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may be, e.g., at least 0.001 mg/kg/day, at least 0.01 mg/kg/day, at least 0.1 mg/kg/day, at least 1.0 mg/kg/day, at least 5.0 mg/kg/day, at least 10 mg/kg/day, at least 15 mg/kg/day, at least 20 mg/kg/day, at least 25 mg/kg/day, at least 30 mg/kg/day, at least 35 mg/kg/day, at least 40 mg/kg/day, at least 45 mg/kg/day, or at least 50 mg/kg/day.\",\n \"In other aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may be in the range of, e.g., about 0.001 mg/kg/day to about 10 mg/kg/day, about 0.001 mg/kg/day to about 15 mg/kg/day, about 0.001 mg/kg/day to about 20 mg/kg/day, about 0.001 mg/kg/day to about 25 mg/kg/day, about 0.001 mg/kg/day to about 30 mg/kg/day, about 0.001 mg/kg/day to about 35 mg/kg/day, about 0.001 mg/kg/day to about 40 mg/kg/day, about 0.001 mg/kg/day to about 45 mg/kg/day, about 0.001 mg/kg/day to about 50 mg/kg/day, about 0.001 mg/kg/day to about 75 mg/kg/day, or about 0.001 mg/kg/day to about 100 mg/kg/day.\",\n \"In yet other aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may be in the range of, e.g., about 0.01 mg/kg/day to about 10 mg/kg/day, about 0.01 mg/kg/day to about 15 mg/kg/day, about 0.01 mg/kg/day to about 20 mg/kg/day, about 0.01 mg/kg/day to about 25 mg/kg/day, about 0.01 mg/kg/day to about 30 mg/kg/day, about 0.01 mg/kg/day to about 35 mg/kg/day, about 0.01 mg/kg/day to about 40 mg/kg/day, about 0.01 mg/kg/day to about 45 mg/kg/day, about 0.01 mg/kg/day to about 50 mg/kg/day, about 0.01 mg/kg/day to about 75 mg/kg/day, or about 0.01 mg/kg/day to about 100 mg/kg/day.\",\n \"In still other aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may be in the range of, e.g., about 0.1 mg/kg/day to about 10 mg/kg/day, about 0.1 mg/kg/day to about 15 mg/kg/day, about 0.1 mg/kg/day to about 20 mg/kg/day, about 0.1 mg/kg/day to about 25 mg/kg/day, about 0.1 mg/kg/day to about 30 mg/kg/day, about 0.1 mg/kg/day to about 35 mg/kg/day, about 0.1 mg/kg/day to about 40 mg/kg/day, about 0.1 mg/kg/day to about 45 mg/kg/day, about 0.1 mg/kg/day to about 50 mg/kg/day, about 0.1 mg/kg/day to about 75 mg/kg/day, or about 0.1 mg/kg/day to about 100 mg/kg/day.\",\n \"In other aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may be in the range of, e.g., about 1 mg/kg/day to about 10 mg/kg/day, about 1 mg/kg/day to about 15 mg/kg/day, about 1 mg/kg/day to about 20 mg/kg/day, about 1 mg/kg/day to about 25 mg/kg/day, about 1 mg/kg/day to about 30 mg/kg/day, about 1 mg/kg/day to about 35 mg/kg/day, about 1 mg/kg/day to about 40 mg/kg/day, about 1 mg/kg/day to about 45 mg/kg/day, about 1 mg/kg/day to about 50 mg/kg/day, about 1 mg/kg/day to about 75 mg/kg/day, or about 1 mg/kg/day to about 100 mg/kg/day.\",\n \"In yet other aspects of this embodiment, an effective amount of a therapeutic compound disclosed herein may be in the range of, e.g., about 5 mg/kg/day to about 10 mg/kg/day, about 5 mg/kg/day to about 15 mg/kg/day, about 5 mg/kg/day to about 20 mg/kg/day, about 5 mg/kg/day to about 25 mg/kg/day, about 5 mg/kg/day to about 30 mg/kg/day, about 5 mg/kg/day to about 35 mg/kg/day, about 5 mg/kg/day to about 40 mg/kg/day, about 5 mg/kg/day to about 45 mg/kg/day, about 5 mg/kg/day to about 50 mg/kg/day, about 5 mg/kg/day to about 75 mg/kg/day, or about 5 mg/kg/day to about 100 mg/kg/day.\",\n \"Dosing can be single dosage or cumulative (serial dosing), and can be readily determined by one skilled in the art.\",\n \"For instance, treatment of a substance addiction may comprise a one-time administration of an effective dose of a pharmaceutical composition disclosed herein.\",\n \"Alternatively, treatment may comprise multiple administrations of an effective dose of a pharmaceutical composition carried out over a range of time periods, such as, e.g., once daily, twice daily, trice daily, once every few days, or once weekly.\",\n \"The timing of administration can vary from individual to individual, depending upon such factors as the severity of an individual's symptoms.\",\n \"For example, an effective dose of a pharmaceutical composition disclosed herein can be administered to an individual once daily for an indefinite period of time, or until the individual no longer requires therapy.\",\n \"A person of ordinary skill in the art will recognize that the condition of the individual can be monitored throughout the course of treatment and that the effective amount of a pharmaceutical composition disclosed herein that is administered can be adjusted accordingly.\",\n \"A pharmaceutical composition disclosed herein can also be administered to an individual in combination with other therapeutic compounds to increase the overall therapeutic effect of the treatment.\",\n \"The use of multiple compounds to treat an indication can increase the beneficial effects while reducing the presence of side effects.\",\n \"The following example illustrates but does not limit the scope of the disclosure set forth above.\",\n \"Example 1 This example describes experiments for determining monoamine oxidase (MAO) inhibition for isomyosmine and other alkaloids.\",\n \"MAOs are enzymes located on the outer membrane of mitochondria and are involved in the catabolism of monoamine neurotransmitters.\",\n \"There are two well-characterized isoenzymes: MAO-A, which predominantly catabolizes serotonin and norepinephrine, and MAO-B, which preferentially catabolizes benzylamine and phenylethylamine.\",\n \"Dopamine and tyramine are metabolized by both isoforms.\",\n \"To detect the activity of MAO, a luminescent method (MAO-Glo Assay kit, from Promega, Cat # V1401) was used.\",\n \"In this method, a MAO substrate (a derivative of beetle luciferin provided in the kit) is mixed with the compound to be tested (in this case, myosmine and control compounds).\",\n \"Then, the MAO enzymes (either A or B, purchased separately) are added to the mixture and incubated with the reaction for 1 hour at room temperature.\",\n \"The MAO enzymes, if not inhibited by the test compound, will convert the substrate into methyl ester luciferin.\",\n \"Finally, a luciferin detection reagent (provided by the kit) is added (20 minutes at room temperature) to stop the MAO reaction and convert methyl ester luciferin into D-luciferin.\",\n \"D-luciferin reacts with luciferase to produce a luminescent signal, which is directly proportional to the D-luciferin concentration and thus the MAO activity: the greater the amount of light produced the higher the activity of MAO.\",\n \"The luminescent signal is measured and recorded using a luminometer.\",\n \"The following materials were obtained from Toronto Research Chemicals, North York, ON: isomyosmine, catalog #1821350; myosmine, catalog # M835000; anabasine, catalog # A637175; and nornicotine, catalog # N756995.Anatabine was obtained from Emerson Resources, Norristown, Pa. As positive controls for the experiment, clorgyline (a well-characterized potent inhibitor of MAO-A) and deprenyl (a well-characterized potent inhibitor of MAO-B) were used.\",\n \"Results for MAO-A Activity When the pure alkaloids isomyosmine, myosmine, anatabine, anabasine, and nornicotine were compared, isomyosmine was the most potent of the five in inhibiting the enzymatic activity of MAO-A (FIG.\",\n \"1).\",\n \"The way to read this line graph is the following: a 100% activity means that the test compound has no effect on the enzyme; a 0% activity means that the test compound completely kills the enzyme.\",\n \"The more the curve is shifted to the left, the greater the inhibition the test compound exerts on the enzyme.\",\n \"As can be seen in FIG.\",\n \"1, the curve for isomyosmine is more shifted to the left among the five alkaloids tested.\",\n \"A 2 mM concentration (2,000 micromolar) gives an inhibition of about 50%.\",\n \"The curve for clorgyline, the positive control for the experiment, is greatly shifted leftward.\",\n \"Results for MAO-B Activity Similar results were obtained when testing the five pure alkaloids isomyosmine, myosmine, anatabine, anabasine, and nornicotine for the inhibition of MAO-B.\",\n \"Isomyosmine was the most potent among the five alkaloids tested at inhibiting the activity of MAO-B, followed by myosmine (FIG.\",\n \"2).\",\n \"Example 2 This example shows that isomyosmine is effective to increase oxygen saturation (%) levels.\",\n \"As shown in FIG.\",\n \"3, oxygen saturation (%) was found to dramatically increase in fourteen individuals when measured one hour after oral administration of isomyosmine at a dose of 100-300 mg depending on body weight.\",\n \"Increasing oxygen saturation levels is believed to make isomyosmine particularly effective for treating substance addictions, including tobacco/nicotine addictions, as well as addictions to heroin, cocaine, opioids, methadone, d-methamphetamine, barbiturates, alcohol, benzodiazepines, amphetamines, or buprenorphine.\",\n \"For example, substances such as cocaine are known to cause blood vessels to constrict, resulting in increased heartrate and blood pressure and increased stress on the heart's ability to circulate blood and oxygen through the body.\",\n \"Increasing oxygen saturation levels may, among other things, counteract these types of effects associated with substance abuse by increasing blood oxygen levels, aiding in the treatment of the underlying addiction.\",\n \"While the invention has been described with respect to specific examples, those skilled in the art will appreciate that there are numerous variations and permutations of the above described systems and techniques that fall within the spirit and scope of the invention as set forth in the appended claims.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875692"}}},{"rowIdx":4494952,"cells":{"text":{"kind":"list like","value":[["Display Device with Integrated Touch Screen and Method for Driving the Same","Discussed are a display device with an integrated touch screen and a method of operating the same.","The display device according to an embodiment includes a display panel including a plurality of pixel electrodes; a touch screen including m number of electrodes which are formed to overlap with the plurality of pixel electrodes, wherein m is a multiple of n, and n is an integer equal to or greater than two, and wherein the m electrodes are divided into n number of electrode groups; a touch driver configured to generate a touch scan signal and to supply the generated touch scan signal to a display driver; and the display driver configured to apply a common voltage or the touch scan signal to one or more of the m electrodes depending on a driving mode of the display device."],["1.A display driver integrated circuit (IC) for driving a self-capacitive touch sensitive display device comprising a display panel having a plurality of touch electrodes including at least a first group of touch electrodes including a first touch electrode and a second touch electrode and a second group of touch electrodes including a third touch electrode and a fourth touch electrode, a plurality of touch lines including at least a first touch line, a second touch line, a third touch line and a fourth touch line, a plurality of pixel electrodes in a pixel area of the display panel, and a plurality of data lines electrically connected to the plurality of pixel electrodes, the display driver IC comprising: a first multiplexer; a second multiplexer; and a plurality of touch channel outputs, the plurality of touch channel outputs including at least a first touch channel output, a second touch channel output, a third touch channel output and a forth touch channel output; wherein the first multiplexer is configured to selectively connect to the first touch channel output or the third touch channel output during a touch period, wherein the second multiplexer is configured to selectively connect to the second touch channel output or the fourth touch channel output during the touch period, wherein the first touch electrode is connected to the first channel output via the first touch line, the second touch electrode is connected to the second channel output via the second touch line, the third touch electrode is connected to the third channel output via the third touch line, the fourth touch electrode is connected to the fourth channel output via the fourth touch line, 2.The display driver IC of claim 1, wherein the display driver IC is configured to supply a touch scan signal to the plurality of touch electrodes during the touch period.","3.The display driver IC of claim 1, wherein the display driver IC is configured to supply a common voltage to the plurality of touch electrodes and to respectively supply data voltages to the plurality of pixel electrodes via the plurality of data lines during a display period.","4.The display driver IC of claim 1, wherein the display driver IC is configured to supply the touch scan signal to the first touch electrode and the second touch electrode simultaneously during a first part of the touch period, and wherein the display driver IC is configured to supply the touch scan signal to the third touch electrode and the fourth touch electrode simultaneously during a second part of the touch period.","5.The display driver IC of claim 1, further comprising a first switching unit and second switching unit, the first switching unit configured to selectively supply a common voltage or a touch scan signal to the first multiplexer, the second switching unit configured to selectively supply the common voltage or the touch scan signal to the second multiplexer.","6.The display driver IC of claim 1, wherein the first touch electrode is not overlapped with the second touch electrode in the first touch electrode group of the touch electrodes, and the third touch electrode is not overlapped with the fourth touch electrode in the second touch electrode group of the touch electrodes.","7.The display driver IC of claim 1, wherein the first touch line is not overlapped with the second touch line in a touch screen area of the display panel, wherein the third touch line is not overlapped with the fourth touch line in the touch screen area of the display panel.","8.The display driver IC of claim 1, wherein the first touch line and the second touch line are arranged in a same direction in the touch screen area of the display panel, wherein the third touch line and the fourth touch line are arranged in a same direction in the touch screen area of the display panel.","9.The display driver IC of claim 1, wherein the plurality of pixel electrodes of the display panel are respectively connected to the plurality of data channel outputs of the display driver IC via the plurality of data lines.","10.A method for driving a self-capacitive touch sensitive display device comprising a display panel having a plurality of touch electrodes including at least a first group of touch electrodes including a first touch electrode and a second touch electrode and a second group of touch electrodes including a third touch electrode and a fourth touch electrode, a plurality of touch lines including at least a first touch line, a second touch line, a third touch line and a fourth touch line, a plurality of pixel electrodes in a pixel area of the display panel, and a plurality of data lines electrically connected to the plurality of pixel electrodes, the method comprising: providing a common voltage to the first touch electrode, the second touch electrode, the third touch electrode and the fourth touch electrode during a display period via the plurality of touch lines; providing a touch scan signal to the first touch electrode and the second touch electrode simultaneously during a first part of a touch period; and providing the touch scan signal to the third touch electrode and the fourth touch electrode simultaneously during a second part of the touch period; 11.The method of claim 10, wherein the self-capacitive touch sensitive display device further comprises a display driver Integrated Circuit (IC) including a first multiplexer and the second multiplexer, wherein the display driver IC comprises a plurality of touch channel outputs, the plurality of touch channel outputs including at least a first touch channel output, a second touch channel output, a third touch channel output and a forth touch channel output.","12.The method of claim 11, further comprising: selectively connecting to the first touch channel output or the third touch channel output by the first multiplexer during a touch period, and selectively connecting to the second touch channel output or the fourth touch channel by the second multiplexer during the touch period.","13.The method of claim 11, wherein the first touch electrode is connected to the first channel output via the first touch line, the second touch electrode is connected to the second channel output via the second touch line, the third touch electrode is connected to the third channel output via the third touch line, and the fourth touch electrode is connected to the fourth channel output via the fourth touch line.","14.The method of claim 10, wherein the self-capacitive touch sensitive display device further comprises a display driver IC including a plurality of data channel outputs, and wherein the plurality of pixel electrodes of the display panel are respectively connected to the plurality of data channel outputs of the display driver IC via the plurality of data lines.","15.A touch sensitive display device comprising: a display panel comprising: a plurality of touch electrodes, the plurality of touch electrodes including at least a first group of touch electrodes including a first touch electrode and a second touch electrode and a second group of touch electrodes including a third touch electrode and a fourth touch electrode, a plurality of touch lines, the plurality of touch lines including at least a first touch line, a second touch line, a third touch line and a fourth touch line, a plurality of pixel electrodes in a pixel area of the display panel, and a plurality of data lines electrically connected to the plurality of pixel electrodes; and a display driver IC comprising a plurality of touch channel outputs and a plurality of data channel outputs, the plurality of touch channel outputs including at least a first touch channel output, a second touch channel output, a third touch channel output and a fourth touch channel output; wherein the first touch electrode is connected to the first channel output via the first touch line, the second touch electrode is connected to the second channel output via the second touch line, the third touch electrode is connected to the third channel output via the third touch line, the fourth touch electrode is connected to the fourth channel output via the fourth touch line, wherein the first touch electrode is not overlapped with the second touch electrode in the first touch electrode group of the touch electrodes, and the third touch electrode is not overlapped with the fourth touch electrode in the second touch electrode group of the touch electrodes, wherein the first touch line is not overlapped with the second touch line in a touch screen area of the display panel, the third touch line is not overlapped with the fourth touch line in the touch screen area of the display panel, wherein the plurality of pixel electrodes of the display panel are respectively connected to the plurality of data channel outputs of the display driver IC via the plurality of data lines.","16.The touch sensitive display device of claim 15, wherein the first touch line and the second touch line are arranged in a same direction in the touch screen area of the display panel, the third touch line and the fourth touch line arranged in a same direction in the touch screen area of the display panel.","17.The touch sensitive display device of claim 15, wherein the display driver IC is configured to supply a common voltage to the plurality of touch electrodes and to respectively supply data voltages to the plurality of pixel electrodes via the plurality of data lines during a display period.","18.The touch sensitive display device of claim 15, wherein the display driver IC is configured to supply a touch scan signal to the plurality of touch electrodes during a touch period, wherein the display driver IC is configured to supply the touch scan signal to the first touch electrode and the second touch electrode simultaneously during a first part of the touch period, and wherein the display driver IC is configured to supply the touch scan signal to the third touch electrode and the fourth touch electrode simultaneously during a second part of the touch period."],["<SOH> BACKGROUND <EOH>"],["<SOH> SUMMARY <EOH>Accordingly, the present invention is directed to provide a display device with an integrated touch screen that substantially obviates one or more problems due to limitations and disadvantages of the related art.","An aspect of the present invention is directed to provide a display device with an integrated touch screen, which applies a common voltage or a touch scan signal to a plurality of electrodes through a switching unit that is connected to at least two or more electrode groups of a self-capacitive touch screen.","Another aspect of the present invention is directed to provide a display device with an integrated touch screen, which enables the reduction in the number of touch IC channels that connect a display driver IC and a touch IC by using only one touch IC.","Another aspect of the present invention is directed to provide a display device with an integrated touch screen, which applies a common voltage directly from a display driver IC to an electrode without applying the common voltage to the electrode though a touch IC, thus preventing image quality from being degraded.","Additional advantages and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.","The objectives and other advantages of the invention may be realized and attained by the structure particularly pointed out in the written description and claims hereof as well as the appended drawings.","To achieve these and other advantages and in accordance with the purpose of the invention, as embodied and broadly described herein, there is provided according to an embodiment a display device with an integrated touch screen including: a touch screen including m number of electrodes which are formed to respectively overlap with a plurality of pixel electrodes in a pixel area of a panel, m being a multiple of n wherein n is an integer more than or equal to two; a display driver IC applying a common voltage to the electrodes, or applying a touch scan signal sequentially to n number of groups into which the m electrodes are divided, according to a driving mode of the panel; and a touch IC generating the touch scan signal to apply the touch scan signal to the display driver IC.","When the driving mode is a display driving mode, each of the electrodes may operate as a common electrode, or when the driving mode is a touch driving mode, each of the electrodes may operate as a touch electrode.","The number of electrodes included in each of the groups may be m/n number.","The n groups may be block type groups.","The groups may be divided and formed in a short side direction of the pixel area.","The display driver IC may include: a common voltage generator generating the common voltage; a sync signal generator generating a sync signal indicating the driving mode; a switching control signal generator generating a control signal which allows the electrodes to be simultaneously connected to the common voltage generator or allows the electrodes to be sequentially connected to the touch IC for each group, according to the sync signal; and a switching unit operating according to the sync signal and the control signal.","The switching unit may include a plurality of first switching units and a plurality of second switching units, the first switching units being connected to the common voltage generator and the touch IC, and the second switching units being connected to the respective first switching units and one electrode for each group.","When the sync signal is a first sync signal indicating the display driving mode, the first switching units may connect the common voltage generator to the second switching units, or when the sync signal is a second sync signal indicating the touch driving mode, the first switching units may connect the touch IC to the second switching units.","When the control signal is a first control signal conforming to the first sync signal, the second switching units may connect the respective electrodes to the first switching units, or when the control signal is a second control signal conforming to the second sync signal, the second switching units may sequentially connect the respective electrodes to the first switching units for each group.","The second control signal may include n number of group selection signals which allow the first switching units to be respectively connected to the electrodes for each group.","Each of the second switching units may include a plurality of CMOS transistors, and control respective gates of the CMOS transistors to simultaneously connect the first switching units and the groups or sequentially connect the first switching units and the groups for each group.","The number of first switching units may be m/n number.","In another aspect of the present invention, there is provided a driving method of a display device with an integrated touch screen, which includes: a touch screen including m number of electrodes in a pixel area of a panel (where m is a multiple of n and n is an integer more than or equal to two); a display driver IC applying a common voltage or a touch scan signal to the electrodes; and a touch IC generating the touch scan signal to apply the touch scan signal to the display driver IC, the method including: applying the common voltage to the electrodes when a driving mode of the panel is a display driving mode; and sequentially applying the touch scan signal to n number of groups into which the electrodes are divided, when the driving mode of the panel is a touch driving mode.","The number of electrodes included in each of the groups may be m/n number.","The n groups may be block type groups.","The groups may be divided and formed in a short side direction of the pixel area.","The applying of the common voltage may include: generating the common voltage; generating a first sync signal according to the display driving mode, and generating a first control signal according to the first sync signal; switching a first switching unit to output the common voltage according to the first sync signal; and switching a second switching unit to simultaneously apply the common voltage, outputted from the first switching unit, to the electrodes according to the first control signal.","The applying of the touch scan signal may include: generating the touch scan signal; generating a second sync signal according to the touch driving mode, and generating a second control signal according to the second sync signal; switching a first switching unit to output the touch scan signal according to the second sync signal; and switching a second switching unit to sequentially apply the touch scan signal, outputted from the first switching unit, to the n groups according to the second control signal.","According to an embodiment, the present invention provides a display device with integrated touch screen, including: a display panel including a plurality of pixel electrodes; a touch screen including m number of electrodes which are formed to overlap with the plurality of pixel electrodes, wherein m is a multiple of n, and n is an integer equal to or greater than two, and wherein the m electrodes are divided into n number of electrode groups; a touch driver configured to generate a touch scan signal and to supply the generated touch scan signal to a display driver; and the display driver configured to apply a common voltage or the touch scan signal to one or more of the m electrodes depending on a driving mode of the display device.","According to an embodiment, the present invention provides a method of operating a display device, the display device including a display panel including a plurality of pixel electrodes and a touch screen including m number of electrodes which are formed to overlap with the plurality of pixel electrodes, wherein m is a multiple of n, and n is an integer equal to or greater than two, the display device further including a touch driver and a display driver, the method including: dividing the m electrodes into n number of electrode groups; generating, by the touch driver, a touch scan signal; and applying, by the display driver, a common voltage or the generated touch scan signal to one or more of the m electrodes depending on a driving mode of the display device, wherein when the generated touch scan signal is applied to the one or more of the m electrodes, the touch scan signal is selectively applied to each of the electrode groups.","It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed."],["CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation application of U.S. patent application Ser.","No.","14/968,681 filed on Dec. 14, 2015, which is a continuation application of U.S. patent application Ser.","No.","13/448,021 filed on Apr.","16, 2012, which claims the priority benefit of the Korean Patent Application No.","10-2012-0016908 filed on Feb. 20, 2012, all of which are hereby incorporated by reference as if fully set forth herein.","BACKGROUND Field of the Invention The present invention relates to a display device, and more particularly, to a display device with an integrated touch screen and a driving method thereof.","Discussion of the Related Art Touch screens are a type of input device that is included in image display devices such as Liquid Crystal Displays (LCDs), Field Emission Displays (FEDs), Plasma Display Panel (PDPs), Electroluminescent Displays (ELDs), and Electrophoretic Display (EPDs), and allows a user to input predetermined information by applying a pressure (i.e., by pressing or touching) to a touch sensor of a touch screen of the image display device while looking at the image display device.","Particularly, the demand of display devices with an integrated in-cell type touch screen, which include a plurality of built-in elements configuring the touch screen for providing slim portable terminals such as smart phones and tablet Personal Computers (PCs), is recently increasing.","Hereinafter, a related art display device with an integrated touch screen will be described with reference to FIG.","1.FIG.","1 is a diagram illustrating a configuration of a related art display device with an integrated touch screen, and more specifically illustrates a configuration of a display device with an integrated self-capacitive touch screen having an in-cell type.","The related art display device with the integrated self-capacitive touch screen having an in-cell type, as illustrated in FIG.","1, includes: a panel 10 with a built-in touch screen 11; a display driver IC (DD-IC) 20 that is connected to an external system and controls a plurality of gate lines and data lines in the panel 10; a plurality of touch ICs (T-IC1 and T-IC2) 31 and 32 that drive the touch screen 11 in the panel 10.The panel 10 includes m number of electrodes 12, and m number of lines 13 that are respectively extended from the m electrodes 12.Each of the touch ICs 31 and 32 includes m number of touch IC channels respectively corresponding to the m lines 13, for self-capacitive touch sensing.","Since one touch IC channel generally corresponds a line connected to an electrode in one-to-one correspondence relationship, as illustrated in FIG.","1, when the number of lines connected to an electrode is more than the number of channels that are capable of being accommodated by one touch IC, a plurality of touch ICs are required to be used, causing the increase in cost.","In the display device with the integrated touch screen of FIG.","1, each of the electrodes 12 is built in the panel 10 and performs a touch function and a display function, and thus is used as a common electrode for display driving when the display device is driven in a display driving mode, or is used as a touch electrode when the display device is driven in a touch driving mode.","The display driving mode is a display mode for displaying images on the display device, and the touch driving mode is a touch mode for detecting and processing a touch input to the display device.","On the contrary, when the display device is driven in the display driving mode, a common voltage Vcom outputted from inside the display driver IC (DD-IC) 20 is applied to the electrodes 12 through the touch ICs 31 and 32, in which case the touch ICs 31 and 32 need to accommodate a negative voltage when the common voltage Vcom is the negative voltage.","However, the related art touch ICs 31 and 32 cannot accommodate a negative voltage and thus, a special manufacturing process and design for a touch IC that can accommodate the negative voltage are needed, which in turn increases the manufacturing cost of the touch ICs.","Moreover, when the related art touch sensitive display device is driven in the display driving mode, a ground-level voltage instead of a negative voltage may be incidentally supplied to the electrode 12 through the touch IC, thereby causing the degradation of image quality.","To provide a summary on the above-described limitations, the related art display device with the integrated touch screen has at least the following limitations.","First, as the number of touch IC channels matching the respective lines connected to electrodes increases, the number of touch ICs increases, thereby causing the increase in cost for the display device.","Second, a touch IC is separately manufactured by modifying the manufacturing process and design thereof for applying a negative common voltage, thereby causing the increase in the manufacturing cost of the touch IC.","Third, when the related art touch IC is applied to a display device, the ground-level common voltage, instead of the desired negative common voltage, may be incidentally applied to the electrodes in the display driving mode, thereby causing the degradation of image quality.","SUMMARY Accordingly, the present invention is directed to provide a display device with an integrated touch screen that substantially obviates one or more problems due to limitations and disadvantages of the related art.","An aspect of the present invention is directed to provide a display device with an integrated touch screen, which applies a common voltage or a touch scan signal to a plurality of electrodes through a switching unit that is connected to at least two or more electrode groups of a self-capacitive touch screen.","Another aspect of the present invention is directed to provide a display device with an integrated touch screen, which enables the reduction in the number of touch IC channels that connect a display driver IC and a touch IC by using only one touch IC.","Another aspect of the present invention is directed to provide a display device with an integrated touch screen, which applies a common voltage directly from a display driver IC to an electrode without applying the common voltage to the electrode though a touch IC, thus preventing image quality from being degraded.","Additional advantages and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.","The objectives and other advantages of the invention may be realized and attained by the structure particularly pointed out in the written description and claims hereof as well as the appended drawings.","To achieve these and other advantages and in accordance with the purpose of the invention, as embodied and broadly described herein, there is provided according to an embodiment a display device with an integrated touch screen including: a touch screen including m number of electrodes which are formed to respectively overlap with a plurality of pixel electrodes in a pixel area of a panel, m being a multiple of n wherein n is an integer more than or equal to two; a display driver IC applying a common voltage to the electrodes, or applying a touch scan signal sequentially to n number of groups into which the m electrodes are divided, according to a driving mode of the panel; and a touch IC generating the touch scan signal to apply the touch scan signal to the display driver IC.","When the driving mode is a display driving mode, each of the electrodes may operate as a common electrode, or when the driving mode is a touch driving mode, each of the electrodes may operate as a touch electrode.","The number of electrodes included in each of the groups may be m/n number.","The n groups may be block type groups.","The groups may be divided and formed in a short side direction of the pixel area.","The display driver IC may include: a common voltage generator generating the common voltage; a sync signal generator generating a sync signal indicating the driving mode; a switching control signal generator generating a control signal which allows the electrodes to be simultaneously connected to the common voltage generator or allows the electrodes to be sequentially connected to the touch IC for each group, according to the sync signal; and a switching unit operating according to the sync signal and the control signal.","The switching unit may include a plurality of first switching units and a plurality of second switching units, the first switching units being connected to the common voltage generator and the touch IC, and the second switching units being connected to the respective first switching units and one electrode for each group.","When the sync signal is a first sync signal indicating the display driving mode, the first switching units may connect the common voltage generator to the second switching units, or when the sync signal is a second sync signal indicating the touch driving mode, the first switching units may connect the touch IC to the second switching units.","When the control signal is a first control signal conforming to the first sync signal, the second switching units may connect the respective electrodes to the first switching units, or when the control signal is a second control signal conforming to the second sync signal, the second switching units may sequentially connect the respective electrodes to the first switching units for each group.","The second control signal may include n number of group selection signals which allow the first switching units to be respectively connected to the electrodes for each group.","Each of the second switching units may include a plurality of CMOS transistors, and control respective gates of the CMOS transistors to simultaneously connect the first switching units and the groups or sequentially connect the first switching units and the groups for each group.","The number of first switching units may be m/n number.","In another aspect of the present invention, there is provided a driving method of a display device with an integrated touch screen, which includes: a touch screen including m number of electrodes in a pixel area of a panel (where m is a multiple of n and n is an integer more than or equal to two); a display driver IC applying a common voltage or a touch scan signal to the electrodes; and a touch IC generating the touch scan signal to apply the touch scan signal to the display driver IC, the method including: applying the common voltage to the electrodes when a driving mode of the panel is a display driving mode; and sequentially applying the touch scan signal to n number of groups into which the electrodes are divided, when the driving mode of the panel is a touch driving mode.","The number of electrodes included in each of the groups may be m/n number.","The n groups may be block type groups.","The groups may be divided and formed in a short side direction of the pixel area.","The applying of the common voltage may include: generating the common voltage; generating a first sync signal according to the display driving mode, and generating a first control signal according to the first sync signal; switching a first switching unit to output the common voltage according to the first sync signal; and switching a second switching unit to simultaneously apply the common voltage, outputted from the first switching unit, to the electrodes according to the first control signal.","The applying of the touch scan signal may include: generating the touch scan signal; generating a second sync signal according to the touch driving mode, and generating a second control signal according to the second sync signal; switching a first switching unit to output the touch scan signal according to the second sync signal; and switching a second switching unit to sequentially apply the touch scan signal, outputted from the first switching unit, to the n groups according to the second control signal.","According to an embodiment, the present invention provides a display device with integrated touch screen, including: a display panel including a plurality of pixel electrodes; a touch screen including m number of electrodes which are formed to overlap with the plurality of pixel electrodes, wherein m is a multiple of n, and n is an integer equal to or greater than two, and wherein the m electrodes are divided into n number of electrode groups; a touch driver configured to generate a touch scan signal and to supply the generated touch scan signal to a display driver; and the display driver configured to apply a common voltage or the touch scan signal to one or more of the m electrodes depending on a driving mode of the display device.","According to an embodiment, the present invention provides a method of operating a display device, the display device including a display panel including a plurality of pixel electrodes and a touch screen including m number of electrodes which are formed to overlap with the plurality of pixel electrodes, wherein m is a multiple of n, and n is an integer equal to or greater than two, the display device further including a touch driver and a display driver, the method including: dividing the m electrodes into n number of electrode groups; generating, by the touch driver, a touch scan signal; and applying, by the display driver, a common voltage or the generated touch scan signal to one or more of the m electrodes depending on a driving mode of the display device, wherein when the generated touch scan signal is applied to the one or more of the m electrodes, the touch scan signal is selectively applied to each of the electrode groups.","It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.","BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this application, illustrate embodiments of the invention and together with the description serve to explain the principle of the invention.","In the drawings: FIG.","1 is a diagram illustrating a configuration of a related art display device with an integrated touch screen; FIG.","2 is a diagram illustrating a configuration of a display device with an integrated touch screen according to an embodiment of the present invention; FIG.","3A is a diagram illustrating a detailed configuration of each of first and second switching units in FIG.","2; FIG.","3B is a diagram for describing an operation of each of the first and second switching units in FIG.","3A; FIG.","4 is a diagram showing a first embodiment of an electrode division method in a display device with integrated touch screen according to an embodiment of the present invention; FIGS.","5A to 5D are diagrams respectively showing an example of experiment data of touch sensitivity according to the method of FIG.","4; FIG.","6 is a diagram showing a second embodiment of an electrode division method in the display device with integrated touch screen according to an embodiment of the present invention; and FIG.","7 is a diagram showing a third embodiment of an electrode division method in the display device with integrated touch screen according to an embodiment of the present invention.","DETAILED DESCRIPTION OF THE INVENTION Reference will now be made in detail to the exemplary embodiments of the present invention, examples of which are illustrated in the accompanying drawings.","Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts.","Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings.","In a display device with an integrated touch screen according to an embodiment of the present invention, a plurality of electrodes are divided into n number of groups, and a touch scan signal is sequentially applied to the n groups.","However, for convenience of a description, the below description will be made on a method where the electrodes are divided into two groups (i.e., n=2).","However, the present invention is not limited to the method where the electrodes are divided into the two groups, and the electrodes may be divided into three or more groups.","FIG.","2 is a diagram illustrating a configuration of a display device with an integrated touch screen according to an embodiment of the present invention.","The display device with the integrated touch screen according to an embodiment of the present invention, as illustrated in FIG.","2, includes: a touch screen 111 that includes m number of electrodes 112 (where m is a multiple of n, and n is an integer more than or equal to two) which are formed to respectively overlap with a plurality of pixel electrodes in a pixel area of a display panel 110; a display driver IC 120 that applies a common voltage Vcom to the electrodes 112 or sequentially applies a touch scan signal to the electrodes of each of two groups 114 into which the m electrodes 112 are divided, according to a driving mode of the panel 110; and a touch IC 130 that generates the touch scan signal and applies the touch scan signal to the display driver IC 120.The touch screen 111 detects a touch point of a user.","Particularly, the touch screen 111 applied to the present embodiment is an in-cell type touch screen using a self-capacitive type, and a touch screen area is the same area as a pixel array area.","The self-capacitive touch screen includes the m electrodes 112 and the same m number of lines 113, in the panel 110.Herein, the panel 110 may be configured in a structure where a liquid crystal layer is formed between two substrates.","In this case, a lower substrate of the panel 110 can include: a plurality of data lines disposed in parallel to each other; a plurality of gate lines that cross the data lines and are disposed in parallel to each other; a plurality of Thin Film Transistors (TFTs) that are respectively formed in a plurality of intersection areas between the data lines and the gate lines; a plurality of pixel electrodes that respectively charge data voltages into the plurality of pixels; an electrode (also referred to as a common electrode) that drives liquid crystal cells injected into the liquid crystal layer, together with the operation of the pixel electrodes.","The pixels are arranged in a matrix type corresponding to the above-described intersection structure between the date lines and the gate lines.","The m electrodes 112 are formed to overlap with the plurality of pixel electrodes, in the pixel array area of the panel 110.For instance, the m electrodes are not formed in each pixel but are formed in an area overlapping with a plurality of pixels.","That is, the m electrodes 112 are preferably disposed over the area where the pixel electrodes are disposed.","The m electrodes 112 may be disposed substantially through the touch screen 111 so that a touch input thereto may be accurately detected.","When the driving mode of the panel 110 is a display driving mode, each of the electrodes 112 operates as a common electrode that drives liquid crystal cells together with the operation of the pixel electrode(s) formed in corresponding pixel(s).","When the driving mode of the panel 110 is a touch driving mode, each electrode 112 operates as a touch electrode that detects a touch point/input by using the touch scan signal applied from the touch IC 130.For example, as illustrated in FIG.","2, the m electrodes 112 may be formed to be divided into two groups 114, and formed in a block type group 114 but the group can be in a different shape.","Each of the groups 114 may be formed in a touch screen 111 area, and the number of electrodes included in each group 114 is m/2.In FIG.","2, the number of electrodes in each of two groups into which the electrodes 112 are divided is m/2, but when the electrodes 112 are divided into n number of groups, the number of electrodes in each of the n groups is m/n, where m and n are positive integers and preferably m is a multiple of n to provide an even division.","The m lines 113 connect the m electrodes 112 to the display driver IC 120, respectively.","Therefore, the common voltage and the touch scan signal that are outputted from the display driver IC 120 are applied to the electrodes 112 through the respective lines 113.When the driving mode of the panel 110 is in the display driving mode, the display driver IC 120 applies the common voltage to the electrodes 112, and when the driving mode of the panel 110 is in the touch driving mode, the display driver IC 120 sequentially applies the touch scan signal to the electrodes of each of the two groups into which the electrodes 112 are divided.","Embodiments of a group division method according to the present invention will be described below in detail.","The display driver IC 120 drives the data lines and gate lines that are formed in the panel 110, and drives each of the m electrodes 112 as a common electrode or a touch electrode.","For this end, the display driver IC 120 may include a common voltage generator 121, a sync signal generator 122, a switching control signal generator 123, and a switching unit 124.The common voltage generator 121 generates a common voltage Vcom and applies the common voltage Vcom to the switching unit 124.Specifically, when the driving mode of the panel 110 is in the display driving mode, the common voltage generator 121 generates the common voltage Vcom which is then applied to the m electrodes 112 for image output, and applies the common voltage Vcom to the switching unit 124.The sync signal generator 122 generates a sync signal indicating the driving mode of the panel 110.For example, as illustrated in FIG.","2, when the driving mode of the panel 110 is in the display driving mode, the sync signal generator 122 generates a first sync signal “0” that allows the common voltage Vcom of the common voltage generator 121 to be applied to the electrodes 112 through the switching unit 124.When the driving mode of the panel 110 is in the touch driving mode, the sync signal generator 122 generates a second sync signal “1” that allows the touch scan signal of the touch IC 130 to be applied to the electrodes 112.The switching control signal generator 123 generates a control signal that allows the electrodes 112 to be simultaneously connected to the common voltage generator 121 or a control signal that allows the electrodes 112 to be sequentially connected to the touch IC 130 for each group, according to the sync signal of the sync signal generator 122.For example, as illustrated in FIG.","2, when the sync signal of the sync signal generator 123 is the first sync signal “0”, the switching control signal generator 123 generates a first control signal “00” that allows the common voltage (received from the common voltage generator 121) to be simultaneously applied to the m electrodes 112.When the sync signal of the sync signal generator 123 is the second sync signal “1”, the switching control signal generator 123 generates a second control signal “01” or “10” that allows the touch scan signal (received from the touch IC 130) to be sequentially applied to the two electrode groups 114.The second control signal may be generated in plurality, according to the number of groups that are connected to the switching unit 124.In other words, in this example, the second control signal denotes two group selection signals (“01” and “10”) that allow the switching unit 124 to be connected to the electrodes 112 by two groups (CH1 and CH2).","However, the electrodes 112 may be divided into two or more groups.","In such cases, when there are n number of groups (n being greater than or equal 2), the second control signal corresponding to n number of group selection signals that are respectively and selectively applied to the n groups is generated.","For instance, if there are 3 electrode groups 114, then the group selection signals of the second control signal may be, e.g., “001”, “010” and “011” which are used to respectively control the three different electrode groups via the channel outputs CH1, CH2 and CH3 of each of the second switching units 126.The switching unit 124 may be configured with a plurality of first switching units 125 and a plurality of second switching units 126.Each of the second switching units 126 includes channels CH1 and CH2.The switching unit 124 operates according to the sync signal of the sync signal generator 122 and the control signal of the switching control signal generator 123.For example, as illustrated in FIG.","2, when the sync signal of the sync signal generator 122 is the first sync signal “0” and the control signal of the switching control signal generator 123 is the first control signal “00”, the common voltage Vcom generated by the common voltage generator 121 is applied to all the electrodes 122.When the sync signal of the sync signal generator 122 is the second sync signal “1” and the control signal of the switching control signal generator 123 is the second control signal “01” or “10”, the touch scan signal generated by the touch IC 130 is applied to the m electrodes 112.More specifically, when the second control signal of the switching control signal generator 123 is the second control signal “01”, the touch scan signal from the touch IC 130 is applied to the electrodes of one of the groups 114 through the channel CH1 of each of the second switching units 126.On the other hand, when the second control signal of the switching control signal generator 123 is the second control signal “10”, the touch scan signal is applied to the electrodes of the other one of the groups 114 through the channel CH2 of each of the second switching units 126.The detailed configurations and operations of the first switching units 125 and second switching units 126 of the switching unit 124 will now be described in detail with reference to FIGS.","2, 3A and 3B according to an embodiment of the present invention.","FIG.","3A is a diagram illustrating a detailed configuration of each of the first and second switching units in FIG.","2.FIG.","3B is a diagram for describing an operation of each of the first and second switching units in FIG.","3A.","The first switching unit 125 may be configured with a 2:1 multiplexer.","For example, as illustrated in FIG.","3A, the first switching unit 125 may be configured with transistors TR1 and TR2.The transistor TR1 may be connected to the common voltage generator 121 and the second switching unit 126, and the transistor TR2 may be connected to the touch IC 130 and the second switching unit 126.Herein, each of the transistors TR1 and TR2 may be a CMOS transistor.","When the sync signal is the first sync signal “0” indicating the display driving mode, the first switching unit 125 connects the common voltage generator 121 to the second switching unit 126.When the sync signal is the second sync signal “1” indicating the touch driving mode, the first switching unit 125 connects the touch IC 130 to the second switching unit 126.For example, when the sync signal of the sync signal generator 122 is the first sync signal “0”, the transistor TR1 of the first switching unit 125 is turned on and simultaneously the transistor TR2 is turned off, and thus, the common voltage generator 121 and the second switching unit 126 are connected to each other through the transistor TR1 of the first switching unit 125, whereupon the common voltage Vcom generated by the common voltage generator 121 is delivered to the second switching unit 126.When the sync signal of the sync signal generator 122 is the second sync signal “1”, the transistor TR2 of the first switching unit 125 is turned on and simultaneously the transistor TR1 is turned off, and thus, the touch IC 130 and the second switching unit 126 are connected to each other through the transistor TR2 of the first switching unit 125, whereupon the touch scan signal generated by the touch IC 130 is delivered to the second switching unit 126.The second switching unit 126 is a signal selector that has one input channel and a plurality of output channels CH1 and CH2.The second switching unit 126 simultaneously or sequentially outputs a signal, supplied from the first switching unit 125, through the output channels CH1 and CH2.For example, as illustrated in FIG.","3A, the second switching unit 126 may be configured with transistors TR3 and TR4, which are connected to the first switching unit 125 and corresponding electrodes 112 through the lines 113.Herein, each of the transistors TR3 and TR4 may be a CMOS transistor.","The second switching unit 126 is connected only to the first switching unit 125 and one electrode for each group.","When the control signal applied to the second switching unit 126 is the first control signal conforming to the first sync signal (display mode), the second switching unit 126 connects the first switching unit 125 to all the electrodes 112.When the control signal is the second control signal conforming to the second sync signal (touch mode), the second switching unit 126 sequentially connects the first switching unit 125 to a plurality of electrodes for each group 114.For example, when the control signal of the switching control signal generator 123 is the first control signal “00” conforming to the first sync signal “0” of the sync signal generator 122, the transistors TR3 and TR4 of the second switching unit 126 are simultaneously turned on, and thus, the first switching unit 125 and all the electrodes 112 are connected to each other through the channels CH1 and CH2 of the respective transistors TR3 and TR4 in the second switching unit 126, whereupon the common voltage Vcom delivered from the first switching unit 125 is applied to all the electrodes 112 including both groups 114 simultaneously.","When the control signal of the switching control signal generator 123 is the second control signal “01” conforming to the second sync signal “1” of the sync signal generator 122, the transistor TR3 of the second switching unit 126 is turned on and simultaneously the transistor TR4 is turned off, and thus, the first switching unit 125 and the electrodes of any one of the groups 114 are connected to each other through the channel CH1 of the transistor TR3 of the second switching unit 126, whereupon the touch scan signal delivered from the first switching unit 125 is applied to all the electrodes of that one group among the groups 114.When the control signal of the switching control signal generator 123 is the second control signal “10” conforming to the second sync signal “1” of the sync signal generator 122, the transistor TR4 of the second switching unit 126 is turned on and simultaneously the transistor TR3 is turned off, and thus, the first switching unit 125 and the electrodes of the other of the groups 114 are connected to each other through the channel CH2 of the transistor TR4 of the second switching unit 126, whereupon the touch scan signal delivered from the first switching unit 125 is applied to all the electrodes of the other group among the groups 114.Referring again to FIG.","2, the touch IC 130 applies the touch scan signal to the electrodes 112 through display driver IC 120, and then detects the change in the capacitance of each electrode to determine whether an electrode area is touched.","The touch IC 130 and the display driver IC 120 are connected to each other through the touch IC channels, and the total number of touch IC channels is m/2.That is, in the related art, the number of electrodes or lines is equal to the number of touch IC channels, but in the present invention, the number of touch IC channels decreases to a half of the number of electrodes 112 or lines 113, which reduces the manufacturing cost and structure configuration.","Hereinafter, an electrode division method will now be described in detail with reference to FIGS.","4 to 8 according to an embodiment of the present invention.","These methods can be implemented using the devices of FIGS.","1-3 or other suitable display devices.","FIG.","4 is a diagram showing a first example of an electrode division method in a display device with an integrated touch screen according to an embodiment of the present invention.","As illustrated in FIG.","4, 160 electrodes can be divided into two groups, namely, an odd group and an even group.","The odd group is connected to the respective channels CH1 of the second switching units 126 in the display driver IC 120, and the even group is connected to the respective channels CH2 of the second switching units 126.When the sync signal generator 122 generates the second sync signal “1” indicating the touch driving mode and the switching control signal generator 123 generates the second control signal “01” designating the channel CH1, the respective channels CH1 of the second switching units 126 are connected to the electrodes of the odd group.","That is, all the channels CH1 of each of the second switching units 126 are connected to the corresponding electrodes of the odd group.","When the sync signal generator 122 generates the second sync signal “1” indicating the touch driving mode and the switching control signal generator 123 generates the second control signal “10” designating the channel CH2, the respective channels CH2 of the second switching units 126 are connected to the electrodes of the even group.","Thus in the example of FIG.","4, the electrodes 112 may be divided into groups having specific configurations.","FIGS.","5A to 5D are diagrams respectively showing experiment data of touch sensitivity detected according to the method of FIG.","4.In the present experiment data, the X axis indicates time, and the y axis indicates raw count.","A raw count value is a value that becomes fundamental for measuring touch sensing, and is to represent a touch sensing signal as a touch clock count value.","A touch driving pulse is applied selectively to the odd group and even group of electrodes shown in FIG.","4.Since the electrodes immediately neighboring the electrode numbers 39 and 40 belong to the same even group, when the touch driving pulse is applied to such electrodes, a high touch sensitivity is provided.","On the other hand, since some electrodes immediately neighboring the electrode numbers 51 and 66 belong to different electrode groups (i.e., the odd group), the neighboring electrodes are grounded when the touch driving pulse is applied to the electrodes 51 and 66.As a result, the touch sensitivity in such area is lower than the touch sensitivity around the electrode numbers 39 and 40.This can be seen in FIGS.","5A and 5B.","Referring to the experiment data, a raw count difference of the electrode number 39 (highlighted in FIG.","4) is 200, a raw count difference of the electrode number 40 is 230, a raw count difference of the electrode number 51 is 100, and a raw count difference of the electrode number 66 is 160.A large raw count difference denotes that the touch sensitivity is better in proportion thereto.","In the present experiment data, there are no electrodes (which are connected to different channels of the second switching unit 126) respectively adjacent to the electrode number 39 and the electrode number 40, and thus, the raw count difference of each of the electrode number 39 and electrode number 40 is greater than that of each of the electrode number 51 and electrode number 66, which means that the touch sensitivity in the area of the electrode numbers 39 and 40 is better than the touch sensitivity in the area of the electrode numbers 51 and 66.Thus to enhance the touch sensitivity of the touch panel, it would be desirable to minimize the number of adjacent electrodes that belong to a different group of touch electrodes driven at a different time.","Accordingly, FIGS.","6 and 7 provide examples of dividing or grouping the touch electrodes according to the present invention to maximize the touch sensitivity of the display panel.","FIGS.","6 and 7 illustrate the examples of a group division method that enables the obtainment of high touch sensitivity, based on the experiment data of FIG.","5.As illustrated in FIGS.","6 and 7, a plurality of electrodes may be divided into a plurality of block type groups.","For example, when the pixel area of the panel 110 is rectangular in shape, by dividing the electrodes 112 into a plurality of groups along a short (shorter) side direction to have a rectangular shape, RC delay is reduced between the adjacent electrodes included in different groups, thus increasing the touch sensitivity of the display device.","FIG.","6 is a diagram showing a second example of an electrode division method in the display device with the integrated touch screen according to an embodiment of the present invention.","Referring to FIG.","6, the plurality of electrodes 112 are divided into two block type groups 114 along the direction of the shorter side of the touch screen 111.One (114a) of the groups 114 is connected to the channels CH1 of the second switching units 126 in the display driver IC 120, and the other group 114b is connected to the channels CH2 of the second switching units 126.When the sync signal generator 122 generates the second sync signal “1” indicating the touch driving mode and the switching control signal generator 123 generates the second control signal “01” designating the channel CH1, the respective channels CH1 of the second switching units 126 are connected to all the electrodes of the one group 114a.","When the sync signal generator 122 generates the second sync signal “1” indicating the touch driving mode and the switching control signal generator 123 generates the second control signal “10” designating the channel CH2, the respective channels CH2 of the second switching units 126 are connected to all the electrodes of the other group 114b.","In the present example, when the pixel area of the panel 110 is rectangular in shape, the block type groups 114 may be formed by dividing the electrodes 112 along a short/shorter side direction of the touch screen 111 to have a rectangular shape or the like, and the numbers of electrodes in each of the divided groups may be the same.","As in the present embodiment, by dividing the electrodes into a plurality of groups along a short/shorter side direction of the touch screen 111 to have a rectangular shape or the like, a proximal surface between the groups 114 is minimized and thus, a potential difference between the electrodes 112 connected to the respective channels of the different second switching units 126 is minimized, thereby increasing the touch sensitivity of the panel 110.In the above-described example, the pixel area is the same area as that of the touch screen 111.FIG.","7 is a diagram showing a third example of an electrode division method in the display device with the integrated touch screen according to an embodiment of the present invention.","Referring to FIG.","7, the electrodes 112 are divided into three block type groups 114 (114a, 114b, 114c), and if the pixel area of the panel 110 is rectangular in shape, similarly to the example of FIG.","6, the block type groups 114 may be formed by dividing the electrodes 112 into a plurality of groups along a short/shorter side direction of the touch screen 111 to have a rectangular shape or the like.","In this way, by dividing the electrodes 112 into the plurality of groups 114a, 114b, 114c along the short side direction to have the rectangular or other shape, a proximal surface between the groups 114 is minimized and thus, a potential difference between the electrodes 112 connected to the respective channels of the different second switching units 126 is minimized, thereby increasing the touch sensitivity of the touch screen 111.The detailed description of this example is the same as that of the above-described second example, and thus is not provided.","In the example of FIG.","7, because there exist three groups 114a, 114b and 114c of the electrodes 112, each of the second switching units 126 would have one input and three outputs CH1, CH2 and CH3 which respectively control the three groups 114a, 114b and 114c.","As such, the number of second switching units 126 needed may correspond to m/n.","In this regard, the switching control signal generator 123 is configured to output appropriate control signals so that each of the groups 114a, 114b and 114c is selectively and independently driven by controlling the output selection among the outputs CH1, CH2 and CH3.The configuration of the first switching units 125 would be the same as that shown in FIGS.","2 and 3.Thus, depending on the number of groups of electrodes formed, the corresponding same number of touch channels for each of the second switching units 126 may be used.","According to the present embodiments, a plurality of electrodes have been exemplarily described as being divided into two groups or three groups, but may be divided into four or more groups according to the number of electrodes.","A driving method of the display device with the integrated touch screen having the above-described configuration, according to an embodiment of the present invention, will be described in detail with reference to FIG.","2.When the driving mode of the display device with the integrated touch screen according to an embodiment of the present invention is in the display driving mode, the sync signal generator 122 generates the first sync signal “0” to transfer the first sync signal “0” to the first switching units 125, and the switching control signal generator 123 generates the first control signal “00” to transfer the first control signal “00” to the second switching units 126.The first switching units 125 are switched and connect the common voltage generator 121 to the second switching units 126, according to the first sync signal “0”.","The second switching units 126 are switched and connect the m electrodes to the channels CH1 and CH2, according to the first control signal “00”.","The common voltage generated by the common voltage generator 121 is applied simultaneously to all the m electrodes 112 through the first switching units 125 and the second switching units 126.When the driving mode of the display device is in the touch driving mode, the sync signal generator 122 generates the second sync signal “1” to transfer the second sync signal “1” to the first switching units 125, and the switching control signal generator 123 generates the second control signal “01” or “10” to transfer the second control signal “01” or “10” to the second switching units 126.The first switching units 125 are switched and connect the touch IC 130 to the second switching units 126, according to the second sync signal “1”.","The second switching units 126 are switched and connect one of the two groups 114 to the channels CH1 and CH2, according to the second control signal “01” or “10”.","When the second control signal is “01”, the channels CH1 of the second switching units 126 are connected to the electrodes of one of the two groups 114.When the second control signal is “10”, the channels CH2 of the second switching units 126 are connected to the electrodes (which are not connected to the channels CH1) of the other group among the two groups 114.The touch scan signal generated from the touch IC 130 is applied sequentially to the two groups through the first switching units 125 and the second switching units 126.Some of the advantages associated with the above-described display device with the integrated touch screen according to an embodiment of the present invention will now be provided.","In the present invention, by applying the common voltage or the touch scan signal to the electrodes of each group through the switching unit that is connected to at least two or more electrode groups of the self-capacitive touch screen, the number of touch ICs and the number of touch IC channels can be reduced which in turn reduces the manufacturing cost of the display device.","Furthermore, in the present invention, the common voltage Vcom is applied directly from the display driver IC to the electrodes without being applied to the electrodes through the touch IC, and thus, image quality can be prevented from being degraded.","According to the embodiments of the present invention, the switching unit is connected to at least two or more electrode groups of the self-capacitive touch screen, and the common voltage or the touch scan signal is applied to the electrodes of each group through the switching unit, thus reducing the number of touch ICs and the number of touch IC channels which in turn reduces the manufacturing cost of the display device.","Moreover, according to the embodiments of the present invention, the common voltage is not applied to the electrodes though the touch IC, but the common voltage is applied directly from the display driver IC to the electrodes, thus preventing image quality from being degraded.","Moreover, according to the embodiments of the present invention, the plurality of electrodes are divided into the plurality of groups, and inter-electrode RC delay is reduced by minimizing a proximal surface between the electrode groups, thus enabling more accurate touch sensing.","It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the inventions.","Thus, it is intended that the present invention covers the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents."]],"string":"[\n [\n \"Display Device with Integrated Touch Screen and Method for Driving the Same\",\n \"Discussed are a display device with an integrated touch screen and a method of operating the same.\",\n \"The display device according to an embodiment includes a display panel including a plurality of pixel electrodes; a touch screen including m number of electrodes which are formed to overlap with the plurality of pixel electrodes, wherein m is a multiple of n, and n is an integer equal to or greater than two, and wherein the m electrodes are divided into n number of electrode groups; a touch driver configured to generate a touch scan signal and to supply the generated touch scan signal to a display driver; and the display driver configured to apply a common voltage or the touch scan signal to one or more of the m electrodes depending on a driving mode of the display device.\"\n ],\n [\n \"1.A display driver integrated circuit (IC) for driving a self-capacitive touch sensitive display device comprising a display panel having a plurality of touch electrodes including at least a first group of touch electrodes including a first touch electrode and a second touch electrode and a second group of touch electrodes including a third touch electrode and a fourth touch electrode, a plurality of touch lines including at least a first touch line, a second touch line, a third touch line and a fourth touch line, a plurality of pixel electrodes in a pixel area of the display panel, and a plurality of data lines electrically connected to the plurality of pixel electrodes, the display driver IC comprising: a first multiplexer; a second multiplexer; and a plurality of touch channel outputs, the plurality of touch channel outputs including at least a first touch channel output, a second touch channel output, a third touch channel output and a forth touch channel output; wherein the first multiplexer is configured to selectively connect to the first touch channel output or the third touch channel output during a touch period, wherein the second multiplexer is configured to selectively connect to the second touch channel output or the fourth touch channel output during the touch period, wherein the first touch electrode is connected to the first channel output via the first touch line, the second touch electrode is connected to the second channel output via the second touch line, the third touch electrode is connected to the third channel output via the third touch line, the fourth touch electrode is connected to the fourth channel output via the fourth touch line, 2.The display driver IC of claim 1, wherein the display driver IC is configured to supply a touch scan signal to the plurality of touch electrodes during the touch period.\",\n \"3.The display driver IC of claim 1, wherein the display driver IC is configured to supply a common voltage to the plurality of touch electrodes and to respectively supply data voltages to the plurality of pixel electrodes via the plurality of data lines during a display period.\",\n \"4.The display driver IC of claim 1, wherein the display driver IC is configured to supply the touch scan signal to the first touch electrode and the second touch electrode simultaneously during a first part of the touch period, and wherein the display driver IC is configured to supply the touch scan signal to the third touch electrode and the fourth touch electrode simultaneously during a second part of the touch period.\",\n \"5.The display driver IC of claim 1, further comprising a first switching unit and second switching unit, the first switching unit configured to selectively supply a common voltage or a touch scan signal to the first multiplexer, the second switching unit configured to selectively supply the common voltage or the touch scan signal to the second multiplexer.\",\n \"6.The display driver IC of claim 1, wherein the first touch electrode is not overlapped with the second touch electrode in the first touch electrode group of the touch electrodes, and the third touch electrode is not overlapped with the fourth touch electrode in the second touch electrode group of the touch electrodes.\",\n \"7.The display driver IC of claim 1, wherein the first touch line is not overlapped with the second touch line in a touch screen area of the display panel, wherein the third touch line is not overlapped with the fourth touch line in the touch screen area of the display panel.\",\n \"8.The display driver IC of claim 1, wherein the first touch line and the second touch line are arranged in a same direction in the touch screen area of the display panel, wherein the third touch line and the fourth touch line are arranged in a same direction in the touch screen area of the display panel.\",\n \"9.The display driver IC of claim 1, wherein the plurality of pixel electrodes of the display panel are respectively connected to the plurality of data channel outputs of the display driver IC via the plurality of data lines.\",\n \"10.A method for driving a self-capacitive touch sensitive display device comprising a display panel having a plurality of touch electrodes including at least a first group of touch electrodes including a first touch electrode and a second touch electrode and a second group of touch electrodes including a third touch electrode and a fourth touch electrode, a plurality of touch lines including at least a first touch line, a second touch line, a third touch line and a fourth touch line, a plurality of pixel electrodes in a pixel area of the display panel, and a plurality of data lines electrically connected to the plurality of pixel electrodes, the method comprising: providing a common voltage to the first touch electrode, the second touch electrode, the third touch electrode and the fourth touch electrode during a display period via the plurality of touch lines; providing a touch scan signal to the first touch electrode and the second touch electrode simultaneously during a first part of a touch period; and providing the touch scan signal to the third touch electrode and the fourth touch electrode simultaneously during a second part of the touch period; 11.The method of claim 10, wherein the self-capacitive touch sensitive display device further comprises a display driver Integrated Circuit (IC) including a first multiplexer and the second multiplexer, wherein the display driver IC comprises a plurality of touch channel outputs, the plurality of touch channel outputs including at least a first touch channel output, a second touch channel output, a third touch channel output and a forth touch channel output.\",\n \"12.The method of claim 11, further comprising: selectively connecting to the first touch channel output or the third touch channel output by the first multiplexer during a touch period, and selectively connecting to the second touch channel output or the fourth touch channel by the second multiplexer during the touch period.\",\n \"13.The method of claim 11, wherein the first touch electrode is connected to the first channel output via the first touch line, the second touch electrode is connected to the second channel output via the second touch line, the third touch electrode is connected to the third channel output via the third touch line, and the fourth touch electrode is connected to the fourth channel output via the fourth touch line.\",\n \"14.The method of claim 10, wherein the self-capacitive touch sensitive display device further comprises a display driver IC including a plurality of data channel outputs, and wherein the plurality of pixel electrodes of the display panel are respectively connected to the plurality of data channel outputs of the display driver IC via the plurality of data lines.\",\n \"15.A touch sensitive display device comprising: a display panel comprising: a plurality of touch electrodes, the plurality of touch electrodes including at least a first group of touch electrodes including a first touch electrode and a second touch electrode and a second group of touch electrodes including a third touch electrode and a fourth touch electrode, a plurality of touch lines, the plurality of touch lines including at least a first touch line, a second touch line, a third touch line and a fourth touch line, a plurality of pixel electrodes in a pixel area of the display panel, and a plurality of data lines electrically connected to the plurality of pixel electrodes; and a display driver IC comprising a plurality of touch channel outputs and a plurality of data channel outputs, the plurality of touch channel outputs including at least a first touch channel output, a second touch channel output, a third touch channel output and a fourth touch channel output; wherein the first touch electrode is connected to the first channel output via the first touch line, the second touch electrode is connected to the second channel output via the second touch line, the third touch electrode is connected to the third channel output via the third touch line, the fourth touch electrode is connected to the fourth channel output via the fourth touch line, wherein the first touch electrode is not overlapped with the second touch electrode in the first touch electrode group of the touch electrodes, and the third touch electrode is not overlapped with the fourth touch electrode in the second touch electrode group of the touch electrodes, wherein the first touch line is not overlapped with the second touch line in a touch screen area of the display panel, the third touch line is not overlapped with the fourth touch line in the touch screen area of the display panel, wherein the plurality of pixel electrodes of the display panel are respectively connected to the plurality of data channel outputs of the display driver IC via the plurality of data lines.\",\n \"16.The touch sensitive display device of claim 15, wherein the first touch line and the second touch line are arranged in a same direction in the touch screen area of the display panel, the third touch line and the fourth touch line arranged in a same direction in the touch screen area of the display panel.\",\n \"17.The touch sensitive display device of claim 15, wherein the display driver IC is configured to supply a common voltage to the plurality of touch electrodes and to respectively supply data voltages to the plurality of pixel electrodes via the plurality of data lines during a display period.\",\n \"18.The touch sensitive display device of claim 15, wherein the display driver IC is configured to supply a touch scan signal to the plurality of touch electrodes during a touch period, wherein the display driver IC is configured to supply the touch scan signal to the first touch electrode and the second touch electrode simultaneously during a first part of the touch period, and wherein the display driver IC is configured to supply the touch scan signal to the third touch electrode and the fourth touch electrode simultaneously during a second part of the touch period.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>\"\n ],\n [\n \"<SOH> SUMMARY <EOH>Accordingly, the present invention is directed to provide a display device with an integrated touch screen that substantially obviates one or more problems due to limitations and disadvantages of the related art.\",\n \"An aspect of the present invention is directed to provide a display device with an integrated touch screen, which applies a common voltage or a touch scan signal to a plurality of electrodes through a switching unit that is connected to at least two or more electrode groups of a self-capacitive touch screen.\",\n \"Another aspect of the present invention is directed to provide a display device with an integrated touch screen, which enables the reduction in the number of touch IC channels that connect a display driver IC and a touch IC by using only one touch IC.\",\n \"Another aspect of the present invention is directed to provide a display device with an integrated touch screen, which applies a common voltage directly from a display driver IC to an electrode without applying the common voltage to the electrode though a touch IC, thus preventing image quality from being degraded.\",\n \"Additional advantages and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.\",\n \"The objectives and other advantages of the invention may be realized and attained by the structure particularly pointed out in the written description and claims hereof as well as the appended drawings.\",\n \"To achieve these and other advantages and in accordance with the purpose of the invention, as embodied and broadly described herein, there is provided according to an embodiment a display device with an integrated touch screen including: a touch screen including m number of electrodes which are formed to respectively overlap with a plurality of pixel electrodes in a pixel area of a panel, m being a multiple of n wherein n is an integer more than or equal to two; a display driver IC applying a common voltage to the electrodes, or applying a touch scan signal sequentially to n number of groups into which the m electrodes are divided, according to a driving mode of the panel; and a touch IC generating the touch scan signal to apply the touch scan signal to the display driver IC.\",\n \"When the driving mode is a display driving mode, each of the electrodes may operate as a common electrode, or when the driving mode is a touch driving mode, each of the electrodes may operate as a touch electrode.\",\n \"The number of electrodes included in each of the groups may be m/n number.\",\n \"The n groups may be block type groups.\",\n \"The groups may be divided and formed in a short side direction of the pixel area.\",\n \"The display driver IC may include: a common voltage generator generating the common voltage; a sync signal generator generating a sync signal indicating the driving mode; a switching control signal generator generating a control signal which allows the electrodes to be simultaneously connected to the common voltage generator or allows the electrodes to be sequentially connected to the touch IC for each group, according to the sync signal; and a switching unit operating according to the sync signal and the control signal.\",\n \"The switching unit may include a plurality of first switching units and a plurality of second switching units, the first switching units being connected to the common voltage generator and the touch IC, and the second switching units being connected to the respective first switching units and one electrode for each group.\",\n \"When the sync signal is a first sync signal indicating the display driving mode, the first switching units may connect the common voltage generator to the second switching units, or when the sync signal is a second sync signal indicating the touch driving mode, the first switching units may connect the touch IC to the second switching units.\",\n \"When the control signal is a first control signal conforming to the first sync signal, the second switching units may connect the respective electrodes to the first switching units, or when the control signal is a second control signal conforming to the second sync signal, the second switching units may sequentially connect the respective electrodes to the first switching units for each group.\",\n \"The second control signal may include n number of group selection signals which allow the first switching units to be respectively connected to the electrodes for each group.\",\n \"Each of the second switching units may include a plurality of CMOS transistors, and control respective gates of the CMOS transistors to simultaneously connect the first switching units and the groups or sequentially connect the first switching units and the groups for each group.\",\n \"The number of first switching units may be m/n number.\",\n \"In another aspect of the present invention, there is provided a driving method of a display device with an integrated touch screen, which includes: a touch screen including m number of electrodes in a pixel area of a panel (where m is a multiple of n and n is an integer more than or equal to two); a display driver IC applying a common voltage or a touch scan signal to the electrodes; and a touch IC generating the touch scan signal to apply the touch scan signal to the display driver IC, the method including: applying the common voltage to the electrodes when a driving mode of the panel is a display driving mode; and sequentially applying the touch scan signal to n number of groups into which the electrodes are divided, when the driving mode of the panel is a touch driving mode.\",\n \"The number of electrodes included in each of the groups may be m/n number.\",\n \"The n groups may be block type groups.\",\n \"The groups may be divided and formed in a short side direction of the pixel area.\",\n \"The applying of the common voltage may include: generating the common voltage; generating a first sync signal according to the display driving mode, and generating a first control signal according to the first sync signal; switching a first switching unit to output the common voltage according to the first sync signal; and switching a second switching unit to simultaneously apply the common voltage, outputted from the first switching unit, to the electrodes according to the first control signal.\",\n \"The applying of the touch scan signal may include: generating the touch scan signal; generating a second sync signal according to the touch driving mode, and generating a second control signal according to the second sync signal; switching a first switching unit to output the touch scan signal according to the second sync signal; and switching a second switching unit to sequentially apply the touch scan signal, outputted from the first switching unit, to the n groups according to the second control signal.\",\n \"According to an embodiment, the present invention provides a display device with integrated touch screen, including: a display panel including a plurality of pixel electrodes; a touch screen including m number of electrodes which are formed to overlap with the plurality of pixel electrodes, wherein m is a multiple of n, and n is an integer equal to or greater than two, and wherein the m electrodes are divided into n number of electrode groups; a touch driver configured to generate a touch scan signal and to supply the generated touch scan signal to a display driver; and the display driver configured to apply a common voltage or the touch scan signal to one or more of the m electrodes depending on a driving mode of the display device.\",\n \"According to an embodiment, the present invention provides a method of operating a display device, the display device including a display panel including a plurality of pixel electrodes and a touch screen including m number of electrodes which are formed to overlap with the plurality of pixel electrodes, wherein m is a multiple of n, and n is an integer equal to or greater than two, the display device further including a touch driver and a display driver, the method including: dividing the m electrodes into n number of electrode groups; generating, by the touch driver, a touch scan signal; and applying, by the display driver, a common voltage or the generated touch scan signal to one or more of the m electrodes depending on a driving mode of the display device, wherein when the generated touch scan signal is applied to the one or more of the m electrodes, the touch scan signal is selectively applied to each of the electrode groups.\",\n \"It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation application of U.S. patent application Ser.\",\n \"No.\",\n \"14/968,681 filed on Dec. 14, 2015, which is a continuation application of U.S. patent application Ser.\",\n \"No.\",\n \"13/448,021 filed on Apr.\",\n \"16, 2012, which claims the priority benefit of the Korean Patent Application No.\",\n \"10-2012-0016908 filed on Feb. 20, 2012, all of which are hereby incorporated by reference as if fully set forth herein.\",\n \"BACKGROUND Field of the Invention The present invention relates to a display device, and more particularly, to a display device with an integrated touch screen and a driving method thereof.\",\n \"Discussion of the Related Art Touch screens are a type of input device that is included in image display devices such as Liquid Crystal Displays (LCDs), Field Emission Displays (FEDs), Plasma Display Panel (PDPs), Electroluminescent Displays (ELDs), and Electrophoretic Display (EPDs), and allows a user to input predetermined information by applying a pressure (i.e., by pressing or touching) to a touch sensor of a touch screen of the image display device while looking at the image display device.\",\n \"Particularly, the demand of display devices with an integrated in-cell type touch screen, which include a plurality of built-in elements configuring the touch screen for providing slim portable terminals such as smart phones and tablet Personal Computers (PCs), is recently increasing.\",\n \"Hereinafter, a related art display device with an integrated touch screen will be described with reference to FIG.\",\n \"1.FIG.\",\n \"1 is a diagram illustrating a configuration of a related art display device with an integrated touch screen, and more specifically illustrates a configuration of a display device with an integrated self-capacitive touch screen having an in-cell type.\",\n \"The related art display device with the integrated self-capacitive touch screen having an in-cell type, as illustrated in FIG.\",\n \"1, includes: a panel 10 with a built-in touch screen 11; a display driver IC (DD-IC) 20 that is connected to an external system and controls a plurality of gate lines and data lines in the panel 10; a plurality of touch ICs (T-IC1 and T-IC2) 31 and 32 that drive the touch screen 11 in the panel 10.The panel 10 includes m number of electrodes 12, and m number of lines 13 that are respectively extended from the m electrodes 12.Each of the touch ICs 31 and 32 includes m number of touch IC channels respectively corresponding to the m lines 13, for self-capacitive touch sensing.\",\n \"Since one touch IC channel generally corresponds a line connected to an electrode in one-to-one correspondence relationship, as illustrated in FIG.\",\n \"1, when the number of lines connected to an electrode is more than the number of channels that are capable of being accommodated by one touch IC, a plurality of touch ICs are required to be used, causing the increase in cost.\",\n \"In the display device with the integrated touch screen of FIG.\",\n \"1, each of the electrodes 12 is built in the panel 10 and performs a touch function and a display function, and thus is used as a common electrode for display driving when the display device is driven in a display driving mode, or is used as a touch electrode when the display device is driven in a touch driving mode.\",\n \"The display driving mode is a display mode for displaying images on the display device, and the touch driving mode is a touch mode for detecting and processing a touch input to the display device.\",\n \"On the contrary, when the display device is driven in the display driving mode, a common voltage Vcom outputted from inside the display driver IC (DD-IC) 20 is applied to the electrodes 12 through the touch ICs 31 and 32, in which case the touch ICs 31 and 32 need to accommodate a negative voltage when the common voltage Vcom is the negative voltage.\",\n \"However, the related art touch ICs 31 and 32 cannot accommodate a negative voltage and thus, a special manufacturing process and design for a touch IC that can accommodate the negative voltage are needed, which in turn increases the manufacturing cost of the touch ICs.\",\n \"Moreover, when the related art touch sensitive display device is driven in the display driving mode, a ground-level voltage instead of a negative voltage may be incidentally supplied to the electrode 12 through the touch IC, thereby causing the degradation of image quality.\",\n \"To provide a summary on the above-described limitations, the related art display device with the integrated touch screen has at least the following limitations.\",\n \"First, as the number of touch IC channels matching the respective lines connected to electrodes increases, the number of touch ICs increases, thereby causing the increase in cost for the display device.\",\n \"Second, a touch IC is separately manufactured by modifying the manufacturing process and design thereof for applying a negative common voltage, thereby causing the increase in the manufacturing cost of the touch IC.\",\n \"Third, when the related art touch IC is applied to a display device, the ground-level common voltage, instead of the desired negative common voltage, may be incidentally applied to the electrodes in the display driving mode, thereby causing the degradation of image quality.\",\n \"SUMMARY Accordingly, the present invention is directed to provide a display device with an integrated touch screen that substantially obviates one or more problems due to limitations and disadvantages of the related art.\",\n \"An aspect of the present invention is directed to provide a display device with an integrated touch screen, which applies a common voltage or a touch scan signal to a plurality of electrodes through a switching unit that is connected to at least two or more electrode groups of a self-capacitive touch screen.\",\n \"Another aspect of the present invention is directed to provide a display device with an integrated touch screen, which enables the reduction in the number of touch IC channels that connect a display driver IC and a touch IC by using only one touch IC.\",\n \"Another aspect of the present invention is directed to provide a display device with an integrated touch screen, which applies a common voltage directly from a display driver IC to an electrode without applying the common voltage to the electrode though a touch IC, thus preventing image quality from being degraded.\",\n \"Additional advantages and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the invention.\",\n \"The objectives and other advantages of the invention may be realized and attained by the structure particularly pointed out in the written description and claims hereof as well as the appended drawings.\",\n \"To achieve these and other advantages and in accordance with the purpose of the invention, as embodied and broadly described herein, there is provided according to an embodiment a display device with an integrated touch screen including: a touch screen including m number of electrodes which are formed to respectively overlap with a plurality of pixel electrodes in a pixel area of a panel, m being a multiple of n wherein n is an integer more than or equal to two; a display driver IC applying a common voltage to the electrodes, or applying a touch scan signal sequentially to n number of groups into which the m electrodes are divided, according to a driving mode of the panel; and a touch IC generating the touch scan signal to apply the touch scan signal to the display driver IC.\",\n \"When the driving mode is a display driving mode, each of the electrodes may operate as a common electrode, or when the driving mode is a touch driving mode, each of the electrodes may operate as a touch electrode.\",\n \"The number of electrodes included in each of the groups may be m/n number.\",\n \"The n groups may be block type groups.\",\n \"The groups may be divided and formed in a short side direction of the pixel area.\",\n \"The display driver IC may include: a common voltage generator generating the common voltage; a sync signal generator generating a sync signal indicating the driving mode; a switching control signal generator generating a control signal which allows the electrodes to be simultaneously connected to the common voltage generator or allows the electrodes to be sequentially connected to the touch IC for each group, according to the sync signal; and a switching unit operating according to the sync signal and the control signal.\",\n \"The switching unit may include a plurality of first switching units and a plurality of second switching units, the first switching units being connected to the common voltage generator and the touch IC, and the second switching units being connected to the respective first switching units and one electrode for each group.\",\n \"When the sync signal is a first sync signal indicating the display driving mode, the first switching units may connect the common voltage generator to the second switching units, or when the sync signal is a second sync signal indicating the touch driving mode, the first switching units may connect the touch IC to the second switching units.\",\n \"When the control signal is a first control signal conforming to the first sync signal, the second switching units may connect the respective electrodes to the first switching units, or when the control signal is a second control signal conforming to the second sync signal, the second switching units may sequentially connect the respective electrodes to the first switching units for each group.\",\n \"The second control signal may include n number of group selection signals which allow the first switching units to be respectively connected to the electrodes for each group.\",\n \"Each of the second switching units may include a plurality of CMOS transistors, and control respective gates of the CMOS transistors to simultaneously connect the first switching units and the groups or sequentially connect the first switching units and the groups for each group.\",\n \"The number of first switching units may be m/n number.\",\n \"In another aspect of the present invention, there is provided a driving method of a display device with an integrated touch screen, which includes: a touch screen including m number of electrodes in a pixel area of a panel (where m is a multiple of n and n is an integer more than or equal to two); a display driver IC applying a common voltage or a touch scan signal to the electrodes; and a touch IC generating the touch scan signal to apply the touch scan signal to the display driver IC, the method including: applying the common voltage to the electrodes when a driving mode of the panel is a display driving mode; and sequentially applying the touch scan signal to n number of groups into which the electrodes are divided, when the driving mode of the panel is a touch driving mode.\",\n \"The number of electrodes included in each of the groups may be m/n number.\",\n \"The n groups may be block type groups.\",\n \"The groups may be divided and formed in a short side direction of the pixel area.\",\n \"The applying of the common voltage may include: generating the common voltage; generating a first sync signal according to the display driving mode, and generating a first control signal according to the first sync signal; switching a first switching unit to output the common voltage according to the first sync signal; and switching a second switching unit to simultaneously apply the common voltage, outputted from the first switching unit, to the electrodes according to the first control signal.\",\n \"The applying of the touch scan signal may include: generating the touch scan signal; generating a second sync signal according to the touch driving mode, and generating a second control signal according to the second sync signal; switching a first switching unit to output the touch scan signal according to the second sync signal; and switching a second switching unit to sequentially apply the touch scan signal, outputted from the first switching unit, to the n groups according to the second control signal.\",\n \"According to an embodiment, the present invention provides a display device with integrated touch screen, including: a display panel including a plurality of pixel electrodes; a touch screen including m number of electrodes which are formed to overlap with the plurality of pixel electrodes, wherein m is a multiple of n, and n is an integer equal to or greater than two, and wherein the m electrodes are divided into n number of electrode groups; a touch driver configured to generate a touch scan signal and to supply the generated touch scan signal to a display driver; and the display driver configured to apply a common voltage or the touch scan signal to one or more of the m electrodes depending on a driving mode of the display device.\",\n \"According to an embodiment, the present invention provides a method of operating a display device, the display device including a display panel including a plurality of pixel electrodes and a touch screen including m number of electrodes which are formed to overlap with the plurality of pixel electrodes, wherein m is a multiple of n, and n is an integer equal to or greater than two, the display device further including a touch driver and a display driver, the method including: dividing the m electrodes into n number of electrode groups; generating, by the touch driver, a touch scan signal; and applying, by the display driver, a common voltage or the generated touch scan signal to one or more of the m electrodes depending on a driving mode of the display device, wherein when the generated touch scan signal is applied to the one or more of the m electrodes, the touch scan signal is selectively applied to each of the electrode groups.\",\n \"It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this application, illustrate embodiments of the invention and together with the description serve to explain the principle of the invention.\",\n \"In the drawings: FIG.\",\n \"1 is a diagram illustrating a configuration of a related art display device with an integrated touch screen; FIG.\",\n \"2 is a diagram illustrating a configuration of a display device with an integrated touch screen according to an embodiment of the present invention; FIG.\",\n \"3A is a diagram illustrating a detailed configuration of each of first and second switching units in FIG.\",\n \"2; FIG.\",\n \"3B is a diagram for describing an operation of each of the first and second switching units in FIG.\",\n \"3A; FIG.\",\n \"4 is a diagram showing a first embodiment of an electrode division method in a display device with integrated touch screen according to an embodiment of the present invention; FIGS.\",\n \"5A to 5D are diagrams respectively showing an example of experiment data of touch sensitivity according to the method of FIG.\",\n \"4; FIG.\",\n \"6 is a diagram showing a second embodiment of an electrode division method in the display device with integrated touch screen according to an embodiment of the present invention; and FIG.\",\n \"7 is a diagram showing a third embodiment of an electrode division method in the display device with integrated touch screen according to an embodiment of the present invention.\",\n \"DETAILED DESCRIPTION OF THE INVENTION Reference will now be made in detail to the exemplary embodiments of the present invention, examples of which are illustrated in the accompanying drawings.\",\n \"Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts.\",\n \"Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings.\",\n \"In a display device with an integrated touch screen according to an embodiment of the present invention, a plurality of electrodes are divided into n number of groups, and a touch scan signal is sequentially applied to the n groups.\",\n \"However, for convenience of a description, the below description will be made on a method where the electrodes are divided into two groups (i.e., n=2).\",\n \"However, the present invention is not limited to the method where the electrodes are divided into the two groups, and the electrodes may be divided into three or more groups.\",\n \"FIG.\",\n \"2 is a diagram illustrating a configuration of a display device with an integrated touch screen according to an embodiment of the present invention.\",\n \"The display device with the integrated touch screen according to an embodiment of the present invention, as illustrated in FIG.\",\n \"2, includes: a touch screen 111 that includes m number of electrodes 112 (where m is a multiple of n, and n is an integer more than or equal to two) which are formed to respectively overlap with a plurality of pixel electrodes in a pixel area of a display panel 110; a display driver IC 120 that applies a common voltage Vcom to the electrodes 112 or sequentially applies a touch scan signal to the electrodes of each of two groups 114 into which the m electrodes 112 are divided, according to a driving mode of the panel 110; and a touch IC 130 that generates the touch scan signal and applies the touch scan signal to the display driver IC 120.The touch screen 111 detects a touch point of a user.\",\n \"Particularly, the touch screen 111 applied to the present embodiment is an in-cell type touch screen using a self-capacitive type, and a touch screen area is the same area as a pixel array area.\",\n \"The self-capacitive touch screen includes the m electrodes 112 and the same m number of lines 113, in the panel 110.Herein, the panel 110 may be configured in a structure where a liquid crystal layer is formed between two substrates.\",\n \"In this case, a lower substrate of the panel 110 can include: a plurality of data lines disposed in parallel to each other; a plurality of gate lines that cross the data lines and are disposed in parallel to each other; a plurality of Thin Film Transistors (TFTs) that are respectively formed in a plurality of intersection areas between the data lines and the gate lines; a plurality of pixel electrodes that respectively charge data voltages into the plurality of pixels; an electrode (also referred to as a common electrode) that drives liquid crystal cells injected into the liquid crystal layer, together with the operation of the pixel electrodes.\",\n \"The pixels are arranged in a matrix type corresponding to the above-described intersection structure between the date lines and the gate lines.\",\n \"The m electrodes 112 are formed to overlap with the plurality of pixel electrodes, in the pixel array area of the panel 110.For instance, the m electrodes are not formed in each pixel but are formed in an area overlapping with a plurality of pixels.\",\n \"That is, the m electrodes 112 are preferably disposed over the area where the pixel electrodes are disposed.\",\n \"The m electrodes 112 may be disposed substantially through the touch screen 111 so that a touch input thereto may be accurately detected.\",\n \"When the driving mode of the panel 110 is a display driving mode, each of the electrodes 112 operates as a common electrode that drives liquid crystal cells together with the operation of the pixel electrode(s) formed in corresponding pixel(s).\",\n \"When the driving mode of the panel 110 is a touch driving mode, each electrode 112 operates as a touch electrode that detects a touch point/input by using the touch scan signal applied from the touch IC 130.For example, as illustrated in FIG.\",\n \"2, the m electrodes 112 may be formed to be divided into two groups 114, and formed in a block type group 114 but the group can be in a different shape.\",\n \"Each of the groups 114 may be formed in a touch screen 111 area, and the number of electrodes included in each group 114 is m/2.In FIG.\",\n \"2, the number of electrodes in each of two groups into which the electrodes 112 are divided is m/2, but when the electrodes 112 are divided into n number of groups, the number of electrodes in each of the n groups is m/n, where m and n are positive integers and preferably m is a multiple of n to provide an even division.\",\n \"The m lines 113 connect the m electrodes 112 to the display driver IC 120, respectively.\",\n \"Therefore, the common voltage and the touch scan signal that are outputted from the display driver IC 120 are applied to the electrodes 112 through the respective lines 113.When the driving mode of the panel 110 is in the display driving mode, the display driver IC 120 applies the common voltage to the electrodes 112, and when the driving mode of the panel 110 is in the touch driving mode, the display driver IC 120 sequentially applies the touch scan signal to the electrodes of each of the two groups into which the electrodes 112 are divided.\",\n \"Embodiments of a group division method according to the present invention will be described below in detail.\",\n \"The display driver IC 120 drives the data lines and gate lines that are formed in the panel 110, and drives each of the m electrodes 112 as a common electrode or a touch electrode.\",\n \"For this end, the display driver IC 120 may include a common voltage generator 121, a sync signal generator 122, a switching control signal generator 123, and a switching unit 124.The common voltage generator 121 generates a common voltage Vcom and applies the common voltage Vcom to the switching unit 124.Specifically, when the driving mode of the panel 110 is in the display driving mode, the common voltage generator 121 generates the common voltage Vcom which is then applied to the m electrodes 112 for image output, and applies the common voltage Vcom to the switching unit 124.The sync signal generator 122 generates a sync signal indicating the driving mode of the panel 110.For example, as illustrated in FIG.\",\n \"2, when the driving mode of the panel 110 is in the display driving mode, the sync signal generator 122 generates a first sync signal “0” that allows the common voltage Vcom of the common voltage generator 121 to be applied to the electrodes 112 through the switching unit 124.When the driving mode of the panel 110 is in the touch driving mode, the sync signal generator 122 generates a second sync signal “1” that allows the touch scan signal of the touch IC 130 to be applied to the electrodes 112.The switching control signal generator 123 generates a control signal that allows the electrodes 112 to be simultaneously connected to the common voltage generator 121 or a control signal that allows the electrodes 112 to be sequentially connected to the touch IC 130 for each group, according to the sync signal of the sync signal generator 122.For example, as illustrated in FIG.\",\n \"2, when the sync signal of the sync signal generator 123 is the first sync signal “0”, the switching control signal generator 123 generates a first control signal “00” that allows the common voltage (received from the common voltage generator 121) to be simultaneously applied to the m electrodes 112.When the sync signal of the sync signal generator 123 is the second sync signal “1”, the switching control signal generator 123 generates a second control signal “01” or “10” that allows the touch scan signal (received from the touch IC 130) to be sequentially applied to the two electrode groups 114.The second control signal may be generated in plurality, according to the number of groups that are connected to the switching unit 124.In other words, in this example, the second control signal denotes two group selection signals (“01” and “10”) that allow the switching unit 124 to be connected to the electrodes 112 by two groups (CH1 and CH2).\",\n \"However, the electrodes 112 may be divided into two or more groups.\",\n \"In such cases, when there are n number of groups (n being greater than or equal 2), the second control signal corresponding to n number of group selection signals that are respectively and selectively applied to the n groups is generated.\",\n \"For instance, if there are 3 electrode groups 114, then the group selection signals of the second control signal may be, e.g., “001”, “010” and “011” which are used to respectively control the three different electrode groups via the channel outputs CH1, CH2 and CH3 of each of the second switching units 126.The switching unit 124 may be configured with a plurality of first switching units 125 and a plurality of second switching units 126.Each of the second switching units 126 includes channels CH1 and CH2.The switching unit 124 operates according to the sync signal of the sync signal generator 122 and the control signal of the switching control signal generator 123.For example, as illustrated in FIG.\",\n \"2, when the sync signal of the sync signal generator 122 is the first sync signal “0” and the control signal of the switching control signal generator 123 is the first control signal “00”, the common voltage Vcom generated by the common voltage generator 121 is applied to all the electrodes 122.When the sync signal of the sync signal generator 122 is the second sync signal “1” and the control signal of the switching control signal generator 123 is the second control signal “01” or “10”, the touch scan signal generated by the touch IC 130 is applied to the m electrodes 112.More specifically, when the second control signal of the switching control signal generator 123 is the second control signal “01”, the touch scan signal from the touch IC 130 is applied to the electrodes of one of the groups 114 through the channel CH1 of each of the second switching units 126.On the other hand, when the second control signal of the switching control signal generator 123 is the second control signal “10”, the touch scan signal is applied to the electrodes of the other one of the groups 114 through the channel CH2 of each of the second switching units 126.The detailed configurations and operations of the first switching units 125 and second switching units 126 of the switching unit 124 will now be described in detail with reference to FIGS.\",\n \"2, 3A and 3B according to an embodiment of the present invention.\",\n \"FIG.\",\n \"3A is a diagram illustrating a detailed configuration of each of the first and second switching units in FIG.\",\n \"2.FIG.\",\n \"3B is a diagram for describing an operation of each of the first and second switching units in FIG.\",\n \"3A.\",\n \"The first switching unit 125 may be configured with a 2:1 multiplexer.\",\n \"For example, as illustrated in FIG.\",\n \"3A, the first switching unit 125 may be configured with transistors TR1 and TR2.The transistor TR1 may be connected to the common voltage generator 121 and the second switching unit 126, and the transistor TR2 may be connected to the touch IC 130 and the second switching unit 126.Herein, each of the transistors TR1 and TR2 may be a CMOS transistor.\",\n \"When the sync signal is the first sync signal “0” indicating the display driving mode, the first switching unit 125 connects the common voltage generator 121 to the second switching unit 126.When the sync signal is the second sync signal “1” indicating the touch driving mode, the first switching unit 125 connects the touch IC 130 to the second switching unit 126.For example, when the sync signal of the sync signal generator 122 is the first sync signal “0”, the transistor TR1 of the first switching unit 125 is turned on and simultaneously the transistor TR2 is turned off, and thus, the common voltage generator 121 and the second switching unit 126 are connected to each other through the transistor TR1 of the first switching unit 125, whereupon the common voltage Vcom generated by the common voltage generator 121 is delivered to the second switching unit 126.When the sync signal of the sync signal generator 122 is the second sync signal “1”, the transistor TR2 of the first switching unit 125 is turned on and simultaneously the transistor TR1 is turned off, and thus, the touch IC 130 and the second switching unit 126 are connected to each other through the transistor TR2 of the first switching unit 125, whereupon the touch scan signal generated by the touch IC 130 is delivered to the second switching unit 126.The second switching unit 126 is a signal selector that has one input channel and a plurality of output channels CH1 and CH2.The second switching unit 126 simultaneously or sequentially outputs a signal, supplied from the first switching unit 125, through the output channels CH1 and CH2.For example, as illustrated in FIG.\",\n \"3A, the second switching unit 126 may be configured with transistors TR3 and TR4, which are connected to the first switching unit 125 and corresponding electrodes 112 through the lines 113.Herein, each of the transistors TR3 and TR4 may be a CMOS transistor.\",\n \"The second switching unit 126 is connected only to the first switching unit 125 and one electrode for each group.\",\n \"When the control signal applied to the second switching unit 126 is the first control signal conforming to the first sync signal (display mode), the second switching unit 126 connects the first switching unit 125 to all the electrodes 112.When the control signal is the second control signal conforming to the second sync signal (touch mode), the second switching unit 126 sequentially connects the first switching unit 125 to a plurality of electrodes for each group 114.For example, when the control signal of the switching control signal generator 123 is the first control signal “00” conforming to the first sync signal “0” of the sync signal generator 122, the transistors TR3 and TR4 of the second switching unit 126 are simultaneously turned on, and thus, the first switching unit 125 and all the electrodes 112 are connected to each other through the channels CH1 and CH2 of the respective transistors TR3 and TR4 in the second switching unit 126, whereupon the common voltage Vcom delivered from the first switching unit 125 is applied to all the electrodes 112 including both groups 114 simultaneously.\",\n \"When the control signal of the switching control signal generator 123 is the second control signal “01” conforming to the second sync signal “1” of the sync signal generator 122, the transistor TR3 of the second switching unit 126 is turned on and simultaneously the transistor TR4 is turned off, and thus, the first switching unit 125 and the electrodes of any one of the groups 114 are connected to each other through the channel CH1 of the transistor TR3 of the second switching unit 126, whereupon the touch scan signal delivered from the first switching unit 125 is applied to all the electrodes of that one group among the groups 114.When the control signal of the switching control signal generator 123 is the second control signal “10” conforming to the second sync signal “1” of the sync signal generator 122, the transistor TR4 of the second switching unit 126 is turned on and simultaneously the transistor TR3 is turned off, and thus, the first switching unit 125 and the electrodes of the other of the groups 114 are connected to each other through the channel CH2 of the transistor TR4 of the second switching unit 126, whereupon the touch scan signal delivered from the first switching unit 125 is applied to all the electrodes of the other group among the groups 114.Referring again to FIG.\",\n \"2, the touch IC 130 applies the touch scan signal to the electrodes 112 through display driver IC 120, and then detects the change in the capacitance of each electrode to determine whether an electrode area is touched.\",\n \"The touch IC 130 and the display driver IC 120 are connected to each other through the touch IC channels, and the total number of touch IC channels is m/2.That is, in the related art, the number of electrodes or lines is equal to the number of touch IC channels, but in the present invention, the number of touch IC channels decreases to a half of the number of electrodes 112 or lines 113, which reduces the manufacturing cost and structure configuration.\",\n \"Hereinafter, an electrode division method will now be described in detail with reference to FIGS.\",\n \"4 to 8 according to an embodiment of the present invention.\",\n \"These methods can be implemented using the devices of FIGS.\",\n \"1-3 or other suitable display devices.\",\n \"FIG.\",\n \"4 is a diagram showing a first example of an electrode division method in a display device with an integrated touch screen according to an embodiment of the present invention.\",\n \"As illustrated in FIG.\",\n \"4, 160 electrodes can be divided into two groups, namely, an odd group and an even group.\",\n \"The odd group is connected to the respective channels CH1 of the second switching units 126 in the display driver IC 120, and the even group is connected to the respective channels CH2 of the second switching units 126.When the sync signal generator 122 generates the second sync signal “1” indicating the touch driving mode and the switching control signal generator 123 generates the second control signal “01” designating the channel CH1, the respective channels CH1 of the second switching units 126 are connected to the electrodes of the odd group.\",\n \"That is, all the channels CH1 of each of the second switching units 126 are connected to the corresponding electrodes of the odd group.\",\n \"When the sync signal generator 122 generates the second sync signal “1” indicating the touch driving mode and the switching control signal generator 123 generates the second control signal “10” designating the channel CH2, the respective channels CH2 of the second switching units 126 are connected to the electrodes of the even group.\",\n \"Thus in the example of FIG.\",\n \"4, the electrodes 112 may be divided into groups having specific configurations.\",\n \"FIGS.\",\n \"5A to 5D are diagrams respectively showing experiment data of touch sensitivity detected according to the method of FIG.\",\n \"4.In the present experiment data, the X axis indicates time, and the y axis indicates raw count.\",\n \"A raw count value is a value that becomes fundamental for measuring touch sensing, and is to represent a touch sensing signal as a touch clock count value.\",\n \"A touch driving pulse is applied selectively to the odd group and even group of electrodes shown in FIG.\",\n \"4.Since the electrodes immediately neighboring the electrode numbers 39 and 40 belong to the same even group, when the touch driving pulse is applied to such electrodes, a high touch sensitivity is provided.\",\n \"On the other hand, since some electrodes immediately neighboring the electrode numbers 51 and 66 belong to different electrode groups (i.e., the odd group), the neighboring electrodes are grounded when the touch driving pulse is applied to the electrodes 51 and 66.As a result, the touch sensitivity in such area is lower than the touch sensitivity around the electrode numbers 39 and 40.This can be seen in FIGS.\",\n \"5A and 5B.\",\n \"Referring to the experiment data, a raw count difference of the electrode number 39 (highlighted in FIG.\",\n \"4) is 200, a raw count difference of the electrode number 40 is 230, a raw count difference of the electrode number 51 is 100, and a raw count difference of the electrode number 66 is 160.A large raw count difference denotes that the touch sensitivity is better in proportion thereto.\",\n \"In the present experiment data, there are no electrodes (which are connected to different channels of the second switching unit 126) respectively adjacent to the electrode number 39 and the electrode number 40, and thus, the raw count difference of each of the electrode number 39 and electrode number 40 is greater than that of each of the electrode number 51 and electrode number 66, which means that the touch sensitivity in the area of the electrode numbers 39 and 40 is better than the touch sensitivity in the area of the electrode numbers 51 and 66.Thus to enhance the touch sensitivity of the touch panel, it would be desirable to minimize the number of adjacent electrodes that belong to a different group of touch electrodes driven at a different time.\",\n \"Accordingly, FIGS.\",\n \"6 and 7 provide examples of dividing or grouping the touch electrodes according to the present invention to maximize the touch sensitivity of the display panel.\",\n \"FIGS.\",\n \"6 and 7 illustrate the examples of a group division method that enables the obtainment of high touch sensitivity, based on the experiment data of FIG.\",\n \"5.As illustrated in FIGS.\",\n \"6 and 7, a plurality of electrodes may be divided into a plurality of block type groups.\",\n \"For example, when the pixel area of the panel 110 is rectangular in shape, by dividing the electrodes 112 into a plurality of groups along a short (shorter) side direction to have a rectangular shape, RC delay is reduced between the adjacent electrodes included in different groups, thus increasing the touch sensitivity of the display device.\",\n \"FIG.\",\n \"6 is a diagram showing a second example of an electrode division method in the display device with the integrated touch screen according to an embodiment of the present invention.\",\n \"Referring to FIG.\",\n \"6, the plurality of electrodes 112 are divided into two block type groups 114 along the direction of the shorter side of the touch screen 111.One (114a) of the groups 114 is connected to the channels CH1 of the second switching units 126 in the display driver IC 120, and the other group 114b is connected to the channels CH2 of the second switching units 126.When the sync signal generator 122 generates the second sync signal “1” indicating the touch driving mode and the switching control signal generator 123 generates the second control signal “01” designating the channel CH1, the respective channels CH1 of the second switching units 126 are connected to all the electrodes of the one group 114a.\",\n \"When the sync signal generator 122 generates the second sync signal “1” indicating the touch driving mode and the switching control signal generator 123 generates the second control signal “10” designating the channel CH2, the respective channels CH2 of the second switching units 126 are connected to all the electrodes of the other group 114b.\",\n \"In the present example, when the pixel area of the panel 110 is rectangular in shape, the block type groups 114 may be formed by dividing the electrodes 112 along a short/shorter side direction of the touch screen 111 to have a rectangular shape or the like, and the numbers of electrodes in each of the divided groups may be the same.\",\n \"As in the present embodiment, by dividing the electrodes into a plurality of groups along a short/shorter side direction of the touch screen 111 to have a rectangular shape or the like, a proximal surface between the groups 114 is minimized and thus, a potential difference between the electrodes 112 connected to the respective channels of the different second switching units 126 is minimized, thereby increasing the touch sensitivity of the panel 110.In the above-described example, the pixel area is the same area as that of the touch screen 111.FIG.\",\n \"7 is a diagram showing a third example of an electrode division method in the display device with the integrated touch screen according to an embodiment of the present invention.\",\n \"Referring to FIG.\",\n \"7, the electrodes 112 are divided into three block type groups 114 (114a, 114b, 114c), and if the pixel area of the panel 110 is rectangular in shape, similarly to the example of FIG.\",\n \"6, the block type groups 114 may be formed by dividing the electrodes 112 into a plurality of groups along a short/shorter side direction of the touch screen 111 to have a rectangular shape or the like.\",\n \"In this way, by dividing the electrodes 112 into the plurality of groups 114a, 114b, 114c along the short side direction to have the rectangular or other shape, a proximal surface between the groups 114 is minimized and thus, a potential difference between the electrodes 112 connected to the respective channels of the different second switching units 126 is minimized, thereby increasing the touch sensitivity of the touch screen 111.The detailed description of this example is the same as that of the above-described second example, and thus is not provided.\",\n \"In the example of FIG.\",\n \"7, because there exist three groups 114a, 114b and 114c of the electrodes 112, each of the second switching units 126 would have one input and three outputs CH1, CH2 and CH3 which respectively control the three groups 114a, 114b and 114c.\",\n \"As such, the number of second switching units 126 needed may correspond to m/n.\",\n \"In this regard, the switching control signal generator 123 is configured to output appropriate control signals so that each of the groups 114a, 114b and 114c is selectively and independently driven by controlling the output selection among the outputs CH1, CH2 and CH3.The configuration of the first switching units 125 would be the same as that shown in FIGS.\",\n \"2 and 3.Thus, depending on the number of groups of electrodes formed, the corresponding same number of touch channels for each of the second switching units 126 may be used.\",\n \"According to the present embodiments, a plurality of electrodes have been exemplarily described as being divided into two groups or three groups, but may be divided into four or more groups according to the number of electrodes.\",\n \"A driving method of the display device with the integrated touch screen having the above-described configuration, according to an embodiment of the present invention, will be described in detail with reference to FIG.\",\n \"2.When the driving mode of the display device with the integrated touch screen according to an embodiment of the present invention is in the display driving mode, the sync signal generator 122 generates the first sync signal “0” to transfer the first sync signal “0” to the first switching units 125, and the switching control signal generator 123 generates the first control signal “00” to transfer the first control signal “00” to the second switching units 126.The first switching units 125 are switched and connect the common voltage generator 121 to the second switching units 126, according to the first sync signal “0”.\",\n \"The second switching units 126 are switched and connect the m electrodes to the channels CH1 and CH2, according to the first control signal “00”.\",\n \"The common voltage generated by the common voltage generator 121 is applied simultaneously to all the m electrodes 112 through the first switching units 125 and the second switching units 126.When the driving mode of the display device is in the touch driving mode, the sync signal generator 122 generates the second sync signal “1” to transfer the second sync signal “1” to the first switching units 125, and the switching control signal generator 123 generates the second control signal “01” or “10” to transfer the second control signal “01” or “10” to the second switching units 126.The first switching units 125 are switched and connect the touch IC 130 to the second switching units 126, according to the second sync signal “1”.\",\n \"The second switching units 126 are switched and connect one of the two groups 114 to the channels CH1 and CH2, according to the second control signal “01” or “10”.\",\n \"When the second control signal is “01”, the channels CH1 of the second switching units 126 are connected to the electrodes of one of the two groups 114.When the second control signal is “10”, the channels CH2 of the second switching units 126 are connected to the electrodes (which are not connected to the channels CH1) of the other group among the two groups 114.The touch scan signal generated from the touch IC 130 is applied sequentially to the two groups through the first switching units 125 and the second switching units 126.Some of the advantages associated with the above-described display device with the integrated touch screen according to an embodiment of the present invention will now be provided.\",\n \"In the present invention, by applying the common voltage or the touch scan signal to the electrodes of each group through the switching unit that is connected to at least two or more electrode groups of the self-capacitive touch screen, the number of touch ICs and the number of touch IC channels can be reduced which in turn reduces the manufacturing cost of the display device.\",\n \"Furthermore, in the present invention, the common voltage Vcom is applied directly from the display driver IC to the electrodes without being applied to the electrodes through the touch IC, and thus, image quality can be prevented from being degraded.\",\n \"According to the embodiments of the present invention, the switching unit is connected to at least two or more electrode groups of the self-capacitive touch screen, and the common voltage or the touch scan signal is applied to the electrodes of each group through the switching unit, thus reducing the number of touch ICs and the number of touch IC channels which in turn reduces the manufacturing cost of the display device.\",\n \"Moreover, according to the embodiments of the present invention, the common voltage is not applied to the electrodes though the touch IC, but the common voltage is applied directly from the display driver IC to the electrodes, thus preventing image quality from being degraded.\",\n \"Moreover, according to the embodiments of the present invention, the plurality of electrodes are divided into the plurality of groups, and inter-electrode RC delay is reduced by minimizing a proximal surface between the electrode groups, thus enabling more accurate touch sensing.\",\n \"It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the inventions.\",\n \"Thus, it is intended that the present invention covers the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875696"}}},{"rowIdx":4494953,"cells":{"text":{"kind":"list like","value":[["HETEROJUNCTION BIPOLAR TRANSISTOR","A heterojunction bipolar transistor, comprising an elongated base mesa, an elongated base electrode, two elongated emitters, an elongated collector, and two elongated collector electrodes.","The elongated base electrode is formed on the base mesa along the long axis of the base mesa, and the base electrode has a base via hole at or near the center of the base electrode.","The two elongated emitter are formed on the base mesa respectively at two opposite sides of the base electrode, and each of two emitters has an elongated emitter electrode formed on the emitter.","The elongated collector is formed below the base mesa.","The two elongated collector electrodes are formed on the collector respectively at two opposite sides of the base mesa."],["1.A heterojunction bipolar transistor, comprising: an elongated base mesa having a long axis and a short axis, the base mesa having a length and a width, and the ratio of the length to width is between 4:1 and 15:1; an elongated base electrode having a long axis and a short axis, formed on the base mesa with the long axis of the base electrode essentially parallel to the long axis of the base mesa, and the base electrode having a base via hole at or near the center of the base electrode; two elongated emitters formed on the base mesa respectively at two opposite sides of the base electrode along the long axis of the base electrode, each emitter having an elongated emitter electrode formed on the emitter; an elongated collector formed below the base mesa; and two elongated collector electrodes formed on the collector respectively at two opposite sides of the base mesa along the long axis of the base mesa.","2.The heterojunction bipolar transistor according to claim 1, wherein the base electrode is formed on the base mesa with the long axis of the base electrode essentially parallel to the long axis of the base mesa at or near the center of the short axis of base electrode.","3.The heterojunction bipolar transistor according to claim 2, wherein the base mesa, the emitter electrodes, and the collector electrodes are in rectangular shapes.","4.The heterojunction bipolar transistor according to claim 2, wherein the base mesa, the emitters, and the collector are in bent elongated shapes each having a bending position, and the bending position located at or near the center of the elongated shape.","5.The heterojunction bipolar transistor according to claim 1, wherein the base mesa, the emitter electrodes, and the collector electrodes are in rectangular shapes.","6.The heterojunction bipolar transistor according to claim 1, wherein the base mesa, the emitters, and the collector are in bent elongated shapes each having a bending position, and the bending position located at or near the center of the elongated shape.","7.The heterojunction bipolar transistor according to claim 1, wherein the base mesa, the emitters, and the collector are in bent elongated shapes each having a bending position, and the bending position located at or near the center of the elongated shape with a bending angle of 90°."],["<SOH> BACKGROUND OF THE INVENTION <EOH>In recent years, with the rapid development of mobile devices industry, the demand of high power, high power gain and high power added efficiency devices is also growing.","The integrated circuits using compound semiconductor heterojunction bipolar transistors (HBTs) have been widely used in the power amplifier of mobile devices for their high power, high power gain, and high linearity.","Therefore, by improving the layout design of the compound semiconductor HBT circuit, the power gain and power added efficiency of the HBT can be enhanced, and the competitiveness of the product containing the HBT can be increased.","The output power gain of an HBT is related to the base-collector junction capacitance, and the capacitance is proportional to the base area.","The larger the ratio of the emitter area to the base area (EA/BA) is, the smaller the base-collector junction capacitance is.","Therefore, by increasing the ratio of the emitter area to the base area, the base-collector junction capacitance can be effectively decreased, thereby enhancing the output power gain."],["<SOH> SUMMARY OF THE INVENTION <EOH>The main objective of the present invention is to provide a heterojunction bipolar transistor (HBT) having the following technical features: 1.a high ratio of the emitter area to the base area (EA/BA) to enhance the power gain of the HBT; 2.a lower collector resistance to improve the power added efficiency of the HBT; 3.a better emitter current distribution to improve the high power performance of the HBT.","To reach the objective stated above, the present invention provides a heterojunction bipolar transistor, which comprises an elongated base mesa, an elongated base electrode, two elongated emitters, an elongated collector, and two elongated collector electrodes, in which the elongated base mesa has a long axis and a short axis; the elongated base electrode has a long axis and a short axis and is formed on the base mesa with the long axis of the base electrode essentially parallel to the long axis of the base mesa, and the base electrode has a base via hole at or near the center of the base electrode; the two elongated emitters are formed on the base mesa respectively at two opposite sides of the base electrode along the long axis of the base electrode, and each emitter has an elongated emitter electrode formed on the emitter; the elongated collector is formed below the base mesa; and the two elongated collector electrodes are formed on the collector respectively at two opposite sides of the base mesa along the long axis of the base mesa.","Moreover, the present invention provides another heterojunction bipolar transistor, which comprises an elongated base mesa, an “H” shaped emitter, two base electrodes, an elongated collector, and two elongated collector electrodes, in which the elongated base mesa has a long axis and a short axis; the “H” shaped emitter is formed on the base mesa, the “H” shaped emitter has two parallel bars connected by a cross-bar, two elongated emitter electrodes are formed respectively on the two parallel bars of the “H” shaped emitter, and the “H” shaped emitter has two recesses respectively on two opposite sides of the cross-bar between the two parallel bars; the two base electrodes are formed on the base mesa respectively at the two recesses of the “H” shaped emitter, and each of the base electrode has a base via hole near a center of the base mesa; the elongated collector is formed below the base mesa; and the two elongated collector electrodes are formed on the collector respectively at two opposite sides of the base mesa along the long axis of the base mesa.","In implementation, the base electrode is formed on the base mesa with the long axis of the base electrode essentially parallel to the long axis of the base mesa at or near the center of the short axis of base electrode.","In implementation, the base mesa having a length and a width, and the ratio of the length to width is between 1.2:1 and 15:1.In implementation, the base mesa, the emitter electrodes, and the collector electrodes are in rectangular shapes.","In implementation, recesses of the “H” shaped emitter are provided at or near the center of the short axis of the base mesa.","In implementation, the base mesa, the emitters, and the collector are in bent elongated shapes each having a bending position, and the bending position located at or near the center of the elongated shape.","In implementation, the base mesa, the emitters, and the collector are in bent elongated shapes each having a bending position, and the bending position located at or near the center of the elongated shape with a bending angle of 90°.","The present invention will be understood more fully by reference to the detailed description of the drawings and the preferred embodiments below."],["CROSS-REFERENCE TO RELATED DOCUMENTS The present invention is a divisional application of U.S. patent application Ser.","No 15/204,659 entitled “Heterojunction Bipolar Transistor” filed on Jul.","7, 2016.FIELD OF THE INVENTION The present invention relates to a heterojunction bipolar transistor, and more particular to a heterojunction bipolar transistor has a high ratio of the emitter area to the base area, so that the power gain can be enhanced.","BACKGROUND OF THE INVENTION In recent years, with the rapid development of mobile devices industry, the demand of high power, high power gain and high power added efficiency devices is also growing.","The integrated circuits using compound semiconductor heterojunction bipolar transistors (HBTs) have been widely used in the power amplifier of mobile devices for their high power, high power gain, and high linearity.","Therefore, by improving the layout design of the compound semiconductor HBT circuit, the power gain and power added efficiency of the HBT can be enhanced, and the competitiveness of the product containing the HBT can be increased.","The output power gain of an HBT is related to the base-collector junction capacitance, and the capacitance is proportional to the base area.","The larger the ratio of the emitter area to the base area (EA/BA) is, the smaller the base-collector junction capacitance is.","Therefore, by increasing the ratio of the emitter area to the base area, the base-collector junction capacitance can be effectively decreased, thereby enhancing the output power gain.","SUMMARY OF THE INVENTION The main objective of the present invention is to provide a heterojunction bipolar transistor (HBT) having the following technical features: 1.a high ratio of the emitter area to the base area (EA/BA) to enhance the power gain of the HBT; 2.a lower collector resistance to improve the power added efficiency of the HBT; 3.a better emitter current distribution to improve the high power performance of the HBT.","To reach the objective stated above, the present invention provides a heterojunction bipolar transistor, which comprises an elongated base mesa, an elongated base electrode, two elongated emitters, an elongated collector, and two elongated collector electrodes, in which the elongated base mesa has a long axis and a short axis; the elongated base electrode has a long axis and a short axis and is formed on the base mesa with the long axis of the base electrode essentially parallel to the long axis of the base mesa, and the base electrode has a base via hole at or near the center of the base electrode; the two elongated emitters are formed on the base mesa respectively at two opposite sides of the base electrode along the long axis of the base electrode, and each emitter has an elongated emitter electrode formed on the emitter; the elongated collector is formed below the base mesa; and the two elongated collector electrodes are formed on the collector respectively at two opposite sides of the base mesa along the long axis of the base mesa.","Moreover, the present invention provides another heterojunction bipolar transistor, which comprises an elongated base mesa, an “H” shaped emitter, two base electrodes, an elongated collector, and two elongated collector electrodes, in which the elongated base mesa has a long axis and a short axis; the “H” shaped emitter is formed on the base mesa, the “H” shaped emitter has two parallel bars connected by a cross-bar, two elongated emitter electrodes are formed respectively on the two parallel bars of the “H” shaped emitter, and the “H” shaped emitter has two recesses respectively on two opposite sides of the cross-bar between the two parallel bars; the two base electrodes are formed on the base mesa respectively at the two recesses of the “H” shaped emitter, and each of the base electrode has a base via hole near a center of the base mesa; the elongated collector is formed below the base mesa; and the two elongated collector electrodes are formed on the collector respectively at two opposite sides of the base mesa along the long axis of the base mesa.","In implementation, the base electrode is formed on the base mesa with the long axis of the base electrode essentially parallel to the long axis of the base mesa at or near the center of the short axis of base electrode.","In implementation, the base mesa having a length and a width, and the ratio of the length to width is between 1.2:1 and 15:1.In implementation, the base mesa, the emitter electrodes, and the collector electrodes are in rectangular shapes.","In implementation, recesses of the “H” shaped emitter are provided at or near the center of the short axis of the base mesa.","In implementation, the base mesa, the emitters, and the collector are in bent elongated shapes each having a bending position, and the bending position located at or near the center of the elongated shape.","In implementation, the base mesa, the emitters, and the collector are in bent elongated shapes each having a bending position, and the bending position located at or near the center of the elongated shape with a bending angle of 90°.","The present invention will be understood more fully by reference to the detailed description of the drawings and the preferred embodiments below.","BRIEF DESCRIPTION OF DRAWINGS FIG 1A and 1B are top views of an embodiment of a heterojunction bipolar transistor provided by the present invention.","FIG.","2A and 2B are cross-sectional views of an embodiment of a heterojunction bipolar transistor provided by the present invention along the line A-A′ and line B-B′ in FIG.","1A, respectively.","FIG.","3A and 3B are top views of another embodiment of a heterojunction bipolar transistor provided by the present invention.","FIGS.","4, 5, and 6 are top views of embodiments of a heterojunction bipolar transistor provided by the present invention.","DETAILED DESCRIPTIONS OF PREFERRED EMBODIMENTS FIG.","1A, 1B, 2A, and 2B are embodiments of an I type heterojunction bipolar transistor (HBT) provided by the present invention, which comprises a rectangular base mesa 110, a rectangular base electrode 111, two rectangular emitters 120a and 120b, a rectangular collector 130, and two rectangular collector electrodes 131a and 131b, in which the rectangular base mesa 110 has a long axis along the y direction and a short axis along the x direction; the rectangular base electrode 111 has a long axis and a short axis and is formed on the base mesa 110 with the long axis of the base electrode 111 essentially parallel to the long axis of the base mesa 110, and the base electrode 111 has a base via hole 112 at or near the center of the base electrode 111; the two rectangular emitters 120a and 120b are formed on the base mesa 110 respectively at two opposite sides of the base electrode 111 along the long axis of the base electrode 111, and emitters 120a and 120b have rectangular emitter electrodes 121a and 121b formed on emitters 120a and 120b, respectively; the rectangular collector 130 is formed below the base mesa 110; and the two rectangular collector electrodes 131a and 131b are formed on the collector 130 respectively at two opposite sides of the base mesa 110 along the long axis of the base mesa 110.In an embodiment, the abovementioned base electrode 111, emitter electrodes 121a and 121b, and collector electrodes 131a and 131b are electrically connected to the metal conduction lines (140a-140e) formed by a first metal layer, and further electrically connected to the metal conduction line 150 formed by a second metal layer through the first metal layer.","Through the connection of the first or the second metal layers to other electronic devices, a requested circuit is constructed.","The portion of the I type HBT 100 that does not electrically connected to the first metal layer is isolated by one or more protection layers (e.g.","160a), and the portion of the first metal layer that does not electrically connected to the second metal layer is isolated by at least one protection layer (e.g.","160b, 160c).","The material forming the protective layer must be electrically insulating, and must be able to prevent the materials of the metal layers or other structure diffusing into the HBT.","In the present embodiment, the one or more protective layers can be formed of materials of good isolation property, such as silicon nitride (SiN), polyimide, etc.","The resistance between the collector and emitter (RCE) is related to the adjacent periphery between the collector electrode and emitter.","The longer the adjacent periphery between the collector and emitter is, the lower the RCE is.","In the HBT provided by the present invention, the design of the collectors located on two sides of the emitter increases the adjacent periphery between the collector and emitter, thereby reducing the collector resistance RCE and improving the power added efficiency of the HBT.","In addition, in the design provided by the present invention, the transistor receives the input signal via the first metal layer through the base via hole.","Since the base via hole is located at the center of the transistor, the distribution of the emitter current is symmetric or nearly symmetric, and therefore the high power performance of the HBT can be enhanced.","In the present embodiment, to increase the ratio of the emitter area to the base area (EA/BA), the ratio of the length to width of the emitter and the base mesa should be increased.","However, the emitter area will be increased as well, leading to a higher thermal resistance of the transistor.","In order to achieve the largest ratio of the emitter area to the base area (EA/BA) and to keep the thermal resistance in a lower value, the ratio of the length to width of the rectangular base mesa may be any value between 1.2:1 and 15:1, such as 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1 or 15:1, in which the ratio between 1.2:1 to 10:1 is preferred, 1.5:1 to 8:1 is more preferred, and 2:1 to 7:1 is most preferred.","The aforementioned base, emitter, and collector and the base electrode, emitter electrode, and collector electrode provided thereon respectively may also be in any other elongated shapes, such as an oblong, as long as the long axes of the elongated base, emitter, and collector and their electrodes remain parallel to each other, as shown in FIG.","4.The aforementioned base, emitter, and collector and the base electrode, emitter electrode, and collector electrode provided thereon respectively may also be in a bent elongated shape, which may have one or more bending positions.","FIG.","6 shows an embodiment of an “L” shape HBT 300 with one bending position, in which the base mesa 310, two emitters 320a and 320b, and the collector 330 are all in “L” shapes.","The bending angle at the bending position may be in a range greater than 0° and less than 180°.","In the embodiment shown in FIG.","6, the bending angle of the “L” shape is about 90 °.","FIG.","3A and 3B are top views showing embodiments of an H type HBT 200 provided by the present invention, which comprises an rectangular base mesa 210, an “H” shaped emitter 220, two base electrodes 211a and 211b, an rectangular collector 230, and two rectangular collector electrodes 231a and 231b, in which the rectangular base mesa 210 has a long axis and a short axis; the “H” shaped emitter 220 is formed on the base mesa 210, and the “H” shaped emitter 220 has two recesses 222a and 222b respectively on two opposite sides of the “H” shape, and the emitter 220 has two elongated emitter electrodes 221a and 221b formed on the “H” shaped emitter 220; the two base electrodes 211a and 211b are formed on the base mesa 210 respectively at the two recesses 222a and 222b of the “H” shaped emitter 220, and each of the base electrode 211a and 211b has a base via hole (212a and 212b) near the center along the long axis of the base mesa 210; the rectangular collector 230 is formed below the base mesa 210; and the two rectangular collector electrodes 231a and 231b are formed on the collector 230 respectively at two opposite sides of the base mesa 210 along the long axis of the base mesa 210.In an embodiment, the abovementioned base electrode 211a and 211b, emitter electrodes 221, and collector electrodes 231a and 231b are electrically connected to the metal conduction lines (240a-240d) formed by a first metal layer, and further electrically connected to the metal conduction line 250 formed by a second metal layer through the first metal layer.","Through the connection of the first or the second metal layers to other electronic devices, a requested circuit is constructed.","The portion of the H type HBT 200 that does not electrically connected to the first metal layer is isolated by one or more protection layers, and the portion of the first metal layer that does not electrically connected to the second metal layer is isolated by at least one protection layer.","The material forming the protective layer must be electrically insulating, and must be able to prevent the materials of the metal layers or other structure diffusing into the HBT.","In the present embodiment, the one or more protective layers may be formed of materials of good isolation property, such as silicon nitride (SiN), polyimide, etc.","In the present embodiment, in order to achieve the largest ratio of the emitter area to the base area (EA/BA) and to keep the thermal resistance in a lower value, the ratio of the length to width of the rectangular base mesa may be any value between 1.2:1 and 15:1, such as 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1 or 15:1, in which the ratio between 1.2:1 to 10:1 is preferred, 1.5:1 to 8:1 is more preferred, and 2:1 to 7:1 is most preferred.","The aforementioned base, emitter, and collector and the base electrode, emitter electrode, and collector electrode provided thereon respectively may also be in any other elongated shapes, such as an oblong, as long as the long axes of the elongated base, emitter, and collector and their electrodes remain parallel to each other, as shown in FIG.","5.The present invention has the following advantages: 1.The elongated HBT provided by the present invention has a higher ratio of the emitter area to the base area (EA/BA), thus leading an enhanced power gain of the HBT.","2.The design of disposing the collector at two opposite sides of the emitter can extend the adjacent periphery between the collector and the emitter, and the design of elongated collector and emitter further extend the adjacent periphery.","A lower resistance between the collector and emitter RCE can thus be reached, which improve the power added efficiency of the HBT.","3.The emitter current distribution is symmetric or nearly symmetric, and therefore the high power performance of the HBT can be enhanced.","To sum up, the HBT provided by the present invention can indeed meet its anticipated objective to provide higher ratio of the emitter area to the base area, so that the power gain of the HBT can be enhanced.","Moreover, the HBT provided by the present invention has a lower resistance between the collector and emitter, so that the power added efficiency of the HBT is improved, which is the major demand of the performance of a HBT in the fabrication of a power amplifier.","The description referred to in the drawings and stated above is only for the preferred embodiments of the present invention.","Many equivalent local variations and modifications can still be made by those skilled at the field related with the present invention and do not depart from the spirit of the present invention, so they should be regarded to fall into the scope defined by the appended claims."]],"string":"[\n [\n \"HETEROJUNCTION BIPOLAR TRANSISTOR\",\n \"A heterojunction bipolar transistor, comprising an elongated base mesa, an elongated base electrode, two elongated emitters, an elongated collector, and two elongated collector electrodes.\",\n \"The elongated base electrode is formed on the base mesa along the long axis of the base mesa, and the base electrode has a base via hole at or near the center of the base electrode.\",\n \"The two elongated emitter are formed on the base mesa respectively at two opposite sides of the base electrode, and each of two emitters has an elongated emitter electrode formed on the emitter.\",\n \"The elongated collector is formed below the base mesa.\",\n \"The two elongated collector electrodes are formed on the collector respectively at two opposite sides of the base mesa.\"\n ],\n [\n \"1.A heterojunction bipolar transistor, comprising: an elongated base mesa having a long axis and a short axis, the base mesa having a length and a width, and the ratio of the length to width is between 4:1 and 15:1; an elongated base electrode having a long axis and a short axis, formed on the base mesa with the long axis of the base electrode essentially parallel to the long axis of the base mesa, and the base electrode having a base via hole at or near the center of the base electrode; two elongated emitters formed on the base mesa respectively at two opposite sides of the base electrode along the long axis of the base electrode, each emitter having an elongated emitter electrode formed on the emitter; an elongated collector formed below the base mesa; and two elongated collector electrodes formed on the collector respectively at two opposite sides of the base mesa along the long axis of the base mesa.\",\n \"2.The heterojunction bipolar transistor according to claim 1, wherein the base electrode is formed on the base mesa with the long axis of the base electrode essentially parallel to the long axis of the base mesa at or near the center of the short axis of base electrode.\",\n \"3.The heterojunction bipolar transistor according to claim 2, wherein the base mesa, the emitter electrodes, and the collector electrodes are in rectangular shapes.\",\n \"4.The heterojunction bipolar transistor according to claim 2, wherein the base mesa, the emitters, and the collector are in bent elongated shapes each having a bending position, and the bending position located at or near the center of the elongated shape.\",\n \"5.The heterojunction bipolar transistor according to claim 1, wherein the base mesa, the emitter electrodes, and the collector electrodes are in rectangular shapes.\",\n \"6.The heterojunction bipolar transistor according to claim 1, wherein the base mesa, the emitters, and the collector are in bent elongated shapes each having a bending position, and the bending position located at or near the center of the elongated shape.\",\n \"7.The heterojunction bipolar transistor according to claim 1, wherein the base mesa, the emitters, and the collector are in bent elongated shapes each having a bending position, and the bending position located at or near the center of the elongated shape with a bending angle of 90°.\"\n ],\n [\n \"<SOH> BACKGROUND OF THE INVENTION <EOH>In recent years, with the rapid development of mobile devices industry, the demand of high power, high power gain and high power added efficiency devices is also growing.\",\n \"The integrated circuits using compound semiconductor heterojunction bipolar transistors (HBTs) have been widely used in the power amplifier of mobile devices for their high power, high power gain, and high linearity.\",\n \"Therefore, by improving the layout design of the compound semiconductor HBT circuit, the power gain and power added efficiency of the HBT can be enhanced, and the competitiveness of the product containing the HBT can be increased.\",\n \"The output power gain of an HBT is related to the base-collector junction capacitance, and the capacitance is proportional to the base area.\",\n \"The larger the ratio of the emitter area to the base area (EA/BA) is, the smaller the base-collector junction capacitance is.\",\n \"Therefore, by increasing the ratio of the emitter area to the base area, the base-collector junction capacitance can be effectively decreased, thereby enhancing the output power gain.\"\n ],\n [\n \"<SOH> SUMMARY OF THE INVENTION <EOH>The main objective of the present invention is to provide a heterojunction bipolar transistor (HBT) having the following technical features: 1.a high ratio of the emitter area to the base area (EA/BA) to enhance the power gain of the HBT; 2.a lower collector resistance to improve the power added efficiency of the HBT; 3.a better emitter current distribution to improve the high power performance of the HBT.\",\n \"To reach the objective stated above, the present invention provides a heterojunction bipolar transistor, which comprises an elongated base mesa, an elongated base electrode, two elongated emitters, an elongated collector, and two elongated collector electrodes, in which the elongated base mesa has a long axis and a short axis; the elongated base electrode has a long axis and a short axis and is formed on the base mesa with the long axis of the base electrode essentially parallel to the long axis of the base mesa, and the base electrode has a base via hole at or near the center of the base electrode; the two elongated emitters are formed on the base mesa respectively at two opposite sides of the base electrode along the long axis of the base electrode, and each emitter has an elongated emitter electrode formed on the emitter; the elongated collector is formed below the base mesa; and the two elongated collector electrodes are formed on the collector respectively at two opposite sides of the base mesa along the long axis of the base mesa.\",\n \"Moreover, the present invention provides another heterojunction bipolar transistor, which comprises an elongated base mesa, an “H” shaped emitter, two base electrodes, an elongated collector, and two elongated collector electrodes, in which the elongated base mesa has a long axis and a short axis; the “H” shaped emitter is formed on the base mesa, the “H” shaped emitter has two parallel bars connected by a cross-bar, two elongated emitter electrodes are formed respectively on the two parallel bars of the “H” shaped emitter, and the “H” shaped emitter has two recesses respectively on two opposite sides of the cross-bar between the two parallel bars; the two base electrodes are formed on the base mesa respectively at the two recesses of the “H” shaped emitter, and each of the base electrode has a base via hole near a center of the base mesa; the elongated collector is formed below the base mesa; and the two elongated collector electrodes are formed on the collector respectively at two opposite sides of the base mesa along the long axis of the base mesa.\",\n \"In implementation, the base electrode is formed on the base mesa with the long axis of the base electrode essentially parallel to the long axis of the base mesa at or near the center of the short axis of base electrode.\",\n \"In implementation, the base mesa having a length and a width, and the ratio of the length to width is between 1.2:1 and 15:1.In implementation, the base mesa, the emitter electrodes, and the collector electrodes are in rectangular shapes.\",\n \"In implementation, recesses of the “H” shaped emitter are provided at or near the center of the short axis of the base mesa.\",\n \"In implementation, the base mesa, the emitters, and the collector are in bent elongated shapes each having a bending position, and the bending position located at or near the center of the elongated shape.\",\n \"In implementation, the base mesa, the emitters, and the collector are in bent elongated shapes each having a bending position, and the bending position located at or near the center of the elongated shape with a bending angle of 90°.\",\n \"The present invention will be understood more fully by reference to the detailed description of the drawings and the preferred embodiments below.\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED DOCUMENTS The present invention is a divisional application of U.S. patent application Ser.\",\n \"No 15/204,659 entitled “Heterojunction Bipolar Transistor” filed on Jul.\",\n \"7, 2016.FIELD OF THE INVENTION The present invention relates to a heterojunction bipolar transistor, and more particular to a heterojunction bipolar transistor has a high ratio of the emitter area to the base area, so that the power gain can be enhanced.\",\n \"BACKGROUND OF THE INVENTION In recent years, with the rapid development of mobile devices industry, the demand of high power, high power gain and high power added efficiency devices is also growing.\",\n \"The integrated circuits using compound semiconductor heterojunction bipolar transistors (HBTs) have been widely used in the power amplifier of mobile devices for their high power, high power gain, and high linearity.\",\n \"Therefore, by improving the layout design of the compound semiconductor HBT circuit, the power gain and power added efficiency of the HBT can be enhanced, and the competitiveness of the product containing the HBT can be increased.\",\n \"The output power gain of an HBT is related to the base-collector junction capacitance, and the capacitance is proportional to the base area.\",\n \"The larger the ratio of the emitter area to the base area (EA/BA) is, the smaller the base-collector junction capacitance is.\",\n \"Therefore, by increasing the ratio of the emitter area to the base area, the base-collector junction capacitance can be effectively decreased, thereby enhancing the output power gain.\",\n \"SUMMARY OF THE INVENTION The main objective of the present invention is to provide a heterojunction bipolar transistor (HBT) having the following technical features: 1.a high ratio of the emitter area to the base area (EA/BA) to enhance the power gain of the HBT; 2.a lower collector resistance to improve the power added efficiency of the HBT; 3.a better emitter current distribution to improve the high power performance of the HBT.\",\n \"To reach the objective stated above, the present invention provides a heterojunction bipolar transistor, which comprises an elongated base mesa, an elongated base electrode, two elongated emitters, an elongated collector, and two elongated collector electrodes, in which the elongated base mesa has a long axis and a short axis; the elongated base electrode has a long axis and a short axis and is formed on the base mesa with the long axis of the base electrode essentially parallel to the long axis of the base mesa, and the base electrode has a base via hole at or near the center of the base electrode; the two elongated emitters are formed on the base mesa respectively at two opposite sides of the base electrode along the long axis of the base electrode, and each emitter has an elongated emitter electrode formed on the emitter; the elongated collector is formed below the base mesa; and the two elongated collector electrodes are formed on the collector respectively at two opposite sides of the base mesa along the long axis of the base mesa.\",\n \"Moreover, the present invention provides another heterojunction bipolar transistor, which comprises an elongated base mesa, an “H” shaped emitter, two base electrodes, an elongated collector, and two elongated collector electrodes, in which the elongated base mesa has a long axis and a short axis; the “H” shaped emitter is formed on the base mesa, the “H” shaped emitter has two parallel bars connected by a cross-bar, two elongated emitter electrodes are formed respectively on the two parallel bars of the “H” shaped emitter, and the “H” shaped emitter has two recesses respectively on two opposite sides of the cross-bar between the two parallel bars; the two base electrodes are formed on the base mesa respectively at the two recesses of the “H” shaped emitter, and each of the base electrode has a base via hole near a center of the base mesa; the elongated collector is formed below the base mesa; and the two elongated collector electrodes are formed on the collector respectively at two opposite sides of the base mesa along the long axis of the base mesa.\",\n \"In implementation, the base electrode is formed on the base mesa with the long axis of the base electrode essentially parallel to the long axis of the base mesa at or near the center of the short axis of base electrode.\",\n \"In implementation, the base mesa having a length and a width, and the ratio of the length to width is between 1.2:1 and 15:1.In implementation, the base mesa, the emitter electrodes, and the collector electrodes are in rectangular shapes.\",\n \"In implementation, recesses of the “H” shaped emitter are provided at or near the center of the short axis of the base mesa.\",\n \"In implementation, the base mesa, the emitters, and the collector are in bent elongated shapes each having a bending position, and the bending position located at or near the center of the elongated shape.\",\n \"In implementation, the base mesa, the emitters, and the collector are in bent elongated shapes each having a bending position, and the bending position located at or near the center of the elongated shape with a bending angle of 90°.\",\n \"The present invention will be understood more fully by reference to the detailed description of the drawings and the preferred embodiments below.\",\n \"BRIEF DESCRIPTION OF DRAWINGS FIG 1A and 1B are top views of an embodiment of a heterojunction bipolar transistor provided by the present invention.\",\n \"FIG.\",\n \"2A and 2B are cross-sectional views of an embodiment of a heterojunction bipolar transistor provided by the present invention along the line A-A′ and line B-B′ in FIG.\",\n \"1A, respectively.\",\n \"FIG.\",\n \"3A and 3B are top views of another embodiment of a heterojunction bipolar transistor provided by the present invention.\",\n \"FIGS.\",\n \"4, 5, and 6 are top views of embodiments of a heterojunction bipolar transistor provided by the present invention.\",\n \"DETAILED DESCRIPTIONS OF PREFERRED EMBODIMENTS FIG.\",\n \"1A, 1B, 2A, and 2B are embodiments of an I type heterojunction bipolar transistor (HBT) provided by the present invention, which comprises a rectangular base mesa 110, a rectangular base electrode 111, two rectangular emitters 120a and 120b, a rectangular collector 130, and two rectangular collector electrodes 131a and 131b, in which the rectangular base mesa 110 has a long axis along the y direction and a short axis along the x direction; the rectangular base electrode 111 has a long axis and a short axis and is formed on the base mesa 110 with the long axis of the base electrode 111 essentially parallel to the long axis of the base mesa 110, and the base electrode 111 has a base via hole 112 at or near the center of the base electrode 111; the two rectangular emitters 120a and 120b are formed on the base mesa 110 respectively at two opposite sides of the base electrode 111 along the long axis of the base electrode 111, and emitters 120a and 120b have rectangular emitter electrodes 121a and 121b formed on emitters 120a and 120b, respectively; the rectangular collector 130 is formed below the base mesa 110; and the two rectangular collector electrodes 131a and 131b are formed on the collector 130 respectively at two opposite sides of the base mesa 110 along the long axis of the base mesa 110.In an embodiment, the abovementioned base electrode 111, emitter electrodes 121a and 121b, and collector electrodes 131a and 131b are electrically connected to the metal conduction lines (140a-140e) formed by a first metal layer, and further electrically connected to the metal conduction line 150 formed by a second metal layer through the first metal layer.\",\n \"Through the connection of the first or the second metal layers to other electronic devices, a requested circuit is constructed.\",\n \"The portion of the I type HBT 100 that does not electrically connected to the first metal layer is isolated by one or more protection layers (e.g.\",\n \"160a), and the portion of the first metal layer that does not electrically connected to the second metal layer is isolated by at least one protection layer (e.g.\",\n \"160b, 160c).\",\n \"The material forming the protective layer must be electrically insulating, and must be able to prevent the materials of the metal layers or other structure diffusing into the HBT.\",\n \"In the present embodiment, the one or more protective layers can be formed of materials of good isolation property, such as silicon nitride (SiN), polyimide, etc.\",\n \"The resistance between the collector and emitter (RCE) is related to the adjacent periphery between the collector electrode and emitter.\",\n \"The longer the adjacent periphery between the collector and emitter is, the lower the RCE is.\",\n \"In the HBT provided by the present invention, the design of the collectors located on two sides of the emitter increases the adjacent periphery between the collector and emitter, thereby reducing the collector resistance RCE and improving the power added efficiency of the HBT.\",\n \"In addition, in the design provided by the present invention, the transistor receives the input signal via the first metal layer through the base via hole.\",\n \"Since the base via hole is located at the center of the transistor, the distribution of the emitter current is symmetric or nearly symmetric, and therefore the high power performance of the HBT can be enhanced.\",\n \"In the present embodiment, to increase the ratio of the emitter area to the base area (EA/BA), the ratio of the length to width of the emitter and the base mesa should be increased.\",\n \"However, the emitter area will be increased as well, leading to a higher thermal resistance of the transistor.\",\n \"In order to achieve the largest ratio of the emitter area to the base area (EA/BA) and to keep the thermal resistance in a lower value, the ratio of the length to width of the rectangular base mesa may be any value between 1.2:1 and 15:1, such as 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1 or 15:1, in which the ratio between 1.2:1 to 10:1 is preferred, 1.5:1 to 8:1 is more preferred, and 2:1 to 7:1 is most preferred.\",\n \"The aforementioned base, emitter, and collector and the base electrode, emitter electrode, and collector electrode provided thereon respectively may also be in any other elongated shapes, such as an oblong, as long as the long axes of the elongated base, emitter, and collector and their electrodes remain parallel to each other, as shown in FIG.\",\n \"4.The aforementioned base, emitter, and collector and the base electrode, emitter electrode, and collector electrode provided thereon respectively may also be in a bent elongated shape, which may have one or more bending positions.\",\n \"FIG.\",\n \"6 shows an embodiment of an “L” shape HBT 300 with one bending position, in which the base mesa 310, two emitters 320a and 320b, and the collector 330 are all in “L” shapes.\",\n \"The bending angle at the bending position may be in a range greater than 0° and less than 180°.\",\n \"In the embodiment shown in FIG.\",\n \"6, the bending angle of the “L” shape is about 90 °.\",\n \"FIG.\",\n \"3A and 3B are top views showing embodiments of an H type HBT 200 provided by the present invention, which comprises an rectangular base mesa 210, an “H” shaped emitter 220, two base electrodes 211a and 211b, an rectangular collector 230, and two rectangular collector electrodes 231a and 231b, in which the rectangular base mesa 210 has a long axis and a short axis; the “H” shaped emitter 220 is formed on the base mesa 210, and the “H” shaped emitter 220 has two recesses 222a and 222b respectively on two opposite sides of the “H” shape, and the emitter 220 has two elongated emitter electrodes 221a and 221b formed on the “H” shaped emitter 220; the two base electrodes 211a and 211b are formed on the base mesa 210 respectively at the two recesses 222a and 222b of the “H” shaped emitter 220, and each of the base electrode 211a and 211b has a base via hole (212a and 212b) near the center along the long axis of the base mesa 210; the rectangular collector 230 is formed below the base mesa 210; and the two rectangular collector electrodes 231a and 231b are formed on the collector 230 respectively at two opposite sides of the base mesa 210 along the long axis of the base mesa 210.In an embodiment, the abovementioned base electrode 211a and 211b, emitter electrodes 221, and collector electrodes 231a and 231b are electrically connected to the metal conduction lines (240a-240d) formed by a first metal layer, and further electrically connected to the metal conduction line 250 formed by a second metal layer through the first metal layer.\",\n \"Through the connection of the first or the second metal layers to other electronic devices, a requested circuit is constructed.\",\n \"The portion of the H type HBT 200 that does not electrically connected to the first metal layer is isolated by one or more protection layers, and the portion of the first metal layer that does not electrically connected to the second metal layer is isolated by at least one protection layer.\",\n \"The material forming the protective layer must be electrically insulating, and must be able to prevent the materials of the metal layers or other structure diffusing into the HBT.\",\n \"In the present embodiment, the one or more protective layers may be formed of materials of good isolation property, such as silicon nitride (SiN), polyimide, etc.\",\n \"In the present embodiment, in order to achieve the largest ratio of the emitter area to the base area (EA/BA) and to keep the thermal resistance in a lower value, the ratio of the length to width of the rectangular base mesa may be any value between 1.2:1 and 15:1, such as 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1 or 15:1, in which the ratio between 1.2:1 to 10:1 is preferred, 1.5:1 to 8:1 is more preferred, and 2:1 to 7:1 is most preferred.\",\n \"The aforementioned base, emitter, and collector and the base electrode, emitter electrode, and collector electrode provided thereon respectively may also be in any other elongated shapes, such as an oblong, as long as the long axes of the elongated base, emitter, and collector and their electrodes remain parallel to each other, as shown in FIG.\",\n \"5.The present invention has the following advantages: 1.The elongated HBT provided by the present invention has a higher ratio of the emitter area to the base area (EA/BA), thus leading an enhanced power gain of the HBT.\",\n \"2.The design of disposing the collector at two opposite sides of the emitter can extend the adjacent periphery between the collector and the emitter, and the design of elongated collector and emitter further extend the adjacent periphery.\",\n \"A lower resistance between the collector and emitter RCE can thus be reached, which improve the power added efficiency of the HBT.\",\n \"3.The emitter current distribution is symmetric or nearly symmetric, and therefore the high power performance of the HBT can be enhanced.\",\n \"To sum up, the HBT provided by the present invention can indeed meet its anticipated objective to provide higher ratio of the emitter area to the base area, so that the power gain of the HBT can be enhanced.\",\n \"Moreover, the HBT provided by the present invention has a lower resistance between the collector and emitter, so that the power added efficiency of the HBT is improved, which is the major demand of the performance of a HBT in the fabrication of a power amplifier.\",\n \"The description referred to in the drawings and stated above is only for the preferred embodiments of the present invention.\",\n \"Many equivalent local variations and modifications can still be made by those skilled at the field related with the present invention and do not depart from the spirit of the present invention, so they should be regarded to fall into the scope defined by the appended claims.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875700"}}},{"rowIdx":4494954,"cells":{"text":{"kind":"list like","value":[["METHOD FOR DETERMINING AMPLITUDE OF STICK-SLIP ON A VALVE ASSEMBLY AND IMPLEMENTATION THEREOF","A method for processing operating data (e.g., position, setpoint, and pressure) for a valve assembly.","The method is configured to associate characteristics of operation for the valve assembly with a root cause and/or a contributing factor.","In one embodiment, the method can assign a first amplitude with a value that quantifies movement or “jump” of the valve stem that results from stick-slip on the valve assembly.","The method can also assign a second amplitude with a value that quantifies a change in the data for the setpoint.","The method can further ascertain the relationship or “position” of the first amplitude relative to the second amplitude, or vice versa.","The method can use the relationship between the first amplitude and the second amplitude to indicate the root cause of the operation of the valve assembly."],["1.A method, comprising: calculating a metric from set point data and position data for a valve assembly; using the metric to identify a cycling condition on the valve assembly; selecting a process in response to the cycling condition; using the process to identify a contributing factor to the cycling condition; and generating an alert in response to the contributing factor, the alert comprising one or more of, instructions to change process parameters, and instructions to perform maintenance on the valve assembly.","2.The method of claim 1, wherein the metric corresponds to a ratio of the position data to the set point data.","3.The method of claim 1, wherein the metric corresponds to a ratio of a first p-norm function to a second p-norm function that use the position data and the set point data, respectively.","4.The method of claim 1, further comprising: comparing the metric to a threshold criteria, wherein the threshold criteria has a value that correlates the metric with stick slip on the valve assembly.","5.The method of claim 1, wherein the process includes, setting the contributing factor according to a relationship between the set point data and the position data.","6.The method of claim 1, wherein the process includes, setting the contributing factor according to a relationship between amplitude of the set point data and amplitude of the position data.","7.The method of claim 1, wherein the process includes, setting the contributing factor according to a relationship between a first amplitude of the position data and a second amplitude of the position data, wherein one of the first amplitude and the second amplitude indicates that the position data forms a square wave.","8.An apparatus, comprising: a processor configured to access a memory that has one or more executable instructions stored thereon, the executable instruction comprising one or more instructions that configure the apparatus for, calculating a metric from set point data and position data for a valve assembly; using the metric to identify a cycling condition on the valve assembly; selecting a process in response to the cycling condition; using the process to identify a contributing factor to the cycling condition; and generating an alert in response to the contributing factor, the alert comprising one or more of, instructions to change process parameters, and instructions to perform maintenance on the valve assembly.","9.The apparatus of claim 8, wherein the metric corresponds to a ratio of the position data to the set point data.","10.The apparatus of claim 8, wherein the metric corresponds to a ratio of a first p-norm function to a second p-norm function that use the position data and the set point data, respectively.","11.The apparatus of claim 8, wherein the executable instruction comprise one or more instructions that configure the processor for: comparing the metric to a threshold criteria, wherein the threshold criteria has a value that correlates the metric with stick slip on the valve assembly.","12.The apparatus of claim 8, wherein the process includes, setting the contributing factor according to a relationship between the set point data and the position data.","13.The apparatus of claim 8, wherein the process includes, setting the contributing factor according to a relationship between amplitude of the set point data and amplitude of the position data.","14.The apparatus of claim 8, wherein the process includes, setting the contributing factor according to a relationship between a first amplitude of the position data and a second amplitude of the position data, wherein one of the first amplitude and the second amplitude indicates that the position data forms a square wave.","15.A valve assembly, comprising a seat; a closure member that moves relative to the seat, an actuator coupled with the closure member; and a valve positioner coupled with the actuator, the valve positioner configured to, calculate a metric from set point data and position data; use the metric to identify a cycling condition of the closure member; select a process in response to the cycling condition; using the process to identify a contributing factor to the cycling condition; and generate an alert in response to the contributing factor, the alert comprising one or more of, instructions to change process parameters, and instructions to perform maintenance.","16.The valve assembly of claim 15, wherein the metric corresponds to a ratio of the position data to the set point data.","17.The valve assembly of claim 15, wherein the metric corresponds to a ratio of a first p-norm function to a second p-norm function that use the position data and the set point data, respectively.","18.The valve assembly of claim 15, wherein the valve positioner is configured to: compare the metric to a threshold criteria, wherein the threshold criteria has a value that correlates the metric with stick slip.","19.The valve assembly of claim 15, wherein the process includes, setting the contributing factor according to a relationship between the set point data and the position data.","13.The valve assembly of claim 15, wherein the process includes, setting the contributing factor according to a relationship between amplitude of the set point data and amplitude of the position data.","20.The valve assembly of claim 15, wherein the process includes, setting the contributing factor according to a relationship between a first amplitude of the position data and a second amplitude of the position data, wherein one of the first amplitude and the second amplitude indicates that the position data forms a square wave."],["<SOH> BACKGROUND <EOH>The subject matter disclosed herein relates to processing of data that corresponds with operating parameters for a valve assembly, with particular discussion about methods that use this data to quantify movement of the valve stem due to stick-slip to distinguish the root cause and/or contributing factor of cycling on the valve assembly.","Process lines may include many varieties of flow controls.","These process lines typically transfer fluids for use in the chemical industry, refining industry, oil & gas recovery industry, and the like.","Examples of the flow controls include pneumatic and electronic valve assemblies (collectively, “valve assemblies”) that regulate a flow of process fluid (e.g., gas and liquid).","In conventional implementation, these valve assemblies have a number of components that work together to regulate flow of process fluid into and/or out of the process line.","These components include a closure member, a seat, a valve stem, and an actuator.","Examples of the closure member may embody a plug, ball, butterfly valve, and/or like implement that can contact the seat to prevent flow.","In common construction, the actuator couples with the closure member (via the valve stem).","The valve assembly may also incorporate a valve positioner with electrical and/or electro-pneumatic components.","During operation, the valve positioner receives control signals from a controller that is part of a process control system (also “distributed control system” or “DCS”).","These control signals define operating parameters for the valve assembly, namely, a position for the closure member relative to the seat.","In response to the control signal, the valve positioner delivers a pneumatic signal that regulates instrument gas to pressurize the actuator in order to regulate this position.","Cycling of a valve assembly can have many root causes.","At the process level, the process control system may provide setpoint instructions that oscillate back-and-forth between various levels.","The valve assembly will, in turn, modulate the position of the valve stem in response to these instructions.","From the device level, the valve assembly may suffer from improperly tuned components (e.g., valve positioner) and/or have some type of physical problem that can cause cycling to occur on the valve assembly.","Improper tuning (and calibration) of the valve positioner, for example, may translate the setpoint instructions into the pneumatic signal incorrectly and, thus, cause the valve stem to move to improper positions.","On the other hand, physical problems can frustrate operation of the mechanical components on the valve assembly.","Stick-slip describes a condition, for example, that results from high static friction and/or low kinetic friction between the valve stem and the valve packing material that surrounds the valve stem.","This configuration can prevent leaks from inside the valve assembly.","During operation, however, stick-slip can cause internal force, i.e., pressure on the closure member, to exceed normal operating levels in order to overcome the static friction that prevents movement of the valve stem.","These internal forces, while desirable to induce movement of the valve stem, can cause the valve stem to overshoot its desired position.","The process control system will attempt to correct this error.","In response to overshoot, for example, the process control system often issues instructions for the valve assembly to modulate the valve stem in the opposite direction.","However, it is likely that stick-slip will disrupt the movement in the opposite direction.","The resulting errors will again prompt intervention from the control system to move the valve stem in the other direction.","This process repeats itself, resulting in oscillation or cycling of the valve stem that can disrupt the stability of the process line as well as cause unnecessary wear on the valve assembly."],["<SOH> BRIEF DESCRIPTION OF THE INVENTION <EOH>This disclosure describes improvements in valve diagnostics that can more accurately distinguish cycling that is induced by process and tuning issues from cycling that is induced by stick-slip.","These improvements embody methods with steps that can quantify the amplitude of movement of the valve stem because of stick-slip.","These embodiments compare this stick-slip amplitude to an amplitude of other operating parameters (e.g., setpoint) of the valve assembly.","In this way, the embodiments can generate an output that indicates the contributing factor of cycling on the valve assembly.","As noted herein, these contributing factors can identify whether cycling occurs due to stick-slip or that cycling occurs in response to a process control, namely, modulation of a control signal by the process control system to regulate process parameters on a process line."],["CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser.","No.","14/506,047, filed on Oct. 3, 2014, and entitled “METHOD FOR DETERMINING AMPLITUDE OF STICK-SLIP ON A VALVE ASSEMBLY AND IMPLEMENTATION THEREOF,” which is a continuation-in-part of U.S. patent application Ser.","No.","14/231,505, filed on Mar.","31, 2014, and entitled “SYSTEM AND METHOD FOR DETECTING STICK-SLIP,” and which claims the benefit of priority to U.S.","Provisional Application Ser.","No.","62/049,287, filed on Sep. 11, 2014, and entitled “METHOD FOR DETERMINING AMPLITUDE OF STICK-SLIP ON A VALVE ASSEMBLY AND IMPLEMENTATION THEREOF.” The content of these applications is incorporated by reference herein in its entirety.","BACKGROUND The subject matter disclosed herein relates to processing of data that corresponds with operating parameters for a valve assembly, with particular discussion about methods that use this data to quantify movement of the valve stem due to stick-slip to distinguish the root cause and/or contributing factor of cycling on the valve assembly.","Process lines may include many varieties of flow controls.","These process lines typically transfer fluids for use in the chemical industry, refining industry, oil & gas recovery industry, and the like.","Examples of the flow controls include pneumatic and electronic valve assemblies (collectively, “valve assemblies”) that regulate a flow of process fluid (e.g., gas and liquid).","In conventional implementation, these valve assemblies have a number of components that work together to regulate flow of process fluid into and/or out of the process line.","These components include a closure member, a seat, a valve stem, and an actuator.","Examples of the closure member may embody a plug, ball, butterfly valve, and/or like implement that can contact the seat to prevent flow.","In common construction, the actuator couples with the closure member (via the valve stem).","The valve assembly may also incorporate a valve positioner with electrical and/or electro-pneumatic components.","During operation, the valve positioner receives control signals from a controller that is part of a process control system (also “distributed control system” or “DCS”).","These control signals define operating parameters for the valve assembly, namely, a position for the closure member relative to the seat.","In response to the control signal, the valve positioner delivers a pneumatic signal that regulates instrument gas to pressurize the actuator in order to regulate this position.","Cycling of a valve assembly can have many root causes.","At the process level, the process control system may provide setpoint instructions that oscillate back-and-forth between various levels.","The valve assembly will, in turn, modulate the position of the valve stem in response to these instructions.","From the device level, the valve assembly may suffer from improperly tuned components (e.g., valve positioner) and/or have some type of physical problem that can cause cycling to occur on the valve assembly.","Improper tuning (and calibration) of the valve positioner, for example, may translate the setpoint instructions into the pneumatic signal incorrectly and, thus, cause the valve stem to move to improper positions.","On the other hand, physical problems can frustrate operation of the mechanical components on the valve assembly.","Stick-slip describes a condition, for example, that results from high static friction and/or low kinetic friction between the valve stem and the valve packing material that surrounds the valve stem.","This configuration can prevent leaks from inside the valve assembly.","During operation, however, stick-slip can cause internal force, i.e., pressure on the closure member, to exceed normal operating levels in order to overcome the static friction that prevents movement of the valve stem.","These internal forces, while desirable to induce movement of the valve stem, can cause the valve stem to overshoot its desired position.","The process control system will attempt to correct this error.","In response to overshoot, for example, the process control system often issues instructions for the valve assembly to modulate the valve stem in the opposite direction.","However, it is likely that stick-slip will disrupt the movement in the opposite direction.","The resulting errors will again prompt intervention from the control system to move the valve stem in the other direction.","This process repeats itself, resulting in oscillation or cycling of the valve stem that can disrupt the stability of the process line as well as cause unnecessary wear on the valve assembly.","BRIEF DESCRIPTION OF THE INVENTION This disclosure describes improvements in valve diagnostics that can more accurately distinguish cycling that is induced by process and tuning issues from cycling that is induced by stick-slip.","These improvements embody methods with steps that can quantify the amplitude of movement of the valve stem because of stick-slip.","These embodiments compare this stick-slip amplitude to an amplitude of other operating parameters (e.g., setpoint) of the valve assembly.","In this way, the embodiments can generate an output that indicates the contributing factor of cycling on the valve assembly.","As noted herein, these contributing factors can identify whether cycling occurs due to stick-slip or that cycling occurs in response to a process control, namely, modulation of a control signal by the process control system to regulate process parameters on a process line.","BRIEF DESCRIPTION OF THE DRAWINGS Reference is now made briefly to the accompanying drawings, in which: FIG.","1 depicts a flow diagram of an exemplary embodiment of a method for determining a contributing factor for cycling on a valve assembly; FIG.","2 depicts a plot of data that exemplifies operation of a valve assembly that exhibits cycling due to stick-slip; FIG.","3 depicts a plot of data that exemplifies operation of a valve assembly that exhibits cycling due to process controls; FIG.","4 depicts a flow diagram of an exemplary embodiment of a method for determining a contributing factor for cycling on a valve assembly; FIG.","5 depicts a flow diagram of an exemplary embodiment of a method for determining an amplitude that defines a change in position from a first position to a second position; FIG.","6 depicts a flow diagram of an exemplary embodiment of a method for determining an amplitude that defines a change in setpoint from a first setpoint to a second setpoint; FIG.","7.depicts a perspective view of an example of a valve assembly; FIG.","8 depicts an exploded assembly view of an example of a valve positioner for use on the valve assembly of FIG.","7; and FIG.","9 depicts a schematic diagram of the valve assembly of FIG.","7 as part of a process control system.","Where applicable like reference characters designate identical or corresponding components and units throughout the several views, which are not to scale unless otherwise indicated.","Moreover, the embodiments disclosed herein may include elements that appear in one or more of the several views or in combinations of the several views.","DETAILED DESCRIPTION The discussion below offers a solution to determine the root cause of operating conditions on a valve assembly.","Unlike previous techniques, which for the most part only detect or establish the “presence” of the operating condition, the embodiments herein can readily identify what is causing the operating condition to occur on the valve assembly.","This information can enlighten the process owner/operator to better address the operating condition, effectively saving time and money by avoiding unnecessary repairs to valve assemblies that would not otherwise require maintenance.","FIG.","1 depicts a flow diagram of an exemplary embodiment of a method 100 for use on and/or as part of a valve assembly and a process control system.","This diagram outlines steps that may embody instructions for one or more computer-implemented methods and/or programs.","In FIG.","1, the embodiment includes, at step 102, receiving an input with a sample set of data, the sample set comprising data samples collected and/or gathered from, e.g., the valve assembly.","The embodiment also includes, at step 104, determining a first amplitude for the operating parameters and, at step 106, comparing the first amplitude to a second amplitude for the operating parameters.","In one implementation, the embodiment can include, at step 108, generating an output that relates to a position of the first amplitude relative to the second amplitude, namely, a relative position of the first amplitude with respect to the second amplitude.","As discussed more below, in one example the first amplitude has a value that quantifies an amount of stick-slip on the valve assembly.","Broadly, the method 100 can configure the valve assembly and/or the process control system, generally, to process data in a way that associates characteristics of operation of the valve assembly with a root cause and/or a contributing factor.","The data samples may correspond with operating parameters, for example, values for position, setpoint, and pressure for the valve assembly.","These values are readily available and stored as part of normal operation and control of the valve assembly.","In use, the method 100 can assign the first amplitude with a value that quantifies movement or “jump” of the valve stem that results from stick-slip on the valve assembly.","This movement typically occurs between a first position and a second position.","The method 100 can assign the second amplitude with a value that quantifies a change in the data for the setpoint and/or the position, for example, as between a first setpoint and a second setpoint.","As noted above, the method 100 can ascertain the relationship or “relative position” of the first amplitude relative to the second amplitude, or vice versa.","This relative position may convey that the first amplitude is greater than the second amplitude, that the first amplitude is less than the second amplitude, and/or that the first amplitude is the same as (also equal to) the second amplitude.","Notably, the present disclosure contemplates that the method 100 can use the relationship between the first amplitude and the second amplitude to indicate the root cause of the operation of the valve assembly.","This relationship may, for example, indicate that stick slip is the root cause of repeated up-and-down travel of the valve stem (also, “valve stem cycling” and/or “valve cycling”).","On the other hand, the relationship may indicate that abnormal or “out-of-control” process conditions on the process line are the root cause of the valve stem cycling.","Such process conditions often prompt the process control system to issue the command signal in a manner that is the root cause of the valve stem cycling.","The method 100 can tailor the output to provide an alert or like indicator that instructs as to the root cause.","This indicator can focus the response of an end user (e.g., process owner/operator) on the problem, e.g., to avoid unnecessary repairs to the valve assembly in the event that the root cause relates to abnormal process conditions.","FIGS.","2 and 3 depict plots of data for operating parameters of a valve assembly.","The data reflects position POS, setpoint SP, and actuator pressure P (FIG.","2), each collected over a time scale T. In each of the plots, the valve assembly exhibits cycling of the position POS.","The plot of FIG.","2 indicates operation of the valve assembly under stick-slip conditions.","On the other hand, the plot of FIG.","3 indicates operation of the valve assembly that shows signs of stick-slip (as identified, generally, by SLIP), but otherwise is cycling in response to abnormal conditions on the process line.","The embodiments herein can process the data in each of FIGS.","2 and 3 to identify the root cause of operation.","These embodiments can, in one example, discern stick-slip cycling that corresponds with the distinctive pattern of the position POS data in the plot of FIG.","2.This pattern has abrupt changes, or jumps, that have an amplitude that is sufficient to indicate the build-up of pressure and overshoot that occurs due to the inherent friction in the valve stem/packing interface.","The embodiments can also discern that process cycling is the root cause of the pattern of position POS data in the plot of FIG.","3.In this example, while the position POS data shows some areas of stick-slip (e.g., areas SLIP), the amplitude of the jump in the position POS data is not sufficient to associate the cycling issues with stick-slip.","Rather, the pattern of the position POS data overwhelmingly follows the cycling of the setpoint SP, which may occur in response to process-related issues.","FIG.","4 depicts a flow diagram for an exemplary embodiment of a method 200 that can use the stick-slip amplitude to arrive at the root cause and/or contributing factors of valve stem cycling.","The method 200 includes, at step 210, identifying a cycling condition on the valve assembly, which can instruct the method 200 (to return to step 202) to continue to process data until such condition exists on the valve assembly.","The method 200 also includes, at step 212, determining an amplitude of one or more of the operating parameters that exhibit the cycling condition.","The method 200 further includes, at step 214, identifying a stick-slip condition on the valve assembly and/or whether a stick-slip condition is present on the valve assembly.","If the stick slip condition is not present, then the method 200 continues, at step 216, comparing an amplitude for a first operating parameter (A1) to an amplitude for a second operating parameter (A2).","On the other hand, if the stick slip condition is present, then the method 200 continues, at step 204, determining a stick-slip amplitude (as noted, for example, in the method 300 below) and, at step 206, comparing the stick-slip amplitude to the amplitude of the first operating parameter and/or the amplitude for the second operating parameter.","The generated output (e.g., at step 208) can reflect the relative position of the stick-slip amplitude, the amplitude of the first operating parameter, and the amplitude of the second operating parameter, as compared to one another in context of the steps outlined above and in Table 1 below.","TABLE 1 Stick-Slip Relative Contributing Example Present Position Factor 1 No A1 > F1 × A2 Positioner Tuning 2 No A1 < F2 × A2 Process Control 3 Yes A2 > F3 × AST Process Control 4 Yes A2 < F4 × AST Stick-Slip As noted above, the method 200 is configured to identify one or more contributing factors that cause cycling on the valve assembly.","In Table 1, the amplitudes A1, A2, and AST correspond with, respectively, the amplitude of position POS (FIGS.","2 and 3), the amplitude of setpoint SP (FIGS.","2 and 3), and the stick-slip amplitude of position POS (FIGS.","2 and 3).","The configurations of the method 200 may employ one or more factors, noted in the example of Table 1 above as a first factor F1, a second factor F2, a third factor F3, and a fourth factor F4.Values for the factors F1, F2, F3, and F4 can vary as to their effect within the processing of the data, as desired.","In one implementation, the factors serve to increase and/or decrease the relative value of the amplitude A2 and/or AST, e.g., by a factor of 2, 4, 6, etc.","In one example, the stick-slip amplitude is calculated in accordance with the steps outlined in the method 300 below (FIG.","5).","The steps of determining whether the stick-slip condition is present (e.g., at step 214) also analyze the data for the position POS and the setpoint SP.","These steps may include, for example, determining a stick-slip condition metric, an example of which is noted in Equation (1) below, M ST = M P M S , Equation ( 1 ) in which MST is the stick-slip condition metric, MP is a position metric, and MS is a setpoint metric.","The method 300 can include steps for comparing the stick-slip condition metric MST to a threshold criteria, which may identify a value for the ratio of the position metric MP to the setpoint metric MS that corresponds with and/or relates to stick-slip on the valve assembly.","Examples of the value for the threshold criteria may be in a range from about 1 to about 3.In one implementation, if the stick-slip condition metric MST does not satisfy (e.g., is greater than, less than, and/or equal to) this threshold criteria, then the stick-slip condition is not present on the valve assembly.","The output can convey that stick-slip is present and/or not present on the valve assembly.","In one example, the value for the first amplitude corresponds with the stick-slip condition metric being less than or equal to the value for the threshold criteria.","The method 300 can also include steps for calculating the position metric and/or the setpoint metric using “p-norm” functions, as set forth in Equations (2) and (3) below, M P = ∑ ( P i - P i - 1 ) X N X , Equation ( 2 ) M S = ∑ ( S i - S i - 1 ) X N X , Equation ( 3 ) in which Pi-1 is a first data sample for the position, Pi is a second data sample for the position that is adjacent the first data sample in the sample set, Si-1 is a first data sample for the setpoint, Si is a second data sample for the setpoint that is adjacent the first data sample in the sample set, N is a number of data samples in the sample set, and X is a p-norm parameter.","Examples of the p-norm parameter can be in a range of from about 2 to about 6, but this disclosure does contemplate certain configurations of the methods herein in which the p-norm parameter falls outside of this range.","FIG.","5 illustrates a flow diagram of an exemplary embodiment of a method 300 that includes exemplary steps to arrive at values that quantify the amplitude of the “jump” shown in position (e.g., position POS of FIGS.","2 and 3).","This amplitude is also referred to herein (e.g., in FIG.","4 above) as the stick-slip amplitude.","These steps process the data samples in the data set; in one example, this process starts with the second data sample in the data set and ends with the last data sample in the data set.","In FIG.","5, the method 300 includes, at step 302, receiving an input with the sample set of data and, at step 304, selecting a data sample from the data set.","The method 300 also includes, at step 306, determining a first sample interval and, at step 308, comparing the first sample interval to a first threshold value.","If the first sample interval exceeds the first threshold value, then the method 300 can include, at step 310, incrementing a cycle variable and, at step 312, determining a total interval value.","In one embodiment, the method 300 includes, at step 314, determining whether the last data sample has been processed and, if so, then the method 300 can include, at step 316, calculating the first amplitude (e.g., the stick-slip amplitude (AST)) using the values for the total interval value and/or the count variable.","This disclosure contemplates implementation of the method 300 as an iterative process to process a plurality of data samples.","In this connection, the method 300 can include steps for calculating one or more sample intervals, for example, one that occurs between data samples that are adjacent to one another in the sample set of data.","The steps can also include steps for comparing each of the sample intervals to the first threshold value that relates to the position.","Examples of the total interval value may be calculated by steps for adding together (and/or summing and/or aggregating) the one or more sample intervals to arrive at the total interval value.","In one example, the total interval value may only include the one or more sample intervals that satisfy (also, where applicable, deviate from) the first threshold value for the data samples in the data set.","This criteria may indicate that the one or more sample intervals are each greater than, less than, and/or equal to the first threshold value, as desired.","In another example, the steps may include steps for incrementing the cycle variable for each of the one or more sample intervals that exceed the first threshold value.","The steps may also arrive at the value for the first amplitude by incorporating one or both of the cycle variable and the total interval value, for example, where the value for the first amplitude is equal to the ratio of the total interval value to the cycle count.","The method 300 can include steps that provide a value for the first sample interval as positive and/or non-negative (and/or greater than or equal to zero).","This feature is useful to calculate the amplitude of the “jump” independent of the direction of movement of the valve stem—i.e., in both the positive direction and the negative direction.","In one embodiment, the method 300 may include steps to calculate the first sample interval in accordance with Equation (4) below, I=|P2−P1|, Equation (4) in which I is a first sample interval among the one or more sample intervals, P1 is a previously-stored data sample, and P2 is a data sample that is adjacent the previously-stored data sample P1 in the sample set of data.","The method 300 can also include steps to generate a value for the first threshold value that, like the value for the first sample interval, is also positive and/or non-negative.","This value may reflect use of a “p-norm” function.","In one embodiment, the method 300 may include steps to calculate the first threshold value in accordance with Equation (5) below, RMP position = ∑ ( P i - P i - 1 ) X N X , Equation ( 5 ) in which RMPPosition is the first threshold value, Pi-1 is a first data sample for the position in the sample set, Pi is a second data sample for the position that is adjacent the first data sample in the sample set, N is a number of data samples in the sample set, and X is a p-norm parameter.","Examples of the p-norm parameter can be in a range of from about 2 to about 6, but this disclosure does contemplate certain configurations of the methods herein in which the p-norm parameters falls outside of this range.","FIG.","6 depicts a flow diagram of an exemplary embodiment of a method 400 with exemplary steps to determine a value for the position amplitude and the setpoint amplitude.","The method 400 includes, at step 402, receiving an input with the sample set of data and, at step 404, selecting a first data sample (also “starting data sample”), for example, the first data sample among the data samples in the data set.","The method 400 also includes, at step 406, identifying the starting data sample as a first vertex in the data set and, at step 408, comparing a first deviation with a second threshold value.","The first deviation measures the difference between the value of the starting data sample and the value of other data samples in the data set.","Notably, in one implementation, if no deviation is found in excess of the second threshold value, then the valve assembly is considered to be operating normally—i.e., the valve assembly is not cycling.","On the other hand, if the first deviation is found in excess of the second threshold value, then the method 400 continues to include, at step 410, determining a direction of travel for the valve stem.","The direction of travel is, typically, positive (or “increasing”) for situations in which the value of the first vertex is greater than the value of the starting data sample or negative (or “decreasing”) for situations in which the value of the first vertex is less than the value of the starting data sample.","The direction of travel can influence further processing of the data samples.","As also shown in FIG.","6, the method 400 can include, at step 412, selecting a second data sample from the data set, often starting with a data sample that is adjacent or consecutive with the first vertex and ending with the last data sample in the data set.","When the direction of travel is “increasing,” the method 400 continues, at step 414, comparing the selected data sample to the first vertex.","If the selected data sample is greater than the first vertex, then the method 400 includes, at step 416, storing the selected data sample as the first vertex and continues back to step 412 to select a different data sample.","If the selected data sample is less than the first vertex, then the method 400 can include, at step 418, comparing a second deviation between the selected data sample and the first vertex to the second threshold value.","If the second deviation is less than the second threshold value, then the method continues to include, at step 420, incrementing a vertex count that identifies each occurrence of a vertex in the sample set of data, at step 422, identifying the selected data sample as the second vertex, and, at step 424, changing the direction of travel to decreasing.","In one example, the vertex corresponds with a data sample from the sample set of data that has a relative position with respect to a previously-stored data sample from the sample set of data that exceeds the second threshold value.","The method 400 can continue, at step 426, determining whether the selected data sample is the last data sample in the data set.","If the selected data sample is the last data sample in the data set, then the method 400 can continue to include, at step 428 and/or step 430, determining a cycle count and/or a cycle amplitude, as set forth herein.","In one embodiment, the cycle amplitude corresponds with the second amplitude, which in turn may correspond with an average of the relative positions from one vertex to another vertex for the sample set of data.","Thus, the method 400 may include one or more steps for storing each of the deviations (e.g., the second deviation) between the adjacent data samples.","When the direction of travel is “decreasing,” then the method 400 continues, at step 414, comparing the selected data sample to the first vertex.","If the selected data sample is less than the first vertex, then the method 400 includes, at step 416, storing the selected data sample as the first vertex and continues back to step 412 to select a different data sample.","If the selected data sample is greater than the first vertex, the method 400 can include, at step 418, comparing the second deviation between the selected data sample and the first vertex to the second threshold.","If the second deviation is greater than the second threshold value, then the method continues to include, at step 420, incrementing a vertex count that identifies each occurrence of a vertex in the sample set of data.","The method 400 also includes, at step 422, identifying the selected data sample as the first vertex, and, at step 424, changing the direction of travel to increasing.","The method 400 can continue to include, at step 426, determining whether the selected data sample is the last data sample in the data set.","If the selected data sample is the last data sample in the data set, then the method 400 can continue to include, at step 428 and/or step 430, determining a cycle count and/or determining a cycle amplitude, as set forth herein.","FIGS.","7, 8, and 9 depict an example of a valve assembly and a process control system (FIG.","9) that can employ the embodiments disclosed herein.","These examples are useful to regulate process fluids in industrial process lines typical of industries that focus on chemical production, refining production, and resource extraction.","FIG.","7 shows a perspective view of a valve positioner.","FIG.","8 provides an exploded assembly view of components of the valve assembly.","FIG.","9 illustrates a schematic diagram of the valve assembly 10 as part of a process control system.","In FIG.","7, the valve assembly 10 includes a valve positioner 12, an actuator 14, and a fluid coupling 16 with a body 18 that has a first inlet/outlet 20 and a second inlet/outlet 22.The fluid coupling 16 can also include a valve stem 24, which couples the actuator 14 with other valve members (e.g., a closure member) that is found in the interior to the body 18 and, thus, not shown in the present view.","This structure can modulate a flow of process fluid FP between the inlet/outlets 20, 22.During operation, the valve positioner 12 regulates instrument gas (also, “pneumatic signal”) into the actuator 16 to manage the position of the valve members disposed in the body 18.The change in position modulates flow of the process fluid FP across the inlet/outlets 20, 22.FIG.","8 depicts the valve positioner 12 in exploded form.","As noted above, the valve positioner 12 has components that generate the pneumatic signal to the actuator 14 (FIG.","7).","The valve positioner 12 can have a plurality of positioner components (e.g., a converter component 26, a relay component 28, a processing component 30).","The valve positioner 12 can also have a housing 32.One or more covers (e.g., a first cover 34 and a second cover 36) can secure with the housing 32 to form an enclosure about the positioner components 26, 28, 30.This enclosure protects the positioner components from conditions that prevail in the environment surrounding the valve assembly 10.The valve positioner 12 also includes one or more gauges (e.g., a first gauge 38 and a second gauge 40) that can provide an indication of the flow conditions (e.g., pressure, flow rate, etc.)","of the instrument gas that the valve positioner 12 uses to operate the valve in the valve assembly 10.In one example, operation of the positioner components 26, 28, 30 maintain the position of the valve members in the body 18 (FIG.","7) to modulate flow of the process fluid FP across the inlet/outlets 20, 22 (FIG.","7).","FIG.","9 depicts a schematic diagram of the valve assembly 10.Examples of the valve members can include a closure member 42 that can move relative to a seat 44.As also shown in FIG.","9, the valve assembly 10 integrates as part of a control system 46, typically by way of communication between the valve positioner 12 and a network system 48 via a network 50.Examples of the network 50 can transfer data, information, and signals by way of wired protocols (e.g., 4-20 mA, Foundation Fieldbus, etc.)","and/or wireless protocols, many of which find use in a plant or factory automation environment.","These protocols facilitate communication over the network 50 between the valve positioner 12, a process management server 52 (and like “apparatus”) that can run certain diagnostic and/or operative software and programs for data analysis, a process controller 53, a terminal 54, and/or an external server 56.During operation, the process controller 53 can execute one or more computer programs to deliver a command signal to the valve positioner 12.The command signal identifies a commanded position for the closure member 42.The valve positioner 12 uses the commanded position to modulate the instrument gas to the actuator 14 and, effectively, allow the closure member 42 to move relative to the seat 44.In one example, feedback in the assembly can provide the valve positioner 12 with a position of the valve stem 14.The position corresponds with the location and/or position of the closure member 42 relative to the seat 44.In one embodiment, the process management server 52 can comprise a processor configured to access a memory that has one or more executable instructions stored thereon, the executable instructions comprising one or more instructions that configure the server 52 (also, “apparatus”) and that may embody one or more of the method steps as set forth herein.","The memory may be incorporated as part of the process management server 52 or, in one example, separate from the process management server 52.The data may reside on a data source, often locally in one or more memories on the valve positioner 12 (FIG.","7), although this disclosure also contemplates configurations in which the data resides on the control system 46 (FIG.","9).","For example, the data source may integrate with the process management server 52 (FIG.","9) and/or as part of the external server 56 (FIG.","9).","At the data source, the data may be arranged as one or more data sets that include one or more data samples.","The data sets may be identified by an indicator (e.g., a date stamp, a time stamp, a date/time stamp, etc.)","that relates to the chronological time at which the data samples in the data set were gathered and/or stored, e.g., in memory.","For real-time use of the methods, the data samples may be read into a buffer and/or like configured storage medium that allows for ready access to the data samples to afford the methods with chronologically relevant data, taking into consideration necessary data processing time-lag.","In one embodiment, the methods may include one or more steps for obtaining and/or retrieving the data from the data source.","In view of the foregoing, the embodiments above deploy features that can determine the amplitude of jump that results from stick-slip during operation of the valve assembly.","The embodiments are also configured to use this amplitude to identify the root cause or contributing factor to cycling of the valve stem.","A technical effect is to trigger an alarm or an output, generally, that can alert the process owner/operator to the root cause and, thus, direct attention to specific solutions (i.e., process solutions) that can avoid unnecessary repairs and maintenance on the valve assemblies of the process line.","The embodiments may be implemented on any device where relevant data is present and/or otherwise accessible.","For example, the embodiments can be implemented as executable instructions (e.g., firmware, hardware, software, etc.)","on the valve positioner.","The valve positioner can transmit the output of the embodiments to a distributed control system, asset management system, independent monitoring computing device (e.g., a desktop computer, laptop computer, tablet, smartphone, mobile device, etc.).","In another embodiment, the embodiments can obtain data from a historian (e.g., a repository, memory, etc.","), and send to an independent diagnostic computing device.","The historian is conventionally connected to the asset management system or distributed control system.","The diagnostic computing device has all the capabilities of the monitoring computer and, often, the additional capability to execute executable instructions for the embodiment to process the given data.","In another embodiment, the valve positioner is configured to send data by wires or wirelessly to the diagnostic computing device, as well as through peripheral and complimentary channels (e.g., through intermediate devices such as a DCS or may be connected directly to the diagnostic computer).","One or more of the steps of the methods can be coded as one or more executable instructions (e.g., hardware, firmware, software, software programs, etc.).","These executable instructions can be part of a computer-implemented method and/or program, which can be executed by a processor and/or processing device.","The processor may be configured to execute these executable instructions, as well as to process inputs and to generate outputs, as set forth herein.","For example, the software can run on the process device, the diagnostics server, and/or as software, application, or other aggregation of executable instructions on a separate computer, tablet, laptop, smart phone, wearable device, and like computing device.","These devices can display the user interface (also, a “graphical user interface”) that allows the end user to interact with the software to view and input information and data as contemplated herein.","The computing components (e.g., memory and processor) can embody hardware that incorporates with other hardware (e.g., circuitry) to form a unitary and/or monolithic unit devised to execute computer programs and/or executable instructions (e.g., in the form of firmware and software).","Exemplary circuits of this type include discrete elements such as resistors, transistors, diodes, switches, and capacitors.","Examples of a processor include microprocessors and other logic devices such as field programmable gate arrays (“FPGAs”) and application specific integrated circuits (“ASICs”).","Memory includes volatile and non-volatile memory and can store executable instructions in the form of and/or including software (or firmware) instructions and configuration settings.","Although all of the discrete elements, circuits, and devices function individually in a manner that is generally understood by those artisans that have ordinary skill in the electrical arts, it is their combination and integration into functional electrical groups and circuits that generally provide for the concepts that are disclosed and described herein.","Aspects of the present disclosure may be embodied as a system, method, or computer program product.","The embodiments may take the form of an entirely hardware embodiment, an entirely software embodiment (including firmware, software, etc.)","or an embodiment combining software and hardware aspects that may all generally be referred to herein as a “circuit,” “module” or “system.” The computer program product may embody one or more non-transitory computer readable medium(s) having computer readable program code embodied thereon.","Computer program code for carrying out operations for aspects of the present invention may be written in any combination of one or more programming languages, including an object oriented programming language and conventional procedural programming languages.","Program code embodied on a computer readable medium may be transmitted using any appropriate medium, including but not limited to wireless, wireline, optical fiber cable, RF, etc., or any suitable combination of the foregoing.","As used herein, an element or function recited in the singular and proceeded with the word “a” or “an” should be understood as not excluding plural said elements or functions, unless such exclusion is explicitly recited.","Furthermore, references to “one embodiment” of the claimed invention should not be interpreted as excluding the existence of additional embodiments that also incorporate the recited features.","This written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods.","The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art.","Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal language of the claims."]],"string":"[\n [\n \"METHOD FOR DETERMINING AMPLITUDE OF STICK-SLIP ON A VALVE ASSEMBLY AND IMPLEMENTATION THEREOF\",\n \"A method for processing operating data (e.g., position, setpoint, and pressure) for a valve assembly.\",\n \"The method is configured to associate characteristics of operation for the valve assembly with a root cause and/or a contributing factor.\",\n \"In one embodiment, the method can assign a first amplitude with a value that quantifies movement or “jump” of the valve stem that results from stick-slip on the valve assembly.\",\n \"The method can also assign a second amplitude with a value that quantifies a change in the data for the setpoint.\",\n \"The method can further ascertain the relationship or “position” of the first amplitude relative to the second amplitude, or vice versa.\",\n \"The method can use the relationship between the first amplitude and the second amplitude to indicate the root cause of the operation of the valve assembly.\"\n ],\n [\n \"1.A method, comprising: calculating a metric from set point data and position data for a valve assembly; using the metric to identify a cycling condition on the valve assembly; selecting a process in response to the cycling condition; using the process to identify a contributing factor to the cycling condition; and generating an alert in response to the contributing factor, the alert comprising one or more of, instructions to change process parameters, and instructions to perform maintenance on the valve assembly.\",\n \"2.The method of claim 1, wherein the metric corresponds to a ratio of the position data to the set point data.\",\n \"3.The method of claim 1, wherein the metric corresponds to a ratio of a first p-norm function to a second p-norm function that use the position data and the set point data, respectively.\",\n \"4.The method of claim 1, further comprising: comparing the metric to a threshold criteria, wherein the threshold criteria has a value that correlates the metric with stick slip on the valve assembly.\",\n \"5.The method of claim 1, wherein the process includes, setting the contributing factor according to a relationship between the set point data and the position data.\",\n \"6.The method of claim 1, wherein the process includes, setting the contributing factor according to a relationship between amplitude of the set point data and amplitude of the position data.\",\n \"7.The method of claim 1, wherein the process includes, setting the contributing factor according to a relationship between a first amplitude of the position data and a second amplitude of the position data, wherein one of the first amplitude and the second amplitude indicates that the position data forms a square wave.\",\n \"8.An apparatus, comprising: a processor configured to access a memory that has one or more executable instructions stored thereon, the executable instruction comprising one or more instructions that configure the apparatus for, calculating a metric from set point data and position data for a valve assembly; using the metric to identify a cycling condition on the valve assembly; selecting a process in response to the cycling condition; using the process to identify a contributing factor to the cycling condition; and generating an alert in response to the contributing factor, the alert comprising one or more of, instructions to change process parameters, and instructions to perform maintenance on the valve assembly.\",\n \"9.The apparatus of claim 8, wherein the metric corresponds to a ratio of the position data to the set point data.\",\n \"10.The apparatus of claim 8, wherein the metric corresponds to a ratio of a first p-norm function to a second p-norm function that use the position data and the set point data, respectively.\",\n \"11.The apparatus of claim 8, wherein the executable instruction comprise one or more instructions that configure the processor for: comparing the metric to a threshold criteria, wherein the threshold criteria has a value that correlates the metric with stick slip on the valve assembly.\",\n \"12.The apparatus of claim 8, wherein the process includes, setting the contributing factor according to a relationship between the set point data and the position data.\",\n \"13.The apparatus of claim 8, wherein the process includes, setting the contributing factor according to a relationship between amplitude of the set point data and amplitude of the position data.\",\n \"14.The apparatus of claim 8, wherein the process includes, setting the contributing factor according to a relationship between a first amplitude of the position data and a second amplitude of the position data, wherein one of the first amplitude and the second amplitude indicates that the position data forms a square wave.\",\n \"15.A valve assembly, comprising a seat; a closure member that moves relative to the seat, an actuator coupled with the closure member; and a valve positioner coupled with the actuator, the valve positioner configured to, calculate a metric from set point data and position data; use the metric to identify a cycling condition of the closure member; select a process in response to the cycling condition; using the process to identify a contributing factor to the cycling condition; and generate an alert in response to the contributing factor, the alert comprising one or more of, instructions to change process parameters, and instructions to perform maintenance.\",\n \"16.The valve assembly of claim 15, wherein the metric corresponds to a ratio of the position data to the set point data.\",\n \"17.The valve assembly of claim 15, wherein the metric corresponds to a ratio of a first p-norm function to a second p-norm function that use the position data and the set point data, respectively.\",\n \"18.The valve assembly of claim 15, wherein the valve positioner is configured to: compare the metric to a threshold criteria, wherein the threshold criteria has a value that correlates the metric with stick slip.\",\n \"19.The valve assembly of claim 15, wherein the process includes, setting the contributing factor according to a relationship between the set point data and the position data.\",\n \"13.The valve assembly of claim 15, wherein the process includes, setting the contributing factor according to a relationship between amplitude of the set point data and amplitude of the position data.\",\n \"20.The valve assembly of claim 15, wherein the process includes, setting the contributing factor according to a relationship between a first amplitude of the position data and a second amplitude of the position data, wherein one of the first amplitude and the second amplitude indicates that the position data forms a square wave.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>The subject matter disclosed herein relates to processing of data that corresponds with operating parameters for a valve assembly, with particular discussion about methods that use this data to quantify movement of the valve stem due to stick-slip to distinguish the root cause and/or contributing factor of cycling on the valve assembly.\",\n \"Process lines may include many varieties of flow controls.\",\n \"These process lines typically transfer fluids for use in the chemical industry, refining industry, oil & gas recovery industry, and the like.\",\n \"Examples of the flow controls include pneumatic and electronic valve assemblies (collectively, “valve assemblies”) that regulate a flow of process fluid (e.g., gas and liquid).\",\n \"In conventional implementation, these valve assemblies have a number of components that work together to regulate flow of process fluid into and/or out of the process line.\",\n \"These components include a closure member, a seat, a valve stem, and an actuator.\",\n \"Examples of the closure member may embody a plug, ball, butterfly valve, and/or like implement that can contact the seat to prevent flow.\",\n \"In common construction, the actuator couples with the closure member (via the valve stem).\",\n \"The valve assembly may also incorporate a valve positioner with electrical and/or electro-pneumatic components.\",\n \"During operation, the valve positioner receives control signals from a controller that is part of a process control system (also “distributed control system” or “DCS”).\",\n \"These control signals define operating parameters for the valve assembly, namely, a position for the closure member relative to the seat.\",\n \"In response to the control signal, the valve positioner delivers a pneumatic signal that regulates instrument gas to pressurize the actuator in order to regulate this position.\",\n \"Cycling of a valve assembly can have many root causes.\",\n \"At the process level, the process control system may provide setpoint instructions that oscillate back-and-forth between various levels.\",\n \"The valve assembly will, in turn, modulate the position of the valve stem in response to these instructions.\",\n \"From the device level, the valve assembly may suffer from improperly tuned components (e.g., valve positioner) and/or have some type of physical problem that can cause cycling to occur on the valve assembly.\",\n \"Improper tuning (and calibration) of the valve positioner, for example, may translate the setpoint instructions into the pneumatic signal incorrectly and, thus, cause the valve stem to move to improper positions.\",\n \"On the other hand, physical problems can frustrate operation of the mechanical components on the valve assembly.\",\n \"Stick-slip describes a condition, for example, that results from high static friction and/or low kinetic friction between the valve stem and the valve packing material that surrounds the valve stem.\",\n \"This configuration can prevent leaks from inside the valve assembly.\",\n \"During operation, however, stick-slip can cause internal force, i.e., pressure on the closure member, to exceed normal operating levels in order to overcome the static friction that prevents movement of the valve stem.\",\n \"These internal forces, while desirable to induce movement of the valve stem, can cause the valve stem to overshoot its desired position.\",\n \"The process control system will attempt to correct this error.\",\n \"In response to overshoot, for example, the process control system often issues instructions for the valve assembly to modulate the valve stem in the opposite direction.\",\n \"However, it is likely that stick-slip will disrupt the movement in the opposite direction.\",\n \"The resulting errors will again prompt intervention from the control system to move the valve stem in the other direction.\",\n \"This process repeats itself, resulting in oscillation or cycling of the valve stem that can disrupt the stability of the process line as well as cause unnecessary wear on the valve assembly.\"\n ],\n [\n \"<SOH> BRIEF DESCRIPTION OF THE INVENTION <EOH>This disclosure describes improvements in valve diagnostics that can more accurately distinguish cycling that is induced by process and tuning issues from cycling that is induced by stick-slip.\",\n \"These improvements embody methods with steps that can quantify the amplitude of movement of the valve stem because of stick-slip.\",\n \"These embodiments compare this stick-slip amplitude to an amplitude of other operating parameters (e.g., setpoint) of the valve assembly.\",\n \"In this way, the embodiments can generate an output that indicates the contributing factor of cycling on the valve assembly.\",\n \"As noted herein, these contributing factors can identify whether cycling occurs due to stick-slip or that cycling occurs in response to a process control, namely, modulation of a control signal by the process control system to regulate process parameters on a process line.\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser.\",\n \"No.\",\n \"14/506,047, filed on Oct. 3, 2014, and entitled “METHOD FOR DETERMINING AMPLITUDE OF STICK-SLIP ON A VALVE ASSEMBLY AND IMPLEMENTATION THEREOF,” which is a continuation-in-part of U.S. patent application Ser.\",\n \"No.\",\n \"14/231,505, filed on Mar.\",\n \"31, 2014, and entitled “SYSTEM AND METHOD FOR DETECTING STICK-SLIP,” and which claims the benefit of priority to U.S.\",\n \"Provisional Application Ser.\",\n \"No.\",\n \"62/049,287, filed on Sep. 11, 2014, and entitled “METHOD FOR DETERMINING AMPLITUDE OF STICK-SLIP ON A VALVE ASSEMBLY AND IMPLEMENTATION THEREOF.” The content of these applications is incorporated by reference herein in its entirety.\",\n \"BACKGROUND The subject matter disclosed herein relates to processing of data that corresponds with operating parameters for a valve assembly, with particular discussion about methods that use this data to quantify movement of the valve stem due to stick-slip to distinguish the root cause and/or contributing factor of cycling on the valve assembly.\",\n \"Process lines may include many varieties of flow controls.\",\n \"These process lines typically transfer fluids for use in the chemical industry, refining industry, oil & gas recovery industry, and the like.\",\n \"Examples of the flow controls include pneumatic and electronic valve assemblies (collectively, “valve assemblies”) that regulate a flow of process fluid (e.g., gas and liquid).\",\n \"In conventional implementation, these valve assemblies have a number of components that work together to regulate flow of process fluid into and/or out of the process line.\",\n \"These components include a closure member, a seat, a valve stem, and an actuator.\",\n \"Examples of the closure member may embody a plug, ball, butterfly valve, and/or like implement that can contact the seat to prevent flow.\",\n \"In common construction, the actuator couples with the closure member (via the valve stem).\",\n \"The valve assembly may also incorporate a valve positioner with electrical and/or electro-pneumatic components.\",\n \"During operation, the valve positioner receives control signals from a controller that is part of a process control system (also “distributed control system” or “DCS”).\",\n \"These control signals define operating parameters for the valve assembly, namely, a position for the closure member relative to the seat.\",\n \"In response to the control signal, the valve positioner delivers a pneumatic signal that regulates instrument gas to pressurize the actuator in order to regulate this position.\",\n \"Cycling of a valve assembly can have many root causes.\",\n \"At the process level, the process control system may provide setpoint instructions that oscillate back-and-forth between various levels.\",\n \"The valve assembly will, in turn, modulate the position of the valve stem in response to these instructions.\",\n \"From the device level, the valve assembly may suffer from improperly tuned components (e.g., valve positioner) and/or have some type of physical problem that can cause cycling to occur on the valve assembly.\",\n \"Improper tuning (and calibration) of the valve positioner, for example, may translate the setpoint instructions into the pneumatic signal incorrectly and, thus, cause the valve stem to move to improper positions.\",\n \"On the other hand, physical problems can frustrate operation of the mechanical components on the valve assembly.\",\n \"Stick-slip describes a condition, for example, that results from high static friction and/or low kinetic friction between the valve stem and the valve packing material that surrounds the valve stem.\",\n \"This configuration can prevent leaks from inside the valve assembly.\",\n \"During operation, however, stick-slip can cause internal force, i.e., pressure on the closure member, to exceed normal operating levels in order to overcome the static friction that prevents movement of the valve stem.\",\n \"These internal forces, while desirable to induce movement of the valve stem, can cause the valve stem to overshoot its desired position.\",\n \"The process control system will attempt to correct this error.\",\n \"In response to overshoot, for example, the process control system often issues instructions for the valve assembly to modulate the valve stem in the opposite direction.\",\n \"However, it is likely that stick-slip will disrupt the movement in the opposite direction.\",\n \"The resulting errors will again prompt intervention from the control system to move the valve stem in the other direction.\",\n \"This process repeats itself, resulting in oscillation or cycling of the valve stem that can disrupt the stability of the process line as well as cause unnecessary wear on the valve assembly.\",\n \"BRIEF DESCRIPTION OF THE INVENTION This disclosure describes improvements in valve diagnostics that can more accurately distinguish cycling that is induced by process and tuning issues from cycling that is induced by stick-slip.\",\n \"These improvements embody methods with steps that can quantify the amplitude of movement of the valve stem because of stick-slip.\",\n \"These embodiments compare this stick-slip amplitude to an amplitude of other operating parameters (e.g., setpoint) of the valve assembly.\",\n \"In this way, the embodiments can generate an output that indicates the contributing factor of cycling on the valve assembly.\",\n \"As noted herein, these contributing factors can identify whether cycling occurs due to stick-slip or that cycling occurs in response to a process control, namely, modulation of a control signal by the process control system to regulate process parameters on a process line.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS Reference is now made briefly to the accompanying drawings, in which: FIG.\",\n \"1 depicts a flow diagram of an exemplary embodiment of a method for determining a contributing factor for cycling on a valve assembly; FIG.\",\n \"2 depicts a plot of data that exemplifies operation of a valve assembly that exhibits cycling due to stick-slip; FIG.\",\n \"3 depicts a plot of data that exemplifies operation of a valve assembly that exhibits cycling due to process controls; FIG.\",\n \"4 depicts a flow diagram of an exemplary embodiment of a method for determining a contributing factor for cycling on a valve assembly; FIG.\",\n \"5 depicts a flow diagram of an exemplary embodiment of a method for determining an amplitude that defines a change in position from a first position to a second position; FIG.\",\n \"6 depicts a flow diagram of an exemplary embodiment of a method for determining an amplitude that defines a change in setpoint from a first setpoint to a second setpoint; FIG.\",\n \"7.depicts a perspective view of an example of a valve assembly; FIG.\",\n \"8 depicts an exploded assembly view of an example of a valve positioner for use on the valve assembly of FIG.\",\n \"7; and FIG.\",\n \"9 depicts a schematic diagram of the valve assembly of FIG.\",\n \"7 as part of a process control system.\",\n \"Where applicable like reference characters designate identical or corresponding components and units throughout the several views, which are not to scale unless otherwise indicated.\",\n \"Moreover, the embodiments disclosed herein may include elements that appear in one or more of the several views or in combinations of the several views.\",\n \"DETAILED DESCRIPTION The discussion below offers a solution to determine the root cause of operating conditions on a valve assembly.\",\n \"Unlike previous techniques, which for the most part only detect or establish the “presence” of the operating condition, the embodiments herein can readily identify what is causing the operating condition to occur on the valve assembly.\",\n \"This information can enlighten the process owner/operator to better address the operating condition, effectively saving time and money by avoiding unnecessary repairs to valve assemblies that would not otherwise require maintenance.\",\n \"FIG.\",\n \"1 depicts a flow diagram of an exemplary embodiment of a method 100 for use on and/or as part of a valve assembly and a process control system.\",\n \"This diagram outlines steps that may embody instructions for one or more computer-implemented methods and/or programs.\",\n \"In FIG.\",\n \"1, the embodiment includes, at step 102, receiving an input with a sample set of data, the sample set comprising data samples collected and/or gathered from, e.g., the valve assembly.\",\n \"The embodiment also includes, at step 104, determining a first amplitude for the operating parameters and, at step 106, comparing the first amplitude to a second amplitude for the operating parameters.\",\n \"In one implementation, the embodiment can include, at step 108, generating an output that relates to a position of the first amplitude relative to the second amplitude, namely, a relative position of the first amplitude with respect to the second amplitude.\",\n \"As discussed more below, in one example the first amplitude has a value that quantifies an amount of stick-slip on the valve assembly.\",\n \"Broadly, the method 100 can configure the valve assembly and/or the process control system, generally, to process data in a way that associates characteristics of operation of the valve assembly with a root cause and/or a contributing factor.\",\n \"The data samples may correspond with operating parameters, for example, values for position, setpoint, and pressure for the valve assembly.\",\n \"These values are readily available and stored as part of normal operation and control of the valve assembly.\",\n \"In use, the method 100 can assign the first amplitude with a value that quantifies movement or “jump” of the valve stem that results from stick-slip on the valve assembly.\",\n \"This movement typically occurs between a first position and a second position.\",\n \"The method 100 can assign the second amplitude with a value that quantifies a change in the data for the setpoint and/or the position, for example, as between a first setpoint and a second setpoint.\",\n \"As noted above, the method 100 can ascertain the relationship or “relative position” of the first amplitude relative to the second amplitude, or vice versa.\",\n \"This relative position may convey that the first amplitude is greater than the second amplitude, that the first amplitude is less than the second amplitude, and/or that the first amplitude is the same as (also equal to) the second amplitude.\",\n \"Notably, the present disclosure contemplates that the method 100 can use the relationship between the first amplitude and the second amplitude to indicate the root cause of the operation of the valve assembly.\",\n \"This relationship may, for example, indicate that stick slip is the root cause of repeated up-and-down travel of the valve stem (also, “valve stem cycling” and/or “valve cycling”).\",\n \"On the other hand, the relationship may indicate that abnormal or “out-of-control” process conditions on the process line are the root cause of the valve stem cycling.\",\n \"Such process conditions often prompt the process control system to issue the command signal in a manner that is the root cause of the valve stem cycling.\",\n \"The method 100 can tailor the output to provide an alert or like indicator that instructs as to the root cause.\",\n \"This indicator can focus the response of an end user (e.g., process owner/operator) on the problem, e.g., to avoid unnecessary repairs to the valve assembly in the event that the root cause relates to abnormal process conditions.\",\n \"FIGS.\",\n \"2 and 3 depict plots of data for operating parameters of a valve assembly.\",\n \"The data reflects position POS, setpoint SP, and actuator pressure P (FIG.\",\n \"2), each collected over a time scale T. In each of the plots, the valve assembly exhibits cycling of the position POS.\",\n \"The plot of FIG.\",\n \"2 indicates operation of the valve assembly under stick-slip conditions.\",\n \"On the other hand, the plot of FIG.\",\n \"3 indicates operation of the valve assembly that shows signs of stick-slip (as identified, generally, by SLIP), but otherwise is cycling in response to abnormal conditions on the process line.\",\n \"The embodiments herein can process the data in each of FIGS.\",\n \"2 and 3 to identify the root cause of operation.\",\n \"These embodiments can, in one example, discern stick-slip cycling that corresponds with the distinctive pattern of the position POS data in the plot of FIG.\",\n \"2.This pattern has abrupt changes, or jumps, that have an amplitude that is sufficient to indicate the build-up of pressure and overshoot that occurs due to the inherent friction in the valve stem/packing interface.\",\n \"The embodiments can also discern that process cycling is the root cause of the pattern of position POS data in the plot of FIG.\",\n \"3.In this example, while the position POS data shows some areas of stick-slip (e.g., areas SLIP), the amplitude of the jump in the position POS data is not sufficient to associate the cycling issues with stick-slip.\",\n \"Rather, the pattern of the position POS data overwhelmingly follows the cycling of the setpoint SP, which may occur in response to process-related issues.\",\n \"FIG.\",\n \"4 depicts a flow diagram for an exemplary embodiment of a method 200 that can use the stick-slip amplitude to arrive at the root cause and/or contributing factors of valve stem cycling.\",\n \"The method 200 includes, at step 210, identifying a cycling condition on the valve assembly, which can instruct the method 200 (to return to step 202) to continue to process data until such condition exists on the valve assembly.\",\n \"The method 200 also includes, at step 212, determining an amplitude of one or more of the operating parameters that exhibit the cycling condition.\",\n \"The method 200 further includes, at step 214, identifying a stick-slip condition on the valve assembly and/or whether a stick-slip condition is present on the valve assembly.\",\n \"If the stick slip condition is not present, then the method 200 continues, at step 216, comparing an amplitude for a first operating parameter (A1) to an amplitude for a second operating parameter (A2).\",\n \"On the other hand, if the stick slip condition is present, then the method 200 continues, at step 204, determining a stick-slip amplitude (as noted, for example, in the method 300 below) and, at step 206, comparing the stick-slip amplitude to the amplitude of the first operating parameter and/or the amplitude for the second operating parameter.\",\n \"The generated output (e.g., at step 208) can reflect the relative position of the stick-slip amplitude, the amplitude of the first operating parameter, and the amplitude of the second operating parameter, as compared to one another in context of the steps outlined above and in Table 1 below.\",\n \"TABLE 1 Stick-Slip Relative Contributing Example Present Position Factor 1 No A1 > F1 × A2 Positioner Tuning 2 No A1 < F2 × A2 Process Control 3 Yes A2 > F3 × AST Process Control 4 Yes A2 < F4 × AST Stick-Slip As noted above, the method 200 is configured to identify one or more contributing factors that cause cycling on the valve assembly.\",\n \"In Table 1, the amplitudes A1, A2, and AST correspond with, respectively, the amplitude of position POS (FIGS.\",\n \"2 and 3), the amplitude of setpoint SP (FIGS.\",\n \"2 and 3), and the stick-slip amplitude of position POS (FIGS.\",\n \"2 and 3).\",\n \"The configurations of the method 200 may employ one or more factors, noted in the example of Table 1 above as a first factor F1, a second factor F2, a third factor F3, and a fourth factor F4.Values for the factors F1, F2, F3, and F4 can vary as to their effect within the processing of the data, as desired.\",\n \"In one implementation, the factors serve to increase and/or decrease the relative value of the amplitude A2 and/or AST, e.g., by a factor of 2, 4, 6, etc.\",\n \"In one example, the stick-slip amplitude is calculated in accordance with the steps outlined in the method 300 below (FIG.\",\n \"5).\",\n \"The steps of determining whether the stick-slip condition is present (e.g., at step 214) also analyze the data for the position POS and the setpoint SP.\",\n \"These steps may include, for example, determining a stick-slip condition metric, an example of which is noted in Equation (1) below, M ST = M P M S , Equation ( 1 ) in which MST is the stick-slip condition metric, MP is a position metric, and MS is a setpoint metric.\",\n \"The method 300 can include steps for comparing the stick-slip condition metric MST to a threshold criteria, which may identify a value for the ratio of the position metric MP to the setpoint metric MS that corresponds with and/or relates to stick-slip on the valve assembly.\",\n \"Examples of the value for the threshold criteria may be in a range from about 1 to about 3.In one implementation, if the stick-slip condition metric MST does not satisfy (e.g., is greater than, less than, and/or equal to) this threshold criteria, then the stick-slip condition is not present on the valve assembly.\",\n \"The output can convey that stick-slip is present and/or not present on the valve assembly.\",\n \"In one example, the value for the first amplitude corresponds with the stick-slip condition metric being less than or equal to the value for the threshold criteria.\",\n \"The method 300 can also include steps for calculating the position metric and/or the setpoint metric using “p-norm” functions, as set forth in Equations (2) and (3) below, M P = ∑ ( P i - P i - 1 ) X N X , Equation ( 2 ) M S = ∑ ( S i - S i - 1 ) X N X , Equation ( 3 ) in which Pi-1 is a first data sample for the position, Pi is a second data sample for the position that is adjacent the first data sample in the sample set, Si-1 is a first data sample for the setpoint, Si is a second data sample for the setpoint that is adjacent the first data sample in the sample set, N is a number of data samples in the sample set, and X is a p-norm parameter.\",\n \"Examples of the p-norm parameter can be in a range of from about 2 to about 6, but this disclosure does contemplate certain configurations of the methods herein in which the p-norm parameter falls outside of this range.\",\n \"FIG.\",\n \"5 illustrates a flow diagram of an exemplary embodiment of a method 300 that includes exemplary steps to arrive at values that quantify the amplitude of the “jump” shown in position (e.g., position POS of FIGS.\",\n \"2 and 3).\",\n \"This amplitude is also referred to herein (e.g., in FIG.\",\n \"4 above) as the stick-slip amplitude.\",\n \"These steps process the data samples in the data set; in one example, this process starts with the second data sample in the data set and ends with the last data sample in the data set.\",\n \"In FIG.\",\n \"5, the method 300 includes, at step 302, receiving an input with the sample set of data and, at step 304, selecting a data sample from the data set.\",\n \"The method 300 also includes, at step 306, determining a first sample interval and, at step 308, comparing the first sample interval to a first threshold value.\",\n \"If the first sample interval exceeds the first threshold value, then the method 300 can include, at step 310, incrementing a cycle variable and, at step 312, determining a total interval value.\",\n \"In one embodiment, the method 300 includes, at step 314, determining whether the last data sample has been processed and, if so, then the method 300 can include, at step 316, calculating the first amplitude (e.g., the stick-slip amplitude (AST)) using the values for the total interval value and/or the count variable.\",\n \"This disclosure contemplates implementation of the method 300 as an iterative process to process a plurality of data samples.\",\n \"In this connection, the method 300 can include steps for calculating one or more sample intervals, for example, one that occurs between data samples that are adjacent to one another in the sample set of data.\",\n \"The steps can also include steps for comparing each of the sample intervals to the first threshold value that relates to the position.\",\n \"Examples of the total interval value may be calculated by steps for adding together (and/or summing and/or aggregating) the one or more sample intervals to arrive at the total interval value.\",\n \"In one example, the total interval value may only include the one or more sample intervals that satisfy (also, where applicable, deviate from) the first threshold value for the data samples in the data set.\",\n \"This criteria may indicate that the one or more sample intervals are each greater than, less than, and/or equal to the first threshold value, as desired.\",\n \"In another example, the steps may include steps for incrementing the cycle variable for each of the one or more sample intervals that exceed the first threshold value.\",\n \"The steps may also arrive at the value for the first amplitude by incorporating one or both of the cycle variable and the total interval value, for example, where the value for the first amplitude is equal to the ratio of the total interval value to the cycle count.\",\n \"The method 300 can include steps that provide a value for the first sample interval as positive and/or non-negative (and/or greater than or equal to zero).\",\n \"This feature is useful to calculate the amplitude of the “jump” independent of the direction of movement of the valve stem—i.e., in both the positive direction and the negative direction.\",\n \"In one embodiment, the method 300 may include steps to calculate the first sample interval in accordance with Equation (4) below, I=|P2−P1|, Equation (4) in which I is a first sample interval among the one or more sample intervals, P1 is a previously-stored data sample, and P2 is a data sample that is adjacent the previously-stored data sample P1 in the sample set of data.\",\n \"The method 300 can also include steps to generate a value for the first threshold value that, like the value for the first sample interval, is also positive and/or non-negative.\",\n \"This value may reflect use of a “p-norm” function.\",\n \"In one embodiment, the method 300 may include steps to calculate the first threshold value in accordance with Equation (5) below, RMP position = ∑ ( P i - P i - 1 ) X N X , Equation ( 5 ) in which RMPPosition is the first threshold value, Pi-1 is a first data sample for the position in the sample set, Pi is a second data sample for the position that is adjacent the first data sample in the sample set, N is a number of data samples in the sample set, and X is a p-norm parameter.\",\n \"Examples of the p-norm parameter can be in a range of from about 2 to about 6, but this disclosure does contemplate certain configurations of the methods herein in which the p-norm parameters falls outside of this range.\",\n \"FIG.\",\n \"6 depicts a flow diagram of an exemplary embodiment of a method 400 with exemplary steps to determine a value for the position amplitude and the setpoint amplitude.\",\n \"The method 400 includes, at step 402, receiving an input with the sample set of data and, at step 404, selecting a first data sample (also “starting data sample”), for example, the first data sample among the data samples in the data set.\",\n \"The method 400 also includes, at step 406, identifying the starting data sample as a first vertex in the data set and, at step 408, comparing a first deviation with a second threshold value.\",\n \"The first deviation measures the difference between the value of the starting data sample and the value of other data samples in the data set.\",\n \"Notably, in one implementation, if no deviation is found in excess of the second threshold value, then the valve assembly is considered to be operating normally—i.e., the valve assembly is not cycling.\",\n \"On the other hand, if the first deviation is found in excess of the second threshold value, then the method 400 continues to include, at step 410, determining a direction of travel for the valve stem.\",\n \"The direction of travel is, typically, positive (or “increasing”) for situations in which the value of the first vertex is greater than the value of the starting data sample or negative (or “decreasing”) for situations in which the value of the first vertex is less than the value of the starting data sample.\",\n \"The direction of travel can influence further processing of the data samples.\",\n \"As also shown in FIG.\",\n \"6, the method 400 can include, at step 412, selecting a second data sample from the data set, often starting with a data sample that is adjacent or consecutive with the first vertex and ending with the last data sample in the data set.\",\n \"When the direction of travel is “increasing,” the method 400 continues, at step 414, comparing the selected data sample to the first vertex.\",\n \"If the selected data sample is greater than the first vertex, then the method 400 includes, at step 416, storing the selected data sample as the first vertex and continues back to step 412 to select a different data sample.\",\n \"If the selected data sample is less than the first vertex, then the method 400 can include, at step 418, comparing a second deviation between the selected data sample and the first vertex to the second threshold value.\",\n \"If the second deviation is less than the second threshold value, then the method continues to include, at step 420, incrementing a vertex count that identifies each occurrence of a vertex in the sample set of data, at step 422, identifying the selected data sample as the second vertex, and, at step 424, changing the direction of travel to decreasing.\",\n \"In one example, the vertex corresponds with a data sample from the sample set of data that has a relative position with respect to a previously-stored data sample from the sample set of data that exceeds the second threshold value.\",\n \"The method 400 can continue, at step 426, determining whether the selected data sample is the last data sample in the data set.\",\n \"If the selected data sample is the last data sample in the data set, then the method 400 can continue to include, at step 428 and/or step 430, determining a cycle count and/or a cycle amplitude, as set forth herein.\",\n \"In one embodiment, the cycle amplitude corresponds with the second amplitude, which in turn may correspond with an average of the relative positions from one vertex to another vertex for the sample set of data.\",\n \"Thus, the method 400 may include one or more steps for storing each of the deviations (e.g., the second deviation) between the adjacent data samples.\",\n \"When the direction of travel is “decreasing,” then the method 400 continues, at step 414, comparing the selected data sample to the first vertex.\",\n \"If the selected data sample is less than the first vertex, then the method 400 includes, at step 416, storing the selected data sample as the first vertex and continues back to step 412 to select a different data sample.\",\n \"If the selected data sample is greater than the first vertex, the method 400 can include, at step 418, comparing the second deviation between the selected data sample and the first vertex to the second threshold.\",\n \"If the second deviation is greater than the second threshold value, then the method continues to include, at step 420, incrementing a vertex count that identifies each occurrence of a vertex in the sample set of data.\",\n \"The method 400 also includes, at step 422, identifying the selected data sample as the first vertex, and, at step 424, changing the direction of travel to increasing.\",\n \"The method 400 can continue to include, at step 426, determining whether the selected data sample is the last data sample in the data set.\",\n \"If the selected data sample is the last data sample in the data set, then the method 400 can continue to include, at step 428 and/or step 430, determining a cycle count and/or determining a cycle amplitude, as set forth herein.\",\n \"FIGS.\",\n \"7, 8, and 9 depict an example of a valve assembly and a process control system (FIG.\",\n \"9) that can employ the embodiments disclosed herein.\",\n \"These examples are useful to regulate process fluids in industrial process lines typical of industries that focus on chemical production, refining production, and resource extraction.\",\n \"FIG.\",\n \"7 shows a perspective view of a valve positioner.\",\n \"FIG.\",\n \"8 provides an exploded assembly view of components of the valve assembly.\",\n \"FIG.\",\n \"9 illustrates a schematic diagram of the valve assembly 10 as part of a process control system.\",\n \"In FIG.\",\n \"7, the valve assembly 10 includes a valve positioner 12, an actuator 14, and a fluid coupling 16 with a body 18 that has a first inlet/outlet 20 and a second inlet/outlet 22.The fluid coupling 16 can also include a valve stem 24, which couples the actuator 14 with other valve members (e.g., a closure member) that is found in the interior to the body 18 and, thus, not shown in the present view.\",\n \"This structure can modulate a flow of process fluid FP between the inlet/outlets 20, 22.During operation, the valve positioner 12 regulates instrument gas (also, “pneumatic signal”) into the actuator 16 to manage the position of the valve members disposed in the body 18.The change in position modulates flow of the process fluid FP across the inlet/outlets 20, 22.FIG.\",\n \"8 depicts the valve positioner 12 in exploded form.\",\n \"As noted above, the valve positioner 12 has components that generate the pneumatic signal to the actuator 14 (FIG.\",\n \"7).\",\n \"The valve positioner 12 can have a plurality of positioner components (e.g., a converter component 26, a relay component 28, a processing component 30).\",\n \"The valve positioner 12 can also have a housing 32.One or more covers (e.g., a first cover 34 and a second cover 36) can secure with the housing 32 to form an enclosure about the positioner components 26, 28, 30.This enclosure protects the positioner components from conditions that prevail in the environment surrounding the valve assembly 10.The valve positioner 12 also includes one or more gauges (e.g., a first gauge 38 and a second gauge 40) that can provide an indication of the flow conditions (e.g., pressure, flow rate, etc.)\",\n \"of the instrument gas that the valve positioner 12 uses to operate the valve in the valve assembly 10.In one example, operation of the positioner components 26, 28, 30 maintain the position of the valve members in the body 18 (FIG.\",\n \"7) to modulate flow of the process fluid FP across the inlet/outlets 20, 22 (FIG.\",\n \"7).\",\n \"FIG.\",\n \"9 depicts a schematic diagram of the valve assembly 10.Examples of the valve members can include a closure member 42 that can move relative to a seat 44.As also shown in FIG.\",\n \"9, the valve assembly 10 integrates as part of a control system 46, typically by way of communication between the valve positioner 12 and a network system 48 via a network 50.Examples of the network 50 can transfer data, information, and signals by way of wired protocols (e.g., 4-20 mA, Foundation Fieldbus, etc.)\",\n \"and/or wireless protocols, many of which find use in a plant or factory automation environment.\",\n \"These protocols facilitate communication over the network 50 between the valve positioner 12, a process management server 52 (and like “apparatus”) that can run certain diagnostic and/or operative software and programs for data analysis, a process controller 53, a terminal 54, and/or an external server 56.During operation, the process controller 53 can execute one or more computer programs to deliver a command signal to the valve positioner 12.The command signal identifies a commanded position for the closure member 42.The valve positioner 12 uses the commanded position to modulate the instrument gas to the actuator 14 and, effectively, allow the closure member 42 to move relative to the seat 44.In one example, feedback in the assembly can provide the valve positioner 12 with a position of the valve stem 14.The position corresponds with the location and/or position of the closure member 42 relative to the seat 44.In one embodiment, the process management server 52 can comprise a processor configured to access a memory that has one or more executable instructions stored thereon, the executable instructions comprising one or more instructions that configure the server 52 (also, “apparatus”) and that may embody one or more of the method steps as set forth herein.\",\n \"The memory may be incorporated as part of the process management server 52 or, in one example, separate from the process management server 52.The data may reside on a data source, often locally in one or more memories on the valve positioner 12 (FIG.\",\n \"7), although this disclosure also contemplates configurations in which the data resides on the control system 46 (FIG.\",\n \"9).\",\n \"For example, the data source may integrate with the process management server 52 (FIG.\",\n \"9) and/or as part of the external server 56 (FIG.\",\n \"9).\",\n \"At the data source, the data may be arranged as one or more data sets that include one or more data samples.\",\n \"The data sets may be identified by an indicator (e.g., a date stamp, a time stamp, a date/time stamp, etc.)\",\n \"that relates to the chronological time at which the data samples in the data set were gathered and/or stored, e.g., in memory.\",\n \"For real-time use of the methods, the data samples may be read into a buffer and/or like configured storage medium that allows for ready access to the data samples to afford the methods with chronologically relevant data, taking into consideration necessary data processing time-lag.\",\n \"In one embodiment, the methods may include one or more steps for obtaining and/or retrieving the data from the data source.\",\n \"In view of the foregoing, the embodiments above deploy features that can determine the amplitude of jump that results from stick-slip during operation of the valve assembly.\",\n \"The embodiments are also configured to use this amplitude to identify the root cause or contributing factor to cycling of the valve stem.\",\n \"A technical effect is to trigger an alarm or an output, generally, that can alert the process owner/operator to the root cause and, thus, direct attention to specific solutions (i.e., process solutions) that can avoid unnecessary repairs and maintenance on the valve assemblies of the process line.\",\n \"The embodiments may be implemented on any device where relevant data is present and/or otherwise accessible.\",\n \"For example, the embodiments can be implemented as executable instructions (e.g., firmware, hardware, software, etc.)\",\n \"on the valve positioner.\",\n \"The valve positioner can transmit the output of the embodiments to a distributed control system, asset management system, independent monitoring computing device (e.g., a desktop computer, laptop computer, tablet, smartphone, mobile device, etc.).\",\n \"In another embodiment, the embodiments can obtain data from a historian (e.g., a repository, memory, etc.\",\n \"), and send to an independent diagnostic computing device.\",\n \"The historian is conventionally connected to the asset management system or distributed control system.\",\n \"The diagnostic computing device has all the capabilities of the monitoring computer and, often, the additional capability to execute executable instructions for the embodiment to process the given data.\",\n \"In another embodiment, the valve positioner is configured to send data by wires or wirelessly to the diagnostic computing device, as well as through peripheral and complimentary channels (e.g., through intermediate devices such as a DCS or may be connected directly to the diagnostic computer).\",\n \"One or more of the steps of the methods can be coded as one or more executable instructions (e.g., hardware, firmware, software, software programs, etc.).\",\n \"These executable instructions can be part of a computer-implemented method and/or program, which can be executed by a processor and/or processing device.\",\n \"The processor may be configured to execute these executable instructions, as well as to process inputs and to generate outputs, as set forth herein.\",\n \"For example, the software can run on the process device, the diagnostics server, and/or as software, application, or other aggregation of executable instructions on a separate computer, tablet, laptop, smart phone, wearable device, and like computing device.\",\n \"These devices can display the user interface (also, a “graphical user interface”) that allows the end user to interact with the software to view and input information and data as contemplated herein.\",\n \"The computing components (e.g., memory and processor) can embody hardware that incorporates with other hardware (e.g., circuitry) to form a unitary and/or monolithic unit devised to execute computer programs and/or executable instructions (e.g., in the form of firmware and software).\",\n \"Exemplary circuits of this type include discrete elements such as resistors, transistors, diodes, switches, and capacitors.\",\n \"Examples of a processor include microprocessors and other logic devices such as field programmable gate arrays (“FPGAs”) and application specific integrated circuits (“ASICs”).\",\n \"Memory includes volatile and non-volatile memory and can store executable instructions in the form of and/or including software (or firmware) instructions and configuration settings.\",\n \"Although all of the discrete elements, circuits, and devices function individually in a manner that is generally understood by those artisans that have ordinary skill in the electrical arts, it is their combination and integration into functional electrical groups and circuits that generally provide for the concepts that are disclosed and described herein.\",\n \"Aspects of the present disclosure may be embodied as a system, method, or computer program product.\",\n \"The embodiments may take the form of an entirely hardware embodiment, an entirely software embodiment (including firmware, software, etc.)\",\n \"or an embodiment combining software and hardware aspects that may all generally be referred to herein as a “circuit,” “module” or “system.” The computer program product may embody one or more non-transitory computer readable medium(s) having computer readable program code embodied thereon.\",\n \"Computer program code for carrying out operations for aspects of the present invention may be written in any combination of one or more programming languages, including an object oriented programming language and conventional procedural programming languages.\",\n \"Program code embodied on a computer readable medium may be transmitted using any appropriate medium, including but not limited to wireless, wireline, optical fiber cable, RF, etc., or any suitable combination of the foregoing.\",\n \"As used herein, an element or function recited in the singular and proceeded with the word “a” or “an” should be understood as not excluding plural said elements or functions, unless such exclusion is explicitly recited.\",\n \"Furthermore, references to “one embodiment” of the claimed invention should not be interpreted as excluding the existence of additional embodiments that also incorporate the recited features.\",\n \"This written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods.\",\n \"The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art.\",\n \"Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal language of the claims.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875702"}}},{"rowIdx":4494955,"cells":{"text":{"kind":"list like","value":[["TREATMENT INSTRUMENT FOR ENDOSCOPE","A treatment instrument for an endoscope is equipped with a sheath; and a balloon which is provided at the sheath, the balloon being configured to be expandable to an unfolded inflated shape from a folded initial shape by supplying a fluid, the balloon having a first region and a second region provided at both end portions in a longitudinal direction, and an intermediate section provided between the first region and the second region.","In the initial shape of the balloon, an amount of residual strain of the intermediate section is larger than the amount of residual strain of the first region and the amount of residual strain of the second region.","When an internal pressure of the balloon has a first internal pressure value, the first region and the second region are unfolded to be faster than the intermediate section, thereby having a greater diameter than the intermediate section."],["1.A treatment instrument for an endoscope, comprising: a sheath; and a balloon which is provided at the sheath, the balloon being configured to be expandable to an unfolded inflated shape from a folded initial shape by supplying a fluid, the balloon having a first region and a second region provided at both end portions in a longitudinal direction, and an intermediate section provided between the first region and the second region, wherein, in the initial shape of the balloon, an amount of residual strain of the intermediate section is larger than the amount of residual strain of the first region and the amount of residual strain of the second region, when an internal pressure of the balloon has a first internal pressure value, the first region and the second region are unfolded to be faster than the intermediate section, thereby having a greater diameter than the intermediate section, when the internal pressure of the balloon has a second internal pressure value greater than the first internal pressure value, the first region, the second region, and the intermediate section are unfolded to have the inflated shape, and when the internal pressure of the balloon is greater than a third internal pressure value greater than the second internal pressure value, a material forming the balloon stretches and expands to be greater than the diameter at the second internal pressure value.","2.The treatment instrument for the endoscope according to claim 1, wherein the balloon is folded to have a plurality of wing sections protruding radially outward in the initial shape, and the wing sections are folded by being wound around an axis of the balloon.","3.The treatment instrument for the endoscope according to claim 1, wherein the balloon is configured such that an outer diameter increases up to the second internal pressure value, depending on the inflation due to the progress of the unfolding rather than the expansion due to the stretching of the balloon material, and at an internal pressure greater than the third internal pressure value, the outer diameter increases, depending on the expansion due to the stretching of the balloon material rather than the inflation due to the progress of the unfolding.","4.The treatment instrument for the endoscope according to claim 1, wherein, in the initial shape, the outer diameter of the intermediate section is smaller than the outer diameters of the first region and the second region.","5.The treatment instrument for the endoscope according to claim 1, further comprising: a marker provided at a boundary between the intermediate section, the first region, and the second region.","6.The treatment instrument for the endoscope according to claim 5, wherein the marker is configured to be visible under an endoscope or X-ray fluoroscopy."],["<SOH> FIELD OF THE INVENTION <EOH>The present invention relates to a treatment instrument for an endoscope used when performing a dilation treatment on a stenosed part or an occluded part in a luminal organ of a living body."],["<SOH> SUMMARY OF THE INVENTION <EOH>A treatment instrument for an endoscope according to a first aspect of the present invention is equipped with a sheath; and a balloon which is provided at the sheath, the balloon being configured to be expandable to an unfolded inflated shape from a folded initial shape by supplying a fluid, the balloon having a first region and a second region provided at both end portions in a longitudinal direction, and an intermediate section provided between the first region and the second region.","In the initial shape of the balloon, an amount of residual strain of the intermediate section is larger than the amount of residual strain of the first region and the amount of residual strain of the second region.","When an internal pressure of the balloon has a first internal pressure value, the first region and the second region are unfolded faster than the intermediate section, thereby having a greater diameter than the intermediate section.","When the internal pressure of the balloon has a second internal pressure value greater than the first internal pressure value, the first region, the second region, and the intermediate section are unfolded to have the inflated shape.","When the internal pressure of the balloon is greater than a third internal pressure value greater than the second internal pressure value, a material forming the balloon stretches and expands to be greater than the diameter at the second internal pressure value.","According to a second aspect of the present invention, in the treatment instrument for an endoscope according to the first aspect, the balloon may be folded to have a plurality of wing sections protruding radially outward in the initial shape, and the wing sections may be folded by being wound around an axis of the balloon.","According to a third aspect of the present invention, in the treatment instrument for the endoscope according to the first aspect, the balloon may be configured such that an outer diameter increases up to the second internal pressure value, according to the inflation due to the progress of the unfolding rather than the expansion due to the stretching of the balloon material, and at an internal pressure greater than the third internal pressure value, the outer diameter increases, according to the expansion due to the stretching of the balloon material rather than the inflation due to the progress of the unfolding.","According to a fourth aspect of the present invention, in the treatment instrument for the endoscope according to any one of the first to third aspects, in the initial shape, the outer diameter of the intermediate section may be smaller than the outer diameters of the first region and the second region.","According to a fifth aspect of the present invention, the treatment instrument for the endoscope according to any one of the first to fourth aspects may further include markers provided at boundaries between the intermediate section, the first region, and the second region.","According to a fifth aspect of the present invention, in the treatment instrument for the endoscope according to the fourth aspect, the marker may be configured to be visible under an endoscope or X-ray fluoroscopy."],["This application is a continuation application based on a PCT International Application No.","PCT/JP2016/063985, filed on May 11, 2016, whose priority is claimed on Japanese Patent Application No.","2015-148480, filed Jul.","28, 2015.Both of the content of the PCT International Application and the Japanese Application are incorporated herein by reference.","FIELD OF THE INVENTION The present invention relates to a treatment instrument for an endoscope used when performing a dilation treatment on a stenosed part or an occluded part in a luminal organ of a living body.","DESCRIPTION OF RELATED ART Conventionally, a procedure for performing a dilation treatment or the like of a stenosed part or an occluded part (hereinafter referred to as “stenosed part or the like”) of the digestive tract while using an endoscope is performed.","In such a procedure, for example, a treatment instrument for an endoscope equipped with a balloon is used.","Specifically, the endoscope and the treatment instrument for the endoscope are inserted into the luminal organ of the living body together, and the balloon is inflated while the balloon is inserted into the stenosed part or the like to dilate the stenosed part or the like.","When the treatment instrument for an endoscope is disposed to dilate the stenosed part in the luminal organ of the living body in this manner, the balloon slides against the stenosed part or the like while the balloon is inflated, and the balloon may become detached from the part to be dilated.","In this case, it is necessary for a surgeon to temporarily deflate the balloon and perform positioning of the balloon again, which makes the operation complicated.","Therefore, in order to prevent the balloon from slipping with respect to the stenosed part or the like in a state of being inflated, a treatment instrument for an endoscope using a balloon having a small-diameter portion between a distal end portion and a proximal end portion in a state of being inflated has been proposed (see, for example, PCT International Publication No.","WO2010/042869, Japanese Unexamined Patent Application, First Publication No.","2010-4915, PCT International Publication No.","WO00/057945).","SUMMARY OF THE INVENTION A treatment instrument for an endoscope according to a first aspect of the present invention is equipped with a sheath; and a balloon which is provided at the sheath, the balloon being configured to be expandable to an unfolded inflated shape from a folded initial shape by supplying a fluid, the balloon having a first region and a second region provided at both end portions in a longitudinal direction, and an intermediate section provided between the first region and the second region.","In the initial shape of the balloon, an amount of residual strain of the intermediate section is larger than the amount of residual strain of the first region and the amount of residual strain of the second region.","When an internal pressure of the balloon has a first internal pressure value, the first region and the second region are unfolded faster than the intermediate section, thereby having a greater diameter than the intermediate section.","When the internal pressure of the balloon has a second internal pressure value greater than the first internal pressure value, the first region, the second region, and the intermediate section are unfolded to have the inflated shape.","When the internal pressure of the balloon is greater than a third internal pressure value greater than the second internal pressure value, a material forming the balloon stretches and expands to be greater than the diameter at the second internal pressure value.","According to a second aspect of the present invention, in the treatment instrument for an endoscope according to the first aspect, the balloon may be folded to have a plurality of wing sections protruding radially outward in the initial shape, and the wing sections may be folded by being wound around an axis of the balloon.","According to a third aspect of the present invention, in the treatment instrument for the endoscope according to the first aspect, the balloon may be configured such that an outer diameter increases up to the second internal pressure value, according to the inflation due to the progress of the unfolding rather than the expansion due to the stretching of the balloon material, and at an internal pressure greater than the third internal pressure value, the outer diameter increases, according to the expansion due to the stretching of the balloon material rather than the inflation due to the progress of the unfolding.","According to a fourth aspect of the present invention, in the treatment instrument for the endoscope according to any one of the first to third aspects, in the initial shape, the outer diameter of the intermediate section may be smaller than the outer diameters of the first region and the second region.","According to a fifth aspect of the present invention, the treatment instrument for the endoscope according to any one of the first to fourth aspects may further include markers provided at boundaries between the intermediate section, the first region, and the second region.","According to a fifth aspect of the present invention, in the treatment instrument for the endoscope according to the fourth aspect, the marker may be configured to be visible under an endoscope or X-ray fluoroscopy.","BRIEF DESCRIPTION OF THE DRAWINGS FIG.","1 is a cross-sectional view illustrating a treatment instrument for an endoscope according to an embodiment of the present invention.","FIG.","2 is a diagram illustrating an initial shape of a balloon in the treatment instrument for the endoscope according to an embodiment of the present invention.","FIG.","3 is a diagram illustrating an example of a procedure of forming the initial shape of the balloon in the treatment instrument for the endoscope according to an embodiment of the present invention.","FIG.","4 is a diagram illustrating an example of a procedure of forming an initial shape of the balloon in a treatment instrument for the endoscope according to an embodiment of the present invention.","FIG.","5 is a diagram illustrating an example of a procedure of forming the initial shape of the balloon in the treatment instrument for the endoscope according to an embodiment of the present invention.","FIG.","6 is a diagram illustrating an example of a procedure of forming the initial shape of the balloon in the treatment instrument for the endoscope according to an embodiment of the present invention.","FIG.","7 is a diagram illustrating one operation at the time of use of the treatment instrument for the endoscope according to an embodiment of the present invention.","FIG.","8 is a graph illustrating a relationship between an inner pressure and an outer diameter of the balloon in the treatment instrument for the endoscope according to an embodiment of the present invention.","FIG.","9 is a diagram illustrating a balloon at the first internal pressure value of the treatment instrument for the endoscope according to an embodiment of the present invention.","FIG.","10 is a diagram illustrating a balloon at a second internal pressure value of the treatment instrument for the endoscope according to an embodiment of the present invention.","FIG.","11 is an enlarged cross-sectional view illustrating part of the balloon in the treatment instrument for the endoscope according to an embodiment of the present invention.","FIG.","12 is a diagram illustrating a modified example of a distal end portion of the treatment instrument for the endoscope according to an embodiment of the present invention.","FIG.","13 is a diagram illustrating a modified example of the distal end portion of the treatment instrument for the endoscope according to an embodiment of the present invention.","DETAILED DESCRIPTION OF THE INVENTION An embodiment of the present invention will be described with reference to FIGS.","1 to 10.FIG.","1 is a cross-sectional view illustrating a treatment instrument for the endoscope 1 according to this embodiment.","The treatment instrument for the endoscope 1 is equipped with a sheath 2, a balloon 3, a connecting section 4, a distal end tip 5, and a stylet 6.The sheath 2 is a member which has a lumen 21, is long in a direction of a longitudinal axis L, and has flexibility.","A proximal end portion of the balloon 3 is tightly connected to the distal end portion of the sheath 2.The connecting section 4 is provided at the proximal end portion of the sheath 2.The connecting section 4 has a communication passage 41, which allows communication from the distal end to the proximal end along the longitudinal axis L, formed therein.","A lumen 21 of the sheath 2 communicates with the interior of the balloon 3 and a communication passage 41 of the connecting section 4.Therefore, the balloon 3 can be inflated, by supplying fluid to the balloon 3 via the communication passage 41 and the lumen 21, using a syringe or the like connected to the connecting section 4 or the like.","At the distal end portion of the sheath 2, a marker 22 capable of being checked under X-ray fluoroscopy is provided.","The balloon 3 is a bag-like member made up of, for example, a transparent film (for example, PEBAX (registered trademark) manufactured by ARKEMA Co.) made of polyamide resin.","The balloon 3 is folded by forming folds such that a plurality of wing sections extending in the longitudinal direction are formed after forming the material into a substantially cylindrical shape.","Hereinafter, a shape in which a diameter is reduced by this folding is referred to as an “initial shape” of the balloon 3.Details of the initial shape will be described later.","When the fluid is injected, the balloon 3 is deployed while unfolding by the wing section spreading, and inflates to a substantially cylindrical shape.","In this way, a shape after inflating substantially only by unfolding is hereinafter referred to as the “inflated shape” of the balloon 3.By removing the fluid injected into the inflated balloon 3, the balloon 3 can fold again and deflate in a dimension in a radial direction.","When the internal pressure of the balloon 3 having the inflated shape becomes a predetermined value or more, the balloon 3 expands to increase in diameter, while the constituent film stretches.","That is, the balloon 3 is a so-called semi-compliant balloon.","The distal end tip 5 is provided at the distal end of the treatment instrument for the endoscope 1.The distal end tip 5 is a substantially conical member extending in the direction of the longitudinal axis L, and its distal end portion is formed in a spherical shape in order to prevent damage to tissue when inserted into a body cavity.","The distal end portion of the balloon 3 is tightly fixed to the proximal end portion of the distal end tip 5.The stylet 6 is a shaft member, is inserted through the inside of the balloon 3, and extends along the longitudinal axis L from the distal end to the proximal end of the balloon 3.The distal end portion of the stylet 6 is connected to the proximal end of the distal end tip 5.The stylet 6 extends through the interior of the balloon 3, the lumen 21 of the sheath 2, and the communication passage 41 of the connecting section 4 and is fixed to the inner wall of the communication passage 41 of the connecting section 4.The stylet 6 is made of, for example, stainless steel, a nickel-titanium alloy or the like.","FIG.","2 illustrates the initial shape which is the shape of the balloon 3 before inflation.","In the initial configuration, the balloon 3 has a first region 31 adjacent to the distal end tip 5, a second region 32 adjacent to the sheath 2, and an intermediate section 33 between the first region 31 and the second region 32.An outer diameter D1 of the first region 31 and the second region 32 located at both ends in the longitudinal direction (the same as an axial direction of the balloon 3) of the balloon 3 is larger than an outer diameter D2 of the intermediate section 33.A method of a folding process for forming the aforementioned initial shape will be described.","The folding process of the balloon 3 is performed by combining the folding process illustrated in FIGS.","3 and 4 and the winding process illustrated in FIGS.","5 and 6.First, as illustrated in FIG.","3, a plurality of folding members 100 are brought into close contact with each other from the outer side of the balloon 3 in the radial direction.","Then, part of the balloon 3 is sandwiched between the folding members 100 and bent.","Thus, as illustrated in FIG.","4, a folding line 35 extending in the longitudinal direction of the balloon 3 is formed, and the balloon 3 has a plurality of wing sections 36 formed to protrude radially outward with the folding line 35 as a ridge line.","The number of wing sections 36 to be formed can be appropriately set by changing the number of folding members 100.Next, as illustrated in FIG.","5, a plurality of diaphragm members 101 are brought into close contact with each other from the radially outer side of the balloon 3 having the wing section 36 formed thereon.","By combining the plurality of the diaphragm members 101, a columnar internal space can be formed at the center portion thereof, and by appropriately relatively moving the plurality of diaphragm members 101, it is possible to change the dimension of the internal space in the radial direction.","When the plurality of diaphragm members 101 are relatively moved in the state of the balloon 3 being disposed in the internal space and the radial dimension of the internal space is gradually reduced, the diaphragm member 101 and the ridge line of the wing section 36 are first brought into contact with each other.","Thereafter, due to friction between the diaphragm member 101 and the wing section 36, the ridge line of the wing section 36 moves in the circumferential direction of the balloon 3, and the protruding direction of the wing section 36 is inclined in the circumferential direction.","Thereafter, as the radial dimension of the internal space is reduced, as illustrated in FIG.","6, the wing section 36 is wound around the axis of the balloon 3 about the stylet 6 to provide curling.","At this time, a plurality of valley sections 37 are formed to protrude radially inward at a base side of the wing section 36.The outer diameter of the curled balloon 3 is substantially the same as the inner diameter of the internal space formed by the diaphragm member 101.Accordingly, a pair of diaphragm members 101 having sizes corresponding to the first region 31, the second region 32, and the intermediate section 33 are prepared, respectively, and the diaphragm member 101 disposed around the first region 31 and the second region 32 is relatively moved until the inner diameter of the internal space becomes D1, and the diaphragm member 101 disposed around the intermediate section 33 is relatively moved until the inner diameter of the internal space becomes D2.Accordingly, it is possible to form the balloon 3 having the initial shape illustrated in FIG.","2.The above-described forming method of the initial shape is an example, and the method for forming the balloon according to the present embodiment is not limited thereto.","In the balloon 3 having this initial shape, the amount of residual strain differs between the first region 31, the second region 32 and the intermediate section 33, due to a difference in amount of deformation of the film caused by the folding process.","In the present specification, the “amount of residual strain” means the total amount of residual strain within a predetermined unit length range in the axial direction of the balloon.","When a certain region has a length equal to or longer than the unit length in the axial direction, the amount of residual strain per unit length calculated by averaging the amount of residual strain of each part is taken as the amount of residual strain in the region.","In the balloon 3 having the initial shape, the residual strain exclusively occurs in the portion of the folding line 35, which is the top portion of the wing section 36, and the valley section 37 bent so as to be convex toward the stylet 6 at the middle between two adjacent wing sections 36.As the amount of deformation occurring in the film constituting the balloon 3 due to the folding process increases, the residual strain generated in the folding line 35 and the valley section 37 increases.","Accordingly, the balloon 3 according to the present embodiment is configured so that the amount of residual strain is larger in the intermediate section 33 than in the first region 31 and the second region 32.In the aforementioned method for forming the initial shape, it is possible to adjust the amount of deformation of the balloon 3, for example, by adjusting the movement distance of the diaphragm member 101 inward in the radial direction of the balloon at the time of the winding process.","Therefore, in the balloon 3 according to the present embodiment, at the time of forming the initial shape, by setting the movement distance of the diaphragm member 101 disposed around the intermediate section 33 to be larger than the movement distance of the diaphragm member 101 disposed around the first region 31 and the second region 32, the amount of deformation of the intermediate section 33 is set to be larger than the amounts of deformation of the first region 31 and the second region 32.Therefore, the amount of residual strain in the intermediate section 33 can be set to be larger than the amount of residual strain in the first region 31 and the second region 32.The method for adjusting the amount of residual strain is not limited thereto, and for example, by setting the amount of driving force of the diaphragm member 101 at the time of winding process, or the amount of driving force or movement distance of the folding member 100 at the time of folding process, the amount of residual strain may be set to be larger at the intermediate section 33 than at the first region 31 and the second region 32.Further, the amount of residual strain may be adjusted by performing a heat treatment on the balloon 3 at the time of winding process or the folding processing.","An operation at the time of use of the treatment instrument for the endoscope 1 configured as described above will be described.","The treatment instrument for the endoscope 1 is introduced into the body of the patient P via a channel provided in the insertion portion 151 of the endoscope 150.As illustrated in FIG.","7, the user connects an inflator 200 to the connecting section 4, and inserts the inflator into the insertion portion 151 from a forceps port 152 of the endoscope 150.Thereafter, the endoscope 150 is inserted into the body of the patient P, and the distal end of the endoscope 150 is moved forward to a region in which the dilation procedure is performed, for example, to the vicinity of a predetermined part of the esophagus.","Connection between the treatment instrument for the endoscope 1 and the inflator 200 or insertion of the treatment instrument for the endoscope 1 into the endoscope 150 may be performed after the endoscope 150 is inserted into the body of the patient P. While observing a target site to be subjected to the dilation procedure with the endoscope 150, the user causes the instrument for an endoscope 1 to protrude from the endoscope 150 and inserts the distal end tip 5 into the target site.","The user further moves the treatment instrument for the endoscope 1 forward and holds the treatment instrument for the endoscope 1 so that the balloon 3 breaks through the target site, that is, the distal end portion and the proximal end portion of the balloon 3 are located on the distal side and the proximal side with respect to the target site, respectively.","The user actuates the inflator 200 to supply a fluid such as water or air to the balloon 3.The balloon 3 inflates while the internal pressure is raised by the supplied fluid.","Since the amount of residual strain of the intermediate section 33 is larger than that of the first region 31 and the second region 32, a larger force is required such that the folding line 35 and the valley section 37 linearly stretch and the wing section 36 spreads.","FIG.","8 is a graph illustrating a relationship between the internal pressure of the balloon 3 and the outer diameters of the first region 31, the second region 32, and the intermediate section 33.In a state in which the internal pressure of the balloon 3 has reached a predetermined first internal pressure value P1 due to the supply of the fluid, in the first region 31 and the second region 32, unfolding has progressed faster than at the intermediate section 33.On the other hand, since the progress of unfolding of the intermediate section 33 is slow, the diameter of the intermediate section 33 is smaller than that of the first region 31 and the second region 32, and the balloon 3 overall has a dumbbell shape as illustrated in FIG.","9.Therefore, even if the balloon 3 slips due to mucus or the like on the surface of the luminal organ, the first region 31 and the second region 32 serve as an anchor to suppress the movement, and thereby a situation such as detachment of the balloon 3 from the target site St is suitably prevented.","In FIG.","9, the shape of the intermediate section 33 illustrates the same state as the initial shape, but this is an example, and it is obvious that the shape may be a state when the intermediate section starts to inflate.","When the internal pressure of the balloon 3 reaches the second internal pressure value P2, which is higher than the first internal pressure value, the folding is released at all of the first region 31, the second region 32, and the intermediate section 33, and the balloon 3 is restored to almost a substantially cylindrical shape (inflated shape) before the folding process as illustrated in FIG.","10.At this time, the radial dimensions of the first region 31, the second region 32, and the intermediate section 33 are the same or substantially the same.","Since the intermediate section 33 inflates to substantially the same diameter as the first region 31 and the second region 32, the target site St can be sufficiently dilated.","At the second internal pressure value P2, the film itself forming the balloon 3 is hardly stretched.","Here, since the balloon 3 is a semi-compliant type, by setting the internal pressure to be larger than a third internal pressure value P3 which is higher than the second internal pressure value as necessary, the whole of the balloon 3 is further inflated, while stretching the material, and a larger dilation force can be applied to the target site St.","In more detail, since the material forming the balloon 3 itself hardly stretches until the internal pressure of the balloon 3 reaches the second internal pressure value P2, the balloon 3 inflates exclusively depending on the progress of unfolding, and the outer diameters of the first region 31, the second region 32, and the intermediate section 33 increase.","Since the folding is almost released after the internal pressure of the balloon 3 reaches the second internal pressure value P2, even if the internal pressure rises, almost no increase in the external diameter occurs.","When the internal pressure of the balloon 3 rises further and becomes larger than the third internal pressure value P3, the film material forming the balloon 3 starts to stretch.","However, since expansion due to the progress of unfolding hardly occurs, the outer diameters of the first region 31, the second region 32, and the intermediate section 33 increase exclusively depending on the stretching of the film material.","As described above, according to the treatment instrument for the endoscope 1 of the present embodiment, the amount of residual strain of the intermediate section 33 in the balloon 3 is set to be larger than the amount of residual strain of the first region 31 and the second region 32 disposed with the intermediate section 33 interposed therebetween.","As a result, at the first internal pressure value P1, a dumbbell shape in which the first region 31 and the second region 32 have inflated to have an outer diameter larger than that of the intermediate section 33 is obtained, and it is possible to suitably prevent the balloon from being detached or displaced from the target site St during the treatment process on the target site St. Further, at the second internal pressure value P2, the intermediate section 33 can be inflated to substantially the same diameter as the first region 31 and the second region 32, and the target site St can be sufficiently dilated.","As a result, prevention of misalignment with respect to the target site and sufficient expansion of the target site are compatible, and it is possible to perform an appropriate expansion treatment at the target site such as a stenosed part.","In the present embodiment, the first internal pressure value and the second internal pressure value can be set to desired values, by appropriately setting the amounts of residual strain of the first region 31, the second region 32, and the intermediate section 33.The second internal pressure value may be set on the basis of the pressure intended to act on the target site, and may be, for example, 3 atmospheres (atm).","It is preferable to set the first internal pressure value to be sufficiently lower than the second internal pressure value, for example, 0.5 atm, so that the positional deviation prevention effect can be exhibited at an early stage.","Further, in the aforementioned example, the description has been given of a case where the outer diameter in the initial shape is set to be different between the first region 31, the second region 32, and the intermediate section to set amounts of residual strain of both regions different from each other.","However, the method for setting different amounts of residual strain for both is not limited thereto.","Several methods for generating different amounts of residual strain in the first region 31, the second region 32 and the intermediate section 33 will be described below.","First, by changing an angle formed by the material of the balloon with the folding line 35 between the intermediate section and the other region, the amount of residual strain can be adjusted.","That is, in the folding process, as an angle θ1 illustrated in FIG.","11 decreases, the amount of residual strain increases.","The angle θ1 can be changed, for example, by changing the shape of the surface in contact with the balloon 3 in the folding member 100 described above.","Further, when the radius of curvature of the top of the wing section increases, the amount of residual strain decreases.","Therefore, by forming the folding line 35 at the intermediate section and increasing the radius of curvature of the top of the wing section to such an extent that no ridge line is formed which is clear in the other region, the amount of residual strain at the intermediate section can be relatively increased.","Also, by changing the number of wing sections in the intermediate section and the other region, the amount of residual strain can be adjusted.","As the number of wing sections increases, since the number of folding lines 35 and valley sections 37 increases, the amount of residual strain increases.","In addition, when forming the initial shape, if the diameter is reduced without forming the wing sections, a large number of irregular folding lines folded to be weaker than the folding line 35 are formed.","Thus, the amount of residual strain decreases.","Therefore, it is possible to relatively increase the amount of residual strain in the intermediate section, also by forming the wing section only in the intermediate section and not forming the wing section in the other regions.","Further, when forming the initial shape, if the wing section is pulled and wound while applying tension, the valley section is strongly bent and the amount of residual strain increases.","Therefore, by applying a tension only to the intermediate section or by applying a larger tension to the intermediate section, the amount of residual strain at the intermediate section can be relatively increased.","Furthermore, when incorporating heat treatment at the time of forming the initial shape, the amount of residual strain can be changed, by switching between the presence or absence of heat treatment and the temperature conditions.","In general, the amount of residual strain is higher when the heat treatment is performed, and the amount of residual strain is higher when the heat treatment is performed at a higher temperature.","Therefore, by applying a heat treatment only to the intermediate section or by setting the temperature of the heat treatment at the intermediate section to be higher than at other regions, the amount of residual strain at the intermediate section can be relatively increased.","Further, when the material of the balloon 3 is partially modified, the amount of residual strain at the intermediate section can be set to be relatively large without changing the process at the time of forming the initial shape for each region.","For example, by forming a balloon with a crosslinked polymer and accelerating crosslinking by irradiating only the intermediate section with an electron beam, the rigidity of the intermediate section is relatively enhanced.","When a uniform initial shape forming process is performed on this balloon, since the degree of plastic deformation becomes strong at the intermediate section, the amount of residual strain increases.","Each of the above-described methods can be appropriately combined, respectively.","Since the amounts of residual strain of each region change complicatedly in combination, for example, it is also possible to set the amount of residual strain of the intermediate section 33 to be relatively large, while setting the outer diameters of the first region 31, the second region 32, and the intermediate section 33 in the initial shape to be the same or substantially the same.","Although the embodiment of the present invention has been described in detail with reference to the drawings, the specific configuration is not limited to this embodiment, and changes in design and the like within the scope not departing from the gist of the present invention are also included.","Further, the constituent elements described in each of the embodiments and each of the modified examples described above can be configured by being appropriately combined.","For example, in the above-described embodiment, the example in which the stylet 6 is inserted into the balloon 3 has been described.","However, a configuration in which a sheath having a guide wire lumen and a fluid supply lumen is inserted through the balloon instead of the stylet may be provided.","In this case, the guide wire inserted into the guide wire lumen can be made to protrude to the distal end of the balloon, and can be used as a guide for breaking through a site in which a strong constriction occurs, an occlusion part or the like.","Further, as in the modified example illustrated in FIG.","12, a marker 40 that is visible under endoscope observation or under X-ray fluoroscopy may be provided at a boundary between the first region 31, the second region 32, and the intermediate section 33.With this configuration, the balloon can be disposed at a more appropriate position with respect to the target site, and the positional deviation prevention effect can be reliably exerted.","As long as the boundary between the intermediate section and another region can be recognized, the marker 40 may be provided in either the intermediate section or the other region.","Further, in the initial shape of the balloon, when the outer diameter difference between the intermediate section and another region is large, a step caused by the outer diameter difference can be used as a marker that can be visually recognized under endoscope observation.","Furthermore, at the time of shipping of the treatment instrument for the endoscope of the present invention, as illustrated in a modified example illustrated in FIG.","13, the balloon 3 may be covered with a cover 70 having an internal space corresponding to the initial shape.","In this way, it is possible to suitably maintain the initial shape until usage and to suppress change in amount of residual strain or the like.","Further, in the above embodiment, an example in which the balloon is a semi-compliant type has been described.","However, a so-called non-compliant type balloon in which, even if the internal pressure is equal to or higher than the second internal pressure value, the material forming the balloon does not substantially stretch, may be used."]],"string":"[\n [\n \"TREATMENT INSTRUMENT FOR ENDOSCOPE\",\n \"A treatment instrument for an endoscope is equipped with a sheath; and a balloon which is provided at the sheath, the balloon being configured to be expandable to an unfolded inflated shape from a folded initial shape by supplying a fluid, the balloon having a first region and a second region provided at both end portions in a longitudinal direction, and an intermediate section provided between the first region and the second region.\",\n \"In the initial shape of the balloon, an amount of residual strain of the intermediate section is larger than the amount of residual strain of the first region and the amount of residual strain of the second region.\",\n \"When an internal pressure of the balloon has a first internal pressure value, the first region and the second region are unfolded to be faster than the intermediate section, thereby having a greater diameter than the intermediate section.\"\n ],\n [\n \"1.A treatment instrument for an endoscope, comprising: a sheath; and a balloon which is provided at the sheath, the balloon being configured to be expandable to an unfolded inflated shape from a folded initial shape by supplying a fluid, the balloon having a first region and a second region provided at both end portions in a longitudinal direction, and an intermediate section provided between the first region and the second region, wherein, in the initial shape of the balloon, an amount of residual strain of the intermediate section is larger than the amount of residual strain of the first region and the amount of residual strain of the second region, when an internal pressure of the balloon has a first internal pressure value, the first region and the second region are unfolded to be faster than the intermediate section, thereby having a greater diameter than the intermediate section, when the internal pressure of the balloon has a second internal pressure value greater than the first internal pressure value, the first region, the second region, and the intermediate section are unfolded to have the inflated shape, and when the internal pressure of the balloon is greater than a third internal pressure value greater than the second internal pressure value, a material forming the balloon stretches and expands to be greater than the diameter at the second internal pressure value.\",\n \"2.The treatment instrument for the endoscope according to claim 1, wherein the balloon is folded to have a plurality of wing sections protruding radially outward in the initial shape, and the wing sections are folded by being wound around an axis of the balloon.\",\n \"3.The treatment instrument for the endoscope according to claim 1, wherein the balloon is configured such that an outer diameter increases up to the second internal pressure value, depending on the inflation due to the progress of the unfolding rather than the expansion due to the stretching of the balloon material, and at an internal pressure greater than the third internal pressure value, the outer diameter increases, depending on the expansion due to the stretching of the balloon material rather than the inflation due to the progress of the unfolding.\",\n \"4.The treatment instrument for the endoscope according to claim 1, wherein, in the initial shape, the outer diameter of the intermediate section is smaller than the outer diameters of the first region and the second region.\",\n \"5.The treatment instrument for the endoscope according to claim 1, further comprising: a marker provided at a boundary between the intermediate section, the first region, and the second region.\",\n \"6.The treatment instrument for the endoscope according to claim 5, wherein the marker is configured to be visible under an endoscope or X-ray fluoroscopy.\"\n ],\n [\n \"<SOH> FIELD OF THE INVENTION <EOH>The present invention relates to a treatment instrument for an endoscope used when performing a dilation treatment on a stenosed part or an occluded part in a luminal organ of a living body.\"\n ],\n [\n \"<SOH> SUMMARY OF THE INVENTION <EOH>A treatment instrument for an endoscope according to a first aspect of the present invention is equipped with a sheath; and a balloon which is provided at the sheath, the balloon being configured to be expandable to an unfolded inflated shape from a folded initial shape by supplying a fluid, the balloon having a first region and a second region provided at both end portions in a longitudinal direction, and an intermediate section provided between the first region and the second region.\",\n \"In the initial shape of the balloon, an amount of residual strain of the intermediate section is larger than the amount of residual strain of the first region and the amount of residual strain of the second region.\",\n \"When an internal pressure of the balloon has a first internal pressure value, the first region and the second region are unfolded faster than the intermediate section, thereby having a greater diameter than the intermediate section.\",\n \"When the internal pressure of the balloon has a second internal pressure value greater than the first internal pressure value, the first region, the second region, and the intermediate section are unfolded to have the inflated shape.\",\n \"When the internal pressure of the balloon is greater than a third internal pressure value greater than the second internal pressure value, a material forming the balloon stretches and expands to be greater than the diameter at the second internal pressure value.\",\n \"According to a second aspect of the present invention, in the treatment instrument for an endoscope according to the first aspect, the balloon may be folded to have a plurality of wing sections protruding radially outward in the initial shape, and the wing sections may be folded by being wound around an axis of the balloon.\",\n \"According to a third aspect of the present invention, in the treatment instrument for the endoscope according to the first aspect, the balloon may be configured such that an outer diameter increases up to the second internal pressure value, according to the inflation due to the progress of the unfolding rather than the expansion due to the stretching of the balloon material, and at an internal pressure greater than the third internal pressure value, the outer diameter increases, according to the expansion due to the stretching of the balloon material rather than the inflation due to the progress of the unfolding.\",\n \"According to a fourth aspect of the present invention, in the treatment instrument for the endoscope according to any one of the first to third aspects, in the initial shape, the outer diameter of the intermediate section may be smaller than the outer diameters of the first region and the second region.\",\n \"According to a fifth aspect of the present invention, the treatment instrument for the endoscope according to any one of the first to fourth aspects may further include markers provided at boundaries between the intermediate section, the first region, and the second region.\",\n \"According to a fifth aspect of the present invention, in the treatment instrument for the endoscope according to the fourth aspect, the marker may be configured to be visible under an endoscope or X-ray fluoroscopy.\"\n ],\n [\n \"This application is a continuation application based on a PCT International Application No.\",\n \"PCT/JP2016/063985, filed on May 11, 2016, whose priority is claimed on Japanese Patent Application No.\",\n \"2015-148480, filed Jul.\",\n \"28, 2015.Both of the content of the PCT International Application and the Japanese Application are incorporated herein by reference.\",\n \"FIELD OF THE INVENTION The present invention relates to a treatment instrument for an endoscope used when performing a dilation treatment on a stenosed part or an occluded part in a luminal organ of a living body.\",\n \"DESCRIPTION OF RELATED ART Conventionally, a procedure for performing a dilation treatment or the like of a stenosed part or an occluded part (hereinafter referred to as “stenosed part or the like”) of the digestive tract while using an endoscope is performed.\",\n \"In such a procedure, for example, a treatment instrument for an endoscope equipped with a balloon is used.\",\n \"Specifically, the endoscope and the treatment instrument for the endoscope are inserted into the luminal organ of the living body together, and the balloon is inflated while the balloon is inserted into the stenosed part or the like to dilate the stenosed part or the like.\",\n \"When the treatment instrument for an endoscope is disposed to dilate the stenosed part in the luminal organ of the living body in this manner, the balloon slides against the stenosed part or the like while the balloon is inflated, and the balloon may become detached from the part to be dilated.\",\n \"In this case, it is necessary for a surgeon to temporarily deflate the balloon and perform positioning of the balloon again, which makes the operation complicated.\",\n \"Therefore, in order to prevent the balloon from slipping with respect to the stenosed part or the like in a state of being inflated, a treatment instrument for an endoscope using a balloon having a small-diameter portion between a distal end portion and a proximal end portion in a state of being inflated has been proposed (see, for example, PCT International Publication No.\",\n \"WO2010/042869, Japanese Unexamined Patent Application, First Publication No.\",\n \"2010-4915, PCT International Publication No.\",\n \"WO00/057945).\",\n \"SUMMARY OF THE INVENTION A treatment instrument for an endoscope according to a first aspect of the present invention is equipped with a sheath; and a balloon which is provided at the sheath, the balloon being configured to be expandable to an unfolded inflated shape from a folded initial shape by supplying a fluid, the balloon having a first region and a second region provided at both end portions in a longitudinal direction, and an intermediate section provided between the first region and the second region.\",\n \"In the initial shape of the balloon, an amount of residual strain of the intermediate section is larger than the amount of residual strain of the first region and the amount of residual strain of the second region.\",\n \"When an internal pressure of the balloon has a first internal pressure value, the first region and the second region are unfolded faster than the intermediate section, thereby having a greater diameter than the intermediate section.\",\n \"When the internal pressure of the balloon has a second internal pressure value greater than the first internal pressure value, the first region, the second region, and the intermediate section are unfolded to have the inflated shape.\",\n \"When the internal pressure of the balloon is greater than a third internal pressure value greater than the second internal pressure value, a material forming the balloon stretches and expands to be greater than the diameter at the second internal pressure value.\",\n \"According to a second aspect of the present invention, in the treatment instrument for an endoscope according to the first aspect, the balloon may be folded to have a plurality of wing sections protruding radially outward in the initial shape, and the wing sections may be folded by being wound around an axis of the balloon.\",\n \"According to a third aspect of the present invention, in the treatment instrument for the endoscope according to the first aspect, the balloon may be configured such that an outer diameter increases up to the second internal pressure value, according to the inflation due to the progress of the unfolding rather than the expansion due to the stretching of the balloon material, and at an internal pressure greater than the third internal pressure value, the outer diameter increases, according to the expansion due to the stretching of the balloon material rather than the inflation due to the progress of the unfolding.\",\n \"According to a fourth aspect of the present invention, in the treatment instrument for the endoscope according to any one of the first to third aspects, in the initial shape, the outer diameter of the intermediate section may be smaller than the outer diameters of the first region and the second region.\",\n \"According to a fifth aspect of the present invention, the treatment instrument for the endoscope according to any one of the first to fourth aspects may further include markers provided at boundaries between the intermediate section, the first region, and the second region.\",\n \"According to a fifth aspect of the present invention, in the treatment instrument for the endoscope according to the fourth aspect, the marker may be configured to be visible under an endoscope or X-ray fluoroscopy.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS FIG.\",\n \"1 is a cross-sectional view illustrating a treatment instrument for an endoscope according to an embodiment of the present invention.\",\n \"FIG.\",\n \"2 is a diagram illustrating an initial shape of a balloon in the treatment instrument for the endoscope according to an embodiment of the present invention.\",\n \"FIG.\",\n \"3 is a diagram illustrating an example of a procedure of forming the initial shape of the balloon in the treatment instrument for the endoscope according to an embodiment of the present invention.\",\n \"FIG.\",\n \"4 is a diagram illustrating an example of a procedure of forming an initial shape of the balloon in a treatment instrument for the endoscope according to an embodiment of the present invention.\",\n \"FIG.\",\n \"5 is a diagram illustrating an example of a procedure of forming the initial shape of the balloon in the treatment instrument for the endoscope according to an embodiment of the present invention.\",\n \"FIG.\",\n \"6 is a diagram illustrating an example of a procedure of forming the initial shape of the balloon in the treatment instrument for the endoscope according to an embodiment of the present invention.\",\n \"FIG.\",\n \"7 is a diagram illustrating one operation at the time of use of the treatment instrument for the endoscope according to an embodiment of the present invention.\",\n \"FIG.\",\n \"8 is a graph illustrating a relationship between an inner pressure and an outer diameter of the balloon in the treatment instrument for the endoscope according to an embodiment of the present invention.\",\n \"FIG.\",\n \"9 is a diagram illustrating a balloon at the first internal pressure value of the treatment instrument for the endoscope according to an embodiment of the present invention.\",\n \"FIG.\",\n \"10 is a diagram illustrating a balloon at a second internal pressure value of the treatment instrument for the endoscope according to an embodiment of the present invention.\",\n \"FIG.\",\n \"11 is an enlarged cross-sectional view illustrating part of the balloon in the treatment instrument for the endoscope according to an embodiment of the present invention.\",\n \"FIG.\",\n \"12 is a diagram illustrating a modified example of a distal end portion of the treatment instrument for the endoscope according to an embodiment of the present invention.\",\n \"FIG.\",\n \"13 is a diagram illustrating a modified example of the distal end portion of the treatment instrument for the endoscope according to an embodiment of the present invention.\",\n \"DETAILED DESCRIPTION OF THE INVENTION An embodiment of the present invention will be described with reference to FIGS.\",\n \"1 to 10.FIG.\",\n \"1 is a cross-sectional view illustrating a treatment instrument for the endoscope 1 according to this embodiment.\",\n \"The treatment instrument for the endoscope 1 is equipped with a sheath 2, a balloon 3, a connecting section 4, a distal end tip 5, and a stylet 6.The sheath 2 is a member which has a lumen 21, is long in a direction of a longitudinal axis L, and has flexibility.\",\n \"A proximal end portion of the balloon 3 is tightly connected to the distal end portion of the sheath 2.The connecting section 4 is provided at the proximal end portion of the sheath 2.The connecting section 4 has a communication passage 41, which allows communication from the distal end to the proximal end along the longitudinal axis L, formed therein.\",\n \"A lumen 21 of the sheath 2 communicates with the interior of the balloon 3 and a communication passage 41 of the connecting section 4.Therefore, the balloon 3 can be inflated, by supplying fluid to the balloon 3 via the communication passage 41 and the lumen 21, using a syringe or the like connected to the connecting section 4 or the like.\",\n \"At the distal end portion of the sheath 2, a marker 22 capable of being checked under X-ray fluoroscopy is provided.\",\n \"The balloon 3 is a bag-like member made up of, for example, a transparent film (for example, PEBAX (registered trademark) manufactured by ARKEMA Co.) made of polyamide resin.\",\n \"The balloon 3 is folded by forming folds such that a plurality of wing sections extending in the longitudinal direction are formed after forming the material into a substantially cylindrical shape.\",\n \"Hereinafter, a shape in which a diameter is reduced by this folding is referred to as an “initial shape” of the balloon 3.Details of the initial shape will be described later.\",\n \"When the fluid is injected, the balloon 3 is deployed while unfolding by the wing section spreading, and inflates to a substantially cylindrical shape.\",\n \"In this way, a shape after inflating substantially only by unfolding is hereinafter referred to as the “inflated shape” of the balloon 3.By removing the fluid injected into the inflated balloon 3, the balloon 3 can fold again and deflate in a dimension in a radial direction.\",\n \"When the internal pressure of the balloon 3 having the inflated shape becomes a predetermined value or more, the balloon 3 expands to increase in diameter, while the constituent film stretches.\",\n \"That is, the balloon 3 is a so-called semi-compliant balloon.\",\n \"The distal end tip 5 is provided at the distal end of the treatment instrument for the endoscope 1.The distal end tip 5 is a substantially conical member extending in the direction of the longitudinal axis L, and its distal end portion is formed in a spherical shape in order to prevent damage to tissue when inserted into a body cavity.\",\n \"The distal end portion of the balloon 3 is tightly fixed to the proximal end portion of the distal end tip 5.The stylet 6 is a shaft member, is inserted through the inside of the balloon 3, and extends along the longitudinal axis L from the distal end to the proximal end of the balloon 3.The distal end portion of the stylet 6 is connected to the proximal end of the distal end tip 5.The stylet 6 extends through the interior of the balloon 3, the lumen 21 of the sheath 2, and the communication passage 41 of the connecting section 4 and is fixed to the inner wall of the communication passage 41 of the connecting section 4.The stylet 6 is made of, for example, stainless steel, a nickel-titanium alloy or the like.\",\n \"FIG.\",\n \"2 illustrates the initial shape which is the shape of the balloon 3 before inflation.\",\n \"In the initial configuration, the balloon 3 has a first region 31 adjacent to the distal end tip 5, a second region 32 adjacent to the sheath 2, and an intermediate section 33 between the first region 31 and the second region 32.An outer diameter D1 of the first region 31 and the second region 32 located at both ends in the longitudinal direction (the same as an axial direction of the balloon 3) of the balloon 3 is larger than an outer diameter D2 of the intermediate section 33.A method of a folding process for forming the aforementioned initial shape will be described.\",\n \"The folding process of the balloon 3 is performed by combining the folding process illustrated in FIGS.\",\n \"3 and 4 and the winding process illustrated in FIGS.\",\n \"5 and 6.First, as illustrated in FIG.\",\n \"3, a plurality of folding members 100 are brought into close contact with each other from the outer side of the balloon 3 in the radial direction.\",\n \"Then, part of the balloon 3 is sandwiched between the folding members 100 and bent.\",\n \"Thus, as illustrated in FIG.\",\n \"4, a folding line 35 extending in the longitudinal direction of the balloon 3 is formed, and the balloon 3 has a plurality of wing sections 36 formed to protrude radially outward with the folding line 35 as a ridge line.\",\n \"The number of wing sections 36 to be formed can be appropriately set by changing the number of folding members 100.Next, as illustrated in FIG.\",\n \"5, a plurality of diaphragm members 101 are brought into close contact with each other from the radially outer side of the balloon 3 having the wing section 36 formed thereon.\",\n \"By combining the plurality of the diaphragm members 101, a columnar internal space can be formed at the center portion thereof, and by appropriately relatively moving the plurality of diaphragm members 101, it is possible to change the dimension of the internal space in the radial direction.\",\n \"When the plurality of diaphragm members 101 are relatively moved in the state of the balloon 3 being disposed in the internal space and the radial dimension of the internal space is gradually reduced, the diaphragm member 101 and the ridge line of the wing section 36 are first brought into contact with each other.\",\n \"Thereafter, due to friction between the diaphragm member 101 and the wing section 36, the ridge line of the wing section 36 moves in the circumferential direction of the balloon 3, and the protruding direction of the wing section 36 is inclined in the circumferential direction.\",\n \"Thereafter, as the radial dimension of the internal space is reduced, as illustrated in FIG.\",\n \"6, the wing section 36 is wound around the axis of the balloon 3 about the stylet 6 to provide curling.\",\n \"At this time, a plurality of valley sections 37 are formed to protrude radially inward at a base side of the wing section 36.The outer diameter of the curled balloon 3 is substantially the same as the inner diameter of the internal space formed by the diaphragm member 101.Accordingly, a pair of diaphragm members 101 having sizes corresponding to the first region 31, the second region 32, and the intermediate section 33 are prepared, respectively, and the diaphragm member 101 disposed around the first region 31 and the second region 32 is relatively moved until the inner diameter of the internal space becomes D1, and the diaphragm member 101 disposed around the intermediate section 33 is relatively moved until the inner diameter of the internal space becomes D2.Accordingly, it is possible to form the balloon 3 having the initial shape illustrated in FIG.\",\n \"2.The above-described forming method of the initial shape is an example, and the method for forming the balloon according to the present embodiment is not limited thereto.\",\n \"In the balloon 3 having this initial shape, the amount of residual strain differs between the first region 31, the second region 32 and the intermediate section 33, due to a difference in amount of deformation of the film caused by the folding process.\",\n \"In the present specification, the “amount of residual strain” means the total amount of residual strain within a predetermined unit length range in the axial direction of the balloon.\",\n \"When a certain region has a length equal to or longer than the unit length in the axial direction, the amount of residual strain per unit length calculated by averaging the amount of residual strain of each part is taken as the amount of residual strain in the region.\",\n \"In the balloon 3 having the initial shape, the residual strain exclusively occurs in the portion of the folding line 35, which is the top portion of the wing section 36, and the valley section 37 bent so as to be convex toward the stylet 6 at the middle between two adjacent wing sections 36.As the amount of deformation occurring in the film constituting the balloon 3 due to the folding process increases, the residual strain generated in the folding line 35 and the valley section 37 increases.\",\n \"Accordingly, the balloon 3 according to the present embodiment is configured so that the amount of residual strain is larger in the intermediate section 33 than in the first region 31 and the second region 32.In the aforementioned method for forming the initial shape, it is possible to adjust the amount of deformation of the balloon 3, for example, by adjusting the movement distance of the diaphragm member 101 inward in the radial direction of the balloon at the time of the winding process.\",\n \"Therefore, in the balloon 3 according to the present embodiment, at the time of forming the initial shape, by setting the movement distance of the diaphragm member 101 disposed around the intermediate section 33 to be larger than the movement distance of the diaphragm member 101 disposed around the first region 31 and the second region 32, the amount of deformation of the intermediate section 33 is set to be larger than the amounts of deformation of the first region 31 and the second region 32.Therefore, the amount of residual strain in the intermediate section 33 can be set to be larger than the amount of residual strain in the first region 31 and the second region 32.The method for adjusting the amount of residual strain is not limited thereto, and for example, by setting the amount of driving force of the diaphragm member 101 at the time of winding process, or the amount of driving force or movement distance of the folding member 100 at the time of folding process, the amount of residual strain may be set to be larger at the intermediate section 33 than at the first region 31 and the second region 32.Further, the amount of residual strain may be adjusted by performing a heat treatment on the balloon 3 at the time of winding process or the folding processing.\",\n \"An operation at the time of use of the treatment instrument for the endoscope 1 configured as described above will be described.\",\n \"The treatment instrument for the endoscope 1 is introduced into the body of the patient P via a channel provided in the insertion portion 151 of the endoscope 150.As illustrated in FIG.\",\n \"7, the user connects an inflator 200 to the connecting section 4, and inserts the inflator into the insertion portion 151 from a forceps port 152 of the endoscope 150.Thereafter, the endoscope 150 is inserted into the body of the patient P, and the distal end of the endoscope 150 is moved forward to a region in which the dilation procedure is performed, for example, to the vicinity of a predetermined part of the esophagus.\",\n \"Connection between the treatment instrument for the endoscope 1 and the inflator 200 or insertion of the treatment instrument for the endoscope 1 into the endoscope 150 may be performed after the endoscope 150 is inserted into the body of the patient P. While observing a target site to be subjected to the dilation procedure with the endoscope 150, the user causes the instrument for an endoscope 1 to protrude from the endoscope 150 and inserts the distal end tip 5 into the target site.\",\n \"The user further moves the treatment instrument for the endoscope 1 forward and holds the treatment instrument for the endoscope 1 so that the balloon 3 breaks through the target site, that is, the distal end portion and the proximal end portion of the balloon 3 are located on the distal side and the proximal side with respect to the target site, respectively.\",\n \"The user actuates the inflator 200 to supply a fluid such as water or air to the balloon 3.The balloon 3 inflates while the internal pressure is raised by the supplied fluid.\",\n \"Since the amount of residual strain of the intermediate section 33 is larger than that of the first region 31 and the second region 32, a larger force is required such that the folding line 35 and the valley section 37 linearly stretch and the wing section 36 spreads.\",\n \"FIG.\",\n \"8 is a graph illustrating a relationship between the internal pressure of the balloon 3 and the outer diameters of the first region 31, the second region 32, and the intermediate section 33.In a state in which the internal pressure of the balloon 3 has reached a predetermined first internal pressure value P1 due to the supply of the fluid, in the first region 31 and the second region 32, unfolding has progressed faster than at the intermediate section 33.On the other hand, since the progress of unfolding of the intermediate section 33 is slow, the diameter of the intermediate section 33 is smaller than that of the first region 31 and the second region 32, and the balloon 3 overall has a dumbbell shape as illustrated in FIG.\",\n \"9.Therefore, even if the balloon 3 slips due to mucus or the like on the surface of the luminal organ, the first region 31 and the second region 32 serve as an anchor to suppress the movement, and thereby a situation such as detachment of the balloon 3 from the target site St is suitably prevented.\",\n \"In FIG.\",\n \"9, the shape of the intermediate section 33 illustrates the same state as the initial shape, but this is an example, and it is obvious that the shape may be a state when the intermediate section starts to inflate.\",\n \"When the internal pressure of the balloon 3 reaches the second internal pressure value P2, which is higher than the first internal pressure value, the folding is released at all of the first region 31, the second region 32, and the intermediate section 33, and the balloon 3 is restored to almost a substantially cylindrical shape (inflated shape) before the folding process as illustrated in FIG.\",\n \"10.At this time, the radial dimensions of the first region 31, the second region 32, and the intermediate section 33 are the same or substantially the same.\",\n \"Since the intermediate section 33 inflates to substantially the same diameter as the first region 31 and the second region 32, the target site St can be sufficiently dilated.\",\n \"At the second internal pressure value P2, the film itself forming the balloon 3 is hardly stretched.\",\n \"Here, since the balloon 3 is a semi-compliant type, by setting the internal pressure to be larger than a third internal pressure value P3 which is higher than the second internal pressure value as necessary, the whole of the balloon 3 is further inflated, while stretching the material, and a larger dilation force can be applied to the target site St.\",\n \"In more detail, since the material forming the balloon 3 itself hardly stretches until the internal pressure of the balloon 3 reaches the second internal pressure value P2, the balloon 3 inflates exclusively depending on the progress of unfolding, and the outer diameters of the first region 31, the second region 32, and the intermediate section 33 increase.\",\n \"Since the folding is almost released after the internal pressure of the balloon 3 reaches the second internal pressure value P2, even if the internal pressure rises, almost no increase in the external diameter occurs.\",\n \"When the internal pressure of the balloon 3 rises further and becomes larger than the third internal pressure value P3, the film material forming the balloon 3 starts to stretch.\",\n \"However, since expansion due to the progress of unfolding hardly occurs, the outer diameters of the first region 31, the second region 32, and the intermediate section 33 increase exclusively depending on the stretching of the film material.\",\n \"As described above, according to the treatment instrument for the endoscope 1 of the present embodiment, the amount of residual strain of the intermediate section 33 in the balloon 3 is set to be larger than the amount of residual strain of the first region 31 and the second region 32 disposed with the intermediate section 33 interposed therebetween.\",\n \"As a result, at the first internal pressure value P1, a dumbbell shape in which the first region 31 and the second region 32 have inflated to have an outer diameter larger than that of the intermediate section 33 is obtained, and it is possible to suitably prevent the balloon from being detached or displaced from the target site St during the treatment process on the target site St. Further, at the second internal pressure value P2, the intermediate section 33 can be inflated to substantially the same diameter as the first region 31 and the second region 32, and the target site St can be sufficiently dilated.\",\n \"As a result, prevention of misalignment with respect to the target site and sufficient expansion of the target site are compatible, and it is possible to perform an appropriate expansion treatment at the target site such as a stenosed part.\",\n \"In the present embodiment, the first internal pressure value and the second internal pressure value can be set to desired values, by appropriately setting the amounts of residual strain of the first region 31, the second region 32, and the intermediate section 33.The second internal pressure value may be set on the basis of the pressure intended to act on the target site, and may be, for example, 3 atmospheres (atm).\",\n \"It is preferable to set the first internal pressure value to be sufficiently lower than the second internal pressure value, for example, 0.5 atm, so that the positional deviation prevention effect can be exhibited at an early stage.\",\n \"Further, in the aforementioned example, the description has been given of a case where the outer diameter in the initial shape is set to be different between the first region 31, the second region 32, and the intermediate section to set amounts of residual strain of both regions different from each other.\",\n \"However, the method for setting different amounts of residual strain for both is not limited thereto.\",\n \"Several methods for generating different amounts of residual strain in the first region 31, the second region 32 and the intermediate section 33 will be described below.\",\n \"First, by changing an angle formed by the material of the balloon with the folding line 35 between the intermediate section and the other region, the amount of residual strain can be adjusted.\",\n \"That is, in the folding process, as an angle θ1 illustrated in FIG.\",\n \"11 decreases, the amount of residual strain increases.\",\n \"The angle θ1 can be changed, for example, by changing the shape of the surface in contact with the balloon 3 in the folding member 100 described above.\",\n \"Further, when the radius of curvature of the top of the wing section increases, the amount of residual strain decreases.\",\n \"Therefore, by forming the folding line 35 at the intermediate section and increasing the radius of curvature of the top of the wing section to such an extent that no ridge line is formed which is clear in the other region, the amount of residual strain at the intermediate section can be relatively increased.\",\n \"Also, by changing the number of wing sections in the intermediate section and the other region, the amount of residual strain can be adjusted.\",\n \"As the number of wing sections increases, since the number of folding lines 35 and valley sections 37 increases, the amount of residual strain increases.\",\n \"In addition, when forming the initial shape, if the diameter is reduced without forming the wing sections, a large number of irregular folding lines folded to be weaker than the folding line 35 are formed.\",\n \"Thus, the amount of residual strain decreases.\",\n \"Therefore, it is possible to relatively increase the amount of residual strain in the intermediate section, also by forming the wing section only in the intermediate section and not forming the wing section in the other regions.\",\n \"Further, when forming the initial shape, if the wing section is pulled and wound while applying tension, the valley section is strongly bent and the amount of residual strain increases.\",\n \"Therefore, by applying a tension only to the intermediate section or by applying a larger tension to the intermediate section, the amount of residual strain at the intermediate section can be relatively increased.\",\n \"Furthermore, when incorporating heat treatment at the time of forming the initial shape, the amount of residual strain can be changed, by switching between the presence or absence of heat treatment and the temperature conditions.\",\n \"In general, the amount of residual strain is higher when the heat treatment is performed, and the amount of residual strain is higher when the heat treatment is performed at a higher temperature.\",\n \"Therefore, by applying a heat treatment only to the intermediate section or by setting the temperature of the heat treatment at the intermediate section to be higher than at other regions, the amount of residual strain at the intermediate section can be relatively increased.\",\n \"Further, when the material of the balloon 3 is partially modified, the amount of residual strain at the intermediate section can be set to be relatively large without changing the process at the time of forming the initial shape for each region.\",\n \"For example, by forming a balloon with a crosslinked polymer and accelerating crosslinking by irradiating only the intermediate section with an electron beam, the rigidity of the intermediate section is relatively enhanced.\",\n \"When a uniform initial shape forming process is performed on this balloon, since the degree of plastic deformation becomes strong at the intermediate section, the amount of residual strain increases.\",\n \"Each of the above-described methods can be appropriately combined, respectively.\",\n \"Since the amounts of residual strain of each region change complicatedly in combination, for example, it is also possible to set the amount of residual strain of the intermediate section 33 to be relatively large, while setting the outer diameters of the first region 31, the second region 32, and the intermediate section 33 in the initial shape to be the same or substantially the same.\",\n \"Although the embodiment of the present invention has been described in detail with reference to the drawings, the specific configuration is not limited to this embodiment, and changes in design and the like within the scope not departing from the gist of the present invention are also included.\",\n \"Further, the constituent elements described in each of the embodiments and each of the modified examples described above can be configured by being appropriately combined.\",\n \"For example, in the above-described embodiment, the example in which the stylet 6 is inserted into the balloon 3 has been described.\",\n \"However, a configuration in which a sheath having a guide wire lumen and a fluid supply lumen is inserted through the balloon instead of the stylet may be provided.\",\n \"In this case, the guide wire inserted into the guide wire lumen can be made to protrude to the distal end of the balloon, and can be used as a guide for breaking through a site in which a strong constriction occurs, an occlusion part or the like.\",\n \"Further, as in the modified example illustrated in FIG.\",\n \"12, a marker 40 that is visible under endoscope observation or under X-ray fluoroscopy may be provided at a boundary between the first region 31, the second region 32, and the intermediate section 33.With this configuration, the balloon can be disposed at a more appropriate position with respect to the target site, and the positional deviation prevention effect can be reliably exerted.\",\n \"As long as the boundary between the intermediate section and another region can be recognized, the marker 40 may be provided in either the intermediate section or the other region.\",\n \"Further, in the initial shape of the balloon, when the outer diameter difference between the intermediate section and another region is large, a step caused by the outer diameter difference can be used as a marker that can be visually recognized under endoscope observation.\",\n \"Furthermore, at the time of shipping of the treatment instrument for the endoscope of the present invention, as illustrated in a modified example illustrated in FIG.\",\n \"13, the balloon 3 may be covered with a cover 70 having an internal space corresponding to the initial shape.\",\n \"In this way, it is possible to suitably maintain the initial shape until usage and to suppress change in amount of residual strain or the like.\",\n \"Further, in the above embodiment, an example in which the balloon is a semi-compliant type has been described.\",\n \"However, a so-called non-compliant type balloon in which, even if the internal pressure is equal to or higher than the second internal pressure value, the material forming the balloon does not substantially stretch, may be used.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875707"}}},{"rowIdx":4494956,"cells":{"text":{"kind":"list like","value":[["ENGINE GOVERNOR","An electronic governor system includes a motor, a transmission coupled to the motor, a throttle plate coupled to the transmission, the throttle plate movable to multiple positions between closed and wide-open, wherein power is supplied to the motor to move the throttle pate to a desired position and wherein power is not supplied to the motor to maintain the throttle plate in the desired position."],["1.An electronic governor system, comprising: a motor; a transmission coupled to the motor; a throttle plate coupled to the transmission, the throttle plate movable to a plurality of positions between closed and wide-open; an engine speed sensor; and a controller including a feedback control module and an adaptive control module; wherein the feedback control module is configured to: determine an engine speed error based on a comparison of a current engine speed input signal from the engine speed sensor and a desired engine speed; and provide an engine speed output signal to the motor to control the position of the throttle plate to correct the engine speed error, wherein the engine speed output signal is determined by a control algorithm using the engine speed error as an input; wherein the adaptive control module is configured to: determine an expected engine speed error correction based on the engine speed output signal provided by the feedback control module; determine an actual engine speed error correction based on a current engine speed input signal from the engine speed sensor and a previous engine speed input signal from the engine speed sensor; determine a correction error based on the expected engine speed error correction and the actual engine speed correction; and adjust a parameter of the control algorithm of the feedback control module when the correction error is within a predetermined range or outside of a predetermined range.","2.The electronic governor system of claim 1, wherein the feedback control module utilizes a proportional-integral-derivative control algorithm to provide the engine speed output signal and the parameter adjusted by the adaptive control module is at least one of a proportional parameter, an integral parameter, and a derivative parameter.","The electronic governor system of claim 2, wherein the proportional-integral-derivative control algorithm utilizes a plurality of parameter sets, each parameter set including a proportional parameter, an integral parameter, and a derivative parameter, and wherein the feedback control module is configured to utilize a specific parameter set based on the position of the throttle plate.","3.The electronic governor system of claim 3, wherein a first parameter set is utilized by the proportional-integral-derivative control algorithm when the throttle plate is near the closed position and a second parameter set is utilized by the proportional-integral-derivative control algorithm when the throttle plate is near the wide-open position.","4.The electronic governor system of claim 3, further comprising a temperature sensor configured to detect a temperature, wherein a first parameter set is utilized by the proportional-integral-derivative control algorithm when the detected temperature is below a threshold and a second parameter set is utilized by the proportional-integral-derivative control algorithm when the detected temperature is above the threshold.","5.The electronic governor system of claim 1, wherein the feedback control module utilizes a fuzzy logic control algorithm to provide the engine speed output signal and the parameter adjusted by the adaptive control module is at least one parameter of at least one rule of the fuzzy logic control algorithm.","6.The electronic governor system of claim 6, further comprising a temperature sensor configured to detect a temperature, wherein the detected temperature is an input to the fuzzy logic control algorithm.","7.The electronic governor system of claim 1, further comprising an ignition system, wherein excess energy from the ignition system is used to power the motor.","8.The electronic governor system of claim 1, wherein power is not supplied to the motor when the throttle plate position is not changing.","9.The electronic governor system of claim 1, wherein the adaptive control module is configured to adjust a parameter of the feedback control module such that a subsequent engine speed output signal is more aggressive when the expected engine speed error correction is less than the actual engine speed correction.","10.The electronic governor system of claim 1, wherein the adaptive control module is configured to adjust a parameter of the feedback control module such that a subsequent engine speed output signal is less aggressive when the expected engine speed error correction is greater than the actual engine speed correction.","11.A four-cycle small internal combustion engine, comprising: an engine speed sensor configured to detect an engine speed; an electronic governor system configured to change an engine operating speed in response to a load input; and a load sensing system configured to determine an engine load based on changes in the detected engine speed and provide the load input to the electronic governor system based on the determined engine load.","12.The engine of claim 12, wherein the electronic governor system is configured to provide at least two operating modes, wherein the electronic governor system is configured to set the engine operating speed to a first speed in the first operating mode and set the engine operating speed to a second speed greater than the first speed in the second operating mode.","13.The engine of claim 13, wherein the electronic governor system is configured to implement the first operating mode when the load input is below a first predetermined threshold value and implement the second operating mode when the load input is above a second predetermined threshold value.","14.The engine of claim 14, wherein the first predetermined threshold value and the second predetermined threshold value are the same."],["<SOH> BACKGROUND <EOH>The present invention relates generally to the field of electronic governors, and more particularly to electronic governors for small engines.","A typical electronic governor controls engine speed by controlling throttle plate position with a stepper motor."],["<SOH> SUMMARY <EOH>One embodiment of the invention relates to an electronic governor system including a motor, a transmission coupled to the motor, a throttle plate coupled to the transmission, an engine speed sensor, and a controller including a feedback control module and an adaptive control module.","The throttle plate is movable to a plurality of positions between closed and wide-open.","The feedback control module is configured to determine an engine speed error based on a comparison of a current engine speed input signal from the engine speed sensor and a desired engine speed and provide an engine speed output signal to the motor to control the position of the throttle plate to correct the engine speed error.","The engine speed output signal is determined by a control algorithm using the engine speed error as an input.","The adaptive control module is configured to determine an expected engine speed error correction based on the engine speed output signal provided by the feedback control module, determine an actual engine speed error correction based on a current engine speed input signal from the engine speed sensor and a previous engine speed input signal from the engine speed sensor, determine a correction error based on the expected engine speed error correction and the actual engine speed correction, and adjust a parameter of the control algorithm of the feedback control module when the correction error is within a predetermined range or outside of a predetermined range.","Another embodiment of the invention relates to a four-cycle small internal combustion engine including an engine speed sensor configured to detect an engine speed, an electronic governor system configured to change an engine operating speed in response to a load input, and a load sensing system configured to determine an engine load based on changes in the detected engine speed and provide the load input to the electronic governor system based on the determined engine load.","Alternative exemplary embodiments relate to other features and combinations of features as may be generally recited in the claims."],["CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisional of U.S. patent application Ser.","No.","14/702,435 filed May 1, 2015, which claims the benefit of U.S.","Provisional Application No.","62/081,221, filed Nov. 18, 2014 and U.S.","Provisional Application No.","61/987,350, filed May 1, 2014, all of which are incorporated herein by reference in their entireties.","BACKGROUND The present invention relates generally to the field of electronic governors, and more particularly to electronic governors for small engines.","A typical electronic governor controls engine speed by controlling throttle plate position with a stepper motor.","SUMMARY One embodiment of the invention relates to an electronic governor system including a motor, a transmission coupled to the motor, a throttle plate coupled to the transmission, an engine speed sensor, and a controller including a feedback control module and an adaptive control module.","The throttle plate is movable to a plurality of positions between closed and wide-open.","The feedback control module is configured to determine an engine speed error based on a comparison of a current engine speed input signal from the engine speed sensor and a desired engine speed and provide an engine speed output signal to the motor to control the position of the throttle plate to correct the engine speed error.","The engine speed output signal is determined by a control algorithm using the engine speed error as an input.","The adaptive control module is configured to determine an expected engine speed error correction based on the engine speed output signal provided by the feedback control module, determine an actual engine speed error correction based on a current engine speed input signal from the engine speed sensor and a previous engine speed input signal from the engine speed sensor, determine a correction error based on the expected engine speed error correction and the actual engine speed correction, and adjust a parameter of the control algorithm of the feedback control module when the correction error is within a predetermined range or outside of a predetermined range.","Another embodiment of the invention relates to a four-cycle small internal combustion engine including an engine speed sensor configured to detect an engine speed, an electronic governor system configured to change an engine operating speed in response to a load input, and a load sensing system configured to determine an engine load based on changes in the detected engine speed and provide the load input to the electronic governor system based on the determined engine load.","Alternative exemplary embodiments relate to other features and combinations of features as may be generally recited in the claims.","BRIEF DESCRIPTION OF THE DRAWINGS The invention will become more fully understood from the following detailed description, taken in conjunction with the accompanying drawings, in which: FIG.","1 is a perspective view of a portion of an internal combustion engine including an electronic governor system according to an exemplary embodiment; FIG.","2 is a schematic representation of an electronic governor system according to an exemplary embodiment; FIG.","3 is a block diagram of the controller of an electronic governor system according to an exemplary embodiment; and FIG.","4 is a perspective view of a portion of the internal combustion engine of FIG.","1 including the electronic governor system.","FIG.","5 is a perspective view of the internal combustion engine of FIG.","1 including the electronic governor system.","FIG.","6 is a schematic representation of a portion of an electronic governor system, according to an exemplary embodiment, with an elliptical gear set in a first operating position.","FIG.","7 is a schematic representation of the portion of the electronic governor system of FIG.","6 with the elliptical gear set in a second operating position.","DETAILED DESCRIPTION Before turning to the figures, which illustrate the exemplary embodiments in detail, it should be understood that the application is not limited to the details or methodology set forth in the description or illustrated in the figures.","It should also be understood that the terminology is for the purpose of description only and should not be regarded as limiting.","Referring to FIGS.","1-2 and 4-5, an electronic governor system is illustrated according to an exemplary embodiment.","The electronic governor system 100 is shown in use on a small engine 105.The electronic governor system 100 includes a carburetor 110, a motor 115 (e.g., a direct current (“DC”) motor), a transmission 120, a throttle plate 125, a throttle lever 130 and a linkage 135 connecting the throttle lever to the transmission.","In the carburetor 110, fuel is mixed with air to produce an air/fuel mixture for combustion in one or more cylinders of the engine 105.The throttle plate 125 controls the flow of the air/fuel mixture out of the carburetor 110 and in doing so controls the speed of the engine 105.As illustrated, the linkage 135 includes a link 140 and a crank arm 145.In some embodiments the electronic governor system 100 also includes an encoder 150 that is coupled to the motor 115 and the transmission 120.The motor assembly (i.e., the motor 115 and the transmission 120) is used to control the position of the throttle plate 125, thereby controlling the engine speed.","The throttle plate 125 is movable between a closed position and a wide-open position.","The position of the throttle plate 125 is adjusted so that the engine speed is maintained at a desired engine speed.","The desired engine speed can be a constant or can be varied by a user or a controller in response to inputs from the engine (e.g., inputs related to engine load, desired output, or other engine operating conditions or objectives).","The motor 115 is relatively low cost, particularly with respect to the stepper motor typically used in other electronic governor systems.","The motor 115 does not track steps of the motor's rotation like a stepper motor.","In some embodiments, the motor 115 is a brushed motor.","The transmission 120 provides a large reduction ratio (i.e., input speed/output speed).","For example, the motor 115 may have a top speed of 4,000 revolutions per minute (rpm).","The transmission 120 may provide a reduction so that the output from the transmission turns at 100 rpm (i.e., a 40:1 reduction ratio).","This will result in a transmission output speed that is relatively fast as compared to the amount of rotation necessary to adjust the throttle plate position (e.g., 75 to 100 rpm), with the throttle plate's range of motion (i.e., between the closed position and the wide-open position) being less than a full revolution, and produces a relatively large amount of torque.","At this relatively fast transmission output speed the throttle plate 125 is able to move from closed to wide open in about 40 milliseconds.","As another example, the motor 115 may have an output speed of at about 10,000 rpm and the transmission may provide a gear reduction such that the output of the transmission is about 60 rpm (i.e.","a reduction ratio of about 167:1).","In some embodiments, the transmission 120 is a series of gears that provides a reduction from the input of the motor to the output of the transmission.","The transmission 120 providing a large reduction ratio produces an output from the transmission 120 with a relatively large amount of torque.","The output shaft of the transmission 120 only needs to rotate a small amount to adjust the throttle plate position within the throttle plate's range of motion and in doing so is able to produce a lot of torque.","Another advantage of this large reduction ratio is that power only needs to be supplied to the motor 115 when moving the output shaft of the transmission 120 to the desired position.","This position corresponds with the desired position of the throttle plate 125.After the output shaft of the transmission 120, and therefore the throttle plate 125, has reached the desired position, the motor 115 is no longer powered (i.e., the motor 115 is turned off).","In this way, power is not needed to maintain the position of the output shaft of the transmission 120 and of the throttle plate 125.The relatively large reduction ratio provided by the transmission 120 is able to maintain or hold the throttle plate 125 in position without power being supplied to the motor 115 to maintain the desired position of the throttle plate 125.In some embodiments several components of the electronic governor system 100 are included within a single housing.","For example, the motor 115 and the transmission 120 could form a single unit.","This unit may be combined with the controller 155 and its associated circuit board.","As shown in FIG.","1, the linkage 135 connects the output shaft of the transmission 120 to the throttle lever 130.The throttle lever 130 is connected to the throttle plate 125, such that the motor 115 drives the transmission 120 which moves the linkage 135 which moves the throttle lever 130 which moves the throttle plate 125.In this way, powering the motor 115 causes the throttle plate 125 to change position.","Though the linkage 135 is shown as a two-piece linkage, other appropriate mechanisms for connecting the output shaft of the transmission 120 to the throttle plate 125 may be utilized.","For example, the output shaft of the transmission 120 could be directly connected to the throttle plate 125 or one or more components could be used to connect the output shaft of the transmission 120 to the throttle plate 125.In some embodiments, one or more gears are used to connect the output shaft of the transmission 120 to the throttle plate 125.In some embodiments, the encoder 150 is connected to the motor 115 and the transmission 120 to determine the position of the output shaft of the transmission 120.In some embodiments, the encoder 150 is an absolute encoder and can be used to keep track of the position of the output shaft of the transmission 120 and therefore the position of the throttle plate 125.As shown in FIG.","2, the electronic governor system 100 includes a controller 155 that controls the operation of the motor 115.In some embodiments, the controller 155 also controls the operation of other components of the electronic governor system 100 that will be described in more detail below.","These components may include an engine speed sensor 160, a user interface 165, a temperature sensor 170, a current sensor 175, an ignition system 180, and a rev limiter 185.Different embodiments of the electronic governor system 100 may include some, none or all of these additional components.","As shown in FIG.","3, the controller 155 includes a processing circuit 190, an input interface 195, and an output interface 200.The processing circuit 190 includes a processor 205 and memory 210.The processing circuit 190 and processor 205 are configured to receive inputs from input interface 195 (e.g., via a wired or wireless communication link with other components of the engine and/or electronic governor system) and to provide an output (e.g., a control signal, an actuator output, etc.)","via output interface 200 (e.g., via a wired or wireless communication link to the motor 115, other components of the engine, and/or other components of the electronic governor system).","The processing circuit 190 can be a circuit containing one or more processing components (e.g., the processor 205) or a group of distributed processing components.","The processor 205 may be a general purpose or specific purpose processor configured to execute computer code or instructions stored in the memory or received from other computer readable media (e.g., CD-ROM, network storage, a remote server, etc.).","The processing circuit 190 is also shown to include the memory 210.Memory 210 may be RAM, hard drive storage, temporary storage, non-volatile memory, flash memory, optical memory, or any other suitable memory for storing software objects and/or computer instructions.","When the processor 205 executes instructions stored in the memory 210 for completing the various activities described herein, the processor 205 generally configures the computer system and more particularly the processing circuit 190 to complete such activities.","The memory 210 may include database components, object code components, script components, and/or any other type of information structure for supporting the various activities described in the present disclosure.","For example, the memory 210 may store data regarding the operation of a controller (e.g., previous setpoints, previous behavior patterns regarding used energy to adjust a current value to a setpoint, etc.).","According to an exemplary embodiment, the memory 210 is communicably connected to the processor 205 and includes computer code for executing one or more processes described herein and the processor 205 is configured to execute the computer code.","The memory 210 is shown to include a feedback control module 215 and an adaptive control module 220.The memory may include a throttle plate position module 225 and an engine shutdown module 230.The feedback control module 215 is the primary logic module configured to provide the feedback-based control activity of the controller 155.In some embodiments, the feedback control module 215 is a proportional-integral-derivative (PID) control module.","In other embodiments, the feedback control module 215 is a fuzzy logic control module.","The feedback control module 215 uses information from the input interface 195 (e.g., detected engine speed) to calculate or otherwise obtain the controlled variable (e.g., throttle plate position).","The feedback control module 215 may also use information stored in the memory 210 (e.g., previous detected engine speed, desired engine speed, etc.)","in calculating or obtaining the controlled variable.","The adaptive control module 220 is configured to determine appropriate values of control parameters (e.g., proportional gain, integral gain, derivative gain, etc.).","The adaptive control module 220 may tune control parameters based on a model identification adaptive control (MIAC) approach or another adaptive tuning approach or algorithm.","The feedback control module 215 is configured to provide an engine speed control output based an engine speed error determined by a comparison of a current engine speed input from the engine speed sensor 160 with the desired engine speed.","The output is provided to the motor 115 to adjust the throttle plate 125 position, thereby controlling the engine speed and correcting any engine speed error so that the detected engine speed and the desired engine speed are the same or substantially the same (e.g., within a predetermined range).","The feedback control module can use different types of feedback control including PID control algorithms or fuzzy logic control rules.","The adaptive control module 220 adjusts one or more parameters (e.g., coefficients, gains, rules, etc.)","of the feedback control module 215 such that the feedback control module learns the appropriate operating parameters for a specific engine and end product (e.g., lawn mower, snow thrower, generator, pressure washer, etc.).","For example, the feedback control module 215 may determine an engine speed error and provide an engine speed output intended to correct that error or a portion of the error (e.g., reduce the error by half).","The adaptive control module 220 determines what an expected engine speed error correction is based on the output provided by the feedback control module 215.The adaptive control module 220 also determines an actual engine speed correction based on the current engine speed input from the engine speed sensor 160 and a previous engine speed input from the engine speed sensor 160.The adaptive control module 220 then is able to determine a correction error based on the expected engine speed error and the actual engine speed correction.","In this way, the adaptive control module 220 is able to determine if the actual engine speed correction is the same as or close to the expected engine speed error correction (e.g., determine a correction error).","If the actual engine speed correction is not the same (or within a predetermined range acceptable as the same) as the expected engine speed correction, the adaptive control module 220 adjusts one or more parameters of the feedback control module 215.When the actual engine speed error correction was less than the expected engine error correction the parameter change is such that the subsequent attempt at correcting engine speed will be more aggressive.","As used herein, more aggressive means that the position change of the throttle plate with adjusted parameter setting will be greater than at the previous parameter setting and less aggressive means that the position change of the throttle plate with adjusted parameter setting will be less than at the previous parameter setting.","For example, in a controller 155 using PID control the adaptive control module 220 can change one or more of the proportional, integral and derivative parameters (e.g., coefficients or gains) of the feedback control module 215 to achieve the desired change in engine speed.","The PID control of the feedback control module 215 may set forth a control algorithm to determine the motor adjustment—the amount of time voltage is supplied to the motor 115 (the duration or “width” of a voltage pulse).","For example, the PID control algorithm may use the following equation to determine the motor adjustment where Error is the engine speed error.","Motor Adjustment = P i Error + D i d Error dt + I i ∫ Error The adaptive control module 220 may be configured to adjust one or more of the proportional, integral and derivative parameters in response to a comparison of the actual change in engine speed following a throttle plate position adjustment (e.g., as measured by the engine speed sensor 160) with the expected change in engine speed following a throttle plate position adjustment (e.g., the engine speed error or a portion (e.g., one half, one third, etc.)","of the engine speed error).","If the actual change in engine speed is less than the expected change in engine speed, one or more of the parameters is adjusted to make the motor adjustment more aggressive (i.e., provide a voltage pulse of a longer duration).","If the actual change in engine speed is greater than the expected change in engine speed, one or more of the parameters is adjusted to make the motor adjustment less aggressive (i.e., provide a voltage pulse of a shorter duration).","The comparison of actual change in engine speed to the expected change in engine speed can be performed at a specific time (e.g., 2-3 engine cycles) after a motor adjustment pulse is sent to the motor 115.In some embodiments, the pulse of the motor adjustment has a duty cycle and the duty cycle of the pulse of the motor adjustment may be adjusted when the actual change in engine speed is different than the expected change in engine speed.","In some embodiments, the motor adjustment algorithm In some embodiments using a PID control algorithm there are multiple parameter sets.","For example, a first parameter set may be used when the throttle plate 125 is close or near to the closed position and a second parameter set may be used when the throttle plate 125 is close or near to the wide open position.","This is helpful because the operating performance (e.g., speed) of the engine is not linear with respect to throttle plate position.","When the throttle plate 125 is near the wide open position, the engine speed is not very responsive to changes in the throttle plate position and when the throttle plate 125 is near the closed position, the engine speed is more responsive to changes in the throttle plate position.","Therefore, the parameter set associated with operation when the throttle plate 125 is near the closed position would be less aggressive than the parameter set that is used when the throttle plate 125 is near the wide open position.","Two or more parameter sets based on the throttle position could be implemented.","For example a curve could be fit so that the parameter sets used change from the closed position to the wide open position.","The adaptive control module 220 may also be configured to perform a comparison of the expected output (i.e., rotational speed) of the motor 115 from a particular duration of applied voltage (voltage pulse) to the back electromotive force (“back-EMF”) actually caused by that particular duration of applied voltage.","Back-EMF is caused by the rotation of the motor and can act as a proxy for a motor sensor for detecting the rotational speed of the motor.","In this way the adaptive control module 220 allows the system to learn or adjust to the operational characteristics of a particular engine.","Variations among particular engines (e.g., individual DC motors, the end use of the engine, etc.)","will result in different duration voltage pulses being necessary to move a throttle plate a specific amount.","For example, in one engine a voltage pulse of 10 milliseconds may move the throttle plate 10 degrees, but may only move the throttle plate of a second engine 5 degrees.","The back-EMF correlation performed by the adaptive control module 220 allows the system to learn the particular voltage pulse duration needed for a particular throttle plate position change within the addition of a motor speed sensor and allows for that correlation to change as engine performance changes over the life of a particular engine.","The back-EMF comparison can also be used to determine when the throttle plate 125 is at either end of its range of motion (i.e., closed position or wide open position) because the throttle plate 125 is at a hard stop at either end of its range of motion and the back-EMF should approach zero as the motor is unable to turn.","The back-EMF comparison can also be used to identify variations between the operational characteristics of individual motors and a curve establishing a known or desired relationship between back-EMF and engine speed (e.g., RPM) and to determine the operational characteristics that need to be modified (e.g., duration of voltage pulses) to fit a specific motor to the known back-EMF and engine speed curve.","As shown in FIGS.","6-7, in some embodiments of the electronic governor system 100, an elliptical gear set 186 is included between the transmission 120 and the throttle lever 130 to account for the non-linearity of engine speed with respect to throttle plate position.","The elliptical gear set 186 includes two elliptical gears—a driving gear 187 and a driven gear 188.The driving gear 187 has a minor radius 189 that is less than a major radius 191.The driving gear 187 is coupled to or a component of the transmission 120.The driven gear 188 is coupled to the throttle plate 125 (e.g., directly or indirectly by one or more links or gears).","The driven gear 188 has a minor radius 192 that is less than a major radius 193.The elliptical gear set 186 is arranged so that the driven gear 188 provides a relatively large amount of movement of the throttle plate 125 in response to specified amount of movement of the driving gear 187 when the throttle plate 125 is near the wide open position (FIG.","6) and so that the driven gear 188 provides a relatively small amount of movement of the throttle plate 125 in response to the same specified amount of movement of the driving gear 187 when the throttle plate 125 is near the closed position (FIG.","7).","As shown in FIG.","6, when the throttle plate 125 is near the wide open position, the major radius 191 of the driving gear 187 engages the minor radius 192 of the driven gear 188.As shown in FIG.","7, when the throttle plate 125 is near the closed position, the minor radius 189 of the driving gear 187 engages the major radius 193 of the driven gear 188.In embodiments where the feedback control module 215 uses a fuzzy logic control algorithm to control the output to the motor 115, a list of fuzzy logic rules is created to control the operation of the motor 115.These rules allow for non-linear control of the non-linear engine operation.","In some embodiments, the temperature sensor 170 provides the detected temperature as an input to the fuzzy logic rule set.","In some embodiments the electronic governor system 100 includes a temperature sensor 170.The temperature sensor 170 is configured to detect a temperature (e.g., an ambient temperature, an engine temperature, or other appropriate temperature).","The detected temperature is provided as an input to the controller 155 and may be utilized as an input to the various logic modules of the controller 155.As the engine may operate differently as relatively cold temperatures and relatively hot temperatures different control parameters (e.g., of the feedback control module 215 and/or the adaptive control module 220) can be used when the detected temperature is either below or above one or more thresholds (e.g.","a hot operating condition threshold and a cold operating condition threshold).","The memory 210 may also include a throttle plate position module 225.The throttle plate position module 225 is configured to determine the position of the throttle plate 125 based on tracking the expected changes in the throttle plate position from an initial throttle plate position.","The initial throttle plate position is known.","For example, the wide open position may be considered to be 90° and the closed position may be considered to be 0°.","Based on that starting position (e.g., the wide open position), the throttle plate position module 225 calculates a current throttle plate position based on the changes to the throttle plate position caused by the motor 115.The product of the voltage applied to the motor 115 and the amount of time for which that voltage is supplied corresponds to an expected change in the position of the throttle plate 125.By keeping track of all expected movements of the throttle plate 125 from the initial known position caused by operation of the motor 115, the throttle plate position module 225 is able to track the position of the throttle plate 125.Alternatively, an encoder (e.g., the encoder 150) may keep track of the throttle plate position.","However, an encoder adds cost that may not be necessary for the electronic governor system 100 to operate as desired.","The engine 105 includes an ignition system 180.In some embodiments excess energy from the ignition system 180 is used to power the motor 115 and/or the controller 155.In this way the electronic governor system 100 is able to operate without a separate or dedicated power supply (e.g., a separate battery or the battery used to power an electric engine starting system).","In a magneto or spark ignition system extra energy in the form of ignition sparks or pulses can be harvested and stored in a capacitor or other energy storage device (e.g., battery) for use to power the motor 115.Though a spark based ignition system is discussed as an example other types of ignition systems are possible.","The excess energy of the ignition system may also be sufficient to power the motor 115 and/or the controller 155.After the engine 105 is started, there is a relatively abundant amount of excess energy that can be harvested to power the electronic governor system 100.For example, the energy from the two positive pulses or sparks of a four-cycle magneto ignition system can yield about one amp of current.","Other types of ignition systems also provide waste energy that could be harvested to power the electronic governor system.","In a four-cycle magneto ignition system there is a waste spark on the exhaust stroke of the cylinder.","In such a system, the two positive pulses or sparks and the waste negative pulse or spark could all be harvested.","In some embodiments, other power supplies that do not include a separate or dedicated power supply (e.g., a separate battery) may be used to power the motor 115 and/or the controller 155.Alternative power supplies include an alternator driven by the engine 105, a thermoelectric power generator that makes use of waste heat from the engine 105, a piezoelectric power generator driven by vibrations of the engine 105 and/or the outdoor power equipment driven by the engine 105, a Faraday power generator including a magnet oscillating within a coil driven in sync with the reciprocating movement of the piston of the engine 105.In some embodiments, an energy storage device (e.g., a rechargeable battery, a capacitor, etc.)","is provided to store the energy produced by the power supplies described above.","In this way, power is available for the motor 115 and/or the controller 155 when the engine 105 is initially started and there is not an immediately available supply of energy to be harvested from the operating engine 105.A rev limiter 185 may be provided to prevent the engine 105 from achieving an overspeed condition in which the engine speed exceeds a threshold (e.g., a redline).","The rev limiter 185 detects the engine speed and when the engine speed exceeds the threshold, shorts the ignition to prevent the engine from continuing to exceed the speed threshold.","To make the reduction in speed associated with shorting the ignition smoother (e.g., less sudden and/or less noisy to the operator), it may be preferable to short a subset of the ignition sparks rather than all of the engine sparks.","Shorting all of the ignition events (e.g., sparks associated with combustion events) would have an audible effect and the engine speed would abruptly drop.","Shorting fewer than 100% of the ignition events (e.g., every second, third, fourth, etc.","ignition event) would slow the engine speed but be less abrupt and less noticeable audibly to the user.","A user interface 165 may be provided so that the user is able to control the desired speed (e.g., expected or targeted speed) of the engine 105.This user interface 165 could be an analog input such as a voltage divider, a fixed resistor, a variable resister (e.g., a potentiometer or sliding variable resistor).","In some embodiments where the engine was used to power a wheel drive train (e.g., on a riding or walk behind lawn mower or snow thrower) a throttle input (e.g., a gas pedal or lever) may be moved to adjust the analog input and therefore adjust the desired speed of the engine.","If the engine is used to power a generator, a discreet two-position analog input could be used to switch the output frequency of the electricity provided by the generator between the 60 Hz electricity used in the United States and Canada, and the 50 Hz electricity used elsewhere in the rest of the world (e.g., Europe and Asia).","Other discreet control modes, for example, could include a quiet operating mode versus a power operating mode.","The quiet operating mode may be configured so that the engine runs at a relatively low speed (e.g., 2,400 rpm) versus the power mode which runs at a relatively high rpm (e.g., 3,000 rpm).","In some embodiments, the user interface is wireless RF, infrared IR, and LED or light pulse interface or capacitive sensing interface (e.g., a touchscreen).","In some embodiments the user interface 165 includes a second microcontroller.","For example, a touch screen or other interface device could provide inputs to a second controller which provide a variable voltage output to the controller operating the electronic governor system.","In some embodiments, the user interface 165 provides a digital input.","Initial performance characteristics of the engine governor system 100 can also be varied (e.g., more or less aggressive engine speed error correction.","These characteristic settings could be preset when the system or engine is assembled (e.g., by setting a specific resistance or voltage value).","For example one setting could be used with relatively low inertia equipment driven by the engine (e.g., the pump of a pressure washer) and a second setting could be used with relatively high inertia equipment driven by the engine (e.g., the blade of a lawn mower).","This provides the controller 155 with some initial performance characteristics (e.g., the relative inertia of the equipment being driven) before it has even had a chance to start adapting the control parameters based on the actual use of the engine.","For example, 1000-4000 rpm could be selected with input resistances of 100-400 ohms and with input resistances of 1100-1400 ohms with settings of 100-400 ohms providing moderately aggressive performance for relative low inertia applications and 1100-1400 ohms providing more aggressive performance for relatively high inertia applications.","Additionally, there could also be more than two performance characteristics settings (e.g., low inertia, moderately low inertia, moderate inertia, moderately high inertia, high inertia, etc.)","that could be selected based on engine type (e.g., size, number of cylinders, rated horsepower, rated torque) and equipment to be driven by the engine.","Alternatively, the performance characteristic settings could be tied to the voltages that will be read by the controller 155.A current sensor 175 may be included to monitor the current draw on the motor 115.For example, a shunt resistor may be used to measure this motor current.","The current sensor 175 is used to detect potential failures in the electronic governor system 100 and shut down the engine 105 (e.g., stop the engine) in response to detecting such a failure.","For example, a detected current above a high current threshold could indicate a jam, obstruction, the end of travel, a motor short, or some other situation in which the motor 115, the transmission 120, the throttle plate 125, the throttle lever 130, the linkage 135, or other movable component is unable to move (e.g., rotate, translate, etc.)","as desired.","When the current sensor 175 detects a current below a low current threshold this could indicate a broken wire or some other loss of electrical communication between the components of the electronic governor system 100.Both a high current above the high threshold and a low current below the low threshold may be indicative of situations in which the engine 105 should be stopped or shut down to prevent possible damage to the engine.","Engine shutdown module 230 is configured to shut down, stop, turn off, or deactivate the engine in response to an appropriate input (e.g., release of a safety interlock, like when the bail of a walk-behind lawn mower is released, movement of an on/off switch to the off position, etc.).","Engine shutdown module 230 may receive an input from the current sensor 172 and shut off the engine in response to low current or high current as described above.","In some embodiments, the engine speed sensor 160 detects the engine speed using an ignition signal from the ignition system 180.For example, the positive sparks or pulses from the ignition system could be counted and used to determine the engine speed.","This method of determining engine speed provides an additional advantage when shorting the negative pulses or sparks with the rev limiter 185.The engine speed detection, which is determined from the positive pulses, is not lost when slowing down the engine 105 with the rev limiter 185 by shorting the negative pulses or sparks.","In other embodiments, other appropriate engine speed sensors are utilized.","The electronic governor systems described herein are able to adjust the operating speed of the engine in response to an input from a load sensing system.","Combining a load sensing system with the electronic governor systems allows the operating speed of the engine to be optimized for various load conditions.","For example, an engine including an electronic governor system and a load sensing system as described herein could operate in one of two modes: a no load or low load mode (e.g., when the blade of a lawn mower is not cutting any grass) where the engine operates at an idle or relatively low speed and a high load mode (e.g., when the blade of the lawn mower is cutting grass) where the engine operates at an high operating or relatively high speed.","More complex systems allow for additional modes of operation for example a moderate load mode (e.g., when the blade of the lawn mower is cutting grass that is thinner than that being cut in the high load mode) where the engine operates at a speed between the idle speed and the high operating speed.","The engine speed could also vary continuously with load or approximately continuously with load (e.g., with a step-function or other appropriate curve fit).","For example, the engine speed could be controlled to always fit within a band or window defined by a high engine speed curve and a low engine speed curve and operate in a manner similar to a continuously variable transmission.","The load sensing system makes use of the principle of rotational motion that the sum of the torques for the system equals zero.","The sum of the torques is equal to inertia times the change in angular velocity as shown in the equation below.","The TorqueProduced is the torque produced from combustion by the engine and the TorqueLoad/Losses is the torque produced from the load on the engine (e.g., mower blade, pressure washer pump, drive system, etc.)","and any losses within the engine (e.g., friction, gas compression, vacuum, etc.)","J{umlaut over (θ)}=TorqueProduced−TorqueLoad/Losses In a first load sensing system for a single cylinder four-cycle engine, the load can be estimated by comparing the rotational speed of the engine for two consecutive engine revolutions.","A “fast” revolution occurs during the expansion and exhaust cycles of the engine.","A “slow” revolution occurs during the intake and compression cycles of the engine.","The difference in revolution speed (e.g., in revolutions per minute (“RPM”)) is a function of the TorqueLoad/Losses and inertia.","When the inertia is known (e.g., the inertia of a specific end use of the engine, for example for a specific lawn mower, pressure washer, tractor, or other piece of outdoor power equipment), then the difference in revolution speed from the fast revolution to the slow revolution (e.g., RPM of the fast revolution minus the RPM of the slow revolution) is a function of the TorqueLoad/Losses.","By calculating this difference, the load sensing system can accurately estimate the load on the engine.","The load can then be used as an input to the electronic governing system to control the speed of the engine.","In a second load sensing system for a single cylinder four-cycle engine, the load can be estimated by comparing the rotational speed of the engine for each of the four cycles.","The sum of the torques for each of the four cycles (expansion, compression, intake, and compression) can be calculated according to the equation shown below.","J{umlaut over (θ)}=TorqueProduced−TorqueLoss−TorqueLoad Using four versions of this equation, one for each cycle, with the inertia remaining constant for all four equations, the load sensing system is able to determine the load based on the measured change in engine speed from one cycle to the next because each of the four equations is left with only one unknown (four equations with four unknowns are solvable).","For the expansion cycle, TorqueLoss is negligible and can be assumed to be zero.","For the exhaust cycle, TorqueProduced and TorqueLoss are negligible and can be assumed to be zero.","For the intake cycle, TorqueProduced and TorqueLoss are negligible and can be assumed to be zero.","For the compression cycle, TorqueProduced is negligible and can be assumed to be zero.","The combustion process can vary from combustion cycle.","The combustion process regularly experiences “bumps” or “pops” due to many possible factors including fuel quality, air availability, variations in the fuel-air ration, etc.","Either of the two load sensing systems described above can reduce the impact of these combustion process variations, which may result in variations of the engine speed, which is the inputs to the calculations used to determine the load for both systems, by using a running average and/or a standard deviation of the engine speed measurements.","The average load value can be calculated using the equation below.","“A” is a factor used to weigh the average load value.","The value of A may be selected based on the intended end use of the engine (e.g., lawn mower, pressure washer, tractor, or other piece of outdoor power equipment) and the desired engine performance for that engine.","As the value of A increases, the average load value becomes smoother, but it delays response time for true changes in load, rather than momentary chances due to combustion variations.","Avg ."," Load Value = ( Avg ."," Load Value * A + New Load Value ) A + 1 The average load value can be used as the trigger to change between operating modes of the electronic governing system.","For example for the two operating mode electronic governing system discussed above, the no load operating mode can be triggered when the average load value is at or below a predetermined threshold value and the high load operating mode can be triggered when the average load value is at or above a predetermined threshold value.","To avoid hunting or hysteresis between the two modes, the predetermined threshold values can be different for the no load operating mode and the high load operating mode.","For example, the no load threshold value could be an average load value of 15 and the high load threshold value could be 20, providing a window between 15 and 20 where mode hunting is avoided.","Alternatively a percentage change threshold (e.g., 20%) in average load value could be used as the trigger to change between operating modes of the electronic governing system.","The threshold values, whether absolute or a percentage, can be tied to specific engine sizes and end products.","Another way to avoid mode hunting is to include a minimum predetermined time period between operating mode changes.","For example, each operating mode could be required to run for at least 5 seconds before be able to switch based on the current average load value.","A standard deviation of the load value could be used in similar manners on its own or in combination with the average load value to provide a trigger to change between operating modes of the electronic governing system.","The standard deviation of the measured engine speed may also be used to distinguish between an actual change in engine speed (e.g., due to an increased or decreased load on the engine) and intermittent variations in engine speed due to combustion irregularities.","Measured engine speed includes expected variations on a per-cycle basis.","The expansion (combustion, power) cycle has a faster engine speed than the intake, compression, and exhaust cycles.","The standard deviation accounts for the expected variations on a per-cycle basis so that only engine speed changes in excess of the standard deviation, or in excess of the standard deviation modified by an error factor (e.g., multiplied or added to the standard deviation), are used to trigger a change in throttle plate position by the engine governing system.","Both load sensing systems make use of an appropriate controller to implement the control schemes discussed above and of an appropriate engine speed sensor to detect the engine speed for use as an input as discussed above.","Possible engine speed sensors include a magnetic field sensor (e.g., a Hall Effect sensor or reed switch) in combination with a magnet on the flywheel.","The magnet on the flywheel could be the same used to generate the spark for the ignition system, but could also be a separate second magnet.","Both load sensing systems could also include an operating mode input to provide a verification that the detected change in load based on the engine speed calculations as an intended change in load based on the user's intended operating mode.","For example, a tilt sensor could indicate when the front wheels of a walk behind lawn mower are lifted off the ground, thereby confirming a reduced load.","A switch on the bail of walk behind lawn mower could indicate when the operator engages the drive system.","A vacuum sensor could detect changes in engine vacuum as a redundant check on load changes.","A user-actuated switch could also be used as a feedforward input to the load sensing system.","For example, a switch actuated by a user operated lever (e.g., the bail of a walk-behind mower, the trigger of a pressure washer spray gun, a control lever of a snowthrower, a power takeoff engage switch on a riding tractor, etc.)","would indicate an expected engine load to the load sensing system (e.g., operation of the tool driven by the engine, a load on the tool driven by the engine, engagement of a drive train, etc.).","The load sensing system could use this feedforward input to override or supplement the load output provided by the load sensing system.","The same controller or separate controllers can be used to implement the controls schemes used by the electronic governor system and by the load sensing system.","For example, as shown in FIG.","2, the controller 155 could be used to control both the electronic governor system 100 and a load sensing system as described above via a load sensing module 235 configured to implement a load sensing system as described herein.","The engine speed sensor 160 could be used to provide the necessary engine speed inputs to the load sensing module 235 to implement the load sensing system.","The construction and arrangement of the apparatus, systems and methods as shown in the various exemplary embodiments are illustrative only.","Although only a few embodiments have been described in detail in this disclosure, many modifications are possible (e.g., variations in sizes, dimensions, structures, shapes and proportions of the various elements, values of parameters, mounting arrangements, use of materials, colors, orientations, etc.).","For example, some elements shown as integrally formed may be constructed from multiple parts or elements, the position of elements may be reversed or otherwise varied and the nature or number of discrete elements or positions may be altered or varied.","Accordingly, all such modifications are intended to be included within the scope of the present disclosure.","The order or sequence of any process or method steps may be varied or re-sequenced according to alternative embodiments.","Other substitutions, modifications, changes, and omissions may be made in the design, operating conditions and arrangement of the exemplary embodiments without departing from the scope of the present disclosure.","The present disclosure contemplates methods, systems and program products on any machine-readable media for accomplishing various operations.","The embodiments of the present disclosure may be implemented using existing computer processors, or by a special purpose computer processor for an appropriate system, incorporated for this or another purpose, or by a hardwired system.","Embodiments within the scope of the present disclosure include program products comprising machine-readable media for carrying or having machine-executable instructions or data structures stored thereon.","Such machine-readable media can be any available media that can be accessed by a general purpose or special purpose computer or other machine with a processor.","By way of example, such machine-readable media can comprise RAM, ROM, EPROM, EEPROM, CD-ROM or other optical disk storage, magnetic disk storage or other magnetic storage devices, or any other medium which can be used to carry or store desired program code in the form of machine-executable instructions or data structures and which can be accessed by a general purpose or special purpose computer or other machine with a processor.","When information is transferred or provided over a network or another communications connection (either hardwired, wireless, or a combination of hardwired or wireless) to a machine, the machine properly views the connection as a machine-readable medium.","Thus, any such connection is properly termed a machine-readable medium.","Combinations of the above are also included within the scope of machine-readable media.","Machine-executable instructions include, for example, instructions and data which cause a general purpose computer, special purpose computer, or special purpose processing machines to perform a certain function or group of functions.","Although the figures may show or the description may provide a specific order of method steps, the order of the steps may differ from what is depicted.","Also two or more steps may be performed concurrently or with partial concurrence.","Such variation will depend on various factors, including software and hardware systems chosen and on designer choice.","All such variations are within the scope of the disclosure.","Likewise, software implementations could be accomplished with standard programming techniques with rule based logic and other logic to accomplish the various connection steps, processing steps, comparison steps and decision steps."]],"string":"[\n [\n \"ENGINE GOVERNOR\",\n \"An electronic governor system includes a motor, a transmission coupled to the motor, a throttle plate coupled to the transmission, the throttle plate movable to multiple positions between closed and wide-open, wherein power is supplied to the motor to move the throttle pate to a desired position and wherein power is not supplied to the motor to maintain the throttle plate in the desired position.\"\n ],\n [\n \"1.An electronic governor system, comprising: a motor; a transmission coupled to the motor; a throttle plate coupled to the transmission, the throttle plate movable to a plurality of positions between closed and wide-open; an engine speed sensor; and a controller including a feedback control module and an adaptive control module; wherein the feedback control module is configured to: determine an engine speed error based on a comparison of a current engine speed input signal from the engine speed sensor and a desired engine speed; and provide an engine speed output signal to the motor to control the position of the throttle plate to correct the engine speed error, wherein the engine speed output signal is determined by a control algorithm using the engine speed error as an input; wherein the adaptive control module is configured to: determine an expected engine speed error correction based on the engine speed output signal provided by the feedback control module; determine an actual engine speed error correction based on a current engine speed input signal from the engine speed sensor and a previous engine speed input signal from the engine speed sensor; determine a correction error based on the expected engine speed error correction and the actual engine speed correction; and adjust a parameter of the control algorithm of the feedback control module when the correction error is within a predetermined range or outside of a predetermined range.\",\n \"2.The electronic governor system of claim 1, wherein the feedback control module utilizes a proportional-integral-derivative control algorithm to provide the engine speed output signal and the parameter adjusted by the adaptive control module is at least one of a proportional parameter, an integral parameter, and a derivative parameter.\",\n \"The electronic governor system of claim 2, wherein the proportional-integral-derivative control algorithm utilizes a plurality of parameter sets, each parameter set including a proportional parameter, an integral parameter, and a derivative parameter, and wherein the feedback control module is configured to utilize a specific parameter set based on the position of the throttle plate.\",\n \"3.The electronic governor system of claim 3, wherein a first parameter set is utilized by the proportional-integral-derivative control algorithm when the throttle plate is near the closed position and a second parameter set is utilized by the proportional-integral-derivative control algorithm when the throttle plate is near the wide-open position.\",\n \"4.The electronic governor system of claim 3, further comprising a temperature sensor configured to detect a temperature, wherein a first parameter set is utilized by the proportional-integral-derivative control algorithm when the detected temperature is below a threshold and a second parameter set is utilized by the proportional-integral-derivative control algorithm when the detected temperature is above the threshold.\",\n \"5.The electronic governor system of claim 1, wherein the feedback control module utilizes a fuzzy logic control algorithm to provide the engine speed output signal and the parameter adjusted by the adaptive control module is at least one parameter of at least one rule of the fuzzy logic control algorithm.\",\n \"6.The electronic governor system of claim 6, further comprising a temperature sensor configured to detect a temperature, wherein the detected temperature is an input to the fuzzy logic control algorithm.\",\n \"7.The electronic governor system of claim 1, further comprising an ignition system, wherein excess energy from the ignition system is used to power the motor.\",\n \"8.The electronic governor system of claim 1, wherein power is not supplied to the motor when the throttle plate position is not changing.\",\n \"9.The electronic governor system of claim 1, wherein the adaptive control module is configured to adjust a parameter of the feedback control module such that a subsequent engine speed output signal is more aggressive when the expected engine speed error correction is less than the actual engine speed correction.\",\n \"10.The electronic governor system of claim 1, wherein the adaptive control module is configured to adjust a parameter of the feedback control module such that a subsequent engine speed output signal is less aggressive when the expected engine speed error correction is greater than the actual engine speed correction.\",\n \"11.A four-cycle small internal combustion engine, comprising: an engine speed sensor configured to detect an engine speed; an electronic governor system configured to change an engine operating speed in response to a load input; and a load sensing system configured to determine an engine load based on changes in the detected engine speed and provide the load input to the electronic governor system based on the determined engine load.\",\n \"12.The engine of claim 12, wherein the electronic governor system is configured to provide at least two operating modes, wherein the electronic governor system is configured to set the engine operating speed to a first speed in the first operating mode and set the engine operating speed to a second speed greater than the first speed in the second operating mode.\",\n \"13.The engine of claim 13, wherein the electronic governor system is configured to implement the first operating mode when the load input is below a first predetermined threshold value and implement the second operating mode when the load input is above a second predetermined threshold value.\",\n \"14.The engine of claim 14, wherein the first predetermined threshold value and the second predetermined threshold value are the same.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>The present invention relates generally to the field of electronic governors, and more particularly to electronic governors for small engines.\",\n \"A typical electronic governor controls engine speed by controlling throttle plate position with a stepper motor.\"\n ],\n [\n \"<SOH> SUMMARY <EOH>One embodiment of the invention relates to an electronic governor system including a motor, a transmission coupled to the motor, a throttle plate coupled to the transmission, an engine speed sensor, and a controller including a feedback control module and an adaptive control module.\",\n \"The throttle plate is movable to a plurality of positions between closed and wide-open.\",\n \"The feedback control module is configured to determine an engine speed error based on a comparison of a current engine speed input signal from the engine speed sensor and a desired engine speed and provide an engine speed output signal to the motor to control the position of the throttle plate to correct the engine speed error.\",\n \"The engine speed output signal is determined by a control algorithm using the engine speed error as an input.\",\n \"The adaptive control module is configured to determine an expected engine speed error correction based on the engine speed output signal provided by the feedback control module, determine an actual engine speed error correction based on a current engine speed input signal from the engine speed sensor and a previous engine speed input signal from the engine speed sensor, determine a correction error based on the expected engine speed error correction and the actual engine speed correction, and adjust a parameter of the control algorithm of the feedback control module when the correction error is within a predetermined range or outside of a predetermined range.\",\n \"Another embodiment of the invention relates to a four-cycle small internal combustion engine including an engine speed sensor configured to detect an engine speed, an electronic governor system configured to change an engine operating speed in response to a load input, and a load sensing system configured to determine an engine load based on changes in the detected engine speed and provide the load input to the electronic governor system based on the determined engine load.\",\n \"Alternative exemplary embodiments relate to other features and combinations of features as may be generally recited in the claims.\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisional of U.S. patent application Ser.\",\n \"No.\",\n \"14/702,435 filed May 1, 2015, which claims the benefit of U.S.\",\n \"Provisional Application No.\",\n \"62/081,221, filed Nov. 18, 2014 and U.S.\",\n \"Provisional Application No.\",\n \"61/987,350, filed May 1, 2014, all of which are incorporated herein by reference in their entireties.\",\n \"BACKGROUND The present invention relates generally to the field of electronic governors, and more particularly to electronic governors for small engines.\",\n \"A typical electronic governor controls engine speed by controlling throttle plate position with a stepper motor.\",\n \"SUMMARY One embodiment of the invention relates to an electronic governor system including a motor, a transmission coupled to the motor, a throttle plate coupled to the transmission, an engine speed sensor, and a controller including a feedback control module and an adaptive control module.\",\n \"The throttle plate is movable to a plurality of positions between closed and wide-open.\",\n \"The feedback control module is configured to determine an engine speed error based on a comparison of a current engine speed input signal from the engine speed sensor and a desired engine speed and provide an engine speed output signal to the motor to control the position of the throttle plate to correct the engine speed error.\",\n \"The engine speed output signal is determined by a control algorithm using the engine speed error as an input.\",\n \"The adaptive control module is configured to determine an expected engine speed error correction based on the engine speed output signal provided by the feedback control module, determine an actual engine speed error correction based on a current engine speed input signal from the engine speed sensor and a previous engine speed input signal from the engine speed sensor, determine a correction error based on the expected engine speed error correction and the actual engine speed correction, and adjust a parameter of the control algorithm of the feedback control module when the correction error is within a predetermined range or outside of a predetermined range.\",\n \"Another embodiment of the invention relates to a four-cycle small internal combustion engine including an engine speed sensor configured to detect an engine speed, an electronic governor system configured to change an engine operating speed in response to a load input, and a load sensing system configured to determine an engine load based on changes in the detected engine speed and provide the load input to the electronic governor system based on the determined engine load.\",\n \"Alternative exemplary embodiments relate to other features and combinations of features as may be generally recited in the claims.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS The invention will become more fully understood from the following detailed description, taken in conjunction with the accompanying drawings, in which: FIG.\",\n \"1 is a perspective view of a portion of an internal combustion engine including an electronic governor system according to an exemplary embodiment; FIG.\",\n \"2 is a schematic representation of an electronic governor system according to an exemplary embodiment; FIG.\",\n \"3 is a block diagram of the controller of an electronic governor system according to an exemplary embodiment; and FIG.\",\n \"4 is a perspective view of a portion of the internal combustion engine of FIG.\",\n \"1 including the electronic governor system.\",\n \"FIG.\",\n \"5 is a perspective view of the internal combustion engine of FIG.\",\n \"1 including the electronic governor system.\",\n \"FIG.\",\n \"6 is a schematic representation of a portion of an electronic governor system, according to an exemplary embodiment, with an elliptical gear set in a first operating position.\",\n \"FIG.\",\n \"7 is a schematic representation of the portion of the electronic governor system of FIG.\",\n \"6 with the elliptical gear set in a second operating position.\",\n \"DETAILED DESCRIPTION Before turning to the figures, which illustrate the exemplary embodiments in detail, it should be understood that the application is not limited to the details or methodology set forth in the description or illustrated in the figures.\",\n \"It should also be understood that the terminology is for the purpose of description only and should not be regarded as limiting.\",\n \"Referring to FIGS.\",\n \"1-2 and 4-5, an electronic governor system is illustrated according to an exemplary embodiment.\",\n \"The electronic governor system 100 is shown in use on a small engine 105.The electronic governor system 100 includes a carburetor 110, a motor 115 (e.g., a direct current (“DC”) motor), a transmission 120, a throttle plate 125, a throttle lever 130 and a linkage 135 connecting the throttle lever to the transmission.\",\n \"In the carburetor 110, fuel is mixed with air to produce an air/fuel mixture for combustion in one or more cylinders of the engine 105.The throttle plate 125 controls the flow of the air/fuel mixture out of the carburetor 110 and in doing so controls the speed of the engine 105.As illustrated, the linkage 135 includes a link 140 and a crank arm 145.In some embodiments the electronic governor system 100 also includes an encoder 150 that is coupled to the motor 115 and the transmission 120.The motor assembly (i.e., the motor 115 and the transmission 120) is used to control the position of the throttle plate 125, thereby controlling the engine speed.\",\n \"The throttle plate 125 is movable between a closed position and a wide-open position.\",\n \"The position of the throttle plate 125 is adjusted so that the engine speed is maintained at a desired engine speed.\",\n \"The desired engine speed can be a constant or can be varied by a user or a controller in response to inputs from the engine (e.g., inputs related to engine load, desired output, or other engine operating conditions or objectives).\",\n \"The motor 115 is relatively low cost, particularly with respect to the stepper motor typically used in other electronic governor systems.\",\n \"The motor 115 does not track steps of the motor's rotation like a stepper motor.\",\n \"In some embodiments, the motor 115 is a brushed motor.\",\n \"The transmission 120 provides a large reduction ratio (i.e., input speed/output speed).\",\n \"For example, the motor 115 may have a top speed of 4,000 revolutions per minute (rpm).\",\n \"The transmission 120 may provide a reduction so that the output from the transmission turns at 100 rpm (i.e., a 40:1 reduction ratio).\",\n \"This will result in a transmission output speed that is relatively fast as compared to the amount of rotation necessary to adjust the throttle plate position (e.g., 75 to 100 rpm), with the throttle plate's range of motion (i.e., between the closed position and the wide-open position) being less than a full revolution, and produces a relatively large amount of torque.\",\n \"At this relatively fast transmission output speed the throttle plate 125 is able to move from closed to wide open in about 40 milliseconds.\",\n \"As another example, the motor 115 may have an output speed of at about 10,000 rpm and the transmission may provide a gear reduction such that the output of the transmission is about 60 rpm (i.e.\",\n \"a reduction ratio of about 167:1).\",\n \"In some embodiments, the transmission 120 is a series of gears that provides a reduction from the input of the motor to the output of the transmission.\",\n \"The transmission 120 providing a large reduction ratio produces an output from the transmission 120 with a relatively large amount of torque.\",\n \"The output shaft of the transmission 120 only needs to rotate a small amount to adjust the throttle plate position within the throttle plate's range of motion and in doing so is able to produce a lot of torque.\",\n \"Another advantage of this large reduction ratio is that power only needs to be supplied to the motor 115 when moving the output shaft of the transmission 120 to the desired position.\",\n \"This position corresponds with the desired position of the throttle plate 125.After the output shaft of the transmission 120, and therefore the throttle plate 125, has reached the desired position, the motor 115 is no longer powered (i.e., the motor 115 is turned off).\",\n \"In this way, power is not needed to maintain the position of the output shaft of the transmission 120 and of the throttle plate 125.The relatively large reduction ratio provided by the transmission 120 is able to maintain or hold the throttle plate 125 in position without power being supplied to the motor 115 to maintain the desired position of the throttle plate 125.In some embodiments several components of the electronic governor system 100 are included within a single housing.\",\n \"For example, the motor 115 and the transmission 120 could form a single unit.\",\n \"This unit may be combined with the controller 155 and its associated circuit board.\",\n \"As shown in FIG.\",\n \"1, the linkage 135 connects the output shaft of the transmission 120 to the throttle lever 130.The throttle lever 130 is connected to the throttle plate 125, such that the motor 115 drives the transmission 120 which moves the linkage 135 which moves the throttle lever 130 which moves the throttle plate 125.In this way, powering the motor 115 causes the throttle plate 125 to change position.\",\n \"Though the linkage 135 is shown as a two-piece linkage, other appropriate mechanisms for connecting the output shaft of the transmission 120 to the throttle plate 125 may be utilized.\",\n \"For example, the output shaft of the transmission 120 could be directly connected to the throttle plate 125 or one or more components could be used to connect the output shaft of the transmission 120 to the throttle plate 125.In some embodiments, one or more gears are used to connect the output shaft of the transmission 120 to the throttle plate 125.In some embodiments, the encoder 150 is connected to the motor 115 and the transmission 120 to determine the position of the output shaft of the transmission 120.In some embodiments, the encoder 150 is an absolute encoder and can be used to keep track of the position of the output shaft of the transmission 120 and therefore the position of the throttle plate 125.As shown in FIG.\",\n \"2, the electronic governor system 100 includes a controller 155 that controls the operation of the motor 115.In some embodiments, the controller 155 also controls the operation of other components of the electronic governor system 100 that will be described in more detail below.\",\n \"These components may include an engine speed sensor 160, a user interface 165, a temperature sensor 170, a current sensor 175, an ignition system 180, and a rev limiter 185.Different embodiments of the electronic governor system 100 may include some, none or all of these additional components.\",\n \"As shown in FIG.\",\n \"3, the controller 155 includes a processing circuit 190, an input interface 195, and an output interface 200.The processing circuit 190 includes a processor 205 and memory 210.The processing circuit 190 and processor 205 are configured to receive inputs from input interface 195 (e.g., via a wired or wireless communication link with other components of the engine and/or electronic governor system) and to provide an output (e.g., a control signal, an actuator output, etc.)\",\n \"via output interface 200 (e.g., via a wired or wireless communication link to the motor 115, other components of the engine, and/or other components of the electronic governor system).\",\n \"The processing circuit 190 can be a circuit containing one or more processing components (e.g., the processor 205) or a group of distributed processing components.\",\n \"The processor 205 may be a general purpose or specific purpose processor configured to execute computer code or instructions stored in the memory or received from other computer readable media (e.g., CD-ROM, network storage, a remote server, etc.).\",\n \"The processing circuit 190 is also shown to include the memory 210.Memory 210 may be RAM, hard drive storage, temporary storage, non-volatile memory, flash memory, optical memory, or any other suitable memory for storing software objects and/or computer instructions.\",\n \"When the processor 205 executes instructions stored in the memory 210 for completing the various activities described herein, the processor 205 generally configures the computer system and more particularly the processing circuit 190 to complete such activities.\",\n \"The memory 210 may include database components, object code components, script components, and/or any other type of information structure for supporting the various activities described in the present disclosure.\",\n \"For example, the memory 210 may store data regarding the operation of a controller (e.g., previous setpoints, previous behavior patterns regarding used energy to adjust a current value to a setpoint, etc.).\",\n \"According to an exemplary embodiment, the memory 210 is communicably connected to the processor 205 and includes computer code for executing one or more processes described herein and the processor 205 is configured to execute the computer code.\",\n \"The memory 210 is shown to include a feedback control module 215 and an adaptive control module 220.The memory may include a throttle plate position module 225 and an engine shutdown module 230.The feedback control module 215 is the primary logic module configured to provide the feedback-based control activity of the controller 155.In some embodiments, the feedback control module 215 is a proportional-integral-derivative (PID) control module.\",\n \"In other embodiments, the feedback control module 215 is a fuzzy logic control module.\",\n \"The feedback control module 215 uses information from the input interface 195 (e.g., detected engine speed) to calculate or otherwise obtain the controlled variable (e.g., throttle plate position).\",\n \"The feedback control module 215 may also use information stored in the memory 210 (e.g., previous detected engine speed, desired engine speed, etc.)\",\n \"in calculating or obtaining the controlled variable.\",\n \"The adaptive control module 220 is configured to determine appropriate values of control parameters (e.g., proportional gain, integral gain, derivative gain, etc.).\",\n \"The adaptive control module 220 may tune control parameters based on a model identification adaptive control (MIAC) approach or another adaptive tuning approach or algorithm.\",\n \"The feedback control module 215 is configured to provide an engine speed control output based an engine speed error determined by a comparison of a current engine speed input from the engine speed sensor 160 with the desired engine speed.\",\n \"The output is provided to the motor 115 to adjust the throttle plate 125 position, thereby controlling the engine speed and correcting any engine speed error so that the detected engine speed and the desired engine speed are the same or substantially the same (e.g., within a predetermined range).\",\n \"The feedback control module can use different types of feedback control including PID control algorithms or fuzzy logic control rules.\",\n \"The adaptive control module 220 adjusts one or more parameters (e.g., coefficients, gains, rules, etc.)\",\n \"of the feedback control module 215 such that the feedback control module learns the appropriate operating parameters for a specific engine and end product (e.g., lawn mower, snow thrower, generator, pressure washer, etc.).\",\n \"For example, the feedback control module 215 may determine an engine speed error and provide an engine speed output intended to correct that error or a portion of the error (e.g., reduce the error by half).\",\n \"The adaptive control module 220 determines what an expected engine speed error correction is based on the output provided by the feedback control module 215.The adaptive control module 220 also determines an actual engine speed correction based on the current engine speed input from the engine speed sensor 160 and a previous engine speed input from the engine speed sensor 160.The adaptive control module 220 then is able to determine a correction error based on the expected engine speed error and the actual engine speed correction.\",\n \"In this way, the adaptive control module 220 is able to determine if the actual engine speed correction is the same as or close to the expected engine speed error correction (e.g., determine a correction error).\",\n \"If the actual engine speed correction is not the same (or within a predetermined range acceptable as the same) as the expected engine speed correction, the adaptive control module 220 adjusts one or more parameters of the feedback control module 215.When the actual engine speed error correction was less than the expected engine error correction the parameter change is such that the subsequent attempt at correcting engine speed will be more aggressive.\",\n \"As used herein, more aggressive means that the position change of the throttle plate with adjusted parameter setting will be greater than at the previous parameter setting and less aggressive means that the position change of the throttle plate with adjusted parameter setting will be less than at the previous parameter setting.\",\n \"For example, in a controller 155 using PID control the adaptive control module 220 can change one or more of the proportional, integral and derivative parameters (e.g., coefficients or gains) of the feedback control module 215 to achieve the desired change in engine speed.\",\n \"The PID control of the feedback control module 215 may set forth a control algorithm to determine the motor adjustment—the amount of time voltage is supplied to the motor 115 (the duration or “width” of a voltage pulse).\",\n \"For example, the PID control algorithm may use the following equation to determine the motor adjustment where Error is the engine speed error.\",\n \"Motor Adjustment = P i Error + D i d Error dt + I i ∫ Error The adaptive control module 220 may be configured to adjust one or more of the proportional, integral and derivative parameters in response to a comparison of the actual change in engine speed following a throttle plate position adjustment (e.g., as measured by the engine speed sensor 160) with the expected change in engine speed following a throttle plate position adjustment (e.g., the engine speed error or a portion (e.g., one half, one third, etc.)\",\n \"of the engine speed error).\",\n \"If the actual change in engine speed is less than the expected change in engine speed, one or more of the parameters is adjusted to make the motor adjustment more aggressive (i.e., provide a voltage pulse of a longer duration).\",\n \"If the actual change in engine speed is greater than the expected change in engine speed, one or more of the parameters is adjusted to make the motor adjustment less aggressive (i.e., provide a voltage pulse of a shorter duration).\",\n \"The comparison of actual change in engine speed to the expected change in engine speed can be performed at a specific time (e.g., 2-3 engine cycles) after a motor adjustment pulse is sent to the motor 115.In some embodiments, the pulse of the motor adjustment has a duty cycle and the duty cycle of the pulse of the motor adjustment may be adjusted when the actual change in engine speed is different than the expected change in engine speed.\",\n \"In some embodiments, the motor adjustment algorithm In some embodiments using a PID control algorithm there are multiple parameter sets.\",\n \"For example, a first parameter set may be used when the throttle plate 125 is close or near to the closed position and a second parameter set may be used when the throttle plate 125 is close or near to the wide open position.\",\n \"This is helpful because the operating performance (e.g., speed) of the engine is not linear with respect to throttle plate position.\",\n \"When the throttle plate 125 is near the wide open position, the engine speed is not very responsive to changes in the throttle plate position and when the throttle plate 125 is near the closed position, the engine speed is more responsive to changes in the throttle plate position.\",\n \"Therefore, the parameter set associated with operation when the throttle plate 125 is near the closed position would be less aggressive than the parameter set that is used when the throttle plate 125 is near the wide open position.\",\n \"Two or more parameter sets based on the throttle position could be implemented.\",\n \"For example a curve could be fit so that the parameter sets used change from the closed position to the wide open position.\",\n \"The adaptive control module 220 may also be configured to perform a comparison of the expected output (i.e., rotational speed) of the motor 115 from a particular duration of applied voltage (voltage pulse) to the back electromotive force (“back-EMF”) actually caused by that particular duration of applied voltage.\",\n \"Back-EMF is caused by the rotation of the motor and can act as a proxy for a motor sensor for detecting the rotational speed of the motor.\",\n \"In this way the adaptive control module 220 allows the system to learn or adjust to the operational characteristics of a particular engine.\",\n \"Variations among particular engines (e.g., individual DC motors, the end use of the engine, etc.)\",\n \"will result in different duration voltage pulses being necessary to move a throttle plate a specific amount.\",\n \"For example, in one engine a voltage pulse of 10 milliseconds may move the throttle plate 10 degrees, but may only move the throttle plate of a second engine 5 degrees.\",\n \"The back-EMF correlation performed by the adaptive control module 220 allows the system to learn the particular voltage pulse duration needed for a particular throttle plate position change within the addition of a motor speed sensor and allows for that correlation to change as engine performance changes over the life of a particular engine.\",\n \"The back-EMF comparison can also be used to determine when the throttle plate 125 is at either end of its range of motion (i.e., closed position or wide open position) because the throttle plate 125 is at a hard stop at either end of its range of motion and the back-EMF should approach zero as the motor is unable to turn.\",\n \"The back-EMF comparison can also be used to identify variations between the operational characteristics of individual motors and a curve establishing a known or desired relationship between back-EMF and engine speed (e.g., RPM) and to determine the operational characteristics that need to be modified (e.g., duration of voltage pulses) to fit a specific motor to the known back-EMF and engine speed curve.\",\n \"As shown in FIGS.\",\n \"6-7, in some embodiments of the electronic governor system 100, an elliptical gear set 186 is included between the transmission 120 and the throttle lever 130 to account for the non-linearity of engine speed with respect to throttle plate position.\",\n \"The elliptical gear set 186 includes two elliptical gears—a driving gear 187 and a driven gear 188.The driving gear 187 has a minor radius 189 that is less than a major radius 191.The driving gear 187 is coupled to or a component of the transmission 120.The driven gear 188 is coupled to the throttle plate 125 (e.g., directly or indirectly by one or more links or gears).\",\n \"The driven gear 188 has a minor radius 192 that is less than a major radius 193.The elliptical gear set 186 is arranged so that the driven gear 188 provides a relatively large amount of movement of the throttle plate 125 in response to specified amount of movement of the driving gear 187 when the throttle plate 125 is near the wide open position (FIG.\",\n \"6) and so that the driven gear 188 provides a relatively small amount of movement of the throttle plate 125 in response to the same specified amount of movement of the driving gear 187 when the throttle plate 125 is near the closed position (FIG.\",\n \"7).\",\n \"As shown in FIG.\",\n \"6, when the throttle plate 125 is near the wide open position, the major radius 191 of the driving gear 187 engages the minor radius 192 of the driven gear 188.As shown in FIG.\",\n \"7, when the throttle plate 125 is near the closed position, the minor radius 189 of the driving gear 187 engages the major radius 193 of the driven gear 188.In embodiments where the feedback control module 215 uses a fuzzy logic control algorithm to control the output to the motor 115, a list of fuzzy logic rules is created to control the operation of the motor 115.These rules allow for non-linear control of the non-linear engine operation.\",\n \"In some embodiments, the temperature sensor 170 provides the detected temperature as an input to the fuzzy logic rule set.\",\n \"In some embodiments the electronic governor system 100 includes a temperature sensor 170.The temperature sensor 170 is configured to detect a temperature (e.g., an ambient temperature, an engine temperature, or other appropriate temperature).\",\n \"The detected temperature is provided as an input to the controller 155 and may be utilized as an input to the various logic modules of the controller 155.As the engine may operate differently as relatively cold temperatures and relatively hot temperatures different control parameters (e.g., of the feedback control module 215 and/or the adaptive control module 220) can be used when the detected temperature is either below or above one or more thresholds (e.g.\",\n \"a hot operating condition threshold and a cold operating condition threshold).\",\n \"The memory 210 may also include a throttle plate position module 225.The throttle plate position module 225 is configured to determine the position of the throttle plate 125 based on tracking the expected changes in the throttle plate position from an initial throttle plate position.\",\n \"The initial throttle plate position is known.\",\n \"For example, the wide open position may be considered to be 90° and the closed position may be considered to be 0°.\",\n \"Based on that starting position (e.g., the wide open position), the throttle plate position module 225 calculates a current throttle plate position based on the changes to the throttle plate position caused by the motor 115.The product of the voltage applied to the motor 115 and the amount of time for which that voltage is supplied corresponds to an expected change in the position of the throttle plate 125.By keeping track of all expected movements of the throttle plate 125 from the initial known position caused by operation of the motor 115, the throttle plate position module 225 is able to track the position of the throttle plate 125.Alternatively, an encoder (e.g., the encoder 150) may keep track of the throttle plate position.\",\n \"However, an encoder adds cost that may not be necessary for the electronic governor system 100 to operate as desired.\",\n \"The engine 105 includes an ignition system 180.In some embodiments excess energy from the ignition system 180 is used to power the motor 115 and/or the controller 155.In this way the electronic governor system 100 is able to operate without a separate or dedicated power supply (e.g., a separate battery or the battery used to power an electric engine starting system).\",\n \"In a magneto or spark ignition system extra energy in the form of ignition sparks or pulses can be harvested and stored in a capacitor or other energy storage device (e.g., battery) for use to power the motor 115.Though a spark based ignition system is discussed as an example other types of ignition systems are possible.\",\n \"The excess energy of the ignition system may also be sufficient to power the motor 115 and/or the controller 155.After the engine 105 is started, there is a relatively abundant amount of excess energy that can be harvested to power the electronic governor system 100.For example, the energy from the two positive pulses or sparks of a four-cycle magneto ignition system can yield about one amp of current.\",\n \"Other types of ignition systems also provide waste energy that could be harvested to power the electronic governor system.\",\n \"In a four-cycle magneto ignition system there is a waste spark on the exhaust stroke of the cylinder.\",\n \"In such a system, the two positive pulses or sparks and the waste negative pulse or spark could all be harvested.\",\n \"In some embodiments, other power supplies that do not include a separate or dedicated power supply (e.g., a separate battery) may be used to power the motor 115 and/or the controller 155.Alternative power supplies include an alternator driven by the engine 105, a thermoelectric power generator that makes use of waste heat from the engine 105, a piezoelectric power generator driven by vibrations of the engine 105 and/or the outdoor power equipment driven by the engine 105, a Faraday power generator including a magnet oscillating within a coil driven in sync with the reciprocating movement of the piston of the engine 105.In some embodiments, an energy storage device (e.g., a rechargeable battery, a capacitor, etc.)\",\n \"is provided to store the energy produced by the power supplies described above.\",\n \"In this way, power is available for the motor 115 and/or the controller 155 when the engine 105 is initially started and there is not an immediately available supply of energy to be harvested from the operating engine 105.A rev limiter 185 may be provided to prevent the engine 105 from achieving an overspeed condition in which the engine speed exceeds a threshold (e.g., a redline).\",\n \"The rev limiter 185 detects the engine speed and when the engine speed exceeds the threshold, shorts the ignition to prevent the engine from continuing to exceed the speed threshold.\",\n \"To make the reduction in speed associated with shorting the ignition smoother (e.g., less sudden and/or less noisy to the operator), it may be preferable to short a subset of the ignition sparks rather than all of the engine sparks.\",\n \"Shorting all of the ignition events (e.g., sparks associated with combustion events) would have an audible effect and the engine speed would abruptly drop.\",\n \"Shorting fewer than 100% of the ignition events (e.g., every second, third, fourth, etc.\",\n \"ignition event) would slow the engine speed but be less abrupt and less noticeable audibly to the user.\",\n \"A user interface 165 may be provided so that the user is able to control the desired speed (e.g., expected or targeted speed) of the engine 105.This user interface 165 could be an analog input such as a voltage divider, a fixed resistor, a variable resister (e.g., a potentiometer or sliding variable resistor).\",\n \"In some embodiments where the engine was used to power a wheel drive train (e.g., on a riding or walk behind lawn mower or snow thrower) a throttle input (e.g., a gas pedal or lever) may be moved to adjust the analog input and therefore adjust the desired speed of the engine.\",\n \"If the engine is used to power a generator, a discreet two-position analog input could be used to switch the output frequency of the electricity provided by the generator between the 60 Hz electricity used in the United States and Canada, and the 50 Hz electricity used elsewhere in the rest of the world (e.g., Europe and Asia).\",\n \"Other discreet control modes, for example, could include a quiet operating mode versus a power operating mode.\",\n \"The quiet operating mode may be configured so that the engine runs at a relatively low speed (e.g., 2,400 rpm) versus the power mode which runs at a relatively high rpm (e.g., 3,000 rpm).\",\n \"In some embodiments, the user interface is wireless RF, infrared IR, and LED or light pulse interface or capacitive sensing interface (e.g., a touchscreen).\",\n \"In some embodiments the user interface 165 includes a second microcontroller.\",\n \"For example, a touch screen or other interface device could provide inputs to a second controller which provide a variable voltage output to the controller operating the electronic governor system.\",\n \"In some embodiments, the user interface 165 provides a digital input.\",\n \"Initial performance characteristics of the engine governor system 100 can also be varied (e.g., more or less aggressive engine speed error correction.\",\n \"These characteristic settings could be preset when the system or engine is assembled (e.g., by setting a specific resistance or voltage value).\",\n \"For example one setting could be used with relatively low inertia equipment driven by the engine (e.g., the pump of a pressure washer) and a second setting could be used with relatively high inertia equipment driven by the engine (e.g., the blade of a lawn mower).\",\n \"This provides the controller 155 with some initial performance characteristics (e.g., the relative inertia of the equipment being driven) before it has even had a chance to start adapting the control parameters based on the actual use of the engine.\",\n \"For example, 1000-4000 rpm could be selected with input resistances of 100-400 ohms and with input resistances of 1100-1400 ohms with settings of 100-400 ohms providing moderately aggressive performance for relative low inertia applications and 1100-1400 ohms providing more aggressive performance for relatively high inertia applications.\",\n \"Additionally, there could also be more than two performance characteristics settings (e.g., low inertia, moderately low inertia, moderate inertia, moderately high inertia, high inertia, etc.)\",\n \"that could be selected based on engine type (e.g., size, number of cylinders, rated horsepower, rated torque) and equipment to be driven by the engine.\",\n \"Alternatively, the performance characteristic settings could be tied to the voltages that will be read by the controller 155.A current sensor 175 may be included to monitor the current draw on the motor 115.For example, a shunt resistor may be used to measure this motor current.\",\n \"The current sensor 175 is used to detect potential failures in the electronic governor system 100 and shut down the engine 105 (e.g., stop the engine) in response to detecting such a failure.\",\n \"For example, a detected current above a high current threshold could indicate a jam, obstruction, the end of travel, a motor short, or some other situation in which the motor 115, the transmission 120, the throttle plate 125, the throttle lever 130, the linkage 135, or other movable component is unable to move (e.g., rotate, translate, etc.)\",\n \"as desired.\",\n \"When the current sensor 175 detects a current below a low current threshold this could indicate a broken wire or some other loss of electrical communication between the components of the electronic governor system 100.Both a high current above the high threshold and a low current below the low threshold may be indicative of situations in which the engine 105 should be stopped or shut down to prevent possible damage to the engine.\",\n \"Engine shutdown module 230 is configured to shut down, stop, turn off, or deactivate the engine in response to an appropriate input (e.g., release of a safety interlock, like when the bail of a walk-behind lawn mower is released, movement of an on/off switch to the off position, etc.).\",\n \"Engine shutdown module 230 may receive an input from the current sensor 172 and shut off the engine in response to low current or high current as described above.\",\n \"In some embodiments, the engine speed sensor 160 detects the engine speed using an ignition signal from the ignition system 180.For example, the positive sparks or pulses from the ignition system could be counted and used to determine the engine speed.\",\n \"This method of determining engine speed provides an additional advantage when shorting the negative pulses or sparks with the rev limiter 185.The engine speed detection, which is determined from the positive pulses, is not lost when slowing down the engine 105 with the rev limiter 185 by shorting the negative pulses or sparks.\",\n \"In other embodiments, other appropriate engine speed sensors are utilized.\",\n \"The electronic governor systems described herein are able to adjust the operating speed of the engine in response to an input from a load sensing system.\",\n \"Combining a load sensing system with the electronic governor systems allows the operating speed of the engine to be optimized for various load conditions.\",\n \"For example, an engine including an electronic governor system and a load sensing system as described herein could operate in one of two modes: a no load or low load mode (e.g., when the blade of a lawn mower is not cutting any grass) where the engine operates at an idle or relatively low speed and a high load mode (e.g., when the blade of the lawn mower is cutting grass) where the engine operates at an high operating or relatively high speed.\",\n \"More complex systems allow for additional modes of operation for example a moderate load mode (e.g., when the blade of the lawn mower is cutting grass that is thinner than that being cut in the high load mode) where the engine operates at a speed between the idle speed and the high operating speed.\",\n \"The engine speed could also vary continuously with load or approximately continuously with load (e.g., with a step-function or other appropriate curve fit).\",\n \"For example, the engine speed could be controlled to always fit within a band or window defined by a high engine speed curve and a low engine speed curve and operate in a manner similar to a continuously variable transmission.\",\n \"The load sensing system makes use of the principle of rotational motion that the sum of the torques for the system equals zero.\",\n \"The sum of the torques is equal to inertia times the change in angular velocity as shown in the equation below.\",\n \"The TorqueProduced is the torque produced from combustion by the engine and the TorqueLoad/Losses is the torque produced from the load on the engine (e.g., mower blade, pressure washer pump, drive system, etc.)\",\n \"and any losses within the engine (e.g., friction, gas compression, vacuum, etc.)\",\n \"J{umlaut over (θ)}=TorqueProduced−TorqueLoad/Losses In a first load sensing system for a single cylinder four-cycle engine, the load can be estimated by comparing the rotational speed of the engine for two consecutive engine revolutions.\",\n \"A “fast” revolution occurs during the expansion and exhaust cycles of the engine.\",\n \"A “slow” revolution occurs during the intake and compression cycles of the engine.\",\n \"The difference in revolution speed (e.g., in revolutions per minute (“RPM”)) is a function of the TorqueLoad/Losses and inertia.\",\n \"When the inertia is known (e.g., the inertia of a specific end use of the engine, for example for a specific lawn mower, pressure washer, tractor, or other piece of outdoor power equipment), then the difference in revolution speed from the fast revolution to the slow revolution (e.g., RPM of the fast revolution minus the RPM of the slow revolution) is a function of the TorqueLoad/Losses.\",\n \"By calculating this difference, the load sensing system can accurately estimate the load on the engine.\",\n \"The load can then be used as an input to the electronic governing system to control the speed of the engine.\",\n \"In a second load sensing system for a single cylinder four-cycle engine, the load can be estimated by comparing the rotational speed of the engine for each of the four cycles.\",\n \"The sum of the torques for each of the four cycles (expansion, compression, intake, and compression) can be calculated according to the equation shown below.\",\n \"J{umlaut over (θ)}=TorqueProduced−TorqueLoss−TorqueLoad Using four versions of this equation, one for each cycle, with the inertia remaining constant for all four equations, the load sensing system is able to determine the load based on the measured change in engine speed from one cycle to the next because each of the four equations is left with only one unknown (four equations with four unknowns are solvable).\",\n \"For the expansion cycle, TorqueLoss is negligible and can be assumed to be zero.\",\n \"For the exhaust cycle, TorqueProduced and TorqueLoss are negligible and can be assumed to be zero.\",\n \"For the intake cycle, TorqueProduced and TorqueLoss are negligible and can be assumed to be zero.\",\n \"For the compression cycle, TorqueProduced is negligible and can be assumed to be zero.\",\n \"The combustion process can vary from combustion cycle.\",\n \"The combustion process regularly experiences “bumps” or “pops” due to many possible factors including fuel quality, air availability, variations in the fuel-air ration, etc.\",\n \"Either of the two load sensing systems described above can reduce the impact of these combustion process variations, which may result in variations of the engine speed, which is the inputs to the calculations used to determine the load for both systems, by using a running average and/or a standard deviation of the engine speed measurements.\",\n \"The average load value can be calculated using the equation below.\",\n \"“A” is a factor used to weigh the average load value.\",\n \"The value of A may be selected based on the intended end use of the engine (e.g., lawn mower, pressure washer, tractor, or other piece of outdoor power equipment) and the desired engine performance for that engine.\",\n \"As the value of A increases, the average load value becomes smoother, but it delays response time for true changes in load, rather than momentary chances due to combustion variations.\",\n \"Avg .\",\n \" Load Value = ( Avg .\",\n \" Load Value * A + New Load Value ) A + 1 The average load value can be used as the trigger to change between operating modes of the electronic governing system.\",\n \"For example for the two operating mode electronic governing system discussed above, the no load operating mode can be triggered when the average load value is at or below a predetermined threshold value and the high load operating mode can be triggered when the average load value is at or above a predetermined threshold value.\",\n \"To avoid hunting or hysteresis between the two modes, the predetermined threshold values can be different for the no load operating mode and the high load operating mode.\",\n \"For example, the no load threshold value could be an average load value of 15 and the high load threshold value could be 20, providing a window between 15 and 20 where mode hunting is avoided.\",\n \"Alternatively a percentage change threshold (e.g., 20%) in average load value could be used as the trigger to change between operating modes of the electronic governing system.\",\n \"The threshold values, whether absolute or a percentage, can be tied to specific engine sizes and end products.\",\n \"Another way to avoid mode hunting is to include a minimum predetermined time period between operating mode changes.\",\n \"For example, each operating mode could be required to run for at least 5 seconds before be able to switch based on the current average load value.\",\n \"A standard deviation of the load value could be used in similar manners on its own or in combination with the average load value to provide a trigger to change between operating modes of the electronic governing system.\",\n \"The standard deviation of the measured engine speed may also be used to distinguish between an actual change in engine speed (e.g., due to an increased or decreased load on the engine) and intermittent variations in engine speed due to combustion irregularities.\",\n \"Measured engine speed includes expected variations on a per-cycle basis.\",\n \"The expansion (combustion, power) cycle has a faster engine speed than the intake, compression, and exhaust cycles.\",\n \"The standard deviation accounts for the expected variations on a per-cycle basis so that only engine speed changes in excess of the standard deviation, or in excess of the standard deviation modified by an error factor (e.g., multiplied or added to the standard deviation), are used to trigger a change in throttle plate position by the engine governing system.\",\n \"Both load sensing systems make use of an appropriate controller to implement the control schemes discussed above and of an appropriate engine speed sensor to detect the engine speed for use as an input as discussed above.\",\n \"Possible engine speed sensors include a magnetic field sensor (e.g., a Hall Effect sensor or reed switch) in combination with a magnet on the flywheel.\",\n \"The magnet on the flywheel could be the same used to generate the spark for the ignition system, but could also be a separate second magnet.\",\n \"Both load sensing systems could also include an operating mode input to provide a verification that the detected change in load based on the engine speed calculations as an intended change in load based on the user's intended operating mode.\",\n \"For example, a tilt sensor could indicate when the front wheels of a walk behind lawn mower are lifted off the ground, thereby confirming a reduced load.\",\n \"A switch on the bail of walk behind lawn mower could indicate when the operator engages the drive system.\",\n \"A vacuum sensor could detect changes in engine vacuum as a redundant check on load changes.\",\n \"A user-actuated switch could also be used as a feedforward input to the load sensing system.\",\n \"For example, a switch actuated by a user operated lever (e.g., the bail of a walk-behind mower, the trigger of a pressure washer spray gun, a control lever of a snowthrower, a power takeoff engage switch on a riding tractor, etc.)\",\n \"would indicate an expected engine load to the load sensing system (e.g., operation of the tool driven by the engine, a load on the tool driven by the engine, engagement of a drive train, etc.).\",\n \"The load sensing system could use this feedforward input to override or supplement the load output provided by the load sensing system.\",\n \"The same controller or separate controllers can be used to implement the controls schemes used by the electronic governor system and by the load sensing system.\",\n \"For example, as shown in FIG.\",\n \"2, the controller 155 could be used to control both the electronic governor system 100 and a load sensing system as described above via a load sensing module 235 configured to implement a load sensing system as described herein.\",\n \"The engine speed sensor 160 could be used to provide the necessary engine speed inputs to the load sensing module 235 to implement the load sensing system.\",\n \"The construction and arrangement of the apparatus, systems and methods as shown in the various exemplary embodiments are illustrative only.\",\n \"Although only a few embodiments have been described in detail in this disclosure, many modifications are possible (e.g., variations in sizes, dimensions, structures, shapes and proportions of the various elements, values of parameters, mounting arrangements, use of materials, colors, orientations, etc.).\",\n \"For example, some elements shown as integrally formed may be constructed from multiple parts or elements, the position of elements may be reversed or otherwise varied and the nature or number of discrete elements or positions may be altered or varied.\",\n \"Accordingly, all such modifications are intended to be included within the scope of the present disclosure.\",\n \"The order or sequence of any process or method steps may be varied or re-sequenced according to alternative embodiments.\",\n \"Other substitutions, modifications, changes, and omissions may be made in the design, operating conditions and arrangement of the exemplary embodiments without departing from the scope of the present disclosure.\",\n \"The present disclosure contemplates methods, systems and program products on any machine-readable media for accomplishing various operations.\",\n \"The embodiments of the present disclosure may be implemented using existing computer processors, or by a special purpose computer processor for an appropriate system, incorporated for this or another purpose, or by a hardwired system.\",\n \"Embodiments within the scope of the present disclosure include program products comprising machine-readable media for carrying or having machine-executable instructions or data structures stored thereon.\",\n \"Such machine-readable media can be any available media that can be accessed by a general purpose or special purpose computer or other machine with a processor.\",\n \"By way of example, such machine-readable media can comprise RAM, ROM, EPROM, EEPROM, CD-ROM or other optical disk storage, magnetic disk storage or other magnetic storage devices, or any other medium which can be used to carry or store desired program code in the form of machine-executable instructions or data structures and which can be accessed by a general purpose or special purpose computer or other machine with a processor.\",\n \"When information is transferred or provided over a network or another communications connection (either hardwired, wireless, or a combination of hardwired or wireless) to a machine, the machine properly views the connection as a machine-readable medium.\",\n \"Thus, any such connection is properly termed a machine-readable medium.\",\n \"Combinations of the above are also included within the scope of machine-readable media.\",\n \"Machine-executable instructions include, for example, instructions and data which cause a general purpose computer, special purpose computer, or special purpose processing machines to perform a certain function or group of functions.\",\n \"Although the figures may show or the description may provide a specific order of method steps, the order of the steps may differ from what is depicted.\",\n \"Also two or more steps may be performed concurrently or with partial concurrence.\",\n \"Such variation will depend on various factors, including software and hardware systems chosen and on designer choice.\",\n \"All such variations are within the scope of the disclosure.\",\n \"Likewise, software implementations could be accomplished with standard programming techniques with rule based logic and other logic to accomplish the various connection steps, processing steps, comparison steps and decision steps.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875712"}}},{"rowIdx":4494957,"cells":{"text":{"kind":"list like","value":[["Neural Progenitor Cell Differentiation","Differentiation and stability of neural stem cells can be enhanced by in vitro or in vivo culturing with one or more extracellular matrix (ECM) compositions, such as collagen I, IV, laminin and/or a heparan sulfate proteoglycan.","In one aspect of the invention, adult mammalian enteric neuronal progenitor cells can be induced to differentiate on various substrates derived from components or combinations of neural ECM compositions.","Collagen I and IV supported neuronal differentiation and extensive glial differentiation individually and in combination.","Addition of laminin or heparan sulfate to collagen substrates unexpectedly improved neuronal differentiation, increasing neuron number, branching of neuronal processes, and initiation of neuronal network formation.","In another aspect, neuronal subtype differentiation was affected by varying ECM compositions in hydrogels overlaid on intestinal smooth muscle sheets.","The matrix compositions of the present invention can be used to tissue engineer transplantable innervated GI smooth muscle constructs to remedy aganglionic disorders."],["1-13.","(canceled) 14.A method of preparing an innervated smooth muscle construct, the method comprising: obtaining a population of longitudinal smooth muscle cells; culturing the longitudinal smooth muscle cells to form a uniaxially-aligned smooth muscle sheet; obtaining a population of neural stem cells; and co-culturing the neural stem cells and longitudinal smooth muscle cells on a substrate comprising at least one extracellular matrix (ECM) material component.","15.","(canceled) 16.The method of claim 14 wherein the step of culturing the longitudinal smooth muscle cells further comprises culturing the muscle cells on a mold containing a wavy microtopography to form the uniaxially-aligned smooth muscle sheet.","17.The method of claim 14 wherein the substrate further comprises a hydrogel.","18.The method of claim 17 wherein the hydrogel comprises at least one of collagen, laminin and heparan sulfate.","19.The method of claim 17 wherein the hydrogel comprises collagen.","20.The method of claim 17 wherein the hydrogel comprises at least 800 μg/ml of collagen type I.","21.The method of claim 20, wherein the hydrogel comprises between about 800 μg/ml and about 1600 μm/ml collagen I.","22.The method of claim 17 wherein the hydrogel further comprises at least 200 μg/ml of collagen type IV.","23.The method of claim 17 wherein the hydrogel further comprises at least 5 μg/ml of laminin.","24.The method of claim 17 wherein the hydrogel is substantially free of laminin.","25.The method of claim 17 wherein the hydrogel is substantially free of heparan sulfate.","26.The method of claim 14 wherein the method further comprises administering the construct to a patient.","27.The method of claim 26, wherein the step of administering the construct further comprises implanting the construct into the patient.","28.The method of claim 27 wherein the construct comprises a hydrogel sponge with effective pore sizes ranging from 10 nanometers to 10 micrometers."],["<SOH> BACKGROUND <EOH>An uninterrupted enteric nervous system with the preservation of myenteric ganglia is required for intestinal motility and function.","Motor neurons of the myenteric ganglia predominantly express acetylcholine/tachykinins (excitatory) or nitric oxide/inhibitory peptides/purines (inhibitory) to mediate smooth muscle contraction and relaxation.","Partial, selective, or total loss of nerve function and/or loss of nerve cell populations within organs and other body structures are characteristic of numerous diseases and disorders.","For example, aganglionosis of various lengths of distal gut is the central pathology in Hirschsprung's disease.","Enteric neuropathy is also secondary to several other disorders (e.g., diabetes, Parkinson's disease, and inflammation) resulting in gastrointestinal dysfunction.","Gastrointestinal motor function is controlled by the intramural enteric nervous system.","It is a complex interplay between the smooth muscle of the muscularis externa and the two enteric neuronal plexi.","Neural stem cell therapy is an emerging therapy that aims to reinstate neuronal function and thus gastrointestinal motor function by repopulating the enteric plexi.","The research is driven by two significant findings: i) neural stem cells can be isolated from adult mammalian gut, including the ganglionated colon of Hirschsprung's patients; and ii) neural stem cells can be induced to differentiate into several neuronal subtypes and glia characteristic of the enteric nervous system (ENS) upon transplantation into explant cultures of aganglionic/aneural gut, or in vivo into distal colo-rectums in animal models.","While neural-crest derived enteric neural stem cells have been isolated from adult mammalian guts, including ganglionic bowel of patients with Hirschsprung's disease, there is little information or understanding of microenvironment-driven differentiation, and only limited studies describing subsequent functional behavior of these differentiated neurons in vitro.","Moreover, restoration of nerve functions by neural stem cell transplantations as a treatment for nerve-loss associated disorders has not yet been clinically demonstrated, and there exists a need for methods and materials to support neuroglial cells, and to ensure phenotypic stability and long term survival of transplanted or implanted neural stem cells."],["<SOH> SUMMARY <EOH>It has been discovered that extracellular matrix (ECM) compositions can modulate neural stem cell fate and direct differentiation.","The term “extracellular matrix” or “ECM” is used herein to denote composition comprising one or more of the following: collagen I, collagen IV, laminin, heparan sulfate, or fragments of one or more of such proteins.","One aspect of the invention includes a method of biasing neural stem cell differentiation having the steps of obtaining a population of smooth muscle cells, culturing the smooth muscle cells to form a uniaxially-aligned smooth muscle sheet, obtaining a population of neural stem cells, culturing the neural stem cells in a hydrogel, wherein the hydrogel is applied to the uniaxially-aligned smooth muscle sheet, and exposing the neural stem cells to at least one extracellular matrix (ECM) component, wherein the ECM component biases differentiation of the neural stem cells into differentiated neural stem cells that are enriched for a neuronal subtype.","For example, the neuronal subtype are cholinergic neurons, where the hydrogel can include collagen I, or at least at least about 800 μg/ml collagen I, or between about 800 μg/ml and about 1600 μg/ml collagen I.","In another example, the neuronal subtype are nitrergic neurons, where the hydrogel can include collagen IV and be substantially free of laminin, or at least about 200 μg/ml collagen IV and be substantially free of laminin.","In another example, the neuronal subtype are peptidergic neurons, where the hydrogel can include collagen I, collagen IV, and laminin, or at least about 800 μg/ml collagen I, at least about 200 μg/ml collagen IV, and at least about 5 μg/ml laminin.","Another aspect of the invention can include isolating the differentiated neural stem cells and administering the differentiated neural stem cells to a patient.","For example, the administering can include injecting, into the patient, the differentiated stem cells in the hydrogel.","In another example, the differentiated neural stem cells innervate the uniaxially-aligned smooth muscle sheet to form an innervated smooth muscle sheet and can include the additional step of implanting the innervated smooth muscle sheet into a patient.","Another aspect of the invention includes a method of biasing neural stem cell differentiation having the steps of obtaining a population of neural stem cells, obtaining a population of smooth muscle cells, culturing the neural stem cells in the presence of the smooth muscle cells, wherein the neural stem cells adhere on a substrate with a substrate coating comprising at least one extracellular matrix (ECM) component, wherein the ECM component biases differentiation of the neural stem cells into differentiated neural stem cells that are enriched for neurons.","For example, the substrate coating comprises at least one of laminin, collagen I, and collagen IV, or the substrate coating comprises laminin, and at least one of collagen I and collagen IV, or the substrate coating comprises collagen I and collagen IV, and at least one of laminin and heparan sulfate.","Another aspect of the invention can also include isolating the differentiated neural stem cells and administering the differentiated neural stem cells to a patient.","For example, the administering can include injecting the differentiated neural stem cells into the patient.","Another aspect of the invention includes a method of biasing neural stem cell differentiation by obtaining a population of neural stem cells, obtaining a population of smooth muscle cells, culturing the neural stem cells in the presence of the smooth muscle cells, wherein the neural stem cells adhere on a substrate with a substrate coating comprising at least one extracellular matrix (ECM) component, wherein the ECM component biases differentiation of the neural stem cells into differentiated neural stem cells that are enriched for glial cells.","For example, the substrate coating can include at least collagen I and collagen IV, and be substantially free of at least one of laminin and heparan sulfate, or the substrate coating can comprises at least 5 μg/cm2 collagen I and at least 5 μg/cm2 collagen IV, and be substantially free of at least one of laminin and heparan sulfate.","Another aspect further includes the step of isolating the differentiated neural stem cells and administering the differentiated neural stem cells to a patient.","For example, the administering comprises injecting the differentiated neural stem cells into the patient.","In one aspect of the invention, adult mammalian enteric neural progenitor cells can be induced to differentiate on various substrates derived from components or combinations of ECM compositions.","Neuronal and glial differentiation was studied as a function of ECM composition.","Collagen I and collagen IV substrates supported neuronal differentiation and extensive glial differentiation individually and in combination.","The addition of laminin or heparan sulfate to collagen substrates improved neuronal differentiation, increasing the number of neurons and the branching of neuronal processes and initiation of neuronal network formation.","Various neural ECM components were evaluated individually and in combination to study their effect of neuroglial differentiation of adult enteric neural progenitor cells.","In another aspect of the invention, tissue-engineered intestinal longitudinal smooth muscle sheets can be innervated using enteric neuronal progenitor cells embedded with hydrogels of varying ECM composition.","Differentiated neuronal composition (cholinergic, nitrergic, peptidergic), as well as functional neuronal physiology mediating smooth muscle contraction/relaxations, were evaluated.","Several functional differentiated neuronal subtypes were present in tissue-engineered intestinal sheets, capable of mediating smooth muscle contraction/relaxation.","Neuronal populations varied from being highly cholinergic (collagen I), highly nitrergic (composite collagen I and collagen IV), or balanced between the two (composite collagen I and collagen IV, and laminin and/or heparan sulfate).","Additionally, an increase in peptidergic neurons was detected with laminin and heparan sulfate.","The feasibility of transplantation of various types of neuronal progenitor cells (CNS-derived, neural tube-derived, embryonic and adult ENS-derived) in explant cultures of aneural gut is well established.","However, conditions required for successful engraftment and long-term survival, focusing on a permissive environment heretofore have not been identified.","Studies related to in vitro differentiation of adult enteric neuronal progenitor cells with a focus on the role of the ECM can help optimize the survivability and maintenance of both neuronal and neuroglial phenotypes.","Moreover, our studies indicate that neuronal differentiation can be modulated by varying the composition of ECM microenvironments.","Enriched populations of differentiated neuronal subtypes can be derived within transplantable tissue engineered sheets, using ECM microenvironments.","ECM microenvironments may also facilitate adequate trophic support and phenotype maintenance of differentiated neurons.","In certain embodiments, neural differentiation is induced by administering an effective amount of laminin or a composition comprising laminin, including fragments, derivatives, or analogs thereof.","In a specific example, the laminin can be a complete laminin protein.","In further examples, the laminin is selected from laminin-1, laminin-2, laminin-4, and fragments or combinations thereof.","In further examples, the laminin or laminin composition includes a substance at least substantially homologous to laminin-1, laminin-2, or laminin-4.In yet further implementations, the laminin or laminin composition comprises a polypeptide at least substantially homologous to the laminin al chain, e.g., having at least 80%, or 85%, or 90%, or 95% sequence identical to at least a fragment of the laminin α 1 chain that retains the capacity to induce neuroglial differentiation.","Amounts effective for various therapeutic treatments of the present disclosure may, of course, depend on the severity of the disease and the weight and general state of the subject, as well as the absorption, inactivation, and excretion rates of the therapeutically-active compound or component, the dosage schedule, and amount administered, as well as other factors known to those of ordinary skill in the art.","It also should be apparent to one of ordinary skill in the art that the exact dosage and frequency of administration will depend on the particular laminin, laminin composition, or other therapeutic substance being administered, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular subject, and other medication the subject may be taking.","Typically, dosages used in vitro may provide useful guidance in the amounts useful for in vivo administration of the pharmaceutical composition, and animal models may be used to determine effective dosages for treatment of particular disorders.","For example, animal models of neural disorders may be used to determine effective dosages that can then be translated to dosage amount for other subjects, such as humans, as known in the art.","Various considerations in dosage determination are described, e.g., in Gilman et al., eds., Goodman And Gilman's: The Pharmacological Bases of Therapeutics, 8th ed., Pergamon Press (1990); and Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Co., Easton, Pa. (1990), which is herein incorporated by reference.","In another example, the laminin or laminin composition can be introduced into an in vitro culture of neural stem cells (or co-administered with neural stem cells to a subject) in an amount sufficient to provide a dose of laminin of between about 10 fmol/g and about 500 nmol/g, such as between about 2 nmol/g and about 20 nmol/g or between about 2 nmol/g and about 10 nmol/g.","In additional examples, the laminin or laminin composition can be provided in vitro or administered to a subject in an amount sufficient to provide a dose of laminin of between about 0.01 μg/kg and about 1000 mg/kg or between about 0.1 mg/kg and about 1000 mg/kg, in particular examples this amount is provided per day or per week.","In another example, the laminin or laminin composition is administered to a subject in an amount sufficient to provide a dose of laminin of between about 0.2 mg/kg and about 2 mg/kg.","In further examples, the laminin or laminin composition is administered to a subject in an amount sufficient to provide a concentration of laminin in the administrated material of between about 5 nM and about 500 nM, such as between about 50 nM and about 200 nm, or about 100 nM.","Addition of heparan sulfate to composite collagen mixtures can improve neuronal differentiation as well.","Neuronal networking and neuronal clustering was visible at the later time point.","Heparan sulfate and its interaction with glial cell-derived neurotrophic factor (GDNF) and other neurotrophic factors stabilizes and makes these factors locally available, possibly modulating neurite outgrowth and neuronal differentiation.","Heparan sulfate interacts with both collagen IV and with laminin, to positive modulate neuronal differentiation, evidenced by the enhanced neurite outgrowth, axonal lengths and initiation of neuronal networking ( FIG.","4 A-H).","Composite collagen substrates with laminin and/or heparan sulfate all maintained a low level of glial fibrillary acidic protein (GFAP) positive glial cells, with initiation of astrocytic networking becoming more obvious at the later time point.","In general, substrates that supported neuronal differentiation demonstrated a bare minimum of glial cells required to possibly support neuronal cell phenotype or survival.","Taken together, these results help identify optimal 3D matrix compositions to encapsulate neuronal progenitor cells.","In certain embodiments, three dimensional hydrogel environments can also provide the mechanical cues for neural differentiation.","For example, in some embodiments, three dimensional ECM hydrogels can comprise: collagen I (about 800 μg/ml to about 1600 μg/ml); collagen I (about 800 μg/ml) and collagen IV (about 200 μg/ml); collagen I and collagen IV with laminin (about 5 μg/ml to about 10 μg/ml); collagen I and collagen IV with laminin and heparan sulfate (about 10 μg/ml to about 20 μg/ml); Other components of the gel can include: at least 1% fetal calf serum and at least 0.1× antibiotics in Dulbecco's modified Eagle's medium.","Sodium hydroxide (0.1N) can be used to adjust pH to about 7.4 for gelation.","Accordingly, methods and systems for treating neurodegenerative conditions are disclosed whereby neural stem cells (NSCs) can be transplanted into a subject in need such that the cells can differentiate and ameliorate the neurodegenerative condition.","In certain embodiments, the neural stem cells, upon transplantation, generate an amount of neurons or glial cells sufficient to integrate within the neural infrastructure to ameliorate a disease state or condition.","In one embodiment, the disclosed methods include treating neurodegenerative diseases or conditions by transplanting multipotential neural progenitors or neural stem cells isolated from the central nervous system of a mammal and that have been expanded in vitro and induced to differentiate by exposure to at least one component of an extracellular matrix material (ECM).","In another aspect of the invention, treatments can include supplying a suitable number of NSCs to an injured neural area, via transplantation, such that the transplanted cells differentiate into a sufficient number of neurons and/or glial cells to rehabilitate defective neural circuits.","In an embodiment, the disclosed methods include restoring motor function in a motor neuron disease.","A suitable number or a therapeutically effective amount of NSCs or neural progenitors which are capable of differentiating into motor neurons can be provided to at least one area of neurodegeneration.","The NSCs can exert their therapeutic effect by replacing degenerated neuromuscular junctions.","In certain embodiments, the disclosed methods and systems include providing neural stem cells or neural progenitors that integrate with the host tissue and provide one or more factors to the host neurons thereby protecting them from degenerative influences present in the tissue.","In one preferred embodiment, the disclosed methods include increasing differentiation efficiency of transplanted NSCs into neurons or glial cells by exposure of the stem cells to one or more extracellular matrix materials (ECMs).","The method can also include expanding highly enriched NSCs or neural progenitors in their undifferentiated state and then inducing differentiation so that, upon transplantation, a sufficient number of the cells in the graft adopt a desired phenotype.","The cells of the disclosed methods can be isolated or obtained from fetal, neonatal, juvenile, adult, or post-mortem tissues of a mammal.","The cells of the disclosed methods can be isolated or obtained from the central nervous system, blood, or any other suitable source of stem cells that differentiate into neurons.","The cells can also be obtained from embryonic stem cells.","In certain preferred embodiments, the cells are autologous neural stem cells obtained from a subject and that returned to the subject to ameliorate a neural disorder.","In certain embodiments, the neural stem cells can be expanded in culture.","In some embodiments, the neural precursor cells can be multipotential NSCs capable of expansion in culture and of generating both neurons and glia upon differentiation.","The cells can be either undifferentiated, pre-differentiated or fully differentiated in vitro at the time of transplantation.","In an embodiment, the cells are induced to differentiate into neural lineage.","The cells of the disclosed methods can undergo neuronal differentiation in situ in the presence of EMCs and/or pro-inflammatory cytokines and other environmental factors existing in an injured tissue.","Using the present methods, neural circuits can be treated by transplanting or introducing the cells into appropriate regions for amelioration of the disease, disorder, or condition.","Generally, transplantation occurs into nervous tissue or non-neural tissues that support survival of the grafted cells.","NSC grafts employed in the disclosed methods survive well in a neurodegenerative environment where the NSCs can exert powerful clinical effects in the form of delaying the onset and progression of neurodegenerative conditions or disease.","The present invention can be used in conjunction with various other tissue engineering methods and compositions including those disclosed in commonly-owned, co-pending Applications No.","PCT/US2013/024080 entitled “Innervation of Engineered Structures” filed Jan. 31, 2013 and No.","PCT/US2013/024024 entitled “Tubular Bioengineered Muscle Structures” also filed Jan. 31, 2013, each of which is incorporated herein in its entirety by reference."],["RELATED APPLICATIONS This application is a Divisional Application of Ser.","No.","14/216,391, filed Mar.","17, 2014, which claims priority of U.S.","Provisional Application No.","61/788,285, filed Mar.","15, 2013, which is hereby incorporated in its entirety by reference.","GOVERNMENT RIGHTS This invention was made with U.S. government support by the National Institutes of Health Grant Nos.","RO1DK071614 and RO1DK042876.The U.S. government has certain rights in the invention.","TECHNICAL FIELD The field of this invention is tissue engineering and, in particular, re-innervation of organs and body tissue.","BACKGROUND An uninterrupted enteric nervous system with the preservation of myenteric ganglia is required for intestinal motility and function.","Motor neurons of the myenteric ganglia predominantly express acetylcholine/tachykinins (excitatory) or nitric oxide/inhibitory peptides/purines (inhibitory) to mediate smooth muscle contraction and relaxation.","Partial, selective, or total loss of nerve function and/or loss of nerve cell populations within organs and other body structures are characteristic of numerous diseases and disorders.","For example, aganglionosis of various lengths of distal gut is the central pathology in Hirschsprung's disease.","Enteric neuropathy is also secondary to several other disorders (e.g., diabetes, Parkinson's disease, and inflammation) resulting in gastrointestinal dysfunction.","Gastrointestinal motor function is controlled by the intramural enteric nervous system.","It is a complex interplay between the smooth muscle of the muscularis externa and the two enteric neuronal plexi.","Neural stem cell therapy is an emerging therapy that aims to reinstate neuronal function and thus gastrointestinal motor function by repopulating the enteric plexi.","The research is driven by two significant findings: i) neural stem cells can be isolated from adult mammalian gut, including the ganglionated colon of Hirschsprung's patients; and ii) neural stem cells can be induced to differentiate into several neuronal subtypes and glia characteristic of the enteric nervous system (ENS) upon transplantation into explant cultures of aganglionic/aneural gut, or in vivo into distal colo-rectums in animal models.","While neural-crest derived enteric neural stem cells have been isolated from adult mammalian guts, including ganglionic bowel of patients with Hirschsprung's disease, there is little information or understanding of microenvironment-driven differentiation, and only limited studies describing subsequent functional behavior of these differentiated neurons in vitro.","Moreover, restoration of nerve functions by neural stem cell transplantations as a treatment for nerve-loss associated disorders has not yet been clinically demonstrated, and there exists a need for methods and materials to support neuroglial cells, and to ensure phenotypic stability and long term survival of transplanted or implanted neural stem cells.","SUMMARY It has been discovered that extracellular matrix (ECM) compositions can modulate neural stem cell fate and direct differentiation.","The term “extracellular matrix” or “ECM” is used herein to denote composition comprising one or more of the following: collagen I, collagen IV, laminin, heparan sulfate, or fragments of one or more of such proteins.","One aspect of the invention includes a method of biasing neural stem cell differentiation having the steps of obtaining a population of smooth muscle cells, culturing the smooth muscle cells to form a uniaxially-aligned smooth muscle sheet, obtaining a population of neural stem cells, culturing the neural stem cells in a hydrogel, wherein the hydrogel is applied to the uniaxially-aligned smooth muscle sheet, and exposing the neural stem cells to at least one extracellular matrix (ECM) component, wherein the ECM component biases differentiation of the neural stem cells into differentiated neural stem cells that are enriched for a neuronal subtype.","For example, the neuronal subtype are cholinergic neurons, where the hydrogel can include collagen I, or at least at least about 800 μg/ml collagen I, or between about 800 μg/ml and about 1600 μg/ml collagen I.","In another example, the neuronal subtype are nitrergic neurons, where the hydrogel can include collagen IV and be substantially free of laminin, or at least about 200 μg/ml collagen IV and be substantially free of laminin.","In another example, the neuronal subtype are peptidergic neurons, where the hydrogel can include collagen I, collagen IV, and laminin, or at least about 800 μg/ml collagen I, at least about 200 μg/ml collagen IV, and at least about 5 μg/ml laminin.","Another aspect of the invention can include isolating the differentiated neural stem cells and administering the differentiated neural stem cells to a patient.","For example, the administering can include injecting, into the patient, the differentiated stem cells in the hydrogel.","In another example, the differentiated neural stem cells innervate the uniaxially-aligned smooth muscle sheet to form an innervated smooth muscle sheet and can include the additional step of implanting the innervated smooth muscle sheet into a patient.","Another aspect of the invention includes a method of biasing neural stem cell differentiation having the steps of obtaining a population of neural stem cells, obtaining a population of smooth muscle cells, culturing the neural stem cells in the presence of the smooth muscle cells, wherein the neural stem cells adhere on a substrate with a substrate coating comprising at least one extracellular matrix (ECM) component, wherein the ECM component biases differentiation of the neural stem cells into differentiated neural stem cells that are enriched for neurons.","For example, the substrate coating comprises at least one of laminin, collagen I, and collagen IV, or the substrate coating comprises laminin, and at least one of collagen I and collagen IV, or the substrate coating comprises collagen I and collagen IV, and at least one of laminin and heparan sulfate.","Another aspect of the invention can also include isolating the differentiated neural stem cells and administering the differentiated neural stem cells to a patient.","For example, the administering can include injecting the differentiated neural stem cells into the patient.","Another aspect of the invention includes a method of biasing neural stem cell differentiation by obtaining a population of neural stem cells, obtaining a population of smooth muscle cells, culturing the neural stem cells in the presence of the smooth muscle cells, wherein the neural stem cells adhere on a substrate with a substrate coating comprising at least one extracellular matrix (ECM) component, wherein the ECM component biases differentiation of the neural stem cells into differentiated neural stem cells that are enriched for glial cells.","For example, the substrate coating can include at least collagen I and collagen IV, and be substantially free of at least one of laminin and heparan sulfate, or the substrate coating can comprises at least 5 μg/cm2 collagen I and at least 5 μg/cm2 collagen IV, and be substantially free of at least one of laminin and heparan sulfate.","Another aspect further includes the step of isolating the differentiated neural stem cells and administering the differentiated neural stem cells to a patient.","For example, the administering comprises injecting the differentiated neural stem cells into the patient.","In one aspect of the invention, adult mammalian enteric neural progenitor cells can be induced to differentiate on various substrates derived from components or combinations of ECM compositions.","Neuronal and glial differentiation was studied as a function of ECM composition.","Collagen I and collagen IV substrates supported neuronal differentiation and extensive glial differentiation individually and in combination.","The addition of laminin or heparan sulfate to collagen substrates improved neuronal differentiation, increasing the number of neurons and the branching of neuronal processes and initiation of neuronal network formation.","Various neural ECM components were evaluated individually and in combination to study their effect of neuroglial differentiation of adult enteric neural progenitor cells.","In another aspect of the invention, tissue-engineered intestinal longitudinal smooth muscle sheets can be innervated using enteric neuronal progenitor cells embedded with hydrogels of varying ECM composition.","Differentiated neuronal composition (cholinergic, nitrergic, peptidergic), as well as functional neuronal physiology mediating smooth muscle contraction/relaxations, were evaluated.","Several functional differentiated neuronal subtypes were present in tissue-engineered intestinal sheets, capable of mediating smooth muscle contraction/relaxation.","Neuronal populations varied from being highly cholinergic (collagen I), highly nitrergic (composite collagen I and collagen IV), or balanced between the two (composite collagen I and collagen IV, and laminin and/or heparan sulfate).","Additionally, an increase in peptidergic neurons was detected with laminin and heparan sulfate.","The feasibility of transplantation of various types of neuronal progenitor cells (CNS-derived, neural tube-derived, embryonic and adult ENS-derived) in explant cultures of aneural gut is well established.","However, conditions required for successful engraftment and long-term survival, focusing on a permissive environment heretofore have not been identified.","Studies related to in vitro differentiation of adult enteric neuronal progenitor cells with a focus on the role of the ECM can help optimize the survivability and maintenance of both neuronal and neuroglial phenotypes.","Moreover, our studies indicate that neuronal differentiation can be modulated by varying the composition of ECM microenvironments.","Enriched populations of differentiated neuronal subtypes can be derived within transplantable tissue engineered sheets, using ECM microenvironments.","ECM microenvironments may also facilitate adequate trophic support and phenotype maintenance of differentiated neurons.","In certain embodiments, neural differentiation is induced by administering an effective amount of laminin or a composition comprising laminin, including fragments, derivatives, or analogs thereof.","In a specific example, the laminin can be a complete laminin protein.","In further examples, the laminin is selected from laminin-1, laminin-2, laminin-4, and fragments or combinations thereof.","In further examples, the laminin or laminin composition includes a substance at least substantially homologous to laminin-1, laminin-2, or laminin-4.In yet further implementations, the laminin or laminin composition comprises a polypeptide at least substantially homologous to the laminin al chain, e.g., having at least 80%, or 85%, or 90%, or 95% sequence identical to at least a fragment of the laminin α1 chain that retains the capacity to induce neuroglial differentiation.","Amounts effective for various therapeutic treatments of the present disclosure may, of course, depend on the severity of the disease and the weight and general state of the subject, as well as the absorption, inactivation, and excretion rates of the therapeutically-active compound or component, the dosage schedule, and amount administered, as well as other factors known to those of ordinary skill in the art.","It also should be apparent to one of ordinary skill in the art that the exact dosage and frequency of administration will depend on the particular laminin, laminin composition, or other therapeutic substance being administered, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular subject, and other medication the subject may be taking.","Typically, dosages used in vitro may provide useful guidance in the amounts useful for in vivo administration of the pharmaceutical composition, and animal models may be used to determine effective dosages for treatment of particular disorders.","For example, animal models of neural disorders may be used to determine effective dosages that can then be translated to dosage amount for other subjects, such as humans, as known in the art.","Various considerations in dosage determination are described, e.g., in Gilman et al., eds., Goodman And Gilman's: The Pharmacological Bases of Therapeutics, 8th ed., Pergamon Press (1990); and Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Co., Easton, Pa. (1990), which is herein incorporated by reference.","In another example, the laminin or laminin composition can be introduced into an in vitro culture of neural stem cells (or co-administered with neural stem cells to a subject) in an amount sufficient to provide a dose of laminin of between about 10 fmol/g and about 500 nmol/g, such as between about 2 nmol/g and about 20 nmol/g or between about 2 nmol/g and about 10 nmol/g.","In additional examples, the laminin or laminin composition can be provided in vitro or administered to a subject in an amount sufficient to provide a dose of laminin of between about 0.01 μg/kg and about 1000 mg/kg or between about 0.1 mg/kg and about 1000 mg/kg, in particular examples this amount is provided per day or per week.","In another example, the laminin or laminin composition is administered to a subject in an amount sufficient to provide a dose of laminin of between about 0.2 mg/kg and about 2 mg/kg.","In further examples, the laminin or laminin composition is administered to a subject in an amount sufficient to provide a concentration of laminin in the administrated material of between about 5 nM and about 500 nM, such as between about 50 nM and about 200 nm, or about 100 nM.","Addition of heparan sulfate to composite collagen mixtures can improve neuronal differentiation as well.","Neuronal networking and neuronal clustering was visible at the later time point.","Heparan sulfate and its interaction with glial cell-derived neurotrophic factor (GDNF) and other neurotrophic factors stabilizes and makes these factors locally available, possibly modulating neurite outgrowth and neuronal differentiation.","Heparan sulfate interacts with both collagen IV and with laminin, to positive modulate neuronal differentiation, evidenced by the enhanced neurite outgrowth, axonal lengths and initiation of neuronal networking (FIG.","4 A-H).","Composite collagen substrates with laminin and/or heparan sulfate all maintained a low level of glial fibrillary acidic protein (GFAP) positive glial cells, with initiation of astrocytic networking becoming more obvious at the later time point.","In general, substrates that supported neuronal differentiation demonstrated a bare minimum of glial cells required to possibly support neuronal cell phenotype or survival.","Taken together, these results help identify optimal 3D matrix compositions to encapsulate neuronal progenitor cells.","In certain embodiments, three dimensional hydrogel environments can also provide the mechanical cues for neural differentiation.","For example, in some embodiments, three dimensional ECM hydrogels can comprise: collagen I (about 800 μg/ml to about 1600 μg/ml); collagen I (about 800 μg/ml) and collagen IV (about 200 μg/ml); collagen I and collagen IV with laminin (about 5 μg/ml to about 10 μg/ml); collagen I and collagen IV with laminin and heparan sulfate (about 10 μg/ml to about 20 μg/ml); Other components of the gel can include: at least 1% fetal calf serum and at least 0.1× antibiotics in Dulbecco's modified Eagle's medium.","Sodium hydroxide (0.1N) can be used to adjust pH to about 7.4 for gelation.","Accordingly, methods and systems for treating neurodegenerative conditions are disclosed whereby neural stem cells (NSCs) can be transplanted into a subject in need such that the cells can differentiate and ameliorate the neurodegenerative condition.","In certain embodiments, the neural stem cells, upon transplantation, generate an amount of neurons or glial cells sufficient to integrate within the neural infrastructure to ameliorate a disease state or condition.","In one embodiment, the disclosed methods include treating neurodegenerative diseases or conditions by transplanting multipotential neural progenitors or neural stem cells isolated from the central nervous system of a mammal and that have been expanded in vitro and induced to differentiate by exposure to at least one component of an extracellular matrix material (ECM).","In another aspect of the invention, treatments can include supplying a suitable number of NSCs to an injured neural area, via transplantation, such that the transplanted cells differentiate into a sufficient number of neurons and/or glial cells to rehabilitate defective neural circuits.","In an embodiment, the disclosed methods include restoring motor function in a motor neuron disease.","A suitable number or a therapeutically effective amount of NSCs or neural progenitors which are capable of differentiating into motor neurons can be provided to at least one area of neurodegeneration.","The NSCs can exert their therapeutic effect by replacing degenerated neuromuscular junctions.","In certain embodiments, the disclosed methods and systems include providing neural stem cells or neural progenitors that integrate with the host tissue and provide one or more factors to the host neurons thereby protecting them from degenerative influences present in the tissue.","In one preferred embodiment, the disclosed methods include increasing differentiation efficiency of transplanted NSCs into neurons or glial cells by exposure of the stem cells to one or more extracellular matrix materials (ECMs).","The method can also include expanding highly enriched NSCs or neural progenitors in their undifferentiated state and then inducing differentiation so that, upon transplantation, a sufficient number of the cells in the graft adopt a desired phenotype.","The cells of the disclosed methods can be isolated or obtained from fetal, neonatal, juvenile, adult, or post-mortem tissues of a mammal.","The cells of the disclosed methods can be isolated or obtained from the central nervous system, blood, or any other suitable source of stem cells that differentiate into neurons.","The cells can also be obtained from embryonic stem cells.","In certain preferred embodiments, the cells are autologous neural stem cells obtained from a subject and that returned to the subject to ameliorate a neural disorder.","In certain embodiments, the neural stem cells can be expanded in culture.","In some embodiments, the neural precursor cells can be multipotential NSCs capable of expansion in culture and of generating both neurons and glia upon differentiation.","The cells can be either undifferentiated, pre-differentiated or fully differentiated in vitro at the time of transplantation.","In an embodiment, the cells are induced to differentiate into neural lineage.","The cells of the disclosed methods can undergo neuronal differentiation in situ in the presence of EMCs and/or pro-inflammatory cytokines and other environmental factors existing in an injured tissue.","Using the present methods, neural circuits can be treated by transplanting or introducing the cells into appropriate regions for amelioration of the disease, disorder, or condition.","Generally, transplantation occurs into nervous tissue or non-neural tissues that support survival of the grafted cells.","NSC grafts employed in the disclosed methods survive well in a neurodegenerative environment where the NSCs can exert powerful clinical effects in the form of delaying the onset and progression of neurodegenerative conditions or disease.","The present invention can be used in conjunction with various other tissue engineering methods and compositions including those disclosed in commonly-owned, co-pending Applications No.","PCT/US2013/024080 entitled “Innervation of Engineered Structures” filed Jan. 31, 2013 and No.","PCT/US2013/024024 entitled “Tubular Bioengineered Muscle Structures” also filed Jan. 31, 2013, each of which is incorporated herein in its entirety by reference.","BRIEF DESCRIPTION OF THE DRAWINGS FIG.","1 A-D are micrographs of rabbitenteric neuro spheres—FIG.","1A is a phase contrast micrograph of rabbit enteric neurospheres in culture.","Upon primary isolation and culture, progenitor cells proliferated and aggregated to form neurosphere-like bodies (enteric neurospheres).","Immunohistochemistry for initial phenotype (FIGS.","1 B-D): Rabbit enteric neurospheres are p75NTR (FIG.","1B), Sox2 (FIG.","1C) and Nestin (FIG.","1D) positive—indicating that they are comprised of neural crest-derived neuronal and glial progenitor cells.","Scale bar 100 um.","FIG.","2 is a schematic illustration of enteric neuro sphere differentiation as a function of extracellular matrix (ECM) composition: 22×11 mm coverslips were coated with poly-L-lysine (PLL), collagen I, collagen IV, laminin or heparan sulfate individually or in combination.","Enteric neurospheres were allowed to adhere to the coated coverslips for 6 hours.","Separately, uncoated glass coverslips were seeded with colonic smooth muscle cells, and allowed to grow to confluence.","In order to stimulate differentiation of enteric neurospheres, a coverslip containing confluent smooth muscle was placed within the same dish, so the two coverslips shared soluble factors.","FIG.","3 illustrates neuronal differentiation on individual coated coverslips—βIII Tubulin antibody (white) was used to visualize neurons on day 5 (Figs.","A-D) and day 15 (Figs.","E-H) coverslips coated with PLL (Figs.","A,E), laminin (Figs.","B,F), type I collagen (Figs.","C,G) and type IV collagen (Figs.","D,H).","Enteric neurospheres on PLL barely initiated neuronal differentiation at day 15.Neurospheres on laminin, collagen I and collagen IV showed branching and several neuronal processes both at the early and late time points in vitro.","FIG.","4 illustrates neuronal differentiation on collagen-laminin substrates—Neurons stained with βIII tubulin (white) on day 5 (Figs.","A-D) and day 15 (Figs.","E-H) coverslips coated with type I collagen and 5 μm/cm2 laminin (Figs.","A,E) or 10 μm/cm2 laminin (Figs.","B,F) or type IV collagen with 5 (Figs.","C,G) or 10 (Figs.","D,H) μm/cm2 of laminin.","Addition of laminin to collagen substrates enhanced early and late neuronal differentiation, but no significant difference was observable between 5 and 10 μg/cm2 of laminin.","Type IV collagen substrates (Figs.","C,D,G,H) demonstrated enhanced neuronal branching and differentiation compared to type I collagen (Figs.","A,B,E,F) substrates.","FIG.","5 illustrates neuronal differentiation on composite collagen-laminin-heparan sulfate (HS) substrates—Neurons stained with βIII tubulin (white) on day 5 (Figs.","A-D) and day 15 (Figs.","E-H) coverslips coated with type I and IV collagen with either 5 μm/cm2 laminin (Figs.","B,F), 0.1 μm/cm2 heparan sulfate (HS) (Figs.","C,G), both (Figs.","D,H) or none (Figs.","A,E).","Addition of laminin or HS to collagen substrates enhanced early and late neuronal differentiation, with visible networking by day 15.Substrates without laminin or HS demonstrated minimal neuronal differentiation (Figs.","A,E).","FIG.","6 illustrates glial differentiation on primary coated substrates—Glia stained with GFAP (white) on day 5 (Figs.","A-D) and day 15 (Figs.","E-H) coverslips coated with poly-L-lysine (PLL) (Figs.","A,E), laminin (Figs.","B,F), type I collagen (Figs.","C,G) and type IV collagen (Figs.","D,H).","Enteric neurospheres on PLL demonstrated maximal glial differentiation starting at day 5 up to day 15.While neurospheres on collagen substrates demonstrated good early and late glial differentiation, laminin coated substrates showed no early glial differentiation by day 5 (B), but differentiated subsequently by day 15 (F).","FIG.","7 illustrates glial differentiation on collagen-laminin substrates—Glia stained with glial fibrillary acidic protein (GFAP) (white) on day 5 (Figs.","A-D) and day 15 (Figs.","E-H) coverslips coated with type I collagen and 5 μm/cm2 laminin (Figs.","A,E) or 10 μm/cm2 laminin (Figs.","B,F) or type IV collagen with 5 (Figs.","C,G) or 10 (Figs.","D,H) μm/cm2 of laminin.","Addition of laminin to collagen substrates promoted glial differentiation both at days 5 and 15.No significant difference was observable in GFAP+ glial differentiation between 5 and 10 μg/cm2 of laminin.","FIG.","8 illustrates glial differentiation on composite collagen-laminin-heparan sulfate (HS) substrates—Glia stained with GFAP (white) on day 5 (Figs.","A-D) and day 15 (Figs.","E-H) coverslips coated with type I and IV collagen with either 5 μg/cm2 laminin (Figs.","B,F), 0.1 μm/cm2 heparan sulfate (Figs.","C,G), both (Figs.","D,H) or none (Figs.","A,E).","Addition of laminin or HS to composite collagen substrates demonstrated glial differentiation that peaked at day 5 (Figs.","B-D) that was sustained at the later time point (Figs.","E-H); and FIG.","9 illustrates neurite lengths were measured on coated culture substrata and compared using one way ANOVA.","Two bars for each substrate show mean neurite lengths at day 5 and day 15.FIG.","9A shows that neurite lengths on PLL were significantly (***p<0.001) shorter than any primary coating substrate.","Laminin substrates had the longer neurites (*p<0.05).","FIG.","9B shows no significant difference was observed in neurite lengths with the addition of 5 or 10 μg/cm2 laminin.","FIG.","9C shows that the addition of laminin or heparan sulphate significantly increased neurite lengths over composite collagen substrata (*p<0.05).","FIG.","9D shows that mean GFAP immunofluorescence was quantified: PLL substrates (***p<0.001) and composite collagen substrates (*p<0.05) supported extensive glial differentiation.","FIG.","10 illustrates scanning electron micrographs of dehydrated ECM gels.","Images were obtained at constant magnification and constant working distance.","(A) Collagen I fibers were randomly oriented, and presented a dense fibrous structure; (B) Composite Collagen I/IV sheets demonstrated evidence of the formation of network-like structures; (C) There was no difference in ultrastructure with the addition of laminin; (D) Evidence of cabling and cross-linking was observed with the addition of heparan sulfate.","Average porosity was determined and summarized in the accompanying table.","Viscoelastic modulus was calculated using oscillatory rheometry of ECM gels in their hydrated state, and tabulated in the table.","Scale bar 10 μm.","FIG.","11 illustrates neuronal differentiation within tissue engineered sheets.","Phase contrast micrographs were obtained at the edge of the tissue engineered sheets.","Evidence of neuronal differentiation and initiation of network formation was observed in all ECM compositions at day 10.The arrows indicate instances of preliminary neuronal networking.","Scale bar 200 μm.","FIG.","12 illustrates immunoblot analysis of tissue engineered longitudinal sheets.","Sheets were assessed for expression of neuronal differentiation, constituent smooth muscle phenotype, and excitatory and inhibitory neural markers.","Densitometry was used to quantify band intensities, to quantify and compare expression.","(A) Neuronal βIII Tubulin expression was similar amongst all four matrices suggesting that all ECM compositions supported neuronal differentiation; (B) Constituent smooth muscle within the tissue engineered sheets maintained contractile phenotype, demonstrated by similar Smoothelin expression; (C) Choline acetyltransferase (ChAT) expression was significantly (*p<0.05) elevated in Col I and Col I/IV/Laminin sheets compared to Col I/IV and Col I/IV/Lam/HS sheets; (D) Neuronal nitric oxide synthase (nNOS) expression was significantly lower (**p<0.001) in Col I sheets compared to elevated levels in all tissue engineered sheets containing Col4 with or without laminin and/or heparan sulfate.","(E) Representative immunoblots are provided along with β Actin, demonstrating equal loading.","FIG.","13 illustrates immunofluorescence for differentiated neurons within tissue engineered sheets.","Differentiated neurons within tissue engineered sheets were stained with markers for vasoactive intestinal peptide (VIP), choline acetyltransferase (ChAT) or neuronal nitric oxide synthase (nNOS).","(A-D) Numerous differentiated VIP-ergic neurons were present in tissue engineered sheets.","(E-H) Differentiated excitatory cholinergic neurons expressing ChAT were present within tissue engineered sheets; (I-L) Differentiated inhibitory nitrergic neurons expressing nNOS were present within tissue engineered sheets.","Scale bar 100 μm.","FIG.","14 illustrates potassium chloride induced contraction of tissue engineered sheets.","60 mM Potassium chloride (KCl) was used to examine the electromechanical coupling integrity of the constituent smooth muscle cells within the tissue engineered sheets.","The black traces indicate the contraction in response to the addition of KCl.","The grey traces indicate the addition of KCl in the presence of a neuronal blocker, TTX.","Pre-treatment with TTX did not inhibit KCl-induced contraction.","The ECM composition of the tissue engineered sheets did not affect smooth muscle contraction, evidenced by similar contractile patterns in response to KCl stimulation.","A robust and immediate contraction was observed upon addition of KCl (indicated by the arrows) in all tissue engineered sheets (A-D), similar to native rabbit intestinal tissue (E).","Peak contraction in response to KCl ranged between 279.5 μN and 296.5 μN in tissue engineered sheets, and averaged at 373.3±10.63 in native tissue.","(F) The area under the curve of KCl-induced contraction was quantified to demonstrate no significant (ns) difference in contraction in tissue engineered sheets, with a slightly elevated (*p<0.05) magnitude in native tissue.","FIG.","15 illustrates acetylcholine induced contraction.","Addition of 1 μM Acetylcholine (Ach; arrow) resulted in contraction of tissue engineered sheets, as well as native tissue.","Gray traces demonstrate Ach treatment in the presence of neuronal blocker, TTX.","(A-E) Representative tracings of Ach-induced contraction in tissue engineered sheets and native tissue.","Magnitude of Ach-induced contraction varied between tissue engineered sheets.","Comparison of the area under the curve of contraction demonstrated that tissue engineered sheets approached 31.5% (Col4)-67.6% (Laminin) of contraction observed in native tissue.","In the presence of TTX, magnitude of Ach-induced contraction was attenuated.","Quantification of inhibition (F) revealed that the degree of inhibition with TTX varied amongst the tissue engineered sheets with different ECM compositions.","Highest inhibition was observed in Col i (72.77±2.5%) and Col I/IV/Laminin (60.58±1.7%) sheets, indicating an elevated presence of cholinergic neurons contributing to Ach-induced contraction.","Significantly lower inhibition (*p<0.05; 48.36±4.3-50.31±4.2%) was seen in Col I/IV and Col I/IV/Lam/Heparan sulfate sheets.","TTX pre-treatment attenuated Ach-induced contraction by 72.73±3.7% in native tissue.","FIG.","16 illustrates electrical Field Stimulation induced relaxation in tissue engineered sheets.","Electrical Field stimulation (EFS; shaded gray area) was used to stimulate relaxation in tissue engineered sheets (A-D) and native tissue (E).","Grey traces indicate TTX pre-treatment.","EFS induced relaxation was significantly attenuated by TTX-pretreatment (90.9±2.41%-94.41±0.93%), indicating that differentiated neurons within the tissue engineered sheets were capable of evoking smooth muscle relaxation.","The magnitude of relaxation varied amongst the tissue engineered sheets (summarized in Table 3).","(F) Quantification of the area under the curve of relaxation indicated that Col I sheets had a significantly low (***p<0.001; 23142±4921 AU) magnitude of relaxation.","Relaxation in Col I/IV sheets (109693±8465 AU) were similar to those observed in native tissue (101550±11279 AU) in response to the electrical field, indicating the presence of elevated levels of inhibitory motor neurons capable of mediating relaxation.","Relaxation was higher in Col I/IV/Laminin (69025±7154 AU) and Col I/IV/Lam/Heparan sulfate (68395±8228 AU) sheets, when compared to Col I, also indicating a similar increase in the presence of inhibitory motor neurons.","FIG.","17 illustrates inhibition of relaxation with L-NAME.","The functionality of nitrergic neurons was studied by inhibiting EFS-induced relaxation with L-NAME, a non-metabolizable substrate for nNOS.","The grey traces indicate EFS in the presence of L-NAME.","Pretreatment with L-NAME attenuated EFS-induced relaxation in all tissue engineered sheets (A-D) and native tissue (E).","(F) Quantification of the area under the curve for relaxation indicated that the extent of L-NAME inhibition varied amongst the tissue engineered sheets.","Col I sheets had a significantly lower % inhibition with L-NAME (*p<0.05; 33.4±8.4%) corresponding to the lowest immunoblot expression of nNOS.","The degree of L-NAME inhibition was higher in tissue engineered sheets containing Col I/IV and/or laminin and/or heparan sulfate (57.16%-62.28%), corresponding to the higher immunoblot expression of nNOS.","Attenuation of relaxation in the presence of L-NAME was 78±2.9% in native tissue.","FIG.","18 illustrates inhibition of relaxation with VIP-Ra.","The functionality of VIP-ergic neurons was studied by inhibiting EFS-induced relaxation with VIP-Ra, a VIP-receptor antagonist.","Grey traces indicate EFS in the presence of VIP-Ra.","In the presence of VIP-Ra, EFS-induced relaxation was attenuated in tissue engineered sheets (A-D) and in native tissue (E), indicating the presence of functional VIP-ergic neurons capable of mediating smooth muscle relaxation upon electrical field stimulation.","Area under the curve of relaxation was quantified, to calculate the % inhibition of relaxation in the presence of VIP-Ra (F).","Extent of VIP-Ra induced inhibition of relaxation varied from 56.55±3.12%-63.11±3.2% in tissue engineered sheets, and averaged at 73.32±3.23% in native tissue.","DETAILED DESCRIPTION Definitions As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise.","Thus, for example, references to “the method” includes one or more methods, and/or steps of the type described herein which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.","The steps of any method can be practice in feasible order and are restricted to a sequential order merely because they are so recited in a claim.","Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.","Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are now described.","“Differentiation” refers to a change that occurs in cells to cause those cells to assume certain specialized functions and to lose the ability to change into certain other specialized functional units.","Cells capable of differentiation may be any of totipotent, pluripotent or multipotent cells.","Differentiation may be partial or complete with respect to mature adult cells.","Stem cells are undifferentiated cells defined by the ability of a single cell both to self-renew, and to differentiate to produce progeny cells, including self-renewing progenitors, non-renewing progenitors, and terminally differentiated cells.","Stem cells are also characterized by their ability to differentiate in vitro into functional cells of various cell lineages from multiple germ layers (endoderm, mesoderm and ectoderm), as well as to give rise to tissues of multiple germ layers following transplantation, and to contribute substantially to most, if not all, tissues following injection into blastocysts.","Neural stem cells can be isolated from embryonic and adult central nervous system (CNS) tissue, neural tube tissue or enteric nervous system (ENS) tissue.","Stem cells can be further classified according to their developmental potential as: (1) totipotent; (2) pluripotent; (3) multipotent; (4) oligopotent; and (5) unipotent.","Totipotent cells are able to give rise to all embryonic and extra-embryonic cell types.","Pluripotent cells are able to give rise to all embryonic cell types.","Multipotent cells include those able to give rise to a subset of cell lineages, but all within a particular tissue, organ, or physiological system (for example, hematopoietic stem cells (HSC) can produce progeny that include HSC (self-renewal), blood cell-restricted oligopotent progenitors, and all cell types and elements (e.g., platelets) that are normal components of the blood).","Cells that are oligopotent can give rise to a more restricted subset of cell lineages than multipotent stem cells; and cells that are unipotent typically are only able to give rise to a single cell lineage.","In a broader sense, a progenitor cell is a cell that has the capacity to create progeny that are more differentiated than itself, and yet retains the capacity to replenish the pool of progenitors.","By that definition, stem cells themselves are also progenitor cells, as are the more immediate precursors to terminally differentiated cells.","When referring to the cells of the present invention, as described in greater detail below, this broad definition of progenitor cell may be used.","In a narrower sense, a progenitor cell is often defined as a cell that is intermediate in the differentiation pathway, i.e., it arises from a stem cell and is intermediate in the production of a mature cell type or subset of cell types.","This type of progenitor cell is generally not able to self-renew.","Accordingly, if this type of cell is referred to herein, it will be referred to as a non-renewing progenitor cell or as an intermediate progenitor or precursor cell.","As used herein, the phrase “differentiates into a neural lineage or phenotype” refers to a cell that becomes partially or fully committed to a specific neural phenotype of the CNS or PNS, i.e., a neuron or a glial cell, the latter category including without limitation astrocytes, oligodendrocytes, Schwann cells and microglia.","The term “neural” as used herein is intended to encompass all electrical active cells, e.g., cells that can process or transmit information through electrical or chemical signals, including the aforementioned neurons, glial cells, astrocytes, oligodendrocytes, Schwann cells and microglia.","For the purposes of this disclosure, the terms “neural progenitor cell” or “neural precursor cell” mean a cell that can generate progeny that are either neuronal cells (such as neuronal precursors or mature neurons) or glial cells (such as glial precursors, mature astrocytes, or mature oligodendrocytes).","Typically, the cells express some of the phenotypic markers that are characteristic of the neural lineage.","Typically, they do not produce progeny of other embryonic germ layers when cultured by themselves in vitro, unless dedifferentiated or reprogrammed in some fashion.","A “neuronal progenitor cell” or “neuronal precursor cell” is a cell that can generate progeny that are mature neurons.","These cells may or may not also have the capability to generate glial cells.","A “glial progenitor cell” or “glial precursor cell” is a cell that can generate progeny that are mature astrocytes or mature oligodendrocytes.","These cells may or may not also have the capability to generate neuronal cells.","The phrase “biocompatible substance” and the terms “biomaterial” and “substrate” are used interchangeably and refer to a material that is suitable for implantation or injection into a subject.","A biocompatible substance does not cause toxic or injurious effects once implanted in the subject.","In one embodiment, the biocompatible substrate includes at least one component of extracellular matrix.","In other embodiments, the substrate can also include a polymer with a surface that can be shaped into the desired structure that requires repairing or replacing.","The polymer can also be shaped into a part of a body structure that requires repairing or replacing.","In another embodiment, the biocompatible substrate can be injected into a subject at a target site.","In one embodiment, the substrate is an injectable or implantable biomaterial that can be composed of crosslinked polymer networks which are typically insoluble or poorly soluble in water, but can swell to an equilibrium size in the presence of excess water.","For example, a hydrogel can be injected into desired locations within the organ.","In one embodiment, the collagen can be injected alone.","In another embodiment, the collagen can be injected with other hydrogels.","The hydrogel compositions can include, without limitation, for example, poly(esters), poly(hydroxy acids), poly(lactones), poly(amides), poly(ester-amides), poly(amino acids), poly(anhydrides), poly(ortho-esters), poly(carbonates), poly(phosphazines), poly(thioesters), polysaccharides and mixtures thereof.","Furthermore, the compositions can also include, for example, a poly(hydroxy) acid including poly(alpha-hydroxy) acids and poly(beta-hydroxy) acids.","Such poly(hydroxy) acids include, for example, polylactic acid, polyglycolic acid, polycaproic acid, polybutyric acid, polyvaleric acid, and copolymers and mixtures thereof.","Hydrogels with effective pore sizes in the 10-100 nm range and in the 100 nm-10 micrometer range are termed “microporous” and “macroporous” hydrogels, respectively.","Microporous and macroporous hydrogels are often called polymer “sponges.” When a monomer, e.g., hydroxyethyl methacrylate (HEMA), is polymerized at an initial monomer concentration of 45 (w/w) % or higher in water, a hydrogel is produced with a porosity higher than the homogeneous hydrogels.","Hydrogels can also expand in the presence of diluent (usually water).","The matrix materials of present invention encompass both conventional foam or sponge materials and the so-called “hydrogel sponges.” For a further description of hydrogels, see U.S. Pat.","No.","5,451,613 (issued to Smith et al.)","herein incorporated by reference.","The term “extracellular matrix” or “ECM” is used herein to denote compositions comprising one or more of the following: collagen I, collagen IV, laminin, heparan sulfate, or fragments of one or more of such proteins.","“Collagen I” refers to collagen I or collagen I compositions derived from cell culture, animal tissue, or recombinant means, and may be derived from human, murine, porcine, or bovine sources.","“Collagen I” also refers to substances or polypeptide(s) at least substantially homologous to collagen I or collagen I compositions.","Additionally, “collagen I” refers to collagen I or collagen I compositions that do not include a collagen I fragment, e.g., including essentially only a complete collagen I protein.","“Collagen IV” refers to collagen IV or collagen IV compositions derived from cell culture, animal tissue, or recombinant means, and may be derived from human, murine, porcine, or bovine sources.","“Collagen IV” also refers to substances or polypeptide(s) at least substantially homologous to collagen IV or collagen IV compositions.","Additionally, “collagen IV” refers to collagen IV or collagen IV compositions that do not include a collagen IV fragment, e.g., including essentially only a complete collagen I protein.","“Laminin” refers to laminin, laminin fragments, laminin derivatives, laminin analogs, or laminin compositions derived from cell culture, recombinant means, or animal tissue.","“Laminin” can be derived from human, murine, porcine, or bovine sources.","“Laminin” refers to laminin or laminin compositions comprising laminin-1, laminin-2, laminin-4, or combinations thereof.","“Laminin” also refers to substances or polypeptide(s) at least substantially homologous to laminin-1, laminin-2, or laminin-4.Additionally, “laminin” refers to laminin or laminin compositions that do not include a laminin fragment, e.g., including essentially only a complete laminin protein.","The term “substantially free of laminin” and “free of laminin” are used interchangeably herein to denote compositions in which laminin is absent or present in such low concentrations that it does not play any significant role in neural stem cell differentiation, e.g., where laminin is only present in concentrations less than 5 μg/ml in hydrogels or 5 μg/cm on substrate coatings, or more preferably less than 2 μg/ml in hydrogels or 2 μg/cm2 on substrate coatings, or less than 1 μg/ml in hydrogels or 1 μg/cm on substrate coatings, and in some instances less than 0.1 μm/ml in hydrogels or 0.1 μm/cm2 on substrate coatings.","The term “substantially free of heparan sulfate” and “free of heparan sulfate” are used interchangeably herein to denote compositions in which heparin sulfate is absent or present in such low concentrations that it does not play any significant role in neural stem cell differentiation, e.g., where heparan sulfate is only present in concentrations less than 5 μg/ml in hydrogels or 5 μg/cm2 on substrate coatings, or more preferably less than 2 μg/ml in hydrogels or 2 μg/cm2 on substrate coatings, or less than 1 μg/ml in hydrogels or 1 μg/cm2 on substrate coatings, and in some instances less than 0.1 μm/ml in hydrogels or 0.1 μm/cm2 on substrate coatings.","General Techniques For further elaboration of general techniques useful in the practice of this invention, the practitioner can refer to standard textbooks and reviews in cell biology, tissue culture, and embryology.","Included are Teratocarcinomas and embryonic stem cells: A practical approach (E. J. Robertson, ed., IRL Press Ltd. 1987); Guide to Techniques in Mouse Development (P. M. Wasserman et al.","eds., Academic Press 1993); Embryonic Stem Cell Differentiation in Vitro (M. V. Wiles, Meth.","Enzymol.","225:900, 1993); Properties and uses of Embryonic Stem Cells: Prospects for Application to Human Biology and Gene Therapy (P. D. Rathjen et al., Reprod.","Fertil.","Dev.","10:31, 1998), For elaboration of nervous system abnormalities, and the characterization of various types of nerve cells, markers, and related soluble factors, the reader is referred to CNS Regeneration: Basic Science and Clinical Advances, M. H. Tuszynski & J. H. Kordower, eds., Academic Press, 1999.Methods in molecular genetics and genetic engineering are described in Molecular Cloning: A Laboratory Manual, 2nd Ed.","(Sambrook et al., 1989); Oligonucleotide Synthesis (M. J. Gait, ed., 1984); Animal Cell Culture (R. I. Freshney, ed., 1987); the series Methods in Enzymology (Academic Press); Gene Transfer Vectors for Mammalian Cells (J. M. Miller & M. P. Calos, eds., 1987); Current Protocols in Molecular Biology and Short Protocols in Molecular Biology, 3rd Edition (F. M. Ausubel et al., eds., 1987 & 1995); and Recombinant DNA Methodology II (R. Wu ed., Academic Press 1995).","Reagents, cloning vectors, and kits for genetic manipulation referred to in this disclosure are available from commercial vendors such as BioRad, Stratagene, Invitrogen, and ClonTech.","General techniques used in raising, purifying and modifying antibodies, and the design and execution of immunoassays including immunohistochemistry are described in Handbook of Experimental Immunology (D. M. Weir & C. C. Blackwell, eds.","); Current Protocols in Immunology (J. E. Coligan et al., eds., 1991); and R. Masseyeff, W. H. Albert, and N. A. Staines, eds.","Methods of Immunological Analysis (Weinheim: VCH Verlags GmbH, 1993).","Sources of Stem Cells This invention can be practiced using stem cells of various types, which may include the following non-limiting examples: U.S. Pat.","No.","5,851,832 reports multipotent neural stem cells obtained from brain tissue.","U.S. Pat.","No.","5,766,948 reports producing neuroblasts from newborn cerebral hemispheres.","U.S. Pat.","Nos.","5,654,183 and 5,849,553 report the use of mammalian neural crest stem cells.","U.S. Pat.","No.","6,040,180 reports in vitro generation of differentiated neurons from cultures of mammalian multipotential CNS stem cells.","WO 98/50526 and WO 99/01159 report generation and isolation of neuroepithelial stem cells, oligodendrocyte-astrocyte precursors, and lineage-restricted neuronal precursors.","U.S. Pat.","No.","5,968,829 reports neural stem cells obtained from embryonic forebrain and cultured with a medium comprising glucose, transferrin, insulin, selenium, progesterone, and several other growth factors.","Except where otherwise required, the invention can be practiced using stem cells of any vertebrate species.","Included are stem cells from humans; as well as non-human primates, domestic animals, livestock, and other non-human mammals.","Neural Glial Differentiation Enteric neuronal progenitor cells have been identified in the adult mammalian gut, and have been isolated from humans up to and over 80 years of age.","Previously, several groups have shown that a self-renewing population of Sox 2, Sox10, Nestin and p75 positive neural-crest derived progenitor cells can be isolated either from full-thickness, muscularis or mucosal biopsies of the adult mammalian gut.","These cells have been demonstrated to have the potential to differentiate into several neuronal subtypes including inhibitory and excitatory motor neurons and glia.","Various types of neuronal progenitor cells (CNS-derived, neural tube-derived, embryonic and adult ENS-derived) from explant cultures of aneural gut can also be transplanted.","Alterations in the extracellular matrix of the gut mesenchyme has been documented in aganglionic regions of rodent gut, suggesting the importance of a permissive extracellular environment to promote effective in utero colonization and differentiation of neural crest cells in the developing gut.","Since transplantation and subsequent functional neo-innervation is one clinical goal of neural stem cell transplantation, in vitro studies should mimic developmental conditions in vivo, in terms of providing a permissive and favorable ECM (such as a three-dimensional environment).","Understanding the role of the ECM in affecting neuroglial differentiation of adult enteric neuronal progenitor cells can enhance the survivability and maintenance of a stable phenotype upon transplantation.","Mammalian myenteric ganglia in vivo are surrounded by a matrix comprised predominantly of type IV collagen, laminin, heparan sulphate proteoglycan, and entactin.","The enteric plexus lacks large connective tissue spaces for blood vessels like the peripheral nervous system.","The two-dimensional culture substratum may modulate neuronal and glial differentiation based on ECM composition.","Different ECM components may influence enteric glia and neurons come in to contact with in vivo in the adult myenteric plexus, such as collagen IV, laminin and heparan sulfate.","Addition of laminin to collagen substrates unexpectedly improved neurite outgrowth with longer neurite lengths (compare 156.1±7.2 μm to 215.1±7.6 μm).","while there was an overall enhancement in neuronal differentiation as well as neurite outgrowth, there was no significant difference between the additions of 5 or 10 μg/cm2 of laminin.","This empirical determination was important in determining a minimal amount of laminin that can influence neuroglial differentiation without affecting neurite outgrowth adversely in a situation that requires neo-innervation of denervated tissues.","Addition of heparan sulfate to composite collagen mixtures improved neuronal differentiation as well.","Neuronal networking and neuronal clustering was visible at the later time point.","Heparan sulfate may interact with GDNF and other neurotrophic factors to stabilize and make the factors locally available.","Heparan sulfate interacts with both collagen IV and with laminin, to positively modulate neuronal differentiation.","In one embodiment, heparan sulfate is added to the collagen mixture.","Composite collagen substrates with laminin and/or heparan sulfate all maintained a low level of GFAP positive glial cells, with initiation of astrocytic networking becoming more obvious at the later time point.","In general, substrates that supported neuronal differentiation demonstrated a bare minimum of glial cells required to possibly support neuronal cell phenotype or survival.","Substrates that supported neuronal differentiation may result in enriched populations of neuronal cells comprising greater than 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, or any intermediate percentage.","Enteric neurospheres demonstrated a tendency to differentiate into glia on PLL coated substrates as well as on composite collagen substrates in the absence of laminin and heparan sulfate.","In contract, culture substrates with laminin and heparan sulfate promoted extensive neuronal differentiation while simultaneously supporting only a minimal glial cell population.","Laminin and collagen IV coated coverslips positively modulated neuronal differentiation by increased number of neurites per neuron and longer neurite lengths compared to fibrillar collagen I (FIG.","2B-D, F-H).","Taken together, these results identify suitable 3D matrix compositions to deliver neuronal progenitor cells.","Three dimensional hydrogel environments also provide the mechanical cues for neural differentiation, more readily translatable to in vivo conditions than infinitely stiff glass substrates.","The extracellular matrix (ECM) plays an enormous role in dictating stem cell fate.","The ECM composition, structure and mechanical properties can all modulate progenitor cell differentiation.","The adult mammalian myenteric ganglia are surrounded by an extracellular matrix primarily composed of collagen IV, laminin and a heparan sulfate proteoglycan, with enteric glia always in direct contact with the ECM.","Enteric neurons also come in direct contact with this ECM, though much less frequently than glia.","Laminin, fibronectin and proteoglycans are expressed within the embyonic gut to aid its colonization by vagal neural crest cells.","Collagen IV is distributed in the developing nervous system along the neural crest.","Additionally, laminin promotes neural cell adhesion and axonal outgrowth.","Heparan sulfate is important for GDNF signaling in the gut, and stabilizes and influences neuronal differentiation in vitro.","It has been discovered that components of neural ECM can affect the differentiation of gut-derived neuronal progenitor cells of neural-crest lineage.","Two timepoints were defined to identify early and late differentiation events—day 5 (early) and day 15 (late) based on previous experiments.","Immunohistochemistry for βIII tubulin (neuron specific microtubule) and GFAP (Glial fibrillary acidic protein) was used to identify differentiated neurons and glia on coated culture substrata.","Substrates that supported glial differentiation may result in enriched populations of glial cells comprising greater than 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, or any intermediate percentage.","Neuronal Subtype Differentiation Neural stem cell transplantation is a promising therapeutic approach to repopulate neurons within enteric ganglia.","A complete loss of neurons is reported in HSCR, and a partial loss of selective neuronal subtypes is documented in achalasia and stenosis.","Several groups have injected enteric neuronal progenitor cells into experimental models of aganglionosis, demonstrating the feasibility of transplantation.","However, there is inadequate focus on differentiation of progenitor cells into mature neuronal subtypes, and subsequent assessment of functionality.","Here, we describe one embodiment of the invention, whereby we describe a novel method to bias differentiation of enteric neuronal progenitor cells in vitro, prior to transplantation.","The ECM microenvironment, consisting of collagens, laminin and proteoglycans, not only acts as a structural framework for cells, but also plays an active role in aiding neurotrophic signaling.","In an embodiment of this invention, four ECM components (collagen I, collagen IV, laminin and heparan sulfate) were evaluated, three of which are known to be present in adult myenteric ganglia.","Collagen IV has been documented to be favorable for neurite outgrowth and neuronal differentiation.","Laminin has long been known for its neurite promoting activity, in central, peripheral, and enteric neurons.","The role of the heparan sulfate proteoglycan in neuronal differentiation is also well documented, both developmentally and in regenerative medicine applications.","Fibrillar Collagen I was used additionally in these studies for ease of gelation and incorporation of other ECM components within a 3D hydrogel.","Apart from composition, substrate elasticity has been demonstrated to affect the differentiation of adult neural stem cells, with neuronal differentiation reported between 100-500 Pa. ECM hydrogel compositions were adjusted in order to maintain their viscoelastic modulus within the range suitable for neuronal differentiation (FIG.","10, table).","Structural architecture was verified using scanning electron microscopy, wherein the addition of collagen IV demonstrated the presence of network structures, similar to self-assembled collagen IV in the mammalian basement membrane.","The addition of laminin did not alter the ultrastructure, because it was expected to coat collagen fibers evenly.","Additionally, laminin was also not expected to alter the stiffness/viscoelasticity of the gels, given the manner of its interaction with the collagen.","The glycosaminoglycan chains of heparan sulfate are documented to cross link between laminin and collagen IV, thereby pulling fibers into a more compact structure, and slightly increasing the viscoelasticity of ECM gels.","Smooth muscle cells within tissue engineered sheets drive the differentiation of enteric neuronal progenitor cells.","Tissue engineered sheets provided a good modality to assess variability of differentiated neurons due to ECM composition as well as the functionality of differentiated neurons.","The proximity to smooth muscle promoted the differentiation of enteric neuronal progenitor cells extensively.","In vitro differentiation of neural stem cells in the presence of gut-derived factors has been demonstrated previously by us and others.","Neurotrophic factors (NT-3, Neurturin, GDNF) and morphogens (BMP-2/4) capable of driving enteric neuronal progenitor cell proliferation and differentiation have been demonstrated to arise from the smooth muscle and mesenchyme of the developing and adult gut.","Recently, the postnatal bowel was demonstrated to support the differentiation of enteric neuronal progenitor cells, strengthening the fact that cues for differentiation can be derived from the postnatal gut.","Hence, it was expected that smooth muscle cells within the tissue engineered sheets would drive the differentiation of enteric neuronal progenitor cells.","We evaluated all tissue engineered sheets to ensure that the constituent smooth muscle cells demonstrated a contractile phenotype expressing Smoothelin (FIG.","14B).","Smoothelin expression has been previously demonstrated to be essential for contractility of smooth muscle.","In line with the equivalent expression of smoothelin, myogenic electromechanical coupling integrity was also equivalent in the tissue engineered sheets (FIG.","14A-D) Similar patterns of contractions were observed in tissue engineered sheets in response to KCl, regardless of ECM composition.","The ECM modulates differential neuronal subtypes while supporting overall smooth muscle-driven neuronal differentiation.","In the presence of the smooth muscle, enteric neuronal progenitor cells differentiated, and expressed similar amounts of pan-neuronal marker βIII Tubulin (FIG.","14A), suggesting that smooth muscle derived factors and substrate viscoelasticity were suitable for overall neuronal differentiation.","However, on closer examination of neural subtypes, there was a differential expression of excitatory and inhibitory markers within tissue engineered sheets with varying ECM compositions (FIG.","14).","Sheets containing laminin had a balanced expression of both ChAT and nNOS.","Kinetics of Ach-induced contraction in laminin sheets was most similar to native tissue, indicating the presence of an increased viable cholinergic neuronal component in composite collagen/laminin sheets.","Furthermore, attenuation of EFS-induced relaxation by L-NAME (˜62%) was also kinetically similar to native tissue (˜78%), indicating the presence of a nitrergic neuronal component.","Collagen I, in the absence of any other matrix components, was the ECM of choice when an enriched cholinergic neuronal population was required, with a significantly diminished nitrergic neuronal population (FIG.","14C-D).","While these sheets demonstrated a robust TTX-sensitive Ach-induced contraction commensurate with the heightened ChAT protein expression, relaxation in response to an electrical field was diminished.","Furthermore, there was minimal attenuation of relaxation upon the inhibition of nNOS, correlating with the low nNOS expression.","Substrates that supported cholinergic neuron differentiation may result in enriched populations of cholinergic neurons comprising greater than 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, or any intermediate percentage.","Composite Collagen I/IV sheets had an enhanced nNOS protein expression, with an associated increase in EFS induced relaxation (FIG.","18B).","AUC of relaxation in composite Collagen I/IV sheets was comparable to native intestinal tissue.","However, both ChAT expression and contraction was lower in composite collagen sheets.","Substrates that supported nitrergic neuron differentiation may result in enriched populations of nitrergic neurons comprising greater than 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, or any intermediate percentage.","The ECM is a framework upon which smooth muscle derived factors regulate differentiation of neural subtypes.","We demonstrate a critical role of collagen I and collagen IV containing ECM environments in promoting excitatory and inhibitory motor neurons, respectively.","The ECM microenvironment plays a role in modulating neurotrophic as well as morphogenetic signaling.","Morphogenetic signaling via the BMP family expressed in fetal gut is important for the phenotypic diversity of enteric ganglia, including nitrergic and VIP-ergic neuron differentiation.","Collagen IV is documented to modulate BMP signaling, and heparan sulfate modulates GDNF signaling in the gut.","Immunoreactivity of neurotrophic factor, NT-3, has been observed in ganglia and in the ECM molecules surrounding them, suggesting a role for a Collagen IV-based ECM to modulate NT-3 signaling.","The constituent smooth muscle phenotype in tissue engineered sheets was contractile, expressing smoothelin, and generating contractions and relaxations approaching ˜60% of those generated by native intestinal tissue.","Differentiation cues arising from the constituent smooth muscle cells drove enteric neuronal differentiation.","Furthermore, it is likely that the ECM could act as a framework for smooth muscle-derived factors, enhancing or inhibiting their effects, resulting in the generation of differential neuronal phenotypes.","EXAMPLES Reagents All tissue culture reagents were purchased from Invitrogen (Carlsbad, Calif.) unless specified otherwise.","Primary and fluorophore conjugated secondary antibodies were purchased from Abcam (Cambridge, Mass.).","Rat tail type I collagen and natural mouse type IV collagen were purchased from BD Biosciences (Bedford, Mass.)","and laminin was from Invitrogen (Carlsbad, Calif.).","Heparan sulfate was purchased from Celsus Labs (Cincinnati, Ohio).","Isolation of Rabbit Enteric Neuronal Progenitor Cells and Intestinal Smooth Muscle Cells.","New Zealand white rabbits were euthanized using ketamine/xylazine.","Smooth muscle cells were isolated and cultured using standard protocols (See, for example, Somara et al.","Am J Physiol Gastrointest Liver Physiol.","2006; 291(4):G630-9).","For the isolation of enteric neuronal progenitor cells, 5 cm2 biopsies were dissected from the jejunum, and retrieved in Hank's Buffered Salt Solution (HBSS) with 2× antibiotics/antimycotics and 1× gentamicin sulfate.","Luminal content was cleaned and tissues were washed extensively with HBSS.","Enteric neuronal progenitor cells were isolated from these tissues using a collagenase/dispase digestion method.","(see, for example, Almond et al., Characterisation and transplantation of enteric nervous system progenitor cells.","Gut.","2007; 56(4):489-96.PMCID: 1856871).","Cells were plated on to bacterial petri dishes in neuronal growth media (Neurobasal+1× N2 supplement+1× antibiotics) following filtration through a 40 μm mesh.","Isolation and Culture of Rabbit Longitudinal Smooth Muscle Cells (LSMCs) Rabbit sigmoid colon was removed by dissection, and relieved of fecal content.","The tissue was kept on ice and moist with Hank's balanced salt solution (HBSS) containing antibiotics and sodium bicarbonate.","The cleaned colon was slipped onto a plastic pipette.","Blood vessels and adherent fat were picked off with forceps.","Kimwipe® (Kimberly-Clark, Neenah, Wis.) wetted with HBSS was used to wipe the outer layer of the colon.","Fine-tip forceps were used to pick off the longitudinal muscle layer from the colon and store them in ice-cold HBSS.","The tissue was finely minced, digested twice with type II collagenase (0.1%) at 32° C. for 1 h, and filtered through a 500-μm Nytex® (Tetko, Elmsford, N.Y.) mesh.","The filtrate was washed three times and plated in DMEM with 10% FBS, 1.5% antibiotics, and 0.5% L-glutamine onto regular tissue culture flasks.","Immunohistochemical Characterization of Rabbit Enteric Neurospheres In order to characterize the initial phenotype of rabbit enteric neurospheres in culture, neurospheres were harvested by centrifugation at 1000 g for 10 minutes in microfuge tubes.","The growth media was gently aspirated, and neurospheres were fixed with 3.7% neutral buffered formaldehyde and blocked with 10% horse serum.","Primary antibodies for p75 (Millipore, Billerica Mass.","), Sox2 and Nestin were incubated for 30 minutes at room temperature.","Unbound antibody was washed using phosphate buffered saline (PBS), and appropriate fluorophore-conjugated secondary antibodies were incubated for an additional 30 minutes.","Neurospheres were mounted using Prolong Gold antifade mounting medium (Invitrogen, Carlsbad Calif.), and visualized using an inverted Nikon TiE fluorescent microscope.","Rheological Characterization of ECM Hydrogels Oscillatory rheometry (ATS RheoSystems) was used to measure viscoelastic moduli of ECM gels.","20 mm parallel base plates were used to perform a stress sweep of the sample at 1 Hz.","ECM gels were allowed to gel in situ between the parallel plates at 37° C. The viscoelastic modulus was obtained from a linear region of the stress-strain curve, at strains lower than 10%, within the sensitivity ranges for torque and strain of the rheometer.","3-5 individually manufactured ECM gels were measured to determine an average viscoelastic modulus.","Compositions that resulted in a matrix viscoelasticity within the range of 150-300 Pa were utilized for further experimentation, so as not to let stiffness be a variable in influencing neuroglial differentiation.","Characterization of Ultrastructure of ECM Hydrogels Sample preparation of ECM hydrogels for scanning electron microscopy was adapted from Stuart et al.","[31].","Gels were dehydrated through graded ethanol (10% to 100%).","Hydrogels were dried at critical point using carbon dioxide exchange.","The resulting dehydrated ECM discs were mounted onto metallic stubs with conducting carbon tape, sputter coated with gold, and visualized using an AMRAY 1910 Field Emission Scanning Electron Microscope.","Constant working distance and magnification were maintained to image all samples.","NIH Image J was used to measure and compare fiber diameters.","Porosity was determined using Image J from micrographs obtained from at least three-independent samples of dehydrated ECM gels.","Tissue Engineering Innervated Intestinal Smooth Muscle Sheets Briefly, 500,000 longitudinal smooth muscle cells were aligned uniaxially for 4 days on 35 mm diameter circular Sylgard molds containing wavy microtopographies.","Enteric neurospheres were treated with Accutase to obtain single cell suspensions.","200,000 cells were resuspended in the appropriate ECM solution and overlaid on the aligned smooth muscle monolayer.","Upon gelation, neuronal differentiation medium (neurobasal-A) was added, supplemented with B27 and 1% fetal bovine serum.","Differentiation medium was exchanged every second day.","Enteric neuronal progenitor cells were allowed to differentiate within the hydrogel for a period of 10 days.","Smooth muscle cells compacted the ECM hydrogel over the next 10 days, forming ˜1 cm long innervated smooth muscle sheets, anchored between silk sutures.","Phase microscopy was used to image neuronal differentiation at the edge of the tissue engineered sheets.","Biochemical Characterization of Neuroglial Composition in Tissue Engineered Sheets At day 10, tissue engineered sheets were harvested in radioimmunoprecipitation buffer to isolate protein.","Protein concentration was estimated spectrophotometrically using the Bradford assay.","20 μg of protein from each sample was resolved electrophoretically and transferred to polyvinylidene difluoride membranes.","Membranes were blotted with antibodies for neuronal βIII Tubulin, neuronal nitric oxide synthase (nNOS), choline acetyltransferase (ChAT), and Smoothelin.","β-Actin was used to confirm equal loading.","HRP-conjugated secondary antibodies were used to visualize proteins using enhanced chemiluminescence.","Immunohistochemical Characterization of Neuron Composition in Tissue Engineered Sheets Tissue engineered sheets were fixed in 4% formaldehyde and washed extensively in glycine buffer.","Immunohistochemical staining was performed following previously established protocols utilized for staining differentiated neurons within bioengineered tissues.","Sheets were blocked with 10% horse serum and permeabilized in 0.15% Triton-X for 45 minutes.","Permeabilized sheets were incubated with primary antibodies directed against Vasoactive Intestinal Peptide (VIP), ChAT and nNOS for 60 minutes at room temperature.","Following antibody incubation, sheets were washed three times with phosphate buffered saline, pH 7.4.Tissue engineered sheets were incubated with appropriate fluorophore conjugated secondary antibodies for 45 minutes, washed in phosphate buffered saline and imaged using an inverted fluorescence microscopy (Nikon Ti-E, Japan).","For a negative control, incubation with the primary antibody was skipped, and only fluorophore conjugated secondary antibodies were used to visualize background fluorescence.","Measurement of Physiological Function in Inntervated Tissue Engineered Sheets Myogenic and neuronal functionality were assessed using real-time force generation as previously described [30, 33].","4-5 individual tissue engineered sheets for each ECM composition were tested.","Tissue engineered sheets were anchored between a stationary pin and measuring pin of a force transducer (Harvard Apparatus, Holliston Mass.)","at 0% stretch.","The organ bath maintained temperature at 37° C. An additional 10% stretch was applied using a vernier control.","Tissues were immersed in 4 ml of medium, which was exchanged at the end of every experiment following a brief wash with fresh medium.","Peak contraction or maximal relaxation was quantified following pharmacological or electrical stimuli, and compared between tissue engineered sheets with varying ECM compositions.","Before each treatment, tissues were washed in fresh warm medium and allowed to equilibrate to a baseline.","The following stimuli were used independently to assess physiological functionality of the tissue engineered sheets: 1) 60 mM Potassium chloride to assess electromechanical coupling integrity of the smooth muscle; 2) 1 μM Acetylcholine (contractile agonist); 3) Electrical field stimulation (5 Hz, 0.5 ms, 40V) applied using parallel plate platinum electrodes.","Preincubation with neuronal blocker, tetrodotoxin (TTX) was used to dissect myogenic and neuronal components of contraction/relaxation.","Preincubation with specific inhibitors were used to identify functional neuronal subtypes: 1) nNOS-blocker Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME; 300 μM); and 2) VIP-receptor antagonist [D-p-Cl-Phe6, Leu17]-Vasoactive Intestinal Peptide (VIP-Ra; 2 μM).","Following stimulation and subsequent contraction/relaxation and recovery, tissues were washed with fresh medium, and allowed to re-establish a baseline before the next treatment.","Equilibrated baseline was arbitrarily set to zero, to measure contraction/relaxation due to a stimulus.","Neurosphere Differentiation as a Function of Extracellular Matrix Composition 22×11 mm substrates were washed in Neutrad (Decon Labs, King of Prussia Pa.) and rinsed extensively in deionized water.","Coverslips were sterilized by 70% ethanol, and subsequent UV exposure for 45 minutes.","Coverslips were coated with poly-L-lysine (PLL; 1 mg/ml), PLL+10 μg/cm2 type I collagen, PLL+10 μg/cm2 type IV collagen or PLL+10 μg/cm2 laminin.","Composite coatings included: 5 μg/cm2 Collagen I+5 μg/cm2 type IV Collagen; 5 μg/cm2 Collagen I+5 or 10 μg/cm2 Laminin; 5 μg/cm2 Collagen IV+5 or 10 μg/cm2 Laminin; 5 μg/cm2 Collagen I+5 μg/cm2 Collagen IV+0.1 μg/cm2 Heparan Sulfate (HS); 5 μg/cm2 Collagen I+5 μg/cm2 Collagen IV+5 μg/cm2 Laminin+0.1 μg/cm2 HS.","Uncoated glass substrates were seeded with rabbit colonic smooth muscle cells, and allowed to reach confluence.","Rabbit enteric neurospheres were harvested and treated with Accutase to obtain a mixture of single cells as well as small neurospheres.","10,000 neuronal progenitor cells were harvested and plated on to coated coverslips.","To stimulate differentiation induced via soluble smooth muscle factors, each plate was shared by one confluent smooth muscle coverslip along with a coated coverslip containing adhered neurospheres.","Enteric neurospheres were allowed to differentiate for a period of fifteen days, with a supplementation of neuronal differentiation medium every 2 days (Neurobasal-A medium+1× B27 supplement+2% fetal calf serum+1× antibiotics).","Immunohistochemical Analysis of Neuronal and Glial Differentiation Two time points were analyzed for neuronal and glial differentiation—day 5 and day 15 post initiation of differentiation.","Medium was aspirated and cells on coverslips were fixed with 3.7 neutral buffered formaldehyde.","Cells were permeabilized with 0.15% Triton-X 100 and blocked with 10% horse serum.","βIII tubulin was used to stain neuronal cells, and glial fibrillary acidic protein (GFAP) was used to stain glial cells.","Primary antibodies were incubated for 1 hour at room temperature and unbound antibody was washed with PBS.","Fluorophore conjugated secondary antibodies (FITC-anti mouse and TRITC-anti rabbit) were used to visualize fluorescence using an inverted Nikon TiE fluorescent microscope.","Staining with FITC-conjugated secondary antibody without the primary antibody was used as a negative control.","Confluent smooth muscle coverslips were stained with neuronal or glial markers to avoid a false positive staining while identifying differentiated neurons or glia.","Data Analysis Neurite lengths were measured from individual 10× micrographs obtained at the same amplifier gain and exposure.","Neurites were identified primarily by expression of immunoreactivity for βIII tubulin concurrently with neuronal morphology.","Up to five sequential fields of view were measured on each coverslip starting from one edge to the other, covering the area of the coverslip.","All cells were measured on each coverslip, covering the entire area of the neuronal coverslip.","The number of neurites measured for each substrate coating varied between 20-50 readings.","The length of the longest neurite from each cell was measured using NIH Image J using the freeform tool.","Neurite lengths between coatings were compared using one way ANOVA, with Bonferroni post-test to identify a significant difference (p<0.05) in neurite lengths by varying culture substrata.","GFAP immunofluorescence was quantified using the Nikon Elements imaging software.","Mean red (TRITC) fluorescence was calculated from 10× micrographs, using a constant rectangular area tool that covered 100% of the field of view.","Multiple (at least 5) sequential fields of view at the same magnification were chosen for each sample to obtain mean fluorescence.","One way ANOVA with Bonferroni post-test was used to identify a significant difference in red fluorescent intensity between coated culture substrata.","GraphPad Prism 5.1 for Windows (San Diego, Calif.) was used to perform statistical analysis.","All statistics are from experiments between 3-5 individual sets, with multiple micrographs within each set.","Reported numbers are mean±standard error of the mean.","For neuronal subtype analysis, densitometry on western blots was performed using BioRad Quantity One (Hercules, Calif.).","Raw data was acquired from the force transducer at 1000 samples/second.","Second order Savitsky-Golay smoothing was applied to data using GraphPad Prism 5.0 for Windows (GraphPad Software, San Diego, Calif.).","Area under the curve (AUC) was measured from the time of addition of pharmacological agonist/electrical field to the end of the contraction/relaxation response.","Extent of inhibition by pharmacological inhibitors was calculated by expressing the AUC of contraction/relaxation in the presence of the inhibitor as a percentage of the AUC in the absence of the inhibitor.","One way ANOVAs with Tukey post-tests were used to compare means using GraphPad Prism.","p≤0.05 was considered significant.","Physiological evaluation and densitometry was carried out between 3-5 tissue engineered sheets within each experimental set; all values are expressed as mean±SEM.","Neuroglial Differentiation Initial Phenotype of Rabbit Enteric Neurospheres Upon digestion of rabbit jejunal biopsies with dispase, near single cell suspensions were obtained by filtration through 70 μm and 40 μm meshes.","Single cells were approximately 7 μm in diameter.","These cells were plated in non-adherent culture dishes.","Over the course of two weeks post plating, rabbit enteric neuronal progenitor cells aggregated and proliferated in culture and formed floating spherical structures, called enteric neurospheres (FIG.","1A).","Average neurospheres were 98.17±8.33 μm (n=34) two weeks post plating.","The neurospheres continued to grow and aggregate, approaching 200-300 μm, whereupon they were broken down by trituration.","Upon immunohistochemical examination, the cells within enteric neurospheres were positive for the low affinity nerve growth factor receptor p75NTR (FIG.","1B).","They were additionally also positive for Sox2 (FIG.","1C, SRY related homeobox factor 2) and Nestin (FIG.","1D), a neuroepithelial stem cell marker.","The results indicate that neurospheres derived from the rabbit intestine following this procedure contained neural-crest derived cells, capable of differentiation in to enteric neurons and/or enteric glia.","Neuronal progenitor cells were isolated from full thickness biopsies of adult rabbit jejunums that aggregate in culture to form floating spherical colonies, dubbed enteric neurospheres (FIG.","1A).","The enteric neurospheres were comprised of cells positive for p75, Sox2 and Nestin (FIG.","1 B-D).","The presence of p75NTR confirms the neural-crest lineage of the isolated cells.","The presence of Sox2 and Nestin confirms the progenitor status of the isolated cells, indicating that these cells are similar to enteric neuronal progenitor cells previously isolated from the gut that have the potential to differentiate into both neurons and glia.","Neuronal Differentiation on Individual ECM Substrates (Collagen I, Collagen IV or Laminin) Poly-L-lysine (PLL) coating was a pre-requisite to enteric neurosphere adhesion to glass substrates.","Glass coverslips that lacked any coating did not support enteric neurosphere adhesion sufficiently to differentiate into neurons or glia.","In order to maintain uniformity, all coverslips were initially coated with PLL and additionally with laminin, collagen I or collagen IV.","All coated coverslips required between 2-4 hours for enteric neurospheres to attach.","Enteric neurospheres on coated coverslips were allowed to differentiate initially using neuronal differentiation medium alone.","However, several sets of experiments demonstrated no morphological evidence of differentiation at the day 15 timepoint.","Thereby, in order to render the soluble environment conducive to differentiation, a confluent coverslip containing colonic smooth muscle cells was placed in the same culture dish (FIG.","2).","The neuronal coverslip (coated with ECM substrate and containing enteric neurospheres) and the smooth muscle coverslips thereby shared soluble factors.","The addition of the smooth muscle coverslip marked the initiation of differentiation (day 0).","Morphological evidence of neuronal or glial differentiation was readily visible by day 5.A later time point (day 15) was identified to study the development of mature neurons or glia in vitro as a function of ECM composition.","During the differentiation process, the culture dishes remained undisturbed till the early time point (day 5) or the late time point (day 15), except for medium supplementation.","Neuronal differentiation was identified by immunofluorescent staining of the neuronal coverslip at either day 5 or day 15 with an antibody directed against βIII Tubulin.","Day 5 Timepoint: Even in the presence of smooth muscle, enteric neurospheres on PLL remained undifferentiated, with some progenitor cells within neurospheres expressing low levels of βIII tubulin (FIG.","3A).","However, with the addition of laminin, collagen I or collagen IV to PLL on the culture substrata, neuronal differentiation was evident by day 5 (FIG.","3B-D).","Neurite lengths varied non-significantly between 193 μm and 288 μm on ECM substrata at the early time point (FIG.","9A).","Neurons on collagen IV and laminin coated coverslips demonstrated a higher level of branching (two or more neurites per cell; FIG.","3B,D).","Neurospheres and neuronal progenitor cells attached to the PLL coated coverslips, and stayed attached at day 5, but did not initiate neuronal differentiation.","However, glial differentiation was readily visible by day 5, and improved by day 15 (FIG.","3A,E; FIG.","6A,E).","Enteric neurospheres on PLL substrates indicated a preference towards glial differentiation versus neuronal differentiation.","Day 15 Timepoint: At the day 15 timepoint, neurospheres on PLL coverslips barely initiated neuronal differentiation, evidenced by a flatter morphology and the appearances of faint tubulin-positive extensions (FIG.","3E).","With the addition of laminin, collagen I or collagen IV, neurite lengths were significantly longer compared to PLL (p<0.001).","Differentiated neurons on laminin coverslips demonstrated the longest neurite extensions (326.9±13.25 μm, n=27, FIG.","3F), significantly longer than collagen I or collagen IV (p<0.05, FIG.","9A).","By day 15, neurons on collagen I-coated coverslips still had no significant branching compared to those on collagen IV-coated coverslips (FIGS.","3G-H).","Neuronal Differentiation on Collagen Laminin Substrates In the next set of experiments, combinations of collagens and laminin were evaluated.","Two concentrations of laminin were evaluated to identify the minimum amount of laminin required to influence neuronal differentiation.","Coverslips were coated with either collagen I or collagen IV with 5 μg/cm2 or 10 μg/cm2 of laminin.","The addition of laminin enhanced neuronal differentiation when compared to individual collagen substrates (compare FIG.","4 with FIG.","3), but no significant difference was observed in neurite length between the two concentrations of laminin.","Collagen I and Laminin: At the day 5 timepoint, addition of laminin to collagen I increased the number of progenitor cells undergoing neuronal differentiation, but did not alter neuronal branching or neurite lengths significantly (FIG.","4A,B,E,F).","At the day 15 timepoint, significantly (p<0.05) enhanced neuronal differentiation was observed compared to collagen I. Neurite lengths on collagen-laminin substrates at day 15 (280 μm-290 μm; n=27-34) were longer than collagen I substrates (235.5±10.05 μm; FIG.","9B).","Collagen IV and Laminin: The addition of laminin to collagen IV enhanced neuronal differentiation when compared to coverslips coated individually with collagen IV only (compare FIG.","4C,D,G,H to FIG.","3D,H).","At the day 5 timepoint, the addition of laminin increased the number of cells undergoing neuronal differentiation.","No significant difference was observed in neurite lengths at day 5 (247 μm-288 μm; FIG.","9B).","At the day 15 time point, coverslips coated with both collagen IV and laminin had significantly (p<0.05) longer neurites (324 μm compared to 281 μm, FIG.","4G-H).","Initiation of inter-neuronal networking was also observed.","There was no observable or significant difference in neurite lengths between the two concentrations of laminin used (5 μg/cm2 or 10 μg/cm2; FIG.","9B).","Neuronal Differentiation on Composite ECM Substrates with Laiminin and Heparan Sulfate In this additional set, the effect of a combination of collagens on neuronal differentiation was investigated.","Composite coatings were evaluated with a 2:1 mix of Collagen I/Collagen IV as the base.","This composite collagen base was evaluated first.","Additionally, neuronal differentiation was evaluated on substrates that included laminin and/or heparan sulfate in combination with composite collagen.","Heparan sulfate interacted with both collagen IV and with laminin to positively modulate neuronal differentiation, evidenced by the enhanced neurite lengths and initiation of neuronal networking (FIG.","4 A-H).","Composite collagen substrates with laminin and/or heparan sulfate all maintained a low level of GFAP positive glial cells, with initiation of astrocytic networking becoming more obvious at the later time point.","Composite Collagen I/Collagen IV: Several cells underwent neuronal differentiation (FIG.","5A, E; similar to individual coatings of either collagen I or collagen IV), but neurite lengths were significantly shorter on composite collagen substrates at day 5.Neurite lengths measured at 156±7.23 μm on day 5.At day 5, neuronal differentiation progressed and individual neurons had multiple branches and long neurites (FIG.","5E).","Neurite lengths averaged at 241.2±9.387 μm on day 15 (FIG.","9C).","Addition of Laminin: Addition of laminin to composite collagen substrates increased the number of differentiated neurons visible by day 5 (FIG.","5B).","Neurite lengths were significantly (p<0.05) longer on substrates containing laminin (215±7.57 μm; n=43).","At the day 15 time point, substrates containing composite collagen and laminin demonstrated significant clustering of neurons (FIG.","5F), with an additional 71 μm increase in neurite length, averaging at 286.8±9.521 μm, n=50.Addition of Heparan Sulfate: Addition of heparan sulfate also dramatically increased the number of progenitor cells undergoing neuronal differentiation by day 5 (FIG.","5C).","Average neurite lengths on substrates containing heparan sulfate along with composite collagen was 212.8±9.46 μm; n=43 at day 5.At day 15, the initiation of neuronal networking was visible with βIII Tubulin staining (FIG.","5G).","Addition of Laminin and Heparan Sulfate: The addition of laminin and heparan sulfate together with the composite collagen increased the number of differentiated neurons as well as the length of the individual neuronal processes and neurite branching (FIG.","5D).","At day 15, initiation of neuronal networking with significant clustering of neurons was observed (FIG.","5H).","Neurite lengths were significantly longer (325±19.37 μm) compared to composite collagen alone (FIG.","9C).","Glial Differentiation on Individual ECM Coatings (Collagen I, Collagen IV or Laminin) In addition to neuronal differentiation studies described above, glial differentiation was also studied as a function of ECM composition of culture substrata.","Enteric neurospheres were plated on to coated coverslips in duplicate, and one coverslip was used to evaluate neuronal differentiation while a duplicate coverslip was used to evaluate glial differentiation.","A primary antibody directed against Glial fibrillary acidic protein (GFAP) was utilized to identify glial differentiation.","Fluorescent microscopy was used to visualize differentiated glia, using a TRITC fluorophore conjugated secondary antibody.","The Nikon documentation software was used to calculate mean red fluorescence indicating the number of differentiated glia in a field of view of constant area.","The presence of several axolemmal fragments can arrest the proliferation of glia.","This is in line with the low levels of GFAP immunofluorescence observed on substrates that supported extensive neuronal differentiation.","The only substrates that supported differentiation of enteric neuroglial progenitor cells into glia extensively were PLL and individual coatings of collagen I/IV.","Neuronal differentiation was present on these substrates, but not as extensively as any of the other composite coatings that included laminin and heparan sulfate.","Day 5 Timepoint: In the presence of smooth muscle, enteric neurospheres on PLL coated coverslips demonstrated significant GFAP staining by day 5 (15.29±1.29 AU; FIG.","6A).","In contrast, enteric neurospheres on PLL coverslips did not demonstrate significant neuronal differentiation at day 5, indicating the preferential differentiation in to glia at the early time point on PLL coverslips.","With the addition of laminin, enteric neurospheres demonstrated highly significantly reduced GFAP staining (0.3825±0.2 AU).","Undifferentiated neurospheres on the laminin coverslips contained several progenitor cells that were positive for GFAP (FIG.","6B).","On the same laminin coated coverslips, neuronal differentiation was extensive at the early timepoint, indicating an early preference for neuronal differentiation in the presence of laminin (FIG.","3B).","Minimal glial differentiation was observed on either of the collagen substrates (FIG.","6C-D).","Day 15 Timepoint: By the late day 15 time point, PLL coated coverslips had the highest number of glia, indicated by a highly significant (p<0.0001) GFAP fluorescent intensity, averaging at 28.56±1.14 AU (FIG.","6E, 9D).","Glia were apparent on ECM-coated coverslips as well, but to a lower extent than on PLL.","In contrast to day 5, laminin coated coverslips demonstrated the presence of several glia at the day 15 time point and a robust GFAP fluorescent intensity was observed (FIG.","5F, 16.54±0.32 AU).","Several glia were observed by day 15 on each of the collagen substrates, with fluorescence ranging from 11.84 to 13.38 AU.","(FIGS.","6G-H).","Glial Differentiation on Collagen-Laminin Substrates Similar to neuronal differentiation, glial differentiation was evaluated on substrates that were coated with either collagen I or cCollagen IV with laminin.","The addition of laminin to collagen coated coverslips did not inhibit glial differentiation.","Several differentiated glia were observed on day 5 (8.4±0.75-14.08±0.3 AU) on collagen-laminin substrates (FIG.","7A-D).","There was no significant difference in the number of GFAP positive cells at the early time point with the addition of laminin (5 μg/cm2 or 10 μg/cm2) to either collagen I or collagen IV substrates FIG.","9D).","Robust GFAP expression (12.6±1.29-14.22±1.01 AU) was observed at the day 15 time point on all collagen-laminin substrates, not significantly different from one another (FIG.","7E-H).","Glial Differentiation on Composite ECM Substrates with Laminin and Heparan Sulfate Glial differentiation was evaluated by varying the culture substratum with a combination of collagen I and IV.","Additionally, the effect of the addition of laminin and/or heparan sulfate was also studied on glial differentiation.","Composite Collagen I/Collagen IV: Glial differentiation peaked on day 5, on coverslips coated with the collagen I/IV mixture (FIG.","8A).","Red fluorescence (15.75±0.49 AU) was comparable to that on PLL coated coverslips at day 5 (FIG.","9D).","In contrast, neuronal differentiation on composite collagen coated coverslips was poor at the early time point, indicating a preferential differentiation into glia early on.","By day 15, initiation of clustering of glial cells was observable (FIG.","8E), with no significant increase in red fluorescence.","Addition of Laminin and/or Heparan Sulfate: Early glial differentiation at day 5 was significantly reduced (10.16±0.8 to 11.06±0.5) with the addition of laminin and/or heparan sulfate to composite collagen substrates (FIG.","8B-D).","In contrast, these substrates supported neuronal differentiation extensively (compare FIG.","8A-D to FIG.","5A-D), indicating a preferential neuronal differentiation at the early time point.","At the later day 15 time point, a non-significant increase in the number of glia and thereby increase in red fluorescence was observed (FIG.","8E-H, FIG.","9D).","Neuronal Subtype Differentiation Ultrastructure and Viscoelastic Properties of ECM Hydrogels: All compositions of ECM hydrogels gelled at 37° C. within 30 minutes.","Scanning electron micrographs revealed a fibrous structure in type I Collagen gels (FIG.","10A).","The fibers were randomly oriented, with diameters averaging at 478.3±19.31 μm.","With the addition of type IV Collagen, network-like structures were observed (FIG.","10B).","Cables of fibers within the networked structures were thicker, with average diameters of 714.8±36.67 μm.","Addition of laminin to the hydrogels did not alter the ultrastructure or the networked suprastructure (FIG.","10C).","With the addition of heparan sulfate, the fibers within the networked structures were pulled more tightly together and cabled (FIG.","10D).","The dehydrated ECM gels displayed a porous appearance, with average porosity ranging from 40.77%-43.95% (FIG.","1, table).","Viscoelastic moduli were measured in hydrated ECM gels using oscillatory rheometry.","Type I Collagen gels had increasing viscoelastic moduli with increasing collagen concentration ranging from 72.6±4.86 Pa (800 μm/ml) to 182.3±2.6 (1600 μm/ml) to 424±2 Pa (3200 μm/ml).","The addition of 200 μm/ml collagen IV to 800 μm/ml collagen I increased the modulus of the gels to 236±13.53 Pa.","The addition of laminin had no effect on viscoelastic moduli (compare 236±13.53 Pa to 220.7±16.27 Pa).","10 μm/ml of heparan sulfate caused an increase in the modulus of ECM hydrogels (287±20.11 Pa, p<0.05).","FIG.","1 (table) summarizes that the final ECM gels evaluated had viscoelastic moduli ranging from 182 Pa to 287 Pa. Neuronal Differentiation in Engineered Innervated Intestinal Smooth Muscle Sheets: Uniaxially-aligned smooth muscle cells compacted overlaying ECM hydrogels over 10 days in culture as described before.","The resultant tissue engineered sheets were ˜1 cm long, and a few cell layers thick.","In the presence of smooth muscle, the enteric neuronal progenitor cells differentiated within the ECM hydrogel.","Neuronal differentiation was identified morphologically by microscopic examination at day 10, demonstrating similar differentiation profiles expressed by enteric neuronal progenitor cells, both in vitro and in tissue engineered constructs.","Several differentiated neurons were observed in tissue engineered sheets, regardless of the ECM composition (FIG.","11).","Arrows in the figures indicate numerous instances of neuronal clustering and preliminary neuronal networking.","Neuronal Composition in Engineered Innervated Intestinal Smooth Muscle Sheets: Immunoblotting was used to assess neuronal composition within tissue engineered innervated intestinal smooth muscle sheets.","Blotting for β-actin demonstrated that equal amounts of protein were assayed.","Representative blots for each protein are shown, indicating the approximate molecular weight at which they appear on the gels (FIG.","12E).","Contractile phenotype of constituent smooth muscle was demonstrated by the similar expression of smoothelin, within the tissue engineered sheets (FIG.","12B).","The expression of Smoothelin was constant, regardless of the ECM composition of the sheets, indicating that the constituent smooth muscle cells maintained a contractile phenotype.","Neuronal Differentiation: Pan neuronal marker βIII Tubulin expression was similar amongst all tissue engineered sheets, despite the ECM composition (FIG.","12A).","This suggested that irrespective of the ECM composition, neuronal differentiation of enteric neurospheres proceeded similarly in the presence of smooth muscle cells.","βIII Tubulin expression ranged from 21.65±1.43 AU-28.98±0.85 AU.","βIII Tubulin expression was similar amongst various ECM gel compositions (ns; FIG.","12A), indicating similar neuronal differentiation.","Cholinergic Neurons: Choline acetyltransferase (ChAT) expression was used to detect the presence of cholinergic neurons (FIG.","12C).","Collagen I (33.73±1.13 AU) and collagen I/IV/laminin (28.82±1.21 AU) sheets had a significantly elevated expression of ChAT compared to sheets with composite collagen and/or heparan sulfate.","Immunoblotting demonstrated an enriched cholinergic neuron population in tissue engineered sheets manufactured with collagen I only or composite collagen I/IV with laminin.","The presence of cholinergic neurons was additionally confirmed using immunohistochemistry (FIG.","13E-H).","Nitrergic Inhibitory Motor Neurons: Neuronal nitric oxide synthase (nNOS) expression was used to detect the presence of inhibitory nitrergic motor neurons (FIG.","12D).","Sheets with collagen IV (with or without laminin/heparan sulfate) had a significantly higher nNOS expression ranging from 26.37±1.29 AU-28.15±2.69 AU.","Conversely to ChAT, collagen I sheets had minimal nNOS expression (11.33±2.85 AU).","Presence of nNOS was additionally confirmed using immunohistochemistry (FIG.","13I-L).","VIP-Ergic Inhibitory Motor Neurons: Vasoactive intestinal peptide (VIP) motor neurons were identified using immunohistochemistry.","VIP neurons were abundant, with increased immunofluorescence in composite hydrogels with laminin and heparan sulfate (FIG.","13A-D).","Substrates that supported peptidergic neuron differentiation may result in enriched populations of peptidergic neurons comprising greater than 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, or any intermediate percentage.","Agonist Induced Contractility of Tissue Engineered Innervated Smooth Muscle Sheets Potassium Chloride-Induced Contraction: Electromechanical coupling integrity of constituent smooth muscle cells was first evaluated using potassium chloride (KCl).","KCl treatment elicited rapid contractions that were sustained for ˜5 minutes (FIG.","14).","Peak maximal contraction in response to KCl was similar between the different tissue engineered sheets (FIG.","14A-D), ranging from 279.5±4.79 μN to 296.5±6.26 μN.","This correlated with the equivalent expression of contractile smooth muscle marker, Smoothelin, indicating that the constituent smooth muscle cells within the tissue engineered sheets maintained a contractile phenotype regardless of ECM composition.","Furthermore, KCl-induced contractions in tissue engineered sheets were similar to native rabbit intestinal tissues (FIG.","14E) in time course, but slightly reduced in magnitude.","Peak KCl-induced contractions in native tissue averaged 373.5±10.63 μN.","KCl-induced contraction was unaffected by pre-treatment with neuronal blocker TTX (grey traces; FIG.","14), indicating myogenic electromechanical coupling integrity.","FIG.","16F demonstrates that the area under the curve of contraction was similar in all tissue engineered sheets, and was significantly higher in native rabbit intestinal tissues.","Although reduced in magnitude compared to native tissue, KCl-induced contractions were similar among the different tissue engineered sheets, indicating a robust contractile smooth muscle phenotype unaffected by the ECM composition.","Acetylcholine-Induced Contraction: Exogenous addition of 1 μM Acetylcholine (Ach) was used to simulate agonist-induced contraction.","All tissue engineered sheets contracted in response to Ach, and sustained contractions up to ˜5 minutes post stimulation with Ach (FIG.","15A-D).","Tissue engineered sheets with composite collagen I/IV with laminin had a significantly elevated peak maximal Ach-induced contraction (FIG.","15C; 232.9±8.167 μN), as well as an elevated area under the curve of contraction (47606±2054 AU).","Magnitude of Ach-induced contraction was still significantly lower compared to contraction in native tissue (342.6±3.15 μN; 70448±5876 AU).","However, the time course of contraction was very similar to native tissue in tissue engineered sheets containing laminin, reaching maximal contraction within a minute of agonist stimulation.","Collagen I sheets also had an elevated Ach-induced contraction (FIG.","15A; 238.9±13.72 μN; 42668±2172 AU) corresponding to the elevated ChAT protein expression.","However, the kinetics of contraction did not match native tissue.","In order to estimate the smooth muscle (myogenic) component of Ach-induced contraction, neurotoxin TTX was used as a pretreatment (grey traces, FIG.","15).","Area under the curves of contraction was compared with and without TTX pre-treatment in order to estimate % inhibition (FIG.","15F).","Percent inhibition of Ach-induced contraction in the presence of TTX was highest in two ECM conditions: i) collagen I sheets (72.77±2.45%); and ii) collagen I/IV/laminin sheets (60.58±1.66%).","These values of % inhibition were similar to that observed in native tissue (72.73±3.66%) upon TTX-pretreatment.","This increased neuronal contribution to Ach-induced contraction also correlated with the elevated protein expression of ChAT in collagen I and composite collagen I/IV/laminin sheets (FIG.","12E, G).","TTX-pretreatment inhibited Ach-induced contraction to a significantly lower extent in collagen I/IV±heparan sulfate sheets, ranging from 48.36±4.36% (Heparan sulfate) to 50.31±4.22% (collagen IV; FIG.","15F).","Relaxation in Engineered Innervated Sheets in Response to Electrical Field Stimulation: Electrical field stimulation (EFS) at 5 Hz, 0.5 ms was used to stimulate neurons within the tissue engineered sheets to produce relaxation of smooth muscle (FIG.","16).","The extent of relaxation was quantified as area under the curve of relaxation.","Extent of relaxation significantly varied amongst the tissue engineered sheets with varying ECM compositions.","Sheets bioengineered with collagen IV, which displayed elevated nNOS expression, had higher relaxation compared to sheets bioengineered with collagen I only (compare 109693±8465 AU in collagen I/IV sheets to 23142±4921 in collagen I sheets).","Sheets containing laminin and/or heparan sulfate also had significantly elevated relaxation compared to collagen I sheets (68395-69025 AU).","In response to EFS, native tissues relaxed generating 101550±11279 AU.","Tissue engineered sheets with collagen IV and/or laminin and/or heparan sulfate additionally had a time course of relaxation most similar to native tissue.","Maximal relaxation was achieved within 2 minutes of EFS, and a subsequent recovery of basal force was complete within 10 minutes.","Upon pre-treatment with TTX, EFS-induced relaxation was inhibited entirely (grey traces, FIG.","16).","Inhibition of Nitric Oxide Synthase: In order to identify the presence and functionality of nitrergic neurons, an inhibitor of nitric oxide synthase (L-NAME) was used (grey traces, FIG.","17).","Percent inhibition was determined by comparing areas under the curves of maximal relaxation with and without the L-NAME pre-treatment.","Percent inhibition with L-NAME treatment was the lowest in collagen I sheets (33.37±8.37%; grey trace, FIG.","17A).","This corresponded to the low protein expression of nNOS in collagen I sheets compared to sheets containing collagen IV (FIG.","12D).","In contrast, the inhibition of nNOS activity attenuated relaxation up to 61.71±2.82% (grey trace, FIG.","17B) in collagen I/IV sheets.","In sheets containing laminin and heparan sulfate, % inhibition with L-NAME varied between 62.28±2.75% (laminin, FIG.","17C) to 57.16±1.91% (heparan sulfate).","This inhibition is significantly elevated compared to collagen I sheets, corresponding to the increased expression of nNOS observed in the collagen I/collagen IV sheets (FIG.","12C).","Native tissues had a higher % inhibition with L-NAME (78.02±2.85%).","Inhibition of the VIP-Receptor: The functionality of VIP-ergic neurons was assessed using a VIP receptor antagonist (VIP-Ra).","Pre-treatment with VIP-Ra inhibited maximal relaxation in all tissue engineered sheets to varying extents ranging from 55.55±3.92%-65.92±5.38% (grey traces, FIG.","18).","Inhibition of EFS-induced relaxation indicated the presence of differentiated VIP-ergic neurons in tissue engineered sheets.","The section headings used herein are for organizational purposes only and are not to be construed as limiting.","While the applicants' teachings are described in conjunction with various embodiments, it is not intended that the applicants' teachings be limited to such embodiments.","On the contrary, the applicants' teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art."]],"string":"[\n [\n \"Neural Progenitor Cell Differentiation\",\n \"Differentiation and stability of neural stem cells can be enhanced by in vitro or in vivo culturing with one or more extracellular matrix (ECM) compositions, such as collagen I, IV, laminin and/or a heparan sulfate proteoglycan.\",\n \"In one aspect of the invention, adult mammalian enteric neuronal progenitor cells can be induced to differentiate on various substrates derived from components or combinations of neural ECM compositions.\",\n \"Collagen I and IV supported neuronal differentiation and extensive glial differentiation individually and in combination.\",\n \"Addition of laminin or heparan sulfate to collagen substrates unexpectedly improved neuronal differentiation, increasing neuron number, branching of neuronal processes, and initiation of neuronal network formation.\",\n \"In another aspect, neuronal subtype differentiation was affected by varying ECM compositions in hydrogels overlaid on intestinal smooth muscle sheets.\",\n \"The matrix compositions of the present invention can be used to tissue engineer transplantable innervated GI smooth muscle constructs to remedy aganglionic disorders.\"\n ],\n [\n \"1-13.\",\n \"(canceled) 14.A method of preparing an innervated smooth muscle construct, the method comprising: obtaining a population of longitudinal smooth muscle cells; culturing the longitudinal smooth muscle cells to form a uniaxially-aligned smooth muscle sheet; obtaining a population of neural stem cells; and co-culturing the neural stem cells and longitudinal smooth muscle cells on a substrate comprising at least one extracellular matrix (ECM) material component.\",\n \"15.\",\n \"(canceled) 16.The method of claim 14 wherein the step of culturing the longitudinal smooth muscle cells further comprises culturing the muscle cells on a mold containing a wavy microtopography to form the uniaxially-aligned smooth muscle sheet.\",\n \"17.The method of claim 14 wherein the substrate further comprises a hydrogel.\",\n \"18.The method of claim 17 wherein the hydrogel comprises at least one of collagen, laminin and heparan sulfate.\",\n \"19.The method of claim 17 wherein the hydrogel comprises collagen.\",\n \"20.The method of claim 17 wherein the hydrogel comprises at least 800 μg/ml of collagen type I.\",\n \"21.The method of claim 20, wherein the hydrogel comprises between about 800 μg/ml and about 1600 μm/ml collagen I.\",\n \"22.The method of claim 17 wherein the hydrogel further comprises at least 200 μg/ml of collagen type IV.\",\n \"23.The method of claim 17 wherein the hydrogel further comprises at least 5 μg/ml of laminin.\",\n \"24.The method of claim 17 wherein the hydrogel is substantially free of laminin.\",\n \"25.The method of claim 17 wherein the hydrogel is substantially free of heparan sulfate.\",\n \"26.The method of claim 14 wherein the method further comprises administering the construct to a patient.\",\n \"27.The method of claim 26, wherein the step of administering the construct further comprises implanting the construct into the patient.\",\n \"28.The method of claim 27 wherein the construct comprises a hydrogel sponge with effective pore sizes ranging from 10 nanometers to 10 micrometers.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>An uninterrupted enteric nervous system with the preservation of myenteric ganglia is required for intestinal motility and function.\",\n \"Motor neurons of the myenteric ganglia predominantly express acetylcholine/tachykinins (excitatory) or nitric oxide/inhibitory peptides/purines (inhibitory) to mediate smooth muscle contraction and relaxation.\",\n \"Partial, selective, or total loss of nerve function and/or loss of nerve cell populations within organs and other body structures are characteristic of numerous diseases and disorders.\",\n \"For example, aganglionosis of various lengths of distal gut is the central pathology in Hirschsprung's disease.\",\n \"Enteric neuropathy is also secondary to several other disorders (e.g., diabetes, Parkinson's disease, and inflammation) resulting in gastrointestinal dysfunction.\",\n \"Gastrointestinal motor function is controlled by the intramural enteric nervous system.\",\n \"It is a complex interplay between the smooth muscle of the muscularis externa and the two enteric neuronal plexi.\",\n \"Neural stem cell therapy is an emerging therapy that aims to reinstate neuronal function and thus gastrointestinal motor function by repopulating the enteric plexi.\",\n \"The research is driven by two significant findings: i) neural stem cells can be isolated from adult mammalian gut, including the ganglionated colon of Hirschsprung's patients; and ii) neural stem cells can be induced to differentiate into several neuronal subtypes and glia characteristic of the enteric nervous system (ENS) upon transplantation into explant cultures of aganglionic/aneural gut, or in vivo into distal colo-rectums in animal models.\",\n \"While neural-crest derived enteric neural stem cells have been isolated from adult mammalian guts, including ganglionic bowel of patients with Hirschsprung's disease, there is little information or understanding of microenvironment-driven differentiation, and only limited studies describing subsequent functional behavior of these differentiated neurons in vitro.\",\n \"Moreover, restoration of nerve functions by neural stem cell transplantations as a treatment for nerve-loss associated disorders has not yet been clinically demonstrated, and there exists a need for methods and materials to support neuroglial cells, and to ensure phenotypic stability and long term survival of transplanted or implanted neural stem cells.\"\n ],\n [\n \"<SOH> SUMMARY <EOH>It has been discovered that extracellular matrix (ECM) compositions can modulate neural stem cell fate and direct differentiation.\",\n \"The term “extracellular matrix” or “ECM” is used herein to denote composition comprising one or more of the following: collagen I, collagen IV, laminin, heparan sulfate, or fragments of one or more of such proteins.\",\n \"One aspect of the invention includes a method of biasing neural stem cell differentiation having the steps of obtaining a population of smooth muscle cells, culturing the smooth muscle cells to form a uniaxially-aligned smooth muscle sheet, obtaining a population of neural stem cells, culturing the neural stem cells in a hydrogel, wherein the hydrogel is applied to the uniaxially-aligned smooth muscle sheet, and exposing the neural stem cells to at least one extracellular matrix (ECM) component, wherein the ECM component biases differentiation of the neural stem cells into differentiated neural stem cells that are enriched for a neuronal subtype.\",\n \"For example, the neuronal subtype are cholinergic neurons, where the hydrogel can include collagen I, or at least at least about 800 μg/ml collagen I, or between about 800 μg/ml and about 1600 μg/ml collagen I.\",\n \"In another example, the neuronal subtype are nitrergic neurons, where the hydrogel can include collagen IV and be substantially free of laminin, or at least about 200 μg/ml collagen IV and be substantially free of laminin.\",\n \"In another example, the neuronal subtype are peptidergic neurons, where the hydrogel can include collagen I, collagen IV, and laminin, or at least about 800 μg/ml collagen I, at least about 200 μg/ml collagen IV, and at least about 5 μg/ml laminin.\",\n \"Another aspect of the invention can include isolating the differentiated neural stem cells and administering the differentiated neural stem cells to a patient.\",\n \"For example, the administering can include injecting, into the patient, the differentiated stem cells in the hydrogel.\",\n \"In another example, the differentiated neural stem cells innervate the uniaxially-aligned smooth muscle sheet to form an innervated smooth muscle sheet and can include the additional step of implanting the innervated smooth muscle sheet into a patient.\",\n \"Another aspect of the invention includes a method of biasing neural stem cell differentiation having the steps of obtaining a population of neural stem cells, obtaining a population of smooth muscle cells, culturing the neural stem cells in the presence of the smooth muscle cells, wherein the neural stem cells adhere on a substrate with a substrate coating comprising at least one extracellular matrix (ECM) component, wherein the ECM component biases differentiation of the neural stem cells into differentiated neural stem cells that are enriched for neurons.\",\n \"For example, the substrate coating comprises at least one of laminin, collagen I, and collagen IV, or the substrate coating comprises laminin, and at least one of collagen I and collagen IV, or the substrate coating comprises collagen I and collagen IV, and at least one of laminin and heparan sulfate.\",\n \"Another aspect of the invention can also include isolating the differentiated neural stem cells and administering the differentiated neural stem cells to a patient.\",\n \"For example, the administering can include injecting the differentiated neural stem cells into the patient.\",\n \"Another aspect of the invention includes a method of biasing neural stem cell differentiation by obtaining a population of neural stem cells, obtaining a population of smooth muscle cells, culturing the neural stem cells in the presence of the smooth muscle cells, wherein the neural stem cells adhere on a substrate with a substrate coating comprising at least one extracellular matrix (ECM) component, wherein the ECM component biases differentiation of the neural stem cells into differentiated neural stem cells that are enriched for glial cells.\",\n \"For example, the substrate coating can include at least collagen I and collagen IV, and be substantially free of at least one of laminin and heparan sulfate, or the substrate coating can comprises at least 5 μg/cm2 collagen I and at least 5 μg/cm2 collagen IV, and be substantially free of at least one of laminin and heparan sulfate.\",\n \"Another aspect further includes the step of isolating the differentiated neural stem cells and administering the differentiated neural stem cells to a patient.\",\n \"For example, the administering comprises injecting the differentiated neural stem cells into the patient.\",\n \"In one aspect of the invention, adult mammalian enteric neural progenitor cells can be induced to differentiate on various substrates derived from components or combinations of ECM compositions.\",\n \"Neuronal and glial differentiation was studied as a function of ECM composition.\",\n \"Collagen I and collagen IV substrates supported neuronal differentiation and extensive glial differentiation individually and in combination.\",\n \"The addition of laminin or heparan sulfate to collagen substrates improved neuronal differentiation, increasing the number of neurons and the branching of neuronal processes and initiation of neuronal network formation.\",\n \"Various neural ECM components were evaluated individually and in combination to study their effect of neuroglial differentiation of adult enteric neural progenitor cells.\",\n \"In another aspect of the invention, tissue-engineered intestinal longitudinal smooth muscle sheets can be innervated using enteric neuronal progenitor cells embedded with hydrogels of varying ECM composition.\",\n \"Differentiated neuronal composition (cholinergic, nitrergic, peptidergic), as well as functional neuronal physiology mediating smooth muscle contraction/relaxations, were evaluated.\",\n \"Several functional differentiated neuronal subtypes were present in tissue-engineered intestinal sheets, capable of mediating smooth muscle contraction/relaxation.\",\n \"Neuronal populations varied from being highly cholinergic (collagen I), highly nitrergic (composite collagen I and collagen IV), or balanced between the two (composite collagen I and collagen IV, and laminin and/or heparan sulfate).\",\n \"Additionally, an increase in peptidergic neurons was detected with laminin and heparan sulfate.\",\n \"The feasibility of transplantation of various types of neuronal progenitor cells (CNS-derived, neural tube-derived, embryonic and adult ENS-derived) in explant cultures of aneural gut is well established.\",\n \"However, conditions required for successful engraftment and long-term survival, focusing on a permissive environment heretofore have not been identified.\",\n \"Studies related to in vitro differentiation of adult enteric neuronal progenitor cells with a focus on the role of the ECM can help optimize the survivability and maintenance of both neuronal and neuroglial phenotypes.\",\n \"Moreover, our studies indicate that neuronal differentiation can be modulated by varying the composition of ECM microenvironments.\",\n \"Enriched populations of differentiated neuronal subtypes can be derived within transplantable tissue engineered sheets, using ECM microenvironments.\",\n \"ECM microenvironments may also facilitate adequate trophic support and phenotype maintenance of differentiated neurons.\",\n \"In certain embodiments, neural differentiation is induced by administering an effective amount of laminin or a composition comprising laminin, including fragments, derivatives, or analogs thereof.\",\n \"In a specific example, the laminin can be a complete laminin protein.\",\n \"In further examples, the laminin is selected from laminin-1, laminin-2, laminin-4, and fragments or combinations thereof.\",\n \"In further examples, the laminin or laminin composition includes a substance at least substantially homologous to laminin-1, laminin-2, or laminin-4.In yet further implementations, the laminin or laminin composition comprises a polypeptide at least substantially homologous to the laminin al chain, e.g., having at least 80%, or 85%, or 90%, or 95% sequence identical to at least a fragment of the laminin α 1 chain that retains the capacity to induce neuroglial differentiation.\",\n \"Amounts effective for various therapeutic treatments of the present disclosure may, of course, depend on the severity of the disease and the weight and general state of the subject, as well as the absorption, inactivation, and excretion rates of the therapeutically-active compound or component, the dosage schedule, and amount administered, as well as other factors known to those of ordinary skill in the art.\",\n \"It also should be apparent to one of ordinary skill in the art that the exact dosage and frequency of administration will depend on the particular laminin, laminin composition, or other therapeutic substance being administered, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular subject, and other medication the subject may be taking.\",\n \"Typically, dosages used in vitro may provide useful guidance in the amounts useful for in vivo administration of the pharmaceutical composition, and animal models may be used to determine effective dosages for treatment of particular disorders.\",\n \"For example, animal models of neural disorders may be used to determine effective dosages that can then be translated to dosage amount for other subjects, such as humans, as known in the art.\",\n \"Various considerations in dosage determination are described, e.g., in Gilman et al., eds., Goodman And Gilman's: The Pharmacological Bases of Therapeutics, 8th ed., Pergamon Press (1990); and Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Co., Easton, Pa. (1990), which is herein incorporated by reference.\",\n \"In another example, the laminin or laminin composition can be introduced into an in vitro culture of neural stem cells (or co-administered with neural stem cells to a subject) in an amount sufficient to provide a dose of laminin of between about 10 fmol/g and about 500 nmol/g, such as between about 2 nmol/g and about 20 nmol/g or between about 2 nmol/g and about 10 nmol/g.\",\n \"In additional examples, the laminin or laminin composition can be provided in vitro or administered to a subject in an amount sufficient to provide a dose of laminin of between about 0.01 μg/kg and about 1000 mg/kg or between about 0.1 mg/kg and about 1000 mg/kg, in particular examples this amount is provided per day or per week.\",\n \"In another example, the laminin or laminin composition is administered to a subject in an amount sufficient to provide a dose of laminin of between about 0.2 mg/kg and about 2 mg/kg.\",\n \"In further examples, the laminin or laminin composition is administered to a subject in an amount sufficient to provide a concentration of laminin in the administrated material of between about 5 nM and about 500 nM, such as between about 50 nM and about 200 nm, or about 100 nM.\",\n \"Addition of heparan sulfate to composite collagen mixtures can improve neuronal differentiation as well.\",\n \"Neuronal networking and neuronal clustering was visible at the later time point.\",\n \"Heparan sulfate and its interaction with glial cell-derived neurotrophic factor (GDNF) and other neurotrophic factors stabilizes and makes these factors locally available, possibly modulating neurite outgrowth and neuronal differentiation.\",\n \"Heparan sulfate interacts with both collagen IV and with laminin, to positive modulate neuronal differentiation, evidenced by the enhanced neurite outgrowth, axonal lengths and initiation of neuronal networking ( FIG.\",\n \"4 A-H).\",\n \"Composite collagen substrates with laminin and/or heparan sulfate all maintained a low level of glial fibrillary acidic protein (GFAP) positive glial cells, with initiation of astrocytic networking becoming more obvious at the later time point.\",\n \"In general, substrates that supported neuronal differentiation demonstrated a bare minimum of glial cells required to possibly support neuronal cell phenotype or survival.\",\n \"Taken together, these results help identify optimal 3D matrix compositions to encapsulate neuronal progenitor cells.\",\n \"In certain embodiments, three dimensional hydrogel environments can also provide the mechanical cues for neural differentiation.\",\n \"For example, in some embodiments, three dimensional ECM hydrogels can comprise: collagen I (about 800 μg/ml to about 1600 μg/ml); collagen I (about 800 μg/ml) and collagen IV (about 200 μg/ml); collagen I and collagen IV with laminin (about 5 μg/ml to about 10 μg/ml); collagen I and collagen IV with laminin and heparan sulfate (about 10 μg/ml to about 20 μg/ml); Other components of the gel can include: at least 1% fetal calf serum and at least 0.1× antibiotics in Dulbecco's modified Eagle's medium.\",\n \"Sodium hydroxide (0.1N) can be used to adjust pH to about 7.4 for gelation.\",\n \"Accordingly, methods and systems for treating neurodegenerative conditions are disclosed whereby neural stem cells (NSCs) can be transplanted into a subject in need such that the cells can differentiate and ameliorate the neurodegenerative condition.\",\n \"In certain embodiments, the neural stem cells, upon transplantation, generate an amount of neurons or glial cells sufficient to integrate within the neural infrastructure to ameliorate a disease state or condition.\",\n \"In one embodiment, the disclosed methods include treating neurodegenerative diseases or conditions by transplanting multipotential neural progenitors or neural stem cells isolated from the central nervous system of a mammal and that have been expanded in vitro and induced to differentiate by exposure to at least one component of an extracellular matrix material (ECM).\",\n \"In another aspect of the invention, treatments can include supplying a suitable number of NSCs to an injured neural area, via transplantation, such that the transplanted cells differentiate into a sufficient number of neurons and/or glial cells to rehabilitate defective neural circuits.\",\n \"In an embodiment, the disclosed methods include restoring motor function in a motor neuron disease.\",\n \"A suitable number or a therapeutically effective amount of NSCs or neural progenitors which are capable of differentiating into motor neurons can be provided to at least one area of neurodegeneration.\",\n \"The NSCs can exert their therapeutic effect by replacing degenerated neuromuscular junctions.\",\n \"In certain embodiments, the disclosed methods and systems include providing neural stem cells or neural progenitors that integrate with the host tissue and provide one or more factors to the host neurons thereby protecting them from degenerative influences present in the tissue.\",\n \"In one preferred embodiment, the disclosed methods include increasing differentiation efficiency of transplanted NSCs into neurons or glial cells by exposure of the stem cells to one or more extracellular matrix materials (ECMs).\",\n \"The method can also include expanding highly enriched NSCs or neural progenitors in their undifferentiated state and then inducing differentiation so that, upon transplantation, a sufficient number of the cells in the graft adopt a desired phenotype.\",\n \"The cells of the disclosed methods can be isolated or obtained from fetal, neonatal, juvenile, adult, or post-mortem tissues of a mammal.\",\n \"The cells of the disclosed methods can be isolated or obtained from the central nervous system, blood, or any other suitable source of stem cells that differentiate into neurons.\",\n \"The cells can also be obtained from embryonic stem cells.\",\n \"In certain preferred embodiments, the cells are autologous neural stem cells obtained from a subject and that returned to the subject to ameliorate a neural disorder.\",\n \"In certain embodiments, the neural stem cells can be expanded in culture.\",\n \"In some embodiments, the neural precursor cells can be multipotential NSCs capable of expansion in culture and of generating both neurons and glia upon differentiation.\",\n \"The cells can be either undifferentiated, pre-differentiated or fully differentiated in vitro at the time of transplantation.\",\n \"In an embodiment, the cells are induced to differentiate into neural lineage.\",\n \"The cells of the disclosed methods can undergo neuronal differentiation in situ in the presence of EMCs and/or pro-inflammatory cytokines and other environmental factors existing in an injured tissue.\",\n \"Using the present methods, neural circuits can be treated by transplanting or introducing the cells into appropriate regions for amelioration of the disease, disorder, or condition.\",\n \"Generally, transplantation occurs into nervous tissue or non-neural tissues that support survival of the grafted cells.\",\n \"NSC grafts employed in the disclosed methods survive well in a neurodegenerative environment where the NSCs can exert powerful clinical effects in the form of delaying the onset and progression of neurodegenerative conditions or disease.\",\n \"The present invention can be used in conjunction with various other tissue engineering methods and compositions including those disclosed in commonly-owned, co-pending Applications No.\",\n \"PCT/US2013/024080 entitled “Innervation of Engineered Structures” filed Jan. 31, 2013 and No.\",\n \"PCT/US2013/024024 entitled “Tubular Bioengineered Muscle Structures” also filed Jan. 31, 2013, each of which is incorporated herein in its entirety by reference.\"\n ],\n [\n \"RELATED APPLICATIONS This application is a Divisional Application of Ser.\",\n \"No.\",\n \"14/216,391, filed Mar.\",\n \"17, 2014, which claims priority of U.S.\",\n \"Provisional Application No.\",\n \"61/788,285, filed Mar.\",\n \"15, 2013, which is hereby incorporated in its entirety by reference.\",\n \"GOVERNMENT RIGHTS This invention was made with U.S. government support by the National Institutes of Health Grant Nos.\",\n \"RO1DK071614 and RO1DK042876.The U.S. government has certain rights in the invention.\",\n \"TECHNICAL FIELD The field of this invention is tissue engineering and, in particular, re-innervation of organs and body tissue.\",\n \"BACKGROUND An uninterrupted enteric nervous system with the preservation of myenteric ganglia is required for intestinal motility and function.\",\n \"Motor neurons of the myenteric ganglia predominantly express acetylcholine/tachykinins (excitatory) or nitric oxide/inhibitory peptides/purines (inhibitory) to mediate smooth muscle contraction and relaxation.\",\n \"Partial, selective, or total loss of nerve function and/or loss of nerve cell populations within organs and other body structures are characteristic of numerous diseases and disorders.\",\n \"For example, aganglionosis of various lengths of distal gut is the central pathology in Hirschsprung's disease.\",\n \"Enteric neuropathy is also secondary to several other disorders (e.g., diabetes, Parkinson's disease, and inflammation) resulting in gastrointestinal dysfunction.\",\n \"Gastrointestinal motor function is controlled by the intramural enteric nervous system.\",\n \"It is a complex interplay between the smooth muscle of the muscularis externa and the two enteric neuronal plexi.\",\n \"Neural stem cell therapy is an emerging therapy that aims to reinstate neuronal function and thus gastrointestinal motor function by repopulating the enteric plexi.\",\n \"The research is driven by two significant findings: i) neural stem cells can be isolated from adult mammalian gut, including the ganglionated colon of Hirschsprung's patients; and ii) neural stem cells can be induced to differentiate into several neuronal subtypes and glia characteristic of the enteric nervous system (ENS) upon transplantation into explant cultures of aganglionic/aneural gut, or in vivo into distal colo-rectums in animal models.\",\n \"While neural-crest derived enteric neural stem cells have been isolated from adult mammalian guts, including ganglionic bowel of patients with Hirschsprung's disease, there is little information or understanding of microenvironment-driven differentiation, and only limited studies describing subsequent functional behavior of these differentiated neurons in vitro.\",\n \"Moreover, restoration of nerve functions by neural stem cell transplantations as a treatment for nerve-loss associated disorders has not yet been clinically demonstrated, and there exists a need for methods and materials to support neuroglial cells, and to ensure phenotypic stability and long term survival of transplanted or implanted neural stem cells.\",\n \"SUMMARY It has been discovered that extracellular matrix (ECM) compositions can modulate neural stem cell fate and direct differentiation.\",\n \"The term “extracellular matrix” or “ECM” is used herein to denote composition comprising one or more of the following: collagen I, collagen IV, laminin, heparan sulfate, or fragments of one or more of such proteins.\",\n \"One aspect of the invention includes a method of biasing neural stem cell differentiation having the steps of obtaining a population of smooth muscle cells, culturing the smooth muscle cells to form a uniaxially-aligned smooth muscle sheet, obtaining a population of neural stem cells, culturing the neural stem cells in a hydrogel, wherein the hydrogel is applied to the uniaxially-aligned smooth muscle sheet, and exposing the neural stem cells to at least one extracellular matrix (ECM) component, wherein the ECM component biases differentiation of the neural stem cells into differentiated neural stem cells that are enriched for a neuronal subtype.\",\n \"For example, the neuronal subtype are cholinergic neurons, where the hydrogel can include collagen I, or at least at least about 800 μg/ml collagen I, or between about 800 μg/ml and about 1600 μg/ml collagen I.\",\n \"In another example, the neuronal subtype are nitrergic neurons, where the hydrogel can include collagen IV and be substantially free of laminin, or at least about 200 μg/ml collagen IV and be substantially free of laminin.\",\n \"In another example, the neuronal subtype are peptidergic neurons, where the hydrogel can include collagen I, collagen IV, and laminin, or at least about 800 μg/ml collagen I, at least about 200 μg/ml collagen IV, and at least about 5 μg/ml laminin.\",\n \"Another aspect of the invention can include isolating the differentiated neural stem cells and administering the differentiated neural stem cells to a patient.\",\n \"For example, the administering can include injecting, into the patient, the differentiated stem cells in the hydrogel.\",\n \"In another example, the differentiated neural stem cells innervate the uniaxially-aligned smooth muscle sheet to form an innervated smooth muscle sheet and can include the additional step of implanting the innervated smooth muscle sheet into a patient.\",\n \"Another aspect of the invention includes a method of biasing neural stem cell differentiation having the steps of obtaining a population of neural stem cells, obtaining a population of smooth muscle cells, culturing the neural stem cells in the presence of the smooth muscle cells, wherein the neural stem cells adhere on a substrate with a substrate coating comprising at least one extracellular matrix (ECM) component, wherein the ECM component biases differentiation of the neural stem cells into differentiated neural stem cells that are enriched for neurons.\",\n \"For example, the substrate coating comprises at least one of laminin, collagen I, and collagen IV, or the substrate coating comprises laminin, and at least one of collagen I and collagen IV, or the substrate coating comprises collagen I and collagen IV, and at least one of laminin and heparan sulfate.\",\n \"Another aspect of the invention can also include isolating the differentiated neural stem cells and administering the differentiated neural stem cells to a patient.\",\n \"For example, the administering can include injecting the differentiated neural stem cells into the patient.\",\n \"Another aspect of the invention includes a method of biasing neural stem cell differentiation by obtaining a population of neural stem cells, obtaining a population of smooth muscle cells, culturing the neural stem cells in the presence of the smooth muscle cells, wherein the neural stem cells adhere on a substrate with a substrate coating comprising at least one extracellular matrix (ECM) component, wherein the ECM component biases differentiation of the neural stem cells into differentiated neural stem cells that are enriched for glial cells.\",\n \"For example, the substrate coating can include at least collagen I and collagen IV, and be substantially free of at least one of laminin and heparan sulfate, or the substrate coating can comprises at least 5 μg/cm2 collagen I and at least 5 μg/cm2 collagen IV, and be substantially free of at least one of laminin and heparan sulfate.\",\n \"Another aspect further includes the step of isolating the differentiated neural stem cells and administering the differentiated neural stem cells to a patient.\",\n \"For example, the administering comprises injecting the differentiated neural stem cells into the patient.\",\n \"In one aspect of the invention, adult mammalian enteric neural progenitor cells can be induced to differentiate on various substrates derived from components or combinations of ECM compositions.\",\n \"Neuronal and glial differentiation was studied as a function of ECM composition.\",\n \"Collagen I and collagen IV substrates supported neuronal differentiation and extensive glial differentiation individually and in combination.\",\n \"The addition of laminin or heparan sulfate to collagen substrates improved neuronal differentiation, increasing the number of neurons and the branching of neuronal processes and initiation of neuronal network formation.\",\n \"Various neural ECM components were evaluated individually and in combination to study their effect of neuroglial differentiation of adult enteric neural progenitor cells.\",\n \"In another aspect of the invention, tissue-engineered intestinal longitudinal smooth muscle sheets can be innervated using enteric neuronal progenitor cells embedded with hydrogels of varying ECM composition.\",\n \"Differentiated neuronal composition (cholinergic, nitrergic, peptidergic), as well as functional neuronal physiology mediating smooth muscle contraction/relaxations, were evaluated.\",\n \"Several functional differentiated neuronal subtypes were present in tissue-engineered intestinal sheets, capable of mediating smooth muscle contraction/relaxation.\",\n \"Neuronal populations varied from being highly cholinergic (collagen I), highly nitrergic (composite collagen I and collagen IV), or balanced between the two (composite collagen I and collagen IV, and laminin and/or heparan sulfate).\",\n \"Additionally, an increase in peptidergic neurons was detected with laminin and heparan sulfate.\",\n \"The feasibility of transplantation of various types of neuronal progenitor cells (CNS-derived, neural tube-derived, embryonic and adult ENS-derived) in explant cultures of aneural gut is well established.\",\n \"However, conditions required for successful engraftment and long-term survival, focusing on a permissive environment heretofore have not been identified.\",\n \"Studies related to in vitro differentiation of adult enteric neuronal progenitor cells with a focus on the role of the ECM can help optimize the survivability and maintenance of both neuronal and neuroglial phenotypes.\",\n \"Moreover, our studies indicate that neuronal differentiation can be modulated by varying the composition of ECM microenvironments.\",\n \"Enriched populations of differentiated neuronal subtypes can be derived within transplantable tissue engineered sheets, using ECM microenvironments.\",\n \"ECM microenvironments may also facilitate adequate trophic support and phenotype maintenance of differentiated neurons.\",\n \"In certain embodiments, neural differentiation is induced by administering an effective amount of laminin or a composition comprising laminin, including fragments, derivatives, or analogs thereof.\",\n \"In a specific example, the laminin can be a complete laminin protein.\",\n \"In further examples, the laminin is selected from laminin-1, laminin-2, laminin-4, and fragments or combinations thereof.\",\n \"In further examples, the laminin or laminin composition includes a substance at least substantially homologous to laminin-1, laminin-2, or laminin-4.In yet further implementations, the laminin or laminin composition comprises a polypeptide at least substantially homologous to the laminin al chain, e.g., having at least 80%, or 85%, or 90%, or 95% sequence identical to at least a fragment of the laminin α1 chain that retains the capacity to induce neuroglial differentiation.\",\n \"Amounts effective for various therapeutic treatments of the present disclosure may, of course, depend on the severity of the disease and the weight and general state of the subject, as well as the absorption, inactivation, and excretion rates of the therapeutically-active compound or component, the dosage schedule, and amount administered, as well as other factors known to those of ordinary skill in the art.\",\n \"It also should be apparent to one of ordinary skill in the art that the exact dosage and frequency of administration will depend on the particular laminin, laminin composition, or other therapeutic substance being administered, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular subject, and other medication the subject may be taking.\",\n \"Typically, dosages used in vitro may provide useful guidance in the amounts useful for in vivo administration of the pharmaceutical composition, and animal models may be used to determine effective dosages for treatment of particular disorders.\",\n \"For example, animal models of neural disorders may be used to determine effective dosages that can then be translated to dosage amount for other subjects, such as humans, as known in the art.\",\n \"Various considerations in dosage determination are described, e.g., in Gilman et al., eds., Goodman And Gilman's: The Pharmacological Bases of Therapeutics, 8th ed., Pergamon Press (1990); and Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Co., Easton, Pa. (1990), which is herein incorporated by reference.\",\n \"In another example, the laminin or laminin composition can be introduced into an in vitro culture of neural stem cells (or co-administered with neural stem cells to a subject) in an amount sufficient to provide a dose of laminin of between about 10 fmol/g and about 500 nmol/g, such as between about 2 nmol/g and about 20 nmol/g or between about 2 nmol/g and about 10 nmol/g.\",\n \"In additional examples, the laminin or laminin composition can be provided in vitro or administered to a subject in an amount sufficient to provide a dose of laminin of between about 0.01 μg/kg and about 1000 mg/kg or between about 0.1 mg/kg and about 1000 mg/kg, in particular examples this amount is provided per day or per week.\",\n \"In another example, the laminin or laminin composition is administered to a subject in an amount sufficient to provide a dose of laminin of between about 0.2 mg/kg and about 2 mg/kg.\",\n \"In further examples, the laminin or laminin composition is administered to a subject in an amount sufficient to provide a concentration of laminin in the administrated material of between about 5 nM and about 500 nM, such as between about 50 nM and about 200 nm, or about 100 nM.\",\n \"Addition of heparan sulfate to composite collagen mixtures can improve neuronal differentiation as well.\",\n \"Neuronal networking and neuronal clustering was visible at the later time point.\",\n \"Heparan sulfate and its interaction with glial cell-derived neurotrophic factor (GDNF) and other neurotrophic factors stabilizes and makes these factors locally available, possibly modulating neurite outgrowth and neuronal differentiation.\",\n \"Heparan sulfate interacts with both collagen IV and with laminin, to positive modulate neuronal differentiation, evidenced by the enhanced neurite outgrowth, axonal lengths and initiation of neuronal networking (FIG.\",\n \"4 A-H).\",\n \"Composite collagen substrates with laminin and/or heparan sulfate all maintained a low level of glial fibrillary acidic protein (GFAP) positive glial cells, with initiation of astrocytic networking becoming more obvious at the later time point.\",\n \"In general, substrates that supported neuronal differentiation demonstrated a bare minimum of glial cells required to possibly support neuronal cell phenotype or survival.\",\n \"Taken together, these results help identify optimal 3D matrix compositions to encapsulate neuronal progenitor cells.\",\n \"In certain embodiments, three dimensional hydrogel environments can also provide the mechanical cues for neural differentiation.\",\n \"For example, in some embodiments, three dimensional ECM hydrogels can comprise: collagen I (about 800 μg/ml to about 1600 μg/ml); collagen I (about 800 μg/ml) and collagen IV (about 200 μg/ml); collagen I and collagen IV with laminin (about 5 μg/ml to about 10 μg/ml); collagen I and collagen IV with laminin and heparan sulfate (about 10 μg/ml to about 20 μg/ml); Other components of the gel can include: at least 1% fetal calf serum and at least 0.1× antibiotics in Dulbecco's modified Eagle's medium.\",\n \"Sodium hydroxide (0.1N) can be used to adjust pH to about 7.4 for gelation.\",\n \"Accordingly, methods and systems for treating neurodegenerative conditions are disclosed whereby neural stem cells (NSCs) can be transplanted into a subject in need such that the cells can differentiate and ameliorate the neurodegenerative condition.\",\n \"In certain embodiments, the neural stem cells, upon transplantation, generate an amount of neurons or glial cells sufficient to integrate within the neural infrastructure to ameliorate a disease state or condition.\",\n \"In one embodiment, the disclosed methods include treating neurodegenerative diseases or conditions by transplanting multipotential neural progenitors or neural stem cells isolated from the central nervous system of a mammal and that have been expanded in vitro and induced to differentiate by exposure to at least one component of an extracellular matrix material (ECM).\",\n \"In another aspect of the invention, treatments can include supplying a suitable number of NSCs to an injured neural area, via transplantation, such that the transplanted cells differentiate into a sufficient number of neurons and/or glial cells to rehabilitate defective neural circuits.\",\n \"In an embodiment, the disclosed methods include restoring motor function in a motor neuron disease.\",\n \"A suitable number or a therapeutically effective amount of NSCs or neural progenitors which are capable of differentiating into motor neurons can be provided to at least one area of neurodegeneration.\",\n \"The NSCs can exert their therapeutic effect by replacing degenerated neuromuscular junctions.\",\n \"In certain embodiments, the disclosed methods and systems include providing neural stem cells or neural progenitors that integrate with the host tissue and provide one or more factors to the host neurons thereby protecting them from degenerative influences present in the tissue.\",\n \"In one preferred embodiment, the disclosed methods include increasing differentiation efficiency of transplanted NSCs into neurons or glial cells by exposure of the stem cells to one or more extracellular matrix materials (ECMs).\",\n \"The method can also include expanding highly enriched NSCs or neural progenitors in their undifferentiated state and then inducing differentiation so that, upon transplantation, a sufficient number of the cells in the graft adopt a desired phenotype.\",\n \"The cells of the disclosed methods can be isolated or obtained from fetal, neonatal, juvenile, adult, or post-mortem tissues of a mammal.\",\n \"The cells of the disclosed methods can be isolated or obtained from the central nervous system, blood, or any other suitable source of stem cells that differentiate into neurons.\",\n \"The cells can also be obtained from embryonic stem cells.\",\n \"In certain preferred embodiments, the cells are autologous neural stem cells obtained from a subject and that returned to the subject to ameliorate a neural disorder.\",\n \"In certain embodiments, the neural stem cells can be expanded in culture.\",\n \"In some embodiments, the neural precursor cells can be multipotential NSCs capable of expansion in culture and of generating both neurons and glia upon differentiation.\",\n \"The cells can be either undifferentiated, pre-differentiated or fully differentiated in vitro at the time of transplantation.\",\n \"In an embodiment, the cells are induced to differentiate into neural lineage.\",\n \"The cells of the disclosed methods can undergo neuronal differentiation in situ in the presence of EMCs and/or pro-inflammatory cytokines and other environmental factors existing in an injured tissue.\",\n \"Using the present methods, neural circuits can be treated by transplanting or introducing the cells into appropriate regions for amelioration of the disease, disorder, or condition.\",\n \"Generally, transplantation occurs into nervous tissue or non-neural tissues that support survival of the grafted cells.\",\n \"NSC grafts employed in the disclosed methods survive well in a neurodegenerative environment where the NSCs can exert powerful clinical effects in the form of delaying the onset and progression of neurodegenerative conditions or disease.\",\n \"The present invention can be used in conjunction with various other tissue engineering methods and compositions including those disclosed in commonly-owned, co-pending Applications No.\",\n \"PCT/US2013/024080 entitled “Innervation of Engineered Structures” filed Jan. 31, 2013 and No.\",\n \"PCT/US2013/024024 entitled “Tubular Bioengineered Muscle Structures” also filed Jan. 31, 2013, each of which is incorporated herein in its entirety by reference.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS FIG.\",\n \"1 A-D are micrographs of rabbitenteric neuro spheres—FIG.\",\n \"1A is a phase contrast micrograph of rabbit enteric neurospheres in culture.\",\n \"Upon primary isolation and culture, progenitor cells proliferated and aggregated to form neurosphere-like bodies (enteric neurospheres).\",\n \"Immunohistochemistry for initial phenotype (FIGS.\",\n \"1 B-D): Rabbit enteric neurospheres are p75NTR (FIG.\",\n \"1B), Sox2 (FIG.\",\n \"1C) and Nestin (FIG.\",\n \"1D) positive—indicating that they are comprised of neural crest-derived neuronal and glial progenitor cells.\",\n \"Scale bar 100 um.\",\n \"FIG.\",\n \"2 is a schematic illustration of enteric neuro sphere differentiation as a function of extracellular matrix (ECM) composition: 22×11 mm coverslips were coated with poly-L-lysine (PLL), collagen I, collagen IV, laminin or heparan sulfate individually or in combination.\",\n \"Enteric neurospheres were allowed to adhere to the coated coverslips for 6 hours.\",\n \"Separately, uncoated glass coverslips were seeded with colonic smooth muscle cells, and allowed to grow to confluence.\",\n \"In order to stimulate differentiation of enteric neurospheres, a coverslip containing confluent smooth muscle was placed within the same dish, so the two coverslips shared soluble factors.\",\n \"FIG.\",\n \"3 illustrates neuronal differentiation on individual coated coverslips—βIII Tubulin antibody (white) was used to visualize neurons on day 5 (Figs.\",\n \"A-D) and day 15 (Figs.\",\n \"E-H) coverslips coated with PLL (Figs.\",\n \"A,E), laminin (Figs.\",\n \"B,F), type I collagen (Figs.\",\n \"C,G) and type IV collagen (Figs.\",\n \"D,H).\",\n \"Enteric neurospheres on PLL barely initiated neuronal differentiation at day 15.Neurospheres on laminin, collagen I and collagen IV showed branching and several neuronal processes both at the early and late time points in vitro.\",\n \"FIG.\",\n \"4 illustrates neuronal differentiation on collagen-laminin substrates—Neurons stained with βIII tubulin (white) on day 5 (Figs.\",\n \"A-D) and day 15 (Figs.\",\n \"E-H) coverslips coated with type I collagen and 5 μm/cm2 laminin (Figs.\",\n \"A,E) or 10 μm/cm2 laminin (Figs.\",\n \"B,F) or type IV collagen with 5 (Figs.\",\n \"C,G) or 10 (Figs.\",\n \"D,H) μm/cm2 of laminin.\",\n \"Addition of laminin to collagen substrates enhanced early and late neuronal differentiation, but no significant difference was observable between 5 and 10 μg/cm2 of laminin.\",\n \"Type IV collagen substrates (Figs.\",\n \"C,D,G,H) demonstrated enhanced neuronal branching and differentiation compared to type I collagen (Figs.\",\n \"A,B,E,F) substrates.\",\n \"FIG.\",\n \"5 illustrates neuronal differentiation on composite collagen-laminin-heparan sulfate (HS) substrates—Neurons stained with βIII tubulin (white) on day 5 (Figs.\",\n \"A-D) and day 15 (Figs.\",\n \"E-H) coverslips coated with type I and IV collagen with either 5 μm/cm2 laminin (Figs.\",\n \"B,F), 0.1 μm/cm2 heparan sulfate (HS) (Figs.\",\n \"C,G), both (Figs.\",\n \"D,H) or none (Figs.\",\n \"A,E).\",\n \"Addition of laminin or HS to collagen substrates enhanced early and late neuronal differentiation, with visible networking by day 15.Substrates without laminin or HS demonstrated minimal neuronal differentiation (Figs.\",\n \"A,E).\",\n \"FIG.\",\n \"6 illustrates glial differentiation on primary coated substrates—Glia stained with GFAP (white) on day 5 (Figs.\",\n \"A-D) and day 15 (Figs.\",\n \"E-H) coverslips coated with poly-L-lysine (PLL) (Figs.\",\n \"A,E), laminin (Figs.\",\n \"B,F), type I collagen (Figs.\",\n \"C,G) and type IV collagen (Figs.\",\n \"D,H).\",\n \"Enteric neurospheres on PLL demonstrated maximal glial differentiation starting at day 5 up to day 15.While neurospheres on collagen substrates demonstrated good early and late glial differentiation, laminin coated substrates showed no early glial differentiation by day 5 (B), but differentiated subsequently by day 15 (F).\",\n \"FIG.\",\n \"7 illustrates glial differentiation on collagen-laminin substrates—Glia stained with glial fibrillary acidic protein (GFAP) (white) on day 5 (Figs.\",\n \"A-D) and day 15 (Figs.\",\n \"E-H) coverslips coated with type I collagen and 5 μm/cm2 laminin (Figs.\",\n \"A,E) or 10 μm/cm2 laminin (Figs.\",\n \"B,F) or type IV collagen with 5 (Figs.\",\n \"C,G) or 10 (Figs.\",\n \"D,H) μm/cm2 of laminin.\",\n \"Addition of laminin to collagen substrates promoted glial differentiation both at days 5 and 15.No significant difference was observable in GFAP+ glial differentiation between 5 and 10 μg/cm2 of laminin.\",\n \"FIG.\",\n \"8 illustrates glial differentiation on composite collagen-laminin-heparan sulfate (HS) substrates—Glia stained with GFAP (white) on day 5 (Figs.\",\n \"A-D) and day 15 (Figs.\",\n \"E-H) coverslips coated with type I and IV collagen with either 5 μg/cm2 laminin (Figs.\",\n \"B,F), 0.1 μm/cm2 heparan sulfate (Figs.\",\n \"C,G), both (Figs.\",\n \"D,H) or none (Figs.\",\n \"A,E).\",\n \"Addition of laminin or HS to composite collagen substrates demonstrated glial differentiation that peaked at day 5 (Figs.\",\n \"B-D) that was sustained at the later time point (Figs.\",\n \"E-H); and FIG.\",\n \"9 illustrates neurite lengths were measured on coated culture substrata and compared using one way ANOVA.\",\n \"Two bars for each substrate show mean neurite lengths at day 5 and day 15.FIG.\",\n \"9A shows that neurite lengths on PLL were significantly (***p<0.001) shorter than any primary coating substrate.\",\n \"Laminin substrates had the longer neurites (*p<0.05).\",\n \"FIG.\",\n \"9B shows no significant difference was observed in neurite lengths with the addition of 5 or 10 μg/cm2 laminin.\",\n \"FIG.\",\n \"9C shows that the addition of laminin or heparan sulphate significantly increased neurite lengths over composite collagen substrata (*p<0.05).\",\n \"FIG.\",\n \"9D shows that mean GFAP immunofluorescence was quantified: PLL substrates (***p<0.001) and composite collagen substrates (*p<0.05) supported extensive glial differentiation.\",\n \"FIG.\",\n \"10 illustrates scanning electron micrographs of dehydrated ECM gels.\",\n \"Images were obtained at constant magnification and constant working distance.\",\n \"(A) Collagen I fibers were randomly oriented, and presented a dense fibrous structure; (B) Composite Collagen I/IV sheets demonstrated evidence of the formation of network-like structures; (C) There was no difference in ultrastructure with the addition of laminin; (D) Evidence of cabling and cross-linking was observed with the addition of heparan sulfate.\",\n \"Average porosity was determined and summarized in the accompanying table.\",\n \"Viscoelastic modulus was calculated using oscillatory rheometry of ECM gels in their hydrated state, and tabulated in the table.\",\n \"Scale bar 10 μm.\",\n \"FIG.\",\n \"11 illustrates neuronal differentiation within tissue engineered sheets.\",\n \"Phase contrast micrographs were obtained at the edge of the tissue engineered sheets.\",\n \"Evidence of neuronal differentiation and initiation of network formation was observed in all ECM compositions at day 10.The arrows indicate instances of preliminary neuronal networking.\",\n \"Scale bar 200 μm.\",\n \"FIG.\",\n \"12 illustrates immunoblot analysis of tissue engineered longitudinal sheets.\",\n \"Sheets were assessed for expression of neuronal differentiation, constituent smooth muscle phenotype, and excitatory and inhibitory neural markers.\",\n \"Densitometry was used to quantify band intensities, to quantify and compare expression.\",\n \"(A) Neuronal βIII Tubulin expression was similar amongst all four matrices suggesting that all ECM compositions supported neuronal differentiation; (B) Constituent smooth muscle within the tissue engineered sheets maintained contractile phenotype, demonstrated by similar Smoothelin expression; (C) Choline acetyltransferase (ChAT) expression was significantly (*p<0.05) elevated in Col I and Col I/IV/Laminin sheets compared to Col I/IV and Col I/IV/Lam/HS sheets; (D) Neuronal nitric oxide synthase (nNOS) expression was significantly lower (**p<0.001) in Col I sheets compared to elevated levels in all tissue engineered sheets containing Col4 with or without laminin and/or heparan sulfate.\",\n \"(E) Representative immunoblots are provided along with β Actin, demonstrating equal loading.\",\n \"FIG.\",\n \"13 illustrates immunofluorescence for differentiated neurons within tissue engineered sheets.\",\n \"Differentiated neurons within tissue engineered sheets were stained with markers for vasoactive intestinal peptide (VIP), choline acetyltransferase (ChAT) or neuronal nitric oxide synthase (nNOS).\",\n \"(A-D) Numerous differentiated VIP-ergic neurons were present in tissue engineered sheets.\",\n \"(E-H) Differentiated excitatory cholinergic neurons expressing ChAT were present within tissue engineered sheets; (I-L) Differentiated inhibitory nitrergic neurons expressing nNOS were present within tissue engineered sheets.\",\n \"Scale bar 100 μm.\",\n \"FIG.\",\n \"14 illustrates potassium chloride induced contraction of tissue engineered sheets.\",\n \"60 mM Potassium chloride (KCl) was used to examine the electromechanical coupling integrity of the constituent smooth muscle cells within the tissue engineered sheets.\",\n \"The black traces indicate the contraction in response to the addition of KCl.\",\n \"The grey traces indicate the addition of KCl in the presence of a neuronal blocker, TTX.\",\n \"Pre-treatment with TTX did not inhibit KCl-induced contraction.\",\n \"The ECM composition of the tissue engineered sheets did not affect smooth muscle contraction, evidenced by similar contractile patterns in response to KCl stimulation.\",\n \"A robust and immediate contraction was observed upon addition of KCl (indicated by the arrows) in all tissue engineered sheets (A-D), similar to native rabbit intestinal tissue (E).\",\n \"Peak contraction in response to KCl ranged between 279.5 μN and 296.5 μN in tissue engineered sheets, and averaged at 373.3±10.63 in native tissue.\",\n \"(F) The area under the curve of KCl-induced contraction was quantified to demonstrate no significant (ns) difference in contraction in tissue engineered sheets, with a slightly elevated (*p<0.05) magnitude in native tissue.\",\n \"FIG.\",\n \"15 illustrates acetylcholine induced contraction.\",\n \"Addition of 1 μM Acetylcholine (Ach; arrow) resulted in contraction of tissue engineered sheets, as well as native tissue.\",\n \"Gray traces demonstrate Ach treatment in the presence of neuronal blocker, TTX.\",\n \"(A-E) Representative tracings of Ach-induced contraction in tissue engineered sheets and native tissue.\",\n \"Magnitude of Ach-induced contraction varied between tissue engineered sheets.\",\n \"Comparison of the area under the curve of contraction demonstrated that tissue engineered sheets approached 31.5% (Col4)-67.6% (Laminin) of contraction observed in native tissue.\",\n \"In the presence of TTX, magnitude of Ach-induced contraction was attenuated.\",\n \"Quantification of inhibition (F) revealed that the degree of inhibition with TTX varied amongst the tissue engineered sheets with different ECM compositions.\",\n \"Highest inhibition was observed in Col i (72.77±2.5%) and Col I/IV/Laminin (60.58±1.7%) sheets, indicating an elevated presence of cholinergic neurons contributing to Ach-induced contraction.\",\n \"Significantly lower inhibition (*p<0.05; 48.36±4.3-50.31±4.2%) was seen in Col I/IV and Col I/IV/Lam/Heparan sulfate sheets.\",\n \"TTX pre-treatment attenuated Ach-induced contraction by 72.73±3.7% in native tissue.\",\n \"FIG.\",\n \"16 illustrates electrical Field Stimulation induced relaxation in tissue engineered sheets.\",\n \"Electrical Field stimulation (EFS; shaded gray area) was used to stimulate relaxation in tissue engineered sheets (A-D) and native tissue (E).\",\n \"Grey traces indicate TTX pre-treatment.\",\n \"EFS induced relaxation was significantly attenuated by TTX-pretreatment (90.9±2.41%-94.41±0.93%), indicating that differentiated neurons within the tissue engineered sheets were capable of evoking smooth muscle relaxation.\",\n \"The magnitude of relaxation varied amongst the tissue engineered sheets (summarized in Table 3).\",\n \"(F) Quantification of the area under the curve of relaxation indicated that Col I sheets had a significantly low (***p<0.001; 23142±4921 AU) magnitude of relaxation.\",\n \"Relaxation in Col I/IV sheets (109693±8465 AU) were similar to those observed in native tissue (101550±11279 AU) in response to the electrical field, indicating the presence of elevated levels of inhibitory motor neurons capable of mediating relaxation.\",\n \"Relaxation was higher in Col I/IV/Laminin (69025±7154 AU) and Col I/IV/Lam/Heparan sulfate (68395±8228 AU) sheets, when compared to Col I, also indicating a similar increase in the presence of inhibitory motor neurons.\",\n \"FIG.\",\n \"17 illustrates inhibition of relaxation with L-NAME.\",\n \"The functionality of nitrergic neurons was studied by inhibiting EFS-induced relaxation with L-NAME, a non-metabolizable substrate for nNOS.\",\n \"The grey traces indicate EFS in the presence of L-NAME.\",\n \"Pretreatment with L-NAME attenuated EFS-induced relaxation in all tissue engineered sheets (A-D) and native tissue (E).\",\n \"(F) Quantification of the area under the curve for relaxation indicated that the extent of L-NAME inhibition varied amongst the tissue engineered sheets.\",\n \"Col I sheets had a significantly lower % inhibition with L-NAME (*p<0.05; 33.4±8.4%) corresponding to the lowest immunoblot expression of nNOS.\",\n \"The degree of L-NAME inhibition was higher in tissue engineered sheets containing Col I/IV and/or laminin and/or heparan sulfate (57.16%-62.28%), corresponding to the higher immunoblot expression of nNOS.\",\n \"Attenuation of relaxation in the presence of L-NAME was 78±2.9% in native tissue.\",\n \"FIG.\",\n \"18 illustrates inhibition of relaxation with VIP-Ra.\",\n \"The functionality of VIP-ergic neurons was studied by inhibiting EFS-induced relaxation with VIP-Ra, a VIP-receptor antagonist.\",\n \"Grey traces indicate EFS in the presence of VIP-Ra.\",\n \"In the presence of VIP-Ra, EFS-induced relaxation was attenuated in tissue engineered sheets (A-D) and in native tissue (E), indicating the presence of functional VIP-ergic neurons capable of mediating smooth muscle relaxation upon electrical field stimulation.\",\n \"Area under the curve of relaxation was quantified, to calculate the % inhibition of relaxation in the presence of VIP-Ra (F).\",\n \"Extent of VIP-Ra induced inhibition of relaxation varied from 56.55±3.12%-63.11±3.2% in tissue engineered sheets, and averaged at 73.32±3.23% in native tissue.\",\n \"DETAILED DESCRIPTION Definitions As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise.\",\n \"Thus, for example, references to “the method” includes one or more methods, and/or steps of the type described herein which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.\",\n \"The steps of any method can be practice in feasible order and are restricted to a sequential order merely because they are so recited in a claim.\",\n \"Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.\",\n \"Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are now described.\",\n \"“Differentiation” refers to a change that occurs in cells to cause those cells to assume certain specialized functions and to lose the ability to change into certain other specialized functional units.\",\n \"Cells capable of differentiation may be any of totipotent, pluripotent or multipotent cells.\",\n \"Differentiation may be partial or complete with respect to mature adult cells.\",\n \"Stem cells are undifferentiated cells defined by the ability of a single cell both to self-renew, and to differentiate to produce progeny cells, including self-renewing progenitors, non-renewing progenitors, and terminally differentiated cells.\",\n \"Stem cells are also characterized by their ability to differentiate in vitro into functional cells of various cell lineages from multiple germ layers (endoderm, mesoderm and ectoderm), as well as to give rise to tissues of multiple germ layers following transplantation, and to contribute substantially to most, if not all, tissues following injection into blastocysts.\",\n \"Neural stem cells can be isolated from embryonic and adult central nervous system (CNS) tissue, neural tube tissue or enteric nervous system (ENS) tissue.\",\n \"Stem cells can be further classified according to their developmental potential as: (1) totipotent; (2) pluripotent; (3) multipotent; (4) oligopotent; and (5) unipotent.\",\n \"Totipotent cells are able to give rise to all embryonic and extra-embryonic cell types.\",\n \"Pluripotent cells are able to give rise to all embryonic cell types.\",\n \"Multipotent cells include those able to give rise to a subset of cell lineages, but all within a particular tissue, organ, or physiological system (for example, hematopoietic stem cells (HSC) can produce progeny that include HSC (self-renewal), blood cell-restricted oligopotent progenitors, and all cell types and elements (e.g., platelets) that are normal components of the blood).\",\n \"Cells that are oligopotent can give rise to a more restricted subset of cell lineages than multipotent stem cells; and cells that are unipotent typically are only able to give rise to a single cell lineage.\",\n \"In a broader sense, a progenitor cell is a cell that has the capacity to create progeny that are more differentiated than itself, and yet retains the capacity to replenish the pool of progenitors.\",\n \"By that definition, stem cells themselves are also progenitor cells, as are the more immediate precursors to terminally differentiated cells.\",\n \"When referring to the cells of the present invention, as described in greater detail below, this broad definition of progenitor cell may be used.\",\n \"In a narrower sense, a progenitor cell is often defined as a cell that is intermediate in the differentiation pathway, i.e., it arises from a stem cell and is intermediate in the production of a mature cell type or subset of cell types.\",\n \"This type of progenitor cell is generally not able to self-renew.\",\n \"Accordingly, if this type of cell is referred to herein, it will be referred to as a non-renewing progenitor cell or as an intermediate progenitor or precursor cell.\",\n \"As used herein, the phrase “differentiates into a neural lineage or phenotype” refers to a cell that becomes partially or fully committed to a specific neural phenotype of the CNS or PNS, i.e., a neuron or a glial cell, the latter category including without limitation astrocytes, oligodendrocytes, Schwann cells and microglia.\",\n \"The term “neural” as used herein is intended to encompass all electrical active cells, e.g., cells that can process or transmit information through electrical or chemical signals, including the aforementioned neurons, glial cells, astrocytes, oligodendrocytes, Schwann cells and microglia.\",\n \"For the purposes of this disclosure, the terms “neural progenitor cell” or “neural precursor cell” mean a cell that can generate progeny that are either neuronal cells (such as neuronal precursors or mature neurons) or glial cells (such as glial precursors, mature astrocytes, or mature oligodendrocytes).\",\n \"Typically, the cells express some of the phenotypic markers that are characteristic of the neural lineage.\",\n \"Typically, they do not produce progeny of other embryonic germ layers when cultured by themselves in vitro, unless dedifferentiated or reprogrammed in some fashion.\",\n \"A “neuronal progenitor cell” or “neuronal precursor cell” is a cell that can generate progeny that are mature neurons.\",\n \"These cells may or may not also have the capability to generate glial cells.\",\n \"A “glial progenitor cell” or “glial precursor cell” is a cell that can generate progeny that are mature astrocytes or mature oligodendrocytes.\",\n \"These cells may or may not also have the capability to generate neuronal cells.\",\n \"The phrase “biocompatible substance” and the terms “biomaterial” and “substrate” are used interchangeably and refer to a material that is suitable for implantation or injection into a subject.\",\n \"A biocompatible substance does not cause toxic or injurious effects once implanted in the subject.\",\n \"In one embodiment, the biocompatible substrate includes at least one component of extracellular matrix.\",\n \"In other embodiments, the substrate can also include a polymer with a surface that can be shaped into the desired structure that requires repairing or replacing.\",\n \"The polymer can also be shaped into a part of a body structure that requires repairing or replacing.\",\n \"In another embodiment, the biocompatible substrate can be injected into a subject at a target site.\",\n \"In one embodiment, the substrate is an injectable or implantable biomaterial that can be composed of crosslinked polymer networks which are typically insoluble or poorly soluble in water, but can swell to an equilibrium size in the presence of excess water.\",\n \"For example, a hydrogel can be injected into desired locations within the organ.\",\n \"In one embodiment, the collagen can be injected alone.\",\n \"In another embodiment, the collagen can be injected with other hydrogels.\",\n \"The hydrogel compositions can include, without limitation, for example, poly(esters), poly(hydroxy acids), poly(lactones), poly(amides), poly(ester-amides), poly(amino acids), poly(anhydrides), poly(ortho-esters), poly(carbonates), poly(phosphazines), poly(thioesters), polysaccharides and mixtures thereof.\",\n \"Furthermore, the compositions can also include, for example, a poly(hydroxy) acid including poly(alpha-hydroxy) acids and poly(beta-hydroxy) acids.\",\n \"Such poly(hydroxy) acids include, for example, polylactic acid, polyglycolic acid, polycaproic acid, polybutyric acid, polyvaleric acid, and copolymers and mixtures thereof.\",\n \"Hydrogels with effective pore sizes in the 10-100 nm range and in the 100 nm-10 micrometer range are termed “microporous” and “macroporous” hydrogels, respectively.\",\n \"Microporous and macroporous hydrogels are often called polymer “sponges.” When a monomer, e.g., hydroxyethyl methacrylate (HEMA), is polymerized at an initial monomer concentration of 45 (w/w) % or higher in water, a hydrogel is produced with a porosity higher than the homogeneous hydrogels.\",\n \"Hydrogels can also expand in the presence of diluent (usually water).\",\n \"The matrix materials of present invention encompass both conventional foam or sponge materials and the so-called “hydrogel sponges.” For a further description of hydrogels, see U.S. Pat.\",\n \"No.\",\n \"5,451,613 (issued to Smith et al.)\",\n \"herein incorporated by reference.\",\n \"The term “extracellular matrix” or “ECM” is used herein to denote compositions comprising one or more of the following: collagen I, collagen IV, laminin, heparan sulfate, or fragments of one or more of such proteins.\",\n \"“Collagen I” refers to collagen I or collagen I compositions derived from cell culture, animal tissue, or recombinant means, and may be derived from human, murine, porcine, or bovine sources.\",\n \"“Collagen I” also refers to substances or polypeptide(s) at least substantially homologous to collagen I or collagen I compositions.\",\n \"Additionally, “collagen I” refers to collagen I or collagen I compositions that do not include a collagen I fragment, e.g., including essentially only a complete collagen I protein.\",\n \"“Collagen IV” refers to collagen IV or collagen IV compositions derived from cell culture, animal tissue, or recombinant means, and may be derived from human, murine, porcine, or bovine sources.\",\n \"“Collagen IV” also refers to substances or polypeptide(s) at least substantially homologous to collagen IV or collagen IV compositions.\",\n \"Additionally, “collagen IV” refers to collagen IV or collagen IV compositions that do not include a collagen IV fragment, e.g., including essentially only a complete collagen I protein.\",\n \"“Laminin” refers to laminin, laminin fragments, laminin derivatives, laminin analogs, or laminin compositions derived from cell culture, recombinant means, or animal tissue.\",\n \"“Laminin” can be derived from human, murine, porcine, or bovine sources.\",\n \"“Laminin” refers to laminin or laminin compositions comprising laminin-1, laminin-2, laminin-4, or combinations thereof.\",\n \"“Laminin” also refers to substances or polypeptide(s) at least substantially homologous to laminin-1, laminin-2, or laminin-4.Additionally, “laminin” refers to laminin or laminin compositions that do not include a laminin fragment, e.g., including essentially only a complete laminin protein.\",\n \"The term “substantially free of laminin” and “free of laminin” are used interchangeably herein to denote compositions in which laminin is absent or present in such low concentrations that it does not play any significant role in neural stem cell differentiation, e.g., where laminin is only present in concentrations less than 5 μg/ml in hydrogels or 5 μg/cm on substrate coatings, or more preferably less than 2 μg/ml in hydrogels or 2 μg/cm2 on substrate coatings, or less than 1 μg/ml in hydrogels or 1 μg/cm on substrate coatings, and in some instances less than 0.1 μm/ml in hydrogels or 0.1 μm/cm2 on substrate coatings.\",\n \"The term “substantially free of heparan sulfate” and “free of heparan sulfate” are used interchangeably herein to denote compositions in which heparin sulfate is absent or present in such low concentrations that it does not play any significant role in neural stem cell differentiation, e.g., where heparan sulfate is only present in concentrations less than 5 μg/ml in hydrogels or 5 μg/cm2 on substrate coatings, or more preferably less than 2 μg/ml in hydrogels or 2 μg/cm2 on substrate coatings, or less than 1 μg/ml in hydrogels or 1 μg/cm2 on substrate coatings, and in some instances less than 0.1 μm/ml in hydrogels or 0.1 μm/cm2 on substrate coatings.\",\n \"General Techniques For further elaboration of general techniques useful in the practice of this invention, the practitioner can refer to standard textbooks and reviews in cell biology, tissue culture, and embryology.\",\n \"Included are Teratocarcinomas and embryonic stem cells: A practical approach (E. J. Robertson, ed., IRL Press Ltd. 1987); Guide to Techniques in Mouse Development (P. M. Wasserman et al.\",\n \"eds., Academic Press 1993); Embryonic Stem Cell Differentiation in Vitro (M. V. Wiles, Meth.\",\n \"Enzymol.\",\n \"225:900, 1993); Properties and uses of Embryonic Stem Cells: Prospects for Application to Human Biology and Gene Therapy (P. D. Rathjen et al., Reprod.\",\n \"Fertil.\",\n \"Dev.\",\n \"10:31, 1998), For elaboration of nervous system abnormalities, and the characterization of various types of nerve cells, markers, and related soluble factors, the reader is referred to CNS Regeneration: Basic Science and Clinical Advances, M. H. Tuszynski & J. H. Kordower, eds., Academic Press, 1999.Methods in molecular genetics and genetic engineering are described in Molecular Cloning: A Laboratory Manual, 2nd Ed.\",\n \"(Sambrook et al., 1989); Oligonucleotide Synthesis (M. J. Gait, ed., 1984); Animal Cell Culture (R. I. Freshney, ed., 1987); the series Methods in Enzymology (Academic Press); Gene Transfer Vectors for Mammalian Cells (J. M. Miller & M. P. Calos, eds., 1987); Current Protocols in Molecular Biology and Short Protocols in Molecular Biology, 3rd Edition (F. M. Ausubel et al., eds., 1987 & 1995); and Recombinant DNA Methodology II (R. Wu ed., Academic Press 1995).\",\n \"Reagents, cloning vectors, and kits for genetic manipulation referred to in this disclosure are available from commercial vendors such as BioRad, Stratagene, Invitrogen, and ClonTech.\",\n \"General techniques used in raising, purifying and modifying antibodies, and the design and execution of immunoassays including immunohistochemistry are described in Handbook of Experimental Immunology (D. M. Weir & C. C. Blackwell, eds.\",\n \"); Current Protocols in Immunology (J. E. Coligan et al., eds., 1991); and R. Masseyeff, W. H. Albert, and N. A. Staines, eds.\",\n \"Methods of Immunological Analysis (Weinheim: VCH Verlags GmbH, 1993).\",\n \"Sources of Stem Cells This invention can be practiced using stem cells of various types, which may include the following non-limiting examples: U.S. Pat.\",\n \"No.\",\n \"5,851,832 reports multipotent neural stem cells obtained from brain tissue.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,766,948 reports producing neuroblasts from newborn cerebral hemispheres.\",\n \"U.S. Pat.\",\n \"Nos.\",\n \"5,654,183 and 5,849,553 report the use of mammalian neural crest stem cells.\",\n \"U.S. Pat.\",\n \"No.\",\n \"6,040,180 reports in vitro generation of differentiated neurons from cultures of mammalian multipotential CNS stem cells.\",\n \"WO 98/50526 and WO 99/01159 report generation and isolation of neuroepithelial stem cells, oligodendrocyte-astrocyte precursors, and lineage-restricted neuronal precursors.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,968,829 reports neural stem cells obtained from embryonic forebrain and cultured with a medium comprising glucose, transferrin, insulin, selenium, progesterone, and several other growth factors.\",\n \"Except where otherwise required, the invention can be practiced using stem cells of any vertebrate species.\",\n \"Included are stem cells from humans; as well as non-human primates, domestic animals, livestock, and other non-human mammals.\",\n \"Neural Glial Differentiation Enteric neuronal progenitor cells have been identified in the adult mammalian gut, and have been isolated from humans up to and over 80 years of age.\",\n \"Previously, several groups have shown that a self-renewing population of Sox 2, Sox10, Nestin and p75 positive neural-crest derived progenitor cells can be isolated either from full-thickness, muscularis or mucosal biopsies of the adult mammalian gut.\",\n \"These cells have been demonstrated to have the potential to differentiate into several neuronal subtypes including inhibitory and excitatory motor neurons and glia.\",\n \"Various types of neuronal progenitor cells (CNS-derived, neural tube-derived, embryonic and adult ENS-derived) from explant cultures of aneural gut can also be transplanted.\",\n \"Alterations in the extracellular matrix of the gut mesenchyme has been documented in aganglionic regions of rodent gut, suggesting the importance of a permissive extracellular environment to promote effective in utero colonization and differentiation of neural crest cells in the developing gut.\",\n \"Since transplantation and subsequent functional neo-innervation is one clinical goal of neural stem cell transplantation, in vitro studies should mimic developmental conditions in vivo, in terms of providing a permissive and favorable ECM (such as a three-dimensional environment).\",\n \"Understanding the role of the ECM in affecting neuroglial differentiation of adult enteric neuronal progenitor cells can enhance the survivability and maintenance of a stable phenotype upon transplantation.\",\n \"Mammalian myenteric ganglia in vivo are surrounded by a matrix comprised predominantly of type IV collagen, laminin, heparan sulphate proteoglycan, and entactin.\",\n \"The enteric plexus lacks large connective tissue spaces for blood vessels like the peripheral nervous system.\",\n \"The two-dimensional culture substratum may modulate neuronal and glial differentiation based on ECM composition.\",\n \"Different ECM components may influence enteric glia and neurons come in to contact with in vivo in the adult myenteric plexus, such as collagen IV, laminin and heparan sulfate.\",\n \"Addition of laminin to collagen substrates unexpectedly improved neurite outgrowth with longer neurite lengths (compare 156.1±7.2 μm to 215.1±7.6 μm).\",\n \"while there was an overall enhancement in neuronal differentiation as well as neurite outgrowth, there was no significant difference between the additions of 5 or 10 μg/cm2 of laminin.\",\n \"This empirical determination was important in determining a minimal amount of laminin that can influence neuroglial differentiation without affecting neurite outgrowth adversely in a situation that requires neo-innervation of denervated tissues.\",\n \"Addition of heparan sulfate to composite collagen mixtures improved neuronal differentiation as well.\",\n \"Neuronal networking and neuronal clustering was visible at the later time point.\",\n \"Heparan sulfate may interact with GDNF and other neurotrophic factors to stabilize and make the factors locally available.\",\n \"Heparan sulfate interacts with both collagen IV and with laminin, to positively modulate neuronal differentiation.\",\n \"In one embodiment, heparan sulfate is added to the collagen mixture.\",\n \"Composite collagen substrates with laminin and/or heparan sulfate all maintained a low level of GFAP positive glial cells, with initiation of astrocytic networking becoming more obvious at the later time point.\",\n \"In general, substrates that supported neuronal differentiation demonstrated a bare minimum of glial cells required to possibly support neuronal cell phenotype or survival.\",\n \"Substrates that supported neuronal differentiation may result in enriched populations of neuronal cells comprising greater than 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, or any intermediate percentage.\",\n \"Enteric neurospheres demonstrated a tendency to differentiate into glia on PLL coated substrates as well as on composite collagen substrates in the absence of laminin and heparan sulfate.\",\n \"In contract, culture substrates with laminin and heparan sulfate promoted extensive neuronal differentiation while simultaneously supporting only a minimal glial cell population.\",\n \"Laminin and collagen IV coated coverslips positively modulated neuronal differentiation by increased number of neurites per neuron and longer neurite lengths compared to fibrillar collagen I (FIG.\",\n \"2B-D, F-H).\",\n \"Taken together, these results identify suitable 3D matrix compositions to deliver neuronal progenitor cells.\",\n \"Three dimensional hydrogel environments also provide the mechanical cues for neural differentiation, more readily translatable to in vivo conditions than infinitely stiff glass substrates.\",\n \"The extracellular matrix (ECM) plays an enormous role in dictating stem cell fate.\",\n \"The ECM composition, structure and mechanical properties can all modulate progenitor cell differentiation.\",\n \"The adult mammalian myenteric ganglia are surrounded by an extracellular matrix primarily composed of collagen IV, laminin and a heparan sulfate proteoglycan, with enteric glia always in direct contact with the ECM.\",\n \"Enteric neurons also come in direct contact with this ECM, though much less frequently than glia.\",\n \"Laminin, fibronectin and proteoglycans are expressed within the embyonic gut to aid its colonization by vagal neural crest cells.\",\n \"Collagen IV is distributed in the developing nervous system along the neural crest.\",\n \"Additionally, laminin promotes neural cell adhesion and axonal outgrowth.\",\n \"Heparan sulfate is important for GDNF signaling in the gut, and stabilizes and influences neuronal differentiation in vitro.\",\n \"It has been discovered that components of neural ECM can affect the differentiation of gut-derived neuronal progenitor cells of neural-crest lineage.\",\n \"Two timepoints were defined to identify early and late differentiation events—day 5 (early) and day 15 (late) based on previous experiments.\",\n \"Immunohistochemistry for βIII tubulin (neuron specific microtubule) and GFAP (Glial fibrillary acidic protein) was used to identify differentiated neurons and glia on coated culture substrata.\",\n \"Substrates that supported glial differentiation may result in enriched populations of glial cells comprising greater than 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, or any intermediate percentage.\",\n \"Neuronal Subtype Differentiation Neural stem cell transplantation is a promising therapeutic approach to repopulate neurons within enteric ganglia.\",\n \"A complete loss of neurons is reported in HSCR, and a partial loss of selective neuronal subtypes is documented in achalasia and stenosis.\",\n \"Several groups have injected enteric neuronal progenitor cells into experimental models of aganglionosis, demonstrating the feasibility of transplantation.\",\n \"However, there is inadequate focus on differentiation of progenitor cells into mature neuronal subtypes, and subsequent assessment of functionality.\",\n \"Here, we describe one embodiment of the invention, whereby we describe a novel method to bias differentiation of enteric neuronal progenitor cells in vitro, prior to transplantation.\",\n \"The ECM microenvironment, consisting of collagens, laminin and proteoglycans, not only acts as a structural framework for cells, but also plays an active role in aiding neurotrophic signaling.\",\n \"In an embodiment of this invention, four ECM components (collagen I, collagen IV, laminin and heparan sulfate) were evaluated, three of which are known to be present in adult myenteric ganglia.\",\n \"Collagen IV has been documented to be favorable for neurite outgrowth and neuronal differentiation.\",\n \"Laminin has long been known for its neurite promoting activity, in central, peripheral, and enteric neurons.\",\n \"The role of the heparan sulfate proteoglycan in neuronal differentiation is also well documented, both developmentally and in regenerative medicine applications.\",\n \"Fibrillar Collagen I was used additionally in these studies for ease of gelation and incorporation of other ECM components within a 3D hydrogel.\",\n \"Apart from composition, substrate elasticity has been demonstrated to affect the differentiation of adult neural stem cells, with neuronal differentiation reported between 100-500 Pa. ECM hydrogel compositions were adjusted in order to maintain their viscoelastic modulus within the range suitable for neuronal differentiation (FIG.\",\n \"10, table).\",\n \"Structural architecture was verified using scanning electron microscopy, wherein the addition of collagen IV demonstrated the presence of network structures, similar to self-assembled collagen IV in the mammalian basement membrane.\",\n \"The addition of laminin did not alter the ultrastructure, because it was expected to coat collagen fibers evenly.\",\n \"Additionally, laminin was also not expected to alter the stiffness/viscoelasticity of the gels, given the manner of its interaction with the collagen.\",\n \"The glycosaminoglycan chains of heparan sulfate are documented to cross link between laminin and collagen IV, thereby pulling fibers into a more compact structure, and slightly increasing the viscoelasticity of ECM gels.\",\n \"Smooth muscle cells within tissue engineered sheets drive the differentiation of enteric neuronal progenitor cells.\",\n \"Tissue engineered sheets provided a good modality to assess variability of differentiated neurons due to ECM composition as well as the functionality of differentiated neurons.\",\n \"The proximity to smooth muscle promoted the differentiation of enteric neuronal progenitor cells extensively.\",\n \"In vitro differentiation of neural stem cells in the presence of gut-derived factors has been demonstrated previously by us and others.\",\n \"Neurotrophic factors (NT-3, Neurturin, GDNF) and morphogens (BMP-2/4) capable of driving enteric neuronal progenitor cell proliferation and differentiation have been demonstrated to arise from the smooth muscle and mesenchyme of the developing and adult gut.\",\n \"Recently, the postnatal bowel was demonstrated to support the differentiation of enteric neuronal progenitor cells, strengthening the fact that cues for differentiation can be derived from the postnatal gut.\",\n \"Hence, it was expected that smooth muscle cells within the tissue engineered sheets would drive the differentiation of enteric neuronal progenitor cells.\",\n \"We evaluated all tissue engineered sheets to ensure that the constituent smooth muscle cells demonstrated a contractile phenotype expressing Smoothelin (FIG.\",\n \"14B).\",\n \"Smoothelin expression has been previously demonstrated to be essential for contractility of smooth muscle.\",\n \"In line with the equivalent expression of smoothelin, myogenic electromechanical coupling integrity was also equivalent in the tissue engineered sheets (FIG.\",\n \"14A-D) Similar patterns of contractions were observed in tissue engineered sheets in response to KCl, regardless of ECM composition.\",\n \"The ECM modulates differential neuronal subtypes while supporting overall smooth muscle-driven neuronal differentiation.\",\n \"In the presence of the smooth muscle, enteric neuronal progenitor cells differentiated, and expressed similar amounts of pan-neuronal marker βIII Tubulin (FIG.\",\n \"14A), suggesting that smooth muscle derived factors and substrate viscoelasticity were suitable for overall neuronal differentiation.\",\n \"However, on closer examination of neural subtypes, there was a differential expression of excitatory and inhibitory markers within tissue engineered sheets with varying ECM compositions (FIG.\",\n \"14).\",\n \"Sheets containing laminin had a balanced expression of both ChAT and nNOS.\",\n \"Kinetics of Ach-induced contraction in laminin sheets was most similar to native tissue, indicating the presence of an increased viable cholinergic neuronal component in composite collagen/laminin sheets.\",\n \"Furthermore, attenuation of EFS-induced relaxation by L-NAME (˜62%) was also kinetically similar to native tissue (˜78%), indicating the presence of a nitrergic neuronal component.\",\n \"Collagen I, in the absence of any other matrix components, was the ECM of choice when an enriched cholinergic neuronal population was required, with a significantly diminished nitrergic neuronal population (FIG.\",\n \"14C-D).\",\n \"While these sheets demonstrated a robust TTX-sensitive Ach-induced contraction commensurate with the heightened ChAT protein expression, relaxation in response to an electrical field was diminished.\",\n \"Furthermore, there was minimal attenuation of relaxation upon the inhibition of nNOS, correlating with the low nNOS expression.\",\n \"Substrates that supported cholinergic neuron differentiation may result in enriched populations of cholinergic neurons comprising greater than 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, or any intermediate percentage.\",\n \"Composite Collagen I/IV sheets had an enhanced nNOS protein expression, with an associated increase in EFS induced relaxation (FIG.\",\n \"18B).\",\n \"AUC of relaxation in composite Collagen I/IV sheets was comparable to native intestinal tissue.\",\n \"However, both ChAT expression and contraction was lower in composite collagen sheets.\",\n \"Substrates that supported nitrergic neuron differentiation may result in enriched populations of nitrergic neurons comprising greater than 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, or any intermediate percentage.\",\n \"The ECM is a framework upon which smooth muscle derived factors regulate differentiation of neural subtypes.\",\n \"We demonstrate a critical role of collagen I and collagen IV containing ECM environments in promoting excitatory and inhibitory motor neurons, respectively.\",\n \"The ECM microenvironment plays a role in modulating neurotrophic as well as morphogenetic signaling.\",\n \"Morphogenetic signaling via the BMP family expressed in fetal gut is important for the phenotypic diversity of enteric ganglia, including nitrergic and VIP-ergic neuron differentiation.\",\n \"Collagen IV is documented to modulate BMP signaling, and heparan sulfate modulates GDNF signaling in the gut.\",\n \"Immunoreactivity of neurotrophic factor, NT-3, has been observed in ganglia and in the ECM molecules surrounding them, suggesting a role for a Collagen IV-based ECM to modulate NT-3 signaling.\",\n \"The constituent smooth muscle phenotype in tissue engineered sheets was contractile, expressing smoothelin, and generating contractions and relaxations approaching ˜60% of those generated by native intestinal tissue.\",\n \"Differentiation cues arising from the constituent smooth muscle cells drove enteric neuronal differentiation.\",\n \"Furthermore, it is likely that the ECM could act as a framework for smooth muscle-derived factors, enhancing or inhibiting their effects, resulting in the generation of differential neuronal phenotypes.\",\n \"EXAMPLES Reagents All tissue culture reagents were purchased from Invitrogen (Carlsbad, Calif.) unless specified otherwise.\",\n \"Primary and fluorophore conjugated secondary antibodies were purchased from Abcam (Cambridge, Mass.).\",\n \"Rat tail type I collagen and natural mouse type IV collagen were purchased from BD Biosciences (Bedford, Mass.)\",\n \"and laminin was from Invitrogen (Carlsbad, Calif.).\",\n \"Heparan sulfate was purchased from Celsus Labs (Cincinnati, Ohio).\",\n \"Isolation of Rabbit Enteric Neuronal Progenitor Cells and Intestinal Smooth Muscle Cells.\",\n \"New Zealand white rabbits were euthanized using ketamine/xylazine.\",\n \"Smooth muscle cells were isolated and cultured using standard protocols (See, for example, Somara et al.\",\n \"Am J Physiol Gastrointest Liver Physiol.\",\n \"2006; 291(4):G630-9).\",\n \"For the isolation of enteric neuronal progenitor cells, 5 cm2 biopsies were dissected from the jejunum, and retrieved in Hank's Buffered Salt Solution (HBSS) with 2× antibiotics/antimycotics and 1× gentamicin sulfate.\",\n \"Luminal content was cleaned and tissues were washed extensively with HBSS.\",\n \"Enteric neuronal progenitor cells were isolated from these tissues using a collagenase/dispase digestion method.\",\n \"(see, for example, Almond et al., Characterisation and transplantation of enteric nervous system progenitor cells.\",\n \"Gut.\",\n \"2007; 56(4):489-96.PMCID: 1856871).\",\n \"Cells were plated on to bacterial petri dishes in neuronal growth media (Neurobasal+1× N2 supplement+1× antibiotics) following filtration through a 40 μm mesh.\",\n \"Isolation and Culture of Rabbit Longitudinal Smooth Muscle Cells (LSMCs) Rabbit sigmoid colon was removed by dissection, and relieved of fecal content.\",\n \"The tissue was kept on ice and moist with Hank's balanced salt solution (HBSS) containing antibiotics and sodium bicarbonate.\",\n \"The cleaned colon was slipped onto a plastic pipette.\",\n \"Blood vessels and adherent fat were picked off with forceps.\",\n \"Kimwipe® (Kimberly-Clark, Neenah, Wis.) wetted with HBSS was used to wipe the outer layer of the colon.\",\n \"Fine-tip forceps were used to pick off the longitudinal muscle layer from the colon and store them in ice-cold HBSS.\",\n \"The tissue was finely minced, digested twice with type II collagenase (0.1%) at 32° C. for 1 h, and filtered through a 500-μm Nytex® (Tetko, Elmsford, N.Y.) mesh.\",\n \"The filtrate was washed three times and plated in DMEM with 10% FBS, 1.5% antibiotics, and 0.5% L-glutamine onto regular tissue culture flasks.\",\n \"Immunohistochemical Characterization of Rabbit Enteric Neurospheres In order to characterize the initial phenotype of rabbit enteric neurospheres in culture, neurospheres were harvested by centrifugation at 1000 g for 10 minutes in microfuge tubes.\",\n \"The growth media was gently aspirated, and neurospheres were fixed with 3.7% neutral buffered formaldehyde and blocked with 10% horse serum.\",\n \"Primary antibodies for p75 (Millipore, Billerica Mass.\",\n \"), Sox2 and Nestin were incubated for 30 minutes at room temperature.\",\n \"Unbound antibody was washed using phosphate buffered saline (PBS), and appropriate fluorophore-conjugated secondary antibodies were incubated for an additional 30 minutes.\",\n \"Neurospheres were mounted using Prolong Gold antifade mounting medium (Invitrogen, Carlsbad Calif.), and visualized using an inverted Nikon TiE fluorescent microscope.\",\n \"Rheological Characterization of ECM Hydrogels Oscillatory rheometry (ATS RheoSystems) was used to measure viscoelastic moduli of ECM gels.\",\n \"20 mm parallel base plates were used to perform a stress sweep of the sample at 1 Hz.\",\n \"ECM gels were allowed to gel in situ between the parallel plates at 37° C. The viscoelastic modulus was obtained from a linear region of the stress-strain curve, at strains lower than 10%, within the sensitivity ranges for torque and strain of the rheometer.\",\n \"3-5 individually manufactured ECM gels were measured to determine an average viscoelastic modulus.\",\n \"Compositions that resulted in a matrix viscoelasticity within the range of 150-300 Pa were utilized for further experimentation, so as not to let stiffness be a variable in influencing neuroglial differentiation.\",\n \"Characterization of Ultrastructure of ECM Hydrogels Sample preparation of ECM hydrogels for scanning electron microscopy was adapted from Stuart et al.\",\n \"[31].\",\n \"Gels were dehydrated through graded ethanol (10% to 100%).\",\n \"Hydrogels were dried at critical point using carbon dioxide exchange.\",\n \"The resulting dehydrated ECM discs were mounted onto metallic stubs with conducting carbon tape, sputter coated with gold, and visualized using an AMRAY 1910 Field Emission Scanning Electron Microscope.\",\n \"Constant working distance and magnification were maintained to image all samples.\",\n \"NIH Image J was used to measure and compare fiber diameters.\",\n \"Porosity was determined using Image J from micrographs obtained from at least three-independent samples of dehydrated ECM gels.\",\n \"Tissue Engineering Innervated Intestinal Smooth Muscle Sheets Briefly, 500,000 longitudinal smooth muscle cells were aligned uniaxially for 4 days on 35 mm diameter circular Sylgard molds containing wavy microtopographies.\",\n \"Enteric neurospheres were treated with Accutase to obtain single cell suspensions.\",\n \"200,000 cells were resuspended in the appropriate ECM solution and overlaid on the aligned smooth muscle monolayer.\",\n \"Upon gelation, neuronal differentiation medium (neurobasal-A) was added, supplemented with B27 and 1% fetal bovine serum.\",\n \"Differentiation medium was exchanged every second day.\",\n \"Enteric neuronal progenitor cells were allowed to differentiate within the hydrogel for a period of 10 days.\",\n \"Smooth muscle cells compacted the ECM hydrogel over the next 10 days, forming ˜1 cm long innervated smooth muscle sheets, anchored between silk sutures.\",\n \"Phase microscopy was used to image neuronal differentiation at the edge of the tissue engineered sheets.\",\n \"Biochemical Characterization of Neuroglial Composition in Tissue Engineered Sheets At day 10, tissue engineered sheets were harvested in radioimmunoprecipitation buffer to isolate protein.\",\n \"Protein concentration was estimated spectrophotometrically using the Bradford assay.\",\n \"20 μg of protein from each sample was resolved electrophoretically and transferred to polyvinylidene difluoride membranes.\",\n \"Membranes were blotted with antibodies for neuronal βIII Tubulin, neuronal nitric oxide synthase (nNOS), choline acetyltransferase (ChAT), and Smoothelin.\",\n \"β-Actin was used to confirm equal loading.\",\n \"HRP-conjugated secondary antibodies were used to visualize proteins using enhanced chemiluminescence.\",\n \"Immunohistochemical Characterization of Neuron Composition in Tissue Engineered Sheets Tissue engineered sheets were fixed in 4% formaldehyde and washed extensively in glycine buffer.\",\n \"Immunohistochemical staining was performed following previously established protocols utilized for staining differentiated neurons within bioengineered tissues.\",\n \"Sheets were blocked with 10% horse serum and permeabilized in 0.15% Triton-X for 45 minutes.\",\n \"Permeabilized sheets were incubated with primary antibodies directed against Vasoactive Intestinal Peptide (VIP), ChAT and nNOS for 60 minutes at room temperature.\",\n \"Following antibody incubation, sheets were washed three times with phosphate buffered saline, pH 7.4.Tissue engineered sheets were incubated with appropriate fluorophore conjugated secondary antibodies for 45 minutes, washed in phosphate buffered saline and imaged using an inverted fluorescence microscopy (Nikon Ti-E, Japan).\",\n \"For a negative control, incubation with the primary antibody was skipped, and only fluorophore conjugated secondary antibodies were used to visualize background fluorescence.\",\n \"Measurement of Physiological Function in Inntervated Tissue Engineered Sheets Myogenic and neuronal functionality were assessed using real-time force generation as previously described [30, 33].\",\n \"4-5 individual tissue engineered sheets for each ECM composition were tested.\",\n \"Tissue engineered sheets were anchored between a stationary pin and measuring pin of a force transducer (Harvard Apparatus, Holliston Mass.)\",\n \"at 0% stretch.\",\n \"The organ bath maintained temperature at 37° C. An additional 10% stretch was applied using a vernier control.\",\n \"Tissues were immersed in 4 ml of medium, which was exchanged at the end of every experiment following a brief wash with fresh medium.\",\n \"Peak contraction or maximal relaxation was quantified following pharmacological or electrical stimuli, and compared between tissue engineered sheets with varying ECM compositions.\",\n \"Before each treatment, tissues were washed in fresh warm medium and allowed to equilibrate to a baseline.\",\n \"The following stimuli were used independently to assess physiological functionality of the tissue engineered sheets: 1) 60 mM Potassium chloride to assess electromechanical coupling integrity of the smooth muscle; 2) 1 μM Acetylcholine (contractile agonist); 3) Electrical field stimulation (5 Hz, 0.5 ms, 40V) applied using parallel plate platinum electrodes.\",\n \"Preincubation with neuronal blocker, tetrodotoxin (TTX) was used to dissect myogenic and neuronal components of contraction/relaxation.\",\n \"Preincubation with specific inhibitors were used to identify functional neuronal subtypes: 1) nNOS-blocker Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME; 300 μM); and 2) VIP-receptor antagonist [D-p-Cl-Phe6, Leu17]-Vasoactive Intestinal Peptide (VIP-Ra; 2 μM).\",\n \"Following stimulation and subsequent contraction/relaxation and recovery, tissues were washed with fresh medium, and allowed to re-establish a baseline before the next treatment.\",\n \"Equilibrated baseline was arbitrarily set to zero, to measure contraction/relaxation due to a stimulus.\",\n \"Neurosphere Differentiation as a Function of Extracellular Matrix Composition 22×11 mm substrates were washed in Neutrad (Decon Labs, King of Prussia Pa.) and rinsed extensively in deionized water.\",\n \"Coverslips were sterilized by 70% ethanol, and subsequent UV exposure for 45 minutes.\",\n \"Coverslips were coated with poly-L-lysine (PLL; 1 mg/ml), PLL+10 μg/cm2 type I collagen, PLL+10 μg/cm2 type IV collagen or PLL+10 μg/cm2 laminin.\",\n \"Composite coatings included: 5 μg/cm2 Collagen I+5 μg/cm2 type IV Collagen; 5 μg/cm2 Collagen I+5 or 10 μg/cm2 Laminin; 5 μg/cm2 Collagen IV+5 or 10 μg/cm2 Laminin; 5 μg/cm2 Collagen I+5 μg/cm2 Collagen IV+0.1 μg/cm2 Heparan Sulfate (HS); 5 μg/cm2 Collagen I+5 μg/cm2 Collagen IV+5 μg/cm2 Laminin+0.1 μg/cm2 HS.\",\n \"Uncoated glass substrates were seeded with rabbit colonic smooth muscle cells, and allowed to reach confluence.\",\n \"Rabbit enteric neurospheres were harvested and treated with Accutase to obtain a mixture of single cells as well as small neurospheres.\",\n \"10,000 neuronal progenitor cells were harvested and plated on to coated coverslips.\",\n \"To stimulate differentiation induced via soluble smooth muscle factors, each plate was shared by one confluent smooth muscle coverslip along with a coated coverslip containing adhered neurospheres.\",\n \"Enteric neurospheres were allowed to differentiate for a period of fifteen days, with a supplementation of neuronal differentiation medium every 2 days (Neurobasal-A medium+1× B27 supplement+2% fetal calf serum+1× antibiotics).\",\n \"Immunohistochemical Analysis of Neuronal and Glial Differentiation Two time points were analyzed for neuronal and glial differentiation—day 5 and day 15 post initiation of differentiation.\",\n \"Medium was aspirated and cells on coverslips were fixed with 3.7 neutral buffered formaldehyde.\",\n \"Cells were permeabilized with 0.15% Triton-X 100 and blocked with 10% horse serum.\",\n \"βIII tubulin was used to stain neuronal cells, and glial fibrillary acidic protein (GFAP) was used to stain glial cells.\",\n \"Primary antibodies were incubated for 1 hour at room temperature and unbound antibody was washed with PBS.\",\n \"Fluorophore conjugated secondary antibodies (FITC-anti mouse and TRITC-anti rabbit) were used to visualize fluorescence using an inverted Nikon TiE fluorescent microscope.\",\n \"Staining with FITC-conjugated secondary antibody without the primary antibody was used as a negative control.\",\n \"Confluent smooth muscle coverslips were stained with neuronal or glial markers to avoid a false positive staining while identifying differentiated neurons or glia.\",\n \"Data Analysis Neurite lengths were measured from individual 10× micrographs obtained at the same amplifier gain and exposure.\",\n \"Neurites were identified primarily by expression of immunoreactivity for βIII tubulin concurrently with neuronal morphology.\",\n \"Up to five sequential fields of view were measured on each coverslip starting from one edge to the other, covering the area of the coverslip.\",\n \"All cells were measured on each coverslip, covering the entire area of the neuronal coverslip.\",\n \"The number of neurites measured for each substrate coating varied between 20-50 readings.\",\n \"The length of the longest neurite from each cell was measured using NIH Image J using the freeform tool.\",\n \"Neurite lengths between coatings were compared using one way ANOVA, with Bonferroni post-test to identify a significant difference (p<0.05) in neurite lengths by varying culture substrata.\",\n \"GFAP immunofluorescence was quantified using the Nikon Elements imaging software.\",\n \"Mean red (TRITC) fluorescence was calculated from 10× micrographs, using a constant rectangular area tool that covered 100% of the field of view.\",\n \"Multiple (at least 5) sequential fields of view at the same magnification were chosen for each sample to obtain mean fluorescence.\",\n \"One way ANOVA with Bonferroni post-test was used to identify a significant difference in red fluorescent intensity between coated culture substrata.\",\n \"GraphPad Prism 5.1 for Windows (San Diego, Calif.) was used to perform statistical analysis.\",\n \"All statistics are from experiments between 3-5 individual sets, with multiple micrographs within each set.\",\n \"Reported numbers are mean±standard error of the mean.\",\n \"For neuronal subtype analysis, densitometry on western blots was performed using BioRad Quantity One (Hercules, Calif.).\",\n \"Raw data was acquired from the force transducer at 1000 samples/second.\",\n \"Second order Savitsky-Golay smoothing was applied to data using GraphPad Prism 5.0 for Windows (GraphPad Software, San Diego, Calif.).\",\n \"Area under the curve (AUC) was measured from the time of addition of pharmacological agonist/electrical field to the end of the contraction/relaxation response.\",\n \"Extent of inhibition by pharmacological inhibitors was calculated by expressing the AUC of contraction/relaxation in the presence of the inhibitor as a percentage of the AUC in the absence of the inhibitor.\",\n \"One way ANOVAs with Tukey post-tests were used to compare means using GraphPad Prism.\",\n \"p≤0.05 was considered significant.\",\n \"Physiological evaluation and densitometry was carried out between 3-5 tissue engineered sheets within each experimental set; all values are expressed as mean±SEM.\",\n \"Neuroglial Differentiation Initial Phenotype of Rabbit Enteric Neurospheres Upon digestion of rabbit jejunal biopsies with dispase, near single cell suspensions were obtained by filtration through 70 μm and 40 μm meshes.\",\n \"Single cells were approximately 7 μm in diameter.\",\n \"These cells were plated in non-adherent culture dishes.\",\n \"Over the course of two weeks post plating, rabbit enteric neuronal progenitor cells aggregated and proliferated in culture and formed floating spherical structures, called enteric neurospheres (FIG.\",\n \"1A).\",\n \"Average neurospheres were 98.17±8.33 μm (n=34) two weeks post plating.\",\n \"The neurospheres continued to grow and aggregate, approaching 200-300 μm, whereupon they were broken down by trituration.\",\n \"Upon immunohistochemical examination, the cells within enteric neurospheres were positive for the low affinity nerve growth factor receptor p75NTR (FIG.\",\n \"1B).\",\n \"They were additionally also positive for Sox2 (FIG.\",\n \"1C, SRY related homeobox factor 2) and Nestin (FIG.\",\n \"1D), a neuroepithelial stem cell marker.\",\n \"The results indicate that neurospheres derived from the rabbit intestine following this procedure contained neural-crest derived cells, capable of differentiation in to enteric neurons and/or enteric glia.\",\n \"Neuronal progenitor cells were isolated from full thickness biopsies of adult rabbit jejunums that aggregate in culture to form floating spherical colonies, dubbed enteric neurospheres (FIG.\",\n \"1A).\",\n \"The enteric neurospheres were comprised of cells positive for p75, Sox2 and Nestin (FIG.\",\n \"1 B-D).\",\n \"The presence of p75NTR confirms the neural-crest lineage of the isolated cells.\",\n \"The presence of Sox2 and Nestin confirms the progenitor status of the isolated cells, indicating that these cells are similar to enteric neuronal progenitor cells previously isolated from the gut that have the potential to differentiate into both neurons and glia.\",\n \"Neuronal Differentiation on Individual ECM Substrates (Collagen I, Collagen IV or Laminin) Poly-L-lysine (PLL) coating was a pre-requisite to enteric neurosphere adhesion to glass substrates.\",\n \"Glass coverslips that lacked any coating did not support enteric neurosphere adhesion sufficiently to differentiate into neurons or glia.\",\n \"In order to maintain uniformity, all coverslips were initially coated with PLL and additionally with laminin, collagen I or collagen IV.\",\n \"All coated coverslips required between 2-4 hours for enteric neurospheres to attach.\",\n \"Enteric neurospheres on coated coverslips were allowed to differentiate initially using neuronal differentiation medium alone.\",\n \"However, several sets of experiments demonstrated no morphological evidence of differentiation at the day 15 timepoint.\",\n \"Thereby, in order to render the soluble environment conducive to differentiation, a confluent coverslip containing colonic smooth muscle cells was placed in the same culture dish (FIG.\",\n \"2).\",\n \"The neuronal coverslip (coated with ECM substrate and containing enteric neurospheres) and the smooth muscle coverslips thereby shared soluble factors.\",\n \"The addition of the smooth muscle coverslip marked the initiation of differentiation (day 0).\",\n \"Morphological evidence of neuronal or glial differentiation was readily visible by day 5.A later time point (day 15) was identified to study the development of mature neurons or glia in vitro as a function of ECM composition.\",\n \"During the differentiation process, the culture dishes remained undisturbed till the early time point (day 5) or the late time point (day 15), except for medium supplementation.\",\n \"Neuronal differentiation was identified by immunofluorescent staining of the neuronal coverslip at either day 5 or day 15 with an antibody directed against βIII Tubulin.\",\n \"Day 5 Timepoint: Even in the presence of smooth muscle, enteric neurospheres on PLL remained undifferentiated, with some progenitor cells within neurospheres expressing low levels of βIII tubulin (FIG.\",\n \"3A).\",\n \"However, with the addition of laminin, collagen I or collagen IV to PLL on the culture substrata, neuronal differentiation was evident by day 5 (FIG.\",\n \"3B-D).\",\n \"Neurite lengths varied non-significantly between 193 μm and 288 μm on ECM substrata at the early time point (FIG.\",\n \"9A).\",\n \"Neurons on collagen IV and laminin coated coverslips demonstrated a higher level of branching (two or more neurites per cell; FIG.\",\n \"3B,D).\",\n \"Neurospheres and neuronal progenitor cells attached to the PLL coated coverslips, and stayed attached at day 5, but did not initiate neuronal differentiation.\",\n \"However, glial differentiation was readily visible by day 5, and improved by day 15 (FIG.\",\n \"3A,E; FIG.\",\n \"6A,E).\",\n \"Enteric neurospheres on PLL substrates indicated a preference towards glial differentiation versus neuronal differentiation.\",\n \"Day 15 Timepoint: At the day 15 timepoint, neurospheres on PLL coverslips barely initiated neuronal differentiation, evidenced by a flatter morphology and the appearances of faint tubulin-positive extensions (FIG.\",\n \"3E).\",\n \"With the addition of laminin, collagen I or collagen IV, neurite lengths were significantly longer compared to PLL (p<0.001).\",\n \"Differentiated neurons on laminin coverslips demonstrated the longest neurite extensions (326.9±13.25 μm, n=27, FIG.\",\n \"3F), significantly longer than collagen I or collagen IV (p<0.05, FIG.\",\n \"9A).\",\n \"By day 15, neurons on collagen I-coated coverslips still had no significant branching compared to those on collagen IV-coated coverslips (FIGS.\",\n \"3G-H).\",\n \"Neuronal Differentiation on Collagen Laminin Substrates In the next set of experiments, combinations of collagens and laminin were evaluated.\",\n \"Two concentrations of laminin were evaluated to identify the minimum amount of laminin required to influence neuronal differentiation.\",\n \"Coverslips were coated with either collagen I or collagen IV with 5 μg/cm2 or 10 μg/cm2 of laminin.\",\n \"The addition of laminin enhanced neuronal differentiation when compared to individual collagen substrates (compare FIG.\",\n \"4 with FIG.\",\n \"3), but no significant difference was observed in neurite length between the two concentrations of laminin.\",\n \"Collagen I and Laminin: At the day 5 timepoint, addition of laminin to collagen I increased the number of progenitor cells undergoing neuronal differentiation, but did not alter neuronal branching or neurite lengths significantly (FIG.\",\n \"4A,B,E,F).\",\n \"At the day 15 timepoint, significantly (p<0.05) enhanced neuronal differentiation was observed compared to collagen I. Neurite lengths on collagen-laminin substrates at day 15 (280 μm-290 μm; n=27-34) were longer than collagen I substrates (235.5±10.05 μm; FIG.\",\n \"9B).\",\n \"Collagen IV and Laminin: The addition of laminin to collagen IV enhanced neuronal differentiation when compared to coverslips coated individually with collagen IV only (compare FIG.\",\n \"4C,D,G,H to FIG.\",\n \"3D,H).\",\n \"At the day 5 timepoint, the addition of laminin increased the number of cells undergoing neuronal differentiation.\",\n \"No significant difference was observed in neurite lengths at day 5 (247 μm-288 μm; FIG.\",\n \"9B).\",\n \"At the day 15 time point, coverslips coated with both collagen IV and laminin had significantly (p<0.05) longer neurites (324 μm compared to 281 μm, FIG.\",\n \"4G-H).\",\n \"Initiation of inter-neuronal networking was also observed.\",\n \"There was no observable or significant difference in neurite lengths between the two concentrations of laminin used (5 μg/cm2 or 10 μg/cm2; FIG.\",\n \"9B).\",\n \"Neuronal Differentiation on Composite ECM Substrates with Laiminin and Heparan Sulfate In this additional set, the effect of a combination of collagens on neuronal differentiation was investigated.\",\n \"Composite coatings were evaluated with a 2:1 mix of Collagen I/Collagen IV as the base.\",\n \"This composite collagen base was evaluated first.\",\n \"Additionally, neuronal differentiation was evaluated on substrates that included laminin and/or heparan sulfate in combination with composite collagen.\",\n \"Heparan sulfate interacted with both collagen IV and with laminin to positively modulate neuronal differentiation, evidenced by the enhanced neurite lengths and initiation of neuronal networking (FIG.\",\n \"4 A-H).\",\n \"Composite collagen substrates with laminin and/or heparan sulfate all maintained a low level of GFAP positive glial cells, with initiation of astrocytic networking becoming more obvious at the later time point.\",\n \"Composite Collagen I/Collagen IV: Several cells underwent neuronal differentiation (FIG.\",\n \"5A, E; similar to individual coatings of either collagen I or collagen IV), but neurite lengths were significantly shorter on composite collagen substrates at day 5.Neurite lengths measured at 156±7.23 μm on day 5.At day 5, neuronal differentiation progressed and individual neurons had multiple branches and long neurites (FIG.\",\n \"5E).\",\n \"Neurite lengths averaged at 241.2±9.387 μm on day 15 (FIG.\",\n \"9C).\",\n \"Addition of Laminin: Addition of laminin to composite collagen substrates increased the number of differentiated neurons visible by day 5 (FIG.\",\n \"5B).\",\n \"Neurite lengths were significantly (p<0.05) longer on substrates containing laminin (215±7.57 μm; n=43).\",\n \"At the day 15 time point, substrates containing composite collagen and laminin demonstrated significant clustering of neurons (FIG.\",\n \"5F), with an additional 71 μm increase in neurite length, averaging at 286.8±9.521 μm, n=50.Addition of Heparan Sulfate: Addition of heparan sulfate also dramatically increased the number of progenitor cells undergoing neuronal differentiation by day 5 (FIG.\",\n \"5C).\",\n \"Average neurite lengths on substrates containing heparan sulfate along with composite collagen was 212.8±9.46 μm; n=43 at day 5.At day 15, the initiation of neuronal networking was visible with βIII Tubulin staining (FIG.\",\n \"5G).\",\n \"Addition of Laminin and Heparan Sulfate: The addition of laminin and heparan sulfate together with the composite collagen increased the number of differentiated neurons as well as the length of the individual neuronal processes and neurite branching (FIG.\",\n \"5D).\",\n \"At day 15, initiation of neuronal networking with significant clustering of neurons was observed (FIG.\",\n \"5H).\",\n \"Neurite lengths were significantly longer (325±19.37 μm) compared to composite collagen alone (FIG.\",\n \"9C).\",\n \"Glial Differentiation on Individual ECM Coatings (Collagen I, Collagen IV or Laminin) In addition to neuronal differentiation studies described above, glial differentiation was also studied as a function of ECM composition of culture substrata.\",\n \"Enteric neurospheres were plated on to coated coverslips in duplicate, and one coverslip was used to evaluate neuronal differentiation while a duplicate coverslip was used to evaluate glial differentiation.\",\n \"A primary antibody directed against Glial fibrillary acidic protein (GFAP) was utilized to identify glial differentiation.\",\n \"Fluorescent microscopy was used to visualize differentiated glia, using a TRITC fluorophore conjugated secondary antibody.\",\n \"The Nikon documentation software was used to calculate mean red fluorescence indicating the number of differentiated glia in a field of view of constant area.\",\n \"The presence of several axolemmal fragments can arrest the proliferation of glia.\",\n \"This is in line with the low levels of GFAP immunofluorescence observed on substrates that supported extensive neuronal differentiation.\",\n \"The only substrates that supported differentiation of enteric neuroglial progenitor cells into glia extensively were PLL and individual coatings of collagen I/IV.\",\n \"Neuronal differentiation was present on these substrates, but not as extensively as any of the other composite coatings that included laminin and heparan sulfate.\",\n \"Day 5 Timepoint: In the presence of smooth muscle, enteric neurospheres on PLL coated coverslips demonstrated significant GFAP staining by day 5 (15.29±1.29 AU; FIG.\",\n \"6A).\",\n \"In contrast, enteric neurospheres on PLL coverslips did not demonstrate significant neuronal differentiation at day 5, indicating the preferential differentiation in to glia at the early time point on PLL coverslips.\",\n \"With the addition of laminin, enteric neurospheres demonstrated highly significantly reduced GFAP staining (0.3825±0.2 AU).\",\n \"Undifferentiated neurospheres on the laminin coverslips contained several progenitor cells that were positive for GFAP (FIG.\",\n \"6B).\",\n \"On the same laminin coated coverslips, neuronal differentiation was extensive at the early timepoint, indicating an early preference for neuronal differentiation in the presence of laminin (FIG.\",\n \"3B).\",\n \"Minimal glial differentiation was observed on either of the collagen substrates (FIG.\",\n \"6C-D).\",\n \"Day 15 Timepoint: By the late day 15 time point, PLL coated coverslips had the highest number of glia, indicated by a highly significant (p<0.0001) GFAP fluorescent intensity, averaging at 28.56±1.14 AU (FIG.\",\n \"6E, 9D).\",\n \"Glia were apparent on ECM-coated coverslips as well, but to a lower extent than on PLL.\",\n \"In contrast to day 5, laminin coated coverslips demonstrated the presence of several glia at the day 15 time point and a robust GFAP fluorescent intensity was observed (FIG.\",\n \"5F, 16.54±0.32 AU).\",\n \"Several glia were observed by day 15 on each of the collagen substrates, with fluorescence ranging from 11.84 to 13.38 AU.\",\n \"(FIGS.\",\n \"6G-H).\",\n \"Glial Differentiation on Collagen-Laminin Substrates Similar to neuronal differentiation, glial differentiation was evaluated on substrates that were coated with either collagen I or cCollagen IV with laminin.\",\n \"The addition of laminin to collagen coated coverslips did not inhibit glial differentiation.\",\n \"Several differentiated glia were observed on day 5 (8.4±0.75-14.08±0.3 AU) on collagen-laminin substrates (FIG.\",\n \"7A-D).\",\n \"There was no significant difference in the number of GFAP positive cells at the early time point with the addition of laminin (5 μg/cm2 or 10 μg/cm2) to either collagen I or collagen IV substrates FIG.\",\n \"9D).\",\n \"Robust GFAP expression (12.6±1.29-14.22±1.01 AU) was observed at the day 15 time point on all collagen-laminin substrates, not significantly different from one another (FIG.\",\n \"7E-H).\",\n \"Glial Differentiation on Composite ECM Substrates with Laminin and Heparan Sulfate Glial differentiation was evaluated by varying the culture substratum with a combination of collagen I and IV.\",\n \"Additionally, the effect of the addition of laminin and/or heparan sulfate was also studied on glial differentiation.\",\n \"Composite Collagen I/Collagen IV: Glial differentiation peaked on day 5, on coverslips coated with the collagen I/IV mixture (FIG.\",\n \"8A).\",\n \"Red fluorescence (15.75±0.49 AU) was comparable to that on PLL coated coverslips at day 5 (FIG.\",\n \"9D).\",\n \"In contrast, neuronal differentiation on composite collagen coated coverslips was poor at the early time point, indicating a preferential differentiation into glia early on.\",\n \"By day 15, initiation of clustering of glial cells was observable (FIG.\",\n \"8E), with no significant increase in red fluorescence.\",\n \"Addition of Laminin and/or Heparan Sulfate: Early glial differentiation at day 5 was significantly reduced (10.16±0.8 to 11.06±0.5) with the addition of laminin and/or heparan sulfate to composite collagen substrates (FIG.\",\n \"8B-D).\",\n \"In contrast, these substrates supported neuronal differentiation extensively (compare FIG.\",\n \"8A-D to FIG.\",\n \"5A-D), indicating a preferential neuronal differentiation at the early time point.\",\n \"At the later day 15 time point, a non-significant increase in the number of glia and thereby increase in red fluorescence was observed (FIG.\",\n \"8E-H, FIG.\",\n \"9D).\",\n \"Neuronal Subtype Differentiation Ultrastructure and Viscoelastic Properties of ECM Hydrogels: All compositions of ECM hydrogels gelled at 37° C. within 30 minutes.\",\n \"Scanning electron micrographs revealed a fibrous structure in type I Collagen gels (FIG.\",\n \"10A).\",\n \"The fibers were randomly oriented, with diameters averaging at 478.3±19.31 μm.\",\n \"With the addition of type IV Collagen, network-like structures were observed (FIG.\",\n \"10B).\",\n \"Cables of fibers within the networked structures were thicker, with average diameters of 714.8±36.67 μm.\",\n \"Addition of laminin to the hydrogels did not alter the ultrastructure or the networked suprastructure (FIG.\",\n \"10C).\",\n \"With the addition of heparan sulfate, the fibers within the networked structures were pulled more tightly together and cabled (FIG.\",\n \"10D).\",\n \"The dehydrated ECM gels displayed a porous appearance, with average porosity ranging from 40.77%-43.95% (FIG.\",\n \"1, table).\",\n \"Viscoelastic moduli were measured in hydrated ECM gels using oscillatory rheometry.\",\n \"Type I Collagen gels had increasing viscoelastic moduli with increasing collagen concentration ranging from 72.6±4.86 Pa (800 μm/ml) to 182.3±2.6 (1600 μm/ml) to 424±2 Pa (3200 μm/ml).\",\n \"The addition of 200 μm/ml collagen IV to 800 μm/ml collagen I increased the modulus of the gels to 236±13.53 Pa.\",\n \"The addition of laminin had no effect on viscoelastic moduli (compare 236±13.53 Pa to 220.7±16.27 Pa).\",\n \"10 μm/ml of heparan sulfate caused an increase in the modulus of ECM hydrogels (287±20.11 Pa, p<0.05).\",\n \"FIG.\",\n \"1 (table) summarizes that the final ECM gels evaluated had viscoelastic moduli ranging from 182 Pa to 287 Pa. Neuronal Differentiation in Engineered Innervated Intestinal Smooth Muscle Sheets: Uniaxially-aligned smooth muscle cells compacted overlaying ECM hydrogels over 10 days in culture as described before.\",\n \"The resultant tissue engineered sheets were ˜1 cm long, and a few cell layers thick.\",\n \"In the presence of smooth muscle, the enteric neuronal progenitor cells differentiated within the ECM hydrogel.\",\n \"Neuronal differentiation was identified morphologically by microscopic examination at day 10, demonstrating similar differentiation profiles expressed by enteric neuronal progenitor cells, both in vitro and in tissue engineered constructs.\",\n \"Several differentiated neurons were observed in tissue engineered sheets, regardless of the ECM composition (FIG.\",\n \"11).\",\n \"Arrows in the figures indicate numerous instances of neuronal clustering and preliminary neuronal networking.\",\n \"Neuronal Composition in Engineered Innervated Intestinal Smooth Muscle Sheets: Immunoblotting was used to assess neuronal composition within tissue engineered innervated intestinal smooth muscle sheets.\",\n \"Blotting for β-actin demonstrated that equal amounts of protein were assayed.\",\n \"Representative blots for each protein are shown, indicating the approximate molecular weight at which they appear on the gels (FIG.\",\n \"12E).\",\n \"Contractile phenotype of constituent smooth muscle was demonstrated by the similar expression of smoothelin, within the tissue engineered sheets (FIG.\",\n \"12B).\",\n \"The expression of Smoothelin was constant, regardless of the ECM composition of the sheets, indicating that the constituent smooth muscle cells maintained a contractile phenotype.\",\n \"Neuronal Differentiation: Pan neuronal marker βIII Tubulin expression was similar amongst all tissue engineered sheets, despite the ECM composition (FIG.\",\n \"12A).\",\n \"This suggested that irrespective of the ECM composition, neuronal differentiation of enteric neurospheres proceeded similarly in the presence of smooth muscle cells.\",\n \"βIII Tubulin expression ranged from 21.65±1.43 AU-28.98±0.85 AU.\",\n \"βIII Tubulin expression was similar amongst various ECM gel compositions (ns; FIG.\",\n \"12A), indicating similar neuronal differentiation.\",\n \"Cholinergic Neurons: Choline acetyltransferase (ChAT) expression was used to detect the presence of cholinergic neurons (FIG.\",\n \"12C).\",\n \"Collagen I (33.73±1.13 AU) and collagen I/IV/laminin (28.82±1.21 AU) sheets had a significantly elevated expression of ChAT compared to sheets with composite collagen and/or heparan sulfate.\",\n \"Immunoblotting demonstrated an enriched cholinergic neuron population in tissue engineered sheets manufactured with collagen I only or composite collagen I/IV with laminin.\",\n \"The presence of cholinergic neurons was additionally confirmed using immunohistochemistry (FIG.\",\n \"13E-H).\",\n \"Nitrergic Inhibitory Motor Neurons: Neuronal nitric oxide synthase (nNOS) expression was used to detect the presence of inhibitory nitrergic motor neurons (FIG.\",\n \"12D).\",\n \"Sheets with collagen IV (with or without laminin/heparan sulfate) had a significantly higher nNOS expression ranging from 26.37±1.29 AU-28.15±2.69 AU.\",\n \"Conversely to ChAT, collagen I sheets had minimal nNOS expression (11.33±2.85 AU).\",\n \"Presence of nNOS was additionally confirmed using immunohistochemistry (FIG.\",\n \"13I-L).\",\n \"VIP-Ergic Inhibitory Motor Neurons: Vasoactive intestinal peptide (VIP) motor neurons were identified using immunohistochemistry.\",\n \"VIP neurons were abundant, with increased immunofluorescence in composite hydrogels with laminin and heparan sulfate (FIG.\",\n \"13A-D).\",\n \"Substrates that supported peptidergic neuron differentiation may result in enriched populations of peptidergic neurons comprising greater than 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, or any intermediate percentage.\",\n \"Agonist Induced Contractility of Tissue Engineered Innervated Smooth Muscle Sheets Potassium Chloride-Induced Contraction: Electromechanical coupling integrity of constituent smooth muscle cells was first evaluated using potassium chloride (KCl).\",\n \"KCl treatment elicited rapid contractions that were sustained for ˜5 minutes (FIG.\",\n \"14).\",\n \"Peak maximal contraction in response to KCl was similar between the different tissue engineered sheets (FIG.\",\n \"14A-D), ranging from 279.5±4.79 μN to 296.5±6.26 μN.\",\n \"This correlated with the equivalent expression of contractile smooth muscle marker, Smoothelin, indicating that the constituent smooth muscle cells within the tissue engineered sheets maintained a contractile phenotype regardless of ECM composition.\",\n \"Furthermore, KCl-induced contractions in tissue engineered sheets were similar to native rabbit intestinal tissues (FIG.\",\n \"14E) in time course, but slightly reduced in magnitude.\",\n \"Peak KCl-induced contractions in native tissue averaged 373.5±10.63 μN.\",\n \"KCl-induced contraction was unaffected by pre-treatment with neuronal blocker TTX (grey traces; FIG.\",\n \"14), indicating myogenic electromechanical coupling integrity.\",\n \"FIG.\",\n \"16F demonstrates that the area under the curve of contraction was similar in all tissue engineered sheets, and was significantly higher in native rabbit intestinal tissues.\",\n \"Although reduced in magnitude compared to native tissue, KCl-induced contractions were similar among the different tissue engineered sheets, indicating a robust contractile smooth muscle phenotype unaffected by the ECM composition.\",\n \"Acetylcholine-Induced Contraction: Exogenous addition of 1 μM Acetylcholine (Ach) was used to simulate agonist-induced contraction.\",\n \"All tissue engineered sheets contracted in response to Ach, and sustained contractions up to ˜5 minutes post stimulation with Ach (FIG.\",\n \"15A-D).\",\n \"Tissue engineered sheets with composite collagen I/IV with laminin had a significantly elevated peak maximal Ach-induced contraction (FIG.\",\n \"15C; 232.9±8.167 μN), as well as an elevated area under the curve of contraction (47606±2054 AU).\",\n \"Magnitude of Ach-induced contraction was still significantly lower compared to contraction in native tissue (342.6±3.15 μN; 70448±5876 AU).\",\n \"However, the time course of contraction was very similar to native tissue in tissue engineered sheets containing laminin, reaching maximal contraction within a minute of agonist stimulation.\",\n \"Collagen I sheets also had an elevated Ach-induced contraction (FIG.\",\n \"15A; 238.9±13.72 μN; 42668±2172 AU) corresponding to the elevated ChAT protein expression.\",\n \"However, the kinetics of contraction did not match native tissue.\",\n \"In order to estimate the smooth muscle (myogenic) component of Ach-induced contraction, neurotoxin TTX was used as a pretreatment (grey traces, FIG.\",\n \"15).\",\n \"Area under the curves of contraction was compared with and without TTX pre-treatment in order to estimate % inhibition (FIG.\",\n \"15F).\",\n \"Percent inhibition of Ach-induced contraction in the presence of TTX was highest in two ECM conditions: i) collagen I sheets (72.77±2.45%); and ii) collagen I/IV/laminin sheets (60.58±1.66%).\",\n \"These values of % inhibition were similar to that observed in native tissue (72.73±3.66%) upon TTX-pretreatment.\",\n \"This increased neuronal contribution to Ach-induced contraction also correlated with the elevated protein expression of ChAT in collagen I and composite collagen I/IV/laminin sheets (FIG.\",\n \"12E, G).\",\n \"TTX-pretreatment inhibited Ach-induced contraction to a significantly lower extent in collagen I/IV±heparan sulfate sheets, ranging from 48.36±4.36% (Heparan sulfate) to 50.31±4.22% (collagen IV; FIG.\",\n \"15F).\",\n \"Relaxation in Engineered Innervated Sheets in Response to Electrical Field Stimulation: Electrical field stimulation (EFS) at 5 Hz, 0.5 ms was used to stimulate neurons within the tissue engineered sheets to produce relaxation of smooth muscle (FIG.\",\n \"16).\",\n \"The extent of relaxation was quantified as area under the curve of relaxation.\",\n \"Extent of relaxation significantly varied amongst the tissue engineered sheets with varying ECM compositions.\",\n \"Sheets bioengineered with collagen IV, which displayed elevated nNOS expression, had higher relaxation compared to sheets bioengineered with collagen I only (compare 109693±8465 AU in collagen I/IV sheets to 23142±4921 in collagen I sheets).\",\n \"Sheets containing laminin and/or heparan sulfate also had significantly elevated relaxation compared to collagen I sheets (68395-69025 AU).\",\n \"In response to EFS, native tissues relaxed generating 101550±11279 AU.\",\n \"Tissue engineered sheets with collagen IV and/or laminin and/or heparan sulfate additionally had a time course of relaxation most similar to native tissue.\",\n \"Maximal relaxation was achieved within 2 minutes of EFS, and a subsequent recovery of basal force was complete within 10 minutes.\",\n \"Upon pre-treatment with TTX, EFS-induced relaxation was inhibited entirely (grey traces, FIG.\",\n \"16).\",\n \"Inhibition of Nitric Oxide Synthase: In order to identify the presence and functionality of nitrergic neurons, an inhibitor of nitric oxide synthase (L-NAME) was used (grey traces, FIG.\",\n \"17).\",\n \"Percent inhibition was determined by comparing areas under the curves of maximal relaxation with and without the L-NAME pre-treatment.\",\n \"Percent inhibition with L-NAME treatment was the lowest in collagen I sheets (33.37±8.37%; grey trace, FIG.\",\n \"17A).\",\n \"This corresponded to the low protein expression of nNOS in collagen I sheets compared to sheets containing collagen IV (FIG.\",\n \"12D).\",\n \"In contrast, the inhibition of nNOS activity attenuated relaxation up to 61.71±2.82% (grey trace, FIG.\",\n \"17B) in collagen I/IV sheets.\",\n \"In sheets containing laminin and heparan sulfate, % inhibition with L-NAME varied between 62.28±2.75% (laminin, FIG.\",\n \"17C) to 57.16±1.91% (heparan sulfate).\",\n \"This inhibition is significantly elevated compared to collagen I sheets, corresponding to the increased expression of nNOS observed in the collagen I/collagen IV sheets (FIG.\",\n \"12C).\",\n \"Native tissues had a higher % inhibition with L-NAME (78.02±2.85%).\",\n \"Inhibition of the VIP-Receptor: The functionality of VIP-ergic neurons was assessed using a VIP receptor antagonist (VIP-Ra).\",\n \"Pre-treatment with VIP-Ra inhibited maximal relaxation in all tissue engineered sheets to varying extents ranging from 55.55±3.92%-65.92±5.38% (grey traces, FIG.\",\n \"18).\",\n \"Inhibition of EFS-induced relaxation indicated the presence of differentiated VIP-ergic neurons in tissue engineered sheets.\",\n \"The section headings used herein are for organizational purposes only and are not to be construed as limiting.\",\n \"While the applicants' teachings are described in conjunction with various embodiments, it is not intended that the applicants' teachings be limited to such embodiments.\",\n \"On the contrary, the applicants' teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875717"}}},{"rowIdx":4494958,"cells":{"text":{"kind":"list like","value":[["SYSTEMS AND METHODS FOR PROCESSING AUDIO SIGNALS BASED ON USER DEVICE PARAMETERS","In various applications, the system provides a method for processing audio signals, including: receiving a request for audio content; receiving an identifier encoded in a personal audio device comprising a transducer for playing audio; retrieving at least one parameter associated with the identifier; and processing the audio content using at least the request, the identifier and the at least one parameter, wherein the processing is customized for the personal audio device based on the at least one parameter associated with the identifier.","In various applications the parameter is, one or more of, associated with a specification of the personal audio device, acoustic metrics of the transducer, relates to control of equalization, relates to permission to enable proprietary sonic processing for enhanced acoustic reception of streaming content, relates to acoustic metrics of the transducer and wherein the identifier is associated with permission to enable proprietary sonic processing for enhanced acoustic reception of streaming content, and/or is stored in a chip on the personal audio device, is retrieved from a server in a network, among other things.","In various applications, the personal audio device comprises ear buds and the identifier is stored in a non-volatile memory of the ear buds."],["1.A method for processing audio signals, comprising: receiving a request for audio content; receiving an identifier encoded in a personal audio device comprising a transducer for playing audio; retrieving at least one parameter associated with the identifier; and processing the audio content using at least the request, the identifier and the at least one parameter, wherein the processing is customized for the personal audio device based on the at least one parameter associated with the identifier.","2.The method of claim 1, wherein the at least one parameter is associated with a specification of the personal audio device.","3.The method of claim 2, wherein the at least one parameter relates to acoustic metrics of the transducer.","4.The method of claim 1, wherein the at least one parameter relates to control of equalization.","5.The method of claim 1, wherein the at least one parameter relates to permission to enable proprietary sonic processing for enhanced acoustic reception of streaming content.","6.The method of claim 1, wherein the at least one parameter relates to acoustic metrics of the transducer and wherein the identifier is associated with permission to enable proprietary sonic processing for enhanced acoustic reception of streaming content.","7.The method of claim 1, wherein the at least one parameter is stored in a chip on the personal audio device.","8.The method of claim 1, wherein the at least one parameter is retrieved from a server in a network.","9.The method of claim 1, wherein the processing is done in a batch format and the processed content is stored for a plurality of parameters.","10.The method of claim 1, wherein the processing is done in real-time and the processed content is streamed to the personal audio device.","11.The method of claim 1, wherein the identifier includes a key used for lookup.","12.The method of claim 1, wherein the processing is done at a server, and the processing algorithm executes using the identifier to retrieve at least one parameter associated with the identifier to control parameters of sonic processing algorithms and to provide processed content to the network that can be received by a user of a device associated with the identifier.","13.The method of claim 1, wherein the personal audio device comprises ear buds and the identifier is stored in a non-volatile memory of the ear buds.","14.The method of claim 1, wherein the identifier is a unique identifier of up to 48 bits.","15.The method of claim 1, wherein the identifier is retrieved using a sonic inquiry command.","16.Apparatus, comprising: at least one earbud; a non-volatile memory associated with the at least one earbud, the memory storing at least an identifier; and circuitry for polling the identifier from the memory, wherein the identifier is used for processing audio sent to the at least one earbud.","17.The apparatus of claim 16, further comprising a second earbud.","18.The apparatus of claim 16, further comprising a control to initiate an identification process.","19.The apparatus of claim 16, further comprising a control to disable access to the identifier.","20.The apparatus of claim 16, wherein the circuitry is readable by a mobile phone."],["<SOH> BACKGROUND <EOH>Systems that provide audio playback, such as portable flash players, mobile phones, car players, televisions, and home theater receivers, reproduce the stored audio during playback.","The stored audio is the result of layers of several different sound sources that are frequently mixed electronically for recording.","These systems frequently feature user selectable manual sound controls for adjusting characteristics of the audio, such as volume, equalization, and dynamic range.","These systems may allow the user to set these controls, often under sub-optimal conditions and with no training.","Additionally, these systems may employ a number of different audio transducers for generating audible sound.","As a result, the listening experience is often compromised, because the reproduction of the audio need not take into account the type and manufacture of the audio transducer.","What is needed in the art are systems and methods for providing enhanced audio to provide audio reproduction that is tailored to the audio transducer.","Further needed in the art is a system which will perform signal processing of the audio signal automatically for a particular listening device.","Further needed in the art is a system that will automatically perform signal processing for the particular listening device and for a particular user's preferences of that particular listening device."],["<SOH> BRIEF SUMMARY <EOH>The present subject matter provides various embodiments with systems and methods for enhancing recorded sound.","In various approaches, the various embodiments are used individually or in combination with each other.","In various approaches, the system is combined or distributed using various processing options.","In various embodiments, the system provides a method for processing audio signals, comprising: receiving a request for audio content; receiving an identifier encoded in a personal audio device comprising a transducer for playing audio; retrieving at least one parameter associated with the identifier; and processing the audio content using at least the request, the identifier and the at least one parameter, wherein the processing is customized for the personal audio device based on the at least one parameter associated with the identifier.","In various applications the parameter is, one or more of, associated with a specification of the personal audio device, acoustic metrics of the transducer, relates to control of equalization, relates to permission to enable proprietary sonic processing for enhanced acoustic reception of streaming content, relates to acoustic metrics of the transducer and wherein the identifier is associated with permission to enable proprietary sonic processing for enhanced acoustic reception of streaming content, and/or is stored in a chip on the personal audio device, is retrieved from a server in a network, among other things.","In various embodiments the processing is done in a batch format and the processed content is stored for a plurality of parameters.","In various embodiments, the processing is done in real-time and the processed content is streamed to the personal audio device.","In various embodiments, the processing is done at a server, and the processing algorithm executes using the identifier to retrieve at least one parameter associated with the identifier to control parameters of sonic processing algorithms and to provide processed content to the network that can be received by a user of a device associated with the identifier.","In various embodiments the identifier includes a key used for lookup.","In various embodiments, the personal audio device comprises ear buds and the identifier is stored in a non-volatile memory of the ear buds.","In various embodiments the identifier is a unique identifier of up to 48 bits.","In various embodiments, the identifier is retrieved using a sonic inquiry command.","In various embodiments, the subject matter relates to apparatus including at least one earbud, a non-volatile memory associated with the at least one earbud, the memory storing at least an identifier; and circuitry for polling the identifier from the memory, wherein the identifier is used for processing audio sent to the at least one earbud.","In various embodiments, the apparatus further comprises a second earbud.","In various embodiments, the apparatus further includes a control to initiate an identification process.","In various embodiments, the apparatus further comprises a control to disable access to the identifier.","In various embodiments, the circuitry of the apparatus is readable by a mobile phone.","Additional variations are described in the following detailed description.","This Summary is an overview of some of the teachings of the present application and not intended to be an exclusive or exhaustive treatment of the present subject matter.","Further details about the present subject matter are found in the detailed description and appended claims.","The scope of the present invention is defined by the appended claims and their legal equivalents."],["CLAIM OF PRIORITY This application is a Continuation of U.S. patent application Ser.","No.","15/417,706, filed Jan. 27, 2017, which application is a Continuation of U.S. patent application Ser.","No.","14/477,826, filed Sep. 4, 2014 (now U.S. Pat.","No.","9,560,466), which claims the benefit of priority under 35 U.S.C.","§ 119(e) of all of the following patent applications: U.S.","Provisional Patent Application No.","61/874,099, filed Sep. 5, 2013; U.S.","Provisional Patent Application No.","61/874,120, filed Sep. 5, 2013; U.S.","Provisional Patent Application No.","61/874,150, filed Sep. 5, 2013; U.S.","Provisional Patent Application No.","61/874,125, filed Sep. 5, 2013; U.S.","Provisional Patent Application No.","61/874,137, filed Sep. 5, 2013; U.S.","Provisional Patent Application No.","61/874,103, filed Sep. 5, 2013; and U.S.","Provisional Patent Application No.","61/918,550, filed Dec. 19, 2013, all of which are incorporated herein by reference in their entirety.","FIELD The present subject matter relates generally to systems and methods for audio enhancement.","BACKGROUND Systems that provide audio playback, such as portable flash players, mobile phones, car players, televisions, and home theater receivers, reproduce the stored audio during playback.","The stored audio is the result of layers of several different sound sources that are frequently mixed electronically for recording.","These systems frequently feature user selectable manual sound controls for adjusting characteristics of the audio, such as volume, equalization, and dynamic range.","These systems may allow the user to set these controls, often under sub-optimal conditions and with no training.","Additionally, these systems may employ a number of different audio transducers for generating audible sound.","As a result, the listening experience is often compromised, because the reproduction of the audio need not take into account the type and manufacture of the audio transducer.","What is needed in the art are systems and methods for providing enhanced audio to provide audio reproduction that is tailored to the audio transducer.","Further needed in the art is a system which will perform signal processing of the audio signal automatically for a particular listening device.","Further needed in the art is a system that will automatically perform signal processing for the particular listening device and for a particular user's preferences of that particular listening device.","BRIEF SUMMARY The present subject matter provides various embodiments with systems and methods for enhancing recorded sound.","In various approaches, the various embodiments are used individually or in combination with each other.","In various approaches, the system is combined or distributed using various processing options.","In various embodiments, the system provides a method for processing audio signals, comprising: receiving a request for audio content; receiving an identifier encoded in a personal audio device comprising a transducer for playing audio; retrieving at least one parameter associated with the identifier; and processing the audio content using at least the request, the identifier and the at least one parameter, wherein the processing is customized for the personal audio device based on the at least one parameter associated with the identifier.","In various applications the parameter is, one or more of, associated with a specification of the personal audio device, acoustic metrics of the transducer, relates to control of equalization, relates to permission to enable proprietary sonic processing for enhanced acoustic reception of streaming content, relates to acoustic metrics of the transducer and wherein the identifier is associated with permission to enable proprietary sonic processing for enhanced acoustic reception of streaming content, and/or is stored in a chip on the personal audio device, is retrieved from a server in a network, among other things.","In various embodiments the processing is done in a batch format and the processed content is stored for a plurality of parameters.","In various embodiments, the processing is done in real-time and the processed content is streamed to the personal audio device.","In various embodiments, the processing is done at a server, and the processing algorithm executes using the identifier to retrieve at least one parameter associated with the identifier to control parameters of sonic processing algorithms and to provide processed content to the network that can be received by a user of a device associated with the identifier.","In various embodiments the identifier includes a key used for lookup.","In various embodiments, the personal audio device comprises ear buds and the identifier is stored in a non-volatile memory of the ear buds.","In various embodiments the identifier is a unique identifier of up to 48 bits.","In various embodiments, the identifier is retrieved using a sonic inquiry command.","In various embodiments, the subject matter relates to apparatus including at least one earbud, a non-volatile memory associated with the at least one earbud, the memory storing at least an identifier; and circuitry for polling the identifier from the memory, wherein the identifier is used for processing audio sent to the at least one earbud.","In various embodiments, the apparatus further comprises a second earbud.","In various embodiments, the apparatus further includes a control to initiate an identification process.","In various embodiments, the apparatus further comprises a control to disable access to the identifier.","In various embodiments, the circuitry of the apparatus is readable by a mobile phone.","Additional variations are described in the following detailed description.","This Summary is an overview of some of the teachings of the present application and not intended to be an exclusive or exhaustive treatment of the present subject matter.","Further details about the present subject matter are found in the detailed description and appended claims.","The scope of the present invention is defined by the appended claims and their legal equivalents.","BRIEF DESCRIPTION OF THE DRAWINGS The accompanying figures illustrate certain embodiments of the subject matter and demonstrate certain aspects of the subject matter discussed in the following detailed description.","FIGS.","1A-1D demonstrate systems according to various embodiments of the present subject matter.","FIG.","2 shows a system for simulating linear and nonlinear effects of propagation and mixing of sound in air according to various embodiments of the present subject matter.","FIG.","3 demonstrates a single-source spatial representation of an interaction volume, according to one embodiment of the present subject matter.","FIG.","4 demonstrates a dual-source spatial representation of an interaction volume, according to one embodiment of the present subject matter.","FIG.","5 demonstrates a signal-modification processing subsystem for introduction of a priming signal according to various embodiments of the present subject matter.","FIG.","6 demonstrates an FIR convolution sub-system according to various embodiments of the present subject matter.","FIG.","7 demonstrates adjustable pre-signal content duration examples in the FIR convolution templates according to various embodiments of the present subject matter.","FIGS.","8A-8B demonstrate enforced zero-response examples around the dry signal delay time according to various embodiments of the present subject matter.","FIG.","9 demonstrates a multichannel analysis signal-modifying processing subsystem according to various embodiments of the present subject matter.","FIG.","10 demonstrates a series single-channel analysis subsystem according to various embodiments of the present subject matter.","FIG.","11 demonstrates a parallel single-channel analysis systems signal-analysis subsystem according to various embodiments of the present subject matter.","FIG.","12 shows the dependence of perceived pitch on sound level according to various embodiments of the present subject matter.","FIG.","13 shows the dependence of perceived pitch on sound level at low frequencies according to various embodiments of the present subject matter.","FIG.","14 demonstrates a general multiplexed convolution system architecture according to various embodiments of the present subject matter.","FIG.","15 demonstrates a multiplexed convolution signal-analysis and processing-control architecture according to various embodiments of the present subject matter.","FIG.","16 shows a multiplexed convolution signal analysis processing subsystem according to various embodiments of the present subject matter.","FIG.","17 shows an exemplary three-dimensional, discrete behavior space according to various embodiments of the present subject matter.","FIG.","18 presents an illustrative diagram of behavior space mapping and system-behavior determination operations according to various embodiments of the present subject matter according to various embodiments of the present subject matter.","FIG.","19 shows a digital computer implementation of the system-behavior determination operation based on look-up tables according to various embodiments of the present subject matter.","FIGS.","20A-20D illustrate an audio mixture decomposition according to various embodiments of the present subject matter.","FIGS.","21A-21C show the beginnings of the transient audio events according to various embodiments of the present subject matter.","FIG.","22 demonstrates a Digital Human Interface Identifier (DHI-ID) Serial Protocol according to various embodiments of the present subject matter.","FIG.","23 demonstrates a Digital Human Interface Identifier (DHI-ID) Serial system according to various embodiments of the present subject matter.","FIG.","24 demonstrates a recorded sound processing system according to various embodiments of the present subject matter.","DETAILED DESCRIPTIONS OF THE SUBJECT MATTER FIGS.","1A-1D demonstrate some embodiments of systems 100A-100D according to various embodiments of the present subject matter.","FIG.","1A shows a first overall system topology 100A.","The system topology 100A may include a content source 110A, such as an analog or digital audio recording or a live digital stream.","The content source 110A may provide content to the processor 120A, where the processor 120A may include one or more of the audio enhancement techniques describe below.","The processor 120A may provide enhanced audio through a network (e.g., the internet, “the cloud”) 130A to the device 140A.","The use of a remote content source 110A may provide more storage space than a user smartphone, and the use of a remote processor 120A may provide greater processing power and reduce smartphone power consumption.","At the device 140A, the enhanced audio is controlled via user inputs or reproduced using headphones, speakers, or other audio playback hardware or software.","FIG.","1B shows a second overall system topology 100B.","The system topology 100B may include a content source 110B, such as an analog or digital audio recording or a live digital stream.","The content source 110B may provide audio through a network 130B to the processor 120B, where the processor 120B may include one or more of the audio enhancement techniques describe below.","The use of a remote content source 110A may provide more storage space than a user smartphone, and the use of a remote processor 120A may provide greater processing power and reduce smartphone power consumption.","The processor 120B may provide enhanced audio through the network 130B to the device 140B for playback.","FIG.","1C shows a third overall system topology 100C.","The system topology 100C may include a content source 110C, such as an analog or digital audio recording or a live digital stream.","The content source 110C may provide audio through a network 130C to device 140C, where device 140C includes processor 120C.","For example, the content source 110A could be an internet-based music streaming service, which may stream audio data to a user's smartphone, where the smartphone includes the processor 120A and the device 140.FIG.","1D shows a fourth overall system topology 100D.","The system topology 100D may include a content source 110D, such as an analog or digital audio recording or a live digital stream.","The content source 110D may provide audio to device 140D, where device 140D includes processor 120D.","The use of a local content source 110D may allow a user to use one or more of the audio enhancement techniques describe below without needing a network connection.","The combination of the content source 110A-D, processor 120A-D, network 130A-D, and device 140A-D may enhance audio reproduction using one or more of the audio enhancement techniques describe below.","Digital Audio Processing to Simulate the Nonlinear Properties of Sound Propagation and Mixing in Air The experience of listening to digital audio recordings is improved by making subtle modifications to the recorded audio signals that simulate the linear and nonlinear effects of propagation and mixing of sound in air.","The mixing in a nonlinear medium of multiple or complex sound waves comprised of multiple frequencies is known as heterodyning.","Heterodyning may occur at various locations in the air, including at a speaker or at the user's tympanic membrane.","Because the speed of sound in air is itself dependent upon the particle velocity or pressure of the air at any given moment in time and position in space, air may not be a purely linear propagation medium.","For example, the compression peaks of an acoustic waveform may travel faster than rarefaction troughs, distorting the waveform and transferring energy into higher harmonics of the original signal.","When multiple or complex sound waves comprised of multiple frequencies propagate in such a nonlinear medium, the sound waves transfer energy into sound at new frequencies (e.g., intermodulation products) given by the sums and differences of the original signal frequencies.","While these nonlinear effects of air are generally subtle at auditory frequencies and typical sound pressure levels (SPLs) (e.g., loudness levels), second-order nonlinear effects may generate content at levels as high as only 30 decibels below the primary sound pressure and are often perceptible during live music performances.","These second-order intermodulation products have amplitudes proportional to a derivative of the products, which may result in intermodulation products or other propagation effects that increase with an increase in frequency.","Nonlinear propagation effects of audible frequencies may also interact with lower frequencies in an intermodulation scheme.","Thus, the nonlinear effects of air may play an appreciable role in how the brain processes and perceives sound.","The mixing signal processing technique may improve the ability of a system to reproduce the effects of a live performance using a digital audio recording.","While some music is experienced through live performance, most music is experienced through listening to stored analog or digital audio signals.","Digital audio signals are converted to analog signals using digital-to-analog converters, and the original or converted analog audio signals are reproduced acoustically by headphones, open-air loudspeakers, or other means.","The reproduced signals may contain unnatural content, as the reproduced signals represent recorded or synthesized waveforms that have not propagated through air or otherwise mixed in ways that are naturally encountered with live sound.","For example, many genres of music may use recording techniques known as “close-mic'ing” and “overdubbing,” often in combination.","These techniques may include minimal amounts of propagation and mixing in air, and may result in sterile recordings of sounds.","In close-mic'ing, microphones are placed in close proximity to the sound source.","Close-mic'ing can be used to capture direct sounds, while simultaneously reducing energy captured from other sound sources and reducing acoustic reflections occurring in the room where the recording is taking place.","In contrast to listening to live music at a range from 1 meter to tens of meters, close-mic'ing sound-source-to-microphone distances may range from about 10 centimeters for recording vocalists to 5 centimeters for recording amplified guitar or acoustic drums.","In each case, the recorded sound waveform may experience extremely little propagation in air, and therefore may not include effects generated by propagation associated with a similar sound source heard from a more natural listening distance.","When multiple musicians are recorded performing in a space at the same time, close-mic'ing may enable a mix engineer to control their relative volumes individually or apply special processing to a subset of performers.","While this isolation of sounds is useful during mixing, natural effects of nonlinear propagation and mixing in air evolve gradually over distance and may require up to tens of meters of propagation to fully develop, and close-mic'd recordings may fail to capture these natural effects of nonlinear propagation and mixing in air.","The recording technique of overdubbing may isolate individual sounds more than close-mic'ing, and may also fail to capture natural effects of nonlinear propagation and mixing in air.","In overdubbing, additional sounds are recorded and synchronized with previously recorded sounds in order to build a recording of a full ensemble or song gradually through summation of multiple individual recordings.","Because modern digital audio workstations make it easy to layer a large number of individual recordings, each instrument or performance that contributes to a song is recorded individually.","For example, performers may play an instrument while listening to previously recorded parts of the song or a timing cue (e.g., metronome), and may record each instrument or vocal component individually until every song component has been recorded.","These individually recorded song components may also be close-mic'd to avoid room reflections and capture an isolated audio recording (e.g., dry sound).","Through heavy use of these techniques, many modern recordings include numerous individual close-mic'd waveforms that are mathematically added together by a computer and have not propagated and mixed in air as they typically would have in a natural live performance.","In particular, digital audio waveforms that have been generated electronically or synthesized digitally may not have experienced any propagation or mixing in air.","These digital audio waveforms are an extreme example of modern recording practices, as they are completely isolated from the other sounds contributing to a song or sound mixture, and may include little or no additional content or imprint from the space in which they were recorded.","Furthermore, when these sounds are later reproduced acoustically, it is often in a setting that does not allow for the propagation distance or source SPL (sound pressure level) needed for the generated sound to experience the amount of nonlinear propagation normally incurred during live performances or large-scale concerts.","This is true for many home and car playback systems and listening environments, and is particularly relevant to headphones and earphones.","For example, headphone propagation distance of reproduced sound can be less than 6 millimeters, which may allow a recorded sound to propagate in air for 5 to 10 centimeters from source to microphone and then earphone to the tympanic membrane.","Additionally, headphones may use a lower source SPL, as little spreading or propagation loss occurs.","Because modern recording techniques and common listening settings reduce or eliminate nonlinear propagation effects often present and audible during live performances, it is beneficial to recreate these effects through digital signal processing so a more natural sound is provided by digital recordings in typical listening environments.","The acoustical sidebands created by sound heterodyning in air give an added spectral and harmonic richness to sound that is commonly absent from the modern listening experience and would be beneficial to reproduce digitally.","Additionally, it is desirable to impose some of the frequency-dependent attenuation that accompanies natural propagation of sound in air to restore a more natural tonal balance to close-mic'd recordings, and to improve simulation of nonlinear interactions between or among sound components as they propagate.","Beyond compensating for modern recording techniques and playback settings, the use of digital signal processing to simulate nonlinear propagation and mixing of sound in air may enhance the experience of listening to digital audio.","The nonlinearity of air is most pronounced when high sound pressure levels are present, and listeners often find that higher listening volumes provide a more compelling and immersive listening experience.","Digitally introducing the nonlinear effects that would have occurred at high playback volumes may make playback at lower volumes more exciting and enjoyable by simulating part of the experience of listening at high SPLs.","FIG.","2 shows a system 200 for simulating linear and nonlinear effects of propagation and mixing of sound in air according to various embodiments of the present subject matter.","System 200 may operate on one or more input signals in order to generate intermodulation products that would be generated naturally during acoustic propagation of one or more signals at a given peak sound pressure level and then mixing these products with the original input signal(s).","Additional linear filtering is imposed by the system before, during, or after this process in order to simulate the natural frequency-dependent attenuation of sound as it propagates through air.","System 200 may improve the listening experience by compensating for modern digital recording techniques and listening settings that reduce or eliminate the natural attenuation and nonlinear effects of sound propagation through air and by simulating high SPL playback of audio at lower volumes by introducing the nonlinear effects of sound propagation at high SPLs into the recorded waveform itself.","System 200 modifies source material in a transparent and potentially subtle way while not altering the creative content of processed recordings, making it suitable for application to all varieties of musical or audio content recorded and stored in digital form.","System 200 takes as its input one or more input signals (Xi) 210 that represent the amplitude of one or more audio waveforms over time.","In various embodiments, these input signals 210 are a series of digitally stored values representing the instantaneous amplitude of a band-limited waveform that has been sampled at regularly spaced moments in time.","Each input signal (Xi) 210 may have a corresponding primary sound pressure (P1) 220.The primary sound pressure 220 is provided to a processor 230 for calculation of a secondary soundfield.","Processor 230 is a general purpose processor, a dedicated digital signal processing (DSP) integrated circuit (IC), or another type of processor suitable for the calculation of the secondary soundfield.","The output of processor 230 includes a secondary sound pressure (P2) 240, where the secondary signal 240 may simulate effects that would have occurred at high playback volumes to simulate a live mixing of the various sounds.","Primary and secondary sound pressures 220 and 240 are combined through superposition within an adder 250.Adder 250 includes a digital adder circuit or a summing amplifier and may include additional summation or timing components.","For example, processor 230 may introduce a delay in the secondary signal 240 relative to the primary signal 220, and adder 250 may include a fixed time delay or a synchronization module to detect the delay of the secondary signal 240.Adder 250 may combine primary and secondary sound pressures 220 and 240 to provide a sound pressure output signal (Yi) 260, where output signal 260 may simulate what the listener would hear at a live event.","System 200 may modify the input signal(s) in a manner dependent upon one or more controlling parameters.","Generally, these parameters define physical attributes of the simulated sound propagation and mixing and thus directly influence the formulas used to calculate the intermodulation products generated by the nonlinearity of air.","Alternatively, higher-level parameters are used to control the overall character or extent of the processing.","In some embodiments of the subject matter, these parameters are determined automatically through an additional mathematical analysis of the input's auditory content and the application of a rule or decision system that links analyzed signal content parameters to control parameters.","Because digital audio signals generally contain complex waveforms comprised of multiple frequency components and are applied during the mixing of multiple recorded sounds, the present subject matter in various embodiments uses quasi-linear solutions of Westervelt's general inhomogeneous wave equation to determine the relationship between input signals and generated intermodulation products.","In one embodiment of the subject matter, the Westervelt equation for second-order mixing, ∇ 2 P 2 - 1 c 0 2 ∂ 2 P 2 ∂ t 2 = - ρ 0 ∂ q ∂ t , ( 1 ) is used to capture the second-order intermodulation products generated by the nonlinearity of air, as these are generally the most prominent of intermodulation products.","In equation (1), secondary sound pressure (P2) 240 is the pressure variation associated with the intermodulation products generated by the nonlinearity of air, (ρ0) and (c0) represent the density and small-signal sound speed of air, respectively, and (q) is the virtual source density given by q = β ρ 0 2 c 0 4 ∂ ∂ t P 1 2 , ( 2 ) which is proportional to the time derivative of the square of the primary sound pressure (P1) 220.Here, β represents the second-order nonlinear coefficient of air, which may vary with the interaction angle of component sound fields if the primary sound pressure may be a mixture.","The general solution to differential equation (2), which can be used by one embodiment of the presently disclosed subject matter, is P 2 = - ρ 0 4 π ∫ V ∂ q ∂ t e ik s r ′ r ′ dV , ( 3 ) where (ks) is the wavenumber corresponding to an intermodulation product, (V) is the interaction volume over which the primary sound pressure has sufficient amplitude to contribute to the generation of intermodulation products, and (r′) is the distance from each virtual source point in the interaction volume (V) to the location where the generated secondary field is observed.","In this exemplary embodiment, the primary sound pressure (P1) 220 is comprised of either the single input signal (Xi) 210 or a combination of M individual input signals (Xi) 210, where i=1, .",".",".",", M. Parameters of equation (3) such as the definition of the interaction volume V, the radiation pattern of the sources (if multiple inputs may be being mixed), and the physical sound pressure level being simulated is specified, either directly by a user, based on higher-level specifications, or by some other means, and a solution for the secondary sound field P2 is calculated.","An interaction volume (V) with a single isotropic source is shown in FIG.","3, and an interaction volume (V) with two isotropic sources is shown in FIG.","4.FIG.","3 demonstrates a single-source spatial representation 300 of an interaction volume, according to one embodiment of the present subject matter.","In particular, FIG.","3 demonstrates calculation of the secondary sound pressure (P2) 240 generated by a complex (multiple-frequency) primary sound pressure (P1) 220 radiating from a single isotropic source due to the nonlinear effects of propagation in air.","The single-source representation 300 may include a single isotropic source 310, where the isotropic source 310 represents sound generated using primary sound pressure (P1) 220.The isotropic source 310 may generate an interaction volume (V) 320 as used in equation (3), where interaction volume 320 is the volume over which the primary sound pressure contributes to the generation of intermodulation products.","A virtual source point 330 is selected, where the virtual source density at virtual source point 330 corresponds to virtual source point (q) in equation (2).","An observation point 340 is selected, where the distance from virtual source point 330 in the interaction volume (V) 320 to observation point 340 corresponds to the distance (r′) in equation (3).","FIG.","4 demonstrates a dual-source spatial representation 400 of an interaction volume, according to one embodiment of the present subject matter.","In particular, FIG.","4 demonstrates one method of calculating secondary sound pressure (P2) 240 due to the nonlinear effects of propagation in air, where the secondary sound pressure (P2) 240 can be generated by mixing of two independent isotropic sources.","The single-source representation 400 may include a first isotropic source 410 and a second isotropic source 415.The first and second isotropic sources 410 and 415 may be generated using primary sound pressure (P1) 220.The isotropic source 410 may generate an interaction volume (V) 420 as used in equation (3), where interaction volume 420 may be the volume over which the primary sound pressure contributes to the generation of intermodulation products.","A virtual source point 430 may be selected, where the virtual source density at virtual source point 430 corresponds to virtual source point (q) in equation (2).","An observation point 440 may be selected, where the distance from virtual source point 430 in the interaction volume (V) 420 to observation point 440 corresponds to the distance (r′) in equation (3).","For the interaction volume (V) shown in FIG.","3 and FIG.","4, the sound field may be comprised of the sum of second-order intermodulation products.","The sound fields represent sums and differences between pairs of frequencies present in the input signals.","The sound fields also represent second harmonics of all frequencies present in the input signals, each with amplitudes that may be proportional to the square of their frequencies.","Whether using one, two, or more isotropic sources, sound pressure output signal (Yi) 260 may be formed by mixing the secondary sound field (P2) 240 with input primary sound pressure (P1) 220 to arrive at the total sound field that would be observed in air.","The naturally occurring relative amplitudes of the primary and secondary sound fields 220 and 240 may be given by the solution to equation (1).","The sound pressure output signal (Yi) 260 may be further controlled by additional parameters, either interactively by a user, automatically according to analysis of the input signals 210, or by other means.","Linear filtering may be used to simulate frequency-dependent attenuation of sound as it propagates through air.","Linear filtering may be applied to the input signals 210 before or after calculating output signal 260, depending on computational considerations and other design choices.","Characteristics of such linear filtering may be selected to simulate or reduce attenuation properties of air.","The present subject matter applies the Westervelt equation to audible frequencies to compensate directly for modern recording techniques or simulate accurately the effects of high SPL playback of digitally recorded audio to enhance the listening experience.","Typical uses of the Westervelt equation deal with ultrasonic sound.","Most applications, such as high-intensity focused ultrasound and industrial applications of ultrasound, such as cleaning and welding, may be very different from that of the presently disclosed subject matter.","The Westervelt equation has been used in the field of parametric acoustic arrays, such as in the analysis and design of systems that generate beams of ultrasonic sound in order to produce directionally controllable content at audio frequencies through the nonlinear interactions of these ultrasonic beams in air.","Because the nonlinear effects of air increase with frequency, these effects may be strongly present at ultrasonic frequencies, but may be subtle at audio frequencies.","As a result, mathematical application of these nonlinearities to date has focused on ultrasonic applications, and not on digital audio waveforms with content only in the auditory band for enhancing listening during playback.","Additional methods may be used to simulate intermodulation products generated by audio-band sound due to the nonlinearity of air.","A reduced solution may include second-order effects and intentionally exclude higher-order intermodulation products.","Because of the generally low amplitudes of higher-order intermodulation products generated at reasonable SPLs at audible frequencies, the second-order embodiment discussed above may be sufficient to achieve the desired results, however other embodiments are possible.","In some cases, particularly when simulating very high source SPLs or when input waveforms have particular spectral properties, the calculation of higher-order intermodulation products may be desirable.","Higher-order calculations may be included in an embodiment of the subject matter if deemed necessary by a user or through analysis of the input signal.","Digital Signal Processing of Priming Signal for Reduction of Stress in the Auditory System A priming signal processing technique modifies digital audio recordings to reduce the stress experienced by a listener's auditory system.","A priming signal may reduce the instantaneous stress experienced by the auditory system during sudden changes in signal energy.","The priming signal may be generated such that pre-signal priming additions may not result in obvious differences in perceived sounds, thereby leveraging temporal auditory masking.","A method for processing digital audio signals in order to decrease the stress experienced by the auditory system of a listener without overtly changing the creative or musical content of the signal may be disclosed.","The method consists of an adaptive, time-varying system that responds to characteristics of input signal content according to a rule system, and that alters the signal either by mathematical convolution with one or more response templates or by the momentary addition of noise-like signals.","Unlike existing audio processing techniques, this method may not be intended to generate obvious audible differences in the content of an audio signal, but rather to cause an appreciable difference in the comfort and enjoyment of the listener by conditioning the signal to interact more gently or naturally with the listener's auditory system.","This method may be designed to compensate either directly or indirectly for the deleterious effects of unnaturally synthesized, mixed, or recorded digital audio signals as well as other potential shortcomings of digital audio formats and reproduction.","Due to its ease of implementation, this method may be suitable for application to all varieties of musical or audio content recorded and stored in digital form.","Synthetic generation of acoustic waveforms provides extensive creative opportunities.","However, synthetic waveforms also present the listener with audio material that defies many properties of natural sound.","Because these synthetic waveforms do not adhere to physical laws that the auditory system may be designed to understand, this defiance may cause stress on the human auditory system in processing and interpreting these signals.","While the creative freedom afforded by these signals should not be diminished, it may be desirable to introduce processing that may compensate for differences between expected and experienced characteristics of sound.","Such compensation may allow creation of a more enjoyable listening experience without significantly altering the creative content of the audio.","Furthermore, it may be generally desirable to process audio signals in ways that reduce the stress experienced by a listener's auditory system, whether or not such stress reduction may be achieved by imitating the natural behavior of sound.","There may be many known phenomena in the human auditory system that may be relevant to the present discussion.","At a high level, humans may be able to derive much information about their surroundings from analyses of patterns of reflections or multiple arrivals of the same acoustic signal.","For example, the auditory system may be able to use the filtering and delay imposed by the shape of the human head and ears (e.g., head-related transfer functions) to determine the direction from which a sound originated.","Reflections of a sound arriving after the initial direct path may be used by the auditory system to understand characteristics of the space surrounding a listener such as whether or not it may be enclosed, how distant nearby walls or other solid or semi-solid surfaces (such as groves of trees) might be, and the types of materials present in the surroundings (hard and reflective or soft and absorbent).","Such reflections can also be used to understand the location of a sound source relative to the listener: the pattern of reflections that arrives at a listener varies with changes in the relative locations of the listener and the source, creating auditory cues for distance and obscuration.","All of this high-level auditory information may be derived instinctually, without conscious training or attention, and may be based on the auditory system's understanding of how sound naturally interacts with its environment.","The majority of cues for this understanding may be contained in filtering and arrival patterns during the first 100 milliseconds or so after a direct signal, and our ability to make sense of these cues indicates a specialization of the human auditory system for processing naturally occurring audio signals.","At a lower level, it may be known that a wide range of similar acoustic signals may be perceived to present the same sound.","Although the human auditory system may be complex and not fully understood, this phenomenon has been studied extensively and may be known as auditory masking: the process by which the presence of one sound can render another sound imperceptible.","This effect may be a result of both the mechanics of the human peripheral auditory system, which transduces acoustic energy into electrical neural activity, and higher level processing performed in the central auditory system.","Acoustic energy may be transduced into neural activity in the cochlea by inner hair cells, which release neurotransmitters in response to mechanical deflection and incite action potentials (e.g., electrical spikes) in the primary auditory neurons.","Various encoding schemes, such as first-spike latency, rate-based coding, and detailed temporal codes may be then employed by the auditory system to transmit and analyze these initial excitations.","Stated simply, if a dominant sound may be already exciting a particular group of neurons, it may prevent a weaker sound that would excite the same neurons from being perceived.","This may be known as simultaneous masking.","Additionally, because much of the processing performed by the central auditory system involves integration of neural spike signals over some duration of time and because the human auditory system may temporarily decrease its sensitivity to sound in reaction to loud stimuli, masking can extend over a duration of time: a loud sound may render quieter sounds immediately preceding it or immediately following it imperceptible, with an influence that extends longer afterward than before (approximately 20 milliseconds before and 100 milliseconds after a loud sound, with influence decaying exponentially away from the time of the sound).","This may be known as temporal masking.","Finally, because each point along the length of the cochlea may be tuned to a specific frequency, sounds that may be similar in frequency may primarily excite the same groups of neurons, and may be more likely to mask one another through either type of masking.","This phenomenon of auditory masking means that it may be possible to make significant modifications to an audio signal which do in fact present the human auditory system with a different stimulus but which do not yield obvious differences in the content of the signal.","This may be the principle that underlies lossy compression schemes for digital audio such as the ubiquitous .mp3 standard, which may be designed to throw away a large portion of the information contained in an audio signal without changing the way that it sounds to a listener.","Here, this principle may be exploited to apply processing which has an appreciable effect on the listening experience without obviously altering the auditory system's interpretation of the processed data.","The present system analyzes and modifies this input signal; the exact modification performed on the signal at any given time may be dependent upon the current analysis output, and may vary with momentary changes in characteristics of the input signal.","In various embodiments, two main methods of modifying the input signal may be employed.","One of these methods may be to modify the input signal by performing the mathematical operation of convolution using the input signal and one or more convolution template signals.","The other method may be to introduce additional, momentary noise-like components into the output signal.","Digital Signal Processing of Priming Signal: Methods of Modifying the Input Signal FIG.","5 illustrates an embodiment of a signal-modification processing subsystem 500 for introduction of a priming signal, according to various embodiments of the present subject matter.","Subsystem 500 may take multiple input audio channels (Xi) as input 505, where input 505 represents the amplitude of an audio waveform over time.","In various embodiments, input 505 may be a series of digitally stored values representing the instantaneous amplitude of a band-limited waveform that has been sampled at regularly spaced moments in time.","Subsystem 500 may act on each channel of audio individually in series or in parallel.","For example, input channel one signal 510 may be directed into an FIR convolution subsystem 520.FIR convolution subsystem 520 may convolve the input channel one signal 510 with a convolution template to generate a corresponding priming signal, where the selection of the convolution template may be controlled by control data 530 as discussed in more detail with respect to FIG.","6.Input channel one signal 510 may also be directed into a look-ahead delay 540, where look-ahead delay 540 may delay the input signal by the maximum pre-signal convolution response time, effectively achieving look-ahead into the future of the input signal so that priming signal content may be added just prior to audio transients or other events.","Control data 530 may provide control inputs to a look-ahead amplifier 560, which may amplify or attenuate the signal from the look-ahead delay 540.Subsystem 500 may also include a noise burst generator 550 to contribute noise to the priming signal, where the noise burst generator 550 may be controlled using control data 530.The output of the FIR convolution subsystem 520, the noise burst generator 550, and the look-ahead amplifier 560 may be summed in signal adder 570 to form an output signal for channel one.","Subsystem 500 may provide an output signal (Yi) 580, where the output signal (Yi) 580 may include an output corresponding to each input audio channel (Xi) 505.Subsystem 500 may be implemented in various configurations, including the configuration shown in FIG.","11 or 16.In the embodiment illustrated in FIG.","11, multiple audio channels may be analyzed individually by parallel single-channel analysis systems, the output of which may be further processed by a higher-level multi-channel analysis system that may lead to modifications of the resulting single-channel control decisions.","In the embodiment illustrated in FIG.","16, each type of signal analysis may be performed on a multichannel collection of signals at once, and the results from each type of analysis may inform other analyses.","FIG.","6 illustrates an embodiment of an FIR convolution subsystem 600, according to various embodiments of the present subject matter.","FIR convolution subsystem 600 may take an audio channels (Xi) as input 610.Audio input 610 may be fed into a convolution selector 620, and input control data 630 may cause one or more connections to be opened or closed between the audio input 610 and FIR convolution templates 640 and 645.Each of convolution templates 640 and 645 may be modified using input control data 630, such as selecting modifying or replacing the convolution function within each of convolution templates 640 and 645.Though two convolution templates 640 and 645 are shown, any number of convolution templates may be used, and may be selected using any number of switches within the convolution selector 620.For example, a single convolution template may be used, or all convolution templates may be used simultaneously.","Modification of the input signal through calculation of mathematical convolution results may be performed as follows.","A number of template signals may be stored as representations of signal amplitude over time.","These representations may be digitally stored lists of numbers.","These template signals may be derived from recordings of real-world natural environments, pre-constructed mathematically or otherwise, or derived from parametric specifications, and need not be more than approximately 50 milliseconds in length.","At any given time, one or more of the M template signals, ci, i=1, .",".",".",", M, may be convolved with the input signal depending on the current input signal analysis results, to generate a set of convolution outputs yi, y i [ n ] = ( x * c i ) [ n ] = ∑ k = 0 N - 1 x [ n - k ] c i [ k ] , ( 4 ) where the convolution template signals, ci[n], may be defined for the time period n=0, .",".",".",", N−1.Each output of convolution templates 640 and 645 may be fed into corresponding convolution amplifiers 650 and 655, where they may be scaled by gains, (ai), i=1, .",".",".",", M. Gains (a) may be specified by amplifier input control data 630, where amplifier gains may be selected based on the input signal analysis results.","The output of convolution amplifiers 650 and 655 may be summed within a signal adder 660 to generate the convolution subsystem output 670, given as y conv [ n ] = ∑ i = 1 M a i y i [ n ] .","( 5 ) The output of the signal adder 660 may provide FIR convolution subsystem output 670, which may be summed with additional input channels at signal adder 570 shown in FIG.","5.In many existing systems using convolution operation in digital audio signal processing, these convolution templates are intended to achieve a particular frequency response specified by a user or to alter the perceived timbre, character, musical or creative content of the input signal.","Similarly, in such existing systems, these convolution templates are intended to recreate the full response of any particular linear system or type of linear system such as a real or synthetic acoustic space, or an electrical or acoustic device or instrument.","In contrast, in various embodiments of the present subject matter, the convolution templates are designed to reduce stress on the auditory system of a listener without obviously altering the content of the input signal.","This design goal, and the goals of subtleness and transparency it entails, therefore distinguishes from the design goals of existing audio processing systems.","Additional content may be introduced prior to transients or other triggering events in the input signal by utilizing digital delay to effectively achieve look-ahead into the future of the input signal and applying convolution templates that include pre-signal content.","For example, with a maximum pre-signal response time of tpMAX, the path by which the input signal (x) reaches the output without modification may have an imposed delay of pMAX=ceil(tpMAX··fs), where (fs) denotes the (currently assumed to be regular) sampling frequency of the data contained in (x) and the ceil( ) function denotes rounding up to the next integer value.","Delaying the dry path in this way has the effect of equivalently performing the convolutions as y i [ n ] = ( ( z p MAX x ) * c i ) [ n ] = ∑ k = 0 N - 1 x [ n + p MAX - k ] c i [ k ] .","( 6 ) This expression demonstrates that future values of the input x may contribute to the current output value of each (Yi) if the convolution template signals ci may be defined to be non-zero in the range of time from n=0, .",".",".",", pMAX−1.In practice, the amount of time by which template content leads signal content and the level of the pre-signal content relative to the following signal may be both variable and depend on the current input signal analysis results.","Pre-signal response times of less than 10 milliseconds may be used, with times ranging from 1 millisecond to as little as 50 microseconds being most common.","The introduction of such pre-signal content, particularly in a time-varying and signal-dependent (non-linear) manner, may be designed to prime the human auditory system for the audio content that follows.","Due to the phenomenon of temporal auditory masking, such pre-signal priming additions may not result in obvious differences in the sounds that may be heard, but may reduce the instantaneous stress experienced by the auditory system during sudden changes in signal energy.","FIG.","7 illustrates adjustable pre-signal content duration examples 700 in the FIR convolution templates, according to various embodiments of the present subject matter.","The first example signal waveform 710 may include the entire input signal.","Each of modified signal waveforms 720, 730, and 740 may have increasing dry signal durations, where modified signal waveform represents the maximum dry-signal delay tpMAX=10 ms. As shown in FIG.","5, this dry signal may be implemented as a parallel signal and does not enter a convolution subsystem, such as using parallel channel look-ahead delay 540 shown in FIG.","5.Because this parallel input dry signal may be delayed, template content that occurs at lags smaller than this dry-signal delay may be added effectively to the output in response to input signal content that has not yet appeared at the processing system's output.","This portion of the convolution template reacts to future input signal and may result in the addition of content to the output signal just prior to audio events such as transients.","FIGS.","8A-8B illustrate enforced zero-response examples 800A-800B around the dry signal delay time according to various embodiments of the present subject matter.","Each of example waveforms 810, 820, 830, 840, 850, and 860 depict a different application of a zero-response signal applied to the input signal 710 shown in FIG.","7.Example waveforms 810, 820, 830, 840, 850, and 860 depict a duration of silence enforced in the convolution templates around zero delay, or the point in time corresponding to the current input signal amplitude, given as ci[n]=0,n=pMAC−k, .",".",".",",pMAX+l (7) for some numbers of samples (k) and (l).","Values (k) and (l) may be selected to minimize the alterations of the way that the input signal sounds.","FIG.","8A includes example waveforms 810, 820, and 830, which depict a symmetric short duration of silence enforced in the convolution templates around zero dry-signal delay tpMAX=10 ms.","Example waveform 810 shows a small duration of silence, example waveform 820 shows a medium duration of silence, and example waveform 830 shows a large duration of silence.","Example waveforms 810, 820, and 830 depict an asymmetric short duration of silence enforced in the convolution templates around zero delay.","FIG.","8B includes example waveforms 840, 850, and 860, which depict asymmetric short duration of silence enforced in the convolution templates.","In particular, waveform 840 depicts an asymmetric duration of silence beginning at dry-signal delay tpMAX=10 ms, example waveform 850 depicts an asymmetric duration of silence around tpMAX=10 ms, and example waveform 860 depicts a large asymmetric duration of silence around tpMAX=10 ms. A system may select one of symmetric or asymmetric example waveforms 810, 820, 830, 840, 850, and 860, and therefore select the delay and position of silence, in order to reduce the perception of the artificial duration of silence.","In natural acoustic environments, the sound heard by a listener may be always the combination of an initial direct-path arrival followed by subsequent early reflections.","In nearly all cases, this leaves duration of silence (for example on the order of milliseconds) in the room response between the initial first arrival and the first-arriving reflection.","Although the details of this first-arriving reflection and other soon-arriving early reflections may vary greatly with the positions of a sound source and listener or the acoustic space in which they reside, these changes in response generally do not alter the observed character of a sound in an obvious way.","For example, a particular sound source such as an instrument or a particular person's voice may be recognizable in a wide variety of spaces from a small, enclosed room to a huge cathedral; the sound identified as being produced by the source does not change significantly in character, despite the fact that the sound associated with the space it may be in changes drastically.","This may not be to say that such responses cannot contribute to the perceived character of a sound, but to demonstrate that many convolution templates with some duration of silence trailing the zero-delay component may be expected to yield subtle effects on the sound being processed; in fact, recording engineers often put significant effort into choosing the placement of microphones such that a pleasing portion of a source's radiation pattern and initial reflections may be captured during recording.","This convolution template design technique may apply this subtlety and correspondence to naturally occurring sound phenomena.","While convolution responses longer than approximately 50 milliseconds in duration may be perceived temporally by the human auditory system, convolution responses shorter than this may be heard spectrally in that they tend to alter the perceived character of the sound being convolved with the response rather than introducing new, separate sounds.","The effect of summing multiple, repeated copies of a single signal on that signal's spectrum may be known as comb-filtering.","In comb-filtering, a series of evenly spaced frequencies may be cancelled in the signal's spectrum because the contributions from the multiple delayed copies of the input signal at those frequencies may be out of phase and sum to zero.","In general, this type of comb-filtering may be largely imperceptible to humans (although particular types of comb-filtering that change systematically over time do, however, form a class of obvious audio effects known as flanging and phasing).","The fact that this type of filtering does not create blatantly obvious changes in the character of a sound may be likely because it may be so commonly encountered in natural acoustic spaces, as discussed above.","By enforcing a period of silence around the zero-delay component of convolution templates and applying otherwise subtle or low-level responses, the frequency response of the templates tends to occupy this space of comb-filter-like responses that alter the character of the filtered sound in only subtle ways.","In addition to this convolution-based method of modifying the input signal, the input signal may also be modified through the momentary addition of specific noise-like signals, y-noise.","These noise signals may be added at times determined by the results of the input signal content analysis, such as during or slightly before transient peaks.","This novel procedure may be intended to achieve the goal of auditory stress reduction in a manner similar to that of pre-signal content in convolution templates: the addition of a specific noise-like signal may be designed to prime the auditory system for sudden changes in signal energy and to soften the momentary auditory stress induced by sudden changes in signal energy.","Again, due to the phenomena of temporal and simultaneous masking, such additions may not be expected to result in obviously different sounds, despite the fact that they may present a listener with markedly different acoustic signals.","In some embodiments of the present subject matter, the addition of filtered noise may seem analogous to processing performed by generalized lossy perceptual audio compression schemes.","Lossy perceptual audio compression techniques can generally be interpreted as adding spectrally shaped noise to recorded digital audio signals that may not be readily audible.","However, this interpretation may be based on a typical method for analyzing the results of quantization and does not fully describe the processing performed by such systems.","In practice, these systems quantize information about the input signal such as its spectrum during successive blocks of time with varying resolutions, which may result in highly objectionable audible artifacts and correlations between the input signal and resulting quantization error that cause the additive-noise based interpretation to be inaccurate.","Furthermore, when considered as adding spectrally shaped noise to the recorded digital audio signal, these compression technologies add broadband noise over the full duration of the audio signal.","In contrast to generalized lossy perceptual audio compression techniques that seek to decrease the amount of data required to represent the digital audio signal, this method may be used to improve the experience of listening to an acoustically reproduced version of the audio signal.","To improve the listening experience, specifically shaped noise sequences may be added to the input signal only at specific noise times and for specific noise durations in order to decrease the stress experienced by the auditory system at those moments, where the noise durations may make up a small portion of the duration of the input signal.","This use of additive noise also differentiates it from simulations of tape or vinyl mediums that introduce noise during the full duration of an audio signal in order to simulate properties of those recording media.","Digital Signal Processing of Priming Signal: Automatic and Signal-Aware Control of the Modification Methods In various embodiments, the modification operations discussed above may be controlled automatically by the results of signal content analysis performed on the input signal.","This analysis aims to assess four main characteristics of the input signal: the distribution and complexity of its momentary spectral content, the program, or average, perceived loudness of the signal, the presence of transient bursts of energy or changes in signal content, and, when used on multi-channel recordings, the spatial relationships of these characteristics across the multiple channels.","The results of these analyses in turn drive a rule-based control system that may be designed to provide processing that, at any given moment, reduces the stress experienced by the auditory system of a listener while remaining transparent and not obviously audible.","In exemplary embodiments of the subject matter, this rule-based control system may consist of a digitally stored look-up table, a set of parameterized functions, or a combination of the two, which relate the outputs of the analysis subsystems to the operation of the modification system components.","While in general this control of the modification processes may be performed without intervention from a human operator, in one exemplary embodiment of the subject matter an operator or application that uses the presently disclosed subject matter may specify one or more high-level operation control parameters prior to applying it to a digital audio signal.","Such high-level parameters may describe the kind of content being processed or the type of playback system that may be used to listen to the generated output signal.","With the caveat that higher-level specifications may adjust the interpretations of each analyzed signal characteristic, we may now describe how the outputs of these signal characteristic analyses may be used to control the signal modification processes.","Due to the frequency-dependent nature of many auditory processing phenomena such as masking, analysis may be performed to determine the distribution and complexity of the input signal's momentary spectra.","This analysis, in turn, guides the determination of which convolution templates to use as well as the relative mixing gains applied to the outputs of each convolution, and, when deemed appropriate by other analyses, the type of noise signal to add to the input.","Convolution templates and noise signals may be chosen to complement the current input signal content and to avoid creating obvious audible effects.","Modifications that introduce too much content at frequencies that may not be strongly present in the input signal or that may become obvious due to simple, non-complex material may be avoided.","Because the behavior of the human auditory system may be non-linear and generally responsive to relative changes in energy levels, the analysis system estimates the program level, or the average perceived loudness, of the input signal over time.","For most audio signals, this estimate may vary gradually with changes in signal content.","Relative changes in program level or comparisons between the estimated program level and the known average program level of typical audio recordings (which may vary with the genre of music or type of content contained in the audio signal) may then be used to guide control of the input signal modification system.","For example, characteristics such as the pre-signal lead-time used by convolution templates, the relative amount of processed signal mixed with the raw input signal, and the choice of convolution templates may all be affected by the estimated program level.","Audio transients, or short-duration changes in audio signal energy or spectral content, provide a particular kind of stimulus to the human auditory system that requires special processing by the input signal modification system.","In order to enable such special processing, the input signal may be analyzed to detect transient events in the audio stream.","Once detected, a transient event may be further analyzed for relative energy content, spectral make-up, and duration.","Among other things, the detection of these events may control the choice of convolution templates and corresponding mixing gains, the amount of pre-signal lead-time used by the convolution templates, the addition of momentary noise-like signals to the input signal, and the enforcing of a duration of silence around the zero-delay time in convolution templates.","Finally, because digital audio signals may be commonly reproduced on multichannel systems (with stereo, or 2 channel, systems being the most common), an awareness of the spatial image created by multiple signals may be required to avoid introducing changes into the individual audio signals that result in obvious or undesirable effects, where the changes may be perceived when a user listens to the combined output signals through such a multichannel system.","When processing audio signals intended for multiple-channel playback, all channels may be processed together.","A higher-level analysis that takes as its inputs the single-channel analysis results may be performed, and the output of this higher-level analysis may be used as an additional control input to the single channel modification systems.","The result may be that different modifications may be made to each individual input signal than would have been made were the input signals processed in isolation; the control of the modification system must respect an additional set of rules to ensure that the interaction between multiple channels during playback does not have undesirable effects.","Digital Audio Processing for the Restoration of Motion and Dynamic Timbre The sense of motion, liveliness, and spatial dynamics may be simulated using various methods discussed in this document.","These methods may compensate for the static presentation of sound created by modern recording and sound synthesis techniques and common modern playback equipment such as headphones and ear buds in order to create a more natural, immersive, and enjoyable listening experience.","Modern recorded music and sound, unlike naturally produced acoustic sound, may be spatially and timbrally static.","Perhaps the most pervasive recording technique in modern audio production may be to record musical performances in a close mic'd manner, meaning that one or more microphones may be placed at static positions close to a musician or sound source and a performance may be recorded with minimal motion being made by the musician in order to produce a consistent loudness and tone across the duration of the recording.","While this technique may afford a certain precision in the recording and post-processing of each musician's contribution to a song or musical piece, it deprives the completed recording of the liveliness and timbral dynamics created by motion in more natural performance and listening environments.","The use of digitally synthesized sounds in modern recordings can take this dry, static nature to an extreme, producing recorded sound that may be entirely unchanging in tone or character over time.","These modern recording techniques and technologies give rise to an unnatural and unpleasant stationary-tone audio-reproduction environment (STARE), in which recorded sound may be experienced as both spatially and timbrally static.","In contrast, when performers play together in an acoustic space their movement alters the spatial radiation characteristics of their instruments over time, gradually changing the timbral qualities of their instruments and exciting various resonances and reflections in the space where they may be performing.","Additionally, motion of performers on a stage or of listeners in an audience may change the sound heard by everyone in the audience in small or obvious ways.","Even subtle motions of an audience member's head may create shifts in the delays and filtering experienced by the various sound components reverberating about a space before reaching their ears, and thus alter the tonal and spatial qualities of the sound that they hear.","All of these dynamic effects contribute to a sense of immersion and liveliness that may be desirable to reproduce when listening to recorded audio.","Although post-processing of close-mic recorded audio may add reverberation or panning effects that help to approximate this feeling of immersion and motion, these effects still present a sound with static tonal and spatial qualities in the sense that we have discussed here: a sound may be made to occupy some space or originate from some direction, but none of the natural, motion-driven variability that we have discussed here may be restored.","Certain pieces of revered and highly sought-out analog recording equipment may come closest to providing an existing remedy for this problem of static recorded sound, as such equipment may be known to create subtle, time-varying changes in the tone and imaging of processed signals due to circuit phenomena such as very-low-frequency shifts in the DC-bias points of internal components caused by transient offsets in audio signals; however, this type of equipment may be expensive and thus may not be available to all producers of recorded music.","Furthermore, such currently existing equipment may only provide a portion of the variability and dynamics that may be desirable for the re-creation of natural sound environments and the maximization of listening enjoyment.","With the rise of portable music devices and the accompanying increase in the usage of portable playback equipment such as headphones and ear buds, the STARE problem has been taken to an extreme over the past decade: unlike loudspeakers, these personal playback devices prevent even the natural variability in tone that may be associated with a listener moving about a room or turning their head.","At the same time, the popularity of close-mic recording techniques and synthesized digital audio has shown no signs of recession.","Thus, it may be desirable to introduce digital signal processing techniques that restore a sense of motion and liveliness to digital audio recordings in order to improve the experience of listening to modern digital audio.","A method for processing digital audio signals in order to restore a natural sense of motion and liveliness may be disclosed.","The method consists of analyzing a digital audio recording and applying time-varying phase shifts, inter-aural delays, filtering, and amplitude and frequency modulation (e.g., “flutter,” “wow”) in a subtle way that may be driven by the presence of particular signal characteristics, such as percussive or transient events, that help to make the applied processing non-obvious.","This method may compensate for the static tonal and spatial listening experience created by modern recording techniques, digitally synthesized sounds, and popular personal playback devices such as headphones and ear buds.","This method may improve the experience of listening to digital audio recordings by restoring a sense of motion and immersion to those recordings that may be commonly experienced in live acoustic settings.","FIG.","9 illustrates an exemplary multichannel analysis signal-modifying processing subsystem 900, according to various embodiments of the present subject matter.","Subsystem system architecture 900 demonstrates the general system architecture, consisting of a signal-analysis and processing-control subsystem and a signal-modifying processing subsystem, each of which may handle multiple input signals 910.The system takes one or more input signals 910 that each represent the amplitude of an audio waveform over time.","Typically, these signals may each be a series of digitally stored values representing the instantaneous amplitude of a band-limited waveform that has been sampled at regularly spaced moments in time.","The signal-modifying processing subsystem 900 both analyzes and modifies these input signals 905, with the results of input signal analysis determining the modifications to be performed at each point in time.","In general, any available data may be analyzed and used to determine the exact modifications to be made to the digital audio signals at each point in their durations, though the presence of transient changes in intensity or energy associated with percussive sounds may play a large role in determining when modifications may be to be made because such sounds have the ability to help mask the applied modifications and make them non-obvious.","Each channel in a multichannel processing system, from channel one 920 to channel N 925, may include multiple processing blocks.","For example, channel one 920 may be processed through a frequency-dependent phase shift processing block (e.g., all-pass cascade processing block) 930, a linear relative-delay block 940, a magnitude filtering block 950, and an amplitude and frequency modulation block 960.Each processing block may be modified by control data 970, where control data 970 controls processing parameters within each processing block.","Processing may be governed by parameterized equations that relate numerical results of signal analysis to parameters controlling the signal modification algorithms.","The output of the processing blocks for each channel may be output from the subsystem 900 as output analysis results 980.Additionally, output analysis results 980 may be used to select a particular modification algorithm from a collection of available, implemented algorithms for use on a particular signal or time-region of a signal through some logical or rule-based processing of output analysis results 980.Implementation of the relationship between signal analysis and modification may be controlled or adjusted by higher-level parameters to select a particular relationship from a collection of options: for example, a high-level analysis of the input signals may determine the type of audio content that may be currently being processed (a general, individual instrument or some identified particular instrument, a complex sound mixture of multiple instruments, a sound mixture identified to belong within a particular genre of music, etc.)","and use this determination to choose a particular relationship between analysis output and modification from a collection of relationships that may be each most appropriate for a certain type of content.","Such high-level control and any lower level parameters of the relationship between analysis and modification may be exposed to an end-user through some type of interface for manual adjustment, or may be performed automatically.","Once an analysis configuration and relationship between output analysis results 980 and signal modifications has been determined, time-varying modifications may be made to the input signals 910 to create a sense of motion and liveliness in the recorded audio, thereby improving the experience of listening to it during subsequent playback.","These modifications may be performed in a way that may be subtle enough to avoid being overtly noticeable by listeners and that may be neutral enough to avoid altering the creative content of the audio recording, while still creating an appreciable, pleasing effect.","Significant motion effects may be achieved within the all-pass cascade processing block 930.The all-pass cascade processing block 930 may introduce time-varying, frequency-dependent phase shifts, potentially applying different shifts to each channel in a stereo or multichannel recording.","Such modifications can be performed using digital all-pass filtering, using filters with transition frequencies and orders that vary over time.","It has been demonstrated in psychoacoustics experiments that the effects of such phase shifts, which correspond to sound components moving closer and further away, can be perceptually subtle when compared with magnitude, or non-all-pass, filtering.","To reduce the perception of the phase shift, a bandpass filter may be used to avoid shifting the phase of the bass or treble.","The bandpass filter may include frequencies ranging from 500 Hz to 5 KHz.","This provides a neutral and subtle way of animating sound content.","In various embodiments of the presently disclosed subject matter, changes in imposed phase shift may often occur in-sync with percussive audio transients, with the amount of shift increasing during transients and then slowly drifting back toward zero over the course of approximately 200 to 500 milliseconds, or in a semi-periodic cyclical fashion at a similar rate.","The linear relative-delay block 940 may modify digital audio recordings in order to instill a sense of motion may be using time-varying inter-aural delays.","When a sound source moves about a space relative to a listener or a listener rotates their head relative to a source, varying amounts of delay may be experienced by sound as it travels to the listener's left and right ears.","Because of this, applying small, time-varying amounts of relative delay between the left and right channels of a stereo audio recording or among multiple channels in a multichannel recording can create a sense of movement and variability similar to the motion that naturally occurs when listening to a live performance.","Because listeners have been found in psychoacoustics experiments to be able to detect horizontal displacements of less than one degree in the horizontal plane, the relative delays imposed by the modification system in this way need not be large in order to create a sense of motion.","In fact, using too large a modification may be likely to be distracting and prevent the desired subtlety.","Various embodiments may impose time-varying relative linear delays of approximately 0.1 millisecond or less across channels in a stereo or multichannel recording.","As with imposed frequency-dependent phase shift, the amount of applied relative linear delay may vary in-sync with percussive or transient audio events, or may oscillate in a semi-periodic fashion that may be more loosely driven by signal properties.","The magnitude filtering block 950 may be used to simulate a radiation pattern corresponding to motion of an audible source or listener.","The radiation pattern of a sound source may change in response to the motion of performers around it or the way that a performer makes contact with it, and the transfer function from a source to a listener due to the acoustic space that they occupy may change significantly as either person moves about or rotates within the space.","Typically, these phenomena may give rise to general changes in timbre that may be simulated using low-order IIR (infinite impulse response) filters with transition or cut-off frequencies and gains that change over time or comb-filtering effects caused by the summation of multiple reflections of sound that can similarly be modeled using digital FIR (finite impulse response) or IIR filters that change over time.","Both of these types of filters may be designed to produce subtle effects, and thus provide the types of modification desired by the presently disclosed system; by varying their application in response to characteristics of the input signal, such magnitude-filtering may be performed in a way that creates a sense of motion and liveliness without becoming obvious or altering the creative content of the modified recording.","The amplitude and frequency modulation block 960 may be used to impose subtle time-varying amplitude modulation (e.g., “wow”) and frequency modulation (e.g., “flutter”) on digital audio recordings in order to create an enhanced sense of motion and dynamics.","These effects may be familiar in the audio world because they result from imperfections in common analog playback systems, such as tape and vinyl While these effects may be overt, distracting, or detrimental to playback quality, they may be used subtly to create neutral and subliminal but perceivable motion and complexity in an audio recording.","Various embodiments of the presently disclosed subject matter may apply time-varying, semi-periodic frequency modulation of less than ±1 cent (where 1 cent represents the 1/100 of the difference between each semitone within an octave) and amplitude modulation of less than ±1 dB, at oscillation rates below about 5 Hz.","As with other modifications, the exact amount and rate of modulation may be driven by the analysis of input signal and may vary in response to the low-passed energy envelope of the signal, the presence of discrete, identified transients, momentary spectral complexity, or any other suitable property.","Automatic Level-Dependent Pitch Correction of Digital Audio A pitch correction signal processing technique modifies digital audio recordings to correct for level-dependent shifts in the perceived pitch of audio content.","These corrections compensate for the effects of sound level on perceived pitch, corrections that may be impractical to apply during performance or recording.","These corrections may improve the experience of listening to digital audio recordings by adjusting the perceived pitch of an audio signal dynamically.","The dynamic adjustment may be dependent upon the momentary loudness of the audio signal (e.g., audio signal intensity, audio signal power, audio signal level, audio signal volume).","The concept of auditory or musical pitch may be a perceptual one: while the pitch of a sound tends to be strongly related to mathematical properties of the associated acoustical wave such as its periodicity or frequency content, the relationship between such numerical properties and the perception of pitch may be more complex.","Significant research into this relationship was performed in the 1930's at various academic institutions and at Bell Labs, and this research revealed a strong interaction between the level at which a sound may be heard and its perceived pitch, meaning that the same sound heard at different levels or volumes may be perceived as having different pitches, even when no other mathematical properties of the sound signal (such as periodicity or frequency content) have changed.","At that time, studies were performed that further elucidated this relationship between sound level and pitch.","It was demonstrated that the amount of shift in perceived pitch for a given change in sound level may be dependent upon a complex interaction of signal characteristics, including the frequency content and absolute level of a sound.","One trend characterizing this relationship may be that for a simple tone (e.g., single frequency sinusoid), as level increases, the perceived pitch of that tone decreases for frequencies below about 2000 Hz and increases for frequencies above about 2000 Hz.","A general characterization of the relationship between the level, frequency content, and perceived pitch of complex sounds (sounds with multiple frequency components) has not been fully characterized for all complex sounds.","However, it was found that the shifts in perceived pitch that occur for complex sounds at varying levels may be predicted by a weighted mean of the shifts that would occur for each sinusoidal component of the sound if they were heard individually.","This finding suggests that, because many sounds produced by musical sources contain frequency content both above and below the zero-shift frequency of about 2000 Hz, most musical audio material may demonstrate small shifts in perceived pitch with changes in level relative to the shifts demonstrated by simple tones.","This phenomenon, that perceived pitch may be dependent upon sound level, poses a subtle problem for musicians and recording engineers.","Generally, musicians optimize the tuning of their instruments and their playing techniques to compensate for this effect when performing live together in a group.","Such adjustments may be subconscious or habitual rather than overt and deliberate, with professional musicians constantly making minute adjustments based on instinctual knowledge of their instruments and the feedback provided by their perception of pitch; however, it may be common in modern recording workflows for musicians to record their contributions to a song in isolation so that the individual sounds may later be layered or mixed together to form a final recording by a mix engineer, as this affords much more flexibility for adjusting the individual recordings and applying post-processing to individual sounds.","In this case, performing musicians cannot make the same adjustments to ensure that all parts of the resulting sound mixture may be perceived to have their desired pitches.","Additionally, many instruments do not provide musicians with the capability of making such subtle adjustments to the perceived pitch of the sound they produce, meaning that regardless of the recording situation there may be room for improvement through post-processing of recordings to make these adjustments.","Finally, when numerical tools such as frequency content analysis may be relied upon to tune instruments or later adjust the tuning of recorded sounds, this may not compensate for the phenomenon of perceived pitch may not be solely determined by frequency content may be usually neglected.","This may result in sounds that may be in need of further dynamic pitch adjustment to achieve or maintain desired musical pitches.","Because the perceived pitch of musical sound plays a large role in its emotional impact and perceived quality, even minor pitch adjustments may have a noticeable impact on the listening experience.","Research into psychoacoustics has demonstrated that the perceived pitch of a sound may be effected by the level at which that sound may be heard, meaning that minor adjustments to produced sounds may be required to sustain a particular pitch across differing sound levels.","Because modern recording techniques make it difficult or impossible for musicians to make these adjustments during performance and because such adjustments may not be possible, using digital signal processing techniques to apply dynamic, level-dependent adjustments to the pitch of recorded digital audio, when appropriate, may greatly enhance the listening experience.","A method for processing digital audio signals in order to correct for level-dependent shifts in the perceived pitch of audio content may be disclosed.","The method consists of analyzing a digital audio recording and creating small, dynamic shifts in perceived pitch as required to compensate for the pitch distortion caused by relative changes in momentary sound level.","This method may be suitable for processing of any type of digital sound recording, including individual sound recordings and complex sound mixtures.","This method may compensate for modern recording techniques that make it difficult or impossible for musicians to make such adjustments correctly in produced pitched during recorded performances and to improve the perceived pitch of recorded digital audio across changes in relative level wherever possible.","By correcting these small pitch distortions, the perceived quality of digital audio recordings may be improved without altering their creative content.","FIG.","10 illustrates a series single-channel analysis subsystem 1000, according to various embodiments of the present subject matter.","FIG.","10 demonstrates one embodiment of the signal-analysis subsystem in which channels of audio may be analyzed individually by parallel single-channel analysis systems, the output of which may be then further processed by a higher-level multichannel analysis system that may lead to modifications of the resulting single-channel control decisions.","Series single-channel analysis subsystem 1000 may operate on multiple input audio waveform channels 1010 and 1015.Each input audio waveform channel may be analyzed using a spectral analysis module 1020, a loudness analysis module 1030, a transient analysis module 1040, and a rule-based control signal generator 1050.The output of the spectral analysis module 1020, the loudness analysis module 1030, or the transient analysis module 1040 may be processed within a multichannel analysis module 1060.The output of the rule-based control signal generator 1050 may be combined with outputs from other rule-based control signal generators within an aggregating rule-based control signal generator 1050.The output of the aggregating rule-based control signal generator 1070 may be processed within a processing module 1080, and may generate an output waveform 1090.FIG.","11 illustrates a parallel single-channel analysis systems signal-analysis subsystem 1100 according to various embodiments of the present subject matter.","FIG.","11 demonstrates one embodiment of the signal-analysis subsystem in which channels of audio may be analyzed individually by parallel single-channel analysis systems, the output of which may be then further processed by a higher-level multichannel analysis system that may lead to modifications of the resulting single-channel control decisions.","Parallel single-channel analysis subsystem 1100 may operate on multiple input audio waveform channels 1110.Each input audio waveform channel may be analyzed using a spectral analysis module 1120, a loudness analysis module 1130, a transient analysis module 1140, and a rule-based control signal generator 1150.The output of the spectral analysis module 1120, the loudness analysis module 1130, or the transient analysis module 1140 may be processed within a multichannel analysis module 1160.The output of the rule-based control signal generator 1150 may be combined with outputs from other rule-based control signal generators within an aggregating rule-based control signal generator 1150.The output of the aggregating rule-based control signal generator 1170 may be processed within a processing module 1080, and may generate an output waveform 1090.FIG.","12 shows the dependence of perceived pitch on sound level 1200 according to various embodiments of the present subject matter.","FIG.","12 shows the dependence of perceived pitch on sound level as determined experimentally by Stevens S. for a particular test subject.","This plot shows the percent change in perceived pitch 1220 as a function of sound intensity 1210 for a variety of frequencies spanning the audible range.","Absolute position on the y-axis for each curve may be arbitrary only relative change may be depicted.","FIG.","12 demonstrates the finding that the perceived pitch of simple, sinusoidal tones with frequencies below about 2000 Hz decrease as the level of the tone increases while the perceived pitch of sinusoidal tones with frequencies above about 2000 Hz increase as the level of the tone increases.","The changes depicted here for simple tones may be used to predict the effects of changes in sound level on the perceived pitch of complex musical tones and sounds, which may be used to determine appropriate compensatory pitch-shift amounts.","FIG.","13 shows the dependence of perceived pitch on sound level at low frequencies 1300 according to various embodiments of the present subject matter.","FIG.","13 shows the dependence of perceived pitch on sound level at low frequencies as interpreted from experimental results by Snow, W. in his 1936 paper, “Change of Pitch with Loudness at Low Frequencies” (J. Acoust.","Soc.","Am., vol.","8, no.","1, pp.","14-19, 1936).","Experimentally determined curves such as these may be used in determining appropriate compensatory amounts of pitch-shift to apply in response to changes in signal intensity or level.","As discussed above with respect to Multiplexed Convolution, any implementation of the relationship between signal analysis and modification may be controlled or adjusted by higher-level parameters to select a particular relationship from a collection of options: for example, a high-level analysis of the input signals may determine the type of audio content that may be currently being processed (a general, individual instrument or some identified particular instrument, a complex sound mixture of multiple instruments, a sound mixture identified to belong within a particular genre of music, etc.)","and use this determination to choose a particular relationship between analysis output and modification from a collection of relationships that may be each most appropriate for a certain type of content.","Such high-level control and any lower level parameters of the relationship between analysis and modification may be exposed to an end-user through some type of interface for manual adjustment, or may be performed automatically.","Once an analysis configuration and relationship between analysis results and signal modifications has been determined, time-varying modifications may be made to the perceived pitch of the input signals.","These pitch shifts may be small, such as in the range of a shift in frequency of 0.015 to 1.15 percent (e.g., 0.25 to 20 cents, where 100 cents represents the difference between each semitone within an octave).","These small pitch shifts may be in accordance with the small perceptual shifts in pitch that occur for complex musical sounds with relative changes in level, and different amounts of pitch or frequency shift may be applied to separate spectral bands of the input signal.","In one embodiment of the presently disclosed subject matter, positive pitch-shift may be applied to signal content at frequencies above about 2000 Hz as signal levels fall below a nominal reference level in order to compensate for the decrease in perceived pitch that occurs for sinusoidal components in this frequency range as level decreases.","In another embodiment of the subject matter, the input signal may be split into numerous frequency bands and varying amount of pitch or frequency shift may be applied to each band according to analysis results in order to compensate for the changes in perceived pitch associated with the frequency content of each band during changes in relative sound level.","Several algorithms for applying pitch-shift or frequency-shift may be known to those skilled in the art of audio signal processing.","Any one or multiple of these algorithms may be applied to the input signals or portions of the input signals (isolated frequency bands, for example) to achieve the desired changes in perceived pitch, as determined by signal analysis.","If multiple algorithms were implemented and made available to the operator, the operator may determine which algorithm may be best suited to a particular bit of audio signal.","Alternatively, analysis of that audio signal may be used to determine automatically which algorithm may be best suited to each portion of audio signal.","Multiplexed Convolution A multiplexed convolution signal processing architecture applies multiple distinct types of processing to an input signal simultaneously in an adaptive, signal-aware way through the calculation of one or more time-varying convolutions.","The convolution kernels may be associated with points in a multidimensional behavior space, where coordinates correspond to parameters of the distinct processes being implemented.","The values of these parameters change over time in response to input signal properties, adaptively changing the convolution kernels and thus the results of processing.","In the present case, such processing may be achieved through the calculation of generalized convolution operations between an input signal and a time-varying convolution kernel, where the content of the kernel varies in response to properties of the input signal.","The mathematical operation of convolution between two functions, (f*g)(t)≡∫−∞∞f(τ)g(t−τ)dτ, (8) may be fundamental to linear systems analysis and may be well known in a variety of fields, including the field of signal processing.","The output of any linear time-invariant (LTI) system may be defined for arbitrary input signals as the result of convolution between those input signals and a function known as the system's impulse response.","This input-output relationship provides an extremely concise and powerful way of mathematically characterizing a broad class of systems that may be commonly encountered in the physical world and that may be frequently used in an endless variety of applications.","In more common notation, this relationship can be expressed as (y)(t)≡∫−∞∞h(τ)x(t−τ)dτ, (9) for an input signal x(t), time-invariant system impulse response h(t), and corresponding output signal y(t).","The convolution defined in equation (8) and equation (9) may be a linear operation and thus cannot be used directly to implement nonlinear processing.","However, it may be possible to formulate the input-output relationship of a system whose behavior varies over time in response to characteristics of the input signal as a form of generalized convolution that may achieve nonlinear system behavior.","The main difference between such an alternative formulation of convolution and the standard definition presented in equation (8) may be that the two functions, f and g, do not remain independent of one another.","In terms of the more standard linear system notation presented in equation (9), the system response h(t) becomes dependent upon not just time t, but the input signal x(t) itself.","While this introduced dependence may make the analysis of overall system behavior much more complicated, it also creates the possibility for more complex system behavior such as nonlinear processing.","For example, we may use the definition (y)(t)≡∫−∞∞H{SHIFT−t{X}}(τ)x(t−τ)dτ, (10) where H{⋅} and SHIFTt{⋅} define operators whose domains may be the set X of all functions x with the real numbers as both their domain and range, X={x|x: R→R}, and whose ranges may be the same set of functions, written as H: X→X and SHIFTt: X→X.","In this case, the operator H{⋅} defines the relationship between the input signal x(t) and the system response h(t) in a general way, and the operator SHIFTt{⋅}, defined as SHIFTt{X(α)}≡X(α−t), (11) serves the purpose of making the input-output relationship of the overall system time-invariant, meaning that the relationship between the input signal x(t) and the system response h(t) defined by H{⋅} takes into account only relative differences in time between input and output and has no sense of overall time.","The generalized convolution operation defined in equation (10) characterizes the dynamic system through a particular kind of time-varying system function known as an input delay-spread function, albeit one that has the unusual property of being dependent upon the input signal itself.","A similar definition with slightly different behavior may be written as (y)(t)≡∫−∞∞H{SHIFT−(t-τ){X}}(τ)x(t−τ)dτ, (12) where the dynamic system may be instead characterized through a time-varying system function known as an output delay-spread function.","The difference between these types of time-varying system functions may be in whether the particular system function at time t, ht(τ), may be constant for a time t associated with the output signal being calculated or with the input signal being used to calculate the output.","Otherwise, both definitions capture the same dependence of system behavior upon the input signal x(t) and provide essentially the same definition of a generalized convolution operation.","The system definitions given in equations (10) and (12) make it possible to achieve both linear and nonlinear system behavior with the same general system architecture, and thus provide a unifying framework through which multiple different processes may be applied to a signal simultaneously; however, this type of general, dynamic system description has not been used to unify multiple simultaneous processes in this way previously.","Because multiple distinct processes performed on an input signal can interact in complex ways when some of the processes may be nonlinear, and because various system architectures may exhibit different behavior when made to be time-varying, it may be desirable to devise such a unified system so that all individual processes may be controlled simultaneously in a way that takes their interactions into account and allows for the desired overall processing to be consistently achieved when making changes to parameters of one or more of the individual processes.","A method for processing digital signals in order to simultaneously implement multiple linear and/or nonlinear processes in a general way that allows for control of interactions between each stage of processing and adaptive, signal-aware system behavior is disclosed.","The method consists of defining a range of system behaviors, each designed to achieve the best overall processing results associated with a set of parameter values describing the individual implemented processes, and then analyzing input signal properties to determine the desired values for these parameters at each moment in time.","The connection between analysis results and system behavior may be described by a multidimensional system-behavior space in which coordinates correspond to parameters of the distinct processes being implemented: Each designed system behavior may be associated with a point in this space, and analysis of input signal properties determines where in the space the system should currently be operating.","All possible system behaviors may be described in a consistent and general way as one or more generalized convolutions whose outputs may be combined to generate the system output, allowing for smooth transitions and interpolations between specified system behaviors, control of interactions between the various implemented processes by way of total system behavior specification, and consistent time-varying behavior across all implemented processes.","A unified system may simultaneously implement multiple linear and/or nonlinear processes in a manner that may be time-varying responsive to various characteristics of the input signal.","Because processes implemented through different architectures may exhibit inherently different behavior when made to be time-varying and because the interactions between multiple stages of processing may be complex when nonlinear processes may be performed, such a unified system may be intended to allow for more consistent and detailed control of overall system behavior when multiple processes may be to be applied to an input signal simultaneously in a time-varying, signal-aware manner.","A system that processes digital signals in a way that allows for the simultaneous application of multiple linear and/or nonlinear processes in a general, well-controlled, and signal-aware way is disclosed.","The system takes as its input one or more digital signals.","These signals may each be a series of digitally stored values representing the instantaneous amplitude of a band-limited waveform that has been sampled at regularly spaced moments in time.","In many embodiments of the presently disclosed subject matter, these digital signals may represent digital audio signals, corresponding to the sampled amplitude of an audio waveform over time.","The presently disclosed system both analyzes and modifies these input signals, with the results of input signal analysis determining the modifications to be performed at each point in time.","This relationship between analyzed signal properties and resulting modifications may be established by indexing into a multidimensional system-behavior space with coordinates that correspond to parameters of the various individual processes being implemented.","The results of input signal analysis at any given moment determine the desired parameter values for all of the individual processes, and thus a particular point in behavior space.","The pre-determined (designed) system behavior associated with that particular point in behavior space may be then used to calculate the system output.","As input signal properties vary over time, so do the associated point in behavior space, and thus the overall system behavior.","FIG.","14 demonstrates the multiplexed convolution system architecture 1400 according to various embodiments of the present subject matter.","FIG.","14 consists of a signal-analysis and processing-control subsystem 1420 and a signal-modifying processing subsystem 1440, each of which may handle multiple signals of data at once.","FIG.","15 demonstrates the multiplexed convolution signal-analysis and processing-control architecture 1500 according to various embodiments of the present subject matter.","FIG.","15 illustrates the system architecture of the subject matter with the signal-analysis and processing-control subsystem depicted in more detail as consisting of three main steps: signal analysis 1520, mapping from analysis results to a point in behavior space 1530, and processing a kernel look-up 1550 by determining current system behavior based on the location of that point in behavior space.","Mapping to behavior space 1530 may receive metadata 1540 as input.","Subsystem architecture 1500 may include a processing module 1560 that combines one or more input channels 1510 with the output of the kernel look-up 1550 to generate an output waveform 1570.FIG.","16 shows a multiplexed convolution signal analysis processing subsystem 1600 according to various embodiments of the present subject matter.","FIG.","16 shows an embodiment of the signal analysis subsystem for a case where digital audio signals may be processed.","Several types of analysis, including spectral analysis 1630, loudness analysis 1640, transient analysis 1650, and a multichannel relationship analysis 1660 may be performed.","The analysis results may be combined with each other, or may be combined within a data packager 1670 to determine the desired individual process parameter values associated with current input signal properties, and thus the system's current location in behavior space.","FIG.","17 shows an exemplary three-dimensional, discrete behavior space 1700 according to various embodiments of the present subject matter.","FIG.","17 shows an exemplary three-dimensional, discrete behavior space, denoted Θ, where each parameter, θi (i=1 (1710), i=2 (1720), i=3 (1730)) can take on any of 8 integer values ranging from 0 to 7.In this example, it may be the case that three individual processes may be being implemented simultaneously and that each parameter controls the general degree to which each process may be applied to the input signal.","Each process would thus operate at one of 8 levels.","A system behavior may then be specified for each point in this space, taking potential interactions between the individual processes into account and ensuring that the behavior varies smoothly everywhere.","FIG.","18 presents an illustrative diagram of behavior space mapping and system-behavior determination operations 1800 according to various embodiments of the present subject matter according to various embodiments of the present subject matter.","FIG.","18 presents an illustrative diagram of the overall system architecture, similar to FIG.","15, but using a graphical representation of the behavior space mapping and system-behavior determination operations.","FIG.","18 demonstrates the general system architecture of the subject matter with the signal-analysis and processing-control subsystem depicted in more detail as consisting of three main steps: receiving signal analysis 1810, identifying a behavior space 1820, parameterizing the input signal 1830, mapping the analysis results to a point in behavior space 1840, and processing a kernel look-up 1850 by determining current system behavior based on the location of that point in behavior space, and generating an output waveform 1860.FIG.","19 shows an exemplary digital computer embodiment of the system-behavior determination operation based on look-up tables 1900 according to various embodiments of the present subject matter.","FIG.","19 shows an exemplary digital computer embodiment of the system-behavior determination operation based on look-up tables.","In this embodiment of the present subject matter, the point in behavior space corresponding to the current determined individual process parameter values takes on integer values 1910.The integer values 1910 may each correspond with one or more indices within a multidimensional array of memory addresses 1920 stored in a computer.","At each moment in time, the current parameter value vector 1910 may be used to index into this array 1920, and the memory address at the specified index may be followed to a block of memory 1930 that specifies the system behavior for that particular set of parameter values.","The first entry in this block of memory 1930 may be a code that specifies a combination topology for the outputs of the LTI process 1940 or for the outputs of the generalized convolutions 1950.The remaining entries may contain one memory address per individual process.","For example, the embodiment in FIG.","19 contains P such processes.","The first value pointed to by each of these individual process addresses may be a Boolean flag indicating whether the process may be linear time-invariant (LTI).","If Boolean flag indicates that the process is LTI, the entries following the flag specify the impulse response for that LTI system.","If the process may be nonlinear, the flag may be set to false, and the subsequent single entry may be a function pointer used to evaluate the generalized convolution kernel for that nonlinear process.","This effectively implements the overall system again recursively, as may be discussed in detail later.","This look-up process repeats until all individual processes terminate at a set of LTI system impulse responses, which may be then combined and evaluated according to the indicated output topologies in order to form the system output.","While FIG.","19 shows a simple example, more complex embodiments may require the storing and interpreting of additional metadata for each process and response.","In order to enable the simultaneous implementation of several types of processing in this continuously time-varying and general way, all possible system behaviors may be discussed using a consistent, general architecture: at all times, the system performs one or more generalized convolutions with input signals and combines the results of these convolutions according to a topology consisting of series and parallel connections to form the output signal.","Thus, each point in behavior space dictates a set of generalized convolution kernels and a topology for combining the convolution outputs.","These convolution kernels and combination topologies may be designed to best achieve the overall processing results specified by the associated set of individual process parameters, taking possible interactions between processes into account, and may be designed to vary in such a way across nearby points in behavior space that overall system behavior may be guaranteed to vary smoothly while changing in response to properties of the input signal.","By describing the overall system behavior in this way, the system may be able to manage interactions between multiple individual processes.","It may be often easiest to describe a desired overall processing system as a signal-flow graph consisting of several discrete, well-understood parts that each serve a particular function.","However, complicated interactions between the effects of these individual processes in the presence of nonlinearity generally dictate that when the parameters of one process may be changed, the parameters of other processes must also be changed in order to compensate and keep their contribution to the overall system equivalent.","These compensating changes may be difficult to derive for many multi-process systems when using common parameterizations and implementation architectures for each discrete process, which may vary significantly depending on the type of process being implemented.","Further complication arises when imposing time-varying behavior on a multi-process system in which the various processes may be implemented using different architectures, as each individual architecture may have unique restrictions on its ability to change over time and may produce varying artifacts or undesirable consequences when changing configuration or parameter values.","In order to allow better time-varying control of multiple simultaneous processes, an alternative approach may be used to control overall system behavior through the adjustment of individual process parameters.","In particular, the desired overall system behavior for each combination of individual process parameters may be specified through the use of one or more generalized convolutions that may or may not reflect various discrete processing components, and that can be designed without the restrictions of discrete component parameterizations in order to better maintain overall desired system characteristics.","The system response kernels for these convolutions can then be made to vary smoothly in response to changes in individual process parameters, allowing the system behavior to change smoothly over time and in a way that preserves the desired overall processing across all possible behavior trajectories without the need for directly analyzing the complex interactions between individual processes.","Furthermore, by implementing all processing as generalized convolutions, overall system implementation may be simplified: various processes may be achieved using varying generalized convolution kernels rather than varying architectures and techniques, and consistent time-varying behavior can be achieved across all processes in the system.","Additional analysis and modifications are discussed below in more detail.","Multiplexed Convolution: Adaptive, Signal-Aware Control of System Behavior The first step in determining the system response at any particular moment in time may be to determine where, in behavior space, the system should be operating based on the current input signal content.","If we denote the location of the system in behavior space at time sample n as θ[n], we can express this procedure as evaluating part of the operator H{⋅} presented in equation (10) as θ[n]=Hθ{SHIFT−n{X}}, (13) where H{⋅}=Hh{Hθ{SHIFT−n{X}}} (14) gives a decomposition of the relationship between input signals x and system response h, denoted as H{⋅}, into two separate steps: one operation which analyzes signal properties and maps to a point in system behavior space, Hθ{⋅}, and another operation which maps from that point in system behavior space to a description of system behavior in terms of generalized convolution kernels and system topology, Hh{⋅}.","Here, our behavior space, which we may refer to as Θ, may be a p-dimensional space, where p may be the number of parameters characterizing the operation of the system, and we have that θ[n]ϵΘ for all n. In general, Θ need not be a continuous space; in some cases we may only allow θ[n] to take on values from a specific, discrete collection of settings or values.","Note that FIG.","18 shows signal analysis and Hθ{⋅} as separate blocks.","This may be caused by embodiments of the presently disclosed subject matter in which the types of signal analyses performed and the way that their results map into behavior space may be separable, such as depicted in FIG.","18.However, it may be more useful to describe Hθ{⋅} as representing all processing from input signals to θ[n].","In general, any available data may be analyzed and used to determine the value of θ[n] at each point in time, including additional metadata supplied to the presently disclosed system separately from the input signals themselves.","Furthermore, the relationship between analysis results and θ[n], represented by Hθ{⋅}, may itself be controlled or adjusted by higher-level parameters resulting from signal analysis or external controls.","Depending on the particular implementation, this may be thought of as selecting one Hθ{⋅} from a collection of options or as warping the function mapping between signal analysis results and points in behavior space by some additional operation W: Θ→Θ, as W{Hθ{⋅}}.","An example of a high-level parameter that might be used in this manner would be a specification of the general type of digital signal being processed, either determined through automatic classification or through manual specification by an operator prior to processing.","This capability of altering Hθ{⋅} itself may be most applicable to embodiments of the presently disclosed subject matter that may be used for processing numerous types of signals, where the types of signals are fundamentally different in structure.","In other embodiments, this capability of altering Hθ{⋅} itself may be excluded when not needed.","In embodiments of the presently disclosed subject matter where the disclosed system is applied to audio signals, input signal properties such as spectral content, energy or perceptual loudness, the presence of transient changes in intensity or energy.","Additionally, signal property relationships between multiple input signals designed to be reproduced together acoustically using a multichannel speaker array may play a large role in determining θ[n] at any moment in time.","An exemplary signal-analysis subsystem that considers these properties may be depicted in FIG.","18.In these embodiments, higher-level parameters such as the type of audio content contained in the signal (a specific instrument, speech, a musical recording adhering to a particular genre, etc.)","may be determined automatically from analysis of the audio signals or specified manually by an operator through some type of user interface in order to determine the appropriate behavior space mapping Hθ{⋅} for the current class of signal.","In one embodiment of the present subject matter, the entire durations of previously recorded digital signals may be analyzed and considered when determining the varying modifications to be made across the duration of the signals.","In another embodiment of the presently disclosed subject matter, modifications may be made to digital signals in real-time that may be, as they may be being created, recorded, or presented as a stream of data.","In this embodiment, analysis of the digital signals' previous and current content may be used in determining the modifications to be made to the signals at the present moment, or an overall delay may be imposed on the throughput of the system such that some amount of future data may be considered when determining the modifications to be performed.","Furthermore, analyses of multiple signals that may be somehow related may inform the processing of those signals in any relevant way.","For example, the same modifications may be applied to multiple digital signals as determined by analyses performed on each signal in the collection, multiple signals may be analyzed and modified independently, or an analysis of an entire collection of signals may inform the varying modifications to be made to each signal in the collection.","Each of these exemplary configurations as well as other analysis and control configurations may be relevant and useful in various contexts.","These analysis configurations are presented as illustrations of the wide range of possible configurations, and additional analysis configurations may be used.","Practically, the connection between analyzed signal properties and associated points in behavior space, Hθ{⋅}, may be established in any suitable form that may be accessible by the system.","In one embodiment of the presently disclosed subject matter, this relationship may be stored as a collection of pre-determined digital look-up tables that relate results of signal analysis to points in behavior space.","Such look-up tables may be indexed by raw, numerical analysis results, by higher-level analysis results based on a synthesis of several signal properties including logical, rule-based processing of basic analysis results, or by some other result of signal analysis.","They may map to a discrete-valued behavior space, Θ, or have tabulated values that may be interpolated in order to map into a continuous Θ.","In another embodiment of the subject matter, this relationship may be established by a set of parameterized equations that relate numerical results of signal analysis to coordinates in a continuous Θ.","It should be noted that the parameterizations of individual processes reflected in the coordinates of the behavior space Θ may correspond to a wide range of characteristics varying from low-level mathematical parameter values to high-level parameters describing the overall effects of processing or the degree of processing applied.","The connection between points in behavior space and implemented system behavior, Hh{⋅}, may be chosen during design of a specific embodiment and may be entirely general; the relationship may be any that can be captured by the specification of system behavior associated with each point in behavior space, as may be discussed in more detail in the following subsection.","Multiplexed Convolution: Description and Implementation of System Behavior Various system behaviors may be achieved through the calculation of one or more generalized convolutions, and by combining the convolution outputs according to a specified system output topology.","For applying these behaviors to recorded digital signals, modifications of equations (10) and (12) may be used to calculate the discrete-time generalized convolution outputs as y [ n ] = ∑ m = - ∞ ∞ H { SHIFT - n { x } } [ m ] × [ n - m ] ( 15 ) in the input delay-spread function case and y [ n ] = ∑ m = - ∞ ∞ H { SHIFT - ( n - m ) { x } } [ m ] × [ n - m ] ( 16 ) in the output delay-spread function case, either of which may be used.","Each point in system-behavior space may be associated with a set of generalized convolution kernels and an associated output combination topology designed to achieve the specified underlying individual process parameters.","With H{⋅} subdivided as in equation (14), this may be represented by the operator Hh{⋅}, which provides a mapping from points in behavior space Θ to the overall system response.","Ultimately, this response may be characterized by a collection of traditional convolution kernels, one for each of P individual processes, hi[n], i=1, .",".",".",", P, and a specified topology for evaluating and combining the outputs of these standard convolutions.","Convolution with each kernel may be then evaluated using the standard discrete-time convolution operation, y i [ n ] = ∑ m = - ∞ ∞ h i [ m ] × [ n - m ] , ( 17 ) where hi[m] may be zero for all m<0 (as in causal systems), or at least for all m<M for some negative integer M (as in systems with some finite amount of look-ahead).","In various embodiments, system behavior may not be specified directly for all points in Θ, particularly if Θ may not be a finite set.","The set of points in Θ for which system behavior may be specified may be denoted Θh.","If H74 {⋅} may be allowed to output parameter vectors θ that may not be in the set Θh, system behavior for those points may be determined by interpolating the generalized convolution kernels associated with nearby points in Θh.","In some embodiments of the subject matter, system behavior may be defined for all points in continuous dimensions of Θ using parametric definitions of the generalized convolution kernels or through the re-calculation of these kernels as the result of some parametric system equation whenever changes may be made to that parameter value.","Various embodiments matter may specify other generalized convolution kernels and combination topologies associated with each point in Θh.","For linear time-invariant processes, a single convolution kernel hi[n] corresponding to the impulse response of the LTI process may be specified for each point in Θθ, as this characterizes the process entirely.","For nonlinear processes, a generalized convolution kernel H{⋅} may be specified for each point in Θθ.","Note that this definition may be somewhat recursive, as the overall system may be characterized by a single generalized convolution operation as well; however, the generalized convolution kernels associated with individual processes may be t much simpler than the generalized kernel describing the overall system, as they may be meant to implement one particular function and not a collection of simultaneous functions.","These individual process kernels may involve a mapping into a low-dimensional process-behavior space (one or two dimensions may be common) and performing only low-level analysis of signal properties such as amplitude and average energy.","Furthermore, individual process kernels may associate only traditional convolution kernels, hiθ[n], with each point in their process behavior spaces, meaning that various embodiments of the present subject matter may contain only two levels of generalized convolution kernel hierarchy.","In general, any number of levels of hierarchy may exist; we place no restrictions on the possible complexity of particular embodiments here.","Traditional convolution kernels (as used to characterize LTI systems) may be represented as a series of digitally stored numbers, representing the impulse response of a process, hi[n], over time n. Generalized convolution kernels may be stored in a manner analogous to that discussed here for the overall system: for the i-th process, a relationship between input signal analysis results and process parameter values may be specified through a relationship Hiθ{⋅} stored as discussed in the previous subsection, and a relationship Hih{⋅} may be again specified that maps from these parameter values to actual system responses.","As stated previously, individual process behavior-space mappings Hih{⋅} may only map to a set of traditional convolution kernels, hiθ[n], rather than mapping again to a set of generalized convolution kernels.","These traditional convolution kernels may be then each represented as a series of digitally stored numbers.","In all cases, the hierarchy of processes may eventually terminate at sets of traditional convolution kernels together with a topology for evaluating the sets of traditional convolution kernels.","This information may then be used to reduce the process to a single traditional convolution kernel representing the overall response of that process at time n, starting at the last level of hierarchy and working back up to the first generalized convolution kernel addressed by the overall system.","In this way, evaluation of each individual process by the overall system, whether linear or nonlinear, may yield a single traditional convolution kernel describing that system's behavior at the current time moment, hi[n].","These may be then evaluated at the top level to yield the system's overall output for that time.","A system output topology must be specified in order to evaluate the overall response or output of a generalized convolution with more than one sub-process.","This specification may be made in any way that may be accessible to and usable by the system.","In one embodiment of the presently disclosed subject matter, predefined codes are used to indicate the particular topologies to be used.","A code key containing one value for each possible process topology may be constructed, and a single code value may be associated with each point in behavior space in order to specify the particular topology that may be to be used.","This embodiment may be illustrated in FIG.","18.However, other embodiments may be used where a single topology may be suitable for all possible system behaviors.","Using our developed notation, it should be noted that this method does not pertain to a specific choice of behavior space Θ, or particular choices of the relationships H74 {⋅} or Hh{⋅}, but rather to the overall system architecture and the way in which system behavior may be specified and implemented.","This unified architecture may enable well-controlled, continuously time-varying, and input-signal-dependent system behavior.","Automated Polarity Correction of Digital Audio A polarity correction signal processing technique modifies digital audio recordings to correct the polarity of component waveforms.","These corrections compensate for a lack of standards in recording technique and equipment and improve the experience of listening to digital audio by restoring natural absolute polarity to recorded sounds.","Acoustic waves in air may be comprised of compressions and rarefactions to pressures above and below ambient levels.","During the process of electrically recording and later reproducing these temporary changes in air pressure using microphones, recording media, and loudspeakers, headphones, or other playback devices, it may be easy for the polarity of these pressure changes to become reversed such that the reproduced acoustic waveform has rarefactions at times that the original waveform had compressions and vice-versa.","Whether or not humans can perceive such reversals in the absolute polarity of sound waves has been a topic of research and, at times, controversy; however, both scientific and anecdotal evidence exists that supports the reality and importance of correct absolute polarity in the perception of sound.","At a low level, it has been observed that the peripheral auditory system of cats exhibits “microphonic” electrical responses that differ in polarity when presented with pulses of compression and rarefaction, demonstrating that the absolute polarity of sound does affect the fundamental input signal to the auditory system.","Studies of spatial sound perception in humans have further supported the theory that different neural signals may be transmitted from the peripheral auditory system in response to compression and rarefaction stimuli, in some cases going so far as to indicate that the human auditory system may only respond to one of the two conditions (rarefaction), meaning that the auditory system receives only a half-wave rectified version of full acoustic signals.","At a higher level, evidence of perceptual sensitivity to absolute polarity has been demonstrated in several experiments involving human listeners.","For example, when presented with periodic waveforms that differ in shape during the positive (compression) and negative (rarefaction) portions of each period, listeners have been able to identify reversals in absolute polarity with nearly 100 percent accuracy for some waveforms and listening volumes.","Furthermore, the previously mentioned experiments in spatial hearing have demonstrated that the absolute polarity of transient signals can affect their perceived timing.","Together, these results demonstrate that absolute polarity may be important to the perception of both sustained and transient sounds.","Significant anecdotal evidence in support of sensitivity to absolute polarity exists in the audio community as well, with many advocates stating that correct absolute polarity has substantial positive effects on perceived sound quality and suggesting explanations for why others may feel that they cannot perceive a difference in quality associated with the polarity of recordings.","Often, these explanations include the fact that many modern recordings do not allow for the clear observation of correct absolute polarity during playback because the recordings may be comprised of many channels of audio that have been mixed together with little concern for the preservation of absolute polarity, resulting in recordings that contain a mixture of sounds with both natural and unnatural polarities.","In this case, reversing the polarity of a recording as a whole during playback (by reversing the leads on a speaker, for example) cannot simultaneously correct the polarities of all of the component sounds, resulting in little discernible preference for either overall polarity and masking the perceptual benefits of correct absolute polarity.","Perhaps surprisingly to the layperson, the audio industry has only begun to adopt standards and practices to regularize and preserve the absolute polarity of recorded music in any widespread manner during the last twenty years.","Even through the 1980's, a universal agreement was lacking between recording studios in Europe and the USA (and between studios within the USA itself) on how the leads of the ubiquitous three-wire balanced line, or XLR cable, should be related to absolute polarity.","Because this type of cable can be wired in two configurations that each carry sound but that produce output with opposite polarities, this lack of standardization inevitably resulted in numerous polarity inconsistencies, particularly in recordings where individual tracks were recorded in multiple studios and later combined.","Furthermore, makers of electronic hardware devices that process, amplify, or mix electrical audio signals have never standardized design or reporting of the absolute polarity of their devices; in many cases it may be left to careful engineers to perform tests on equipment themselves in order to determine if the device outputs signal with the same or opposite polarity as its input.","While in many cases modern digital audio workstations can aid in the identification of absolute polarity errors during recording and mixing, the music industry's history of general disregard for absolute polarity has continued to dominate recording and equipment-design practices, and even today the preservation of absolute polarity may be generally only considered at the very highest levels of professional audio work.","Considering that the vast majority of the publics' consumed popular music, including the several trillions of digital multimedia files available online, may be increasingly being produced by small independent studios or personal residential studios where even the most basic polarity-aware practices may be lacking, it may be no surprise that most modern audio recordings continue to exhibit a mix of absolute polarities which cannot be corrected simply by inverting output as a whole during playback.","Because of this, it may be desirable to develop digital signal processing techniques by which the absolute polarities of the individual sounds making up a recorded audio mixture may be corrected independently so that natural absolute polarity can be restored to all elements of a completed recording simultaneously.","A method for processing digital audio signals in order to correct the polarities of the individual component sounds that make up a recorded audio mixture, or song, may be disclosed.","The method consists of analyzing a digital audio recording and inverting component waveforms that may be determined to exhibit unnatural absolute polarity.","Both transient events and sustained content (e.g., steady-state content) may be considered and processed.","This method may compensate for modern recording techniques and equipment that fail to preserve the natural absolute polarity of recorded sounds and thus produce final mixed recordings where component sounds exhibit a combination of natural and inverted polarities.","By establishing natural absolute polarity for all individual sounds without otherwise altering the content of these audio recordings, this method improves their perceived quality without changing their creative content.","FIGS.","20A-20D illustrate an audio mixture decomposition 2000 according to various embodiments of the present subject matter.","FIG.","20A illustrates an audio mixture including recorded sounds with transients and sustained components.","The audio mixture in FIG.","20A may include a sustained component 20B (e.g., steady-state component) and a transient component 20C-20D.","Transient events may include a first transient component 20C or a second transient component 20D.","This mixture may be decomposed into its components for further analysis and polarity correction.","FIGS.","21A-21C show the beginnings of the transient audio events 2100 according to various embodiments of the present subject matter.","FIGS.","21A-21C show the beginnings of the transient audio events shown in FIG.","1, demonstrating that the polarities of these two percussive waveforms may not be consistent; in fact, transient component 1 shown in FIG.","21A, corresponds to the waveform generated by an acoustic kick drum that has been recorded with inverted and unnatural polarity, while transient component 2 shown in FIG.","21B corresponds to a waveform generated by an acoustic snare drum and recorded with absolute polarity preserved.","FIG.","21C shows the effect of inverting the polarity of a component waveform: the sign of the waveform values may be simply inverted, interchanging compression and rarefaction in the eventually reproduced acoustic wave.","The system takes as its input one or more signals that each represent the amplitude of an audio waveform over time.","These signals may each be a series of digitally stored values representing the instantaneous amplitude of a band-limited waveform that has been sampled at regularly spaced moments in time.","In one embodiment, the system initially analyzes the input signal(s) to identify transient events: regions of time where one or more properties of the signal change rapidly.","In audio signals, these events may coincide with percussive sounds, both tuned (mallet instruments, piano, plucked strings, etc.)","and untuned (drums, traditional percussion), but these events may include any kind of signal whose energy level or other properties change significantly over a period of time relevant to the momentary perception of sound (for example, such time periods may be on the order of ones to tens of milliseconds).","Those proficient in the art of audio transient analysis may know of numerous approaches to the detection of various types of transients in audio material.","Any combination of these techniques may be used to identify transient events contained in a digital audio recording.","Once a transient event has been identified, a model of the surrounding audio may be formed, and the transient content may be separated from its background signal content.","In doing so, various modeling techniques may be used.","The particular type of model and modeling parameters used to separate each transient event from its background may depend on an initial analysis of the region of audio under inspection, and may be chosen by automatic means with the goal of optimally preserving all perceivable properties of the recorded sound.","After separation, the polarity of the transient content may be examined to determine if the initial rise of the signal and overall polarity correspond to naturally occurring absolute polarity.","If the component waveform may be already found to have natural absolute polarity, the background model and separated transient waveform may be discarded and that time-region of the original audio recording may be left unaltered.","If the transient component waveform may be found to have unnatural polarity, it may be inverted to restore natural absolute polarity and then recombined with the rest of the audio mixture using the previously established background model.","This corrected and recombined time-region of the mixture may then undergo additional automatic processing to match the regions of the original recording optimally that come before and after it in time.","In addition to this treatment of transient events, the polarity of sustained components (e.g., steady-state components) of an audio mixture may be analyzed.","In this case, a further analysis of the audio recording may be performed after the polarity of transient waveforms have been analyzed in order to determine if the surrounding sustained or steady-state content has natural absolute polarity.","If it may be determined that both the background content and the transient content it surrounds have unnatural polarity in need of correction, the entire waveform of the original recording may be inverted over the duration of the examined time-period in order to restore natural absolute polarity to the entire mixture instead of inverting only the transient component and then recombining it with a model of the mixture.","In general, when considering both transient and sustained sound polarity, the entire digital audio recording may be analyzed to determine where background models should be used and where original waveforms may be inverted in full to restore consistently natural absolute polarity.","Various embodiments may optimize these determinations to avoid the use of background-model-based separation and recombination wherever possible in favor of direct, complete polarity reversals of the original digital audio recording.","It should be noted that in general any processing may be adaptive and may adjust to the content of the particular digital audio recording being processed such that optimal results may be achieved.","In particular, various analysis and modeling techniques may be chosen for use based on automatic analysis of the digital audio recording's content, or may optionally be specified by an operator using either high-level controls that emphasize particular goals or low-level controls that directly indicate and parameterize the algorithms used.","In one embodiment of the present subject matter, an emphasis may be placed on correcting low-frequency transients that often correspond to kick drums and similar low-frequency percussion.","Because these components of an audio recording often contain considerable energy and exhibit waveforms that may be highly asymmetrical in their initial attack period, they may be especially good candidates for perceptual sound improvement by absolute polarity correction.","In this embodiment, transient detection schemes that favor or exclusively target low-frequency transients may be employed, and background signal modeling for isolation of the transient may leverage the fact that only low-frequency content need be isolated.","In other embodiments such an emphasis may be placed on low-frequency transients.","In another embodiment, a digital audio recording may be analyzed in its entirety for a DC bias and inverted if necessary to establish a positive DC bias, thereby establishing a predominantly positive (compressive) polarity for the recording.","This embodiment may be perhaps the simplest illustration of an absolute polarity correction that does not explicitly analyze the initial rise of transients or other component waveforms, and that may be suitable for use in correcting the absolute polarity of sustained waveforms with initial rises and polarities that may be more difficult to identify.","Various techniques may be used to establish correct absolute polarity for sustained or other component sounds.","Use of the Identification Word to Obtain Device, Service, and Settings Information A method enables identification of the audio transducer and application of the identifier to enable enhancement algorithms may be used to enhance the listening experience.","The identification may contain a unique multi-bit identification word, created during manufacture of the device, which may be interrogated by a silent pulse through the audio connection.","The identification word may be used to lookup information in one or more databases.","The databases may reside on the player device, as well as on remotely connected systems, such as cloud-based content delivery systems.","Users of these systems may purchase and register to enable premium audio enhancements, using the identification word to identify the user and the device uniquely.","FIG.","22 demonstrates a Digital Human Interface Identifier (DHI-ID) Serial Protocol 2200 according to various embodiments of the present subject matter.","Various methods may be employed to interrogate the identifier from the audio transducer.","In one method, the identification process may originate with a 16-bit ultra-sonic inquiry command sent from an audio port to the audio transducer.","The transducer may respond with a unique identifier of between 24 and 48 bits, called the Digital Human Interface Identifier (DHI-ID).","In one implementation, a DHI-ID enabled smart phone may poll the ear buds via the same wires that carry the audio signal to the ear buds.","The DC support power for the DHI-ID identification circuit in the ear buds may be derived from the polling command from the smart phone.","As illustrated in FIG.","22, the poll signal may be a series of interrogation pulses, using a 20 msec ramp up 2210, 1 msec sustain 2220, and 20 msec ramp down 2230, so as to be inaudible to the user.","The pulse train may use a voltage level of 1.6 volts to represent a binary 1 value 130 and may use 0 volts to represent a binary 0 value 140, though other voltage levels may be used.","The pulse train may provide the DC power to a passive IC in the ear buds.","FIG.","23 demonstrates a Digital Human Interface Identifier (DHI-ID) Serial system 2300 according to various embodiments of the present subject matter.","In one example, the identification process may originate with a 16-bit ultra-sonic inquiry command sent from an audio port of a playback device 2320 to an audio transducer 2330.The transducer 2330 may respond with a unique identifier of between 24 and 48 bits, called the Digital Human Interface Identifier (DHI-ID).","Once fully powered, upon plugging the DHI-ID ear buds into the smart phone, the bits of the identification word may be sent back to the smart phone during the 1 msec sustain period.","An identification word of 24 to 48 bits may be transmitted, allowing for identification of over 280 trillion devices.","In another implementation, the sustain time 120 may be extended by an additional 750 microseconds, to allow the enabling device to transmit data to the transducer, to write information to non-volatile memory in the DHI-ID transducer device.","On subsequent interrogations, the data in non-volatile memory becomes part of the DHI-ID identification word, and can provide user-customized settings for the device.","A button may also be provided with the audio transducer to initiate the identification process, and enable or disable the use of the DHI-ID.","The identification word (DHI-ID) may be used to obtain the device specifications, service information, and settings, collectively called the DHI-SSS.","The DHI-ID may be a key used for lookup in databases local to the player, and in remote server databases.","The device specifications include the manufacturer, date, model, color, impedance, frequency response, output sensitivity, dimensions, acoustic dimension, and other characteristics of the device.","The specifications may be provided by the manufacturer for each device model that supports DHI-ID features.","The device specifications can be used to control parameters of the sonic processing algorithms, such as frequency response to control equalization.","Service information includes whether the device may be permitted to enable proprietary sonic processing for enhanced acoustic reception at the host device or at a streaming head end content source, such as head end 1 2310, head end 2 2340, or head end 3 2350.These non-manufacturer, non-user settings may be derived from a stored enabling device rewritable look-up table, or, other updatable online file sources, in the player 2320, the transducer 2330, or the cloud storage/processing (e.g., head end 2 2340).","User-controllable settings may include EQ parameters, sensitivity, and other listener/user settings.","Several novel aspect of this system that can be appreciated including (a) allowing the consumer to purchase an Acoustic Processing DHI-SSS enabled set of headphones, or (b) allowing the use of these headphones to enable free premium audio processing or a premium right to listen, which may be built into and sold with the hardware itself.","Because service information may resides in updatable files which can reside either in the rewritable chip in the ear bud or headphone, in the player devices look up tables, or at the head end, a consumer can buy a subscription to an upgraded sound along with their listening hardware, and, can carry that permission within their audio playing device or earphones or ear buds.","As well, the rights could be also be made dynamic, and, if necessary, terminated after a subscription expiration date, in the same three locations, cloud, player or ear bud/DHI enabled hardware.","The system uses the DHI-SSS information to control, acoustically alter and/or process the content that may be being delivered to the audio transducer from various sources, including stored local content and streaming content from a head-end.","The DHI-SSS may be used to control the processing of modified audio and video at the content's storage and consumer streaming source location, for both streamed and broadcast sources, as directed by the DHI-SSS derived from the DHI-ID from the listening device, or by other means.","Processing of the content can be performed on the server and stored for later streaming, or processed in real-time by the server, or processed in real-time by the player if processing bandwidth may be sufficient.","The process controller may select/enable DHI-ID content processing in both streaming and broadcast usage.","The DHI-ID controls the processing originating from streaming web (or any other digital transmission system) head-end server(s), or from broadcasting radio transmitter(s), for the purposes of achieving an enhanced Digital-Human Interface (DHI) customer content experience, or any other processing necessary.","This processing may be used a business-to-consumer function, and may also be used as a business-to-business function.","The user may have content processing available both on-command from the Server/Broadcast end or by selecting one or more control inputs.","Control inputs may include selection of a song (e.g., track), a video, or a duration.","For example, the duration may be selected as always active, active hourly, active for any unit of time, or active according to a pre-determined time pattern.","Example instances may include only active on weekends, only active on afternoons, active for 30 days total, active for the first 10 songs, active for every purchased movie over $12 in cost to the consumer, or another duration.","The duration may be selected by the service providing the content or by the consumer.","The processing software may be installed automatically at any processing location using an automated, process-controller controlled batch process.","Automatic installation may occur instantly or over a pre-determined time.","Installation may be configured to allow the process to be deployed quickly and effectively.","The processing control innovation includes a dual-input, online visual control interface allowing the streaming operators to select which stream(s) may be processed, as well as processing them according to the multiple processing job combinations.","The control interface can have as its input selections for processing made by the consumers' elective (paid for, in general) upstream choices.","An example of this upstream dashboard input would be the use of a consumer smart phone app that would allow the consumer to pay for DHI-ID processing of songs to be streamed to them.","The streaming/broadcast control innovation allows for the operator choice of processing the content a) in a batch format, thereby having the processed content reside on the source storage element permanently, giving two existing versions of the content for the control process controller to select from, or b) in real-time, where each individual content unit (stream or broadcast) may be processed anew for each processor controller request.","Usage configuration (b) may halve the content file storage requirements, and usage configuration (a) may correspond to the instantaneous, no real-time CPU processing necessary.","FIG.","23 demonstrates the use of the DHI-ID and DHI-SSS in an exemplary system.","The Audio Transducer may be polled by a playback device 2320, such as a smart phone or tablet.","The Audio Transducer responds with its identifier, the DHI-ID.","Content may reside in several locations in the system, including the playback device, head-end distribution channels, and cloud storage.","In one use scenario, the DHI-ID may be used to retrieve the DHI-SSS from an internet database.","The service information of the DHI-SSS may be then used to enable processing algorithms of content stored locally on the playback device.","In another use scenario, the DHI-ID may be sent to a head-end processor.","The identifier may be used to enable the real-time processing of content that may be streamed from the head-end to the playback device.","In a third scenario, content has been placed in cloud storage.","The content may be pre-processed by the cloud, or processed in real-time as files may be transferred from the cloud to the playback device.","In all cases, the types of processing may be enabled by the service information and controlled by parameters included in the DHI-SSS.","The following sections describe specific audio enhancement algorithms that can be enabled to provide an improved listening experience.","FIG.","24 demonstrates a recorded sound processing system 2400 according to various embodiments of the present subject matter.","System 2400 may be configured to perform one or more of signal processing methods 2410, 2420, 2430, 2440, 2450, 2460, and 2470.Any of the methods in system 2400 may be used individually or in any combination with any other method in system 2400.All signal processing methods 2410, 2420, 2430, 2440, 2450, 2460, and 2470 may be used simultaneously.","In various embodiments, system 2400 may be configured to perform any one or any combination of methods 2410, 2420, 2430, 2440, 2450, 2460, and 2470.In various embodiments, system 2400 may be configured to perform any combination of methods 2410, 2420, 2430, 2440, 2450, 2460, and 2470 simultaneously, concurrently, and/or at different times.","In various embodiments, any systems and methods including their various examples as discussed in this document and their various combinations may be implemented in a system such as system 2400.The methods in system 2400 may include the methods discussed above.","System 2400 includes a method to simulate nonlinear properties of sound 2410, which may use a sound processor to model in-air mixing and live performance to implement the Digital Audio Processing to Simulate the Nonlinear Properties of Sound Propagation and Mixing in Air.","Method 2420 includes priming signal to implement Digital Signal Processing of Priming Signal for Reduction of Stress in the Auditory System, in which a preconditioned signal is mixed with delayed actual signal to reduce listening stress.","Method 2430 includes Restoration of motion and dynamic timbre, which uses a sound processor to phase and flange to recreate motion and liveliness to implement Digital Audio Processing for the Restoration of Motion and Dynamic Timbre.","Method 2440 includes automatic pitch correction, which uses a sound processor to pitch correct based on level to implement Automatic Level-Dependent Pitch Correction of Digital Audio.","Method 2450 implements Multiplexed Convolution, which processes sound with adaptive and time-varying convolutions.","Method 2460 includes polarity correction, which uses a sound processor to restore natural audio polarity due to lack of recording standards to implement Automated Polarity Correction of Digital Audio.","Method 2470 includes automatic transducer identification, which provides processed sounds as a function of sensed transducer to implement Use of the Identification Word to Obtain Device, Service, and Settings Information.","Various examples of the present subject matter are provided as follows: Example 1 includes a method for simulating propagation and mixing of sounds in air, the method comprising selecting a relationship between a virtual audio listener location and a virtual source location within an audio interaction volume, the audio interaction volume associated with a first audio waveform, the first audio waveform including audio generated using a first audio isotropic source; and, generating a second audio waveform using the first audio waveform, the second audio waveform including a plurality of simulated intermodulation products corresponding to the relationship between the virtual audio listener location and the virtual source location.","Example 2 includes the method of example 1, the first audio waveform further including audio generated using a second isotropic audio source.","Example 3 includes the method of any of examples 1-2, further including generating a simulated mixed output waveform, the generating including applying a first gain to the first audio waveform to generate a first amplified waveform, applying a second gain to the second audio waveform to generate a second amplified waveform, and summing the first amplified waveform and the second amplified waveform to generate the simulated mixed output waveform.","Example 4 includes the method of any of examples 1-3, further including transducing the simulated mixed output waveform into audible sounds.","Example 5 includes the method of any of examples 1-4, further including identifying an audio sample within the second audio waveform, identifying a frequency of the audio sample, and generating a frequency-dependent sample by applying frequency-dependent linear filtering to the audio sample, the frequency-dependent linear filtering simulating a frequency-dependent attenuation of the audio sample as the audio sample propagates through air.","Example 6 includes the method of any of examples 1-5, further including receiving the first audio waveform from a remote source.","Example 7 includes the method of any of examples 1-6, further including sending the simulated mixed output waveform to a remote physical audio listener location.","Example 8 includes a system for simulating propagation and mixing of sounds in air, the system comprising a digital signal processing mixing simulation module, the simulation module configured to select a virtual source location within an audio interaction volume, the audio interaction volume associated with a first audio waveform, the first audio waveform including audio generated using a first audio isotropic source; select an observation location corresponding to a virtual audio listener location; and, determine a second audio waveform using the first audio waveform, the second audio waveform including a plurality of simulated intermodulation products corresponding to the observation location; and, a summing amplifier module configured to generate a second audio waveform, the second audio waveform including the first audio waveform and the second audio waveform.","Example 9 includes the system of example 8, the first audio waveform further including audio generated using a second audio isotropic source.","Example 10 includes the system of any of examples 8-9, further including a speaker, the speaker configured to transduce the second audio waveform into audible sounds.","Example 11 includes the system of any of examples 8-10, further including a first amplifier module configured to apply a first gain to the first audio waveform to generate a first amplified waveform, and a second amplifier module configured to apply a second gain to the second audio waveform to generate a second amplified waveform, wherein the summing amplifier module is configured to sum the first amplified waveform and the second amplified waveform to generate the second audio waveform.","Example 12 includes the system of any of examples 8-11, further including a frequency-dependent linear filter module, the frequency-dependent linear filter module configured to identify an audio sample within the second audio waveform, determine a frequency of the audio sample, and generate a frequency-dependent sample by applying frequency-dependent linear filtering to the audio sample, the frequency-dependent linear filtering simulating a frequency-dependent attenuation of the audio sample as the audio sample propagates through air.","Example 13 includes the system of any of examples 8-12, further including a communication module, the communication module configured to receive the first audio waveform from a remote source.","Example 14 includes the system of any of examples 8-13, the communication module further configured to send the second audio waveform to a remote physical audio listener location.","Although the subject matter has been explained in relation to its preferred embodiment, it may be to be understood that many other possible modifications and variations can be made without departing from the spirit and scope of the subject matter as hereinafter claimed."]],"string":"[\n [\n \"SYSTEMS AND METHODS FOR PROCESSING AUDIO SIGNALS BASED ON USER DEVICE PARAMETERS\",\n \"In various applications, the system provides a method for processing audio signals, including: receiving a request for audio content; receiving an identifier encoded in a personal audio device comprising a transducer for playing audio; retrieving at least one parameter associated with the identifier; and processing the audio content using at least the request, the identifier and the at least one parameter, wherein the processing is customized for the personal audio device based on the at least one parameter associated with the identifier.\",\n \"In various applications the parameter is, one or more of, associated with a specification of the personal audio device, acoustic metrics of the transducer, relates to control of equalization, relates to permission to enable proprietary sonic processing for enhanced acoustic reception of streaming content, relates to acoustic metrics of the transducer and wherein the identifier is associated with permission to enable proprietary sonic processing for enhanced acoustic reception of streaming content, and/or is stored in a chip on the personal audio device, is retrieved from a server in a network, among other things.\",\n \"In various applications, the personal audio device comprises ear buds and the identifier is stored in a non-volatile memory of the ear buds.\"\n ],\n [\n \"1.A method for processing audio signals, comprising: receiving a request for audio content; receiving an identifier encoded in a personal audio device comprising a transducer for playing audio; retrieving at least one parameter associated with the identifier; and processing the audio content using at least the request, the identifier and the at least one parameter, wherein the processing is customized for the personal audio device based on the at least one parameter associated with the identifier.\",\n \"2.The method of claim 1, wherein the at least one parameter is associated with a specification of the personal audio device.\",\n \"3.The method of claim 2, wherein the at least one parameter relates to acoustic metrics of the transducer.\",\n \"4.The method of claim 1, wherein the at least one parameter relates to control of equalization.\",\n \"5.The method of claim 1, wherein the at least one parameter relates to permission to enable proprietary sonic processing for enhanced acoustic reception of streaming content.\",\n \"6.The method of claim 1, wherein the at least one parameter relates to acoustic metrics of the transducer and wherein the identifier is associated with permission to enable proprietary sonic processing for enhanced acoustic reception of streaming content.\",\n \"7.The method of claim 1, wherein the at least one parameter is stored in a chip on the personal audio device.\",\n \"8.The method of claim 1, wherein the at least one parameter is retrieved from a server in a network.\",\n \"9.The method of claim 1, wherein the processing is done in a batch format and the processed content is stored for a plurality of parameters.\",\n \"10.The method of claim 1, wherein the processing is done in real-time and the processed content is streamed to the personal audio device.\",\n \"11.The method of claim 1, wherein the identifier includes a key used for lookup.\",\n \"12.The method of claim 1, wherein the processing is done at a server, and the processing algorithm executes using the identifier to retrieve at least one parameter associated with the identifier to control parameters of sonic processing algorithms and to provide processed content to the network that can be received by a user of a device associated with the identifier.\",\n \"13.The method of claim 1, wherein the personal audio device comprises ear buds and the identifier is stored in a non-volatile memory of the ear buds.\",\n \"14.The method of claim 1, wherein the identifier is a unique identifier of up to 48 bits.\",\n \"15.The method of claim 1, wherein the identifier is retrieved using a sonic inquiry command.\",\n \"16.Apparatus, comprising: at least one earbud; a non-volatile memory associated with the at least one earbud, the memory storing at least an identifier; and circuitry for polling the identifier from the memory, wherein the identifier is used for processing audio sent to the at least one earbud.\",\n \"17.The apparatus of claim 16, further comprising a second earbud.\",\n \"18.The apparatus of claim 16, further comprising a control to initiate an identification process.\",\n \"19.The apparatus of claim 16, further comprising a control to disable access to the identifier.\",\n \"20.The apparatus of claim 16, wherein the circuitry is readable by a mobile phone.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>Systems that provide audio playback, such as portable flash players, mobile phones, car players, televisions, and home theater receivers, reproduce the stored audio during playback.\",\n \"The stored audio is the result of layers of several different sound sources that are frequently mixed electronically for recording.\",\n \"These systems frequently feature user selectable manual sound controls for adjusting characteristics of the audio, such as volume, equalization, and dynamic range.\",\n \"These systems may allow the user to set these controls, often under sub-optimal conditions and with no training.\",\n \"Additionally, these systems may employ a number of different audio transducers for generating audible sound.\",\n \"As a result, the listening experience is often compromised, because the reproduction of the audio need not take into account the type and manufacture of the audio transducer.\",\n \"What is needed in the art are systems and methods for providing enhanced audio to provide audio reproduction that is tailored to the audio transducer.\",\n \"Further needed in the art is a system which will perform signal processing of the audio signal automatically for a particular listening device.\",\n \"Further needed in the art is a system that will automatically perform signal processing for the particular listening device and for a particular user's preferences of that particular listening device.\"\n ],\n [\n \"<SOH> BRIEF SUMMARY <EOH>The present subject matter provides various embodiments with systems and methods for enhancing recorded sound.\",\n \"In various approaches, the various embodiments are used individually or in combination with each other.\",\n \"In various approaches, the system is combined or distributed using various processing options.\",\n \"In various embodiments, the system provides a method for processing audio signals, comprising: receiving a request for audio content; receiving an identifier encoded in a personal audio device comprising a transducer for playing audio; retrieving at least one parameter associated with the identifier; and processing the audio content using at least the request, the identifier and the at least one parameter, wherein the processing is customized for the personal audio device based on the at least one parameter associated with the identifier.\",\n \"In various applications the parameter is, one or more of, associated with a specification of the personal audio device, acoustic metrics of the transducer, relates to control of equalization, relates to permission to enable proprietary sonic processing for enhanced acoustic reception of streaming content, relates to acoustic metrics of the transducer and wherein the identifier is associated with permission to enable proprietary sonic processing for enhanced acoustic reception of streaming content, and/or is stored in a chip on the personal audio device, is retrieved from a server in a network, among other things.\",\n \"In various embodiments the processing is done in a batch format and the processed content is stored for a plurality of parameters.\",\n \"In various embodiments, the processing is done in real-time and the processed content is streamed to the personal audio device.\",\n \"In various embodiments, the processing is done at a server, and the processing algorithm executes using the identifier to retrieve at least one parameter associated with the identifier to control parameters of sonic processing algorithms and to provide processed content to the network that can be received by a user of a device associated with the identifier.\",\n \"In various embodiments the identifier includes a key used for lookup.\",\n \"In various embodiments, the personal audio device comprises ear buds and the identifier is stored in a non-volatile memory of the ear buds.\",\n \"In various embodiments the identifier is a unique identifier of up to 48 bits.\",\n \"In various embodiments, the identifier is retrieved using a sonic inquiry command.\",\n \"In various embodiments, the subject matter relates to apparatus including at least one earbud, a non-volatile memory associated with the at least one earbud, the memory storing at least an identifier; and circuitry for polling the identifier from the memory, wherein the identifier is used for processing audio sent to the at least one earbud.\",\n \"In various embodiments, the apparatus further comprises a second earbud.\",\n \"In various embodiments, the apparatus further includes a control to initiate an identification process.\",\n \"In various embodiments, the apparatus further comprises a control to disable access to the identifier.\",\n \"In various embodiments, the circuitry of the apparatus is readable by a mobile phone.\",\n \"Additional variations are described in the following detailed description.\",\n \"This Summary is an overview of some of the teachings of the present application and not intended to be an exclusive or exhaustive treatment of the present subject matter.\",\n \"Further details about the present subject matter are found in the detailed description and appended claims.\",\n \"The scope of the present invention is defined by the appended claims and their legal equivalents.\"\n ],\n [\n \"CLAIM OF PRIORITY This application is a Continuation of U.S. patent application Ser.\",\n \"No.\",\n \"15/417,706, filed Jan. 27, 2017, which application is a Continuation of U.S. patent application Ser.\",\n \"No.\",\n \"14/477,826, filed Sep. 4, 2014 (now U.S. Pat.\",\n \"No.\",\n \"9,560,466), which claims the benefit of priority under 35 U.S.C.\",\n \"§ 119(e) of all of the following patent applications: U.S.\",\n \"Provisional Patent Application No.\",\n \"61/874,099, filed Sep. 5, 2013; U.S.\",\n \"Provisional Patent Application No.\",\n \"61/874,120, filed Sep. 5, 2013; U.S.\",\n \"Provisional Patent Application No.\",\n \"61/874,150, filed Sep. 5, 2013; U.S.\",\n \"Provisional Patent Application No.\",\n \"61/874,125, filed Sep. 5, 2013; U.S.\",\n \"Provisional Patent Application No.\",\n \"61/874,137, filed Sep. 5, 2013; U.S.\",\n \"Provisional Patent Application No.\",\n \"61/874,103, filed Sep. 5, 2013; and U.S.\",\n \"Provisional Patent Application No.\",\n \"61/918,550, filed Dec. 19, 2013, all of which are incorporated herein by reference in their entirety.\",\n \"FIELD The present subject matter relates generally to systems and methods for audio enhancement.\",\n \"BACKGROUND Systems that provide audio playback, such as portable flash players, mobile phones, car players, televisions, and home theater receivers, reproduce the stored audio during playback.\",\n \"The stored audio is the result of layers of several different sound sources that are frequently mixed electronically for recording.\",\n \"These systems frequently feature user selectable manual sound controls for adjusting characteristics of the audio, such as volume, equalization, and dynamic range.\",\n \"These systems may allow the user to set these controls, often under sub-optimal conditions and with no training.\",\n \"Additionally, these systems may employ a number of different audio transducers for generating audible sound.\",\n \"As a result, the listening experience is often compromised, because the reproduction of the audio need not take into account the type and manufacture of the audio transducer.\",\n \"What is needed in the art are systems and methods for providing enhanced audio to provide audio reproduction that is tailored to the audio transducer.\",\n \"Further needed in the art is a system which will perform signal processing of the audio signal automatically for a particular listening device.\",\n \"Further needed in the art is a system that will automatically perform signal processing for the particular listening device and for a particular user's preferences of that particular listening device.\",\n \"BRIEF SUMMARY The present subject matter provides various embodiments with systems and methods for enhancing recorded sound.\",\n \"In various approaches, the various embodiments are used individually or in combination with each other.\",\n \"In various approaches, the system is combined or distributed using various processing options.\",\n \"In various embodiments, the system provides a method for processing audio signals, comprising: receiving a request for audio content; receiving an identifier encoded in a personal audio device comprising a transducer for playing audio; retrieving at least one parameter associated with the identifier; and processing the audio content using at least the request, the identifier and the at least one parameter, wherein the processing is customized for the personal audio device based on the at least one parameter associated with the identifier.\",\n \"In various applications the parameter is, one or more of, associated with a specification of the personal audio device, acoustic metrics of the transducer, relates to control of equalization, relates to permission to enable proprietary sonic processing for enhanced acoustic reception of streaming content, relates to acoustic metrics of the transducer and wherein the identifier is associated with permission to enable proprietary sonic processing for enhanced acoustic reception of streaming content, and/or is stored in a chip on the personal audio device, is retrieved from a server in a network, among other things.\",\n \"In various embodiments the processing is done in a batch format and the processed content is stored for a plurality of parameters.\",\n \"In various embodiments, the processing is done in real-time and the processed content is streamed to the personal audio device.\",\n \"In various embodiments, the processing is done at a server, and the processing algorithm executes using the identifier to retrieve at least one parameter associated with the identifier to control parameters of sonic processing algorithms and to provide processed content to the network that can be received by a user of a device associated with the identifier.\",\n \"In various embodiments the identifier includes a key used for lookup.\",\n \"In various embodiments, the personal audio device comprises ear buds and the identifier is stored in a non-volatile memory of the ear buds.\",\n \"In various embodiments the identifier is a unique identifier of up to 48 bits.\",\n \"In various embodiments, the identifier is retrieved using a sonic inquiry command.\",\n \"In various embodiments, the subject matter relates to apparatus including at least one earbud, a non-volatile memory associated with the at least one earbud, the memory storing at least an identifier; and circuitry for polling the identifier from the memory, wherein the identifier is used for processing audio sent to the at least one earbud.\",\n \"In various embodiments, the apparatus further comprises a second earbud.\",\n \"In various embodiments, the apparatus further includes a control to initiate an identification process.\",\n \"In various embodiments, the apparatus further comprises a control to disable access to the identifier.\",\n \"In various embodiments, the circuitry of the apparatus is readable by a mobile phone.\",\n \"Additional variations are described in the following detailed description.\",\n \"This Summary is an overview of some of the teachings of the present application and not intended to be an exclusive or exhaustive treatment of the present subject matter.\",\n \"Further details about the present subject matter are found in the detailed description and appended claims.\",\n \"The scope of the present invention is defined by the appended claims and their legal equivalents.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS The accompanying figures illustrate certain embodiments of the subject matter and demonstrate certain aspects of the subject matter discussed in the following detailed description.\",\n \"FIGS.\",\n \"1A-1D demonstrate systems according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"2 shows a system for simulating linear and nonlinear effects of propagation and mixing of sound in air according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"3 demonstrates a single-source spatial representation of an interaction volume, according to one embodiment of the present subject matter.\",\n \"FIG.\",\n \"4 demonstrates a dual-source spatial representation of an interaction volume, according to one embodiment of the present subject matter.\",\n \"FIG.\",\n \"5 demonstrates a signal-modification processing subsystem for introduction of a priming signal according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"6 demonstrates an FIR convolution sub-system according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"7 demonstrates adjustable pre-signal content duration examples in the FIR convolution templates according to various embodiments of the present subject matter.\",\n \"FIGS.\",\n \"8A-8B demonstrate enforced zero-response examples around the dry signal delay time according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"9 demonstrates a multichannel analysis signal-modifying processing subsystem according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"10 demonstrates a series single-channel analysis subsystem according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"11 demonstrates a parallel single-channel analysis systems signal-analysis subsystem according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"12 shows the dependence of perceived pitch on sound level according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"13 shows the dependence of perceived pitch on sound level at low frequencies according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"14 demonstrates a general multiplexed convolution system architecture according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"15 demonstrates a multiplexed convolution signal-analysis and processing-control architecture according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"16 shows a multiplexed convolution signal analysis processing subsystem according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"17 shows an exemplary three-dimensional, discrete behavior space according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"18 presents an illustrative diagram of behavior space mapping and system-behavior determination operations according to various embodiments of the present subject matter according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"19 shows a digital computer implementation of the system-behavior determination operation based on look-up tables according to various embodiments of the present subject matter.\",\n \"FIGS.\",\n \"20A-20D illustrate an audio mixture decomposition according to various embodiments of the present subject matter.\",\n \"FIGS.\",\n \"21A-21C show the beginnings of the transient audio events according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"22 demonstrates a Digital Human Interface Identifier (DHI-ID) Serial Protocol according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"23 demonstrates a Digital Human Interface Identifier (DHI-ID) Serial system according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"24 demonstrates a recorded sound processing system according to various embodiments of the present subject matter.\",\n \"DETAILED DESCRIPTIONS OF THE SUBJECT MATTER FIGS.\",\n \"1A-1D demonstrate some embodiments of systems 100A-100D according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"1A shows a first overall system topology 100A.\",\n \"The system topology 100A may include a content source 110A, such as an analog or digital audio recording or a live digital stream.\",\n \"The content source 110A may provide content to the processor 120A, where the processor 120A may include one or more of the audio enhancement techniques describe below.\",\n \"The processor 120A may provide enhanced audio through a network (e.g., the internet, “the cloud”) 130A to the device 140A.\",\n \"The use of a remote content source 110A may provide more storage space than a user smartphone, and the use of a remote processor 120A may provide greater processing power and reduce smartphone power consumption.\",\n \"At the device 140A, the enhanced audio is controlled via user inputs or reproduced using headphones, speakers, or other audio playback hardware or software.\",\n \"FIG.\",\n \"1B shows a second overall system topology 100B.\",\n \"The system topology 100B may include a content source 110B, such as an analog or digital audio recording or a live digital stream.\",\n \"The content source 110B may provide audio through a network 130B to the processor 120B, where the processor 120B may include one or more of the audio enhancement techniques describe below.\",\n \"The use of a remote content source 110A may provide more storage space than a user smartphone, and the use of a remote processor 120A may provide greater processing power and reduce smartphone power consumption.\",\n \"The processor 120B may provide enhanced audio through the network 130B to the device 140B for playback.\",\n \"FIG.\",\n \"1C shows a third overall system topology 100C.\",\n \"The system topology 100C may include a content source 110C, such as an analog or digital audio recording or a live digital stream.\",\n \"The content source 110C may provide audio through a network 130C to device 140C, where device 140C includes processor 120C.\",\n \"For example, the content source 110A could be an internet-based music streaming service, which may stream audio data to a user's smartphone, where the smartphone includes the processor 120A and the device 140.FIG.\",\n \"1D shows a fourth overall system topology 100D.\",\n \"The system topology 100D may include a content source 110D, such as an analog or digital audio recording or a live digital stream.\",\n \"The content source 110D may provide audio to device 140D, where device 140D includes processor 120D.\",\n \"The use of a local content source 110D may allow a user to use one or more of the audio enhancement techniques describe below without needing a network connection.\",\n \"The combination of the content source 110A-D, processor 120A-D, network 130A-D, and device 140A-D may enhance audio reproduction using one or more of the audio enhancement techniques describe below.\",\n \"Digital Audio Processing to Simulate the Nonlinear Properties of Sound Propagation and Mixing in Air The experience of listening to digital audio recordings is improved by making subtle modifications to the recorded audio signals that simulate the linear and nonlinear effects of propagation and mixing of sound in air.\",\n \"The mixing in a nonlinear medium of multiple or complex sound waves comprised of multiple frequencies is known as heterodyning.\",\n \"Heterodyning may occur at various locations in the air, including at a speaker or at the user's tympanic membrane.\",\n \"Because the speed of sound in air is itself dependent upon the particle velocity or pressure of the air at any given moment in time and position in space, air may not be a purely linear propagation medium.\",\n \"For example, the compression peaks of an acoustic waveform may travel faster than rarefaction troughs, distorting the waveform and transferring energy into higher harmonics of the original signal.\",\n \"When multiple or complex sound waves comprised of multiple frequencies propagate in such a nonlinear medium, the sound waves transfer energy into sound at new frequencies (e.g., intermodulation products) given by the sums and differences of the original signal frequencies.\",\n \"While these nonlinear effects of air are generally subtle at auditory frequencies and typical sound pressure levels (SPLs) (e.g., loudness levels), second-order nonlinear effects may generate content at levels as high as only 30 decibels below the primary sound pressure and are often perceptible during live music performances.\",\n \"These second-order intermodulation products have amplitudes proportional to a derivative of the products, which may result in intermodulation products or other propagation effects that increase with an increase in frequency.\",\n \"Nonlinear propagation effects of audible frequencies may also interact with lower frequencies in an intermodulation scheme.\",\n \"Thus, the nonlinear effects of air may play an appreciable role in how the brain processes and perceives sound.\",\n \"The mixing signal processing technique may improve the ability of a system to reproduce the effects of a live performance using a digital audio recording.\",\n \"While some music is experienced through live performance, most music is experienced through listening to stored analog or digital audio signals.\",\n \"Digital audio signals are converted to analog signals using digital-to-analog converters, and the original or converted analog audio signals are reproduced acoustically by headphones, open-air loudspeakers, or other means.\",\n \"The reproduced signals may contain unnatural content, as the reproduced signals represent recorded or synthesized waveforms that have not propagated through air or otherwise mixed in ways that are naturally encountered with live sound.\",\n \"For example, many genres of music may use recording techniques known as “close-mic'ing” and “overdubbing,” often in combination.\",\n \"These techniques may include minimal amounts of propagation and mixing in air, and may result in sterile recordings of sounds.\",\n \"In close-mic'ing, microphones are placed in close proximity to the sound source.\",\n \"Close-mic'ing can be used to capture direct sounds, while simultaneously reducing energy captured from other sound sources and reducing acoustic reflections occurring in the room where the recording is taking place.\",\n \"In contrast to listening to live music at a range from 1 meter to tens of meters, close-mic'ing sound-source-to-microphone distances may range from about 10 centimeters for recording vocalists to 5 centimeters for recording amplified guitar or acoustic drums.\",\n \"In each case, the recorded sound waveform may experience extremely little propagation in air, and therefore may not include effects generated by propagation associated with a similar sound source heard from a more natural listening distance.\",\n \"When multiple musicians are recorded performing in a space at the same time, close-mic'ing may enable a mix engineer to control their relative volumes individually or apply special processing to a subset of performers.\",\n \"While this isolation of sounds is useful during mixing, natural effects of nonlinear propagation and mixing in air evolve gradually over distance and may require up to tens of meters of propagation to fully develop, and close-mic'd recordings may fail to capture these natural effects of nonlinear propagation and mixing in air.\",\n \"The recording technique of overdubbing may isolate individual sounds more than close-mic'ing, and may also fail to capture natural effects of nonlinear propagation and mixing in air.\",\n \"In overdubbing, additional sounds are recorded and synchronized with previously recorded sounds in order to build a recording of a full ensemble or song gradually through summation of multiple individual recordings.\",\n \"Because modern digital audio workstations make it easy to layer a large number of individual recordings, each instrument or performance that contributes to a song is recorded individually.\",\n \"For example, performers may play an instrument while listening to previously recorded parts of the song or a timing cue (e.g., metronome), and may record each instrument or vocal component individually until every song component has been recorded.\",\n \"These individually recorded song components may also be close-mic'd to avoid room reflections and capture an isolated audio recording (e.g., dry sound).\",\n \"Through heavy use of these techniques, many modern recordings include numerous individual close-mic'd waveforms that are mathematically added together by a computer and have not propagated and mixed in air as they typically would have in a natural live performance.\",\n \"In particular, digital audio waveforms that have been generated electronically or synthesized digitally may not have experienced any propagation or mixing in air.\",\n \"These digital audio waveforms are an extreme example of modern recording practices, as they are completely isolated from the other sounds contributing to a song or sound mixture, and may include little or no additional content or imprint from the space in which they were recorded.\",\n \"Furthermore, when these sounds are later reproduced acoustically, it is often in a setting that does not allow for the propagation distance or source SPL (sound pressure level) needed for the generated sound to experience the amount of nonlinear propagation normally incurred during live performances or large-scale concerts.\",\n \"This is true for many home and car playback systems and listening environments, and is particularly relevant to headphones and earphones.\",\n \"For example, headphone propagation distance of reproduced sound can be less than 6 millimeters, which may allow a recorded sound to propagate in air for 5 to 10 centimeters from source to microphone and then earphone to the tympanic membrane.\",\n \"Additionally, headphones may use a lower source SPL, as little spreading or propagation loss occurs.\",\n \"Because modern recording techniques and common listening settings reduce or eliminate nonlinear propagation effects often present and audible during live performances, it is beneficial to recreate these effects through digital signal processing so a more natural sound is provided by digital recordings in typical listening environments.\",\n \"The acoustical sidebands created by sound heterodyning in air give an added spectral and harmonic richness to sound that is commonly absent from the modern listening experience and would be beneficial to reproduce digitally.\",\n \"Additionally, it is desirable to impose some of the frequency-dependent attenuation that accompanies natural propagation of sound in air to restore a more natural tonal balance to close-mic'd recordings, and to improve simulation of nonlinear interactions between or among sound components as they propagate.\",\n \"Beyond compensating for modern recording techniques and playback settings, the use of digital signal processing to simulate nonlinear propagation and mixing of sound in air may enhance the experience of listening to digital audio.\",\n \"The nonlinearity of air is most pronounced when high sound pressure levels are present, and listeners often find that higher listening volumes provide a more compelling and immersive listening experience.\",\n \"Digitally introducing the nonlinear effects that would have occurred at high playback volumes may make playback at lower volumes more exciting and enjoyable by simulating part of the experience of listening at high SPLs.\",\n \"FIG.\",\n \"2 shows a system 200 for simulating linear and nonlinear effects of propagation and mixing of sound in air according to various embodiments of the present subject matter.\",\n \"System 200 may operate on one or more input signals in order to generate intermodulation products that would be generated naturally during acoustic propagation of one or more signals at a given peak sound pressure level and then mixing these products with the original input signal(s).\",\n \"Additional linear filtering is imposed by the system before, during, or after this process in order to simulate the natural frequency-dependent attenuation of sound as it propagates through air.\",\n \"System 200 may improve the listening experience by compensating for modern digital recording techniques and listening settings that reduce or eliminate the natural attenuation and nonlinear effects of sound propagation through air and by simulating high SPL playback of audio at lower volumes by introducing the nonlinear effects of sound propagation at high SPLs into the recorded waveform itself.\",\n \"System 200 modifies source material in a transparent and potentially subtle way while not altering the creative content of processed recordings, making it suitable for application to all varieties of musical or audio content recorded and stored in digital form.\",\n \"System 200 takes as its input one or more input signals (Xi) 210 that represent the amplitude of one or more audio waveforms over time.\",\n \"In various embodiments, these input signals 210 are a series of digitally stored values representing the instantaneous amplitude of a band-limited waveform that has been sampled at regularly spaced moments in time.\",\n \"Each input signal (Xi) 210 may have a corresponding primary sound pressure (P1) 220.The primary sound pressure 220 is provided to a processor 230 for calculation of a secondary soundfield.\",\n \"Processor 230 is a general purpose processor, a dedicated digital signal processing (DSP) integrated circuit (IC), or another type of processor suitable for the calculation of the secondary soundfield.\",\n \"The output of processor 230 includes a secondary sound pressure (P2) 240, where the secondary signal 240 may simulate effects that would have occurred at high playback volumes to simulate a live mixing of the various sounds.\",\n \"Primary and secondary sound pressures 220 and 240 are combined through superposition within an adder 250.Adder 250 includes a digital adder circuit or a summing amplifier and may include additional summation or timing components.\",\n \"For example, processor 230 may introduce a delay in the secondary signal 240 relative to the primary signal 220, and adder 250 may include a fixed time delay or a synchronization module to detect the delay of the secondary signal 240.Adder 250 may combine primary and secondary sound pressures 220 and 240 to provide a sound pressure output signal (Yi) 260, where output signal 260 may simulate what the listener would hear at a live event.\",\n \"System 200 may modify the input signal(s) in a manner dependent upon one or more controlling parameters.\",\n \"Generally, these parameters define physical attributes of the simulated sound propagation and mixing and thus directly influence the formulas used to calculate the intermodulation products generated by the nonlinearity of air.\",\n \"Alternatively, higher-level parameters are used to control the overall character or extent of the processing.\",\n \"In some embodiments of the subject matter, these parameters are determined automatically through an additional mathematical analysis of the input's auditory content and the application of a rule or decision system that links analyzed signal content parameters to control parameters.\",\n \"Because digital audio signals generally contain complex waveforms comprised of multiple frequency components and are applied during the mixing of multiple recorded sounds, the present subject matter in various embodiments uses quasi-linear solutions of Westervelt's general inhomogeneous wave equation to determine the relationship between input signals and generated intermodulation products.\",\n \"In one embodiment of the subject matter, the Westervelt equation for second-order mixing, ∇ 2 P 2 - 1 c 0 2 ∂ 2 P 2 ∂ t 2 = - ρ 0 ∂ q ∂ t , ( 1 ) is used to capture the second-order intermodulation products generated by the nonlinearity of air, as these are generally the most prominent of intermodulation products.\",\n \"In equation (1), secondary sound pressure (P2) 240 is the pressure variation associated with the intermodulation products generated by the nonlinearity of air, (ρ0) and (c0) represent the density and small-signal sound speed of air, respectively, and (q) is the virtual source density given by q = β ρ 0 2 c 0 4 ∂ ∂ t P 1 2 , ( 2 ) which is proportional to the time derivative of the square of the primary sound pressure (P1) 220.Here, β represents the second-order nonlinear coefficient of air, which may vary with the interaction angle of component sound fields if the primary sound pressure may be a mixture.\",\n \"The general solution to differential equation (2), which can be used by one embodiment of the presently disclosed subject matter, is P 2 = - ρ 0 4 π ∫ V ∂ q ∂ t e ik s r ′ r ′ dV , ( 3 ) where (ks) is the wavenumber corresponding to an intermodulation product, (V) is the interaction volume over which the primary sound pressure has sufficient amplitude to contribute to the generation of intermodulation products, and (r′) is the distance from each virtual source point in the interaction volume (V) to the location where the generated secondary field is observed.\",\n \"In this exemplary embodiment, the primary sound pressure (P1) 220 is comprised of either the single input signal (Xi) 210 or a combination of M individual input signals (Xi) 210, where i=1, .\",\n \".\",\n \".\",\n \", M. Parameters of equation (3) such as the definition of the interaction volume V, the radiation pattern of the sources (if multiple inputs may be being mixed), and the physical sound pressure level being simulated is specified, either directly by a user, based on higher-level specifications, or by some other means, and a solution for the secondary sound field P2 is calculated.\",\n \"An interaction volume (V) with a single isotropic source is shown in FIG.\",\n \"3, and an interaction volume (V) with two isotropic sources is shown in FIG.\",\n \"4.FIG.\",\n \"3 demonstrates a single-source spatial representation 300 of an interaction volume, according to one embodiment of the present subject matter.\",\n \"In particular, FIG.\",\n \"3 demonstrates calculation of the secondary sound pressure (P2) 240 generated by a complex (multiple-frequency) primary sound pressure (P1) 220 radiating from a single isotropic source due to the nonlinear effects of propagation in air.\",\n \"The single-source representation 300 may include a single isotropic source 310, where the isotropic source 310 represents sound generated using primary sound pressure (P1) 220.The isotropic source 310 may generate an interaction volume (V) 320 as used in equation (3), where interaction volume 320 is the volume over which the primary sound pressure contributes to the generation of intermodulation products.\",\n \"A virtual source point 330 is selected, where the virtual source density at virtual source point 330 corresponds to virtual source point (q) in equation (2).\",\n \"An observation point 340 is selected, where the distance from virtual source point 330 in the interaction volume (V) 320 to observation point 340 corresponds to the distance (r′) in equation (3).\",\n \"FIG.\",\n \"4 demonstrates a dual-source spatial representation 400 of an interaction volume, according to one embodiment of the present subject matter.\",\n \"In particular, FIG.\",\n \"4 demonstrates one method of calculating secondary sound pressure (P2) 240 due to the nonlinear effects of propagation in air, where the secondary sound pressure (P2) 240 can be generated by mixing of two independent isotropic sources.\",\n \"The single-source representation 400 may include a first isotropic source 410 and a second isotropic source 415.The first and second isotropic sources 410 and 415 may be generated using primary sound pressure (P1) 220.The isotropic source 410 may generate an interaction volume (V) 420 as used in equation (3), where interaction volume 420 may be the volume over which the primary sound pressure contributes to the generation of intermodulation products.\",\n \"A virtual source point 430 may be selected, where the virtual source density at virtual source point 430 corresponds to virtual source point (q) in equation (2).\",\n \"An observation point 440 may be selected, where the distance from virtual source point 430 in the interaction volume (V) 420 to observation point 440 corresponds to the distance (r′) in equation (3).\",\n \"For the interaction volume (V) shown in FIG.\",\n \"3 and FIG.\",\n \"4, the sound field may be comprised of the sum of second-order intermodulation products.\",\n \"The sound fields represent sums and differences between pairs of frequencies present in the input signals.\",\n \"The sound fields also represent second harmonics of all frequencies present in the input signals, each with amplitudes that may be proportional to the square of their frequencies.\",\n \"Whether using one, two, or more isotropic sources, sound pressure output signal (Yi) 260 may be formed by mixing the secondary sound field (P2) 240 with input primary sound pressure (P1) 220 to arrive at the total sound field that would be observed in air.\",\n \"The naturally occurring relative amplitudes of the primary and secondary sound fields 220 and 240 may be given by the solution to equation (1).\",\n \"The sound pressure output signal (Yi) 260 may be further controlled by additional parameters, either interactively by a user, automatically according to analysis of the input signals 210, or by other means.\",\n \"Linear filtering may be used to simulate frequency-dependent attenuation of sound as it propagates through air.\",\n \"Linear filtering may be applied to the input signals 210 before or after calculating output signal 260, depending on computational considerations and other design choices.\",\n \"Characteristics of such linear filtering may be selected to simulate or reduce attenuation properties of air.\",\n \"The present subject matter applies the Westervelt equation to audible frequencies to compensate directly for modern recording techniques or simulate accurately the effects of high SPL playback of digitally recorded audio to enhance the listening experience.\",\n \"Typical uses of the Westervelt equation deal with ultrasonic sound.\",\n \"Most applications, such as high-intensity focused ultrasound and industrial applications of ultrasound, such as cleaning and welding, may be very different from that of the presently disclosed subject matter.\",\n \"The Westervelt equation has been used in the field of parametric acoustic arrays, such as in the analysis and design of systems that generate beams of ultrasonic sound in order to produce directionally controllable content at audio frequencies through the nonlinear interactions of these ultrasonic beams in air.\",\n \"Because the nonlinear effects of air increase with frequency, these effects may be strongly present at ultrasonic frequencies, but may be subtle at audio frequencies.\",\n \"As a result, mathematical application of these nonlinearities to date has focused on ultrasonic applications, and not on digital audio waveforms with content only in the auditory band for enhancing listening during playback.\",\n \"Additional methods may be used to simulate intermodulation products generated by audio-band sound due to the nonlinearity of air.\",\n \"A reduced solution may include second-order effects and intentionally exclude higher-order intermodulation products.\",\n \"Because of the generally low amplitudes of higher-order intermodulation products generated at reasonable SPLs at audible frequencies, the second-order embodiment discussed above may be sufficient to achieve the desired results, however other embodiments are possible.\",\n \"In some cases, particularly when simulating very high source SPLs or when input waveforms have particular spectral properties, the calculation of higher-order intermodulation products may be desirable.\",\n \"Higher-order calculations may be included in an embodiment of the subject matter if deemed necessary by a user or through analysis of the input signal.\",\n \"Digital Signal Processing of Priming Signal for Reduction of Stress in the Auditory System A priming signal processing technique modifies digital audio recordings to reduce the stress experienced by a listener's auditory system.\",\n \"A priming signal may reduce the instantaneous stress experienced by the auditory system during sudden changes in signal energy.\",\n \"The priming signal may be generated such that pre-signal priming additions may not result in obvious differences in perceived sounds, thereby leveraging temporal auditory masking.\",\n \"A method for processing digital audio signals in order to decrease the stress experienced by the auditory system of a listener without overtly changing the creative or musical content of the signal may be disclosed.\",\n \"The method consists of an adaptive, time-varying system that responds to characteristics of input signal content according to a rule system, and that alters the signal either by mathematical convolution with one or more response templates or by the momentary addition of noise-like signals.\",\n \"Unlike existing audio processing techniques, this method may not be intended to generate obvious audible differences in the content of an audio signal, but rather to cause an appreciable difference in the comfort and enjoyment of the listener by conditioning the signal to interact more gently or naturally with the listener's auditory system.\",\n \"This method may be designed to compensate either directly or indirectly for the deleterious effects of unnaturally synthesized, mixed, or recorded digital audio signals as well as other potential shortcomings of digital audio formats and reproduction.\",\n \"Due to its ease of implementation, this method may be suitable for application to all varieties of musical or audio content recorded and stored in digital form.\",\n \"Synthetic generation of acoustic waveforms provides extensive creative opportunities.\",\n \"However, synthetic waveforms also present the listener with audio material that defies many properties of natural sound.\",\n \"Because these synthetic waveforms do not adhere to physical laws that the auditory system may be designed to understand, this defiance may cause stress on the human auditory system in processing and interpreting these signals.\",\n \"While the creative freedom afforded by these signals should not be diminished, it may be desirable to introduce processing that may compensate for differences between expected and experienced characteristics of sound.\",\n \"Such compensation may allow creation of a more enjoyable listening experience without significantly altering the creative content of the audio.\",\n \"Furthermore, it may be generally desirable to process audio signals in ways that reduce the stress experienced by a listener's auditory system, whether or not such stress reduction may be achieved by imitating the natural behavior of sound.\",\n \"There may be many known phenomena in the human auditory system that may be relevant to the present discussion.\",\n \"At a high level, humans may be able to derive much information about their surroundings from analyses of patterns of reflections or multiple arrivals of the same acoustic signal.\",\n \"For example, the auditory system may be able to use the filtering and delay imposed by the shape of the human head and ears (e.g., head-related transfer functions) to determine the direction from which a sound originated.\",\n \"Reflections of a sound arriving after the initial direct path may be used by the auditory system to understand characteristics of the space surrounding a listener such as whether or not it may be enclosed, how distant nearby walls or other solid or semi-solid surfaces (such as groves of trees) might be, and the types of materials present in the surroundings (hard and reflective or soft and absorbent).\",\n \"Such reflections can also be used to understand the location of a sound source relative to the listener: the pattern of reflections that arrives at a listener varies with changes in the relative locations of the listener and the source, creating auditory cues for distance and obscuration.\",\n \"All of this high-level auditory information may be derived instinctually, without conscious training or attention, and may be based on the auditory system's understanding of how sound naturally interacts with its environment.\",\n \"The majority of cues for this understanding may be contained in filtering and arrival patterns during the first 100 milliseconds or so after a direct signal, and our ability to make sense of these cues indicates a specialization of the human auditory system for processing naturally occurring audio signals.\",\n \"At a lower level, it may be known that a wide range of similar acoustic signals may be perceived to present the same sound.\",\n \"Although the human auditory system may be complex and not fully understood, this phenomenon has been studied extensively and may be known as auditory masking: the process by which the presence of one sound can render another sound imperceptible.\",\n \"This effect may be a result of both the mechanics of the human peripheral auditory system, which transduces acoustic energy into electrical neural activity, and higher level processing performed in the central auditory system.\",\n \"Acoustic energy may be transduced into neural activity in the cochlea by inner hair cells, which release neurotransmitters in response to mechanical deflection and incite action potentials (e.g., electrical spikes) in the primary auditory neurons.\",\n \"Various encoding schemes, such as first-spike latency, rate-based coding, and detailed temporal codes may be then employed by the auditory system to transmit and analyze these initial excitations.\",\n \"Stated simply, if a dominant sound may be already exciting a particular group of neurons, it may prevent a weaker sound that would excite the same neurons from being perceived.\",\n \"This may be known as simultaneous masking.\",\n \"Additionally, because much of the processing performed by the central auditory system involves integration of neural spike signals over some duration of time and because the human auditory system may temporarily decrease its sensitivity to sound in reaction to loud stimuli, masking can extend over a duration of time: a loud sound may render quieter sounds immediately preceding it or immediately following it imperceptible, with an influence that extends longer afterward than before (approximately 20 milliseconds before and 100 milliseconds after a loud sound, with influence decaying exponentially away from the time of the sound).\",\n \"This may be known as temporal masking.\",\n \"Finally, because each point along the length of the cochlea may be tuned to a specific frequency, sounds that may be similar in frequency may primarily excite the same groups of neurons, and may be more likely to mask one another through either type of masking.\",\n \"This phenomenon of auditory masking means that it may be possible to make significant modifications to an audio signal which do in fact present the human auditory system with a different stimulus but which do not yield obvious differences in the content of the signal.\",\n \"This may be the principle that underlies lossy compression schemes for digital audio such as the ubiquitous .mp3 standard, which may be designed to throw away a large portion of the information contained in an audio signal without changing the way that it sounds to a listener.\",\n \"Here, this principle may be exploited to apply processing which has an appreciable effect on the listening experience without obviously altering the auditory system's interpretation of the processed data.\",\n \"The present system analyzes and modifies this input signal; the exact modification performed on the signal at any given time may be dependent upon the current analysis output, and may vary with momentary changes in characteristics of the input signal.\",\n \"In various embodiments, two main methods of modifying the input signal may be employed.\",\n \"One of these methods may be to modify the input signal by performing the mathematical operation of convolution using the input signal and one or more convolution template signals.\",\n \"The other method may be to introduce additional, momentary noise-like components into the output signal.\",\n \"Digital Signal Processing of Priming Signal: Methods of Modifying the Input Signal FIG.\",\n \"5 illustrates an embodiment of a signal-modification processing subsystem 500 for introduction of a priming signal, according to various embodiments of the present subject matter.\",\n \"Subsystem 500 may take multiple input audio channels (Xi) as input 505, where input 505 represents the amplitude of an audio waveform over time.\",\n \"In various embodiments, input 505 may be a series of digitally stored values representing the instantaneous amplitude of a band-limited waveform that has been sampled at regularly spaced moments in time.\",\n \"Subsystem 500 may act on each channel of audio individually in series or in parallel.\",\n \"For example, input channel one signal 510 may be directed into an FIR convolution subsystem 520.FIR convolution subsystem 520 may convolve the input channel one signal 510 with a convolution template to generate a corresponding priming signal, where the selection of the convolution template may be controlled by control data 530 as discussed in more detail with respect to FIG.\",\n \"6.Input channel one signal 510 may also be directed into a look-ahead delay 540, where look-ahead delay 540 may delay the input signal by the maximum pre-signal convolution response time, effectively achieving look-ahead into the future of the input signal so that priming signal content may be added just prior to audio transients or other events.\",\n \"Control data 530 may provide control inputs to a look-ahead amplifier 560, which may amplify or attenuate the signal from the look-ahead delay 540.Subsystem 500 may also include a noise burst generator 550 to contribute noise to the priming signal, where the noise burst generator 550 may be controlled using control data 530.The output of the FIR convolution subsystem 520, the noise burst generator 550, and the look-ahead amplifier 560 may be summed in signal adder 570 to form an output signal for channel one.\",\n \"Subsystem 500 may provide an output signal (Yi) 580, where the output signal (Yi) 580 may include an output corresponding to each input audio channel (Xi) 505.Subsystem 500 may be implemented in various configurations, including the configuration shown in FIG.\",\n \"11 or 16.In the embodiment illustrated in FIG.\",\n \"11, multiple audio channels may be analyzed individually by parallel single-channel analysis systems, the output of which may be further processed by a higher-level multi-channel analysis system that may lead to modifications of the resulting single-channel control decisions.\",\n \"In the embodiment illustrated in FIG.\",\n \"16, each type of signal analysis may be performed on a multichannel collection of signals at once, and the results from each type of analysis may inform other analyses.\",\n \"FIG.\",\n \"6 illustrates an embodiment of an FIR convolution subsystem 600, according to various embodiments of the present subject matter.\",\n \"FIR convolution subsystem 600 may take an audio channels (Xi) as input 610.Audio input 610 may be fed into a convolution selector 620, and input control data 630 may cause one or more connections to be opened or closed between the audio input 610 and FIR convolution templates 640 and 645.Each of convolution templates 640 and 645 may be modified using input control data 630, such as selecting modifying or replacing the convolution function within each of convolution templates 640 and 645.Though two convolution templates 640 and 645 are shown, any number of convolution templates may be used, and may be selected using any number of switches within the convolution selector 620.For example, a single convolution template may be used, or all convolution templates may be used simultaneously.\",\n \"Modification of the input signal through calculation of mathematical convolution results may be performed as follows.\",\n \"A number of template signals may be stored as representations of signal amplitude over time.\",\n \"These representations may be digitally stored lists of numbers.\",\n \"These template signals may be derived from recordings of real-world natural environments, pre-constructed mathematically or otherwise, or derived from parametric specifications, and need not be more than approximately 50 milliseconds in length.\",\n \"At any given time, one or more of the M template signals, ci, i=1, .\",\n \".\",\n \".\",\n \", M, may be convolved with the input signal depending on the current input signal analysis results, to generate a set of convolution outputs yi, y i [ n ] = ( x * c i ) [ n ] = ∑ k = 0 N - 1 x [ n - k ] c i [ k ] , ( 4 ) where the convolution template signals, ci[n], may be defined for the time period n=0, .\",\n \".\",\n \".\",\n \", N−1.Each output of convolution templates 640 and 645 may be fed into corresponding convolution amplifiers 650 and 655, where they may be scaled by gains, (ai), i=1, .\",\n \".\",\n \".\",\n \", M. Gains (a) may be specified by amplifier input control data 630, where amplifier gains may be selected based on the input signal analysis results.\",\n \"The output of convolution amplifiers 650 and 655 may be summed within a signal adder 660 to generate the convolution subsystem output 670, given as y conv [ n ] = ∑ i = 1 M a i y i [ n ] .\",\n \"( 5 ) The output of the signal adder 660 may provide FIR convolution subsystem output 670, which may be summed with additional input channels at signal adder 570 shown in FIG.\",\n \"5.In many existing systems using convolution operation in digital audio signal processing, these convolution templates are intended to achieve a particular frequency response specified by a user or to alter the perceived timbre, character, musical or creative content of the input signal.\",\n \"Similarly, in such existing systems, these convolution templates are intended to recreate the full response of any particular linear system or type of linear system such as a real or synthetic acoustic space, or an electrical or acoustic device or instrument.\",\n \"In contrast, in various embodiments of the present subject matter, the convolution templates are designed to reduce stress on the auditory system of a listener without obviously altering the content of the input signal.\",\n \"This design goal, and the goals of subtleness and transparency it entails, therefore distinguishes from the design goals of existing audio processing systems.\",\n \"Additional content may be introduced prior to transients or other triggering events in the input signal by utilizing digital delay to effectively achieve look-ahead into the future of the input signal and applying convolution templates that include pre-signal content.\",\n \"For example, with a maximum pre-signal response time of tpMAX, the path by which the input signal (x) reaches the output without modification may have an imposed delay of pMAX=ceil(tpMAX··fs), where (fs) denotes the (currently assumed to be regular) sampling frequency of the data contained in (x) and the ceil( ) function denotes rounding up to the next integer value.\",\n \"Delaying the dry path in this way has the effect of equivalently performing the convolutions as y i [ n ] = ( ( z p MAX x ) * c i ) [ n ] = ∑ k = 0 N - 1 x [ n + p MAX - k ] c i [ k ] .\",\n \"( 6 ) This expression demonstrates that future values of the input x may contribute to the current output value of each (Yi) if the convolution template signals ci may be defined to be non-zero in the range of time from n=0, .\",\n \".\",\n \".\",\n \", pMAX−1.In practice, the amount of time by which template content leads signal content and the level of the pre-signal content relative to the following signal may be both variable and depend on the current input signal analysis results.\",\n \"Pre-signal response times of less than 10 milliseconds may be used, with times ranging from 1 millisecond to as little as 50 microseconds being most common.\",\n \"The introduction of such pre-signal content, particularly in a time-varying and signal-dependent (non-linear) manner, may be designed to prime the human auditory system for the audio content that follows.\",\n \"Due to the phenomenon of temporal auditory masking, such pre-signal priming additions may not result in obvious differences in the sounds that may be heard, but may reduce the instantaneous stress experienced by the auditory system during sudden changes in signal energy.\",\n \"FIG.\",\n \"7 illustrates adjustable pre-signal content duration examples 700 in the FIR convolution templates, according to various embodiments of the present subject matter.\",\n \"The first example signal waveform 710 may include the entire input signal.\",\n \"Each of modified signal waveforms 720, 730, and 740 may have increasing dry signal durations, where modified signal waveform represents the maximum dry-signal delay tpMAX=10 ms. As shown in FIG.\",\n \"5, this dry signal may be implemented as a parallel signal and does not enter a convolution subsystem, such as using parallel channel look-ahead delay 540 shown in FIG.\",\n \"5.Because this parallel input dry signal may be delayed, template content that occurs at lags smaller than this dry-signal delay may be added effectively to the output in response to input signal content that has not yet appeared at the processing system's output.\",\n \"This portion of the convolution template reacts to future input signal and may result in the addition of content to the output signal just prior to audio events such as transients.\",\n \"FIGS.\",\n \"8A-8B illustrate enforced zero-response examples 800A-800B around the dry signal delay time according to various embodiments of the present subject matter.\",\n \"Each of example waveforms 810, 820, 830, 840, 850, and 860 depict a different application of a zero-response signal applied to the input signal 710 shown in FIG.\",\n \"7.Example waveforms 810, 820, 830, 840, 850, and 860 depict a duration of silence enforced in the convolution templates around zero delay, or the point in time corresponding to the current input signal amplitude, given as ci[n]=0,n=pMAC−k, .\",\n \".\",\n \".\",\n \",pMAX+l (7) for some numbers of samples (k) and (l).\",\n \"Values (k) and (l) may be selected to minimize the alterations of the way that the input signal sounds.\",\n \"FIG.\",\n \"8A includes example waveforms 810, 820, and 830, which depict a symmetric short duration of silence enforced in the convolution templates around zero dry-signal delay tpMAX=10 ms.\",\n \"Example waveform 810 shows a small duration of silence, example waveform 820 shows a medium duration of silence, and example waveform 830 shows a large duration of silence.\",\n \"Example waveforms 810, 820, and 830 depict an asymmetric short duration of silence enforced in the convolution templates around zero delay.\",\n \"FIG.\",\n \"8B includes example waveforms 840, 850, and 860, which depict asymmetric short duration of silence enforced in the convolution templates.\",\n \"In particular, waveform 840 depicts an asymmetric duration of silence beginning at dry-signal delay tpMAX=10 ms, example waveform 850 depicts an asymmetric duration of silence around tpMAX=10 ms, and example waveform 860 depicts a large asymmetric duration of silence around tpMAX=10 ms. A system may select one of symmetric or asymmetric example waveforms 810, 820, 830, 840, 850, and 860, and therefore select the delay and position of silence, in order to reduce the perception of the artificial duration of silence.\",\n \"In natural acoustic environments, the sound heard by a listener may be always the combination of an initial direct-path arrival followed by subsequent early reflections.\",\n \"In nearly all cases, this leaves duration of silence (for example on the order of milliseconds) in the room response between the initial first arrival and the first-arriving reflection.\",\n \"Although the details of this first-arriving reflection and other soon-arriving early reflections may vary greatly with the positions of a sound source and listener or the acoustic space in which they reside, these changes in response generally do not alter the observed character of a sound in an obvious way.\",\n \"For example, a particular sound source such as an instrument or a particular person's voice may be recognizable in a wide variety of spaces from a small, enclosed room to a huge cathedral; the sound identified as being produced by the source does not change significantly in character, despite the fact that the sound associated with the space it may be in changes drastically.\",\n \"This may not be to say that such responses cannot contribute to the perceived character of a sound, but to demonstrate that many convolution templates with some duration of silence trailing the zero-delay component may be expected to yield subtle effects on the sound being processed; in fact, recording engineers often put significant effort into choosing the placement of microphones such that a pleasing portion of a source's radiation pattern and initial reflections may be captured during recording.\",\n \"This convolution template design technique may apply this subtlety and correspondence to naturally occurring sound phenomena.\",\n \"While convolution responses longer than approximately 50 milliseconds in duration may be perceived temporally by the human auditory system, convolution responses shorter than this may be heard spectrally in that they tend to alter the perceived character of the sound being convolved with the response rather than introducing new, separate sounds.\",\n \"The effect of summing multiple, repeated copies of a single signal on that signal's spectrum may be known as comb-filtering.\",\n \"In comb-filtering, a series of evenly spaced frequencies may be cancelled in the signal's spectrum because the contributions from the multiple delayed copies of the input signal at those frequencies may be out of phase and sum to zero.\",\n \"In general, this type of comb-filtering may be largely imperceptible to humans (although particular types of comb-filtering that change systematically over time do, however, form a class of obvious audio effects known as flanging and phasing).\",\n \"The fact that this type of filtering does not create blatantly obvious changes in the character of a sound may be likely because it may be so commonly encountered in natural acoustic spaces, as discussed above.\",\n \"By enforcing a period of silence around the zero-delay component of convolution templates and applying otherwise subtle or low-level responses, the frequency response of the templates tends to occupy this space of comb-filter-like responses that alter the character of the filtered sound in only subtle ways.\",\n \"In addition to this convolution-based method of modifying the input signal, the input signal may also be modified through the momentary addition of specific noise-like signals, y-noise.\",\n \"These noise signals may be added at times determined by the results of the input signal content analysis, such as during or slightly before transient peaks.\",\n \"This novel procedure may be intended to achieve the goal of auditory stress reduction in a manner similar to that of pre-signal content in convolution templates: the addition of a specific noise-like signal may be designed to prime the auditory system for sudden changes in signal energy and to soften the momentary auditory stress induced by sudden changes in signal energy.\",\n \"Again, due to the phenomena of temporal and simultaneous masking, such additions may not be expected to result in obviously different sounds, despite the fact that they may present a listener with markedly different acoustic signals.\",\n \"In some embodiments of the present subject matter, the addition of filtered noise may seem analogous to processing performed by generalized lossy perceptual audio compression schemes.\",\n \"Lossy perceptual audio compression techniques can generally be interpreted as adding spectrally shaped noise to recorded digital audio signals that may not be readily audible.\",\n \"However, this interpretation may be based on a typical method for analyzing the results of quantization and does not fully describe the processing performed by such systems.\",\n \"In practice, these systems quantize information about the input signal such as its spectrum during successive blocks of time with varying resolutions, which may result in highly objectionable audible artifacts and correlations between the input signal and resulting quantization error that cause the additive-noise based interpretation to be inaccurate.\",\n \"Furthermore, when considered as adding spectrally shaped noise to the recorded digital audio signal, these compression technologies add broadband noise over the full duration of the audio signal.\",\n \"In contrast to generalized lossy perceptual audio compression techniques that seek to decrease the amount of data required to represent the digital audio signal, this method may be used to improve the experience of listening to an acoustically reproduced version of the audio signal.\",\n \"To improve the listening experience, specifically shaped noise sequences may be added to the input signal only at specific noise times and for specific noise durations in order to decrease the stress experienced by the auditory system at those moments, where the noise durations may make up a small portion of the duration of the input signal.\",\n \"This use of additive noise also differentiates it from simulations of tape or vinyl mediums that introduce noise during the full duration of an audio signal in order to simulate properties of those recording media.\",\n \"Digital Signal Processing of Priming Signal: Automatic and Signal-Aware Control of the Modification Methods In various embodiments, the modification operations discussed above may be controlled automatically by the results of signal content analysis performed on the input signal.\",\n \"This analysis aims to assess four main characteristics of the input signal: the distribution and complexity of its momentary spectral content, the program, or average, perceived loudness of the signal, the presence of transient bursts of energy or changes in signal content, and, when used on multi-channel recordings, the spatial relationships of these characteristics across the multiple channels.\",\n \"The results of these analyses in turn drive a rule-based control system that may be designed to provide processing that, at any given moment, reduces the stress experienced by the auditory system of a listener while remaining transparent and not obviously audible.\",\n \"In exemplary embodiments of the subject matter, this rule-based control system may consist of a digitally stored look-up table, a set of parameterized functions, or a combination of the two, which relate the outputs of the analysis subsystems to the operation of the modification system components.\",\n \"While in general this control of the modification processes may be performed without intervention from a human operator, in one exemplary embodiment of the subject matter an operator or application that uses the presently disclosed subject matter may specify one or more high-level operation control parameters prior to applying it to a digital audio signal.\",\n \"Such high-level parameters may describe the kind of content being processed or the type of playback system that may be used to listen to the generated output signal.\",\n \"With the caveat that higher-level specifications may adjust the interpretations of each analyzed signal characteristic, we may now describe how the outputs of these signal characteristic analyses may be used to control the signal modification processes.\",\n \"Due to the frequency-dependent nature of many auditory processing phenomena such as masking, analysis may be performed to determine the distribution and complexity of the input signal's momentary spectra.\",\n \"This analysis, in turn, guides the determination of which convolution templates to use as well as the relative mixing gains applied to the outputs of each convolution, and, when deemed appropriate by other analyses, the type of noise signal to add to the input.\",\n \"Convolution templates and noise signals may be chosen to complement the current input signal content and to avoid creating obvious audible effects.\",\n \"Modifications that introduce too much content at frequencies that may not be strongly present in the input signal or that may become obvious due to simple, non-complex material may be avoided.\",\n \"Because the behavior of the human auditory system may be non-linear and generally responsive to relative changes in energy levels, the analysis system estimates the program level, or the average perceived loudness, of the input signal over time.\",\n \"For most audio signals, this estimate may vary gradually with changes in signal content.\",\n \"Relative changes in program level or comparisons between the estimated program level and the known average program level of typical audio recordings (which may vary with the genre of music or type of content contained in the audio signal) may then be used to guide control of the input signal modification system.\",\n \"For example, characteristics such as the pre-signal lead-time used by convolution templates, the relative amount of processed signal mixed with the raw input signal, and the choice of convolution templates may all be affected by the estimated program level.\",\n \"Audio transients, or short-duration changes in audio signal energy or spectral content, provide a particular kind of stimulus to the human auditory system that requires special processing by the input signal modification system.\",\n \"In order to enable such special processing, the input signal may be analyzed to detect transient events in the audio stream.\",\n \"Once detected, a transient event may be further analyzed for relative energy content, spectral make-up, and duration.\",\n \"Among other things, the detection of these events may control the choice of convolution templates and corresponding mixing gains, the amount of pre-signal lead-time used by the convolution templates, the addition of momentary noise-like signals to the input signal, and the enforcing of a duration of silence around the zero-delay time in convolution templates.\",\n \"Finally, because digital audio signals may be commonly reproduced on multichannel systems (with stereo, or 2 channel, systems being the most common), an awareness of the spatial image created by multiple signals may be required to avoid introducing changes into the individual audio signals that result in obvious or undesirable effects, where the changes may be perceived when a user listens to the combined output signals through such a multichannel system.\",\n \"When processing audio signals intended for multiple-channel playback, all channels may be processed together.\",\n \"A higher-level analysis that takes as its inputs the single-channel analysis results may be performed, and the output of this higher-level analysis may be used as an additional control input to the single channel modification systems.\",\n \"The result may be that different modifications may be made to each individual input signal than would have been made were the input signals processed in isolation; the control of the modification system must respect an additional set of rules to ensure that the interaction between multiple channels during playback does not have undesirable effects.\",\n \"Digital Audio Processing for the Restoration of Motion and Dynamic Timbre The sense of motion, liveliness, and spatial dynamics may be simulated using various methods discussed in this document.\",\n \"These methods may compensate for the static presentation of sound created by modern recording and sound synthesis techniques and common modern playback equipment such as headphones and ear buds in order to create a more natural, immersive, and enjoyable listening experience.\",\n \"Modern recorded music and sound, unlike naturally produced acoustic sound, may be spatially and timbrally static.\",\n \"Perhaps the most pervasive recording technique in modern audio production may be to record musical performances in a close mic'd manner, meaning that one or more microphones may be placed at static positions close to a musician or sound source and a performance may be recorded with minimal motion being made by the musician in order to produce a consistent loudness and tone across the duration of the recording.\",\n \"While this technique may afford a certain precision in the recording and post-processing of each musician's contribution to a song or musical piece, it deprives the completed recording of the liveliness and timbral dynamics created by motion in more natural performance and listening environments.\",\n \"The use of digitally synthesized sounds in modern recordings can take this dry, static nature to an extreme, producing recorded sound that may be entirely unchanging in tone or character over time.\",\n \"These modern recording techniques and technologies give rise to an unnatural and unpleasant stationary-tone audio-reproduction environment (STARE), in which recorded sound may be experienced as both spatially and timbrally static.\",\n \"In contrast, when performers play together in an acoustic space their movement alters the spatial radiation characteristics of their instruments over time, gradually changing the timbral qualities of their instruments and exciting various resonances and reflections in the space where they may be performing.\",\n \"Additionally, motion of performers on a stage or of listeners in an audience may change the sound heard by everyone in the audience in small or obvious ways.\",\n \"Even subtle motions of an audience member's head may create shifts in the delays and filtering experienced by the various sound components reverberating about a space before reaching their ears, and thus alter the tonal and spatial qualities of the sound that they hear.\",\n \"All of these dynamic effects contribute to a sense of immersion and liveliness that may be desirable to reproduce when listening to recorded audio.\",\n \"Although post-processing of close-mic recorded audio may add reverberation or panning effects that help to approximate this feeling of immersion and motion, these effects still present a sound with static tonal and spatial qualities in the sense that we have discussed here: a sound may be made to occupy some space or originate from some direction, but none of the natural, motion-driven variability that we have discussed here may be restored.\",\n \"Certain pieces of revered and highly sought-out analog recording equipment may come closest to providing an existing remedy for this problem of static recorded sound, as such equipment may be known to create subtle, time-varying changes in the tone and imaging of processed signals due to circuit phenomena such as very-low-frequency shifts in the DC-bias points of internal components caused by transient offsets in audio signals; however, this type of equipment may be expensive and thus may not be available to all producers of recorded music.\",\n \"Furthermore, such currently existing equipment may only provide a portion of the variability and dynamics that may be desirable for the re-creation of natural sound environments and the maximization of listening enjoyment.\",\n \"With the rise of portable music devices and the accompanying increase in the usage of portable playback equipment such as headphones and ear buds, the STARE problem has been taken to an extreme over the past decade: unlike loudspeakers, these personal playback devices prevent even the natural variability in tone that may be associated with a listener moving about a room or turning their head.\",\n \"At the same time, the popularity of close-mic recording techniques and synthesized digital audio has shown no signs of recession.\",\n \"Thus, it may be desirable to introduce digital signal processing techniques that restore a sense of motion and liveliness to digital audio recordings in order to improve the experience of listening to modern digital audio.\",\n \"A method for processing digital audio signals in order to restore a natural sense of motion and liveliness may be disclosed.\",\n \"The method consists of analyzing a digital audio recording and applying time-varying phase shifts, inter-aural delays, filtering, and amplitude and frequency modulation (e.g., “flutter,” “wow”) in a subtle way that may be driven by the presence of particular signal characteristics, such as percussive or transient events, that help to make the applied processing non-obvious.\",\n \"This method may compensate for the static tonal and spatial listening experience created by modern recording techniques, digitally synthesized sounds, and popular personal playback devices such as headphones and ear buds.\",\n \"This method may improve the experience of listening to digital audio recordings by restoring a sense of motion and immersion to those recordings that may be commonly experienced in live acoustic settings.\",\n \"FIG.\",\n \"9 illustrates an exemplary multichannel analysis signal-modifying processing subsystem 900, according to various embodiments of the present subject matter.\",\n \"Subsystem system architecture 900 demonstrates the general system architecture, consisting of a signal-analysis and processing-control subsystem and a signal-modifying processing subsystem, each of which may handle multiple input signals 910.The system takes one or more input signals 910 that each represent the amplitude of an audio waveform over time.\",\n \"Typically, these signals may each be a series of digitally stored values representing the instantaneous amplitude of a band-limited waveform that has been sampled at regularly spaced moments in time.\",\n \"The signal-modifying processing subsystem 900 both analyzes and modifies these input signals 905, with the results of input signal analysis determining the modifications to be performed at each point in time.\",\n \"In general, any available data may be analyzed and used to determine the exact modifications to be made to the digital audio signals at each point in their durations, though the presence of transient changes in intensity or energy associated with percussive sounds may play a large role in determining when modifications may be to be made because such sounds have the ability to help mask the applied modifications and make them non-obvious.\",\n \"Each channel in a multichannel processing system, from channel one 920 to channel N 925, may include multiple processing blocks.\",\n \"For example, channel one 920 may be processed through a frequency-dependent phase shift processing block (e.g., all-pass cascade processing block) 930, a linear relative-delay block 940, a magnitude filtering block 950, and an amplitude and frequency modulation block 960.Each processing block may be modified by control data 970, where control data 970 controls processing parameters within each processing block.\",\n \"Processing may be governed by parameterized equations that relate numerical results of signal analysis to parameters controlling the signal modification algorithms.\",\n \"The output of the processing blocks for each channel may be output from the subsystem 900 as output analysis results 980.Additionally, output analysis results 980 may be used to select a particular modification algorithm from a collection of available, implemented algorithms for use on a particular signal or time-region of a signal through some logical or rule-based processing of output analysis results 980.Implementation of the relationship between signal analysis and modification may be controlled or adjusted by higher-level parameters to select a particular relationship from a collection of options: for example, a high-level analysis of the input signals may determine the type of audio content that may be currently being processed (a general, individual instrument or some identified particular instrument, a complex sound mixture of multiple instruments, a sound mixture identified to belong within a particular genre of music, etc.)\",\n \"and use this determination to choose a particular relationship between analysis output and modification from a collection of relationships that may be each most appropriate for a certain type of content.\",\n \"Such high-level control and any lower level parameters of the relationship between analysis and modification may be exposed to an end-user through some type of interface for manual adjustment, or may be performed automatically.\",\n \"Once an analysis configuration and relationship between output analysis results 980 and signal modifications has been determined, time-varying modifications may be made to the input signals 910 to create a sense of motion and liveliness in the recorded audio, thereby improving the experience of listening to it during subsequent playback.\",\n \"These modifications may be performed in a way that may be subtle enough to avoid being overtly noticeable by listeners and that may be neutral enough to avoid altering the creative content of the audio recording, while still creating an appreciable, pleasing effect.\",\n \"Significant motion effects may be achieved within the all-pass cascade processing block 930.The all-pass cascade processing block 930 may introduce time-varying, frequency-dependent phase shifts, potentially applying different shifts to each channel in a stereo or multichannel recording.\",\n \"Such modifications can be performed using digital all-pass filtering, using filters with transition frequencies and orders that vary over time.\",\n \"It has been demonstrated in psychoacoustics experiments that the effects of such phase shifts, which correspond to sound components moving closer and further away, can be perceptually subtle when compared with magnitude, or non-all-pass, filtering.\",\n \"To reduce the perception of the phase shift, a bandpass filter may be used to avoid shifting the phase of the bass or treble.\",\n \"The bandpass filter may include frequencies ranging from 500 Hz to 5 KHz.\",\n \"This provides a neutral and subtle way of animating sound content.\",\n \"In various embodiments of the presently disclosed subject matter, changes in imposed phase shift may often occur in-sync with percussive audio transients, with the amount of shift increasing during transients and then slowly drifting back toward zero over the course of approximately 200 to 500 milliseconds, or in a semi-periodic cyclical fashion at a similar rate.\",\n \"The linear relative-delay block 940 may modify digital audio recordings in order to instill a sense of motion may be using time-varying inter-aural delays.\",\n \"When a sound source moves about a space relative to a listener or a listener rotates their head relative to a source, varying amounts of delay may be experienced by sound as it travels to the listener's left and right ears.\",\n \"Because of this, applying small, time-varying amounts of relative delay between the left and right channels of a stereo audio recording or among multiple channels in a multichannel recording can create a sense of movement and variability similar to the motion that naturally occurs when listening to a live performance.\",\n \"Because listeners have been found in psychoacoustics experiments to be able to detect horizontal displacements of less than one degree in the horizontal plane, the relative delays imposed by the modification system in this way need not be large in order to create a sense of motion.\",\n \"In fact, using too large a modification may be likely to be distracting and prevent the desired subtlety.\",\n \"Various embodiments may impose time-varying relative linear delays of approximately 0.1 millisecond or less across channels in a stereo or multichannel recording.\",\n \"As with imposed frequency-dependent phase shift, the amount of applied relative linear delay may vary in-sync with percussive or transient audio events, or may oscillate in a semi-periodic fashion that may be more loosely driven by signal properties.\",\n \"The magnitude filtering block 950 may be used to simulate a radiation pattern corresponding to motion of an audible source or listener.\",\n \"The radiation pattern of a sound source may change in response to the motion of performers around it or the way that a performer makes contact with it, and the transfer function from a source to a listener due to the acoustic space that they occupy may change significantly as either person moves about or rotates within the space.\",\n \"Typically, these phenomena may give rise to general changes in timbre that may be simulated using low-order IIR (infinite impulse response) filters with transition or cut-off frequencies and gains that change over time or comb-filtering effects caused by the summation of multiple reflections of sound that can similarly be modeled using digital FIR (finite impulse response) or IIR filters that change over time.\",\n \"Both of these types of filters may be designed to produce subtle effects, and thus provide the types of modification desired by the presently disclosed system; by varying their application in response to characteristics of the input signal, such magnitude-filtering may be performed in a way that creates a sense of motion and liveliness without becoming obvious or altering the creative content of the modified recording.\",\n \"The amplitude and frequency modulation block 960 may be used to impose subtle time-varying amplitude modulation (e.g., “wow”) and frequency modulation (e.g., “flutter”) on digital audio recordings in order to create an enhanced sense of motion and dynamics.\",\n \"These effects may be familiar in the audio world because they result from imperfections in common analog playback systems, such as tape and vinyl While these effects may be overt, distracting, or detrimental to playback quality, they may be used subtly to create neutral and subliminal but perceivable motion and complexity in an audio recording.\",\n \"Various embodiments of the presently disclosed subject matter may apply time-varying, semi-periodic frequency modulation of less than ±1 cent (where 1 cent represents the 1/100 of the difference between each semitone within an octave) and amplitude modulation of less than ±1 dB, at oscillation rates below about 5 Hz.\",\n \"As with other modifications, the exact amount and rate of modulation may be driven by the analysis of input signal and may vary in response to the low-passed energy envelope of the signal, the presence of discrete, identified transients, momentary spectral complexity, or any other suitable property.\",\n \"Automatic Level-Dependent Pitch Correction of Digital Audio A pitch correction signal processing technique modifies digital audio recordings to correct for level-dependent shifts in the perceived pitch of audio content.\",\n \"These corrections compensate for the effects of sound level on perceived pitch, corrections that may be impractical to apply during performance or recording.\",\n \"These corrections may improve the experience of listening to digital audio recordings by adjusting the perceived pitch of an audio signal dynamically.\",\n \"The dynamic adjustment may be dependent upon the momentary loudness of the audio signal (e.g., audio signal intensity, audio signal power, audio signal level, audio signal volume).\",\n \"The concept of auditory or musical pitch may be a perceptual one: while the pitch of a sound tends to be strongly related to mathematical properties of the associated acoustical wave such as its periodicity or frequency content, the relationship between such numerical properties and the perception of pitch may be more complex.\",\n \"Significant research into this relationship was performed in the 1930's at various academic institutions and at Bell Labs, and this research revealed a strong interaction between the level at which a sound may be heard and its perceived pitch, meaning that the same sound heard at different levels or volumes may be perceived as having different pitches, even when no other mathematical properties of the sound signal (such as periodicity or frequency content) have changed.\",\n \"At that time, studies were performed that further elucidated this relationship between sound level and pitch.\",\n \"It was demonstrated that the amount of shift in perceived pitch for a given change in sound level may be dependent upon a complex interaction of signal characteristics, including the frequency content and absolute level of a sound.\",\n \"One trend characterizing this relationship may be that for a simple tone (e.g., single frequency sinusoid), as level increases, the perceived pitch of that tone decreases for frequencies below about 2000 Hz and increases for frequencies above about 2000 Hz.\",\n \"A general characterization of the relationship between the level, frequency content, and perceived pitch of complex sounds (sounds with multiple frequency components) has not been fully characterized for all complex sounds.\",\n \"However, it was found that the shifts in perceived pitch that occur for complex sounds at varying levels may be predicted by a weighted mean of the shifts that would occur for each sinusoidal component of the sound if they were heard individually.\",\n \"This finding suggests that, because many sounds produced by musical sources contain frequency content both above and below the zero-shift frequency of about 2000 Hz, most musical audio material may demonstrate small shifts in perceived pitch with changes in level relative to the shifts demonstrated by simple tones.\",\n \"This phenomenon, that perceived pitch may be dependent upon sound level, poses a subtle problem for musicians and recording engineers.\",\n \"Generally, musicians optimize the tuning of their instruments and their playing techniques to compensate for this effect when performing live together in a group.\",\n \"Such adjustments may be subconscious or habitual rather than overt and deliberate, with professional musicians constantly making minute adjustments based on instinctual knowledge of their instruments and the feedback provided by their perception of pitch; however, it may be common in modern recording workflows for musicians to record their contributions to a song in isolation so that the individual sounds may later be layered or mixed together to form a final recording by a mix engineer, as this affords much more flexibility for adjusting the individual recordings and applying post-processing to individual sounds.\",\n \"In this case, performing musicians cannot make the same adjustments to ensure that all parts of the resulting sound mixture may be perceived to have their desired pitches.\",\n \"Additionally, many instruments do not provide musicians with the capability of making such subtle adjustments to the perceived pitch of the sound they produce, meaning that regardless of the recording situation there may be room for improvement through post-processing of recordings to make these adjustments.\",\n \"Finally, when numerical tools such as frequency content analysis may be relied upon to tune instruments or later adjust the tuning of recorded sounds, this may not compensate for the phenomenon of perceived pitch may not be solely determined by frequency content may be usually neglected.\",\n \"This may result in sounds that may be in need of further dynamic pitch adjustment to achieve or maintain desired musical pitches.\",\n \"Because the perceived pitch of musical sound plays a large role in its emotional impact and perceived quality, even minor pitch adjustments may have a noticeable impact on the listening experience.\",\n \"Research into psychoacoustics has demonstrated that the perceived pitch of a sound may be effected by the level at which that sound may be heard, meaning that minor adjustments to produced sounds may be required to sustain a particular pitch across differing sound levels.\",\n \"Because modern recording techniques make it difficult or impossible for musicians to make these adjustments during performance and because such adjustments may not be possible, using digital signal processing techniques to apply dynamic, level-dependent adjustments to the pitch of recorded digital audio, when appropriate, may greatly enhance the listening experience.\",\n \"A method for processing digital audio signals in order to correct for level-dependent shifts in the perceived pitch of audio content may be disclosed.\",\n \"The method consists of analyzing a digital audio recording and creating small, dynamic shifts in perceived pitch as required to compensate for the pitch distortion caused by relative changes in momentary sound level.\",\n \"This method may be suitable for processing of any type of digital sound recording, including individual sound recordings and complex sound mixtures.\",\n \"This method may compensate for modern recording techniques that make it difficult or impossible for musicians to make such adjustments correctly in produced pitched during recorded performances and to improve the perceived pitch of recorded digital audio across changes in relative level wherever possible.\",\n \"By correcting these small pitch distortions, the perceived quality of digital audio recordings may be improved without altering their creative content.\",\n \"FIG.\",\n \"10 illustrates a series single-channel analysis subsystem 1000, according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"10 demonstrates one embodiment of the signal-analysis subsystem in which channels of audio may be analyzed individually by parallel single-channel analysis systems, the output of which may be then further processed by a higher-level multichannel analysis system that may lead to modifications of the resulting single-channel control decisions.\",\n \"Series single-channel analysis subsystem 1000 may operate on multiple input audio waveform channels 1010 and 1015.Each input audio waveform channel may be analyzed using a spectral analysis module 1020, a loudness analysis module 1030, a transient analysis module 1040, and a rule-based control signal generator 1050.The output of the spectral analysis module 1020, the loudness analysis module 1030, or the transient analysis module 1040 may be processed within a multichannel analysis module 1060.The output of the rule-based control signal generator 1050 may be combined with outputs from other rule-based control signal generators within an aggregating rule-based control signal generator 1050.The output of the aggregating rule-based control signal generator 1070 may be processed within a processing module 1080, and may generate an output waveform 1090.FIG.\",\n \"11 illustrates a parallel single-channel analysis systems signal-analysis subsystem 1100 according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"11 demonstrates one embodiment of the signal-analysis subsystem in which channels of audio may be analyzed individually by parallel single-channel analysis systems, the output of which may be then further processed by a higher-level multichannel analysis system that may lead to modifications of the resulting single-channel control decisions.\",\n \"Parallel single-channel analysis subsystem 1100 may operate on multiple input audio waveform channels 1110.Each input audio waveform channel may be analyzed using a spectral analysis module 1120, a loudness analysis module 1130, a transient analysis module 1140, and a rule-based control signal generator 1150.The output of the spectral analysis module 1120, the loudness analysis module 1130, or the transient analysis module 1140 may be processed within a multichannel analysis module 1160.The output of the rule-based control signal generator 1150 may be combined with outputs from other rule-based control signal generators within an aggregating rule-based control signal generator 1150.The output of the aggregating rule-based control signal generator 1170 may be processed within a processing module 1080, and may generate an output waveform 1090.FIG.\",\n \"12 shows the dependence of perceived pitch on sound level 1200 according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"12 shows the dependence of perceived pitch on sound level as determined experimentally by Stevens S. for a particular test subject.\",\n \"This plot shows the percent change in perceived pitch 1220 as a function of sound intensity 1210 for a variety of frequencies spanning the audible range.\",\n \"Absolute position on the y-axis for each curve may be arbitrary only relative change may be depicted.\",\n \"FIG.\",\n \"12 demonstrates the finding that the perceived pitch of simple, sinusoidal tones with frequencies below about 2000 Hz decrease as the level of the tone increases while the perceived pitch of sinusoidal tones with frequencies above about 2000 Hz increase as the level of the tone increases.\",\n \"The changes depicted here for simple tones may be used to predict the effects of changes in sound level on the perceived pitch of complex musical tones and sounds, which may be used to determine appropriate compensatory pitch-shift amounts.\",\n \"FIG.\",\n \"13 shows the dependence of perceived pitch on sound level at low frequencies 1300 according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"13 shows the dependence of perceived pitch on sound level at low frequencies as interpreted from experimental results by Snow, W. in his 1936 paper, “Change of Pitch with Loudness at Low Frequencies” (J. Acoust.\",\n \"Soc.\",\n \"Am., vol.\",\n \"8, no.\",\n \"1, pp.\",\n \"14-19, 1936).\",\n \"Experimentally determined curves such as these may be used in determining appropriate compensatory amounts of pitch-shift to apply in response to changes in signal intensity or level.\",\n \"As discussed above with respect to Multiplexed Convolution, any implementation of the relationship between signal analysis and modification may be controlled or adjusted by higher-level parameters to select a particular relationship from a collection of options: for example, a high-level analysis of the input signals may determine the type of audio content that may be currently being processed (a general, individual instrument or some identified particular instrument, a complex sound mixture of multiple instruments, a sound mixture identified to belong within a particular genre of music, etc.)\",\n \"and use this determination to choose a particular relationship between analysis output and modification from a collection of relationships that may be each most appropriate for a certain type of content.\",\n \"Such high-level control and any lower level parameters of the relationship between analysis and modification may be exposed to an end-user through some type of interface for manual adjustment, or may be performed automatically.\",\n \"Once an analysis configuration and relationship between analysis results and signal modifications has been determined, time-varying modifications may be made to the perceived pitch of the input signals.\",\n \"These pitch shifts may be small, such as in the range of a shift in frequency of 0.015 to 1.15 percent (e.g., 0.25 to 20 cents, where 100 cents represents the difference between each semitone within an octave).\",\n \"These small pitch shifts may be in accordance with the small perceptual shifts in pitch that occur for complex musical sounds with relative changes in level, and different amounts of pitch or frequency shift may be applied to separate spectral bands of the input signal.\",\n \"In one embodiment of the presently disclosed subject matter, positive pitch-shift may be applied to signal content at frequencies above about 2000 Hz as signal levels fall below a nominal reference level in order to compensate for the decrease in perceived pitch that occurs for sinusoidal components in this frequency range as level decreases.\",\n \"In another embodiment of the subject matter, the input signal may be split into numerous frequency bands and varying amount of pitch or frequency shift may be applied to each band according to analysis results in order to compensate for the changes in perceived pitch associated with the frequency content of each band during changes in relative sound level.\",\n \"Several algorithms for applying pitch-shift or frequency-shift may be known to those skilled in the art of audio signal processing.\",\n \"Any one or multiple of these algorithms may be applied to the input signals or portions of the input signals (isolated frequency bands, for example) to achieve the desired changes in perceived pitch, as determined by signal analysis.\",\n \"If multiple algorithms were implemented and made available to the operator, the operator may determine which algorithm may be best suited to a particular bit of audio signal.\",\n \"Alternatively, analysis of that audio signal may be used to determine automatically which algorithm may be best suited to each portion of audio signal.\",\n \"Multiplexed Convolution A multiplexed convolution signal processing architecture applies multiple distinct types of processing to an input signal simultaneously in an adaptive, signal-aware way through the calculation of one or more time-varying convolutions.\",\n \"The convolution kernels may be associated with points in a multidimensional behavior space, where coordinates correspond to parameters of the distinct processes being implemented.\",\n \"The values of these parameters change over time in response to input signal properties, adaptively changing the convolution kernels and thus the results of processing.\",\n \"In the present case, such processing may be achieved through the calculation of generalized convolution operations between an input signal and a time-varying convolution kernel, where the content of the kernel varies in response to properties of the input signal.\",\n \"The mathematical operation of convolution between two functions, (f*g)(t)≡∫−∞∞f(τ)g(t−τ)dτ, (8) may be fundamental to linear systems analysis and may be well known in a variety of fields, including the field of signal processing.\",\n \"The output of any linear time-invariant (LTI) system may be defined for arbitrary input signals as the result of convolution between those input signals and a function known as the system's impulse response.\",\n \"This input-output relationship provides an extremely concise and powerful way of mathematically characterizing a broad class of systems that may be commonly encountered in the physical world and that may be frequently used in an endless variety of applications.\",\n \"In more common notation, this relationship can be expressed as (y)(t)≡∫−∞∞h(τ)x(t−τ)dτ, (9) for an input signal x(t), time-invariant system impulse response h(t), and corresponding output signal y(t).\",\n \"The convolution defined in equation (8) and equation (9) may be a linear operation and thus cannot be used directly to implement nonlinear processing.\",\n \"However, it may be possible to formulate the input-output relationship of a system whose behavior varies over time in response to characteristics of the input signal as a form of generalized convolution that may achieve nonlinear system behavior.\",\n \"The main difference between such an alternative formulation of convolution and the standard definition presented in equation (8) may be that the two functions, f and g, do not remain independent of one another.\",\n \"In terms of the more standard linear system notation presented in equation (9), the system response h(t) becomes dependent upon not just time t, but the input signal x(t) itself.\",\n \"While this introduced dependence may make the analysis of overall system behavior much more complicated, it also creates the possibility for more complex system behavior such as nonlinear processing.\",\n \"For example, we may use the definition (y)(t)≡∫−∞∞H{SHIFT−t{X}}(τ)x(t−τ)dτ, (10) where H{⋅} and SHIFTt{⋅} define operators whose domains may be the set X of all functions x with the real numbers as both their domain and range, X={x|x: R→R}, and whose ranges may be the same set of functions, written as H: X→X and SHIFTt: X→X.\",\n \"In this case, the operator H{⋅} defines the relationship between the input signal x(t) and the system response h(t) in a general way, and the operator SHIFTt{⋅}, defined as SHIFTt{X(α)}≡X(α−t), (11) serves the purpose of making the input-output relationship of the overall system time-invariant, meaning that the relationship between the input signal x(t) and the system response h(t) defined by H{⋅} takes into account only relative differences in time between input and output and has no sense of overall time.\",\n \"The generalized convolution operation defined in equation (10) characterizes the dynamic system through a particular kind of time-varying system function known as an input delay-spread function, albeit one that has the unusual property of being dependent upon the input signal itself.\",\n \"A similar definition with slightly different behavior may be written as (y)(t)≡∫−∞∞H{SHIFT−(t-τ){X}}(τ)x(t−τ)dτ, (12) where the dynamic system may be instead characterized through a time-varying system function known as an output delay-spread function.\",\n \"The difference between these types of time-varying system functions may be in whether the particular system function at time t, ht(τ), may be constant for a time t associated with the output signal being calculated or with the input signal being used to calculate the output.\",\n \"Otherwise, both definitions capture the same dependence of system behavior upon the input signal x(t) and provide essentially the same definition of a generalized convolution operation.\",\n \"The system definitions given in equations (10) and (12) make it possible to achieve both linear and nonlinear system behavior with the same general system architecture, and thus provide a unifying framework through which multiple different processes may be applied to a signal simultaneously; however, this type of general, dynamic system description has not been used to unify multiple simultaneous processes in this way previously.\",\n \"Because multiple distinct processes performed on an input signal can interact in complex ways when some of the processes may be nonlinear, and because various system architectures may exhibit different behavior when made to be time-varying, it may be desirable to devise such a unified system so that all individual processes may be controlled simultaneously in a way that takes their interactions into account and allows for the desired overall processing to be consistently achieved when making changes to parameters of one or more of the individual processes.\",\n \"A method for processing digital signals in order to simultaneously implement multiple linear and/or nonlinear processes in a general way that allows for control of interactions between each stage of processing and adaptive, signal-aware system behavior is disclosed.\",\n \"The method consists of defining a range of system behaviors, each designed to achieve the best overall processing results associated with a set of parameter values describing the individual implemented processes, and then analyzing input signal properties to determine the desired values for these parameters at each moment in time.\",\n \"The connection between analysis results and system behavior may be described by a multidimensional system-behavior space in which coordinates correspond to parameters of the distinct processes being implemented: Each designed system behavior may be associated with a point in this space, and analysis of input signal properties determines where in the space the system should currently be operating.\",\n \"All possible system behaviors may be described in a consistent and general way as one or more generalized convolutions whose outputs may be combined to generate the system output, allowing for smooth transitions and interpolations between specified system behaviors, control of interactions between the various implemented processes by way of total system behavior specification, and consistent time-varying behavior across all implemented processes.\",\n \"A unified system may simultaneously implement multiple linear and/or nonlinear processes in a manner that may be time-varying responsive to various characteristics of the input signal.\",\n \"Because processes implemented through different architectures may exhibit inherently different behavior when made to be time-varying and because the interactions between multiple stages of processing may be complex when nonlinear processes may be performed, such a unified system may be intended to allow for more consistent and detailed control of overall system behavior when multiple processes may be to be applied to an input signal simultaneously in a time-varying, signal-aware manner.\",\n \"A system that processes digital signals in a way that allows for the simultaneous application of multiple linear and/or nonlinear processes in a general, well-controlled, and signal-aware way is disclosed.\",\n \"The system takes as its input one or more digital signals.\",\n \"These signals may each be a series of digitally stored values representing the instantaneous amplitude of a band-limited waveform that has been sampled at regularly spaced moments in time.\",\n \"In many embodiments of the presently disclosed subject matter, these digital signals may represent digital audio signals, corresponding to the sampled amplitude of an audio waveform over time.\",\n \"The presently disclosed system both analyzes and modifies these input signals, with the results of input signal analysis determining the modifications to be performed at each point in time.\",\n \"This relationship between analyzed signal properties and resulting modifications may be established by indexing into a multidimensional system-behavior space with coordinates that correspond to parameters of the various individual processes being implemented.\",\n \"The results of input signal analysis at any given moment determine the desired parameter values for all of the individual processes, and thus a particular point in behavior space.\",\n \"The pre-determined (designed) system behavior associated with that particular point in behavior space may be then used to calculate the system output.\",\n \"As input signal properties vary over time, so do the associated point in behavior space, and thus the overall system behavior.\",\n \"FIG.\",\n \"14 demonstrates the multiplexed convolution system architecture 1400 according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"14 consists of a signal-analysis and processing-control subsystem 1420 and a signal-modifying processing subsystem 1440, each of which may handle multiple signals of data at once.\",\n \"FIG.\",\n \"15 demonstrates the multiplexed convolution signal-analysis and processing-control architecture 1500 according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"15 illustrates the system architecture of the subject matter with the signal-analysis and processing-control subsystem depicted in more detail as consisting of three main steps: signal analysis 1520, mapping from analysis results to a point in behavior space 1530, and processing a kernel look-up 1550 by determining current system behavior based on the location of that point in behavior space.\",\n \"Mapping to behavior space 1530 may receive metadata 1540 as input.\",\n \"Subsystem architecture 1500 may include a processing module 1560 that combines one or more input channels 1510 with the output of the kernel look-up 1550 to generate an output waveform 1570.FIG.\",\n \"16 shows a multiplexed convolution signal analysis processing subsystem 1600 according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"16 shows an embodiment of the signal analysis subsystem for a case where digital audio signals may be processed.\",\n \"Several types of analysis, including spectral analysis 1630, loudness analysis 1640, transient analysis 1650, and a multichannel relationship analysis 1660 may be performed.\",\n \"The analysis results may be combined with each other, or may be combined within a data packager 1670 to determine the desired individual process parameter values associated with current input signal properties, and thus the system's current location in behavior space.\",\n \"FIG.\",\n \"17 shows an exemplary three-dimensional, discrete behavior space 1700 according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"17 shows an exemplary three-dimensional, discrete behavior space, denoted Θ, where each parameter, θi (i=1 (1710), i=2 (1720), i=3 (1730)) can take on any of 8 integer values ranging from 0 to 7.In this example, it may be the case that three individual processes may be being implemented simultaneously and that each parameter controls the general degree to which each process may be applied to the input signal.\",\n \"Each process would thus operate at one of 8 levels.\",\n \"A system behavior may then be specified for each point in this space, taking potential interactions between the individual processes into account and ensuring that the behavior varies smoothly everywhere.\",\n \"FIG.\",\n \"18 presents an illustrative diagram of behavior space mapping and system-behavior determination operations 1800 according to various embodiments of the present subject matter according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"18 presents an illustrative diagram of the overall system architecture, similar to FIG.\",\n \"15, but using a graphical representation of the behavior space mapping and system-behavior determination operations.\",\n \"FIG.\",\n \"18 demonstrates the general system architecture of the subject matter with the signal-analysis and processing-control subsystem depicted in more detail as consisting of three main steps: receiving signal analysis 1810, identifying a behavior space 1820, parameterizing the input signal 1830, mapping the analysis results to a point in behavior space 1840, and processing a kernel look-up 1850 by determining current system behavior based on the location of that point in behavior space, and generating an output waveform 1860.FIG.\",\n \"19 shows an exemplary digital computer embodiment of the system-behavior determination operation based on look-up tables 1900 according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"19 shows an exemplary digital computer embodiment of the system-behavior determination operation based on look-up tables.\",\n \"In this embodiment of the present subject matter, the point in behavior space corresponding to the current determined individual process parameter values takes on integer values 1910.The integer values 1910 may each correspond with one or more indices within a multidimensional array of memory addresses 1920 stored in a computer.\",\n \"At each moment in time, the current parameter value vector 1910 may be used to index into this array 1920, and the memory address at the specified index may be followed to a block of memory 1930 that specifies the system behavior for that particular set of parameter values.\",\n \"The first entry in this block of memory 1930 may be a code that specifies a combination topology for the outputs of the LTI process 1940 or for the outputs of the generalized convolutions 1950.The remaining entries may contain one memory address per individual process.\",\n \"For example, the embodiment in FIG.\",\n \"19 contains P such processes.\",\n \"The first value pointed to by each of these individual process addresses may be a Boolean flag indicating whether the process may be linear time-invariant (LTI).\",\n \"If Boolean flag indicates that the process is LTI, the entries following the flag specify the impulse response for that LTI system.\",\n \"If the process may be nonlinear, the flag may be set to false, and the subsequent single entry may be a function pointer used to evaluate the generalized convolution kernel for that nonlinear process.\",\n \"This effectively implements the overall system again recursively, as may be discussed in detail later.\",\n \"This look-up process repeats until all individual processes terminate at a set of LTI system impulse responses, which may be then combined and evaluated according to the indicated output topologies in order to form the system output.\",\n \"While FIG.\",\n \"19 shows a simple example, more complex embodiments may require the storing and interpreting of additional metadata for each process and response.\",\n \"In order to enable the simultaneous implementation of several types of processing in this continuously time-varying and general way, all possible system behaviors may be discussed using a consistent, general architecture: at all times, the system performs one or more generalized convolutions with input signals and combines the results of these convolutions according to a topology consisting of series and parallel connections to form the output signal.\",\n \"Thus, each point in behavior space dictates a set of generalized convolution kernels and a topology for combining the convolution outputs.\",\n \"These convolution kernels and combination topologies may be designed to best achieve the overall processing results specified by the associated set of individual process parameters, taking possible interactions between processes into account, and may be designed to vary in such a way across nearby points in behavior space that overall system behavior may be guaranteed to vary smoothly while changing in response to properties of the input signal.\",\n \"By describing the overall system behavior in this way, the system may be able to manage interactions between multiple individual processes.\",\n \"It may be often easiest to describe a desired overall processing system as a signal-flow graph consisting of several discrete, well-understood parts that each serve a particular function.\",\n \"However, complicated interactions between the effects of these individual processes in the presence of nonlinearity generally dictate that when the parameters of one process may be changed, the parameters of other processes must also be changed in order to compensate and keep their contribution to the overall system equivalent.\",\n \"These compensating changes may be difficult to derive for many multi-process systems when using common parameterizations and implementation architectures for each discrete process, which may vary significantly depending on the type of process being implemented.\",\n \"Further complication arises when imposing time-varying behavior on a multi-process system in which the various processes may be implemented using different architectures, as each individual architecture may have unique restrictions on its ability to change over time and may produce varying artifacts or undesirable consequences when changing configuration or parameter values.\",\n \"In order to allow better time-varying control of multiple simultaneous processes, an alternative approach may be used to control overall system behavior through the adjustment of individual process parameters.\",\n \"In particular, the desired overall system behavior for each combination of individual process parameters may be specified through the use of one or more generalized convolutions that may or may not reflect various discrete processing components, and that can be designed without the restrictions of discrete component parameterizations in order to better maintain overall desired system characteristics.\",\n \"The system response kernels for these convolutions can then be made to vary smoothly in response to changes in individual process parameters, allowing the system behavior to change smoothly over time and in a way that preserves the desired overall processing across all possible behavior trajectories without the need for directly analyzing the complex interactions between individual processes.\",\n \"Furthermore, by implementing all processing as generalized convolutions, overall system implementation may be simplified: various processes may be achieved using varying generalized convolution kernels rather than varying architectures and techniques, and consistent time-varying behavior can be achieved across all processes in the system.\",\n \"Additional analysis and modifications are discussed below in more detail.\",\n \"Multiplexed Convolution: Adaptive, Signal-Aware Control of System Behavior The first step in determining the system response at any particular moment in time may be to determine where, in behavior space, the system should be operating based on the current input signal content.\",\n \"If we denote the location of the system in behavior space at time sample n as θ[n], we can express this procedure as evaluating part of the operator H{⋅} presented in equation (10) as θ[n]=Hθ{SHIFT−n{X}}, (13) where H{⋅}=Hh{Hθ{SHIFT−n{X}}} (14) gives a decomposition of the relationship between input signals x and system response h, denoted as H{⋅}, into two separate steps: one operation which analyzes signal properties and maps to a point in system behavior space, Hθ{⋅}, and another operation which maps from that point in system behavior space to a description of system behavior in terms of generalized convolution kernels and system topology, Hh{⋅}.\",\n \"Here, our behavior space, which we may refer to as Θ, may be a p-dimensional space, where p may be the number of parameters characterizing the operation of the system, and we have that θ[n]ϵΘ for all n. In general, Θ need not be a continuous space; in some cases we may only allow θ[n] to take on values from a specific, discrete collection of settings or values.\",\n \"Note that FIG.\",\n \"18 shows signal analysis and Hθ{⋅} as separate blocks.\",\n \"This may be caused by embodiments of the presently disclosed subject matter in which the types of signal analyses performed and the way that their results map into behavior space may be separable, such as depicted in FIG.\",\n \"18.However, it may be more useful to describe Hθ{⋅} as representing all processing from input signals to θ[n].\",\n \"In general, any available data may be analyzed and used to determine the value of θ[n] at each point in time, including additional metadata supplied to the presently disclosed system separately from the input signals themselves.\",\n \"Furthermore, the relationship between analysis results and θ[n], represented by Hθ{⋅}, may itself be controlled or adjusted by higher-level parameters resulting from signal analysis or external controls.\",\n \"Depending on the particular implementation, this may be thought of as selecting one Hθ{⋅} from a collection of options or as warping the function mapping between signal analysis results and points in behavior space by some additional operation W: Θ→Θ, as W{Hθ{⋅}}.\",\n \"An example of a high-level parameter that might be used in this manner would be a specification of the general type of digital signal being processed, either determined through automatic classification or through manual specification by an operator prior to processing.\",\n \"This capability of altering Hθ{⋅} itself may be most applicable to embodiments of the presently disclosed subject matter that may be used for processing numerous types of signals, where the types of signals are fundamentally different in structure.\",\n \"In other embodiments, this capability of altering Hθ{⋅} itself may be excluded when not needed.\",\n \"In embodiments of the presently disclosed subject matter where the disclosed system is applied to audio signals, input signal properties such as spectral content, energy or perceptual loudness, the presence of transient changes in intensity or energy.\",\n \"Additionally, signal property relationships between multiple input signals designed to be reproduced together acoustically using a multichannel speaker array may play a large role in determining θ[n] at any moment in time.\",\n \"An exemplary signal-analysis subsystem that considers these properties may be depicted in FIG.\",\n \"18.In these embodiments, higher-level parameters such as the type of audio content contained in the signal (a specific instrument, speech, a musical recording adhering to a particular genre, etc.)\",\n \"may be determined automatically from analysis of the audio signals or specified manually by an operator through some type of user interface in order to determine the appropriate behavior space mapping Hθ{⋅} for the current class of signal.\",\n \"In one embodiment of the present subject matter, the entire durations of previously recorded digital signals may be analyzed and considered when determining the varying modifications to be made across the duration of the signals.\",\n \"In another embodiment of the presently disclosed subject matter, modifications may be made to digital signals in real-time that may be, as they may be being created, recorded, or presented as a stream of data.\",\n \"In this embodiment, analysis of the digital signals' previous and current content may be used in determining the modifications to be made to the signals at the present moment, or an overall delay may be imposed on the throughput of the system such that some amount of future data may be considered when determining the modifications to be performed.\",\n \"Furthermore, analyses of multiple signals that may be somehow related may inform the processing of those signals in any relevant way.\",\n \"For example, the same modifications may be applied to multiple digital signals as determined by analyses performed on each signal in the collection, multiple signals may be analyzed and modified independently, or an analysis of an entire collection of signals may inform the varying modifications to be made to each signal in the collection.\",\n \"Each of these exemplary configurations as well as other analysis and control configurations may be relevant and useful in various contexts.\",\n \"These analysis configurations are presented as illustrations of the wide range of possible configurations, and additional analysis configurations may be used.\",\n \"Practically, the connection between analyzed signal properties and associated points in behavior space, Hθ{⋅}, may be established in any suitable form that may be accessible by the system.\",\n \"In one embodiment of the presently disclosed subject matter, this relationship may be stored as a collection of pre-determined digital look-up tables that relate results of signal analysis to points in behavior space.\",\n \"Such look-up tables may be indexed by raw, numerical analysis results, by higher-level analysis results based on a synthesis of several signal properties including logical, rule-based processing of basic analysis results, or by some other result of signal analysis.\",\n \"They may map to a discrete-valued behavior space, Θ, or have tabulated values that may be interpolated in order to map into a continuous Θ.\",\n \"In another embodiment of the subject matter, this relationship may be established by a set of parameterized equations that relate numerical results of signal analysis to coordinates in a continuous Θ.\",\n \"It should be noted that the parameterizations of individual processes reflected in the coordinates of the behavior space Θ may correspond to a wide range of characteristics varying from low-level mathematical parameter values to high-level parameters describing the overall effects of processing or the degree of processing applied.\",\n \"The connection between points in behavior space and implemented system behavior, Hh{⋅}, may be chosen during design of a specific embodiment and may be entirely general; the relationship may be any that can be captured by the specification of system behavior associated with each point in behavior space, as may be discussed in more detail in the following subsection.\",\n \"Multiplexed Convolution: Description and Implementation of System Behavior Various system behaviors may be achieved through the calculation of one or more generalized convolutions, and by combining the convolution outputs according to a specified system output topology.\",\n \"For applying these behaviors to recorded digital signals, modifications of equations (10) and (12) may be used to calculate the discrete-time generalized convolution outputs as y [ n ] = ∑ m = - ∞ ∞ H { SHIFT - n { x } } [ m ] × [ n - m ] ( 15 ) in the input delay-spread function case and y [ n ] = ∑ m = - ∞ ∞ H { SHIFT - ( n - m ) { x } } [ m ] × [ n - m ] ( 16 ) in the output delay-spread function case, either of which may be used.\",\n \"Each point in system-behavior space may be associated with a set of generalized convolution kernels and an associated output combination topology designed to achieve the specified underlying individual process parameters.\",\n \"With H{⋅} subdivided as in equation (14), this may be represented by the operator Hh{⋅}, which provides a mapping from points in behavior space Θ to the overall system response.\",\n \"Ultimately, this response may be characterized by a collection of traditional convolution kernels, one for each of P individual processes, hi[n], i=1, .\",\n \".\",\n \".\",\n \", P, and a specified topology for evaluating and combining the outputs of these standard convolutions.\",\n \"Convolution with each kernel may be then evaluated using the standard discrete-time convolution operation, y i [ n ] = ∑ m = - ∞ ∞ h i [ m ] × [ n - m ] , ( 17 ) where hi[m] may be zero for all m<0 (as in causal systems), or at least for all m<M for some negative integer M (as in systems with some finite amount of look-ahead).\",\n \"In various embodiments, system behavior may not be specified directly for all points in Θ, particularly if Θ may not be a finite set.\",\n \"The set of points in Θ for which system behavior may be specified may be denoted Θh.\",\n \"If H74 {⋅} may be allowed to output parameter vectors θ that may not be in the set Θh, system behavior for those points may be determined by interpolating the generalized convolution kernels associated with nearby points in Θh.\",\n \"In some embodiments of the subject matter, system behavior may be defined for all points in continuous dimensions of Θ using parametric definitions of the generalized convolution kernels or through the re-calculation of these kernels as the result of some parametric system equation whenever changes may be made to that parameter value.\",\n \"Various embodiments matter may specify other generalized convolution kernels and combination topologies associated with each point in Θh.\",\n \"For linear time-invariant processes, a single convolution kernel hi[n] corresponding to the impulse response of the LTI process may be specified for each point in Θθ, as this characterizes the process entirely.\",\n \"For nonlinear processes, a generalized convolution kernel H{⋅} may be specified for each point in Θθ.\",\n \"Note that this definition may be somewhat recursive, as the overall system may be characterized by a single generalized convolution operation as well; however, the generalized convolution kernels associated with individual processes may be t much simpler than the generalized kernel describing the overall system, as they may be meant to implement one particular function and not a collection of simultaneous functions.\",\n \"These individual process kernels may involve a mapping into a low-dimensional process-behavior space (one or two dimensions may be common) and performing only low-level analysis of signal properties such as amplitude and average energy.\",\n \"Furthermore, individual process kernels may associate only traditional convolution kernels, hiθ[n], with each point in their process behavior spaces, meaning that various embodiments of the present subject matter may contain only two levels of generalized convolution kernel hierarchy.\",\n \"In general, any number of levels of hierarchy may exist; we place no restrictions on the possible complexity of particular embodiments here.\",\n \"Traditional convolution kernels (as used to characterize LTI systems) may be represented as a series of digitally stored numbers, representing the impulse response of a process, hi[n], over time n. Generalized convolution kernels may be stored in a manner analogous to that discussed here for the overall system: for the i-th process, a relationship between input signal analysis results and process parameter values may be specified through a relationship Hiθ{⋅} stored as discussed in the previous subsection, and a relationship Hih{⋅} may be again specified that maps from these parameter values to actual system responses.\",\n \"As stated previously, individual process behavior-space mappings Hih{⋅} may only map to a set of traditional convolution kernels, hiθ[n], rather than mapping again to a set of generalized convolution kernels.\",\n \"These traditional convolution kernels may be then each represented as a series of digitally stored numbers.\",\n \"In all cases, the hierarchy of processes may eventually terminate at sets of traditional convolution kernels together with a topology for evaluating the sets of traditional convolution kernels.\",\n \"This information may then be used to reduce the process to a single traditional convolution kernel representing the overall response of that process at time n, starting at the last level of hierarchy and working back up to the first generalized convolution kernel addressed by the overall system.\",\n \"In this way, evaluation of each individual process by the overall system, whether linear or nonlinear, may yield a single traditional convolution kernel describing that system's behavior at the current time moment, hi[n].\",\n \"These may be then evaluated at the top level to yield the system's overall output for that time.\",\n \"A system output topology must be specified in order to evaluate the overall response or output of a generalized convolution with more than one sub-process.\",\n \"This specification may be made in any way that may be accessible to and usable by the system.\",\n \"In one embodiment of the presently disclosed subject matter, predefined codes are used to indicate the particular topologies to be used.\",\n \"A code key containing one value for each possible process topology may be constructed, and a single code value may be associated with each point in behavior space in order to specify the particular topology that may be to be used.\",\n \"This embodiment may be illustrated in FIG.\",\n \"18.However, other embodiments may be used where a single topology may be suitable for all possible system behaviors.\",\n \"Using our developed notation, it should be noted that this method does not pertain to a specific choice of behavior space Θ, or particular choices of the relationships H74 {⋅} or Hh{⋅}, but rather to the overall system architecture and the way in which system behavior may be specified and implemented.\",\n \"This unified architecture may enable well-controlled, continuously time-varying, and input-signal-dependent system behavior.\",\n \"Automated Polarity Correction of Digital Audio A polarity correction signal processing technique modifies digital audio recordings to correct the polarity of component waveforms.\",\n \"These corrections compensate for a lack of standards in recording technique and equipment and improve the experience of listening to digital audio by restoring natural absolute polarity to recorded sounds.\",\n \"Acoustic waves in air may be comprised of compressions and rarefactions to pressures above and below ambient levels.\",\n \"During the process of electrically recording and later reproducing these temporary changes in air pressure using microphones, recording media, and loudspeakers, headphones, or other playback devices, it may be easy for the polarity of these pressure changes to become reversed such that the reproduced acoustic waveform has rarefactions at times that the original waveform had compressions and vice-versa.\",\n \"Whether or not humans can perceive such reversals in the absolute polarity of sound waves has been a topic of research and, at times, controversy; however, both scientific and anecdotal evidence exists that supports the reality and importance of correct absolute polarity in the perception of sound.\",\n \"At a low level, it has been observed that the peripheral auditory system of cats exhibits “microphonic” electrical responses that differ in polarity when presented with pulses of compression and rarefaction, demonstrating that the absolute polarity of sound does affect the fundamental input signal to the auditory system.\",\n \"Studies of spatial sound perception in humans have further supported the theory that different neural signals may be transmitted from the peripheral auditory system in response to compression and rarefaction stimuli, in some cases going so far as to indicate that the human auditory system may only respond to one of the two conditions (rarefaction), meaning that the auditory system receives only a half-wave rectified version of full acoustic signals.\",\n \"At a higher level, evidence of perceptual sensitivity to absolute polarity has been demonstrated in several experiments involving human listeners.\",\n \"For example, when presented with periodic waveforms that differ in shape during the positive (compression) and negative (rarefaction) portions of each period, listeners have been able to identify reversals in absolute polarity with nearly 100 percent accuracy for some waveforms and listening volumes.\",\n \"Furthermore, the previously mentioned experiments in spatial hearing have demonstrated that the absolute polarity of transient signals can affect their perceived timing.\",\n \"Together, these results demonstrate that absolute polarity may be important to the perception of both sustained and transient sounds.\",\n \"Significant anecdotal evidence in support of sensitivity to absolute polarity exists in the audio community as well, with many advocates stating that correct absolute polarity has substantial positive effects on perceived sound quality and suggesting explanations for why others may feel that they cannot perceive a difference in quality associated with the polarity of recordings.\",\n \"Often, these explanations include the fact that many modern recordings do not allow for the clear observation of correct absolute polarity during playback because the recordings may be comprised of many channels of audio that have been mixed together with little concern for the preservation of absolute polarity, resulting in recordings that contain a mixture of sounds with both natural and unnatural polarities.\",\n \"In this case, reversing the polarity of a recording as a whole during playback (by reversing the leads on a speaker, for example) cannot simultaneously correct the polarities of all of the component sounds, resulting in little discernible preference for either overall polarity and masking the perceptual benefits of correct absolute polarity.\",\n \"Perhaps surprisingly to the layperson, the audio industry has only begun to adopt standards and practices to regularize and preserve the absolute polarity of recorded music in any widespread manner during the last twenty years.\",\n \"Even through the 1980's, a universal agreement was lacking between recording studios in Europe and the USA (and between studios within the USA itself) on how the leads of the ubiquitous three-wire balanced line, or XLR cable, should be related to absolute polarity.\",\n \"Because this type of cable can be wired in two configurations that each carry sound but that produce output with opposite polarities, this lack of standardization inevitably resulted in numerous polarity inconsistencies, particularly in recordings where individual tracks were recorded in multiple studios and later combined.\",\n \"Furthermore, makers of electronic hardware devices that process, amplify, or mix electrical audio signals have never standardized design or reporting of the absolute polarity of their devices; in many cases it may be left to careful engineers to perform tests on equipment themselves in order to determine if the device outputs signal with the same or opposite polarity as its input.\",\n \"While in many cases modern digital audio workstations can aid in the identification of absolute polarity errors during recording and mixing, the music industry's history of general disregard for absolute polarity has continued to dominate recording and equipment-design practices, and even today the preservation of absolute polarity may be generally only considered at the very highest levels of professional audio work.\",\n \"Considering that the vast majority of the publics' consumed popular music, including the several trillions of digital multimedia files available online, may be increasingly being produced by small independent studios or personal residential studios where even the most basic polarity-aware practices may be lacking, it may be no surprise that most modern audio recordings continue to exhibit a mix of absolute polarities which cannot be corrected simply by inverting output as a whole during playback.\",\n \"Because of this, it may be desirable to develop digital signal processing techniques by which the absolute polarities of the individual sounds making up a recorded audio mixture may be corrected independently so that natural absolute polarity can be restored to all elements of a completed recording simultaneously.\",\n \"A method for processing digital audio signals in order to correct the polarities of the individual component sounds that make up a recorded audio mixture, or song, may be disclosed.\",\n \"The method consists of analyzing a digital audio recording and inverting component waveforms that may be determined to exhibit unnatural absolute polarity.\",\n \"Both transient events and sustained content (e.g., steady-state content) may be considered and processed.\",\n \"This method may compensate for modern recording techniques and equipment that fail to preserve the natural absolute polarity of recorded sounds and thus produce final mixed recordings where component sounds exhibit a combination of natural and inverted polarities.\",\n \"By establishing natural absolute polarity for all individual sounds without otherwise altering the content of these audio recordings, this method improves their perceived quality without changing their creative content.\",\n \"FIGS.\",\n \"20A-20D illustrate an audio mixture decomposition 2000 according to various embodiments of the present subject matter.\",\n \"FIG.\",\n \"20A illustrates an audio mixture including recorded sounds with transients and sustained components.\",\n \"The audio mixture in FIG.\",\n \"20A may include a sustained component 20B (e.g., steady-state component) and a transient component 20C-20D.\",\n \"Transient events may include a first transient component 20C or a second transient component 20D.\",\n \"This mixture may be decomposed into its components for further analysis and polarity correction.\",\n \"FIGS.\",\n \"21A-21C show the beginnings of the transient audio events 2100 according to various embodiments of the present subject matter.\",\n \"FIGS.\",\n \"21A-21C show the beginnings of the transient audio events shown in FIG.\",\n \"1, demonstrating that the polarities of these two percussive waveforms may not be consistent; in fact, transient component 1 shown in FIG.\",\n \"21A, corresponds to the waveform generated by an acoustic kick drum that has been recorded with inverted and unnatural polarity, while transient component 2 shown in FIG.\",\n \"21B corresponds to a waveform generated by an acoustic snare drum and recorded with absolute polarity preserved.\",\n \"FIG.\",\n \"21C shows the effect of inverting the polarity of a component waveform: the sign of the waveform values may be simply inverted, interchanging compression and rarefaction in the eventually reproduced acoustic wave.\",\n \"The system takes as its input one or more signals that each represent the amplitude of an audio waveform over time.\",\n \"These signals may each be a series of digitally stored values representing the instantaneous amplitude of a band-limited waveform that has been sampled at regularly spaced moments in time.\",\n \"In one embodiment, the system initially analyzes the input signal(s) to identify transient events: regions of time where one or more properties of the signal change rapidly.\",\n \"In audio signals, these events may coincide with percussive sounds, both tuned (mallet instruments, piano, plucked strings, etc.)\",\n \"and untuned (drums, traditional percussion), but these events may include any kind of signal whose energy level or other properties change significantly over a period of time relevant to the momentary perception of sound (for example, such time periods may be on the order of ones to tens of milliseconds).\",\n \"Those proficient in the art of audio transient analysis may know of numerous approaches to the detection of various types of transients in audio material.\",\n \"Any combination of these techniques may be used to identify transient events contained in a digital audio recording.\",\n \"Once a transient event has been identified, a model of the surrounding audio may be formed, and the transient content may be separated from its background signal content.\",\n \"In doing so, various modeling techniques may be used.\",\n \"The particular type of model and modeling parameters used to separate each transient event from its background may depend on an initial analysis of the region of audio under inspection, and may be chosen by automatic means with the goal of optimally preserving all perceivable properties of the recorded sound.\",\n \"After separation, the polarity of the transient content may be examined to determine if the initial rise of the signal and overall polarity correspond to naturally occurring absolute polarity.\",\n \"If the component waveform may be already found to have natural absolute polarity, the background model and separated transient waveform may be discarded and that time-region of the original audio recording may be left unaltered.\",\n \"If the transient component waveform may be found to have unnatural polarity, it may be inverted to restore natural absolute polarity and then recombined with the rest of the audio mixture using the previously established background model.\",\n \"This corrected and recombined time-region of the mixture may then undergo additional automatic processing to match the regions of the original recording optimally that come before and after it in time.\",\n \"In addition to this treatment of transient events, the polarity of sustained components (e.g., steady-state components) of an audio mixture may be analyzed.\",\n \"In this case, a further analysis of the audio recording may be performed after the polarity of transient waveforms have been analyzed in order to determine if the surrounding sustained or steady-state content has natural absolute polarity.\",\n \"If it may be determined that both the background content and the transient content it surrounds have unnatural polarity in need of correction, the entire waveform of the original recording may be inverted over the duration of the examined time-period in order to restore natural absolute polarity to the entire mixture instead of inverting only the transient component and then recombining it with a model of the mixture.\",\n \"In general, when considering both transient and sustained sound polarity, the entire digital audio recording may be analyzed to determine where background models should be used and where original waveforms may be inverted in full to restore consistently natural absolute polarity.\",\n \"Various embodiments may optimize these determinations to avoid the use of background-model-based separation and recombination wherever possible in favor of direct, complete polarity reversals of the original digital audio recording.\",\n \"It should be noted that in general any processing may be adaptive and may adjust to the content of the particular digital audio recording being processed such that optimal results may be achieved.\",\n \"In particular, various analysis and modeling techniques may be chosen for use based on automatic analysis of the digital audio recording's content, or may optionally be specified by an operator using either high-level controls that emphasize particular goals or low-level controls that directly indicate and parameterize the algorithms used.\",\n \"In one embodiment of the present subject matter, an emphasis may be placed on correcting low-frequency transients that often correspond to kick drums and similar low-frequency percussion.\",\n \"Because these components of an audio recording often contain considerable energy and exhibit waveforms that may be highly asymmetrical in their initial attack period, they may be especially good candidates for perceptual sound improvement by absolute polarity correction.\",\n \"In this embodiment, transient detection schemes that favor or exclusively target low-frequency transients may be employed, and background signal modeling for isolation of the transient may leverage the fact that only low-frequency content need be isolated.\",\n \"In other embodiments such an emphasis may be placed on low-frequency transients.\",\n \"In another embodiment, a digital audio recording may be analyzed in its entirety for a DC bias and inverted if necessary to establish a positive DC bias, thereby establishing a predominantly positive (compressive) polarity for the recording.\",\n \"This embodiment may be perhaps the simplest illustration of an absolute polarity correction that does not explicitly analyze the initial rise of transients or other component waveforms, and that may be suitable for use in correcting the absolute polarity of sustained waveforms with initial rises and polarities that may be more difficult to identify.\",\n \"Various techniques may be used to establish correct absolute polarity for sustained or other component sounds.\",\n \"Use of the Identification Word to Obtain Device, Service, and Settings Information A method enables identification of the audio transducer and application of the identifier to enable enhancement algorithms may be used to enhance the listening experience.\",\n \"The identification may contain a unique multi-bit identification word, created during manufacture of the device, which may be interrogated by a silent pulse through the audio connection.\",\n \"The identification word may be used to lookup information in one or more databases.\",\n \"The databases may reside on the player device, as well as on remotely connected systems, such as cloud-based content delivery systems.\",\n \"Users of these systems may purchase and register to enable premium audio enhancements, using the identification word to identify the user and the device uniquely.\",\n \"FIG.\",\n \"22 demonstrates a Digital Human Interface Identifier (DHI-ID) Serial Protocol 2200 according to various embodiments of the present subject matter.\",\n \"Various methods may be employed to interrogate the identifier from the audio transducer.\",\n \"In one method, the identification process may originate with a 16-bit ultra-sonic inquiry command sent from an audio port to the audio transducer.\",\n \"The transducer may respond with a unique identifier of between 24 and 48 bits, called the Digital Human Interface Identifier (DHI-ID).\",\n \"In one implementation, a DHI-ID enabled smart phone may poll the ear buds via the same wires that carry the audio signal to the ear buds.\",\n \"The DC support power for the DHI-ID identification circuit in the ear buds may be derived from the polling command from the smart phone.\",\n \"As illustrated in FIG.\",\n \"22, the poll signal may be a series of interrogation pulses, using a 20 msec ramp up 2210, 1 msec sustain 2220, and 20 msec ramp down 2230, so as to be inaudible to the user.\",\n \"The pulse train may use a voltage level of 1.6 volts to represent a binary 1 value 130 and may use 0 volts to represent a binary 0 value 140, though other voltage levels may be used.\",\n \"The pulse train may provide the DC power to a passive IC in the ear buds.\",\n \"FIG.\",\n \"23 demonstrates a Digital Human Interface Identifier (DHI-ID) Serial system 2300 according to various embodiments of the present subject matter.\",\n \"In one example, the identification process may originate with a 16-bit ultra-sonic inquiry command sent from an audio port of a playback device 2320 to an audio transducer 2330.The transducer 2330 may respond with a unique identifier of between 24 and 48 bits, called the Digital Human Interface Identifier (DHI-ID).\",\n \"Once fully powered, upon plugging the DHI-ID ear buds into the smart phone, the bits of the identification word may be sent back to the smart phone during the 1 msec sustain period.\",\n \"An identification word of 24 to 48 bits may be transmitted, allowing for identification of over 280 trillion devices.\",\n \"In another implementation, the sustain time 120 may be extended by an additional 750 microseconds, to allow the enabling device to transmit data to the transducer, to write information to non-volatile memory in the DHI-ID transducer device.\",\n \"On subsequent interrogations, the data in non-volatile memory becomes part of the DHI-ID identification word, and can provide user-customized settings for the device.\",\n \"A button may also be provided with the audio transducer to initiate the identification process, and enable or disable the use of the DHI-ID.\",\n \"The identification word (DHI-ID) may be used to obtain the device specifications, service information, and settings, collectively called the DHI-SSS.\",\n \"The DHI-ID may be a key used for lookup in databases local to the player, and in remote server databases.\",\n \"The device specifications include the manufacturer, date, model, color, impedance, frequency response, output sensitivity, dimensions, acoustic dimension, and other characteristics of the device.\",\n \"The specifications may be provided by the manufacturer for each device model that supports DHI-ID features.\",\n \"The device specifications can be used to control parameters of the sonic processing algorithms, such as frequency response to control equalization.\",\n \"Service information includes whether the device may be permitted to enable proprietary sonic processing for enhanced acoustic reception at the host device or at a streaming head end content source, such as head end 1 2310, head end 2 2340, or head end 3 2350.These non-manufacturer, non-user settings may be derived from a stored enabling device rewritable look-up table, or, other updatable online file sources, in the player 2320, the transducer 2330, or the cloud storage/processing (e.g., head end 2 2340).\",\n \"User-controllable settings may include EQ parameters, sensitivity, and other listener/user settings.\",\n \"Several novel aspect of this system that can be appreciated including (a) allowing the consumer to purchase an Acoustic Processing DHI-SSS enabled set of headphones, or (b) allowing the use of these headphones to enable free premium audio processing or a premium right to listen, which may be built into and sold with the hardware itself.\",\n \"Because service information may resides in updatable files which can reside either in the rewritable chip in the ear bud or headphone, in the player devices look up tables, or at the head end, a consumer can buy a subscription to an upgraded sound along with their listening hardware, and, can carry that permission within their audio playing device or earphones or ear buds.\",\n \"As well, the rights could be also be made dynamic, and, if necessary, terminated after a subscription expiration date, in the same three locations, cloud, player or ear bud/DHI enabled hardware.\",\n \"The system uses the DHI-SSS information to control, acoustically alter and/or process the content that may be being delivered to the audio transducer from various sources, including stored local content and streaming content from a head-end.\",\n \"The DHI-SSS may be used to control the processing of modified audio and video at the content's storage and consumer streaming source location, for both streamed and broadcast sources, as directed by the DHI-SSS derived from the DHI-ID from the listening device, or by other means.\",\n \"Processing of the content can be performed on the server and stored for later streaming, or processed in real-time by the server, or processed in real-time by the player if processing bandwidth may be sufficient.\",\n \"The process controller may select/enable DHI-ID content processing in both streaming and broadcast usage.\",\n \"The DHI-ID controls the processing originating from streaming web (or any other digital transmission system) head-end server(s), or from broadcasting radio transmitter(s), for the purposes of achieving an enhanced Digital-Human Interface (DHI) customer content experience, or any other processing necessary.\",\n \"This processing may be used a business-to-consumer function, and may also be used as a business-to-business function.\",\n \"The user may have content processing available both on-command from the Server/Broadcast end or by selecting one or more control inputs.\",\n \"Control inputs may include selection of a song (e.g., track), a video, or a duration.\",\n \"For example, the duration may be selected as always active, active hourly, active for any unit of time, or active according to a pre-determined time pattern.\",\n \"Example instances may include only active on weekends, only active on afternoons, active for 30 days total, active for the first 10 songs, active for every purchased movie over $12 in cost to the consumer, or another duration.\",\n \"The duration may be selected by the service providing the content or by the consumer.\",\n \"The processing software may be installed automatically at any processing location using an automated, process-controller controlled batch process.\",\n \"Automatic installation may occur instantly or over a pre-determined time.\",\n \"Installation may be configured to allow the process to be deployed quickly and effectively.\",\n \"The processing control innovation includes a dual-input, online visual control interface allowing the streaming operators to select which stream(s) may be processed, as well as processing them according to the multiple processing job combinations.\",\n \"The control interface can have as its input selections for processing made by the consumers' elective (paid for, in general) upstream choices.\",\n \"An example of this upstream dashboard input would be the use of a consumer smart phone app that would allow the consumer to pay for DHI-ID processing of songs to be streamed to them.\",\n \"The streaming/broadcast control innovation allows for the operator choice of processing the content a) in a batch format, thereby having the processed content reside on the source storage element permanently, giving two existing versions of the content for the control process controller to select from, or b) in real-time, where each individual content unit (stream or broadcast) may be processed anew for each processor controller request.\",\n \"Usage configuration (b) may halve the content file storage requirements, and usage configuration (a) may correspond to the instantaneous, no real-time CPU processing necessary.\",\n \"FIG.\",\n \"23 demonstrates the use of the DHI-ID and DHI-SSS in an exemplary system.\",\n \"The Audio Transducer may be polled by a playback device 2320, such as a smart phone or tablet.\",\n \"The Audio Transducer responds with its identifier, the DHI-ID.\",\n \"Content may reside in several locations in the system, including the playback device, head-end distribution channels, and cloud storage.\",\n \"In one use scenario, the DHI-ID may be used to retrieve the DHI-SSS from an internet database.\",\n \"The service information of the DHI-SSS may be then used to enable processing algorithms of content stored locally on the playback device.\",\n \"In another use scenario, the DHI-ID may be sent to a head-end processor.\",\n \"The identifier may be used to enable the real-time processing of content that may be streamed from the head-end to the playback device.\",\n \"In a third scenario, content has been placed in cloud storage.\",\n \"The content may be pre-processed by the cloud, or processed in real-time as files may be transferred from the cloud to the playback device.\",\n \"In all cases, the types of processing may be enabled by the service information and controlled by parameters included in the DHI-SSS.\",\n \"The following sections describe specific audio enhancement algorithms that can be enabled to provide an improved listening experience.\",\n \"FIG.\",\n \"24 demonstrates a recorded sound processing system 2400 according to various embodiments of the present subject matter.\",\n \"System 2400 may be configured to perform one or more of signal processing methods 2410, 2420, 2430, 2440, 2450, 2460, and 2470.Any of the methods in system 2400 may be used individually or in any combination with any other method in system 2400.All signal processing methods 2410, 2420, 2430, 2440, 2450, 2460, and 2470 may be used simultaneously.\",\n \"In various embodiments, system 2400 may be configured to perform any one or any combination of methods 2410, 2420, 2430, 2440, 2450, 2460, and 2470.In various embodiments, system 2400 may be configured to perform any combination of methods 2410, 2420, 2430, 2440, 2450, 2460, and 2470 simultaneously, concurrently, and/or at different times.\",\n \"In various embodiments, any systems and methods including their various examples as discussed in this document and their various combinations may be implemented in a system such as system 2400.The methods in system 2400 may include the methods discussed above.\",\n \"System 2400 includes a method to simulate nonlinear properties of sound 2410, which may use a sound processor to model in-air mixing and live performance to implement the Digital Audio Processing to Simulate the Nonlinear Properties of Sound Propagation and Mixing in Air.\",\n \"Method 2420 includes priming signal to implement Digital Signal Processing of Priming Signal for Reduction of Stress in the Auditory System, in which a preconditioned signal is mixed with delayed actual signal to reduce listening stress.\",\n \"Method 2430 includes Restoration of motion and dynamic timbre, which uses a sound processor to phase and flange to recreate motion and liveliness to implement Digital Audio Processing for the Restoration of Motion and Dynamic Timbre.\",\n \"Method 2440 includes automatic pitch correction, which uses a sound processor to pitch correct based on level to implement Automatic Level-Dependent Pitch Correction of Digital Audio.\",\n \"Method 2450 implements Multiplexed Convolution, which processes sound with adaptive and time-varying convolutions.\",\n \"Method 2460 includes polarity correction, which uses a sound processor to restore natural audio polarity due to lack of recording standards to implement Automated Polarity Correction of Digital Audio.\",\n \"Method 2470 includes automatic transducer identification, which provides processed sounds as a function of sensed transducer to implement Use of the Identification Word to Obtain Device, Service, and Settings Information.\",\n \"Various examples of the present subject matter are provided as follows: Example 1 includes a method for simulating propagation and mixing of sounds in air, the method comprising selecting a relationship between a virtual audio listener location and a virtual source location within an audio interaction volume, the audio interaction volume associated with a first audio waveform, the first audio waveform including audio generated using a first audio isotropic source; and, generating a second audio waveform using the first audio waveform, the second audio waveform including a plurality of simulated intermodulation products corresponding to the relationship between the virtual audio listener location and the virtual source location.\",\n \"Example 2 includes the method of example 1, the first audio waveform further including audio generated using a second isotropic audio source.\",\n \"Example 3 includes the method of any of examples 1-2, further including generating a simulated mixed output waveform, the generating including applying a first gain to the first audio waveform to generate a first amplified waveform, applying a second gain to the second audio waveform to generate a second amplified waveform, and summing the first amplified waveform and the second amplified waveform to generate the simulated mixed output waveform.\",\n \"Example 4 includes the method of any of examples 1-3, further including transducing the simulated mixed output waveform into audible sounds.\",\n \"Example 5 includes the method of any of examples 1-4, further including identifying an audio sample within the second audio waveform, identifying a frequency of the audio sample, and generating a frequency-dependent sample by applying frequency-dependent linear filtering to the audio sample, the frequency-dependent linear filtering simulating a frequency-dependent attenuation of the audio sample as the audio sample propagates through air.\",\n \"Example 6 includes the method of any of examples 1-5, further including receiving the first audio waveform from a remote source.\",\n \"Example 7 includes the method of any of examples 1-6, further including sending the simulated mixed output waveform to a remote physical audio listener location.\",\n \"Example 8 includes a system for simulating propagation and mixing of sounds in air, the system comprising a digital signal processing mixing simulation module, the simulation module configured to select a virtual source location within an audio interaction volume, the audio interaction volume associated with a first audio waveform, the first audio waveform including audio generated using a first audio isotropic source; select an observation location corresponding to a virtual audio listener location; and, determine a second audio waveform using the first audio waveform, the second audio waveform including a plurality of simulated intermodulation products corresponding to the observation location; and, a summing amplifier module configured to generate a second audio waveform, the second audio waveform including the first audio waveform and the second audio waveform.\",\n \"Example 9 includes the system of example 8, the first audio waveform further including audio generated using a second audio isotropic source.\",\n \"Example 10 includes the system of any of examples 8-9, further including a speaker, the speaker configured to transduce the second audio waveform into audible sounds.\",\n \"Example 11 includes the system of any of examples 8-10, further including a first amplifier module configured to apply a first gain to the first audio waveform to generate a first amplified waveform, and a second amplifier module configured to apply a second gain to the second audio waveform to generate a second amplified waveform, wherein the summing amplifier module is configured to sum the first amplified waveform and the second amplified waveform to generate the second audio waveform.\",\n \"Example 12 includes the system of any of examples 8-11, further including a frequency-dependent linear filter module, the frequency-dependent linear filter module configured to identify an audio sample within the second audio waveform, determine a frequency of the audio sample, and generate a frequency-dependent sample by applying frequency-dependent linear filtering to the audio sample, the frequency-dependent linear filtering simulating a frequency-dependent attenuation of the audio sample as the audio sample propagates through air.\",\n \"Example 13 includes the system of any of examples 8-12, further including a communication module, the communication module configured to receive the first audio waveform from a remote source.\",\n \"Example 14 includes the system of any of examples 8-13, the communication module further configured to send the second audio waveform to a remote physical audio listener location.\",\n \"Although the subject matter has been explained in relation to its preferred embodiment, it may be to be understood that many other possible modifications and variations can be made without departing from the spirit and scope of the subject matter as hereinafter claimed.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875721"}}},{"rowIdx":4494959,"cells":{"text":{"kind":"list like","value":[["RECURSIVE PUMPING FOR SYMMETRICAL GAS EXHAUST TO CONTROL CRITICAL DIMENSION UNIFORMITY IN PLASMA REACTORS","Embodiments of the present invention provide apparatus and methods for reducing non-uniformity and/or skews during substrate processing.","One embodiment of the present invention provides a flow equalizer assembly for disposing between a vacuum port and a processing volume in a processing chamber.","The flow equalizing assembly includes a first plate having at least one first opening, and a second plate having two or more second openings.","The first and second plates define a flow redistributing volume therebetween, and the at least one first opening and the two or more second openings are staggered."],["1.A method for pumping a processing chamber, comprising: directing fluid flow from a processing volume to a vacuum port through a flow equalizer assembly, wherein the flow equalizer assembly comprises a first plate having at least one first opening, and a second plate having two or more second openings, the at least one first opening and the two or more second openings are staggered, and directing the fluid flow comprises: flowing one or more gases from the processing volume through the two or more second openings to a flow redistributing volume defined between the first and second plates; and flowing the one or more gases from the flow redistributing volume through the at least one first opening to the vacuum port.","2.The method of claim 1, wherein flowing one or more gases to the flow redistributing volume comprises flowing the one or more gases through each of the two or more second openings to a corresponding sub-redistributing volume divided by two or more dividers positioned between the first and second plates, and each of the sub-redistributing volume is in connection with one of the at least one first opening.","3.The method of claim 2, further comprising adjusting locations of the two or more dividers to adjust flow distribution in the flow redistributing volume.","4.The method of claim 2, further comprising adding an additional first divider between the first and second plates to create a sub-redistributing volume that is not in fluid connection with any first openings or second openings.","5.The method of claim 1, further comprising tuning the flow equalizer assembly to obtain symmetric fluid flow in the processing volume.","6.The method of claim 1, further comprising tuning the flow equalizer assembly to compensate structural non-symmetries in the processing chamber."],["<SOH> BACKGROUND <EOH>"],["<SOH> SUMMARY <EOH>Embodiments of the present invention provide apparatus and methods for reducing non-uniformity and/or skews during substrate processing.","One embodiment of the present invention provides a flow equalizer assembly for disposing between a vacuum port and a processing volume in a processing chamber.","The flow equalizing assembly includes a first plate having at least one first opening, and a second plate having two or more second openings.","The first and second plates define a flow redistributing volume therebetween, and the at least one first opening and the two or more second openings are staggered.","Another embodiment of the present invention provides an apparatus for processing one or more substrates.","The apparatus includes a chamber body defining a processing volume, wherein a pumping port is formed through the chamber body for connection with a vacuum pump, a substrate support disposed in the processing volume for supporting a substrate thereon, a gas delivery assembly configured to deliver one or more processing gas to the processing volume, and a flow equalizer assembly disposed between the processing volume and the pumping port.","The flow equalizer assembly includes a first plate having at least one first opening, and a second plate having two or more second openings.","The first plate faces the vacuum port.","The first and second plates define a flow redistributing volume therebetween, the at least one first opening and the two or more second openings are staggered, and the second plate faces the processing volume.","Yet another embodiment of the present invention provides a method for pumping a processing chamber.","The method includes directing fluid flow from a processing volume to a vacuum port through a flow equalizer assembly.","The flow equalizer assembly includes a first plate having at least one first opening, and a second plate having two or more second openings.","The at least one first opening and the two or more second openings are staggered.","Directing the fluid flow includes flowing one or more gases from the processing volume through the two or more second openings to a flow redistributing volume defined between the first and second plates, and flowing the one or more gases from the flow redistributing volume through the at least one first opening to the vacuum port."],["CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisional of U.S. patent application Ser.","No.","14/452,228, filed Aug. 5, 2014, which claims priority to U.S.","Provisional Patent Application No.","61/864,929, filed on Aug. 12, 2013, both of which are herein incorporated by reference in their entireties.","BACKGROUND Field Embodiments of the present invention relate to apparatus and methods for processing semiconductor substrates.","More particularly, embodiments of the present invention provide apparatus and methods for reducing non-uniformity and/or skews during substrate processing.","Description of the Related Art Electronic devices, such as flat panel displays and integrated circuits commonly are fabricated by a series of process steps in which layers are deposited on a substrate and the deposited material is etched into desired patterns.","The process steps commonly include physical vapor deposition (PVD), chemical vapor deposition (CVD), plasma enhanced CVD (PECVD), and other plasma processing.","Specifically, a plasma process requires supplying a process gas mixture to a vacuum chamber, and applying electrical or electromagnetic power (RF power) to excite the process gas into a plasma state.","The plasma decomposes the gas mixture into ion species that perform deposition, etch, implant or other processes.","One problem encountered with plasma processes is the difficulty associated with establishing uniform plasma density over the substrate surface during processing, which leads to non-uniform processing between the center and edge regions of the substrate and non-uniform processing azimuthally within center and edge regions.","One reason for the difficulty in establishing uniform plasma density involves gas flow skews due to asymmetry in the physical process chamber design.","Such skews not only result in naturally, azimuthal, non-uniform plasma density, but also make it difficult to use other processing variables or “knobs” to control center-to-edge plasma uniformity.","Therefore, a need exists for a plasma processing apparatus that improves gas flow symmetry for improved plasma uniformity control.","SUMMARY Embodiments of the present invention provide apparatus and methods for reducing non-uniformity and/or skews during substrate processing.","One embodiment of the present invention provides a flow equalizer assembly for disposing between a vacuum port and a processing volume in a processing chamber.","The flow equalizing assembly includes a first plate having at least one first opening, and a second plate having two or more second openings.","The first and second plates define a flow redistributing volume therebetween, and the at least one first opening and the two or more second openings are staggered.","Another embodiment of the present invention provides an apparatus for processing one or more substrates.","The apparatus includes a chamber body defining a processing volume, wherein a pumping port is formed through the chamber body for connection with a vacuum pump, a substrate support disposed in the processing volume for supporting a substrate thereon, a gas delivery assembly configured to deliver one or more processing gas to the processing volume, and a flow equalizer assembly disposed between the processing volume and the pumping port.","The flow equalizer assembly includes a first plate having at least one first opening, and a second plate having two or more second openings.","The first plate faces the vacuum port.","The first and second plates define a flow redistributing volume therebetween, the at least one first opening and the two or more second openings are staggered, and the second plate faces the processing volume.","Yet another embodiment of the present invention provides a method for pumping a processing chamber.","The method includes directing fluid flow from a processing volume to a vacuum port through a flow equalizer assembly.","The flow equalizer assembly includes a first plate having at least one first opening, and a second plate having two or more second openings.","The at least one first opening and the two or more second openings are staggered.","Directing the fluid flow includes flowing one or more gases from the processing volume through the two or more second openings to a flow redistributing volume defined between the first and second plates, and flowing the one or more gases from the flow redistributing volume through the at least one first opening to the vacuum port.","BRIEF DESCRIPTION OF THE DRAWINGS So that the manner in which the above recited features of the present invention can be understood in detail, a more particular description of the invention, briefly summarized above, may be had by reference to embodiments, some of which are illustrated in the appended drawings.","It is to be noted, however, that the appended drawings illustrate only typical embodiments of this invention and are therefore not to be considered limiting of its scope, for the invention may admit to other equally effective embodiments.","FIG.","1A is a schematic sectional view of a plasma processing chamber according to one embodiment of the present invention.","FIG.","1B is a schematic top view of the plasma processing chamber of FIG.","1A with a chamber lid removed.","FIG.","2A is a schematic perspective sectional view of a flow equalizer assembly according to one embodiment of the present invention.","FIG.","2B is a schematic cylindrical map projection of the flow equalizer assembly of FIG.","2A showing azimuthal flow distributions.","FIG.","3A is a schematic perspective view of a flow equalizer assembly including one or more dividers according to one embodiment of the present invention.","FIG.","3B is a schematic sectional perspective view of a flow equalizer including one or more adjustable dividers according to one embodiment of the present invention.","FIG.","4A is a schematic top view of a flow equalizing plate according to one embodiment of the present invention.","FIG.","4B is a schematic top view of a flow equalizing plate according to one embodiment of the present invention.","To facilitate understanding, identical reference numerals have been used, where possible, to designate identical elements that are common to the figures.","It is contemplated that elements disclosed in one embodiment may be beneficially utilized on other embodiments without specific recitation.","DETAILED DESCRIPTION Embodiments of the present invention generally provide various apparatus and methods for improving gas flow symmetry.","In one embodiment, a flow equalizing assembly positioned between a processing volume and a vacuum port at a non-symmetrical position relative to the processing volume is provided.","The flow equalizing assembly includes at least two plates each having openings formed therethrough.","The flow equalizing assembly forms a plurality of flow paths so that different regions of the processing volume are at substantially the same distance from the vacuum port, thus, achieving symmetrical pumping conductance.","In addition to reducing flow non-symmetry caused by non-symmetrical location of a vacuum port, the flow equalizing assembly can also be used to reduce other non-symmetries in a processing chamber, such as conductance and RF non-symmetry caused by a slit valve door.","In one embodiment, a flow asymmetry may be introduced in the flow equalizing assembly to compensate for RF asymmetry to obtain processing symmetry.","The flow equalizing assembly enables the symmetry of fluid flow in a processing chamber to be tuned, thus, reducing processing skew and improving uniformity of processing.","FIG.","1A is a schematic sectional view of a plasma processing chamber 100 according to one embodiment of the present invention.","The plasma processing chamber 100 includes a flow equalizer assembly 160 to obtain fluid flow symmetry between a processing volume and a vacuum port.","The flow equalizer assembly 160 may be used to obtain a symmetrical fluid flow, or may be used to tune the symmetry of the fluid flow to compensate for other chamber asymmetries to obtain symmetrical processing results.","The plasma processing chamber 100 may be configured to process a variety of substrates, such as semiconductor substrates and reticles, and accommodating a variety of substrate sizes.","The plasma processing chamber 100 includes a chamber body 110.A bottom chamber liner 112 and a top chamber liner 114 are disposed inside the chamber body 110.The bottom chamber liner 112, the top chamber liner 114 and a chamber lid 116 define a chamber volume 118.Slit valve openings 119, 120 may be formed through the chamber body 110 and the top chamber liner 114 to allow passage of a substrate 102 and substrate transfer mechanism (not shown).","A slit valve door 122 may be utilized to selectively open and close the slit valve openings 119, 120.A substrate support assembly 124 is disposed in the chamber volume 118.The substrate support assembly 124 has a substrate supporting surface 126 for supporting a substrate thereon.","A lift 132 may be coupled to lifting pins 134 to raise the substrate 102 from and to lower the substrate 102 on to the substrate support assembly 124.The substrate support assembly 124 may be an electrostatic chuck coupled to a chucking power source 136 to secure the substrate 102 thereon.","The substrate support assembly 124 may also includes one or more embedded heating elements coupled to a heating power source 138 for heating the substrate 102 during processing.","A cooling fluid source 140 may provide cooling or heating and adjust temperature profile of the substrate 102 being processed.","An optional plasma screen 130 may be disposed surrounding the substrate support assembly 124.The plasma screen 130 may be positioned at a vertical level similar to the vertical level of the substrate supporting surface 126 and separates the chamber volume 118 into a processing volume 118a and a lower volume 118b located below the plasma screen 130.A showerhead assembly 142 may be positioned above the processing volume 118a to deliver one or more processing gases from a gas delivery system 144 to the processing volume 118a.","Alternatively, the plasma processing chamber 100 may also include an antenna assembly for generating inductively coupled plasma in the plasma processing chamber 100.A vacuum pump 150 is in fluid communication with the chamber volume 118 to maintain a low pressure environment within the processing volume 118a.","In one embodiment, the vacuum pump 150 may be coupled to the lower chamber volume 118b through a vacuum port 152 formed in the bottom chamber liner 112.As shown in FIG.","1A, the vacuum port 152 is positioned at a bottom of the lower volume 118b and laterally offset from the substrate support assembly 124, and thus, the vacuum port 152 is located non-symmetrical relative to the substrate support assembly 124.The flow equalizer assembly 160 is disposed around the substrate support assembly 124 to azimuthally equalize the gas flow passing from the processing volume 118a to the lower volume 118b.","In one embodiment, the flow equalizer assembly 160 may be disposed under the optional plasma screen 130.The vacuum pump 150 pumps out gas and process by products from the processing volume 118a through the vacuum port 152, the lower volume 118b and flow paths formed through the flow equalizer assembly 160.The flow equalizer assembly 160 may include two or more plates 162, 164 spaced apart from one another.","A flow re-distributing volume 172 is defined between neighboring plates 162, 164.Each of the plates 162, 164 includes openings 168, 170 formed therethrough.","During operation, driven by vacuum suction from vacuum port 152, gases and particles exit the processing volume 118a through the openings 170 of the plate 164, flow through the flow re-distributing volume 172, then flow through the openings 168 of the plate 162 towards the vacuum port 152.Numbers, size, and/or locations of the openings 168, 170 are arranged so that flow paths between the openings 170 to the openings 168 through the flow re-distributing volume 172 can be tuned to correct processing asymmetries by either adjusting or eliminating the flow asymmetries between the processing volume 118a and the vacuum port 152.In one embodiment of the present invention, each of the two or more plates 162, 164 may be a circular plate having a central opening for receiving the substrate support assembly 124 so that the flow equalizer assembly 160 is disposed around the substrate support assembly 124.In one embodiment, the top most plate 164 may be at a horizontal level similar to or slightly lower than the substrate supporting surface of the substrate support assembly 124.The openings 170 may be substantially evenly distributed along an outer edge of the substrate support assembly 124.The circular plates 162, 164 may be arranged parallel to each other.","The openings 168 of the plate 162 and the openings 170 of the plate 164 may be arranged in a vertically staggered manner, instead of vertically aligned with each other, to enable flow equalizing within the flow re-distributing volume 172.The number, shape and sizes of openings 168 and the number of openings 170 may be the same or different.","In one embodiment, the number of openings 170 on the plate 164 which is positioned closer to the processing volume 118a is greater than the number of openings 168 on the plate 162 which is positioned closer to the vacuum port 152.In one embodiment, the number of openings 170 may be at least twice as many as the number of the openings 168.The number, size and/or location of openings in the plates 162, 164 may be arranged to provide equal distances between the vacuum port 152 and different regions of the substrate support assembly 124 so that processing gases within the processing volume 118a can be uniformly and symmetrically pumped around the substrate support assembly 124.FIG.","1B is a schematic top view of the plasma processing chamber 100 of FIG.","1A with the lid 116 removed.","As shown in FIG.","1B, the vacuum port 152 is positioned off center from the centerline of the substrate support assembly 124.The plates 164, 162 are disposed concentric to the substrate support assembly 124.The openings 170 of the top plate 164 may be evenly distributed around the substrate support assembly 124.The number of openings 170 of the top late 164 may be at least twice as many as the number of openings 168 of the bottom plate 162.In the embodiment of FIG.","1B, there are two openings 168 on the bottom plate 162.The two openings 168 are positioned at equal distance away from the vacuum port 152.There are four openings 170 on the top plate 164.The top plate 164 is positioned in an angle so that each opening 170 is located at the substantially the same distance away from a closest opening 168.As a result, each opening 170 on the top plate 164 is positioned at substantially the same distance away from the vacuum port 152, thus reducing the non-symmetry in flow paths through the flow equalizer assembly 160.In the embodiment of FIG.","1B, each of the openings 170 is similar in shape and size and each of the openings 168 is similar in shape and size.","Alternative, the shape and/or size of each opening 170 or opening 168 may be unique or different to provide a target flow resistance.","Although two plates 164, 162 are shown in the flow equalizer assembly 160 of FIG.","1A, additional plates may be included to tune the flow distribution through the flow equalizer assembly 160.For example, an additional plate may be disposed above the top plate 164.The additional plate may have twice as many openings as the top plate 164 to generate a recursive flow splitting and equalizing effect.","FIG.","2A is a schematic perspective view of a flow equalizer assembly 200 according to one embodiment of the present invention.","The flow equalizer assembly 200 includes a first plate 202 having a plurality of openings 204 for receiving fluid flow from a processing volume and a second plate 206 having two or more openings 208 for directing fluid flow towards a vacuum port.","The first plate 202 and the second plate 206 may be positioned parallel to each other.","The first plate 202 may include a central opening 210 and the second plate 206 may include a central opening 212.The central openings 210, 212 are sized to receive a substrate support assembly so that the first plate 202 and the second plate 206 are surrounds the substrate support assembly.","A sidewall 214 may extend above the first plate 202 from an outer perimeter.","The sidewall 214 may be symmetrical, for example having a circular shape or a normal polygonal shape, to retain a symmetrical volume above the substrate support assembly.","In one embodiment, the sidewall 214 may include an upper lip 215 so that the flow equalizer assembly 200 can be supported by a chamber liner.","A sidewall 216 may connect between the first plate 202 and the second plate 206 to enclose a flow re-distributing volume 218.The sidewall 216 may be symmetrical, for example being circular.","The distribution, shape, size and/or relative locations of the openings 204, 208 and the height of the flow re-distributing volume 218 may be tuned to achieve flow redistributing effect.","The plurality of openings 204 may be evenly distributed along the first plate 202.A spacing 217 between the first plate 202 and the second plate may be provided to achieve targeted flow patterns.","In one embodiment, a ratio of the spacing 217 and a width 219 of the flow re-distributing volume 218 may be between about 0.4 to about 0.5.FIG.","2B is a schematic cylindrical map projection of the flow equalizer assembly 200 showing azimuthal flow distributions.","The flow equalizer assembly 200 is arranged so that each opening 204 of the first plate 202 is substantially equal distance to the vacuum port.","Since the openings 204 are positioned along an edge region of the plasma or processing environment, the processing environment can be symmetrically vacuumed by the vacuum port through the flow equalizer assembly 200.The two openings 208 closest to the vacuum port may be positioned at equal distances from the vacuum port.","As shown in FIG.","2B, the vacuum port is located at 180 degrees, while the openings 208 are positioned at 90 degrees and 270 degrees respectively.","Similarly, the openings 204 are arranged such that each opening 204 is at substantial the same distance to a closest opening 208.In FIG.","2B, there are four openings 204 positioned 90 degrees apart at 45 degrees, 135 degrees, 225 degrees and 315 degrees.","Additional plates can be positioned above the first plate 202 to provide for further equalizing.","For example, an additional having twice as many openings as the first plate 202 may be positioned above the first plate 202.In the embodiment of FIG.","2B, the openings in the additional plate may include eight openings positioned 45 degrees apart at 22.5 degrees, 67.5 degrees, 112.5 degrees, 157.5 degrees, 202.5 degrees, 247.5 degrees, 292.5 degrees, and 337.5 degrees.","Alternatively, the additional plate may include only four openings positioned at in staggered manner relative to openings 204 to avoid increased flow resistance caused by smaller openings.","FIG.","3A is a schematic perspective view of a flow equalizer assembly 300 including one or more dividers 302 according to one embodiment of the present invention.","The flow equalizer assembly 300 is similar to the flow equalizer assembly 200 described above except that the two or more dividers 302 may be positioned between the first plate 202 and the second plate 206.The dividers 302 cut the flow re-distributing volume 218 into two or more isolated sub-volumes 306a, 306b, 306c, 306d.","Each sub-volume 306a, 306b, 306c, 306d opens to at least one opening 204 of the first plate 202 and one opening 208 of the second plate 206.The dividers 302 provide additional direction to the flow passing through the flow equalizer assembly 300 to improve flow symmetry tuning.","In the embodiment shown in FIG.","3A, two or more dividers 302 may be positioned above the openings 208 dividing each opening 208 into two sections so that each opening 204 of the first plate 202 is exposed to similar level of suction.","Optionally, the flow equalizer assembly 300 may also include dividers 304 attached to the second plate 206 isolating the two openings 208 from each other.","When installed, one divider 304 may be positioned over the vacuum port so that each opening 208 is exposed to equal amount of suction from a vacuum pump.","FIG.","3B is a schematic sectional perspective view of a flow equalizer assembly 350 including one or more adjustable dividers according to one embodiment of the present invention.","The flow equalizer assembly 350 is similar to the flow equalizer assembly 300 except the dividers 302 may be adjustable.","The location of each divider 302 may be adjusted to obtain target flow resistance in each sub-volume 306.In one embodiment, each divider 302 may be positioned in one of a plurality of pre-determined locations.","For example, a plurality of notches 310 may be formed under the first plate 202 for secure a divider 302 at a plurality of locations.","In one embodiment, the dividers 302 may be arranged to enclose one or more isolated sections 314 within the flow re-distributing volume.","The isolated sections 314 is not fluidly connected to any openings of the first plate 202 or the second plate 206.The isolated sections 314 may be used to reduce flow stagnation.","FIG.","4A is a schematic top view of a flow equalizing plate 400 for using in a flow equalizer assembly according to one embodiment of the present invention.","The flow equalizing plate 400 may include a ring shaped planar body 402 having a plurality of openings 404a, 404b, 404c, 404d formed therethrough.","The shape, size, and distribution of the plurality of openings 404a, 404b, 404c, 404d may be varied according to flow requirement and chamber geometry.","In one embodiment, the plurality of openings 404a, 404b, 404c, 404d may have may be of the same shape or side and be evenly distributed.","Alternatively, one or more openings 404a, 404b, 404c, 404d may be varied to compensate chamber geometry.","For example, an opening 404d positioned adjacent to a slit valve door 406 of a processing chamber may be of a different size or shape to compensate the non-symmetry of the slit valve door 406.FIG.","4B is a schematic top view of a flow equalizing plate 420 according to one embodiment of the present invention.","The flow equalizing plate 420 may include a ring shaped planar body 422 having two or more openings 424 for directing fluid flow there through.","In one embodiment, the flow equalizing plate 420 may include a shutter disk 426 to selectively close a portion of the opening 424 to adjust flow resistance through a particular opening.","Embodiments of the present invention may be used alone or in combination.","Even though plasma chambers are described in the above embodiments, flow equalizer assemblies according to embodiments of the present invention may be used in any suitable chambers.","While the foregoing is directed to embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow."]],"string":"[\n [\n \"RECURSIVE PUMPING FOR SYMMETRICAL GAS EXHAUST TO CONTROL CRITICAL DIMENSION UNIFORMITY IN PLASMA REACTORS\",\n \"Embodiments of the present invention provide apparatus and methods for reducing non-uniformity and/or skews during substrate processing.\",\n \"One embodiment of the present invention provides a flow equalizer assembly for disposing between a vacuum port and a processing volume in a processing chamber.\",\n \"The flow equalizing assembly includes a first plate having at least one first opening, and a second plate having two or more second openings.\",\n \"The first and second plates define a flow redistributing volume therebetween, and the at least one first opening and the two or more second openings are staggered.\"\n ],\n [\n \"1.A method for pumping a processing chamber, comprising: directing fluid flow from a processing volume to a vacuum port through a flow equalizer assembly, wherein the flow equalizer assembly comprises a first plate having at least one first opening, and a second plate having two or more second openings, the at least one first opening and the two or more second openings are staggered, and directing the fluid flow comprises: flowing one or more gases from the processing volume through the two or more second openings to a flow redistributing volume defined between the first and second plates; and flowing the one or more gases from the flow redistributing volume through the at least one first opening to the vacuum port.\",\n \"2.The method of claim 1, wherein flowing one or more gases to the flow redistributing volume comprises flowing the one or more gases through each of the two or more second openings to a corresponding sub-redistributing volume divided by two or more dividers positioned between the first and second plates, and each of the sub-redistributing volume is in connection with one of the at least one first opening.\",\n \"3.The method of claim 2, further comprising adjusting locations of the two or more dividers to adjust flow distribution in the flow redistributing volume.\",\n \"4.The method of claim 2, further comprising adding an additional first divider between the first and second plates to create a sub-redistributing volume that is not in fluid connection with any first openings or second openings.\",\n \"5.The method of claim 1, further comprising tuning the flow equalizer assembly to obtain symmetric fluid flow in the processing volume.\",\n \"6.The method of claim 1, further comprising tuning the flow equalizer assembly to compensate structural non-symmetries in the processing chamber.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>\"\n ],\n [\n \"<SOH> SUMMARY <EOH>Embodiments of the present invention provide apparatus and methods for reducing non-uniformity and/or skews during substrate processing.\",\n \"One embodiment of the present invention provides a flow equalizer assembly for disposing between a vacuum port and a processing volume in a processing chamber.\",\n \"The flow equalizing assembly includes a first plate having at least one first opening, and a second plate having two or more second openings.\",\n \"The first and second plates define a flow redistributing volume therebetween, and the at least one first opening and the two or more second openings are staggered.\",\n \"Another embodiment of the present invention provides an apparatus for processing one or more substrates.\",\n \"The apparatus includes a chamber body defining a processing volume, wherein a pumping port is formed through the chamber body for connection with a vacuum pump, a substrate support disposed in the processing volume for supporting a substrate thereon, a gas delivery assembly configured to deliver one or more processing gas to the processing volume, and a flow equalizer assembly disposed between the processing volume and the pumping port.\",\n \"The flow equalizer assembly includes a first plate having at least one first opening, and a second plate having two or more second openings.\",\n \"The first plate faces the vacuum port.\",\n \"The first and second plates define a flow redistributing volume therebetween, the at least one first opening and the two or more second openings are staggered, and the second plate faces the processing volume.\",\n \"Yet another embodiment of the present invention provides a method for pumping a processing chamber.\",\n \"The method includes directing fluid flow from a processing volume to a vacuum port through a flow equalizer assembly.\",\n \"The flow equalizer assembly includes a first plate having at least one first opening, and a second plate having two or more second openings.\",\n \"The at least one first opening and the two or more second openings are staggered.\",\n \"Directing the fluid flow includes flowing one or more gases from the processing volume through the two or more second openings to a flow redistributing volume defined between the first and second plates, and flowing the one or more gases from the flow redistributing volume through the at least one first opening to the vacuum port.\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisional of U.S. patent application Ser.\",\n \"No.\",\n \"14/452,228, filed Aug. 5, 2014, which claims priority to U.S.\",\n \"Provisional Patent Application No.\",\n \"61/864,929, filed on Aug. 12, 2013, both of which are herein incorporated by reference in their entireties.\",\n \"BACKGROUND Field Embodiments of the present invention relate to apparatus and methods for processing semiconductor substrates.\",\n \"More particularly, embodiments of the present invention provide apparatus and methods for reducing non-uniformity and/or skews during substrate processing.\",\n \"Description of the Related Art Electronic devices, such as flat panel displays and integrated circuits commonly are fabricated by a series of process steps in which layers are deposited on a substrate and the deposited material is etched into desired patterns.\",\n \"The process steps commonly include physical vapor deposition (PVD), chemical vapor deposition (CVD), plasma enhanced CVD (PECVD), and other plasma processing.\",\n \"Specifically, a plasma process requires supplying a process gas mixture to a vacuum chamber, and applying electrical or electromagnetic power (RF power) to excite the process gas into a plasma state.\",\n \"The plasma decomposes the gas mixture into ion species that perform deposition, etch, implant or other processes.\",\n \"One problem encountered with plasma processes is the difficulty associated with establishing uniform plasma density over the substrate surface during processing, which leads to non-uniform processing between the center and edge regions of the substrate and non-uniform processing azimuthally within center and edge regions.\",\n \"One reason for the difficulty in establishing uniform plasma density involves gas flow skews due to asymmetry in the physical process chamber design.\",\n \"Such skews not only result in naturally, azimuthal, non-uniform plasma density, but also make it difficult to use other processing variables or “knobs” to control center-to-edge plasma uniformity.\",\n \"Therefore, a need exists for a plasma processing apparatus that improves gas flow symmetry for improved plasma uniformity control.\",\n \"SUMMARY Embodiments of the present invention provide apparatus and methods for reducing non-uniformity and/or skews during substrate processing.\",\n \"One embodiment of the present invention provides a flow equalizer assembly for disposing between a vacuum port and a processing volume in a processing chamber.\",\n \"The flow equalizing assembly includes a first plate having at least one first opening, and a second plate having two or more second openings.\",\n \"The first and second plates define a flow redistributing volume therebetween, and the at least one first opening and the two or more second openings are staggered.\",\n \"Another embodiment of the present invention provides an apparatus for processing one or more substrates.\",\n \"The apparatus includes a chamber body defining a processing volume, wherein a pumping port is formed through the chamber body for connection with a vacuum pump, a substrate support disposed in the processing volume for supporting a substrate thereon, a gas delivery assembly configured to deliver one or more processing gas to the processing volume, and a flow equalizer assembly disposed between the processing volume and the pumping port.\",\n \"The flow equalizer assembly includes a first plate having at least one first opening, and a second plate having two or more second openings.\",\n \"The first plate faces the vacuum port.\",\n \"The first and second plates define a flow redistributing volume therebetween, the at least one first opening and the two or more second openings are staggered, and the second plate faces the processing volume.\",\n \"Yet another embodiment of the present invention provides a method for pumping a processing chamber.\",\n \"The method includes directing fluid flow from a processing volume to a vacuum port through a flow equalizer assembly.\",\n \"The flow equalizer assembly includes a first plate having at least one first opening, and a second plate having two or more second openings.\",\n \"The at least one first opening and the two or more second openings are staggered.\",\n \"Directing the fluid flow includes flowing one or more gases from the processing volume through the two or more second openings to a flow redistributing volume defined between the first and second plates, and flowing the one or more gases from the flow redistributing volume through the at least one first opening to the vacuum port.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS So that the manner in which the above recited features of the present invention can be understood in detail, a more particular description of the invention, briefly summarized above, may be had by reference to embodiments, some of which are illustrated in the appended drawings.\",\n \"It is to be noted, however, that the appended drawings illustrate only typical embodiments of this invention and are therefore not to be considered limiting of its scope, for the invention may admit to other equally effective embodiments.\",\n \"FIG.\",\n \"1A is a schematic sectional view of a plasma processing chamber according to one embodiment of the present invention.\",\n \"FIG.\",\n \"1B is a schematic top view of the plasma processing chamber of FIG.\",\n \"1A with a chamber lid removed.\",\n \"FIG.\",\n \"2A is a schematic perspective sectional view of a flow equalizer assembly according to one embodiment of the present invention.\",\n \"FIG.\",\n \"2B is a schematic cylindrical map projection of the flow equalizer assembly of FIG.\",\n \"2A showing azimuthal flow distributions.\",\n \"FIG.\",\n \"3A is a schematic perspective view of a flow equalizer assembly including one or more dividers according to one embodiment of the present invention.\",\n \"FIG.\",\n \"3B is a schematic sectional perspective view of a flow equalizer including one or more adjustable dividers according to one embodiment of the present invention.\",\n \"FIG.\",\n \"4A is a schematic top view of a flow equalizing plate according to one embodiment of the present invention.\",\n \"FIG.\",\n \"4B is a schematic top view of a flow equalizing plate according to one embodiment of the present invention.\",\n \"To facilitate understanding, identical reference numerals have been used, where possible, to designate identical elements that are common to the figures.\",\n \"It is contemplated that elements disclosed in one embodiment may be beneficially utilized on other embodiments without specific recitation.\",\n \"DETAILED DESCRIPTION Embodiments of the present invention generally provide various apparatus and methods for improving gas flow symmetry.\",\n \"In one embodiment, a flow equalizing assembly positioned between a processing volume and a vacuum port at a non-symmetrical position relative to the processing volume is provided.\",\n \"The flow equalizing assembly includes at least two plates each having openings formed therethrough.\",\n \"The flow equalizing assembly forms a plurality of flow paths so that different regions of the processing volume are at substantially the same distance from the vacuum port, thus, achieving symmetrical pumping conductance.\",\n \"In addition to reducing flow non-symmetry caused by non-symmetrical location of a vacuum port, the flow equalizing assembly can also be used to reduce other non-symmetries in a processing chamber, such as conductance and RF non-symmetry caused by a slit valve door.\",\n \"In one embodiment, a flow asymmetry may be introduced in the flow equalizing assembly to compensate for RF asymmetry to obtain processing symmetry.\",\n \"The flow equalizing assembly enables the symmetry of fluid flow in a processing chamber to be tuned, thus, reducing processing skew and improving uniformity of processing.\",\n \"FIG.\",\n \"1A is a schematic sectional view of a plasma processing chamber 100 according to one embodiment of the present invention.\",\n \"The plasma processing chamber 100 includes a flow equalizer assembly 160 to obtain fluid flow symmetry between a processing volume and a vacuum port.\",\n \"The flow equalizer assembly 160 may be used to obtain a symmetrical fluid flow, or may be used to tune the symmetry of the fluid flow to compensate for other chamber asymmetries to obtain symmetrical processing results.\",\n \"The plasma processing chamber 100 may be configured to process a variety of substrates, such as semiconductor substrates and reticles, and accommodating a variety of substrate sizes.\",\n \"The plasma processing chamber 100 includes a chamber body 110.A bottom chamber liner 112 and a top chamber liner 114 are disposed inside the chamber body 110.The bottom chamber liner 112, the top chamber liner 114 and a chamber lid 116 define a chamber volume 118.Slit valve openings 119, 120 may be formed through the chamber body 110 and the top chamber liner 114 to allow passage of a substrate 102 and substrate transfer mechanism (not shown).\",\n \"A slit valve door 122 may be utilized to selectively open and close the slit valve openings 119, 120.A substrate support assembly 124 is disposed in the chamber volume 118.The substrate support assembly 124 has a substrate supporting surface 126 for supporting a substrate thereon.\",\n \"A lift 132 may be coupled to lifting pins 134 to raise the substrate 102 from and to lower the substrate 102 on to the substrate support assembly 124.The substrate support assembly 124 may be an electrostatic chuck coupled to a chucking power source 136 to secure the substrate 102 thereon.\",\n \"The substrate support assembly 124 may also includes one or more embedded heating elements coupled to a heating power source 138 for heating the substrate 102 during processing.\",\n \"A cooling fluid source 140 may provide cooling or heating and adjust temperature profile of the substrate 102 being processed.\",\n \"An optional plasma screen 130 may be disposed surrounding the substrate support assembly 124.The plasma screen 130 may be positioned at a vertical level similar to the vertical level of the substrate supporting surface 126 and separates the chamber volume 118 into a processing volume 118a and a lower volume 118b located below the plasma screen 130.A showerhead assembly 142 may be positioned above the processing volume 118a to deliver one or more processing gases from a gas delivery system 144 to the processing volume 118a.\",\n \"Alternatively, the plasma processing chamber 100 may also include an antenna assembly for generating inductively coupled plasma in the plasma processing chamber 100.A vacuum pump 150 is in fluid communication with the chamber volume 118 to maintain a low pressure environment within the processing volume 118a.\",\n \"In one embodiment, the vacuum pump 150 may be coupled to the lower chamber volume 118b through a vacuum port 152 formed in the bottom chamber liner 112.As shown in FIG.\",\n \"1A, the vacuum port 152 is positioned at a bottom of the lower volume 118b and laterally offset from the substrate support assembly 124, and thus, the vacuum port 152 is located non-symmetrical relative to the substrate support assembly 124.The flow equalizer assembly 160 is disposed around the substrate support assembly 124 to azimuthally equalize the gas flow passing from the processing volume 118a to the lower volume 118b.\",\n \"In one embodiment, the flow equalizer assembly 160 may be disposed under the optional plasma screen 130.The vacuum pump 150 pumps out gas and process by products from the processing volume 118a through the vacuum port 152, the lower volume 118b and flow paths formed through the flow equalizer assembly 160.The flow equalizer assembly 160 may include two or more plates 162, 164 spaced apart from one another.\",\n \"A flow re-distributing volume 172 is defined between neighboring plates 162, 164.Each of the plates 162, 164 includes openings 168, 170 formed therethrough.\",\n \"During operation, driven by vacuum suction from vacuum port 152, gases and particles exit the processing volume 118a through the openings 170 of the plate 164, flow through the flow re-distributing volume 172, then flow through the openings 168 of the plate 162 towards the vacuum port 152.Numbers, size, and/or locations of the openings 168, 170 are arranged so that flow paths between the openings 170 to the openings 168 through the flow re-distributing volume 172 can be tuned to correct processing asymmetries by either adjusting or eliminating the flow asymmetries between the processing volume 118a and the vacuum port 152.In one embodiment of the present invention, each of the two or more plates 162, 164 may be a circular plate having a central opening for receiving the substrate support assembly 124 so that the flow equalizer assembly 160 is disposed around the substrate support assembly 124.In one embodiment, the top most plate 164 may be at a horizontal level similar to or slightly lower than the substrate supporting surface of the substrate support assembly 124.The openings 170 may be substantially evenly distributed along an outer edge of the substrate support assembly 124.The circular plates 162, 164 may be arranged parallel to each other.\",\n \"The openings 168 of the plate 162 and the openings 170 of the plate 164 may be arranged in a vertically staggered manner, instead of vertically aligned with each other, to enable flow equalizing within the flow re-distributing volume 172.The number, shape and sizes of openings 168 and the number of openings 170 may be the same or different.\",\n \"In one embodiment, the number of openings 170 on the plate 164 which is positioned closer to the processing volume 118a is greater than the number of openings 168 on the plate 162 which is positioned closer to the vacuum port 152.In one embodiment, the number of openings 170 may be at least twice as many as the number of the openings 168.The number, size and/or location of openings in the plates 162, 164 may be arranged to provide equal distances between the vacuum port 152 and different regions of the substrate support assembly 124 so that processing gases within the processing volume 118a can be uniformly and symmetrically pumped around the substrate support assembly 124.FIG.\",\n \"1B is a schematic top view of the plasma processing chamber 100 of FIG.\",\n \"1A with the lid 116 removed.\",\n \"As shown in FIG.\",\n \"1B, the vacuum port 152 is positioned off center from the centerline of the substrate support assembly 124.The plates 164, 162 are disposed concentric to the substrate support assembly 124.The openings 170 of the top plate 164 may be evenly distributed around the substrate support assembly 124.The number of openings 170 of the top late 164 may be at least twice as many as the number of openings 168 of the bottom plate 162.In the embodiment of FIG.\",\n \"1B, there are two openings 168 on the bottom plate 162.The two openings 168 are positioned at equal distance away from the vacuum port 152.There are four openings 170 on the top plate 164.The top plate 164 is positioned in an angle so that each opening 170 is located at the substantially the same distance away from a closest opening 168.As a result, each opening 170 on the top plate 164 is positioned at substantially the same distance away from the vacuum port 152, thus reducing the non-symmetry in flow paths through the flow equalizer assembly 160.In the embodiment of FIG.\",\n \"1B, each of the openings 170 is similar in shape and size and each of the openings 168 is similar in shape and size.\",\n \"Alternative, the shape and/or size of each opening 170 or opening 168 may be unique or different to provide a target flow resistance.\",\n \"Although two plates 164, 162 are shown in the flow equalizer assembly 160 of FIG.\",\n \"1A, additional plates may be included to tune the flow distribution through the flow equalizer assembly 160.For example, an additional plate may be disposed above the top plate 164.The additional plate may have twice as many openings as the top plate 164 to generate a recursive flow splitting and equalizing effect.\",\n \"FIG.\",\n \"2A is a schematic perspective view of a flow equalizer assembly 200 according to one embodiment of the present invention.\",\n \"The flow equalizer assembly 200 includes a first plate 202 having a plurality of openings 204 for receiving fluid flow from a processing volume and a second plate 206 having two or more openings 208 for directing fluid flow towards a vacuum port.\",\n \"The first plate 202 and the second plate 206 may be positioned parallel to each other.\",\n \"The first plate 202 may include a central opening 210 and the second plate 206 may include a central opening 212.The central openings 210, 212 are sized to receive a substrate support assembly so that the first plate 202 and the second plate 206 are surrounds the substrate support assembly.\",\n \"A sidewall 214 may extend above the first plate 202 from an outer perimeter.\",\n \"The sidewall 214 may be symmetrical, for example having a circular shape or a normal polygonal shape, to retain a symmetrical volume above the substrate support assembly.\",\n \"In one embodiment, the sidewall 214 may include an upper lip 215 so that the flow equalizer assembly 200 can be supported by a chamber liner.\",\n \"A sidewall 216 may connect between the first plate 202 and the second plate 206 to enclose a flow re-distributing volume 218.The sidewall 216 may be symmetrical, for example being circular.\",\n \"The distribution, shape, size and/or relative locations of the openings 204, 208 and the height of the flow re-distributing volume 218 may be tuned to achieve flow redistributing effect.\",\n \"The plurality of openings 204 may be evenly distributed along the first plate 202.A spacing 217 between the first plate 202 and the second plate may be provided to achieve targeted flow patterns.\",\n \"In one embodiment, a ratio of the spacing 217 and a width 219 of the flow re-distributing volume 218 may be between about 0.4 to about 0.5.FIG.\",\n \"2B is a schematic cylindrical map projection of the flow equalizer assembly 200 showing azimuthal flow distributions.\",\n \"The flow equalizer assembly 200 is arranged so that each opening 204 of the first plate 202 is substantially equal distance to the vacuum port.\",\n \"Since the openings 204 are positioned along an edge region of the plasma or processing environment, the processing environment can be symmetrically vacuumed by the vacuum port through the flow equalizer assembly 200.The two openings 208 closest to the vacuum port may be positioned at equal distances from the vacuum port.\",\n \"As shown in FIG.\",\n \"2B, the vacuum port is located at 180 degrees, while the openings 208 are positioned at 90 degrees and 270 degrees respectively.\",\n \"Similarly, the openings 204 are arranged such that each opening 204 is at substantial the same distance to a closest opening 208.In FIG.\",\n \"2B, there are four openings 204 positioned 90 degrees apart at 45 degrees, 135 degrees, 225 degrees and 315 degrees.\",\n \"Additional plates can be positioned above the first plate 202 to provide for further equalizing.\",\n \"For example, an additional having twice as many openings as the first plate 202 may be positioned above the first plate 202.In the embodiment of FIG.\",\n \"2B, the openings in the additional plate may include eight openings positioned 45 degrees apart at 22.5 degrees, 67.5 degrees, 112.5 degrees, 157.5 degrees, 202.5 degrees, 247.5 degrees, 292.5 degrees, and 337.5 degrees.\",\n \"Alternatively, the additional plate may include only four openings positioned at in staggered manner relative to openings 204 to avoid increased flow resistance caused by smaller openings.\",\n \"FIG.\",\n \"3A is a schematic perspective view of a flow equalizer assembly 300 including one or more dividers 302 according to one embodiment of the present invention.\",\n \"The flow equalizer assembly 300 is similar to the flow equalizer assembly 200 described above except that the two or more dividers 302 may be positioned between the first plate 202 and the second plate 206.The dividers 302 cut the flow re-distributing volume 218 into two or more isolated sub-volumes 306a, 306b, 306c, 306d.\",\n \"Each sub-volume 306a, 306b, 306c, 306d opens to at least one opening 204 of the first plate 202 and one opening 208 of the second plate 206.The dividers 302 provide additional direction to the flow passing through the flow equalizer assembly 300 to improve flow symmetry tuning.\",\n \"In the embodiment shown in FIG.\",\n \"3A, two or more dividers 302 may be positioned above the openings 208 dividing each opening 208 into two sections so that each opening 204 of the first plate 202 is exposed to similar level of suction.\",\n \"Optionally, the flow equalizer assembly 300 may also include dividers 304 attached to the second plate 206 isolating the two openings 208 from each other.\",\n \"When installed, one divider 304 may be positioned over the vacuum port so that each opening 208 is exposed to equal amount of suction from a vacuum pump.\",\n \"FIG.\",\n \"3B is a schematic sectional perspective view of a flow equalizer assembly 350 including one or more adjustable dividers according to one embodiment of the present invention.\",\n \"The flow equalizer assembly 350 is similar to the flow equalizer assembly 300 except the dividers 302 may be adjustable.\",\n \"The location of each divider 302 may be adjusted to obtain target flow resistance in each sub-volume 306.In one embodiment, each divider 302 may be positioned in one of a plurality of pre-determined locations.\",\n \"For example, a plurality of notches 310 may be formed under the first plate 202 for secure a divider 302 at a plurality of locations.\",\n \"In one embodiment, the dividers 302 may be arranged to enclose one or more isolated sections 314 within the flow re-distributing volume.\",\n \"The isolated sections 314 is not fluidly connected to any openings of the first plate 202 or the second plate 206.The isolated sections 314 may be used to reduce flow stagnation.\",\n \"FIG.\",\n \"4A is a schematic top view of a flow equalizing plate 400 for using in a flow equalizer assembly according to one embodiment of the present invention.\",\n \"The flow equalizing plate 400 may include a ring shaped planar body 402 having a plurality of openings 404a, 404b, 404c, 404d formed therethrough.\",\n \"The shape, size, and distribution of the plurality of openings 404a, 404b, 404c, 404d may be varied according to flow requirement and chamber geometry.\",\n \"In one embodiment, the plurality of openings 404a, 404b, 404c, 404d may have may be of the same shape or side and be evenly distributed.\",\n \"Alternatively, one or more openings 404a, 404b, 404c, 404d may be varied to compensate chamber geometry.\",\n \"For example, an opening 404d positioned adjacent to a slit valve door 406 of a processing chamber may be of a different size or shape to compensate the non-symmetry of the slit valve door 406.FIG.\",\n \"4B is a schematic top view of a flow equalizing plate 420 according to one embodiment of the present invention.\",\n \"The flow equalizing plate 420 may include a ring shaped planar body 422 having two or more openings 424 for directing fluid flow there through.\",\n \"In one embodiment, the flow equalizing plate 420 may include a shutter disk 426 to selectively close a portion of the opening 424 to adjust flow resistance through a particular opening.\",\n \"Embodiments of the present invention may be used alone or in combination.\",\n \"Even though plasma chambers are described in the above embodiments, flow equalizer assemblies according to embodiments of the present invention may be used in any suitable chambers.\",\n \"While the foregoing is directed to embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875726"}}},{"rowIdx":4494960,"cells":{"text":{"kind":"list like","value":[["EXTRACTION OF LIPID FROM CELLS AND PRODUCTS THEREFROM","The present invention relates to processes for obtaining a lipid from a cell by lysing the cell, contacting the cell with a base and/or salt, and separating the lipid.","The present invention is also directed to a lipid prepared by the processes of the present invention.","The present invention is also directed to microbial lipids having a particular anisidine value, peroxide value, and/or phosphorus content."],["1.A process for obtaining a lipid from a cell composition, comprising: (a) lysing a cell of said cell composition to form a lysed cell composition; (b) demulsifying said lysed cell composition to form a demulsified cell composition, wherein the demulsifying comprises contacting said lysed cell composition with a first base to raise the pH of the lysed cell composition to 8 and contacting the lysed cell composition with a second base to raise the pH of the lysed cell composition to 7 or above to demulsify the cell composition; (c) separating said lipid from the demulsified cell composition; and (d) harvesting said lipid; wherein (b) comprises heating said lysed cell composition to a temperature of at least 70° C.","2.","(canceled) 3.","(canceled) 4.The process of claim 1, wherein (b) comprises contacting said lysed cell composition with a salt to demulsify the cell composition.","5.","(canceled) 6.The process of claim 4, wherein the salt is added in an amount of 0.1% to 20% by weight of the lysed cell composition.","7.","(canceled) 8.The process of claim 4, wherein the salt is selected from: alkali metal salts, alkali earth metal salts, sulfate salts, and combinations thereof.","9-30.","(canceled) 31.The process of claim 1, comprising washing the cell or cell composition.","32.The process of claim 1, comprising pasteurizing the cell or cell composition.","33.The process of claim 1, comprising concentrating the lysed cell composition.","34-38.","(canceled) 39.A lipid obtained by the process of claim 1, the lipid comprising at least 35% by weight docosahexaenoic acid, at least 20% by weight eicosapentaenoic acid and less than 5% by weight each of arachidonic acid, docosapentaenoic acid n-6, oleic acid, linoleic acid, linolenic acid, eicosenoic acid, erucic acid, and stearidonic acid.","40.","(canceled) 41.","(canceled) 42.","(canceled) 43.","(canceled) 44.The lipid of claim 39, wherein the lipid has an anisidine value of 26 or less.","45.The lipid of claim 39, wherein the lipid has a phosphorus content of 100 ppm or less.","46.The lipid of claim 39, wherein the lipid has a peroxide value of 5 or less.","47.","(canceled) 48.","(canceled) 49.The lipid of claim 39, wherein the lipid has a peroxide value of 5 or less.","50.The lipid of claim 39, wherein the lipid is a crude oil.","51.","(canceled) 52-59.","(canceled) 60.The process of claim 1, wherein (b) comprises heating said lysed cell composition to a temperature of from 70° C. to 100° C. 61.The process of claim 1, wherein (b) comprises agitating the lysed cell composition to demulsify the cell composition.","62.The process of claim 1, wherein (a) comprises adding a salt to said cell composition to demulsify the cell composition.","63.The process of claim 1, wherein (a) comprises raising the pH of said cell composition to 8 or above to demulsify or lyse the cell composition.","64.The process of claim 1, wherein the lysed cell composition is in the form of an oil-in-water emulsion comprising a mixture of a continuous aqueous phase and a dispersed lipid phase.","65.The process of claim 1, wherein (c) comprises centrifuging the demulsified cell composition.","66.The process of claim 1, wherein the lipid is a crude lipid.","67.The process of claim 69, comprising (e) refining said crude lipid to obtain a refined lipid.","68.The process of claim 1, wherein said lipid has an anisidine value of 26 or less.","69.The process of claim 1, wherein said lipid has a peroxide value of 5 or less.","70.The process of claim 1, wherein said cell is a microbial cell.","71.The process of claim 73, wherein said microbial cell is of the genus Thraustochytrium, Schizochytrium, or mixtures thereof.","72.The process of claim 1, wherein said lipid comprises omega 3 and/or omega-6 polyunsaturated fatty acids.","73.The process of claim 1, wherein said lipid comprises at least one of DHA, DPA(n-3), DPA(n-6), EPA, and ARA.","74.The process of claim 1, wherein an organic solvent is not added to said cell composition, said lysed cell composition, or said lipid in an amount or concentration sufficient to extract said lipid from said cell.","75.The process of claim 1, wherein the lipid contains less than 5% by weight of an organic solvent."],["<SOH> BACKGROUND OF THE INVENTION <EOH>"],["<SOH> BRIEF SUMMARY OF THE INVENTION <EOH>The present invention is directed to a process for obtaining a lipid from a microbial cell composition, the process comprising raising the pH of the cell composition to 8 or above, and separating a lipid from the cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.","In some embodiments, the raising the pH lyses the cell composition.","In some embodiments, the raising the pH demulsifies the cell composition.","In some embodiments, the process comprises adding a salt to the cell composition to demulsify the cell composition.","In some embodiments, the adding a salt is performed after the raising the pH.","In some embodiments, the process further comprises heating the lysed cell composition to demulsify the cell composition.","In some embodiments, the heating is performed after the raising the pH.","In some embodiments, the process further comprises raising the pH of the cell composition a second time to demulsify the cell composition.","In some embodiments, the raising the pH a second time is performed after the adding a salt or the heating.","The present invention is also directed to a process for obtaining a lipid from a cell, the process comprising lysing a cell to form a lysed cell composition, raising the pH of the lysed cell composition to 8 or above to demulsify the cell composition, adding a salt to the lysed cell composition to demulsify the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.","The present invention is directed to a process for obtaining a lipid from a cell composition, the process comprising raising the pH of the cell composition to 8 or above to lyse the cell composition and demulsify the cell composition, adding a salt to the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.","The present invention is also directed to a process for obtaining a lipid from a cell, the process comprising lysing a cell to form a lysed cell composition, agitating the cell composition to demulsify the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.","In some embodiments, the process further comprises heating the lysed cell composition to demulsify the cell composition.","In some embodiments, the heating is performed after the adding a salt.","In some embodiments, the process further comprises agitating the lysed cell composition to demulsify the cell composition.","In some embodiments, the agitating is for 5 minutes to 96 hours.","In some embodiments, the agitating comprises agitating the cell composition with an impeller having a tip speed of 350 centimeters per second to 900 centimeters per second.","In some embodiments, the process further comprises raising the pH of the lysed cell composition to demulsify the cell composition.","In some embodiments, raising the pH of the lysed cell composition to demulsify the cell composition comprises adding a base.","In some embodiments, a second base is added after the adding of a salt or the heating.","In some embodiments, the heating is for 10 minutes to 96 hours.","In some embodiments, the cell composition is heated to a temperature of 60° C. to 100° C. In some embodiments, the cell composition is heated to a temperature of 90° C. to 100° C. In some embodiments, raising the pH comprises adding a base.","In some embodiments, the base has a pK b of 1 to 12.In some embodiments, the separating a lipid occurs at a temperature of 10° C. to 100° C. In some embodiments, the process comprises agitating the lysed cell composition by stirring, mixing, blending, shaking, vibrating, or a combination thereof.","In some embodiments, the process comprises agitating the lysed cell composition at 0.1 hp/1000 gal to 10 hp/1000 gal of lysed cell composition.","In some embodiments, the process comprises agitating the lysed cell composition with an agitator having an impeller tip speed of 200 ft/min to 1,000 ft/min.","In some embodiments, the lysing comprises mechanical treatment, physical treatment, chemical treatment, enzymatic treatment, or a combination thereof.","In some embodiments, the mechanical treatment is homogenization.","In some embodiments, the salt is added in an amount of 0.1% to 20% by weight of the lysed cell composition.","In some embodiments, the salt is added to the lysed cell composition in an amount of 0.5% to 15% by weight of the lysed cell composition.","In some embodiments, the salt is added to the lysed cell composition in an amount of 2% to 10% by weight of the lysed cell composition.","In some embodiments, the salt is selected from the group consisting of: alkali metal salts, alkali earth metal salts, sulfate salts, and combinations thereof.","In some embodiments, the salt is sodium chloride.","In some embodiments, the salt is sodium sulfate.","In some embodiments, the separating comprises centrifuging.","In some embodiments, the separating comprises centrifuging at a temperature of 30° C. to 90° C. In some embodiments, the process provides a lipid comprising at least 50% by weight triglyceride.","In some embodiments, the process provides a lipid having an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less.","In some embodiments, the process provides a lipid having a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less.","In some embodiments, the process provides a lipid having a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","In some embodiments, the process provides a lipid having at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of a desired polyunsaturated fatty acid (PUFA).","In some embodiments, the process provides a lipid having at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of docosahexaenoic acid (“DHA”), and/or at least 10%, at least 15%, or at least 20% by weight of docosapentaenoic acid (“DPA n-6”), and/or at least 10%, at least 15%, or at least 20% by weight of eicosapentaenoic acid (“EPA”), and/or at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of arachidonic acid (“ARA”).","In some embodiments, the cell is a microbial cell.","In some embodiments, the process comprises concentrating a fermentation broth comprising the microbial cell.","In some embodiments, the cell is an oilseed.","In some embodiments, the oilseed is selected from the group consisting of sunflower seeds, canola seeds, rapeseeds, linseeds, castor oil seeds, coriander seeds, calendula seeds, and genetically modified variants thereof.","In some embodiments, the process comprises washing the cell or cell composition.","In some embodiments, the process comprises pasteurizing the cell or cell composition.","In some embodiments, the process comprises concentrating the lysed cell composition.","In some embodiments, the process comprises refining the lipid.","In some embodiments, the refining is selected from the group consisting of: caustic refining, degumming, acid treatment, alkali treatment, cooling, heating, bleaching, deodorizing, deacidification, and combinations thereof.","In some embodiments, the process comprises harvesting the lipid, wherein the harvesting comprises pumping the lipid without agitation.","The present invention is also directed to a lipid obtained by any of the processes of the present invention.","In some embodiments, the lipid comprises one or more polyunsaturated fatty acids.","In some embodiments, the lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of a desired PUFA.","In some embodiments, the lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of DHA, and/or at least 10%, at least 15%, or at least 20% by weight of DPA n-6, and/or at least 10%, at least 15%, or at least 20% by weight of EPA, and/or at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of ARA.","In some embodiments, the lipid has an overall aroma intensity of 3 or less.","In some embodiments, the lipid has an overall aromatic intensity of 2 or less.","In some embodiments, the lipid comprises a triacylglycerol fraction of at least 10% by weight, wherein at least 12% by weight of the fatty acids in the triacylglycerol fraction is eicosapentaenoic acid, wherein at least 25% by weight of the fatty acids in the triacylglycerol fraction is docosahexaenoic acid, and wherein less than 5% by weight of the fatty acids in the triacylglycerol fraction is arachidonic acid.","In some embodiments, the lipid comprises at least 20% by weight eicosapentaenoic acid and less than 5% by weight each of arachidonic acid, docosapentaenoic acid n-6, oleic acid, linoleic acid, linolenic acid, eicosenoic acid, erucic acid, and stearidonic acid.","In some embodiments, the lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or Less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","In some embodiments, the lipid is a crude lipid.","In some embodiments, the crude lipid optionally has less than 5% by weight or volume of an organic solvent.","The present invention is also directed to a crude microbial lipid having an anisidine value of 26 or less, a peroxide value of 5 or less, a phosphorus content of 100 ppm or less, and optionally less than 5% by weight or volume of an organic solvent.","In some embodiments, the crude microbial lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","In some embodiments, the crude microbial lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of a desired PUFA.","In some embodiments, the crude microbial lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of DI-IA, and/or at least 10%, at least 15%, or at least 20% by weight of DPA n-6, and/or at least 10%, at least 15%, or at least 20% by weight of EPA, and/or at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of ARA.","The present invention is also directed to an extracted microbial lipid comprising a triglyceride fraction of at least 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 50% by weight, wherein the docosapentaenoic acid n-6 content of the triglyceride fraction is from at least 0.5% by weight to 6% by weight, and wherein the oil has an anisidine value of 26 or less.","The present invention is also directed to an extracted microbial lipid comprising a triglyceride fraction of at least 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 40% by weight, wherein the docosapentaenoic acid n-6 content of the triglyceride fraction is from at least 0.5% by weight to 6% by weight, wherein the ratio of docosahexaenoic acid to docosapentaenoic acid n-6 is greater than 6:1, and wherein the oil has an anisidine value of 26 or less.","The present invention is also directed to an extracted microbial lipid comprising a triglyceride fraction of at least about 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 60% by weight and wherein the oil has an anisidine value of 26 or less.","In some embodiments, the extracted lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","In some embodiments, the extracted microbial lipid is a crude lipid or a crude oil.","In some embodiments, the crude lipid optionally has less than 5% by weight or volume of an organic solvent.","The present invention is also directed to a process for obtaining a lipid, the process comprising refining a crude lipid of the present invention.","In some embodiments, the refining is selected from the group consisting of: caustic refining, degumming, acid treatment, alkali treatment, cooling, heating, bleaching, deodorizing, deacidification, and combinations thereof."],["CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S.","Application No.","61/350,363, filed on Jun.","1, 2010, U.S.","Application No.","61/378,923, filed Aug. 31, 2010, and U.S.","Application No.","61/452,721, filed Mar.","15, 2011, each of which is hereby incorporated by reference in its entirety.","BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to processes for obtaining a lipid from a cell by lysing the cell, raising a pH of the cell and/or contacting the cell with a salt, and separating the lipid.","The present invention is also directed to lipids prepared by the processes of the present invention.","The present invention is also directed to microbial lipids having a particular anisidine value, peroxide value, and/or phosphorus content.","Background Art A typical process for obtaining lipids from a microbial cell, such as polyunsaturated fatty acids, involves growing microorganisms that are capable of producing the desired lipid in a fermentor, pond or bioreactor, separating the fermentation broth comprising a microbial cell biomass, drying the microbial cell biomass, and separating the lipids by solvent extraction.","Steps in the separation can include diluting a fermentation broth with water, centrifuging the diluted broth, lysing the microbial cells, and extracting an intracellular lipid from the lysed cells by adding a water-immiscible solvent to the mixture in which the lipid is soluble, e.g., hexane.","Another method of extraction to remove a lipid from a microbial cell is lysing a cell in a fermentation broth using mechanical force (e.g., homogenization), enzymatic treatment, or chemical treatment to disrupt the cell walls.","Lipid can be extracted from the resulting composition comprising lipids, microbial cell biomass, and water using an organic solvent, e.g., isopropyl alcohol.","The lipid can be separated mechanically from the composition and the alcohol must be removed from both the lipid and the aqueous biomass waste stream.","See, e.g., International Pub.","Nos.","WO 01/76385 and WO 01/76715.However, industrial scale production of lipids using either of the above processes requires a large amount of volatile and flammable organic solvent, thereby creating hazardous operating conditions.","The use of organic solvents in the extraction process can also necessitate using an explosion-proof lipid recovery system, thereby adding to the cost of lipid recovery.","Moreover, use of an organic solvent in extracting lipid from a microbial cell can generate an organic solvent waste stream that requires a complete solvent recovery system or a proper method of disposal, which further increases the overall production cost of lipid extraction.","For example, strict limits on volatile organic compound (VOC) emissions require greater manpower and added cost to vessels and other equipment.","Therefore, there is a need for a process for obtaining lipids from a cell which does not use an organic solvent.","Several processes have been proposed for separating a lipid from a cell without the use of an organic solvent.","For example, U.S. Pat.","No.","6,750,048 discloses an aqueous washing process whereby an emulsion is washed with aqueous washing solutions until a substantially non-emulsified lipid is obtained.","However, in some embodiments, this process requires multiple washing steps, which require substantial cost and time.","U.S. Pat.","No.","7,431,952 discloses a process whereby lysed cells are centrifuged to remove cell wall debris and then oils are extracted and purified.","However, this process provides a crude oil that requires extensive further purification.","Thus, what is needed is a process that does not utilize a volatile solvent to extract a lipid from a cell, and which can be performed using readily available equipment and a minimum number of steps to provide a highly pure lipid.","BRIEF SUMMARY OF THE INVENTION The present invention is directed to a process for obtaining a lipid from a microbial cell composition, the process comprising raising the pH of the cell composition to 8 or above, and separating a lipid from the cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.","In some embodiments, the raising the pH lyses the cell composition.","In some embodiments, the raising the pH demulsifies the cell composition.","In some embodiments, the process comprises adding a salt to the cell composition to demulsify the cell composition.","In some embodiments, the adding a salt is performed after the raising the pH.","In some embodiments, the process further comprises heating the lysed cell composition to demulsify the cell composition.","In some embodiments, the heating is performed after the raising the pH.","In some embodiments, the process further comprises raising the pH of the cell composition a second time to demulsify the cell composition.","In some embodiments, the raising the pH a second time is performed after the adding a salt or the heating.","The present invention is also directed to a process for obtaining a lipid from a cell, the process comprising lysing a cell to form a lysed cell composition, raising the pH of the lysed cell composition to 8 or above to demulsify the cell composition, adding a salt to the lysed cell composition to demulsify the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.","The present invention is directed to a process for obtaining a lipid from a cell composition, the process comprising raising the pH of the cell composition to 8 or above to lyse the cell composition and demulsify the cell composition, adding a salt to the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.","The present invention is also directed to a process for obtaining a lipid from a cell, the process comprising lysing a cell to form a lysed cell composition, agitating the cell composition to demulsify the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.","In some embodiments, the process further comprises heating the lysed cell composition to demulsify the cell composition.","In some embodiments, the heating is performed after the adding a salt.","In some embodiments, the process further comprises agitating the lysed cell composition to demulsify the cell composition.","In some embodiments, the agitating is for 5 minutes to 96 hours.","In some embodiments, the agitating comprises agitating the cell composition with an impeller having a tip speed of 350 centimeters per second to 900 centimeters per second.","In some embodiments, the process further comprises raising the pH of the lysed cell composition to demulsify the cell composition.","In some embodiments, raising the pH of the lysed cell composition to demulsify the cell composition comprises adding a base.","In some embodiments, a second base is added after the adding of a salt or the heating.","In some embodiments, the heating is for 10 minutes to 96 hours.","In some embodiments, the cell composition is heated to a temperature of 60° C. to 100° C. In some embodiments, the cell composition is heated to a temperature of 90° C. to 100° C. In some embodiments, raising the pH comprises adding a base.","In some embodiments, the base has a pKb of 1 to 12.In some embodiments, the separating a lipid occurs at a temperature of 10° C. to 100° C. In some embodiments, the process comprises agitating the lysed cell composition by stirring, mixing, blending, shaking, vibrating, or a combination thereof.","In some embodiments, the process comprises agitating the lysed cell composition at 0.1 hp/1000 gal to 10 hp/1000 gal of lysed cell composition.","In some embodiments, the process comprises agitating the lysed cell composition with an agitator having an impeller tip speed of 200 ft/min to 1,000 ft/min.","In some embodiments, the lysing comprises mechanical treatment, physical treatment, chemical treatment, enzymatic treatment, or a combination thereof.","In some embodiments, the mechanical treatment is homogenization.","In some embodiments, the salt is added in an amount of 0.1% to 20% by weight of the lysed cell composition.","In some embodiments, the salt is added to the lysed cell composition in an amount of 0.5% to 15% by weight of the lysed cell composition.","In some embodiments, the salt is added to the lysed cell composition in an amount of 2% to 10% by weight of the lysed cell composition.","In some embodiments, the salt is selected from the group consisting of: alkali metal salts, alkali earth metal salts, sulfate salts, and combinations thereof.","In some embodiments, the salt is sodium chloride.","In some embodiments, the salt is sodium sulfate.","In some embodiments, the separating comprises centrifuging.","In some embodiments, the separating comprises centrifuging at a temperature of 30° C. to 90° C. In some embodiments, the process provides a lipid comprising at least 50% by weight triglyceride.","In some embodiments, the process provides a lipid having an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less.","In some embodiments, the process provides a lipid having a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less.","In some embodiments, the process provides a lipid having a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","In some embodiments, the process provides a lipid having at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of a desired polyunsaturated fatty acid (PUFA).","In some embodiments, the process provides a lipid having at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of docosahexaenoic acid (“DHA”), and/or at least 10%, at least 15%, or at least 20% by weight of docosapentaenoic acid (“DPA n-6”), and/or at least 10%, at least 15%, or at least 20% by weight of eicosapentaenoic acid (“EPA”), and/or at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of arachidonic acid (“ARA”).","In some embodiments, the cell is a microbial cell.","In some embodiments, the process comprises concentrating a fermentation broth comprising the microbial cell.","In some embodiments, the cell is an oilseed.","In some embodiments, the oilseed is selected from the group consisting of sunflower seeds, canola seeds, rapeseeds, linseeds, castor oil seeds, coriander seeds, calendula seeds, and genetically modified variants thereof.","In some embodiments, the process comprises washing the cell or cell composition.","In some embodiments, the process comprises pasteurizing the cell or cell composition.","In some embodiments, the process comprises concentrating the lysed cell composition.","In some embodiments, the process comprises refining the lipid.","In some embodiments, the refining is selected from the group consisting of: caustic refining, degumming, acid treatment, alkali treatment, cooling, heating, bleaching, deodorizing, deacidification, and combinations thereof.","In some embodiments, the process comprises harvesting the lipid, wherein the harvesting comprises pumping the lipid without agitation.","The present invention is also directed to a lipid obtained by any of the processes of the present invention.","In some embodiments, the lipid comprises one or more polyunsaturated fatty acids.","In some embodiments, the lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of a desired PUFA.","In some embodiments, the lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of DHA, and/or at least 10%, at least 15%, or at least 20% by weight of DPA n-6, and/or at least 10%, at least 15%, or at least 20% by weight of EPA, and/or at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of ARA.","In some embodiments, the lipid has an overall aroma intensity of 3 or less.","In some embodiments, the lipid has an overall aromatic intensity of 2 or less.","In some embodiments, the lipid comprises a triacylglycerol fraction of at least 10% by weight, wherein at least 12% by weight of the fatty acids in the triacylglycerol fraction is eicosapentaenoic acid, wherein at least 25% by weight of the fatty acids in the triacylglycerol fraction is docosahexaenoic acid, and wherein less than 5% by weight of the fatty acids in the triacylglycerol fraction is arachidonic acid.","In some embodiments, the lipid comprises at least 20% by weight eicosapentaenoic acid and less than 5% by weight each of arachidonic acid, docosapentaenoic acid n-6, oleic acid, linoleic acid, linolenic acid, eicosenoic acid, erucic acid, and stearidonic acid.","In some embodiments, the lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or Less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","In some embodiments, the lipid is a crude lipid.","In some embodiments, the crude lipid optionally has less than 5% by weight or volume of an organic solvent.","The present invention is also directed to a crude microbial lipid having an anisidine value of 26 or less, a peroxide value of 5 or less, a phosphorus content of 100 ppm or less, and optionally less than 5% by weight or volume of an organic solvent.","In some embodiments, the crude microbial lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","In some embodiments, the crude microbial lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of a desired PUFA.","In some embodiments, the crude microbial lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of DI-IA, and/or at least 10%, at least 15%, or at least 20% by weight of DPA n-6, and/or at least 10%, at least 15%, or at least 20% by weight of EPA, and/or at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of ARA.","The present invention is also directed to an extracted microbial lipid comprising a triglyceride fraction of at least 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 50% by weight, wherein the docosapentaenoic acid n-6 content of the triglyceride fraction is from at least 0.5% by weight to 6% by weight, and wherein the oil has an anisidine value of 26 or less.","The present invention is also directed to an extracted microbial lipid comprising a triglyceride fraction of at least 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 40% by weight, wherein the docosapentaenoic acid n-6 content of the triglyceride fraction is from at least 0.5% by weight to 6% by weight, wherein the ratio of docosahexaenoic acid to docosapentaenoic acid n-6 is greater than 6:1, and wherein the oil has an anisidine value of 26 or less.","The present invention is also directed to an extracted microbial lipid comprising a triglyceride fraction of at least about 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 60% by weight and wherein the oil has an anisidine value of 26 or less.","In some embodiments, the extracted lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","In some embodiments, the extracted microbial lipid is a crude lipid or a crude oil.","In some embodiments, the crude lipid optionally has less than 5% by weight or volume of an organic solvent.","The present invention is also directed to a process for obtaining a lipid, the process comprising refining a crude lipid of the present invention.","In some embodiments, the refining is selected from the group consisting of: caustic refining, degumming, acid treatment, alkali treatment, cooling, heating, bleaching, deodorizing, deacidification, and combinations thereof.","BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES The accompanying drawings, which are incorporated herein and form a part of the specification, illustrate the present invention and, together with the description, further serve to explain the principles of the invention and to enable a person skilled in the pertinent art to make and use the invention.","FIGS.","1-4 provide schematic flow charts describing processes of the present invention.","FIG.","5 is a graph providing the electron paramagnetic resonance (EPR) over time of lysed cells compositions at various pHs.","The present invention will now be described with reference to the accompanying drawings.","In the drawings, like reference numbers indicate identical or functionally similar elements.","Additionally, the left-most digit(s) of a reference number can identify the drawing in which the reference number first appears.","DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to a process for obtaining a lipid from a microbial cell composition, the process comprising raising the pH of the cell composition to 8 or above and separating a lipid from the cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.","In some embodiments, the process further comprises one or more of adding a salt to the cell composition to demulsify the cell composition, heating the cell to demulsify the cell composition, agitating the cell composition to demulsify the cell composition, and raising the pH of the cell composition a second time to demulsify the cell composition.","The present invention is also directed to a process for obtaining a lipid from a cell, the process comprising lysing a cell to form a lysed cell composition, raising the pH of the lysed cell composition to 8 or above to demulsify the cell composition, adding a salt to the lysed cell composition to demulsify the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.","The cell can be a microbial cell or an oilseed cell.","In some embodiments, the process further comprises one or more of: heating the lysed cell composition to demulsify the cell composition, agitating the lysed cell composition to demulsify the cell composition, and raising the pH of the lysed cell composition a second time to demulsify the cell composition.","The present invention is directed to a process for obtaining a lipid from a cell composition, the process comprising raising the pH of the cell composition to 8 or above to lyse the cell composition and demulsify the cell composition, adding a salt to the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.","In some embodiments, the process further comprises one or more of heating the cell composition to demulsify the cell composition, agitating the cell composition to demulsify the cell composition, and raising the pH of the cell composition a second time to demulsify the cell composition.","The present invention is directed to a process for obtaining a lipid from a microbial cell, the process comprising lysing a microbial cell to form a lysed cell composition, adding a base to the lysed cell composition to demulsify the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.","In some embodiments, the process further comprises one or more of: adding a salt to the lysed cell composition to demulsify the cell composition, heating the lysed cell composition to demulsify the cell composition, agitating the lysed cell composition to demulsify the cell composition, and adding a second base to the lysed cell composition to demulsify the cell composition.","The present invention is also directed to a process for obtaining a lipid from a cell, the process comprising lysing a cell to form a lysed cell composition, adding a base to the lysed cell composition to demulsify the cell composition, adding a salt to the lysed cell composition to demulsify the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.","The cell can be a microbial cell or an oilseed cell.","In some embodiments, the process further comprises one or more of: heating the lysed cell composition to demulsify the cell composition, agitating the lysed cell composition to demulsify the cell composition, and adding a second base to the lysed cell composition to demulsify the cell composition.","The present invention is also directed to a process for obtaining a lipid from a cell, the process comprising lysing a cell to form a lysed cell composition, agitating the cell composition to demulsify the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.","The present invention is also directed to a lipid obtained by any of the processes of the present invention.","The present invention is also directed to an extraction process for obtaining a lipid from a cell, the process comprising lysing the cell to form a lysed cell composition, contacting the lysed cell composition with a first base, contacting the lysed cell composition with a salt, heating the lysed cell composition for 5 minutes to 96 hours, contacting the lysed cell composition with a second base, and separating a lipid from the lysed cell composition at a temperature of 10° C. to 100° C. The present invention is also directed to an extraction process for obtaining a lipid from a cell, the process comprising lysing the cell to form a lysed cell composition, contacting the lysed cell composition with a salt, and agitating the lysed cell composition for 5 minutes to 96 hours to provide a treated lysed cell composition, and separating a lipid from the treated lysed cell composition at a temperature of 10° C. to 100° C. The present invention is also directed to an extraction process for obtaining a lipid from a cell, the process comprising lysing the cell to form a lysed cell composition, contacting the lysed cell composition with a salt, and separating a lipid from the lysed cell composition at a temperature of 10° C. to 100° C. In some embodiments, the base or second base have a pKb of 1 to 12.In some embodiments, the base or second base have a pKb of 3 to 5.In some embodiments, a process comprises agitating the lysed cell composition for 5 minutes to 96 hours, 10 minutes to 96 hours, 10 minutes to 4 hours, 12 hours to 84 hours, or 24 hours to 72 hours.","In some embodiments, the process comprises agitating the lysed cell composition by stirring, mixing, blending, shaking, vibrating, or a combination thereof.","In some embodiments, the process comprises agitating the lysed cell composition at 0.1 hp/1000 gal to 10 hp/1000 gal of lysed cell composition.","In some embodiments, the process comprises agitating the lysed cell composition with an agitator having an impeller tip speed of 200 ft/min to 1000 ft/min.","In some embodiments, lysing comprises a process selected from: mechanically treating, physically treating, chemically treating, enzymatically treating, or a combination thereof.","In some embodiments, the lysed cell composition is contacted with a salt in an amount of 0.1% to 20% by weight, 0.5% to 15% by weight, or 2% to 10% by weight of the lysed cell composition.","In some embodiments, the salt is selected from the group consisting of: alkali metal salts, alkali earth metal salts, sulfate salts and combinations thereof.","In some embodiments, the salt is sodium chloride.","In some embodiments, the salt is sodium sulfate.","In some embodiments, the process comprises heating the lysed cell composition for 5 minutes to 96 hours, 10 minutes to 4 hours, 12 hours to 84 hours, or 24 hours to 72 hours.","In some embodiments, the separating comprises centrifuging.","In some embodiments, the separating comprises centrifuging at a temperature of 10° C. to 100° C. In some embodiments, the process comprises prior to the lysing: washing, centrifuging, evaporating, or a combination thereof, a broth that includes the cell.","In some embodiments, the process provides a lipid having an anisidine value of 15 or less.","In some embodiments, the process provides a lipid comprising at least 50% by weight triglycerides.","In some embodiments, the process does not add an organic solvent to the lysed cell composition.","Organic solvents include polar solvents, non-polar solvents, water-miscible solvents, water-immiscible solvents, and combinations thereof.","In some embodiments, the process comprises concentrating a broth comprising a cell.","In some embodiments, the process comprises concentrating the lysed cell composition.","The present invention is also directed to the lipid prepared by a process described herein.","In some embodiments, the lipid comprises one or more polyunsaturated fatty acids.","In some embodiments, the lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of a desired PUFA.","In some embodiments, the lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of DHA, and/or at least 10%, at least 15%, or at least 20% by weight of DPA n-6, and/or at least 10%, at least 15%, or at least 20% by weight of EPA, and/or at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of ARA.","In some embodiments, the lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","In some embodiments, the lipid comprises a triacylglycerol fraction of at least 10% by weight, wherein at least 12% by weight of the fatty acids in the triacylglycerol fraction is eicosapentaenoic acid, wherein at least 25% by weight of the fatty acids in the triacylglycerol fraction is docosahexaenoic acid, and wherein less than 5% by weight of the fatty acids in the triacylglycerol fraction is arachidonic acid.","In some embodiments, the lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","In some embodiments, the lipid is a crude lipid.","In some embodiments, the lipid comprises at least 20% by weight eicosapentaenoic acid and less than 5% by weight each of arachidonic acid, docosapentaenoic acid n-6, oleic acid, linoleic acid, linolenic acid, eicosenoic acid, erucic acid, and stearidonic acid.","In some embodiments, the lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","In some embodiments, the lipid is a crude oil.","The present invention is also directed to a crude microbial lipid having an anisidine value of 26 or less, a peroxide value of 5 or less, a phosphorus content of 100 ppm or less, and optionally less than 5% by weight or volume of an organic solvent.","In some embodiments, the crude microbial lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","In some embodiments, the crude microbial lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of a desired PUFA.","In some embodiments, the crude microbial lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of DHA, and/or at least 10%, at least 15%, or at least 20% by weight of DPA n-6, and/or at least 10%, at least 15%, or at least 20% by weight of EPA, and/or at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of ARA.","The present invention is also directed to an extracted microbial lipid comprising a triglyceride fraction of at least 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 50% by weight, wherein the docosapentaenoic acid n-6 content of the triglyceride fraction is from at least 0.5% by weight to 6% by weight, and wherein the oil has an anisidine value of 26 or less.","In some embodiments, the extracted lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","In some embodiments, the extracted lipid is a crude lipid.","The present invention is also directed to an extracted microbial lipid comprising a triglyceride fraction of at least 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 40% by weight, wherein the docosapentaenoic acid n-6 content of the triglyceride fraction is from at least 0.5% by weight to 6% by weight, wherein the ratio of docosahexaenoic acid to docosapentaenoic acid n-6 is greater than 6:1, and wherein the oil has an anisidine value of 26 or less.","In some embodiments, the extracted lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","In some embodiments, the extracted lipid is a crude lipid.","The present invention is also directed to an extracted microbial lipid comprising a triglyceride fraction of at least about 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 60% by weight and wherein the oil has an anisidine value of 26 or less.","In some embodiments, the extracted lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","In some embodiments, the extracted lipid is a crude lipid.","The present invention is also directed to a crude lipid extracted from a microorganism of the species Crypthecodinium cohnii, having a phosphorus content of 100 ppm or less.","In some embodiments, the crude lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","The present invention is also directed to a process for obtaining a lipid, the process comprising refining a crude lipid of the present invention.","In some embodiments, the refining is selected from the group consisting of: caustic refining, degumming, acid treatment, alkali treatment, cooling, heating, bleaching, deodorizing, deacidification, and combinations thereof.","Overview Generally, the processes of the present invention do not utilize an organic solvent in order to extract or otherwise separate a lipid.","Thus, in some embodiments, an organic solvent is not added to a cell broth comprising plant material or fermentation broth comprising a microbial cell, is not added to a cell composition, is not added to a lysed cell composition, or is not added to a lipid during a process of the present invention in an amount or concentration sufficient to extract a lipid.","In some embodiments, an organic solvent can be added to a cell composition, a lysed cell composition, or a demulsified cell composition.","In such embodiments, the organic solvent is added in a concentration less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.05% by volume.","As used herein, an “organic solvent” refers to a solvent that includes at least one carbon atom.","As used herein, “solvent” refers to an agent that is hydrophobic or lipophilic, and is not a lipid.","As used herein, “hydrophobic” refers to an agent that is repelled from a mass of water.","As used herein, “lipophilic” refers to an agent that dissolves lipids.","Organic solvents that are not used in a process of the present invention include, but are not limited to, polar solvents, non-polar solvents, water-miscible solvents, water-immiscible solvents, and combinations thereof.","Non-limiting examples of organic solvents include substituted and unsubstituted C4-C8 alkyls (e.g., hexane and the like), C5-C12 cylcolalkyls, C4-C12 alkenes, C1-C8 alcohols (e.g., iso-propanol and the like), C1-C8 aldehydes, C4-C8 ethers, C1-C8 esters, C6-C12 aryls, C1-C8 amides, C5-C12 heteroaryls, and combinations thereof.","An organic solvent as defined herein can be optionally added to a lysed cell composition, for example, as a component of a base and/or a salt for contacting with the lysed cell composition.","However, in such embodiments the organic solvent is present in a concentration such that the lipid is not substantially extracted from the cell composition, lysed cell composition, or demulsified cell composition by the solvent (i.e., in a concentration of less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.05% by volume or weight).","In some embodiments, a process of the present invention does not include washing, e.g., with water, or the process reduces the number of washings of, a lysed cell composition or a demulsified cell composition.","“Washing” refers to a process of diluting a composition with, e.g., water or buffer and removing the water or buffer, e.g., by centrifugation.","Washing a cell composition can decrease the overall yield of a lipid obtained from a cell.","In the present invention, the washing can be decreased by 1 time, 2 times, 3 times or more.","Definitions As used herein, “lipid” or “oil” refers to one or more fatty acids (including free fatty acids and esters of fatty acids), phospholipids, triacylglycerols (i.e.","triglycerides), diacylglycerides, monoacylglycerides, lysophospholipids, soaps, phosphatides, waxes, sterols and sterol esters, carotenoids, xanthophylls, hydrocarbons, and other lipids known to one of ordinary skill in the art.","Lipids include polar lipids and neutral lipids.","As used herein, “polar lipid” refers to lipids that contain a polar group and are more readily soluble in polar solvents.","Polar lipids include phospholipids.","As used herein, “phospholipid” refers to lipids having a phosphate group.","As used herein, “neutral lipid” refers to lipids that do not contain areas of polarity and are more readily soluble in non-polar solvents.","Neutral lipids include triacylglycerols (TAG).","Fatty acids are classified based on the length and saturation characteristics of the carbon chain.","Fatty acids are termed short chain, medium chain, or long chain fatty acids based on the number of carbons present in the chain.","Fatty acids are termed saturated fatty acids when no double bonds are present between the carbon atoms, and are termed unsaturated fatty acids when double bonds are present.","Unsaturated long chain fatty acids are monounsaturated when only one double bond is present and are polyunsaturated when more than one double bond is present.","Fatty acids present in the lipid can have 4 to 28 carbon atoms.","In some embodiments, a lipid comprises one or more polyunsaturated fatty acids.","Polyunsaturated fatty acids (PUFAs) are classified based on the position of the first double bond from the methyl end of the fatty acid: omega-3 (n-3) fatty acids contain a first double bond at the third carbon, while omega-6 (n-6) fatty acids contain a first double bond at the sixth carbon.","For example, docosahexaenoic acid (“DHA”) is an omega-3 long chain polyunsaturated fatty acid (LC-PUFA) with a chain length of 22 carbons and 6 double bonds, often designated as “22:6 n-3.” For the purposes of this application, long chain polyunsaturated fatty acids (LC-PUFAs) are defined as fatty acids of 18 and more carbon chain length, and are preferably fatty acids of 20 or more carbon chain length, containing 3 or more double bonds.","LC-PUFAs of the omega-6 series include, but are not limited to, di-homo-gammalinoleic acid (C20:3n-6), arachidonic acid (C20:4n-6) (“ARA”), docosatetraenoic acid or adrenic acid (C22:4n-6), and docosapentaenoic acid (C22:5n-6) (“DPA n-6”).","The LC-PUFAs of the omega-3 series include, but are not limited to, eicosatrienoic acid (C20:3n-3), eicosatetraenoic acid (C20:4n-3), eicosapentaenoic acid (C20:5n-3) (“EPA”), docosapentaenoic acid (C22:5n-3), and docosahexaenoic acid (C22:6n-3).","The LC-PUFAs also include fatty acids with greater than 22 carbons and 4 or more double bonds including, but not limited to, C24:6(n-3) and C28:8(n-3).","The terms “fatty acid,” “polyunsaturated fatty acid,” and “PUFA” include not only the free fatty acid form, but other forms as well, such as the triacylglycerol (TAG) form, the phospholipid (PL) form and other esterified forms.","As used herein, the terms “ester” and “esterified” refer to the replacement of the hydrogen in the carboxylic acid group of a PUFA molecule with another substituent.","Typical esters are known to those in the art, a discussion of which is provided by Higuchi, T. et al., Pro-drugs as Novel Delivery Systems, Vol.","14, A.C.S.","Symposium Series, Bioreversible Carriers in Drug Design, Edward B. Roche ed., Amer.","Pharma.","Assoc., Pergamon Press (1987), and Protective Groups in Organic Chemistry, McOmie ed., Plenum Press, New York (1973), each of which is incorporated herein by reference in its entirety.","Examples of common esters include methyl, ethyl, trichloroethyl, propyl, butyl, pentyl, tert-butyl, benzyl, nitrobenzyl, methoxybenzyl and benzhydryl.","In some embodiments, a lipid comprises at least 10%, at least 20%, at least 30%, at least 35%, at least 40%, at least 50%, at least 60%, at least 70% or at least 80% by weight PUFA.","In some embodiments, a lipid comprises at least 10%, at least 20%, at least 30%, at least 35%, at least 40%, at least 50%, at least 60%, at least 70% or at least 80% by weight DHA.","In some embodiments, a lipid comprises less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, or less than 5% by weight EPA.","In some embodiments, a lipid comprises less than 10%, less than 5%, less than 2%, less than 1%, or less than 0.5% by weight sterols.","In some embodiments, one or more PUFAs are present in a lipid in one or more forms, such as triglycerides, diglycerides, monoglycerides, phospholipids, free fatty acids, esterified fatty acids, alkali metal salts of fatty acids, alkali earth metal salts of fatty acids, and combinations thereof.","In some embodiments, a lipid separated after centrifuging in a process of the present invention comprises at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 50% to 95%, 50% to 90%, 50% to 85%, 50% to 80%, 50% to 75%, 60% to 95%, 60% to 90%, 60% to 85%, 70% to 95%, 70% to 90%, 70% to 85%, 75% to 95%, 75% to 90%, or 75% to 85%, by weight of triglycerides.","In some embodiments, the triglycerides comprise at least 10%, at least 20%, at least 30%, at least 35%, at least 40%, at least 50%, at least 60%, at least 70% or at least 80% by weight DHA.","In some embodiments, the triglycerides comprise at least 50%, at least 40%, at least 30%, at least 20%, at least 15%, at least 10%, or at least 5% by weight EPA.","As discussed herein, additional refining of a lipid after the centrifuging can provide a lipid comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 80% to 99.5%, 80% to 99%, 80% to 97%, 80% to 95%, 80% to 90%, 85% to 99.5%, 85% to 99%, 85% to 97%, 85% to 95%, 85% to 90%, 90% to 99.5%, 90% to 99%, 90% to 97%, 90% to 95%, 95% to 99.5%, 95% to 99%, 95% to 97%, 97% to 99.5%, or 98% to 99.5% triglyceride by weight.","As used herein, a “cell” refers to a lipid-containing biomaterial, such as biomaterial derived from plants or microorganisms.","In some embodiments, suitable plant material includes, but is not limited to, plant parts and oilseeds.","Oilseeds include, but are not limited to, sunflower seeds, canola seeds, rapeseeds, linseeds, castor oil seeds, coriander seeds, calendula seeds or the like, and genetically modified variants thereof.","Oil produced from plant material and/or microorganisms, such as oleaginous microorganisms, according to the processes described herein, is also referred to as vegetable oil.","Oil produced from algae and/or fungi is also referred to as algal and/or fungal oil, respectively.","As used herein, a “microbial cell” or “microorganism” refers to organisms such as algae, bacteria, fungi, protist, and combinations thereof, e.g., unicellular organisms.","In some embodiments, a microbial cell is a eukaryotic cell.","A microbial cell suitable for use with the present invention includes, but is not limited to, golden algae (e.g., microorganisms of the kingdom Stramenopiles), green algae, diatoms, dinoflagellates (e.g., microorganisms of the order Dinophyceae including members of the genus Crypthecodinium such as, for example, Crypthecodinium cohnii or C. cohnii), yeast (Ascomycetes or Basidiomycetes), and fungi of the genera Mucor and Mortierella, including but not limited to Mortierella alpina and Mortierella sect.","schmuckeri.","A microbial cell suitable for use with the present invention can further include, but is not limited to genera found in the following groups of organisms: Stramenopiles, Hamatores, Proteromonads, Opalines, Develpayella, Diplophrys, Labrinthulids, Thraustochytrids, Biosecids, Oomycetes, Hypochytridiomycetes, Commotion, Reticulosphaera, Pelagomonas, Pelagococcus, Ollicola, Aureococcus, Parmales, Diatoms, Xanthophytes, Phaeophytes, Eustigmatophytes, Raphidophytes, Synurids, Axodines (including Rhizochromulinaales, Pedinellales, Dictyochales), Chrysomeridales, Sarcinochrysidales, Hydrurales, Hibberdiales, and Chromulinales.","In some embodiments, a microbial cell for use with the present invention is a microorganism of the phylum Labyrinthulomycota.","In some embodiments, a microbial cell of the phylum Labyrinthulomycota is a thraustochytrid, such as a Schizochytrium or Thraustochytrium.","According to the present invention, the term “thraustochytrid” refers to any member of the order Thraustochytriales, which includes the family Thraustochytriaceae, and the term “labyrinthulid” refers to any member of the order Labyrinthulales, which includes the family Labyrinthulaceae.","Members of the family Labyrinthulaceae were previously considered to be members of the order Thraustochytriales, but in more recent revisions of the taxonomic classification of such organisms, the family Labyrinthulaceae is now considered to be a member of the order Labyrinthulales.","Both Labyrinthulales and Thraustochytriales are considered to be members of the phylum Labyrinthulomycota.","Taxonomic theorists now generally place both of these groups of microorganisms with the algae or algae-like protists of the Stramenopile lineage.","The current taxonomic placement of the thraustochytrids and labyrinthulids can be summarized as follows: Realm: Stramenopila (Chromista) Phylum: Labyrinthulomycota (Heterokonta) Class: Labyrinthulomycetes (Labyrinthulae) Order: Labyrinthulales Family: Labyrinthulaceae Order: Thraustochytriales Family: Thraustochytriaceae For purposes of the present invention, strains of microbial cells described as thraustochytrids include the following organisms: Order: Thraustochytriales; Family: Thraustochytriaceae; Genera: Thraustochytrium (Species: sp., arudimentale, aureum, benthicola, globosum, kinnei, motivum, multirudimentale, pachydermum, proliferum, roseum, and striatum), Ulkenia (Species: sp., amoeboidea, kerguelensis, minuta, profunda, radiata, sailens, sarkariana, schizochytrops, visurgensis, yorkensis, and sp.","BP-5601), Schizochytrium (Species: sp., aggregatum, limnaceum, mangrovei, minutum, and octosporum), Japonochytrium (Species: sp., marinum), Aplanochytrium (Species: sp., haliotidis, kerguelensis, profunda, and stocchinoi), Althornia (Species: sp., crouchii), or Elina (Species: sp., marisalba, and sinorifica).","For the purposes of this invention, species described within Ulkenia will be considered to be members of the genus Thraustochytrium.","Aurantiacochytrium and Oblogospora are two additional genuses encompassed by the phylum Labyrinthulomycota in the present invention.","In some embodiments, a microbial cell is of the genus Thraustochystrium, Schizochytrium, and mixtures thereof.","Microbial cells suitable for use with the present invention include, but are not limited to, Labyrinthulids selected from: Order: Labyrinthulales, Labyrinthulaceae, Genera: Labyrinthula (Species: sp., algeriensis, coenocystis, chattonii, macrocystis, macrocystis atlantica, macrocystis macrocystis, marina, minuta, roscoffensis, valkanovii, vitellina, vitellina pacifica, vitellina vitellina, and zopfii), Labyrinthuloides (Species: sp., haliotidis, and yorkensis), Labyrinthomyxa (Species: sp., marina), Diplophrys (Species: sp., archeri), Pyrrhosorus (Species: sp., marinus), Sorodiplophrys (Species: sp., stercorea), and Chlamydomyxa (Species: sp., labyrinthuloides, and montana) (although there is currently not a consensus on the exact taxonomic placement of Pyrrhosorus, Sorodiplophrys, and Chlamydomyxa).","Host cells of the phylum Labyrinthulomycota include, but are not limited to, deposited strains PTA-10212, PTA-10213, PTA-10214, PTA-10215, PTA-9695, PTA-9696, PTA-9697, PTA-9698, PTA-10208, PTA-10209, PTA-10210, PTA-10211, the microorganism deposited as SAM2179 (named “Ulkenia SAM2179” by the depositor), any Thraustochytrium species (including former Ulkenia species such as U. visurgensis, U. amoeboida, U. sarkariana, U. profunda, U. radiata, U. minuta and Ulkenia sp.","BP-5601), and including Thraustochytrium striatum, Thraustochytrium aureum, Thraustochytrium roseum; and any Japonochytrium species.","Strains of Thraustochytriales include, but are not limited to Thraustochytrium sp.","(23B) (ATCC 20891); Thraustochytrium striatum (Schneider)(ATCC 24473); Thraustochytrium aureum (Goldstein) (ATCC 34304); Thraustochytrium roseum (Goldstein) (ATCC 28210); Japonochytrium sp.","(L1) (ATCC 28207); ATCC 20890; ATCC 20892; a mutant strain derived from any of the aforementioned microorganisms; and mixtures thereof.","Schizochytrium include, but are not limited to Schizochytrium aggregatum, Schizochytrium limacinum, Schizochytrium sp.","(S31) (ATCC 20888), Schizochytrium sp.","(58) (ATCC 20889), Schizochytrium sp.","(LC-RM) (ATCC 18915), Schizochytrium sp, (SR 21), deposited strain ATCC 28209, deposited Schizochytrium limacinum strain IFO 32693, a mutant strain derived from any of the aforementioned microorganisms, and mixtures thereof.","In some embodiments, the host cell is a Schizochytrium or a Thraustochytrium.","Schizochytrium can replicate both by successive bipartition and by forming sporangia, which ultimately release zoospores.","Thraustochytrium, however, replicate only by forming sporangia, which then release zoospores.","In some embodiments, the host cell of the invention is a recombinant host cell.","Effective culture conditions for a microbial cell for use with the invention include, but are not limited to, effective media, bioreactor, temperature, pH, and oxygen conditions that permit lipid production.","An effective medium refers to any medium in which a microbial cell, e.g., Thraustoehytriales microbial cell, is typically cultured.","Such media typically comprises an aqueous medium having assimilable carbon, nitrogen, and phosphate sources, as well as appropriate salts, minerals, metals, and other nutrients, such as vitamins.","Microbial cells for use with the present invention can be cultured in conventional fermentation bioreactors, shake flasks, test tubes, microtiter dishes, and petri plates.","In some embodiments, culturing is carried out at a temperature, pH, and oxygen content appropriate for a recombinant cell.","In some embodiments, a microbial cell is capable of growth at a salinity level of 12 g/L or less, 5 g/L or less, or 3 g/L or less of sodium chloride.","In some embodiments, a microbial cell produces a lipid comprising omega-3 and/or omega-6 PUFAs.","In some embodiments, a microbial cell produces a lipid comprising DHA, DPA (n-3), DPA (n-6), EPA, arachidonic acid (ARA), or the like, and combinations thereof.","Non-limiting examples of microorganisms that produce a lipid comprising a PUFA are disclosed above and are also found in U.S. Pat.","Nos.","5,340,594, 5,340,742 and 5,583,019, each of which is incorporated by reference herein in its entirety.","In some embodiments, a microbial cell comprises at least 30% by weight lipids, at least 35% by weight lipids, at least 40% by weight lipids, at least 50% by weight lipids, at least 60% by weight lipids, at least 70% by weight lipids, or at least 80% by weight lipids.","In some embodiments, a microbial cell for use with the present invention is capable of producing at least 0.1 grams per liter per hour (g/L/h) of DHA, at least 0.2 g/L/h of DHA, at least 0.3 g/L/h of DHA, or at least 0.4 g/L/h of DHA.","Processes The processes of the present invention comprises lysing a cell or cell biomass to form a lysed cell composition.","As used herein, the term “cell biomass” refers to a population of plant or microbial cells.","As used herein, the terms “lyse” and “lysing” refer to a process of rupturing the cell wall and/or cell membrane of a cell.","In some embodiments, lysing comprises a process such as: mechanically treating, chemically treating, enzymatically treating, physically treating, or combinations thereof.","As used herein, mechanically treating includes, but is not limited to, homogenizing a cell, applying ultrasound to a cell, cold-pressing a cell, milling a cell or the like, and combinations thereof.","In some embodiments, a process comprises lysing the cell by homogenization.","In some embodiments, a process comprises lysing the cell with a homogenizer.","Homogenizing a cell can include, but is not limited to, processes utilizing a French pressure cell press, a sonicator, a homogenizer, a ball mill, a rod mill, a pebble mill, a bead mill, a high pressure grinding roll, a vertical shaft impactor, an industrial blender, a high shear mixer, a paddle mixer, a polytron homogenizer or the like, and combinations thereof.","In some embodiments, a cell is flowed through a homogenizer that is optionally heated.","In some embodiments, suitable homogenization can include 1 to 3 passes through a homogenizer at either high and/or low pressures.","In some embodiments, a pressure during homogenization can be 150 bar to 1,400 bar, 150 bar to 1,200 bar, 150 bar to 900 bar, 150 bar to 300 bar, 300 bar to 1,400 bar, 300 bar to 1,200 bar, 300 bar to 900 bar, 400 bar to 800 bar, 500 bar to 700 bar, or 600 bar.","As used herein, physically treating can include, but is not limited to, heating a cell, drying a cell, or the like, and combinations thereof.","Heating a cell can include, but is not limited to, resistive heating, convection heating, steam heating, heating in a fluid bath, heating with solar energy, heating with focused solar energy, and the like, any of which can be performed in a tank, pool, tube, conduit, flask, or other containment device.","In some embodiments, a cell is heated in a tank that includes resistive coils in/on its walls.","In some embodiments, a cell is heated in a liquid bath that includes a tubing passing there through.","Drying a cell can include, but is not limited to, exposing to air flow, exposing to heat (e.g., convection heat, a heated surface, and the like), exposing to solar energy, freeze drying (lyophilizing), spray drying, and combinations thereof.","In some embodiments, drying comprises applying a cell to a rotating drum that is optionally heated.","As used herein, chemically treating includes, but is not limited to, raising a pH of a cell, contacting a cell with a chemical or the like.","Raising a pH of a cell can include, but is not limited to, adding a base to a cell composition.","In some embodiments, bases suitable for use with the present invention include, but are not limited to, hydroxide bases (e.g., LiOH, NaOH, KOH, Ca(OH)2, and the like, and combinations thereof), carbonate bases (e.g., Na2CO3, K2CO3, MgCO3, and the like, and combinations thereof), bicarbonate bases (e.g., LiHCO3, NaHCO3, KHCO3, and the like, and combinations thereof), and combinations thereof.","A base can be in the form of a solid (e.g., crystals, a granulate, pellets, and the like) or a liquid (e.g., an aqueous solution, an alcoholic solution such as a hydroxide base in methanol, ethanol, propanol, and the like), and combinations thereof.","In some embodiments, the pH of the cell composition is raised to 8 or above, 9 or above, 10 or above, 11 or above, 12 or above, or a pH of 7 to 13, 7 to 12, 7 to 11, 7 to 10, 7 to 9, 8 to 13, 8 to 12, 8 to 11, 8 to 10, 8 to 9, 9 to 12, 9 to 11, 9 to 10, 10 to 12, or 10 to 11.In some embodiments, raising a pH of a cell can include, but is not limited to, performing a chloralkali process.","In some embodiments, a fermentation broth containing sodium chloride and a cell composition is subjected to electrolysis, which would result in the formation of sodium hydroxide.","The formation of sodium hydroxide raises the pH of the cell.","In some embodiments, a fermentation broth can include calcium chloride or potassium chloride in place of or in addition to sodium chloride.","Subjecting such a fermentation broth to electrolysis results in the formation of calcium hydroxide or potassium hydroxide, respectively, thereby raising the pH of the cell.","Enzymatic lysing refers to lysis of a cell wall or cell membrane of a cell by contacting the cell with one or more enzymes.","Enzymes suitable for use with the present invention include, but are not limited to, proteases, cellulases, hemicellulases, chitinases, pectinases, and combinations thereof.","Non-limiting examples of proteases include serine proteases, theronine proteases, cysteine proteases, aspartate proteases, metalloproteases, glutamic acid proteases, alacase, and combinations thereof.","Non-limiting examples of cellulases include sucrase, maltase, lactase, alpha-glucosidase, beta-glucosidase, amylase, lysozyme, neuraminidase, galactosidase, alpha-mannosidase, glucuronidase, hyaluronidase, pullulanase, glucocerebrosidase, galactosylceramidase, acetylgalactosaminidase, fucosidase, hexosaminidase, iduronidase, maltase-glucoamylase, and combinations thereof.","A non-limiting example of a chitinase includes chitotriosidase.","Non-limiting examples of pectinases include pectolyase, pectozyme, polygalacturonase, and combinations thereof.","In some embodiments, some enzymes are activated by heating.","As used herein, a “lysed cell composition” refers to a composition comprising one or more lysed cells, including cell debris and other contents of the cell, in combination with a lipid (from the lysed cells), and optionally, broth that contains microbial cells or plant material.","In some embodiments, plant material is contained in a broth or media comprising the plant material and water.","In some embodiments, a microbial cell is contained in a fermentation broth or media comprising the microbial cell and water.","In some embodiments, a lysed cell composition refers to a composition comprising one or more lysed cells, cell debris, a lipid, the natural contents of the cell, and aqueous components from a broth.","In some embodiments, a lysed cell composition is in the form of an oil-in-water emulsion comprising a mixture of a continuous aqueous phase and a dispersed lipid phase.","In some embodiments, a dispersed lipid phase is present in a concentration of 1% to 60%, 1% to 50%, 1% to 40%, 1% to 30%, 1% to 20%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 10% to 60%, 10% to 50%, 10% to 40%, 20% to 60%, 20% to 50%, 20% to 40%, 30% to 60%, 30% to 50%, or 40% to 60% by weight of an emulsified lysed cell composition.","While not being bound to any particular theory, it is believed the processes of the present invention break up or demulsify an emulsified lysed cell composition, allowing a lipid to be separated from the lysed cell composition.","As used herein, the terms “emulsion” and “emulsified” refers to a mixture of two or more immiscible phases or layers wherein one phase or layer is dispersed in another phase or layer.","As used herein, the terms “break,” “break up,” “demulsify,” “demulsification,” “demulsifying,” and “breaking” refer to a process of separating immiscible phases or layers of an emulsion.","For example, demulsifying or breaking an emulsified lysed cell composition refers to a process by which an emulsified lysed cell composition changes from an emulsion having one or more phases or layers to a composition having two or more phases or layers.","For example, in some embodiments, a process of the present invention breaks an emulsified lysed cell composition from a single-phase to two or more phases.","In some embodiments, the two or more phases include a lipid phase and an aqueous phase.","In some embodiments, a process of the present invention breaks an emulsified lysed cell compositions from one or more phases to at least three phases.","In some embodiments, the three phases include a lipid phase, an aqueous phase, and a solid phase.","In some embodiments, the three phases include a lipid phase, an emulsion phase, and an aqueous phase.","In some embodiments, the processes of the present invention demulsify a lysed cell composition to form a demulsified cell composition by removing or breaking at least 75% of the emulsion, at least 80% of the emulsion, at least 85% of the emulsion, at least 90% of the emulsion, at least 95% of the emulsion, at least 99% of the emulsion.","In some embodiments, the process of the present invention demulsify a lysed cell composition by removing or breaking 75% of the emulsion to 99% of the emulsion, 75% of the emulsion to 95% of the emulsion, 75% of the emulsion to 90% of the emulsion, 75% of the emulsion to 85% of the emulsion, 75% of the emulsion to 80% of the emulsion, 80% of the emulsion to 99% of the emulsion, 80% of the emulsion to 95% of the emulsion, 80% of the emulsion to 90% of the emulsion, 80% of the emulsion to 85% of the emulsion, 85% of the emulsion to 99% of the emulsion, 85% of the emulsion to 95% of the emulsion, 85% of the emulsion to 90% of the emulsion, 90% of the emulsion to 99% of the emulsion, 90% of the emulsion to 95% of the emulsion, or 95% of the emulsion to 99% of the emulsion by weight or volume.","In some embodiments, prior to lysing the cell, the cell can be washed and/or pasteurized.","In some embodiments, washing the cell includes using an aqueous solution, such as water, to remove any extracellular water-soluble or water-dispersible compounds.","In some embodiments, the cell can be washed once, twice, thrice, or more.","In some embodiments, pasteurizing the cell includes heating the cell to inactivate any undesirable enzymes, for example any enzymes that might degrade lipid or reduce the yield of PUFAs.","In some embodiments, the cell can be washed first and then pasteurized.","In some embodiments, the cell is plant biomaterial and the plant biomaterial is formed prior to lysing.","In some embodiments, the plant biomaterial is formed by removing or extracting oilseeds from a plant.","In some embodiments, an interior of an oilseed is removed from an outer hull of an oilseed by grinding, milling, extruding, aspirating, crushing, or combinations thereof.","In some embodiments, the dehulled oilseeds can be homogenized or expelled using processes known in the art, such as by passing the oilseeds through a press to grind the dehulled oilseeds into a cake.","In some embodiments, water can be added to the cake to form an emulsified lysed cell composition.","In some embodiments, the emulsified lysed cell composition can be filtered using processes known in the art to remove any excess hull fragments from the lysed cell composition.","In some embodiments, treating a lysed cell composition with a first base breaks up (i.e., demulsifies) an emulsified lysed cell composition.","In some embodiments, treating a lysed cell composition with a second base breaks (i.e., demulsifies) an emulsified lysed cell composition.","In some embodiments, treating a lysed cell composition with a salt breaks (i.e., demulsifies) an emulsified lysed cell composition.","In some embodiments, heating a lysed cell composition breaks (i.e., demulsifies) an emulsified lysed cell composition.","In some embodiments, agitating a lysed cell composition breaks (i.e., demulsifies) an emulsified lysed cell composition.","In some embodiments, simultaneous heating and agitating of a lysed cell composition breaks (i.e., demulsifies) an emulsified lysed cell composition.","In some embodiments, one or more of the preceding treatments breaks up (i.e., demulsifies) an emulsified lysed cell composition.","In some embodiments, the process of the invention comprises raising the pH of a cell composition to lyse and/or demulsify the cell composition.","In some embodiments, the process of the invention comprises raising the pH of a lysed cell composition to demulsify the lysed cell composition.","In some embodiments, raising the pH comprises contacting a cell composition or lysed cell composition with a base.","In some embodiments, the process of the invention comprises contacting a lysed cell composition with a base to demulsify the lysed cell composition.","As used herein, “contacting” refers to combining a cell composition or a lysed cell composition with a second composition (e.g., by adding a composition to a cell composition or a lysed cell composition, by adding a cell composition or a lysed cell composition to a composition, and the like).","As used herein, a “composition” can comprise a pure material or include a combination of two or more materials, substances, excipients, portions, and the like.","Contacting a lysed cell composition with a first base raises the pH of the lysed cell composition.","In some embodiments, a lysed cell composition is contacted with a second base.","In some embodiments, the pH of a lysed cell composition or a demulsified cell composition is raised a second time.","In some embodiments, the second raising of the pH comprises contacting a lysed cell composition or demulsified cell composition with a second base.","In some embodiments, a lysed cell composition is contacted with a first base, then heated, agitated, or a combination thereof, and subsequently contacted with a second base to provide a treated lysed cell emulsion.","In some embodiments, the first base and/or second base has a pKb of 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 5, 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 3 to 10, 3 to 6, 3 to 5, 4 to 10, 4 to 8, 4 to 6, 5 to 10, or 5 to 8.As used herein, the term “pKb” refers to the negative logarithm of the base association constant, Kb, of the base.","Kb refers to the equilibrium constant for the ionization of the base in water, wherein: B+H2O HB++OH−; and the Kb of base, B, is defined as: K b = [ HB + ] [ OH - ] [ B ] .","Bases suitable for use with the present invention include, but are not limited to, hydroxide bases (e.g., LiOH, NaOH, KOH, Ca(OH)2, and the like, and combinations thereof), carbonate bases (e.g., Na2CO3, K2CO3, MgCO3, and the like, and combinations thereof), bicarbonate bases (e.g., LiHCO3, NaHCO3, KHCO3, and the like, and combinations thereof), and combinations thereof.","A base can be in the form of a solid (e.g., crystals, a granulate, pellets, and the like) or a liquid (e.g., an aqueous solution, an alcoholic solution such as a hydroxide base in methanol, ethanol, propanol, and the like), and combinations thereof.","Thus, a solvent can be optionally present in a base for use with the present invention.","As used herein, “solvent” refers to an agent that is hydrophobic or lipophilic.","As used herein, “hydrophobic” refers to an agent that is repelled from a mass of water.","As used herein, “lipophilic” refers to an agent that dissolves in lipids.","In some embodiments, contacting a cell composition or a lysed cell composition with a base raises the pH of the lysed cell composition.","In some embodiments, contacting a lysed cell composition with a base raises the pH of the lysed cell composition to 8 or above, 9 or above, 10 or above, 11 or above, 12 or above, or a pH of 7 to 13, 7 to 12, 7 to 11, 7 to 10, 7 to 9, 8 to 13, 8 to 12, 8 to 11, 8 to 10, 8 to 9, 9 to 12, 9 to 11, 9 to 10, 10 to 12, or 10 to 11.In some embodiments, contacting a lysed cell composition with a base provides a pH of 8 or below, 7 or below, 6 or below, or 5 or below to the composition.","In some embodiments, raising the pH of the cell composition or lysed cell composition with the addition of the base inhibits lipid oxidation, thereby minimizing the amount of free radicals in the lysed cell composition so that the crude lipid obtained from the processes of the invention has a low peroxide value (e.g., 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less) and/or a low anisidine value (e.g., 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less).","As used herein, the terms “peroxide value” or “PV” refer to the measure of primary reaction products, such as peroxides and hydroperoxides, that occur during oxidation of the lipid.","As used herein peroxide value is measured in meq/kg.","As used herein, the terms “anisidine value” or “AV” refer to the measure of secondary reaction products, such as aldehydes and ketones, that occur during oxidation of the lipid.","In some embodiments, free radicals in the lysed cell composition after adjusting the pH with a base are detected using an Electron Paramagnetic Resonance spectrometer, e.g., Bruker BioSpin e-scan EPR (system number SC0274) (Bruker BioSpin, Billerica, Mass.).","In some embodiments, a sample of the lysed cell composition is diluted in about 1:1 ratio with deionized water prior to measuring the EPR.","In some embodiments, in order to measure the EPR, a spin trap chemical is added to a sample of the lysed cell composition.","In some embodiments, the spin trap chemical is any spin trap chemical known in the art, including, but not limited to, POBN (α-(4-Pyridyl 1-oxide)-N-tert-butylnitrone) or DMPO (5,5-dimethyl-1-pyrroline-N-oxide).","In some embodiments, the spin trap chemical is about 1.25 M and about 50 μL is added to about 0.5 gram sample of the lysed cell composition.","In some embodiments, a sample containing the spin trap chemical is incubated at room temperature (e.g., about 20° C.).","In some embodiments, the following spectrometer parameters are used: modulation frequency of about 86 Hz, modulation amplitude of about 2 gauss, microwave power of about 5 mW, time constant of about 20 seconds, sweep time of about 10 seconds, sweep width of about 100 gauss, and a number of scans of about 8.The EPR is measured over time to determine the concentration of free radicals present in the lipid.","In some embodiments, the EPR is measured hourly over a course of four hours.","In some embodiments, the lysed cell composition has an EPR signal strength (intensity or amplitude) at the above listed parameters of less than 0.15×106, less than 0.14×106, less than 0.13×106, less than 0.12×106, less than 0.11×106, less than 0.1×106, less than 0.09×106, less than 0.08×106, less than 0.07×106, less than 0.06×106, or less than 0.05×106 after 4 hours.","In some embodiments, the lysed cell composition has an EPR of 0.05×106 to 0.15×106, 0.05×106 to 0.14×106, 0.05×106 to 0.13×106, 0.05×106 to 0.12×106, 0.05×106 to 0.11×106, 0.05×106 to 0.1×106, 0.05×106 to 0.09×106, 0.07×106 to 0.15×106, 0.07×106 to 0.13×106, 0.07×106 to 0.11×106, 0.08×106 to 0.14×106, 0.08×106 to 0.12×106, 0.08×106 to 0.1×106, 0.09×106 to 0.13×106, or 0.09×106 to 0.11×106.In some embodiments, the pH of the lysed cell composition resulting in an EPR specified above is 8 to 12, 8 to 11, 8 to 10, 8 to 9, 9 to 12, 9 to 11, 9 to 10, 10 to 12, or 10 to 11.In some embodiments, a lysed cell composition having an EPR signal strength specified above results in a crude lipid having an AV of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less.","In some embodiments, a lysed cell composition having an EPR specified above results in a crude lipid having a PV of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less.","In some embodiments, a process comprises contacting a cell composition or lysed cell composition with a salt to demulsify the lysed cell composition.","As used herein, a “salt” refers to an ionic compound formed by replacing a hydrogen ion from an acid with a metal (e.g., an alkali metal, an alkali earth metal, a transition metal, and the like) or a positively charged compound (e.g., NH4+ and the like).","Salts suitable for use with the present invention include, but are not limited to, alkali metal salts, alkali earth metal salts, or the like, and combinations thereof.","Negatively charged ionic species present in a salt for use with the present include, but are not limited to, halides, sulfate, bisulfate, sulfite, phosphate, hydrogen phosphate, dihydrogen phosphate, carbonate, bicarbonate, or the like, and combinations thereof.","In some embodiments, a salt for use with the present invention is selected from: sodium chloride, sodium sulfate, sodium carbonate, calcium chloride, potassium sulfate, magnesium sulfate, monosodium glutamate, ammonium sulfate, potassium chloride, iron chloride, iron sulfate, aluminum sulfate, and combinations thereof.","In some embodiments, a salt does not include NaOH.","A salt can be added as a solid (e.g., in crystalline, amorphous, pelletized, and/or granulated form), and/or as a solution (e.g., a dilute solution, a saturated solution, or a super-saturated solution) containing, for example, water, an alcohol, and the like, and combinations thereof.","In some embodiments, the salt is added in an amount of 5 g/l to 25 g/l, 5 g/l to 10 g/l, 10 g/l to 15 g/l, 15 g/l to 20 g/l, 20 g/l to 25 g/l, or 10 g/l to 20 g/l.","In some embodiments, a temperature of a cell composition or a lysed cell composition is less than or equal to 60° C., less than or equal to 55° C., less than or equal to 45° C., less than or equal to 40° C., less than or equal to 35° C., less than or equal to 30° C., or less than or equal to 25° C. when a salt is added to demulsify the cell composition or the lysed cell composition.","In some embodiments, a temperature of a lysed cell composition is 0° C. to 60° C., 0° C. to 55° C., 0° C. to 50° C., 0° C. to 45° C., 0° C. to 40° C., 0° C. to 35° C., 0° C. to 30° C., 0° C. to 25° C., 20° C. to 60° C., 20° C. to 55° C., 20° C. to 50° C., 20° C. to 45° C., 20° C. to 40° C., 20° C. to 35° C., 20° C. to 30° C., 30° C. to 60° C., 30° C. to 55° C., 30° C. to 50° C., 30° C. to 45° C., 30° C. to 40° C., 30° C. to 40° C., 40° C. to 60° C., 40° C. to 55° C., 40° C. to 50° C., or 50° C. to 60° C. when a salt is added to demulsify the cell composition or the lysed cell composition.","In some embodiments, the process comprises contacting a cell composition or a lysed cell composition with 20% or less, 15% or less, 10% or less, 7.5% or less, 5% or less, or 2% or less salt by weight, of the lysed cell composition or the cell composition.","In some embodiments, a process comprises contacting a cell composition or a lysed cell composition with 0.1% to 20%, 0.1% to 15%, 0.1% to 10%, 0.5% to 20%, 0.5% to 15%, 0.5% to 10%, 0.5% to 5%, 0.5% to 4%, 0.5% to 3%, 0.5% to 2.5%, 0.5% to 2%, 0.5% to 1.5%, 0.5% to 1%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2.5%, 1% to 2%, 1% to 1.5%, 1.5% to 5%, 1.5% to 4%, 1.5% to 3%, 1.5% to 2.5%, 1.5% to 2%, 2% to 20%, 2% to 15%, 2% to 10%, 2% to 5%, 2% to 4%, 2% to 3%, 2% to 2.5%, 2.5% to 5%, 2.5% to 4%, 2.5% to 3%, 3% to 5%, 3% to 4%, 4% to 5%, 5% to 20%, 5% to 15%, 5% to 10%, 10% to 20%, 10% to 15%, or 15% to 20% salt, by weight, of the cell composition or lysed cell composition (e.g., a total broth weight).","For example, when a lysed cell composition weighs 1,000 kg, contacting with 0.5% to 20% salt, by weight, requires combining 5 kg to 200 kg of salt with the lysed cell composition.","In some embodiments, the process comprises heating a cell composition or a lysed cell composition to demulsify the lysed cell composition.","In some embodiments the cell composition or the lysed cell composition is heated for a sufficient period of time for a base and/or a salt to demulsify a cell composition or a lysed cell composition.","In some embodiments, the process comprises heating a cell composition or a lysed cell composition for at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 4 hours, at least 8 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 30 hours, at least 36 hours, at least 42 hours, at least 48 hours, at least 54 hours, at least 60 hours, at least 66 hours, at least 72 hours, at least 78 hours, at least 84 hours, at least 90 hours or at least 96 hours.","In some embodiments, the process comprises heating a lysed cell composition for 5 minutes to 96 hours, 5 minutes to 4 hours, 5 minutes to 2 hours, 5 minutes to 1 hour, 10 minutes to 4 hours, 10 minutes to 2 hours, 10 minutes to 1 hour, 1 hour to 96 hours, 1 hour to 84 hours, 1 hour to 72 hours, 1 hour to 60 hours, 1 hour to 48 hours, 1 hour to 36 hours, 1 hour to 24 hours, 1 hour to 4 hours, 4 hours to 96 hours, 4 hours to 84 hours, 4 hours to 72 hours, 4 hours to 60 hours, 4 hours to 48 hours, 4 hours to 36 hours, 4 hours to 24 hours, 8 hours to 96 hours, 8 hours to 84 hours, 8 hours to 72 hours, 8 hours to 60 hours, 8 hours to 48 hours, 8 hours to 36 hours, 8 hours to 24 hours, 8 hours to 12 hours, 12 hours to 96 hours, 12 hours to 84 hours, 12 hours to 72 hours, 12 hours to 60 hours, 12 hours to 48 hours, 12 hours to 36 hours, 12 hours to 24 hours, 24 hours to 96 hours, 24 hours to 84 hours, 24 hours to 72 hours, 24 hours to 60 hours, 24 hours to 48 hours, or 24 hours to 36 hours.","In some embodiments, a cell composition or a lysed cell composition can be heated at a temperature of at least 10° C., at least 20° C., at least 25° C., at least 30° C., at least 35° C., at least 40° C., at least 45° C., at least 50° C., at least 55° C., at least 60° C., at least 65° C., at least 70° C., at least 75° C., at least 80° C., at least 85° C., at least 90° C., at least 95° C., or at least 100° C. In some embodiments, a process comprises heating a cell composition or a lysed cell composition at a temperature of 10° C. to 100° C., 10° C. to 90° C., 10° C. to 80° C., 10° C. to 70° C., 20° C. to 100° C., 20° C. to 90° C., 20° C. to 80° C., 20° C. to 70° C., 30° C. to 100° C., 30° C. to 90° C., 30° C. to 80° C., 30° C. to 70° C., 40° C. to 100° C., 40° C. to 90° C., 40° C. to 80° C., 50° C. to 100° C., 50° C. to 90° C., 50° C. to 80° C., 50° C. to 70° C., 60° C. to 100° C., 60° C. to 90° C., 60° C. to 80° C., 70° C. to 100° C., 70° C. to 90° C., 80° C. to 100° C., 80° C. to 90° C., or 90° C. to 100° C. In some embodiments, a salt can be added to the cell composition or the lysed cell composition during the heating.","In some embodiments, a cell composition or a lysed cell composition can be heated in a closed system or in a system with an evaporator.","In some embodiments, a cell composition or lysed cell composition can be heated in a system with an evaporator such that a portion of the water present in the cell composition or the lysed cell composition is removed by evaporation.","In some embodiments, a process comprises heating a cell composition or a lysed cell composition in a system with an evaporator to remove up to 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% by weight of water present in the cell composition or lysed cell composition.","In some embodiments, a process comprises heating a cell composition or a lysed cell composition in a system with an evaporator to remove 1% to 50%, 1% to 45%, 1% to 40%, 1% to 35%, 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 5% to 50%, 5% to 45%, 5% to 40%, 5% to 35%, 5% to 30%, 5% to 25%, 5% to 20%, 5% to 15%, 5% to 10%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 10% to 25%, 10% to 20%, 10% to 15%, 15% to 50%, 15% to 45%, 15% to 40%, 15% to 35%, 15% to 30%, 15% to 25%, 15% to 20%, 20% to 50%, 20% to 45%, 20% to 40%, 20% to 35%, 20% to 30%, 20% to 25%, 25% to 50%, 25% to 45%, 25% to 40%, 25% to 35%, 25% to 30%, 30% to 50%, 30% to 45%, 30% to 40%, 30% to 35%, 35% to 50%, 35% to 45%, 35% to 40%, 40% to 50%, 40% to 45%, or 45% to 50%.","In some embodiments, the process comprises holding a cell composition or a lysed cell composition in a vessel for a predetermined time to demulsify the lysed cell composition.","In some embodiments, the process comprises holding a cell composition or a lysed cell composition in a vessel for at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 4 hours, at least 8 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 30 hours, at least 36 hours, at least 42 hours, at least 48 hours, at least 54 hours, at least 60 hours, at least 66 hours, at least 72 hours, at least 78 hours, at least 84 hours, at least 90 hours or at least 96 hours.","In some embodiments, the process comprises holding a cell composition or a lysed cell composition for 5 minutes to 96 hours, 5 minutes to 4 hours, 5 minutes to 2 hours, 5 minutes to 1 hour, 10 minutes to 4 hours, 10 minutes to 2 hours, 10 minutes to 1 hour, 1 hour to 96 hours, 1 hour to 84 hours, 1 hour to 72 hours, 1 hour to 60 hours, 1 hour to 48 hours, 1 hour to 36 hours, 1 hour to 24 hours, 1 hour to 4 hours, 4 hours to 96 hours, 4 hours to 84 hours, 4 hours to 72 hours, 4 hours to 60 hours, 4 hours to 48 hours, 4 hours to 36 hours, 4 hours to 24 hours, 8 hours to 96 hours, 8 hours to 84 hours, 8 hours to 72 hours, 8 hours to 60 hours, 8 hours to 48 hours, 8 hours to 36 hours, 8 hours to 24 hours, 8 hours to 12 hours, 12 hours to 96 hours, 12 hours to 84 hours, 12 hours to 72 hours, 12 hours to 60 hours, 12 hours to 48 hours, 12 hours to 36 hours, 12 hours to 24 hours, 24 hours to 96 hours, 24 hours to 84 hours, 24 hours to 72 hours, 24 hours to 60 hours, 24 hours to 48 hours, or 24 hours to 36 hours.","In some embodiments, the process comprises contacting an antioxidant with a lysed cell emulsion.","Antioxidants suitable for use with the present invention include, but are not limited to, a tocopherol, a tocotrienol, a polyphenol, resveratrol, a flavonoid, a carotenoid, lycopene, a carotene, lutein, ascorbic acid, ascorbyl palmitate, or the like, and combinations thereof.","In some embodiments, the process comprises allowing an emulsified lysed cell composition to stand, wherein the lipid is separated from the emulsified lysed cell composition using gravity.","As used herein, the terms “agitating” and “agitation” refer to a process of affecting motion in a lysed cell composition through an application of force.","In some embodiments, the process of the invention comprises agitating a cell composition or a lysed cell composition by stirring, mixing, blending, shaking, vibrating, or a combination thereof.","In some embodiments, the process of agitating a cell composition or a lysed cell composition demulsifies the cell composition or the lysed cell composition.","In some embodiments, the process of the invention comprises agitating a lysed cell composition at 0.1 hp/1,000 gal to 10 hp/1,000 gal, 0.5 hp/1,000 gal to 8 hp/1,000 gal, 1 hp/1,000 gal to 6 hp/1,000 gal, or 2 hp/1,000 gal to 5 hp/1,000 gal of lysed cell composition.","In some embodiments, the process of the invention comprises agitating a cell composition or a lysed cell composition using an agitator.","In some embodiments, the agitator is a dispersion style agitator that disperses a base and/or salt in the cell composition or the lysed cell composition.","In some embodiments, an agitator has one or more impellers.","As used herein, “impeller” refers to a device arranged to impart motion to a cell composition or a lysed cell composition when rotated.","Impellers suitable for use with the present invention include straight blade impellers, Rushton blade impellers, axial flow impellers, radial flow impellers, concave blade disc impellers, high-efficiency impellers, propellers, paddles, turbines, or the like, and combinations thereof.","In some embodiments, a process includes agitating a cell composition or a lysed cell composition using an agitator having an impeller tip speed of 90 ft/min to 1,200 ft/min, 200 ft/min to 1,000 ft/min, 300 ft/min to 800 ft/min, 400 ft/min to 700 ft/min, or 500 ft/min to 600 ft/min.","In some embodiments, a process includes agitating a cell composition or a lysed cell composition using an agitator having an impeller tip speed of 350 centimeters/second to 900 centimeters per second, 350 centimeters/second to 850 centimeters per second, 350 centimeters/second to 800 centimeters/second, 350 centimeters/second to 750 centimeters/second, 350 centimeters/second to 700 centimeters/second, 350 centimeters/second to 650 centimeters/second, 350 centimeters/second to 600 centimeters/second, 350 centimeters/second to 550 centimeters/second, 350 centimeters/second to 500 centimeters/second, 350 centimeters/second to 450 centimeters/second, 350 centimeters/second to 400 centimeters/second, 400 centimeters/second to 900 centimeters per second, 400 centimeters/second to 850 centimeters per second, 400 centimeters/second to 800 centimeters/second, 400 centimeters/second to 750 centimeters/second, 400 centimeters/second to 700 centimeters/second, 400 centimeters/second to 650 centimeters/second, 400 centimeters/second to 600 centimeters/second, 400 centimeters/second to 550 centimeters/second, 400 centimeters/second to 500 centimeters/second, 400 centimeters/second to 450 centimeters/second, 450 centimeters/second to 900 centimeters per second, 450 centimeters/second to 850 centimeters per second, 450 centimeters/second to 800 centimeters/second, 450 centimeters/second to 750 centimeters/second, 450 centimeters/second to 700 centimeters/second, 450 centimeters/second to 650 centimeters/second, 450 centimeters/second to 600 centimeters/second, 450 centimeters/second to 550 centimeters/second, 450 centimeters/second to 500 centimeters/second, 500 centimeters/second to 900 centimeters per second, 500 centimeters/second to 850 centimeters per second, 500 centimeters/second to 800 centimeters/second, 500 centimeters/second to 750 centimeters/second, 500 centimeters/second to 700 centimeters/second, 500 centimeters/second to 650 centimeters/second, 500 centimeters/second to 600 centimeters/second, 500 centimeters/second to 550 centimeters/second, 550 centimeters/second to 900 centimeters per second, 550 centimeters/second to 850 centimeters per second, 550 centimeters/second to 800 centimeters/second, 550 centimeters/second to 750 centimeters/second, 550 centimeters/second to 700 centimeters/second, 550 centimeters/second to 650 centimeters/second, 550 centimeters/second to 600 centimeters/second, 600 centimeters/second to 900 centimeters per second, 600 centimeters/second to 850 centimeters per second, 600 centimeters/second to 800 centimeters/second, 600 centimeters/second to 750 centimeters/second, 600 centimeters/second to 700 centimeters/second, 600 centimeters/second to 650 centimeters/second, 650 centimeters/second to 900 centimeters per second, 650 centimeters/second to 850 centimeters per second, 650 centimeters/second to 800 centimeters/second, 650 centimeters/second to 750 centimeters/second, 650 centimeters/second to 700 centimeters/second, 700 centimeters/second to 900 centimeters per second, 700 centimeters/second to 850 centimeters per second, 700 centimeters/second to 800 centimeters/second, 700 centimeters/second to 750 centimeters/second, 750 centimeters/second to 900 centimeters per second, 750 centimeters/second to 850 centimeters per second, 750 centimeters/second to 800 centimeters/second, 800 centimeters/second to 900 centimeters per second, 800 centimeters/second to 850 centimeters per second, or 850 centimeters/second to 900 centimeters/second.","As used herein, “impeller tip speed” refers to the speed of the outer most portion of the impeller as it rotates around its central axis.","In some embodiments, the agitating (and optionally additional steps as described herein) is performed in a container comprising an impeller, wherein a ratio of the impeller diameter to the container volume is 0.1 to 0.5, 0.1 to 0.4, 0.2 to 0.5, 0.2 to 0.4, 0.3 to 0.5, or 0.3 to 0.4.In some embodiments, the agitating (and optionally additional steps as described herein) is performed in a container comprising an impeller, wherein a ratio of the impeller diameter to the inner diameter of the container is at least 0.25, at least 0.34, at least 0.65, 0.25 to 0.65, 0.25 to 0.33, 0.3 to 0.6, 0.3 to 0.5, 0.3 to 0.4, 0.34 to 0.65, 0.34 to 0.6, 0.34 to 0.55, 0.37 to 0.55, 0.4 to 0.65, 0.4 to 0.6, 0.4 to 0.5, or 0.42 to 0.55.In some embodiments, agitating comprises mixing a cell composition or a lysed cell composition such that the cell composition or the lysed cell composition is placed under flow conditions described by a Reynolds number of 10 to 10,000, 1,000 to 10,000, 1,500 to 10,000, or 2,000 to 10,000.In some embodiments, a lysed cell emulsion during the agitating has a Reynolds number of 2,000 or more, 3,000 or more, or 5,000 or more, or 2,000 to 10,000, 3,000 to 10,000, or 5,000 to 10,000.In some embodiments, a process comprises agitating a cell composition or a lysed cell composition for at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 4 hours, at least 8 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 30 hours, at least 36 hours, at least 42 hours, at least 48 hours, at least 54 hours, at least 60 hours, at least 66 hours, at least 72 hours, at least 78 hours, at least 84 hours, at least 90 hours or at least 96 hours.","In some embodiments, a process comprises agitating a cell composition or a lysed cell composition for 5 minutes to 96 hours, 5 minutes to 4 hours, 5 minutes to 2 hours, 5 minutes to 1 hour, 10 minutes to 4 hours, 10 minutes to 2 hours, 10 minutes to 1 hour, 1 hour to 96 hours, 1 hour to 84 hours, 1 hour to 72 hours, 1 hour to 60 hours, 1 hour to 48 hours, 1 hour to 36 hours, 1 hour to 24 hours, 1 hour to 4 hours, 4 hours to 96 hours, 4 hours to 84 hours, 4 hours to 72 hours, 4 hours to 60 hours, 4 hours to 48 hours, 4 hours to 36 hours, 4 hours to 24 hours, 8 hours to 96 hours, 8 hours to 84 hours, 8 hours to 72 hours, 8 hours to 60 hours, 8 hours to 48 hours, 8 hours to 36 hours, 8 hours to 24 hours, 8 hours to 12 hours, 12 hours to 96 hours, 12 hours to 84 hours, 12 hours to 72 hours, 12 hours to 60 hours, 12 hours to 48 hours, 12 hours to 36 hours, 12 hours to 24 hours, 20 hours to 40 hours, 24 hours to 96 hours, 24 hours to 84 hours, 24 hours to 72 hours, 24 hours to 60 hours, 24 hours to 48 hours, or 24 hours to 36 hours.","In some embodiments, a process comprises simultaneously agitating and heating a cell composition or a lysed cell composition to demulsify the cell composition or the lysed cell composition.","In some embodiments, a process comprises agitating a cell composition or a lysed cell composition at a temperature of at least 10° C., at least 20° C., at least 25° C., at least 30° C., at least 35° C., at least 40° C., at least 45° C., at least 50° C., at least 55° C., at least 60° C., at least 65° C., at least 70° C., at least 75° C., at least 80° C., at least 85° C., at least 90° C., at least 95° C., or at least 100° C. In some embodiments, a process comprises agitating a cell composition or a lysed cell composition at a temperature of 10° C. to 100° C., 10° C. to 90° C., 10° C. to 80° C., 10° C. to 70° C., 20° C. to 100° C., 20° C. to 90° C., 20° C. to 80° C., 20° C. to 70° C., 30° C. to 100° C., 30° C. to 90° C., 30° C. to 80° C., 30° C. to 70° C., 40° C. to 100° C., 40° C. to 90° C., 40° C. to 80° C., 50° C. to 100° C., 50° C. to 90° C., 50° C. to 80° C., 50° C. to 70° C., 60° C. to 100° C., 60° C. to 90° C., 60° C. to 80° C., 70° C. to 100° C., 70° C. to 90° C., 80° C. to 1000° C., 80° C. to 90° C., or 90° C. to 100° C. In some embodiments, the various combinations of forming a lysed cell composition, contacting a lysed cell composition with a base or raising the pH of a lysed cell composition, contacting a lysed cell composition with a salt, heating the lysed cell composition, and agitating a lysed cell composition can occur in a single vessel.","In some embodiments, the various combinations of forming a cell composition, contacting a cell composition with a base or raising the pH of a cell composition, contacting a cell composition with a salt, heating the cell composition, and agitating a cell composition can occur in a single vessel.","In some embodiments, the single vessel includes a fermentation vessel.","In some embodiments, the fermentation vessel can have a volume of at least 20,000 liters, at least 50,000 liters, at least 100,000 liters, at least 120,000 liters, at least 150,000 liters, at least 200,000 liters, or at least 220,000 liters.","In some embodiments, the fermentation vessel can have a volume of 20,000 liters to 220,000 liters, 20,000 liters to 100,000 liters, 20,000 liters to 50,000 liters, 50,000 liters to 220,000 liters, 50,000 liters to 150,000 liters, 50,000 liters to 100,000 liters, 100,000 liters to 220,000 liters, 100,000 liters to 150,000 liters, 100,000 liters to 120,000 liters, 150,000 liters to 220,000 liters, 150,000 liters to 200,000 liters, or 200,000 liters to 220,000 liters.","In some embodiments, a quantity of cell composition or lysed cell composition formed in a vessel can be transferred into one or more agitation vessels.","In some embodiments, the agitation vessels can have a volume of at least 20,000 liters, at least 30,000 liters, at least 40,000 liters or at least 50,000 liters.","In some embodiments, the agitation vessels can have a volume of 20,000 liters to 50,000 liters, 20,000 liters to 40,000 liters, 20,000 liters to 30,000 liters, 30,000 liters to 50,000 liters, 30,000 liters to 40,000 liters or 40,000 liters to 50,000 liters.","In some embodiments, the agitation vessels can have any combination of the following properties.","In some embodiments, the agitation vessels can have two impellers.","In some embodiments, the impellers are Rushton blade impellers.","In some embodiments, the impellers are separated from each other by a distance at least equal to a diameter of the smallest impeller.","In some embodiments, the impellers are 30 inches to 40 inches, 33 inches to 37 inches, 33 inches, 34 inches, 35 inches, 36 inches or 37 inches from tip to tip.","In some embodiments, the agitation vessels have a volume of at least 10,000 liters, at least 20,000 liters, at least 30,000 liters, at least 40,000 liters or at least 50,000 liters.","In some embodiments, the agitation vessels have an inner diameter of 90 inches to 110 inches, 95 inches to 105 inches, 98 inches, 99 inches, 100 inches, 101 inches, or 102 inches.","In some embodiments, a first impeller is located 15 inches to 20 inches, 16 inches to 19 inches, or 17 inches to 18 inches from a bottom of the agitation vessel and a second impeller is located 60 inches to 80 inches, 65 inches to 75 inches, 68 inches, 69 inches, 70 inches, 71 inches, 72 inches, 73 inches, 74 inches, or 75 inches above the first impeller.","In some embodiments, a lysed cell composition is agitated at least 50 rpm, at least 60 rpm, or at least 70 rpm.","In some embodiments, a lysed cell composition is agitated at 50 rpm to 70 rpm, 50 rpm to 60 rpm, or 60 rpm to 70 rpm.","In some embodiments, the cell composition, the lysed cell composition, or the lipid are harvested from a vessel by pumping the cell composition, the lysed cell composition, or the lipid from the vessel.","In some embodiments, the cell composition, the lysed cell composition, or the lipid are harvested from a vessel without agitating the vessel.","In some embodiments, the cell composition, the lysed cell composition, or the lipid are harvested from a vessel by pumping, without agitation, the cell composition, the lysed cell composition, or the lipid from the vessel.","In some embodiments, the cell composition, the lysed cell composition, or the lipid are harvested from a vessel without blowing air.","In some embodiments, harvesting the cell composition, the lysed cell composition, or the lipid by the techniques described above results in a crude lipid having a low anisidine value (e.g., 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less) and/or a low phosphorus content (e.g., 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less).","As described herein, the present invention utilizes various combinations of contacting a lysed cell composition with a first base or raising the pH of a lysed cell composition, contacting a lysed cell composition with a salt, heating a lysed cell composition, and agitating a lysed cell composition to provide a treated lysed cell composition.","As described herein, the present invention utilizes various combinations of contacting a cell composition with a first base or raising the pH of a cell composition, contacting a cell composition with a salt, heating a cell composition, and agitating a cell composition to provide a treated cell composition.","The treated cell composition or treated lysed cell composition is at least partially demulsified compared with an untreated cell composition or treated lysed cell composition.","Thus, a treated cell composition or treated lysed cell composition can be placed in a centrifuge and a lipid can be separated therefrom.","In some embodiments, after raising the pH of a cell composition or lysed cell composition, e.g., by contacting with a first base, the heating the cell composition or lysed cell composition and/or the agitating the cell composition or lysed cell composition can decrease the pH of the treated cell composition or treated lysed cell composition.","In order for a lipid to be more effectively separated from a treated cell composition or treated lysed cell composition by centrifuging, the pH of the treated cell composition or treated lysed cell composition is raised a second time, e.g., by contacting the treated cell composition or the treated lysed cell composition with a second base.","In some embodiments, contacting a treated lysed cell composition with a second base raises the pH of the treated cell composition or the treated lysed cell composition.","In some embodiments, a treated cell composition or a treated lysed cell composition is contacted with a second base to raise the pH of the treated cell composition or the treated lysed cell composition to 7 or above, 7.5 or above, 8 or above, 8.5 or above, 9 or above, 9.5 or above, 10 or above, 10.5 or above, 11 or above, 11.5 or above, or 12 or above.","In some embodiments, a treated cell composition or a treated lysed cell composition is contacted with a second base to raise the pH of the treated lysed cell composition to 7 to 13, 7 to 12, 7 to 11, 7 to 10, 7 to 9, 7 to 8, 7 to 7.5, 7.5 to 8, 8 to 13, 8 to 12, 8 to 11, 8 to 10, 8 to 9, 8 to 8.5, 8.5 to 9, 9 to 12, 9 to 11, 9 to 10, 9 to 9.5, 9.5 to 10, 10 to 12, or 10 to 11.In some embodiments, the pH of a treated cell composition or a treated lysed cell emulsion is 7 or less, 6 or less, 5 or less, 4 or less, or 3 or less.","The processes of the present invention comprise separating a lipid from a treated cell composition or a treated lysed cell composition.","In some embodiments, a lipid is separated from a lysed cell emulsion after contacting a lysed cell emulsion with a second base, after the agitating a lysed cell emulsion, or after contacting a lysed cell emulsion with a salt by, for example, permitting the treated lysed cell emulsion to rest for a period of time sufficient for a lipid to separate from the treated lysed cell emulsion (e.g., as a separate layer).","The lipid can be subsequently removed, for example, by decanting, skimming, vacuuming, pumping, sucking off, drawing off, siphoning, or otherwise removing the lipid from the surface of the treated lysed cell emulsion.","In some embodiments, the separating comprises centrifuging a treated cell composition or a treated lysed cell composition (e.g., at a temperature of 30° C. to 100° C.), whereby the centrifuging separates a lipid from the treated cell composition or the treated lysed cell composition.","In some embodiments, a process comprises centrifuging a treated cell composition or a treated lysed cell composition at a temperature of at least 10° C., at least 20° C., at least 25° C., at least 30° C., at least 35° C., at least 40° C., at least 45° C., at least 50° C., at least 55° C., at least 60° C., at least 65° C., at least 70° C., at least 75° C., at least 80° C., at least 85° C., at least 90° C., at least 95° C., or at least 100° C. In some embodiments, a process comprises centrifuging a treated cell composition or a treated lysed cell composition at a temperature of 10° C. to 100° C., 10° C. to 90° C., 10° C. to 80° C., 20° C. to 100° C., 20° C. to 90° C., 20° C. to 80° C., 25° C. to 100° C., 25° C. to 90° C., 25° C. to 80° C., 25° C. to 75° C., 30° C. to 100° C., 30° C. to 90° C., 30° C. to 80° C., 40° C. to 100° C., 40° C. to 90° C., 40° C. to 80° C., 50° C. to 100° C., 50° C. to 90° C., 50° C. to 80° C., 50° C. to 70° C., 60° C. to 100° C., 60° C. to 90° C., 60° C. to 80° C., 60° C. to 70° C., 70° C. to 100° C., or 70° C. to 90° C. In some embodiments, centrifuging is conducted at a feed rate (of a treated cell composition or a treated lysed cell composition into a centrifuge) of 1 kilogram per minute (kg/min) to 500 kg/min, 1 kg/min to 400 kg/min, 1 kg/min to 300 kg/min, 1 kg/min to 200 kg/min, 1 kg/min to 100 kg/min, 1 kg/min to 75 kg/min, 1 kg/min to 50 kg/min, 1 kg/min to 40 kg/min, 1 kg/min to 30 kg/min, 1 kg/min to 25 kg/min, 1 kg/min to 10 kg/min, 10 kg/min to 500 kg/min, 10 kg/min to 400 kg/min, 10 kg/min to 300 kg/min, 10 kg/min to 200 kg/min, 10 kg/min to 100 kg/min, 10 kg/min to 75 kg/min, 10 kg/min to 50 kg/min, 10 kg/min to 40 kg/min, 10 kg/min to 30 kg/min, 20 kg/min to 500 kg/min, 20 kg/min to 400 kg/min, 20 kg/min to 300 kg/min, 20 kg/min to 200 kg/min, 20 kg/min to 100 kg/min, 20 kg/min to 75 kg/min, 20 kg/min to 50 kg/min, 20 kg/min to 40 kg/min, 25 kg/min to 500 kg/min, 25 kg/min to 400 kg/min, 25 kg/min to 300 kg/min, 25 kg/min to 200 kg/min, 25 kg/min to 100 kg/min, 25 kg/min to 75 kg/min, 25 kg/min to 50 kg/min, 30 kg/min to 60 kg/min, 30 kg/min to 50 kg/min, 30 kg/min to 40 kg/min, 50 kg/min to 500 kg/min, 100 kg/min to 500 kg/min, or 200 kg/min to 500 kg/min.","The total time required for the separating can vary depending on the volume of the treated cell composition or the treated lysed cell composition.","Typical total time for separation (e.g., centrifuge time) is at least 0.1 hour, at least 0.2 hour, at least 0.5 hour, at least 1 hour, at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, or 0.1 hour to 24 hours, 0.5 hour to 24 hours, 1 hour to 12 hours, 2 hours to 10 hours, or 4 hours to 8 hours.","In some embodiments, a process of the invention comprises centrifuging a treated cell composition or a treated lysed cell composition at a centrifugal force of 1,000 g to 25,000 g, 1,000 g to 20,000 g, 1,000 g to 10,000 g, 2,000 g to 25,000 g, 2,000 g to 20,000 g, 2,000 g to 15,000 g, 3,000 g to 25,000 g, 3,000 g to 20,000 g, 5,000 g to 25,000 g, 5,000 g to 20,000 g, 5,000 g to 15,000 g, 5,000 g to 10,000 g, 5,000 g to 8,000 g, 10,000 g to 25,000 g, 15,000 g to 25,000 g, or at least 1,000 g, at least 2,000, g, at least 4,000 g, at least 5,000 g, at least 7,000 g, at least 8,000 g, at least 10,000 g, at least 15,000 g, at least 20,000 g, or at least 25,000 g. As used herein, “g” refers to standard gravity or approximately 9.8 m/s2.In some embodiments, a process of the invention comprises centrifuging a treated cell composition or a treated lysed cell composition at 4,000 rpm to 14,000 rpm, 4,000 rpm to 10,000 rpm, 6,000 rpm to 14,000 rpm, 6,000 rpm to 12,000 rpm, 8,000 to 14,000 rpm, 8,000 rpm to 12,000 rpm, or 8,000 rpm to 10,000 rpm.","In some embodiments, a process of the invention comprises drying a lipid after separation of the lipid from a treated cell composition or a treated lysed cell composition in order to remove water from the lipid.","In some embodiments, drying the lipid can include, but is not limited to, heating the lipid to evaporate water.","In some embodiments, after drying, the lipid has a water content by weight percentage of lipid that is less than 3%, less than 2.5%, less than 2%, less than 1.5%, less than 1%, less than 0.5%, less than 0.1%, or 0%.","In some embodiments, after drying, the lipid has a water content by weight percentage of lipid of 0% to 3%, 0% to 2.5%, 0% to 2%, 0% to 1.5%, 0% to 1%, 0% to 0.5%, 0.1% to 3%, 0.1% to 2.5%, 0.1% to 2%, 0.1% to 1.5%, 0.1% to 1%, 0.1% to 0.5%, 0.5% to 3%, 0.5% to 2.5%, 0.5% to 2%, 0.5% to 1.5%, 0.5% to 1%, 1% to 3%, 1% to 2.5%, 1% to 2%, 1% to 1.5%, 1.5% to 3%, 1.5% to 2.5%, 1.5% to 2%, 2% to 3%, 2% to 2.5%, or 2.5% to 3%.","In some embodiments, a process further comprises refining a lipid by one or more processes selected from caustic refining, degumming, alkali-refining, bleaching, deodorization, deacidification, or the like, and combinations thereof to remove one or more phospholipids, free fatty acids, phosphatides, color bodies, sterols, odors, and other impurities.","As used herein, a “refined oil” is a crude lipid or crude oil that has been refined.","As used herein, “a crude lipid” or “a crude oil” is a lipid or oil that has not been refined.","In some embodiments, the lipid separated from a demulsified cell composition is a crude lipid.","Various exemplary processes of the present invention are described schematically in FIGS.","1-4.Referring to FIG.","1, in some embodiments, the present invention is directed to a process (100) for obtaining a lipid (110) from a cell (101), comprising lysing (102) the cell (101) to form a lysed cell composition (103).","The lysed cell composition is contacted with a first base (104) to demulsify lysed cell composition (103), contacted with a salt (105) to demulsify lysed cell composition (103), and heated (106), e.g., for 10 minutes to 96 hours, to provide a treated lysed cell composition (107).","The treated lysed cell composition (107) is contacted with a second base (108) and separated (109), e.g., at a temperature of 10° C. to 100° C., to provide a lipid (110).","Referring to FIG.","2, in some embodiments, the present invention is directed to a process (200) for obtaining a lipid (210) from a cell, the process comprising lysing (102) a cell (101) to form a lysed cell composition (103).","The lysed cell composition is then contacted with a base (204) to demulsify lysed cell composition (103) and to provide a treated lysed cell composition (207).","The treated lysed cell composition (207) is separated (209), e.g., at a temperature of 10° C. to 100° C., to provide a lipid (210).","Referring to FIG.","3, in some embodiments, the present invention is directed to a process (300) for obtaining a lipid (310) from a cell, the process comprising lysing (102) a cell (101) to form a lysed cell composition (103).","The lysed cell composition is then contacted with a salt (305) to demulsify lysed cell composition (103) and to provide a treated lysed cell composition (307), which is separated (309), e.g., at a temperature of 10° C. to 100° C., to provide a lipid (310).","Referring to FIG.","4, in some embodiments, the present invention is directed to a process (400) for obtaining a lipid (410) from a cell, the process comprising lysing (102) a cell (101) to form a lysed cell composition (103).","The lysed cell composition is then contacted with a salt (405) to demulsify lysed cell composition (103) and agitated (401), e.g., for 5 minutes to 96 hours, and optionally heated (402), to provide a treated lysed cell composition (407).","The treated lysed cell composition is then separated (409), e.g., at a temperature of 10° C. to 100° C., to provide a lipid (410).","In some embodiments, a process of the present invention comprises concentrating a broth comprising a microbial cell, a broth comprising plant material and/or concentrating a lysed cell composition.","As used herein, “concentrating” refers to removing water from a composition.","Concentrating can include, but is not limited to, evaporating, chemical drying, centrifuging, and the like, and combinations thereof.","In some embodiments, a broth comprising a microbial cell or a broth comprising plant material is concentrated to provide a lipid concentration of at least 4%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% by weight of the broth.","In some embodiments, a broth comprising a microbial cell or a broth comprising plant material is concentrated to provide a lipid concentration of 4% to 40%, 4% to 30%, 4% to 20%, 4% to 15%, 5% to 40%, 5% to 30%, 5% to 20%, 10% to 40%, 10% to 30%, 10% to 20%, 15% to 40%, 15% to 30%, 20% to 40%, 20% to 30%, 25% to 40%, or 30% to 40% by weight of the broth.","In some embodiments, a cell composition or a lysed cell composition is concentrated to provide a lipid concentration of at least 4%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% by weight of the lysed cell composition.","In some embodiments, a cell composition or a lysed cell composition is concentrated to provide a lipid concentration of 4% to 40%, 4% to 30%, 4% to 20%, 4% to 15%, 5% to 40%, 5% to 30%, 5% to 20%, 10% to 40%, 10% to 30%, 10% to 20%, 15% to 40%, 15% to 30%, 20% to 40%, 20% to 30%, 25% to 40%, or 30% to 40% by weight of the lysed cell composition.","In some embodiments, a lipid prepared by a process of the present invention has an overall aroma intensity of 2 or less.","As used herein, the term “overall aroma intensity” refers to the olfactory sensory rating given to the lipid by a panel of sensory analysts.","As used herein, the term “sensory analyst” refers to a trained individual that provides feedback on and/or rates the sensory characteristics of a substance.","In some embodiments, a lipid prepared by a process of the present invention has an overall aromatic intensity of 3 or less.","As used herein, the term “overall aromatic intensity” refers to the gustatory, or taste, sensory rating given to the lipid by a panel of sensory analysts.","In some embodiments, the Universal Spectrum descriptive analysis method is used to assess the aroma and aromatic characteristics of samples.","This method uses an intensity scale of 0-15, where 0=none detected and 15=very high intensity, to measure the aroma and aromatic attributes of the oils.","In some embodiments, a lipid prepared by a process of the present invention does not have an aftertaste characterized as fishy.","As used herein, the term “aftertaste” refers to the persistence of a sensation of a flavor in the lipid, as characterized by a panel of sensory analysts.","In some embodiments, a process of the present invention provides a crude lipid having a peroxide value (PV) of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less.","As used herein, the terms “peroxide value” or “PV” refer to the measure of primary reaction products, such as peroxides and hydroperoxides, that occur during oxidation of the lipid.","In some embodiments, the PV is an indicator of the quality of the lipid and the extent of oxidation which has occurred in the lipid having a low PV (i.e., 5 or less) demonstrates increased stability and sensory profiles than lipids having a PV greater than 5.In some embodiments, adding a base to a lysed cell composition, as discussed above, raises the pH of the lysed cell composition and inhibits lipid oxidation, thereby minimizing the amount of free radicals in the lysed cell composition so that the crude lipid obtained from the processes of the invention has a low PV (i.e., 5 or less).","In some embodiments, a process of the present invention provides a crude lipid having an anisidine value (AV) of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less.","As used herein, the terms “anisidine value” or “AV” refer to the measure of secondary reaction products, such as aldehydes and ketones, that occur during oxidation of the lipid.","In some embodiments, the AV is an indicator of the quality of the lipid and the extent of oxidation which has occurred in the lipid.","A lipid having a low AV (i.e., 26 or less) demonstrates increased stability and sensory profiles than lipids having an AV greater than 26.In some embodiments, adding a base to a lysed cell composition, as discussed above, raises the pH of the lysed cell composition and inhibits lipid oxidation, thereby minimizing the amount of free radicals in the lysed cell composition so that the crude lipid obtained from the processes of the invention has a low AV (i.e., 26 or less).","In some embodiments, a process of the present invention provides a crude lipid having a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","In some embodiments, a process of the present invention provides a crude lipid that has a lower anisidine value, lower peroxide value, lower phosphorus content and/or a higher extraction yield than if extraction was performed using a solvent (e.g., atypical hexane extraction or a FRIOLEX® process (Westfalia Separator AG, Germany)).","The FRIOLEX® process which is a process of extracting lipids with a water-soluble organic solvent as described in U.S. Pat.","No.","5,928,696 and International Pub.","Nos.","WO 01/76385 and WO 01/76715, each of which is incorporated by reference herein in its entirety.","In some embodiments, heating the lysed cell composition causes the secondary reaction products (e.g., aldehydes and ketones) to participate in a reaction similar to the Maillard reaction with proteins present in the lysed cell composition.","The reaction is believed to create products that possess antioxidant activity, which reduces the oxidation of the lipid.","In some embodiments, additional protein, e.g., soy protein, can be added to the lysed cell composition to increase the antioxidant activity.","The reduction in oxidation of the lipid reduces the AV of the lipid, reduces any aftertaste of the lipid and/or increases the stability of the lipid.","In some embodiments, the stability is increased at least 5%, at least 10%, at least 15% or at least 20%.","In some embodiments, a lipid extracted by a process of the present invention, the biomass remaining after extraction of the lipid, or combinations thereof can be used directly as a food or food ingredient, such as an ingredient in baby food, infant formula, beverages, sauces, dairy based foods (such as milk, yogurt, cheese and ice-cream), oils (e.g., cooking oils or salad dressings), and baked goods; nutritional supplements (e.g., in capsule or tablet forms); feed or feed supplement for any non-human animal (e.g., those whose products (e.g., meat, milk, or eggs) are consumed by humans); food supplements; and pharmaceuticals (in direct or adjunct therapy application).","The term “animal” refers to any organism belonging to the kingdom Animalia and includes any human animal, and non-human animal from which products (e.g., milk, eggs, poultry meat, beef, pork or lamb) are derived.","In some embodiments, the lipid and/or biomass can be used in seafood.","Seafood is derived from, without limitation, fish, shrimp and shellfish.","The term “products” includes any product derived from such animals, including, without limitation, meat, eggs, milk or other products.","When the lipid and/or biomass are fed to such animals, polyunsaturated lipids can be incorporated into the flesh, milk, eggs or other products of such animals to increase their content of these lipids.","Microbial Lipids In some embodiments, the present invention is directed to a microbial lipid extracted according to the processes of the present invention.","In some embodiments, a crude microbial lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","In some embodiments, the crude microbial lipid has less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% by weight or volume of an organic solvent.","In some embodiments, the crude microbial lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of a desired PUFA.","In some embodiments, the crude microbial lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of DHA, and/or at least 10%, at least 15%, or at least 20% by weight of DPA n-6, and/or at least 10%, at least 15%, or at least 20% by weight of EPA, and/or at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of ARA.","In some embodiments a crude microbial lipid extracted according to the processes of the present invention result in a lower anisidine value, lower peroxide value, lower phosphorus content and/or a higher extraction yield than if extraction was performed using a solvent (e.g., a typical hexane extraction or a FRIOLEX® process (Westfalia Separator AG, Germany)).","Lipids Extracted from a First Set of Isolated Thraustochytrid Microorganisms In some embodiments, the present invention is further directed to a microbial lipid extracted from a thraustochytrid as described in U.S. Pub.","No.","2010/0239533 and Int'l.","Pub.","No.","WO 2010/107415, each of which is incorporated by reference herein in its entirety.","In some embodiments, the method comprises growing a thraustochytrid in a culture to produce a biomass and extracting a lipid comprising omega-3 fatty acids from the biomass.","The lipid can be extracted from a freshly harvested biomass or can be extracted from a previously harvested biomass that has been stored under conditions that prevent spoilage.","Known methods can be used to culture a thraustochytrid of the invention, to isolate a biomass from the culture, and to analyze the fatty acid profile of oils extracted from the biomass.","See, e.g., U.S. Pat.","No.","5,130,242, incorporated by reference herein in its entirety.","The lipid can be extracted according to the processes of the present invention.","A microbial lipid of the invention can be any lipid derived from a microorganism, including, for example: a crude oil extracted from the biomass of the microorganism without further processing; a refined oil that is obtained by treating a crude microbial oil with further processing steps such as refining, bleaching, and/or deodorizing; a diluted microbial oil obtained by diluting a crude or refined microbial oil; or an enriched oil that is obtained, for example, by treating a crude or refined microbial oil with further methods of purification to increase the concentration of a fatty acid (such as DHA) in the oil.","In some embodiments, the microbial lipid comprises a sterol esters fraction of 0%, at least 0.1%, at least 0.2%, at least 0.5%, at least about 1%, at least 1.5%, at least 2%, or at least 5% by weight.","In some embodiments, the microbial lipid comprises a sterol esters fraction of from 0% to 1.5%, 0% to 2%, 0% to 5%, 1% to 1.5%, 0.2% to 1.5%, 0.2% to 2%, or 0.2% to 5% by weight.","In some embodiments, the microbial lipid comprises a sterol esters fraction of less than 5%, less than 4%, less than 3%, or less than 2% by weight.","In some embodiments, the microbial lipid comprises a triglyceride fraction of at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% by weight.","In some embodiments, the microbial lipid comprises a triglyceride fraction of from 65% to 95%, 75% to 95%, or 80% to 95% by weight, or 97% by weight, or 98% by weight.","In some embodiments, the microbial lipid comprises a free fatty acid fraction of at least 0.5%, at least 1%, at least 1.5%, at least 2%, at least 2.5%, or at least 5% by weight.","In some embodiments, the microbial lipid comprises a free fatty acid fraction of from 0.5% to 5%, 0.5% to 2.5%, 0.5% to 2%, 0.5% to 1.5%, 0.5% to 1%, 1% to 2.5%, 1% to 5%, 1.5% to 2.5%, 2% to 2.5%, or 2% to 5% by weight.","In some embodiments, the microbial lipid comprises a free fatty acid fraction of less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% by weight.","In some embodiments, the microbial lipid comprises a sterol fraction of at least 0.5%, at least 1%, at least 1.5%, at least 2%, or at least 5% by weight.","In some embodiments, the microbial lipid comprises a sterol fraction of from 0.5% to 1.5%, 1% to 1.5%, 0.5% to 2%, 0.5% to 5%, 1% to 2%, or 1% to 5% by weight.","In some embodiments, the microbial lipid comprises a sterol fraction of less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% by weight.","In some embodiments, the microbial lipid comprises a diglyceride fraction of at least 1.5%, at least 2%, at least 2.5%, at least 3%, at least 3.5%, or at least 5% by weight.","In some embodiments, the microbial lipid comprises a diglyceride fraction of from 1.5% to 3%, 2% to 3%, 1.5% to 3.5%, 1.5% to 5%, 2.5% to 3%, 2.5% to 3.5%, or 2.5% to 5% by weight.","In some embodiments, the microbial lipid comprises unsaponifiables of less than 2%, less than 1.5%, less than 1%, or less than 0.5% by weight of the oil.","The lipid classes present in the microbial oil, such as the triglyceride fraction, can be separated by flash chromatography and analyzed by thin layer chromatography (TLC), or separated and analyzed by other methods know in the art.","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, and combinations thereof, comprises at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80% by weight DHA.","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, and combinations thereof, comprises from 40% to 45%, 40% to 50%, 40% to 60%, 50% to 60%, 55% to 60%, 40% to 65%, 50% to 65%, 55% to 65%, 40% to 70%, 40% to 80%, 50% to 80%, 55% to 80%, 60% to 80%, or 70% to 80% by weight DHA.","In some embodiments, the microbial lipid comprises a sterol esters fraction comprising 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, or 13% or less by weight DHA.","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, and combinations thereof, comprises 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less by weight EPA.","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, and combinations thereof, comprises from 2% to 3%, 2% to 3.5%, 2.5% to 3.5%, 2% to 6%, 2.5% to 6%, 3.0% to 6%, 3.5% to 6%, 5% to 6%, or 2% to 10% by weight EPA.","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, is substantially free of EPA.","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, comprises a weight ratio of DHA to EPA of at least 5:1, at least 7:1, at least 9:1, at least 10:1, at least 15:1, at least 20:1, at least 25:1, at least 30:1, or at least 50:1, wherein the microbial lipid and/or one or more fractions thereof comprises 10% or less by weight of EPA.","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, comprises a weight ratio of DHA to EPA of at least 5:1, but less than 20:1.In some embodiments, the weight ratio of DHA to EPA is from 5:1 to 18:1, from 7:1 to 16:1, or from 10:1 to 15:1.In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof comprises from 0.1% to 0.25%, 0.2% to 0.25%, 0.1% to 0.5%, or 0.1% to 1.5% by weight ARA.","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, comprises 1.5% or less, 1% or less, 0.5% or less, 0.2% or less, or 0.1% or less by weight ARA.","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, is substantially free of ARA.","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, comprises a weight ratio of DHA to ARA of at least 20:1, at least 30:1, at least 35:1, at least 40:1, at least 60:1, at least 80:1, at least 100:1, at least 150:1, at least 200:1, at least 250:1, or at least 300:1.In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, comprises from 0.5% to 1%, 0.5% to 2%, 0.5% to 2.5%, 0.5% to 3%, 0.5% to 3.5%, 0.5% to 5%, 0.5% to 6%, 1% to 2%, 2% to 3%, 2% to 3.5%, 1% to 2.5%, 1% to 3%, 1% to 3.5%, 1% to 5%, or 1% to 6% by weight DPA n-6.In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, comprises 6% or less, 5% or less, 3% or less, 2.5% or less, 2% or less, 1% or less, or 0.5% or less by weight DPA n-6.In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, is substantially free of DPA n-6.In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, comprises a weight ratio of DHA to DPA n-6 of greater than 6:1, of at least 8:1, at least 10:1, at least 15:1, at least 20:1, at least 25:1, at least 50:1, or at least 100:1.In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, comprises 5% or less, 4% or less, 3% or less, 2% or less, 1.5% or less, 1% or less, or 0.5% or less by weight each of linoleic acid (18:2 n-6), linolenic acid (18:3 n-3), eicosenoic acid (20:1 n-9), and erucic acid (22:1 n-9).","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, comprises 5% or less, 4% or less, 3% or less, 2% or less, 1.5% or less, or 1% or less by weight of heptadecanoic acid (17:0).","In some embodiments, the microbial lipid and/or one or more fractions thereof comprise 0.01% to 5% by weight, 0.05% to 3% by weight, or 0.1% to 1% by weight of heptadecanoic acid.","In some embodiments, an extracted microbial lipid comprises a triglyceride fraction of at least 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 50% by weight, wherein the docosapentaenoic acid n-6 content of the triglyceride fraction is from at least 0.5% by weight to 6% by weight, and wherein the oil has an anisidine value of 26 or less.","In some embodiments, an extracted microbial lipid comprises a triglyceride fraction of at least 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 40% by weight, wherein the docosapentaenoic acid n-6 content of the triglyceride fraction is from at least 0.5% by weight to 6% by weight, wherein the ratio of docosahexaenoic acid to docosapentaenoic acid n-6 is greater than 6:1, and wherein the lipid has an anisidine value of 26 or less.","In some embodiments, an extracted microbial lipid comprises a triglyceride fraction of at least 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 60% by weight and wherein the lipid has an anisidine value of 26 or less.","In some embodiments, an extracted microbial lipid having any of the above fatty acid profiles has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","In some embodiments, an extracted microbial lipid having any of the above fatty acid profiles is extracted from an isolated thraustochytrid microorganism having the characteristics of the thraustochytrid species deposited under ATCC Accession No.","PTA-9695, PTA-9696, PTA-9697, or PTA-9698.In some embodiments, an extracted microbial lipid having any of the above fatty acid profiles is a crude lipid.","In some embodiments, the crude lipid has less than 5% by weight or volume of an organic solvent.","In some embodiments the microbial lipid extracted according to the processes of the present invention result in a lower anisidine value, lower peroxide value, lower phosphorus content and/or a higher extraction yield if extraction was performed using a solvent (e.g., atypical hexane extraction or a FRIOLEX™ process (Westfalia Separator AG, Germany)).","Lipids Extracted from a Second Set of Isolated Thraustochytrid Microorganisms In some embodiments, the present invention is further directed to a microbial lipid extracted from a thraustochytrid as described in U.S. application Ser.","No.","12/729,013 and PCT/US2010/028175, each of which is incorporated by reference herein in its entirety.","In some embodiments, the method comprises growing a thraustochytrid in a culture to produce a biomass and extracting a lipid comprising omega-3 fatty acids from the biomass.","The lipid can be extracted from a freshly harvested biomass or can be extracted from a previously harvested biomass that has been stored under conditions that prevent spoilage.","Known methods can be used to culture a thraustochytrid of the invention, to isolate a biomass from the culture, and to analyze the fatty acid profile of oils extracted from the biomass.","See, e.g., U.S. Pat.","No.","5,130,242, incorporated by reference herein in its entirety.","The lipid can be extracted according to the processes of the present invention.","A microbial lipid of the invention can be any lipid derived from a microorganism, including, for example: a crude oil extracted from the biomass of the microorganism without further processing; a refined oil that is obtained by treating a crude microbial oil with further processing steps such as refining, bleaching, and/or deodorizing; a diluted microbial oil obtained by diluting a crude or refined microbial oil; or an enriched oil that is obtained, for example, by treating a crude or refined microbial oil with further methods of purification to increase the concentration of a fatty acid (such as DHA) in the oil.","In some embodiments, the microbial lipid comprises a sterol esters fraction of 0%, at least 0.1%, at least 0.2%, at least 0.5%, at least 1%, at least 1.5%, at least 2%, or at least 5% by weight.","In some embodiments, the microbial lipid comprises a sterol esters fraction of 0% to 1.5%, 0% to 2%, 0% to 5%, 1% to 1.5%, 0.2% to 1.5%, 0.2% to 2%, or 0.2% to 5% by weight.","In some embodiments, the microbial lipid comprises a sterol esters fraction of 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, 0.3% or less, 0.2% or less, 0.5% or less, 0.4% or less, 0.3% or less, or 0.2% or less by weight.","In some embodiments, the microbial lipid comprises a triacylglycerol fraction of at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% by weight.","In some embodiments, the microbial lipid comprises a triacylglycerol fraction of 35% to 98%, 35% to 90%, 35% to 80%, 35% to 70%, 35% to 70%, 35% to 65%, 40% to 70%, 40% to 65%, 40% to 55%, 40% to 50%, 65% to 95%, 75% to 95%, 75% to 98%, 80% to 95%, 80% to 98%, 90% to 96%, 90% to 97%, 90% to 98%, 90%, 95%, 97%, or 98% by weight.","In some embodiments, the microbial lipid comprises a diacylglycerol fraction of at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% by weight.","In some embodiments, the microbial lipid comprises a diacylglycerol fraction of 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 15% to 40%, 15% to 35%, or 15% to 30% by weight.","In some embodiments, the microbial lipid comprises a 1,2-diacylglycerol fraction of at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 1%, at least 5%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% by weight.","In some embodiments, the microbial lipid comprises a diacylglycerol fraction of 0.2% to 45%, 0.2% to 30%, 0.2% to 20%, 0.2% to 10%, 0.2% to 5%, 0.2% to 1%, 0.2% to 0.8%, 0.4% to 45%, 0.4% to 30%, 0.4% to 20%, 0.4% to 10%, 0.4% to 5%, 0.4% to 1%, 0.4% to 0.8%, 0.5% to 1%, 0.5% to 0.8%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 15% to 40%, 15% to 35%, 15% to 30%, or 15% to 25% by weight.","In some embodiments, the microbial lipid comprises a 1,3-diacylglycerol fraction of at least 0.1%, at least 0.2%, at least 0.5%, at least 1%, at least 2%, at least 2.5%, or at least 3% by weight.","In some embodiments, the microbial lipid comprises a sterol fraction of at least 0.3%, at least 0.4%, at least 0.5%, at least 1%, at least 1.5%, at least 2%, or at least 5% by weight.","In some embodiments, the microbial lipid comprises a sterol fraction of 0.3% to 5%, 0.3% to 2%, 0.3% to 1.5%, 0.5% to 1.5%, 1% to 1.5%, 0.5% to 2%, 0.5% to 5%, 1% to 2%, or 1% to 5% by weight.","In some embodiments, the microbial lipid comprises a sterol fraction of 5% or less, 4% or less, 3% or less, 2% or less, 1.5% or less, or 1% or less by weight.","In some embodiments, the microbial lipid comprises a phospholipid fraction of at least 2%, at least 5%, or at least 8% by weight.","In some embodiments, the microbial lipid comprises a phospholipid fraction of 2% to 25%, 2% to 20%, 2% to 15%, 2% to 10%, 5% to 25%, 5% to 20%, 5% to 20%, 5% to 10%, or 7% to 9% by weight.","In some embodiments, the microbial lipid comprises a phospholipid fraction of less than 20%, less than 15%, less than 10%, less than 9%, or less than 8% by weight.","In some embodiments, the microbial lipid is substantially free of phospholipids.","In some embodiments, the microbial lipid comprises unsaponifiables of less than 2%, less than 1.5%, less than 1%, or less than 0.5% by weight of the oil.","The lipid classes present in the microbial lipid, such as a triacylglycerol fraction, can be separated by flash chromatography and analyzed by thin layer chromatography (TLC), or separated and analyzed by other methods known in the art.","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the free fatty acid fraction, the sterol fraction, the diacylglycerol fraction, and combinations thereof, comprises at least 5%, at least 10%, more than 10%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 25%, at least 30%, least 35%, at least 40%, or at least 45% by weight EPA.","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the free fatty acid fraction, the sterol fraction, the diacylglycerol fraction, and combinations thereof, comprises 5% to 55%, 5% to 50%, 5% to 45%, 5% to 40%, 5% to 35%, 5% to 30%, 10% to 55%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, at least 12% to 55%, at least 12% to 50%, at least 12% to 45%, at least 12% to 40%, at least 12% to 35%, or at least 12% to 30%, 15% to 55%, 15% to 50%, 15% to 45%, 15% to 40%, 15% to 35%, 15% to 30%, 15% to 25%, 15% to 20%, 20% to 55%, 20% to 50%, 20% to 45%, 20% to 40%, or 20% to 30% by weight EPA.","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, or at least 60% by weight DI-IA.","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, comprises 5% to 60%, 5% to 55%, 5% to 50%, 5% to 40%, 10% to 60%, 10% to 50%, 10% to 40%, 20% to 60%, 25% to 60%, 25% to 50%, 25% to 45%, 30% to 50%, 35% to 50%, or 30% to 40% by weight DHA.","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, comprises 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less by weight DHA.","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, comprises 1% to 10%, 1% to 5%, 2% to 5%, 3% to 5%, or 3% to 10% by weight of the fatty acids as DHA.","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, is substantially free of DHA.","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, comprises 0.1% to 5%, 0.1% to less than 5%, 0.1% to 4%, 0.1% to 3%, 0.1% to 2%, 0.2% to 5%, 0.2% to less than 5%, 0.2% to 4%, 0.2% to 3%, 0.2% to 2%, 0.3% to 2%, 0.1% to 0.5%, 0.2% to 0.5%, 0.1% to 0.4%, 0.2% to 0.4%, 0.5% to 2%, 1% to 2%, 0.5% to 1.5%, or 1% to 1.5% by weight ARA.","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, comprises 5% or less, less than 5%, 4% or less, 3% or less, 2% or less, 1.5% or less, 1% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, or 0.1% or less by weight ARA.","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, is substantially free of ARA.","In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, comprises 0.4% to 2%, 0.4% to 3%, 0.4% to 4%, 0.4% to 5%, 0.4% to less than 5%, 0.5% to 1%, 0.5% to 2%, 0.5% to 3%, 0.5% to 4%, 0.5% to 5%, 0.5% to less than 5%, 1% to 2%, 1% to 3%, 1% to 4%, 1% to 5%, or 1% to less than 5% by weight DPA n-6.In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, comprises 5%, less than 5%, 4% or less, 3% or less, 2% or less, 1% or less, 0.75% or less, 0.6% or less, or 0.5% or less by weight DPA n-6.In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, is substantially free of DPA n-6.In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, comprises fatty acids with 5% or less, less than 5%, 4% or less, 3% or less, or 2% or less by weight of oleic acid (18:1 n-9), linoleic acid (18:2 n-6), linolenic acid (18:3 n-3), eicosenoic acid (20:1 n-9), erucic acid (22:1 n-9), stearidonic acid (18:4 n-3), or combinations thereof.","In some embodiments, an extracted microbial lipid comprises at least 20% by weight eicosapentaenoic acid and less than 5% by weight each of arachidonic acid, docosapentaenoic acid n-6, oleic acid, linoleic acid, linolenic acid, eicosenoic acid, erucic acid, and stearidonic acid.","In some embodiments, an extracted microbial lipid comprises a triacylglycerol fraction of at least 10% by weight, wherein at least 12% by weight of the fatty acids in the triacylglycerol fraction is eicosapentaenoic acid, wherein at least 25% by weight of the fatty acids in the triacylglycerol fraction is docosahexaenoic acid, and wherein less than 5% by weight of the fatty acids in the triacylglycerol fraction is arachidonic acid.","In some embodiments, an extracted microbial lipid having any of the above fatty acid profiles has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","In some embodiments, an extracted microbial lipid having any of the above fatty acid profiles is extracted from an isolated thraustochytrid microorganism having the characteristics of the thraustochytrid species deposited under ATCC Accession No.","PTA-10208, PTA-10209, PTA-10210, PTA-10211, PTA-10212, PTA-10213, PTA-10214, or PTA-10215.In some embodiments, an extracted microbial lipid having any of the above fatty acid profiles is a crude lipid.","In some embodiments, the crude lipid has less than 5% by weight or volume of an organic solvent.","In some embodiments a microbial lipid extracted according to the processes of the present invention result in a lower anisidine value, and/or lower peroxide value, and/or lower phosphorus content than if extraction was performed using a typical hexane extraction or a FRIOLEX® process (Westfalia Separator AG, Germany).","In some embodiments, a lipid obtained by any of the processes of the present invention comprises at least 20% by weight eicosapentaenoic acid and less than 5% by weight each of arachidonic acid, docosapentaenoic acid n-6, oleic acid, linoleic acid, linolenic acid, eicosenoic acid, erucic acid, and stearidonic acid.","In some embodiments, a lipid obtained by any of the processes of the present invention comprises a triacylglycerol fraction of at least 10% by weight, wherein at least 12% by weight of the fatty acids in the triacylglycerol fraction is eicosapentaenoic acid, wherein at least 25% by weight of the fatty acids in the triacylglycerol fraction is docosahexaenoic acid, and wherein less than 5% by weight of the fatty acids in the triacylglycerol fraction is arachidonic acid.","In some embodiments, a lipid obtained by any of the processes of the present invention having any of the above fatty acid profiles has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, or 2 or less, or 1 or less and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","In some embodiments, a lipid obtained by any of the processes of the present invention having any of the above fatty acid profiles is extracted from an isolated thraustochytrid microorganism having the characteristics of the thraustochytrid species deposited under ATCC Accession No.","PTA-10208, PTA-10209, PTA-10210, PTA-10211, PTA-10212, PTA-10213, PTA-10214, or PTA-10215.In some embodiments, a lipid obtained by any of the processes of the present invention having any of the above fatty acid profiles is a crude lipid.","In some embodiments, the crude lipid has less than 5% by weight or volume of an organic solvent.","In some embodiments a lipid extracted according to the processes of the present invention result in a lower anisidine value, lower peroxide value, lower phosphorus content and/or a higher extraction yield if extraction was performed using a solvent (e.g., atypical hexane extraction or a FRIOLEX® process (Westfalia Separator AG, Germany)).","Lipids Extracted from an Isolated Microorganism of the Species Crypthecodinium cohnii In some embodiments, the present invention is further directed to a crude lipid extracted from a microorganism of the species Crypthecodinium cohnii.","In some embodiments, the method comprises growing a microorganism of the species Crypthecodinium cohnii in a culture to produce a biomass and extracting a lipid comprising omega-3 fatty acids from the biomass.","The lipid can be extracted from a freshly harvested biomass or can be extracted from a previously harvested biomass that has been stored under conditions that prevent spoilage.","Known methods can be used to culture a microorganism of the species Crypthecodinium cohnii, and to isolate a biomass from the culture.","See, e.g., U.S. Pat.","No.","7,163,811, incorporated by reference herein in its entirety.","The lipid can be extracted according to the processes of the present invention.","In some embodiments, the crude lipid extracted from a microorganism of the species Crypthecodinium cohnii according to the extraction methods of the present invention can have a lower phosphorus content compared to using a typical hexane extraction method.","In some embodiments, the crude lipid extracted from a microorganism of the species Crypthecodinium cohnii comprises a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.","In some embodiments, the crude oil has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, or 2 or less, or 1 or less and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less.","In some embodiments a crude microbial lipid extracted according to the processes of the present invention result in a lower anisidine value, lower peroxide value, lower phosphorus content and/or a higher extraction yield if extraction was performed using a solvent (e.g., atypical hexane extraction or a FRIOLEX® process (Westfalia Separator AG, Germany)).","Having generally described the invention, a further understanding can be obtained by reference to the examples provided herein.","These examples are given for purposes of illustration only and are not intended to be limiting.","The following examples are illustrative, but not limiting, of a process and a lipid prepared by a process of the present invention.","Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in extraction of a lipid from a cell, and which would become apparent to those skilled in the art, and are within the spirit and scope of the invention.","EXAMPLES Example 1 A cell broth (20,000 kg) containing microbial cells (Schizochytrium) was heated to 60° C. Enzymes (i.e., Alcalase 2.4 L FG 0.5%) were added to the cell biomass to lyse the cells and form an emulsified lysed cell composition.","The emulsified lysed cell composition was first treated with a first base (NaOH, 250 kg of 50% w/w solution) until the pH of the lysed cell composition was from 10.4 to 10.6.Next, a salt (solid NaCl, in an amount of 2%, by weight, of the lysed cell composition) was added to the lysed cell composition.","The lysed cell composition was then heated to a temperature of 85° C. to 102° C. and held at that temperature level for 24 hours to 70 hours.","A second base (NaOH, 50% w/w solution, 40 kg) was then added to the lysed cell composition until the pH was above 8.The lysed cell composition was then centrifuged to separate the lysed cell composition into three phases: a top phase containing a lipid layer, a middle phase containing an emulsion layer, and a bottom phase containing a solid layer.","The lysed cell composition was then centrifuged at 40° C. to 80° C. using a Westfalia RSE110 Centrifuge (Westfalia Separator Industry GmbH, Germany), operating at 6,000 rpms at a feed rate of 30 kg/min to separate a lipid from the lysed cell composition.","The centrifuging provided three phases: an upper phase containing a lipid, a middle phase containing an emulsion, and a bottom phase containing a solid/liquid emulsion.","The pH of the lysed cell composition was maintained at 7.5 to 8.5 during the centrifuging.","The total time to centrifuge the entire 20,000 kg batch was approximately 10 to 11 hours.","The lipid layer was separated and had a moisture content of approximately 1% by weight.","Example 2 A cell broth (500 g) containing microbial cells (Crypthecodinium cohnii) was concentrated from approximately 7% biomass to 13.5% biomass, by weight of the broth.","The broth was homogenized at a pressure of 10,000 psi (2 passes) to form a lysed cell composition.","The lysed cell composition was treated with a base (i.e., NaOH, 10 g of a 50% w/w solution) until the pH of the lysed cell composition was 10.4 to 10.6.A salt (solid NaCl, in an amount of 2% by weight of the lysed cell composition) was added to the lysed cell composition.","The lysed cell composition was then heated to a temperature of 85° C. to 92° C. and held at that temperature range for 15 minutes to 2 hours.","The lysed cell composition was then centrifuged at a temperature of 70° C. to 90° C. using a Bench Top Sigma 6K15 Centrifuge (SIGMA Laborzentrifugen GmbH, Germany), operating at 5,400 rpm to separate the lysed cell composition into three phases: an upper phase containing a lipid, a middle phase containing an emulsion, and a bottom phase containing a solid/liquid emulsion.","The pH of the lysed cell composition during centrifuging was maintained at 6.5 to 8.5.The total time to centrifuge was 5 minutes.","The lipid layer was separated and had a moisture content of approximately 1% by weight.","Example 3 A cell broth (20,000 kg) containing microbial cells (Schizochytrium) was heated to 60° C. Enzymes (i.e., Alcalase 2.4 L FG 0.5%) were added to the cell biomass to lyse the cells and form a lysed cell composition.","Next, a salt (solid Na2SO4, 2,000 kg, or 10%, by weight, of the lysed cell composition) was added to the lysed cell composition.","The lysed cell composition was then agitated for 24 hours to 48 hours at room temperature.","The lysed cell composition was then centrifuged at 40° C. to 75° C. using a Westfalia RSE110 Centrifuge (Westfalia Separator Industry GmbH, Germany), operating at 6,000 rpm at a feed rate of 40 kg/min to separate a lipid from the lysed cell composition.","The centrifuging provided three phases: an upper phase containing a lipid, a middle phase containing an emulsion, and a bottom phase containing a solid/liquid emulsion.","The total time to centrifuge the entire 20,000 kg batch was approximately 8 to 9 hrs.","The lipid layer was separated from the centrifuged lysed cell composition.","Example 4 A pasteurized cell broth (500 g) containing microbial cells (ATCC Accession No.","PTA-10208) was provided.","Enzymes (i.e., Alcalase 2.4 L FG 0.5%) were added to the cell biomass to lyse the cells and form an emulsified lysed cell composition.","The emulsified lysed cell composition was treated with a first base (i.e., a 25% solution of NaOH) to adjust the pH of the lysed cell composition to 10.5.Next, a salt (solid NaCl, in an amount of 2%, by weight, of the lysed cell composition) was added to the lysed cell composition.","The lysed cell composition was then heated to a temperature of 95° C. and held at that temperature level for 2 hours while agitating the lysed cell composition.","A second base (i.e., a 25% solution of NaOH) was then added to the lysed cell composition until the pH was 8.3.The lysed cell composition was then centrifuged at 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer and a small emulsion layer.","Example 5 A cell broth (500 g) that was concentrated and pasteurized containing microbial cells (ATCC Accession No.","PTA-9695) was provided.","Enzymes (i.e., Alcalase 2.4 L FG 0.5%) were added to the cell biomass to lyse the cells and form an emulsified lysed cell composition.","The emulsified lysed cell composition was treated with a base (i.e., a 25% solution of NaOH) to adjust the pH of the lysed cell composition to 10.5.Next, a salt (solid NaCl, in an amount of 2%, by weight, of the lysed cell composition) was added to the lysed cell composition.","The lysed cell composition was then heated to a temperature of 95° C. and held at that temperature level for 1 hour while agitating the lysed cell composition and the pH dropped to 8.5.After an hour in the fermentation broth having a total of 10 ml, there was an about 1 ml layer of oil (lipid) and an about 6 ml layer of emulsion.","The lysed cell composition was heated for a total of 220 minutes and the emulsion layer started to disappear.","The lysed cell composition was then centrifuged at 5,100 rpm for 5 minutes to separate the lysed cell composition.","The extraction yield of the lipid was 58.8 by weight % The anisidine value (AV) of the crude oil was 11.3.The cell breakage yield was in a range of 93% to 95% by weight.","Example 6 A pasteurized cell broth (473 g) containing microbial cells of the isolated thraustochytrid deposited under ATCC Accession No.","PTA-9695 was provided.","Enzymes (i.e., Alcalase 2.4 L FG 0.5%) were added to the cell biomass to lyse the cells and form an emulsified lysed cell composition.","The emulsified lysed cell composition was treated with a first base (i.e., a 25% solution of NaOH) to adjust the pH of the lysed cell composition to 10.62.Next, a salt (solid NaCl, in an amount of 2%, by weight, of the lysed cell composition) was added to the lysed cell composition.","The lysed cell composition was then heated to a temperature of 95° C. and held at that temperature level for 3 hours while agitating the lysed cell composition.","A second base (i.e., a 25% caustic solution of NaOH) was then added to the lysed cell composition until the pH was 8.13.The lysed cell composition was then centrifuged at 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer and an emulsion layer in equal amounts.","In order to determine if raising the pH increased the yield of the lipid layer, additional second base (i.e., a 25% solution of NaOH) was added to the separated lysed cell composition until the pH was 9.02 and the lysed cell composition was again centrifuged at 5,100 rpm for 5 minutes.","This resulted in a similar yield of lipid layer.","Additional second base was added again to the separated lysed cell composition until the pH was 10.12 and the lysed cell composition was again centrifuged at 5,100 rpm for 5 minutes.","Again, this resulted in a similar yield of lipid layer.","Example 7 A pasteurized cell broth (470 g) containing microbial cells (ATCC Accession No.","PTA-9695) was provided.","The cell biomass was mechanically homogenized to lyse the cells and form an emulsified lysed cell composition.","The emulsified lysed cell composition was treated with a first base (i.e., a 25% solution of NaOH) to adjust the pH of the lysed cell composition to 10.5.Next, a salt (solid NaCl, in an amount of 2%, by weight, of the lysed cell composition) was added to the lysed cell composition.","The lysed cell composition was then heated to a temperature of 95° C. and held at that temperature level for 3 hours while agitating the lysed cell composition.","A second base (i.e., a 25% solution of NaOH) was then added to the lysed cell composition until the pH was 8.07.The lysed cell composition was then centrifuged at 5400 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer and an emulsion layer wherein the emulsion layer was larger than the lipid layer.","In order to determine if raising the pH increased the yield of the lipid layer, additional second base was added to the separated lysed cell composition until the pH was 9.11 and the lysed cell composition was again centrifuged at 5,100 rpm for 5 minutes.","This resulted in a similar yield of lipid layer.","Additional second base was added again to the separated lysed cell composition until the pH was 10.09 and the lysed cell composition was again centrifuged at 5,100 rpm for 5 minutes.","Again, the resulted in a similar yield of lipid layer.","Example 8 A cell broth containing microbial cells (Crypthecodinium cohnii) was used in a decreased biotin trial fermentor.","20,000 kg of washed, concentrated, and pasteurized broth was harvested.","This was pulled out at the startup of pasteurization.","It was held for approximately 1 day before being transferred and homogenized.","The material was homogenized at 813 bar/one pass and collected back into a treatment tank.","Through microscopic inspection, it was estimated that approximately 80% of the cells were lysed.","The broth was heated to about 40° C. before treatment began.","The pH was adjusted to 10.5 and 2% NaCl was added and heated to 66° C. At this point a significant oil layer had already formed and the pH had dropped to 9.5 after 1-2 hours.","The broth was held at 66° C. overnight.","The next day, the broth was centrifuged on the Westfalia RSE-110 with a 155 mm ring dam installed.","The viscosity was about 180 cP at 40° C. The centrifuge was fed at 48 kg/min, with 5-10 psi backpressure on the light phase and 30 psi backpressure on the heavy phase.","The feed temperature was maintained at 70° C. No oil was present in the waste phase and only a few drops were visible after isopropyl alcohol was added.","Table 1 shows the results of analyses performed on the crude oil obtained from this procedure.","TABLE 1 Specifications of crude oil obtained using process of Example 8.% Oil 87.79 DHA (mg/g) 531.02 % DHA 60.49 PV 1.95 (0.6*) AV 15 % FFA 0.18 Phosphorus (ppm) 8.65 Copper (ppm) 0.22 Iron (ppm) 0.7 Lead (ppm) 0.63 *PV of the centrifuged oil.","Of the 20,000 kg of broth provided, 10.5% by weight (2,100 kg) was biomass.","Of the biomass, 50% by weight was oil (1,050 kg).","Of the oil, 58.9% by weight was DHA (618 kg).","After running the process described above, there was 592.5 kg of material in the lipid layer, of which about 87.8% by weight (520.2 kg) was oil.","Thus, the extraction yield of oil from the biomass was 49.5%.","Of that oil, 60.5% by weight (314.6 kg) was DHA, thereby resulting in an extraction yield of 51% by weight DHA from the biomass.","Example 9 A cell broth (about 500 g) that was washed, concentrated, and pasteurized containing microbial cells (Schizochytrium) was provided.","The broth was chemically treated with a base (i.e., a 25% solution of NaOH) without a prior cell lysis step.","The addition of the base raised the pH of the broth from 5.8 to 11.2.The addition of the base and the rise in the pH lysed the cells to form a lysed cell composition.","Next, a salt (solid Na2SO4, in an amount of 5%, by weight, of the lysed cell composition) was added to the lysed cell composition.","The lysed cell composition was then heated to a temperature in a range of 90° C. to 95° C. and held at that temperature level for 90 minutes and the pH of the lysed cell composition dropped to 9.7.After the 90 minutes there was an about 2.5 ml of oil layer per 45 ml of fermentation broth and there was no moisture loss.","After 3 hours, the pH had dropped to 9.2.The solution was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer.","The extraction yield of the lipid was 81% by weight.","The anisidine value (AV) of the crude oil was 20.1.The cell breakage yield was in a range of 92% to 98% by weight.","Example 10 A cell broth (about 500 g) that was washed, concentrated, and pasteurized containing microbial cells (Schizochytrium) was provided.","The broth was chemically treated with a base (i.e., a 25% solution of NaOH) without a prior cell lysis step.","The addition of the base raised the pH of the broth from 4.8 to 11.The addition of the base and the rise in the pH lysed the cells to form a lysed cell composition.","Next, a salt (solid NaCl, in an amount of 2%, by weight, of the lysed cell composition) was added to the lysed cell composition.","The lysed cell composition was then heated to a temperature in a range of 90° C. to 95° C. and held at that temperature level for 3.5 hours and the pH of the lysed cell composition dropped to 8.7 and there was no moisture loss.","The solution was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer.","The extraction yield of the lipid after 3.5 hours was 92% by weight.","A portion of the lysed cell composition was held for 6 hours and the pH of the lysed cell composition dropped to 8.6.The solution was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer.","The extraction yield of the lipid after 6 hours was 89% by weight.","The anisidine value (AV) of the crude oil was 14.4.The cell breakage yield was 95% by weight.","Example 11 A cell broth (about 500 g) that was washed, concentrated, and pasteurized containing microbial cells (Schizochytrium) was provided.","The broth was chemically treated with a base (i.e., a 50% solution of NaOH) without a prior cell lysis step.","The addition of the base raised the pH of the broth from 5.8 to 11.2.The addition of the base and the rise in the pH lysed the cells to form a lysed cell composition.","The lysed cell composition was then heated to 70° C. under vacuum to reduce the water content from 88.7% to 85.5%.","During evaporation, the pH dropped to 10.36.The solution was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer.","The extraction yield of the lipid was 83.9% by weight.","The anisidine value (AV) of the crude oil was 10.5.The cell breakage yield was 93.17% by weight.","The process was repeated except the lysed cell composition was heated to 70° C. under vacuum to reduce the water content from 88.7% to 79.2%.","The extraction yield of the lipid was 87.5% by weight when the water content was reduced to 79.2% and the cell breakage yield was 92.3% by weight.","The process was also repeated to reduce the water content from 88.7% to 80.8%.","The extraction yield of the lipid was 90% by weight when the water content was reduced to 80.8% and the cell breakage yield was 95.9% by weight.","Example 12 A cell broth (about 500 g) that was washed, concentrated, and pasteurized containing microbial cells (Schizochytrium) was provided.","The broth was chemically treated with a base (i.e., a 50% solution of NaOH) without a prior cell lysis step.","The addition of the base raised the pH of the broth from 5.6 to 11.1.The addition of the base and the rise in the pH lysed the cells to form a lysed cell composition.","The lysed cell composition was then heated to 90° C. in a closed system for 40 minutes.","After the 40 minutes, there was an about 1 ml layer of oil (lipid) per 40 ml of fermentation broth.","The solution was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer.","The extraction yield of the lipid was 85.1% by weight.","The anisidine value (AV) of the crude oil was 16.3.The cell breakage yield was 97.6% by weight.","Example 13 A cell broth (about 500 g) that was washed, concentrated, and pasteurized containing microbial cells (Schizochytrium) was provided.","The broth was chemically treated with a base (i.e., a 50% solution of NaOH) without a prior cell lysis step.","The addition of the base raised the pH of the broth from 4.9 to 11.2.The addition of the base and the rise in the pH lysed the cells to form a lysed cell composition.","The lysed cell composition was then mixed at room temperature for 4 hours.","The solution was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a small lipid layer.","A portion of the lysed cell composition was mixed at room temperature for about 96 hours.","The solution was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a larger lipid layer.","The extraction yield of lipid was 61.4% by weight.","The anisidine value (AV) of the crude oil was 22.6.Example 14 A cell broth (about 500 g) that was washed, concentrated, and pasteurized containing microbial cells (ATCC Accession No.","PTA-9695) was provided.","The broth was chemically treated with a base (i.e., a 50% solution of NaOH) without a prior cell lysis step.","The addition of the base raised the pH of the broth from 5.6 to 11.1.The addition of the base and the rise in the pH lysed the cells to form a lysed cell composition.","The lysed cell composition was then heated in a range of 70° C. to 75° C. for 3 hours.","The solution was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer.","The extraction yield of the lipid was 84.4% by weight.","A portion of the lysed cell composition was heated for a total of 5 hours.","The solution was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a similar lipid layer.","The extraction yield of lipid was 87.3% by weight.","The cell breakage yield was 89.1% by weight.","Example 15 A cell broth (about 500 g) that was washed, concentrated, and pasteurized containing microbial cells (Schizochytrium) was provided.","The broth was chemically treated with a base (i.e., a 50% solution of NaOH) without a prior cell lysis step.","The addition of the base raised the pH of the broth from 7.3 to 11.The addition of the base and the rise in the pH lysed the cells to form a lysed cell composition.","Next, a salt (solid Na2SO4, in an amount of 5%, by weight, of the lysed cell composition) was added to the lysed cell composition.","The lysed cell composition was then heated to a temperature of 90° C. and held at that temperature level for 2 hours.","While maintaining a temperature of 90° C. for additional 2 to 4 hours, the vessel containing the lysed cell composition was opened to allow evaporation of water.","The solution was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer.","Extraction yield of the lipid was greater than 70% by weight.","The anisidine value (AV) of the crude oil was 11.6.Example 16 A cell broth (9,925 kg) containing microbial cells (ATCC Accession No.","PTA-9695) was provided.","The cell broth was diluted with water in a 1:1 ratio by weight to form a diluted broth of 20,000 kg.","The solid content of the broth prior to dilution was 16.13% by weight and after dilution was 8.25% by weight.","The diluted broth was mixed and centrifuged with a desludging centrifuge at 6,400 rpm to remove extracellular water-soluble or water-dispersible compounds.","The concentrate (10,250 kg) from the centrifuge was collected and had a solids content of 10.5% by weight.","The collected concentrate was heated to 62° C. to 64° C. to pasteurize the concentrate.","Enzymes (i.e., Alcalase 2.4 L FG 0.5%) were added to the pasteurized concentrate to lyse the cells and form an emulsified lysed cell composition.","The emulsified lysed cell composition was treated with a base (i.e., a 25% solution of NaOH) to adjust the pH of the lysed cell composition to 11.Next, a salt (solid Na2SO4, in an amount of 5%, by weight, of the lysed cell composition) was added to the lysed cell composition.","The lysed cell composition was then heated to a temperature of 95° C. and held at that temperature level for 10 hours to 12 hours while agitating the lysed cell composition.","After agitation, the pH of the lysed cell composition was 8.6 and there was a very small emulsion layer.","The agitation tank was allowed to cool to 60° C. and the pH of the lysed cell composition increased to 9.6 while cooling.","The pH of the lysed cell composition was lowered to 8.2 by adding phosphoric acid.","The addition of the phosphoric acid did not harm the separation of the lipid layer and the very small emulsion layer.","The lysed cell composition was then centrifuged at 5,100 rpm at a feed rate of 48 kg/min for 5 minutes at 60° C. to 63° C. to separate the lysed cell composition and yield a lipid layer having a moisture content of 1.7% to 2.3% by weight.","Example 17 A cell broth (500 g) that was washed, concentrated, and pasteurized containing microbial cells (Crypthecodinium cohnii) was provided.","The broth was homogenized at a pressure of 8,000 to 12,000 psi (2 passes) to form a lysed cell composition.","The lysed cell composition was treated with a base (i.e., a 12.5% solution of NaOH) until the lysed cell composition reached a pH of 7.8 to 8.2.A salt (solid Na2SO4, in an amount of 5% by weight of the lysed cell composition) was added to the lysed cell composition.","The lysed cell composition was then heated to a temperature of 60° C. and held at that temperature.","The pH of the lysed cell composition was maintained at the 7.8 to 8.2 level by the addition of base (i.e., a 12.5% solution of NaOH) for 10 to 15 hours in a closed system with little to no moisture loss.","The lysed cell composition was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield an oil layer.","This resulted in an oil layer of about 2 ml in a sample of 40 ml.","The extraction yield of the oil was 73% by weight.","The anisidine value (AV) of the crude oil was 13.5.The cell breakage yield was 82% to 86% by weight.","Example 18 A pasteurized cell broth (1,000 g) containing microbial cells (Schizochytrium) was provided.","Enzymes (i.e., Alcalase 2.4 L FG 0.5%) were added to the cell biomass to lyse the cells and form an emulsified lysed cell composition.","The emulsified lysed cell composition was treated with a base (i.e., a 12.5% solution of NaOH) to adjust the pH of the lysed cell composition from 7.21 to 10.52.Next, a salt (solid NaCl, in an amount of 2%, by weight, of the lysed cell composition) was added to the lysed cell composition.","The broth was then separated into 4 portions with each portion being held at 4 different temperatures and times: 1) Trial #1 was held at 90° C. for 22 hours; 2) Trial #2 was held at 90° C. for 2 hours and then held at 25° C. for 20 hours; 3) Trial #3 was held at 60° C. for 22 hours; and 4) Trial #4 was held at 25° C. for 22 hours.","The individual trials were then centrifuged without further pH adjustment.","For Trials #1, #2, and #3, the broth was centrifuged at approximately 6,600 rpm (a g-force of 4,800) for 5 minutes to separate the lysed cell composition.","Because the separation for Trial #4 was not good (<20%) at a g-force of 4,800, the g-force was increased to 15,000 and the broth was spun at a g-force of 15,000 for 5 minutes.","The extraction yield of the lipid as a weight percent and the anisidine value (AV) are listed in the table below.","TABLE 2 Conditions and Results When Varying Temperature and Heating Time of the Lysed Cell Composition.","Treatment Time Centrifugation Oil Yield Trial # and Temp.","Conditions AV (%) 1 90° C. for 22 hours pH = 6.22 58.7 51.4 g-force = 4,800 2 90° C. for 2 hours, pH = 8.19 109.2 82.2 25° C. for 20 hours g-force = 4,800 3 60° C. for 22 hours pH = 8.38 91.2 27.2 g-force = 4,800 4 25° C. for 22 hours pH = 10.03 105.2 55.7 g-force =15,000 The anisidine values in Table 2 were higher than expected.","One difference between previous examples and this example was that the lysed cell composition was allowed to sit for a long period of time before the lipids were extracted.","It is hypothesized that the long period of time before extraction leads to the oxidation of the dissolved oxygen present in the lysed cell composition.","The increased oxidation then leads to an increase in the anisidine value.","The fact that the trial heated at the highest temperature for the longest time (Trial #1) had the lowest anisidine value supports this hypothesis because the dissolved oxygen content of a lysed cell composition generally decreases as the temperature is increased.","The increased anisidine values are therefore believed to be an anomaly that was a result of the delay in extracting the lipids from the lysed cell composition.","In production, there would be no delay time in extracting the lipids from the lysed cell composition and the anisidine values would be consistent with previous results of anisidine values of 26 or less.","Example 19 A pasteurized cell broth (1,000 g) containing microbial cells (Schizochytrium) was provided.","The broth was then split into 3 portions and diluted as follows: 1) Trial #1 was not diluted at all and served as the control portion; 2) Trial #2 was diluted 25% with water; and 3) Trial #3 was diluted 50% with water.","Enzymes (i.e., Alcalase 2.4 L PG 0.5%) were added to the cell biomass to lyse the cells and form an emulsified lysed cell composition.","The emulsified lysed cell composition was treated with a base (i.e., a 12.5% solution of NaOH) to adjust the pH of the lysed cell composition from 6.8 to 10.6.Next, a salt (solid NaCl, in an amount of 2%, by weight, of the lysed cell composition) was added to the lysed cell composition.","The broth was then heated to 90° C. and held for 20 hours.","After the hold time, the broth for each trial was separated into two with one half being centrifuged as is and the other half having its pH adjusted to approximately 8.5 before centrifugation.","Both portions were then centrifuged at approximately 8,545 rpm (a g-force of 8,000) for 5 minutes.","The extraction yield of the lipid as a weight percent and the anisidine value (AV) are listed in the table below.","TABLE 3 Conditions and Results When Varying Dilution of the Pasteurized Broth.","Centrifugation Trial # Diluted?","Conditions AV Oil Yield (%) 1 No dilution pH = 6.0 51.8 81.2 g-force = 8,000 1a No dilution pH = 8.4 44.3 78.1 g-force = 8,000 2 25% dilution pH = 5.5 76.1 88.9 with water g-force = 8,000 2a 25% dilution pH = 8.4 85.3 82.1 with water g-force = 8,000 3 50% dilution pH = 5.7 68.5 85.0 with water g-force = 8,000 3a 50% dilution pH = 8.5 79.6 84.0 with water g-force = 8,000 The anisidine values in Table 3 were higher than expected.","One difference between previous examples (excluding Example 18) and this example was that the lysed cell composition was allowed to sit for a long period of time before the lipids were extracted.","It is hypothesized that the long period of time before extraction leads to the oxidation of the dissolved oxygen present in the lysed cell composition.","The increased oxidation then leads to an increase in the anisidine value.","The increased anisidine values are therefore believed to be an anomaly that was a result of the delay in extracting the lipids from the lysed cell composition.","In production, there would be no delay time in extracting the lipids from the lysed cell composition and the anisidine values would be consistent with previous results of anisidine values of 26 or less.","Example 20 Cell broths obtained from various fermentation lots were treated using the process described in Example 2 except the timing of adding the salt (e.g., before and after homogenization) and the amount of salt were varied.","The resulting separated lipids were analyzed and the analyses are provided in Table 4.TABLE 4 Specifications of lipids obtained using processes of the present invention varying the timing of salt addition and the amount of salt added.","Fermentation Lot P2137 P2137 P4167 P4167 P2137 P2137 Addition of Before Before After After After After NaCl* % NaCl by 2 5 2 5 5 5 weight % Lipid* 27 37 51 72 59 15 % Starting 13 12.9 19.2 19.2 13.3 7.5+ Solids by weight % Solids by 19.7 21.7 19.7 20.1 20.2 8.6 weight before Centrifugation *Addition of NaCl was before or after homogenization; % lipid refers to the percentage of lipids in triglyceride form +This run was diluted to have a low percentage of starting solids.","The data provided in Table 4 demonstrates that adding the salt after homogenization results in higher % lipid values than adding the salt before homogenization.","The data provided in Table 4 also demonstrates that diluting the sample resulted in lower a % lipid value.","Example 21 A sample of Alcalase enzyme treated lysed cell composition obtained from microbial cells (Schizochytrium) was used.","The sample had a pH of approximately 5.5.The sample was divided into 4 smaller samples and the pH of three of the samples was adjusted to approximately 7.4, approximately 10.5, and approximately 12, respectively, by adding sodium hydroxide.","The samples were diluted in a 1:1 ratio with deionized water.","POBN (α-(4-Pyridyl 1-oxide)-N-tert-butylnitrone, 1.25 M; 50 μL) was added as a spin trap chemical to 0.5 g of each of the diluted samples.","The samples were measured with a Bruker BioSpin c-scan EPR (Electron Paramagnetic Resonance) spectrometer (system number SC0274) (Bruker BioSpin, Billerica, Mass.)","to measure the amount of free radicals present from lipid oxidation.","The samples were incubated at room temperature (20° C.) and 50 μL of each of the POBN containing samples was tested at hourly intervals for four hours after adjusting the pHs using the following spectrometer parameters: modulation frequency of 86 Hz, modulation amplitude of 2.11 gauss, microwave power of 5.19 mW, time constant of 20.48 seconds, sweep time of 10.49 seconds, sweep width of 100 gauss, and a number of scans of 8.The results of the EPR spectrometer readings are provided in FIG.","5.The data in FIG.","5 demonstrates that initially the level of free radicals was highest for the sample at pH 5.5 and lowest for the samples at pH 10.5 and 12.The data also demonstrates that over the 4 hour period the rate of radical formation was slowest for the sample at pH 10.5 and highest for the sample at pH 5.5.The data also demonstrates that the addition of a base to the lysed cell composition inhibits lipid oxidation, and therefore leads to a low AV in the crude lipid and refined oil.","Example 22 Oilseeds are extracted from a rapeseed plant and are then passed through a grinding mill to crack and break the outer hull of the oilseeds.","The oilseeds are then dehulled through known means, such as through aspiration, to remove the meat (interior) of the seeds from the hull of the oilseeds.","The dehulled oilseeds are then homogenized or expelled by passing them through a press to grind the dehulled oilseeds into a cake in order to lyse the cells of the oilseeds.","Water is added to form an emulsified lysed cell composition.","The emulsified lysed cell composition is filtered to remove any excess hull fragments from the lysed cell composition.","The emulsified lysed cell composition is treated with a base (i.e., a 25% solution of NaOH) to adjust the pH of the lysed cell composition to 11.Next a salt (solid NaCl, in an amount 2% by weight of the lysed cell composition) is added to the lysed cell composition.","The lysed cell composition is then heated to a temperature of 90° C. and held at that level for 6 hours to 48 hours while agitating the lysed cell composition.","The lysed cell composition is then centrifuged at 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer and an emulsion layer.","Example 23 Comparative Analysis of Crude Lipids Obtained by Hexane Extraction The crude lipids obtained from a lot using the process described in Example 2 was analyzed to determine various specifications.","Additional crude lipids were obtained using a typical hexane extraction process on the same microbial cell utilized in Example 2.The hexane extraction process included spray drying a fermentation broth, adding hexane to the spray dried biomass to obtain a solution of 15% to 20% solids by weight.","The solution was then homogenized to lyse the cells to form a lysed cell composition.","The lysed cell composition was centrifuged and a layer containing lipid and hexane was removed.","The hexane was then removed from the lipid.","The results of the analyses are provided in Table 5.TABLE 5 Specifications of lipids obtained using processes of the present invention or a hexane extraction process.","Fermentation Lot A B C D E F G Extraction Method Ex.","2 Hexane Hexane Hexane Hexane Hexane Hexane AV* 5.9 ND ND ND 14.7 17.18 6.7 PV* 1.21 0.65 1.56 0.46 ND 0.85 0.3 % Lipid* 89.61 86.94 84.31 86.75 85.53 86.05 86.54 DHA (mg/g) 537.47 508.15 459.32 465.31 510.49 495.82 506.33 % DHA* 59.98 58.39 54.49 53.65 59.71 57.68 58.51 *AV = Anisidine Value; PV = peroxide value; % lipid refers to the percentage of lipids in triglyceride form; % DHA refers to the percentage of DHA in the lipid The data provided in Table 5 demonstrates that the crude lipids obtained by the processes of the present invention exhibit superior anisidine values, percentage of lipid, amount of DHA and percentage of DHA compared to lipids prepared by typical hexane extraction processes.","Comparative Analysis of Crude Lipids Obtained by the FRIOLEX® Processes Example 24 The crude lipids obtained from various fermentation lots using the processes described in Examples 1 and 3 were analyzed to determine various specifications.","Additional crude lipids were obtained using a FRIOLEX® process (Westfalia Separator AG, Germany), which is a process of extracting lipids with a water-soluble organic solvent as described in U.S. Pat.","No.","5,928,696 and International Pub.","Nos.","WO 01/76385 and WO 01/76715.The results of the analyses are provided in Table 6.TABLE 6 Specifications of lipids obtained using processes of the present invention or a FRIOLEX ® process.","Fermentation Lot A B B B B C C C Extraction Method Ex.","1 Ex.","1 Ex.","3 Ex.","1a Ex.","1b Ex.","1 Ex.","1 FRIOLEX ® AV* 3.1 1.6 3.9 300 7.1 3.5 4 36 PV* 1.8 0.17 0.14 6.16 0.34 0 0 0.35 % Lipid* 96.27 93.67 92.55 87.20 94.42 95.14 94.31 93.92 DHA (mg/g) 452.4 458.16 455.17 414.66 471.55 416.41 416.05 415.38 Extraction Yield (%) 93.5 87 ND 96 ND 94 94 94 *AV = Anisidine Value; PV = peroxide value; % lipid refers to the percentage of lipids in triglyceride form aThe lysed cell composition was not heated.","bThe lysed cell composition was allowed to stand for 3 weeks prior to extraction.","The data provided in Table 6 demonstrates that the crude lipids obtained by the processes of the present invention exhibit superior anisidine values (with the exception of the lipid obtained when the lysed cell composition was not heated) compared to lipids prepared by a FRIOLEX® process.","The lipids prepared by a process of the present invention exhibit anisidine values that are from 4.4% to 19.7% of the anisidine values of a lipid prepared using the FRIOLEX® process.","It is believed that a lipid prepared by a process of the present invention has increased stability.","For example, as shown in Table 6, a process of the present invention was used to extract a lipid from a lysed cell composition, wherein the lysed cell composition was allowed to stand for 3 weeks prior to the extraction process.","It is believed that the anisidine value of a lipid in a lysed cell composition increases with time, and thus, it would be expected that a lipid extracted from a 3 week old lysed cell composition have increased anisidine values.","However, as shown in Table 6, the lipid obtained from the 3 week old lysed cell composition using a process of the present invention had an anisidine value which was 19.7% of the anisidine value of a lipid prepared by the FRIOLEX® process.","Example 25 The crude lipids obtained from a broth of microbial cells (ATCC Accession No, PTA-9695) using the process described in Example 16 were analyzed to determine various specifications.","Additional crude lipids were obtained from a broth of microbial cells (ATCC Accession No.","PTA-9695) using a FRIOLEX® process (Westfalia Separator AG, Germany), which is a process of extracting lipids with a water-soluble organic solvent (e.g., isopropyl alcohol) as described in U.S. Pat.","No.","5,928,696 and International Pub.","Nos.","WO 01/76385 and WO 01/76715.The results of the analyses are provided in Table 7.TABLE 7 Crude Lipid Comparison Example 16 FRIOLEX ® % Oil 9.19 93.73 DHA (mg/g) 570.68 574.33 % DHA 62.1 61.27 % FFA 1.13 0.22 PV 0 0.74 AV 10 73.9 Iron (ppm) 0.11 0 Copper (ppm) 0.67 0.3 Lead (ppm) 0.21 0 Phosphorus (ppm) 5.22 7.20 Extraction yield (%) 61.4 45.3 The data provided in Table 7 demonstrates that the crude lipids obtained by the processes of the present invention exhibit superior anisidine values (AV) and peroxide values (PV) compared to lipids prepared by a FRIOLEX® process.","The data also demonstrates that the extraction yield of lipid obtained by the processes of the present invention are superior compared to the extraction yield of lipid obtained by a FRIOLEX® process.","Example 26 Refining of Crude Lipids Crude lipids were obtained using the processes outlined in Example 1 and a FRIOLEX® process.","The crude lipids were further processed by sequentially: 1) degumming and caustic refining; 2) bleaching; 3) chilled filtering; and 4) deodorizing with antioxidants.","The data for the crude lipids, caustic refined lipids, bleached lipids, and deodorized lipids are presented in Tables 8a and 8b.","A comparison of the refined oils is presented in Table 9.TABLE 8a Lipids obtained from the FRIOLEX ® process (Example 24) DHA Yield % Yield % Processing Step FFA % PV AV (mg/g) (Lipid) (DHA) Crude Lipid 0.28 0.37 33.6 413.6 N/A N/A Caustic Refined <0.1 0.29 — 416.4 85.7 86.3 Lipid Bleached Lipid <0.1 0.16 13.9 413.1 71.5 70.9 Filtered Lipid <0.1 0.19 13.3 424.86 70.3 76.0 Deodorized Lipid 0.06 <0.1 14.3 401.5 96.6 89.4 w/AOX* *AOX refers to antioxidants TABLE 8b Lipids obtained from an extraction process using NaCl (Example 1) DHA Yield % Yield % Processing Step FFA % PV AV (mg/g) (Lipid) (DHA) Crude Lipid 1.36 0 3.5 406.7 N/A N/A Caustic Refined <0.1 0.27 2.3 410.8 85.9 86.7 Lipid Bleached Lipid <0.1 0.16 0.8 404.3 97.0 95.5 Filtered Lipid <0.1 0.37 1.0 414.1 59.3 60.7 Deodorized Lipid 0.06 <0.1 1.8 379.9* 94.9 87.1 w/AOX *Note: Increased dilution with high oleic sunflower oil (HOSO) was the reason for the decrease in DHA (mg/g).","TABLE 9 Refined Oil Comparison FRIOLEX ® (Example 24) Example 1 DHA (mg/g) 401.5 379.9* % DHA 42.69 40.18 FFA % 0.06 0.06 PV <0.1 <0.1 AV 14.3 1.8 Iron (ppm) 0.05 <0.02 Copper (ppm) <0.02 <0.02 Lead (ppm) <0.1 <0.1 Arsenic (ppm) <0.1 <0.1 Mercury (ppm) <0.01 <0.01 % Moisture and volatiles <0.01 <0.01 Unsaponifiables (%) 1.17 1.33 Trans-fatty acid by IR (%) <1 <1 *Note: Increased dilution with HOSO was the reason for the decrease in DHA (mg/g).","The data provided in Table 8a, Table 8b, and Table 9 demonstrate that a refined oil prepared by a process of the present invention exhibits lower anisidine values compared to a refined oil prepared by the FRIOLEX® process.","Example 27 Sensory Profile Comparison The refined oils obtained in Example 26 were analyzed by a panel of 8 to 12 sensory analysts.","The sensory analysts rated various lipid specifications based on aroma, aromatics, and aftertaste to provide an “overall aroma intensity” for each lipid.","The Universal Spectrum descriptive analysis method was used to assess the aroma and aromatic characteristics of samples.","This method uses an intensity scale of 0-15, where 0=none detected and 15=very high intensity, to measure the aroma and aromatic attributes of the oils.","The results of the sensory data are provided in Table 10.The data provided in Table 10 demonstrates that a refined oil prepared by a process of the present invention exhibits superior sensory data compared to a refined oil prepared by the FRIOLEX® process.","As shown above, the lipids provided by the present invention had an overall aroma intensity of 3 and 2, whereas, the FRIOLEX® lipids provided an overall aroma intensity of 4 and 3, respectively.","Example 28 Comparative Example An extraction process for obtaining lipids from microorganisms without the use of an organic solvent is disclosed in U.S. Pat.","No.","6,750,048.A comparison of a refined oil obtained from a crude lipid prepared by a process of the present invention and a refined oil obtained from a crude lipid prepared by the extraction process disclosed in U.S. Pat.","No.","6,750,048 is provided in Table 11.TABLE 11 Comparative data for a lipid prepared by a process of the present invention (Example 1) and a lipid prepared by a process disclosed in U.S. Pat.","No.","6,750,048.Example 1 U.S. Pat.","No.","6,750,048 DHA (mg/g) 379.9 346 % DHA 40.18 37.3 FFA % 0.06 ND PV <0.1 0.46 AV 1.8 ND Iron (ppm) <0.02 0.26 Copper (ppm) <0.02 <0.05 Lead (ppm) <0.1 <0.20 Arsenic (ppm) <0.1 <0.20 Mercury (ppm) <0.01 <0.20 % Moisture and volatiles <0.01 0.02 Unsaponifiables (%) 1.33 ND Trans-fatty acid by IR (%) <1 ND The data provided in Table 11 demonstrates that a refined oil obtained from a crude lipid prepared by a process of the present invention exhibits superior properties compared to a refined oil obtained from a crude lipid prepared by the extraction process disclosed in U.S. Pat.","No.","6,750,048.Example 29 The isolated thraustochytrid (ATCC Accession No.","PTA-9695) was characterized for taxonomic classification.","Samples were collected from intertidal habitats during low tide.","Water, sediment, living plant material and decaying plant/animal debris were placed into sterile 50 ml tubes.","Portions of each sample along with the water were spread onto solid agar plates of isolation media.","Isolation media consisted of: 500 ml of artificial seawater, 500 ml of distilled water, 1 g of glucose, 1 g of glycerol, 13 g of agar, 1 g of glutamate, 0.5 g of yeast extract, 0.5 g casein hydrolysate, 1 ml of a vitamin solution (100 mg/L thiamine, 0.5 mg/L biotin, 0.5 mg B12), 1 ml of a trace mineral solution (PII metals, containing per liter: 6.0 g FeCl36H2O, 6.84 g H3BO3, 0.86 g MnCl24H2O, 0.06 g ZnCl2, 0.026 CoCl26H2O, 0.052 g NiSO4H2O, 0.002 g CuSO45H2O and 0.005 g Na2MoO42H2O), and 500 mg each of penicillin G and streptomycin sulfate.","The agar plates were incubated in the dark at 20-25° C. After 2-4 days the agar plates were examined under magnification, and colonies of cells were picked with a sterile toothpick and restreaked onto a fresh plate of media.","Cells were repeatedly streaked onto fresh media until contaminated organisms were removed.","Colonies from agar plates were transferred to petri dishes with half-strength seawater and (1 ml) of a suspension of autoclaved newly hatched brine shrimp larvae.","The brine shrimp larvae became heavily overgrown with clusters of sporangia after 2-3 days.","Released zoospores were biflagellate at discharge, swimming actively away from the mature sporangium, wall remnants of which are clearly visible (in phase contrast) after spore release.","Sporangia measured 12.5 μm to 25 μm in diameter, and zoospores were 2.5 μm to 2.8 μm×4.5 μm to 4.8 μm in size.","There were 8 to 24 spores per individual sporangium.","Settled zoospores enlarged and rapidly underwent binary divisions leading to tetrads, octads, and finally to clusters of sporangia.","Tetrad formation commenced at a very early stage prior to maturity of the sporangia.","These characteristics are in agreement with the genus Schizochytrium.","The isolated thraustochytrid (ATCC Accession No.","PTA-9695) was further characterized based on the similarity of its 18s rRNA gene to that of known species.","Total genomic DNA from the thraustochytrid (ATCC Accession No.","PTA-9695) was prepared by standard procedures (Sambrook J. and Russell D. 2001.Molecular cloning: A laboratory manual, 3rd edition.","Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.) and used for PCR amplification of the 18s RNA gene.","The PCR amplification of the 18s rRNA gene was carried out with primers previously described (Honda et.","al., J. Eukaryot.","Microbial.","46(6) 1999).","The PCR conditions with chromosomal DNA template were as follows: 0.2 μM dNTPs, 0.1 uM each primer, 8% DMSO, 200 ng chromosomal DNA, 2.5 U PfuUltra® II fusion HS DNA polymerase (Stratagene), and 1× PfuUltra® buffer (Stratagene) in a 50 μL total volume.","The PCR Protocol included the following steps: (1) 95° C. for 2 minutes; (2) 95° C. for 45 seconds; (3) 55° C. for 30 seconds; (4) 72° C. for 2 minutes; (5) repeat steps 2-4 for 40 cycles; (6) 72° C. for 5 minutes; and (7) hold at 6° C.: PCR amplification yielded a distinct DNA product with the expected size using chromosomal template described above.","The PCR product was cloned into the vector pJET1.2/blunt (Fermentas) according to the manufacturer's instructions, and the insert sequence was determined using supplied standard primers.","Table 12 shows a comparison of the 18s rRNA sequence from the thraustochytrid (ATCC Accession No.","PTA-9695) to DNA sequences in the National Center for Biotechnology Information (NCBI) electronic database.","Briefly, “% Identity” was determined by the scoring matrix “swgapdnamt” within the “AlignX” program of the VectorNTI program (Invitrogen), a standard for DNA alignment.","The “% Coverage” was taken from the results of a Basic Local Alignment Search Tool (BLAST) calculation from the NCBI electronic database and is the percent of the query length that is included in the aligned segments.","TABLE 12 Comparison of 18s rRNA Sequences % Identity % Coverage Thraustochytrids Calculation #1 Calculation #2 Thraustochytrium aggregatum (p) 98 90 Thraustochutriidae sp.","HU1 84 86 Thraustochutriidae sp.","8-7 84 91 Thraustochytrium multirudimentale 81 88 Thraustochutriidae sp.","PW19 81 85 Schizochytrium sp.","ATCC 20888 81 95 (p): indicates partial sequence As shown in Table 12, it was found that, in terms of % identity, the 18s rRNA gene sequence from the thraustochytrid (ATCC Accession No.","PTA-9695) is closely related, though not identical, to the 18s rRNA gene sequence of T. aggregatum provided in Honda, D. et al., J. Euk.","Micro.","46(6): 637-647 (1999).","The 18s rRNA sequence published for Thraustochytrium aggregatum is a partial sequence, with an approximately 71 DNA nucleotide gap in the middle of the sequence.","In terms of percent coverage, the 18s rRNA gene sequence of the isolate of the invention is more closely related to Schizochytrium sp.","ATCC 20888 than to T. aggregatum.","Highly conserved proteins such as actin and beta-tubulin have been widely used, along with 18s rRNA gene, as markers for assessing phylogenetic relationships between organisms (Baldauf, S. M. Am.","Nat.","154, S178 (1999)).","Total genomic DNA from the thraustochytrid (ATCC Accession No.","PTA-9695) was also used as a template for PCR amplification of both the actin and beta-tubulin genes.","The PCR amplification was carried out with primers designed to conserved regions from the actin and beta-tubulin DNA sequences from T. aggregatum.","The PCR conditions with chromosomal DNA template were as follows: 0.2 μM dNTPs, 0.1 uM each primer, 8% DMSO, 200 ng chromosomal DNA, 2.5 U Herculase® II fusion DNA polymerase (Stratagene), and 1× Herculase® buffer (Stratagene) in a 50 μL total volume.","The PCR Protocol included the following steps: (1) 95° C. for 2 minutes; (2) 95° C. for 30 seconds; (3) 55° C. for 30 seconds; (4) 72° C. for 2 minutes; (5) repeat steps 2-4 for 40 cycles; (6) 72° C. for 5 minutes; and (7) hold at 6° C. PCR amplification yielded distinct DNA products with the expected sizes using chromosomal template described above.","The respective PCR products were cloned into the vector pJET1.2/blunt (Fermentas) according to the manufacturer's instructions, and the insert sequence of each were determined using supplied standard primers.","Table 13 shows identities for the actin amino acid sequence from the thraustochytrid (ATCC Accession No.","PTA-9695) as compared to actin sequences available in the public database.","Identities were determined through use of the scoring matrix “blosum62mt2” within the “AlignX” program of the VectorNTI program, a standard for protein alignment.","TABLE 13 Comparison of Actin Protein Sequence % Identities Thraustochytrids % Identity Thraustochytriidae sp.","RT49 98 Schizochytrium sp.","ATCC 20888 96 Thraustochytrium striatum 96 Thraustochytrium aggregatum 96 Japonochytrium marinum 95 Thraustochytrium aureum 95 Table 14 shows identities for the beta-tubulin amino acid sequence from the thraustochytrid (ATCC Accession No.","PTA-9695) as compared to beta-tubulin sequences available in the public database.","Identities were determined through use of the scoring matrix “blosum62mt2” within the “AlignX” program of the VectorNTI program, a standard for protein alignment.","TABLE 14 Comparison of Beta-Tubulin Protein Sequence % Identities Thraustochytrids % Identity Aplanochytrium kerguelense 100 Aplanochytrium stocchinoi 100 Japonochytrium marinum 100 Labyrinthula sp.","N8 100 Thraustochytriidae sp.","RT49 100 Thraustochytrium aggregatum 100 Thraustochytriidae sp.","HU1 100 Thraustochytrium aureum 100 Thraustochytrium kinnei 100 Thraustochytriidae sp.","#32 100 Thraustochytriidae sp.","PW19 100 Schizochytrium aggregatum 100 Schizochytrium sp.","ATCC 20888 100 Based on the above characterizations, the isolated thraustochytrid (ATCC Accession No.","PTA-9695) is believed to represent a new Schizochytrium species and is therefore also designated as Schizochytrium sp.","ATCC PTA-9695.Example 30 The isolated thraustochytrid (ATCC Accession No.","PTA-9695) produced high levels of cell growth under varying culture conditions, as described below.","Typical media and cultivation conditions are shown in Table 15.Also, high levels of fatty acids and DHA were observed (i.e., greater than 50% by weight of the dry cell weight were fatty acids and greater than 50% by weight of the fatty acid methyl esters was DHA).","TABLE 15 Vessel Media Ingredient concentration ranges NaCl g/L 12.5 0-25, 5-20, or 10-15 KCl g/L 1.0 0-5, 0.25-3, or 0.5-2 MgSO4•7H2O g/L 5.0 0-10, 2-8, or 3-6 (NH4)2SO4 g/L 0.6 0-10, 0.25-5, or 0.5-3 CaCl2 g/L 0.29 0.1-5, 0.15-3, or 0.2-1 T 154 (yeast g/L 6.0 0-20, 1-15, or 5-10 extract) KH2PO4 g/L 1.2 0.1-10, 0.5-5, or 1-3 Post autoclave (Metals) Citric acid mg/L 3.5 0.1-100, 1-50, or 2-25 FeSO4•7H2O mg/L 10.30 0.1-100, 1-50, or 5-25 MnCl2•4H2O mg/L 3.10 0.1-100, 1-50, or 2-25 ZnSO4•7H2O mg/L 3.10 0.1-100, 1-50, or 2-25 CoCl2•6H2O mg/L 0.04 0.001-1, 0.005-0.5, or 0.01-0.1 Na2MoO4•2H2O mg/L 0.04 0.001-1, 0.005-0.5, or 0.01-0.1 CuSO4•5H2O mg/L 2.07 0.1-100, 0.5-50, or 1-25 NiSO4•6H2O mg/L 2.07 0.1-100, 0.5-50, or 1-25 Post autoclave (Vitamins) Thiamine mg/L 9.75 0.1-100, 1-50, or 5-25 Vitamin B12 mg/L 0.16 0.1-100, 0.1-10, or 0.1-1 Ca½-panto- mg/L 3.33 0.1-100, 0.1-50, or 1-10 thenate Post autoclave (Carbon) Glucose g/L 30.0 5-150, 10-100, or 20-50 Nitrogen Feed: NH4OH mL/L 21.6 0-150, 10-100, or 15-50 Typical cultivation conditions would include the following: pH about 6.5-about 8.5, about 6.5-about 8.0, or about 7.0-about 7.5 temperature: about 17-about 30 degrees Celsius, about 20-about 25 degrees Celsius, or about 22 to about 23 degrees Celsius dissolved oxygen: about 5-about 100% saturation, about 10-about 80% saturation, or about 20-about 50% saturation glucose about 5-about 50 g/L, about 10-about 40 g/L, or controlled @: about 20-about 35 g/L.","In carbon and nitrogen-fed cultures with 8200 ppm at 22.5° C. with 20% dissolved oxygen at pH 7.0, the isolate produced a dry cell weight of 140 g/L after 7 days of culture, with a fatty acid content of 70% by weight.","Closed loop ammonia feed was used and the pH was maintained at 7.0.The omega-3 productivity was 8.92 g/(L*day) under these conditions, with 4.7 g/L EPA (5% by weight of fatty acids) and 56.3 g/L DHA (57% by weight of fatty acids) in 7 days.","In carbon and nitrogen-fed cultures with 3640 ppm Cl− at 22.5° C. with 20% dissolved oxygen at pH 7.0, the isolate produced a dry cell weight of 82 g/L after 7 days of culture, with a fatty acid content of 58% by weight.","The omega-3 productivity was 4.5 g/(L*day) under these conditions, with 2.1 g/L EPA (4.3% by weight of fatty acids) and 28.5 g/L DHA (58.7% by weight of fatty acids) in 7 days.","In carbon and nitrogen-fed cultures with 980 ppm CF at 22.5° C. with 20% dissolved oxygen at pH 7.0, the isolate produced a dry cell weight of 60 g/L after 7 days of culture, with a fatty acid content of 53% by weight.","The omega-3 productivity was 2.8 g/(L*day) under these conditions, with 1.1 g/L EPA (3.4% by weight of fatty acids) and 18.4 g/L DHA (56.8% by weight of fatty acids) in 7 days.","Example 31 Oils were extracted from a biomass sample (Sample A) of the isolated thraustochytrid (ATCC Accession No.","PTA-9695).","The biomass sample was produced in a carbon and nitrogen-fed culture with 980 ppm Cl− at 22.5° C. with 20% dissolved oxygen at pH 7.0.Oils were extracted from biomass Sample A by the hexane extraction process to yield microbial oil Sample A1.Briefly, dried biomass was ground with hexane using stainless steel tubes and stainless steel ball bearings for approximately 2 hours.","The slurry was vacuum filtered and the filtrate was collected.","The hexane was removed using a rotary evaporator.","Oils were also extracted from biomass Sample A using the FRIOLEX® process (GEA Westfalia Separator UK Ltd., Milton Keynes, England) to yield microbial oil Sample A2.Individual lipid classes were isolated from microbial oil Samples A1 and A2 using low pressure flash chromatography, and the weight percent of each class was determined.","The fatty acid profile of each class was determined using gas chromatography with flame ionization detection (GC-FID) as fatty acid methyl esters (FAME).","Flash Chromatography— Flash chromatography was used to separate the lipid classes present in the crude oils, and to determine the weight percent of each class present in the oils.","The chromatography system utilized Silica Gel 60 (EMD Chemical, Gibbstown, N.J.) with mobile phase composed of Petroleum Ether and Ethyl Acetate at 3 mL/min.","A step gradient was used to selectively elute each lipid class from the column.","The mobile phase gradient started from 100% petroleum ether and finished with 50% ethyl acetate (followed by a 100% methanol wash).","Fractions were collected in 10 mL test tubes using a Gilson FC 204 large-bed fraction collector (Gilson, Inc., Middleton, Wis.).","Each tube was analyzed by thin layer chromatography (TLC) and the tubes containing individual lipid classes (as judged by single spots on TLC plate with expected retention factor (RI)) were pooled, concentrated to dryness, and weighed.","The total fraction content was then determined gravimetrically.","TLC Analysis— Thin layer chromatography was conducted on silica gel plates.","The plates were eluted using a solvent system consisting of petroleum ether:ethyl ether:acetic acid (80:20:1) and were visualized using iodine vapor.","The Rf values of each spot were then compared with reported literature values for each lipid class.","Fatty Acid Analysis— The samples of biomass and isolated lipid classes were analyzed for fatty acid composition as FAMEs.","Samples were weighed directly into screw cap test tubes, and 1 mL of C19:0 internal standard (NuCheck, Elysian, Minn.) in toluene and 2 mL of 1.5 N HCl in methanol was added to each tube.","The tubes were vortexed briefly and placed in a heating block for 2 hours at 100° C. The tubes were removed from the heating block, allowed to cool, and 1 mL of saturated NaCl in water was added.","The tubes were vortexed again, centrifuged, and a portion of the top (organic) layer was placed in a GC vial and analyzed by GC-FID.","FAME's were quantified using a 3-point internal standard calibration curve generated using Nu-Chek-Prep GLC reference standard (Nu-Chek Prep, Inc., Elysian, Minn.) and tentatively identified based on retention time.","Fatty acids present were expressed as mg/g and % of total FAME.","Sample A1 was prepared by dissolving the crude oil in hexane and applying to the head of the column.","After fractionation of the sample using flash chromatography, the sterol ester fraction accounted for 1.2% by weight, the triacylglycerol (TAG) fraction accounted for 82.7% by weight, the free fatty acid (FFA) fraction accounted for 0.9% by weight, and the diacylglycerol (DAG) fraction accounted for 2.9% by weight of the crude oil.","The total fatty acid profiles of the Sample A1 crude oil and isolated fractions are shown below in Table 16 and Table 17 calculated as mg/g and % FAME, respectively.","TABLE 16 Sample A1 Fatty Acid Profiles Calculated as Milligrams per Gram FAME Crude Sterol Biomass Oil Esters TAG FFA DAG Wt.","% NA 38% 1.2% 82.7% 0.9 2.9% FAME FAME FAME FAME FAME FAME Fatty Acid (mg/g) (mg/g) (mg/g) (mg/g) (mg/g) (mg/g) C12:0* 0.6 0.0 1.9 3.2 1.7 0.0 C14:0* 5.7 13.6 12.8 20.2 13.0 17.6 C14:1* 0.0 0.0 0.0 0.0 0.0 0.0 C15:0 1.3 3.4 3.1 3.1 2.1 2.6 C16:0* 105.5 239.5 222.2 274.3 183.3 225.1 C16:1* 0.0 0.0 0.8 0.0 0.8 0.0 C18:0* 6.4 16.4 43.1 16.8 9.8 14.0 C18:1 N9* 0.0 3.8 1.9 3.3 1.0 3.5 C18:1 N7 0.0 0.0 0.0 0.0 0.0 0.0 C18:2 N6* 0.0 0.0 0.0 0.0 0.0 0.0 C20:0* 1.8 5.5 13.0 4.7 2.0 2.9 C18:3 N3* 0.0 0.0 0.0 0.0 0.0 0.0 C20:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C18:4 N3 0.0 0.0 0.0 0.0 0.6 0.0 C20:2 N6* 0.0 0.0 0.0 0.0 0.0 0.0 C20:3 N6 0.0 0.0 0.0 0.0 0.0 0.0 C22:0* 0.0 0.8 7.3 0.8 0.0 1.2 C20:4 N7 0.0 0.0 0.8 0.0 0.0 0.0 C20:3 N3 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N6* 1.0 3.4 0.0 2.6 2.0 1.9 C22:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N5 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N3 1.5 4.1 1.5 3.5 2.1 2.1 C20:5 N3* 18.2 39.5 3.5 38.4 30.6 42.8 C24:0* 0.0 0.0 6.3 0.0 0.0 0.0 C22:4 N9 0.0 0.0 0.0 0.0 0.0 0.0 C24:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C22:5 N6* 11.9 29.5 8.9 26.9 14.8 18.7 C22:5 N3* 1.1 4.7 0.9 3.6 3.4 2.7 C22:6 N3* 253.5 569.7 107.3 556.5 352.8 451.4 Sum of 408.6 934.0 435.4 958.0 620.1 786.4 all FAME's TABLE 17 Sample A1 Fatty Acid Profiles as a Percent of Total FAME Crude Sterol Biomass Oil Esters TAG FFA DAG Fatty Acid % FAME % FAME % FAME % FAME % FAME % FAME C12:0* 0.1 0.0 0.4 0.3 0.3 0.0 C14:0* 1.4 1.5 2.9 2.1 2.1 2.2 C14:1* 0.0 0.0 0.0 0.0 0.0 0.0 C15:0 0.3 0.4 0.7 0.3 0.3 0.3 C16:0* 25.8 25.6 51.0 28.6 29.6 28.6 C16:1* 0.0 0.0 0.2 0.0 0.1 0.0 C18:0* 1.6 1.8 9.9 1.8 1.6 1.8 C18:1 N9* 0.0 0.4 0.4 0.3 0.2 0.4 C18:1 N7 0.0 0.0 0.0 0.0 0.0 0.0 C18:2 N6* 0.0 0.0 0.0 0.0 0.0 0.0 C20:0* 0.4 0.6 3.0 0.5 0.3 0.4 C18:3 N3* 0.0 0.0 0.0 0.0 0.0 0.0 C20:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C18:4 N3 0.0 0.0 0.0 0.0 0.1 0.0 C20:2 N6* 0.0 0.0 0.0 0.0 0.0 0.0 C20:3 N6 0.0 0.0 0.0 0.0 0.0 0.0 C22:0* 0.0 0.1 1.7 0.1 0.0 0.1 C20:4 N7 0.0 0.0 0.2 0.0 0.0 0.0 C20:3 N3 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N6* 0.3 0.4 0.0 0.3 0.3 0.2 C22:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N5 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N3 0.4 0.4 0.4 0.4 0.3 0.3 C20:5 N3* 4.5 4.2 0.8 4.0 4.9 5.4 C24:0* 0.0 0.0 1.4 0.0 0.0 0.0 C22:4 N9 0.0 0.0 0.0 0.0 0.0 0.0 C24:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C22:5 N6* 2.9 3.2 2.1 2.8 2.4 2.4 C22:5 N3* 0.3 0.5 0.2 0.4 0.5 0.3 C22:6 N3* 62.0 61.0 24.6 58.1 56.9 57.4 Sum of 100.0 100.0 100.0 100.0 100.0 100.0 FAME % Sample A2 was prepared by dissolving the crude oil in hexane and applying to the head of the column.","After fractionation of the sample using flash chromatography, the sterol ester fraction accounted for 0.8% by weight, the triacylglycerol (TAG) fraction accounted for 83.4% by weight, the free fatty acid (FFA) fraction accounted for 1.8% by weight, and the diacylglycerol (DAG) fraction accounted for 5.6% by weight of the crude oil.","The total fatty acid profiles of the Sample A2 crude oil and isolated fractions are shown below in Table 18 and Table 19 calculated as mg/g and % FAME, respectively.","TABLE 18 Sample A2 Fatty Acid Profiles Calculated as Milligrams per Gram FAME Crude Sterol Biomass Oil Esters TAG FFA DAG Wt.","% NA NA 0.8% 83.4% 1.8% 5.6% FAME FAME FAME FAME FAME FAME Fatty Acid (mg/g) (mg/g) (mg/g) (mg/g) (mg/g) (mg/g) C12:0* 0.6 0.0 0.0 1.5 0.0 1.0 C14:0* 5.7 13.2 8.9 14.1 9.5 5.4 C14:1* 0.0 0.0 0.0 0.0 0.0 0.0 C15:0 1.3 3.3 2.8 3.4 2.1 2.2 C16:0* 105.5 233.7 183.8 246.1 159.7 137.3 C16:1* 0.0 0.0 0.0 0.8 0.0 0.0 C18:0* 6.4 16.6 23.6 16.9 11.3 5.6 C18:1 N9* 0.0 7.6 5.0 4.3 2.4 2.6 C18:1 N7 0.0 0.0 0.0 0.0 0.0 0.0 C18:2 N6* 0.0 2.2 0.7 1.6 0.8 5.1 C20:0* 1.8 5.2 12.1 5.5 2.6 1.1 C18:3 N3* 0.0 0.0 0.0 0.0 0.0 0.0 C20:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C18:4 N3 0.0 0.0 0.0 0.8 1.0 0.0 C20:2 N6* 0.0 0.0 0.0 0.0 0.0 0.0 C20:3 N6 0.0 0.0 0.0 0.3 0.0 0.0 C22:0* 0.0 0.7 6.0 1.3 0.8 0.0 C20:4 N7 0.0 0.0 0.0 0.0 0.0 0.0 C20:3 N3 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N6* 1.0 3.0 0.0 3.1 2.3 1.2 C22:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N5 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N3 1.5 4.1 1.4 4.3 2.7 1.0 C20:5 N3* 18.2 38.6 2.7 38.6 39.5 45.5 C24:0* 0.0 0.0 4.7 0.6 0.0 0.3 C22:4 N9 0.0 0.0 0.0 0.0 0.0 0.0 C24:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C22:5 N6* 11.9 28.2 8.6 29.6 18.0 14.7 C22:5 N3* 1.1 3.4 0.0 3.5 2.5 2.2 C22:6 N3* 253.5 566.7 102.2 575.0 475.3 447.2 Sum of 408.6 926.5 362.3 951.3 730.4 672.5 all FAME's TABLE 19 Sample A2 Fatty Acid Profiles as a Percent of Total FAME Crude Sterol Biomass Oil Esters TAG FFA DAG Fatty Acid % FAME % FAME % FAME % FAME % FAME % FAME C12:0* 0.1 0.0 0.0 0.2 0.0 0.2 C14:0* 1.4 1.4 2.4 1.5 1.3 0.8 C14:1* 0.0 0.0 0.0 0.0 0.0 0.0 C15:0 0.3 0.4 0.8 0.4 0.3 0.3 C16:0* 25.8 25.2 50.7 25.9 21.9 20.4 C16:1* 0.0 0.0 0.0 0.1 0.0 0.0 C18:0* 1.6 1.8 6.5 1.8 1.5 0.8 C18:1 N9* 0.0 0.8 1.4 0.5 0.3 0.4 C18:1 N7 0.0 0.0 0.0 0.0 0.0 0.0 C18:2 N6* 0.0 0.2 0.2 0.2 0.1 0.8 C20:0* 0.4 0.6 3.3 0.6 0.4 0.2 C18:3 N3* 0.0 0.0 0.0 0.0 0.0 0.0 C20:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C18:4 N3 0.0 0.0 0.0 0.1 0.1 0.0 C20:2 N6* 0.0 0.0 0.0 0.0 0.0 0.0 C20:3 N6 0.0 0.0 0.0 0.0 0.0 0.0 C22:0* 0.0 0.1 1.7 0.1 0.1 0.0 C20:4 N7 0.0 0.0 0.0 0.0 0.0 0.0 C20:3 N3 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N6* 0.3 0.3 0.0 0.3 0.3 0.2 C22:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N5 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N3 0.4 0.4 0.4 0.4 0.4 0.2 C20:5 N3* 4.5 4.2 0.7 4.1 5.4 6.8 C24:0* 0.0 0.0 1.3 0.1 0.0 0.0 C22:4 N9 0.0 0.0 0.0 0.0 0.0 0.0 C24:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C22:5 N6* 2.9 3.0 2.4 3.1 2.5 2.2 C22:5 N3* 0.3 0.4 0.0 0.4 0.3 0.3 C22:6 N3* 62.0 61.2 28.2 60.4 65.1 66.5 Sum of 100.0 100.0 100.0 100.0 100.0 100.0 FAME % It is noted that Samples A1 and A2 were extracted using a typical hexane extraction and a FRIOLEX® process, respectively.","The fatty acid profiles of Tables 16-19 are expected to be the substantially the same if the samples were extracted using the processes of the present invention.","Example 32 After oil was extracted from the fermentation broth using the Friolex process, as described in Example 31, the crude oil was further processed via refining, bleaching, and deodorizing steps to obtain a final oil.","The final oil was diluted with high oleic sunflower oil to obtain finished commercial oil with a DHA content of approximately 400 mg/g.","Individual lipid classes were isolated and the fatty acid profiles of each class was determined using gas chromatography with flame ionization detection (GC-FID) as fatty acid methyl esters (FAME).","Flash Chromatography— Flash chromatography was used to separate the lipid classes present in the final oil, and to determine the weight percent of each class present in the oil.","The chromatography system utilized Silica Gel 60 (EMD Chemical, Gibbstown, N.J.) with mobile phase composed of Petroleum Ether and Ethyl Acetate at 3 mL/min.","A step gradient was used to selectively elute each lipid class from the column.","The mobile phase gradient started from 100% petroleum ether and finished with 50% ethyl acetate (followed by a 100% methanol wash).","Fractions were collected in 10 mL test tubes using a Gilson FC 204 large-bed fraction collector (Gilson, Inc., Middleton, Wis.).","Each tube was analyzed by thin layer chromatography (TLC) and the tubes containing individual lipid classes (as judged by single spots on TLC plate with expected retention factor (Rf)) were pooled, concentrated to dryness, and weighed.","The total fraction content was then determined gravimetrically.","TLC Analysis— Thin layer chromatography was conducted on silica gel plates.","The plates were eluted using a solvent system consisting of petroleum ether:ethyl ether:acetic acid (80:20:1) and were visualized using iodine vapor.","The Rf values of each spot were then compared with reported literature values for each lipid class.","Fatty Acid Analysis— The final oil sample and isolated lipid classes were analyzed for fatty acid composition as FAMEs.","Samples were weighed directly into screw cap test tubes, and 1 mL of C19:0 internal standard (NuCheck, Elysian, Minn.) in toluene and 2 mL of 1.5 N HCl in methanol was added to each tube.","The tubes were vortexed briefly and placed in a heating block for 2 hours at 100° C. The tubes were removed from the heating block, allowed to cool, and 1 mL of saturated NaCl in water was added.","The tubes were vortexed again, centrifuged, and a portion of the top (organic) layer was placed in a GC vial and analyzed by GC-FID.","FAME's were quantified using a 3-point internal standard calibration curve generated using Nu-Chek-Prep GLC reference standard (Nu-Chek Prep, Inc., Elysian, Minn.) and tentatively identified based on retention time.","Fatty acids present were expressed as mg/g and % of total FAME.","The sample was prepared by dissolving 250 mg of final oil in 600 μL of hexane and applying to the head of the column.","After fractionation of the sample using flash chromatography, the sterol ester fraction accounted for 1.2% by weight, the triacylglyceride (TAG) fraction accounted for 92.1% by weight, the free fatty acid (FFA) fraction accounted for 2.1% by weight, the sterol fraction accounted for 1.1%, the diacylglyceride (DAG) fraction accounted for 2.8% by weight of the final oil.","The TLC analysis of the pooled fractions showed that the FFA and sterol fractions were mixed with TAG and DAG respectively.","The total fatty acid profiles of the FRIOLEX® final oil and isolated fractions are shown below in Table 20 and Table 21 calculated as mg/g and % FAME, respectively.","TABLE 20 Fatty Acid Profile Calculated as Milligrams per Gram of FAME Final Sterol Oil Esters TAG FFA Sterol DAG Wt.","% NA 1.2 92.1 2.1 1.1 2.8 Fatty Acid FAME FAME FAME FAME FAME FAME (mg/g) (mg/g) (mg/g) (mg/g) (mg/g) (mg/g) C12:0* 0.0 0.0 1.0 0.0 1.2 0.6 C14:0* 11.5 5.1 11.3 6.0 9.6 5.7 C14:1* 0.0 0.0 0.0 0.0 0.0 0.0 C15:0 2.3 0.0 2.3 1.2 2.0 1.9 C16:0* 183.3 80.0 180.8 99.9 149.3 132.2 C16:1* 0.0 0.0 0.9 0.0 0.8 0.6 C18:0* 19.6 17.5 19.6 7.5 16.2 6.7 C18:1 N9* 243.3 242.8 249.6 62.9 190.5 84.0 C18:1 N7 1.9 1.7 2.0 0.8 1.9 0.9 C18:2 N6* 13.8 5.6 13.8 6.2 14.3 9.1 C20:0* 4.3 6.6 4.5 1.5 3.6 1.4 C18:3 N3* 0.0 0.0 0.3 0.0 0.0 0.0 C20:1 N9* 0.0 0.0 0.8 0.0 0.8 0.0 C18:4 N3 0.0 0.0 0.7 1.3 0.9 0.4 C20:2 N6* 0.0 0.0 0.6 0.0 0.0 0.0 C20:3 N6 0.0 0.0 0.3 0.0 0.0 0.0 C22:0* 3.3 61.0 3.2 1.1 3.0 1.2 C20:4 N7 0.0 0.0 0.0 0.0 0.0 0.0 C20:3 N3 0.0 0.0 0.0 0.0 0.0 0.0 C20:4N6* 1.7 0.0 2.3 1.4 1.9 1.3 C22:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N5 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N3 2.4 4.5 3.0 2.2 2.6 1.3 C20:5 N3* 28.1 3.0 27.7 38.6 25.6 43.2 C24:0* 1.4 64.3 1.4 0.0 2.0 1.0 C22:4 N9 0.0 0.0 0.0 0.0 0.0 0.0 C24:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C22:5 N6* 20.0 7.6 21.0 10.1 17.2 14.4 C22:5 N3* 2.8 0.0 3.1 3.7 3.4 2.9 C22:6 N3* 407.1 72.5 417.4 443.6 350.5 428.5 Sum of all 936.1 572.1 967.6 688.0 797.3 737.3 FAME's TABLE 21 Fatty Acid Profiles as a Percent of Total FAME Final Sterol Oil Esters TAG FFA Sterol DAG Fatty Acid % % % % % % FAME FAME FAME FAME FAME FAME C12:0* 0.0 0.0 0.1 0.0 0.2 0.1 C14:0* 1.2 0.9 1.2 0.9 1.2 0.8 C14:1* 0.0 0.0 0.0 0.0 0.0 0.0 C15:0 0.2 0.0 0.2 0.2 0.2 0.3 C16:0* 19.6 14.0 18.7 14.5 18.7 17.9 C16:1* 0.0 0.0 0.1 0.0 0.1 0.1 C18:0* 2.1 3.1 2.0 1.1 2.0 0.9 C18:1 N9* 26.0 42.4 25.8 9.1 23.9 11.4 C18:1 N7 0.2 0.3 0.2 0.1 0.2 0.1 C18:2 N6* 1.5 1.0 1.4 0.9 1.8 1.2 C20:0* 0.5 1.1 0.5 0.2 0.5 0.2 C18:3 N3* 0.0 0.0 0.0 0.0 0.0 0.0 C20:1 N9* 0.0 0.0 0.1 0.0 0.1 0.0 C18:4 N3 0.0 0.0 0.1 0.2 0.1 0.1 C20:2 N6* 0.0 0.0 0.1 0.0 0.0 0.0 C20:3 N6 0.0 0.0 0.0 0.0 0.0 0.0 C22:0* 0.4 10.7 0.3 0.2 0.4 0.2 C20:4 N7 0.0 0.0 0.0 0.0 0.0 0.0 C20:3 N3 0.0 0.0 0.0 0.0 0.0 0.0 C20:4N6* 0.2 0.0 0.2 0.2 0.2 0.2 C22:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N5 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N3 0.3 0.8 0.3 0.3 0.3 0.2 C20:5 N3* 3.0 0.5 2.9 5.6 3.2 5.9 C24:0* 0.2 11.2 0.1 0.0 0.2 0.1 C22:4 N9 0.0 0.0 0.0 0.0 0.0 0.0 C24:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C22:5 N6* 2.1 1.3 2.2 1.5 2.2 1.9 C22:5 N3* 0.3 0.0 0.3 0.5 0.4 0.4 C22:6 N3* 43.6 12.7 43.1 64.5 44.0 58.1 Sum of 100 100 100 100 100 100 FAME % It is noted that fatty acid profiles of Tables 20 and 21 were obtained from samples extracted using a FRIOLEX® process.","The fatty acid profiles of Tables 20 and 21 are expected to be the substantially the same if the samples were extracted using the processes of the present invention.","Example 33 A two-day old inoculum flask of the isolated thraustochytrid (ATCC Accession No.","PTA-9695) was prepared in a carbon and nitrogen-fed culture with 980 ppm (thraustochytrid media).","Mutagenesis was carried out according to following procedure: A sterile T=2 day old flask, approximately 50 ml, was poured into a sterile 40 ml glass homogenizer.","The culture received 50 plunges in the homogenizer.","The culture was pipetted out and filtered through a sterile 50 micron mesh filter, which was placed in a 50 ml sterile tube (the mesh was used as a means of retaining the larger clumps of colonies while letting the smaller clusters and single cells pass through the 50 micron mesh.).","The entire concentrated macerate was collected in a sterile 50 ml tube.","The macerated culture was vortexed and dilutions at levels up to 1:100 fold were made in tubes containing thraustochytrid media.","The diluted macerate samples were vortexed prior to adding 200 μl of inoculum to a thraustochytrid media agar petri dish, 100×15 mm, containing 4-5 glass beads (3 mm glass beads).","Each plate was gently agitated in an effort to have the beads spread the inoculum evenly around the plate.","Beads were dumped off of plates and plates were left to sit with covers on for approximately 5 minutes to dry.","Lights in both the sterile hood and adjoining areas were turned off as the procedure was performed in dim light.","There was minimal light available to be able to run the procedure but only indirect and dim.","Five replicate plates were placed on the floor of the XL crosslinker (Spectronics Corporation, New York) with the lids off while the samples were irradiated.","The crosslinker delivered power in terms of microjoules and a level was sought that achieved a 90%-95% Kill.","Five replicate control plates were inoculated with un-mutagenized cells using the same protocol.","These cell counts were used to calculate the % Kill.","Once the irradiation was finished the plates were taken out, the lids were replaced, and the plates were wrapped in parafilm followed by a wrap in aluminum foil.","It was imperative that the plates grew for the first week in the dark so that they were not able to repair the damaged genes.","Plates were placed in a 22.5° C. room for about 10 days prior to counting the colonies.","When final counts were made, individual colonies were picked with a sterile inoculating loop and re-streaked on new thraustochytrid media plates.","Each colony was plated on an individual plate.","As plates grew dense a sample was taken, using a inoculating loop, and inoculated into a sterile 250 ml shake flask containing 50 ml of thraustochytrid media.","This flask was placed on a shaker at 200 rpm in a 22.5° C. room.","On T=7 days the shake flask culture was harvested into a 50 ml sterile tube.","The pH was taken and the sample was spun down to collect the biomass pellet.","Each sample was rinsed and re-suspended in a 50:50 mixture of isopropyl alcohol and distilled water prior to being re-spun.","The collected pellet was freeze dried, weighed, and a FAME analysis was performed.","The data in Tables 22-28 represents mutants produced with the above process.","TABLE 22 Mutants of Thraustochytrid Strain ATCC Accession No.","PTA-9695 control ATCC Fatty Acids PTA-9695 Mutant 1 Mutant 2 Mutant 3 Mutant 4 Mutant 5 Mutant 8 Mutant 9 Mutant 10 % 08:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 09:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 10:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 12:0 0.10 0.10 0.08 0.08 0.13 0.07 0.11 0.08 0.08 % 12:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 13:0 0.11 0.11 0.17 0.13 0.12 0.18 0.11 0.15 0.14 % 13:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 14:0 1.79 1.85 1.49 1.37 2.36 1.29 1.85 1.72 1.57 % 14:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 15:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 16:0 30.98 28.75 29.96 29.97 30.33 29.86 30.97 30.11 29.20 % 16:1 0.27 0.20 0.31 0.14 0.25 0.27 0.16 0.27 0.24 % 16:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 16:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 17:0 0.12 0.15 0.13 0.17 0.27 0.12 0.16 0.13 0.13 % 18:0 1.29 1.22 1.38 1.47 1.22 1.57 1.25 1.34 1.34 % 18:1 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:1 n-7 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:3 n-6 0.00 0.03 0.00 0.00 0.07 0.00 0.03 0.00 0.00 % 18:3 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:4 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:0 0.39 0.36 0.42 0.45 0.34 0.46 0.37 0.40 0.40 % 20:1 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-3 0.37 0.38 0.32 0.42 0.44 0.32 0.41 0.33 0.36 % 20:4 ARA 0.55 0.55 0.94 0.57 0.80 0.89 0.60 0.73 0.75 % 20:5 n-3 EPA 2.62 2.94 3.01 2.40 3.64 2.83 2.54 2.81 2.81 % 22:0 0.08 0.08 0.09 0.09 0.07 0.10 0.07 0.09 0.09 % 22:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:4 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:5 n-6 3.19 3.19 2.94 3.43 3.35 2.87 3.34 3.01 3.15 % 22:5 n-3 0.18 0.18 0.21 0.23 0.20 0.18 0.20 0.17 0.18 % 22:6 n-3 DHA 56.88 58.63 57.56 57.85 54.87 57.98 56.62 57.53 58.52 % 24:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 24:1 0.00 0.08 0.00 0.00 0.00 0.00 0.00 0.09 0.00 % Fat 46.83 46.10 31.23 47.39 49.78 30.62 54.71 37.72 37.87 % Unknown 0.85 0.46 0.35 0.51 0.51 0.36 0.50 0.38 0.39 TABLE 23 Mutants of Thraustochytrid Strain ATCC Accession No.","PTA-9695 control ATCC Fatty Acids PTA-9695 Mutant 11 Mutant 13 Mutant 14 Mutant 15 Mutant 16 Mutant 20 Mutant 21 Mutant 22 % 08:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 09:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 10:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 12:0 0.10 0.10 0.08 0.09 0.11 0.11 0.09 0.09 0.10 % 12:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 13:0 0.11 0.15 0.16 0.14 0.13 0.12 0.17 0.16 0.13 % 13:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 14:0 1.79 1.89 1.43 1.75 1.83 1.98 1.76 1.77 1.81 % 14:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 15:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 16:0 30.98 31.08 30.27 29.92 31.79 30.18 28.84 30.05 30.81 % 16:1 0.27 0.32 0.26 0.28 0.21 0.24 0.23 0.23 0.33 % 16:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 16:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 17:0 0.12 0.24 0.15 0.13 0.15 0.12 0.14 0.16 0.14 % 18:0 1.29 1.36 1.44 1.31 1.36 1.21 1.28 1.34 1.33 % 18:1 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:1 n-7 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:3 n-6 0.00 0.05 0.00 0.00 0.00 0.03 0.00 0.00 0.00 % 18:3 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:4 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:0 0.39 0.38 0.42 0.39 0.40 0.37 0.37 0.38 0.38 % 20:1 n-9 0.00 0.00 0.06 0.00 0.00 0.00 0.00 0.00 0.00 % 20:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-3 0.37 0.43 0.36 0.33 0.36 0.37 0.33 0.35 0.34 % 20:4 ARA 0.55 0.79 0.72 0.80 0.64 0.62 0.83 0.73 0.69 % 20:5 n-3 EPA 2.62 3.17 2.72 2.97 2.52 2.66 3.03 2.90 2.87 % 22:0 0.08 0.08 0.09 0.08 0.08 0.08 0.08 0.08 0.08 % 22:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:4 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:5 n-6 3.19 3.25 3.06 2.97 3.07 3.16 2.98 3.01 3.02 % 22:5 n-3 0.18 0.20 0.19 0.17 0.19 0.16 0.17 0.18 0.18 % 22:6 n-3 DHA 56.88 55.17 57.52 57.63 56.02 57.38 58.58 57.45 56.65 % 24:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 24:1 0.00 0.00 0.00 0.00 0.00 0.07 0.00 0.00 0.08 % Fat 46.83 46.19 37.00 38.41 48.46 47.32 37.71 40.23 43.55 % Unknown 0.85 0.47 0.39 0.36 0.47 0.44 0.37 0.39 0.38 TABLE 24 Mutants of Thraustochytrid Strain ATCC Accession No.","PTA-9695 control ATCC Fatty Acids PTA-9695 Mutant 24 Mutant 26 Mutant 27 Mutant 29 Mutant 30 Mutant 33 Mutant 34 Mutant 35 % 08:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 09:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 10:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 12:0 0.10 0.11 0.09 0.09 0.08 0.08 0.10 0.11 0.09 % 12:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 13:0 0.11 0.12 0.13 0.14 0.16 0.14 0.12 0.12 0.10 % 13:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 14:0 1.79 1.98 1.71 1.69 1.63 1.66 1.93 2.01 1.59 % 14:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 15:1 0.00 0.00 0.00 0.00 0.00 0.00 0.70 0.54 0.39 % 16:0 30.98 30.61 30.32 30.21 29.70 29.50 30.26 32.28 30.78 % 16:1 0.27 0.19 0.22 0.22 0.26 0.26 0.29 0.26 0.16 % 16:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 16:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 17:0 0.12 0.15 0.18 0.16 0.13 0.13 0.26 0.16 0.12 % 18:0 1.29 1.24 1.31 1.31 1.32 1.30 1.32 1.37 1.34 % 18:1 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.10 0.11 0.09 % 18:1 n-7 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:3 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:3 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:4 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:0 0.39 0.37 0.39 0.40 0.40 0.39 0.37 0.40 0.40 % 20:1 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.13 0.14 % 20:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-3 0.37 0.38 0.37 0.35 0.35 0.35 0.00 0.00 0.00 % 20:4 ARA 0.55 0.61 0.59 0.69 0.68 0.32 0.34 0.24 0.28 % 20:5 n-3 EPA 2.62 2.62 2.70 2.85 2.90 2.91 3.28 2.51 2.59 % 22:0 0.08 0.08 0.08 0.08 0.09 0.08 0.08 0.08 0.08 % 22:1 0.00 0.00 0.00 0.00.0.00 0.00 0.00 0.00 0.00 % 22:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:4 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:5 n-6 3.19 3.10 3.11 3.05 3.10 3.11 3.43 3.26 3.56 % 22:5 n-3 0.18 0.16 0.18 0.19 0.18 0.18 0.18 0.15 0.24 % 22:6 n-3 DHA 56.88 57.03 57.46 57.46 57.96 58.52 55.92 54.96 56.73 % 24:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 24:1 0.00 0.08 0.00 0.00 0.00 0.00 0.07 0.07 0.07 % Fat 46.83 47.80 43.50 38.86 38.60 38.16 46.95 46.43 51.55 % Unknown 0.85 0.45 0.42 0.39 0.37 0.82 1.25 1.23 1.25 TABLE 25 Mutants of Thraustochytrid Strain ATCC Accession No.","PTA-9695 control ATCC Fatty Acids PTA-9695 Mutant 36 Mutant 37 Mutant 38 Mutant 39 Mutant 40 Mutant 42 Mutant 43 Mutant 44 % 08:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 09:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 10:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 12:0 0.10 0.00 0.11 0.00 0.11 0.09 0.08 0.12 0.09 % 12:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 13:0 0.11 0.44 0.09 0.24 0.12 0.11 0.12 0.08 0.15 % 13:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 14:0 1.79 1.25 1.99 1.48 1.96 1.76 1.43 2.17 1.75 % 14:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 15:1 0.00 2.12 0.48 0.71 0.54 0.55 0.36 0.62 0.50 % 16:0 30.98 26.95 28.04 32.28 30.84 30.25 25.77 43.37 30.18 % 16:1 0.27 0.00 0.26 0.23 0.22 0.21 0.10 1.05 0.22 % 16:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 16:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 17:0 0.12 0.95 0.13 0.28 0.16 0.16 0.10 0.26 0.13 % 18:0 1.29 1.58 1.11 1.79 1.30 1.29 1.25 2.21 1.34 % 18:1 n-9 0.00 0.37 0.08 0.25 0.09 0.09 0.12 0.09 0.10 % 18:1 n-7 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.05 0.00 % 18:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:3 n-6 0.00 0.00 0.06 0.00 0.00 0.00 0.00 0.00 0.00 % 18:3 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:4 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:0 0.39 0.34 0.31 0.43 0.38 0.39 0.36 0.61 0.40 % 20:1 n-9 0.00 0.00 0.00 0.43 0.00 0.14 0.15 0.15 0.49 % 20:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-3 0.37 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:4 ARA 0.55 0.41 0.31 0.24 0.27 0.24 0.30 0.35 0.23 % 20:5 n-3 EPA 2.62 5.36 2.77 4.00 2.72 2.80 3.21 3.47 2.80 % 22:0 0.08 0.00 0.07 0.14 0.07 0.08 0.07 0.14 0.08 % 22:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:4 n-6 0.00 0.00 0.06 0.00 0.00 0.00 0.00 0.00 0.00 % 22:5 n-6 3.19 2.40 3.94 2.57 3.48 3.29 3.89 2.37 3.33 % 22:5 n-3 0.18 0.00 0.19 0.00 0.17 0.17 0.30 0.33 0.17 % 22:6 n-3 DHA 56.88 57.52 58.57 54.20 56.24 57.09 60.99 41.61 56.76 % 24:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 24:1 0.00 0.00 0.08 0.00 0.08 0.09 0.08 0.06 0.09 % Fat 46.83 12.73 54.86 18.08 45.74 42.59 42.48 56.44 41.20 % Unknown 0.85 0.29 1.36 0.73 1.28 1.20 1.31 0.90 1.20 TABLE 26 Mutants of Thraustochytrid Strain ATCC Accession No.","PTA-9695 control ATCC PTA- Fatty Acids 9695 Mutant 45 Mutant 46 Mutant 47 Mutant 48 Mutant 49 Mutant 50 Mutant 51 Mutant 52 % 08:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 09:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 10:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 12:0 0.10 0.10 0.13 0.11 0.07 0.09 0.09 0.09 0.11 % 12:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 13:0 0.11 0.11 0.10 0.09 0.13 0.09 0.13 0.10 0.09 % 13:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 14:0 1.79 1.79 2.07 1.86 1.52 1.62 1.78 1.78 1.85 % 14:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 15:1 0.00 0.41 0.76 0.57 0.46 0.48 0.55 0.53 0.53 % 16:0 30.98 28.79 24.90 30.07 29.07 31.21 30.46 30.79 32.53 % 16:1 0.27 0.19 0.24 0.18 0.17 0.17 0.18 0.21 0.22 % 16:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 16:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 17:0 0.12 0.11 0.24 0.16 0.12 0.14 0.17 0.18 0.15 % 18:0 1.29 1.24 1.07 1.28 1.41 1.43 1.36 1.48 1.35 % 18:1 n-9 0.00 0.08 0.07 0.09 0.09 0.08 0.10 0.09 0.06 % 18:1 n-7 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:3 n-6 0.00 0.00 0.12 0.05 0.00 0.00 0.00 0.00 0.00 % 18:3 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:4 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:0 0.39 0.36 0.29 0.37 0.42 0.42 0.39 0.40 0.41 % 20:1 n-9 0.00 0.15 0.13 0.11 0.24 0.13 0.19 0.16 0.19 % 20:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-6 0.00 0.00 0.05 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-3 0.37 0.00 0.12 0.00 0.00 0.00 0.00 0.00 0.00 % 20:4 ARA 0.55 0.29 0.65 0.26 0.18 0.21 0.22 0.24 0.24 % 20:5 n-3 2.62 3.05 4.28 2.66 2.93 2.46 2.71 2.94 2.44 EPA % 22:0 0.08 0.07 0.06 0.07 0.09 0.09 0.08 0.08 0.08 % 22:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:4 n-6 0.00 0.06 0.07 0.05 0.00 0.00 0.00 0.00 0.00 % 22:5 n-6 3.19 3.59 4.28 3.46 3.07 3.32 3.17 3.18 3.24 % 22:5 n-3 0.18 0.25 0.27 0.18 0.17 0.17 0.16 0.17 0.17 % 22:6 n-3 DHA 56.88 57.74 58.32 56.70 58.65 56.45 56.83 56.19 55.06 % 24:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 24:1 0.00 0.07 0.15 0.10 0.10 0.11 0.10 0.10 0.07 % Fat 46.83 48.91 58.95 54.80 35.41 48.60 44.93 43.01 51.93 % Unknown 0.85 1.55 1.63 1.57 1.09 1.35 1.31 1.28 1.19 TABLE 27 Mutants of Thraustochytrid Strain ATCC Accession No.","PTA-9695 control ATCC Fatty Acids PTA-9695 Mutant 53 Mutant 54 Mutant 55 Mutant 56 Mutant 57 Mutant 58 Mutant 60 Mutant 61 Mutant 65 % 08:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 09:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 10:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 12:0 0.10 0.09 0.08 0.12 0.08 0.08 0.08 0.08 0.10 0.08 % 12:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 13:0 0.11 0.11 0.12 0.08 0.09 0.13 0.16 0.14 0.09 0.14 % 13:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 14:0 1.79 1.74 1.63 2.13 1.67 1.59 1.59 1.59 1.85 1.58 % 14:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 15:1 0.00 0.53 0.52 0.48 0.51 0.52 0.45 0.50 0.51 0.48 % 16:0 30.98 30.13 29.54 33.01 31.08 29.37 30.65 29.39 31.15 30.03 % 16:1 0.27 0.21 0.23 0.26 0.26 0.14 0.25 0.22 0.26 0.25 % 16:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 16:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 17:0 0.12 0.15 0.14 0.14 0.14 0.16 0.12 0.13 0.14 0.13 % 18:0 1.29 1.30 1.30 1.37 1.38 1.37 1.46 1.30 1.30 1.35 % 18:1 n-9 0.00 0.08 0.08 0.00 0.06 0.11 0.09 0.10 0.07 0.07 % 18:1 n-7 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:3 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:3 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:4 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:0 0.39 0.38 0.39 0.40 0.42 0.38 0.43 0.39 0.39 0.41 % 20:1 n-9 0.00 0.19 0.16 0.13 0.19 0.20 0.17 0.14 0.13 0.21 % 20:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-3 0.37 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:4 ARA 0.55 0.25 0.21 0.26 0.22 0.25 0.51 0.20 0.24 0.19 % 20:5 n-3 EPA 2.62 2.75 2.78 2.81 2.67 2.78 5.76 2.72 2.59 2.82 % 22:0 0.08 0.08 0.08 0.08 0.09 0.08 0.09 0.08 0.08 0.09 % 22:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:4 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.06 0.00 % 22:5 n-6 3.19 3.47 3.20 3.25 3.19 3.43 2.62 3.30 3.42 3.18 % 22:5 n-3 0.18 0.18 0.18 0.17 0.17 0.20 0.59 0.17 0.17 0.17 % 22:6 n-3 DHA 56.88 56.99 58.07 54.04 56.38 57.76 54.09 58.21 55.91 57.56 % 24:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 24:1 0.00 0.09 0.09 0.07 0.10 0.09 0.11 0.10 0.07 0.08 % Fat 46.83 45.83 39.59 48.81 41.92 43.97 33.96 36.97 50.40 36.21 % Unknown 0.85 1.28 1.19 1.19 1.29 1.35 0.77 1.24 1.48 1.17 TABLE 28 Mutants of Thraustochytrid Strain ATCC Accession No.","PTA-9695 control Mutant 68 Mutant 70 Mutant 72 Fatty ATCC Mutant Mutant ATCC Mutant ATCC Mutant ATCC Mutant Mutant Acids PTA-9695 66 67 PTA-9696 69 PTA-9697 71 PTA-9698 73 74 % 08:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 09:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 10:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 12:0 0.15 0.00 0.00 0.00 0.00 0.00 0.00 0.13 0.00 0.00 % 12:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 13:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 13:1 0.00 0.00 0.00 0.00 0.00 0.00 0.22 0.00 0.00 0.00 % 14:0 2.42 2.29 2.07 2.09 2.11 2.21 2.27 2.29 1.97 2.06 % 14:1 0.00 0.00 0.00 0.00 0.00 0.00 0.19 0.00 0.00 0.00 % 15:1 0.55 0.47 0.48 0.47 0.47 0.44 0.46 0.40 0.50 0.47 % 16:0 39.19 31.02 26.20 25.84 27.79 28.14 28.89 33.49 24.50 23.95 % 16:1 0.43 0.19 0.00 0.00 0.00 0.00 0.19 0.21 0.00 0.00 % 16:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 16:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 17:0 0.16 0.00 0.00 0.00 0.00 0.00 0.00 0.13 0.00 0.00 % 18:0 1.67 1.68 1.22 1.22 1.44 1.49 1.51 2.24 1.11 1.02 % 18:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 % 18:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-7 % 18:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 % 18:3 0.00 0.18 0.20 0.21 0.19 0.17 0.22 0.16 0.22 0.22 n-3 % 18:4 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-3 % 20:0 0.49 0.41 0.32 0.31 0.35 0.37 0.44 0.52 0.29 0.27 % 20:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 % 20:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 % 20:3 0.00 0.00 0.00 0.00 0.15 0.00 0.00 0.00 0.00 0.00 n-6 % 20:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-3 % 20:4 0.18 0.16 0.33 0.27 0.24 0.37 0.30 0.27 0.38 0.39 ARA % 20:5 1.76 2.30 3.86 3.97 3.32 4.12 3.09 2.74 4.43 4.53 n-3 EPA % 22:0 0.33 0.46 0.35 0.44 0.48 0.38 0.43 0.12 0.35 0.34 % 22:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:4 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 % 22:5 2.62 2.83 3.17 2.66 2.72 2.95 3.46 2.79 3.17 3.19 n-6 % 22:5 0.18 0.18 0.46 0.42 0.34 0.61 0.25 0.27 0.48 0.57 n-3 % 22:6 49.52 57.01 60.60 61.42 59.74 58.03 55.62 53.06 61.83 62.23 n-3 DHA % 24:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 24:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % Fat 52.70 49.32 48.51 49.49 48.80 53.65 40.38 63.40 48.27 46.63 % 0.35 0.82 0.73 0.66 0.67 0.73 2.46 1.18 0.78 0.76 Unknown Example 34 Isolation of Microorganisms Samples were collected from intertidal habitats during low tide, including bays and estuaries along the West Coast of North America (California, Oregon, and Washington) and Hawaii.","Water, sediment, living plant material, and decaying plant/animal debris were placed into sterile 50 ml tubes.","Portions of each sample along with the water were spread onto solid agar plates of isolation media.","Isolation media consisted of: 500 ml of artificial seawater, 500 ml of distilled water, 1 g of glucose, 1 g of glycerol, 13 g of agar, 1 g of glutamate, 0.5 g of yeast extract, 0.5 g casein hydrolysate, 1 ml of a vitamin solution (100 mg/L thiamine, 0.5 mg/L biotin, 0.5 mg B12), 1 ml of a trace mineral solution (PH metals, containing per liter: 6.0 g FeCl36H2O, 6.84 g H3BO3, 0.86 g MnCl24H2O, 0.06 g ZnCl2, 0.026 CoCl26H2O, 0.052 g NiSO4H2O, 0.002 g CuSO45H2O and 0.005 g Na2MoO42H2O), and 500 mg each of penicillin G and streptomycin sulfate.","The agar plates were incubated in the dark at 20-25° C. After 2-4 days the agar plates were examined under magnification, and colonies of cells were picked with a sterile toothpick and restreaked onto a fresh plate of media.","Cells were repeatedly streaked onto fresh media until contaminated organisms were removed.","Two of the isolated microorganisms were deposited under ATCC Accession Nos.","PTA-10212 and PTA-10208.Taxonomic Characteristics of the Isolated Microorganism Deposited Under ATCC Accession No.","PTA-10212 Cultures of the isolated microorganism deposited under ATCC Accession No.","PTA-10212 (“PTA-10212”) appeared as white, wet, smeared colonies without visible isolated sori.","PTA-10212 was grown on solid and liquid FFM, solid KMV, KMV slush (1%), KMV broth, and MH broth to further examine growth characteristics.","PTA-10212 was observed to grow rapidly on KMV and MH.","See, e.g., Porter D., 1989.Phylum Labyrinthulomycota.","In Margulis, L., Corliss, J. O., Melkonian, M., Chapman, D. J.","(Eds.)","Handbook of Protoctista, Jones and Bartlett, Boston, pp.","388-398 (KMV); Honda et al., Mycol.","Res.","102:439-448 (1998) (MH); and U.S. Pat.","No.","5,130,242 (FFM).","The following observations were made after growth of PTA-10212 over several days on solid FFM media, after 72 hours growth in KMV medias, and MH broth.","Sporangia were not clumped in/on any media and were very small (5-10 μm).","PTA-10212 did not demonstrate the copious tetrads characteristic of Schizochytrium cleavage patterns.","Amoeboid cells appeared about 24 hours after transfer to fresh solid media.","These amoeboid cells were gone after a few days and were not evident in liquid or slush media.","Unlike Aurantiochytrium, described by Yokoyama, R. et al., Mycoscience 48(6): 329-341 (2007), as having the appearance of “small sandgrains on the bottom of the flask” when grown in liquid media, PTA-10212 did not settle at the bottom of the flask but was suspended in both KMV and MH liquid media.","The sporangia were not as dense as typical of Schizochytrium or Oligochytrium, which also have robust ectoplasmic networks that were absent from PTA-10212.While most species undergo vegetative cleavage of small sporangia or assimilative cells by the division of a larger sporangium over several hours, PTA-10212 formed dumbbell-shaped elongated assimilative cells, which then formed a thin isthmus that pulled apart as the ends of the dumbbell separated.","The resulting cells appeared to be small assimilative cells.","Direct transformation of an amoeboid cell into the dumbbell shaped assimilative cell was not observed.","Typical biflagellate zoospores were observed swimming but were relatively rare.","PTA-10212 was non-prolific, dividing by vegetative cleavage.","Direct release of zoospores was not observed, although zoospores were observed swimming.","Vegetative cells were very small (2 μm to 5 μm).","PTA-10212 was further examined using the flow-through technique, in which microscopic slides were prepared by suspending a small portion of an agar-grown colony in a drop of half-strength sea water.","With this technique, primary sporangia were observed to be globose and approximately 10 μm in diameter.","Walls were very thin and remnants were not observed when binary division of the protoplast was initiated.","Repeated binary division produced 8-16 smaller (4-5 μm in diameter) secondary sporangia.","The secondary sporangia remained quiescent for several hours before again releasing an amorphous protoplast.","The amorphous protoplast divided by pinching and pulling, initially producing typical dumbbell-shaped intermediate stages and finally resulting in 4-8 small globose bodies 2.5-2.8 μm in diameter.","The latter rested for several minutes up to 1-2 hours, then changed shape (elongated) and turned into biflagellate zoospores, 2.3-2.5×3.7-3.9 μm.","Zoospores were abundant and could be precisely measured when they came to rest.","Zoospores then rounded off and started a new cycle of development.","The zoospores were larger than Sicyoldochytrium minutum and smaller than Ulkenia visurgensis.","PTA-10212 was further characterized based on the similarity of its 18s rRNA gene to that of known species.","Genomic DNA was prepared from PTA-10212 by standard procedures.","See, for example, Sambrook J. and Russell D. 2001.Molecular cloning: A laboratory manual, 3rd edition.","Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.","Briefly: (1) 500 pit of cells were centrifuged from mid-log culture.","The cells were re-centrifuged, and all traces of liquid were removed from the cell pellet with a small-bore tip; (2) pellets were resuspended with 200 μL lysis buffer (20 mM Tris pH 8.0, 125 μg/mL Proteinase K, 50 mM NaCl, 10 mM EDTA pH 8.0, 0.5% SDS); (3) cells were lysed at 50° C. for 1 hour; (4) the lysis mixture was pipetted into phase-lock gel (PLG-Eppendorf) 2 mL tubes; (5) equal volume of P:C:I was added and allowed to mix for 1.5 hours; (6) the tubes were centrifuged at 12,000×g for 5 minutes; (7) the aqueous phase was removed from above the gel within the PLG tube and an equal volume of chloroform was added to the aqueous phase, and mixed for 30 minutes; (8) the tubes were centrifuged at 14,000×g for approximately 5 minutes; (9) the top layer (aqueous phase) was pipetted away from the chloroform, and placed in a new tube; (10) 0.1 volume of 3 M NaOAC was added and mixed (inverted several times); (11) 2 volumes of 100% EtOH were added and mixed (inverted several times) with genomic DNA precipitant forming at this stage; (12) the tubes were centrifuged at 4° C. in a microcentrifuge at 14,000×g for approximately 15 minutes; (13) the liquid was gently poured off with genomic DNA remaining at the bottom of the tube; (14) the pellet was washed with 0.5 mL 70% EtOH; (15) the tubes were centrifuged at 4° C. in a microcentrifuge at 14,000×g for approximately 5 minutes; (16) the EtOH was gently poured off and the genomic DNA pellet was dried; and (17) a suitable volume of H2O and RNase was added directly to the genomic DNA pellet.","The PCR amplification of the 18s rRNA gene was carried out with primers previously described (Honda et.","al., 0.1 Euk.","Micro.","46(6): 637-647 (1999).","The PCR conditions with chromosomal DNA template were as follows: 0.2 μM dNTPs, 0.1 μM each primer, 8% DMSO, 200 ng chromosomal DNA, 2.5 U Herculase® II Fusion DNA Polymerase (Stratagene), and Herculase® buffer (Stratagene) in a 50 μL total volume.","The PCR Protocol included the following steps: (1) 95° C. for 2 minutes; (2) 95° C. for 35 seconds; (3) 55° C. for 35 seconds; (4) 72° C. for 1 minute and 30 seconds; (5) repeat steps 2-4 for 30 cycles; (6) 72° C. for 5 minutes; and (7) hold at 4° C. PCR amplification yielded a distinct DNA product with the expected size using chromosomal template described above.","The PCR product was cloned into the vector pJET1.2/blunt (Fermentas) according to the manufacturer's instructions, and the insert sequence was determined using supplied standard primers.","Phylogenetic analysis places PTA-10212 within the lineage that includes Thraustochytrium pachydermum and Thraustochytrium aggregatum with moderate support.","The sporangia of T. pachydermum have very thick cell walls.","T. aggregatum forms clearly visible clumps of sori that are opaque.","PTA-10212 shows neither of these characteristics.","The presence of many amoeboid cells has been described in other taxa, such as Ulkenia, T. gaertnerium, A. limiacinum, and S. mangrovei; however, the descriptions associated with those taxa differ from the observed characteristics of the isolate.","Moreover, PTA-10212 did not show phylogenetic affinity towards any of these taxa.","Table 29 shows a comparison of the 18s rRNA sequence from the microorganism deposited under ATCC Accession No.","PTA-10212 to DNA sequences in the National Center for Biotechnology Information (NCBI) electronic database.","The percent identity was determined using two different calculations.","“Calculation #1” takes into consideration any “gaps” that occurs in the sequences, either from non-homologous regions or partial sequence (AlignX-VectorNTI default settings).","“Calculation #2” does not include calculated penalties for gaps (AlignX-VectorNTI “IDENTITY” matrix setting).","TABLE 29 Comparison of 18s rRNA Sequences % Identity % Identity Thraustochytrids Calculation #1 Calculation #2 Thraustochytrium pachydermum 85% 93% Thraustochytrium aggregatum (p) 83% 92% Thraustochytrium gaertnerium 82% 92% Ulkenia visurgensis 82% 92% Schizochytrium sp.","PTA-9695 80% 92% Schizochytrium mangrovei 80% 91% Schizochytrium sp.","ATCC 20888 80% 90% Aurantiochytrium limiacinum 79% 90% (p): indicates partial sequence As shown in Table 29, it was found that, in terms of % identity, the 18s rRNA gene sequence from the microorganism deposited under ATCC Accession No.","PTA-10212 is related, though not identical, to 18s rRNA gene sequences available in the NCBI database.","It is generally recognized that organisms can have closely related 18s rRNA gene sequences while belonging to a different genus or species.","Based on the above characterization, the isolated microorganism (ATCC Accession No.","PTA-10212) is believed to represent a new Thraustochytrium species and is therefore also designated as Thraustochytrium sp.","ATCC PTA-10212.Taxonomic Characteristics of the Isolated Microorganism Deposited Under ATCC Accession No.","PTA-10208 The microorganism deposited under ATCC Accession No.","PTA-10208 (“PTA-10208”) was identified as a sub-isolate (an individual cell isolated from a culture and maintained as a new separate and distinct culture) of the microorganism deposited under ATCC Accession No.","PTA-9695 (“PTA-9695”), described in U.S. Pub.","No.","2010/0239533 and Int'l.","Pub.","No.","WO 2010/107415.PTA-10208 shares taxonomic characteristics with PTA-9695.PTA-9695 was found to have biflagellate zoospores at discharge that swim actively away from the mature sporangium, wall remnants of which were clearly visible (in phase contrast) after spore release.","PTA-9695 sporangia measured 12.5 μm to 25 μm in diameter, and zoospores were 2.5 μm to 2.8 μm×4.5 μm to 4.8 μm in size.","There were 8 to 24 spores per individual PTA-9695 sporangium.","Settled PTA-9695 zoospores enlarged and rapidly underwent binary divisions leading to tetrads, octads, and finally to clusters of sporangia.","Tetrad formation commenced at a very early stage prior to maturity of the sporangia.","These characteristics are in agreement with the genus Schizochytrium.","In terms of % identity, the PTA-9695 18s rRNA gene sequence, which is shared by PTA-10208, was found to be closely related, though not identical, to the 18s rRNA gene sequence of T. aggregatum provided in Honda, D. et al., J. Euk.","Micro.","46(6): 637-647 (1999).","The 18s rRNA sequence published for Thraustochytrium aggregatum is a partial sequence, with an approximately 71 DNA nucleotide gap in the middle of the sequence.","PTA-9695 is believed to represent a new Schizochytrium species.","As such, the sub-isolate PTA-10208 is also designated as Schizochytrium sp.","ATCC PTA-10208.Example 35 Growth Characteristics of the Isolated Microorganism Deposited Under ATCC Accession No.","PTA-10212 The isolated microorganism (ATCC Accession No.","PTA-10212) was examined for growth characteristics in individual fermentation runs, as described below.","Typical media and cultivation conditions are shown in Table 30.TABLE 30 PTA-10212 Vessel Media Ingredient concentration ranges Na2SO4 g/L 31.0 0-50, 15-45, or 25-35 NaCl g/L 0.625 0-25, 0.1-10, or 0.5-5 KCl g/L 1.0 0-5, 0.25-3, or 0.5-2 MgSO4•7H2O g/L 5.0 0-10, 2-8, or 3-6 (NH4)2SO4 g/L 0.44 0-10, 0.25-5, or 0.05-3 MSG•1H2O g/L 6.0 0-10, 4-8, or 5-7 CaCl2 g/L 0.29 0.1-5, 0.15-3, or 0.2-1 T 154 (yeast g/L 6.0 0-20, 0.1-10, or 1-7 extract) KH2PO4 g/L 0.8 0.1-10, 0.5-5, or 0.6-1.8 Post autoclave (Metals) Citric acid mg/L 3.5 0.1-5000, 10-3000, or 3-2500 FeSO4•7H2O mg/L 10.30 0.1-100, 1-50, or 5-25 MnCl2•4H2O mg/L 3.10 0.1-100, 1-50, or 2-25 ZnSO4•7H2O mg/L 3.10 0.01-100, 1-50, or 2-25 CoCl2•6H2O mg/L 0.04 0-1, 0.001-0.1, or 0.01-0.1 Na2MoO4•2H2O mg/L 0.04 0.001-1, 0.005-0.5, or 0.01-0.1 CuSO4•5H2O mg/L 2.07 0.1-100, 0.5-50, or 1-25 NiSO4•6H2O mg/L 2.07 0.1-100, 0.5-50, or 1-25 Post autoclave (Vitamins) Thiamine mg/L 9.75 0.1-100, 1-50, or 5-25 Vitamin B12 mg/L 0.16 0.01-100, 0.05-5, or 0.1-1 Ca½-panto- mg/L 2.06 0.1-100, 0.1-50, or 1-10 thenate Biotin mg/L 3.21 0.1-100, 0.1-50, or 1-10 Post autoclave (Carbon) Glycerol g/L 30.0 5-150, 10-100, or 20-50 Nitrogen Feed: MSG•1H2O g/L 17 0-150, 10-100, or 15-50 Typical cultivation conditions would include the following pH about 6.5-about 9.5, about 6.5-about 8.0, or about 6.8-about 7.8; temperature: about 15-about 30 degrees Celsius, about 18-about 28 degrees Celsius, or about 21 to about 23 degrees Celsius; dissolved oxygen: about 0.1-about 100% saturation, about 5-about 50% saturation, or about 10-about 30% saturation; and/or glycerol about 5-about 50 g/L, about 10-about 40 g/L, or controlled @: about 15-about 35 g/L.","In carbon (glycerol) and nitrogen-fed cultures with 1000 ppm CF at 22.5° C. with 20% dissolved oxygen at pH 7.3, PTA-10212 produced a dry cell weight of 26.2 g/L after 138 hours of culture in a 10 L fermentor volume.","The lipid yield was 7.9 g/L; the omega-3 yield was 5.3 g/L; the EPA yield was 3.3 g/L; and the DHA yield was 1.8 g/L.","The fatty acid content was 30.3% by weight; the EPA content was 41.4% of fatty acid methyl esters (FAME); and the DHA content was 26.2% of FAME.","The lipid productivity was 1.38 g/L/day, and the omega-3 productivity was 0.92 g/L/day under these conditions, with 0.57 g/L/day EPA productivity and 0.31 g/L/day DHA productivity.","In carbon (glycerol) and nitrogen-fed cultures with 1000 ppm Cl− at 22.5° C. with 20% dissolved oxygen at pH 7.3, PTA-10212 produced a dry cell weight of 38.4 g/L after 189 hours of culture in a 10 L fermentor volume.","The lipid yield was 18 g/L; the omega-3 yield was 12 g/L; the EPA yield was 5 g/L; and the DHA yield was 6.8 g/L.","The fatty acid content was 45% by weight; the EPA content was 27.8% of FAME; and the DHA content was 37.9% of FAME.","The lipid productivity was 2.3 g/L/day, and the omega-3 productivity was 1.5 g/L/day under these conditions, with 0.63 g/L/day EPA productivity and 0.86 g/L/day DHA productivity.","In carbon (glycerol) and nitrogen-fed cultures with 1000 ppm Cl− at 22.5° C. with 20% dissolved oxygen at pH 6.8-7.7, PTA-10212 produced a dry cell weight of 13 g/L after 189 hours of culture in a 10 L fermentor volume.","The lipid yield was 5.6 g/L; the omega-3 yield was 3.5 g/L; the EPA yield was 1.55 g/L; and the DHA yield was 1.9 g/L.","The fatty acid content was 38% by weight; the EPA content was 29.5% of FAME; and the DHA content was 36% of FAME.","The lipid productivity was 0.67 g/L/day, and the omega-3 productivity was 0.4 g/L/day under these conditions, with 0.20 g/L/day EPA productivity and 0.24 g/L/day DHA productivity.","In carbon (glycerol) and nitrogen-fed cultures with 1000 ppm at 22.5-28.5° C. with 20% dissolved oxygen at pH 6.6-7.2, PTA-10212 produced a dry cell weight of 36.7 g/L-48.7 g/L after 191 hours of culture in a 10 L fermentor volume.","The lipid yield was 15.2 g/L-25.3 g/L; the omega-3 yield was 9.3 g/L-13.8 g/L; the EPA yield was 2.5 g/L-3.3 g/L; and the DHA yield was 5.8 g/L-11 g/L.","The fatty acid content was 42.4%-53% by weight; the EPA content was 9.8%-22% of FAME; and the DHA content was 38.1%-43.6% of FAME.","The lipid productivity was 1.9 g/L/day-3.2 g/L/day, and the omega-3 productivity was 1.2 g/L/day-1.7 g/L/day under these conditions, with 0.31 g/L/day-0.41 g/L/day EPA productivity and 0.72 g/L/day-1.4 g/L/day DHA productivity.","Growth Characteristics of the Isolated Microorganism Deposited Under ATCC Accession No.","PTA-10208 The isolated microorganism (ATCC Accession No.","PTA-10208) was examined for growth characteristics in individual fermentation runs, as described below.","Typical media and cultivation conditions are shown in Table 31.TABLE 31 PTA-10208 Vessel Media Ingredient concentration ranges Na2SO4 g/L 8.8 0-25, 2-20, or 3-10 NaCl g/L 0.625 0-25, 0.1-10, or 0.5-5 KCl g/L 1.0 0-5, 0.25-3, or 0.5-2 MgSO4•7H2O g/L 5.0 0-10, 2-8, or 3-6 (NH4)2SO4 g/L 0.42 0-10, 0.25-5, or 0.05-3 CaCl2 g/L 0.29 0.1-5, 0.15-3, or 0.2-1 T 154 (yeast g/L 1.0 0-20, 0.1-10, or 0.5-5 extract) KH2PO4 g/L 1.765 0.1-10, 0.5-5, or 1-3 Post autoclave (Metals) Citric acid mg/L 46.82 0.1-5000, 10-3000, or 40-2500 FeSO4•7H2O mg/L 10.30 0.1-100, 1-50, or 5-25 MnCl2•4H2O mg/L 3.10 0.1-100, 1-50, or 2-25 ZnSO4•7H2O mg/L 9.3 0.01-100, 1-50, or 2-25 CoCl2•6H2O mg/L 0.04 0-1, 0.001-0.1, or 0.01-0.1 Na2MoO4•2H2O mg/L 0.04 0.001-1, 0.005-0.5, or 0.01-0.1 CuSO4•5H2O mg/L 2.07 0.1-100, 0.5-50, or 1-25 NiSO4•6H2O mg/L 2.07 0.1-100, 0.5-50, or 1-25 Post autoclave (Vitamins) Thiamine mg/L 9.75 0.1-100, 1-50, or 5-25 Ca½-panto- mg/L 3.33 0.1-100, 0.1-50, or 1-10 thenate Biotin mg/L 3.58 0.1-100, 0.1-50, or 1-10 Post autoclave (Carbon) Glucose g/L 30.0 5-150, 10-100, or 20-50 Nitrogen Feed: NH4OH mL/L 23.6 0-150, 10-100, or 15-50 Typical cultivation conditions would include the following: pH about 6.5-about 8.5, about 6.5-about 8.0, or about 7.0-about 8.0; temperature: about 17-about 30 degrees Celsius, about 20-about 28 degrees Celsius, or about 22 to about 24 degrees Celsius; dissolved oxygen: about 2-about 100% saturation, about 5-about 50% saturation, or about 7-about 20% saturation; and/or glucose about 5-about 50 g/L, about 10-about 40 g/L, or controlled @: about 20-about 35 g/L.","In carbon (glucose) and nitrogen-fed cultures with 1000 ppm Cl− at 22.5° C. at pH 7.0 with 20% dissolved oxygen during the nitrogen feed and 10% dissolved oxygen thereafter, PTA-10208 produced a dry cell weight of 95 g/L after 200 hours of culture in a 10 L fermentor volume.","The lipid yield was 53.7 g/L; the omega-3 yield was 37 g/L; the EPA yield was 14.3 g/L; and the DHA yield was 21 g/L.","The fatty acid content was 57% by weight; the EPA content was 27.7% of FAME; and the DHA content was 39.1% of FAME.","The lipid productivity was 6.4 g/L/day, and the omega-3 productivity was 4.4 g/L/day under these conditions, with 1.7 g/L/day EPA productivity and 2.5 g/L/day DHA productivity.","In carbon (glucose) and nitrogen-fed cultures with 1000 ppm Cl− at 22.5° C. at pH 7.5 with 20% dissolved oxygen during the nitrogen feed and 10% dissolved oxygen thereafter, PTA-10208 produced a dry cell weight of 56 g/L after 139 hours of culture in a 10 L fermentor volume.","The lipid yield was 53 g/L; the omega-3 yield was 34 g/L; the EPA yield was 11.5 g/L; and the DHA yield was 22 g/L.","The fatty acid content was 58% by weight; the EPA content was 21.7% of FAME; and the DHA content was 41.7% of FAME.","The lipid productivity was 9.2 g/L/day, and the omega-3 productivity was 5.9 g/L/day under these conditions, with 2 g/L/day EPA productivity and 3.8 g/L/day DHA productivity.","In carbon (glucose) and nitrogen-fed cultures with 1000 ppm Cl− at 22.5° C. at pH 7.0 with 20% dissolved oxygen during the nitrogen feed and 10% dissolved oxygen thereafter, PTA-10208 produced a dry cell weight of 93.8 g/L after 167 hours of culture in a 2000 L fermentor volume.","The lipid yield was 47.2 g/L; the omega-3 yield was 33.1 g/L; the EPA yield was 10.5 g/L; and the DHA yield was 20.4 g/L.","The fatty acid content was 50.6% by weight; the EPA content was 23% of FAME; and the DHA content was 42.6% of FAME.","The lipid productivity was 6.8 g/L/day, and the omega-3 productivity was 4.7 g/L/day under these conditions, with 1.5 g/L/day EPA productivity and 2.9 g/L/day DHA productivity.","In carbon (glucose) and nitrogen-fed cultures with 1000 ppm Cl− at 22.5° C. at pH 7.0 with 20% dissolved oxygen during the nitrogen feed and 10% dissolved oxygen thereafter, PTA-10208 produced a dry cell weight of 105 g/L after 168 hours of culture in a 2000 L fermentor volume.","The lipid yield was 46.4 g/L; the omega-3 yield was 33 g/L; the EPA yield was 10.7 g/L; and the DHA yield was 20.3 g/L.","The fatty acid content was 43.9% by weight; the EPA content was 24% of FAME; and the DHA content was 43.7% of FAME.","The lipid productivity was 6.6 g/L/day, and the omega-3 productivity was 4.7 g/L/day under these conditions, with 1.5 g/L/day EPA productivity and 2.9 g/L/day DHA productivity.","In carbon (glucose) and nitrogen-fed cultures with 1000 ppm Cl− at 22.5° C. at pH 7.0 with 20% dissolved oxygen during the nitrogen feed and 10% dissolved oxygen thereafter, PTA-10208 produced a dry cell weight of 64.8 g/L after 168 hours of culture in a 2000 L fermentor volume.","The lipid yield was 38.7 g/L; the omega-3 yield was 29.9 g/L; the EPA yield was 8.5 g/L; and the DHA yield was 16.7 g/L.","The fatty acid content was 59.6% by weight; the EPA content was 23% of FAME; and the DHA content was 42.3% of FAME.","The lipid productivity was 5.53 g/L/day, and the omega-3 productivity was 3.8 g/L/day under these conditions, with 1.2 g/L/day EPA productivity and 2.3 g/L/day DHA productivity.","Example 36 Fatty Acid Profiles of Microorganism Strains ATCC PTA-10208 and PTA-10212 Four samples of biomass (PTA-10208 Sample #1; PTA-10208 Sample #2; PTA-10212 Sample #1; and PTA-10212 Sample #2) were analyzed for total crude oil content by solvent extraction, lipid classes were determined by high performance liquid chromatography/evaporative light scattering detection (HPLC/ELSD), triacylglycerol (TAG) were analyzed by HPLC/mass spectrometry (HPLC/MS), and fatty acid (FA) profiles were determined by gas chromatography with flame ionization detection (GC-FID).","The crude lipid content of each freeze dried biomass was determined using solvent grinding with hexane and compared to the sum of FAME (mg/g) generated by direct transesterification, and the resultant fatty acid methyl esters (FAME) were quantified by GC/FID analysis.","Fatty acids in the extracted crude lipid were also quantified by transesterification and quantified using GC/FID analysis of the resultant FAME.","The weight percent of all neutral lipids (NL) and free fatty acids (FFA) were determined in the extracted crude lipid using normal phase HPLC with ELSD and atmospheric pressure chemical ionization-MS (APCI-MS) identification.","The method separates and quantifies sterol esters (SE), TAG, free fatty acids (FFA), 1,3-diacylglycerols (1,3-DAG), sterols, 1,2-diacylglycerols (1,2-DAG), and monoacylglycerols (MAG).","Results are shown in Tables 32 and 33, below.","It is noted that fatty acid profiles of Tables 32 and 33 were obtained from samples extracted using a solvent.","The fatty acid profiles of Tables 32 and 33 are expected to be the substantially the same if the samples were extracted using the processes of the present invention.","TAG and phospholipids (PL) were isolated from the crude oils extracted from the four samples of biomass (PTA-10208 Sample #1; PTA-10208 Sample #2; PTA-10212 Sample #1; and PTA-10212 Sample #2).","TAG was isolated using low pressure flash chromatography and PL was isolated using solid phase extraction (SPE).","The identity of each isolated fraction was confirmed by thin layer chromatography (TLC).","The fatty acid profiles of the isolated TAG and PL fractions were determined following direct transesterification using GC-FID as FAME.","Results are shown in Tables 34 and 35, below.","The total crude oil content and fatty acid profiles of isolated lipid classes were also determined for two additional samples of biomass from microorganism strain ATCC PTA-10212 (PTA-10212 Sample #3 and PTA-10212 Sample #4).","Crude oil was obtained from each sample by hexane extraction, and individual lipid classes were isolated using low pressure flash chromatography.","The fatty acid profiles of the biomass, crude oil, and isolated fractions were determined using GC-FID as FAME.","Results are shown in Tables 36-39, below.","It is noted that fatty acid profiles of Tables 36-39 were obtained from samples extracted using a typical hexane extraction.","The fatty acid profiles of Tables 36-39 are expected to be the substantially the same if the samples were extracted using the processes of the present invention.","Individual lipid classes were isolated from a sample of crude oil from microorganism strain ATCC PTA-10212 (PTA-10212 Sample #5) previously extracted using the FRIOLEX® process, and the fatty acid profiles of each class were determined using GC-FID as FAME.","Results are shown in Tables 40 and 41, below.","It is noted that fatty acid profiles of Tables 40 and 41 were obtained from samples extracted using a FRIOLEX® process.","The fatty acid profiles of Tables 40 and 41 are expected to be the substantially the same if the samples were extracted using the processes of the present invention.","Individual lipid classes were isolated from a sample of crude oil from microorganism strain ATCC PTA-10208 (PTA-10208 Sample #3) using normal HPLC with ELSD and APCI-MS identification.","Experimental Procedures Crude Oil Extraction— Crude oil was extracted from samples of freeze-dried biomass using solvent grinding.","For example, approximately 3 grams of biomass was weighed into a Swedish tube.","Three ball bearings and 30 mL of hexane were added to the Swedish tube, which was sealed with a neoprene stopper and placed in a shaker for 2 hours.","The resultant slurry was filtered using a Buchner funnel and Whatman filter paper.","The filtered liquid was collected, the solvent removed under vacuum, and the amount of remaining crude lipid determined gravimetrically.","Fatty Acid Analysis— The samples of biomass, extracted crude lipid, and isolated lipid classes were analyzed for fatty acid composition as FAME.","Briefly, freeze-dried biomass and isolated lipid classes were weighed directly into a screw cap test tubes, while samples of the crude oil were dissolved in hexane to give a concentration of approximately 2 mg/mL.","Toluene, containing internal standard, and 1.5 N HCl in methanol was added to each tube.","The tubes were vortexed, then capped and heated to 100° C. for 2 hours.","The tubes were allowed to cool, and saturated NaCl in water was added.","The tubes were vortexed again and centrifuged to allow the layers to separate.","A portion of the organic layer was then placed in a GC vial and analyzed by GC-FID.","FAME was quantified using a 3-point calibration curve generated using Nu-Check-Prep GLC Reference Standard (NuCheck, Elysian, Minn.).","Fatty acids present in the extract were expressed as mg/g and as a weight percent.","Fat content in the samples was estimated assuming equal response to the internal standard when analyzed by GC-FID.","HPLC/ELSD/MS Method— Instrument Agilent 1100 HPLC, Alltech 3300 ELSD, Agilent 1100 MSD Column Phenomenex Luna Silica, 250 × 4.6 mm, 5 μm particle size w/Guard Column Mobile Phase A - 99.5% Hexanes (Omnisolv) 0.4% Isopropyl alcohol (Omnisolv) 0.1% Acetic Acid B - 99.9% Ethanol (Omnisolv, 95:5 Ethanol:IPA) 0.1% Acetic Acid Gradient Time, min.","% A % B 0 100 0 5 100 0 15 85 10 20 0 100 25 0 100 26 100 0 35 100 0 Column Temp.","30° C. Flow Rate 1.5 mL/min Injection Volume 5 μL ELSD Detection Temperature 35° C., Gas flow 1.2 L/min MSD Mass Range 200-1200, Fragmentor 225 V Drying Gas Temperature 350° C. Vaporizer Temperature 325° C. Capillary Voltage 3500 V Corona Current 10 μA Solid Phase Extraction— PL fractions were separated from the crude lipid by solid phase extraction (SPE) using 2 g aminopropyl cartridges (Biotage, Uppsala, Sweden) placed in a Vac Elut apparatus (Varian Inc, Palo Alto, USA).","The cartridge was conditioned with 15 mL of hexane, and ˜60 mg of each sample was dissolved in 1 mL CHCl3 and applied to the cartridge.","The column was washed with 15 mL of 2:1 CHCl3:isopropyl alcohol to elute all the neutral lipids, which was discarded.","The fatty acids were then eluted with 15 mL of 2% acetic acid (HOAc) in ether, which was discarded.","The PL portion was eluted with 15 mL of 6:1 Methanol:Chloroform, which was collected, dried under nitrogen, and weighed.","Flash Chromatography— Flash chromatography was used to separate the lipid classes present in the crude oil.","Approximately 200 mg of crude oil dissolved in hexane was injected onto the head of the column.","The chromatography system utilized Silica Gel 60 (EMD Chemical, Gibbstown, N.J.) with mobile phase composed of Petroleum Ether and Ethyl Acetate at 5 mL/min (Tables 6-7) or 3 mL/min (Tables 8-13).","A step gradient was used to selectively elute each lipid class from the column.","The mobile phase gradient started from 100% petroleum ether and finished with 50% ethyl acetate.","Fractions were collected in 10 mL test tubes using a Gilson FC 204 large-bed fraction collector (Gilson, Inc., Middleton, Wis.).","Each tube was analyzed by thin layer chromatography (TLC) and the tubes containing individual lipid classes (as judged by single spots on TLC plate with expected retention factor (Rf)) were pooled, concentrated to dryness, and weighed.","The total fraction content was then determined gravimetrically.","TLC Analysis— Thin layer chromatography was conducted on silica gel plates.","The plates were eluted using a solvent system consisting of petroleum ether:ethyl ether:acetic acid (80:20:1) and were visualized using iodine vapor.","The Rf values of each spot were then compared with reported literature values for each lipid class.","Analysis of TAG and PL Fractions— The isolated TAG and PL fractions were analyzed for fatty acid composition as fatty acid methyl esters (FAME).","The TAG fractions were dissolved in hexane to give a concentration of approximately 1-2 mg/mL.","1 mL aliquots of the solutions were concentrated to dryness under nitrogen.","Toluene, containing internal standard, and 1.5 N HCl in methanol was added to each tube.","The tubes were vortexed, then capped and heated to 100° C. for 2 hours.","Internal standard and HCl methanol were added directly to the tubes containing the PL fraction and heated.","The tubes were allowed to cool, and saturated NaCl in water was added.","The tubes were vortexed again and centrifuged to allow the layers to separate.","A portion of the organic layer was then placed in a GC vial and analyzed by GC-FID.","FAMEs were quantified using a 3-point calibration curve generated using Nu-Check-Prep GLC 502B Reference Standard (NuCheck, Elysian, Minn.).","Fatty acids present in the extract were expressed as mg/g and as a % of FAME.","Results PTA-10208 Sample #1 The fatty acid profile of the biomass and extracted crude lipid for PTA-10208 Sample #1 was determined using GC/FID.","Fatty acids in the biomass were transesterified in situ by weighing 28.6 mg of biomass directly into a FAME tube, while a sample of the extracted crude lipid was prepared by weighing 55.0 mg of crude lipid into a 50 mL volumetric flask and transferring 1 ml to a separate FAME tube.","The estimated crude lipid content of the biomass was determined to be 53.2% (as SUM of FAME) using GC with FID detection, while 52.0% (wt/wt) lipid was extracted from the dry biomass, giving a 97.8% recovery of total lipid.","The crude lipid was determined to be 91.9% fatty acids (as SUM of FAME) using GC/FID.","The major fatty acids contained in the crude lipid were C16:0 (182.5 mg/g), C20:5 n-3 (186.8 mg/g), and C22:6 n-3 (423.1 mg/g).","The lipid class profile of the extracted crude lipid was determined by weighing 55.0 mg of crude lipid into a 50 mL volumetric flask and transferring an aliquot into an HPLC vial for HPLC/ELSD/MS analysis.","According to the HPLC/ELSD/MS analysis, the crude lipid contained 0.2% sterol esters (SE), 95.1% TAG, 0.4% sterols, and 0.5% 1,2-diacylglycerol (DAG).","5% of the TAG fraction included a peak that eluted directly after the TAG peak, but did not give a recognizable mass spectrum.","Isolated TAG from this sample as determined by flash chromatography made up approximately 92.4% of the crude oil.","PL was not detected by weight or TLC after SPE isolation.","The major fatty acids (>50 mg/g) contained in the TAG were C16:0 (189 mg/g), C20:5 n-3 (197 mg/g), and C22:6 n-3 (441 mg/g).","PTA-10208 Sample #2 The fatty acid profile of the biomass and extracted crude lipid for PTA-10208 Sample #2 was determined using GC/FID.","Fatty acids in the biomass were transesterified in situ by weighing 32.0 mg of biomass directly into a FAME tube, while a sample of the extracted crude lipid was prepared by weighing 60.1 mg of crude lipid into a 50 mL volumetric flask and transferring 1 ml to a separate FAME tube.","The estimated crude lipid content of the biomass was determined to be 52.4% (as SUM of FAME) using GC with FID detection, while 48.0% (wt/wt) lipid was extracted from the dry biomass, giving a 91.7% recovery of total lipid.","The crude lipid was determined to be 95.3% fatty acids (as SUM of FAME) using GC/FID.","The major fatty acids contained in the crude lipid were C16:0 (217.5 mg/g), C20:5 n-3 (169.3 mg/g), and C22:6 n-3 (444.1 mg/g).","The lipid class profile of the extracted crude lipid was determined by weighing 60.1 mg of crude lipid into a 50 mL volumetric flask and transferring an aliquot into an HPLC vial for HPLC/ELSD/MS analysis.","According to the HPLC/ELSD/MS analysis, the crude lipid contained 0.2% SE, 95.7% TAG, 0.3% sterols, and 0.7% 1,2-DAG.","5.1% of the TAG fraction included a peak that eluted directly after the TAG peak, but did not give a recognizable mass spectrum.","Isolated TAG from this sample made up approximately 93.9% of the crude oil.","PL was not detected by weight or TLC after SPE isolation.","The major fatty acids (>50 mg/g) contained in the TAG were C16:0 (218 mg/g), C20:5 n-3 (167 mg/g) and C22:6 n-3 (430 mg/g).","PTA-10208 Sample #3 A sample of crude oil from the microorganism deposited under ATCC Accession No.","PTA-10208 (Sample PTA-10208 #3) was analyzed using HPLC/ELSD/MS.","A total of 98.38% of lipids were recovered, with the sterol ester (SE) fraction accounting for 0.32%, the TAG fraction accounting for 96.13%, the 1,3-diacylglycerol (DAG) fraction accounting for 0.22%, the 1,2-DAG fraction accounting for 0.78%, and the sterol fraction accounting for 0.93%.","PTA-10212 Sample #1 The fatty acid profile of the biomass and extracted crude lipid for PTA-10212 Sample #1 was determined using GC/FID.","Fatty acids in the biomass were transesterified in situ by weighing 27.0 mg of biomass directly into a FAME tube, while a sample of the extracted crude lipid was prepared by weighing 52.5 mg of crude lipid into a 50 mL volumetric flask and transferring 1 ml to a separate FAME tube.","The estimated crude lipid content of the biomass was determined to be 38.3% (as SUM of FAME) using GC with FID detection, while 36.3% (wt/wt) lipid was extracted from the dry biomass, giving a 94.6% recovery of total lipid.","The crude lipid was determined to be 83.2% fatty acids (as SUM of FAME) using GC/FID.","The major fatty acids contained in the crude lipid were C16:0 (328.5 mg/g), C20:5 n-3 (90.08 mg/g), and C22:6 n-3 (289.3 mg/g).","The lipid class profile of the extracted crude lipid was determined by weighing 52.5 mg of crude lipid into a 50 mL volumetric flask and transferring an aliquot into an HPLC vial for HPLC/ELSD/MS analysis.","According to the HPLC/ELSD/MS analysis, the crude lipid contained 0.2% SE, 64.2% TAG, 1.9% FFA, 2.8% 1,3-DAG, 1.4% sterols, 18.8% 1,2-DAG, and 0.5% MAG.","3.4% of the TAG fraction included a peak that eluted directly after the TAG peak, but did not give a recognizable mass spectrum.","Isolated TAG from this sample made up approximately 49.8% of the crude oil.","Isolated PL made up approximately 8.1% of the crude oil.","The major fatty acids (>50 mg/g) contained in the TAG fraction are C16:0 (400 mg/g), C20:5 n-3 (91 mg/g), and C22:6 n-3 (273 mg/g).","The major fatty acids (>50 mg/g) contained in the PL fraction are C16:0 (98 mg/g), C20:5 n-3 (33 mg/g), and C22:6 n-3 (227 mg/g).","PTA-10212 Sample #2 The fatty acid profile of the biomass and extracted crude lipid PTA-10212 Sample #2 was determined using GC/FID.","Fatty acids in the biomass were transesterified in situ by weighing 29.5 mg of biomass directly into a FAME tube, while a sample of the extracted crude lipid was prepared by weighing 56.5 mg of crude lipid into a 50 mL volumetric flask and transferring 1 ml to a separate FAME tube.","The estimated crude lipid content of the biomass was determined to be 40.0% (as SUM of FAME) using GC with FID detection, while 41.3% (wt/wt) lipid was extracted from the dry biomass, giving a 106.1% recovery of total lipid.","The crude lipid was determined to be 82.8% fatty acids (as SUM of FAME) using GC/FID.","The major fatty acids contained in the crude lipid were C16:0 (327.3 mg/g), C20:5 n-3 (92.5 mg/g), and C22:6 11-3 (277.6 mg/g).","The lipid class profile of the extracted crude lipid was determined by weighing 56.5 mg of crude lipid into a 50 mL volumetric flask and transferring an aliquot into an HPLC vial for HPLC/ELSD/MS analysis.","According to the HPLC/ELSD/MS analysis, the crude lipid contained 0.2% SE, 58.2% TAG, 2.3% FFA, 3.4% 1,3-DAG, 1.7% sterols, 23.4% 1,2-DAG, and 0.6% MAG.","3.3% of the TAG fraction included a peak that eluted directly after the TAG peak, but did not give a recognizable mass spectrum.","Isolated TAG from this sample made up approximately 51.9% of the crude oil.","Isolated PL made up approximately 8.8% of the crude oil.","The major fatty acids (>50 mg/g) contained in the TAG fraction are C16:0 (402 mg/g), C20:5 n-3 (92 mg/g), and C22:6 n-3 (245 mg/g).","The major fatty acids (>50 mg/g) contained in the PL fraction are C16:0 (121 mg/g), C20:5 n-3 (48 mg/g), and C22:6 n-3 (246 mg/g).","TABLE 32 Fatty Acid Profiles of PTA-10208 and PTA-10212 Biomasses and Extracted Crude Lipids (mg/g) PTA- PTA- PTA- PTA- PTA- 10208 PTA- 10208 PTA- 10212 PTA- 10212 10208 Sample 10208 Sample 10212 Sample 10212 Sample Sample #1 Sample #2 Sample #1 Sample #2 #1 Crude #2 Crude #1 Crude #2 Crude Biomass Lipid Biomass Lipid Biomass Lipid Biomass Lipid Fatty FAME FAME FAME FAME FAME FAME FAME FAME Acid (mg/g) mg/g) (mg/g) (mg/g) (mg/g (mg/g (mg/g (mg/g) C12:0 1.47 2.43 1.80 3.14 0.99 1.90 0.87 1.91 C14:0 11.62 20.12 16.72 31.03 5.51 12.91 5.97 13.69 C14:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 C15:0 2.43 3.75 3.60 6.22 9.13 20.42 9.39 20.81 C16:0 105.04 182.47 117.72 217.49 145.87 328.45 147.87 327.27 C16:1 0.00 0.00 0.06 0.01 6.26 14.53 7.46 16.89 C18:0 5.37 8.96 4.77 8.37 6.77 15.39 6.77 15.15 C18:1 0.00 3.26 0.00 3.09 0.03 4.04 0.08 5.87 n-9 C18:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-7 C18:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 C20:0 1.48 1.79 1.40 1.85 1.60 3.09 1.67 3.20 C18:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-3 C20:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 C18:4 0.91 1.61 1.10 2.00 2.28 2.56 2.21 2.64 n-3 C20:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 C20:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 C22:0 0.10 0.00 0.08 0.00 0.30 0.12 0.35 0.24 C20:4 0.81 0.45 0.67 0.41 0.00 0.00 0.00 0.00 n-7 C20:4 7.22 12.23 6.84 12.18 1.19 2.26 1.31 2.32 n-6 C22:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 C20:4 0.63 0.52 0.00 0.46 0.00 0.00 0.00 0.00 n-5 C20:4 3.45 5.45 3.33 5.58 0.00 2.40 0.00 2.34 n-3 C20:3 0.09 0.00 0.11 0.00 0.00 0.00 0.00 0.00 n-3 C20:5 107.31 186.83 92.99 169.32 40.32 90.08 43.15 92.54 n-3 C22:4 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 C24:0 0.60 0.00 0.52 0.00 2.81 6.83 2.74 6.53 C24:1 1.55 3.26 0.85 2.04 0.43 1.34 0.42 1.24 n-9 C22:5 9.66 15.84 10.27 17.98 2.42 4.68 2.32 4.21 n-6 C22.5 20.44 35.13 9.92 17.50 2.41 4.94 2.69 5.23 n-3 C22:6 246.98 423.10 245.96 444.08 139.58 289.34 137.35 277.57 n-3 Sum 527.15 907.18 518.71 942.75 367.89 805.29 372.63 799.68 of FAME TABLE 33 Fatty Acid Profiles of PTA-10208 and PTA-10212 Biomasses and Extracted Crude Lipids (%) PTA- PTA- PTA- PTA- PTA- 10208 PTA- 10208 PTA- 10212 PTA- 10212 10208 Sample 10208 Sample 10212 Sample 10212 Sample Sample #1 Sample #2 Sample #1 Sample #2 #1 Crude #2 Crude #1 Crude #2 Crude Biomass Lipid Biomass Lipid Biomass Lipid Biomass Lipid Fatty % % % % % % % % Acid FAME FAME FAME FAME FAME FAME FAME FAME C12:0 0.28 0.27 0.35 0.33 0.27 0.24 0.23 0.24 C14:0 2.20 2.22 3.22 3.29 1.50 1.60 1.60 1.71 C14:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 C15:0 0.46 0.41 0.69 0.66 2.48 2.54 2.52 2.60 C16:0 19.93 20.11 22.70 23.07 39.65 40.79 39.68 40.93 C16:1 0.00 0.00 0.01 0.00 1.70 1.80 2.00 2.11 C18:0 1.02 0.99 0.92 0.89 1.84 1.91 1.82 1.89 C18:1 0.00 0.36 0.00 0.33 0.01 0.50 0.02 0.73 n-9 C18:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-7 C18:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 C20:0 0.28 0.20 0.27 0.20 0.43 0.38 0.45 0.40 C18:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-3 C20:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 C18:4 0.17 0.18 0.21 0.21 0.62 0.32 0.59 0.33 n-3 C20:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 C20:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 C22:0 0.02 0.00 0.01 0.00 0.08 0.02 0.09 0.03 C20:4 0.15 0.05 0.13 0.04 0.00 0.00 0.00 0.00 n-7 C204 1.37 1.35 1.32 1.29 0.32 0.28 0.35 0.29 n-6 C22:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 C20:4 0.12 0.06 0.00 0.05 0.00 0.00 0.00 0.00 n-5 C20:4 0.65 0.60 0.64 0.59 0.00 0.30 0.00 0.29 n-3 C20:3 0.02 0.00 0.02 0.00 0.00 0.00 0.00 0.00 n-3 C20:5 20.36 20.59 17.93 17.96 10.96 11.19 11.58 11.57 n-3 C22:4 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 C24:0 0.11 0.00 0.10 0.00 0.76 0.85 0.74 0.82 C24:1 0.29 0.36 0.16 0.22 0.12 0.17 0.11 0.16 n-9 C22:5 1.83 1.75 1.98 1.91 0.66 0.58 0.62 0.53 n-6 C22:5 3.88 3.87 1.91 1.86 0.65 0.61 0.72 0.65 n-3 C22:6 46.85 46.64 47.42 47.10 37.94 35.93 36.86 34.71 n-3 Sum 100 100 100 100 100 100 100 100 of FAME % TABLE 34 Fatty Acid Profiles of PTA-10208 and PTA-10212 Isolated TAG PTA- PTA- PTA- PTA- PTA- PTA- PTA- PTA- 10208 10208 10208 10208 10212 10212 10212 10212 Sample Sample Sample Sample Sample Sample Sample Sample #1 #1 #2 #2 #1 #1 #2 #2 Fatty FAME % FAME % FAME % FAME % Acid (mg/g) FAME (mg/g) FAME (mg/g) FAME (mg/g) FAME C12:0 2.57 0.27 3.35 0.36 0,00 0.00 0.00 0.00 C14:0 21.07 2.23 31.37 3.41 14.05 1,61 14.45 1.69 C14:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 C15:0 3.89 0.41 6.17 0.67 23.27 2.66 23.14 2.71 C16:0 189.28 20.07 218.78 23.75 399.51 45.75 402.43 47.07 C16:1 0.00 0.00 0.00 0.00 15.23 1.74 17.62 2.06 C18:0 9.21 0.98 8.07 0.88 22.70 2.60 23.10 2.70 C18:1 3.35 0.36 3.64 0.40 6.12 0.70 7.48 0.87 n-9 C18:1 0.00 0.00 0.00 0.00 <0.1 <0.1 <0.1 <0.1 n-7 C18:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 C20:0 1.86 0.20 1.55 0.17 4.76 0.55 5.32 0.62 C18:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-3 C20:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 C18:4 1.64 0.17 2.00 0.22 2.25 0.26 2.24 0.26 n-3 C20:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 C20:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 C22:0 0.00 0.00 0.00 0.00 0.55 0.06 0.89 0.10 Un- 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 known C20:4 0.39 0.04 0.05 0.01 0.00 0.00 0.00 0.00 n-7 C20:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-3 C20:4 12.79 1.36 11.82 1.28 2.33 0.27 2.25 0.26 n-6 C22:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 C20:4 0.39 0.04 0.07 0.01 0.00 0.00 0.00 0.00 n-5 C20:4 5.52 0.59 5.09 0.55 2.87 0.33 2.98 0.35 n-3 C20:5 197.14 20.90 166.68 18.10 91.17 10.44 91.78 10.74 n-3 C24:0 0.00 0.00 0.00 0.00 6.93 0.79 7.36 0.86 C22:4 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 C24:1 1.08 0.11 <0.1 <0.1 0.00 0.00 0.00 0.00 n-9 C22:5 15.88 1.68 16.57 1.80 4.01 0.46 3.39 0.40 n-6 C22:5 36.05 3.82 16.00 1.74 4.53 0.52 5.07 0.59 n-3 C22:6 440.99 46.76 429.83 46.67 273.02 31.26 245.38 28.70 n-3 Sum 943.11 — 921.03 — 873.31 — 854.89 — of FAME Total — 100.00 — 100.00 — 100.00 — 100.00 % FAME TABLE 35 Fatty Acid Profiles of PTA-10212 Isolated PL PTA-10212 PTA-10212 PTA-10212 PTA-10212 Sample # 1 Sample #1 Sample #2 Sample #2 Fatty Acid FAME (mg/g) % FAME FAME (mg/g) % FAME C12:0 0.00 0.00 0.00 0.00 C14:0 0.93 0.22 1.89 0.39 C14:1 0.00 0.00 0.00 0.00 C15:0 3.44 0.82 5.07 1.05 C16:0 98.29 23.50 120.98 25.00 C16:1 1.15 0.27 3.07 0.63 C18:0 3.25 0.78 3.72 0.77 C18:1 n-9 1.12 0.27 0.95 0.20 C18:1 n-7 <0.1 <0.1 0.02 0.003 C18:2 n-6 0.00 0.00 0.00 0.00 C20:0 <0.1 <0.1 <0.1 <0.1 C18:3 n-3 0.00 0.00 0.00 0.00 C20:1 n-9 0.00 0.00 0.00 0.00 C18:4 n-3 3.71 0.89 3.24 0.67 C20:2 n-6 0.00 0.00 0.00 0.00 C20:3 n-6 0.00 0.00 0.00 0.00 C22:0 0.00 0.00 0.00 0.00 Unknown 42.33 10.12 44.71 9.24 C20:4 n-7 0.00 0.00 0.00 0.00 C20:3 n-3 0.00 0.00 0.00 0.00 C20:4 n-6 0.84 0.20 1.54 0.32 C22:1 n-9 0.00 0.00 0.00 0.00 C20:4 n-5 0.00 0.00 0.00 0.00 C20:4 n-3 <0.1 <0.1 0.27 0.06 C20:5 n-3 33.39 7.98 47.91 9.90 C24:0 0.1 <0.1 0.01 0.001 C22:4 n-9 0.00 0.00 0.00 0.00 C24:1 n-9 0.00 0.00 0.00 0.00 C22:5 n-6 3.08 0.74 3.82 0.79 C22:5 n-3 <0.1 <0.1 0.66 0.14 C22:6 n-3 226.68 54.20 246.09 50.85 Sum of 418.21 — 483.94 — FAME Total % — 100 — 100 FAME PTA-10212 Sample #3 The lipid content of the biomass for PTA-10212 Sample #3 was estimated to be 34% as the sum of FAME, and the amount of crude oil obtained after solvent extraction was 37% by weight, giving a 109% recovery of fat present in the biomass.","After fractionation using flash chromatography, approximately 46% of the crude oil was isolated as TAG, 28% was isolated as DAG.","The crude oil contained 309 mg/g DHA and 264 mg/g EPA.","The isolated TAG contained 341 mg/g DHA and 274 mg/g EPA.","The isolated DAG fraction contained 262 mg/g DHA and 237 mg/g EPA.","The total fatty acid profiles of the biomass, extracted crude oil, and isolated fractions are shown below in Table 36 and Table 37 calculated as mg/g and % FAME, respectively.","TABLE 36 Fatty Acid Profiles of PTA-10212 Sample #3 Biomass and Extracted Crude Lipid (mg/g) Crude Biomass Oil TAG DAG Wt.","% NA 37.2% 46.0% 27.9% FAME FAME FAME FAME Fatty Acid (mg/g) (mg/g) (mg/g) (mg/g) C12:0 0.0 0.0 0.0 0.0 C14:0 3.6 10.3 11.5 9.4 C14:1 0.0 0.0 0.0 0.0 C15:0 4.1 10.6 9.8 6.6 C16:0 70.5 181.8 231.7 111.3 C16:1 6.7 19.1 18.7 17.1 C18:0 2.4 10.2 14.2 0.0 C18:1 n-9 0.0 6.7 0.0 0.0 C18:1 n-7 0.0 1.2 0.0 0.0 C18:2 n-6 0.0 1.8 0.0 0.0 C20:0 0.0 2.4 0.0 0.0 C18:3 n-3 0.0 0.0 0.0 0.0 C20:1 n-9 0.0 0.3 0.0 1.7 C18:4 n-3 1.9 3.4 3.2 4.4 C20:2 n-6 0.0 0.0 0.0 0.0 C20:3 n-6 0.0 0.0 0.0 0.0 C22:0 3.3 0.0 0.0 0.0 C20:4 n-7 0.0 2.1 1.5 0.0 C20:3 n-3 0.0 0.0 0.0 0.0 C20:4 n-6 6.8 17.9 21.4 13.8 C22:1 n-9 0.0 0.0 0.0 0.0 C20:4 n-5 0.0 1.3 1.3 0.0 C20:4 n-3 3.0 8.5 10.9 6.4 C20:5 n-3 102.0 263.6 274.2 237.4 C24:0 0.0 1.7 3.9 0.0 C22:4 n-9 0.0 0.0 0.0 0.0 C24:1 n-9 0.0 0.0 4.2 0.0 C22:5 n-6 3.2 8.3 10.7 6.1 C22:5 n-3 3.8 10.4 15.1 6.6 C22:6 n-3 131.2 309.4 341.1 261.9 Sum of FAME 342.4 871.1 973.2 682.6 TABLE 37 Fatty Acid Profiles of PTA-10212 Sample #3 Biomass and Extracted Crude Lipid (%) Crude Biomass Oil TAG DAG Wt.","% NA 37.2% 46.0% 27.9% FAME FAME FAME FAME Fatty Acid (mg/g) (mg/g) (mg/g) (mg/g) C12:0 0.0 0.0 0.0 0.0 C14:0 1.1 1.2 1.2 1.4 C14:1 0.0 0.0 0.0 0.0 C15:0 1.2 1.2 1.0 1.0 C16:0 20.6 20.9 23.8 16.3 C16:1 2.0 2.2 1.9 2.5 C18:0 0.7 1.2 1.5 0.0 C18:1 n-9 0.0 0.8 0.0 0.0 C18:1 n-7 0.0 0.1 0.0 0.0 C18:2 n-6 0.0 0.2 0.0 0.0 C20:0 0.0 0.3 0.0 0.0 C18:3 n-3 0.0 0.0 0.0 0.0 C20:1 n-9 0.0 0.0 0.0 0.2 C18:4 n-3 0.6 0.4 0.3 0.6 C20:2 n-6 0.0 0.0 0.0 0.0 C20:3 n-6 0.0 0.0 0.0 0.0 C22:0 1.0 0.0 0.0 0.0 C20:4 n-7 0.0 0.2 0.2 0.0 C20:3 n-3 0.0 0.0 0.0 0.0 C20:4 n-6 2.0 2.1 2.2 2.0 C22:1 n-9 0.0 0.0 0.0 0.0 C20:4 n-5 0.0 0.1 0.1 0.0 C20:4 n-3 0.9 1.0 1.1 0.9 C20:5 n-3 29.8 30.3 28.2 34.8 C24:0 0.0 0.2 0.4 0.0 C22:4 n-9 0.0 0.0 0.0 0.0 C24:1 n-9 0.0 0.0 0.4 0.0 C22:5 n-6 0.9 1.0 1.1 0.9 C22:5 n-3 1.1 1.2 1.6 1.0 C22:6 n-3 38.3 35.5 35.1 38.4 Total % FAME 100.0 100.0 100.0 100.0 PTA-10212 Sample #4 PTA-10212 Sample #4 contained approximately 23% lipid determined as the sum of FAME, of which 107% was recovered using hexane extraction.","After fractionation using flash chromatography, approximately 42% of the crude oil was isolated as TAG, 18% was isolated as DAG.","The crude oil contained 275 mg/g DHA and 209 mg/g EPA.","The isolated TAG contained 296 mg/g DHA and 205 mg/g EPA.","The isolated DAG fraction contained 245 mg/g DHA and 219 mg/g EPA.","The total fatty acid profiles of the biomass, extracted crude oil, and isolated fractions are shown below in Table 38 (mg/g) and Table 39 (% FAME).","TABLE 38 Fatty Acid Profiles of PTA-10212 Sample #4 Biomass and Extracted Crude Lipid (mg/g) Crude Biomass Oil TAG DAG Wt.","% NA 24.7% 42.2% 18.4% FAME FAME FAME FAME Fatty Acid (mg/g) (mg/g) (mg/g) (mg/g) C12:0 0.0 0.0 2.1 2.4 C14:0 2.0 8.3 9.8 9.6 C14:1 0.0 0.0 0.0 0.0 C15:0 4.8 16.8 0.4 0.9 C16:0 63.3 210.6 285.7 138.0 C16:1 1.6 6.7 7.4 7.5 C18:0 2.8 12.2 19.9 4.6 C18:1 n-9 0.0 3.7 0.7 1.1 C18:1 n-7 0.0 0.0 0.3 1.2 C18:2 n-6 0.0 0.0 0.0 0.0 C20:0 0.0 3.3 6.0 1.5 C18:3 n-3 0.0 0.0 0.0 0.0 C20:1 n-9 0.0 0.0 0.7 1.2 C18:4 n-3 1.4 3.8 3.6 5.0 C20:2 n-6 0.0 0.0 0.0 0.0 C20:3 n-6 0.0 0.0 0.4 0.0 C22:0 1.5 0.0 1.9 0.0 C20:4 n-7 0.0 0.0 0.9 0.6 C20:3 n-3 0.0 0.0 0.0 0.0 C20:4 n-6 2.5 10.1 13.0 10.3 C22:1 n-9 0.0 0.0 0.0 0.0 C20:4 n-5 0.0 0.0 0.8 0.7 C20:4 n-3 1.4 6.3 8.6 6.0 C20:5 n-3 57.6 209.1 205.4 219.0 C24:0 0.0 2.6 0.8 0.0 C22:4 n-9 0.1 0.0 0.0 0.0 C24:1 n-9 0.0 0.0 1.1 0.5 C22:5 n-6 1.4 6.1 7.9 4.5 C22:5 n-3 4.0 15.8 20.8 12.9 C22:6 n-3 87.7 275.0 296.4 244.8 Sum of FAME 232.2 790.1 894.8 672.4 TABLE 39 Fatty Acid Profiles of PTA-10212 Sample #4 Biomass and Extracted Crude Lipid (%) Crude Biomass Oil TAG DAG Wt.","% NA 24.7% 42.2% 18.4% FAME FAME FAME FAME Fatty Acid (mg/g) (mg/g) (mg/g) (mg/g) C12:0 0.0 0.0 0.2 0.4 C14:0 0.9 1.0 1.1 1.4 C14:1 0.0 0.0 0.0 0.0 C15:0 2.1 2.1 0.0 0.1 C16:0 27.3 26.7 31.9 20.5 C16:1 0.7 0.8 0.8 1.1 C18:0 1.2 1.5 2.2 0.7 C18:1 n-9 0.0 0.5 0.1 0.2 C18:1 n-7 0.0 0.0 0.0 0.2 C18:2 n-6 0.0 0.0 0.0 0.0 C20:0 0.0 0.4 0.7 0.2 C18:3 n-3 0.0 0.0 0.0 0.0 C20:1 n-9 0.0 0.0 0.1 0.2 C18:4 n-3 0.6 0.5 0.4 0.7 C20:2 n-6 0.0 0.0 0.0 0.0 C20:3 n-6 0.0 0.0 0.0 0.0 C22:0 0.6 0.0 0.2 0.0 C20:4 n-7 0.0 0.0 0.1 0.1 C20:3 n-3 0.0 0.0 0.0 0.0 C20:4 n-6 1.1 1.3 1.5 1.5 C22:1 n-9 0.0 0.0 0.0 0.0 C20:4 n-5 0.0 0.0 0.1 0.1 C20:4 n-3 0.6 0.8 1.0 0.9 C20:5 n-3 24.8 26.5 23.0 32.6 C24:0 0.0 0.3 0.1 0.0 C22:4 n-9 0.0 0.0 0.0 0.0 C24:1 n-9 0.0 0.0 0.1 0.1 C22:5 n-6 0.6 0.8 0.9 0.7 C22:5 n-3 1.7 2.0 2.3 1.9 C22:6 n-3 37.8 34.8 33.1 36.4 Total % FAME 100.0 100.0 100.0 100.0 PTA-10212 Sample #5 A sample of crude oil was extracted from a biomass of PTA-10212 using the FRIOLEX® process (GEA Westfalia Separator UK Ltd., Milton Keynes, England) to yield microbial oil PTA-10212 Sample #5.Individual lipid classes were isolated from PTA-10212 Sample #5 using low pressure flash chromatography, and the weight percent of each class was determined.","The fatty acid profile of each class was determined using GC-FID.","Briefly, the sample was prepared by dissolving 240 mg of crude oil in 600 μL of hexane and applying to the head of the column.","After fractionation of the sample using flash chromatography, the combined weights of all the fractions was 240 mg giving a 100% recovery.","The sterol ester fraction accounted for 0.9%, the TAG fraction accounted for 42.6%, the free fatty acid (FFA) fraction accounted for 1.3%, the sterol fraction accounted for 2.2%, and the DAG fraction accounted for 41.6%.","The total fatty acid profiles of the FRIOLEX® crude oil and isolated fractions are shown below in Table 40 and Table 41 calculated as mg/g and % FAME, respectively.","TABLE 40 Fatty Acid Profiles of PTA-10212 Sample #5 Crude Oil (mg/g) Crude Oil TAG DAG Wt.","% NA 42.6% 41.6% FAME FAME FAME Fatty Acid (mg/g) (mg/g) (mg/g) C12:0 0 0.7 1.0 C14:0 7.7 7.7 8.5 C14:1 0 0.0 0.0 C15:0 10.3 11.7 9.3 C16:0 179.3 217.7 134.6 C16:1 18.1 16.3 25.9 C18:0 8.1 13.2 2.3 C18:1 n-9 4.7 8.4 0.7 C18:1 n-7 0 1.8 1.0 C18:2 n-6 1.8 3.3 0.7 C20:0 1.9 3.6 0.2 C18:3 n-3 0 0.0 0.0 C20:1 n-9 0 0.7 1.0 C18:4 n-3 3.1 2.8 3.8 C20:2 n-6 0 0.0 0.0 C20:3 n-6 0 0.6 0.4 C22:0 0 1.5 0.0 C20:4 n-7 0 1.0 0.7 C20:3 n-3 0 0.0 0.0 C20:4 n-6 12.7 16.1 13.6 C22:1 n-9 0 0.0 0.0 C20:4 n-5 0 1.5 0.8 C20:4 n-3 6.5 9.3 6.4 C20:5 n-3 213.3 223.7 252.8 C24:0 2.3 4.4 0.6 C22:4 n-9 0 1.9 0.9 C24:1 n-9 0 0.0 0.0 C22:5 n-6 7.9 9.5 8.3 C22:5 n-3 13 20.6 9.7 C22:6 n-3 305.6 327.4 353.8 Sum of FAME 796.6 905.3 837.4 TABLE 41 Fatty Acid Profiles of PTA-10212 Sample #5 Crude Oil (%) Crude Oil TAG DAG Fatty Acid % FAME % FAME % FAME C12:0 0 0.1 0.1 C14:0 1 0.9 1.0 C14:1 0 0.0 0.0 C15:0 1.3 1.3 1.1 C16:0 22.5 24.0 16.1 C16:1 2.3 1.8 3.1 C18:0 1 1.5 0.3 C18:1 n-9 0.6 0.9 0.1 C18:1 n-7 0 0.2 0.1 C18:2 n-6 0.2 0.4 0.1 C20:0 0.2 0.4 0.0 C18:3 n-3 0 0.0 0.0 C20:1 n-9 0 0.1 0.1 C18:4 n-3 0.4 0.3 0.5 C20:2 n-6 0 0.0 0.0 C20:3 n-6 0 0.1 0.0 C22:0 0 0.2 0.0 C20:4 n-7 0 0.1 0.1 C20:3 n-3 0 0.0 0.0 C20:4 n-6 1.6 1.8 1.6 C22:1 n-9 0 0.0 0.0 C20:4 n-5 0 0.2 0.1 C20:4 n-3 0.8 1.0 0.8 C20:5 n-3 26.8 24.7 30.2 C24:0 0.3 0.5 0.1 C22:4 n-9 0 0.2 0.1 C24:1 n-9 0 0.0 0.0 C22:5 n-6 1 1.1 1.0 C22:5 n-3 1.6 2.3 1.2 C22:6 n-3 38.4 36.2 42.3 Total % FAME 100 100 100 Example 37 Crude oils were further processed via refining, bleaching, and deodorizing to obtain refined oils.","The refined oils were diluted with high oleic sunflower oil to obtain final oils with a DHA content of approximately 400 mg/g.","Individual lipid classes were isolated and the fatty acid profiles of each class were determined using GC-FID as FAME.","PTA-10208 Final Oils The fatty acid profiles for PTA-10208 Final Oils #1-5 are summarized in Tables 42-43, including profiles associated within the isolated TAG fraction (Tables 44-45) and the isolated sterols/DAG fraction (Tables 46-47).","Individual lipid classes in the final oils were also determined using flash chromatography (Table 48) and normal HPLC with ELSD and APCI-MS confirmation (Table 49).","TABLE 42 Fatty Acid Profiles of PTA-10208 Final Oils (mg/g) PTA-10208 PTA-10208 PTA-10208 PTA-10208 PTA-10208 Final Oil #1 Final Oil #2 Final Oil #3 Final Oil #4 Final Oil #5 FAME FAME FAME FAME FAME Fatty Acid (mg/g) (mg/g) (mg/g) (mg/g) (mg/g) C12:0 2.5 2.4 2.8 2.7 2.7 C14:0 16.1 14.9 21.0 18.4 17.5 C14:1 0.0 0.0 0.0 0.0 0.0 C15:0 3.8 3.6 4.4 3.9 3.9 C16:0 192.1 179.1 193.1 184.3 194.6 C16:1 0.4 0.5 0.5 0.5 0.5 C17:0 0.6 0.5 0.9 0.8 2.1 C18:0 12.8 13.9 11.5 12.3 12.9 C18:1 n-9 23.5 82.0 25.7 26.0 29.5 C18:1 n-7 0.2 0.7 0.1 0.1 0.1 C18:2 n-6 3.7 8.1 4.0 4.1 4.3 C20:0 4.3 4.1 3.7 4.0 4.0 C18:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:1 n-9 <0.1 0.1 <0.1 <0.1 <0.1 C18:4 n-3 2.4 2.5 2.8 2.7 2.8 C20:2 n-6 0.0 0.0 0.0 0.0 0.0 C20:3 n-6 0.2 0.1 0.1 0.1 0.1 C22:0 1.2 1.8 1.0 1.1 1.1 C20:4 n-7 1.7 1.6 1.7 1.8 1.6 C20:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:4 n-6 12.9 12.1 13.5 13.5 13.3 C22:1 n-9 0.0 0.0 0.0 0.0 0.0 C20:4 n-5 1.6 1.4 1.5 1.7 1.5 C20:4 n-3 6.0 5.7 6.0 6.0 6.1 C20:5 n-3 173.8 163.3 196.4 209.6 197.9 C24:0 1.4 1.6 1.3 1.3 1.0 C22:4 \\n-9 0.0 0.0 0.0 0.0 0.0 C24:1 n-9 3.4 3.2 2.3 2.6 2.3 C22:5 n-6 14.9 14.0 14.4 13.0 12.9 C22:5 n-3 43.9 41.3 32.8 40.3 36.9 C22:6 n-3 394.8 373.7 373.2 374.3 364.2 Sum of FAME 918.1 932.2 914.7 925.1 914.1 TABLE 43 Fatty Acid Profiles of PTA-10208 Final Oils (%) PTA-10208 PTA-10208 PTA-10208 PTA-10208 PTA-10208 Final Oil #1 Final Oil #2 Final Oil #3 Final Oil #4 Final Oil #5 Fatty Acid % FAME % FAME % FAME % FAME % FAME C12:0 0.3 0.3 0.3 0.3 0.3 C14:0 1.8 1.6 2.3 2.0 1.9 C14:1 0.0 0.0 0.0 0.0 0.0 C15:0 0.4 0.4 0.5 0.4 0.4 C16:0 20.9 19.2 21.1 19.9 21.3 C16:1 <0.1 <0.1 <0.1 <0.1 0.1 C17:0 0.1 0.1 0.1 0.1 0.2 C18:0 1.4 1.5 1.3 1.3 1.4 C18:1 n-9 2.6 8.8 2.8 2.8 3.2 C18:1 n-7 <0.1 0.1 <0.1 <0.1 <0.1 C18:2 n-6 0.4 0.9 0.4 0.4 0.5 C20:0 0.5 0.4 0.4 0.4 0.4 C18:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:1 n-9 <0.1 <0.1 <0.1 <0.1 <0.1 C18:4 n-3 0.3 0.3 0.3 0.3 0.3 C20:2 n-6 0.0 0.0 0.0 0.0 0.0 C20:3 n-6 <0.1 <0.1 <0.1 <0.1 <0.1 C22:0 0.1 0.2 0.1 0.1 0.1 C20:4 n-7 0.2 0.2 0.2 0.2 0.2 C20:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:4 n-6 1.4 1.3 1.5 1.5 1.5 C22:1 n-9 0.0 0.0 0.0 0.0 0.0 C20:4 \\n-5 0.2 0.2 0.2 0.2 0.2 C20:4 \\n-3 0.7 0.6 0.7 0.7 0.7 C20:5 n-3 18.9 17.5 21.5 22.7 21.6 C24:0 0.1 0.2 0.1 0.1 0.1 C22:4 n-9 0.0 0.0 0.0 0.0 0.0 C24:1 n-9 0.4 0.3 0.2 0.3 0.2 C22:5 n-6 1.6 1.5 1.6 1.4 1.4 C22:5 n-3 4.8 4.4 3.6 4.4 4.0 C22:6 n-3 43.0 40.1 40.8 40.5 39.9 TABLE 44 Isolated TAG Fatty Acid Profiles: PTA-10208 Final Oils (mg/g) PTA-10208 PTA-10208 PTA-10208 PTA-10208 PTA-10208 Final Oil #1 Final Oil #2 Final Oil #3 Final Oil #4 Final Oil #5 FAME FAME FAME FAME FAME Fatty Acid (mg/g) (mg/g) (mg/g) (mg/g) (mg/g) C12:0 2.5 2.3 2.7 2.5 2.6 C14:0 16.3 15.1 21.3 18.6 18.1 C14:1 0.0 0.0 0.0 0.0 0.0 C15:0 3.9 3.6 4.4 4.0 4.0 C16:0 194.2 181.9 196.1 186.1 199.8 C16:1 0.4 0.4 0.6 0.5 0.7 C17:0 0.6 0.5 0.9 0.8 0.8 C18:0 12.9 14.2 11.7 12.5 13.2 C18:1 n-9 24.3 84.0 26.8 26.1 34.0 C18:1 n-7 0.1 0.7 0.1 0.1 0.3 C18:2 n-6 3.2 7.7 3.4 3.5 4.0 C20:0 4.4 4.2 3.8 4.0 4.2 C18:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:1 n-9 <0.1 0.2 <0.1 <0.1 0.1 C18:4 n-3 2.5 2.4 2.8 2.6 2.7 C20:2 n-6 0.0 0.0 0.0 0.0 0.0 C20:3 n-6 0.2 0.2 0.1 0.1 0.1 C22:0 1.2 1.9 1.0 1.1 1.1 C20:4 n-7 1.7 1.6 1.8 1.8 1.7 C20:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:4 n-6 13.2 12.3 13.8 13.7 13.8 C22:1 n-9 0.0 0.0 0.0 0.0 0.0 C20:4 n-5 1.6 1.5 1.6 1.7 1.5 C20:4 n-3 6.1 5.7 6.1 5.9 6.2 C20:5 n-3 176.0 166.1 199.0 211.2 204.2 C24:0 1.2 1.3 1.0 1.1 1.2 C22:4 n-9 0.0 0.0 0.0 0.0 0.0 C24:1 n-9 3.3 3.2 2.2 2.5 2.4 C22:5 n-6 15.0 14.2 14.7 13.2 13.5 C22:5 n-3 44.4 42.0 33.3 40.5 38.3 C22:6 n-3 397.9 378.4 376.4 375.5 375.5 Sum of FAME 926.9 945.7 925.5 929.6 944.1 TABLE 45 Isolated TAG Fatty Acid Profiles: PTA-10208 Final Oils (%) PTA-10208 PTA-10208 PTA-10208 PTA-10208 PTA-10208 Final Oil #1 Final Oil #2 Final Oil #3 Final Oil #4 Final Oil #5 Fatty Acid % FAME % FAME % FAME % FAME % FAME C12:0 0.3 0.2 0.3 0.3 0.3 C14:0 1.8 1.6 0.3 0.3 0.3 C14:1 0.0 0.0 0.0 0.0 0.0 C15:0 0.4 0.4 0.5 0.4 0.4 C16:0 20.9 19.2 21.2 20.0 21.2 C16:1 <0.1 <0.1 0.1 0.1 0.1 C17:0 0.1 0.1 0.1 0.1 0.1 C18:0 1.4 1.5 1.3 1.3 1.4 C18:1 n-9 2.6 8.9 2.9 2.8 3.6 C18:1 n-7 <0.1 0.1 <0.1 <0.1 <0.1 C18:2 n-6 0.3 0.8 0.4 0.4 0.4 C20:0 0.5 0.4 0.4 0.4 0.4 C18:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:1 n-9 <0.1 <0.1 <0.1 <0.1 <0.1 C18:4 n-3 0.3 0.3 0.3 0.3 0.3 C20:2 n-6 0.0 0.0 0.0 0.0 0.0 C20:3 n-6 <0.1 <0.1 <0.1 <0.1 <0.1 C22:0 0.1 0.2 0.1 0.1 0.1 C20:4 n-7 0.2 0.2 0.2 0.2 0.2 C20:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:4 n-6 1.4 1.3 1.5 1.5 1.5 C22:1 n-9 0.0 0.0 0.0 0.0 0.0 C20:4 n-5 0.2 0.2 0.2 0.2 0.2 C20:4 n-3 0.7 0.6 0.7 0.6 0.7 C20:5 n-3 19.0 17.6 21.5 22.7 21.6 C24:0 0.1 0.1 0.1 0.1 0.1 C22:4 n-9 0.0 0.0 0.0 0.0 0.0 C24:1 n-9 0.4 0.3 0.2 0.3 0.3 C22:5 n-6 1.6 1.5 1.6 1.4 1.4 C22:5 n-3 4.8 4.4 3.6 4.4 4.1 C22:6 n-3 42.9 40.0 40.7 40.4 39.8 TABLE 46 Isolated Sterols/DAG Fatty Acid Profiles: PTA-10208 Final Oils (mg/g) PTA-10208 PTA-10208 PTA-10208 PTA-10208 PTA-10208 Final Oil #1 Final Oil #2 Final Oil #3 Final Oil #4 Final Oil #5 FAME FAME FAME FAME FAME Fatty Acid (mg/g) (mg/g) (mg/g) (mg/g) (mg/g) C12:0 1.9 2.1 2.9 2.1 1.9 C14:0 9.9 9.5 9.7 10.3 8.0 C14:1 0.0 0.0 0.0 0.0 0.0 C15:0 2.4 2.3 2.2 2.3 2.0 C16:0 132.6 128.6 110.1 116.8 106.4 C16:1 0.2 0.3 <0.1 0.3 0.4 C17:0 0.3 0.2 0.3 0.3 0.3 C18:0 7.3 8.1 6.4 6.8 6.1 C18:1 n-9 15.0 55.1 47.4 19.0 30.1 C18:1 n-7 0.4 0.7 0.1 <0.1 0.2 C18:2 n-6 13.1 16.7 21.6 13.5 18.4 C20:0 2.0 2.1 1.2 1.8 1.4 C18:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:1 n-9 <0.1 <0.1 <0.1 <0.1 <0.1 C18:4 n-3 2.3 2.4 2.4 2.4 2.0 C20:2 n-6 0.0 0.0 0.0 0.0 0.0 C20:3 n-6 <0.1 <0.1 <0.1 <0.1 <0.1 C22:0 0.6 1.0 0.5 0.6 0.5 C20:4 n-7 0.8 0.9 2.1 0.9 0.7 C20:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:4 n-6 5.7 5.8 4.8 6.1 4.5 C22:1 n-9 0.0 0.0 0.0 0.0 0.0 C20:4 n-5 <0.1 <0.1 <0.1 0.6 <0.1 C20:4 n-3 2.7 2.7 2.1 2.7 2.0 C20:5 n-3 92.9 94.5 91.9 111.6 84.8 C24:0 1.2 1.3 1.1 1.1 1.3 C22:4 n-9 0.0 0.0 0.0 0.0 0.0 C24:1 n-9 1.9 2.0 1.2 1.5 1.2 C22:5 n-6 7.8 8.0 6.7 7.0 5.5 C22:5 n-3 22.2 22.9 13.9 20.7 14.2 C22:6 n-3 246.3 252.7 223.5 240.3 196.3 Sum of FAME 569.3 619.8 552.1 568.7 488.2 TABLE 47 Isolated Sterols/DAG Fatty Acid Profiles: PTA-10208 Final Oils (%) PTA-10208 PTA-10208 PTA-10208 PTA-10208 PTA-10208 Final Oil #1 Final Oil #2 Final Oil #3 Final Oil #4 Final Oil #5 Fatty Acid % FAME % FAME % FAME % FAME % FAME C12:0 0.3 0.3 0.5 0.4 0.4 C14:0 1.7 1.5 1.8 1.8 1.6 C14:1 0.0 0.0 0.0 0.0 0.0 C15:0 0.4 0.4 0.4 0.4 0.4 C16:0 23.3 20.8 19.9 20.5 21.8 C16:1 <0.1 <0.1 <0.1 <0.1 0.1 C17:0 0.0 0.0 0.1 0.1 0.1 C18:0 1.3 1.3 1.2 1.2 1.2 C18:1 n-9 2.6 8.9 8.6 3.3 6.2 C18:1 n-7 0.1 0.1 <0.1 <0.1 <0.1 C18:2 n-6 2.3 2.7 3.9 2.4 3.8 C20:0 0.4 0.3 0.2 0.3 0.3 C18:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:1 n-9 <0.1 <0.1 <0.1 <0.1 <0.1 C18:4 n-3 0.4 0.4 0.4 0.4 0.4 C20:2 n-6 0.0 0.0 0.0 0.0 0.0 C20:3 n-6 <0.1 <0.1 <0.1 <0.1 <0.1 C22:0 0.1 0.2 0.1 0.1 0.1 C20:4 n-7 0.1 0.1 0.4 0.2 0.1 C20:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:4 n-6 1.0 0.9 0.9 1.1 0.9 C22:1 n-9 0.0 0.0 0.0 0.0 0.0 C20:4 n-5 <0.1 <0.1 <0.1 0.1 <0.1 C20:4 n-3 0.5 0.4 0.4 0.5 0.4 C20:5 n-3 16.3 15.2 16.6 19.6 17.4 C24:0 0.2 0.2 0.2 0.2 0.3 C22:4 n-9 0.0 0.0 0.0 0.0 0.0 C24:1 n-9 0.3 0.3 0.2 0.3 0.2 C22:5 n-6 1.4 1.3 1.2 1.2 1.1 C22:5 n-3 3.9 3.7 2.5 3.6 2.9 C22:6 n-3 43.3 40.8 40.5 42.3 40.2 TABLE 48 Lipid class separation by flash chromatography (wt %) Lipid Class PTA-10208 PTA-10208 PTA-10208 PTA-10208 PTA-10208 Separation Final Oil #1 Final Oil #2 Final Oil #3 Final Oil #4 Final Oil #5 TAG 93.4 95.4 94.0 95.7 95.1 Sterols/DAG 3.1 2.9 2.6 3.0 2.9 Recovery (%) 96.5 98.3 96.6 98.7 98.0 TABLE 49 Lipid class separation by HPLC-ELSD (wt %) Sterol 1,3- 1,2- Esters TAG FFA Sterols DAG DAG MAG Total PTA-10208 0.4 90.8 ND 0.8 0.5 0.5 N.D. 93.0 Final Oil #1 PTA-10208 0.4 88.5 ND 0.6 0.6 0.6 N.D. 90.7 Final Oil #2 PTA-10208 0.3 89.4 ND 0.8 0.6 0.5 N.D. 91.6 Final Oil 43 PTA-10208 0.3 88.0 ND 0.8 0.5 0.5 N.D. 90.1 Final Oil #4 PTA-10208 0.3 86.3 ND 0.7 0.8 0.5 N.D. 88.6 Final Oil #5 PTA-10208 0.36 100.76 ND 0.84 0.54 0.61 N.D. 103.11 Final Oil #16 ND = Not Detected PTA-10212 Final Oil DHA was present in a PTA-10212 Final Oil at 41.63% and 366.9 mg/g, while EPA was present at 16.52%.","Individual fatty acid profiles were determined and are summarized in Table 50.TABLE 50 Fatty Acid Profiles of PTA-10212 Final Oil (% FAME) Fatty Acid % FAME C6:0 ND C7:0 ND C8:0 ND C9:0 ND C10:0 ND C11:0 ND C12:0 ND C13:0 ND C14:0 0.84 C14:1 ND C15:0 1.33 C16:0 27.09 C16:1 1.03 C17:0 0.34 C17:1 ND C18:0 1.26 C18:1 n-9 2.14 C18:1 n-7 0.18 C19:0 ND C18:2 n-6 0.58 C20:0 0.32 C18:3 n-3 ND C20:1 n-9 ND C18:3 n-6 ND C20:2 n-6 0.26 C20:3 n-6 ND C22:0 0.14 C20:3 n-3 ND C20:4 n-6 1.34 C22:1 n-9 ND C23:0 ND C20:5 n-3 16.53 C24:0 0.53 C24:1 n-9 ND C22:5 n-6 1.50 C22:5 n-3 1.30 C22:6 n-3 41.63 Unknown 0.87 ND = Not Detected Example 38 A two-day old inoculum flask of the isolated microorganisms deposited under ATCC Accession Nos.","PTA-10208 and 10212 was prepared as a carbon and nitrogen-fed culture in media according to Tables 30 and 31.Mutagenesis was carried out according to following procedure: A sterile T=2 day old flask, approximately 50 ml, was poured into a sterile 40 ml glass homogenizer.","The culture received 50 plunges in the homogenizer.","The culture was pipetted out and filtered through a sterile 50 micron mesh filter, which was placed in a 50 ml sterile tube (the mesh was used as a means of retaining the larger clumps of colonies while letting the smaller clusters and single cells pass through the 50 micron mesh.).","The entire concentrated macerate was collected in a sterile 50 ml tube.","The macerated culture was vortexed and dilutions at levels up to 1:100 fold were made.","The diluted macerate samples were vortexed prior to adding 200 μl of inoculum to a media agar plate, 100×15 mm, containing 4-5 glass beads (3 mm glass beads).","Each plate was gently agitated in an effort to have the beads spread the inoculum evenly around the plate.","Beads were dumped off of plates and plates were left to sit with covers on for approximately 5 minutes to dry.","Lights in both the sterile hood and adjoining areas were turned off as the procedure was performed in dim light.","There was minimal light available to be able to run the procedure but only indirect and dim.","Five replicate plates were placed on the floor of the XL crosslinker (Spectronics Corporation, New York) with the lids off while the samples were irradiated.","The crosslinker delivered power in terms of microjoules and a level was sought that achieved a 90%-95% Kill.","Five replicate control plates were inoculated with un-mutagenized cells using the same protocol.","These cell counts were used to calculate the % Kill.","Once the irradiation was finished the plates were taken out, the lids were replaced, and the plates were wrapped in parafilm followed by a wrap in aluminum foil.","It was imperative that the plates grew for the first week in the dark so that they were not able to repair the damaged genes.","Plates were placed in a 22.5° C. room for about 10 days prior to counting the colonies.","When final counts were made, individual colonies were picked with a sterile inoculating loop and re-streaked on new media plates.","Each colony was plated on an individual plate.","As plates grew dense a sample was taken, using a inoculating loop, and inoculated into a sterile 250 ml shake flask containing 50 ml of media.","This flask was placed on a shaker at 200 rpm in a 22.5° C. room.","On T=7 days the shake flask culture was harvested into a 50 ml sterile tube.","The pH was taken and the sample was centrifuged to collect the biomass pellet.","Each sample was rinsed and re-suspended in a 50:50 mixture of isopropyl alcohol and distilled water prior to being re-centrifuged.","The collected pellet was freeze dried, weighed, and a FAME analysis was performed.","The data in Tables 51 and 52 represents mutants produced with the above process from strains PTA-10208 and PTA-10212, respectively.","TABLE 51 PTA-10208 Mutants control Mutant 1 Mutant 2 Mutant 3 Fatty Acids PTA-10208 PTA-10209 PTA-10210 PTA-10211 % 08:0 0.00 0.00 0.00 0.00 % 09:0 0.00 0.00 0.00 0.00 % 10:0 0.00 0.00 0.00 0.00 % 11:0 0.00 0.00 0.00 0.00 % 11:1 0.00 0.00 0.00 0.00 % 12:0 0.11 0.10 0.22 0.19 % 12:1 0.00 0.00 0.00 0.00 % 13:0 0.19 0.19 0.15 0.16 % 13:1 0.00 0.00 0.00 0.00 % 14:0 1.94 1.82 2.98 2.59 % 14:1 0.00 0.00 0.00 0.00 % 15:1 2.66 2.22 1.76 1.66 % 16:0 24.87 24.97 23.71 25.01 % 16:1 0.20 0.25 0.07 0.07 % 16:2 0.00 0.00 0.00 0.00 % 16:3 0.00 0.00 0.00 0.00 % 17:0 1.49 1.21 0.62 0.66 % 18:0 1.13 1.14 0.91 1.01 % 18:1 n-9 0.07 0.07 0.06 0.06 % 18:1 n-7 0.00 0.00 0.00 0.00 % 18:2 0.00 0.00 0.00 0.00 % 18:3 n-6 0.00 0.00 0.05 0.04 % 18:3 n-3 0.09 0.08 0.17 0.14 % 18:4 n-3 0.00 0.00 0.00 0.00 % 20:0 0.31 0.33 0.24 0.30 % 20:1 n-9 0.00 0.04 0.00 0.00 % 20:2 0.00 0.00 0.05 0.00 % 20:3 n-9 0.00 0.00 0.00 0.00 % 20:3 n-6 0.12 0.13 0.08 0.04 % 20:3 n-3 0.42 0.42 0.08 0.06 % 20:4 ARA 0.68 0.67 1.44 1.11 % 20:5 n-3 6.56 6.47 11.99 9.87 EPA % 22:0 0.07 0.07 0.06 0.07 % 22:1 0.00 0.00 0.00 0.00 % 22:2 0.11 0.09 0.10 0.08 % 22:3 0.00 0.00 0.00 0.00 % 22:4 n-6 0.00 0.00 0.00 0.00 % 22:5 n-6 2.32 2.36 2.36 2.36 % 22:5 n-3 0.48 0.66 0.66 0.52 % 22:6 n-3 51.58 52.27 48.17 49.35 DHA % 24:0 0.00 0.00 0.00 0.00 % 24:1 0.00 0.00 0.00 0.00 % Fat 47.87 49.41 66.00 63.12 % Unknown 4.61 4.45 4.07 4.64 TABLE 52 PTA-10212 Mutants Control Mutant 1 Mutant 2 Mutant 3 Fatty Acids PTA-10212 PTA-10213 PTA-10214 PTA-10215 % 08:0 0.00 0.00 0.00 0.00 % 09:0 0.00 0.00 0.00 0.00 % 10:0 0.00 0.00 0.00 0.00 % 11:0 0.00 0.00 0.00 0.00 % 11:1 0.00 0.00 0.00 0.00 % 12:0 0.00 0.00 0.00 0.00 % 12:1 0.00 0.00 0.00 0.00 % 13:0 0.00 0.00 0.21 0.20 % 13:1 0.00 0.00 0.00 0.00 % 14:0 0.68 0.77 0.62 0.97 % 14:1 0.00 0.00 0.00 0.00 % 15:1 0.00 0.00 0.00 0.00 % 16:0 17.36 19.94 15.27 23.61 % 16:1 1.45 2.33 1.40 2.57 % 16:2 0.00 0.00 0.00 0.00 % 16:3 0.00 0.00 0.00 0.00 % 17:0 0.20 0.21 0.18 0.27 % 18:0 0.78 0.82 0.79 0.81 % 18:1 n-9 0.00 0.00 0.00 0.00 % 18:1 n-7 0.18 0.27 0.20 0.19 % 18:2 0.00 0.00 0.00 0.00 % 18:3 n-6 0.00 0.00 0.00 0.00 % 18:3 n-3 0.00 0.00 0.00 0.00 % 18:4 n-3 0.00 0.00 0.00 0.00 % 20:0 0.00 0.00 0.00 0.00 % 20:1 n-9 0.00 0.00 0.00 0.00 % 20:2 0.00 0.00 0.00 0.00 % 20:3 n-9 0.00 0.00 0.00 0.00 % 20:3 n-6 0.00 0.00 0.00 0.00 % 20:3 n-3 0.90 0.77 0.99 0.66 % 20:4 ARA 1.43 1.32 1.65 0.72 % 20:5 n-3 13.33 14.93 14.14 8.54 EPA % 22:0 0.00 0.00 0.00 0.00 % 22:1 0.00 0.00 0.00 0.00 % 22:2 0.00 0.00 0.00 0.00 % 22:3 0.00 0.00 0.00 0.00 % 22:4 n-6 0.00 0.00 0.00 0.00 % 22:5 n-6 2.39 1.95 2.59 2.18 % 22:5 n-3 0.73 0.79 0.80 0.68 % 22:6 n-3 59.18 54.31 59.89 56.39 DHA % 24:0 0.00 0.00 0.00 0.00 % 24:1 0.00 0.00 0.00 0.00 % Fat 45.69 38.08 42.88 48.48 % Unknown 1.38 1.58 1.27 2.19 Example 39 Two cell broths (approximately 13.3 kg) containing microbial cells (Schizochytrium) were heated to 60° C. in a 20 liter fermentor.","The fermentor had two 6-blade Rushton impellers having a diameter of 15 cm.","The top impeller was positioned at the 12 liter mark and the bottom impeller was positioned 10 cm below the top impeller.","The first cell broth was continuously agitated at 307 centimeters/second.","The second cell broth was continuously agitated at 464 centimeters/second.","Enzymes (i.e., Alcalase 2.4 L FG 0.5%) were added to the cell biomass to lyse the cells and form an emulsified lysed cell composition.","The emulsified lysed cell composition was first treated with a base (NaOH, 250 kg of 50% w/w solution) until the pH of the lysed cell composition was from 10.4 to 10.6.Next, a salt (solid NaCl, in an amount of 2%, by weight, of the lysed cell composition) was added to the lysed cell composition.","The lysed cell composition was then heated to a temperature of 90° C. and held at that temperature level for 20 hours.","A sample of each cell broth was taken and the pH was adjusted to 8.0 and placed in 50 ml test tubes.","The test tubes were centrifuged and the oil extraction data was measured.","The oil extraction data is provided in Table 53.TABLE 53 Results from extraction testing in 50 mL tubes at pH 8.0.Wet broth tested for Mass of Oil % yield % yield Extraction (g) Recovered (g) (oil/broth) (oil/solids)* 307 centimeters/second 49.990 3.881 7.76 27.81 50.814 2.747 5.41 19.36 50.772 2.418 4.76 17.05 464 centimeters/second 51.154 7.067 13.81 49.13 51.092 7.055 13.81 49.11 50.132 6.606 13.18 46.86 *based on solids content of untreated pasteurized broth The data provided in Table 53 demonstrates that the higher agitation speed resulted in a greater mass of oil recovered, a greater % yield of oil from the broth, and a greater % yield of oil from the solids content of the untreated pasteurized broth.","CONCLUSION All of the various embodiments or options described herein can be combined in any and all variations.","While the invention has been particularly shown and described with reference to some embodiments thereof, it will be understood by those skilled in the art that they have been presented by way of example only, and not limitation, and various changes in form and details can be made therein without departing from the spirit and scope of the invention.","Thus, the breadth and scope of the present invention should not be limited by any of the above described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.","All documents cited herein, including journal articles or abstracts, published or corresponding U.S. or foreign patent applications, issued or foreign patents, or any other documents, are each entirely incorporated by reference herein, including all data, tables, figures, and text presented in the cited documents."]],"string":"[\n [\n \"EXTRACTION OF LIPID FROM CELLS AND PRODUCTS THEREFROM\",\n \"The present invention relates to processes for obtaining a lipid from a cell by lysing the cell, contacting the cell with a base and/or salt, and separating the lipid.\",\n \"The present invention is also directed to a lipid prepared by the processes of the present invention.\",\n \"The present invention is also directed to microbial lipids having a particular anisidine value, peroxide value, and/or phosphorus content.\"\n ],\n [\n \"1.A process for obtaining a lipid from a cell composition, comprising: (a) lysing a cell of said cell composition to form a lysed cell composition; (b) demulsifying said lysed cell composition to form a demulsified cell composition, wherein the demulsifying comprises contacting said lysed cell composition with a first base to raise the pH of the lysed cell composition to 8 and contacting the lysed cell composition with a second base to raise the pH of the lysed cell composition to 7 or above to demulsify the cell composition; (c) separating said lipid from the demulsified cell composition; and (d) harvesting said lipid; wherein (b) comprises heating said lysed cell composition to a temperature of at least 70° C.\",\n \"2.\",\n \"(canceled) 3.\",\n \"(canceled) 4.The process of claim 1, wherein (b) comprises contacting said lysed cell composition with a salt to demulsify the cell composition.\",\n \"5.\",\n \"(canceled) 6.The process of claim 4, wherein the salt is added in an amount of 0.1% to 20% by weight of the lysed cell composition.\",\n \"7.\",\n \"(canceled) 8.The process of claim 4, wherein the salt is selected from: alkali metal salts, alkali earth metal salts, sulfate salts, and combinations thereof.\",\n \"9-30.\",\n \"(canceled) 31.The process of claim 1, comprising washing the cell or cell composition.\",\n \"32.The process of claim 1, comprising pasteurizing the cell or cell composition.\",\n \"33.The process of claim 1, comprising concentrating the lysed cell composition.\",\n \"34-38.\",\n \"(canceled) 39.A lipid obtained by the process of claim 1, the lipid comprising at least 35% by weight docosahexaenoic acid, at least 20% by weight eicosapentaenoic acid and less than 5% by weight each of arachidonic acid, docosapentaenoic acid n-6, oleic acid, linoleic acid, linolenic acid, eicosenoic acid, erucic acid, and stearidonic acid.\",\n \"40.\",\n \"(canceled) 41.\",\n \"(canceled) 42.\",\n \"(canceled) 43.\",\n \"(canceled) 44.The lipid of claim 39, wherein the lipid has an anisidine value of 26 or less.\",\n \"45.The lipid of claim 39, wherein the lipid has a phosphorus content of 100 ppm or less.\",\n \"46.The lipid of claim 39, wherein the lipid has a peroxide value of 5 or less.\",\n \"47.\",\n \"(canceled) 48.\",\n \"(canceled) 49.The lipid of claim 39, wherein the lipid has a peroxide value of 5 or less.\",\n \"50.The lipid of claim 39, wherein the lipid is a crude oil.\",\n \"51.\",\n \"(canceled) 52-59.\",\n \"(canceled) 60.The process of claim 1, wherein (b) comprises heating said lysed cell composition to a temperature of from 70° C. to 100° C. 61.The process of claim 1, wherein (b) comprises agitating the lysed cell composition to demulsify the cell composition.\",\n \"62.The process of claim 1, wherein (a) comprises adding a salt to said cell composition to demulsify the cell composition.\",\n \"63.The process of claim 1, wherein (a) comprises raising the pH of said cell composition to 8 or above to demulsify or lyse the cell composition.\",\n \"64.The process of claim 1, wherein the lysed cell composition is in the form of an oil-in-water emulsion comprising a mixture of a continuous aqueous phase and a dispersed lipid phase.\",\n \"65.The process of claim 1, wherein (c) comprises centrifuging the demulsified cell composition.\",\n \"66.The process of claim 1, wherein the lipid is a crude lipid.\",\n \"67.The process of claim 69, comprising (e) refining said crude lipid to obtain a refined lipid.\",\n \"68.The process of claim 1, wherein said lipid has an anisidine value of 26 or less.\",\n \"69.The process of claim 1, wherein said lipid has a peroxide value of 5 or less.\",\n \"70.The process of claim 1, wherein said cell is a microbial cell.\",\n \"71.The process of claim 73, wherein said microbial cell is of the genus Thraustochytrium, Schizochytrium, or mixtures thereof.\",\n \"72.The process of claim 1, wherein said lipid comprises omega 3 and/or omega-6 polyunsaturated fatty acids.\",\n \"73.The process of claim 1, wherein said lipid comprises at least one of DHA, DPA(n-3), DPA(n-6), EPA, and ARA.\",\n \"74.The process of claim 1, wherein an organic solvent is not added to said cell composition, said lysed cell composition, or said lipid in an amount or concentration sufficient to extract said lipid from said cell.\",\n \"75.The process of claim 1, wherein the lipid contains less than 5% by weight of an organic solvent.\"\n ],\n [\n \"<SOH> BACKGROUND OF THE INVENTION <EOH>\"\n ],\n [\n \"<SOH> BRIEF SUMMARY OF THE INVENTION <EOH>The present invention is directed to a process for obtaining a lipid from a microbial cell composition, the process comprising raising the pH of the cell composition to 8 or above, and separating a lipid from the cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.\",\n \"In some embodiments, the raising the pH lyses the cell composition.\",\n \"In some embodiments, the raising the pH demulsifies the cell composition.\",\n \"In some embodiments, the process comprises adding a salt to the cell composition to demulsify the cell composition.\",\n \"In some embodiments, the adding a salt is performed after the raising the pH.\",\n \"In some embodiments, the process further comprises heating the lysed cell composition to demulsify the cell composition.\",\n \"In some embodiments, the heating is performed after the raising the pH.\",\n \"In some embodiments, the process further comprises raising the pH of the cell composition a second time to demulsify the cell composition.\",\n \"In some embodiments, the raising the pH a second time is performed after the adding a salt or the heating.\",\n \"The present invention is also directed to a process for obtaining a lipid from a cell, the process comprising lysing a cell to form a lysed cell composition, raising the pH of the lysed cell composition to 8 or above to demulsify the cell composition, adding a salt to the lysed cell composition to demulsify the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.\",\n \"The present invention is directed to a process for obtaining a lipid from a cell composition, the process comprising raising the pH of the cell composition to 8 or above to lyse the cell composition and demulsify the cell composition, adding a salt to the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.\",\n \"The present invention is also directed to a process for obtaining a lipid from a cell, the process comprising lysing a cell to form a lysed cell composition, agitating the cell composition to demulsify the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.\",\n \"In some embodiments, the process further comprises heating the lysed cell composition to demulsify the cell composition.\",\n \"In some embodiments, the heating is performed after the adding a salt.\",\n \"In some embodiments, the process further comprises agitating the lysed cell composition to demulsify the cell composition.\",\n \"In some embodiments, the agitating is for 5 minutes to 96 hours.\",\n \"In some embodiments, the agitating comprises agitating the cell composition with an impeller having a tip speed of 350 centimeters per second to 900 centimeters per second.\",\n \"In some embodiments, the process further comprises raising the pH of the lysed cell composition to demulsify the cell composition.\",\n \"In some embodiments, raising the pH of the lysed cell composition to demulsify the cell composition comprises adding a base.\",\n \"In some embodiments, a second base is added after the adding of a salt or the heating.\",\n \"In some embodiments, the heating is for 10 minutes to 96 hours.\",\n \"In some embodiments, the cell composition is heated to a temperature of 60° C. to 100° C. In some embodiments, the cell composition is heated to a temperature of 90° C. to 100° C. In some embodiments, raising the pH comprises adding a base.\",\n \"In some embodiments, the base has a pK b of 1 to 12.In some embodiments, the separating a lipid occurs at a temperature of 10° C. to 100° C. In some embodiments, the process comprises agitating the lysed cell composition by stirring, mixing, blending, shaking, vibrating, or a combination thereof.\",\n \"In some embodiments, the process comprises agitating the lysed cell composition at 0.1 hp/1000 gal to 10 hp/1000 gal of lysed cell composition.\",\n \"In some embodiments, the process comprises agitating the lysed cell composition with an agitator having an impeller tip speed of 200 ft/min to 1,000 ft/min.\",\n \"In some embodiments, the lysing comprises mechanical treatment, physical treatment, chemical treatment, enzymatic treatment, or a combination thereof.\",\n \"In some embodiments, the mechanical treatment is homogenization.\",\n \"In some embodiments, the salt is added in an amount of 0.1% to 20% by weight of the lysed cell composition.\",\n \"In some embodiments, the salt is added to the lysed cell composition in an amount of 0.5% to 15% by weight of the lysed cell composition.\",\n \"In some embodiments, the salt is added to the lysed cell composition in an amount of 2% to 10% by weight of the lysed cell composition.\",\n \"In some embodiments, the salt is selected from the group consisting of: alkali metal salts, alkali earth metal salts, sulfate salts, and combinations thereof.\",\n \"In some embodiments, the salt is sodium chloride.\",\n \"In some embodiments, the salt is sodium sulfate.\",\n \"In some embodiments, the separating comprises centrifuging.\",\n \"In some embodiments, the separating comprises centrifuging at a temperature of 30° C. to 90° C. In some embodiments, the process provides a lipid comprising at least 50% by weight triglyceride.\",\n \"In some embodiments, the process provides a lipid having an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less.\",\n \"In some embodiments, the process provides a lipid having a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less.\",\n \"In some embodiments, the process provides a lipid having a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"In some embodiments, the process provides a lipid having at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of a desired polyunsaturated fatty acid (PUFA).\",\n \"In some embodiments, the process provides a lipid having at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of docosahexaenoic acid (“DHA”), and/or at least 10%, at least 15%, or at least 20% by weight of docosapentaenoic acid (“DPA n-6”), and/or at least 10%, at least 15%, or at least 20% by weight of eicosapentaenoic acid (“EPA”), and/or at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of arachidonic acid (“ARA”).\",\n \"In some embodiments, the cell is a microbial cell.\",\n \"In some embodiments, the process comprises concentrating a fermentation broth comprising the microbial cell.\",\n \"In some embodiments, the cell is an oilseed.\",\n \"In some embodiments, the oilseed is selected from the group consisting of sunflower seeds, canola seeds, rapeseeds, linseeds, castor oil seeds, coriander seeds, calendula seeds, and genetically modified variants thereof.\",\n \"In some embodiments, the process comprises washing the cell or cell composition.\",\n \"In some embodiments, the process comprises pasteurizing the cell or cell composition.\",\n \"In some embodiments, the process comprises concentrating the lysed cell composition.\",\n \"In some embodiments, the process comprises refining the lipid.\",\n \"In some embodiments, the refining is selected from the group consisting of: caustic refining, degumming, acid treatment, alkali treatment, cooling, heating, bleaching, deodorizing, deacidification, and combinations thereof.\",\n \"In some embodiments, the process comprises harvesting the lipid, wherein the harvesting comprises pumping the lipid without agitation.\",\n \"The present invention is also directed to a lipid obtained by any of the processes of the present invention.\",\n \"In some embodiments, the lipid comprises one or more polyunsaturated fatty acids.\",\n \"In some embodiments, the lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of a desired PUFA.\",\n \"In some embodiments, the lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of DHA, and/or at least 10%, at least 15%, or at least 20% by weight of DPA n-6, and/or at least 10%, at least 15%, or at least 20% by weight of EPA, and/or at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of ARA.\",\n \"In some embodiments, the lipid has an overall aroma intensity of 3 or less.\",\n \"In some embodiments, the lipid has an overall aromatic intensity of 2 or less.\",\n \"In some embodiments, the lipid comprises a triacylglycerol fraction of at least 10% by weight, wherein at least 12% by weight of the fatty acids in the triacylglycerol fraction is eicosapentaenoic acid, wherein at least 25% by weight of the fatty acids in the triacylglycerol fraction is docosahexaenoic acid, and wherein less than 5% by weight of the fatty acids in the triacylglycerol fraction is arachidonic acid.\",\n \"In some embodiments, the lipid comprises at least 20% by weight eicosapentaenoic acid and less than 5% by weight each of arachidonic acid, docosapentaenoic acid n-6, oleic acid, linoleic acid, linolenic acid, eicosenoic acid, erucic acid, and stearidonic acid.\",\n \"In some embodiments, the lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or Less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"In some embodiments, the lipid is a crude lipid.\",\n \"In some embodiments, the crude lipid optionally has less than 5% by weight or volume of an organic solvent.\",\n \"The present invention is also directed to a crude microbial lipid having an anisidine value of 26 or less, a peroxide value of 5 or less, a phosphorus content of 100 ppm or less, and optionally less than 5% by weight or volume of an organic solvent.\",\n \"In some embodiments, the crude microbial lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"In some embodiments, the crude microbial lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of a desired PUFA.\",\n \"In some embodiments, the crude microbial lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of DI-IA, and/or at least 10%, at least 15%, or at least 20% by weight of DPA n-6, and/or at least 10%, at least 15%, or at least 20% by weight of EPA, and/or at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of ARA.\",\n \"The present invention is also directed to an extracted microbial lipid comprising a triglyceride fraction of at least 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 50% by weight, wherein the docosapentaenoic acid n-6 content of the triglyceride fraction is from at least 0.5% by weight to 6% by weight, and wherein the oil has an anisidine value of 26 or less.\",\n \"The present invention is also directed to an extracted microbial lipid comprising a triglyceride fraction of at least 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 40% by weight, wherein the docosapentaenoic acid n-6 content of the triglyceride fraction is from at least 0.5% by weight to 6% by weight, wherein the ratio of docosahexaenoic acid to docosapentaenoic acid n-6 is greater than 6:1, and wherein the oil has an anisidine value of 26 or less.\",\n \"The present invention is also directed to an extracted microbial lipid comprising a triglyceride fraction of at least about 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 60% by weight and wherein the oil has an anisidine value of 26 or less.\",\n \"In some embodiments, the extracted lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"In some embodiments, the extracted microbial lipid is a crude lipid or a crude oil.\",\n \"In some embodiments, the crude lipid optionally has less than 5% by weight or volume of an organic solvent.\",\n \"The present invention is also directed to a process for obtaining a lipid, the process comprising refining a crude lipid of the present invention.\",\n \"In some embodiments, the refining is selected from the group consisting of: caustic refining, degumming, acid treatment, alkali treatment, cooling, heating, bleaching, deodorizing, deacidification, and combinations thereof.\"\n ],\n [\n \"CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S.\",\n \"Application No.\",\n \"61/350,363, filed on Jun.\",\n \"1, 2010, U.S.\",\n \"Application No.\",\n \"61/378,923, filed Aug. 31, 2010, and U.S.\",\n \"Application No.\",\n \"61/452,721, filed Mar.\",\n \"15, 2011, each of which is hereby incorporated by reference in its entirety.\",\n \"BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to processes for obtaining a lipid from a cell by lysing the cell, raising a pH of the cell and/or contacting the cell with a salt, and separating the lipid.\",\n \"The present invention is also directed to lipids prepared by the processes of the present invention.\",\n \"The present invention is also directed to microbial lipids having a particular anisidine value, peroxide value, and/or phosphorus content.\",\n \"Background Art A typical process for obtaining lipids from a microbial cell, such as polyunsaturated fatty acids, involves growing microorganisms that are capable of producing the desired lipid in a fermentor, pond or bioreactor, separating the fermentation broth comprising a microbial cell biomass, drying the microbial cell biomass, and separating the lipids by solvent extraction.\",\n \"Steps in the separation can include diluting a fermentation broth with water, centrifuging the diluted broth, lysing the microbial cells, and extracting an intracellular lipid from the lysed cells by adding a water-immiscible solvent to the mixture in which the lipid is soluble, e.g., hexane.\",\n \"Another method of extraction to remove a lipid from a microbial cell is lysing a cell in a fermentation broth using mechanical force (e.g., homogenization), enzymatic treatment, or chemical treatment to disrupt the cell walls.\",\n \"Lipid can be extracted from the resulting composition comprising lipids, microbial cell biomass, and water using an organic solvent, e.g., isopropyl alcohol.\",\n \"The lipid can be separated mechanically from the composition and the alcohol must be removed from both the lipid and the aqueous biomass waste stream.\",\n \"See, e.g., International Pub.\",\n \"Nos.\",\n \"WO 01/76385 and WO 01/76715.However, industrial scale production of lipids using either of the above processes requires a large amount of volatile and flammable organic solvent, thereby creating hazardous operating conditions.\",\n \"The use of organic solvents in the extraction process can also necessitate using an explosion-proof lipid recovery system, thereby adding to the cost of lipid recovery.\",\n \"Moreover, use of an organic solvent in extracting lipid from a microbial cell can generate an organic solvent waste stream that requires a complete solvent recovery system or a proper method of disposal, which further increases the overall production cost of lipid extraction.\",\n \"For example, strict limits on volatile organic compound (VOC) emissions require greater manpower and added cost to vessels and other equipment.\",\n \"Therefore, there is a need for a process for obtaining lipids from a cell which does not use an organic solvent.\",\n \"Several processes have been proposed for separating a lipid from a cell without the use of an organic solvent.\",\n \"For example, U.S. Pat.\",\n \"No.\",\n \"6,750,048 discloses an aqueous washing process whereby an emulsion is washed with aqueous washing solutions until a substantially non-emulsified lipid is obtained.\",\n \"However, in some embodiments, this process requires multiple washing steps, which require substantial cost and time.\",\n \"U.S. Pat.\",\n \"No.\",\n \"7,431,952 discloses a process whereby lysed cells are centrifuged to remove cell wall debris and then oils are extracted and purified.\",\n \"However, this process provides a crude oil that requires extensive further purification.\",\n \"Thus, what is needed is a process that does not utilize a volatile solvent to extract a lipid from a cell, and which can be performed using readily available equipment and a minimum number of steps to provide a highly pure lipid.\",\n \"BRIEF SUMMARY OF THE INVENTION The present invention is directed to a process for obtaining a lipid from a microbial cell composition, the process comprising raising the pH of the cell composition to 8 or above, and separating a lipid from the cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.\",\n \"In some embodiments, the raising the pH lyses the cell composition.\",\n \"In some embodiments, the raising the pH demulsifies the cell composition.\",\n \"In some embodiments, the process comprises adding a salt to the cell composition to demulsify the cell composition.\",\n \"In some embodiments, the adding a salt is performed after the raising the pH.\",\n \"In some embodiments, the process further comprises heating the lysed cell composition to demulsify the cell composition.\",\n \"In some embodiments, the heating is performed after the raising the pH.\",\n \"In some embodiments, the process further comprises raising the pH of the cell composition a second time to demulsify the cell composition.\",\n \"In some embodiments, the raising the pH a second time is performed after the adding a salt or the heating.\",\n \"The present invention is also directed to a process for obtaining a lipid from a cell, the process comprising lysing a cell to form a lysed cell composition, raising the pH of the lysed cell composition to 8 or above to demulsify the cell composition, adding a salt to the lysed cell composition to demulsify the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.\",\n \"The present invention is directed to a process for obtaining a lipid from a cell composition, the process comprising raising the pH of the cell composition to 8 or above to lyse the cell composition and demulsify the cell composition, adding a salt to the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.\",\n \"The present invention is also directed to a process for obtaining a lipid from a cell, the process comprising lysing a cell to form a lysed cell composition, agitating the cell composition to demulsify the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.\",\n \"In some embodiments, the process further comprises heating the lysed cell composition to demulsify the cell composition.\",\n \"In some embodiments, the heating is performed after the adding a salt.\",\n \"In some embodiments, the process further comprises agitating the lysed cell composition to demulsify the cell composition.\",\n \"In some embodiments, the agitating is for 5 minutes to 96 hours.\",\n \"In some embodiments, the agitating comprises agitating the cell composition with an impeller having a tip speed of 350 centimeters per second to 900 centimeters per second.\",\n \"In some embodiments, the process further comprises raising the pH of the lysed cell composition to demulsify the cell composition.\",\n \"In some embodiments, raising the pH of the lysed cell composition to demulsify the cell composition comprises adding a base.\",\n \"In some embodiments, a second base is added after the adding of a salt or the heating.\",\n \"In some embodiments, the heating is for 10 minutes to 96 hours.\",\n \"In some embodiments, the cell composition is heated to a temperature of 60° C. to 100° C. In some embodiments, the cell composition is heated to a temperature of 90° C. to 100° C. In some embodiments, raising the pH comprises adding a base.\",\n \"In some embodiments, the base has a pKb of 1 to 12.In some embodiments, the separating a lipid occurs at a temperature of 10° C. to 100° C. In some embodiments, the process comprises agitating the lysed cell composition by stirring, mixing, blending, shaking, vibrating, or a combination thereof.\",\n \"In some embodiments, the process comprises agitating the lysed cell composition at 0.1 hp/1000 gal to 10 hp/1000 gal of lysed cell composition.\",\n \"In some embodiments, the process comprises agitating the lysed cell composition with an agitator having an impeller tip speed of 200 ft/min to 1,000 ft/min.\",\n \"In some embodiments, the lysing comprises mechanical treatment, physical treatment, chemical treatment, enzymatic treatment, or a combination thereof.\",\n \"In some embodiments, the mechanical treatment is homogenization.\",\n \"In some embodiments, the salt is added in an amount of 0.1% to 20% by weight of the lysed cell composition.\",\n \"In some embodiments, the salt is added to the lysed cell composition in an amount of 0.5% to 15% by weight of the lysed cell composition.\",\n \"In some embodiments, the salt is added to the lysed cell composition in an amount of 2% to 10% by weight of the lysed cell composition.\",\n \"In some embodiments, the salt is selected from the group consisting of: alkali metal salts, alkali earth metal salts, sulfate salts, and combinations thereof.\",\n \"In some embodiments, the salt is sodium chloride.\",\n \"In some embodiments, the salt is sodium sulfate.\",\n \"In some embodiments, the separating comprises centrifuging.\",\n \"In some embodiments, the separating comprises centrifuging at a temperature of 30° C. to 90° C. In some embodiments, the process provides a lipid comprising at least 50% by weight triglyceride.\",\n \"In some embodiments, the process provides a lipid having an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less.\",\n \"In some embodiments, the process provides a lipid having a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less.\",\n \"In some embodiments, the process provides a lipid having a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"In some embodiments, the process provides a lipid having at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of a desired polyunsaturated fatty acid (PUFA).\",\n \"In some embodiments, the process provides a lipid having at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of docosahexaenoic acid (“DHA”), and/or at least 10%, at least 15%, or at least 20% by weight of docosapentaenoic acid (“DPA n-6”), and/or at least 10%, at least 15%, or at least 20% by weight of eicosapentaenoic acid (“EPA”), and/or at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of arachidonic acid (“ARA”).\",\n \"In some embodiments, the cell is a microbial cell.\",\n \"In some embodiments, the process comprises concentrating a fermentation broth comprising the microbial cell.\",\n \"In some embodiments, the cell is an oilseed.\",\n \"In some embodiments, the oilseed is selected from the group consisting of sunflower seeds, canola seeds, rapeseeds, linseeds, castor oil seeds, coriander seeds, calendula seeds, and genetically modified variants thereof.\",\n \"In some embodiments, the process comprises washing the cell or cell composition.\",\n \"In some embodiments, the process comprises pasteurizing the cell or cell composition.\",\n \"In some embodiments, the process comprises concentrating the lysed cell composition.\",\n \"In some embodiments, the process comprises refining the lipid.\",\n \"In some embodiments, the refining is selected from the group consisting of: caustic refining, degumming, acid treatment, alkali treatment, cooling, heating, bleaching, deodorizing, deacidification, and combinations thereof.\",\n \"In some embodiments, the process comprises harvesting the lipid, wherein the harvesting comprises pumping the lipid without agitation.\",\n \"The present invention is also directed to a lipid obtained by any of the processes of the present invention.\",\n \"In some embodiments, the lipid comprises one or more polyunsaturated fatty acids.\",\n \"In some embodiments, the lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of a desired PUFA.\",\n \"In some embodiments, the lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of DHA, and/or at least 10%, at least 15%, or at least 20% by weight of DPA n-6, and/or at least 10%, at least 15%, or at least 20% by weight of EPA, and/or at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of ARA.\",\n \"In some embodiments, the lipid has an overall aroma intensity of 3 or less.\",\n \"In some embodiments, the lipid has an overall aromatic intensity of 2 or less.\",\n \"In some embodiments, the lipid comprises a triacylglycerol fraction of at least 10% by weight, wherein at least 12% by weight of the fatty acids in the triacylglycerol fraction is eicosapentaenoic acid, wherein at least 25% by weight of the fatty acids in the triacylglycerol fraction is docosahexaenoic acid, and wherein less than 5% by weight of the fatty acids in the triacylglycerol fraction is arachidonic acid.\",\n \"In some embodiments, the lipid comprises at least 20% by weight eicosapentaenoic acid and less than 5% by weight each of arachidonic acid, docosapentaenoic acid n-6, oleic acid, linoleic acid, linolenic acid, eicosenoic acid, erucic acid, and stearidonic acid.\",\n \"In some embodiments, the lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or Less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"In some embodiments, the lipid is a crude lipid.\",\n \"In some embodiments, the crude lipid optionally has less than 5% by weight or volume of an organic solvent.\",\n \"The present invention is also directed to a crude microbial lipid having an anisidine value of 26 or less, a peroxide value of 5 or less, a phosphorus content of 100 ppm or less, and optionally less than 5% by weight or volume of an organic solvent.\",\n \"In some embodiments, the crude microbial lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"In some embodiments, the crude microbial lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of a desired PUFA.\",\n \"In some embodiments, the crude microbial lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of DI-IA, and/or at least 10%, at least 15%, or at least 20% by weight of DPA n-6, and/or at least 10%, at least 15%, or at least 20% by weight of EPA, and/or at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of ARA.\",\n \"The present invention is also directed to an extracted microbial lipid comprising a triglyceride fraction of at least 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 50% by weight, wherein the docosapentaenoic acid n-6 content of the triglyceride fraction is from at least 0.5% by weight to 6% by weight, and wherein the oil has an anisidine value of 26 or less.\",\n \"The present invention is also directed to an extracted microbial lipid comprising a triglyceride fraction of at least 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 40% by weight, wherein the docosapentaenoic acid n-6 content of the triglyceride fraction is from at least 0.5% by weight to 6% by weight, wherein the ratio of docosahexaenoic acid to docosapentaenoic acid n-6 is greater than 6:1, and wherein the oil has an anisidine value of 26 or less.\",\n \"The present invention is also directed to an extracted microbial lipid comprising a triglyceride fraction of at least about 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 60% by weight and wherein the oil has an anisidine value of 26 or less.\",\n \"In some embodiments, the extracted lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"In some embodiments, the extracted microbial lipid is a crude lipid or a crude oil.\",\n \"In some embodiments, the crude lipid optionally has less than 5% by weight or volume of an organic solvent.\",\n \"The present invention is also directed to a process for obtaining a lipid, the process comprising refining a crude lipid of the present invention.\",\n \"In some embodiments, the refining is selected from the group consisting of: caustic refining, degumming, acid treatment, alkali treatment, cooling, heating, bleaching, deodorizing, deacidification, and combinations thereof.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES The accompanying drawings, which are incorporated herein and form a part of the specification, illustrate the present invention and, together with the description, further serve to explain the principles of the invention and to enable a person skilled in the pertinent art to make and use the invention.\",\n \"FIGS.\",\n \"1-4 provide schematic flow charts describing processes of the present invention.\",\n \"FIG.\",\n \"5 is a graph providing the electron paramagnetic resonance (EPR) over time of lysed cells compositions at various pHs.\",\n \"The present invention will now be described with reference to the accompanying drawings.\",\n \"In the drawings, like reference numbers indicate identical or functionally similar elements.\",\n \"Additionally, the left-most digit(s) of a reference number can identify the drawing in which the reference number first appears.\",\n \"DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to a process for obtaining a lipid from a microbial cell composition, the process comprising raising the pH of the cell composition to 8 or above and separating a lipid from the cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.\",\n \"In some embodiments, the process further comprises one or more of adding a salt to the cell composition to demulsify the cell composition, heating the cell to demulsify the cell composition, agitating the cell composition to demulsify the cell composition, and raising the pH of the cell composition a second time to demulsify the cell composition.\",\n \"The present invention is also directed to a process for obtaining a lipid from a cell, the process comprising lysing a cell to form a lysed cell composition, raising the pH of the lysed cell composition to 8 or above to demulsify the cell composition, adding a salt to the lysed cell composition to demulsify the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.\",\n \"The cell can be a microbial cell or an oilseed cell.\",\n \"In some embodiments, the process further comprises one or more of: heating the lysed cell composition to demulsify the cell composition, agitating the lysed cell composition to demulsify the cell composition, and raising the pH of the lysed cell composition a second time to demulsify the cell composition.\",\n \"The present invention is directed to a process for obtaining a lipid from a cell composition, the process comprising raising the pH of the cell composition to 8 or above to lyse the cell composition and demulsify the cell composition, adding a salt to the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.\",\n \"In some embodiments, the process further comprises one or more of heating the cell composition to demulsify the cell composition, agitating the cell composition to demulsify the cell composition, and raising the pH of the cell composition a second time to demulsify the cell composition.\",\n \"The present invention is directed to a process for obtaining a lipid from a microbial cell, the process comprising lysing a microbial cell to form a lysed cell composition, adding a base to the lysed cell composition to demulsify the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.\",\n \"In some embodiments, the process further comprises one or more of: adding a salt to the lysed cell composition to demulsify the cell composition, heating the lysed cell composition to demulsify the cell composition, agitating the lysed cell composition to demulsify the cell composition, and adding a second base to the lysed cell composition to demulsify the cell composition.\",\n \"The present invention is also directed to a process for obtaining a lipid from a cell, the process comprising lysing a cell to form a lysed cell composition, adding a base to the lysed cell composition to demulsify the cell composition, adding a salt to the lysed cell composition to demulsify the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.\",\n \"The cell can be a microbial cell or an oilseed cell.\",\n \"In some embodiments, the process further comprises one or more of: heating the lysed cell composition to demulsify the cell composition, agitating the lysed cell composition to demulsify the cell composition, and adding a second base to the lysed cell composition to demulsify the cell composition.\",\n \"The present invention is also directed to a process for obtaining a lipid from a cell, the process comprising lysing a cell to form a lysed cell composition, agitating the cell composition to demulsify the cell composition, and separating a lipid from the demulsified cell composition, wherein the lipid optionally contains less than 5% by weight or volume of an organic solvent.\",\n \"The present invention is also directed to a lipid obtained by any of the processes of the present invention.\",\n \"The present invention is also directed to an extraction process for obtaining a lipid from a cell, the process comprising lysing the cell to form a lysed cell composition, contacting the lysed cell composition with a first base, contacting the lysed cell composition with a salt, heating the lysed cell composition for 5 minutes to 96 hours, contacting the lysed cell composition with a second base, and separating a lipid from the lysed cell composition at a temperature of 10° C. to 100° C. The present invention is also directed to an extraction process for obtaining a lipid from a cell, the process comprising lysing the cell to form a lysed cell composition, contacting the lysed cell composition with a salt, and agitating the lysed cell composition for 5 minutes to 96 hours to provide a treated lysed cell composition, and separating a lipid from the treated lysed cell composition at a temperature of 10° C. to 100° C. The present invention is also directed to an extraction process for obtaining a lipid from a cell, the process comprising lysing the cell to form a lysed cell composition, contacting the lysed cell composition with a salt, and separating a lipid from the lysed cell composition at a temperature of 10° C. to 100° C. In some embodiments, the base or second base have a pKb of 1 to 12.In some embodiments, the base or second base have a pKb of 3 to 5.In some embodiments, a process comprises agitating the lysed cell composition for 5 minutes to 96 hours, 10 minutes to 96 hours, 10 minutes to 4 hours, 12 hours to 84 hours, or 24 hours to 72 hours.\",\n \"In some embodiments, the process comprises agitating the lysed cell composition by stirring, mixing, blending, shaking, vibrating, or a combination thereof.\",\n \"In some embodiments, the process comprises agitating the lysed cell composition at 0.1 hp/1000 gal to 10 hp/1000 gal of lysed cell composition.\",\n \"In some embodiments, the process comprises agitating the lysed cell composition with an agitator having an impeller tip speed of 200 ft/min to 1000 ft/min.\",\n \"In some embodiments, lysing comprises a process selected from: mechanically treating, physically treating, chemically treating, enzymatically treating, or a combination thereof.\",\n \"In some embodiments, the lysed cell composition is contacted with a salt in an amount of 0.1% to 20% by weight, 0.5% to 15% by weight, or 2% to 10% by weight of the lysed cell composition.\",\n \"In some embodiments, the salt is selected from the group consisting of: alkali metal salts, alkali earth metal salts, sulfate salts and combinations thereof.\",\n \"In some embodiments, the salt is sodium chloride.\",\n \"In some embodiments, the salt is sodium sulfate.\",\n \"In some embodiments, the process comprises heating the lysed cell composition for 5 minutes to 96 hours, 10 minutes to 4 hours, 12 hours to 84 hours, or 24 hours to 72 hours.\",\n \"In some embodiments, the separating comprises centrifuging.\",\n \"In some embodiments, the separating comprises centrifuging at a temperature of 10° C. to 100° C. In some embodiments, the process comprises prior to the lysing: washing, centrifuging, evaporating, or a combination thereof, a broth that includes the cell.\",\n \"In some embodiments, the process provides a lipid having an anisidine value of 15 or less.\",\n \"In some embodiments, the process provides a lipid comprising at least 50% by weight triglycerides.\",\n \"In some embodiments, the process does not add an organic solvent to the lysed cell composition.\",\n \"Organic solvents include polar solvents, non-polar solvents, water-miscible solvents, water-immiscible solvents, and combinations thereof.\",\n \"In some embodiments, the process comprises concentrating a broth comprising a cell.\",\n \"In some embodiments, the process comprises concentrating the lysed cell composition.\",\n \"The present invention is also directed to the lipid prepared by a process described herein.\",\n \"In some embodiments, the lipid comprises one or more polyunsaturated fatty acids.\",\n \"In some embodiments, the lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of a desired PUFA.\",\n \"In some embodiments, the lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of DHA, and/or at least 10%, at least 15%, or at least 20% by weight of DPA n-6, and/or at least 10%, at least 15%, or at least 20% by weight of EPA, and/or at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of ARA.\",\n \"In some embodiments, the lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"In some embodiments, the lipid comprises a triacylglycerol fraction of at least 10% by weight, wherein at least 12% by weight of the fatty acids in the triacylglycerol fraction is eicosapentaenoic acid, wherein at least 25% by weight of the fatty acids in the triacylglycerol fraction is docosahexaenoic acid, and wherein less than 5% by weight of the fatty acids in the triacylglycerol fraction is arachidonic acid.\",\n \"In some embodiments, the lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"In some embodiments, the lipid is a crude lipid.\",\n \"In some embodiments, the lipid comprises at least 20% by weight eicosapentaenoic acid and less than 5% by weight each of arachidonic acid, docosapentaenoic acid n-6, oleic acid, linoleic acid, linolenic acid, eicosenoic acid, erucic acid, and stearidonic acid.\",\n \"In some embodiments, the lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"In some embodiments, the lipid is a crude oil.\",\n \"The present invention is also directed to a crude microbial lipid having an anisidine value of 26 or less, a peroxide value of 5 or less, a phosphorus content of 100 ppm or less, and optionally less than 5% by weight or volume of an organic solvent.\",\n \"In some embodiments, the crude microbial lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"In some embodiments, the crude microbial lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of a desired PUFA.\",\n \"In some embodiments, the crude microbial lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of DHA, and/or at least 10%, at least 15%, or at least 20% by weight of DPA n-6, and/or at least 10%, at least 15%, or at least 20% by weight of EPA, and/or at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of ARA.\",\n \"The present invention is also directed to an extracted microbial lipid comprising a triglyceride fraction of at least 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 50% by weight, wherein the docosapentaenoic acid n-6 content of the triglyceride fraction is from at least 0.5% by weight to 6% by weight, and wherein the oil has an anisidine value of 26 or less.\",\n \"In some embodiments, the extracted lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"In some embodiments, the extracted lipid is a crude lipid.\",\n \"The present invention is also directed to an extracted microbial lipid comprising a triglyceride fraction of at least 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 40% by weight, wherein the docosapentaenoic acid n-6 content of the triglyceride fraction is from at least 0.5% by weight to 6% by weight, wherein the ratio of docosahexaenoic acid to docosapentaenoic acid n-6 is greater than 6:1, and wherein the oil has an anisidine value of 26 or less.\",\n \"In some embodiments, the extracted lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"In some embodiments, the extracted lipid is a crude lipid.\",\n \"The present invention is also directed to an extracted microbial lipid comprising a triglyceride fraction of at least about 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 60% by weight and wherein the oil has an anisidine value of 26 or less.\",\n \"In some embodiments, the extracted lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"In some embodiments, the extracted lipid is a crude lipid.\",\n \"The present invention is also directed to a crude lipid extracted from a microorganism of the species Crypthecodinium cohnii, having a phosphorus content of 100 ppm or less.\",\n \"In some embodiments, the crude lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"The present invention is also directed to a process for obtaining a lipid, the process comprising refining a crude lipid of the present invention.\",\n \"In some embodiments, the refining is selected from the group consisting of: caustic refining, degumming, acid treatment, alkali treatment, cooling, heating, bleaching, deodorizing, deacidification, and combinations thereof.\",\n \"Overview Generally, the processes of the present invention do not utilize an organic solvent in order to extract or otherwise separate a lipid.\",\n \"Thus, in some embodiments, an organic solvent is not added to a cell broth comprising plant material or fermentation broth comprising a microbial cell, is not added to a cell composition, is not added to a lysed cell composition, or is not added to a lipid during a process of the present invention in an amount or concentration sufficient to extract a lipid.\",\n \"In some embodiments, an organic solvent can be added to a cell composition, a lysed cell composition, or a demulsified cell composition.\",\n \"In such embodiments, the organic solvent is added in a concentration less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.05% by volume.\",\n \"As used herein, an “organic solvent” refers to a solvent that includes at least one carbon atom.\",\n \"As used herein, “solvent” refers to an agent that is hydrophobic or lipophilic, and is not a lipid.\",\n \"As used herein, “hydrophobic” refers to an agent that is repelled from a mass of water.\",\n \"As used herein, “lipophilic” refers to an agent that dissolves lipids.\",\n \"Organic solvents that are not used in a process of the present invention include, but are not limited to, polar solvents, non-polar solvents, water-miscible solvents, water-immiscible solvents, and combinations thereof.\",\n \"Non-limiting examples of organic solvents include substituted and unsubstituted C4-C8 alkyls (e.g., hexane and the like), C5-C12 cylcolalkyls, C4-C12 alkenes, C1-C8 alcohols (e.g., iso-propanol and the like), C1-C8 aldehydes, C4-C8 ethers, C1-C8 esters, C6-C12 aryls, C1-C8 amides, C5-C12 heteroaryls, and combinations thereof.\",\n \"An organic solvent as defined herein can be optionally added to a lysed cell composition, for example, as a component of a base and/or a salt for contacting with the lysed cell composition.\",\n \"However, in such embodiments the organic solvent is present in a concentration such that the lipid is not substantially extracted from the cell composition, lysed cell composition, or demulsified cell composition by the solvent (i.e., in a concentration of less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.05% by volume or weight).\",\n \"In some embodiments, a process of the present invention does not include washing, e.g., with water, or the process reduces the number of washings of, a lysed cell composition or a demulsified cell composition.\",\n \"“Washing” refers to a process of diluting a composition with, e.g., water or buffer and removing the water or buffer, e.g., by centrifugation.\",\n \"Washing a cell composition can decrease the overall yield of a lipid obtained from a cell.\",\n \"In the present invention, the washing can be decreased by 1 time, 2 times, 3 times or more.\",\n \"Definitions As used herein, “lipid” or “oil” refers to one or more fatty acids (including free fatty acids and esters of fatty acids), phospholipids, triacylglycerols (i.e.\",\n \"triglycerides), diacylglycerides, monoacylglycerides, lysophospholipids, soaps, phosphatides, waxes, sterols and sterol esters, carotenoids, xanthophylls, hydrocarbons, and other lipids known to one of ordinary skill in the art.\",\n \"Lipids include polar lipids and neutral lipids.\",\n \"As used herein, “polar lipid” refers to lipids that contain a polar group and are more readily soluble in polar solvents.\",\n \"Polar lipids include phospholipids.\",\n \"As used herein, “phospholipid” refers to lipids having a phosphate group.\",\n \"As used herein, “neutral lipid” refers to lipids that do not contain areas of polarity and are more readily soluble in non-polar solvents.\",\n \"Neutral lipids include triacylglycerols (TAG).\",\n \"Fatty acids are classified based on the length and saturation characteristics of the carbon chain.\",\n \"Fatty acids are termed short chain, medium chain, or long chain fatty acids based on the number of carbons present in the chain.\",\n \"Fatty acids are termed saturated fatty acids when no double bonds are present between the carbon atoms, and are termed unsaturated fatty acids when double bonds are present.\",\n \"Unsaturated long chain fatty acids are monounsaturated when only one double bond is present and are polyunsaturated when more than one double bond is present.\",\n \"Fatty acids present in the lipid can have 4 to 28 carbon atoms.\",\n \"In some embodiments, a lipid comprises one or more polyunsaturated fatty acids.\",\n \"Polyunsaturated fatty acids (PUFAs) are classified based on the position of the first double bond from the methyl end of the fatty acid: omega-3 (n-3) fatty acids contain a first double bond at the third carbon, while omega-6 (n-6) fatty acids contain a first double bond at the sixth carbon.\",\n \"For example, docosahexaenoic acid (“DHA”) is an omega-3 long chain polyunsaturated fatty acid (LC-PUFA) with a chain length of 22 carbons and 6 double bonds, often designated as “22:6 n-3.” For the purposes of this application, long chain polyunsaturated fatty acids (LC-PUFAs) are defined as fatty acids of 18 and more carbon chain length, and are preferably fatty acids of 20 or more carbon chain length, containing 3 or more double bonds.\",\n \"LC-PUFAs of the omega-6 series include, but are not limited to, di-homo-gammalinoleic acid (C20:3n-6), arachidonic acid (C20:4n-6) (“ARA”), docosatetraenoic acid or adrenic acid (C22:4n-6), and docosapentaenoic acid (C22:5n-6) (“DPA n-6”).\",\n \"The LC-PUFAs of the omega-3 series include, but are not limited to, eicosatrienoic acid (C20:3n-3), eicosatetraenoic acid (C20:4n-3), eicosapentaenoic acid (C20:5n-3) (“EPA”), docosapentaenoic acid (C22:5n-3), and docosahexaenoic acid (C22:6n-3).\",\n \"The LC-PUFAs also include fatty acids with greater than 22 carbons and 4 or more double bonds including, but not limited to, C24:6(n-3) and C28:8(n-3).\",\n \"The terms “fatty acid,” “polyunsaturated fatty acid,” and “PUFA” include not only the free fatty acid form, but other forms as well, such as the triacylglycerol (TAG) form, the phospholipid (PL) form and other esterified forms.\",\n \"As used herein, the terms “ester” and “esterified” refer to the replacement of the hydrogen in the carboxylic acid group of a PUFA molecule with another substituent.\",\n \"Typical esters are known to those in the art, a discussion of which is provided by Higuchi, T. et al., Pro-drugs as Novel Delivery Systems, Vol.\",\n \"14, A.C.S.\",\n \"Symposium Series, Bioreversible Carriers in Drug Design, Edward B. Roche ed., Amer.\",\n \"Pharma.\",\n \"Assoc., Pergamon Press (1987), and Protective Groups in Organic Chemistry, McOmie ed., Plenum Press, New York (1973), each of which is incorporated herein by reference in its entirety.\",\n \"Examples of common esters include methyl, ethyl, trichloroethyl, propyl, butyl, pentyl, tert-butyl, benzyl, nitrobenzyl, methoxybenzyl and benzhydryl.\",\n \"In some embodiments, a lipid comprises at least 10%, at least 20%, at least 30%, at least 35%, at least 40%, at least 50%, at least 60%, at least 70% or at least 80% by weight PUFA.\",\n \"In some embodiments, a lipid comprises at least 10%, at least 20%, at least 30%, at least 35%, at least 40%, at least 50%, at least 60%, at least 70% or at least 80% by weight DHA.\",\n \"In some embodiments, a lipid comprises less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, or less than 5% by weight EPA.\",\n \"In some embodiments, a lipid comprises less than 10%, less than 5%, less than 2%, less than 1%, or less than 0.5% by weight sterols.\",\n \"In some embodiments, one or more PUFAs are present in a lipid in one or more forms, such as triglycerides, diglycerides, monoglycerides, phospholipids, free fatty acids, esterified fatty acids, alkali metal salts of fatty acids, alkali earth metal salts of fatty acids, and combinations thereof.\",\n \"In some embodiments, a lipid separated after centrifuging in a process of the present invention comprises at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 50% to 95%, 50% to 90%, 50% to 85%, 50% to 80%, 50% to 75%, 60% to 95%, 60% to 90%, 60% to 85%, 70% to 95%, 70% to 90%, 70% to 85%, 75% to 95%, 75% to 90%, or 75% to 85%, by weight of triglycerides.\",\n \"In some embodiments, the triglycerides comprise at least 10%, at least 20%, at least 30%, at least 35%, at least 40%, at least 50%, at least 60%, at least 70% or at least 80% by weight DHA.\",\n \"In some embodiments, the triglycerides comprise at least 50%, at least 40%, at least 30%, at least 20%, at least 15%, at least 10%, or at least 5% by weight EPA.\",\n \"As discussed herein, additional refining of a lipid after the centrifuging can provide a lipid comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 80% to 99.5%, 80% to 99%, 80% to 97%, 80% to 95%, 80% to 90%, 85% to 99.5%, 85% to 99%, 85% to 97%, 85% to 95%, 85% to 90%, 90% to 99.5%, 90% to 99%, 90% to 97%, 90% to 95%, 95% to 99.5%, 95% to 99%, 95% to 97%, 97% to 99.5%, or 98% to 99.5% triglyceride by weight.\",\n \"As used herein, a “cell” refers to a lipid-containing biomaterial, such as biomaterial derived from plants or microorganisms.\",\n \"In some embodiments, suitable plant material includes, but is not limited to, plant parts and oilseeds.\",\n \"Oilseeds include, but are not limited to, sunflower seeds, canola seeds, rapeseeds, linseeds, castor oil seeds, coriander seeds, calendula seeds or the like, and genetically modified variants thereof.\",\n \"Oil produced from plant material and/or microorganisms, such as oleaginous microorganisms, according to the processes described herein, is also referred to as vegetable oil.\",\n \"Oil produced from algae and/or fungi is also referred to as algal and/or fungal oil, respectively.\",\n \"As used herein, a “microbial cell” or “microorganism” refers to organisms such as algae, bacteria, fungi, protist, and combinations thereof, e.g., unicellular organisms.\",\n \"In some embodiments, a microbial cell is a eukaryotic cell.\",\n \"A microbial cell suitable for use with the present invention includes, but is not limited to, golden algae (e.g., microorganisms of the kingdom Stramenopiles), green algae, diatoms, dinoflagellates (e.g., microorganisms of the order Dinophyceae including members of the genus Crypthecodinium such as, for example, Crypthecodinium cohnii or C. cohnii), yeast (Ascomycetes or Basidiomycetes), and fungi of the genera Mucor and Mortierella, including but not limited to Mortierella alpina and Mortierella sect.\",\n \"schmuckeri.\",\n \"A microbial cell suitable for use with the present invention can further include, but is not limited to genera found in the following groups of organisms: Stramenopiles, Hamatores, Proteromonads, Opalines, Develpayella, Diplophrys, Labrinthulids, Thraustochytrids, Biosecids, Oomycetes, Hypochytridiomycetes, Commotion, Reticulosphaera, Pelagomonas, Pelagococcus, Ollicola, Aureococcus, Parmales, Diatoms, Xanthophytes, Phaeophytes, Eustigmatophytes, Raphidophytes, Synurids, Axodines (including Rhizochromulinaales, Pedinellales, Dictyochales), Chrysomeridales, Sarcinochrysidales, Hydrurales, Hibberdiales, and Chromulinales.\",\n \"In some embodiments, a microbial cell for use with the present invention is a microorganism of the phylum Labyrinthulomycota.\",\n \"In some embodiments, a microbial cell of the phylum Labyrinthulomycota is a thraustochytrid, such as a Schizochytrium or Thraustochytrium.\",\n \"According to the present invention, the term “thraustochytrid” refers to any member of the order Thraustochytriales, which includes the family Thraustochytriaceae, and the term “labyrinthulid” refers to any member of the order Labyrinthulales, which includes the family Labyrinthulaceae.\",\n \"Members of the family Labyrinthulaceae were previously considered to be members of the order Thraustochytriales, but in more recent revisions of the taxonomic classification of such organisms, the family Labyrinthulaceae is now considered to be a member of the order Labyrinthulales.\",\n \"Both Labyrinthulales and Thraustochytriales are considered to be members of the phylum Labyrinthulomycota.\",\n \"Taxonomic theorists now generally place both of these groups of microorganisms with the algae or algae-like protists of the Stramenopile lineage.\",\n \"The current taxonomic placement of the thraustochytrids and labyrinthulids can be summarized as follows: Realm: Stramenopila (Chromista) Phylum: Labyrinthulomycota (Heterokonta) Class: Labyrinthulomycetes (Labyrinthulae) Order: Labyrinthulales Family: Labyrinthulaceae Order: Thraustochytriales Family: Thraustochytriaceae For purposes of the present invention, strains of microbial cells described as thraustochytrids include the following organisms: Order: Thraustochytriales; Family: Thraustochytriaceae; Genera: Thraustochytrium (Species: sp., arudimentale, aureum, benthicola, globosum, kinnei, motivum, multirudimentale, pachydermum, proliferum, roseum, and striatum), Ulkenia (Species: sp., amoeboidea, kerguelensis, minuta, profunda, radiata, sailens, sarkariana, schizochytrops, visurgensis, yorkensis, and sp.\",\n \"BP-5601), Schizochytrium (Species: sp., aggregatum, limnaceum, mangrovei, minutum, and octosporum), Japonochytrium (Species: sp., marinum), Aplanochytrium (Species: sp., haliotidis, kerguelensis, profunda, and stocchinoi), Althornia (Species: sp., crouchii), or Elina (Species: sp., marisalba, and sinorifica).\",\n \"For the purposes of this invention, species described within Ulkenia will be considered to be members of the genus Thraustochytrium.\",\n \"Aurantiacochytrium and Oblogospora are two additional genuses encompassed by the phylum Labyrinthulomycota in the present invention.\",\n \"In some embodiments, a microbial cell is of the genus Thraustochystrium, Schizochytrium, and mixtures thereof.\",\n \"Microbial cells suitable for use with the present invention include, but are not limited to, Labyrinthulids selected from: Order: Labyrinthulales, Labyrinthulaceae, Genera: Labyrinthula (Species: sp., algeriensis, coenocystis, chattonii, macrocystis, macrocystis atlantica, macrocystis macrocystis, marina, minuta, roscoffensis, valkanovii, vitellina, vitellina pacifica, vitellina vitellina, and zopfii), Labyrinthuloides (Species: sp., haliotidis, and yorkensis), Labyrinthomyxa (Species: sp., marina), Diplophrys (Species: sp., archeri), Pyrrhosorus (Species: sp., marinus), Sorodiplophrys (Species: sp., stercorea), and Chlamydomyxa (Species: sp., labyrinthuloides, and montana) (although there is currently not a consensus on the exact taxonomic placement of Pyrrhosorus, Sorodiplophrys, and Chlamydomyxa).\",\n \"Host cells of the phylum Labyrinthulomycota include, but are not limited to, deposited strains PTA-10212, PTA-10213, PTA-10214, PTA-10215, PTA-9695, PTA-9696, PTA-9697, PTA-9698, PTA-10208, PTA-10209, PTA-10210, PTA-10211, the microorganism deposited as SAM2179 (named “Ulkenia SAM2179” by the depositor), any Thraustochytrium species (including former Ulkenia species such as U. visurgensis, U. amoeboida, U. sarkariana, U. profunda, U. radiata, U. minuta and Ulkenia sp.\",\n \"BP-5601), and including Thraustochytrium striatum, Thraustochytrium aureum, Thraustochytrium roseum; and any Japonochytrium species.\",\n \"Strains of Thraustochytriales include, but are not limited to Thraustochytrium sp.\",\n \"(23B) (ATCC 20891); Thraustochytrium striatum (Schneider)(ATCC 24473); Thraustochytrium aureum (Goldstein) (ATCC 34304); Thraustochytrium roseum (Goldstein) (ATCC 28210); Japonochytrium sp.\",\n \"(L1) (ATCC 28207); ATCC 20890; ATCC 20892; a mutant strain derived from any of the aforementioned microorganisms; and mixtures thereof.\",\n \"Schizochytrium include, but are not limited to Schizochytrium aggregatum, Schizochytrium limacinum, Schizochytrium sp.\",\n \"(S31) (ATCC 20888), Schizochytrium sp.\",\n \"(58) (ATCC 20889), Schizochytrium sp.\",\n \"(LC-RM) (ATCC 18915), Schizochytrium sp, (SR 21), deposited strain ATCC 28209, deposited Schizochytrium limacinum strain IFO 32693, a mutant strain derived from any of the aforementioned microorganisms, and mixtures thereof.\",\n \"In some embodiments, the host cell is a Schizochytrium or a Thraustochytrium.\",\n \"Schizochytrium can replicate both by successive bipartition and by forming sporangia, which ultimately release zoospores.\",\n \"Thraustochytrium, however, replicate only by forming sporangia, which then release zoospores.\",\n \"In some embodiments, the host cell of the invention is a recombinant host cell.\",\n \"Effective culture conditions for a microbial cell for use with the invention include, but are not limited to, effective media, bioreactor, temperature, pH, and oxygen conditions that permit lipid production.\",\n \"An effective medium refers to any medium in which a microbial cell, e.g., Thraustoehytriales microbial cell, is typically cultured.\",\n \"Such media typically comprises an aqueous medium having assimilable carbon, nitrogen, and phosphate sources, as well as appropriate salts, minerals, metals, and other nutrients, such as vitamins.\",\n \"Microbial cells for use with the present invention can be cultured in conventional fermentation bioreactors, shake flasks, test tubes, microtiter dishes, and petri plates.\",\n \"In some embodiments, culturing is carried out at a temperature, pH, and oxygen content appropriate for a recombinant cell.\",\n \"In some embodiments, a microbial cell is capable of growth at a salinity level of 12 g/L or less, 5 g/L or less, or 3 g/L or less of sodium chloride.\",\n \"In some embodiments, a microbial cell produces a lipid comprising omega-3 and/or omega-6 PUFAs.\",\n \"In some embodiments, a microbial cell produces a lipid comprising DHA, DPA (n-3), DPA (n-6), EPA, arachidonic acid (ARA), or the like, and combinations thereof.\",\n \"Non-limiting examples of microorganisms that produce a lipid comprising a PUFA are disclosed above and are also found in U.S. Pat.\",\n \"Nos.\",\n \"5,340,594, 5,340,742 and 5,583,019, each of which is incorporated by reference herein in its entirety.\",\n \"In some embodiments, a microbial cell comprises at least 30% by weight lipids, at least 35% by weight lipids, at least 40% by weight lipids, at least 50% by weight lipids, at least 60% by weight lipids, at least 70% by weight lipids, or at least 80% by weight lipids.\",\n \"In some embodiments, a microbial cell for use with the present invention is capable of producing at least 0.1 grams per liter per hour (g/L/h) of DHA, at least 0.2 g/L/h of DHA, at least 0.3 g/L/h of DHA, or at least 0.4 g/L/h of DHA.\",\n \"Processes The processes of the present invention comprises lysing a cell or cell biomass to form a lysed cell composition.\",\n \"As used herein, the term “cell biomass” refers to a population of plant or microbial cells.\",\n \"As used herein, the terms “lyse” and “lysing” refer to a process of rupturing the cell wall and/or cell membrane of a cell.\",\n \"In some embodiments, lysing comprises a process such as: mechanically treating, chemically treating, enzymatically treating, physically treating, or combinations thereof.\",\n \"As used herein, mechanically treating includes, but is not limited to, homogenizing a cell, applying ultrasound to a cell, cold-pressing a cell, milling a cell or the like, and combinations thereof.\",\n \"In some embodiments, a process comprises lysing the cell by homogenization.\",\n \"In some embodiments, a process comprises lysing the cell with a homogenizer.\",\n \"Homogenizing a cell can include, but is not limited to, processes utilizing a French pressure cell press, a sonicator, a homogenizer, a ball mill, a rod mill, a pebble mill, a bead mill, a high pressure grinding roll, a vertical shaft impactor, an industrial blender, a high shear mixer, a paddle mixer, a polytron homogenizer or the like, and combinations thereof.\",\n \"In some embodiments, a cell is flowed through a homogenizer that is optionally heated.\",\n \"In some embodiments, suitable homogenization can include 1 to 3 passes through a homogenizer at either high and/or low pressures.\",\n \"In some embodiments, a pressure during homogenization can be 150 bar to 1,400 bar, 150 bar to 1,200 bar, 150 bar to 900 bar, 150 bar to 300 bar, 300 bar to 1,400 bar, 300 bar to 1,200 bar, 300 bar to 900 bar, 400 bar to 800 bar, 500 bar to 700 bar, or 600 bar.\",\n \"As used herein, physically treating can include, but is not limited to, heating a cell, drying a cell, or the like, and combinations thereof.\",\n \"Heating a cell can include, but is not limited to, resistive heating, convection heating, steam heating, heating in a fluid bath, heating with solar energy, heating with focused solar energy, and the like, any of which can be performed in a tank, pool, tube, conduit, flask, or other containment device.\",\n \"In some embodiments, a cell is heated in a tank that includes resistive coils in/on its walls.\",\n \"In some embodiments, a cell is heated in a liquid bath that includes a tubing passing there through.\",\n \"Drying a cell can include, but is not limited to, exposing to air flow, exposing to heat (e.g., convection heat, a heated surface, and the like), exposing to solar energy, freeze drying (lyophilizing), spray drying, and combinations thereof.\",\n \"In some embodiments, drying comprises applying a cell to a rotating drum that is optionally heated.\",\n \"As used herein, chemically treating includes, but is not limited to, raising a pH of a cell, contacting a cell with a chemical or the like.\",\n \"Raising a pH of a cell can include, but is not limited to, adding a base to a cell composition.\",\n \"In some embodiments, bases suitable for use with the present invention include, but are not limited to, hydroxide bases (e.g., LiOH, NaOH, KOH, Ca(OH)2, and the like, and combinations thereof), carbonate bases (e.g., Na2CO3, K2CO3, MgCO3, and the like, and combinations thereof), bicarbonate bases (e.g., LiHCO3, NaHCO3, KHCO3, and the like, and combinations thereof), and combinations thereof.\",\n \"A base can be in the form of a solid (e.g., crystals, a granulate, pellets, and the like) or a liquid (e.g., an aqueous solution, an alcoholic solution such as a hydroxide base in methanol, ethanol, propanol, and the like), and combinations thereof.\",\n \"In some embodiments, the pH of the cell composition is raised to 8 or above, 9 or above, 10 or above, 11 or above, 12 or above, or a pH of 7 to 13, 7 to 12, 7 to 11, 7 to 10, 7 to 9, 8 to 13, 8 to 12, 8 to 11, 8 to 10, 8 to 9, 9 to 12, 9 to 11, 9 to 10, 10 to 12, or 10 to 11.In some embodiments, raising a pH of a cell can include, but is not limited to, performing a chloralkali process.\",\n \"In some embodiments, a fermentation broth containing sodium chloride and a cell composition is subjected to electrolysis, which would result in the formation of sodium hydroxide.\",\n \"The formation of sodium hydroxide raises the pH of the cell.\",\n \"In some embodiments, a fermentation broth can include calcium chloride or potassium chloride in place of or in addition to sodium chloride.\",\n \"Subjecting such a fermentation broth to electrolysis results in the formation of calcium hydroxide or potassium hydroxide, respectively, thereby raising the pH of the cell.\",\n \"Enzymatic lysing refers to lysis of a cell wall or cell membrane of a cell by contacting the cell with one or more enzymes.\",\n \"Enzymes suitable for use with the present invention include, but are not limited to, proteases, cellulases, hemicellulases, chitinases, pectinases, and combinations thereof.\",\n \"Non-limiting examples of proteases include serine proteases, theronine proteases, cysteine proteases, aspartate proteases, metalloproteases, glutamic acid proteases, alacase, and combinations thereof.\",\n \"Non-limiting examples of cellulases include sucrase, maltase, lactase, alpha-glucosidase, beta-glucosidase, amylase, lysozyme, neuraminidase, galactosidase, alpha-mannosidase, glucuronidase, hyaluronidase, pullulanase, glucocerebrosidase, galactosylceramidase, acetylgalactosaminidase, fucosidase, hexosaminidase, iduronidase, maltase-glucoamylase, and combinations thereof.\",\n \"A non-limiting example of a chitinase includes chitotriosidase.\",\n \"Non-limiting examples of pectinases include pectolyase, pectozyme, polygalacturonase, and combinations thereof.\",\n \"In some embodiments, some enzymes are activated by heating.\",\n \"As used herein, a “lysed cell composition” refers to a composition comprising one or more lysed cells, including cell debris and other contents of the cell, in combination with a lipid (from the lysed cells), and optionally, broth that contains microbial cells or plant material.\",\n \"In some embodiments, plant material is contained in a broth or media comprising the plant material and water.\",\n \"In some embodiments, a microbial cell is contained in a fermentation broth or media comprising the microbial cell and water.\",\n \"In some embodiments, a lysed cell composition refers to a composition comprising one or more lysed cells, cell debris, a lipid, the natural contents of the cell, and aqueous components from a broth.\",\n \"In some embodiments, a lysed cell composition is in the form of an oil-in-water emulsion comprising a mixture of a continuous aqueous phase and a dispersed lipid phase.\",\n \"In some embodiments, a dispersed lipid phase is present in a concentration of 1% to 60%, 1% to 50%, 1% to 40%, 1% to 30%, 1% to 20%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 10% to 60%, 10% to 50%, 10% to 40%, 20% to 60%, 20% to 50%, 20% to 40%, 30% to 60%, 30% to 50%, or 40% to 60% by weight of an emulsified lysed cell composition.\",\n \"While not being bound to any particular theory, it is believed the processes of the present invention break up or demulsify an emulsified lysed cell composition, allowing a lipid to be separated from the lysed cell composition.\",\n \"As used herein, the terms “emulsion” and “emulsified” refers to a mixture of two or more immiscible phases or layers wherein one phase or layer is dispersed in another phase or layer.\",\n \"As used herein, the terms “break,” “break up,” “demulsify,” “demulsification,” “demulsifying,” and “breaking” refer to a process of separating immiscible phases or layers of an emulsion.\",\n \"For example, demulsifying or breaking an emulsified lysed cell composition refers to a process by which an emulsified lysed cell composition changes from an emulsion having one or more phases or layers to a composition having two or more phases or layers.\",\n \"For example, in some embodiments, a process of the present invention breaks an emulsified lysed cell composition from a single-phase to two or more phases.\",\n \"In some embodiments, the two or more phases include a lipid phase and an aqueous phase.\",\n \"In some embodiments, a process of the present invention breaks an emulsified lysed cell compositions from one or more phases to at least three phases.\",\n \"In some embodiments, the three phases include a lipid phase, an aqueous phase, and a solid phase.\",\n \"In some embodiments, the three phases include a lipid phase, an emulsion phase, and an aqueous phase.\",\n \"In some embodiments, the processes of the present invention demulsify a lysed cell composition to form a demulsified cell composition by removing or breaking at least 75% of the emulsion, at least 80% of the emulsion, at least 85% of the emulsion, at least 90% of the emulsion, at least 95% of the emulsion, at least 99% of the emulsion.\",\n \"In some embodiments, the process of the present invention demulsify a lysed cell composition by removing or breaking 75% of the emulsion to 99% of the emulsion, 75% of the emulsion to 95% of the emulsion, 75% of the emulsion to 90% of the emulsion, 75% of the emulsion to 85% of the emulsion, 75% of the emulsion to 80% of the emulsion, 80% of the emulsion to 99% of the emulsion, 80% of the emulsion to 95% of the emulsion, 80% of the emulsion to 90% of the emulsion, 80% of the emulsion to 85% of the emulsion, 85% of the emulsion to 99% of the emulsion, 85% of the emulsion to 95% of the emulsion, 85% of the emulsion to 90% of the emulsion, 90% of the emulsion to 99% of the emulsion, 90% of the emulsion to 95% of the emulsion, or 95% of the emulsion to 99% of the emulsion by weight or volume.\",\n \"In some embodiments, prior to lysing the cell, the cell can be washed and/or pasteurized.\",\n \"In some embodiments, washing the cell includes using an aqueous solution, such as water, to remove any extracellular water-soluble or water-dispersible compounds.\",\n \"In some embodiments, the cell can be washed once, twice, thrice, or more.\",\n \"In some embodiments, pasteurizing the cell includes heating the cell to inactivate any undesirable enzymes, for example any enzymes that might degrade lipid or reduce the yield of PUFAs.\",\n \"In some embodiments, the cell can be washed first and then pasteurized.\",\n \"In some embodiments, the cell is plant biomaterial and the plant biomaterial is formed prior to lysing.\",\n \"In some embodiments, the plant biomaterial is formed by removing or extracting oilseeds from a plant.\",\n \"In some embodiments, an interior of an oilseed is removed from an outer hull of an oilseed by grinding, milling, extruding, aspirating, crushing, or combinations thereof.\",\n \"In some embodiments, the dehulled oilseeds can be homogenized or expelled using processes known in the art, such as by passing the oilseeds through a press to grind the dehulled oilseeds into a cake.\",\n \"In some embodiments, water can be added to the cake to form an emulsified lysed cell composition.\",\n \"In some embodiments, the emulsified lysed cell composition can be filtered using processes known in the art to remove any excess hull fragments from the lysed cell composition.\",\n \"In some embodiments, treating a lysed cell composition with a first base breaks up (i.e., demulsifies) an emulsified lysed cell composition.\",\n \"In some embodiments, treating a lysed cell composition with a second base breaks (i.e., demulsifies) an emulsified lysed cell composition.\",\n \"In some embodiments, treating a lysed cell composition with a salt breaks (i.e., demulsifies) an emulsified lysed cell composition.\",\n \"In some embodiments, heating a lysed cell composition breaks (i.e., demulsifies) an emulsified lysed cell composition.\",\n \"In some embodiments, agitating a lysed cell composition breaks (i.e., demulsifies) an emulsified lysed cell composition.\",\n \"In some embodiments, simultaneous heating and agitating of a lysed cell composition breaks (i.e., demulsifies) an emulsified lysed cell composition.\",\n \"In some embodiments, one or more of the preceding treatments breaks up (i.e., demulsifies) an emulsified lysed cell composition.\",\n \"In some embodiments, the process of the invention comprises raising the pH of a cell composition to lyse and/or demulsify the cell composition.\",\n \"In some embodiments, the process of the invention comprises raising the pH of a lysed cell composition to demulsify the lysed cell composition.\",\n \"In some embodiments, raising the pH comprises contacting a cell composition or lysed cell composition with a base.\",\n \"In some embodiments, the process of the invention comprises contacting a lysed cell composition with a base to demulsify the lysed cell composition.\",\n \"As used herein, “contacting” refers to combining a cell composition or a lysed cell composition with a second composition (e.g., by adding a composition to a cell composition or a lysed cell composition, by adding a cell composition or a lysed cell composition to a composition, and the like).\",\n \"As used herein, a “composition” can comprise a pure material or include a combination of two or more materials, substances, excipients, portions, and the like.\",\n \"Contacting a lysed cell composition with a first base raises the pH of the lysed cell composition.\",\n \"In some embodiments, a lysed cell composition is contacted with a second base.\",\n \"In some embodiments, the pH of a lysed cell composition or a demulsified cell composition is raised a second time.\",\n \"In some embodiments, the second raising of the pH comprises contacting a lysed cell composition or demulsified cell composition with a second base.\",\n \"In some embodiments, a lysed cell composition is contacted with a first base, then heated, agitated, or a combination thereof, and subsequently contacted with a second base to provide a treated lysed cell emulsion.\",\n \"In some embodiments, the first base and/or second base has a pKb of 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 5, 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 3 to 10, 3 to 6, 3 to 5, 4 to 10, 4 to 8, 4 to 6, 5 to 10, or 5 to 8.As used herein, the term “pKb” refers to the negative logarithm of the base association constant, Kb, of the base.\",\n \"Kb refers to the equilibrium constant for the ionization of the base in water, wherein: B+H2O HB++OH−; and the Kb of base, B, is defined as: K b = [ HB + ] [ OH - ] [ B ] .\",\n \"Bases suitable for use with the present invention include, but are not limited to, hydroxide bases (e.g., LiOH, NaOH, KOH, Ca(OH)2, and the like, and combinations thereof), carbonate bases (e.g., Na2CO3, K2CO3, MgCO3, and the like, and combinations thereof), bicarbonate bases (e.g., LiHCO3, NaHCO3, KHCO3, and the like, and combinations thereof), and combinations thereof.\",\n \"A base can be in the form of a solid (e.g., crystals, a granulate, pellets, and the like) or a liquid (e.g., an aqueous solution, an alcoholic solution such as a hydroxide base in methanol, ethanol, propanol, and the like), and combinations thereof.\",\n \"Thus, a solvent can be optionally present in a base for use with the present invention.\",\n \"As used herein, “solvent” refers to an agent that is hydrophobic or lipophilic.\",\n \"As used herein, “hydrophobic” refers to an agent that is repelled from a mass of water.\",\n \"As used herein, “lipophilic” refers to an agent that dissolves in lipids.\",\n \"In some embodiments, contacting a cell composition or a lysed cell composition with a base raises the pH of the lysed cell composition.\",\n \"In some embodiments, contacting a lysed cell composition with a base raises the pH of the lysed cell composition to 8 or above, 9 or above, 10 or above, 11 or above, 12 or above, or a pH of 7 to 13, 7 to 12, 7 to 11, 7 to 10, 7 to 9, 8 to 13, 8 to 12, 8 to 11, 8 to 10, 8 to 9, 9 to 12, 9 to 11, 9 to 10, 10 to 12, or 10 to 11.In some embodiments, contacting a lysed cell composition with a base provides a pH of 8 or below, 7 or below, 6 or below, or 5 or below to the composition.\",\n \"In some embodiments, raising the pH of the cell composition or lysed cell composition with the addition of the base inhibits lipid oxidation, thereby minimizing the amount of free radicals in the lysed cell composition so that the crude lipid obtained from the processes of the invention has a low peroxide value (e.g., 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less) and/or a low anisidine value (e.g., 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less).\",\n \"As used herein, the terms “peroxide value” or “PV” refer to the measure of primary reaction products, such as peroxides and hydroperoxides, that occur during oxidation of the lipid.\",\n \"As used herein peroxide value is measured in meq/kg.\",\n \"As used herein, the terms “anisidine value” or “AV” refer to the measure of secondary reaction products, such as aldehydes and ketones, that occur during oxidation of the lipid.\",\n \"In some embodiments, free radicals in the lysed cell composition after adjusting the pH with a base are detected using an Electron Paramagnetic Resonance spectrometer, e.g., Bruker BioSpin e-scan EPR (system number SC0274) (Bruker BioSpin, Billerica, Mass.).\",\n \"In some embodiments, a sample of the lysed cell composition is diluted in about 1:1 ratio with deionized water prior to measuring the EPR.\",\n \"In some embodiments, in order to measure the EPR, a spin trap chemical is added to a sample of the lysed cell composition.\",\n \"In some embodiments, the spin trap chemical is any spin trap chemical known in the art, including, but not limited to, POBN (α-(4-Pyridyl 1-oxide)-N-tert-butylnitrone) or DMPO (5,5-dimethyl-1-pyrroline-N-oxide).\",\n \"In some embodiments, the spin trap chemical is about 1.25 M and about 50 μL is added to about 0.5 gram sample of the lysed cell composition.\",\n \"In some embodiments, a sample containing the spin trap chemical is incubated at room temperature (e.g., about 20° C.).\",\n \"In some embodiments, the following spectrometer parameters are used: modulation frequency of about 86 Hz, modulation amplitude of about 2 gauss, microwave power of about 5 mW, time constant of about 20 seconds, sweep time of about 10 seconds, sweep width of about 100 gauss, and a number of scans of about 8.The EPR is measured over time to determine the concentration of free radicals present in the lipid.\",\n \"In some embodiments, the EPR is measured hourly over a course of four hours.\",\n \"In some embodiments, the lysed cell composition has an EPR signal strength (intensity or amplitude) at the above listed parameters of less than 0.15×106, less than 0.14×106, less than 0.13×106, less than 0.12×106, less than 0.11×106, less than 0.1×106, less than 0.09×106, less than 0.08×106, less than 0.07×106, less than 0.06×106, or less than 0.05×106 after 4 hours.\",\n \"In some embodiments, the lysed cell composition has an EPR of 0.05×106 to 0.15×106, 0.05×106 to 0.14×106, 0.05×106 to 0.13×106, 0.05×106 to 0.12×106, 0.05×106 to 0.11×106, 0.05×106 to 0.1×106, 0.05×106 to 0.09×106, 0.07×106 to 0.15×106, 0.07×106 to 0.13×106, 0.07×106 to 0.11×106, 0.08×106 to 0.14×106, 0.08×106 to 0.12×106, 0.08×106 to 0.1×106, 0.09×106 to 0.13×106, or 0.09×106 to 0.11×106.In some embodiments, the pH of the lysed cell composition resulting in an EPR specified above is 8 to 12, 8 to 11, 8 to 10, 8 to 9, 9 to 12, 9 to 11, 9 to 10, 10 to 12, or 10 to 11.In some embodiments, a lysed cell composition having an EPR signal strength specified above results in a crude lipid having an AV of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less.\",\n \"In some embodiments, a lysed cell composition having an EPR specified above results in a crude lipid having a PV of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less.\",\n \"In some embodiments, a process comprises contacting a cell composition or lysed cell composition with a salt to demulsify the lysed cell composition.\",\n \"As used herein, a “salt” refers to an ionic compound formed by replacing a hydrogen ion from an acid with a metal (e.g., an alkali metal, an alkali earth metal, a transition metal, and the like) or a positively charged compound (e.g., NH4+ and the like).\",\n \"Salts suitable for use with the present invention include, but are not limited to, alkali metal salts, alkali earth metal salts, or the like, and combinations thereof.\",\n \"Negatively charged ionic species present in a salt for use with the present include, but are not limited to, halides, sulfate, bisulfate, sulfite, phosphate, hydrogen phosphate, dihydrogen phosphate, carbonate, bicarbonate, or the like, and combinations thereof.\",\n \"In some embodiments, a salt for use with the present invention is selected from: sodium chloride, sodium sulfate, sodium carbonate, calcium chloride, potassium sulfate, magnesium sulfate, monosodium glutamate, ammonium sulfate, potassium chloride, iron chloride, iron sulfate, aluminum sulfate, and combinations thereof.\",\n \"In some embodiments, a salt does not include NaOH.\",\n \"A salt can be added as a solid (e.g., in crystalline, amorphous, pelletized, and/or granulated form), and/or as a solution (e.g., a dilute solution, a saturated solution, or a super-saturated solution) containing, for example, water, an alcohol, and the like, and combinations thereof.\",\n \"In some embodiments, the salt is added in an amount of 5 g/l to 25 g/l, 5 g/l to 10 g/l, 10 g/l to 15 g/l, 15 g/l to 20 g/l, 20 g/l to 25 g/l, or 10 g/l to 20 g/l.\",\n \"In some embodiments, a temperature of a cell composition or a lysed cell composition is less than or equal to 60° C., less than or equal to 55° C., less than or equal to 45° C., less than or equal to 40° C., less than or equal to 35° C., less than or equal to 30° C., or less than or equal to 25° C. when a salt is added to demulsify the cell composition or the lysed cell composition.\",\n \"In some embodiments, a temperature of a lysed cell composition is 0° C. to 60° C., 0° C. to 55° C., 0° C. to 50° C., 0° C. to 45° C., 0° C. to 40° C., 0° C. to 35° C., 0° C. to 30° C., 0° C. to 25° C., 20° C. to 60° C., 20° C. to 55° C., 20° C. to 50° C., 20° C. to 45° C., 20° C. to 40° C., 20° C. to 35° C., 20° C. to 30° C., 30° C. to 60° C., 30° C. to 55° C., 30° C. to 50° C., 30° C. to 45° C., 30° C. to 40° C., 30° C. to 40° C., 40° C. to 60° C., 40° C. to 55° C., 40° C. to 50° C., or 50° C. to 60° C. when a salt is added to demulsify the cell composition or the lysed cell composition.\",\n \"In some embodiments, the process comprises contacting a cell composition or a lysed cell composition with 20% or less, 15% or less, 10% or less, 7.5% or less, 5% or less, or 2% or less salt by weight, of the lysed cell composition or the cell composition.\",\n \"In some embodiments, a process comprises contacting a cell composition or a lysed cell composition with 0.1% to 20%, 0.1% to 15%, 0.1% to 10%, 0.5% to 20%, 0.5% to 15%, 0.5% to 10%, 0.5% to 5%, 0.5% to 4%, 0.5% to 3%, 0.5% to 2.5%, 0.5% to 2%, 0.5% to 1.5%, 0.5% to 1%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2.5%, 1% to 2%, 1% to 1.5%, 1.5% to 5%, 1.5% to 4%, 1.5% to 3%, 1.5% to 2.5%, 1.5% to 2%, 2% to 20%, 2% to 15%, 2% to 10%, 2% to 5%, 2% to 4%, 2% to 3%, 2% to 2.5%, 2.5% to 5%, 2.5% to 4%, 2.5% to 3%, 3% to 5%, 3% to 4%, 4% to 5%, 5% to 20%, 5% to 15%, 5% to 10%, 10% to 20%, 10% to 15%, or 15% to 20% salt, by weight, of the cell composition or lysed cell composition (e.g., a total broth weight).\",\n \"For example, when a lysed cell composition weighs 1,000 kg, contacting with 0.5% to 20% salt, by weight, requires combining 5 kg to 200 kg of salt with the lysed cell composition.\",\n \"In some embodiments, the process comprises heating a cell composition or a lysed cell composition to demulsify the lysed cell composition.\",\n \"In some embodiments the cell composition or the lysed cell composition is heated for a sufficient period of time for a base and/or a salt to demulsify a cell composition or a lysed cell composition.\",\n \"In some embodiments, the process comprises heating a cell composition or a lysed cell composition for at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 4 hours, at least 8 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 30 hours, at least 36 hours, at least 42 hours, at least 48 hours, at least 54 hours, at least 60 hours, at least 66 hours, at least 72 hours, at least 78 hours, at least 84 hours, at least 90 hours or at least 96 hours.\",\n \"In some embodiments, the process comprises heating a lysed cell composition for 5 minutes to 96 hours, 5 minutes to 4 hours, 5 minutes to 2 hours, 5 minutes to 1 hour, 10 minutes to 4 hours, 10 minutes to 2 hours, 10 minutes to 1 hour, 1 hour to 96 hours, 1 hour to 84 hours, 1 hour to 72 hours, 1 hour to 60 hours, 1 hour to 48 hours, 1 hour to 36 hours, 1 hour to 24 hours, 1 hour to 4 hours, 4 hours to 96 hours, 4 hours to 84 hours, 4 hours to 72 hours, 4 hours to 60 hours, 4 hours to 48 hours, 4 hours to 36 hours, 4 hours to 24 hours, 8 hours to 96 hours, 8 hours to 84 hours, 8 hours to 72 hours, 8 hours to 60 hours, 8 hours to 48 hours, 8 hours to 36 hours, 8 hours to 24 hours, 8 hours to 12 hours, 12 hours to 96 hours, 12 hours to 84 hours, 12 hours to 72 hours, 12 hours to 60 hours, 12 hours to 48 hours, 12 hours to 36 hours, 12 hours to 24 hours, 24 hours to 96 hours, 24 hours to 84 hours, 24 hours to 72 hours, 24 hours to 60 hours, 24 hours to 48 hours, or 24 hours to 36 hours.\",\n \"In some embodiments, a cell composition or a lysed cell composition can be heated at a temperature of at least 10° C., at least 20° C., at least 25° C., at least 30° C., at least 35° C., at least 40° C., at least 45° C., at least 50° C., at least 55° C., at least 60° C., at least 65° C., at least 70° C., at least 75° C., at least 80° C., at least 85° C., at least 90° C., at least 95° C., or at least 100° C. In some embodiments, a process comprises heating a cell composition or a lysed cell composition at a temperature of 10° C. to 100° C., 10° C. to 90° C., 10° C. to 80° C., 10° C. to 70° C., 20° C. to 100° C., 20° C. to 90° C., 20° C. to 80° C., 20° C. to 70° C., 30° C. to 100° C., 30° C. to 90° C., 30° C. to 80° C., 30° C. to 70° C., 40° C. to 100° C., 40° C. to 90° C., 40° C. to 80° C., 50° C. to 100° C., 50° C. to 90° C., 50° C. to 80° C., 50° C. to 70° C., 60° C. to 100° C., 60° C. to 90° C., 60° C. to 80° C., 70° C. to 100° C., 70° C. to 90° C., 80° C. to 100° C., 80° C. to 90° C., or 90° C. to 100° C. In some embodiments, a salt can be added to the cell composition or the lysed cell composition during the heating.\",\n \"In some embodiments, a cell composition or a lysed cell composition can be heated in a closed system or in a system with an evaporator.\",\n \"In some embodiments, a cell composition or lysed cell composition can be heated in a system with an evaporator such that a portion of the water present in the cell composition or the lysed cell composition is removed by evaporation.\",\n \"In some embodiments, a process comprises heating a cell composition or a lysed cell composition in a system with an evaporator to remove up to 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% by weight of water present in the cell composition or lysed cell composition.\",\n \"In some embodiments, a process comprises heating a cell composition or a lysed cell composition in a system with an evaporator to remove 1% to 50%, 1% to 45%, 1% to 40%, 1% to 35%, 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 5% to 50%, 5% to 45%, 5% to 40%, 5% to 35%, 5% to 30%, 5% to 25%, 5% to 20%, 5% to 15%, 5% to 10%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 10% to 25%, 10% to 20%, 10% to 15%, 15% to 50%, 15% to 45%, 15% to 40%, 15% to 35%, 15% to 30%, 15% to 25%, 15% to 20%, 20% to 50%, 20% to 45%, 20% to 40%, 20% to 35%, 20% to 30%, 20% to 25%, 25% to 50%, 25% to 45%, 25% to 40%, 25% to 35%, 25% to 30%, 30% to 50%, 30% to 45%, 30% to 40%, 30% to 35%, 35% to 50%, 35% to 45%, 35% to 40%, 40% to 50%, 40% to 45%, or 45% to 50%.\",\n \"In some embodiments, the process comprises holding a cell composition or a lysed cell composition in a vessel for a predetermined time to demulsify the lysed cell composition.\",\n \"In some embodiments, the process comprises holding a cell composition or a lysed cell composition in a vessel for at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 4 hours, at least 8 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 30 hours, at least 36 hours, at least 42 hours, at least 48 hours, at least 54 hours, at least 60 hours, at least 66 hours, at least 72 hours, at least 78 hours, at least 84 hours, at least 90 hours or at least 96 hours.\",\n \"In some embodiments, the process comprises holding a cell composition or a lysed cell composition for 5 minutes to 96 hours, 5 minutes to 4 hours, 5 minutes to 2 hours, 5 minutes to 1 hour, 10 minutes to 4 hours, 10 minutes to 2 hours, 10 minutes to 1 hour, 1 hour to 96 hours, 1 hour to 84 hours, 1 hour to 72 hours, 1 hour to 60 hours, 1 hour to 48 hours, 1 hour to 36 hours, 1 hour to 24 hours, 1 hour to 4 hours, 4 hours to 96 hours, 4 hours to 84 hours, 4 hours to 72 hours, 4 hours to 60 hours, 4 hours to 48 hours, 4 hours to 36 hours, 4 hours to 24 hours, 8 hours to 96 hours, 8 hours to 84 hours, 8 hours to 72 hours, 8 hours to 60 hours, 8 hours to 48 hours, 8 hours to 36 hours, 8 hours to 24 hours, 8 hours to 12 hours, 12 hours to 96 hours, 12 hours to 84 hours, 12 hours to 72 hours, 12 hours to 60 hours, 12 hours to 48 hours, 12 hours to 36 hours, 12 hours to 24 hours, 24 hours to 96 hours, 24 hours to 84 hours, 24 hours to 72 hours, 24 hours to 60 hours, 24 hours to 48 hours, or 24 hours to 36 hours.\",\n \"In some embodiments, the process comprises contacting an antioxidant with a lysed cell emulsion.\",\n \"Antioxidants suitable for use with the present invention include, but are not limited to, a tocopherol, a tocotrienol, a polyphenol, resveratrol, a flavonoid, a carotenoid, lycopene, a carotene, lutein, ascorbic acid, ascorbyl palmitate, or the like, and combinations thereof.\",\n \"In some embodiments, the process comprises allowing an emulsified lysed cell composition to stand, wherein the lipid is separated from the emulsified lysed cell composition using gravity.\",\n \"As used herein, the terms “agitating” and “agitation” refer to a process of affecting motion in a lysed cell composition through an application of force.\",\n \"In some embodiments, the process of the invention comprises agitating a cell composition or a lysed cell composition by stirring, mixing, blending, shaking, vibrating, or a combination thereof.\",\n \"In some embodiments, the process of agitating a cell composition or a lysed cell composition demulsifies the cell composition or the lysed cell composition.\",\n \"In some embodiments, the process of the invention comprises agitating a lysed cell composition at 0.1 hp/1,000 gal to 10 hp/1,000 gal, 0.5 hp/1,000 gal to 8 hp/1,000 gal, 1 hp/1,000 gal to 6 hp/1,000 gal, or 2 hp/1,000 gal to 5 hp/1,000 gal of lysed cell composition.\",\n \"In some embodiments, the process of the invention comprises agitating a cell composition or a lysed cell composition using an agitator.\",\n \"In some embodiments, the agitator is a dispersion style agitator that disperses a base and/or salt in the cell composition or the lysed cell composition.\",\n \"In some embodiments, an agitator has one or more impellers.\",\n \"As used herein, “impeller” refers to a device arranged to impart motion to a cell composition or a lysed cell composition when rotated.\",\n \"Impellers suitable for use with the present invention include straight blade impellers, Rushton blade impellers, axial flow impellers, radial flow impellers, concave blade disc impellers, high-efficiency impellers, propellers, paddles, turbines, or the like, and combinations thereof.\",\n \"In some embodiments, a process includes agitating a cell composition or a lysed cell composition using an agitator having an impeller tip speed of 90 ft/min to 1,200 ft/min, 200 ft/min to 1,000 ft/min, 300 ft/min to 800 ft/min, 400 ft/min to 700 ft/min, or 500 ft/min to 600 ft/min.\",\n \"In some embodiments, a process includes agitating a cell composition or a lysed cell composition using an agitator having an impeller tip speed of 350 centimeters/second to 900 centimeters per second, 350 centimeters/second to 850 centimeters per second, 350 centimeters/second to 800 centimeters/second, 350 centimeters/second to 750 centimeters/second, 350 centimeters/second to 700 centimeters/second, 350 centimeters/second to 650 centimeters/second, 350 centimeters/second to 600 centimeters/second, 350 centimeters/second to 550 centimeters/second, 350 centimeters/second to 500 centimeters/second, 350 centimeters/second to 450 centimeters/second, 350 centimeters/second to 400 centimeters/second, 400 centimeters/second to 900 centimeters per second, 400 centimeters/second to 850 centimeters per second, 400 centimeters/second to 800 centimeters/second, 400 centimeters/second to 750 centimeters/second, 400 centimeters/second to 700 centimeters/second, 400 centimeters/second to 650 centimeters/second, 400 centimeters/second to 600 centimeters/second, 400 centimeters/second to 550 centimeters/second, 400 centimeters/second to 500 centimeters/second, 400 centimeters/second to 450 centimeters/second, 450 centimeters/second to 900 centimeters per second, 450 centimeters/second to 850 centimeters per second, 450 centimeters/second to 800 centimeters/second, 450 centimeters/second to 750 centimeters/second, 450 centimeters/second to 700 centimeters/second, 450 centimeters/second to 650 centimeters/second, 450 centimeters/second to 600 centimeters/second, 450 centimeters/second to 550 centimeters/second, 450 centimeters/second to 500 centimeters/second, 500 centimeters/second to 900 centimeters per second, 500 centimeters/second to 850 centimeters per second, 500 centimeters/second to 800 centimeters/second, 500 centimeters/second to 750 centimeters/second, 500 centimeters/second to 700 centimeters/second, 500 centimeters/second to 650 centimeters/second, 500 centimeters/second to 600 centimeters/second, 500 centimeters/second to 550 centimeters/second, 550 centimeters/second to 900 centimeters per second, 550 centimeters/second to 850 centimeters per second, 550 centimeters/second to 800 centimeters/second, 550 centimeters/second to 750 centimeters/second, 550 centimeters/second to 700 centimeters/second, 550 centimeters/second to 650 centimeters/second, 550 centimeters/second to 600 centimeters/second, 600 centimeters/second to 900 centimeters per second, 600 centimeters/second to 850 centimeters per second, 600 centimeters/second to 800 centimeters/second, 600 centimeters/second to 750 centimeters/second, 600 centimeters/second to 700 centimeters/second, 600 centimeters/second to 650 centimeters/second, 650 centimeters/second to 900 centimeters per second, 650 centimeters/second to 850 centimeters per second, 650 centimeters/second to 800 centimeters/second, 650 centimeters/second to 750 centimeters/second, 650 centimeters/second to 700 centimeters/second, 700 centimeters/second to 900 centimeters per second, 700 centimeters/second to 850 centimeters per second, 700 centimeters/second to 800 centimeters/second, 700 centimeters/second to 750 centimeters/second, 750 centimeters/second to 900 centimeters per second, 750 centimeters/second to 850 centimeters per second, 750 centimeters/second to 800 centimeters/second, 800 centimeters/second to 900 centimeters per second, 800 centimeters/second to 850 centimeters per second, or 850 centimeters/second to 900 centimeters/second.\",\n \"As used herein, “impeller tip speed” refers to the speed of the outer most portion of the impeller as it rotates around its central axis.\",\n \"In some embodiments, the agitating (and optionally additional steps as described herein) is performed in a container comprising an impeller, wherein a ratio of the impeller diameter to the container volume is 0.1 to 0.5, 0.1 to 0.4, 0.2 to 0.5, 0.2 to 0.4, 0.3 to 0.5, or 0.3 to 0.4.In some embodiments, the agitating (and optionally additional steps as described herein) is performed in a container comprising an impeller, wherein a ratio of the impeller diameter to the inner diameter of the container is at least 0.25, at least 0.34, at least 0.65, 0.25 to 0.65, 0.25 to 0.33, 0.3 to 0.6, 0.3 to 0.5, 0.3 to 0.4, 0.34 to 0.65, 0.34 to 0.6, 0.34 to 0.55, 0.37 to 0.55, 0.4 to 0.65, 0.4 to 0.6, 0.4 to 0.5, or 0.42 to 0.55.In some embodiments, agitating comprises mixing a cell composition or a lysed cell composition such that the cell composition or the lysed cell composition is placed under flow conditions described by a Reynolds number of 10 to 10,000, 1,000 to 10,000, 1,500 to 10,000, or 2,000 to 10,000.In some embodiments, a lysed cell emulsion during the agitating has a Reynolds number of 2,000 or more, 3,000 or more, or 5,000 or more, or 2,000 to 10,000, 3,000 to 10,000, or 5,000 to 10,000.In some embodiments, a process comprises agitating a cell composition or a lysed cell composition for at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 1 hour, at least 2 hours, at least 4 hours, at least 8 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 30 hours, at least 36 hours, at least 42 hours, at least 48 hours, at least 54 hours, at least 60 hours, at least 66 hours, at least 72 hours, at least 78 hours, at least 84 hours, at least 90 hours or at least 96 hours.\",\n \"In some embodiments, a process comprises agitating a cell composition or a lysed cell composition for 5 minutes to 96 hours, 5 minutes to 4 hours, 5 minutes to 2 hours, 5 minutes to 1 hour, 10 minutes to 4 hours, 10 minutes to 2 hours, 10 minutes to 1 hour, 1 hour to 96 hours, 1 hour to 84 hours, 1 hour to 72 hours, 1 hour to 60 hours, 1 hour to 48 hours, 1 hour to 36 hours, 1 hour to 24 hours, 1 hour to 4 hours, 4 hours to 96 hours, 4 hours to 84 hours, 4 hours to 72 hours, 4 hours to 60 hours, 4 hours to 48 hours, 4 hours to 36 hours, 4 hours to 24 hours, 8 hours to 96 hours, 8 hours to 84 hours, 8 hours to 72 hours, 8 hours to 60 hours, 8 hours to 48 hours, 8 hours to 36 hours, 8 hours to 24 hours, 8 hours to 12 hours, 12 hours to 96 hours, 12 hours to 84 hours, 12 hours to 72 hours, 12 hours to 60 hours, 12 hours to 48 hours, 12 hours to 36 hours, 12 hours to 24 hours, 20 hours to 40 hours, 24 hours to 96 hours, 24 hours to 84 hours, 24 hours to 72 hours, 24 hours to 60 hours, 24 hours to 48 hours, or 24 hours to 36 hours.\",\n \"In some embodiments, a process comprises simultaneously agitating and heating a cell composition or a lysed cell composition to demulsify the cell composition or the lysed cell composition.\",\n \"In some embodiments, a process comprises agitating a cell composition or a lysed cell composition at a temperature of at least 10° C., at least 20° C., at least 25° C., at least 30° C., at least 35° C., at least 40° C., at least 45° C., at least 50° C., at least 55° C., at least 60° C., at least 65° C., at least 70° C., at least 75° C., at least 80° C., at least 85° C., at least 90° C., at least 95° C., or at least 100° C. In some embodiments, a process comprises agitating a cell composition or a lysed cell composition at a temperature of 10° C. to 100° C., 10° C. to 90° C., 10° C. to 80° C., 10° C. to 70° C., 20° C. to 100° C., 20° C. to 90° C., 20° C. to 80° C., 20° C. to 70° C., 30° C. to 100° C., 30° C. to 90° C., 30° C. to 80° C., 30° C. to 70° C., 40° C. to 100° C., 40° C. to 90° C., 40° C. to 80° C., 50° C. to 100° C., 50° C. to 90° C., 50° C. to 80° C., 50° C. to 70° C., 60° C. to 100° C., 60° C. to 90° C., 60° C. to 80° C., 70° C. to 100° C., 70° C. to 90° C., 80° C. to 1000° C., 80° C. to 90° C., or 90° C. to 100° C. In some embodiments, the various combinations of forming a lysed cell composition, contacting a lysed cell composition with a base or raising the pH of a lysed cell composition, contacting a lysed cell composition with a salt, heating the lysed cell composition, and agitating a lysed cell composition can occur in a single vessel.\",\n \"In some embodiments, the various combinations of forming a cell composition, contacting a cell composition with a base or raising the pH of a cell composition, contacting a cell composition with a salt, heating the cell composition, and agitating a cell composition can occur in a single vessel.\",\n \"In some embodiments, the single vessel includes a fermentation vessel.\",\n \"In some embodiments, the fermentation vessel can have a volume of at least 20,000 liters, at least 50,000 liters, at least 100,000 liters, at least 120,000 liters, at least 150,000 liters, at least 200,000 liters, or at least 220,000 liters.\",\n \"In some embodiments, the fermentation vessel can have a volume of 20,000 liters to 220,000 liters, 20,000 liters to 100,000 liters, 20,000 liters to 50,000 liters, 50,000 liters to 220,000 liters, 50,000 liters to 150,000 liters, 50,000 liters to 100,000 liters, 100,000 liters to 220,000 liters, 100,000 liters to 150,000 liters, 100,000 liters to 120,000 liters, 150,000 liters to 220,000 liters, 150,000 liters to 200,000 liters, or 200,000 liters to 220,000 liters.\",\n \"In some embodiments, a quantity of cell composition or lysed cell composition formed in a vessel can be transferred into one or more agitation vessels.\",\n \"In some embodiments, the agitation vessels can have a volume of at least 20,000 liters, at least 30,000 liters, at least 40,000 liters or at least 50,000 liters.\",\n \"In some embodiments, the agitation vessels can have a volume of 20,000 liters to 50,000 liters, 20,000 liters to 40,000 liters, 20,000 liters to 30,000 liters, 30,000 liters to 50,000 liters, 30,000 liters to 40,000 liters or 40,000 liters to 50,000 liters.\",\n \"In some embodiments, the agitation vessels can have any combination of the following properties.\",\n \"In some embodiments, the agitation vessels can have two impellers.\",\n \"In some embodiments, the impellers are Rushton blade impellers.\",\n \"In some embodiments, the impellers are separated from each other by a distance at least equal to a diameter of the smallest impeller.\",\n \"In some embodiments, the impellers are 30 inches to 40 inches, 33 inches to 37 inches, 33 inches, 34 inches, 35 inches, 36 inches or 37 inches from tip to tip.\",\n \"In some embodiments, the agitation vessels have a volume of at least 10,000 liters, at least 20,000 liters, at least 30,000 liters, at least 40,000 liters or at least 50,000 liters.\",\n \"In some embodiments, the agitation vessels have an inner diameter of 90 inches to 110 inches, 95 inches to 105 inches, 98 inches, 99 inches, 100 inches, 101 inches, or 102 inches.\",\n \"In some embodiments, a first impeller is located 15 inches to 20 inches, 16 inches to 19 inches, or 17 inches to 18 inches from a bottom of the agitation vessel and a second impeller is located 60 inches to 80 inches, 65 inches to 75 inches, 68 inches, 69 inches, 70 inches, 71 inches, 72 inches, 73 inches, 74 inches, or 75 inches above the first impeller.\",\n \"In some embodiments, a lysed cell composition is agitated at least 50 rpm, at least 60 rpm, or at least 70 rpm.\",\n \"In some embodiments, a lysed cell composition is agitated at 50 rpm to 70 rpm, 50 rpm to 60 rpm, or 60 rpm to 70 rpm.\",\n \"In some embodiments, the cell composition, the lysed cell composition, or the lipid are harvested from a vessel by pumping the cell composition, the lysed cell composition, or the lipid from the vessel.\",\n \"In some embodiments, the cell composition, the lysed cell composition, or the lipid are harvested from a vessel without agitating the vessel.\",\n \"In some embodiments, the cell composition, the lysed cell composition, or the lipid are harvested from a vessel by pumping, without agitation, the cell composition, the lysed cell composition, or the lipid from the vessel.\",\n \"In some embodiments, the cell composition, the lysed cell composition, or the lipid are harvested from a vessel without blowing air.\",\n \"In some embodiments, harvesting the cell composition, the lysed cell composition, or the lipid by the techniques described above results in a crude lipid having a low anisidine value (e.g., 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less) and/or a low phosphorus content (e.g., 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less).\",\n \"As described herein, the present invention utilizes various combinations of contacting a lysed cell composition with a first base or raising the pH of a lysed cell composition, contacting a lysed cell composition with a salt, heating a lysed cell composition, and agitating a lysed cell composition to provide a treated lysed cell composition.\",\n \"As described herein, the present invention utilizes various combinations of contacting a cell composition with a first base or raising the pH of a cell composition, contacting a cell composition with a salt, heating a cell composition, and agitating a cell composition to provide a treated cell composition.\",\n \"The treated cell composition or treated lysed cell composition is at least partially demulsified compared with an untreated cell composition or treated lysed cell composition.\",\n \"Thus, a treated cell composition or treated lysed cell composition can be placed in a centrifuge and a lipid can be separated therefrom.\",\n \"In some embodiments, after raising the pH of a cell composition or lysed cell composition, e.g., by contacting with a first base, the heating the cell composition or lysed cell composition and/or the agitating the cell composition or lysed cell composition can decrease the pH of the treated cell composition or treated lysed cell composition.\",\n \"In order for a lipid to be more effectively separated from a treated cell composition or treated lysed cell composition by centrifuging, the pH of the treated cell composition or treated lysed cell composition is raised a second time, e.g., by contacting the treated cell composition or the treated lysed cell composition with a second base.\",\n \"In some embodiments, contacting a treated lysed cell composition with a second base raises the pH of the treated cell composition or the treated lysed cell composition.\",\n \"In some embodiments, a treated cell composition or a treated lysed cell composition is contacted with a second base to raise the pH of the treated cell composition or the treated lysed cell composition to 7 or above, 7.5 or above, 8 or above, 8.5 or above, 9 or above, 9.5 or above, 10 or above, 10.5 or above, 11 or above, 11.5 or above, or 12 or above.\",\n \"In some embodiments, a treated cell composition or a treated lysed cell composition is contacted with a second base to raise the pH of the treated lysed cell composition to 7 to 13, 7 to 12, 7 to 11, 7 to 10, 7 to 9, 7 to 8, 7 to 7.5, 7.5 to 8, 8 to 13, 8 to 12, 8 to 11, 8 to 10, 8 to 9, 8 to 8.5, 8.5 to 9, 9 to 12, 9 to 11, 9 to 10, 9 to 9.5, 9.5 to 10, 10 to 12, or 10 to 11.In some embodiments, the pH of a treated cell composition or a treated lysed cell emulsion is 7 or less, 6 or less, 5 or less, 4 or less, or 3 or less.\",\n \"The processes of the present invention comprise separating a lipid from a treated cell composition or a treated lysed cell composition.\",\n \"In some embodiments, a lipid is separated from a lysed cell emulsion after contacting a lysed cell emulsion with a second base, after the agitating a lysed cell emulsion, or after contacting a lysed cell emulsion with a salt by, for example, permitting the treated lysed cell emulsion to rest for a period of time sufficient for a lipid to separate from the treated lysed cell emulsion (e.g., as a separate layer).\",\n \"The lipid can be subsequently removed, for example, by decanting, skimming, vacuuming, pumping, sucking off, drawing off, siphoning, or otherwise removing the lipid from the surface of the treated lysed cell emulsion.\",\n \"In some embodiments, the separating comprises centrifuging a treated cell composition or a treated lysed cell composition (e.g., at a temperature of 30° C. to 100° C.), whereby the centrifuging separates a lipid from the treated cell composition or the treated lysed cell composition.\",\n \"In some embodiments, a process comprises centrifuging a treated cell composition or a treated lysed cell composition at a temperature of at least 10° C., at least 20° C., at least 25° C., at least 30° C., at least 35° C., at least 40° C., at least 45° C., at least 50° C., at least 55° C., at least 60° C., at least 65° C., at least 70° C., at least 75° C., at least 80° C., at least 85° C., at least 90° C., at least 95° C., or at least 100° C. In some embodiments, a process comprises centrifuging a treated cell composition or a treated lysed cell composition at a temperature of 10° C. to 100° C., 10° C. to 90° C., 10° C. to 80° C., 20° C. to 100° C., 20° C. to 90° C., 20° C. to 80° C., 25° C. to 100° C., 25° C. to 90° C., 25° C. to 80° C., 25° C. to 75° C., 30° C. to 100° C., 30° C. to 90° C., 30° C. to 80° C., 40° C. to 100° C., 40° C. to 90° C., 40° C. to 80° C., 50° C. to 100° C., 50° C. to 90° C., 50° C. to 80° C., 50° C. to 70° C., 60° C. to 100° C., 60° C. to 90° C., 60° C. to 80° C., 60° C. to 70° C., 70° C. to 100° C., or 70° C. to 90° C. In some embodiments, centrifuging is conducted at a feed rate (of a treated cell composition or a treated lysed cell composition into a centrifuge) of 1 kilogram per minute (kg/min) to 500 kg/min, 1 kg/min to 400 kg/min, 1 kg/min to 300 kg/min, 1 kg/min to 200 kg/min, 1 kg/min to 100 kg/min, 1 kg/min to 75 kg/min, 1 kg/min to 50 kg/min, 1 kg/min to 40 kg/min, 1 kg/min to 30 kg/min, 1 kg/min to 25 kg/min, 1 kg/min to 10 kg/min, 10 kg/min to 500 kg/min, 10 kg/min to 400 kg/min, 10 kg/min to 300 kg/min, 10 kg/min to 200 kg/min, 10 kg/min to 100 kg/min, 10 kg/min to 75 kg/min, 10 kg/min to 50 kg/min, 10 kg/min to 40 kg/min, 10 kg/min to 30 kg/min, 20 kg/min to 500 kg/min, 20 kg/min to 400 kg/min, 20 kg/min to 300 kg/min, 20 kg/min to 200 kg/min, 20 kg/min to 100 kg/min, 20 kg/min to 75 kg/min, 20 kg/min to 50 kg/min, 20 kg/min to 40 kg/min, 25 kg/min to 500 kg/min, 25 kg/min to 400 kg/min, 25 kg/min to 300 kg/min, 25 kg/min to 200 kg/min, 25 kg/min to 100 kg/min, 25 kg/min to 75 kg/min, 25 kg/min to 50 kg/min, 30 kg/min to 60 kg/min, 30 kg/min to 50 kg/min, 30 kg/min to 40 kg/min, 50 kg/min to 500 kg/min, 100 kg/min to 500 kg/min, or 200 kg/min to 500 kg/min.\",\n \"The total time required for the separating can vary depending on the volume of the treated cell composition or the treated lysed cell composition.\",\n \"Typical total time for separation (e.g., centrifuge time) is at least 0.1 hour, at least 0.2 hour, at least 0.5 hour, at least 1 hour, at least 2 hours, at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, or 0.1 hour to 24 hours, 0.5 hour to 24 hours, 1 hour to 12 hours, 2 hours to 10 hours, or 4 hours to 8 hours.\",\n \"In some embodiments, a process of the invention comprises centrifuging a treated cell composition or a treated lysed cell composition at a centrifugal force of 1,000 g to 25,000 g, 1,000 g to 20,000 g, 1,000 g to 10,000 g, 2,000 g to 25,000 g, 2,000 g to 20,000 g, 2,000 g to 15,000 g, 3,000 g to 25,000 g, 3,000 g to 20,000 g, 5,000 g to 25,000 g, 5,000 g to 20,000 g, 5,000 g to 15,000 g, 5,000 g to 10,000 g, 5,000 g to 8,000 g, 10,000 g to 25,000 g, 15,000 g to 25,000 g, or at least 1,000 g, at least 2,000, g, at least 4,000 g, at least 5,000 g, at least 7,000 g, at least 8,000 g, at least 10,000 g, at least 15,000 g, at least 20,000 g, or at least 25,000 g. As used herein, “g” refers to standard gravity or approximately 9.8 m/s2.In some embodiments, a process of the invention comprises centrifuging a treated cell composition or a treated lysed cell composition at 4,000 rpm to 14,000 rpm, 4,000 rpm to 10,000 rpm, 6,000 rpm to 14,000 rpm, 6,000 rpm to 12,000 rpm, 8,000 to 14,000 rpm, 8,000 rpm to 12,000 rpm, or 8,000 rpm to 10,000 rpm.\",\n \"In some embodiments, a process of the invention comprises drying a lipid after separation of the lipid from a treated cell composition or a treated lysed cell composition in order to remove water from the lipid.\",\n \"In some embodiments, drying the lipid can include, but is not limited to, heating the lipid to evaporate water.\",\n \"In some embodiments, after drying, the lipid has a water content by weight percentage of lipid that is less than 3%, less than 2.5%, less than 2%, less than 1.5%, less than 1%, less than 0.5%, less than 0.1%, or 0%.\",\n \"In some embodiments, after drying, the lipid has a water content by weight percentage of lipid of 0% to 3%, 0% to 2.5%, 0% to 2%, 0% to 1.5%, 0% to 1%, 0% to 0.5%, 0.1% to 3%, 0.1% to 2.5%, 0.1% to 2%, 0.1% to 1.5%, 0.1% to 1%, 0.1% to 0.5%, 0.5% to 3%, 0.5% to 2.5%, 0.5% to 2%, 0.5% to 1.5%, 0.5% to 1%, 1% to 3%, 1% to 2.5%, 1% to 2%, 1% to 1.5%, 1.5% to 3%, 1.5% to 2.5%, 1.5% to 2%, 2% to 3%, 2% to 2.5%, or 2.5% to 3%.\",\n \"In some embodiments, a process further comprises refining a lipid by one or more processes selected from caustic refining, degumming, alkali-refining, bleaching, deodorization, deacidification, or the like, and combinations thereof to remove one or more phospholipids, free fatty acids, phosphatides, color bodies, sterols, odors, and other impurities.\",\n \"As used herein, a “refined oil” is a crude lipid or crude oil that has been refined.\",\n \"As used herein, “a crude lipid” or “a crude oil” is a lipid or oil that has not been refined.\",\n \"In some embodiments, the lipid separated from a demulsified cell composition is a crude lipid.\",\n \"Various exemplary processes of the present invention are described schematically in FIGS.\",\n \"1-4.Referring to FIG.\",\n \"1, in some embodiments, the present invention is directed to a process (100) for obtaining a lipid (110) from a cell (101), comprising lysing (102) the cell (101) to form a lysed cell composition (103).\",\n \"The lysed cell composition is contacted with a first base (104) to demulsify lysed cell composition (103), contacted with a salt (105) to demulsify lysed cell composition (103), and heated (106), e.g., for 10 minutes to 96 hours, to provide a treated lysed cell composition (107).\",\n \"The treated lysed cell composition (107) is contacted with a second base (108) and separated (109), e.g., at a temperature of 10° C. to 100° C., to provide a lipid (110).\",\n \"Referring to FIG.\",\n \"2, in some embodiments, the present invention is directed to a process (200) for obtaining a lipid (210) from a cell, the process comprising lysing (102) a cell (101) to form a lysed cell composition (103).\",\n \"The lysed cell composition is then contacted with a base (204) to demulsify lysed cell composition (103) and to provide a treated lysed cell composition (207).\",\n \"The treated lysed cell composition (207) is separated (209), e.g., at a temperature of 10° C. to 100° C., to provide a lipid (210).\",\n \"Referring to FIG.\",\n \"3, in some embodiments, the present invention is directed to a process (300) for obtaining a lipid (310) from a cell, the process comprising lysing (102) a cell (101) to form a lysed cell composition (103).\",\n \"The lysed cell composition is then contacted with a salt (305) to demulsify lysed cell composition (103) and to provide a treated lysed cell composition (307), which is separated (309), e.g., at a temperature of 10° C. to 100° C., to provide a lipid (310).\",\n \"Referring to FIG.\",\n \"4, in some embodiments, the present invention is directed to a process (400) for obtaining a lipid (410) from a cell, the process comprising lysing (102) a cell (101) to form a lysed cell composition (103).\",\n \"The lysed cell composition is then contacted with a salt (405) to demulsify lysed cell composition (103) and agitated (401), e.g., for 5 minutes to 96 hours, and optionally heated (402), to provide a treated lysed cell composition (407).\",\n \"The treated lysed cell composition is then separated (409), e.g., at a temperature of 10° C. to 100° C., to provide a lipid (410).\",\n \"In some embodiments, a process of the present invention comprises concentrating a broth comprising a microbial cell, a broth comprising plant material and/or concentrating a lysed cell composition.\",\n \"As used herein, “concentrating” refers to removing water from a composition.\",\n \"Concentrating can include, but is not limited to, evaporating, chemical drying, centrifuging, and the like, and combinations thereof.\",\n \"In some embodiments, a broth comprising a microbial cell or a broth comprising plant material is concentrated to provide a lipid concentration of at least 4%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% by weight of the broth.\",\n \"In some embodiments, a broth comprising a microbial cell or a broth comprising plant material is concentrated to provide a lipid concentration of 4% to 40%, 4% to 30%, 4% to 20%, 4% to 15%, 5% to 40%, 5% to 30%, 5% to 20%, 10% to 40%, 10% to 30%, 10% to 20%, 15% to 40%, 15% to 30%, 20% to 40%, 20% to 30%, 25% to 40%, or 30% to 40% by weight of the broth.\",\n \"In some embodiments, a cell composition or a lysed cell composition is concentrated to provide a lipid concentration of at least 4%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, or at least 30% by weight of the lysed cell composition.\",\n \"In some embodiments, a cell composition or a lysed cell composition is concentrated to provide a lipid concentration of 4% to 40%, 4% to 30%, 4% to 20%, 4% to 15%, 5% to 40%, 5% to 30%, 5% to 20%, 10% to 40%, 10% to 30%, 10% to 20%, 15% to 40%, 15% to 30%, 20% to 40%, 20% to 30%, 25% to 40%, or 30% to 40% by weight of the lysed cell composition.\",\n \"In some embodiments, a lipid prepared by a process of the present invention has an overall aroma intensity of 2 or less.\",\n \"As used herein, the term “overall aroma intensity” refers to the olfactory sensory rating given to the lipid by a panel of sensory analysts.\",\n \"As used herein, the term “sensory analyst” refers to a trained individual that provides feedback on and/or rates the sensory characteristics of a substance.\",\n \"In some embodiments, a lipid prepared by a process of the present invention has an overall aromatic intensity of 3 or less.\",\n \"As used herein, the term “overall aromatic intensity” refers to the gustatory, or taste, sensory rating given to the lipid by a panel of sensory analysts.\",\n \"In some embodiments, the Universal Spectrum descriptive analysis method is used to assess the aroma and aromatic characteristics of samples.\",\n \"This method uses an intensity scale of 0-15, where 0=none detected and 15=very high intensity, to measure the aroma and aromatic attributes of the oils.\",\n \"In some embodiments, a lipid prepared by a process of the present invention does not have an aftertaste characterized as fishy.\",\n \"As used herein, the term “aftertaste” refers to the persistence of a sensation of a flavor in the lipid, as characterized by a panel of sensory analysts.\",\n \"In some embodiments, a process of the present invention provides a crude lipid having a peroxide value (PV) of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less.\",\n \"As used herein, the terms “peroxide value” or “PV” refer to the measure of primary reaction products, such as peroxides and hydroperoxides, that occur during oxidation of the lipid.\",\n \"In some embodiments, the PV is an indicator of the quality of the lipid and the extent of oxidation which has occurred in the lipid having a low PV (i.e., 5 or less) demonstrates increased stability and sensory profiles than lipids having a PV greater than 5.In some embodiments, adding a base to a lysed cell composition, as discussed above, raises the pH of the lysed cell composition and inhibits lipid oxidation, thereby minimizing the amount of free radicals in the lysed cell composition so that the crude lipid obtained from the processes of the invention has a low PV (i.e., 5 or less).\",\n \"In some embodiments, a process of the present invention provides a crude lipid having an anisidine value (AV) of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less.\",\n \"As used herein, the terms “anisidine value” or “AV” refer to the measure of secondary reaction products, such as aldehydes and ketones, that occur during oxidation of the lipid.\",\n \"In some embodiments, the AV is an indicator of the quality of the lipid and the extent of oxidation which has occurred in the lipid.\",\n \"A lipid having a low AV (i.e., 26 or less) demonstrates increased stability and sensory profiles than lipids having an AV greater than 26.In some embodiments, adding a base to a lysed cell composition, as discussed above, raises the pH of the lysed cell composition and inhibits lipid oxidation, thereby minimizing the amount of free radicals in the lysed cell composition so that the crude lipid obtained from the processes of the invention has a low AV (i.e., 26 or less).\",\n \"In some embodiments, a process of the present invention provides a crude lipid having a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"In some embodiments, a process of the present invention provides a crude lipid that has a lower anisidine value, lower peroxide value, lower phosphorus content and/or a higher extraction yield than if extraction was performed using a solvent (e.g., atypical hexane extraction or a FRIOLEX® process (Westfalia Separator AG, Germany)).\",\n \"The FRIOLEX® process which is a process of extracting lipids with a water-soluble organic solvent as described in U.S. Pat.\",\n \"No.\",\n \"5,928,696 and International Pub.\",\n \"Nos.\",\n \"WO 01/76385 and WO 01/76715, each of which is incorporated by reference herein in its entirety.\",\n \"In some embodiments, heating the lysed cell composition causes the secondary reaction products (e.g., aldehydes and ketones) to participate in a reaction similar to the Maillard reaction with proteins present in the lysed cell composition.\",\n \"The reaction is believed to create products that possess antioxidant activity, which reduces the oxidation of the lipid.\",\n \"In some embodiments, additional protein, e.g., soy protein, can be added to the lysed cell composition to increase the antioxidant activity.\",\n \"The reduction in oxidation of the lipid reduces the AV of the lipid, reduces any aftertaste of the lipid and/or increases the stability of the lipid.\",\n \"In some embodiments, the stability is increased at least 5%, at least 10%, at least 15% or at least 20%.\",\n \"In some embodiments, a lipid extracted by a process of the present invention, the biomass remaining after extraction of the lipid, or combinations thereof can be used directly as a food or food ingredient, such as an ingredient in baby food, infant formula, beverages, sauces, dairy based foods (such as milk, yogurt, cheese and ice-cream), oils (e.g., cooking oils or salad dressings), and baked goods; nutritional supplements (e.g., in capsule or tablet forms); feed or feed supplement for any non-human animal (e.g., those whose products (e.g., meat, milk, or eggs) are consumed by humans); food supplements; and pharmaceuticals (in direct or adjunct therapy application).\",\n \"The term “animal” refers to any organism belonging to the kingdom Animalia and includes any human animal, and non-human animal from which products (e.g., milk, eggs, poultry meat, beef, pork or lamb) are derived.\",\n \"In some embodiments, the lipid and/or biomass can be used in seafood.\",\n \"Seafood is derived from, without limitation, fish, shrimp and shellfish.\",\n \"The term “products” includes any product derived from such animals, including, without limitation, meat, eggs, milk or other products.\",\n \"When the lipid and/or biomass are fed to such animals, polyunsaturated lipids can be incorporated into the flesh, milk, eggs or other products of such animals to increase their content of these lipids.\",\n \"Microbial Lipids In some embodiments, the present invention is directed to a microbial lipid extracted according to the processes of the present invention.\",\n \"In some embodiments, a crude microbial lipid has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"In some embodiments, the crude microbial lipid has less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% by weight or volume of an organic solvent.\",\n \"In some embodiments, the crude microbial lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of a desired PUFA.\",\n \"In some embodiments, the crude microbial lipid has at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of DHA, and/or at least 10%, at least 15%, or at least 20% by weight of DPA n-6, and/or at least 10%, at least 15%, or at least 20% by weight of EPA, and/or at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% by weight of ARA.\",\n \"In some embodiments a crude microbial lipid extracted according to the processes of the present invention result in a lower anisidine value, lower peroxide value, lower phosphorus content and/or a higher extraction yield than if extraction was performed using a solvent (e.g., a typical hexane extraction or a FRIOLEX® process (Westfalia Separator AG, Germany)).\",\n \"Lipids Extracted from a First Set of Isolated Thraustochytrid Microorganisms In some embodiments, the present invention is further directed to a microbial lipid extracted from a thraustochytrid as described in U.S. Pub.\",\n \"No.\",\n \"2010/0239533 and Int'l.\",\n \"Pub.\",\n \"No.\",\n \"WO 2010/107415, each of which is incorporated by reference herein in its entirety.\",\n \"In some embodiments, the method comprises growing a thraustochytrid in a culture to produce a biomass and extracting a lipid comprising omega-3 fatty acids from the biomass.\",\n \"The lipid can be extracted from a freshly harvested biomass or can be extracted from a previously harvested biomass that has been stored under conditions that prevent spoilage.\",\n \"Known methods can be used to culture a thraustochytrid of the invention, to isolate a biomass from the culture, and to analyze the fatty acid profile of oils extracted from the biomass.\",\n \"See, e.g., U.S. Pat.\",\n \"No.\",\n \"5,130,242, incorporated by reference herein in its entirety.\",\n \"The lipid can be extracted according to the processes of the present invention.\",\n \"A microbial lipid of the invention can be any lipid derived from a microorganism, including, for example: a crude oil extracted from the biomass of the microorganism without further processing; a refined oil that is obtained by treating a crude microbial oil with further processing steps such as refining, bleaching, and/or deodorizing; a diluted microbial oil obtained by diluting a crude or refined microbial oil; or an enriched oil that is obtained, for example, by treating a crude or refined microbial oil with further methods of purification to increase the concentration of a fatty acid (such as DHA) in the oil.\",\n \"In some embodiments, the microbial lipid comprises a sterol esters fraction of 0%, at least 0.1%, at least 0.2%, at least 0.5%, at least about 1%, at least 1.5%, at least 2%, or at least 5% by weight.\",\n \"In some embodiments, the microbial lipid comprises a sterol esters fraction of from 0% to 1.5%, 0% to 2%, 0% to 5%, 1% to 1.5%, 0.2% to 1.5%, 0.2% to 2%, or 0.2% to 5% by weight.\",\n \"In some embodiments, the microbial lipid comprises a sterol esters fraction of less than 5%, less than 4%, less than 3%, or less than 2% by weight.\",\n \"In some embodiments, the microbial lipid comprises a triglyceride fraction of at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% by weight.\",\n \"In some embodiments, the microbial lipid comprises a triglyceride fraction of from 65% to 95%, 75% to 95%, or 80% to 95% by weight, or 97% by weight, or 98% by weight.\",\n \"In some embodiments, the microbial lipid comprises a free fatty acid fraction of at least 0.5%, at least 1%, at least 1.5%, at least 2%, at least 2.5%, or at least 5% by weight.\",\n \"In some embodiments, the microbial lipid comprises a free fatty acid fraction of from 0.5% to 5%, 0.5% to 2.5%, 0.5% to 2%, 0.5% to 1.5%, 0.5% to 1%, 1% to 2.5%, 1% to 5%, 1.5% to 2.5%, 2% to 2.5%, or 2% to 5% by weight.\",\n \"In some embodiments, the microbial lipid comprises a free fatty acid fraction of less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% by weight.\",\n \"In some embodiments, the microbial lipid comprises a sterol fraction of at least 0.5%, at least 1%, at least 1.5%, at least 2%, or at least 5% by weight.\",\n \"In some embodiments, the microbial lipid comprises a sterol fraction of from 0.5% to 1.5%, 1% to 1.5%, 0.5% to 2%, 0.5% to 5%, 1% to 2%, or 1% to 5% by weight.\",\n \"In some embodiments, the microbial lipid comprises a sterol fraction of less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% by weight.\",\n \"In some embodiments, the microbial lipid comprises a diglyceride fraction of at least 1.5%, at least 2%, at least 2.5%, at least 3%, at least 3.5%, or at least 5% by weight.\",\n \"In some embodiments, the microbial lipid comprises a diglyceride fraction of from 1.5% to 3%, 2% to 3%, 1.5% to 3.5%, 1.5% to 5%, 2.5% to 3%, 2.5% to 3.5%, or 2.5% to 5% by weight.\",\n \"In some embodiments, the microbial lipid comprises unsaponifiables of less than 2%, less than 1.5%, less than 1%, or less than 0.5% by weight of the oil.\",\n \"The lipid classes present in the microbial oil, such as the triglyceride fraction, can be separated by flash chromatography and analyzed by thin layer chromatography (TLC), or separated and analyzed by other methods know in the art.\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, and combinations thereof, comprises at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80% by weight DHA.\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, and combinations thereof, comprises from 40% to 45%, 40% to 50%, 40% to 60%, 50% to 60%, 55% to 60%, 40% to 65%, 50% to 65%, 55% to 65%, 40% to 70%, 40% to 80%, 50% to 80%, 55% to 80%, 60% to 80%, or 70% to 80% by weight DHA.\",\n \"In some embodiments, the microbial lipid comprises a sterol esters fraction comprising 45% or less, 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, or 13% or less by weight DHA.\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, and combinations thereof, comprises 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less by weight EPA.\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, and combinations thereof, comprises from 2% to 3%, 2% to 3.5%, 2.5% to 3.5%, 2% to 6%, 2.5% to 6%, 3.0% to 6%, 3.5% to 6%, 5% to 6%, or 2% to 10% by weight EPA.\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, is substantially free of EPA.\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, comprises a weight ratio of DHA to EPA of at least 5:1, at least 7:1, at least 9:1, at least 10:1, at least 15:1, at least 20:1, at least 25:1, at least 30:1, or at least 50:1, wherein the microbial lipid and/or one or more fractions thereof comprises 10% or less by weight of EPA.\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, comprises a weight ratio of DHA to EPA of at least 5:1, but less than 20:1.In some embodiments, the weight ratio of DHA to EPA is from 5:1 to 18:1, from 7:1 to 16:1, or from 10:1 to 15:1.In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof comprises from 0.1% to 0.25%, 0.2% to 0.25%, 0.1% to 0.5%, or 0.1% to 1.5% by weight ARA.\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, comprises 1.5% or less, 1% or less, 0.5% or less, 0.2% or less, or 0.1% or less by weight ARA.\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, is substantially free of ARA.\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, comprises a weight ratio of DHA to ARA of at least 20:1, at least 30:1, at least 35:1, at least 40:1, at least 60:1, at least 80:1, at least 100:1, at least 150:1, at least 200:1, at least 250:1, or at least 300:1.In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, comprises from 0.5% to 1%, 0.5% to 2%, 0.5% to 2.5%, 0.5% to 3%, 0.5% to 3.5%, 0.5% to 5%, 0.5% to 6%, 1% to 2%, 2% to 3%, 2% to 3.5%, 1% to 2.5%, 1% to 3%, 1% to 3.5%, 1% to 5%, or 1% to 6% by weight DPA n-6.In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, comprises 6% or less, 5% or less, 3% or less, 2.5% or less, 2% or less, 1% or less, or 0.5% or less by weight DPA n-6.In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, is substantially free of DPA n-6.In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, comprises a weight ratio of DHA to DPA n-6 of greater than 6:1, of at least 8:1, at least 10:1, at least 15:1, at least 20:1, at least 25:1, at least 50:1, or at least 100:1.In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, comprises 5% or less, 4% or less, 3% or less, 2% or less, 1.5% or less, 1% or less, or 0.5% or less by weight each of linoleic acid (18:2 n-6), linolenic acid (18:3 n-3), eicosenoic acid (20:1 n-9), and erucic acid (22:1 n-9).\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the sterol esters fraction, the triglyceride fraction, the free fatty acid fraction, the sterol fraction, the diglyceride fraction, the polar fraction (including the phospholipid fraction), and combinations thereof, comprises 5% or less, 4% or less, 3% or less, 2% or less, 1.5% or less, or 1% or less by weight of heptadecanoic acid (17:0).\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof comprise 0.01% to 5% by weight, 0.05% to 3% by weight, or 0.1% to 1% by weight of heptadecanoic acid.\",\n \"In some embodiments, an extracted microbial lipid comprises a triglyceride fraction of at least 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 50% by weight, wherein the docosapentaenoic acid n-6 content of the triglyceride fraction is from at least 0.5% by weight to 6% by weight, and wherein the oil has an anisidine value of 26 or less.\",\n \"In some embodiments, an extracted microbial lipid comprises a triglyceride fraction of at least 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 40% by weight, wherein the docosapentaenoic acid n-6 content of the triglyceride fraction is from at least 0.5% by weight to 6% by weight, wherein the ratio of docosahexaenoic acid to docosapentaenoic acid n-6 is greater than 6:1, and wherein the lipid has an anisidine value of 26 or less.\",\n \"In some embodiments, an extracted microbial lipid comprises a triglyceride fraction of at least 70% by weight, wherein the docosahexaenoic acid content of the triglyceride fraction is at least 60% by weight and wherein the lipid has an anisidine value of 26 or less.\",\n \"In some embodiments, an extracted microbial lipid having any of the above fatty acid profiles has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"In some embodiments, an extracted microbial lipid having any of the above fatty acid profiles is extracted from an isolated thraustochytrid microorganism having the characteristics of the thraustochytrid species deposited under ATCC Accession No.\",\n \"PTA-9695, PTA-9696, PTA-9697, or PTA-9698.In some embodiments, an extracted microbial lipid having any of the above fatty acid profiles is a crude lipid.\",\n \"In some embodiments, the crude lipid has less than 5% by weight or volume of an organic solvent.\",\n \"In some embodiments the microbial lipid extracted according to the processes of the present invention result in a lower anisidine value, lower peroxide value, lower phosphorus content and/or a higher extraction yield if extraction was performed using a solvent (e.g., atypical hexane extraction or a FRIOLEX™ process (Westfalia Separator AG, Germany)).\",\n \"Lipids Extracted from a Second Set of Isolated Thraustochytrid Microorganisms In some embodiments, the present invention is further directed to a microbial lipid extracted from a thraustochytrid as described in U.S. application Ser.\",\n \"No.\",\n \"12/729,013 and PCT/US2010/028175, each of which is incorporated by reference herein in its entirety.\",\n \"In some embodiments, the method comprises growing a thraustochytrid in a culture to produce a biomass and extracting a lipid comprising omega-3 fatty acids from the biomass.\",\n \"The lipid can be extracted from a freshly harvested biomass or can be extracted from a previously harvested biomass that has been stored under conditions that prevent spoilage.\",\n \"Known methods can be used to culture a thraustochytrid of the invention, to isolate a biomass from the culture, and to analyze the fatty acid profile of oils extracted from the biomass.\",\n \"See, e.g., U.S. Pat.\",\n \"No.\",\n \"5,130,242, incorporated by reference herein in its entirety.\",\n \"The lipid can be extracted according to the processes of the present invention.\",\n \"A microbial lipid of the invention can be any lipid derived from a microorganism, including, for example: a crude oil extracted from the biomass of the microorganism without further processing; a refined oil that is obtained by treating a crude microbial oil with further processing steps such as refining, bleaching, and/or deodorizing; a diluted microbial oil obtained by diluting a crude or refined microbial oil; or an enriched oil that is obtained, for example, by treating a crude or refined microbial oil with further methods of purification to increase the concentration of a fatty acid (such as DHA) in the oil.\",\n \"In some embodiments, the microbial lipid comprises a sterol esters fraction of 0%, at least 0.1%, at least 0.2%, at least 0.5%, at least 1%, at least 1.5%, at least 2%, or at least 5% by weight.\",\n \"In some embodiments, the microbial lipid comprises a sterol esters fraction of 0% to 1.5%, 0% to 2%, 0% to 5%, 1% to 1.5%, 0.2% to 1.5%, 0.2% to 2%, or 0.2% to 5% by weight.\",\n \"In some embodiments, the microbial lipid comprises a sterol esters fraction of 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, 0.3% or less, 0.2% or less, 0.5% or less, 0.4% or less, 0.3% or less, or 0.2% or less by weight.\",\n \"In some embodiments, the microbial lipid comprises a triacylglycerol fraction of at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% by weight.\",\n \"In some embodiments, the microbial lipid comprises a triacylglycerol fraction of 35% to 98%, 35% to 90%, 35% to 80%, 35% to 70%, 35% to 70%, 35% to 65%, 40% to 70%, 40% to 65%, 40% to 55%, 40% to 50%, 65% to 95%, 75% to 95%, 75% to 98%, 80% to 95%, 80% to 98%, 90% to 96%, 90% to 97%, 90% to 98%, 90%, 95%, 97%, or 98% by weight.\",\n \"In some embodiments, the microbial lipid comprises a diacylglycerol fraction of at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% by weight.\",\n \"In some embodiments, the microbial lipid comprises a diacylglycerol fraction of 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 15% to 40%, 15% to 35%, or 15% to 30% by weight.\",\n \"In some embodiments, the microbial lipid comprises a 1,2-diacylglycerol fraction of at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 1%, at least 5%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% by weight.\",\n \"In some embodiments, the microbial lipid comprises a diacylglycerol fraction of 0.2% to 45%, 0.2% to 30%, 0.2% to 20%, 0.2% to 10%, 0.2% to 5%, 0.2% to 1%, 0.2% to 0.8%, 0.4% to 45%, 0.4% to 30%, 0.4% to 20%, 0.4% to 10%, 0.4% to 5%, 0.4% to 1%, 0.4% to 0.8%, 0.5% to 1%, 0.5% to 0.8%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 15% to 40%, 15% to 35%, 15% to 30%, or 15% to 25% by weight.\",\n \"In some embodiments, the microbial lipid comprises a 1,3-diacylglycerol fraction of at least 0.1%, at least 0.2%, at least 0.5%, at least 1%, at least 2%, at least 2.5%, or at least 3% by weight.\",\n \"In some embodiments, the microbial lipid comprises a sterol fraction of at least 0.3%, at least 0.4%, at least 0.5%, at least 1%, at least 1.5%, at least 2%, or at least 5% by weight.\",\n \"In some embodiments, the microbial lipid comprises a sterol fraction of 0.3% to 5%, 0.3% to 2%, 0.3% to 1.5%, 0.5% to 1.5%, 1% to 1.5%, 0.5% to 2%, 0.5% to 5%, 1% to 2%, or 1% to 5% by weight.\",\n \"In some embodiments, the microbial lipid comprises a sterol fraction of 5% or less, 4% or less, 3% or less, 2% or less, 1.5% or less, or 1% or less by weight.\",\n \"In some embodiments, the microbial lipid comprises a phospholipid fraction of at least 2%, at least 5%, or at least 8% by weight.\",\n \"In some embodiments, the microbial lipid comprises a phospholipid fraction of 2% to 25%, 2% to 20%, 2% to 15%, 2% to 10%, 5% to 25%, 5% to 20%, 5% to 20%, 5% to 10%, or 7% to 9% by weight.\",\n \"In some embodiments, the microbial lipid comprises a phospholipid fraction of less than 20%, less than 15%, less than 10%, less than 9%, or less than 8% by weight.\",\n \"In some embodiments, the microbial lipid is substantially free of phospholipids.\",\n \"In some embodiments, the microbial lipid comprises unsaponifiables of less than 2%, less than 1.5%, less than 1%, or less than 0.5% by weight of the oil.\",\n \"The lipid classes present in the microbial lipid, such as a triacylglycerol fraction, can be separated by flash chromatography and analyzed by thin layer chromatography (TLC), or separated and analyzed by other methods known in the art.\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the free fatty acid fraction, the sterol fraction, the diacylglycerol fraction, and combinations thereof, comprises at least 5%, at least 10%, more than 10%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 25%, at least 30%, least 35%, at least 40%, or at least 45% by weight EPA.\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the free fatty acid fraction, the sterol fraction, the diacylglycerol fraction, and combinations thereof, comprises 5% to 55%, 5% to 50%, 5% to 45%, 5% to 40%, 5% to 35%, 5% to 30%, 10% to 55%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, at least 12% to 55%, at least 12% to 50%, at least 12% to 45%, at least 12% to 40%, at least 12% to 35%, or at least 12% to 30%, 15% to 55%, 15% to 50%, 15% to 45%, 15% to 40%, 15% to 35%, 15% to 30%, 15% to 25%, 15% to 20%, 20% to 55%, 20% to 50%, 20% to 45%, 20% to 40%, or 20% to 30% by weight EPA.\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, comprises at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, or at least 60% by weight DI-IA.\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, comprises 5% to 60%, 5% to 55%, 5% to 50%, 5% to 40%, 10% to 60%, 10% to 50%, 10% to 40%, 20% to 60%, 25% to 60%, 25% to 50%, 25% to 45%, 30% to 50%, 35% to 50%, or 30% to 40% by weight DHA.\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, comprises 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less by weight DHA.\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, comprises 1% to 10%, 1% to 5%, 2% to 5%, 3% to 5%, or 3% to 10% by weight of the fatty acids as DHA.\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, is substantially free of DHA.\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, comprises 0.1% to 5%, 0.1% to less than 5%, 0.1% to 4%, 0.1% to 3%, 0.1% to 2%, 0.2% to 5%, 0.2% to less than 5%, 0.2% to 4%, 0.2% to 3%, 0.2% to 2%, 0.3% to 2%, 0.1% to 0.5%, 0.2% to 0.5%, 0.1% to 0.4%, 0.2% to 0.4%, 0.5% to 2%, 1% to 2%, 0.5% to 1.5%, or 1% to 1.5% by weight ARA.\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, comprises 5% or less, less than 5%, 4% or less, 3% or less, 2% or less, 1.5% or less, 1% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, or 0.1% or less by weight ARA.\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, is substantially free of ARA.\",\n \"In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, comprises 0.4% to 2%, 0.4% to 3%, 0.4% to 4%, 0.4% to 5%, 0.4% to less than 5%, 0.5% to 1%, 0.5% to 2%, 0.5% to 3%, 0.5% to 4%, 0.5% to 5%, 0.5% to less than 5%, 1% to 2%, 1% to 3%, 1% to 4%, 1% to 5%, or 1% to less than 5% by weight DPA n-6.In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, comprises 5%, less than 5%, 4% or less, 3% or less, 2% or less, 1% or less, 0.75% or less, 0.6% or less, or 0.5% or less by weight DPA n-6.In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, is substantially free of DPA n-6.In some embodiments, the microbial lipid and/or one or more fractions thereof selected from the triacylglycerol fraction, the diacylglycerol fraction, the sterol fraction, the sterol esters fraction, the free fatty acids fraction, the phospholipid fraction, and combinations thereof, comprises fatty acids with 5% or less, less than 5%, 4% or less, 3% or less, or 2% or less by weight of oleic acid (18:1 n-9), linoleic acid (18:2 n-6), linolenic acid (18:3 n-3), eicosenoic acid (20:1 n-9), erucic acid (22:1 n-9), stearidonic acid (18:4 n-3), or combinations thereof.\",\n \"In some embodiments, an extracted microbial lipid comprises at least 20% by weight eicosapentaenoic acid and less than 5% by weight each of arachidonic acid, docosapentaenoic acid n-6, oleic acid, linoleic acid, linolenic acid, eicosenoic acid, erucic acid, and stearidonic acid.\",\n \"In some embodiments, an extracted microbial lipid comprises a triacylglycerol fraction of at least 10% by weight, wherein at least 12% by weight of the fatty acids in the triacylglycerol fraction is eicosapentaenoic acid, wherein at least 25% by weight of the fatty acids in the triacylglycerol fraction is docosahexaenoic acid, and wherein less than 5% by weight of the fatty acids in the triacylglycerol fraction is arachidonic acid.\",\n \"In some embodiments, an extracted microbial lipid having any of the above fatty acid profiles has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, 2 or less, or 1 or less, and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"In some embodiments, an extracted microbial lipid having any of the above fatty acid profiles is extracted from an isolated thraustochytrid microorganism having the characteristics of the thraustochytrid species deposited under ATCC Accession No.\",\n \"PTA-10208, PTA-10209, PTA-10210, PTA-10211, PTA-10212, PTA-10213, PTA-10214, or PTA-10215.In some embodiments, an extracted microbial lipid having any of the above fatty acid profiles is a crude lipid.\",\n \"In some embodiments, the crude lipid has less than 5% by weight or volume of an organic solvent.\",\n \"In some embodiments a microbial lipid extracted according to the processes of the present invention result in a lower anisidine value, and/or lower peroxide value, and/or lower phosphorus content than if extraction was performed using a typical hexane extraction or a FRIOLEX® process (Westfalia Separator AG, Germany).\",\n \"In some embodiments, a lipid obtained by any of the processes of the present invention comprises at least 20% by weight eicosapentaenoic acid and less than 5% by weight each of arachidonic acid, docosapentaenoic acid n-6, oleic acid, linoleic acid, linolenic acid, eicosenoic acid, erucic acid, and stearidonic acid.\",\n \"In some embodiments, a lipid obtained by any of the processes of the present invention comprises a triacylglycerol fraction of at least 10% by weight, wherein at least 12% by weight of the fatty acids in the triacylglycerol fraction is eicosapentaenoic acid, wherein at least 25% by weight of the fatty acids in the triacylglycerol fraction is docosahexaenoic acid, and wherein less than 5% by weight of the fatty acids in the triacylglycerol fraction is arachidonic acid.\",\n \"In some embodiments, a lipid obtained by any of the processes of the present invention having any of the above fatty acid profiles has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, or 2 or less, or 1 or less and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less, and/or a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"In some embodiments, a lipid obtained by any of the processes of the present invention having any of the above fatty acid profiles is extracted from an isolated thraustochytrid microorganism having the characteristics of the thraustochytrid species deposited under ATCC Accession No.\",\n \"PTA-10208, PTA-10209, PTA-10210, PTA-10211, PTA-10212, PTA-10213, PTA-10214, or PTA-10215.In some embodiments, a lipid obtained by any of the processes of the present invention having any of the above fatty acid profiles is a crude lipid.\",\n \"In some embodiments, the crude lipid has less than 5% by weight or volume of an organic solvent.\",\n \"In some embodiments a lipid extracted according to the processes of the present invention result in a lower anisidine value, lower peroxide value, lower phosphorus content and/or a higher extraction yield if extraction was performed using a solvent (e.g., atypical hexane extraction or a FRIOLEX® process (Westfalia Separator AG, Germany)).\",\n \"Lipids Extracted from an Isolated Microorganism of the Species Crypthecodinium cohnii In some embodiments, the present invention is further directed to a crude lipid extracted from a microorganism of the species Crypthecodinium cohnii.\",\n \"In some embodiments, the method comprises growing a microorganism of the species Crypthecodinium cohnii in a culture to produce a biomass and extracting a lipid comprising omega-3 fatty acids from the biomass.\",\n \"The lipid can be extracted from a freshly harvested biomass or can be extracted from a previously harvested biomass that has been stored under conditions that prevent spoilage.\",\n \"Known methods can be used to culture a microorganism of the species Crypthecodinium cohnii, and to isolate a biomass from the culture.\",\n \"See, e.g., U.S. Pat.\",\n \"No.\",\n \"7,163,811, incorporated by reference herein in its entirety.\",\n \"The lipid can be extracted according to the processes of the present invention.\",\n \"In some embodiments, the crude lipid extracted from a microorganism of the species Crypthecodinium cohnii according to the extraction methods of the present invention can have a lower phosphorus content compared to using a typical hexane extraction method.\",\n \"In some embodiments, the crude lipid extracted from a microorganism of the species Crypthecodinium cohnii comprises a phosphorus content of 100 ppm or less, 95 ppm or less, 90 ppm or less, 85 ppm or less, 80 ppm or less, 75 ppm or less, 70 ppm or less, 65 ppm or less, 60 ppm or less, 55 ppm or less, 50 ppm or less, 45 ppm or less, 40 ppm or less, 35 ppm or less, 30 ppm or less, 25 ppm or less, 20 ppm or less, 15 ppm or less, 10 ppm or less, 5 ppm or less, 4 ppm or less, 3 ppm or less, 2 ppm or less, or 1 ppm or less.\",\n \"In some embodiments, the crude oil has an anisidine value of 26 or less, 25 or less, 20 or less, 15 or less, 10 or less, 5 or less, or 2 or less, or 1 or less and/or a peroxide value of 5 or less, 4.5 or less, 4 or less, 3.5 or less, 3 or less, 2.5 or less, 2 or less, 1.5 or less, 1 or less, 0.5 or less, 0.2 or less, or 0.1 or less.\",\n \"In some embodiments a crude microbial lipid extracted according to the processes of the present invention result in a lower anisidine value, lower peroxide value, lower phosphorus content and/or a higher extraction yield if extraction was performed using a solvent (e.g., atypical hexane extraction or a FRIOLEX® process (Westfalia Separator AG, Germany)).\",\n \"Having generally described the invention, a further understanding can be obtained by reference to the examples provided herein.\",\n \"These examples are given for purposes of illustration only and are not intended to be limiting.\",\n \"The following examples are illustrative, but not limiting, of a process and a lipid prepared by a process of the present invention.\",\n \"Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered in extraction of a lipid from a cell, and which would become apparent to those skilled in the art, and are within the spirit and scope of the invention.\",\n \"EXAMPLES Example 1 A cell broth (20,000 kg) containing microbial cells (Schizochytrium) was heated to 60° C. Enzymes (i.e., Alcalase 2.4 L FG 0.5%) were added to the cell biomass to lyse the cells and form an emulsified lysed cell composition.\",\n \"The emulsified lysed cell composition was first treated with a first base (NaOH, 250 kg of 50% w/w solution) until the pH of the lysed cell composition was from 10.4 to 10.6.Next, a salt (solid NaCl, in an amount of 2%, by weight, of the lysed cell composition) was added to the lysed cell composition.\",\n \"The lysed cell composition was then heated to a temperature of 85° C. to 102° C. and held at that temperature level for 24 hours to 70 hours.\",\n \"A second base (NaOH, 50% w/w solution, 40 kg) was then added to the lysed cell composition until the pH was above 8.The lysed cell composition was then centrifuged to separate the lysed cell composition into three phases: a top phase containing a lipid layer, a middle phase containing an emulsion layer, and a bottom phase containing a solid layer.\",\n \"The lysed cell composition was then centrifuged at 40° C. to 80° C. using a Westfalia RSE110 Centrifuge (Westfalia Separator Industry GmbH, Germany), operating at 6,000 rpms at a feed rate of 30 kg/min to separate a lipid from the lysed cell composition.\",\n \"The centrifuging provided three phases: an upper phase containing a lipid, a middle phase containing an emulsion, and a bottom phase containing a solid/liquid emulsion.\",\n \"The pH of the lysed cell composition was maintained at 7.5 to 8.5 during the centrifuging.\",\n \"The total time to centrifuge the entire 20,000 kg batch was approximately 10 to 11 hours.\",\n \"The lipid layer was separated and had a moisture content of approximately 1% by weight.\",\n \"Example 2 A cell broth (500 g) containing microbial cells (Crypthecodinium cohnii) was concentrated from approximately 7% biomass to 13.5% biomass, by weight of the broth.\",\n \"The broth was homogenized at a pressure of 10,000 psi (2 passes) to form a lysed cell composition.\",\n \"The lysed cell composition was treated with a base (i.e., NaOH, 10 g of a 50% w/w solution) until the pH of the lysed cell composition was 10.4 to 10.6.A salt (solid NaCl, in an amount of 2% by weight of the lysed cell composition) was added to the lysed cell composition.\",\n \"The lysed cell composition was then heated to a temperature of 85° C. to 92° C. and held at that temperature range for 15 minutes to 2 hours.\",\n \"The lysed cell composition was then centrifuged at a temperature of 70° C. to 90° C. using a Bench Top Sigma 6K15 Centrifuge (SIGMA Laborzentrifugen GmbH, Germany), operating at 5,400 rpm to separate the lysed cell composition into three phases: an upper phase containing a lipid, a middle phase containing an emulsion, and a bottom phase containing a solid/liquid emulsion.\",\n \"The pH of the lysed cell composition during centrifuging was maintained at 6.5 to 8.5.The total time to centrifuge was 5 minutes.\",\n \"The lipid layer was separated and had a moisture content of approximately 1% by weight.\",\n \"Example 3 A cell broth (20,000 kg) containing microbial cells (Schizochytrium) was heated to 60° C. Enzymes (i.e., Alcalase 2.4 L FG 0.5%) were added to the cell biomass to lyse the cells and form a lysed cell composition.\",\n \"Next, a salt (solid Na2SO4, 2,000 kg, or 10%, by weight, of the lysed cell composition) was added to the lysed cell composition.\",\n \"The lysed cell composition was then agitated for 24 hours to 48 hours at room temperature.\",\n \"The lysed cell composition was then centrifuged at 40° C. to 75° C. using a Westfalia RSE110 Centrifuge (Westfalia Separator Industry GmbH, Germany), operating at 6,000 rpm at a feed rate of 40 kg/min to separate a lipid from the lysed cell composition.\",\n \"The centrifuging provided three phases: an upper phase containing a lipid, a middle phase containing an emulsion, and a bottom phase containing a solid/liquid emulsion.\",\n \"The total time to centrifuge the entire 20,000 kg batch was approximately 8 to 9 hrs.\",\n \"The lipid layer was separated from the centrifuged lysed cell composition.\",\n \"Example 4 A pasteurized cell broth (500 g) containing microbial cells (ATCC Accession No.\",\n \"PTA-10208) was provided.\",\n \"Enzymes (i.e., Alcalase 2.4 L FG 0.5%) were added to the cell biomass to lyse the cells and form an emulsified lysed cell composition.\",\n \"The emulsified lysed cell composition was treated with a first base (i.e., a 25% solution of NaOH) to adjust the pH of the lysed cell composition to 10.5.Next, a salt (solid NaCl, in an amount of 2%, by weight, of the lysed cell composition) was added to the lysed cell composition.\",\n \"The lysed cell composition was then heated to a temperature of 95° C. and held at that temperature level for 2 hours while agitating the lysed cell composition.\",\n \"A second base (i.e., a 25% solution of NaOH) was then added to the lysed cell composition until the pH was 8.3.The lysed cell composition was then centrifuged at 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer and a small emulsion layer.\",\n \"Example 5 A cell broth (500 g) that was concentrated and pasteurized containing microbial cells (ATCC Accession No.\",\n \"PTA-9695) was provided.\",\n \"Enzymes (i.e., Alcalase 2.4 L FG 0.5%) were added to the cell biomass to lyse the cells and form an emulsified lysed cell composition.\",\n \"The emulsified lysed cell composition was treated with a base (i.e., a 25% solution of NaOH) to adjust the pH of the lysed cell composition to 10.5.Next, a salt (solid NaCl, in an amount of 2%, by weight, of the lysed cell composition) was added to the lysed cell composition.\",\n \"The lysed cell composition was then heated to a temperature of 95° C. and held at that temperature level for 1 hour while agitating the lysed cell composition and the pH dropped to 8.5.After an hour in the fermentation broth having a total of 10 ml, there was an about 1 ml layer of oil (lipid) and an about 6 ml layer of emulsion.\",\n \"The lysed cell composition was heated for a total of 220 minutes and the emulsion layer started to disappear.\",\n \"The lysed cell composition was then centrifuged at 5,100 rpm for 5 minutes to separate the lysed cell composition.\",\n \"The extraction yield of the lipid was 58.8 by weight % The anisidine value (AV) of the crude oil was 11.3.The cell breakage yield was in a range of 93% to 95% by weight.\",\n \"Example 6 A pasteurized cell broth (473 g) containing microbial cells of the isolated thraustochytrid deposited under ATCC Accession No.\",\n \"PTA-9695 was provided.\",\n \"Enzymes (i.e., Alcalase 2.4 L FG 0.5%) were added to the cell biomass to lyse the cells and form an emulsified lysed cell composition.\",\n \"The emulsified lysed cell composition was treated with a first base (i.e., a 25% solution of NaOH) to adjust the pH of the lysed cell composition to 10.62.Next, a salt (solid NaCl, in an amount of 2%, by weight, of the lysed cell composition) was added to the lysed cell composition.\",\n \"The lysed cell composition was then heated to a temperature of 95° C. and held at that temperature level for 3 hours while agitating the lysed cell composition.\",\n \"A second base (i.e., a 25% caustic solution of NaOH) was then added to the lysed cell composition until the pH was 8.13.The lysed cell composition was then centrifuged at 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer and an emulsion layer in equal amounts.\",\n \"In order to determine if raising the pH increased the yield of the lipid layer, additional second base (i.e., a 25% solution of NaOH) was added to the separated lysed cell composition until the pH was 9.02 and the lysed cell composition was again centrifuged at 5,100 rpm for 5 minutes.\",\n \"This resulted in a similar yield of lipid layer.\",\n \"Additional second base was added again to the separated lysed cell composition until the pH was 10.12 and the lysed cell composition was again centrifuged at 5,100 rpm for 5 minutes.\",\n \"Again, this resulted in a similar yield of lipid layer.\",\n \"Example 7 A pasteurized cell broth (470 g) containing microbial cells (ATCC Accession No.\",\n \"PTA-9695) was provided.\",\n \"The cell biomass was mechanically homogenized to lyse the cells and form an emulsified lysed cell composition.\",\n \"The emulsified lysed cell composition was treated with a first base (i.e., a 25% solution of NaOH) to adjust the pH of the lysed cell composition to 10.5.Next, a salt (solid NaCl, in an amount of 2%, by weight, of the lysed cell composition) was added to the lysed cell composition.\",\n \"The lysed cell composition was then heated to a temperature of 95° C. and held at that temperature level for 3 hours while agitating the lysed cell composition.\",\n \"A second base (i.e., a 25% solution of NaOH) was then added to the lysed cell composition until the pH was 8.07.The lysed cell composition was then centrifuged at 5400 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer and an emulsion layer wherein the emulsion layer was larger than the lipid layer.\",\n \"In order to determine if raising the pH increased the yield of the lipid layer, additional second base was added to the separated lysed cell composition until the pH was 9.11 and the lysed cell composition was again centrifuged at 5,100 rpm for 5 minutes.\",\n \"This resulted in a similar yield of lipid layer.\",\n \"Additional second base was added again to the separated lysed cell composition until the pH was 10.09 and the lysed cell composition was again centrifuged at 5,100 rpm for 5 minutes.\",\n \"Again, the resulted in a similar yield of lipid layer.\",\n \"Example 8 A cell broth containing microbial cells (Crypthecodinium cohnii) was used in a decreased biotin trial fermentor.\",\n \"20,000 kg of washed, concentrated, and pasteurized broth was harvested.\",\n \"This was pulled out at the startup of pasteurization.\",\n \"It was held for approximately 1 day before being transferred and homogenized.\",\n \"The material was homogenized at 813 bar/one pass and collected back into a treatment tank.\",\n \"Through microscopic inspection, it was estimated that approximately 80% of the cells were lysed.\",\n \"The broth was heated to about 40° C. before treatment began.\",\n \"The pH was adjusted to 10.5 and 2% NaCl was added and heated to 66° C. At this point a significant oil layer had already formed and the pH had dropped to 9.5 after 1-2 hours.\",\n \"The broth was held at 66° C. overnight.\",\n \"The next day, the broth was centrifuged on the Westfalia RSE-110 with a 155 mm ring dam installed.\",\n \"The viscosity was about 180 cP at 40° C. The centrifuge was fed at 48 kg/min, with 5-10 psi backpressure on the light phase and 30 psi backpressure on the heavy phase.\",\n \"The feed temperature was maintained at 70° C. No oil was present in the waste phase and only a few drops were visible after isopropyl alcohol was added.\",\n \"Table 1 shows the results of analyses performed on the crude oil obtained from this procedure.\",\n \"TABLE 1 Specifications of crude oil obtained using process of Example 8.% Oil 87.79 DHA (mg/g) 531.02 % DHA 60.49 PV 1.95 (0.6*) AV 15 % FFA 0.18 Phosphorus (ppm) 8.65 Copper (ppm) 0.22 Iron (ppm) 0.7 Lead (ppm) 0.63 *PV of the centrifuged oil.\",\n \"Of the 20,000 kg of broth provided, 10.5% by weight (2,100 kg) was biomass.\",\n \"Of the biomass, 50% by weight was oil (1,050 kg).\",\n \"Of the oil, 58.9% by weight was DHA (618 kg).\",\n \"After running the process described above, there was 592.5 kg of material in the lipid layer, of which about 87.8% by weight (520.2 kg) was oil.\",\n \"Thus, the extraction yield of oil from the biomass was 49.5%.\",\n \"Of that oil, 60.5% by weight (314.6 kg) was DHA, thereby resulting in an extraction yield of 51% by weight DHA from the biomass.\",\n \"Example 9 A cell broth (about 500 g) that was washed, concentrated, and pasteurized containing microbial cells (Schizochytrium) was provided.\",\n \"The broth was chemically treated with a base (i.e., a 25% solution of NaOH) without a prior cell lysis step.\",\n \"The addition of the base raised the pH of the broth from 5.8 to 11.2.The addition of the base and the rise in the pH lysed the cells to form a lysed cell composition.\",\n \"Next, a salt (solid Na2SO4, in an amount of 5%, by weight, of the lysed cell composition) was added to the lysed cell composition.\",\n \"The lysed cell composition was then heated to a temperature in a range of 90° C. to 95° C. and held at that temperature level for 90 minutes and the pH of the lysed cell composition dropped to 9.7.After the 90 minutes there was an about 2.5 ml of oil layer per 45 ml of fermentation broth and there was no moisture loss.\",\n \"After 3 hours, the pH had dropped to 9.2.The solution was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer.\",\n \"The extraction yield of the lipid was 81% by weight.\",\n \"The anisidine value (AV) of the crude oil was 20.1.The cell breakage yield was in a range of 92% to 98% by weight.\",\n \"Example 10 A cell broth (about 500 g) that was washed, concentrated, and pasteurized containing microbial cells (Schizochytrium) was provided.\",\n \"The broth was chemically treated with a base (i.e., a 25% solution of NaOH) without a prior cell lysis step.\",\n \"The addition of the base raised the pH of the broth from 4.8 to 11.The addition of the base and the rise in the pH lysed the cells to form a lysed cell composition.\",\n \"Next, a salt (solid NaCl, in an amount of 2%, by weight, of the lysed cell composition) was added to the lysed cell composition.\",\n \"The lysed cell composition was then heated to a temperature in a range of 90° C. to 95° C. and held at that temperature level for 3.5 hours and the pH of the lysed cell composition dropped to 8.7 and there was no moisture loss.\",\n \"The solution was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer.\",\n \"The extraction yield of the lipid after 3.5 hours was 92% by weight.\",\n \"A portion of the lysed cell composition was held for 6 hours and the pH of the lysed cell composition dropped to 8.6.The solution was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer.\",\n \"The extraction yield of the lipid after 6 hours was 89% by weight.\",\n \"The anisidine value (AV) of the crude oil was 14.4.The cell breakage yield was 95% by weight.\",\n \"Example 11 A cell broth (about 500 g) that was washed, concentrated, and pasteurized containing microbial cells (Schizochytrium) was provided.\",\n \"The broth was chemically treated with a base (i.e., a 50% solution of NaOH) without a prior cell lysis step.\",\n \"The addition of the base raised the pH of the broth from 5.8 to 11.2.The addition of the base and the rise in the pH lysed the cells to form a lysed cell composition.\",\n \"The lysed cell composition was then heated to 70° C. under vacuum to reduce the water content from 88.7% to 85.5%.\",\n \"During evaporation, the pH dropped to 10.36.The solution was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer.\",\n \"The extraction yield of the lipid was 83.9% by weight.\",\n \"The anisidine value (AV) of the crude oil was 10.5.The cell breakage yield was 93.17% by weight.\",\n \"The process was repeated except the lysed cell composition was heated to 70° C. under vacuum to reduce the water content from 88.7% to 79.2%.\",\n \"The extraction yield of the lipid was 87.5% by weight when the water content was reduced to 79.2% and the cell breakage yield was 92.3% by weight.\",\n \"The process was also repeated to reduce the water content from 88.7% to 80.8%.\",\n \"The extraction yield of the lipid was 90% by weight when the water content was reduced to 80.8% and the cell breakage yield was 95.9% by weight.\",\n \"Example 12 A cell broth (about 500 g) that was washed, concentrated, and pasteurized containing microbial cells (Schizochytrium) was provided.\",\n \"The broth was chemically treated with a base (i.e., a 50% solution of NaOH) without a prior cell lysis step.\",\n \"The addition of the base raised the pH of the broth from 5.6 to 11.1.The addition of the base and the rise in the pH lysed the cells to form a lysed cell composition.\",\n \"The lysed cell composition was then heated to 90° C. in a closed system for 40 minutes.\",\n \"After the 40 minutes, there was an about 1 ml layer of oil (lipid) per 40 ml of fermentation broth.\",\n \"The solution was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer.\",\n \"The extraction yield of the lipid was 85.1% by weight.\",\n \"The anisidine value (AV) of the crude oil was 16.3.The cell breakage yield was 97.6% by weight.\",\n \"Example 13 A cell broth (about 500 g) that was washed, concentrated, and pasteurized containing microbial cells (Schizochytrium) was provided.\",\n \"The broth was chemically treated with a base (i.e., a 50% solution of NaOH) without a prior cell lysis step.\",\n \"The addition of the base raised the pH of the broth from 4.9 to 11.2.The addition of the base and the rise in the pH lysed the cells to form a lysed cell composition.\",\n \"The lysed cell composition was then mixed at room temperature for 4 hours.\",\n \"The solution was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a small lipid layer.\",\n \"A portion of the lysed cell composition was mixed at room temperature for about 96 hours.\",\n \"The solution was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a larger lipid layer.\",\n \"The extraction yield of lipid was 61.4% by weight.\",\n \"The anisidine value (AV) of the crude oil was 22.6.Example 14 A cell broth (about 500 g) that was washed, concentrated, and pasteurized containing microbial cells (ATCC Accession No.\",\n \"PTA-9695) was provided.\",\n \"The broth was chemically treated with a base (i.e., a 50% solution of NaOH) without a prior cell lysis step.\",\n \"The addition of the base raised the pH of the broth from 5.6 to 11.1.The addition of the base and the rise in the pH lysed the cells to form a lysed cell composition.\",\n \"The lysed cell composition was then heated in a range of 70° C. to 75° C. for 3 hours.\",\n \"The solution was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer.\",\n \"The extraction yield of the lipid was 84.4% by weight.\",\n \"A portion of the lysed cell composition was heated for a total of 5 hours.\",\n \"The solution was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a similar lipid layer.\",\n \"The extraction yield of lipid was 87.3% by weight.\",\n \"The cell breakage yield was 89.1% by weight.\",\n \"Example 15 A cell broth (about 500 g) that was washed, concentrated, and pasteurized containing microbial cells (Schizochytrium) was provided.\",\n \"The broth was chemically treated with a base (i.e., a 50% solution of NaOH) without a prior cell lysis step.\",\n \"The addition of the base raised the pH of the broth from 7.3 to 11.The addition of the base and the rise in the pH lysed the cells to form a lysed cell composition.\",\n \"Next, a salt (solid Na2SO4, in an amount of 5%, by weight, of the lysed cell composition) was added to the lysed cell composition.\",\n \"The lysed cell composition was then heated to a temperature of 90° C. and held at that temperature level for 2 hours.\",\n \"While maintaining a temperature of 90° C. for additional 2 to 4 hours, the vessel containing the lysed cell composition was opened to allow evaporation of water.\",\n \"The solution was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer.\",\n \"Extraction yield of the lipid was greater than 70% by weight.\",\n \"The anisidine value (AV) of the crude oil was 11.6.Example 16 A cell broth (9,925 kg) containing microbial cells (ATCC Accession No.\",\n \"PTA-9695) was provided.\",\n \"The cell broth was diluted with water in a 1:1 ratio by weight to form a diluted broth of 20,000 kg.\",\n \"The solid content of the broth prior to dilution was 16.13% by weight and after dilution was 8.25% by weight.\",\n \"The diluted broth was mixed and centrifuged with a desludging centrifuge at 6,400 rpm to remove extracellular water-soluble or water-dispersible compounds.\",\n \"The concentrate (10,250 kg) from the centrifuge was collected and had a solids content of 10.5% by weight.\",\n \"The collected concentrate was heated to 62° C. to 64° C. to pasteurize the concentrate.\",\n \"Enzymes (i.e., Alcalase 2.4 L FG 0.5%) were added to the pasteurized concentrate to lyse the cells and form an emulsified lysed cell composition.\",\n \"The emulsified lysed cell composition was treated with a base (i.e., a 25% solution of NaOH) to adjust the pH of the lysed cell composition to 11.Next, a salt (solid Na2SO4, in an amount of 5%, by weight, of the lysed cell composition) was added to the lysed cell composition.\",\n \"The lysed cell composition was then heated to a temperature of 95° C. and held at that temperature level for 10 hours to 12 hours while agitating the lysed cell composition.\",\n \"After agitation, the pH of the lysed cell composition was 8.6 and there was a very small emulsion layer.\",\n \"The agitation tank was allowed to cool to 60° C. and the pH of the lysed cell composition increased to 9.6 while cooling.\",\n \"The pH of the lysed cell composition was lowered to 8.2 by adding phosphoric acid.\",\n \"The addition of the phosphoric acid did not harm the separation of the lipid layer and the very small emulsion layer.\",\n \"The lysed cell composition was then centrifuged at 5,100 rpm at a feed rate of 48 kg/min for 5 minutes at 60° C. to 63° C. to separate the lysed cell composition and yield a lipid layer having a moisture content of 1.7% to 2.3% by weight.\",\n \"Example 17 A cell broth (500 g) that was washed, concentrated, and pasteurized containing microbial cells (Crypthecodinium cohnii) was provided.\",\n \"The broth was homogenized at a pressure of 8,000 to 12,000 psi (2 passes) to form a lysed cell composition.\",\n \"The lysed cell composition was treated with a base (i.e., a 12.5% solution of NaOH) until the lysed cell composition reached a pH of 7.8 to 8.2.A salt (solid Na2SO4, in an amount of 5% by weight of the lysed cell composition) was added to the lysed cell composition.\",\n \"The lysed cell composition was then heated to a temperature of 60° C. and held at that temperature.\",\n \"The pH of the lysed cell composition was maintained at the 7.8 to 8.2 level by the addition of base (i.e., a 12.5% solution of NaOH) for 10 to 15 hours in a closed system with little to no moisture loss.\",\n \"The lysed cell composition was then centrifuged at about 5,100 rpm for 5 minutes to separate the lysed cell composition and yield an oil layer.\",\n \"This resulted in an oil layer of about 2 ml in a sample of 40 ml.\",\n \"The extraction yield of the oil was 73% by weight.\",\n \"The anisidine value (AV) of the crude oil was 13.5.The cell breakage yield was 82% to 86% by weight.\",\n \"Example 18 A pasteurized cell broth (1,000 g) containing microbial cells (Schizochytrium) was provided.\",\n \"Enzymes (i.e., Alcalase 2.4 L FG 0.5%) were added to the cell biomass to lyse the cells and form an emulsified lysed cell composition.\",\n \"The emulsified lysed cell composition was treated with a base (i.e., a 12.5% solution of NaOH) to adjust the pH of the lysed cell composition from 7.21 to 10.52.Next, a salt (solid NaCl, in an amount of 2%, by weight, of the lysed cell composition) was added to the lysed cell composition.\",\n \"The broth was then separated into 4 portions with each portion being held at 4 different temperatures and times: 1) Trial #1 was held at 90° C. for 22 hours; 2) Trial #2 was held at 90° C. for 2 hours and then held at 25° C. for 20 hours; 3) Trial #3 was held at 60° C. for 22 hours; and 4) Trial #4 was held at 25° C. for 22 hours.\",\n \"The individual trials were then centrifuged without further pH adjustment.\",\n \"For Trials #1, #2, and #3, the broth was centrifuged at approximately 6,600 rpm (a g-force of 4,800) for 5 minutes to separate the lysed cell composition.\",\n \"Because the separation for Trial #4 was not good (<20%) at a g-force of 4,800, the g-force was increased to 15,000 and the broth was spun at a g-force of 15,000 for 5 minutes.\",\n \"The extraction yield of the lipid as a weight percent and the anisidine value (AV) are listed in the table below.\",\n \"TABLE 2 Conditions and Results When Varying Temperature and Heating Time of the Lysed Cell Composition.\",\n \"Treatment Time Centrifugation Oil Yield Trial # and Temp.\",\n \"Conditions AV (%) 1 90° C. for 22 hours pH = 6.22 58.7 51.4 g-force = 4,800 2 90° C. for 2 hours, pH = 8.19 109.2 82.2 25° C. for 20 hours g-force = 4,800 3 60° C. for 22 hours pH = 8.38 91.2 27.2 g-force = 4,800 4 25° C. for 22 hours pH = 10.03 105.2 55.7 g-force =15,000 The anisidine values in Table 2 were higher than expected.\",\n \"One difference between previous examples and this example was that the lysed cell composition was allowed to sit for a long period of time before the lipids were extracted.\",\n \"It is hypothesized that the long period of time before extraction leads to the oxidation of the dissolved oxygen present in the lysed cell composition.\",\n \"The increased oxidation then leads to an increase in the anisidine value.\",\n \"The fact that the trial heated at the highest temperature for the longest time (Trial #1) had the lowest anisidine value supports this hypothesis because the dissolved oxygen content of a lysed cell composition generally decreases as the temperature is increased.\",\n \"The increased anisidine values are therefore believed to be an anomaly that was a result of the delay in extracting the lipids from the lysed cell composition.\",\n \"In production, there would be no delay time in extracting the lipids from the lysed cell composition and the anisidine values would be consistent with previous results of anisidine values of 26 or less.\",\n \"Example 19 A pasteurized cell broth (1,000 g) containing microbial cells (Schizochytrium) was provided.\",\n \"The broth was then split into 3 portions and diluted as follows: 1) Trial #1 was not diluted at all and served as the control portion; 2) Trial #2 was diluted 25% with water; and 3) Trial #3 was diluted 50% with water.\",\n \"Enzymes (i.e., Alcalase 2.4 L PG 0.5%) were added to the cell biomass to lyse the cells and form an emulsified lysed cell composition.\",\n \"The emulsified lysed cell composition was treated with a base (i.e., a 12.5% solution of NaOH) to adjust the pH of the lysed cell composition from 6.8 to 10.6.Next, a salt (solid NaCl, in an amount of 2%, by weight, of the lysed cell composition) was added to the lysed cell composition.\",\n \"The broth was then heated to 90° C. and held for 20 hours.\",\n \"After the hold time, the broth for each trial was separated into two with one half being centrifuged as is and the other half having its pH adjusted to approximately 8.5 before centrifugation.\",\n \"Both portions were then centrifuged at approximately 8,545 rpm (a g-force of 8,000) for 5 minutes.\",\n \"The extraction yield of the lipid as a weight percent and the anisidine value (AV) are listed in the table below.\",\n \"TABLE 3 Conditions and Results When Varying Dilution of the Pasteurized Broth.\",\n \"Centrifugation Trial # Diluted?\",\n \"Conditions AV Oil Yield (%) 1 No dilution pH = 6.0 51.8 81.2 g-force = 8,000 1a No dilution pH = 8.4 44.3 78.1 g-force = 8,000 2 25% dilution pH = 5.5 76.1 88.9 with water g-force = 8,000 2a 25% dilution pH = 8.4 85.3 82.1 with water g-force = 8,000 3 50% dilution pH = 5.7 68.5 85.0 with water g-force = 8,000 3a 50% dilution pH = 8.5 79.6 84.0 with water g-force = 8,000 The anisidine values in Table 3 were higher than expected.\",\n \"One difference between previous examples (excluding Example 18) and this example was that the lysed cell composition was allowed to sit for a long period of time before the lipids were extracted.\",\n \"It is hypothesized that the long period of time before extraction leads to the oxidation of the dissolved oxygen present in the lysed cell composition.\",\n \"The increased oxidation then leads to an increase in the anisidine value.\",\n \"The increased anisidine values are therefore believed to be an anomaly that was a result of the delay in extracting the lipids from the lysed cell composition.\",\n \"In production, there would be no delay time in extracting the lipids from the lysed cell composition and the anisidine values would be consistent with previous results of anisidine values of 26 or less.\",\n \"Example 20 Cell broths obtained from various fermentation lots were treated using the process described in Example 2 except the timing of adding the salt (e.g., before and after homogenization) and the amount of salt were varied.\",\n \"The resulting separated lipids were analyzed and the analyses are provided in Table 4.TABLE 4 Specifications of lipids obtained using processes of the present invention varying the timing of salt addition and the amount of salt added.\",\n \"Fermentation Lot P2137 P2137 P4167 P4167 P2137 P2137 Addition of Before Before After After After After NaCl* % NaCl by 2 5 2 5 5 5 weight % Lipid* 27 37 51 72 59 15 % Starting 13 12.9 19.2 19.2 13.3 7.5+ Solids by weight % Solids by 19.7 21.7 19.7 20.1 20.2 8.6 weight before Centrifugation *Addition of NaCl was before or after homogenization; % lipid refers to the percentage of lipids in triglyceride form +This run was diluted to have a low percentage of starting solids.\",\n \"The data provided in Table 4 demonstrates that adding the salt after homogenization results in higher % lipid values than adding the salt before homogenization.\",\n \"The data provided in Table 4 also demonstrates that diluting the sample resulted in lower a % lipid value.\",\n \"Example 21 A sample of Alcalase enzyme treated lysed cell composition obtained from microbial cells (Schizochytrium) was used.\",\n \"The sample had a pH of approximately 5.5.The sample was divided into 4 smaller samples and the pH of three of the samples was adjusted to approximately 7.4, approximately 10.5, and approximately 12, respectively, by adding sodium hydroxide.\",\n \"The samples were diluted in a 1:1 ratio with deionized water.\",\n \"POBN (α-(4-Pyridyl 1-oxide)-N-tert-butylnitrone, 1.25 M; 50 μL) was added as a spin trap chemical to 0.5 g of each of the diluted samples.\",\n \"The samples were measured with a Bruker BioSpin c-scan EPR (Electron Paramagnetic Resonance) spectrometer (system number SC0274) (Bruker BioSpin, Billerica, Mass.)\",\n \"to measure the amount of free radicals present from lipid oxidation.\",\n \"The samples were incubated at room temperature (20° C.) and 50 μL of each of the POBN containing samples was tested at hourly intervals for four hours after adjusting the pHs using the following spectrometer parameters: modulation frequency of 86 Hz, modulation amplitude of 2.11 gauss, microwave power of 5.19 mW, time constant of 20.48 seconds, sweep time of 10.49 seconds, sweep width of 100 gauss, and a number of scans of 8.The results of the EPR spectrometer readings are provided in FIG.\",\n \"5.The data in FIG.\",\n \"5 demonstrates that initially the level of free radicals was highest for the sample at pH 5.5 and lowest for the samples at pH 10.5 and 12.The data also demonstrates that over the 4 hour period the rate of radical formation was slowest for the sample at pH 10.5 and highest for the sample at pH 5.5.The data also demonstrates that the addition of a base to the lysed cell composition inhibits lipid oxidation, and therefore leads to a low AV in the crude lipid and refined oil.\",\n \"Example 22 Oilseeds are extracted from a rapeseed plant and are then passed through a grinding mill to crack and break the outer hull of the oilseeds.\",\n \"The oilseeds are then dehulled through known means, such as through aspiration, to remove the meat (interior) of the seeds from the hull of the oilseeds.\",\n \"The dehulled oilseeds are then homogenized or expelled by passing them through a press to grind the dehulled oilseeds into a cake in order to lyse the cells of the oilseeds.\",\n \"Water is added to form an emulsified lysed cell composition.\",\n \"The emulsified lysed cell composition is filtered to remove any excess hull fragments from the lysed cell composition.\",\n \"The emulsified lysed cell composition is treated with a base (i.e., a 25% solution of NaOH) to adjust the pH of the lysed cell composition to 11.Next a salt (solid NaCl, in an amount 2% by weight of the lysed cell composition) is added to the lysed cell composition.\",\n \"The lysed cell composition is then heated to a temperature of 90° C. and held at that level for 6 hours to 48 hours while agitating the lysed cell composition.\",\n \"The lysed cell composition is then centrifuged at 5,100 rpm for 5 minutes to separate the lysed cell composition and yield a lipid layer and an emulsion layer.\",\n \"Example 23 Comparative Analysis of Crude Lipids Obtained by Hexane Extraction The crude lipids obtained from a lot using the process described in Example 2 was analyzed to determine various specifications.\",\n \"Additional crude lipids were obtained using a typical hexane extraction process on the same microbial cell utilized in Example 2.The hexane extraction process included spray drying a fermentation broth, adding hexane to the spray dried biomass to obtain a solution of 15% to 20% solids by weight.\",\n \"The solution was then homogenized to lyse the cells to form a lysed cell composition.\",\n \"The lysed cell composition was centrifuged and a layer containing lipid and hexane was removed.\",\n \"The hexane was then removed from the lipid.\",\n \"The results of the analyses are provided in Table 5.TABLE 5 Specifications of lipids obtained using processes of the present invention or a hexane extraction process.\",\n \"Fermentation Lot A B C D E F G Extraction Method Ex.\",\n \"2 Hexane Hexane Hexane Hexane Hexane Hexane AV* 5.9 ND ND ND 14.7 17.18 6.7 PV* 1.21 0.65 1.56 0.46 ND 0.85 0.3 % Lipid* 89.61 86.94 84.31 86.75 85.53 86.05 86.54 DHA (mg/g) 537.47 508.15 459.32 465.31 510.49 495.82 506.33 % DHA* 59.98 58.39 54.49 53.65 59.71 57.68 58.51 *AV = Anisidine Value; PV = peroxide value; % lipid refers to the percentage of lipids in triglyceride form; % DHA refers to the percentage of DHA in the lipid The data provided in Table 5 demonstrates that the crude lipids obtained by the processes of the present invention exhibit superior anisidine values, percentage of lipid, amount of DHA and percentage of DHA compared to lipids prepared by typical hexane extraction processes.\",\n \"Comparative Analysis of Crude Lipids Obtained by the FRIOLEX® Processes Example 24 The crude lipids obtained from various fermentation lots using the processes described in Examples 1 and 3 were analyzed to determine various specifications.\",\n \"Additional crude lipids were obtained using a FRIOLEX® process (Westfalia Separator AG, Germany), which is a process of extracting lipids with a water-soluble organic solvent as described in U.S. Pat.\",\n \"No.\",\n \"5,928,696 and International Pub.\",\n \"Nos.\",\n \"WO 01/76385 and WO 01/76715.The results of the analyses are provided in Table 6.TABLE 6 Specifications of lipids obtained using processes of the present invention or a FRIOLEX ® process.\",\n \"Fermentation Lot A B B B B C C C Extraction Method Ex.\",\n \"1 Ex.\",\n \"1 Ex.\",\n \"3 Ex.\",\n \"1a Ex.\",\n \"1b Ex.\",\n \"1 Ex.\",\n \"1 FRIOLEX ® AV* 3.1 1.6 3.9 300 7.1 3.5 4 36 PV* 1.8 0.17 0.14 6.16 0.34 0 0 0.35 % Lipid* 96.27 93.67 92.55 87.20 94.42 95.14 94.31 93.92 DHA (mg/g) 452.4 458.16 455.17 414.66 471.55 416.41 416.05 415.38 Extraction Yield (%) 93.5 87 ND 96 ND 94 94 94 *AV = Anisidine Value; PV = peroxide value; % lipid refers to the percentage of lipids in triglyceride form aThe lysed cell composition was not heated.\",\n \"bThe lysed cell composition was allowed to stand for 3 weeks prior to extraction.\",\n \"The data provided in Table 6 demonstrates that the crude lipids obtained by the processes of the present invention exhibit superior anisidine values (with the exception of the lipid obtained when the lysed cell composition was not heated) compared to lipids prepared by a FRIOLEX® process.\",\n \"The lipids prepared by a process of the present invention exhibit anisidine values that are from 4.4% to 19.7% of the anisidine values of a lipid prepared using the FRIOLEX® process.\",\n \"It is believed that a lipid prepared by a process of the present invention has increased stability.\",\n \"For example, as shown in Table 6, a process of the present invention was used to extract a lipid from a lysed cell composition, wherein the lysed cell composition was allowed to stand for 3 weeks prior to the extraction process.\",\n \"It is believed that the anisidine value of a lipid in a lysed cell composition increases with time, and thus, it would be expected that a lipid extracted from a 3 week old lysed cell composition have increased anisidine values.\",\n \"However, as shown in Table 6, the lipid obtained from the 3 week old lysed cell composition using a process of the present invention had an anisidine value which was 19.7% of the anisidine value of a lipid prepared by the FRIOLEX® process.\",\n \"Example 25 The crude lipids obtained from a broth of microbial cells (ATCC Accession No, PTA-9695) using the process described in Example 16 were analyzed to determine various specifications.\",\n \"Additional crude lipids were obtained from a broth of microbial cells (ATCC Accession No.\",\n \"PTA-9695) using a FRIOLEX® process (Westfalia Separator AG, Germany), which is a process of extracting lipids with a water-soluble organic solvent (e.g., isopropyl alcohol) as described in U.S. Pat.\",\n \"No.\",\n \"5,928,696 and International Pub.\",\n \"Nos.\",\n \"WO 01/76385 and WO 01/76715.The results of the analyses are provided in Table 7.TABLE 7 Crude Lipid Comparison Example 16 FRIOLEX ® % Oil 9.19 93.73 DHA (mg/g) 570.68 574.33 % DHA 62.1 61.27 % FFA 1.13 0.22 PV 0 0.74 AV 10 73.9 Iron (ppm) 0.11 0 Copper (ppm) 0.67 0.3 Lead (ppm) 0.21 0 Phosphorus (ppm) 5.22 7.20 Extraction yield (%) 61.4 45.3 The data provided in Table 7 demonstrates that the crude lipids obtained by the processes of the present invention exhibit superior anisidine values (AV) and peroxide values (PV) compared to lipids prepared by a FRIOLEX® process.\",\n \"The data also demonstrates that the extraction yield of lipid obtained by the processes of the present invention are superior compared to the extraction yield of lipid obtained by a FRIOLEX® process.\",\n \"Example 26 Refining of Crude Lipids Crude lipids were obtained using the processes outlined in Example 1 and a FRIOLEX® process.\",\n \"The crude lipids were further processed by sequentially: 1) degumming and caustic refining; 2) bleaching; 3) chilled filtering; and 4) deodorizing with antioxidants.\",\n \"The data for the crude lipids, caustic refined lipids, bleached lipids, and deodorized lipids are presented in Tables 8a and 8b.\",\n \"A comparison of the refined oils is presented in Table 9.TABLE 8a Lipids obtained from the FRIOLEX ® process (Example 24) DHA Yield % Yield % Processing Step FFA % PV AV (mg/g) (Lipid) (DHA) Crude Lipid 0.28 0.37 33.6 413.6 N/A N/A Caustic Refined <0.1 0.29 — 416.4 85.7 86.3 Lipid Bleached Lipid <0.1 0.16 13.9 413.1 71.5 70.9 Filtered Lipid <0.1 0.19 13.3 424.86 70.3 76.0 Deodorized Lipid 0.06 <0.1 14.3 401.5 96.6 89.4 w/AOX* *AOX refers to antioxidants TABLE 8b Lipids obtained from an extraction process using NaCl (Example 1) DHA Yield % Yield % Processing Step FFA % PV AV (mg/g) (Lipid) (DHA) Crude Lipid 1.36 0 3.5 406.7 N/A N/A Caustic Refined <0.1 0.27 2.3 410.8 85.9 86.7 Lipid Bleached Lipid <0.1 0.16 0.8 404.3 97.0 95.5 Filtered Lipid <0.1 0.37 1.0 414.1 59.3 60.7 Deodorized Lipid 0.06 <0.1 1.8 379.9* 94.9 87.1 w/AOX *Note: Increased dilution with high oleic sunflower oil (HOSO) was the reason for the decrease in DHA (mg/g).\",\n \"TABLE 9 Refined Oil Comparison FRIOLEX ® (Example 24) Example 1 DHA (mg/g) 401.5 379.9* % DHA 42.69 40.18 FFA % 0.06 0.06 PV <0.1 <0.1 AV 14.3 1.8 Iron (ppm) 0.05 <0.02 Copper (ppm) <0.02 <0.02 Lead (ppm) <0.1 <0.1 Arsenic (ppm) <0.1 <0.1 Mercury (ppm) <0.01 <0.01 % Moisture and volatiles <0.01 <0.01 Unsaponifiables (%) 1.17 1.33 Trans-fatty acid by IR (%) <1 <1 *Note: Increased dilution with HOSO was the reason for the decrease in DHA (mg/g).\",\n \"The data provided in Table 8a, Table 8b, and Table 9 demonstrate that a refined oil prepared by a process of the present invention exhibits lower anisidine values compared to a refined oil prepared by the FRIOLEX® process.\",\n \"Example 27 Sensory Profile Comparison The refined oils obtained in Example 26 were analyzed by a panel of 8 to 12 sensory analysts.\",\n \"The sensory analysts rated various lipid specifications based on aroma, aromatics, and aftertaste to provide an “overall aroma intensity” for each lipid.\",\n \"The Universal Spectrum descriptive analysis method was used to assess the aroma and aromatic characteristics of samples.\",\n \"This method uses an intensity scale of 0-15, where 0=none detected and 15=very high intensity, to measure the aroma and aromatic attributes of the oils.\",\n \"The results of the sensory data are provided in Table 10.The data provided in Table 10 demonstrates that a refined oil prepared by a process of the present invention exhibits superior sensory data compared to a refined oil prepared by the FRIOLEX® process.\",\n \"As shown above, the lipids provided by the present invention had an overall aroma intensity of 3 and 2, whereas, the FRIOLEX® lipids provided an overall aroma intensity of 4 and 3, respectively.\",\n \"Example 28 Comparative Example An extraction process for obtaining lipids from microorganisms without the use of an organic solvent is disclosed in U.S. Pat.\",\n \"No.\",\n \"6,750,048.A comparison of a refined oil obtained from a crude lipid prepared by a process of the present invention and a refined oil obtained from a crude lipid prepared by the extraction process disclosed in U.S. Pat.\",\n \"No.\",\n \"6,750,048 is provided in Table 11.TABLE 11 Comparative data for a lipid prepared by a process of the present invention (Example 1) and a lipid prepared by a process disclosed in U.S. Pat.\",\n \"No.\",\n \"6,750,048.Example 1 U.S. Pat.\",\n \"No.\",\n \"6,750,048 DHA (mg/g) 379.9 346 % DHA 40.18 37.3 FFA % 0.06 ND PV <0.1 0.46 AV 1.8 ND Iron (ppm) <0.02 0.26 Copper (ppm) <0.02 <0.05 Lead (ppm) <0.1 <0.20 Arsenic (ppm) <0.1 <0.20 Mercury (ppm) <0.01 <0.20 % Moisture and volatiles <0.01 0.02 Unsaponifiables (%) 1.33 ND Trans-fatty acid by IR (%) <1 ND The data provided in Table 11 demonstrates that a refined oil obtained from a crude lipid prepared by a process of the present invention exhibits superior properties compared to a refined oil obtained from a crude lipid prepared by the extraction process disclosed in U.S. Pat.\",\n \"No.\",\n \"6,750,048.Example 29 The isolated thraustochytrid (ATCC Accession No.\",\n \"PTA-9695) was characterized for taxonomic classification.\",\n \"Samples were collected from intertidal habitats during low tide.\",\n \"Water, sediment, living plant material and decaying plant/animal debris were placed into sterile 50 ml tubes.\",\n \"Portions of each sample along with the water were spread onto solid agar plates of isolation media.\",\n \"Isolation media consisted of: 500 ml of artificial seawater, 500 ml of distilled water, 1 g of glucose, 1 g of glycerol, 13 g of agar, 1 g of glutamate, 0.5 g of yeast extract, 0.5 g casein hydrolysate, 1 ml of a vitamin solution (100 mg/L thiamine, 0.5 mg/L biotin, 0.5 mg B12), 1 ml of a trace mineral solution (PII metals, containing per liter: 6.0 g FeCl36H2O, 6.84 g H3BO3, 0.86 g MnCl24H2O, 0.06 g ZnCl2, 0.026 CoCl26H2O, 0.052 g NiSO4H2O, 0.002 g CuSO45H2O and 0.005 g Na2MoO42H2O), and 500 mg each of penicillin G and streptomycin sulfate.\",\n \"The agar plates were incubated in the dark at 20-25° C. After 2-4 days the agar plates were examined under magnification, and colonies of cells were picked with a sterile toothpick and restreaked onto a fresh plate of media.\",\n \"Cells were repeatedly streaked onto fresh media until contaminated organisms were removed.\",\n \"Colonies from agar plates were transferred to petri dishes with half-strength seawater and (1 ml) of a suspension of autoclaved newly hatched brine shrimp larvae.\",\n \"The brine shrimp larvae became heavily overgrown with clusters of sporangia after 2-3 days.\",\n \"Released zoospores were biflagellate at discharge, swimming actively away from the mature sporangium, wall remnants of which are clearly visible (in phase contrast) after spore release.\",\n \"Sporangia measured 12.5 μm to 25 μm in diameter, and zoospores were 2.5 μm to 2.8 μm×4.5 μm to 4.8 μm in size.\",\n \"There were 8 to 24 spores per individual sporangium.\",\n \"Settled zoospores enlarged and rapidly underwent binary divisions leading to tetrads, octads, and finally to clusters of sporangia.\",\n \"Tetrad formation commenced at a very early stage prior to maturity of the sporangia.\",\n \"These characteristics are in agreement with the genus Schizochytrium.\",\n \"The isolated thraustochytrid (ATCC Accession No.\",\n \"PTA-9695) was further characterized based on the similarity of its 18s rRNA gene to that of known species.\",\n \"Total genomic DNA from the thraustochytrid (ATCC Accession No.\",\n \"PTA-9695) was prepared by standard procedures (Sambrook J. and Russell D. 2001.Molecular cloning: A laboratory manual, 3rd edition.\",\n \"Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.) and used for PCR amplification of the 18s RNA gene.\",\n \"The PCR amplification of the 18s rRNA gene was carried out with primers previously described (Honda et.\",\n \"al., J. Eukaryot.\",\n \"Microbial.\",\n \"46(6) 1999).\",\n \"The PCR conditions with chromosomal DNA template were as follows: 0.2 μM dNTPs, 0.1 uM each primer, 8% DMSO, 200 ng chromosomal DNA, 2.5 U PfuUltra® II fusion HS DNA polymerase (Stratagene), and 1× PfuUltra® buffer (Stratagene) in a 50 μL total volume.\",\n \"The PCR Protocol included the following steps: (1) 95° C. for 2 minutes; (2) 95° C. for 45 seconds; (3) 55° C. for 30 seconds; (4) 72° C. for 2 minutes; (5) repeat steps 2-4 for 40 cycles; (6) 72° C. for 5 minutes; and (7) hold at 6° C.: PCR amplification yielded a distinct DNA product with the expected size using chromosomal template described above.\",\n \"The PCR product was cloned into the vector pJET1.2/blunt (Fermentas) according to the manufacturer's instructions, and the insert sequence was determined using supplied standard primers.\",\n \"Table 12 shows a comparison of the 18s rRNA sequence from the thraustochytrid (ATCC Accession No.\",\n \"PTA-9695) to DNA sequences in the National Center for Biotechnology Information (NCBI) electronic database.\",\n \"Briefly, “% Identity” was determined by the scoring matrix “swgapdnamt” within the “AlignX” program of the VectorNTI program (Invitrogen), a standard for DNA alignment.\",\n \"The “% Coverage” was taken from the results of a Basic Local Alignment Search Tool (BLAST) calculation from the NCBI electronic database and is the percent of the query length that is included in the aligned segments.\",\n \"TABLE 12 Comparison of 18s rRNA Sequences % Identity % Coverage Thraustochytrids Calculation #1 Calculation #2 Thraustochytrium aggregatum (p) 98 90 Thraustochutriidae sp.\",\n \"HU1 84 86 Thraustochutriidae sp.\",\n \"8-7 84 91 Thraustochytrium multirudimentale 81 88 Thraustochutriidae sp.\",\n \"PW19 81 85 Schizochytrium sp.\",\n \"ATCC 20888 81 95 (p): indicates partial sequence As shown in Table 12, it was found that, in terms of % identity, the 18s rRNA gene sequence from the thraustochytrid (ATCC Accession No.\",\n \"PTA-9695) is closely related, though not identical, to the 18s rRNA gene sequence of T. aggregatum provided in Honda, D. et al., J. Euk.\",\n \"Micro.\",\n \"46(6): 637-647 (1999).\",\n \"The 18s rRNA sequence published for Thraustochytrium aggregatum is a partial sequence, with an approximately 71 DNA nucleotide gap in the middle of the sequence.\",\n \"In terms of percent coverage, the 18s rRNA gene sequence of the isolate of the invention is more closely related to Schizochytrium sp.\",\n \"ATCC 20888 than to T. aggregatum.\",\n \"Highly conserved proteins such as actin and beta-tubulin have been widely used, along with 18s rRNA gene, as markers for assessing phylogenetic relationships between organisms (Baldauf, S. M. Am.\",\n \"Nat.\",\n \"154, S178 (1999)).\",\n \"Total genomic DNA from the thraustochytrid (ATCC Accession No.\",\n \"PTA-9695) was also used as a template for PCR amplification of both the actin and beta-tubulin genes.\",\n \"The PCR amplification was carried out with primers designed to conserved regions from the actin and beta-tubulin DNA sequences from T. aggregatum.\",\n \"The PCR conditions with chromosomal DNA template were as follows: 0.2 μM dNTPs, 0.1 uM each primer, 8% DMSO, 200 ng chromosomal DNA, 2.5 U Herculase® II fusion DNA polymerase (Stratagene), and 1× Herculase® buffer (Stratagene) in a 50 μL total volume.\",\n \"The PCR Protocol included the following steps: (1) 95° C. for 2 minutes; (2) 95° C. for 30 seconds; (3) 55° C. for 30 seconds; (4) 72° C. for 2 minutes; (5) repeat steps 2-4 for 40 cycles; (6) 72° C. for 5 minutes; and (7) hold at 6° C. PCR amplification yielded distinct DNA products with the expected sizes using chromosomal template described above.\",\n \"The respective PCR products were cloned into the vector pJET1.2/blunt (Fermentas) according to the manufacturer's instructions, and the insert sequence of each were determined using supplied standard primers.\",\n \"Table 13 shows identities for the actin amino acid sequence from the thraustochytrid (ATCC Accession No.\",\n \"PTA-9695) as compared to actin sequences available in the public database.\",\n \"Identities were determined through use of the scoring matrix “blosum62mt2” within the “AlignX” program of the VectorNTI program, a standard for protein alignment.\",\n \"TABLE 13 Comparison of Actin Protein Sequence % Identities Thraustochytrids % Identity Thraustochytriidae sp.\",\n \"RT49 98 Schizochytrium sp.\",\n \"ATCC 20888 96 Thraustochytrium striatum 96 Thraustochytrium aggregatum 96 Japonochytrium marinum 95 Thraustochytrium aureum 95 Table 14 shows identities for the beta-tubulin amino acid sequence from the thraustochytrid (ATCC Accession No.\",\n \"PTA-9695) as compared to beta-tubulin sequences available in the public database.\",\n \"Identities were determined through use of the scoring matrix “blosum62mt2” within the “AlignX” program of the VectorNTI program, a standard for protein alignment.\",\n \"TABLE 14 Comparison of Beta-Tubulin Protein Sequence % Identities Thraustochytrids % Identity Aplanochytrium kerguelense 100 Aplanochytrium stocchinoi 100 Japonochytrium marinum 100 Labyrinthula sp.\",\n \"N8 100 Thraustochytriidae sp.\",\n \"RT49 100 Thraustochytrium aggregatum 100 Thraustochytriidae sp.\",\n \"HU1 100 Thraustochytrium aureum 100 Thraustochytrium kinnei 100 Thraustochytriidae sp.\",\n \"#32 100 Thraustochytriidae sp.\",\n \"PW19 100 Schizochytrium aggregatum 100 Schizochytrium sp.\",\n \"ATCC 20888 100 Based on the above characterizations, the isolated thraustochytrid (ATCC Accession No.\",\n \"PTA-9695) is believed to represent a new Schizochytrium species and is therefore also designated as Schizochytrium sp.\",\n \"ATCC PTA-9695.Example 30 The isolated thraustochytrid (ATCC Accession No.\",\n \"PTA-9695) produced high levels of cell growth under varying culture conditions, as described below.\",\n \"Typical media and cultivation conditions are shown in Table 15.Also, high levels of fatty acids and DHA were observed (i.e., greater than 50% by weight of the dry cell weight were fatty acids and greater than 50% by weight of the fatty acid methyl esters was DHA).\",\n \"TABLE 15 Vessel Media Ingredient concentration ranges NaCl g/L 12.5 0-25, 5-20, or 10-15 KCl g/L 1.0 0-5, 0.25-3, or 0.5-2 MgSO4•7H2O g/L 5.0 0-10, 2-8, or 3-6 (NH4)2SO4 g/L 0.6 0-10, 0.25-5, or 0.5-3 CaCl2 g/L 0.29 0.1-5, 0.15-3, or 0.2-1 T 154 (yeast g/L 6.0 0-20, 1-15, or 5-10 extract) KH2PO4 g/L 1.2 0.1-10, 0.5-5, or 1-3 Post autoclave (Metals) Citric acid mg/L 3.5 0.1-100, 1-50, or 2-25 FeSO4•7H2O mg/L 10.30 0.1-100, 1-50, or 5-25 MnCl2•4H2O mg/L 3.10 0.1-100, 1-50, or 2-25 ZnSO4•7H2O mg/L 3.10 0.1-100, 1-50, or 2-25 CoCl2•6H2O mg/L 0.04 0.001-1, 0.005-0.5, or 0.01-0.1 Na2MoO4•2H2O mg/L 0.04 0.001-1, 0.005-0.5, or 0.01-0.1 CuSO4•5H2O mg/L 2.07 0.1-100, 0.5-50, or 1-25 NiSO4•6H2O mg/L 2.07 0.1-100, 0.5-50, or 1-25 Post autoclave (Vitamins) Thiamine mg/L 9.75 0.1-100, 1-50, or 5-25 Vitamin B12 mg/L 0.16 0.1-100, 0.1-10, or 0.1-1 Ca½-panto- mg/L 3.33 0.1-100, 0.1-50, or 1-10 thenate Post autoclave (Carbon) Glucose g/L 30.0 5-150, 10-100, or 20-50 Nitrogen Feed: NH4OH mL/L 21.6 0-150, 10-100, or 15-50 Typical cultivation conditions would include the following: pH about 6.5-about 8.5, about 6.5-about 8.0, or about 7.0-about 7.5 temperature: about 17-about 30 degrees Celsius, about 20-about 25 degrees Celsius, or about 22 to about 23 degrees Celsius dissolved oxygen: about 5-about 100% saturation, about 10-about 80% saturation, or about 20-about 50% saturation glucose about 5-about 50 g/L, about 10-about 40 g/L, or controlled @: about 20-about 35 g/L.\",\n \"In carbon and nitrogen-fed cultures with 8200 ppm at 22.5° C. with 20% dissolved oxygen at pH 7.0, the isolate produced a dry cell weight of 140 g/L after 7 days of culture, with a fatty acid content of 70% by weight.\",\n \"Closed loop ammonia feed was used and the pH was maintained at 7.0.The omega-3 productivity was 8.92 g/(L*day) under these conditions, with 4.7 g/L EPA (5% by weight of fatty acids) and 56.3 g/L DHA (57% by weight of fatty acids) in 7 days.\",\n \"In carbon and nitrogen-fed cultures with 3640 ppm Cl− at 22.5° C. with 20% dissolved oxygen at pH 7.0, the isolate produced a dry cell weight of 82 g/L after 7 days of culture, with a fatty acid content of 58% by weight.\",\n \"The omega-3 productivity was 4.5 g/(L*day) under these conditions, with 2.1 g/L EPA (4.3% by weight of fatty acids) and 28.5 g/L DHA (58.7% by weight of fatty acids) in 7 days.\",\n \"In carbon and nitrogen-fed cultures with 980 ppm CF at 22.5° C. with 20% dissolved oxygen at pH 7.0, the isolate produced a dry cell weight of 60 g/L after 7 days of culture, with a fatty acid content of 53% by weight.\",\n \"The omega-3 productivity was 2.8 g/(L*day) under these conditions, with 1.1 g/L EPA (3.4% by weight of fatty acids) and 18.4 g/L DHA (56.8% by weight of fatty acids) in 7 days.\",\n \"Example 31 Oils were extracted from a biomass sample (Sample A) of the isolated thraustochytrid (ATCC Accession No.\",\n \"PTA-9695).\",\n \"The biomass sample was produced in a carbon and nitrogen-fed culture with 980 ppm Cl− at 22.5° C. with 20% dissolved oxygen at pH 7.0.Oils were extracted from biomass Sample A by the hexane extraction process to yield microbial oil Sample A1.Briefly, dried biomass was ground with hexane using stainless steel tubes and stainless steel ball bearings for approximately 2 hours.\",\n \"The slurry was vacuum filtered and the filtrate was collected.\",\n \"The hexane was removed using a rotary evaporator.\",\n \"Oils were also extracted from biomass Sample A using the FRIOLEX® process (GEA Westfalia Separator UK Ltd., Milton Keynes, England) to yield microbial oil Sample A2.Individual lipid classes were isolated from microbial oil Samples A1 and A2 using low pressure flash chromatography, and the weight percent of each class was determined.\",\n \"The fatty acid profile of each class was determined using gas chromatography with flame ionization detection (GC-FID) as fatty acid methyl esters (FAME).\",\n \"Flash Chromatography— Flash chromatography was used to separate the lipid classes present in the crude oils, and to determine the weight percent of each class present in the oils.\",\n \"The chromatography system utilized Silica Gel 60 (EMD Chemical, Gibbstown, N.J.) with mobile phase composed of Petroleum Ether and Ethyl Acetate at 3 mL/min.\",\n \"A step gradient was used to selectively elute each lipid class from the column.\",\n \"The mobile phase gradient started from 100% petroleum ether and finished with 50% ethyl acetate (followed by a 100% methanol wash).\",\n \"Fractions were collected in 10 mL test tubes using a Gilson FC 204 large-bed fraction collector (Gilson, Inc., Middleton, Wis.).\",\n \"Each tube was analyzed by thin layer chromatography (TLC) and the tubes containing individual lipid classes (as judged by single spots on TLC plate with expected retention factor (RI)) were pooled, concentrated to dryness, and weighed.\",\n \"The total fraction content was then determined gravimetrically.\",\n \"TLC Analysis— Thin layer chromatography was conducted on silica gel plates.\",\n \"The plates were eluted using a solvent system consisting of petroleum ether:ethyl ether:acetic acid (80:20:1) and were visualized using iodine vapor.\",\n \"The Rf values of each spot were then compared with reported literature values for each lipid class.\",\n \"Fatty Acid Analysis— The samples of biomass and isolated lipid classes were analyzed for fatty acid composition as FAMEs.\",\n \"Samples were weighed directly into screw cap test tubes, and 1 mL of C19:0 internal standard (NuCheck, Elysian, Minn.) in toluene and 2 mL of 1.5 N HCl in methanol was added to each tube.\",\n \"The tubes were vortexed briefly and placed in a heating block for 2 hours at 100° C. The tubes were removed from the heating block, allowed to cool, and 1 mL of saturated NaCl in water was added.\",\n \"The tubes were vortexed again, centrifuged, and a portion of the top (organic) layer was placed in a GC vial and analyzed by GC-FID.\",\n \"FAME's were quantified using a 3-point internal standard calibration curve generated using Nu-Chek-Prep GLC reference standard (Nu-Chek Prep, Inc., Elysian, Minn.) and tentatively identified based on retention time.\",\n \"Fatty acids present were expressed as mg/g and % of total FAME.\",\n \"Sample A1 was prepared by dissolving the crude oil in hexane and applying to the head of the column.\",\n \"After fractionation of the sample using flash chromatography, the sterol ester fraction accounted for 1.2% by weight, the triacylglycerol (TAG) fraction accounted for 82.7% by weight, the free fatty acid (FFA) fraction accounted for 0.9% by weight, and the diacylglycerol (DAG) fraction accounted for 2.9% by weight of the crude oil.\",\n \"The total fatty acid profiles of the Sample A1 crude oil and isolated fractions are shown below in Table 16 and Table 17 calculated as mg/g and % FAME, respectively.\",\n \"TABLE 16 Sample A1 Fatty Acid Profiles Calculated as Milligrams per Gram FAME Crude Sterol Biomass Oil Esters TAG FFA DAG Wt.\",\n \"% NA 38% 1.2% 82.7% 0.9 2.9% FAME FAME FAME FAME FAME FAME Fatty Acid (mg/g) (mg/g) (mg/g) (mg/g) (mg/g) (mg/g) C12:0* 0.6 0.0 1.9 3.2 1.7 0.0 C14:0* 5.7 13.6 12.8 20.2 13.0 17.6 C14:1* 0.0 0.0 0.0 0.0 0.0 0.0 C15:0 1.3 3.4 3.1 3.1 2.1 2.6 C16:0* 105.5 239.5 222.2 274.3 183.3 225.1 C16:1* 0.0 0.0 0.8 0.0 0.8 0.0 C18:0* 6.4 16.4 43.1 16.8 9.8 14.0 C18:1 N9* 0.0 3.8 1.9 3.3 1.0 3.5 C18:1 N7 0.0 0.0 0.0 0.0 0.0 0.0 C18:2 N6* 0.0 0.0 0.0 0.0 0.0 0.0 C20:0* 1.8 5.5 13.0 4.7 2.0 2.9 C18:3 N3* 0.0 0.0 0.0 0.0 0.0 0.0 C20:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C18:4 N3 0.0 0.0 0.0 0.0 0.6 0.0 C20:2 N6* 0.0 0.0 0.0 0.0 0.0 0.0 C20:3 N6 0.0 0.0 0.0 0.0 0.0 0.0 C22:0* 0.0 0.8 7.3 0.8 0.0 1.2 C20:4 N7 0.0 0.0 0.8 0.0 0.0 0.0 C20:3 N3 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N6* 1.0 3.4 0.0 2.6 2.0 1.9 C22:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N5 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N3 1.5 4.1 1.5 3.5 2.1 2.1 C20:5 N3* 18.2 39.5 3.5 38.4 30.6 42.8 C24:0* 0.0 0.0 6.3 0.0 0.0 0.0 C22:4 N9 0.0 0.0 0.0 0.0 0.0 0.0 C24:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C22:5 N6* 11.9 29.5 8.9 26.9 14.8 18.7 C22:5 N3* 1.1 4.7 0.9 3.6 3.4 2.7 C22:6 N3* 253.5 569.7 107.3 556.5 352.8 451.4 Sum of 408.6 934.0 435.4 958.0 620.1 786.4 all FAME's TABLE 17 Sample A1 Fatty Acid Profiles as a Percent of Total FAME Crude Sterol Biomass Oil Esters TAG FFA DAG Fatty Acid % FAME % FAME % FAME % FAME % FAME % FAME C12:0* 0.1 0.0 0.4 0.3 0.3 0.0 C14:0* 1.4 1.5 2.9 2.1 2.1 2.2 C14:1* 0.0 0.0 0.0 0.0 0.0 0.0 C15:0 0.3 0.4 0.7 0.3 0.3 0.3 C16:0* 25.8 25.6 51.0 28.6 29.6 28.6 C16:1* 0.0 0.0 0.2 0.0 0.1 0.0 C18:0* 1.6 1.8 9.9 1.8 1.6 1.8 C18:1 N9* 0.0 0.4 0.4 0.3 0.2 0.4 C18:1 N7 0.0 0.0 0.0 0.0 0.0 0.0 C18:2 N6* 0.0 0.0 0.0 0.0 0.0 0.0 C20:0* 0.4 0.6 3.0 0.5 0.3 0.4 C18:3 N3* 0.0 0.0 0.0 0.0 0.0 0.0 C20:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C18:4 N3 0.0 0.0 0.0 0.0 0.1 0.0 C20:2 N6* 0.0 0.0 0.0 0.0 0.0 0.0 C20:3 N6 0.0 0.0 0.0 0.0 0.0 0.0 C22:0* 0.0 0.1 1.7 0.1 0.0 0.1 C20:4 N7 0.0 0.0 0.2 0.0 0.0 0.0 C20:3 N3 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N6* 0.3 0.4 0.0 0.3 0.3 0.2 C22:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N5 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N3 0.4 0.4 0.4 0.4 0.3 0.3 C20:5 N3* 4.5 4.2 0.8 4.0 4.9 5.4 C24:0* 0.0 0.0 1.4 0.0 0.0 0.0 C22:4 N9 0.0 0.0 0.0 0.0 0.0 0.0 C24:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C22:5 N6* 2.9 3.2 2.1 2.8 2.4 2.4 C22:5 N3* 0.3 0.5 0.2 0.4 0.5 0.3 C22:6 N3* 62.0 61.0 24.6 58.1 56.9 57.4 Sum of 100.0 100.0 100.0 100.0 100.0 100.0 FAME % Sample A2 was prepared by dissolving the crude oil in hexane and applying to the head of the column.\",\n \"After fractionation of the sample using flash chromatography, the sterol ester fraction accounted for 0.8% by weight, the triacylglycerol (TAG) fraction accounted for 83.4% by weight, the free fatty acid (FFA) fraction accounted for 1.8% by weight, and the diacylglycerol (DAG) fraction accounted for 5.6% by weight of the crude oil.\",\n \"The total fatty acid profiles of the Sample A2 crude oil and isolated fractions are shown below in Table 18 and Table 19 calculated as mg/g and % FAME, respectively.\",\n \"TABLE 18 Sample A2 Fatty Acid Profiles Calculated as Milligrams per Gram FAME Crude Sterol Biomass Oil Esters TAG FFA DAG Wt.\",\n \"% NA NA 0.8% 83.4% 1.8% 5.6% FAME FAME FAME FAME FAME FAME Fatty Acid (mg/g) (mg/g) (mg/g) (mg/g) (mg/g) (mg/g) C12:0* 0.6 0.0 0.0 1.5 0.0 1.0 C14:0* 5.7 13.2 8.9 14.1 9.5 5.4 C14:1* 0.0 0.0 0.0 0.0 0.0 0.0 C15:0 1.3 3.3 2.8 3.4 2.1 2.2 C16:0* 105.5 233.7 183.8 246.1 159.7 137.3 C16:1* 0.0 0.0 0.0 0.8 0.0 0.0 C18:0* 6.4 16.6 23.6 16.9 11.3 5.6 C18:1 N9* 0.0 7.6 5.0 4.3 2.4 2.6 C18:1 N7 0.0 0.0 0.0 0.0 0.0 0.0 C18:2 N6* 0.0 2.2 0.7 1.6 0.8 5.1 C20:0* 1.8 5.2 12.1 5.5 2.6 1.1 C18:3 N3* 0.0 0.0 0.0 0.0 0.0 0.0 C20:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C18:4 N3 0.0 0.0 0.0 0.8 1.0 0.0 C20:2 N6* 0.0 0.0 0.0 0.0 0.0 0.0 C20:3 N6 0.0 0.0 0.0 0.3 0.0 0.0 C22:0* 0.0 0.7 6.0 1.3 0.8 0.0 C20:4 N7 0.0 0.0 0.0 0.0 0.0 0.0 C20:3 N3 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N6* 1.0 3.0 0.0 3.1 2.3 1.2 C22:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N5 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N3 1.5 4.1 1.4 4.3 2.7 1.0 C20:5 N3* 18.2 38.6 2.7 38.6 39.5 45.5 C24:0* 0.0 0.0 4.7 0.6 0.0 0.3 C22:4 N9 0.0 0.0 0.0 0.0 0.0 0.0 C24:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C22:5 N6* 11.9 28.2 8.6 29.6 18.0 14.7 C22:5 N3* 1.1 3.4 0.0 3.5 2.5 2.2 C22:6 N3* 253.5 566.7 102.2 575.0 475.3 447.2 Sum of 408.6 926.5 362.3 951.3 730.4 672.5 all FAME's TABLE 19 Sample A2 Fatty Acid Profiles as a Percent of Total FAME Crude Sterol Biomass Oil Esters TAG FFA DAG Fatty Acid % FAME % FAME % FAME % FAME % FAME % FAME C12:0* 0.1 0.0 0.0 0.2 0.0 0.2 C14:0* 1.4 1.4 2.4 1.5 1.3 0.8 C14:1* 0.0 0.0 0.0 0.0 0.0 0.0 C15:0 0.3 0.4 0.8 0.4 0.3 0.3 C16:0* 25.8 25.2 50.7 25.9 21.9 20.4 C16:1* 0.0 0.0 0.0 0.1 0.0 0.0 C18:0* 1.6 1.8 6.5 1.8 1.5 0.8 C18:1 N9* 0.0 0.8 1.4 0.5 0.3 0.4 C18:1 N7 0.0 0.0 0.0 0.0 0.0 0.0 C18:2 N6* 0.0 0.2 0.2 0.2 0.1 0.8 C20:0* 0.4 0.6 3.3 0.6 0.4 0.2 C18:3 N3* 0.0 0.0 0.0 0.0 0.0 0.0 C20:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C18:4 N3 0.0 0.0 0.0 0.1 0.1 0.0 C20:2 N6* 0.0 0.0 0.0 0.0 0.0 0.0 C20:3 N6 0.0 0.0 0.0 0.0 0.0 0.0 C22:0* 0.0 0.1 1.7 0.1 0.1 0.0 C20:4 N7 0.0 0.0 0.0 0.0 0.0 0.0 C20:3 N3 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N6* 0.3 0.3 0.0 0.3 0.3 0.2 C22:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N5 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N3 0.4 0.4 0.4 0.4 0.4 0.2 C20:5 N3* 4.5 4.2 0.7 4.1 5.4 6.8 C24:0* 0.0 0.0 1.3 0.1 0.0 0.0 C22:4 N9 0.0 0.0 0.0 0.0 0.0 0.0 C24:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C22:5 N6* 2.9 3.0 2.4 3.1 2.5 2.2 C22:5 N3* 0.3 0.4 0.0 0.4 0.3 0.3 C22:6 N3* 62.0 61.2 28.2 60.4 65.1 66.5 Sum of 100.0 100.0 100.0 100.0 100.0 100.0 FAME % It is noted that Samples A1 and A2 were extracted using a typical hexane extraction and a FRIOLEX® process, respectively.\",\n \"The fatty acid profiles of Tables 16-19 are expected to be the substantially the same if the samples were extracted using the processes of the present invention.\",\n \"Example 32 After oil was extracted from the fermentation broth using the Friolex process, as described in Example 31, the crude oil was further processed via refining, bleaching, and deodorizing steps to obtain a final oil.\",\n \"The final oil was diluted with high oleic sunflower oil to obtain finished commercial oil with a DHA content of approximately 400 mg/g.\",\n \"Individual lipid classes were isolated and the fatty acid profiles of each class was determined using gas chromatography with flame ionization detection (GC-FID) as fatty acid methyl esters (FAME).\",\n \"Flash Chromatography— Flash chromatography was used to separate the lipid classes present in the final oil, and to determine the weight percent of each class present in the oil.\",\n \"The chromatography system utilized Silica Gel 60 (EMD Chemical, Gibbstown, N.J.) with mobile phase composed of Petroleum Ether and Ethyl Acetate at 3 mL/min.\",\n \"A step gradient was used to selectively elute each lipid class from the column.\",\n \"The mobile phase gradient started from 100% petroleum ether and finished with 50% ethyl acetate (followed by a 100% methanol wash).\",\n \"Fractions were collected in 10 mL test tubes using a Gilson FC 204 large-bed fraction collector (Gilson, Inc., Middleton, Wis.).\",\n \"Each tube was analyzed by thin layer chromatography (TLC) and the tubes containing individual lipid classes (as judged by single spots on TLC plate with expected retention factor (Rf)) were pooled, concentrated to dryness, and weighed.\",\n \"The total fraction content was then determined gravimetrically.\",\n \"TLC Analysis— Thin layer chromatography was conducted on silica gel plates.\",\n \"The plates were eluted using a solvent system consisting of petroleum ether:ethyl ether:acetic acid (80:20:1) and were visualized using iodine vapor.\",\n \"The Rf values of each spot were then compared with reported literature values for each lipid class.\",\n \"Fatty Acid Analysis— The final oil sample and isolated lipid classes were analyzed for fatty acid composition as FAMEs.\",\n \"Samples were weighed directly into screw cap test tubes, and 1 mL of C19:0 internal standard (NuCheck, Elysian, Minn.) in toluene and 2 mL of 1.5 N HCl in methanol was added to each tube.\",\n \"The tubes were vortexed briefly and placed in a heating block for 2 hours at 100° C. The tubes were removed from the heating block, allowed to cool, and 1 mL of saturated NaCl in water was added.\",\n \"The tubes were vortexed again, centrifuged, and a portion of the top (organic) layer was placed in a GC vial and analyzed by GC-FID.\",\n \"FAME's were quantified using a 3-point internal standard calibration curve generated using Nu-Chek-Prep GLC reference standard (Nu-Chek Prep, Inc., Elysian, Minn.) and tentatively identified based on retention time.\",\n \"Fatty acids present were expressed as mg/g and % of total FAME.\",\n \"The sample was prepared by dissolving 250 mg of final oil in 600 μL of hexane and applying to the head of the column.\",\n \"After fractionation of the sample using flash chromatography, the sterol ester fraction accounted for 1.2% by weight, the triacylglyceride (TAG) fraction accounted for 92.1% by weight, the free fatty acid (FFA) fraction accounted for 2.1% by weight, the sterol fraction accounted for 1.1%, the diacylglyceride (DAG) fraction accounted for 2.8% by weight of the final oil.\",\n \"The TLC analysis of the pooled fractions showed that the FFA and sterol fractions were mixed with TAG and DAG respectively.\",\n \"The total fatty acid profiles of the FRIOLEX® final oil and isolated fractions are shown below in Table 20 and Table 21 calculated as mg/g and % FAME, respectively.\",\n \"TABLE 20 Fatty Acid Profile Calculated as Milligrams per Gram of FAME Final Sterol Oil Esters TAG FFA Sterol DAG Wt.\",\n \"% NA 1.2 92.1 2.1 1.1 2.8 Fatty Acid FAME FAME FAME FAME FAME FAME (mg/g) (mg/g) (mg/g) (mg/g) (mg/g) (mg/g) C12:0* 0.0 0.0 1.0 0.0 1.2 0.6 C14:0* 11.5 5.1 11.3 6.0 9.6 5.7 C14:1* 0.0 0.0 0.0 0.0 0.0 0.0 C15:0 2.3 0.0 2.3 1.2 2.0 1.9 C16:0* 183.3 80.0 180.8 99.9 149.3 132.2 C16:1* 0.0 0.0 0.9 0.0 0.8 0.6 C18:0* 19.6 17.5 19.6 7.5 16.2 6.7 C18:1 N9* 243.3 242.8 249.6 62.9 190.5 84.0 C18:1 N7 1.9 1.7 2.0 0.8 1.9 0.9 C18:2 N6* 13.8 5.6 13.8 6.2 14.3 9.1 C20:0* 4.3 6.6 4.5 1.5 3.6 1.4 C18:3 N3* 0.0 0.0 0.3 0.0 0.0 0.0 C20:1 N9* 0.0 0.0 0.8 0.0 0.8 0.0 C18:4 N3 0.0 0.0 0.7 1.3 0.9 0.4 C20:2 N6* 0.0 0.0 0.6 0.0 0.0 0.0 C20:3 N6 0.0 0.0 0.3 0.0 0.0 0.0 C22:0* 3.3 61.0 3.2 1.1 3.0 1.2 C20:4 N7 0.0 0.0 0.0 0.0 0.0 0.0 C20:3 N3 0.0 0.0 0.0 0.0 0.0 0.0 C20:4N6* 1.7 0.0 2.3 1.4 1.9 1.3 C22:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N5 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N3 2.4 4.5 3.0 2.2 2.6 1.3 C20:5 N3* 28.1 3.0 27.7 38.6 25.6 43.2 C24:0* 1.4 64.3 1.4 0.0 2.0 1.0 C22:4 N9 0.0 0.0 0.0 0.0 0.0 0.0 C24:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C22:5 N6* 20.0 7.6 21.0 10.1 17.2 14.4 C22:5 N3* 2.8 0.0 3.1 3.7 3.4 2.9 C22:6 N3* 407.1 72.5 417.4 443.6 350.5 428.5 Sum of all 936.1 572.1 967.6 688.0 797.3 737.3 FAME's TABLE 21 Fatty Acid Profiles as a Percent of Total FAME Final Sterol Oil Esters TAG FFA Sterol DAG Fatty Acid % % % % % % FAME FAME FAME FAME FAME FAME C12:0* 0.0 0.0 0.1 0.0 0.2 0.1 C14:0* 1.2 0.9 1.2 0.9 1.2 0.8 C14:1* 0.0 0.0 0.0 0.0 0.0 0.0 C15:0 0.2 0.0 0.2 0.2 0.2 0.3 C16:0* 19.6 14.0 18.7 14.5 18.7 17.9 C16:1* 0.0 0.0 0.1 0.0 0.1 0.1 C18:0* 2.1 3.1 2.0 1.1 2.0 0.9 C18:1 N9* 26.0 42.4 25.8 9.1 23.9 11.4 C18:1 N7 0.2 0.3 0.2 0.1 0.2 0.1 C18:2 N6* 1.5 1.0 1.4 0.9 1.8 1.2 C20:0* 0.5 1.1 0.5 0.2 0.5 0.2 C18:3 N3* 0.0 0.0 0.0 0.0 0.0 0.0 C20:1 N9* 0.0 0.0 0.1 0.0 0.1 0.0 C18:4 N3 0.0 0.0 0.1 0.2 0.1 0.1 C20:2 N6* 0.0 0.0 0.1 0.0 0.0 0.0 C20:3 N6 0.0 0.0 0.0 0.0 0.0 0.0 C22:0* 0.4 10.7 0.3 0.2 0.4 0.2 C20:4 N7 0.0 0.0 0.0 0.0 0.0 0.0 C20:3 N3 0.0 0.0 0.0 0.0 0.0 0.0 C20:4N6* 0.2 0.0 0.2 0.2 0.2 0.2 C22:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N5 0.0 0.0 0.0 0.0 0.0 0.0 C20:4 N3 0.3 0.8 0.3 0.3 0.3 0.2 C20:5 N3* 3.0 0.5 2.9 5.6 3.2 5.9 C24:0* 0.2 11.2 0.1 0.0 0.2 0.1 C22:4 N9 0.0 0.0 0.0 0.0 0.0 0.0 C24:1 N9* 0.0 0.0 0.0 0.0 0.0 0.0 C22:5 N6* 2.1 1.3 2.2 1.5 2.2 1.9 C22:5 N3* 0.3 0.0 0.3 0.5 0.4 0.4 C22:6 N3* 43.6 12.7 43.1 64.5 44.0 58.1 Sum of 100 100 100 100 100 100 FAME % It is noted that fatty acid profiles of Tables 20 and 21 were obtained from samples extracted using a FRIOLEX® process.\",\n \"The fatty acid profiles of Tables 20 and 21 are expected to be the substantially the same if the samples were extracted using the processes of the present invention.\",\n \"Example 33 A two-day old inoculum flask of the isolated thraustochytrid (ATCC Accession No.\",\n \"PTA-9695) was prepared in a carbon and nitrogen-fed culture with 980 ppm (thraustochytrid media).\",\n \"Mutagenesis was carried out according to following procedure: A sterile T=2 day old flask, approximately 50 ml, was poured into a sterile 40 ml glass homogenizer.\",\n \"The culture received 50 plunges in the homogenizer.\",\n \"The culture was pipetted out and filtered through a sterile 50 micron mesh filter, which was placed in a 50 ml sterile tube (the mesh was used as a means of retaining the larger clumps of colonies while letting the smaller clusters and single cells pass through the 50 micron mesh.).\",\n \"The entire concentrated macerate was collected in a sterile 50 ml tube.\",\n \"The macerated culture was vortexed and dilutions at levels up to 1:100 fold were made in tubes containing thraustochytrid media.\",\n \"The diluted macerate samples were vortexed prior to adding 200 μl of inoculum to a thraustochytrid media agar petri dish, 100×15 mm, containing 4-5 glass beads (3 mm glass beads).\",\n \"Each plate was gently agitated in an effort to have the beads spread the inoculum evenly around the plate.\",\n \"Beads were dumped off of plates and plates were left to sit with covers on for approximately 5 minutes to dry.\",\n \"Lights in both the sterile hood and adjoining areas were turned off as the procedure was performed in dim light.\",\n \"There was minimal light available to be able to run the procedure but only indirect and dim.\",\n \"Five replicate plates were placed on the floor of the XL crosslinker (Spectronics Corporation, New York) with the lids off while the samples were irradiated.\",\n \"The crosslinker delivered power in terms of microjoules and a level was sought that achieved a 90%-95% Kill.\",\n \"Five replicate control plates were inoculated with un-mutagenized cells using the same protocol.\",\n \"These cell counts were used to calculate the % Kill.\",\n \"Once the irradiation was finished the plates were taken out, the lids were replaced, and the plates were wrapped in parafilm followed by a wrap in aluminum foil.\",\n \"It was imperative that the plates grew for the first week in the dark so that they were not able to repair the damaged genes.\",\n \"Plates were placed in a 22.5° C. room for about 10 days prior to counting the colonies.\",\n \"When final counts were made, individual colonies were picked with a sterile inoculating loop and re-streaked on new thraustochytrid media plates.\",\n \"Each colony was plated on an individual plate.\",\n \"As plates grew dense a sample was taken, using a inoculating loop, and inoculated into a sterile 250 ml shake flask containing 50 ml of thraustochytrid media.\",\n \"This flask was placed on a shaker at 200 rpm in a 22.5° C. room.\",\n \"On T=7 days the shake flask culture was harvested into a 50 ml sterile tube.\",\n \"The pH was taken and the sample was spun down to collect the biomass pellet.\",\n \"Each sample was rinsed and re-suspended in a 50:50 mixture of isopropyl alcohol and distilled water prior to being re-spun.\",\n \"The collected pellet was freeze dried, weighed, and a FAME analysis was performed.\",\n \"The data in Tables 22-28 represents mutants produced with the above process.\",\n \"TABLE 22 Mutants of Thraustochytrid Strain ATCC Accession No.\",\n \"PTA-9695 control ATCC Fatty Acids PTA-9695 Mutant 1 Mutant 2 Mutant 3 Mutant 4 Mutant 5 Mutant 8 Mutant 9 Mutant 10 % 08:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 09:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 10:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 12:0 0.10 0.10 0.08 0.08 0.13 0.07 0.11 0.08 0.08 % 12:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 13:0 0.11 0.11 0.17 0.13 0.12 0.18 0.11 0.15 0.14 % 13:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 14:0 1.79 1.85 1.49 1.37 2.36 1.29 1.85 1.72 1.57 % 14:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 15:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 16:0 30.98 28.75 29.96 29.97 30.33 29.86 30.97 30.11 29.20 % 16:1 0.27 0.20 0.31 0.14 0.25 0.27 0.16 0.27 0.24 % 16:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 16:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 17:0 0.12 0.15 0.13 0.17 0.27 0.12 0.16 0.13 0.13 % 18:0 1.29 1.22 1.38 1.47 1.22 1.57 1.25 1.34 1.34 % 18:1 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:1 n-7 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:3 n-6 0.00 0.03 0.00 0.00 0.07 0.00 0.03 0.00 0.00 % 18:3 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:4 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:0 0.39 0.36 0.42 0.45 0.34 0.46 0.37 0.40 0.40 % 20:1 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-3 0.37 0.38 0.32 0.42 0.44 0.32 0.41 0.33 0.36 % 20:4 ARA 0.55 0.55 0.94 0.57 0.80 0.89 0.60 0.73 0.75 % 20:5 n-3 EPA 2.62 2.94 3.01 2.40 3.64 2.83 2.54 2.81 2.81 % 22:0 0.08 0.08 0.09 0.09 0.07 0.10 0.07 0.09 0.09 % 22:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:4 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:5 n-6 3.19 3.19 2.94 3.43 3.35 2.87 3.34 3.01 3.15 % 22:5 n-3 0.18 0.18 0.21 0.23 0.20 0.18 0.20 0.17 0.18 % 22:6 n-3 DHA 56.88 58.63 57.56 57.85 54.87 57.98 56.62 57.53 58.52 % 24:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 24:1 0.00 0.08 0.00 0.00 0.00 0.00 0.00 0.09 0.00 % Fat 46.83 46.10 31.23 47.39 49.78 30.62 54.71 37.72 37.87 % Unknown 0.85 0.46 0.35 0.51 0.51 0.36 0.50 0.38 0.39 TABLE 23 Mutants of Thraustochytrid Strain ATCC Accession No.\",\n \"PTA-9695 control ATCC Fatty Acids PTA-9695 Mutant 11 Mutant 13 Mutant 14 Mutant 15 Mutant 16 Mutant 20 Mutant 21 Mutant 22 % 08:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 09:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 10:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 12:0 0.10 0.10 0.08 0.09 0.11 0.11 0.09 0.09 0.10 % 12:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 13:0 0.11 0.15 0.16 0.14 0.13 0.12 0.17 0.16 0.13 % 13:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 14:0 1.79 1.89 1.43 1.75 1.83 1.98 1.76 1.77 1.81 % 14:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 15:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 16:0 30.98 31.08 30.27 29.92 31.79 30.18 28.84 30.05 30.81 % 16:1 0.27 0.32 0.26 0.28 0.21 0.24 0.23 0.23 0.33 % 16:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 16:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 17:0 0.12 0.24 0.15 0.13 0.15 0.12 0.14 0.16 0.14 % 18:0 1.29 1.36 1.44 1.31 1.36 1.21 1.28 1.34 1.33 % 18:1 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:1 n-7 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:3 n-6 0.00 0.05 0.00 0.00 0.00 0.03 0.00 0.00 0.00 % 18:3 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:4 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:0 0.39 0.38 0.42 0.39 0.40 0.37 0.37 0.38 0.38 % 20:1 n-9 0.00 0.00 0.06 0.00 0.00 0.00 0.00 0.00 0.00 % 20:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-3 0.37 0.43 0.36 0.33 0.36 0.37 0.33 0.35 0.34 % 20:4 ARA 0.55 0.79 0.72 0.80 0.64 0.62 0.83 0.73 0.69 % 20:5 n-3 EPA 2.62 3.17 2.72 2.97 2.52 2.66 3.03 2.90 2.87 % 22:0 0.08 0.08 0.09 0.08 0.08 0.08 0.08 0.08 0.08 % 22:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:4 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:5 n-6 3.19 3.25 3.06 2.97 3.07 3.16 2.98 3.01 3.02 % 22:5 n-3 0.18 0.20 0.19 0.17 0.19 0.16 0.17 0.18 0.18 % 22:6 n-3 DHA 56.88 55.17 57.52 57.63 56.02 57.38 58.58 57.45 56.65 % 24:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 24:1 0.00 0.00 0.00 0.00 0.00 0.07 0.00 0.00 0.08 % Fat 46.83 46.19 37.00 38.41 48.46 47.32 37.71 40.23 43.55 % Unknown 0.85 0.47 0.39 0.36 0.47 0.44 0.37 0.39 0.38 TABLE 24 Mutants of Thraustochytrid Strain ATCC Accession No.\",\n \"PTA-9695 control ATCC Fatty Acids PTA-9695 Mutant 24 Mutant 26 Mutant 27 Mutant 29 Mutant 30 Mutant 33 Mutant 34 Mutant 35 % 08:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 09:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 10:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 12:0 0.10 0.11 0.09 0.09 0.08 0.08 0.10 0.11 0.09 % 12:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 13:0 0.11 0.12 0.13 0.14 0.16 0.14 0.12 0.12 0.10 % 13:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 14:0 1.79 1.98 1.71 1.69 1.63 1.66 1.93 2.01 1.59 % 14:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 15:1 0.00 0.00 0.00 0.00 0.00 0.00 0.70 0.54 0.39 % 16:0 30.98 30.61 30.32 30.21 29.70 29.50 30.26 32.28 30.78 % 16:1 0.27 0.19 0.22 0.22 0.26 0.26 0.29 0.26 0.16 % 16:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 16:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 17:0 0.12 0.15 0.18 0.16 0.13 0.13 0.26 0.16 0.12 % 18:0 1.29 1.24 1.31 1.31 1.32 1.30 1.32 1.37 1.34 % 18:1 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.10 0.11 0.09 % 18:1 n-7 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:3 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:3 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:4 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:0 0.39 0.37 0.39 0.40 0.40 0.39 0.37 0.40 0.40 % 20:1 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.13 0.14 % 20:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-3 0.37 0.38 0.37 0.35 0.35 0.35 0.00 0.00 0.00 % 20:4 ARA 0.55 0.61 0.59 0.69 0.68 0.32 0.34 0.24 0.28 % 20:5 n-3 EPA 2.62 2.62 2.70 2.85 2.90 2.91 3.28 2.51 2.59 % 22:0 0.08 0.08 0.08 0.08 0.09 0.08 0.08 0.08 0.08 % 22:1 0.00 0.00 0.00 0.00.0.00 0.00 0.00 0.00 0.00 % 22:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:4 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:5 n-6 3.19 3.10 3.11 3.05 3.10 3.11 3.43 3.26 3.56 % 22:5 n-3 0.18 0.16 0.18 0.19 0.18 0.18 0.18 0.15 0.24 % 22:6 n-3 DHA 56.88 57.03 57.46 57.46 57.96 58.52 55.92 54.96 56.73 % 24:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 24:1 0.00 0.08 0.00 0.00 0.00 0.00 0.07 0.07 0.07 % Fat 46.83 47.80 43.50 38.86 38.60 38.16 46.95 46.43 51.55 % Unknown 0.85 0.45 0.42 0.39 0.37 0.82 1.25 1.23 1.25 TABLE 25 Mutants of Thraustochytrid Strain ATCC Accession No.\",\n \"PTA-9695 control ATCC Fatty Acids PTA-9695 Mutant 36 Mutant 37 Mutant 38 Mutant 39 Mutant 40 Mutant 42 Mutant 43 Mutant 44 % 08:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 09:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 10:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 12:0 0.10 0.00 0.11 0.00 0.11 0.09 0.08 0.12 0.09 % 12:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 13:0 0.11 0.44 0.09 0.24 0.12 0.11 0.12 0.08 0.15 % 13:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 14:0 1.79 1.25 1.99 1.48 1.96 1.76 1.43 2.17 1.75 % 14:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 15:1 0.00 2.12 0.48 0.71 0.54 0.55 0.36 0.62 0.50 % 16:0 30.98 26.95 28.04 32.28 30.84 30.25 25.77 43.37 30.18 % 16:1 0.27 0.00 0.26 0.23 0.22 0.21 0.10 1.05 0.22 % 16:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 16:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 17:0 0.12 0.95 0.13 0.28 0.16 0.16 0.10 0.26 0.13 % 18:0 1.29 1.58 1.11 1.79 1.30 1.29 1.25 2.21 1.34 % 18:1 n-9 0.00 0.37 0.08 0.25 0.09 0.09 0.12 0.09 0.10 % 18:1 n-7 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.05 0.00 % 18:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:3 n-6 0.00 0.00 0.06 0.00 0.00 0.00 0.00 0.00 0.00 % 18:3 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:4 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:0 0.39 0.34 0.31 0.43 0.38 0.39 0.36 0.61 0.40 % 20:1 n-9 0.00 0.00 0.00 0.43 0.00 0.14 0.15 0.15 0.49 % 20:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-3 0.37 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:4 ARA 0.55 0.41 0.31 0.24 0.27 0.24 0.30 0.35 0.23 % 20:5 n-3 EPA 2.62 5.36 2.77 4.00 2.72 2.80 3.21 3.47 2.80 % 22:0 0.08 0.00 0.07 0.14 0.07 0.08 0.07 0.14 0.08 % 22:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:4 n-6 0.00 0.00 0.06 0.00 0.00 0.00 0.00 0.00 0.00 % 22:5 n-6 3.19 2.40 3.94 2.57 3.48 3.29 3.89 2.37 3.33 % 22:5 n-3 0.18 0.00 0.19 0.00 0.17 0.17 0.30 0.33 0.17 % 22:6 n-3 DHA 56.88 57.52 58.57 54.20 56.24 57.09 60.99 41.61 56.76 % 24:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 24:1 0.00 0.00 0.08 0.00 0.08 0.09 0.08 0.06 0.09 % Fat 46.83 12.73 54.86 18.08 45.74 42.59 42.48 56.44 41.20 % Unknown 0.85 0.29 1.36 0.73 1.28 1.20 1.31 0.90 1.20 TABLE 26 Mutants of Thraustochytrid Strain ATCC Accession No.\",\n \"PTA-9695 control ATCC PTA- Fatty Acids 9695 Mutant 45 Mutant 46 Mutant 47 Mutant 48 Mutant 49 Mutant 50 Mutant 51 Mutant 52 % 08:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 09:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 10:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 12:0 0.10 0.10 0.13 0.11 0.07 0.09 0.09 0.09 0.11 % 12:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 13:0 0.11 0.11 0.10 0.09 0.13 0.09 0.13 0.10 0.09 % 13:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 14:0 1.79 1.79 2.07 1.86 1.52 1.62 1.78 1.78 1.85 % 14:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 15:1 0.00 0.41 0.76 0.57 0.46 0.48 0.55 0.53 0.53 % 16:0 30.98 28.79 24.90 30.07 29.07 31.21 30.46 30.79 32.53 % 16:1 0.27 0.19 0.24 0.18 0.17 0.17 0.18 0.21 0.22 % 16:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 16:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 17:0 0.12 0.11 0.24 0.16 0.12 0.14 0.17 0.18 0.15 % 18:0 1.29 1.24 1.07 1.28 1.41 1.43 1.36 1.48 1.35 % 18:1 n-9 0.00 0.08 0.07 0.09 0.09 0.08 0.10 0.09 0.06 % 18:1 n-7 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:3 n-6 0.00 0.00 0.12 0.05 0.00 0.00 0.00 0.00 0.00 % 18:3 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:4 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:0 0.39 0.36 0.29 0.37 0.42 0.42 0.39 0.40 0.41 % 20:1 n-9 0.00 0.15 0.13 0.11 0.24 0.13 0.19 0.16 0.19 % 20:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-6 0.00 0.00 0.05 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-3 0.37 0.00 0.12 0.00 0.00 0.00 0.00 0.00 0.00 % 20:4 ARA 0.55 0.29 0.65 0.26 0.18 0.21 0.22 0.24 0.24 % 20:5 n-3 2.62 3.05 4.28 2.66 2.93 2.46 2.71 2.94 2.44 EPA % 22:0 0.08 0.07 0.06 0.07 0.09 0.09 0.08 0.08 0.08 % 22:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:4 n-6 0.00 0.06 0.07 0.05 0.00 0.00 0.00 0.00 0.00 % 22:5 n-6 3.19 3.59 4.28 3.46 3.07 3.32 3.17 3.18 3.24 % 22:5 n-3 0.18 0.25 0.27 0.18 0.17 0.17 0.16 0.17 0.17 % 22:6 n-3 DHA 56.88 57.74 58.32 56.70 58.65 56.45 56.83 56.19 55.06 % 24:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 24:1 0.00 0.07 0.15 0.10 0.10 0.11 0.10 0.10 0.07 % Fat 46.83 48.91 58.95 54.80 35.41 48.60 44.93 43.01 51.93 % Unknown 0.85 1.55 1.63 1.57 1.09 1.35 1.31 1.28 1.19 TABLE 27 Mutants of Thraustochytrid Strain ATCC Accession No.\",\n \"PTA-9695 control ATCC Fatty Acids PTA-9695 Mutant 53 Mutant 54 Mutant 55 Mutant 56 Mutant 57 Mutant 58 Mutant 60 Mutant 61 Mutant 65 % 08:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 09:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 10:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 12:0 0.10 0.09 0.08 0.12 0.08 0.08 0.08 0.08 0.10 0.08 % 12:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 13:0 0.11 0.11 0.12 0.08 0.09 0.13 0.16 0.14 0.09 0.14 % 13:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 14:0 1.79 1.74 1.63 2.13 1.67 1.59 1.59 1.59 1.85 1.58 % 14:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 15:1 0.00 0.53 0.52 0.48 0.51 0.52 0.45 0.50 0.51 0.48 % 16:0 30.98 30.13 29.54 33.01 31.08 29.37 30.65 29.39 31.15 30.03 % 16:1 0.27 0.21 0.23 0.26 0.26 0.14 0.25 0.22 0.26 0.25 % 16:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 16:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 17:0 0.12 0.15 0.14 0.14 0.14 0.16 0.12 0.13 0.14 0.13 % 18:0 1.29 1.30 1.30 1.37 1.38 1.37 1.46 1.30 1.30 1.35 % 18:1 n-9 0.00 0.08 0.08 0.00 0.06 0.11 0.09 0.10 0.07 0.07 % 18:1 n-7 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:3 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:3 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:4 n-3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:0 0.39 0.38 0.39 0.40 0.42 0.38 0.43 0.39 0.39 0.41 % 20:1 n-9 0.00 0.19 0.16 0.13 0.19 0.20 0.17 0.14 0.13 0.21 % 20:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-9 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 n-3 0.37 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:4 ARA 0.55 0.25 0.21 0.26 0.22 0.25 0.51 0.20 0.24 0.19 % 20:5 n-3 EPA 2.62 2.75 2.78 2.81 2.67 2.78 5.76 2.72 2.59 2.82 % 22:0 0.08 0.08 0.08 0.08 0.09 0.08 0.09 0.08 0.08 0.09 % 22:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:4 n-6 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.06 0.00 % 22:5 n-6 3.19 3.47 3.20 3.25 3.19 3.43 2.62 3.30 3.42 3.18 % 22:5 n-3 0.18 0.18 0.18 0.17 0.17 0.20 0.59 0.17 0.17 0.17 % 22:6 n-3 DHA 56.88 56.99 58.07 54.04 56.38 57.76 54.09 58.21 55.91 57.56 % 24:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 24:1 0.00 0.09 0.09 0.07 0.10 0.09 0.11 0.10 0.07 0.08 % Fat 46.83 45.83 39.59 48.81 41.92 43.97 33.96 36.97 50.40 36.21 % Unknown 0.85 1.28 1.19 1.19 1.29 1.35 0.77 1.24 1.48 1.17 TABLE 28 Mutants of Thraustochytrid Strain ATCC Accession No.\",\n \"PTA-9695 control Mutant 68 Mutant 70 Mutant 72 Fatty ATCC Mutant Mutant ATCC Mutant ATCC Mutant ATCC Mutant Mutant Acids PTA-9695 66 67 PTA-9696 69 PTA-9697 71 PTA-9698 73 74 % 08:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 09:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 10:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 11:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 12:0 0.15 0.00 0.00 0.00 0.00 0.00 0.00 0.13 0.00 0.00 % 12:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 13:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 13:1 0.00 0.00 0.00 0.00 0.00 0.00 0.22 0.00 0.00 0.00 % 14:0 2.42 2.29 2.07 2.09 2.11 2.21 2.27 2.29 1.97 2.06 % 14:1 0.00 0.00 0.00 0.00 0.00 0.00 0.19 0.00 0.00 0.00 % 15:1 0.55 0.47 0.48 0.47 0.47 0.44 0.46 0.40 0.50 0.47 % 16:0 39.19 31.02 26.20 25.84 27.79 28.14 28.89 33.49 24.50 23.95 % 16:1 0.43 0.19 0.00 0.00 0.00 0.00 0.19 0.21 0.00 0.00 % 16:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 16:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 17:0 0.16 0.00 0.00 0.00 0.00 0.00 0.00 0.13 0.00 0.00 % 18:0 1.67 1.68 1.22 1.22 1.44 1.49 1.51 2.24 1.11 1.02 % 18:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 % 18:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-7 % 18:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 18:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 % 18:3 0.00 0.18 0.20 0.21 0.19 0.17 0.22 0.16 0.22 0.22 n-3 % 18:4 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-3 % 20:0 0.49 0.41 0.32 0.31 0.35 0.37 0.44 0.52 0.29 0.27 % 20:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 % 20:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 20:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 % 20:3 0.00 0.00 0.00 0.00 0.15 0.00 0.00 0.00 0.00 0.00 n-6 % 20:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-3 % 20:4 0.18 0.16 0.33 0.27 0.24 0.37 0.30 0.27 0.38 0.39 ARA % 20:5 1.76 2.30 3.86 3.97 3.32 4.12 3.09 2.74 4.43 4.53 n-3 EPA % 22:0 0.33 0.46 0.35 0.44 0.48 0.38 0.43 0.12 0.35 0.34 % 22:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 22:4 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 % 22:5 2.62 2.83 3.17 2.66 2.72 2.95 3.46 2.79 3.17 3.19 n-6 % 22:5 0.18 0.18 0.46 0.42 0.34 0.61 0.25 0.27 0.48 0.57 n-3 % 22:6 49.52 57.01 60.60 61.42 59.74 58.03 55.62 53.06 61.83 62.23 n-3 DHA % 24:0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % 24:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 % Fat 52.70 49.32 48.51 49.49 48.80 53.65 40.38 63.40 48.27 46.63 % 0.35 0.82 0.73 0.66 0.67 0.73 2.46 1.18 0.78 0.76 Unknown Example 34 Isolation of Microorganisms Samples were collected from intertidal habitats during low tide, including bays and estuaries along the West Coast of North America (California, Oregon, and Washington) and Hawaii.\",\n \"Water, sediment, living plant material, and decaying plant/animal debris were placed into sterile 50 ml tubes.\",\n \"Portions of each sample along with the water were spread onto solid agar plates of isolation media.\",\n \"Isolation media consisted of: 500 ml of artificial seawater, 500 ml of distilled water, 1 g of glucose, 1 g of glycerol, 13 g of agar, 1 g of glutamate, 0.5 g of yeast extract, 0.5 g casein hydrolysate, 1 ml of a vitamin solution (100 mg/L thiamine, 0.5 mg/L biotin, 0.5 mg B12), 1 ml of a trace mineral solution (PH metals, containing per liter: 6.0 g FeCl36H2O, 6.84 g H3BO3, 0.86 g MnCl24H2O, 0.06 g ZnCl2, 0.026 CoCl26H2O, 0.052 g NiSO4H2O, 0.002 g CuSO45H2O and 0.005 g Na2MoO42H2O), and 500 mg each of penicillin G and streptomycin sulfate.\",\n \"The agar plates were incubated in the dark at 20-25° C. After 2-4 days the agar plates were examined under magnification, and colonies of cells were picked with a sterile toothpick and restreaked onto a fresh plate of media.\",\n \"Cells were repeatedly streaked onto fresh media until contaminated organisms were removed.\",\n \"Two of the isolated microorganisms were deposited under ATCC Accession Nos.\",\n \"PTA-10212 and PTA-10208.Taxonomic Characteristics of the Isolated Microorganism Deposited Under ATCC Accession No.\",\n \"PTA-10212 Cultures of the isolated microorganism deposited under ATCC Accession No.\",\n \"PTA-10212 (“PTA-10212”) appeared as white, wet, smeared colonies without visible isolated sori.\",\n \"PTA-10212 was grown on solid and liquid FFM, solid KMV, KMV slush (1%), KMV broth, and MH broth to further examine growth characteristics.\",\n \"PTA-10212 was observed to grow rapidly on KMV and MH.\",\n \"See, e.g., Porter D., 1989.Phylum Labyrinthulomycota.\",\n \"In Margulis, L., Corliss, J. O., Melkonian, M., Chapman, D. J.\",\n \"(Eds.)\",\n \"Handbook of Protoctista, Jones and Bartlett, Boston, pp.\",\n \"388-398 (KMV); Honda et al., Mycol.\",\n \"Res.\",\n \"102:439-448 (1998) (MH); and U.S. Pat.\",\n \"No.\",\n \"5,130,242 (FFM).\",\n \"The following observations were made after growth of PTA-10212 over several days on solid FFM media, after 72 hours growth in KMV medias, and MH broth.\",\n \"Sporangia were not clumped in/on any media and were very small (5-10 μm).\",\n \"PTA-10212 did not demonstrate the copious tetrads characteristic of Schizochytrium cleavage patterns.\",\n \"Amoeboid cells appeared about 24 hours after transfer to fresh solid media.\",\n \"These amoeboid cells were gone after a few days and were not evident in liquid or slush media.\",\n \"Unlike Aurantiochytrium, described by Yokoyama, R. et al., Mycoscience 48(6): 329-341 (2007), as having the appearance of “small sandgrains on the bottom of the flask” when grown in liquid media, PTA-10212 did not settle at the bottom of the flask but was suspended in both KMV and MH liquid media.\",\n \"The sporangia were not as dense as typical of Schizochytrium or Oligochytrium, which also have robust ectoplasmic networks that were absent from PTA-10212.While most species undergo vegetative cleavage of small sporangia or assimilative cells by the division of a larger sporangium over several hours, PTA-10212 formed dumbbell-shaped elongated assimilative cells, which then formed a thin isthmus that pulled apart as the ends of the dumbbell separated.\",\n \"The resulting cells appeared to be small assimilative cells.\",\n \"Direct transformation of an amoeboid cell into the dumbbell shaped assimilative cell was not observed.\",\n \"Typical biflagellate zoospores were observed swimming but were relatively rare.\",\n \"PTA-10212 was non-prolific, dividing by vegetative cleavage.\",\n \"Direct release of zoospores was not observed, although zoospores were observed swimming.\",\n \"Vegetative cells were very small (2 μm to 5 μm).\",\n \"PTA-10212 was further examined using the flow-through technique, in which microscopic slides were prepared by suspending a small portion of an agar-grown colony in a drop of half-strength sea water.\",\n \"With this technique, primary sporangia were observed to be globose and approximately 10 μm in diameter.\",\n \"Walls were very thin and remnants were not observed when binary division of the protoplast was initiated.\",\n \"Repeated binary division produced 8-16 smaller (4-5 μm in diameter) secondary sporangia.\",\n \"The secondary sporangia remained quiescent for several hours before again releasing an amorphous protoplast.\",\n \"The amorphous protoplast divided by pinching and pulling, initially producing typical dumbbell-shaped intermediate stages and finally resulting in 4-8 small globose bodies 2.5-2.8 μm in diameter.\",\n \"The latter rested for several minutes up to 1-2 hours, then changed shape (elongated) and turned into biflagellate zoospores, 2.3-2.5×3.7-3.9 μm.\",\n \"Zoospores were abundant and could be precisely measured when they came to rest.\",\n \"Zoospores then rounded off and started a new cycle of development.\",\n \"The zoospores were larger than Sicyoldochytrium minutum and smaller than Ulkenia visurgensis.\",\n \"PTA-10212 was further characterized based on the similarity of its 18s rRNA gene to that of known species.\",\n \"Genomic DNA was prepared from PTA-10212 by standard procedures.\",\n \"See, for example, Sambrook J. and Russell D. 2001.Molecular cloning: A laboratory manual, 3rd edition.\",\n \"Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.\",\n \"Briefly: (1) 500 pit of cells were centrifuged from mid-log culture.\",\n \"The cells were re-centrifuged, and all traces of liquid were removed from the cell pellet with a small-bore tip; (2) pellets were resuspended with 200 μL lysis buffer (20 mM Tris pH 8.0, 125 μg/mL Proteinase K, 50 mM NaCl, 10 mM EDTA pH 8.0, 0.5% SDS); (3) cells were lysed at 50° C. for 1 hour; (4) the lysis mixture was pipetted into phase-lock gel (PLG-Eppendorf) 2 mL tubes; (5) equal volume of P:C:I was added and allowed to mix for 1.5 hours; (6) the tubes were centrifuged at 12,000×g for 5 minutes; (7) the aqueous phase was removed from above the gel within the PLG tube and an equal volume of chloroform was added to the aqueous phase, and mixed for 30 minutes; (8) the tubes were centrifuged at 14,000×g for approximately 5 minutes; (9) the top layer (aqueous phase) was pipetted away from the chloroform, and placed in a new tube; (10) 0.1 volume of 3 M NaOAC was added and mixed (inverted several times); (11) 2 volumes of 100% EtOH were added and mixed (inverted several times) with genomic DNA precipitant forming at this stage; (12) the tubes were centrifuged at 4° C. in a microcentrifuge at 14,000×g for approximately 15 minutes; (13) the liquid was gently poured off with genomic DNA remaining at the bottom of the tube; (14) the pellet was washed with 0.5 mL 70% EtOH; (15) the tubes were centrifuged at 4° C. in a microcentrifuge at 14,000×g for approximately 5 minutes; (16) the EtOH was gently poured off and the genomic DNA pellet was dried; and (17) a suitable volume of H2O and RNase was added directly to the genomic DNA pellet.\",\n \"The PCR amplification of the 18s rRNA gene was carried out with primers previously described (Honda et.\",\n \"al., 0.1 Euk.\",\n \"Micro.\",\n \"46(6): 637-647 (1999).\",\n \"The PCR conditions with chromosomal DNA template were as follows: 0.2 μM dNTPs, 0.1 μM each primer, 8% DMSO, 200 ng chromosomal DNA, 2.5 U Herculase® II Fusion DNA Polymerase (Stratagene), and Herculase® buffer (Stratagene) in a 50 μL total volume.\",\n \"The PCR Protocol included the following steps: (1) 95° C. for 2 minutes; (2) 95° C. for 35 seconds; (3) 55° C. for 35 seconds; (4) 72° C. for 1 minute and 30 seconds; (5) repeat steps 2-4 for 30 cycles; (6) 72° C. for 5 minutes; and (7) hold at 4° C. PCR amplification yielded a distinct DNA product with the expected size using chromosomal template described above.\",\n \"The PCR product was cloned into the vector pJET1.2/blunt (Fermentas) according to the manufacturer's instructions, and the insert sequence was determined using supplied standard primers.\",\n \"Phylogenetic analysis places PTA-10212 within the lineage that includes Thraustochytrium pachydermum and Thraustochytrium aggregatum with moderate support.\",\n \"The sporangia of T. pachydermum have very thick cell walls.\",\n \"T. aggregatum forms clearly visible clumps of sori that are opaque.\",\n \"PTA-10212 shows neither of these characteristics.\",\n \"The presence of many amoeboid cells has been described in other taxa, such as Ulkenia, T. gaertnerium, A. limiacinum, and S. mangrovei; however, the descriptions associated with those taxa differ from the observed characteristics of the isolate.\",\n \"Moreover, PTA-10212 did not show phylogenetic affinity towards any of these taxa.\",\n \"Table 29 shows a comparison of the 18s rRNA sequence from the microorganism deposited under ATCC Accession No.\",\n \"PTA-10212 to DNA sequences in the National Center for Biotechnology Information (NCBI) electronic database.\",\n \"The percent identity was determined using two different calculations.\",\n \"“Calculation #1” takes into consideration any “gaps” that occurs in the sequences, either from non-homologous regions or partial sequence (AlignX-VectorNTI default settings).\",\n \"“Calculation #2” does not include calculated penalties for gaps (AlignX-VectorNTI “IDENTITY” matrix setting).\",\n \"TABLE 29 Comparison of 18s rRNA Sequences % Identity % Identity Thraustochytrids Calculation #1 Calculation #2 Thraustochytrium pachydermum 85% 93% Thraustochytrium aggregatum (p) 83% 92% Thraustochytrium gaertnerium 82% 92% Ulkenia visurgensis 82% 92% Schizochytrium sp.\",\n \"PTA-9695 80% 92% Schizochytrium mangrovei 80% 91% Schizochytrium sp.\",\n \"ATCC 20888 80% 90% Aurantiochytrium limiacinum 79% 90% (p): indicates partial sequence As shown in Table 29, it was found that, in terms of % identity, the 18s rRNA gene sequence from the microorganism deposited under ATCC Accession No.\",\n \"PTA-10212 is related, though not identical, to 18s rRNA gene sequences available in the NCBI database.\",\n \"It is generally recognized that organisms can have closely related 18s rRNA gene sequences while belonging to a different genus or species.\",\n \"Based on the above characterization, the isolated microorganism (ATCC Accession No.\",\n \"PTA-10212) is believed to represent a new Thraustochytrium species and is therefore also designated as Thraustochytrium sp.\",\n \"ATCC PTA-10212.Taxonomic Characteristics of the Isolated Microorganism Deposited Under ATCC Accession No.\",\n \"PTA-10208 The microorganism deposited under ATCC Accession No.\",\n \"PTA-10208 (“PTA-10208”) was identified as a sub-isolate (an individual cell isolated from a culture and maintained as a new separate and distinct culture) of the microorganism deposited under ATCC Accession No.\",\n \"PTA-9695 (“PTA-9695”), described in U.S. Pub.\",\n \"No.\",\n \"2010/0239533 and Int'l.\",\n \"Pub.\",\n \"No.\",\n \"WO 2010/107415.PTA-10208 shares taxonomic characteristics with PTA-9695.PTA-9695 was found to have biflagellate zoospores at discharge that swim actively away from the mature sporangium, wall remnants of which were clearly visible (in phase contrast) after spore release.\",\n \"PTA-9695 sporangia measured 12.5 μm to 25 μm in diameter, and zoospores were 2.5 μm to 2.8 μm×4.5 μm to 4.8 μm in size.\",\n \"There were 8 to 24 spores per individual PTA-9695 sporangium.\",\n \"Settled PTA-9695 zoospores enlarged and rapidly underwent binary divisions leading to tetrads, octads, and finally to clusters of sporangia.\",\n \"Tetrad formation commenced at a very early stage prior to maturity of the sporangia.\",\n \"These characteristics are in agreement with the genus Schizochytrium.\",\n \"In terms of % identity, the PTA-9695 18s rRNA gene sequence, which is shared by PTA-10208, was found to be closely related, though not identical, to the 18s rRNA gene sequence of T. aggregatum provided in Honda, D. et al., J. Euk.\",\n \"Micro.\",\n \"46(6): 637-647 (1999).\",\n \"The 18s rRNA sequence published for Thraustochytrium aggregatum is a partial sequence, with an approximately 71 DNA nucleotide gap in the middle of the sequence.\",\n \"PTA-9695 is believed to represent a new Schizochytrium species.\",\n \"As such, the sub-isolate PTA-10208 is also designated as Schizochytrium sp.\",\n \"ATCC PTA-10208.Example 35 Growth Characteristics of the Isolated Microorganism Deposited Under ATCC Accession No.\",\n \"PTA-10212 The isolated microorganism (ATCC Accession No.\",\n \"PTA-10212) was examined for growth characteristics in individual fermentation runs, as described below.\",\n \"Typical media and cultivation conditions are shown in Table 30.TABLE 30 PTA-10212 Vessel Media Ingredient concentration ranges Na2SO4 g/L 31.0 0-50, 15-45, or 25-35 NaCl g/L 0.625 0-25, 0.1-10, or 0.5-5 KCl g/L 1.0 0-5, 0.25-3, or 0.5-2 MgSO4•7H2O g/L 5.0 0-10, 2-8, or 3-6 (NH4)2SO4 g/L 0.44 0-10, 0.25-5, or 0.05-3 MSG•1H2O g/L 6.0 0-10, 4-8, or 5-7 CaCl2 g/L 0.29 0.1-5, 0.15-3, or 0.2-1 T 154 (yeast g/L 6.0 0-20, 0.1-10, or 1-7 extract) KH2PO4 g/L 0.8 0.1-10, 0.5-5, or 0.6-1.8 Post autoclave (Metals) Citric acid mg/L 3.5 0.1-5000, 10-3000, or 3-2500 FeSO4•7H2O mg/L 10.30 0.1-100, 1-50, or 5-25 MnCl2•4H2O mg/L 3.10 0.1-100, 1-50, or 2-25 ZnSO4•7H2O mg/L 3.10 0.01-100, 1-50, or 2-25 CoCl2•6H2O mg/L 0.04 0-1, 0.001-0.1, or 0.01-0.1 Na2MoO4•2H2O mg/L 0.04 0.001-1, 0.005-0.5, or 0.01-0.1 CuSO4•5H2O mg/L 2.07 0.1-100, 0.5-50, or 1-25 NiSO4•6H2O mg/L 2.07 0.1-100, 0.5-50, or 1-25 Post autoclave (Vitamins) Thiamine mg/L 9.75 0.1-100, 1-50, or 5-25 Vitamin B12 mg/L 0.16 0.01-100, 0.05-5, or 0.1-1 Ca½-panto- mg/L 2.06 0.1-100, 0.1-50, or 1-10 thenate Biotin mg/L 3.21 0.1-100, 0.1-50, or 1-10 Post autoclave (Carbon) Glycerol g/L 30.0 5-150, 10-100, or 20-50 Nitrogen Feed: MSG•1H2O g/L 17 0-150, 10-100, or 15-50 Typical cultivation conditions would include the following pH about 6.5-about 9.5, about 6.5-about 8.0, or about 6.8-about 7.8; temperature: about 15-about 30 degrees Celsius, about 18-about 28 degrees Celsius, or about 21 to about 23 degrees Celsius; dissolved oxygen: about 0.1-about 100% saturation, about 5-about 50% saturation, or about 10-about 30% saturation; and/or glycerol about 5-about 50 g/L, about 10-about 40 g/L, or controlled @: about 15-about 35 g/L.\",\n \"In carbon (glycerol) and nitrogen-fed cultures with 1000 ppm CF at 22.5° C. with 20% dissolved oxygen at pH 7.3, PTA-10212 produced a dry cell weight of 26.2 g/L after 138 hours of culture in a 10 L fermentor volume.\",\n \"The lipid yield was 7.9 g/L; the omega-3 yield was 5.3 g/L; the EPA yield was 3.3 g/L; and the DHA yield was 1.8 g/L.\",\n \"The fatty acid content was 30.3% by weight; the EPA content was 41.4% of fatty acid methyl esters (FAME); and the DHA content was 26.2% of FAME.\",\n \"The lipid productivity was 1.38 g/L/day, and the omega-3 productivity was 0.92 g/L/day under these conditions, with 0.57 g/L/day EPA productivity and 0.31 g/L/day DHA productivity.\",\n \"In carbon (glycerol) and nitrogen-fed cultures with 1000 ppm Cl− at 22.5° C. with 20% dissolved oxygen at pH 7.3, PTA-10212 produced a dry cell weight of 38.4 g/L after 189 hours of culture in a 10 L fermentor volume.\",\n \"The lipid yield was 18 g/L; the omega-3 yield was 12 g/L; the EPA yield was 5 g/L; and the DHA yield was 6.8 g/L.\",\n \"The fatty acid content was 45% by weight; the EPA content was 27.8% of FAME; and the DHA content was 37.9% of FAME.\",\n \"The lipid productivity was 2.3 g/L/day, and the omega-3 productivity was 1.5 g/L/day under these conditions, with 0.63 g/L/day EPA productivity and 0.86 g/L/day DHA productivity.\",\n \"In carbon (glycerol) and nitrogen-fed cultures with 1000 ppm Cl− at 22.5° C. with 20% dissolved oxygen at pH 6.8-7.7, PTA-10212 produced a dry cell weight of 13 g/L after 189 hours of culture in a 10 L fermentor volume.\",\n \"The lipid yield was 5.6 g/L; the omega-3 yield was 3.5 g/L; the EPA yield was 1.55 g/L; and the DHA yield was 1.9 g/L.\",\n \"The fatty acid content was 38% by weight; the EPA content was 29.5% of FAME; and the DHA content was 36% of FAME.\",\n \"The lipid productivity was 0.67 g/L/day, and the omega-3 productivity was 0.4 g/L/day under these conditions, with 0.20 g/L/day EPA productivity and 0.24 g/L/day DHA productivity.\",\n \"In carbon (glycerol) and nitrogen-fed cultures with 1000 ppm at 22.5-28.5° C. with 20% dissolved oxygen at pH 6.6-7.2, PTA-10212 produced a dry cell weight of 36.7 g/L-48.7 g/L after 191 hours of culture in a 10 L fermentor volume.\",\n \"The lipid yield was 15.2 g/L-25.3 g/L; the omega-3 yield was 9.3 g/L-13.8 g/L; the EPA yield was 2.5 g/L-3.3 g/L; and the DHA yield was 5.8 g/L-11 g/L.\",\n \"The fatty acid content was 42.4%-53% by weight; the EPA content was 9.8%-22% of FAME; and the DHA content was 38.1%-43.6% of FAME.\",\n \"The lipid productivity was 1.9 g/L/day-3.2 g/L/day, and the omega-3 productivity was 1.2 g/L/day-1.7 g/L/day under these conditions, with 0.31 g/L/day-0.41 g/L/day EPA productivity and 0.72 g/L/day-1.4 g/L/day DHA productivity.\",\n \"Growth Characteristics of the Isolated Microorganism Deposited Under ATCC Accession No.\",\n \"PTA-10208 The isolated microorganism (ATCC Accession No.\",\n \"PTA-10208) was examined for growth characteristics in individual fermentation runs, as described below.\",\n \"Typical media and cultivation conditions are shown in Table 31.TABLE 31 PTA-10208 Vessel Media Ingredient concentration ranges Na2SO4 g/L 8.8 0-25, 2-20, or 3-10 NaCl g/L 0.625 0-25, 0.1-10, or 0.5-5 KCl g/L 1.0 0-5, 0.25-3, or 0.5-2 MgSO4•7H2O g/L 5.0 0-10, 2-8, or 3-6 (NH4)2SO4 g/L 0.42 0-10, 0.25-5, or 0.05-3 CaCl2 g/L 0.29 0.1-5, 0.15-3, or 0.2-1 T 154 (yeast g/L 1.0 0-20, 0.1-10, or 0.5-5 extract) KH2PO4 g/L 1.765 0.1-10, 0.5-5, or 1-3 Post autoclave (Metals) Citric acid mg/L 46.82 0.1-5000, 10-3000, or 40-2500 FeSO4•7H2O mg/L 10.30 0.1-100, 1-50, or 5-25 MnCl2•4H2O mg/L 3.10 0.1-100, 1-50, or 2-25 ZnSO4•7H2O mg/L 9.3 0.01-100, 1-50, or 2-25 CoCl2•6H2O mg/L 0.04 0-1, 0.001-0.1, or 0.01-0.1 Na2MoO4•2H2O mg/L 0.04 0.001-1, 0.005-0.5, or 0.01-0.1 CuSO4•5H2O mg/L 2.07 0.1-100, 0.5-50, or 1-25 NiSO4•6H2O mg/L 2.07 0.1-100, 0.5-50, or 1-25 Post autoclave (Vitamins) Thiamine mg/L 9.75 0.1-100, 1-50, or 5-25 Ca½-panto- mg/L 3.33 0.1-100, 0.1-50, or 1-10 thenate Biotin mg/L 3.58 0.1-100, 0.1-50, or 1-10 Post autoclave (Carbon) Glucose g/L 30.0 5-150, 10-100, or 20-50 Nitrogen Feed: NH4OH mL/L 23.6 0-150, 10-100, or 15-50 Typical cultivation conditions would include the following: pH about 6.5-about 8.5, about 6.5-about 8.0, or about 7.0-about 8.0; temperature: about 17-about 30 degrees Celsius, about 20-about 28 degrees Celsius, or about 22 to about 24 degrees Celsius; dissolved oxygen: about 2-about 100% saturation, about 5-about 50% saturation, or about 7-about 20% saturation; and/or glucose about 5-about 50 g/L, about 10-about 40 g/L, or controlled @: about 20-about 35 g/L.\",\n \"In carbon (glucose) and nitrogen-fed cultures with 1000 ppm Cl− at 22.5° C. at pH 7.0 with 20% dissolved oxygen during the nitrogen feed and 10% dissolved oxygen thereafter, PTA-10208 produced a dry cell weight of 95 g/L after 200 hours of culture in a 10 L fermentor volume.\",\n \"The lipid yield was 53.7 g/L; the omega-3 yield was 37 g/L; the EPA yield was 14.3 g/L; and the DHA yield was 21 g/L.\",\n \"The fatty acid content was 57% by weight; the EPA content was 27.7% of FAME; and the DHA content was 39.1% of FAME.\",\n \"The lipid productivity was 6.4 g/L/day, and the omega-3 productivity was 4.4 g/L/day under these conditions, with 1.7 g/L/day EPA productivity and 2.5 g/L/day DHA productivity.\",\n \"In carbon (glucose) and nitrogen-fed cultures with 1000 ppm Cl− at 22.5° C. at pH 7.5 with 20% dissolved oxygen during the nitrogen feed and 10% dissolved oxygen thereafter, PTA-10208 produced a dry cell weight of 56 g/L after 139 hours of culture in a 10 L fermentor volume.\",\n \"The lipid yield was 53 g/L; the omega-3 yield was 34 g/L; the EPA yield was 11.5 g/L; and the DHA yield was 22 g/L.\",\n \"The fatty acid content was 58% by weight; the EPA content was 21.7% of FAME; and the DHA content was 41.7% of FAME.\",\n \"The lipid productivity was 9.2 g/L/day, and the omega-3 productivity was 5.9 g/L/day under these conditions, with 2 g/L/day EPA productivity and 3.8 g/L/day DHA productivity.\",\n \"In carbon (glucose) and nitrogen-fed cultures with 1000 ppm Cl− at 22.5° C. at pH 7.0 with 20% dissolved oxygen during the nitrogen feed and 10% dissolved oxygen thereafter, PTA-10208 produced a dry cell weight of 93.8 g/L after 167 hours of culture in a 2000 L fermentor volume.\",\n \"The lipid yield was 47.2 g/L; the omega-3 yield was 33.1 g/L; the EPA yield was 10.5 g/L; and the DHA yield was 20.4 g/L.\",\n \"The fatty acid content was 50.6% by weight; the EPA content was 23% of FAME; and the DHA content was 42.6% of FAME.\",\n \"The lipid productivity was 6.8 g/L/day, and the omega-3 productivity was 4.7 g/L/day under these conditions, with 1.5 g/L/day EPA productivity and 2.9 g/L/day DHA productivity.\",\n \"In carbon (glucose) and nitrogen-fed cultures with 1000 ppm Cl− at 22.5° C. at pH 7.0 with 20% dissolved oxygen during the nitrogen feed and 10% dissolved oxygen thereafter, PTA-10208 produced a dry cell weight of 105 g/L after 168 hours of culture in a 2000 L fermentor volume.\",\n \"The lipid yield was 46.4 g/L; the omega-3 yield was 33 g/L; the EPA yield was 10.7 g/L; and the DHA yield was 20.3 g/L.\",\n \"The fatty acid content was 43.9% by weight; the EPA content was 24% of FAME; and the DHA content was 43.7% of FAME.\",\n \"The lipid productivity was 6.6 g/L/day, and the omega-3 productivity was 4.7 g/L/day under these conditions, with 1.5 g/L/day EPA productivity and 2.9 g/L/day DHA productivity.\",\n \"In carbon (glucose) and nitrogen-fed cultures with 1000 ppm Cl− at 22.5° C. at pH 7.0 with 20% dissolved oxygen during the nitrogen feed and 10% dissolved oxygen thereafter, PTA-10208 produced a dry cell weight of 64.8 g/L after 168 hours of culture in a 2000 L fermentor volume.\",\n \"The lipid yield was 38.7 g/L; the omega-3 yield was 29.9 g/L; the EPA yield was 8.5 g/L; and the DHA yield was 16.7 g/L.\",\n \"The fatty acid content was 59.6% by weight; the EPA content was 23% of FAME; and the DHA content was 42.3% of FAME.\",\n \"The lipid productivity was 5.53 g/L/day, and the omega-3 productivity was 3.8 g/L/day under these conditions, with 1.2 g/L/day EPA productivity and 2.3 g/L/day DHA productivity.\",\n \"Example 36 Fatty Acid Profiles of Microorganism Strains ATCC PTA-10208 and PTA-10212 Four samples of biomass (PTA-10208 Sample #1; PTA-10208 Sample #2; PTA-10212 Sample #1; and PTA-10212 Sample #2) were analyzed for total crude oil content by solvent extraction, lipid classes were determined by high performance liquid chromatography/evaporative light scattering detection (HPLC/ELSD), triacylglycerol (TAG) were analyzed by HPLC/mass spectrometry (HPLC/MS), and fatty acid (FA) profiles were determined by gas chromatography with flame ionization detection (GC-FID).\",\n \"The crude lipid content of each freeze dried biomass was determined using solvent grinding with hexane and compared to the sum of FAME (mg/g) generated by direct transesterification, and the resultant fatty acid methyl esters (FAME) were quantified by GC/FID analysis.\",\n \"Fatty acids in the extracted crude lipid were also quantified by transesterification and quantified using GC/FID analysis of the resultant FAME.\",\n \"The weight percent of all neutral lipids (NL) and free fatty acids (FFA) were determined in the extracted crude lipid using normal phase HPLC with ELSD and atmospheric pressure chemical ionization-MS (APCI-MS) identification.\",\n \"The method separates and quantifies sterol esters (SE), TAG, free fatty acids (FFA), 1,3-diacylglycerols (1,3-DAG), sterols, 1,2-diacylglycerols (1,2-DAG), and monoacylglycerols (MAG).\",\n \"Results are shown in Tables 32 and 33, below.\",\n \"It is noted that fatty acid profiles of Tables 32 and 33 were obtained from samples extracted using a solvent.\",\n \"The fatty acid profiles of Tables 32 and 33 are expected to be the substantially the same if the samples were extracted using the processes of the present invention.\",\n \"TAG and phospholipids (PL) were isolated from the crude oils extracted from the four samples of biomass (PTA-10208 Sample #1; PTA-10208 Sample #2; PTA-10212 Sample #1; and PTA-10212 Sample #2).\",\n \"TAG was isolated using low pressure flash chromatography and PL was isolated using solid phase extraction (SPE).\",\n \"The identity of each isolated fraction was confirmed by thin layer chromatography (TLC).\",\n \"The fatty acid profiles of the isolated TAG and PL fractions were determined following direct transesterification using GC-FID as FAME.\",\n \"Results are shown in Tables 34 and 35, below.\",\n \"The total crude oil content and fatty acid profiles of isolated lipid classes were also determined for two additional samples of biomass from microorganism strain ATCC PTA-10212 (PTA-10212 Sample #3 and PTA-10212 Sample #4).\",\n \"Crude oil was obtained from each sample by hexane extraction, and individual lipid classes were isolated using low pressure flash chromatography.\",\n \"The fatty acid profiles of the biomass, crude oil, and isolated fractions were determined using GC-FID as FAME.\",\n \"Results are shown in Tables 36-39, below.\",\n \"It is noted that fatty acid profiles of Tables 36-39 were obtained from samples extracted using a typical hexane extraction.\",\n \"The fatty acid profiles of Tables 36-39 are expected to be the substantially the same if the samples were extracted using the processes of the present invention.\",\n \"Individual lipid classes were isolated from a sample of crude oil from microorganism strain ATCC PTA-10212 (PTA-10212 Sample #5) previously extracted using the FRIOLEX® process, and the fatty acid profiles of each class were determined using GC-FID as FAME.\",\n \"Results are shown in Tables 40 and 41, below.\",\n \"It is noted that fatty acid profiles of Tables 40 and 41 were obtained from samples extracted using a FRIOLEX® process.\",\n \"The fatty acid profiles of Tables 40 and 41 are expected to be the substantially the same if the samples were extracted using the processes of the present invention.\",\n \"Individual lipid classes were isolated from a sample of crude oil from microorganism strain ATCC PTA-10208 (PTA-10208 Sample #3) using normal HPLC with ELSD and APCI-MS identification.\",\n \"Experimental Procedures Crude Oil Extraction— Crude oil was extracted from samples of freeze-dried biomass using solvent grinding.\",\n \"For example, approximately 3 grams of biomass was weighed into a Swedish tube.\",\n \"Three ball bearings and 30 mL of hexane were added to the Swedish tube, which was sealed with a neoprene stopper and placed in a shaker for 2 hours.\",\n \"The resultant slurry was filtered using a Buchner funnel and Whatman filter paper.\",\n \"The filtered liquid was collected, the solvent removed under vacuum, and the amount of remaining crude lipid determined gravimetrically.\",\n \"Fatty Acid Analysis— The samples of biomass, extracted crude lipid, and isolated lipid classes were analyzed for fatty acid composition as FAME.\",\n \"Briefly, freeze-dried biomass and isolated lipid classes were weighed directly into a screw cap test tubes, while samples of the crude oil were dissolved in hexane to give a concentration of approximately 2 mg/mL.\",\n \"Toluene, containing internal standard, and 1.5 N HCl in methanol was added to each tube.\",\n \"The tubes were vortexed, then capped and heated to 100° C. for 2 hours.\",\n \"The tubes were allowed to cool, and saturated NaCl in water was added.\",\n \"The tubes were vortexed again and centrifuged to allow the layers to separate.\",\n \"A portion of the organic layer was then placed in a GC vial and analyzed by GC-FID.\",\n \"FAME was quantified using a 3-point calibration curve generated using Nu-Check-Prep GLC Reference Standard (NuCheck, Elysian, Minn.).\",\n \"Fatty acids present in the extract were expressed as mg/g and as a weight percent.\",\n \"Fat content in the samples was estimated assuming equal response to the internal standard when analyzed by GC-FID.\",\n \"HPLC/ELSD/MS Method— Instrument Agilent 1100 HPLC, Alltech 3300 ELSD, Agilent 1100 MSD Column Phenomenex Luna Silica, 250 × 4.6 mm, 5 μm particle size w/Guard Column Mobile Phase A - 99.5% Hexanes (Omnisolv) 0.4% Isopropyl alcohol (Omnisolv) 0.1% Acetic Acid B - 99.9% Ethanol (Omnisolv, 95:5 Ethanol:IPA) 0.1% Acetic Acid Gradient Time, min.\",\n \"% A % B 0 100 0 5 100 0 15 85 10 20 0 100 25 0 100 26 100 0 35 100 0 Column Temp.\",\n \"30° C. Flow Rate 1.5 mL/min Injection Volume 5 μL ELSD Detection Temperature 35° C., Gas flow 1.2 L/min MSD Mass Range 200-1200, Fragmentor 225 V Drying Gas Temperature 350° C. Vaporizer Temperature 325° C. Capillary Voltage 3500 V Corona Current 10 μA Solid Phase Extraction— PL fractions were separated from the crude lipid by solid phase extraction (SPE) using 2 g aminopropyl cartridges (Biotage, Uppsala, Sweden) placed in a Vac Elut apparatus (Varian Inc, Palo Alto, USA).\",\n \"The cartridge was conditioned with 15 mL of hexane, and ˜60 mg of each sample was dissolved in 1 mL CHCl3 and applied to the cartridge.\",\n \"The column was washed with 15 mL of 2:1 CHCl3:isopropyl alcohol to elute all the neutral lipids, which was discarded.\",\n \"The fatty acids were then eluted with 15 mL of 2% acetic acid (HOAc) in ether, which was discarded.\",\n \"The PL portion was eluted with 15 mL of 6:1 Methanol:Chloroform, which was collected, dried under nitrogen, and weighed.\",\n \"Flash Chromatography— Flash chromatography was used to separate the lipid classes present in the crude oil.\",\n \"Approximately 200 mg of crude oil dissolved in hexane was injected onto the head of the column.\",\n \"The chromatography system utilized Silica Gel 60 (EMD Chemical, Gibbstown, N.J.) with mobile phase composed of Petroleum Ether and Ethyl Acetate at 5 mL/min (Tables 6-7) or 3 mL/min (Tables 8-13).\",\n \"A step gradient was used to selectively elute each lipid class from the column.\",\n \"The mobile phase gradient started from 100% petroleum ether and finished with 50% ethyl acetate.\",\n \"Fractions were collected in 10 mL test tubes using a Gilson FC 204 large-bed fraction collector (Gilson, Inc., Middleton, Wis.).\",\n \"Each tube was analyzed by thin layer chromatography (TLC) and the tubes containing individual lipid classes (as judged by single spots on TLC plate with expected retention factor (Rf)) were pooled, concentrated to dryness, and weighed.\",\n \"The total fraction content was then determined gravimetrically.\",\n \"TLC Analysis— Thin layer chromatography was conducted on silica gel plates.\",\n \"The plates were eluted using a solvent system consisting of petroleum ether:ethyl ether:acetic acid (80:20:1) and were visualized using iodine vapor.\",\n \"The Rf values of each spot were then compared with reported literature values for each lipid class.\",\n \"Analysis of TAG and PL Fractions— The isolated TAG and PL fractions were analyzed for fatty acid composition as fatty acid methyl esters (FAME).\",\n \"The TAG fractions were dissolved in hexane to give a concentration of approximately 1-2 mg/mL.\",\n \"1 mL aliquots of the solutions were concentrated to dryness under nitrogen.\",\n \"Toluene, containing internal standard, and 1.5 N HCl in methanol was added to each tube.\",\n \"The tubes were vortexed, then capped and heated to 100° C. for 2 hours.\",\n \"Internal standard and HCl methanol were added directly to the tubes containing the PL fraction and heated.\",\n \"The tubes were allowed to cool, and saturated NaCl in water was added.\",\n \"The tubes were vortexed again and centrifuged to allow the layers to separate.\",\n \"A portion of the organic layer was then placed in a GC vial and analyzed by GC-FID.\",\n \"FAMEs were quantified using a 3-point calibration curve generated using Nu-Check-Prep GLC 502B Reference Standard (NuCheck, Elysian, Minn.).\",\n \"Fatty acids present in the extract were expressed as mg/g and as a % of FAME.\",\n \"Results PTA-10208 Sample #1 The fatty acid profile of the biomass and extracted crude lipid for PTA-10208 Sample #1 was determined using GC/FID.\",\n \"Fatty acids in the biomass were transesterified in situ by weighing 28.6 mg of biomass directly into a FAME tube, while a sample of the extracted crude lipid was prepared by weighing 55.0 mg of crude lipid into a 50 mL volumetric flask and transferring 1 ml to a separate FAME tube.\",\n \"The estimated crude lipid content of the biomass was determined to be 53.2% (as SUM of FAME) using GC with FID detection, while 52.0% (wt/wt) lipid was extracted from the dry biomass, giving a 97.8% recovery of total lipid.\",\n \"The crude lipid was determined to be 91.9% fatty acids (as SUM of FAME) using GC/FID.\",\n \"The major fatty acids contained in the crude lipid were C16:0 (182.5 mg/g), C20:5 n-3 (186.8 mg/g), and C22:6 n-3 (423.1 mg/g).\",\n \"The lipid class profile of the extracted crude lipid was determined by weighing 55.0 mg of crude lipid into a 50 mL volumetric flask and transferring an aliquot into an HPLC vial for HPLC/ELSD/MS analysis.\",\n \"According to the HPLC/ELSD/MS analysis, the crude lipid contained 0.2% sterol esters (SE), 95.1% TAG, 0.4% sterols, and 0.5% 1,2-diacylglycerol (DAG).\",\n \"5% of the TAG fraction included a peak that eluted directly after the TAG peak, but did not give a recognizable mass spectrum.\",\n \"Isolated TAG from this sample as determined by flash chromatography made up approximately 92.4% of the crude oil.\",\n \"PL was not detected by weight or TLC after SPE isolation.\",\n \"The major fatty acids (>50 mg/g) contained in the TAG were C16:0 (189 mg/g), C20:5 n-3 (197 mg/g), and C22:6 n-3 (441 mg/g).\",\n \"PTA-10208 Sample #2 The fatty acid profile of the biomass and extracted crude lipid for PTA-10208 Sample #2 was determined using GC/FID.\",\n \"Fatty acids in the biomass were transesterified in situ by weighing 32.0 mg of biomass directly into a FAME tube, while a sample of the extracted crude lipid was prepared by weighing 60.1 mg of crude lipid into a 50 mL volumetric flask and transferring 1 ml to a separate FAME tube.\",\n \"The estimated crude lipid content of the biomass was determined to be 52.4% (as SUM of FAME) using GC with FID detection, while 48.0% (wt/wt) lipid was extracted from the dry biomass, giving a 91.7% recovery of total lipid.\",\n \"The crude lipid was determined to be 95.3% fatty acids (as SUM of FAME) using GC/FID.\",\n \"The major fatty acids contained in the crude lipid were C16:0 (217.5 mg/g), C20:5 n-3 (169.3 mg/g), and C22:6 n-3 (444.1 mg/g).\",\n \"The lipid class profile of the extracted crude lipid was determined by weighing 60.1 mg of crude lipid into a 50 mL volumetric flask and transferring an aliquot into an HPLC vial for HPLC/ELSD/MS analysis.\",\n \"According to the HPLC/ELSD/MS analysis, the crude lipid contained 0.2% SE, 95.7% TAG, 0.3% sterols, and 0.7% 1,2-DAG.\",\n \"5.1% of the TAG fraction included a peak that eluted directly after the TAG peak, but did not give a recognizable mass spectrum.\",\n \"Isolated TAG from this sample made up approximately 93.9% of the crude oil.\",\n \"PL was not detected by weight or TLC after SPE isolation.\",\n \"The major fatty acids (>50 mg/g) contained in the TAG were C16:0 (218 mg/g), C20:5 n-3 (167 mg/g) and C22:6 n-3 (430 mg/g).\",\n \"PTA-10208 Sample #3 A sample of crude oil from the microorganism deposited under ATCC Accession No.\",\n \"PTA-10208 (Sample PTA-10208 #3) was analyzed using HPLC/ELSD/MS.\",\n \"A total of 98.38% of lipids were recovered, with the sterol ester (SE) fraction accounting for 0.32%, the TAG fraction accounting for 96.13%, the 1,3-diacylglycerol (DAG) fraction accounting for 0.22%, the 1,2-DAG fraction accounting for 0.78%, and the sterol fraction accounting for 0.93%.\",\n \"PTA-10212 Sample #1 The fatty acid profile of the biomass and extracted crude lipid for PTA-10212 Sample #1 was determined using GC/FID.\",\n \"Fatty acids in the biomass were transesterified in situ by weighing 27.0 mg of biomass directly into a FAME tube, while a sample of the extracted crude lipid was prepared by weighing 52.5 mg of crude lipid into a 50 mL volumetric flask and transferring 1 ml to a separate FAME tube.\",\n \"The estimated crude lipid content of the biomass was determined to be 38.3% (as SUM of FAME) using GC with FID detection, while 36.3% (wt/wt) lipid was extracted from the dry biomass, giving a 94.6% recovery of total lipid.\",\n \"The crude lipid was determined to be 83.2% fatty acids (as SUM of FAME) using GC/FID.\",\n \"The major fatty acids contained in the crude lipid were C16:0 (328.5 mg/g), C20:5 n-3 (90.08 mg/g), and C22:6 n-3 (289.3 mg/g).\",\n \"The lipid class profile of the extracted crude lipid was determined by weighing 52.5 mg of crude lipid into a 50 mL volumetric flask and transferring an aliquot into an HPLC vial for HPLC/ELSD/MS analysis.\",\n \"According to the HPLC/ELSD/MS analysis, the crude lipid contained 0.2% SE, 64.2% TAG, 1.9% FFA, 2.8% 1,3-DAG, 1.4% sterols, 18.8% 1,2-DAG, and 0.5% MAG.\",\n \"3.4% of the TAG fraction included a peak that eluted directly after the TAG peak, but did not give a recognizable mass spectrum.\",\n \"Isolated TAG from this sample made up approximately 49.8% of the crude oil.\",\n \"Isolated PL made up approximately 8.1% of the crude oil.\",\n \"The major fatty acids (>50 mg/g) contained in the TAG fraction are C16:0 (400 mg/g), C20:5 n-3 (91 mg/g), and C22:6 n-3 (273 mg/g).\",\n \"The major fatty acids (>50 mg/g) contained in the PL fraction are C16:0 (98 mg/g), C20:5 n-3 (33 mg/g), and C22:6 n-3 (227 mg/g).\",\n \"PTA-10212 Sample #2 The fatty acid profile of the biomass and extracted crude lipid PTA-10212 Sample #2 was determined using GC/FID.\",\n \"Fatty acids in the biomass were transesterified in situ by weighing 29.5 mg of biomass directly into a FAME tube, while a sample of the extracted crude lipid was prepared by weighing 56.5 mg of crude lipid into a 50 mL volumetric flask and transferring 1 ml to a separate FAME tube.\",\n \"The estimated crude lipid content of the biomass was determined to be 40.0% (as SUM of FAME) using GC with FID detection, while 41.3% (wt/wt) lipid was extracted from the dry biomass, giving a 106.1% recovery of total lipid.\",\n \"The crude lipid was determined to be 82.8% fatty acids (as SUM of FAME) using GC/FID.\",\n \"The major fatty acids contained in the crude lipid were C16:0 (327.3 mg/g), C20:5 n-3 (92.5 mg/g), and C22:6 11-3 (277.6 mg/g).\",\n \"The lipid class profile of the extracted crude lipid was determined by weighing 56.5 mg of crude lipid into a 50 mL volumetric flask and transferring an aliquot into an HPLC vial for HPLC/ELSD/MS analysis.\",\n \"According to the HPLC/ELSD/MS analysis, the crude lipid contained 0.2% SE, 58.2% TAG, 2.3% FFA, 3.4% 1,3-DAG, 1.7% sterols, 23.4% 1,2-DAG, and 0.6% MAG.\",\n \"3.3% of the TAG fraction included a peak that eluted directly after the TAG peak, but did not give a recognizable mass spectrum.\",\n \"Isolated TAG from this sample made up approximately 51.9% of the crude oil.\",\n \"Isolated PL made up approximately 8.8% of the crude oil.\",\n \"The major fatty acids (>50 mg/g) contained in the TAG fraction are C16:0 (402 mg/g), C20:5 n-3 (92 mg/g), and C22:6 n-3 (245 mg/g).\",\n \"The major fatty acids (>50 mg/g) contained in the PL fraction are C16:0 (121 mg/g), C20:5 n-3 (48 mg/g), and C22:6 n-3 (246 mg/g).\",\n \"TABLE 32 Fatty Acid Profiles of PTA-10208 and PTA-10212 Biomasses and Extracted Crude Lipids (mg/g) PTA- PTA- PTA- PTA- PTA- 10208 PTA- 10208 PTA- 10212 PTA- 10212 10208 Sample 10208 Sample 10212 Sample 10212 Sample Sample #1 Sample #2 Sample #1 Sample #2 #1 Crude #2 Crude #1 Crude #2 Crude Biomass Lipid Biomass Lipid Biomass Lipid Biomass Lipid Fatty FAME FAME FAME FAME FAME FAME FAME FAME Acid (mg/g) mg/g) (mg/g) (mg/g) (mg/g (mg/g (mg/g (mg/g) C12:0 1.47 2.43 1.80 3.14 0.99 1.90 0.87 1.91 C14:0 11.62 20.12 16.72 31.03 5.51 12.91 5.97 13.69 C14:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 C15:0 2.43 3.75 3.60 6.22 9.13 20.42 9.39 20.81 C16:0 105.04 182.47 117.72 217.49 145.87 328.45 147.87 327.27 C16:1 0.00 0.00 0.06 0.01 6.26 14.53 7.46 16.89 C18:0 5.37 8.96 4.77 8.37 6.77 15.39 6.77 15.15 C18:1 0.00 3.26 0.00 3.09 0.03 4.04 0.08 5.87 n-9 C18:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-7 C18:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 C20:0 1.48 1.79 1.40 1.85 1.60 3.09 1.67 3.20 C18:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-3 C20:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 C18:4 0.91 1.61 1.10 2.00 2.28 2.56 2.21 2.64 n-3 C20:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 C20:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 C22:0 0.10 0.00 0.08 0.00 0.30 0.12 0.35 0.24 C20:4 0.81 0.45 0.67 0.41 0.00 0.00 0.00 0.00 n-7 C20:4 7.22 12.23 6.84 12.18 1.19 2.26 1.31 2.32 n-6 C22:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 C20:4 0.63 0.52 0.00 0.46 0.00 0.00 0.00 0.00 n-5 C20:4 3.45 5.45 3.33 5.58 0.00 2.40 0.00 2.34 n-3 C20:3 0.09 0.00 0.11 0.00 0.00 0.00 0.00 0.00 n-3 C20:5 107.31 186.83 92.99 169.32 40.32 90.08 43.15 92.54 n-3 C22:4 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 C24:0 0.60 0.00 0.52 0.00 2.81 6.83 2.74 6.53 C24:1 1.55 3.26 0.85 2.04 0.43 1.34 0.42 1.24 n-9 C22:5 9.66 15.84 10.27 17.98 2.42 4.68 2.32 4.21 n-6 C22.5 20.44 35.13 9.92 17.50 2.41 4.94 2.69 5.23 n-3 C22:6 246.98 423.10 245.96 444.08 139.58 289.34 137.35 277.57 n-3 Sum 527.15 907.18 518.71 942.75 367.89 805.29 372.63 799.68 of FAME TABLE 33 Fatty Acid Profiles of PTA-10208 and PTA-10212 Biomasses and Extracted Crude Lipids (%) PTA- PTA- PTA- PTA- PTA- 10208 PTA- 10208 PTA- 10212 PTA- 10212 10208 Sample 10208 Sample 10212 Sample 10212 Sample Sample #1 Sample #2 Sample #1 Sample #2 #1 Crude #2 Crude #1 Crude #2 Crude Biomass Lipid Biomass Lipid Biomass Lipid Biomass Lipid Fatty % % % % % % % % Acid FAME FAME FAME FAME FAME FAME FAME FAME C12:0 0.28 0.27 0.35 0.33 0.27 0.24 0.23 0.24 C14:0 2.20 2.22 3.22 3.29 1.50 1.60 1.60 1.71 C14:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 C15:0 0.46 0.41 0.69 0.66 2.48 2.54 2.52 2.60 C16:0 19.93 20.11 22.70 23.07 39.65 40.79 39.68 40.93 C16:1 0.00 0.00 0.01 0.00 1.70 1.80 2.00 2.11 C18:0 1.02 0.99 0.92 0.89 1.84 1.91 1.82 1.89 C18:1 0.00 0.36 0.00 0.33 0.01 0.50 0.02 0.73 n-9 C18:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-7 C18:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 C20:0 0.28 0.20 0.27 0.20 0.43 0.38 0.45 0.40 C18:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-3 C20:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 C18:4 0.17 0.18 0.21 0.21 0.62 0.32 0.59 0.33 n-3 C20:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 C20:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 C22:0 0.02 0.00 0.01 0.00 0.08 0.02 0.09 0.03 C20:4 0.15 0.05 0.13 0.04 0.00 0.00 0.00 0.00 n-7 C204 1.37 1.35 1.32 1.29 0.32 0.28 0.35 0.29 n-6 C22:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 C20:4 0.12 0.06 0.00 0.05 0.00 0.00 0.00 0.00 n-5 C20:4 0.65 0.60 0.64 0.59 0.00 0.30 0.00 0.29 n-3 C20:3 0.02 0.00 0.02 0.00 0.00 0.00 0.00 0.00 n-3 C20:5 20.36 20.59 17.93 17.96 10.96 11.19 11.58 11.57 n-3 C22:4 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 C24:0 0.11 0.00 0.10 0.00 0.76 0.85 0.74 0.82 C24:1 0.29 0.36 0.16 0.22 0.12 0.17 0.11 0.16 n-9 C22:5 1.83 1.75 1.98 1.91 0.66 0.58 0.62 0.53 n-6 C22:5 3.88 3.87 1.91 1.86 0.65 0.61 0.72 0.65 n-3 C22:6 46.85 46.64 47.42 47.10 37.94 35.93 36.86 34.71 n-3 Sum 100 100 100 100 100 100 100 100 of FAME % TABLE 34 Fatty Acid Profiles of PTA-10208 and PTA-10212 Isolated TAG PTA- PTA- PTA- PTA- PTA- PTA- PTA- PTA- 10208 10208 10208 10208 10212 10212 10212 10212 Sample Sample Sample Sample Sample Sample Sample Sample #1 #1 #2 #2 #1 #1 #2 #2 Fatty FAME % FAME % FAME % FAME % Acid (mg/g) FAME (mg/g) FAME (mg/g) FAME (mg/g) FAME C12:0 2.57 0.27 3.35 0.36 0,00 0.00 0.00 0.00 C14:0 21.07 2.23 31.37 3.41 14.05 1,61 14.45 1.69 C14:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 C15:0 3.89 0.41 6.17 0.67 23.27 2.66 23.14 2.71 C16:0 189.28 20.07 218.78 23.75 399.51 45.75 402.43 47.07 C16:1 0.00 0.00 0.00 0.00 15.23 1.74 17.62 2.06 C18:0 9.21 0.98 8.07 0.88 22.70 2.60 23.10 2.70 C18:1 3.35 0.36 3.64 0.40 6.12 0.70 7.48 0.87 n-9 C18:1 0.00 0.00 0.00 0.00 <0.1 <0.1 <0.1 <0.1 n-7 C18:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 C20:0 1.86 0.20 1.55 0.17 4.76 0.55 5.32 0.62 C18:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-3 C20:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 C18:4 1.64 0.17 2.00 0.22 2.25 0.26 2.24 0.26 n-3 C20:2 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 C20:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-6 C22:0 0.00 0.00 0.00 0.00 0.55 0.06 0.89 0.10 Un- 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 known C20:4 0.39 0.04 0.05 0.01 0.00 0.00 0.00 0.00 n-7 C20:3 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-3 C20:4 12.79 1.36 11.82 1.28 2.33 0.27 2.25 0.26 n-6 C22:1 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 C20:4 0.39 0.04 0.07 0.01 0.00 0.00 0.00 0.00 n-5 C20:4 5.52 0.59 5.09 0.55 2.87 0.33 2.98 0.35 n-3 C20:5 197.14 20.90 166.68 18.10 91.17 10.44 91.78 10.74 n-3 C24:0 0.00 0.00 0.00 0.00 6.93 0.79 7.36 0.86 C22:4 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 n-9 C24:1 1.08 0.11 <0.1 <0.1 0.00 0.00 0.00 0.00 n-9 C22:5 15.88 1.68 16.57 1.80 4.01 0.46 3.39 0.40 n-6 C22:5 36.05 3.82 16.00 1.74 4.53 0.52 5.07 0.59 n-3 C22:6 440.99 46.76 429.83 46.67 273.02 31.26 245.38 28.70 n-3 Sum 943.11 — 921.03 — 873.31 — 854.89 — of FAME Total — 100.00 — 100.00 — 100.00 — 100.00 % FAME TABLE 35 Fatty Acid Profiles of PTA-10212 Isolated PL PTA-10212 PTA-10212 PTA-10212 PTA-10212 Sample # 1 Sample #1 Sample #2 Sample #2 Fatty Acid FAME (mg/g) % FAME FAME (mg/g) % FAME C12:0 0.00 0.00 0.00 0.00 C14:0 0.93 0.22 1.89 0.39 C14:1 0.00 0.00 0.00 0.00 C15:0 3.44 0.82 5.07 1.05 C16:0 98.29 23.50 120.98 25.00 C16:1 1.15 0.27 3.07 0.63 C18:0 3.25 0.78 3.72 0.77 C18:1 n-9 1.12 0.27 0.95 0.20 C18:1 n-7 <0.1 <0.1 0.02 0.003 C18:2 n-6 0.00 0.00 0.00 0.00 C20:0 <0.1 <0.1 <0.1 <0.1 C18:3 n-3 0.00 0.00 0.00 0.00 C20:1 n-9 0.00 0.00 0.00 0.00 C18:4 n-3 3.71 0.89 3.24 0.67 C20:2 n-6 0.00 0.00 0.00 0.00 C20:3 n-6 0.00 0.00 0.00 0.00 C22:0 0.00 0.00 0.00 0.00 Unknown 42.33 10.12 44.71 9.24 C20:4 n-7 0.00 0.00 0.00 0.00 C20:3 n-3 0.00 0.00 0.00 0.00 C20:4 n-6 0.84 0.20 1.54 0.32 C22:1 n-9 0.00 0.00 0.00 0.00 C20:4 n-5 0.00 0.00 0.00 0.00 C20:4 n-3 <0.1 <0.1 0.27 0.06 C20:5 n-3 33.39 7.98 47.91 9.90 C24:0 0.1 <0.1 0.01 0.001 C22:4 n-9 0.00 0.00 0.00 0.00 C24:1 n-9 0.00 0.00 0.00 0.00 C22:5 n-6 3.08 0.74 3.82 0.79 C22:5 n-3 <0.1 <0.1 0.66 0.14 C22:6 n-3 226.68 54.20 246.09 50.85 Sum of 418.21 — 483.94 — FAME Total % — 100 — 100 FAME PTA-10212 Sample #3 The lipid content of the biomass for PTA-10212 Sample #3 was estimated to be 34% as the sum of FAME, and the amount of crude oil obtained after solvent extraction was 37% by weight, giving a 109% recovery of fat present in the biomass.\",\n \"After fractionation using flash chromatography, approximately 46% of the crude oil was isolated as TAG, 28% was isolated as DAG.\",\n \"The crude oil contained 309 mg/g DHA and 264 mg/g EPA.\",\n \"The isolated TAG contained 341 mg/g DHA and 274 mg/g EPA.\",\n \"The isolated DAG fraction contained 262 mg/g DHA and 237 mg/g EPA.\",\n \"The total fatty acid profiles of the biomass, extracted crude oil, and isolated fractions are shown below in Table 36 and Table 37 calculated as mg/g and % FAME, respectively.\",\n \"TABLE 36 Fatty Acid Profiles of PTA-10212 Sample #3 Biomass and Extracted Crude Lipid (mg/g) Crude Biomass Oil TAG DAG Wt.\",\n \"% NA 37.2% 46.0% 27.9% FAME FAME FAME FAME Fatty Acid (mg/g) (mg/g) (mg/g) (mg/g) C12:0 0.0 0.0 0.0 0.0 C14:0 3.6 10.3 11.5 9.4 C14:1 0.0 0.0 0.0 0.0 C15:0 4.1 10.6 9.8 6.6 C16:0 70.5 181.8 231.7 111.3 C16:1 6.7 19.1 18.7 17.1 C18:0 2.4 10.2 14.2 0.0 C18:1 n-9 0.0 6.7 0.0 0.0 C18:1 n-7 0.0 1.2 0.0 0.0 C18:2 n-6 0.0 1.8 0.0 0.0 C20:0 0.0 2.4 0.0 0.0 C18:3 n-3 0.0 0.0 0.0 0.0 C20:1 n-9 0.0 0.3 0.0 1.7 C18:4 n-3 1.9 3.4 3.2 4.4 C20:2 n-6 0.0 0.0 0.0 0.0 C20:3 n-6 0.0 0.0 0.0 0.0 C22:0 3.3 0.0 0.0 0.0 C20:4 n-7 0.0 2.1 1.5 0.0 C20:3 n-3 0.0 0.0 0.0 0.0 C20:4 n-6 6.8 17.9 21.4 13.8 C22:1 n-9 0.0 0.0 0.0 0.0 C20:4 n-5 0.0 1.3 1.3 0.0 C20:4 n-3 3.0 8.5 10.9 6.4 C20:5 n-3 102.0 263.6 274.2 237.4 C24:0 0.0 1.7 3.9 0.0 C22:4 n-9 0.0 0.0 0.0 0.0 C24:1 n-9 0.0 0.0 4.2 0.0 C22:5 n-6 3.2 8.3 10.7 6.1 C22:5 n-3 3.8 10.4 15.1 6.6 C22:6 n-3 131.2 309.4 341.1 261.9 Sum of FAME 342.4 871.1 973.2 682.6 TABLE 37 Fatty Acid Profiles of PTA-10212 Sample #3 Biomass and Extracted Crude Lipid (%) Crude Biomass Oil TAG DAG Wt.\",\n \"% NA 37.2% 46.0% 27.9% FAME FAME FAME FAME Fatty Acid (mg/g) (mg/g) (mg/g) (mg/g) C12:0 0.0 0.0 0.0 0.0 C14:0 1.1 1.2 1.2 1.4 C14:1 0.0 0.0 0.0 0.0 C15:0 1.2 1.2 1.0 1.0 C16:0 20.6 20.9 23.8 16.3 C16:1 2.0 2.2 1.9 2.5 C18:0 0.7 1.2 1.5 0.0 C18:1 n-9 0.0 0.8 0.0 0.0 C18:1 n-7 0.0 0.1 0.0 0.0 C18:2 n-6 0.0 0.2 0.0 0.0 C20:0 0.0 0.3 0.0 0.0 C18:3 n-3 0.0 0.0 0.0 0.0 C20:1 n-9 0.0 0.0 0.0 0.2 C18:4 n-3 0.6 0.4 0.3 0.6 C20:2 n-6 0.0 0.0 0.0 0.0 C20:3 n-6 0.0 0.0 0.0 0.0 C22:0 1.0 0.0 0.0 0.0 C20:4 n-7 0.0 0.2 0.2 0.0 C20:3 n-3 0.0 0.0 0.0 0.0 C20:4 n-6 2.0 2.1 2.2 2.0 C22:1 n-9 0.0 0.0 0.0 0.0 C20:4 n-5 0.0 0.1 0.1 0.0 C20:4 n-3 0.9 1.0 1.1 0.9 C20:5 n-3 29.8 30.3 28.2 34.8 C24:0 0.0 0.2 0.4 0.0 C22:4 n-9 0.0 0.0 0.0 0.0 C24:1 n-9 0.0 0.0 0.4 0.0 C22:5 n-6 0.9 1.0 1.1 0.9 C22:5 n-3 1.1 1.2 1.6 1.0 C22:6 n-3 38.3 35.5 35.1 38.4 Total % FAME 100.0 100.0 100.0 100.0 PTA-10212 Sample #4 PTA-10212 Sample #4 contained approximately 23% lipid determined as the sum of FAME, of which 107% was recovered using hexane extraction.\",\n \"After fractionation using flash chromatography, approximately 42% of the crude oil was isolated as TAG, 18% was isolated as DAG.\",\n \"The crude oil contained 275 mg/g DHA and 209 mg/g EPA.\",\n \"The isolated TAG contained 296 mg/g DHA and 205 mg/g EPA.\",\n \"The isolated DAG fraction contained 245 mg/g DHA and 219 mg/g EPA.\",\n \"The total fatty acid profiles of the biomass, extracted crude oil, and isolated fractions are shown below in Table 38 (mg/g) and Table 39 (% FAME).\",\n \"TABLE 38 Fatty Acid Profiles of PTA-10212 Sample #4 Biomass and Extracted Crude Lipid (mg/g) Crude Biomass Oil TAG DAG Wt.\",\n \"% NA 24.7% 42.2% 18.4% FAME FAME FAME FAME Fatty Acid (mg/g) (mg/g) (mg/g) (mg/g) C12:0 0.0 0.0 2.1 2.4 C14:0 2.0 8.3 9.8 9.6 C14:1 0.0 0.0 0.0 0.0 C15:0 4.8 16.8 0.4 0.9 C16:0 63.3 210.6 285.7 138.0 C16:1 1.6 6.7 7.4 7.5 C18:0 2.8 12.2 19.9 4.6 C18:1 n-9 0.0 3.7 0.7 1.1 C18:1 n-7 0.0 0.0 0.3 1.2 C18:2 n-6 0.0 0.0 0.0 0.0 C20:0 0.0 3.3 6.0 1.5 C18:3 n-3 0.0 0.0 0.0 0.0 C20:1 n-9 0.0 0.0 0.7 1.2 C18:4 n-3 1.4 3.8 3.6 5.0 C20:2 n-6 0.0 0.0 0.0 0.0 C20:3 n-6 0.0 0.0 0.4 0.0 C22:0 1.5 0.0 1.9 0.0 C20:4 n-7 0.0 0.0 0.9 0.6 C20:3 n-3 0.0 0.0 0.0 0.0 C20:4 n-6 2.5 10.1 13.0 10.3 C22:1 n-9 0.0 0.0 0.0 0.0 C20:4 n-5 0.0 0.0 0.8 0.7 C20:4 n-3 1.4 6.3 8.6 6.0 C20:5 n-3 57.6 209.1 205.4 219.0 C24:0 0.0 2.6 0.8 0.0 C22:4 n-9 0.1 0.0 0.0 0.0 C24:1 n-9 0.0 0.0 1.1 0.5 C22:5 n-6 1.4 6.1 7.9 4.5 C22:5 n-3 4.0 15.8 20.8 12.9 C22:6 n-3 87.7 275.0 296.4 244.8 Sum of FAME 232.2 790.1 894.8 672.4 TABLE 39 Fatty Acid Profiles of PTA-10212 Sample #4 Biomass and Extracted Crude Lipid (%) Crude Biomass Oil TAG DAG Wt.\",\n \"% NA 24.7% 42.2% 18.4% FAME FAME FAME FAME Fatty Acid (mg/g) (mg/g) (mg/g) (mg/g) C12:0 0.0 0.0 0.2 0.4 C14:0 0.9 1.0 1.1 1.4 C14:1 0.0 0.0 0.0 0.0 C15:0 2.1 2.1 0.0 0.1 C16:0 27.3 26.7 31.9 20.5 C16:1 0.7 0.8 0.8 1.1 C18:0 1.2 1.5 2.2 0.7 C18:1 n-9 0.0 0.5 0.1 0.2 C18:1 n-7 0.0 0.0 0.0 0.2 C18:2 n-6 0.0 0.0 0.0 0.0 C20:0 0.0 0.4 0.7 0.2 C18:3 n-3 0.0 0.0 0.0 0.0 C20:1 n-9 0.0 0.0 0.1 0.2 C18:4 n-3 0.6 0.5 0.4 0.7 C20:2 n-6 0.0 0.0 0.0 0.0 C20:3 n-6 0.0 0.0 0.0 0.0 C22:0 0.6 0.0 0.2 0.0 C20:4 n-7 0.0 0.0 0.1 0.1 C20:3 n-3 0.0 0.0 0.0 0.0 C20:4 n-6 1.1 1.3 1.5 1.5 C22:1 n-9 0.0 0.0 0.0 0.0 C20:4 n-5 0.0 0.0 0.1 0.1 C20:4 n-3 0.6 0.8 1.0 0.9 C20:5 n-3 24.8 26.5 23.0 32.6 C24:0 0.0 0.3 0.1 0.0 C22:4 n-9 0.0 0.0 0.0 0.0 C24:1 n-9 0.0 0.0 0.1 0.1 C22:5 n-6 0.6 0.8 0.9 0.7 C22:5 n-3 1.7 2.0 2.3 1.9 C22:6 n-3 37.8 34.8 33.1 36.4 Total % FAME 100.0 100.0 100.0 100.0 PTA-10212 Sample #5 A sample of crude oil was extracted from a biomass of PTA-10212 using the FRIOLEX® process (GEA Westfalia Separator UK Ltd., Milton Keynes, England) to yield microbial oil PTA-10212 Sample #5.Individual lipid classes were isolated from PTA-10212 Sample #5 using low pressure flash chromatography, and the weight percent of each class was determined.\",\n \"The fatty acid profile of each class was determined using GC-FID.\",\n \"Briefly, the sample was prepared by dissolving 240 mg of crude oil in 600 μL of hexane and applying to the head of the column.\",\n \"After fractionation of the sample using flash chromatography, the combined weights of all the fractions was 240 mg giving a 100% recovery.\",\n \"The sterol ester fraction accounted for 0.9%, the TAG fraction accounted for 42.6%, the free fatty acid (FFA) fraction accounted for 1.3%, the sterol fraction accounted for 2.2%, and the DAG fraction accounted for 41.6%.\",\n \"The total fatty acid profiles of the FRIOLEX® crude oil and isolated fractions are shown below in Table 40 and Table 41 calculated as mg/g and % FAME, respectively.\",\n \"TABLE 40 Fatty Acid Profiles of PTA-10212 Sample #5 Crude Oil (mg/g) Crude Oil TAG DAG Wt.\",\n \"% NA 42.6% 41.6% FAME FAME FAME Fatty Acid (mg/g) (mg/g) (mg/g) C12:0 0 0.7 1.0 C14:0 7.7 7.7 8.5 C14:1 0 0.0 0.0 C15:0 10.3 11.7 9.3 C16:0 179.3 217.7 134.6 C16:1 18.1 16.3 25.9 C18:0 8.1 13.2 2.3 C18:1 n-9 4.7 8.4 0.7 C18:1 n-7 0 1.8 1.0 C18:2 n-6 1.8 3.3 0.7 C20:0 1.9 3.6 0.2 C18:3 n-3 0 0.0 0.0 C20:1 n-9 0 0.7 1.0 C18:4 n-3 3.1 2.8 3.8 C20:2 n-6 0 0.0 0.0 C20:3 n-6 0 0.6 0.4 C22:0 0 1.5 0.0 C20:4 n-7 0 1.0 0.7 C20:3 n-3 0 0.0 0.0 C20:4 n-6 12.7 16.1 13.6 C22:1 n-9 0 0.0 0.0 C20:4 n-5 0 1.5 0.8 C20:4 n-3 6.5 9.3 6.4 C20:5 n-3 213.3 223.7 252.8 C24:0 2.3 4.4 0.6 C22:4 n-9 0 1.9 0.9 C24:1 n-9 0 0.0 0.0 C22:5 n-6 7.9 9.5 8.3 C22:5 n-3 13 20.6 9.7 C22:6 n-3 305.6 327.4 353.8 Sum of FAME 796.6 905.3 837.4 TABLE 41 Fatty Acid Profiles of PTA-10212 Sample #5 Crude Oil (%) Crude Oil TAG DAG Fatty Acid % FAME % FAME % FAME C12:0 0 0.1 0.1 C14:0 1 0.9 1.0 C14:1 0 0.0 0.0 C15:0 1.3 1.3 1.1 C16:0 22.5 24.0 16.1 C16:1 2.3 1.8 3.1 C18:0 1 1.5 0.3 C18:1 n-9 0.6 0.9 0.1 C18:1 n-7 0 0.2 0.1 C18:2 n-6 0.2 0.4 0.1 C20:0 0.2 0.4 0.0 C18:3 n-3 0 0.0 0.0 C20:1 n-9 0 0.1 0.1 C18:4 n-3 0.4 0.3 0.5 C20:2 n-6 0 0.0 0.0 C20:3 n-6 0 0.1 0.0 C22:0 0 0.2 0.0 C20:4 n-7 0 0.1 0.1 C20:3 n-3 0 0.0 0.0 C20:4 n-6 1.6 1.8 1.6 C22:1 n-9 0 0.0 0.0 C20:4 n-5 0 0.2 0.1 C20:4 n-3 0.8 1.0 0.8 C20:5 n-3 26.8 24.7 30.2 C24:0 0.3 0.5 0.1 C22:4 n-9 0 0.2 0.1 C24:1 n-9 0 0.0 0.0 C22:5 n-6 1 1.1 1.0 C22:5 n-3 1.6 2.3 1.2 C22:6 n-3 38.4 36.2 42.3 Total % FAME 100 100 100 Example 37 Crude oils were further processed via refining, bleaching, and deodorizing to obtain refined oils.\",\n \"The refined oils were diluted with high oleic sunflower oil to obtain final oils with a DHA content of approximately 400 mg/g.\",\n \"Individual lipid classes were isolated and the fatty acid profiles of each class were determined using GC-FID as FAME.\",\n \"PTA-10208 Final Oils The fatty acid profiles for PTA-10208 Final Oils #1-5 are summarized in Tables 42-43, including profiles associated within the isolated TAG fraction (Tables 44-45) and the isolated sterols/DAG fraction (Tables 46-47).\",\n \"Individual lipid classes in the final oils were also determined using flash chromatography (Table 48) and normal HPLC with ELSD and APCI-MS confirmation (Table 49).\",\n \"TABLE 42 Fatty Acid Profiles of PTA-10208 Final Oils (mg/g) PTA-10208 PTA-10208 PTA-10208 PTA-10208 PTA-10208 Final Oil #1 Final Oil #2 Final Oil #3 Final Oil #4 Final Oil #5 FAME FAME FAME FAME FAME Fatty Acid (mg/g) (mg/g) (mg/g) (mg/g) (mg/g) C12:0 2.5 2.4 2.8 2.7 2.7 C14:0 16.1 14.9 21.0 18.4 17.5 C14:1 0.0 0.0 0.0 0.0 0.0 C15:0 3.8 3.6 4.4 3.9 3.9 C16:0 192.1 179.1 193.1 184.3 194.6 C16:1 0.4 0.5 0.5 0.5 0.5 C17:0 0.6 0.5 0.9 0.8 2.1 C18:0 12.8 13.9 11.5 12.3 12.9 C18:1 n-9 23.5 82.0 25.7 26.0 29.5 C18:1 n-7 0.2 0.7 0.1 0.1 0.1 C18:2 n-6 3.7 8.1 4.0 4.1 4.3 C20:0 4.3 4.1 3.7 4.0 4.0 C18:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:1 n-9 <0.1 0.1 <0.1 <0.1 <0.1 C18:4 n-3 2.4 2.5 2.8 2.7 2.8 C20:2 n-6 0.0 0.0 0.0 0.0 0.0 C20:3 n-6 0.2 0.1 0.1 0.1 0.1 C22:0 1.2 1.8 1.0 1.1 1.1 C20:4 n-7 1.7 1.6 1.7 1.8 1.6 C20:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:4 n-6 12.9 12.1 13.5 13.5 13.3 C22:1 n-9 0.0 0.0 0.0 0.0 0.0 C20:4 n-5 1.6 1.4 1.5 1.7 1.5 C20:4 n-3 6.0 5.7 6.0 6.0 6.1 C20:5 n-3 173.8 163.3 196.4 209.6 197.9 C24:0 1.4 1.6 1.3 1.3 1.0 C22:4 \\\\n-9 0.0 0.0 0.0 0.0 0.0 C24:1 n-9 3.4 3.2 2.3 2.6 2.3 C22:5 n-6 14.9 14.0 14.4 13.0 12.9 C22:5 n-3 43.9 41.3 32.8 40.3 36.9 C22:6 n-3 394.8 373.7 373.2 374.3 364.2 Sum of FAME 918.1 932.2 914.7 925.1 914.1 TABLE 43 Fatty Acid Profiles of PTA-10208 Final Oils (%) PTA-10208 PTA-10208 PTA-10208 PTA-10208 PTA-10208 Final Oil #1 Final Oil #2 Final Oil #3 Final Oil #4 Final Oil #5 Fatty Acid % FAME % FAME % FAME % FAME % FAME C12:0 0.3 0.3 0.3 0.3 0.3 C14:0 1.8 1.6 2.3 2.0 1.9 C14:1 0.0 0.0 0.0 0.0 0.0 C15:0 0.4 0.4 0.5 0.4 0.4 C16:0 20.9 19.2 21.1 19.9 21.3 C16:1 <0.1 <0.1 <0.1 <0.1 0.1 C17:0 0.1 0.1 0.1 0.1 0.2 C18:0 1.4 1.5 1.3 1.3 1.4 C18:1 n-9 2.6 8.8 2.8 2.8 3.2 C18:1 n-7 <0.1 0.1 <0.1 <0.1 <0.1 C18:2 n-6 0.4 0.9 0.4 0.4 0.5 C20:0 0.5 0.4 0.4 0.4 0.4 C18:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:1 n-9 <0.1 <0.1 <0.1 <0.1 <0.1 C18:4 n-3 0.3 0.3 0.3 0.3 0.3 C20:2 n-6 0.0 0.0 0.0 0.0 0.0 C20:3 n-6 <0.1 <0.1 <0.1 <0.1 <0.1 C22:0 0.1 0.2 0.1 0.1 0.1 C20:4 n-7 0.2 0.2 0.2 0.2 0.2 C20:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:4 n-6 1.4 1.3 1.5 1.5 1.5 C22:1 n-9 0.0 0.0 0.0 0.0 0.0 C20:4 \\\\n-5 0.2 0.2 0.2 0.2 0.2 C20:4 \\\\n-3 0.7 0.6 0.7 0.7 0.7 C20:5 n-3 18.9 17.5 21.5 22.7 21.6 C24:0 0.1 0.2 0.1 0.1 0.1 C22:4 n-9 0.0 0.0 0.0 0.0 0.0 C24:1 n-9 0.4 0.3 0.2 0.3 0.2 C22:5 n-6 1.6 1.5 1.6 1.4 1.4 C22:5 n-3 4.8 4.4 3.6 4.4 4.0 C22:6 n-3 43.0 40.1 40.8 40.5 39.9 TABLE 44 Isolated TAG Fatty Acid Profiles: PTA-10208 Final Oils (mg/g) PTA-10208 PTA-10208 PTA-10208 PTA-10208 PTA-10208 Final Oil #1 Final Oil #2 Final Oil #3 Final Oil #4 Final Oil #5 FAME FAME FAME FAME FAME Fatty Acid (mg/g) (mg/g) (mg/g) (mg/g) (mg/g) C12:0 2.5 2.3 2.7 2.5 2.6 C14:0 16.3 15.1 21.3 18.6 18.1 C14:1 0.0 0.0 0.0 0.0 0.0 C15:0 3.9 3.6 4.4 4.0 4.0 C16:0 194.2 181.9 196.1 186.1 199.8 C16:1 0.4 0.4 0.6 0.5 0.7 C17:0 0.6 0.5 0.9 0.8 0.8 C18:0 12.9 14.2 11.7 12.5 13.2 C18:1 n-9 24.3 84.0 26.8 26.1 34.0 C18:1 n-7 0.1 0.7 0.1 0.1 0.3 C18:2 n-6 3.2 7.7 3.4 3.5 4.0 C20:0 4.4 4.2 3.8 4.0 4.2 C18:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:1 n-9 <0.1 0.2 <0.1 <0.1 0.1 C18:4 n-3 2.5 2.4 2.8 2.6 2.7 C20:2 n-6 0.0 0.0 0.0 0.0 0.0 C20:3 n-6 0.2 0.2 0.1 0.1 0.1 C22:0 1.2 1.9 1.0 1.1 1.1 C20:4 n-7 1.7 1.6 1.8 1.8 1.7 C20:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:4 n-6 13.2 12.3 13.8 13.7 13.8 C22:1 n-9 0.0 0.0 0.0 0.0 0.0 C20:4 n-5 1.6 1.5 1.6 1.7 1.5 C20:4 n-3 6.1 5.7 6.1 5.9 6.2 C20:5 n-3 176.0 166.1 199.0 211.2 204.2 C24:0 1.2 1.3 1.0 1.1 1.2 C22:4 n-9 0.0 0.0 0.0 0.0 0.0 C24:1 n-9 3.3 3.2 2.2 2.5 2.4 C22:5 n-6 15.0 14.2 14.7 13.2 13.5 C22:5 n-3 44.4 42.0 33.3 40.5 38.3 C22:6 n-3 397.9 378.4 376.4 375.5 375.5 Sum of FAME 926.9 945.7 925.5 929.6 944.1 TABLE 45 Isolated TAG Fatty Acid Profiles: PTA-10208 Final Oils (%) PTA-10208 PTA-10208 PTA-10208 PTA-10208 PTA-10208 Final Oil #1 Final Oil #2 Final Oil #3 Final Oil #4 Final Oil #5 Fatty Acid % FAME % FAME % FAME % FAME % FAME C12:0 0.3 0.2 0.3 0.3 0.3 C14:0 1.8 1.6 0.3 0.3 0.3 C14:1 0.0 0.0 0.0 0.0 0.0 C15:0 0.4 0.4 0.5 0.4 0.4 C16:0 20.9 19.2 21.2 20.0 21.2 C16:1 <0.1 <0.1 0.1 0.1 0.1 C17:0 0.1 0.1 0.1 0.1 0.1 C18:0 1.4 1.5 1.3 1.3 1.4 C18:1 n-9 2.6 8.9 2.9 2.8 3.6 C18:1 n-7 <0.1 0.1 <0.1 <0.1 <0.1 C18:2 n-6 0.3 0.8 0.4 0.4 0.4 C20:0 0.5 0.4 0.4 0.4 0.4 C18:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:1 n-9 <0.1 <0.1 <0.1 <0.1 <0.1 C18:4 n-3 0.3 0.3 0.3 0.3 0.3 C20:2 n-6 0.0 0.0 0.0 0.0 0.0 C20:3 n-6 <0.1 <0.1 <0.1 <0.1 <0.1 C22:0 0.1 0.2 0.1 0.1 0.1 C20:4 n-7 0.2 0.2 0.2 0.2 0.2 C20:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:4 n-6 1.4 1.3 1.5 1.5 1.5 C22:1 n-9 0.0 0.0 0.0 0.0 0.0 C20:4 n-5 0.2 0.2 0.2 0.2 0.2 C20:4 n-3 0.7 0.6 0.7 0.6 0.7 C20:5 n-3 19.0 17.6 21.5 22.7 21.6 C24:0 0.1 0.1 0.1 0.1 0.1 C22:4 n-9 0.0 0.0 0.0 0.0 0.0 C24:1 n-9 0.4 0.3 0.2 0.3 0.3 C22:5 n-6 1.6 1.5 1.6 1.4 1.4 C22:5 n-3 4.8 4.4 3.6 4.4 4.1 C22:6 n-3 42.9 40.0 40.7 40.4 39.8 TABLE 46 Isolated Sterols/DAG Fatty Acid Profiles: PTA-10208 Final Oils (mg/g) PTA-10208 PTA-10208 PTA-10208 PTA-10208 PTA-10208 Final Oil #1 Final Oil #2 Final Oil #3 Final Oil #4 Final Oil #5 FAME FAME FAME FAME FAME Fatty Acid (mg/g) (mg/g) (mg/g) (mg/g) (mg/g) C12:0 1.9 2.1 2.9 2.1 1.9 C14:0 9.9 9.5 9.7 10.3 8.0 C14:1 0.0 0.0 0.0 0.0 0.0 C15:0 2.4 2.3 2.2 2.3 2.0 C16:0 132.6 128.6 110.1 116.8 106.4 C16:1 0.2 0.3 <0.1 0.3 0.4 C17:0 0.3 0.2 0.3 0.3 0.3 C18:0 7.3 8.1 6.4 6.8 6.1 C18:1 n-9 15.0 55.1 47.4 19.0 30.1 C18:1 n-7 0.4 0.7 0.1 <0.1 0.2 C18:2 n-6 13.1 16.7 21.6 13.5 18.4 C20:0 2.0 2.1 1.2 1.8 1.4 C18:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:1 n-9 <0.1 <0.1 <0.1 <0.1 <0.1 C18:4 n-3 2.3 2.4 2.4 2.4 2.0 C20:2 n-6 0.0 0.0 0.0 0.0 0.0 C20:3 n-6 <0.1 <0.1 <0.1 <0.1 <0.1 C22:0 0.6 1.0 0.5 0.6 0.5 C20:4 n-7 0.8 0.9 2.1 0.9 0.7 C20:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:4 n-6 5.7 5.8 4.8 6.1 4.5 C22:1 n-9 0.0 0.0 0.0 0.0 0.0 C20:4 n-5 <0.1 <0.1 <0.1 0.6 <0.1 C20:4 n-3 2.7 2.7 2.1 2.7 2.0 C20:5 n-3 92.9 94.5 91.9 111.6 84.8 C24:0 1.2 1.3 1.1 1.1 1.3 C22:4 n-9 0.0 0.0 0.0 0.0 0.0 C24:1 n-9 1.9 2.0 1.2 1.5 1.2 C22:5 n-6 7.8 8.0 6.7 7.0 5.5 C22:5 n-3 22.2 22.9 13.9 20.7 14.2 C22:6 n-3 246.3 252.7 223.5 240.3 196.3 Sum of FAME 569.3 619.8 552.1 568.7 488.2 TABLE 47 Isolated Sterols/DAG Fatty Acid Profiles: PTA-10208 Final Oils (%) PTA-10208 PTA-10208 PTA-10208 PTA-10208 PTA-10208 Final Oil #1 Final Oil #2 Final Oil #3 Final Oil #4 Final Oil #5 Fatty Acid % FAME % FAME % FAME % FAME % FAME C12:0 0.3 0.3 0.5 0.4 0.4 C14:0 1.7 1.5 1.8 1.8 1.6 C14:1 0.0 0.0 0.0 0.0 0.0 C15:0 0.4 0.4 0.4 0.4 0.4 C16:0 23.3 20.8 19.9 20.5 21.8 C16:1 <0.1 <0.1 <0.1 <0.1 0.1 C17:0 0.0 0.0 0.1 0.1 0.1 C18:0 1.3 1.3 1.2 1.2 1.2 C18:1 n-9 2.6 8.9 8.6 3.3 6.2 C18:1 n-7 0.1 0.1 <0.1 <0.1 <0.1 C18:2 n-6 2.3 2.7 3.9 2.4 3.8 C20:0 0.4 0.3 0.2 0.3 0.3 C18:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:1 n-9 <0.1 <0.1 <0.1 <0.1 <0.1 C18:4 n-3 0.4 0.4 0.4 0.4 0.4 C20:2 n-6 0.0 0.0 0.0 0.0 0.0 C20:3 n-6 <0.1 <0.1 <0.1 <0.1 <0.1 C22:0 0.1 0.2 0.1 0.1 0.1 C20:4 n-7 0.1 0.1 0.4 0.2 0.1 C20:3 n-3 0.0 0.0 0.0 0.0 0.0 C20:4 n-6 1.0 0.9 0.9 1.1 0.9 C22:1 n-9 0.0 0.0 0.0 0.0 0.0 C20:4 n-5 <0.1 <0.1 <0.1 0.1 <0.1 C20:4 n-3 0.5 0.4 0.4 0.5 0.4 C20:5 n-3 16.3 15.2 16.6 19.6 17.4 C24:0 0.2 0.2 0.2 0.2 0.3 C22:4 n-9 0.0 0.0 0.0 0.0 0.0 C24:1 n-9 0.3 0.3 0.2 0.3 0.2 C22:5 n-6 1.4 1.3 1.2 1.2 1.1 C22:5 n-3 3.9 3.7 2.5 3.6 2.9 C22:6 n-3 43.3 40.8 40.5 42.3 40.2 TABLE 48 Lipid class separation by flash chromatography (wt %) Lipid Class PTA-10208 PTA-10208 PTA-10208 PTA-10208 PTA-10208 Separation Final Oil #1 Final Oil #2 Final Oil #3 Final Oil #4 Final Oil #5 TAG 93.4 95.4 94.0 95.7 95.1 Sterols/DAG 3.1 2.9 2.6 3.0 2.9 Recovery (%) 96.5 98.3 96.6 98.7 98.0 TABLE 49 Lipid class separation by HPLC-ELSD (wt %) Sterol 1,3- 1,2- Esters TAG FFA Sterols DAG DAG MAG Total PTA-10208 0.4 90.8 ND 0.8 0.5 0.5 N.D. 93.0 Final Oil #1 PTA-10208 0.4 88.5 ND 0.6 0.6 0.6 N.D. 90.7 Final Oil #2 PTA-10208 0.3 89.4 ND 0.8 0.6 0.5 N.D. 91.6 Final Oil 43 PTA-10208 0.3 88.0 ND 0.8 0.5 0.5 N.D. 90.1 Final Oil #4 PTA-10208 0.3 86.3 ND 0.7 0.8 0.5 N.D. 88.6 Final Oil #5 PTA-10208 0.36 100.76 ND 0.84 0.54 0.61 N.D. 103.11 Final Oil #16 ND = Not Detected PTA-10212 Final Oil DHA was present in a PTA-10212 Final Oil at 41.63% and 366.9 mg/g, while EPA was present at 16.52%.\",\n \"Individual fatty acid profiles were determined and are summarized in Table 50.TABLE 50 Fatty Acid Profiles of PTA-10212 Final Oil (% FAME) Fatty Acid % FAME C6:0 ND C7:0 ND C8:0 ND C9:0 ND C10:0 ND C11:0 ND C12:0 ND C13:0 ND C14:0 0.84 C14:1 ND C15:0 1.33 C16:0 27.09 C16:1 1.03 C17:0 0.34 C17:1 ND C18:0 1.26 C18:1 n-9 2.14 C18:1 n-7 0.18 C19:0 ND C18:2 n-6 0.58 C20:0 0.32 C18:3 n-3 ND C20:1 n-9 ND C18:3 n-6 ND C20:2 n-6 0.26 C20:3 n-6 ND C22:0 0.14 C20:3 n-3 ND C20:4 n-6 1.34 C22:1 n-9 ND C23:0 ND C20:5 n-3 16.53 C24:0 0.53 C24:1 n-9 ND C22:5 n-6 1.50 C22:5 n-3 1.30 C22:6 n-3 41.63 Unknown 0.87 ND = Not Detected Example 38 A two-day old inoculum flask of the isolated microorganisms deposited under ATCC Accession Nos.\",\n \"PTA-10208 and 10212 was prepared as a carbon and nitrogen-fed culture in media according to Tables 30 and 31.Mutagenesis was carried out according to following procedure: A sterile T=2 day old flask, approximately 50 ml, was poured into a sterile 40 ml glass homogenizer.\",\n \"The culture received 50 plunges in the homogenizer.\",\n \"The culture was pipetted out and filtered through a sterile 50 micron mesh filter, which was placed in a 50 ml sterile tube (the mesh was used as a means of retaining the larger clumps of colonies while letting the smaller clusters and single cells pass through the 50 micron mesh.).\",\n \"The entire concentrated macerate was collected in a sterile 50 ml tube.\",\n \"The macerated culture was vortexed and dilutions at levels up to 1:100 fold were made.\",\n \"The diluted macerate samples were vortexed prior to adding 200 μl of inoculum to a media agar plate, 100×15 mm, containing 4-5 glass beads (3 mm glass beads).\",\n \"Each plate was gently agitated in an effort to have the beads spread the inoculum evenly around the plate.\",\n \"Beads were dumped off of plates and plates were left to sit with covers on for approximately 5 minutes to dry.\",\n \"Lights in both the sterile hood and adjoining areas were turned off as the procedure was performed in dim light.\",\n \"There was minimal light available to be able to run the procedure but only indirect and dim.\",\n \"Five replicate plates were placed on the floor of the XL crosslinker (Spectronics Corporation, New York) with the lids off while the samples were irradiated.\",\n \"The crosslinker delivered power in terms of microjoules and a level was sought that achieved a 90%-95% Kill.\",\n \"Five replicate control plates were inoculated with un-mutagenized cells using the same protocol.\",\n \"These cell counts were used to calculate the % Kill.\",\n \"Once the irradiation was finished the plates were taken out, the lids were replaced, and the plates were wrapped in parafilm followed by a wrap in aluminum foil.\",\n \"It was imperative that the plates grew for the first week in the dark so that they were not able to repair the damaged genes.\",\n \"Plates were placed in a 22.5° C. room for about 10 days prior to counting the colonies.\",\n \"When final counts were made, individual colonies were picked with a sterile inoculating loop and re-streaked on new media plates.\",\n \"Each colony was plated on an individual plate.\",\n \"As plates grew dense a sample was taken, using a inoculating loop, and inoculated into a sterile 250 ml shake flask containing 50 ml of media.\",\n \"This flask was placed on a shaker at 200 rpm in a 22.5° C. room.\",\n \"On T=7 days the shake flask culture was harvested into a 50 ml sterile tube.\",\n \"The pH was taken and the sample was centrifuged to collect the biomass pellet.\",\n \"Each sample was rinsed and re-suspended in a 50:50 mixture of isopropyl alcohol and distilled water prior to being re-centrifuged.\",\n \"The collected pellet was freeze dried, weighed, and a FAME analysis was performed.\",\n \"The data in Tables 51 and 52 represents mutants produced with the above process from strains PTA-10208 and PTA-10212, respectively.\",\n \"TABLE 51 PTA-10208 Mutants control Mutant 1 Mutant 2 Mutant 3 Fatty Acids PTA-10208 PTA-10209 PTA-10210 PTA-10211 % 08:0 0.00 0.00 0.00 0.00 % 09:0 0.00 0.00 0.00 0.00 % 10:0 0.00 0.00 0.00 0.00 % 11:0 0.00 0.00 0.00 0.00 % 11:1 0.00 0.00 0.00 0.00 % 12:0 0.11 0.10 0.22 0.19 % 12:1 0.00 0.00 0.00 0.00 % 13:0 0.19 0.19 0.15 0.16 % 13:1 0.00 0.00 0.00 0.00 % 14:0 1.94 1.82 2.98 2.59 % 14:1 0.00 0.00 0.00 0.00 % 15:1 2.66 2.22 1.76 1.66 % 16:0 24.87 24.97 23.71 25.01 % 16:1 0.20 0.25 0.07 0.07 % 16:2 0.00 0.00 0.00 0.00 % 16:3 0.00 0.00 0.00 0.00 % 17:0 1.49 1.21 0.62 0.66 % 18:0 1.13 1.14 0.91 1.01 % 18:1 n-9 0.07 0.07 0.06 0.06 % 18:1 n-7 0.00 0.00 0.00 0.00 % 18:2 0.00 0.00 0.00 0.00 % 18:3 n-6 0.00 0.00 0.05 0.04 % 18:3 n-3 0.09 0.08 0.17 0.14 % 18:4 n-3 0.00 0.00 0.00 0.00 % 20:0 0.31 0.33 0.24 0.30 % 20:1 n-9 0.00 0.04 0.00 0.00 % 20:2 0.00 0.00 0.05 0.00 % 20:3 n-9 0.00 0.00 0.00 0.00 % 20:3 n-6 0.12 0.13 0.08 0.04 % 20:3 n-3 0.42 0.42 0.08 0.06 % 20:4 ARA 0.68 0.67 1.44 1.11 % 20:5 n-3 6.56 6.47 11.99 9.87 EPA % 22:0 0.07 0.07 0.06 0.07 % 22:1 0.00 0.00 0.00 0.00 % 22:2 0.11 0.09 0.10 0.08 % 22:3 0.00 0.00 0.00 0.00 % 22:4 n-6 0.00 0.00 0.00 0.00 % 22:5 n-6 2.32 2.36 2.36 2.36 % 22:5 n-3 0.48 0.66 0.66 0.52 % 22:6 n-3 51.58 52.27 48.17 49.35 DHA % 24:0 0.00 0.00 0.00 0.00 % 24:1 0.00 0.00 0.00 0.00 % Fat 47.87 49.41 66.00 63.12 % Unknown 4.61 4.45 4.07 4.64 TABLE 52 PTA-10212 Mutants Control Mutant 1 Mutant 2 Mutant 3 Fatty Acids PTA-10212 PTA-10213 PTA-10214 PTA-10215 % 08:0 0.00 0.00 0.00 0.00 % 09:0 0.00 0.00 0.00 0.00 % 10:0 0.00 0.00 0.00 0.00 % 11:0 0.00 0.00 0.00 0.00 % 11:1 0.00 0.00 0.00 0.00 % 12:0 0.00 0.00 0.00 0.00 % 12:1 0.00 0.00 0.00 0.00 % 13:0 0.00 0.00 0.21 0.20 % 13:1 0.00 0.00 0.00 0.00 % 14:0 0.68 0.77 0.62 0.97 % 14:1 0.00 0.00 0.00 0.00 % 15:1 0.00 0.00 0.00 0.00 % 16:0 17.36 19.94 15.27 23.61 % 16:1 1.45 2.33 1.40 2.57 % 16:2 0.00 0.00 0.00 0.00 % 16:3 0.00 0.00 0.00 0.00 % 17:0 0.20 0.21 0.18 0.27 % 18:0 0.78 0.82 0.79 0.81 % 18:1 n-9 0.00 0.00 0.00 0.00 % 18:1 n-7 0.18 0.27 0.20 0.19 % 18:2 0.00 0.00 0.00 0.00 % 18:3 n-6 0.00 0.00 0.00 0.00 % 18:3 n-3 0.00 0.00 0.00 0.00 % 18:4 n-3 0.00 0.00 0.00 0.00 % 20:0 0.00 0.00 0.00 0.00 % 20:1 n-9 0.00 0.00 0.00 0.00 % 20:2 0.00 0.00 0.00 0.00 % 20:3 n-9 0.00 0.00 0.00 0.00 % 20:3 n-6 0.00 0.00 0.00 0.00 % 20:3 n-3 0.90 0.77 0.99 0.66 % 20:4 ARA 1.43 1.32 1.65 0.72 % 20:5 n-3 13.33 14.93 14.14 8.54 EPA % 22:0 0.00 0.00 0.00 0.00 % 22:1 0.00 0.00 0.00 0.00 % 22:2 0.00 0.00 0.00 0.00 % 22:3 0.00 0.00 0.00 0.00 % 22:4 n-6 0.00 0.00 0.00 0.00 % 22:5 n-6 2.39 1.95 2.59 2.18 % 22:5 n-3 0.73 0.79 0.80 0.68 % 22:6 n-3 59.18 54.31 59.89 56.39 DHA % 24:0 0.00 0.00 0.00 0.00 % 24:1 0.00 0.00 0.00 0.00 % Fat 45.69 38.08 42.88 48.48 % Unknown 1.38 1.58 1.27 2.19 Example 39 Two cell broths (approximately 13.3 kg) containing microbial cells (Schizochytrium) were heated to 60° C. in a 20 liter fermentor.\",\n \"The fermentor had two 6-blade Rushton impellers having a diameter of 15 cm.\",\n \"The top impeller was positioned at the 12 liter mark and the bottom impeller was positioned 10 cm below the top impeller.\",\n \"The first cell broth was continuously agitated at 307 centimeters/second.\",\n \"The second cell broth was continuously agitated at 464 centimeters/second.\",\n \"Enzymes (i.e., Alcalase 2.4 L FG 0.5%) were added to the cell biomass to lyse the cells and form an emulsified lysed cell composition.\",\n \"The emulsified lysed cell composition was first treated with a base (NaOH, 250 kg of 50% w/w solution) until the pH of the lysed cell composition was from 10.4 to 10.6.Next, a salt (solid NaCl, in an amount of 2%, by weight, of the lysed cell composition) was added to the lysed cell composition.\",\n \"The lysed cell composition was then heated to a temperature of 90° C. and held at that temperature level for 20 hours.\",\n \"A sample of each cell broth was taken and the pH was adjusted to 8.0 and placed in 50 ml test tubes.\",\n \"The test tubes were centrifuged and the oil extraction data was measured.\",\n \"The oil extraction data is provided in Table 53.TABLE 53 Results from extraction testing in 50 mL tubes at pH 8.0.Wet broth tested for Mass of Oil % yield % yield Extraction (g) Recovered (g) (oil/broth) (oil/solids)* 307 centimeters/second 49.990 3.881 7.76 27.81 50.814 2.747 5.41 19.36 50.772 2.418 4.76 17.05 464 centimeters/second 51.154 7.067 13.81 49.13 51.092 7.055 13.81 49.11 50.132 6.606 13.18 46.86 *based on solids content of untreated pasteurized broth The data provided in Table 53 demonstrates that the higher agitation speed resulted in a greater mass of oil recovered, a greater % yield of oil from the broth, and a greater % yield of oil from the solids content of the untreated pasteurized broth.\",\n \"CONCLUSION All of the various embodiments or options described herein can be combined in any and all variations.\",\n \"While the invention has been particularly shown and described with reference to some embodiments thereof, it will be understood by those skilled in the art that they have been presented by way of example only, and not limitation, and various changes in form and details can be made therein without departing from the spirit and scope of the invention.\",\n \"Thus, the breadth and scope of the present invention should not be limited by any of the above described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.\",\n \"All documents cited herein, including journal articles or abstracts, published or corresponding U.S. or foreign patent applications, issued or foreign patents, or any other documents, are each entirely incorporated by reference herein, including all data, tables, figures, and text presented in the cited documents.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875733"}}},{"rowIdx":4494961,"cells":{"text":{"kind":"list like","value":[["DEVICES, SYSTEMS AND METHODS FOR PAIN MANAGEMENT AND BONE HEALING","Systems and methods disclosed herein provide efficacious therapies based on delivery of combinations of thermoceuticals, electroceuticals, ultrasound via computer-implemented systems.","Sensors coupled to the device are configured to measure changes in tissue and bone conditions, physiological data resulting from the delivered therapy.","The personalized therapy can be adjusted based on the changes in the physiological or sensor data and/or patient feedback.","The patient information, information about the applied therapy, and therapy outcome information can be added to the analytics database."],["1.A portable therapy device configured to drive inputs to one or more switches controlling combination treatments comprising a combination of at least one thermoceutical, electroceutical, and ultrasound therapy while measuring physiological, musculoskeletal characteristics related parameters via sensors; an applicator coupled to the one or more switches and configured to deliver ultrasonic energy in a pulsed or continuous mode, wherein ultrasound frequency ranges from about 0.1 MHz to about 10 MHZ, and wherein intensities range from about 0.01 W/cm2 to about 3.0 W/cm2 in various combinations; the same or an additional applicator coupled to the one or more switches and configured to deliver thermoceutical energy in a pulsed or continuous mode, wherein thermal energy ranges from about 0 ° C. to about 50° C.; the same or an additional applicator comprising electrodes coupled to the one or more switches and configured to deliver electroceutical energy in a pulsed or continuous in the frequency range from about 1-200 Hz; pulse amplitude 0 mA to 500 mA and at least one or more sensors integrated into the same or additional applicators and coupled to a processing device to measure at least one physiological parameter or musculoskeletal characteristics related parameter comprising body temperature, tissue temperature, local blood flow, local blood oxygen levels, local tissue thickness, local tissue composition/structure, bone strength, bone fracture type, callus stiffness, and velocity and attenuation properties of sound waves in tissue or bone.","2.The device of claim 1, comprising a first applicator configured to deliver thermoceutical therapy as well as ultrasound therapy and a second applicator configured to deliver electroceutical therapy.","3.The device of claim 1, comprising a single applicator configured to deliver thermoceutical, ultrasound, and electroceutical therapy.","4.The device of claim 1, used to treat arthritis, joint pain, bursitis, muscle pain or injuries, muscle spasm or strain, soft tissue injuries, musculoskeletal injuries, back pain, joint stiffness, cold hands, rheumatism, neuralgia, inflammation, edema, ischemia, spasm, to stimulate enzyme activity and immune system, bone healing, tendon healing, or wound healing.","5.The device of claim 1, used to stimulate or accelerate fractured bone or tissue healing.","6.The device of claim 1, used for faster healing of damaged or fractured bones, and for monitoring bone healing progress through sensor feedback.","7.A medical device for the application of a therapy, comprising: a processing device configured to drive inputs for one or more switches controlling characteristics of treatments comprising thermoceuticals, electroceuticals, ultrasound, or a combination thereof, the characteristics of the treatments corresponding to the therapy; an applicator, coupled to the one or more switches, the applicator configured to apply the treatments or a combination thereof based on the inputs to the one or more switches; one or more sensors coupled to the processing device, the one or more sensors configured to 1) detect physiological/musculoskeletal parameters responsive to the application of the treatments or combination thereof and 2) provide the physiological/musculoskeletal parameters to the processing device; and a patient feedback interface communicatively coupled to the processing device, the patient feedback interface configured to receive user inputs indicating patient feedback information responsive to the application of the treatments or combination thereof.","8.The medical device of claim 7, wherein the characteristics of the treatments or the combination thereof include intensity levels and time durations.","9.The medical device of claim 7, wherein the physiological parameters comprise one or more of body temperature, tissue temperature, local blood flow, local blood oxygen levels, local tissue thickness, local tissue composition/structure, local tissue imaging, local tissue bone strength, bone fracture type, callus stiffness, and velocity and attenuation properties of sound waves in tissue or bone.","10.A method for delivering a bone healing treatment, comprising: receiving patient information comprising patient data and symptoms; comparing the received patient information with bone healing analytics data compiled on a plurality of individuals to determine a personalized bone healing therapy; applying the personalized bone healing therapy to deliver one or more of thermoceuticals, electroceuticals, or ultrasound, in various combinations; receiving updated patient information in response to the applied personalized bone healing therapy; and storing the updated patient information and the personalized pain management therapy in a database to add to the bone healing analytics data compiled on the plurality of individuals.","11.The method of claim 10, further comprising: adjusting, in response to the updated patient information, the personalized bone healing therapy by adjusting the combination of thermoceuticals, electroceuticals, or ultrasound; and storing the adjusted personalized bone healing therapy in the database to add to the bone healing analytics data.","12.The method of claim 11, wherein the patient data and the updated patient information further comprise patient physiological data including one or more of patient vital signs, body or tissue temperature, blood flow rate, blood oxygen levels, or body tissue thickness or density.","13.The method of claim 10, wherein the patient data and the updated patient information are received at a bone healing therapy device, and wherein the personalized bone healing therapy is applied by transmitting electronic signals to an applicator to deliver the thermoceuticals, electroceuticals, ultrasound, or combination thereof via one or more applicators.","14.The method of claim 13, wherein the patient data and the bone healing analytics data are stored in a memory of the bone healing therapy device or in a remotely connected database, and wherein the bone healing analytics data includes correlated patient information and patient feedback regarding bone healing therapy outcomes on the plurality of individuals.","15.The method of claim 14, wherein comparing the received patient information with bone healing analytics data to determine the personalized bone healing therapy comprises: identifying a subset of individuals from the plurality of individuals that have similar characteristics as the patient as indicated in the patient information; and identifying, from the bone healing analytics data on the subset of individuals, a stored applied therapy associated with a stored therapy outcome indicating enhanced bone healing symptoms, wherein the identified stored applied therapy corresponds to the personalized bone healing therapy.","16.The method of claim 10, wherein the patient data and the updated patient information are received by one or more sensors communicatively coupled to a bone healing therapy device or by user inputs received at a patient feedback interface.","17.The method of claim 10, wherein the personalized bone healing therapy comprises a combination therapy of: delivering thermoceuticals comprising heat in a temperature range of about 0-50° C.; and delivering ultrasonic energy at ultrasound frequency ranges of from about 0.1 MHz to about 3 MHZ and intensities from about 0.01 W/cm2 to about 1.0 W/cm2, wherein the delivery of thermoceuticals and ultrasonic energy may be in a pulsed or continuous mode and in various combinations of duration and intensities."],["<SOH> BACKGROUND <EOH>An individual with a disease, particularly a chronic disease or any ailment that takes more than one or two months to heal, may be required to monitor various health parameters on a regular basis in support of any treatment or therapy that he or she is undergoing or receiving.","Today, advances in medical research enable a range of therapeutic options to treat a given disease, or ailment and/or their symptoms, where each of the proposed therapies targets a particular biochemical or physiochemical process underlying or associated with the disease to provide either a cure or relief from the disease symptoms.","For example, if one were to consider various options available for treating pain symptoms, the possible diagnoses, medicaments and therapies are many; similarly there are several options available for accelerating fractured bone healing.","It is possible that the therapy/medication a patient receives could be subjective and depend upon the particular doctor/physician, i.e., his/her background, expertise and past experiences.","For example, a physiotherapist or an orthopedic physician may treat a pain symptom differently than a physician or pain management specialist.","Although a doctor plays a critical role in diagnosing and prescribing the therapy, the patient (and his/her family members or care givers) also has great responsibility in complying with the prescription, and following the course of action for achieving improved health and better quality of life.","However, unfortunately, depending upon the patient demographics and nature of the disease, health care management of pain management and implementation of pain management has become a daunting task and an expensive affair.","For example, of the all diseases, chronic pain is one of the most underestimated health care problems in the world today, causing major consequences for the quality of life of the patients and the family members and has been a major burden on the health care system.","The most common causes of chronic pain are musculoskeletal problems (fractures, dislocations, soft injuries) and inflammatory conditions, with back pain and arthritis pain symptoms accounting for a significant portion of the overall chronic pain population.","The four most common ways to treat pain are: (1) pharmaceutical (e.g., analgesics, aspirin; NSAIDs, Ibuprofen, COX-2 inhibitors, celecoxib; opioids, morphine), (2) procedural (neuro-stimulators, pulsed radiofrequency, intrathecal), (3) psychological (behavioral, cognitive), and (4) physical (e.g., heat, cold, transcutaneous electric nerve simulation (TENS), therapeutic ultrasound, infrared, microwave or shortwave diathermy, electro-magnetic radiation, acupuncture, massage Although pharmaceutical methods (e.g., drugs) are most widely used for treating pain, individuals on over the counter or prescription drugs for pain are frequently dissatisfied with the results of the pharmaceutical treatment.","Further, the adverse side effects that drugs may cause on prolonged usage is shifting the focus away from drugs toward alternate methods for managing chronic pain.","The procedural methods are invasive, expensive and their effectiveness has been difficult to quantify.","Psychological therapies often lack practicality and their success rates have been limited.","Finally, physiotherapy based methods have been proven attractive, but they are inconvenient, require bulky/complex instruments, and regular office/hospital visits, all of which lowers compliance.","In addition, these therapies are often not supported by quality clinical data despite tremendous advances made in understanding pathophysiology and pain signaling.","Although, a number of physical medicine/modalities based therapies have been administered to treat musculoskeletal pain, identifying the optimal therapy and dosage for pain symptoms has been elusive.","For example, clinical data published in the literature indicates that the application of physical medicine is appropriate/beneficial in some cases and not particularly beneficial in other cases.","The response from patients to these methods is similarly mixed.","Given this background, the patient (or his/her doctor) has no way of knowing what is the best treatment method.","If one were to consider the combined use of these the application of physical therapies, the possible variations may be several (including dosage, therapy session and duration), but combination therapies may provide an opportunity to fine tune the therapy in order to make it efficacious or even personalized, especially when one takes advantage of modern technological advances such as computing, internet of things, sensing, connectivity, big data, and analytics in conjunction with electronic medication/therapy or remote administering/dispensing of medicines electronically.","Therefore, there exists a need for a medical device and an associated system for offering improved therapies for sustained pain relief that takes into account objective and subjective patient feedback and further takes into account the statistical certainty of obtaining a satisfactory outcome.","Another healthcare industry that can benefit from improved treatments relates to healing of fractured bones.","Over 50 million bone fractures occur worldwide, leading to about 10 million doctor or emergency room visits per year in the United States alone.","Delayed bone healing can result in increased pain, as well as loss of function and decreased quality of life.","Current therapies or treatment approaches for healing fractured bones include delivering bone morphogenetic proteins (“BMPs”), platelet-rich plasma (PRP), or anabolic agents such as teriparatide (“TPD”).","These treatments can be invasive and are not always successful.","Other proposed solutions have been to implement bone growth stimulation devices.","Such devices deliver low intensity pulsed ultrasound (“LIPUS”), which is believed to result in faster bone healing, but requires personalization of therapy dosage, that is, normalization of therapy dosage for a given composition (fat and muscle) and thickness of tissue surrounding a fractured bone.","However, the existing therapies do not offer personalized solutions.","For example, delivering a certain amount of ultrasound to one patient having one body composition will not achieve the same result as delivering that same amount of ultrasound to a different patient having a different body composition, or for that matter, different body parts of an individual contain different tissue thicknesses and compositions.","Ultrasound penetration into deep tissue is limited by tissue thickness and composition.","An identical dosage of low intensity pulsed ultrasound (LIPUS) may deliver inconsistent or suboptimal dosages to different patients.","Accordingly, the present inventors have determined that the personalized pain management therapies described herein may also be useful in order to promote faster healing of fractured bones or other tissues.","They have combined the personalized temperature therapy/ultrasound therapy/electrical stimulation therapy that may be delivered by the disclosed device in order to offer improved therapies for faster bone healing.","Typically, the attenuation coefficient, loss of ultrasound energy due to absorption, scattering, and mode conversion, decreases as temperature of tissue raise from 0 to 50° C. Penetration of low intensity pulsed ultrasound through deep tissue to heal fractured bones varies depending tissue temperature.","In theory, one can take advantage of this phenomena by preconditioning tissue temperature during LIPUS therapy to maximize therapeutic benefits.","Use of the disclosed device has been found to provide controls for enabling deeper penetration of low intensity ultrasound or modulating ultrasound energy profile delivered to the injure tissue/bone areas, while personalizing the delivered therapy using sensors (that measure tissue thickness, rate of bone healing, blood flow etc.)","and accompanied software tools."],["<SOH> SUMMARY <EOH>The present disclosure provides a method and system for providing efficacious, personalized, pain management therapies.","The present disclosure provides a method and system for providing efficacious and personalized bone healing therapies.","A patient is provided with a therapy device capable of delivering individual, or multiple or combination physical therapies accompanied with a computer-implemented system that automatically or manually adjusts the applied pain management treatment based on physiological responses, objective measurements gathered by sensors, and/or user feedback.","Physical therapies can be applied using a combination of thermoceuticals (e.g., temperature application based therapies such as surface heating/cooling using heat pack or cold packs or microwave/shortwave/ultrasound/infrared/laser radiation based thermal therapies, contrast therapies), or combination of thermoceuticals and electroceuticals (e.g., electrical stimulation based therapies such as TENS), or a combination of these treatments with ultrasound.","Ultrasound, when applied in pulses, can produce non-thermal effects (acoustic streaming, cavitation) and facilitates healing in the inflammatory and proliferative phase following soft tissue injury, increases local circulation because of the increased capillary density, and bone healing.","In some embodiments, physical therapies can also be administered by including infrared heating or electromagnetic radiation or radio frequency ablation.","Physiological responses may be measured via one or more sensors that measure blood flow, blood oxygen levels, tissue thickness, bone strength, callus stiffness, acoustic emissions or vibrational properties of fractured vs. normal bone, ultrasound velocity and attenuation across a healing fractured bone and or superficial or deep tissue temperatures or other physiological metrics that are associated with pain symptoms.","Upon applying a particular therapy, the disclosed device can receive updated physiological responses and adjust the therapy applied until a desired physiological response and/or user feedback indicates a satisfactory pain management or bone healing or other treatment outcome.","In additional embodiments, the computer-implemented system identifies a correlation between the patient information (e.g., patient demographics, pain symptoms, nature of bone fracture, bone strength, callus stiffness, tissue density and composition, applied treatment options, and/or treatment outcomes) and analytics data compiled on a plurality of individuals.","The analytics data tracks historical data on previous patients, treatments applied, and treatment outcomes.","The analytics data can indicate for example, a treatment option that was previously applied to patients with similar demographic or physical information and a statistical likelihood that the therapy option/dosage results satisfactory pain relief or bone healing.","The device can receive the identified treatment option from the analytics data and adjust the applied treatment to match the identified treatment option.","The computer-implemented system can further store pain the patient information and the applied treatment in a database, thereby adding to the analytics data.","The disclosed device, methodology and intelligent pain management (or bone healing) algorithm together provide a powerful tool for managing pain efficiently and effectively, as well as treating and encouraging bone growth or healing.","Embodiments herein further relieve patients of the burden of having to try a plethora of devices or other treatment modalities in search of finding relief.","These illustrative embodiments are mentioned not to limit or define the disclosure, but to provide examples to aid understanding thereof.","Additional embodiments are discussed in the Detailed Description, and further description is provided there."],["CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation in part of U.S. application Ser.","No.","15/021,143 filed on Mar.","10, 2016 titled “Personalized Pain Management Treatments,” which application claims priority to U.S.","Provisional Application Ser.","No.","62/110,017, filed on January 30, 2015 and titled “Devices, Systems, and Methods for Pain Management,” and which application is also a continuation-in-part of application Ser.","No.","14/011,273, filed Aug. 27, 2013, now issued as U.S. Pat.","No.","9,710,607, titled “Portable Electronic Therapy Device and Method Thereof,” the contents of each of which are hereby incorporated by reference.","TECHNICAL FIELD This disclosure provides a portable, electronic therapy device that is capable of delivering thermal energies, electrical energies, ultrasonic energies, and various combinations thereof in order to promote various therapeutic purposes.","In a particular embodiment, delivery of these energies, either alone or in various combinations, has been found to be useful in improving bone healing processes.","The therapy device can include automatic controlled application of energies along with feedback control using sensors for improved synergistic effects and dose titration.","The device can be used for pain management, bone healing, tissue healing, fitness, cosmetic and topical delivery, and other related applications.","The methods and systems provide improved uses for devices configured to deliver pain management or bone or other tissue healing therapies.","BACKGROUND An individual with a disease, particularly a chronic disease or any ailment that takes more than one or two months to heal, may be required to monitor various health parameters on a regular basis in support of any treatment or therapy that he or she is undergoing or receiving.","Today, advances in medical research enable a range of therapeutic options to treat a given disease, or ailment and/or their symptoms, where each of the proposed therapies targets a particular biochemical or physiochemical process underlying or associated with the disease to provide either a cure or relief from the disease symptoms.","For example, if one were to consider various options available for treating pain symptoms, the possible diagnoses, medicaments and therapies are many; similarly there are several options available for accelerating fractured bone healing.","It is possible that the therapy/medication a patient receives could be subjective and depend upon the particular doctor/physician, i.e., his/her background, expertise and past experiences.","For example, a physiotherapist or an orthopedic physician may treat a pain symptom differently than a physician or pain management specialist.","Although a doctor plays a critical role in diagnosing and prescribing the therapy, the patient (and his/her family members or care givers) also has great responsibility in complying with the prescription, and following the course of action for achieving improved health and better quality of life.","However, unfortunately, depending upon the patient demographics and nature of the disease, health care management of pain management and implementation of pain management has become a daunting task and an expensive affair.","For example, of the all diseases, chronic pain is one of the most underestimated health care problems in the world today, causing major consequences for the quality of life of the patients and the family members and has been a major burden on the health care system.","The most common causes of chronic pain are musculoskeletal problems (fractures, dislocations, soft injuries) and inflammatory conditions, with back pain and arthritis pain symptoms accounting for a significant portion of the overall chronic pain population.","The four most common ways to treat pain are: (1) pharmaceutical (e.g., analgesics, aspirin; NSAIDs, Ibuprofen, COX-2 inhibitors, celecoxib; opioids, morphine), (2) procedural (neuro-stimulators, pulsed radiofrequency, intrathecal), (3) psychological (behavioral, cognitive), and (4) physical (e.g., heat, cold, transcutaneous electric nerve simulation (TENS), therapeutic ultrasound, infrared, microwave or shortwave diathermy, electro-magnetic radiation, acupuncture, massage Although pharmaceutical methods (e.g., drugs) are most widely used for treating pain, individuals on over the counter or prescription drugs for pain are frequently dissatisfied with the results of the pharmaceutical treatment.","Further, the adverse side effects that drugs may cause on prolonged usage is shifting the focus away from drugs toward alternate methods for managing chronic pain.","The procedural methods are invasive, expensive and their effectiveness has been difficult to quantify.","Psychological therapies often lack practicality and their success rates have been limited.","Finally, physiotherapy based methods have been proven attractive, but they are inconvenient, require bulky/complex instruments, and regular office/hospital visits, all of which lowers compliance.","In addition, these therapies are often not supported by quality clinical data despite tremendous advances made in understanding pathophysiology and pain signaling.","Although, a number of physical medicine/modalities based therapies have been administered to treat musculoskeletal pain, identifying the optimal therapy and dosage for pain symptoms has been elusive.","For example, clinical data published in the literature indicates that the application of physical medicine is appropriate/beneficial in some cases and not particularly beneficial in other cases.","The response from patients to these methods is similarly mixed.","Given this background, the patient (or his/her doctor) has no way of knowing what is the best treatment method.","If one were to consider the combined use of these the application of physical therapies, the possible variations may be several (including dosage, therapy session and duration), but combination therapies may provide an opportunity to fine tune the therapy in order to make it efficacious or even personalized, especially when one takes advantage of modern technological advances such as computing, internet of things, sensing, connectivity, big data, and analytics in conjunction with electronic medication/therapy or remote administering/dispensing of medicines electronically.","Therefore, there exists a need for a medical device and an associated system for offering improved therapies for sustained pain relief that takes into account objective and subjective patient feedback and further takes into account the statistical certainty of obtaining a satisfactory outcome.","Another healthcare industry that can benefit from improved treatments relates to healing of fractured bones.","Over 50 million bone fractures occur worldwide, leading to about 10 million doctor or emergency room visits per year in the United States alone.","Delayed bone healing can result in increased pain, as well as loss of function and decreased quality of life.","Current therapies or treatment approaches for healing fractured bones include delivering bone morphogenetic proteins (“BMPs”), platelet-rich plasma (PRP), or anabolic agents such as teriparatide (“TPD”).","These treatments can be invasive and are not always successful.","Other proposed solutions have been to implement bone growth stimulation devices.","Such devices deliver low intensity pulsed ultrasound (“LIPUS”), which is believed to result in faster bone healing, but requires personalization of therapy dosage, that is, normalization of therapy dosage for a given composition (fat and muscle) and thickness of tissue surrounding a fractured bone.","However, the existing therapies do not offer personalized solutions.","For example, delivering a certain amount of ultrasound to one patient having one body composition will not achieve the same result as delivering that same amount of ultrasound to a different patient having a different body composition, or for that matter, different body parts of an individual contain different tissue thicknesses and compositions.","Ultrasound penetration into deep tissue is limited by tissue thickness and composition.","An identical dosage of low intensity pulsed ultrasound (LIPUS) may deliver inconsistent or suboptimal dosages to different patients.","Accordingly, the present inventors have determined that the personalized pain management therapies described herein may also be useful in order to promote faster healing of fractured bones or other tissues.","They have combined the personalized temperature therapy/ultrasound therapy/electrical stimulation therapy that may be delivered by the disclosed device in order to offer improved therapies for faster bone healing.","Typically, the attenuation coefficient, loss of ultrasound energy due to absorption, scattering, and mode conversion, decreases as temperature of tissue raise from 0 to 50° C. Penetration of low intensity pulsed ultrasound through deep tissue to heal fractured bones varies depending tissue temperature.","In theory, one can take advantage of this phenomena by preconditioning tissue temperature during LIPUS therapy to maximize therapeutic benefits.","Use of the disclosed device has been found to provide controls for enabling deeper penetration of low intensity ultrasound or modulating ultrasound energy profile delivered to the injure tissue/bone areas, while personalizing the delivered therapy using sensors (that measure tissue thickness, rate of bone healing, blood flow etc.)","and accompanied software tools.","SUMMARY The present disclosure provides a method and system for providing efficacious, personalized, pain management therapies.","The present disclosure provides a method and system for providing efficacious and personalized bone healing therapies.","A patient is provided with a therapy device capable of delivering individual, or multiple or combination physical therapies accompanied with a computer-implemented system that automatically or manually adjusts the applied pain management treatment based on physiological responses, objective measurements gathered by sensors, and/or user feedback.","Physical therapies can be applied using a combination of thermoceuticals (e.g., temperature application based therapies such as surface heating/cooling using heat pack or cold packs or microwave/shortwave/ultrasound/infrared/laser radiation based thermal therapies, contrast therapies), or combination of thermoceuticals and electroceuticals (e.g., electrical stimulation based therapies such as TENS), or a combination of these treatments with ultrasound.","Ultrasound, when applied in pulses, can produce non-thermal effects (acoustic streaming, cavitation) and facilitates healing in the inflammatory and proliferative phase following soft tissue injury, increases local circulation because of the increased capillary density, and bone healing.","In some embodiments, physical therapies can also be administered by including infrared heating or electromagnetic radiation or radio frequency ablation.","Physiological responses may be measured via one or more sensors that measure blood flow, blood oxygen levels, tissue thickness, bone strength, callus stiffness, acoustic emissions or vibrational properties of fractured vs. normal bone, ultrasound velocity and attenuation across a healing fractured bone and or superficial or deep tissue temperatures or other physiological metrics that are associated with pain symptoms.","Upon applying a particular therapy, the disclosed device can receive updated physiological responses and adjust the therapy applied until a desired physiological response and/or user feedback indicates a satisfactory pain management or bone healing or other treatment outcome.","In additional embodiments, the computer-implemented system identifies a correlation between the patient information (e.g., patient demographics, pain symptoms, nature of bone fracture, bone strength, callus stiffness, tissue density and composition, applied treatment options, and/or treatment outcomes) and analytics data compiled on a plurality of individuals.","The analytics data tracks historical data on previous patients, treatments applied, and treatment outcomes.","The analytics data can indicate for example, a treatment option that was previously applied to patients with similar demographic or physical information and a statistical likelihood that the therapy option/dosage results satisfactory pain relief or bone healing.","The device can receive the identified treatment option from the analytics data and adjust the applied treatment to match the identified treatment option.","The computer-implemented system can further store pain the patient information and the applied treatment in a database, thereby adding to the analytics data.","The disclosed device, methodology and intelligent pain management (or bone healing) algorithm together provide a powerful tool for managing pain efficiently and effectively, as well as treating and encouraging bone growth or healing.","Embodiments herein further relieve patients of the burden of having to try a plethora of devices or other treatment modalities in search of finding relief.","These illustrative embodiments are mentioned not to limit or define the disclosure, but to provide examples to aid understanding thereof.","Additional embodiments are discussed in the Detailed Description, and further description is provided there.","BRIEF DESCRIPTION OF THE FIGURES These and other features, embodiments, and advantages of the present disclosure are better understood when the following Detailed Description is read with reference to the accompanying drawings.","FIG.","1 is a block diagram depicting a pain therapy device communicating with a server system to provide personalized pain therapy that is adjusted based on subjective and objective feedback in response to the applied pain therapy.","FIG.","2 is a block diagram illustrating the logical components of the pain therapy device shown in FIG.","1.FIG.","3 is a block diagram depicting the various components present in the applicator for applying the pain management therapy.","FIG.","4 is an flowchart depicting an example process for applying a personalized pain management therapy based on stored analytics data and adjusting the applied therapy based on feedback.","FIGS.","5 and 6 are block diagrams depicting example hardware implementations for some of the components shown in FIG.","1.FIG.","7 is a block diagram depicting one example of a pain therapy device.","FIGS.","8A and 8B illustrate schematic cross sections of exemplary configurations of the pain therapy device.","FIGS.","9A, 9B, and 9C illustrate schematic cross sections of exemplary applicator configurations and corresponding transducer arrangements.","FIGS.","10A and 10B illustrate further schematic cross sections of exemplary applicator configurations and corresponding transducer arrangements.","FIGS.","11A and 11B illustrate further schematic cross sections of exemplary applicator configurations and corresponding transducer arrangements.","FIGS.","12A and 12B illustrate further schematic cross sections of exemplary applicator configurations and corresponding transducer arrangements.","FIGS.","13A and 13B illustrate further schematic cross sections of exemplary applicator configurations and corresponding transducer arrangements.","FIG.","14 shows a schematic of patient data analytics and treatment indications for efficacious or personalized bone healing treatment described herein by applying concepts depicted in FIG.","4.DETAILED DESCRIPTION Systems and methods are disclosed for pain management therapies and devices.","The systems and methods described also find particular benefit for encouraging faster bone healing.","Although the present disclosure will relate to and use the term “pain management” therapies and devices, it should be understood that the same pain management therapies and devices described may also be used in order to encourage the bone healing process described herein.","Systems and methods are also disclosed for computer-implemented pain management or bone healing through the use of a device that applies a combination of physical therapies to alleviate pain symptoms and/or to encourage faster bone healing, and it adjusts the application of the physical therapies based on feedback information.","Feedback information includes physiological responses resulting from the applied therapy, patient feedback received as a pain relief score (e.g., a score from 0-10 or 0-5 as the case may be), and analytics information indicating the personalized therapy for patients with similar demographics/pre-existing medical conditions and other characteristics as the current patient.","The therapy includes application of physical therapies via an applicator.","Physical therapies include electroceuticals (i.e., any type electrical stimulation used for therapeutic benefit), thermoceuticals (e.g., defined as a thermal or heat therapy method or device designed to affect biological systems and modify function(s) of the body, and/or ultrasound therapies (i.e., any system that can deliver ultrasound waves such as low intensity pulsed ultrasound (LIPUS) to the patient), or any combination thereof.","As part of thermal therapy, thermal energy is delivered to the body or superficial or deep tissue using a variety of devices and methods known to those skilled in the art.","The temperatures applied to the body locally or systemically and may vary from about−100° C. to+about 100° C.).","In other examples, the temperature may range from 0-50° C. Any combination of these treatments may be combined, depending upon the patient and the condition to be treated.","One exemplary device for managing pain is described in U.S. Pat.","No.","9,710,607, titled “Portable Electronic Therapy Device and the Method Thereof,” which is incorporated by reference herein.","The physical therapies applied via the computer-implemented therapy target specific physiological functions (i.e., without using any drugs) of the tissue through external non-invasive stimulation (or invasive stimulation) to provide pain relief and/or bone healing.","A variety of physiological functions can be influenced, simply by changing the temperature of the tissue (e.g., cold, or heat at superficial or deeper levels) using a variety of methods such as cold or hot packs/baths, infrared lamps, lasers, shortwave diathermy, microwave diathermy, therapeutic ultrasound, and radio frequency application.","Some of the physical medicine-induced changes include variations in cell membrane, or protein or nucleic acid structure and function, enzymatic activity, cell apoptosis, nerve conduction, coagulation, collagen fiber contraction, collagen synthesis, vasodilation, vasoconstriction, viscosity of body fluids/blood, cellular fluid crystallization or dehydration, pain signaling, production of endorphins, spasm, tissue metabolism, blood flow, inflammation, edema extensibility, supply of oxygen & nutrients, tissue/muscle repair or healing, fibroblast activity, collagen fibril density, protein synthesis, and tissue regeneration.","Some of the physical parameters that alter based on tissue temperature include the propagation profiles of energy waves, such as ultrasound velocity and attenuation as a function of tissue temperature, depth, and composition.","Some of the physical medicine based therapeutic indications include pain (chronic or acute) relief, musculoskeletal pain relief, sports injuries, post surgical pain, post surgical edema, reduction in inflammation, reduction of joint contractures, fibromyalgia, migraine, tissue healing, swelling reduction, Hematoma resolution, acute bone healing, wound healing, face lift, wrinkle reduction, angiogenesis, removal of warts, cancer therapy, strains, contracture, decrease in muscle spasticity, tumors, capsulitis, bursitis, myositis, tendonitis, improving range of motion, rheumatoid arthritis and osteoarthritis.","Application of thermoceuticals or thermal therapy includes both heat therapy and cold therapy.","Heat therapy can ease pain by increasing blood flow to affected areas, which can help decrease inflammation, relax tight muscles and eliminate waste products such as lactic acid that cause stiffness and soreness.","Likewise, application of cold may facilitate healing after injuries and limits musculoskeletal pain.","Cold therapy induces a drop in skin temperature and a modest decline in temperatures within the muscles and joints, thereby causes arteriolar and capillary vasoconstriction in the skin leading to decrease in local synovial blood flow to reduce swelling.","Further, the propagation speeds of ultrasound waves increase as the tissue temperature raises up to 50° C., while the attenuation coefficient (loss of energy due to absorption and scattering) decreases.","Thermoceuticals can be applied via any suitable mechanism for changing the temperature of the tissue.","For example, thermoceuticals can be applied via surface heating/cooling using heat pack or cold packs or by microwave radiation, shortwave radiation, ultrasound application, infrared radiation.","In some examples, the applicator described herein is configured to deliver thermoceutical energy to the body continuously or in a pulsed mode, or combinations thereof.","The thermal energy delivered may be in temperature range of from about 0-60° C. In a specific example, the device can deliver thermal energy at about 42° C. Application of ultrasound therapies stimulates tissue beneath the skin's surface using sound waves.","Exemplary ranges include from about 0.1 MHz to about 10 MHz.","Other specific ranges may include from about 0.5-3.0 MHz (with tolerances including±20%) A specific low intensity pulsed ultrasound frequency may be about 1.5 MHz.","In some examples, the ultrasound may be pulsed.","In some examples, the ultrasound may be pulsed while the tissue temperature is altered between 0 to 50° C. In some examples, the ultrasound may be delivered continuously.","In further examples, the ultrasound may vacillate between continuous delivery and pulsed delivery.","The ultrasound frequency range delivered may depend upon set parameters, for example, may be based upon the patient's tissue composition.","The intensity of the ultrasound may range from about 0.005 W/cm2 to about 3.0 W/ cm2.In some examples, ultrasound can cause a temperature rise up to 10° C. in 2-8 cm deep tissue or at least up to 5° C. The ultrasound can also imparts non-thermal effects such as acoustic streaming and cavitation to provide pain relief.","Thermal changes also result in activation of a wide variety of thermal receptors (transient receptor potential channels (TRP)) in the skin/tissue that range from 0-60° C. and may mask pain signals to the brain.","Activation of these receptors either chemically (e.g., menthol activates TRPA1, TRPM8, while capsaicin activates TRPV1, TRPV3) or physically can lead to masking of the pain sensation.","In some embodiments of the present disclosure, the pain signal to the brain is masked by providing a method/mechanism to maximize/overwhelm the signal(s) from an individual or multiple TRP channels located around painful musculoskeletal region.","The distribution ratio of various temperature sensitive receptors in the body varies depending upon the body location.","For example, upper part of the body comprises more heat temperature receptors than cold temperature receptors.","The present inventors believe that pulsing low intensity ultrasound while controlling the tissue temperature help minimize the losses of ultrasound energy due to attenuation and increases ultrasound velocities inside the tissue, and thereby encourages more effective and efficient bone healing.","Preheating or Pre-cooling or Pre-conditioning of the tissue around injured area (that is injured bone or tissue) can help encourage greater penetration of the ultrasound.","Without wishing to be bound to any theory, it is believed that raising the patient's tissue temperature to about 50° C., while also delivering ultrasound waves (pulsed or continuous), can help reach the underlying bone tissue more effectively (i.e., with higher velocities and low attenuation coefficients).","It is believed that this treatment may help improve bone healing by up to about 30 to 40% or even more.","However, not all patients have the same tissue composition.","Some patients may present with more fat tissue, others with more muscle tissue, and different densities of tissue or body mass indices will require different dosages for treatment to ensure the right dosage of ultrasound energy is experienced by the injured bones/tissue therapy point.","Ultrasound waves are absorbed more as they extend deeper into tissue.","The ultrasound intensity that reaches the bone will vary based on the delivered parameters such as ultrasound frequency, intensity, pulsing profile, tissue temperature, tissue thickness/composition in a therapeutic area.","Embodiments disclosed herein also include computer-implemented therapy that applies electroceuticals as electrical stimulation of nerves.","In electric stimulation, electrical current at distinct voltages, frequencies and intensities is delivered to the skin through electrodes (e.g., TENS, electric muscle stimulation, EMS, or neuromuscular electric stimulation, LAMES, IFT, inferential therapy).","Pain is relieved by means of the pain gate mechanism involving activation of sensory fibers that mask the pain and/or suppressing of pain signals to the brain.","It is also believed possible that delivery of electric stimulation may help healing of fractured bones, the bone healing may be accelerated in conjunction with low intensity pulsed ultrasound while keeping the tissue temperature at native body temperature or by externally altering it with the aid of thermoceuticals.","Additionally, electrical stimulation can generate a physiological response to the irritation produced by electrical stimuli which leads to the release of endorphins.","Electrically pulsed stimulation also causes enhanced localized muscle activity and thereby increases blood circulation to remove metabolic toxins, thereby reducing pain symptoms and/or may encourage bone growth.","The electroceuticals can be applied to the body using either low (1-20 Hz) or high frequencies (20-200 Hz) for treating pain and several other therapeutic indications.","In other words, the energy delivered may range from about 2-200 Hz, or any range there between.","The voltages used for electric stimulation may vary from 3 V to 120V, while the wave forms applied could assume different shapes such as square, asymmetrical biphasic, and symmetrical biphasic.","In other examples, the range may be from 10 V to 120V.","The stimulation could be applied to the body continuously or in pulsed mode or in burst mode to trigger different therapeutic mechanisms for treating ailments.","Although, the therapeutic mechanism behind electric stimulation has not yet been unequivocally established, it is generally believed that electric stimulation enables the body to produce its own endorphins, increases local blood flow and mask pain signals via pain gate mechanism and several other hypotheses as proposed in the literature.","It is believed that combining electrical stimulation, thermal therapy, and ultrasound together can offer efficient pain management options.","It is also believed that combining electrical stimulation, thermal and ultrasound therapies together can offer rapid healing of fractured bones.","For any of the treatments described, the delivery of the thermal therapy, ultrasound, and/or electrical stimulation or any combination thereof described may be pulsed.","The delivery of the heat therapy, ultrasound, and/or electrical stimulation or any combination thereof described may be continuous.","The delivery of the heat therapy, ultrasound, and/or electrical stimulation or any combination thereof described may be alternated.","The delivery of the heat therapy, ultrasound, and/or electrical stimulation or any combination thereof described may alternate between pulsed and/or continuous.","The particular therapy may be optimized for the patient.","If pulsed, it is possible for the time range of the pulsing to the separated by microseconds, milliseconds or seconds.","Typically, electric stimulation pulsing could be in the order of micro to milliseconds.","Acoustic pulsing could be in the order of milliseconds.","Thermal pulsing may be in the order of seconds to minutes.","In some embodiments, the therapy device may communicate with a physician computing device to provide personalized care via application of personalized pain management therapy through customized application of electroceuticals, and thermoceuticals.","For example, a physician computing device can receive inputs from a healthcare provider for setting the initial physical therapy and adjusting the therapy as the treatment is applied.","The initial pain management therapy may also be set via a patient computing device communicatively coupled to the pain therapy device.","The initial pain management therapy indicates the specific combination and intensity levels of electroceuticals, thermoceuticals, and/or ultrasound.","During treatment, sensors communicatively coupled to the pain management device detect the physiological responses resulting from the application of the pain management therapy.","The pain therapy device also receives patient feedback indicating pain relief scores via a user interface for the patient computing device (or entered directly from the graphic user interface of pain therapy device).","The pain therapy device continues to apply the physical therapies (e.g., the electroceuticals, thermoceuticals, ultrasound, acupuncture, pressure/massage based therapies) indicated in the therapy until the physiological responses/patient feedback indicates a threshold pain management level has been reached.","For example, as the pain management therapy is applied, the sensors coupled to the pain therapy device may detect an increase in blood flow or an increase in blood-oxygen levels at the localized area of pain.","If the rate of blood flow (or bone healing) and the value of the blood-oxygen levels reach a threshold value specified in the pain management treatment, the pain therapy device reduces or completes the application of the physical therapies.","Similarly, the pain therapy device may receive feedback from the patient via a user interface indicating the pain has decreased (e.g., by indicating a pain relief score on a 0-5 or a 0-10 scale).","In response, the pain therapy device continues or completes or modifies the application of the physical therapies.","For example, a therapy analysis engine executing on the pain therapy device receives updates from a physiological data collection engine and from a patient feedback interface and uses the collected information to iterate the dosage of the physical medicine.","Embodiments disclosed herein also recognize that the demographics of chronic pain patients (or patients with fractured bones) and the physical therapy requirements are unique.","It has been well documented in the literature that people with certain pain symptoms, do not respond to electroceuticals and thermoceuticals (or even pharmaceuticals) in similar fashion.","For example, some people may get pain relief using TENS, and others may not respond to such a therapy at all, and may even have allergic reaction.","Therefore, the physiology of individuals and the patient feedback plays an extremely important role in determining the ideal/optimal therapy.","In addition to being responsive to patient feedback and physiological response from an applied pain therapy, the pain therapy device further tailors or “titrates” physical medicine(s) dosage (energy type(s), intensity, exposure depth and duration) based on the patient demographics (e.g.","age, gender, body mass index, ethnicity, pre-existing health conditions and cultural background).","For example, the server system includes a patient analytics database that stores patient demographics and applied therapy information (e.g., the specific combination of the physical therapies applied and the dosage levels) as well as information on outcomes of the applied pain management therapy on multiple individuals that had previously applied pain management therapies.","The database may comprise enormous amount of information from hundreds or thousands or even millions of individual patients and provides a powerful tool to conduct data analytics (analogous to an automated virtual/crowd-sourced clinical study that constantly gets updated with addition of ever increasing data sets) and customize the pain therapy for individuals either in an automated fashion or through prompt response from the physician.","The analytics data can indicate the statistical likelihood of satisfactory pain management outcomes from application of the pain therapy.","The pain therapy device connects with the server system over a network to compare the patient information for a specific patient with the patient information in the analytics data to identify a subset of individuals that have similar characteristics as the patient.","For example, the therapy analysis engine may comprise a software application or software module executing in either the pain therapy device or the server system.","The therapy analysis engine identifies a subset of individuals that are with the same age range, gender, body mass index, and other pre-existing medical conditions, pain therapies received in the past or on-going (including drugs, or surgical procedures or alternate medicines), physical characteristics as the patient.","The therapy analysis engine also identifies one or more pain management therapies that were applied to the subset of individuals that resulted in favorable pain management outcome.","The pain therapy device can thus personalize the applied pain management therapy based on subjective data such as patient feedback, objective data such as physiological responses to the applied therapy, as well as analytics data that can indicate the personalized pain management therapy as collected from other patients with similar characteristics as the patient.","The pain therapy device can transfer the patient information and the pain management therapy information through wireless connectivity to the database for storage in the analytics system.","In this way, the pain management adds the current patient's information (e.g., demographic information, symptoms, etc.","), applied pain management therapy, and therapy outcomes (e.g., patient relief scores and physiological changes resulting from the therapy) to the analytics database.","These illustrative aspects and examples are given to introduce the reader to the general subject matter discussed here and are not intended to limit the scope of the disclosed concepts.","The following sections describe various additional features and examples with reference to the drawings in which like numerals indicate like elements, and directional descriptions may be used to describe the illustrative aspects but, like the illustrative aspects, should not be used to limit the present disclosure.","FIG.","1 is a block diagram depicting a pain therapy device 100 that connects to a server system 130 over a network 115 to provide personalized pain management therapies based on measured physiological/sensor feedback data (including blood flow and musculoskeletal characterization related data), subjective patient input data (e.g., a pain relief score), and analytics data compiled on other patients and applied pain therapies.","The pain therapy device 100 can be communicatively coupled to a patient computing device 120 and/or a physician computing device 110 for receiving feedback to adjust the applied pain management therapy.","The pain therapy device 100 includes a memory 101 that stores executable program code for performing operations described herein.","For example, memory 101 includes program code for execution of a physiological/sensor data collection engine 102, a therapy analysis engine 104, a server system interface engine 106, and a patient feedback interface 107.In another embodiment, the server system 130 includes program code for the therapy analysis engine 131.An initial pain management therapy may be programmed via physician computing device 110 or patient computing device 120.In some embodiments, the patient using the pain therapy device 100 may communicate directly with a health care provider via patient computing device 120 and physician computing device 110.The patient computing device 120 and the physician computing device 110 may comprise any suitable computing device, such as a personal computer, a tablet computer, or a cell phone.","The initial pain management therapy may be personalized based on patient information (i.e.","information on the user of pain therapy device 100).","For example, the physician computing device 110 includes a physician interface application 112 that presents options for inputting patient information (e.g., patient pain symptoms, demographic information, medical history, and additional information) and a personalized pain management therapy based on the patient information.","A healthcare provider operating the physician computing device 110 can prescribe the personalized pain management therapy via the physician interface application 112.For example, the physician interface application 112 presents a user interface for selecting a physical medicine via a combination of electroceuticals, or thermoceuticals.","In other embodiments, the patient computing device 120 includes a patient interface application 122 for inputting patient information.","Via the patient interface application 122, the patient provides inputs regarding the personalized pain management therapy as discussed or otherwise prescribed by the healthcare provider.","The personalized pain management therapy can thus be administered via the health care provider or self-administered via the patient.","One or more applicators 124 connected to the pain therapy device 100 apply the personalized pain management therapy input via physician interface application 112 or patient interface application 122 or directly through physical therapy device 100.The personalized pain management therapy comprises of physical therapies that include a combination of electrical stimulation, hot and cold stimulation, and ultrasonic pulses.","In some embodiments, based on feedback received from physician computing device 110 and patient computing device 120, the therapy analysis engine 104 executing on the pain therapy device 100 adjusts the applied personalized pain therapy accordingly.","For example, inputs received via a patient feedback interface 111 presented on physician computing device 110 or patient feedback interface 121 presented on patient computing device 120 may indicate a pain relief score from a value of 0-10, with 10 indicating the most intense pain and 0 indicating no pain.","It should be understood that other values or indications could be used, such as emoticons, descriptive text, color, or a selection on a continuum.","As the personalized pain management therapy is applied via applicator 124, a pain relief score may be received indicating a low measurement of pain.","A satisfactory application of personalized pain management therapy can be based, for example, on reduction of a pain relief score by a certain pre-programmed threshold.","In response, the therapy analysis engine 104 may adjust the personalized pain management therapy by adjusting the dosages and intensities of physical therapies to accommodate for lesser pain.","The feedback comprising the pain relief score may also be received directly on a user interface on pain therapy device 100.For example, memory 101 of patient therapy device 100 may include program code for executing a patient feedback interface 107 used to receive feedback to the therapy from the patient.","In further embodiments, the therapy analysis engine 104 adjusts the personalized pain therapy in response to physiological measurements detected via one or more sensors coupled to pain therapy device 100.For example, a physiological data collection engine 102 executing in memory 101 of pain therapy device 100 may receive information on the blood-oxygen levels, rate of blood flow, and tissue thickness from connected sensors.","The personalized pain management therapy may include instructions on applying physical therapies at specific dosage levels and adjust the applied physical therapies in response to changes in physiological measurements.","For example, the therapy analysis engine 104 may apply a combination of electrical stimulation at a certain intensity level, heat stimulation at a certain temperature, and ultrasonic pulses until a physiological responses indicate a blood flow of a certain rate.","Once the specified blood flow rate (or blood oxygen levels) is achieved, pain therapy device 100 may apply physical therapies with different intensity levels/temperature values.","This process continues until the pain management therapy is complete (e.g., the prescribed physical therapies are fully administered).","In additional embodiments, patient symptoms and demographic information on the patient (i.e.","user of pain therapy device 100) may be compared with analytics information stored on multiple other patients to determine the personalized pain management therapy.","The analytics data is stored on a patient analytics database 132 in server system 130 and comprises patient information compiled on numerous other patients.","For example, the stored patient information includes data on prior patient demographics, prior patient pain symptoms, the pain management therapies previously applied on the other patients, and the outcomes of the pain management therapies (e.g., indicating satisfactory outcome, unsatisfactory outcome, etc.).","The analytics data can also include the average pain feedback score that was indicated by the prior patients in response to previously applied pain management therapies.","In one embodiment, a server system interface engine 106 is a software application or module executing in pain therapy device 100.The server interface engine 106 transmits data comprising the patient information to server system 130.The server system interface engine 106 provides instructions for communicating the patient information to server system 130 and receiving information in response from server system 130.Based on the received patient information, a therapy analysis engine 131 executing on the server system 130 identifies a subset of individuals that have similar characteristics as the user of pain therapy device 100.For example, therapy analysis engine 131 may identify a subset of individuals that are in the same age range, have the same gender, have a similar body mass index as the user of pain therapy device 100, and/or have similar pain symptoms, or any combination thereof.","The therapy analysis engine 131 may also identify a prior applied pain therapy among the subset of individuals that is associated with a pain therapy outcome indicating reduced pain symptoms.","For example, the therapy analysis engine 131 may identify a prior applied pain therapy among the subset of individuals that indicates a satisfactory pain management outcome.","A pain therapy with a satisfactory pain management outcome may include pain therapies that have resulted in reduced pain relief scores by a certain threshold (e.g., 2 points or more).","A pain therapy with a satisfactory pain management outcome may also be indicated when a health care provider has approved a given therapy or removed a patient who has had a successful result with the therapy.","A pain therapy with a satisfactory pain management outcome may also be indicated by accomplishment of objective physiological measurements such as reduction in inflammation or improvement in range of motion, improvement in local blood oxygen levels or flushing out toxins in the injured body part or visually observation of parameters such as wound healing or bone healing or any measurable parameters that either directly or indirectly correlate with reduction in pain as deemed appropriate by physician.","The selected pain management therapy based on the analytics data is transmitted to the pain therapy device 100.Because the received pain management therapy is determined from prior therapies applied on patients with similar characteristics to user of pain therapy device 100, the received pain management therapy is personalized to the user of pain therapy device 100.In another embodiment, the pain therapy device receives the analytics data on other patients from the server system 130.The therapy analysis engine 104 executing in pain therapy device 100 uses the received analytics data to select the subset of individuals that have similar characteristics as the user of pain therapy device 100.In this embodiment, the therapy analysis engine 104 identifies a personalized pain management therapy that, from the analytics data, indicates prior satisfactory outcome (e.g., reduction in pain symptoms).","The analytics data is depicted as stored in patient analytics database 132 in server system 130 for illustrative purposes.","In other embodiments pain therapy device 100 stores the analytics data.","FIG.","2 depicts a block diagram illustrating the logical components of pain therapy device 100.Pain therapy device 100 includes a micro-controller unit (MCU) 210.MCU 210 includes processing devices such as an application specific integrated circuit (ASIC), or any general-purpose processor.","MCU 210 can include logic for connecting to external interfaces 250-264.For example, MCU 210 includes an audible transducer 250, an LCD interface 252 (or interface for any other type of user interface device), a reset switch 254, an RS232 port 256, an Inter Circuit Serial Programming (ICSP) and Joint Test Action Group (JTAG) port 258, a Bluetooth interface 260, a WiFi interface 262, and a network interface 264 (e.g., an Ethernet port).","The MCU 210 is also coupled to sensors for receiving physiological measurements from the user of pain therapy device 100.Said sensors include temperature sensor 230 (for measuring the body temperature of the patient at the point of contact of the applicator 124, blood flow sensor 232 (for measuring the blood flow rate at the point of contact of the applicator 124), oxygen sensor 234 (for measuring the blood-oxygen level at the point of contact of the applicator 124), tissue thickness sensor 236 (for measuring the thickness of the tissue at point of contact of applicator 124), and an applicator surface contact sensor 238 (for detecting if the applicator 124 is in contact with tissue.","In some embodiments, sensors 230-238 can be included as part of applicator 124 (as shown further below in FIG.","3).","The MCU can also include or be in communication with a computer-readable medium storing instructions that, when executed by the MCU 210, cause the MCU 210 to perform the operations described herein.","For example, the MCU 210 is in communication with memory 101, which includes any suitable non-transitory computer-readable medium.","The computer-readable medium includes any electronic, optical, magnetic, or other storage device capable of providing a processor with computer-readable instructions or other program code.","Non-limiting examples of a computer-readable medium include a magnetic disk, memory chip, ROM, RAM, an ASIC, a configured processor, optical storage, magnetic tape or other magnetic storage, or any other medium from which a computer processor can read instructions.","The instructions include processor-specific instructions generated by a compiler and/or an interpreter from program code written in any suitable computer-programming language, including, for example, C, C++, C#, Visual Basic, Java, Python, Perl, JavaScript, and ActionScript.","The program code includes one or more of a physiological data collection engine 102, therapy analysis engine 104, server system interface engine 106, and patient feedback interface 107.The MCU 210 can also be communicatively coupled to control inputs 222-234 for controlling the characteristics of the pain management therapy as applied by applicator 124.Control inputs 222-234 include a heat switch 222, cold switch 224, ultrasound switch 226, ultrasound intensity control 228, ultrasound duty cycle 230, electric stimulation switch 232, and infrared switch 234.Ultrasound switch 226, ultrasound intensity control 228, and ultrasound duty cycle control 230 (which control the respective characteristics of the ultrasound pulses that are part of the pain management therapy) are fed to ultrasound power amplifier 236.Ultrasound power amplifier 236 provides necessary amplification of the signals before driving the ultrasound output of applicator 124.The output from electric stimulation switch 232 can be fed to electric stimulation circuit 238 before driving the electrical characteristics of applicator 124.Similarly, output from infrared switch 234 can be fed to infrared circuit 240 before driving infrared output of applicator 124.Via heat switch 222 and cold switch 224, temperature characteristics of applicator 124 can be specified.","The output of heat switch 222 and cold switch 224 for controlling the temperature characteristics are provided to applicator 124.In some embodiments, the control inputs 222-234 can be coupled to MCU 210 via an I2C expander port 220.A medical grade power supply 202 can provide the power requirements to the components herein.","For example, medical grade power supply 202 provides power to ultrasound power amplifier 236, applicator 124, electric stimulation circuit 238, and infrared circuit 240.FIG.","3 illustrates a representation of the various components present in the applicator 124, as shown as different layers.","The sequencing of the various layers could be altered and does not necessarily have to be in the order shown in FIG.","2.Further, multiple layers/components of the applicator 124 could be embedded into a single layer or form physically distinct layers.","The control inputs 222-234 provide the electrical signals that control the various layers of applicator 124.The layers for applicator 124 can be placed on the surface area of the tissue of the patient for whom the pain management therapy is applied.","Applicator 124 can include a heat sink component 302, which measures the temperature of the tissue on which the applicator 124 is applied.","The thermoelectric element component 304 applies the hot or cold temperature as specified by heat switch 222, cold switch 224, and the specific temperature as set by MCU 210.The applicator 124 can also include a PCB & LED component 306 that can display.","The PCB inside the applicator integrates the thermoelectric elements, sensors, ultrasonic transducer and TENS electrodes and simplifies the connectivity.","The PCB is also capable of connecting to any additional sensors or thermal energy generating transducers integrated into the applicator (e.g., blood flow detection sensor, infra-red radiation source etc.).","The LED component visually indicates the status of applicator such as ON or OFF (especially, for the convenience of care providers).","In some embodiments, the applicator 124 can also include built in sensors 308, which include one or more of the temperature sensor 230, blood flow sensor 232, oxygen sensor 234, tissue thickness sensor 236, and applicator surface contact sensor 238.Some of the described sensors could be used to characterize several musculoskeletal characteristics, such as tissue healing and/or bone healing properties.","Applicator 124 can also include a substrate component 310 and/or electrode component 311 for applying the electrical impulses as driven by electric stimulation circuit 238.Applicator 124 can also include an ultrasound transducer for applying the ultrasound impulses driven by ultrasound power amplifier 236.In some embodiments, the sensors 308 measure the substrate 310 and/or electrode 311 temperature and send the temperature to the MCU 210.The sensors 308 could gather a variety of medically useful/diagnostic data related to treating pain, healing fracture bones, and may help monitoring the progress of healing or administering right dosage for a given therapy as defined.","The ultrasound transducer 312 can be utilized by the therapy analysis engine 104 to identify the thickness or depth of the tissue based on ultrasound reflection intensity measured.","This kind of sensing feature helps provide for the inclusion of safety features regarding the device usage on different parts of the body (e.g., it is possible to prevent the usage of the device on the head or skull of the patient).","The sensing feature also enables the determination of physical dosage to be delivered to a targeted area.","FIG.","4 is a flowchart depicting an example process 400 for applying a personalized pain management therapy based on stored analytics data on numerous other prior patients and adjusting the applied therapy based on physiological feedback.","This is conceptually similar to a flow chart that could be used for rapid/personalized healing of fractured bones.","The process 400 may be performed by one or more of the components listed in FIGS.","1-3 or in any suitable computing and/or communication environment.","The process 400 involves receiving patient information specifying patient demographic data, patient physiological data, and patient pain symptoms, as shown in block 410.Demographic data can include information on patient such as age, gender, body weight and BMI, race, and geographic information.","Patient pain symptoms include descriptions of patient pain symptoms and indications of pain.","For example, patient pain symptoms can include a graphical indication of a body part (e.g., by selection of an area of a body on a touch screen) to show areas of localized pain, textual descriptions of the areas of localized pain, and a numeric pain relief score indicating the severity of the pain at the specified location.","Pain symptoms can also be more or less detailed.","All common chronic pains and musculoskeletal pains such as back pain, neck pain, shoulder pain, arthritis, muscle spasms, tendonitis, bursitis, sports injuries are either visually or verbally represented.","Any other form of pain that requires diagnosis by qualified physician (e.g., fibromyalgia) or that cannot be treated using pain therapy device (visceral pain, especially involving cutting, burning and/or involving internal organ damage) will not be included in the system as a default.","Patient physiological data includes physiological measurements of a measured tissue area.","Physiological measurements include, for example, the measured rate of blood flow, blood-oxygen levels, tissue depth, tissue composition, tissue temperature, bone strength, callus stiffness, acoustic emissions/reflections from fractured/partially healed/fully healed or normal/healthy bones, ultrasound velocity and attenuation across a healing fractured bone and other measurements.","The patient information may be received via inputs in physician interface application 112 in physician computing device 110 or patient interface application 122 in patient computing device 120 and transmitted to pain therapy device 100.In other embodiments, the patient information can be directly entered in pain therapy device 100 via a user interface on the pain therapy device 100.While the pain therapy device 100 can process the patient information to determine the personalized pain management therapy, in other embodiments, the patient information is transmitted to server system 130.Process 400 also includes comparing the received patient information with pain analytics data compiled on a plurality of individuals to determine a recommended pain management therapy, as shown in block 420.For example, the server system 130 includes a patient analytics database 132 that stores the pain analytics data on numerous prior patients.","The pain therapy device 100 can transmit the patient information to the server system 130 for the comparison.","In other embodiments, the pain therapy device 100 can receive the analytics data from the server system 130 via network 115 for the comparison.","Therapy analysis engine 104 (executing in pain therapy device 100) or therapy analysis engine 131 (executing in server system 130) compares patient information with the pain analytics data to determine a subset of individuals with similar characteristics as the patient as explained above with respect to FIG.","1.Additionally, therapy analysis engine 104 or therapy analysis engine 131 identifies the recommended pain management therapy that previously depicted a satisfactory outcome (e.g., by lower received pain relief scores from other patients, from objective measurements of physiological data indicating lesser pain symptoms).","As shown in block 430, the recommended pain management therapy is applied via an applicator device 124.For example, the applicator device 124 provides one or more electroceuticals, or thermoceuticals, or ultrasound, or any combination at a specific frequency, intensity, and/or duration as specified by the recommended pain management therapy.","Note in some aspects, the recommended pain management therapy can be overridden and manually input via inputs received from physician computing device 110 or patient computing device 120.After application of the recommended pain management therapy (which is initially based on the analytics data on pain management therapies applied on other patients), the pain therapy device 100 can further adjust and personalize the therapy based on feedback from the patient.","As shown in block 440, process 400 further involves receiving, from one or more sensors, updated physiological data reflecting changes in the patient physiological data, and subjective patient feedback (in the form of pain score) in response to the applied recommended pain management therapy.","For example, as the recommended pain management therapy is applied by applicator 124, sensors 230-238 measure changes in the temperature, blood flow rate, blood-oxygen levels, and tissue thickness resulting from the therapy.","The sensor data can be received via a physiological data collection engine 102.The changes in the physiological data in response to the applied pain management therapy can be considered objective feedback to the pain management therapy.","Note that while the type of feedback in response to the applied pain management therapy described in block 440 is feedback from physiological data, other types of feedback are also possible.","For example, the pain therapy device 100 can receive subjective feedback from the patient in the form of a patient relief score (e.g., a numeric value from 0-10) as discussed above with respect to FIG.","1.The therapy analysis engine 104 can adjust the applied pain management therapy (or bone healing therapy) in response to the changes in physiological data (or in response to other feedback), as shown in block 450.For example, the applied voltage or current of the electrical stimulation, the temperature of the heating element, or the intensity of the ultrasonic pulses can be adjusted based on the changes in the physiological data or sensor data or based on patient feedback.","Probably, the pain relief scores from patients in conjunction with objective physiological data (whenever available) could be used to adjust or titrate the dosage of the physical medicine involving single or combination of therapies.","For example, the thermoceutical dosage may be defined by three parameters, i.e., intensity (e.g., temperature range; frequency, intensity and duty cycle in case of ultrasound), energy exposure time, and course duration for a given tissue thickness or composition (or BMI).","If the physical medicine dosage delivered does not increase the tissue temperature or raise the deep tissue temperature in stipulated time frame and/or for sustained time period, and/or do not provide pain relief to the patient, one could consider the dosage delivered is sub optimal.","At present, our understanding about how distinct physical modalities or their combination therapies at what dosage levels provide efficient pain relief is relatively limited.","Further complexity stems from the fact that pain is a subjective personal experience, and the physiology of individual is different from each other and the way each individual responds to given therapy is unknown.","If a patient does not respond to a particular electroceutical or thermoceutical pain therapy, it is not generally implied that the given therapy does not work; it only implies that given therapy is not appropriate for that patient.","Therefore, it is important to identify the patterns from various therapies provided to patients with diverse backgrounds and profiles to develop a personalized pain therapy.","Typically, the dosage delivered will always be within the safety limitations as outlined by data published in the literature, the dosages will be titrated based on positive response from patients (i.e., lower pain scores).","Once adequate data is accumulated from patient responses, it is possible to correlate pain relief (or rate of bone healing) measured in response to given physical medicine dosage with quantifiable physiological data or body reflex related measurements (e.g., increase local blood flow of injured body part, thermal imaging, tissue temperatures, blood oxygen levels, sensitivity to pressure etc.)","and constitutes one of the inventive aspect of this innovation.","As shown in block 460, the therapy analysis engine 104 makes a determination as to whether the updated physiological data indicates reduced pain symptoms (or faster bone healing).","For example, the physiological changes in treated body part may include vasodilation, vasoconstriction as quantified by blood flow volume or velocity or by variation in blood oxygen levels or simply by measurement of tissue temperature or measurement of pressure sensitivity to pain (using algometer) or it could even include identification/measurement of certain cellular or molecular changes or electrical signals caused in response to external stimulation.","If the updated physiological data or patient feedback indicates reduced pain symptoms (it is possible that subjective and objective evaluation results may not converge, the patient feedback coupled with statistics may precede physiological measurements), the patient information, patient feedback, the updated physiological data, the recommended pain management therapy, and the adjusted pain management therapy are stored in the analytics database, as shown in block 470.For example, physiological data indicating reduced pain symptoms can be considered a satisfactory application of the pain management therapy.","To add to the pain analytics database, the server system interface engine 106 executing on pain therapy device 100 can transmit one or more of the patient information (indicating the initial set of physiological measurements), the updated physiological measurements, the recommended pain management therapy (as derived from the pain analytics database), and/or the adjusted pain management therapy (as adjusted based on this individual patient's physiological responses) to the server system 130.The server system 130 stores the received information in patient analytics database 132.If the updated physiological data and/or patient feedback does not indicate reduced pain symptoms, a different pain management therapy may need to be selected.","In response to the lack of reduction of pain symptoms, the patient information, updated physiological measurements, recommended pain management therapy, and adjusted pain management therapy are first stored in the analytics database, as shown in block 480.This adds to the database and indicates a therapy that does not necessarily work for patients with characteristics similar to the user of pain therapy device 100.The process 400 then returns to block 420, where the therapy analysis engine 104 compares the patient information with pain analytics data to determine a different pain management therapy.","The process 400 continues until a satisfactory pain management therapy is found.","Any suitable computing system or group of computing systems can be used to implement the physician computing device 110 and the patient computing device 120 described in FIG.","1.For example, FIGS.","5-6 are block diagrams depicting examples of implementations of such components.","As shown in FIG.","5, the physician computing device 110 includes a processor 1002 that is communicatively coupled to a memory 1004 and that executes computer-executable program code and/or accesses information stored in the memory 1004.The processor 1002 comprises, for example, a microprocessor, an application-specific integrated circuit (“ASIC”), a state machine, or other processing device.","The processor 1002 includes one processing device or more than one processing device.","Such a processor is included or may be in communication with a computer-readable medium storing instructions that, when executed by the processor 1002, cause the processor to perform the operations described herein.","The memory 1004 includes any suitable non-transitory computer-readable medium.","The computer-readable medium includes any electronic, optical, magnetic, or other storage device capable of providing a processor with computer-readable instructions or other program code.","Non-limiting examples of a computer-readable medium include a magnetic disk, memory chip, ROM, RAM, an ASIC, a configured processor, optical storage, magnetic tape or other magnetic storage, or any other medium from which a computer processor can read instructions.","The instructions include processor-specific instructions generated by a compiler and/or an interpreter from code written in any suitable computer-programming language, including, for example, C, C++, C#, Visual Basic, Java, Python, Perl, JavaScript, and ActionScript.","The physician computing device 110 also comprises a number of external or internal devices such as input or output devices.","For example, the physician computing device 110 is shown with an input/output (“I/O”) interface 1008 that receives input from input devices or provide output to output devices.","A bus 1006 is also included in the physician computing device 110.The bus 1006 communicatively couples one or more components of the physician computing device 110.The physician computing device 110 executes program code that configures the processor 1002 to perform one or more of the operations described above.","The program code includes one or more of the patient feedback interface 111 or the physician interface application 112.The program code is resident in the memory 1004 or any suitable computer-readable medium and is executed by the processor 1002 or any other suitable processor.","In additional or alternative embodiments, one or more modules are resident in a memory that is accessible via a data network, such as a memory accessible to a cloud service.","The physician computing device 110 also includes a communication interface 1010.The communication interface 1010 includes any device or group of devices suitable for establishing a wired or wireless data connection to one or more data networks 115.Non-limiting examples of the communication interface 1010 include an Ethernet network adapter, a modem, and/or the like.","The physician computing device 110 transmits messages as electronic or optical signals via the communication interface 1010.Similar to the physician computing device 110, the patient computing device 120 also includes a processor 1102, I/O interface 1108, communication interface 1110, and memory 1104 communicatively coupled via a bus 1106.The memory 1104 includes non-transitory computer-readable memory as described above and stores program code defining operations of the patient computing device 120.The processor 1102 executes the computer-executable program code and/or accesses information stored in the memory 1104.For example, the patient computing device 120 includes memory 1104 that stores program code for the physician interface application 121 and the patient interface application 122.The following paragraphs describe further illustrative embodiments for the pain therapy device 100.There may be provided a pain therapy device that is useful in treating various physiological conditions.","The device may include a controller, sensors and an applicator.","The applicator generally features a plurality of transducers that produce electrical, heat, cold and ultrasound energies respectively.","The controller provides the required electronics to control energies produced by the transducers.","The controller is configured to modify the intensity, timing, or duration of the different energies, which are applied over the treatment area (skin) over the feedback control signal obtained from the sensors.","Both the controller and the applicator may be cooperate either by wired communication or can communicate wirelessly.","They may be integrated into a single product.","The pain therapy for use herein can carry out therapeutic treatment using the lowest possible energy intensities in order to achieve a therapeutic effect.","One or more of a combination of electric stimulation (electroceuticals), thermal stimulation (thermoceuticals via application of heat, cold) or ultrasound (pulsed or continuous), when applied to the treatment area in a systematic manner, has been demonstrated to show synergistic effect leading to better and faster therapeutic relief Superficially applied heat follows a top-down heating mechanism through conduction and heat may not get transferred beyond top 1 cm to 2 cm depth of the tissue (note that skin and tissue beneath it are poor thermal conductors).","On the other hand, ultrasonic energy can heat up both surface and deep tissue (from 1 cm to 5 cm) easily as the acoustic energy absorbed by the tissue gets converted into thermal energy.","Because of these fundamentally distinct modes of heating (conductive heating vs. converted heating), use of ultrasound and superficial heat combination rapidly creates a thermal gradient across the treated tissue leading to significantly higher blood flow rates quickly unlike conventional single form of thermal energy based therapies.","Therefore, it is possible to provide improved oxygen supply to injured body part for sustained periods of time, and flush out unwanted inflammation causing chemicals to provide rapid and sustained pain relief Cold also follows a top-down thermal conduction, where cooling of the dermal and sub-dermal layers (top 1 cm to 2 cm) shows several beneficial effects with regard to treating acute injuries.","Cold can decrease cellular metabolism and causes vasoconstriction of the blood vessels in the area and decreases the inflammation in the area and thus the associated pain and swelling.","In combination with ultrasound, cold may provide an additive effect.","For example, combination of cold and ultrasound energies together can create an inverse thermal gradient for improved blood flow, that is, the surface temperatures of the top most tissue layer will be below body temperature, while the deep tissue temperatures will be above body temperature.","Indeed, such an inverse thermal gradient, which is practically impossible to accomplish from conventional thermal therapies may be extremely useful for safely heating deep tissue to 45-70° C. rapidly for shorter time periods for face lifting and cosmetic applications.","Providing these energies in a controlled pulsatile manner can help reduce the risk of adverse effects, while still achieving the desired therapeutic effect.","Because a larger volume of dermal and sub-dermal tissues can be exposed to the energies when used in combination, especially thermal energy and ultrasound, there may be increased blood flow around the treatment area providing fresh oxygen and nutrients, and increasing subsequent tissue metabolism.","Similarly, the combination of electric stimulation (e.g., TENS) and thermal stimulation may offer synergetic benefits both in terms of improving local blood flow and efficiently masking pain signals.","Therefore, combination therapies not only account for individual patient related physiologies, but also provide an opportunity to precisely fine tune or titrate body reflexes across the deep tissue to provide rapid pain relief and other related therapeutic benefits (e.g., faster tissue regeneration giving relief from pain, wound healing, blocking pain sensation reducing pain, inflammation, spasms, and other side effects).","In one example, pulsed heating may be synchronized with pulses of pressure waves such that both pulses reach the target simultaneously.","In another example, pulsed cooling may be synchronized with pulses of pressure waves such that both pulses reach the target simultaneously.","In another example, pulsed heating is followed by pulsed cooling and both are synchronized with pulses of pressure waves such that both pulses reach the target simultaneously.","In another example, TENS, ultrasound and surface heating can be synergistically applied to treat the entire cross section of the tissue.","In another example, TENS, ultrasound and cold could be synergistically applied to accomplish targeted goals.","The recent scientific advances made in medicine us realize that personalizing the medication or therapies is critical for achieving efficacious therapeutic benefits across the diverse population.","The current approaches of using physical medicine indiscriminately across the various patient population leads to application of inconsistent therapies, and dosages and results in inefficient or inferior therapies, which may be randomly successful or unsuccessful.","For example, the tissue thickness of a 300 pound person is different from 100 pound person, and so is the composition of the tissue, but if one applies electroceuticals or thermoceuticals identically to both these weight groups, the results may not be identical—after all, the applied energies are identical, but not the injured body parts.","Further, the pathophysiology of each individual is different, and it is difficult to provide universal medicine for pain without personalizing it, especially physical medicines that do not cause adverse side effects.","One more complex problem associated with pain is that patients' opinions/perceptions regarding pain are subjective and cannot be measured independently/objectively.","Patients' perceptions about pain (especially chronic pain) may dynamically change; their response to a particular therapy may also change either positively or negatively over a period of time.","Therefore, personalization of precisely dosed combination therapies accounting patient feedback provides an unprecedented opportunity to treat pain safely and efficiently.","FIG.","7 shows a schematic block diagram of an exemplary pain therapy device.","This device may be used with the treatment methods described herein.","The device includes a controller and applicator.","The power is provided by a battery or capacitor of a suitable power supply unit.","The controller includes a microprocessor unit and controls a plurality of electronic circuit modules for the generation of different energy, such as thermal energy (0 to 70° C., more specifically from about 0-50 ° C.) and ultrasound (0.2 to 20 MHz, or in other examples from about 0.1 to about 10 MHz).","Alternatively, or in addition, the controller may deliver electro stimulation to the body in a post or continuously in the frequency range of about 1-200 Hz, pulse amplitude in the range of 0 mA to 500 mA, pulse width in that 1 micro second to millisecond range.","The controller may be programmed for the duration, switching sequence and intensity of each of these energies.","The applicator may include transducers capable of delivering heat, cold and ultrasound and/or electro stimulation to the skin/treatment area.","The applicator also features a plurality of sensors for the purpose of feedback and control.","The sequencing of the various layers could be altered and does not necessarily have to be in the order as shown in figures.","FIGS.","8A and 8B show the schematic cross sections of different possible pain therapy device designs.","Controller (1) comprises of electronic circuitry (3), rechargeable battery (4), on/off switch (6) and an LED indicator (5).","FIG.","8A illustrates the integrated design where both the controller and applicator makes a single unit.","Whereas FIG.","8B illustrates the two piece design in which both the controller and applicator are two separate entities and are connected through a wire/wireless.","FIGS.","9A to 9C, FIGS.","10A and 10B, FIGS.","11A and 11B, FIGS.","12A and 12B, and FIGS.","13A and 13B illustrate schematic cross sections of different exemplary applicator designs.","The applicator generally includes an ultrasound transducer (8), heat/cold transducer (10), insulation layer (9), temperature sensors/PCB (11), top cover (7) and bottom cover.","In some embodiments, applicator may also include internal PCB, multiple sensors, and electrodes.","In some of the embodiments this also includes side support (13).","In some embodiments the ultrasonic energy from applicator is transferred into the body through conducting media.","U.S. Pat.","No.","9,710,607 provides more detail about these devices, the entire disclosure of which is incorporated herein by reference.","In one example, the power source used to operate the device can be a rechargeable battery, an AC power adapter and/or a capacitor.","The input power unit may be configured for delivering current of range 0.1 mA to 4000 mA and delivering potential of range 2V to 120V to deliver multiple therapies at different currents or voltages.","For example, the current and voltages used for accomplishing, heat, cold, ultrasonic and TENS (or IFT, interferential therapy) energies may be different.","The device can include a plurality of circuit blocks configured and connected to various transducers for converting the input energy to heat, cold and ultrasound.","This section may have a switch to keep the device in on/off/standby mode to conserve energy when not in use.","The standby function is optionally automated based on the program in the controller.","A controller can be provided for containing the required software for operation.","The controller also interfaces with the detecting transducers for the required computation for quantifying the detected values.","When various forms of energy are supplied to the treatment area via a combination effect of control signals, the controller and the transducer can supply pulses with a minimum duration of 1 millisecond or more.","The controller may be further configured/programmed for altering the outputs on the basis of the feedback signals provided by the sensors disposed over the said applicator.","Based on the settings and the program running in the controller, the exact temperature and duration of application of heat or cold or electric treatment or ultrasound can be precisely controlled by this circuit block.","Various durations of temperature and frequencies are possible.","The applicator can have an ultrasound sound transducer and heat and/or cold transducers or TENS (IFT) electrodes along with sensors that gather key diagnostic and therapy related information.","As shown in FIGS.","9A to 9C, 10A, 10B, 11A, 11B, 12A, 12B, 13A and 13B illustrate, these transducers may be aligned one above the other.","In one example, the ultrasound transducer may be positioned above the heat/cold transducer, or the ultrasound transducer can surround the heat/cold transducer and vice versa, or the transducers can be side by side, or the design may be an irregular design to utilize the produced energies efficiently and treat the physiological condition very effectively.","The applicator may also have temperature sensors placed on or around the heating/cooling element to measure the temperatures and send the information to the controller through feedback loop mechanism to maintain constant exposure temperatures.","The sensors can be configured for feedback control of the device.","For example, the sensors can provide control signals to the controller for the optimized and efficient use of the different energies to be applied over the treatment area.","The sensors (which may include ultrasonic transducers that have dual function as sensor and therapeutic agent) can provide additional information regarding blood flow, tissue thickness, tissue composition, tissue image, bone strength, callus stiffness, blood oxygen levels, pain-pressure sensitivity, applicator contact with body and so on.","This can reduce the power usage of the power source/battery and allow for prolonged use without repeated charging.","In use, a gel or other material may be positioned on a patient's skin.","This may help the ultrasound, electrical stimulation and any other form of physical medicine that needs an efficient conductive media to transfer energy into the body.","For example, thermal energy from ultrasound can only be transferred efficiently through a conductive (electrically or thermally or acoustically) gel, while thermal energy from superficial heating may be transferred directly into the body without including any additional conducting medium.","The electrical stimulation also requires conductive gel pads to pass electric current into the body and in between the electrodes.","Further the applicator may also require an adhesive tape to attach it to the body.","It is also possible that the adhesive pads could act as conductive elements, or vice versa.","The gel could be applied in the form of liquid, semi-solid, solid, suspension or slurry.","The applicators can also be attached to the body through strap mechanism.","Therefore, the applicator may come in direct contact with the body partially or fully through an additional conducting medium as required or applicator may come in contact with skin without any conductive medium, if applied therapy do not require such a medium.","In an exemplary embodiment, the method can include directing ultrasound waves at a tissue and heating the tissue with thermal energy.","The thermal energy pulses may be synchronized to arrive at the tissue simultaneously with the ultrasound waves within a preset range, and the heat of each thermal energy pulse can be dissipated in an environment that includes the tissue before a subsequent thermal energy pulse arrives at the tissue.","The deposited heat energy per pulse, the number of pulses, and the repetition rate of the pulses may be determined by a processor according to the temperature and the heat dissipation capability of the tissue.","The electrical energy can be delivered continuously or in pulses at low frequency (2-20 Hz) or high frequency (20 Hz to 200 Hz) in combination with pulsed or continuous thermoceuticals.","Therefore, the above-described intelligent pain management computer systems and methods for managing pain therapy may be implemented using a variety of pain therapy devices or physical medicine delivery systems described herein.","Additionally or alternatively, the method can include directing electro stimulation at the tissue as well.","The compact design of the disclosed device can give a patient the freedom to use the device on the move and/or at home, reducing the clinic visits.","The device can be used/placed on any part of the body and also for any ailment that will respond to these energies.","To provide further explanation, the following examples are provided as additional illustrative embodiments and use cases for the computer-implemented pain management system disclosed herein.","The present disclosure provides, in one aspect, a pain therapy device for delivering at least one form of physical medicine having a microprocessor and wired/wireless networking capability that communicates with mobile or smart phones or computers either through physical connectivity or remotely (e.g., via Bluetooth or wife) and enables users to manage and track therapeutic treatments (e.g., pain therapy).","In one implementation, the application includes software that is stored on a memory of the mobile therapeutic device and is executed by the processor.","The present disclosure also provides a solution for efficiently managing pain without drugs and invasive procedures, by delivering one or more forms of physical therapies either individually, sequentially or in combination.","The physical therapies are compliant and can be self-administered conveniently, safely and cost effectively.","Further, the present disclosure provides a method for connecting patients with the health care providers.","In some examples, it enables them to communicate the progression or regression of the therapy as they experience it along with measurable feedback, compliance data, sensor data, if any.","It also allows them to receive a safe, compliant and efficient therapy.","The present disclosure also provides a method employing an intelligent means for delivering physical medicine to a plurality of patients, with an option from a remote location, comprising the steps of: (i) providing each of the patients with a personal pain therapy device(s) capable of providing one or more forms of physical medicine to patients on demand (at home or at doctor's office); (ii) providing a microprocessor associated with therapy device capable of controlling physical medicine delivery and simultaneously send and receive the information over network(s) to suggest or carry out preferred prescription(s), monitoring and compliance related activities; (iii) providing the usage information, sensing information and compiling the status report of the said therapy device(s) via a network(s); (iv) providing a quantified patient response measurement after each compliance of prescription that is transmitted to the remote computing system for a report; and (v) providing an analysis algorithm on the local or remote computing system for processing the data collected or monitored from the device, sensors, and patients for formulating an automated prescription, modifying a prescription, and assessing the therapy compliance and thereof In a sense, the most efficacious therapy is identified akin to clinical trials, by comparing and contrasting and conducting statistical analysis of various therapy related parameters.","In one embodiment of the present disclosure, a repository database gathers and stores the information regarding individual or collective patient profiles, demographics, disease symptoms, diagnosis, prescription, sensing data, physiological data, device usage/compliance and quantified response from patient and/or health care provider manually, semi-automatically, or automatically over the network.","If the prescribed therapy does not lead to satisfactory results in a given time frame as indicated by the patient feedback, an analytical algorithm recommends alternate therapies involving same physical medicine with different dosages or alternate physical medicine or combination of physical therapies as defined by the rules for providing various physical therapies until the patient experiences most efficacious therapy as indicated by his/her feedback.","Further, the algorithm with access to wider patient database comprising above information, can have the ability to compare the pain symptoms or diagnosis or profile or demographics of the patient to be treated with those in the database and thereby identify the best possible prescription(s) or dosage of physical medicine such that the therapy administered can lead to efficacious therapy.","In another embodiment of the present disclosure, the pain therapy device provided is a wearable pain therapy device that is compact, convenient, and is capable of providing a combination of physical medicine for efficacious and sustainable pain relief.","In another embodiment of the present disclosure, the disclosed system intelligently personalizes pain therapy by electronically connecting the pain therapy device to a physician computing device, enabling the health care provider to receive and view the feedback from the patient seamlessly and search a network-based database comprising data on numerous pain patients along with their patient profiles (i.e.","indicating patient demographic and other information), physiological responses to the therapies, and pain relief scores received in response to the various physical medicine therapies administered.","The disclosed system thereby allows the physician to identify data/statistics driven preferred therapeutic options for personalizing the pain therapy.","The system provides reports and/or graphs of the recorded data such that the compliance and progression of the therapy is monitored, trends are identified, prescription rules are framed or the outcome of the therapy is correlated with the therapy or therapies administered in conjunction with multiple patient profiles with related symptoms, therapies, patient feedback, diagnosis and/or sensing data such as vital signs, tissue temperature, blood flow in painful part of the body etc.","for further evaluation.","In another embodiment, the present disclosure provides a software application (e.g., a mobile application or other program that is executable by a portable device having a processor) that includes a therapy tracking feature that enables patients to record and review various parameter data related to applied pain management therapies.","The parameters may include testable and quantitatively measureable aspects of certain symptoms associated with the therapy.","For example, a symptom of pain may be recorded on a recurring basis (e.g., daily) by the patient ranking the extent of the pain on a fixed scale, such as 0 (for no pain) to 10 (severe pain) or 0 (no pain) to 5 (severe pain) as defined (one could also use painful and smiley faces as a graphical user interface to quantify the pain).","The disclosed software application can provide reports and/or graphs of the recorded data such that trends may be identified, or such that the outcome of the therapy is correlated with the therapy or therapies administered in conjunction with the patient profile and/or physiological data such as vital signs, tissue temperature, blood flow, blood oxygen level, tissue thickness, tissue imaging etc.","for further evaluation.","Some of the parametric values graphed/tabulated or stored include, level of compliance, progression/regression of the therapy, patient profile, demographics, physical modality/dosage administered, and physiological data captured from sensors.","The progression or regression of the pain management therapy may be tracked in response to the historical data being requested; such tracking may include retrieving at least one of the parameters from the repository, and displaying the retrieved parameter in a tabular and/or graphical format.","The tracking of pain management therapy progress and on demand/automated prescription or suggestion options can be tailored (e.g., made compliant with any governing law).","In some embodiments, the patient can request the prescription and the history related to his/her treatment can also be revealed/shared with the patient.","In another embodiment of the present disclosure, the software application includes a calendar/timing feature for scheduling administrations of the pain management therapy treatments and/or appointments, or ensuring the compliance of the prescription provided.","For example, if treatment involves administration of a pain management therapy on a recurring basis, and the calendar feature allows the patient to schedule such administrations and may include reminders.","Similarly, if the patient does not follow the prescription or misses a dosage, the event can be recorded and evaluated as part of the comprehensive therapy review by the physician.","In another embodiment of the present disclosure, the software application provides information related to the pain management therapy and/or ongoing treatments, which is viewable on the communicating device.","The information may include news, company alerts, and/or the parameters related to the therapy outcome.","In some embodiments, the information is received on demand remotely or stored in the memory.","For example, each of the news items may include a news story and/or a company alert.","The said method may also include communicating, through the network interface, one or more messages between the patient and a case manager.","Any one of the messages may be an address change notification, an insurance notification, and/or a vacation notification.","In yet another embodiment of the present disclosure, the software application provides a support feature that enables the user to communicate with, for example, a health care provider, a physician or care manager or head nurse.","In other examples, the user may use the support feature to select a care manager from a list of service providers to ask questions related to the pain management therapy, and/or to request scheduling appointments and other support services.","According to another embodiment of the present disclosure, a system for managing therapeutic treatment of a disease of a patient by a user is provided, including a communicating device having a processor and a memory coupled to the processor.","The said communicating device is constructed and adapted to communicate with at least one server.","A software application is stored on the memory.","The software application is executable by the processor and comprises a physiological data collection engine for collecting physiological data, a data storage module for storing one or more parameters related to the treatment, a tracking module for tracking the parameters, a therapy analysis engine for determining a personalized pain management therapy, and a server system interface engine for communicating information related to the treatment with a health physician, a company, and/or a case manager.","In some embodiments, the communicating device may be a smart phone having a wireless network device, or a personal digital assistant having a wireless network device or a computer.","The information may include news, company alerts, and/or the parameters related to therapy outcome.","The parameters and/or the information are optionally displayed to the user in an interface of the computing device.","The software application may also include a calendar module for scheduling treatment administrations and/or appointments.","The information may include the treatment administrations and/or the appointments.","The parameters may further include parameter data acquired from a medical test and diagnosis of the patient.","The parameters may include a parameter type, a parameter value, and/or a test date.","The parameter type may involve various types of pain symptom such as somatic pain, neuropathic pain, musculoskeletal pains of various body parts, back pain, arthritis (rheumatoid or osteo), elbow pain, bursitis, tendonitis, migraine, headaches, fibromyalgia, post-operative pain, joint pain, tunnel syndrome, tendon or ligament pain, acute injuries; extensibility of collagen tissue, skin lift, skin rejuvenation, facial tightening, decreases in joint stiffness, improvement in range of motion, relief in muscle spasms, increase in global and local blood flow, global and local blood oxygen levels, body/skin temperature, tissue temperature, heart rate, tenderness of the tissue (as measured by algometry), skin pH, vital signs such as blood pressure, body temperature, local metabolism, nerve conduction velocities and so on.","In another embodiment of the present disclosure, the repository database in a server system stores patient profile.","The patient profile may include patient information comprising a patient name, demographics, vital signs, patient street address, a patient telephone number, time and date of therapy administration, therapy compliance, and/or a patient e-mail address.","The server system may generate the messages based on the patient profile, the case manager, and/or a message type.","The message type may be an address change notification, an insurance notification, and/or a vacation notification.","In another embodiment of the present disclosure, the repository database at the server system stores various physical therapies administered, the dosage, such as electric stimulation applied (voltage, current, pulsing time, duration), ultrasound (frequency, intensity, duty cycle, duration), heat (temperature [e,g, 25-60° C., in some examples, 25-50° C.], duration, pulsing), cold (0-25° C., duration, pulsing), and combinations involving simultaneous and sequential applications of aforementioned physical therapies with the corresponding parameters that define the physical medicine dosage, exposure intensity, therapy duration.","In another embodiment of the present disclosure, a system and method are provided that enable entry of the patient profile, pain symptom, and prescription for physical medicine to be administered.","The entered information is stored in a database for immediate or future reference to personalize the therapy.","In another embodiment of the present disclosure, a system and method are provided which enable a single device with the capability of delivering more than one physical medicine or modalities or combination of medical devices to deliver multiple physical modalities to targeted tissue such as temperature (heat or cold), ultrasound (e.g., 0.5 to 3 MHz) and electrical stimulation (e.g., TENS or IFT) to a targeted live tissue to provide optimum therapeutic benefits.","Further, the system may have the capability collect non-invasive sensing information of patient such as vital signs, tissue thickness, tissue images, tissue temperature at different depths, blood flow rates in the skin or in the tissue, blood oxygen levels, pressure point depth or pressure-pain threshold, and skin pH, if required.","In addition, the system may be configured for retrieving and storing treatment information (including day and time), subject information, sensing information, demographics, billing information and outcome of the therapy session as defined by the subject on a given pain relief score from unsatisfactory to fully satisfied and further capable of communicating with a database located on a server either locally or in cloud.","In another embodiment of the present disclosure, a system and method are provided which are configured to perform analysis of the compiled or stored data to determine whether the prescribed treatment is compliant, progressing or regressing or needs alteration.","The system and method may be designed in such a way that it conducts comprehensive analytics regularly on ever increasing data being gathered and intelligently refines its recommendation for prescription or automatically titrates the physical medicine delivery/prescription.","It may normalize the pain relief score from multitude of patients and may make recommendations for personalized physical medicine, i.e., individual or combination modalities, method, dosage and therapy duration, for individuals or a group or section of demographics and may generate automatic messages regarding pain therapy status.","In another embodiment of the present disclosure, a graphical user interface for the entry of data (i.e., prior to the treatment) is provided, such as patient profile, demographics, symptoms, diagnosis, pre-existing condition.","Further, the interface may display information correlating pertinent entry data in a graphical manner, to show the relationship between individual (or a group of) patient profile(s) or demographics, with regard to physical medicine(s) administered and the outcome of the therapy, risk and benefit ratios with respect to any type of clinical application or therapy as warranted to make the therapy safe, personable and efficient.","The disclosed graphical user interface can also display the population exposures and outcomes, costs and benefits, antecedents and outcomes, causes and effects, and comorbidities of any number of health care scenarios.","The graphical user interface can provide a graphical representation of the relationship between any such information or events.","In another embodiment of the present disclosure, a computer readable medium is provided for storing executable instructions for execution by a computer having memory, where medium stores instructions for inputting contact information into a data storage device, transmitting an electronic message based on the contact information, receiving a response, storing the response and a timestamp into the data storage device, storing a time and date of receipt of the response into the data storage device, and querying the database for trends based on the response.","In some embodiments, the ever increasing amount of information stored in the database with regard to patient profiles, pain symptoms, physical therapies administered, outcomes measured, sensing data gathered, compliance levels monitored would be collectively and intelligently evaluated to propose/recommend a preferred prescription either automatically or upon request to personalize the pain therapy for an individual or classified group.","The disclosed system is capable of self-correcting/fine tuning the prescription recommendation or optimizing the physical medicine delivery as the data sampling size increases from a broad spectrum of the society.","In another embodiment of the present disclosure, a medical device is provided which is capable of delivering multiple modes of physical medicine (e.g., electric stimulation, ultrasound, heat and cold either individually or in combination), collecting non-invasive sensing information relevant to assessing the progression or regression of the therapy, connects wirelessly to a database, and transmits the entry data, therapy data, sensing data and the patient feedback, conducts analytics, identifies the trends/correlations, and thereby intelligently recommends the prescription or automatically administers the therapy.","In another embodiment, a portable and versatile pain therapy device is presented that provides an applicator, a plurality of sensors and an electronic controller powered by a rechargeable battery/power source.","The said device is capable of producing and applying different forms of energies when placed on the treatment area (the skin).","The generated energies penetrate through the skin into the deeper layers to produce soothing and palliative effects to give the sense of relief In another embodiment, disclosed is provided a pain therapy device, comprising: an applicator and a controller wherein the applicator is configured for accepting at least one electrical input; a controller configured for providing the intensity, sequence, nature, and timing information for the different energies supplied to the said applicator; and the applicator comprising of plurality of transducers configured for converting input electrical energy to different forms of output energies that are transmitted to the dermal and sub-dermal layers; and a plurality of sensors disposed over the applicator configured for providing a feedback control signal to the controller.","Further herein disclosed is a method for performing electronic therapy using a portable electronic device comprising the steps of: attaching the device to the skin of the subject; inputting electrical energy from a power source; controlling the electrical energy power input using a controller; converting the electrical energy to different forms of output energy using a plurality of configured circuit blocks; and providing the intensity, sequence, nature, and timing signals for activating therapy using different energies or at least one energy through an applicator; and modifying the intensity, sequence, nature, and timing signals as per the feedback control signals from a plurality of sensors.","In a further embodiment of the present invention there is provided a feedback control mechanism enabled by a plurality of sensors disposed over the applicator, which provides further control over the application of the different energies to the treatment area.","The sensors can collect and send the data to the feedback control mechanism of the controller to control various parameters such as temperature, frequency, intensity, input power, time, or any other parameters.","The data collected can be sent to the feedback loop of the controller.","In another example, the data collected can be delivered as outlined above with respect to the intelligent pain management system described.","The device/platform disclosed herein may also be used for intelligent and personalized fracture healing.","The device may be used to offer low intensity pulsed ultrasound (LIPUS) combination therapies.","Deliver of LIPUS in combination with thermoceuticals, electroceuticals and bone healing rate determining sensors provides an opportunity for personalizing faster bone healing therapies.","The disclosed device/software platform can allow easy selection of the appropriate therapy with feedback loop mechanisms, which may involve (automatic) selection of dosage, duration, and any other appropriate features.","Use of the device in combination with the intelligent data systems described herein can allow a doctor to monitor therapy compliance by a patient.","The sensor feedback can automatically measure the tissue temperature and the rate of bone healing in response to applied therapy.","FIG.","14 illustrates a flow chart that illustrates various patient profile data, sensor data related to physiological parameters, tissue and bone, therapy data and the bone fracture type to be treated.","This data collected on hundreds/thousands or even millions of patients can be mined to provide personalized treatment for faster/efficient bone healing.","Disclosed herein is a portable therapy device configured to drive inputs to one or more switches controlling combination treatments comprising a combination of at least one thermoceutical, electroceutical, and ultrasound therapy while measuring physiological, musculoskeletal characteristics related parameters via sensors.","The device may include one or more applicators.","It is possible to provide three separate applicators for the therapies.","It is possible to provide one or more therapies combined into one applicator.","In a specific example, heat/cold therapy (thermoceuticals) and ultrasound therapy may be provided in a single applicator.","In another example, heat/cold therapy (thermoceuticals), ultrasound, and electrical stimulation (electroceuticals) may be provided in a single application.","In one example, an applicator is coupled to the one or more switches and configured to deliver ultrasonic energy in a pulsed or continuous mode, wherein ultrasound frequency ranges from about 0.1 MHz to about 10 MHZ, and wherein intensities range from about 0.01 W/cm2 to about 3.0 W/cm2 in various combinations.","The same or an additional applicator coupled to the one or more switches and configured to deliver thermoceutical energy in a pulsed or continuous mode, wherein thermal energy ranges from about 0 ° C. to about 50° C. The same or an additional applicator comprising electrodes coupled to the one or more switches and configured to deliver electroceutical energy in a pulsed or continuous in the frequency range from about 1-200 Hz; pulse amplitude 0 mA to 500 mA.","It is understood that any of the proposed or defined parameters can operate with±20% error margin.","The device may also feature at least one or more sensors integrated into the same or additional applicators and coupled to a processing device to measure at least one physiological parameter or musculoskeletal characteristics related parameter comprising body temperature, tissue temperature, local blood flow, local blood oxygen levels, local tissue thickness, local tissue composition/structure, bone strength, bone fracture type, callus stiffness, and velocity and attenuation properties of sound waves in tissue or bone.","The device may be used to treat arthritis, joint pain, bursitis, muscle pain or injuries, muscle spasm or strain, soft tissue injuries, musculoskeletal injuries, back pain, joint stiffness, cold hands, rheumatism, neuralgia, inflammation, edema, ischemia, spasm, to stimulate enzyme activity and immune system, bone healing, tendon healing, or wound healing.","In other examples, it may be used to stimulate or accelerate fractured bone or tissue healing.","The device may be used for faster healing of damaged or fractured bones, and for monitoring bone healing progress through sensor feedback.","Other embodiments provide a medical device for the application of a therapy, comprising: a processing device configured to drive inputs for one or more switches controlling characteristics of treatments comprising thermoceuticals, electroceuticals, ultrasound, or a combination thereof, the characteristics of the treatments corresponding to the therapy; an applicator, coupled to the one or more switches, the applicator configured to apply the treatments or a combination thereof based on the inputs to the one or more switches; one or more sensors coupled to the processing device, the one or more sensors configured to 1) detect physiological parameters responsive to the application of the treatments or combination thereof and 2) provide the physiological parameters to the processing device; and a patient feedback interface communicatively coupled to the processing device, the patient feedback interface configured to receive user inputs indicating patient feedback information responsive to the application of the treatments or combination thereof.","The characteristics of the treatments or the combination thereof may include intensity levels and time durations.","The physiological parameters may comprise one or more of body temperature, tissue temperature, local blood flow, local blood oxygen levels, local tissue thickness, local tissue composition/structure, local tissue imaging, local tissue bone strength, bone fracture type, callus stiffness, and velocity and attenuation properties of sound waves in tissue or bone.","In other embodiments, there is disclosed a method for delivering a bone healing treatment, comprising: receiving patient information comprising patient data and symptoms; comparing the received patient information with bone healing analytics data compiled on a plurality of individuals to determine a personalized bone healing therapy; applying the personalized bone healing therapy to deliver one or more of thermoceuticals, electroceuticals, or ultrasound, in various combinations; receiving updated patient information in response to the applied personalized bone healing therapy; and storing the updated patient information and the personalized pain management therapy in a database to add to the bone healing analytics data compiled on the plurality of individuals.","It is possible to adjust, in response to the updated patient information, the personalized bone healing therapy by adjusting the combination of thermoceuticals, electroceuticals, or ultrasound; and store the adjusted personalized bone healing therapy in the database to add to the bone healing analytics data.","The patient data and the updated patient information may further comprise patient physiological data including one or more of patient vital signs, body or tissue temperature, blood flow rate, blood oxygen levels, or body tissue thickness or density.","The patient data and the updated patient information may be received at a bone healing therapy device, and wherein the personalized bone healing therapy is applied by transmitting electronic signals to an applicator to deliver the thermoceuticals, electroceuticals, ultrasound, or combination thereof via one or more applicators.","The patient data and the bone healing analytics data may be stored in a memory of the bone healing therapy device or in a remotely connected database, and the bone healing analytics data may include correlated patient information and patient feedback regarding bone healing therapy outcomes on the plurality of individuals.","Comparing the received patient information with bone healing analytics data to determine the personalized bone healing therapy may comprises: identifying a subset of individuals from the plurality of individuals that have similar characteristics as the patient as indicated in the patient information; and identifying, from the bone healing analytics data on the subset of individuals, a stored applied therapy associated with a stored therapy outcome indicating enhanced bone healing symptoms, wherein the identified stored applied therapy corresponds to the personalized bone healing therapy.","It is possible for the patient data and the updated patient information to be received by one or more sensors communicatively coupled to a bone healing therapy device or by user inputs received at a patient feedback interface.","The personalized bone healing therapy may comprise a combination therapy of: delivering thermoceuticals comprising heat in a temperature range of about 0-50° C.; and delivering ultrasonic energy at ultrasound frequency ranges of from about 0.1 MHz to about 10 MHZ and intensities from about 0.01 W/cm2 to about 3.0 W/cm2, wherein the delivery of thermoceuticals and ultrasonic energy may be in a pulsed or continuous mode and in various combinations of duration and intensities.","Numerous specific details are set forth herein to provide a thorough understanding of the claimed subject matter.","However, those skilled in the art will understand that the claimed subject matter may be practiced without these specific details.","In other instances, methods, apparatuses, or systems that would be known by one of ordinary skill have not been described in detail so as not to obscure claimed subject matter.","Unless specifically stated otherwise, it is appreciated that throughout this specification discussions utilizing terms such as “processing,” “computing,” “calculating,” “determining,” and “identifying” or the like refer to actions or processes of a computing device, such as one or more computers or a similar electronic computing device or devices, that manipulate or transform data represented as physical electronic or magnetic quantities within memories, registers, or other information storage devices, transmission devices, or display devices of the computing platform.","The system or systems discussed herein are not limited to any particular hardware architecture or configuration.","A computing device can include any suitable arrangement of components that provides a result conditioned on one or more inputs.","Suitable computing devices include multipurpose microprocessor-based computer systems accessing stored software that programs or configures the computing system from a general purpose computing apparatus to a specialized computing apparatus implementing one or more embodiments of the present subject matter.","Any suitable programming, scripting, or other type of language or combinations of languages may be used to implement the teachings contained herein in software to be used in programming or configuring a computing device.","Embodiments of the methods disclosed herein may be performed in the operation of such computing devices.","The order of the blocks presented in the examples above can be varied—for example, blocks can be re-ordered, combined, and/or broken into sub-blocks.","Certain blocks or processes can be performed in parallel.","The use of “adapted to” or “configured to” herein is meant as open and inclusive language that does not foreclose devices adapted to or configured to perform additional tasks or steps.","Additionally, the use of “based on” is meant to be open and inclusive, in that a process, step, calculation, or other action “based on” one or more recited conditions or values may, in practice, be based on additional conditions or values beyond those recited.","Headings, lists, and numbering included herein are for ease of explanation only and are not meant to be limiting.","While the present subject matter has been described in detail with respect to specific embodiments thereof, it will be appreciated that those skilled in the art, upon attaining an understanding of the foregoing, may readily produce alterations to, variations of, and equivalents to such embodiments.","Accordingly, it should be understood that the present disclosure has been presented for purposes of example rather than limitation, and does not preclude inclusion of such modifications, variations, and/or additions to the present subject matter as would be readily apparent to one of ordinary skill in the art."]],"string":"[\n [\n \"DEVICES, SYSTEMS AND METHODS FOR PAIN MANAGEMENT AND BONE HEALING\",\n \"Systems and methods disclosed herein provide efficacious therapies based on delivery of combinations of thermoceuticals, electroceuticals, ultrasound via computer-implemented systems.\",\n \"Sensors coupled to the device are configured to measure changes in tissue and bone conditions, physiological data resulting from the delivered therapy.\",\n \"The personalized therapy can be adjusted based on the changes in the physiological or sensor data and/or patient feedback.\",\n \"The patient information, information about the applied therapy, and therapy outcome information can be added to the analytics database.\"\n ],\n [\n \"1.A portable therapy device configured to drive inputs to one or more switches controlling combination treatments comprising a combination of at least one thermoceutical, electroceutical, and ultrasound therapy while measuring physiological, musculoskeletal characteristics related parameters via sensors; an applicator coupled to the one or more switches and configured to deliver ultrasonic energy in a pulsed or continuous mode, wherein ultrasound frequency ranges from about 0.1 MHz to about 10 MHZ, and wherein intensities range from about 0.01 W/cm2 to about 3.0 W/cm2 in various combinations; the same or an additional applicator coupled to the one or more switches and configured to deliver thermoceutical energy in a pulsed or continuous mode, wherein thermal energy ranges from about 0 ° C. to about 50° C.; the same or an additional applicator comprising electrodes coupled to the one or more switches and configured to deliver electroceutical energy in a pulsed or continuous in the frequency range from about 1-200 Hz; pulse amplitude 0 mA to 500 mA and at least one or more sensors integrated into the same or additional applicators and coupled to a processing device to measure at least one physiological parameter or musculoskeletal characteristics related parameter comprising body temperature, tissue temperature, local blood flow, local blood oxygen levels, local tissue thickness, local tissue composition/structure, bone strength, bone fracture type, callus stiffness, and velocity and attenuation properties of sound waves in tissue or bone.\",\n \"2.The device of claim 1, comprising a first applicator configured to deliver thermoceutical therapy as well as ultrasound therapy and a second applicator configured to deliver electroceutical therapy.\",\n \"3.The device of claim 1, comprising a single applicator configured to deliver thermoceutical, ultrasound, and electroceutical therapy.\",\n \"4.The device of claim 1, used to treat arthritis, joint pain, bursitis, muscle pain or injuries, muscle spasm or strain, soft tissue injuries, musculoskeletal injuries, back pain, joint stiffness, cold hands, rheumatism, neuralgia, inflammation, edema, ischemia, spasm, to stimulate enzyme activity and immune system, bone healing, tendon healing, or wound healing.\",\n \"5.The device of claim 1, used to stimulate or accelerate fractured bone or tissue healing.\",\n \"6.The device of claim 1, used for faster healing of damaged or fractured bones, and for monitoring bone healing progress through sensor feedback.\",\n \"7.A medical device for the application of a therapy, comprising: a processing device configured to drive inputs for one or more switches controlling characteristics of treatments comprising thermoceuticals, electroceuticals, ultrasound, or a combination thereof, the characteristics of the treatments corresponding to the therapy; an applicator, coupled to the one or more switches, the applicator configured to apply the treatments or a combination thereof based on the inputs to the one or more switches; one or more sensors coupled to the processing device, the one or more sensors configured to 1) detect physiological/musculoskeletal parameters responsive to the application of the treatments or combination thereof and 2) provide the physiological/musculoskeletal parameters to the processing device; and a patient feedback interface communicatively coupled to the processing device, the patient feedback interface configured to receive user inputs indicating patient feedback information responsive to the application of the treatments or combination thereof.\",\n \"8.The medical device of claim 7, wherein the characteristics of the treatments or the combination thereof include intensity levels and time durations.\",\n \"9.The medical device of claim 7, wherein the physiological parameters comprise one or more of body temperature, tissue temperature, local blood flow, local blood oxygen levels, local tissue thickness, local tissue composition/structure, local tissue imaging, local tissue bone strength, bone fracture type, callus stiffness, and velocity and attenuation properties of sound waves in tissue or bone.\",\n \"10.A method for delivering a bone healing treatment, comprising: receiving patient information comprising patient data and symptoms; comparing the received patient information with bone healing analytics data compiled on a plurality of individuals to determine a personalized bone healing therapy; applying the personalized bone healing therapy to deliver one or more of thermoceuticals, electroceuticals, or ultrasound, in various combinations; receiving updated patient information in response to the applied personalized bone healing therapy; and storing the updated patient information and the personalized pain management therapy in a database to add to the bone healing analytics data compiled on the plurality of individuals.\",\n \"11.The method of claim 10, further comprising: adjusting, in response to the updated patient information, the personalized bone healing therapy by adjusting the combination of thermoceuticals, electroceuticals, or ultrasound; and storing the adjusted personalized bone healing therapy in the database to add to the bone healing analytics data.\",\n \"12.The method of claim 11, wherein the patient data and the updated patient information further comprise patient physiological data including one or more of patient vital signs, body or tissue temperature, blood flow rate, blood oxygen levels, or body tissue thickness or density.\",\n \"13.The method of claim 10, wherein the patient data and the updated patient information are received at a bone healing therapy device, and wherein the personalized bone healing therapy is applied by transmitting electronic signals to an applicator to deliver the thermoceuticals, electroceuticals, ultrasound, or combination thereof via one or more applicators.\",\n \"14.The method of claim 13, wherein the patient data and the bone healing analytics data are stored in a memory of the bone healing therapy device or in a remotely connected database, and wherein the bone healing analytics data includes correlated patient information and patient feedback regarding bone healing therapy outcomes on the plurality of individuals.\",\n \"15.The method of claim 14, wherein comparing the received patient information with bone healing analytics data to determine the personalized bone healing therapy comprises: identifying a subset of individuals from the plurality of individuals that have similar characteristics as the patient as indicated in the patient information; and identifying, from the bone healing analytics data on the subset of individuals, a stored applied therapy associated with a stored therapy outcome indicating enhanced bone healing symptoms, wherein the identified stored applied therapy corresponds to the personalized bone healing therapy.\",\n \"16.The method of claim 10, wherein the patient data and the updated patient information are received by one or more sensors communicatively coupled to a bone healing therapy device or by user inputs received at a patient feedback interface.\",\n \"17.The method of claim 10, wherein the personalized bone healing therapy comprises a combination therapy of: delivering thermoceuticals comprising heat in a temperature range of about 0-50° C.; and delivering ultrasonic energy at ultrasound frequency ranges of from about 0.1 MHz to about 3 MHZ and intensities from about 0.01 W/cm2 to about 1.0 W/cm2, wherein the delivery of thermoceuticals and ultrasonic energy may be in a pulsed or continuous mode and in various combinations of duration and intensities.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>An individual with a disease, particularly a chronic disease or any ailment that takes more than one or two months to heal, may be required to monitor various health parameters on a regular basis in support of any treatment or therapy that he or she is undergoing or receiving.\",\n \"Today, advances in medical research enable a range of therapeutic options to treat a given disease, or ailment and/or their symptoms, where each of the proposed therapies targets a particular biochemical or physiochemical process underlying or associated with the disease to provide either a cure or relief from the disease symptoms.\",\n \"For example, if one were to consider various options available for treating pain symptoms, the possible diagnoses, medicaments and therapies are many; similarly there are several options available for accelerating fractured bone healing.\",\n \"It is possible that the therapy/medication a patient receives could be subjective and depend upon the particular doctor/physician, i.e., his/her background, expertise and past experiences.\",\n \"For example, a physiotherapist or an orthopedic physician may treat a pain symptom differently than a physician or pain management specialist.\",\n \"Although a doctor plays a critical role in diagnosing and prescribing the therapy, the patient (and his/her family members or care givers) also has great responsibility in complying with the prescription, and following the course of action for achieving improved health and better quality of life.\",\n \"However, unfortunately, depending upon the patient demographics and nature of the disease, health care management of pain management and implementation of pain management has become a daunting task and an expensive affair.\",\n \"For example, of the all diseases, chronic pain is one of the most underestimated health care problems in the world today, causing major consequences for the quality of life of the patients and the family members and has been a major burden on the health care system.\",\n \"The most common causes of chronic pain are musculoskeletal problems (fractures, dislocations, soft injuries) and inflammatory conditions, with back pain and arthritis pain symptoms accounting for a significant portion of the overall chronic pain population.\",\n \"The four most common ways to treat pain are: (1) pharmaceutical (e.g., analgesics, aspirin; NSAIDs, Ibuprofen, COX-2 inhibitors, celecoxib; opioids, morphine), (2) procedural (neuro-stimulators, pulsed radiofrequency, intrathecal), (3) psychological (behavioral, cognitive), and (4) physical (e.g., heat, cold, transcutaneous electric nerve simulation (TENS), therapeutic ultrasound, infrared, microwave or shortwave diathermy, electro-magnetic radiation, acupuncture, massage Although pharmaceutical methods (e.g., drugs) are most widely used for treating pain, individuals on over the counter or prescription drugs for pain are frequently dissatisfied with the results of the pharmaceutical treatment.\",\n \"Further, the adverse side effects that drugs may cause on prolonged usage is shifting the focus away from drugs toward alternate methods for managing chronic pain.\",\n \"The procedural methods are invasive, expensive and their effectiveness has been difficult to quantify.\",\n \"Psychological therapies often lack practicality and their success rates have been limited.\",\n \"Finally, physiotherapy based methods have been proven attractive, but they are inconvenient, require bulky/complex instruments, and regular office/hospital visits, all of which lowers compliance.\",\n \"In addition, these therapies are often not supported by quality clinical data despite tremendous advances made in understanding pathophysiology and pain signaling.\",\n \"Although, a number of physical medicine/modalities based therapies have been administered to treat musculoskeletal pain, identifying the optimal therapy and dosage for pain symptoms has been elusive.\",\n \"For example, clinical data published in the literature indicates that the application of physical medicine is appropriate/beneficial in some cases and not particularly beneficial in other cases.\",\n \"The response from patients to these methods is similarly mixed.\",\n \"Given this background, the patient (or his/her doctor) has no way of knowing what is the best treatment method.\",\n \"If one were to consider the combined use of these the application of physical therapies, the possible variations may be several (including dosage, therapy session and duration), but combination therapies may provide an opportunity to fine tune the therapy in order to make it efficacious or even personalized, especially when one takes advantage of modern technological advances such as computing, internet of things, sensing, connectivity, big data, and analytics in conjunction with electronic medication/therapy or remote administering/dispensing of medicines electronically.\",\n \"Therefore, there exists a need for a medical device and an associated system for offering improved therapies for sustained pain relief that takes into account objective and subjective patient feedback and further takes into account the statistical certainty of obtaining a satisfactory outcome.\",\n \"Another healthcare industry that can benefit from improved treatments relates to healing of fractured bones.\",\n \"Over 50 million bone fractures occur worldwide, leading to about 10 million doctor or emergency room visits per year in the United States alone.\",\n \"Delayed bone healing can result in increased pain, as well as loss of function and decreased quality of life.\",\n \"Current therapies or treatment approaches for healing fractured bones include delivering bone morphogenetic proteins (“BMPs”), platelet-rich plasma (PRP), or anabolic agents such as teriparatide (“TPD”).\",\n \"These treatments can be invasive and are not always successful.\",\n \"Other proposed solutions have been to implement bone growth stimulation devices.\",\n \"Such devices deliver low intensity pulsed ultrasound (“LIPUS”), which is believed to result in faster bone healing, but requires personalization of therapy dosage, that is, normalization of therapy dosage for a given composition (fat and muscle) and thickness of tissue surrounding a fractured bone.\",\n \"However, the existing therapies do not offer personalized solutions.\",\n \"For example, delivering a certain amount of ultrasound to one patient having one body composition will not achieve the same result as delivering that same amount of ultrasound to a different patient having a different body composition, or for that matter, different body parts of an individual contain different tissue thicknesses and compositions.\",\n \"Ultrasound penetration into deep tissue is limited by tissue thickness and composition.\",\n \"An identical dosage of low intensity pulsed ultrasound (LIPUS) may deliver inconsistent or suboptimal dosages to different patients.\",\n \"Accordingly, the present inventors have determined that the personalized pain management therapies described herein may also be useful in order to promote faster healing of fractured bones or other tissues.\",\n \"They have combined the personalized temperature therapy/ultrasound therapy/electrical stimulation therapy that may be delivered by the disclosed device in order to offer improved therapies for faster bone healing.\",\n \"Typically, the attenuation coefficient, loss of ultrasound energy due to absorption, scattering, and mode conversion, decreases as temperature of tissue raise from 0 to 50° C. Penetration of low intensity pulsed ultrasound through deep tissue to heal fractured bones varies depending tissue temperature.\",\n \"In theory, one can take advantage of this phenomena by preconditioning tissue temperature during LIPUS therapy to maximize therapeutic benefits.\",\n \"Use of the disclosed device has been found to provide controls for enabling deeper penetration of low intensity ultrasound or modulating ultrasound energy profile delivered to the injure tissue/bone areas, while personalizing the delivered therapy using sensors (that measure tissue thickness, rate of bone healing, blood flow etc.)\",\n \"and accompanied software tools.\"\n ],\n [\n \"<SOH> SUMMARY <EOH>The present disclosure provides a method and system for providing efficacious, personalized, pain management therapies.\",\n \"The present disclosure provides a method and system for providing efficacious and personalized bone healing therapies.\",\n \"A patient is provided with a therapy device capable of delivering individual, or multiple or combination physical therapies accompanied with a computer-implemented system that automatically or manually adjusts the applied pain management treatment based on physiological responses, objective measurements gathered by sensors, and/or user feedback.\",\n \"Physical therapies can be applied using a combination of thermoceuticals (e.g., temperature application based therapies such as surface heating/cooling using heat pack or cold packs or microwave/shortwave/ultrasound/infrared/laser radiation based thermal therapies, contrast therapies), or combination of thermoceuticals and electroceuticals (e.g., electrical stimulation based therapies such as TENS), or a combination of these treatments with ultrasound.\",\n \"Ultrasound, when applied in pulses, can produce non-thermal effects (acoustic streaming, cavitation) and facilitates healing in the inflammatory and proliferative phase following soft tissue injury, increases local circulation because of the increased capillary density, and bone healing.\",\n \"In some embodiments, physical therapies can also be administered by including infrared heating or electromagnetic radiation or radio frequency ablation.\",\n \"Physiological responses may be measured via one or more sensors that measure blood flow, blood oxygen levels, tissue thickness, bone strength, callus stiffness, acoustic emissions or vibrational properties of fractured vs. normal bone, ultrasound velocity and attenuation across a healing fractured bone and or superficial or deep tissue temperatures or other physiological metrics that are associated with pain symptoms.\",\n \"Upon applying a particular therapy, the disclosed device can receive updated physiological responses and adjust the therapy applied until a desired physiological response and/or user feedback indicates a satisfactory pain management or bone healing or other treatment outcome.\",\n \"In additional embodiments, the computer-implemented system identifies a correlation between the patient information (e.g., patient demographics, pain symptoms, nature of bone fracture, bone strength, callus stiffness, tissue density and composition, applied treatment options, and/or treatment outcomes) and analytics data compiled on a plurality of individuals.\",\n \"The analytics data tracks historical data on previous patients, treatments applied, and treatment outcomes.\",\n \"The analytics data can indicate for example, a treatment option that was previously applied to patients with similar demographic or physical information and a statistical likelihood that the therapy option/dosage results satisfactory pain relief or bone healing.\",\n \"The device can receive the identified treatment option from the analytics data and adjust the applied treatment to match the identified treatment option.\",\n \"The computer-implemented system can further store pain the patient information and the applied treatment in a database, thereby adding to the analytics data.\",\n \"The disclosed device, methodology and intelligent pain management (or bone healing) algorithm together provide a powerful tool for managing pain efficiently and effectively, as well as treating and encouraging bone growth or healing.\",\n \"Embodiments herein further relieve patients of the burden of having to try a plethora of devices or other treatment modalities in search of finding relief.\",\n \"These illustrative embodiments are mentioned not to limit or define the disclosure, but to provide examples to aid understanding thereof.\",\n \"Additional embodiments are discussed in the Detailed Description, and further description is provided there.\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation in part of U.S. application Ser.\",\n \"No.\",\n \"15/021,143 filed on Mar.\",\n \"10, 2016 titled “Personalized Pain Management Treatments,” which application claims priority to U.S.\",\n \"Provisional Application Ser.\",\n \"No.\",\n \"62/110,017, filed on January 30, 2015 and titled “Devices, Systems, and Methods for Pain Management,” and which application is also a continuation-in-part of application Ser.\",\n \"No.\",\n \"14/011,273, filed Aug. 27, 2013, now issued as U.S. Pat.\",\n \"No.\",\n \"9,710,607, titled “Portable Electronic Therapy Device and Method Thereof,” the contents of each of which are hereby incorporated by reference.\",\n \"TECHNICAL FIELD This disclosure provides a portable, electronic therapy device that is capable of delivering thermal energies, electrical energies, ultrasonic energies, and various combinations thereof in order to promote various therapeutic purposes.\",\n \"In a particular embodiment, delivery of these energies, either alone or in various combinations, has been found to be useful in improving bone healing processes.\",\n \"The therapy device can include automatic controlled application of energies along with feedback control using sensors for improved synergistic effects and dose titration.\",\n \"The device can be used for pain management, bone healing, tissue healing, fitness, cosmetic and topical delivery, and other related applications.\",\n \"The methods and systems provide improved uses for devices configured to deliver pain management or bone or other tissue healing therapies.\",\n \"BACKGROUND An individual with a disease, particularly a chronic disease or any ailment that takes more than one or two months to heal, may be required to monitor various health parameters on a regular basis in support of any treatment or therapy that he or she is undergoing or receiving.\",\n \"Today, advances in medical research enable a range of therapeutic options to treat a given disease, or ailment and/or their symptoms, where each of the proposed therapies targets a particular biochemical or physiochemical process underlying or associated with the disease to provide either a cure or relief from the disease symptoms.\",\n \"For example, if one were to consider various options available for treating pain symptoms, the possible diagnoses, medicaments and therapies are many; similarly there are several options available for accelerating fractured bone healing.\",\n \"It is possible that the therapy/medication a patient receives could be subjective and depend upon the particular doctor/physician, i.e., his/her background, expertise and past experiences.\",\n \"For example, a physiotherapist or an orthopedic physician may treat a pain symptom differently than a physician or pain management specialist.\",\n \"Although a doctor plays a critical role in diagnosing and prescribing the therapy, the patient (and his/her family members or care givers) also has great responsibility in complying with the prescription, and following the course of action for achieving improved health and better quality of life.\",\n \"However, unfortunately, depending upon the patient demographics and nature of the disease, health care management of pain management and implementation of pain management has become a daunting task and an expensive affair.\",\n \"For example, of the all diseases, chronic pain is one of the most underestimated health care problems in the world today, causing major consequences for the quality of life of the patients and the family members and has been a major burden on the health care system.\",\n \"The most common causes of chronic pain are musculoskeletal problems (fractures, dislocations, soft injuries) and inflammatory conditions, with back pain and arthritis pain symptoms accounting for a significant portion of the overall chronic pain population.\",\n \"The four most common ways to treat pain are: (1) pharmaceutical (e.g., analgesics, aspirin; NSAIDs, Ibuprofen, COX-2 inhibitors, celecoxib; opioids, morphine), (2) procedural (neuro-stimulators, pulsed radiofrequency, intrathecal), (3) psychological (behavioral, cognitive), and (4) physical (e.g., heat, cold, transcutaneous electric nerve simulation (TENS), therapeutic ultrasound, infrared, microwave or shortwave diathermy, electro-magnetic radiation, acupuncture, massage Although pharmaceutical methods (e.g., drugs) are most widely used for treating pain, individuals on over the counter or prescription drugs for pain are frequently dissatisfied with the results of the pharmaceutical treatment.\",\n \"Further, the adverse side effects that drugs may cause on prolonged usage is shifting the focus away from drugs toward alternate methods for managing chronic pain.\",\n \"The procedural methods are invasive, expensive and their effectiveness has been difficult to quantify.\",\n \"Psychological therapies often lack practicality and their success rates have been limited.\",\n \"Finally, physiotherapy based methods have been proven attractive, but they are inconvenient, require bulky/complex instruments, and regular office/hospital visits, all of which lowers compliance.\",\n \"In addition, these therapies are often not supported by quality clinical data despite tremendous advances made in understanding pathophysiology and pain signaling.\",\n \"Although, a number of physical medicine/modalities based therapies have been administered to treat musculoskeletal pain, identifying the optimal therapy and dosage for pain symptoms has been elusive.\",\n \"For example, clinical data published in the literature indicates that the application of physical medicine is appropriate/beneficial in some cases and not particularly beneficial in other cases.\",\n \"The response from patients to these methods is similarly mixed.\",\n \"Given this background, the patient (or his/her doctor) has no way of knowing what is the best treatment method.\",\n \"If one were to consider the combined use of these the application of physical therapies, the possible variations may be several (including dosage, therapy session and duration), but combination therapies may provide an opportunity to fine tune the therapy in order to make it efficacious or even personalized, especially when one takes advantage of modern technological advances such as computing, internet of things, sensing, connectivity, big data, and analytics in conjunction with electronic medication/therapy or remote administering/dispensing of medicines electronically.\",\n \"Therefore, there exists a need for a medical device and an associated system for offering improved therapies for sustained pain relief that takes into account objective and subjective patient feedback and further takes into account the statistical certainty of obtaining a satisfactory outcome.\",\n \"Another healthcare industry that can benefit from improved treatments relates to healing of fractured bones.\",\n \"Over 50 million bone fractures occur worldwide, leading to about 10 million doctor or emergency room visits per year in the United States alone.\",\n \"Delayed bone healing can result in increased pain, as well as loss of function and decreased quality of life.\",\n \"Current therapies or treatment approaches for healing fractured bones include delivering bone morphogenetic proteins (“BMPs”), platelet-rich plasma (PRP), or anabolic agents such as teriparatide (“TPD”).\",\n \"These treatments can be invasive and are not always successful.\",\n \"Other proposed solutions have been to implement bone growth stimulation devices.\",\n \"Such devices deliver low intensity pulsed ultrasound (“LIPUS”), which is believed to result in faster bone healing, but requires personalization of therapy dosage, that is, normalization of therapy dosage for a given composition (fat and muscle) and thickness of tissue surrounding a fractured bone.\",\n \"However, the existing therapies do not offer personalized solutions.\",\n \"For example, delivering a certain amount of ultrasound to one patient having one body composition will not achieve the same result as delivering that same amount of ultrasound to a different patient having a different body composition, or for that matter, different body parts of an individual contain different tissue thicknesses and compositions.\",\n \"Ultrasound penetration into deep tissue is limited by tissue thickness and composition.\",\n \"An identical dosage of low intensity pulsed ultrasound (LIPUS) may deliver inconsistent or suboptimal dosages to different patients.\",\n \"Accordingly, the present inventors have determined that the personalized pain management therapies described herein may also be useful in order to promote faster healing of fractured bones or other tissues.\",\n \"They have combined the personalized temperature therapy/ultrasound therapy/electrical stimulation therapy that may be delivered by the disclosed device in order to offer improved therapies for faster bone healing.\",\n \"Typically, the attenuation coefficient, loss of ultrasound energy due to absorption, scattering, and mode conversion, decreases as temperature of tissue raise from 0 to 50° C. Penetration of low intensity pulsed ultrasound through deep tissue to heal fractured bones varies depending tissue temperature.\",\n \"In theory, one can take advantage of this phenomena by preconditioning tissue temperature during LIPUS therapy to maximize therapeutic benefits.\",\n \"Use of the disclosed device has been found to provide controls for enabling deeper penetration of low intensity ultrasound or modulating ultrasound energy profile delivered to the injure tissue/bone areas, while personalizing the delivered therapy using sensors (that measure tissue thickness, rate of bone healing, blood flow etc.)\",\n \"and accompanied software tools.\",\n \"SUMMARY The present disclosure provides a method and system for providing efficacious, personalized, pain management therapies.\",\n \"The present disclosure provides a method and system for providing efficacious and personalized bone healing therapies.\",\n \"A patient is provided with a therapy device capable of delivering individual, or multiple or combination physical therapies accompanied with a computer-implemented system that automatically or manually adjusts the applied pain management treatment based on physiological responses, objective measurements gathered by sensors, and/or user feedback.\",\n \"Physical therapies can be applied using a combination of thermoceuticals (e.g., temperature application based therapies such as surface heating/cooling using heat pack or cold packs or microwave/shortwave/ultrasound/infrared/laser radiation based thermal therapies, contrast therapies), or combination of thermoceuticals and electroceuticals (e.g., electrical stimulation based therapies such as TENS), or a combination of these treatments with ultrasound.\",\n \"Ultrasound, when applied in pulses, can produce non-thermal effects (acoustic streaming, cavitation) and facilitates healing in the inflammatory and proliferative phase following soft tissue injury, increases local circulation because of the increased capillary density, and bone healing.\",\n \"In some embodiments, physical therapies can also be administered by including infrared heating or electromagnetic radiation or radio frequency ablation.\",\n \"Physiological responses may be measured via one or more sensors that measure blood flow, blood oxygen levels, tissue thickness, bone strength, callus stiffness, acoustic emissions or vibrational properties of fractured vs. normal bone, ultrasound velocity and attenuation across a healing fractured bone and or superficial or deep tissue temperatures or other physiological metrics that are associated with pain symptoms.\",\n \"Upon applying a particular therapy, the disclosed device can receive updated physiological responses and adjust the therapy applied until a desired physiological response and/or user feedback indicates a satisfactory pain management or bone healing or other treatment outcome.\",\n \"In additional embodiments, the computer-implemented system identifies a correlation between the patient information (e.g., patient demographics, pain symptoms, nature of bone fracture, bone strength, callus stiffness, tissue density and composition, applied treatment options, and/or treatment outcomes) and analytics data compiled on a plurality of individuals.\",\n \"The analytics data tracks historical data on previous patients, treatments applied, and treatment outcomes.\",\n \"The analytics data can indicate for example, a treatment option that was previously applied to patients with similar demographic or physical information and a statistical likelihood that the therapy option/dosage results satisfactory pain relief or bone healing.\",\n \"The device can receive the identified treatment option from the analytics data and adjust the applied treatment to match the identified treatment option.\",\n \"The computer-implemented system can further store pain the patient information and the applied treatment in a database, thereby adding to the analytics data.\",\n \"The disclosed device, methodology and intelligent pain management (or bone healing) algorithm together provide a powerful tool for managing pain efficiently and effectively, as well as treating and encouraging bone growth or healing.\",\n \"Embodiments herein further relieve patients of the burden of having to try a plethora of devices or other treatment modalities in search of finding relief.\",\n \"These illustrative embodiments are mentioned not to limit or define the disclosure, but to provide examples to aid understanding thereof.\",\n \"Additional embodiments are discussed in the Detailed Description, and further description is provided there.\",\n \"BRIEF DESCRIPTION OF THE FIGURES These and other features, embodiments, and advantages of the present disclosure are better understood when the following Detailed Description is read with reference to the accompanying drawings.\",\n \"FIG.\",\n \"1 is a block diagram depicting a pain therapy device communicating with a server system to provide personalized pain therapy that is adjusted based on subjective and objective feedback in response to the applied pain therapy.\",\n \"FIG.\",\n \"2 is a block diagram illustrating the logical components of the pain therapy device shown in FIG.\",\n \"1.FIG.\",\n \"3 is a block diagram depicting the various components present in the applicator for applying the pain management therapy.\",\n \"FIG.\",\n \"4 is an flowchart depicting an example process for applying a personalized pain management therapy based on stored analytics data and adjusting the applied therapy based on feedback.\",\n \"FIGS.\",\n \"5 and 6 are block diagrams depicting example hardware implementations for some of the components shown in FIG.\",\n \"1.FIG.\",\n \"7 is a block diagram depicting one example of a pain therapy device.\",\n \"FIGS.\",\n \"8A and 8B illustrate schematic cross sections of exemplary configurations of the pain therapy device.\",\n \"FIGS.\",\n \"9A, 9B, and 9C illustrate schematic cross sections of exemplary applicator configurations and corresponding transducer arrangements.\",\n \"FIGS.\",\n \"10A and 10B illustrate further schematic cross sections of exemplary applicator configurations and corresponding transducer arrangements.\",\n \"FIGS.\",\n \"11A and 11B illustrate further schematic cross sections of exemplary applicator configurations and corresponding transducer arrangements.\",\n \"FIGS.\",\n \"12A and 12B illustrate further schematic cross sections of exemplary applicator configurations and corresponding transducer arrangements.\",\n \"FIGS.\",\n \"13A and 13B illustrate further schematic cross sections of exemplary applicator configurations and corresponding transducer arrangements.\",\n \"FIG.\",\n \"14 shows a schematic of patient data analytics and treatment indications for efficacious or personalized bone healing treatment described herein by applying concepts depicted in FIG.\",\n \"4.DETAILED DESCRIPTION Systems and methods are disclosed for pain management therapies and devices.\",\n \"The systems and methods described also find particular benefit for encouraging faster bone healing.\",\n \"Although the present disclosure will relate to and use the term “pain management” therapies and devices, it should be understood that the same pain management therapies and devices described may also be used in order to encourage the bone healing process described herein.\",\n \"Systems and methods are also disclosed for computer-implemented pain management or bone healing through the use of a device that applies a combination of physical therapies to alleviate pain symptoms and/or to encourage faster bone healing, and it adjusts the application of the physical therapies based on feedback information.\",\n \"Feedback information includes physiological responses resulting from the applied therapy, patient feedback received as a pain relief score (e.g., a score from 0-10 or 0-5 as the case may be), and analytics information indicating the personalized therapy for patients with similar demographics/pre-existing medical conditions and other characteristics as the current patient.\",\n \"The therapy includes application of physical therapies via an applicator.\",\n \"Physical therapies include electroceuticals (i.e., any type electrical stimulation used for therapeutic benefit), thermoceuticals (e.g., defined as a thermal or heat therapy method or device designed to affect biological systems and modify function(s) of the body, and/or ultrasound therapies (i.e., any system that can deliver ultrasound waves such as low intensity pulsed ultrasound (LIPUS) to the patient), or any combination thereof.\",\n \"As part of thermal therapy, thermal energy is delivered to the body or superficial or deep tissue using a variety of devices and methods known to those skilled in the art.\",\n \"The temperatures applied to the body locally or systemically and may vary from about−100° C. to+about 100° C.).\",\n \"In other examples, the temperature may range from 0-50° C. Any combination of these treatments may be combined, depending upon the patient and the condition to be treated.\",\n \"One exemplary device for managing pain is described in U.S. Pat.\",\n \"No.\",\n \"9,710,607, titled “Portable Electronic Therapy Device and the Method Thereof,” which is incorporated by reference herein.\",\n \"The physical therapies applied via the computer-implemented therapy target specific physiological functions (i.e., without using any drugs) of the tissue through external non-invasive stimulation (or invasive stimulation) to provide pain relief and/or bone healing.\",\n \"A variety of physiological functions can be influenced, simply by changing the temperature of the tissue (e.g., cold, or heat at superficial or deeper levels) using a variety of methods such as cold or hot packs/baths, infrared lamps, lasers, shortwave diathermy, microwave diathermy, therapeutic ultrasound, and radio frequency application.\",\n \"Some of the physical medicine-induced changes include variations in cell membrane, or protein or nucleic acid structure and function, enzymatic activity, cell apoptosis, nerve conduction, coagulation, collagen fiber contraction, collagen synthesis, vasodilation, vasoconstriction, viscosity of body fluids/blood, cellular fluid crystallization or dehydration, pain signaling, production of endorphins, spasm, tissue metabolism, blood flow, inflammation, edema extensibility, supply of oxygen & nutrients, tissue/muscle repair or healing, fibroblast activity, collagen fibril density, protein synthesis, and tissue regeneration.\",\n \"Some of the physical parameters that alter based on tissue temperature include the propagation profiles of energy waves, such as ultrasound velocity and attenuation as a function of tissue temperature, depth, and composition.\",\n \"Some of the physical medicine based therapeutic indications include pain (chronic or acute) relief, musculoskeletal pain relief, sports injuries, post surgical pain, post surgical edema, reduction in inflammation, reduction of joint contractures, fibromyalgia, migraine, tissue healing, swelling reduction, Hematoma resolution, acute bone healing, wound healing, face lift, wrinkle reduction, angiogenesis, removal of warts, cancer therapy, strains, contracture, decrease in muscle spasticity, tumors, capsulitis, bursitis, myositis, tendonitis, improving range of motion, rheumatoid arthritis and osteoarthritis.\",\n \"Application of thermoceuticals or thermal therapy includes both heat therapy and cold therapy.\",\n \"Heat therapy can ease pain by increasing blood flow to affected areas, which can help decrease inflammation, relax tight muscles and eliminate waste products such as lactic acid that cause stiffness and soreness.\",\n \"Likewise, application of cold may facilitate healing after injuries and limits musculoskeletal pain.\",\n \"Cold therapy induces a drop in skin temperature and a modest decline in temperatures within the muscles and joints, thereby causes arteriolar and capillary vasoconstriction in the skin leading to decrease in local synovial blood flow to reduce swelling.\",\n \"Further, the propagation speeds of ultrasound waves increase as the tissue temperature raises up to 50° C., while the attenuation coefficient (loss of energy due to absorption and scattering) decreases.\",\n \"Thermoceuticals can be applied via any suitable mechanism for changing the temperature of the tissue.\",\n \"For example, thermoceuticals can be applied via surface heating/cooling using heat pack or cold packs or by microwave radiation, shortwave radiation, ultrasound application, infrared radiation.\",\n \"In some examples, the applicator described herein is configured to deliver thermoceutical energy to the body continuously or in a pulsed mode, or combinations thereof.\",\n \"The thermal energy delivered may be in temperature range of from about 0-60° C. In a specific example, the device can deliver thermal energy at about 42° C. Application of ultrasound therapies stimulates tissue beneath the skin's surface using sound waves.\",\n \"Exemplary ranges include from about 0.1 MHz to about 10 MHz.\",\n \"Other specific ranges may include from about 0.5-3.0 MHz (with tolerances including±20%) A specific low intensity pulsed ultrasound frequency may be about 1.5 MHz.\",\n \"In some examples, the ultrasound may be pulsed.\",\n \"In some examples, the ultrasound may be pulsed while the tissue temperature is altered between 0 to 50° C. In some examples, the ultrasound may be delivered continuously.\",\n \"In further examples, the ultrasound may vacillate between continuous delivery and pulsed delivery.\",\n \"The ultrasound frequency range delivered may depend upon set parameters, for example, may be based upon the patient's tissue composition.\",\n \"The intensity of the ultrasound may range from about 0.005 W/cm2 to about 3.0 W/ cm2.In some examples, ultrasound can cause a temperature rise up to 10° C. in 2-8 cm deep tissue or at least up to 5° C. The ultrasound can also imparts non-thermal effects such as acoustic streaming and cavitation to provide pain relief.\",\n \"Thermal changes also result in activation of a wide variety of thermal receptors (transient receptor potential channels (TRP)) in the skin/tissue that range from 0-60° C. and may mask pain signals to the brain.\",\n \"Activation of these receptors either chemically (e.g., menthol activates TRPA1, TRPM8, while capsaicin activates TRPV1, TRPV3) or physically can lead to masking of the pain sensation.\",\n \"In some embodiments of the present disclosure, the pain signal to the brain is masked by providing a method/mechanism to maximize/overwhelm the signal(s) from an individual or multiple TRP channels located around painful musculoskeletal region.\",\n \"The distribution ratio of various temperature sensitive receptors in the body varies depending upon the body location.\",\n \"For example, upper part of the body comprises more heat temperature receptors than cold temperature receptors.\",\n \"The present inventors believe that pulsing low intensity ultrasound while controlling the tissue temperature help minimize the losses of ultrasound energy due to attenuation and increases ultrasound velocities inside the tissue, and thereby encourages more effective and efficient bone healing.\",\n \"Preheating or Pre-cooling or Pre-conditioning of the tissue around injured area (that is injured bone or tissue) can help encourage greater penetration of the ultrasound.\",\n \"Without wishing to be bound to any theory, it is believed that raising the patient's tissue temperature to about 50° C., while also delivering ultrasound waves (pulsed or continuous), can help reach the underlying bone tissue more effectively (i.e., with higher velocities and low attenuation coefficients).\",\n \"It is believed that this treatment may help improve bone healing by up to about 30 to 40% or even more.\",\n \"However, not all patients have the same tissue composition.\",\n \"Some patients may present with more fat tissue, others with more muscle tissue, and different densities of tissue or body mass indices will require different dosages for treatment to ensure the right dosage of ultrasound energy is experienced by the injured bones/tissue therapy point.\",\n \"Ultrasound waves are absorbed more as they extend deeper into tissue.\",\n \"The ultrasound intensity that reaches the bone will vary based on the delivered parameters such as ultrasound frequency, intensity, pulsing profile, tissue temperature, tissue thickness/composition in a therapeutic area.\",\n \"Embodiments disclosed herein also include computer-implemented therapy that applies electroceuticals as electrical stimulation of nerves.\",\n \"In electric stimulation, electrical current at distinct voltages, frequencies and intensities is delivered to the skin through electrodes (e.g., TENS, electric muscle stimulation, EMS, or neuromuscular electric stimulation, LAMES, IFT, inferential therapy).\",\n \"Pain is relieved by means of the pain gate mechanism involving activation of sensory fibers that mask the pain and/or suppressing of pain signals to the brain.\",\n \"It is also believed possible that delivery of electric stimulation may help healing of fractured bones, the bone healing may be accelerated in conjunction with low intensity pulsed ultrasound while keeping the tissue temperature at native body temperature or by externally altering it with the aid of thermoceuticals.\",\n \"Additionally, electrical stimulation can generate a physiological response to the irritation produced by electrical stimuli which leads to the release of endorphins.\",\n \"Electrically pulsed stimulation also causes enhanced localized muscle activity and thereby increases blood circulation to remove metabolic toxins, thereby reducing pain symptoms and/or may encourage bone growth.\",\n \"The electroceuticals can be applied to the body using either low (1-20 Hz) or high frequencies (20-200 Hz) for treating pain and several other therapeutic indications.\",\n \"In other words, the energy delivered may range from about 2-200 Hz, or any range there between.\",\n \"The voltages used for electric stimulation may vary from 3 V to 120V, while the wave forms applied could assume different shapes such as square, asymmetrical biphasic, and symmetrical biphasic.\",\n \"In other examples, the range may be from 10 V to 120V.\",\n \"The stimulation could be applied to the body continuously or in pulsed mode or in burst mode to trigger different therapeutic mechanisms for treating ailments.\",\n \"Although, the therapeutic mechanism behind electric stimulation has not yet been unequivocally established, it is generally believed that electric stimulation enables the body to produce its own endorphins, increases local blood flow and mask pain signals via pain gate mechanism and several other hypotheses as proposed in the literature.\",\n \"It is believed that combining electrical stimulation, thermal therapy, and ultrasound together can offer efficient pain management options.\",\n \"It is also believed that combining electrical stimulation, thermal and ultrasound therapies together can offer rapid healing of fractured bones.\",\n \"For any of the treatments described, the delivery of the thermal therapy, ultrasound, and/or electrical stimulation or any combination thereof described may be pulsed.\",\n \"The delivery of the heat therapy, ultrasound, and/or electrical stimulation or any combination thereof described may be continuous.\",\n \"The delivery of the heat therapy, ultrasound, and/or electrical stimulation or any combination thereof described may be alternated.\",\n \"The delivery of the heat therapy, ultrasound, and/or electrical stimulation or any combination thereof described may alternate between pulsed and/or continuous.\",\n \"The particular therapy may be optimized for the patient.\",\n \"If pulsed, it is possible for the time range of the pulsing to the separated by microseconds, milliseconds or seconds.\",\n \"Typically, electric stimulation pulsing could be in the order of micro to milliseconds.\",\n \"Acoustic pulsing could be in the order of milliseconds.\",\n \"Thermal pulsing may be in the order of seconds to minutes.\",\n \"In some embodiments, the therapy device may communicate with a physician computing device to provide personalized care via application of personalized pain management therapy through customized application of electroceuticals, and thermoceuticals.\",\n \"For example, a physician computing device can receive inputs from a healthcare provider for setting the initial physical therapy and adjusting the therapy as the treatment is applied.\",\n \"The initial pain management therapy may also be set via a patient computing device communicatively coupled to the pain therapy device.\",\n \"The initial pain management therapy indicates the specific combination and intensity levels of electroceuticals, thermoceuticals, and/or ultrasound.\",\n \"During treatment, sensors communicatively coupled to the pain management device detect the physiological responses resulting from the application of the pain management therapy.\",\n \"The pain therapy device also receives patient feedback indicating pain relief scores via a user interface for the patient computing device (or entered directly from the graphic user interface of pain therapy device).\",\n \"The pain therapy device continues to apply the physical therapies (e.g., the electroceuticals, thermoceuticals, ultrasound, acupuncture, pressure/massage based therapies) indicated in the therapy until the physiological responses/patient feedback indicates a threshold pain management level has been reached.\",\n \"For example, as the pain management therapy is applied, the sensors coupled to the pain therapy device may detect an increase in blood flow or an increase in blood-oxygen levels at the localized area of pain.\",\n \"If the rate of blood flow (or bone healing) and the value of the blood-oxygen levels reach a threshold value specified in the pain management treatment, the pain therapy device reduces or completes the application of the physical therapies.\",\n \"Similarly, the pain therapy device may receive feedback from the patient via a user interface indicating the pain has decreased (e.g., by indicating a pain relief score on a 0-5 or a 0-10 scale).\",\n \"In response, the pain therapy device continues or completes or modifies the application of the physical therapies.\",\n \"For example, a therapy analysis engine executing on the pain therapy device receives updates from a physiological data collection engine and from a patient feedback interface and uses the collected information to iterate the dosage of the physical medicine.\",\n \"Embodiments disclosed herein also recognize that the demographics of chronic pain patients (or patients with fractured bones) and the physical therapy requirements are unique.\",\n \"It has been well documented in the literature that people with certain pain symptoms, do not respond to electroceuticals and thermoceuticals (or even pharmaceuticals) in similar fashion.\",\n \"For example, some people may get pain relief using TENS, and others may not respond to such a therapy at all, and may even have allergic reaction.\",\n \"Therefore, the physiology of individuals and the patient feedback plays an extremely important role in determining the ideal/optimal therapy.\",\n \"In addition to being responsive to patient feedback and physiological response from an applied pain therapy, the pain therapy device further tailors or “titrates” physical medicine(s) dosage (energy type(s), intensity, exposure depth and duration) based on the patient demographics (e.g.\",\n \"age, gender, body mass index, ethnicity, pre-existing health conditions and cultural background).\",\n \"For example, the server system includes a patient analytics database that stores patient demographics and applied therapy information (e.g., the specific combination of the physical therapies applied and the dosage levels) as well as information on outcomes of the applied pain management therapy on multiple individuals that had previously applied pain management therapies.\",\n \"The database may comprise enormous amount of information from hundreds or thousands or even millions of individual patients and provides a powerful tool to conduct data analytics (analogous to an automated virtual/crowd-sourced clinical study that constantly gets updated with addition of ever increasing data sets) and customize the pain therapy for individuals either in an automated fashion or through prompt response from the physician.\",\n \"The analytics data can indicate the statistical likelihood of satisfactory pain management outcomes from application of the pain therapy.\",\n \"The pain therapy device connects with the server system over a network to compare the patient information for a specific patient with the patient information in the analytics data to identify a subset of individuals that have similar characteristics as the patient.\",\n \"For example, the therapy analysis engine may comprise a software application or software module executing in either the pain therapy device or the server system.\",\n \"The therapy analysis engine identifies a subset of individuals that are with the same age range, gender, body mass index, and other pre-existing medical conditions, pain therapies received in the past or on-going (including drugs, or surgical procedures or alternate medicines), physical characteristics as the patient.\",\n \"The therapy analysis engine also identifies one or more pain management therapies that were applied to the subset of individuals that resulted in favorable pain management outcome.\",\n \"The pain therapy device can thus personalize the applied pain management therapy based on subjective data such as patient feedback, objective data such as physiological responses to the applied therapy, as well as analytics data that can indicate the personalized pain management therapy as collected from other patients with similar characteristics as the patient.\",\n \"The pain therapy device can transfer the patient information and the pain management therapy information through wireless connectivity to the database for storage in the analytics system.\",\n \"In this way, the pain management adds the current patient's information (e.g., demographic information, symptoms, etc.\",\n \"), applied pain management therapy, and therapy outcomes (e.g., patient relief scores and physiological changes resulting from the therapy) to the analytics database.\",\n \"These illustrative aspects and examples are given to introduce the reader to the general subject matter discussed here and are not intended to limit the scope of the disclosed concepts.\",\n \"The following sections describe various additional features and examples with reference to the drawings in which like numerals indicate like elements, and directional descriptions may be used to describe the illustrative aspects but, like the illustrative aspects, should not be used to limit the present disclosure.\",\n \"FIG.\",\n \"1 is a block diagram depicting a pain therapy device 100 that connects to a server system 130 over a network 115 to provide personalized pain management therapies based on measured physiological/sensor feedback data (including blood flow and musculoskeletal characterization related data), subjective patient input data (e.g., a pain relief score), and analytics data compiled on other patients and applied pain therapies.\",\n \"The pain therapy device 100 can be communicatively coupled to a patient computing device 120 and/or a physician computing device 110 for receiving feedback to adjust the applied pain management therapy.\",\n \"The pain therapy device 100 includes a memory 101 that stores executable program code for performing operations described herein.\",\n \"For example, memory 101 includes program code for execution of a physiological/sensor data collection engine 102, a therapy analysis engine 104, a server system interface engine 106, and a patient feedback interface 107.In another embodiment, the server system 130 includes program code for the therapy analysis engine 131.An initial pain management therapy may be programmed via physician computing device 110 or patient computing device 120.In some embodiments, the patient using the pain therapy device 100 may communicate directly with a health care provider via patient computing device 120 and physician computing device 110.The patient computing device 120 and the physician computing device 110 may comprise any suitable computing device, such as a personal computer, a tablet computer, or a cell phone.\",\n \"The initial pain management therapy may be personalized based on patient information (i.e.\",\n \"information on the user of pain therapy device 100).\",\n \"For example, the physician computing device 110 includes a physician interface application 112 that presents options for inputting patient information (e.g., patient pain symptoms, demographic information, medical history, and additional information) and a personalized pain management therapy based on the patient information.\",\n \"A healthcare provider operating the physician computing device 110 can prescribe the personalized pain management therapy via the physician interface application 112.For example, the physician interface application 112 presents a user interface for selecting a physical medicine via a combination of electroceuticals, or thermoceuticals.\",\n \"In other embodiments, the patient computing device 120 includes a patient interface application 122 for inputting patient information.\",\n \"Via the patient interface application 122, the patient provides inputs regarding the personalized pain management therapy as discussed or otherwise prescribed by the healthcare provider.\",\n \"The personalized pain management therapy can thus be administered via the health care provider or self-administered via the patient.\",\n \"One or more applicators 124 connected to the pain therapy device 100 apply the personalized pain management therapy input via physician interface application 112 or patient interface application 122 or directly through physical therapy device 100.The personalized pain management therapy comprises of physical therapies that include a combination of electrical stimulation, hot and cold stimulation, and ultrasonic pulses.\",\n \"In some embodiments, based on feedback received from physician computing device 110 and patient computing device 120, the therapy analysis engine 104 executing on the pain therapy device 100 adjusts the applied personalized pain therapy accordingly.\",\n \"For example, inputs received via a patient feedback interface 111 presented on physician computing device 110 or patient feedback interface 121 presented on patient computing device 120 may indicate a pain relief score from a value of 0-10, with 10 indicating the most intense pain and 0 indicating no pain.\",\n \"It should be understood that other values or indications could be used, such as emoticons, descriptive text, color, or a selection on a continuum.\",\n \"As the personalized pain management therapy is applied via applicator 124, a pain relief score may be received indicating a low measurement of pain.\",\n \"A satisfactory application of personalized pain management therapy can be based, for example, on reduction of a pain relief score by a certain pre-programmed threshold.\",\n \"In response, the therapy analysis engine 104 may adjust the personalized pain management therapy by adjusting the dosages and intensities of physical therapies to accommodate for lesser pain.\",\n \"The feedback comprising the pain relief score may also be received directly on a user interface on pain therapy device 100.For example, memory 101 of patient therapy device 100 may include program code for executing a patient feedback interface 107 used to receive feedback to the therapy from the patient.\",\n \"In further embodiments, the therapy analysis engine 104 adjusts the personalized pain therapy in response to physiological measurements detected via one or more sensors coupled to pain therapy device 100.For example, a physiological data collection engine 102 executing in memory 101 of pain therapy device 100 may receive information on the blood-oxygen levels, rate of blood flow, and tissue thickness from connected sensors.\",\n \"The personalized pain management therapy may include instructions on applying physical therapies at specific dosage levels and adjust the applied physical therapies in response to changes in physiological measurements.\",\n \"For example, the therapy analysis engine 104 may apply a combination of electrical stimulation at a certain intensity level, heat stimulation at a certain temperature, and ultrasonic pulses until a physiological responses indicate a blood flow of a certain rate.\",\n \"Once the specified blood flow rate (or blood oxygen levels) is achieved, pain therapy device 100 may apply physical therapies with different intensity levels/temperature values.\",\n \"This process continues until the pain management therapy is complete (e.g., the prescribed physical therapies are fully administered).\",\n \"In additional embodiments, patient symptoms and demographic information on the patient (i.e.\",\n \"user of pain therapy device 100) may be compared with analytics information stored on multiple other patients to determine the personalized pain management therapy.\",\n \"The analytics data is stored on a patient analytics database 132 in server system 130 and comprises patient information compiled on numerous other patients.\",\n \"For example, the stored patient information includes data on prior patient demographics, prior patient pain symptoms, the pain management therapies previously applied on the other patients, and the outcomes of the pain management therapies (e.g., indicating satisfactory outcome, unsatisfactory outcome, etc.).\",\n \"The analytics data can also include the average pain feedback score that was indicated by the prior patients in response to previously applied pain management therapies.\",\n \"In one embodiment, a server system interface engine 106 is a software application or module executing in pain therapy device 100.The server interface engine 106 transmits data comprising the patient information to server system 130.The server system interface engine 106 provides instructions for communicating the patient information to server system 130 and receiving information in response from server system 130.Based on the received patient information, a therapy analysis engine 131 executing on the server system 130 identifies a subset of individuals that have similar characteristics as the user of pain therapy device 100.For example, therapy analysis engine 131 may identify a subset of individuals that are in the same age range, have the same gender, have a similar body mass index as the user of pain therapy device 100, and/or have similar pain symptoms, or any combination thereof.\",\n \"The therapy analysis engine 131 may also identify a prior applied pain therapy among the subset of individuals that is associated with a pain therapy outcome indicating reduced pain symptoms.\",\n \"For example, the therapy analysis engine 131 may identify a prior applied pain therapy among the subset of individuals that indicates a satisfactory pain management outcome.\",\n \"A pain therapy with a satisfactory pain management outcome may include pain therapies that have resulted in reduced pain relief scores by a certain threshold (e.g., 2 points or more).\",\n \"A pain therapy with a satisfactory pain management outcome may also be indicated when a health care provider has approved a given therapy or removed a patient who has had a successful result with the therapy.\",\n \"A pain therapy with a satisfactory pain management outcome may also be indicated by accomplishment of objective physiological measurements such as reduction in inflammation or improvement in range of motion, improvement in local blood oxygen levels or flushing out toxins in the injured body part or visually observation of parameters such as wound healing or bone healing or any measurable parameters that either directly or indirectly correlate with reduction in pain as deemed appropriate by physician.\",\n \"The selected pain management therapy based on the analytics data is transmitted to the pain therapy device 100.Because the received pain management therapy is determined from prior therapies applied on patients with similar characteristics to user of pain therapy device 100, the received pain management therapy is personalized to the user of pain therapy device 100.In another embodiment, the pain therapy device receives the analytics data on other patients from the server system 130.The therapy analysis engine 104 executing in pain therapy device 100 uses the received analytics data to select the subset of individuals that have similar characteristics as the user of pain therapy device 100.In this embodiment, the therapy analysis engine 104 identifies a personalized pain management therapy that, from the analytics data, indicates prior satisfactory outcome (e.g., reduction in pain symptoms).\",\n \"The analytics data is depicted as stored in patient analytics database 132 in server system 130 for illustrative purposes.\",\n \"In other embodiments pain therapy device 100 stores the analytics data.\",\n \"FIG.\",\n \"2 depicts a block diagram illustrating the logical components of pain therapy device 100.Pain therapy device 100 includes a micro-controller unit (MCU) 210.MCU 210 includes processing devices such as an application specific integrated circuit (ASIC), or any general-purpose processor.\",\n \"MCU 210 can include logic for connecting to external interfaces 250-264.For example, MCU 210 includes an audible transducer 250, an LCD interface 252 (or interface for any other type of user interface device), a reset switch 254, an RS232 port 256, an Inter Circuit Serial Programming (ICSP) and Joint Test Action Group (JTAG) port 258, a Bluetooth interface 260, a WiFi interface 262, and a network interface 264 (e.g., an Ethernet port).\",\n \"The MCU 210 is also coupled to sensors for receiving physiological measurements from the user of pain therapy device 100.Said sensors include temperature sensor 230 (for measuring the body temperature of the patient at the point of contact of the applicator 124, blood flow sensor 232 (for measuring the blood flow rate at the point of contact of the applicator 124), oxygen sensor 234 (for measuring the blood-oxygen level at the point of contact of the applicator 124), tissue thickness sensor 236 (for measuring the thickness of the tissue at point of contact of applicator 124), and an applicator surface contact sensor 238 (for detecting if the applicator 124 is in contact with tissue.\",\n \"In some embodiments, sensors 230-238 can be included as part of applicator 124 (as shown further below in FIG.\",\n \"3).\",\n \"The MCU can also include or be in communication with a computer-readable medium storing instructions that, when executed by the MCU 210, cause the MCU 210 to perform the operations described herein.\",\n \"For example, the MCU 210 is in communication with memory 101, which includes any suitable non-transitory computer-readable medium.\",\n \"The computer-readable medium includes any electronic, optical, magnetic, or other storage device capable of providing a processor with computer-readable instructions or other program code.\",\n \"Non-limiting examples of a computer-readable medium include a magnetic disk, memory chip, ROM, RAM, an ASIC, a configured processor, optical storage, magnetic tape or other magnetic storage, or any other medium from which a computer processor can read instructions.\",\n \"The instructions include processor-specific instructions generated by a compiler and/or an interpreter from program code written in any suitable computer-programming language, including, for example, C, C++, C#, Visual Basic, Java, Python, Perl, JavaScript, and ActionScript.\",\n \"The program code includes one or more of a physiological data collection engine 102, therapy analysis engine 104, server system interface engine 106, and patient feedback interface 107.The MCU 210 can also be communicatively coupled to control inputs 222-234 for controlling the characteristics of the pain management therapy as applied by applicator 124.Control inputs 222-234 include a heat switch 222, cold switch 224, ultrasound switch 226, ultrasound intensity control 228, ultrasound duty cycle 230, electric stimulation switch 232, and infrared switch 234.Ultrasound switch 226, ultrasound intensity control 228, and ultrasound duty cycle control 230 (which control the respective characteristics of the ultrasound pulses that are part of the pain management therapy) are fed to ultrasound power amplifier 236.Ultrasound power amplifier 236 provides necessary amplification of the signals before driving the ultrasound output of applicator 124.The output from electric stimulation switch 232 can be fed to electric stimulation circuit 238 before driving the electrical characteristics of applicator 124.Similarly, output from infrared switch 234 can be fed to infrared circuit 240 before driving infrared output of applicator 124.Via heat switch 222 and cold switch 224, temperature characteristics of applicator 124 can be specified.\",\n \"The output of heat switch 222 and cold switch 224 for controlling the temperature characteristics are provided to applicator 124.In some embodiments, the control inputs 222-234 can be coupled to MCU 210 via an I2C expander port 220.A medical grade power supply 202 can provide the power requirements to the components herein.\",\n \"For example, medical grade power supply 202 provides power to ultrasound power amplifier 236, applicator 124, electric stimulation circuit 238, and infrared circuit 240.FIG.\",\n \"3 illustrates a representation of the various components present in the applicator 124, as shown as different layers.\",\n \"The sequencing of the various layers could be altered and does not necessarily have to be in the order shown in FIG.\",\n \"2.Further, multiple layers/components of the applicator 124 could be embedded into a single layer or form physically distinct layers.\",\n \"The control inputs 222-234 provide the electrical signals that control the various layers of applicator 124.The layers for applicator 124 can be placed on the surface area of the tissue of the patient for whom the pain management therapy is applied.\",\n \"Applicator 124 can include a heat sink component 302, which measures the temperature of the tissue on which the applicator 124 is applied.\",\n \"The thermoelectric element component 304 applies the hot or cold temperature as specified by heat switch 222, cold switch 224, and the specific temperature as set by MCU 210.The applicator 124 can also include a PCB & LED component 306 that can display.\",\n \"The PCB inside the applicator integrates the thermoelectric elements, sensors, ultrasonic transducer and TENS electrodes and simplifies the connectivity.\",\n \"The PCB is also capable of connecting to any additional sensors or thermal energy generating transducers integrated into the applicator (e.g., blood flow detection sensor, infra-red radiation source etc.).\",\n \"The LED component visually indicates the status of applicator such as ON or OFF (especially, for the convenience of care providers).\",\n \"In some embodiments, the applicator 124 can also include built in sensors 308, which include one or more of the temperature sensor 230, blood flow sensor 232, oxygen sensor 234, tissue thickness sensor 236, and applicator surface contact sensor 238.Some of the described sensors could be used to characterize several musculoskeletal characteristics, such as tissue healing and/or bone healing properties.\",\n \"Applicator 124 can also include a substrate component 310 and/or electrode component 311 for applying the electrical impulses as driven by electric stimulation circuit 238.Applicator 124 can also include an ultrasound transducer for applying the ultrasound impulses driven by ultrasound power amplifier 236.In some embodiments, the sensors 308 measure the substrate 310 and/or electrode 311 temperature and send the temperature to the MCU 210.The sensors 308 could gather a variety of medically useful/diagnostic data related to treating pain, healing fracture bones, and may help monitoring the progress of healing or administering right dosage for a given therapy as defined.\",\n \"The ultrasound transducer 312 can be utilized by the therapy analysis engine 104 to identify the thickness or depth of the tissue based on ultrasound reflection intensity measured.\",\n \"This kind of sensing feature helps provide for the inclusion of safety features regarding the device usage on different parts of the body (e.g., it is possible to prevent the usage of the device on the head or skull of the patient).\",\n \"The sensing feature also enables the determination of physical dosage to be delivered to a targeted area.\",\n \"FIG.\",\n \"4 is a flowchart depicting an example process 400 for applying a personalized pain management therapy based on stored analytics data on numerous other prior patients and adjusting the applied therapy based on physiological feedback.\",\n \"This is conceptually similar to a flow chart that could be used for rapid/personalized healing of fractured bones.\",\n \"The process 400 may be performed by one or more of the components listed in FIGS.\",\n \"1-3 or in any suitable computing and/or communication environment.\",\n \"The process 400 involves receiving patient information specifying patient demographic data, patient physiological data, and patient pain symptoms, as shown in block 410.Demographic data can include information on patient such as age, gender, body weight and BMI, race, and geographic information.\",\n \"Patient pain symptoms include descriptions of patient pain symptoms and indications of pain.\",\n \"For example, patient pain symptoms can include a graphical indication of a body part (e.g., by selection of an area of a body on a touch screen) to show areas of localized pain, textual descriptions of the areas of localized pain, and a numeric pain relief score indicating the severity of the pain at the specified location.\",\n \"Pain symptoms can also be more or less detailed.\",\n \"All common chronic pains and musculoskeletal pains such as back pain, neck pain, shoulder pain, arthritis, muscle spasms, tendonitis, bursitis, sports injuries are either visually or verbally represented.\",\n \"Any other form of pain that requires diagnosis by qualified physician (e.g., fibromyalgia) or that cannot be treated using pain therapy device (visceral pain, especially involving cutting, burning and/or involving internal organ damage) will not be included in the system as a default.\",\n \"Patient physiological data includes physiological measurements of a measured tissue area.\",\n \"Physiological measurements include, for example, the measured rate of blood flow, blood-oxygen levels, tissue depth, tissue composition, tissue temperature, bone strength, callus stiffness, acoustic emissions/reflections from fractured/partially healed/fully healed or normal/healthy bones, ultrasound velocity and attenuation across a healing fractured bone and other measurements.\",\n \"The patient information may be received via inputs in physician interface application 112 in physician computing device 110 or patient interface application 122 in patient computing device 120 and transmitted to pain therapy device 100.In other embodiments, the patient information can be directly entered in pain therapy device 100 via a user interface on the pain therapy device 100.While the pain therapy device 100 can process the patient information to determine the personalized pain management therapy, in other embodiments, the patient information is transmitted to server system 130.Process 400 also includes comparing the received patient information with pain analytics data compiled on a plurality of individuals to determine a recommended pain management therapy, as shown in block 420.For example, the server system 130 includes a patient analytics database 132 that stores the pain analytics data on numerous prior patients.\",\n \"The pain therapy device 100 can transmit the patient information to the server system 130 for the comparison.\",\n \"In other embodiments, the pain therapy device 100 can receive the analytics data from the server system 130 via network 115 for the comparison.\",\n \"Therapy analysis engine 104 (executing in pain therapy device 100) or therapy analysis engine 131 (executing in server system 130) compares patient information with the pain analytics data to determine a subset of individuals with similar characteristics as the patient as explained above with respect to FIG.\",\n \"1.Additionally, therapy analysis engine 104 or therapy analysis engine 131 identifies the recommended pain management therapy that previously depicted a satisfactory outcome (e.g., by lower received pain relief scores from other patients, from objective measurements of physiological data indicating lesser pain symptoms).\",\n \"As shown in block 430, the recommended pain management therapy is applied via an applicator device 124.For example, the applicator device 124 provides one or more electroceuticals, or thermoceuticals, or ultrasound, or any combination at a specific frequency, intensity, and/or duration as specified by the recommended pain management therapy.\",\n \"Note in some aspects, the recommended pain management therapy can be overridden and manually input via inputs received from physician computing device 110 or patient computing device 120.After application of the recommended pain management therapy (which is initially based on the analytics data on pain management therapies applied on other patients), the pain therapy device 100 can further adjust and personalize the therapy based on feedback from the patient.\",\n \"As shown in block 440, process 400 further involves receiving, from one or more sensors, updated physiological data reflecting changes in the patient physiological data, and subjective patient feedback (in the form of pain score) in response to the applied recommended pain management therapy.\",\n \"For example, as the recommended pain management therapy is applied by applicator 124, sensors 230-238 measure changes in the temperature, blood flow rate, blood-oxygen levels, and tissue thickness resulting from the therapy.\",\n \"The sensor data can be received via a physiological data collection engine 102.The changes in the physiological data in response to the applied pain management therapy can be considered objective feedback to the pain management therapy.\",\n \"Note that while the type of feedback in response to the applied pain management therapy described in block 440 is feedback from physiological data, other types of feedback are also possible.\",\n \"For example, the pain therapy device 100 can receive subjective feedback from the patient in the form of a patient relief score (e.g., a numeric value from 0-10) as discussed above with respect to FIG.\",\n \"1.The therapy analysis engine 104 can adjust the applied pain management therapy (or bone healing therapy) in response to the changes in physiological data (or in response to other feedback), as shown in block 450.For example, the applied voltage or current of the electrical stimulation, the temperature of the heating element, or the intensity of the ultrasonic pulses can be adjusted based on the changes in the physiological data or sensor data or based on patient feedback.\",\n \"Probably, the pain relief scores from patients in conjunction with objective physiological data (whenever available) could be used to adjust or titrate the dosage of the physical medicine involving single or combination of therapies.\",\n \"For example, the thermoceutical dosage may be defined by three parameters, i.e., intensity (e.g., temperature range; frequency, intensity and duty cycle in case of ultrasound), energy exposure time, and course duration for a given tissue thickness or composition (or BMI).\",\n \"If the physical medicine dosage delivered does not increase the tissue temperature or raise the deep tissue temperature in stipulated time frame and/or for sustained time period, and/or do not provide pain relief to the patient, one could consider the dosage delivered is sub optimal.\",\n \"At present, our understanding about how distinct physical modalities or their combination therapies at what dosage levels provide efficient pain relief is relatively limited.\",\n \"Further complexity stems from the fact that pain is a subjective personal experience, and the physiology of individual is different from each other and the way each individual responds to given therapy is unknown.\",\n \"If a patient does not respond to a particular electroceutical or thermoceutical pain therapy, it is not generally implied that the given therapy does not work; it only implies that given therapy is not appropriate for that patient.\",\n \"Therefore, it is important to identify the patterns from various therapies provided to patients with diverse backgrounds and profiles to develop a personalized pain therapy.\",\n \"Typically, the dosage delivered will always be within the safety limitations as outlined by data published in the literature, the dosages will be titrated based on positive response from patients (i.e., lower pain scores).\",\n \"Once adequate data is accumulated from patient responses, it is possible to correlate pain relief (or rate of bone healing) measured in response to given physical medicine dosage with quantifiable physiological data or body reflex related measurements (e.g., increase local blood flow of injured body part, thermal imaging, tissue temperatures, blood oxygen levels, sensitivity to pressure etc.)\",\n \"and constitutes one of the inventive aspect of this innovation.\",\n \"As shown in block 460, the therapy analysis engine 104 makes a determination as to whether the updated physiological data indicates reduced pain symptoms (or faster bone healing).\",\n \"For example, the physiological changes in treated body part may include vasodilation, vasoconstriction as quantified by blood flow volume or velocity or by variation in blood oxygen levels or simply by measurement of tissue temperature or measurement of pressure sensitivity to pain (using algometer) or it could even include identification/measurement of certain cellular or molecular changes or electrical signals caused in response to external stimulation.\",\n \"If the updated physiological data or patient feedback indicates reduced pain symptoms (it is possible that subjective and objective evaluation results may not converge, the patient feedback coupled with statistics may precede physiological measurements), the patient information, patient feedback, the updated physiological data, the recommended pain management therapy, and the adjusted pain management therapy are stored in the analytics database, as shown in block 470.For example, physiological data indicating reduced pain symptoms can be considered a satisfactory application of the pain management therapy.\",\n \"To add to the pain analytics database, the server system interface engine 106 executing on pain therapy device 100 can transmit one or more of the patient information (indicating the initial set of physiological measurements), the updated physiological measurements, the recommended pain management therapy (as derived from the pain analytics database), and/or the adjusted pain management therapy (as adjusted based on this individual patient's physiological responses) to the server system 130.The server system 130 stores the received information in patient analytics database 132.If the updated physiological data and/or patient feedback does not indicate reduced pain symptoms, a different pain management therapy may need to be selected.\",\n \"In response to the lack of reduction of pain symptoms, the patient information, updated physiological measurements, recommended pain management therapy, and adjusted pain management therapy are first stored in the analytics database, as shown in block 480.This adds to the database and indicates a therapy that does not necessarily work for patients with characteristics similar to the user of pain therapy device 100.The process 400 then returns to block 420, where the therapy analysis engine 104 compares the patient information with pain analytics data to determine a different pain management therapy.\",\n \"The process 400 continues until a satisfactory pain management therapy is found.\",\n \"Any suitable computing system or group of computing systems can be used to implement the physician computing device 110 and the patient computing device 120 described in FIG.\",\n \"1.For example, FIGS.\",\n \"5-6 are block diagrams depicting examples of implementations of such components.\",\n \"As shown in FIG.\",\n \"5, the physician computing device 110 includes a processor 1002 that is communicatively coupled to a memory 1004 and that executes computer-executable program code and/or accesses information stored in the memory 1004.The processor 1002 comprises, for example, a microprocessor, an application-specific integrated circuit (“ASIC”), a state machine, or other processing device.\",\n \"The processor 1002 includes one processing device or more than one processing device.\",\n \"Such a processor is included or may be in communication with a computer-readable medium storing instructions that, when executed by the processor 1002, cause the processor to perform the operations described herein.\",\n \"The memory 1004 includes any suitable non-transitory computer-readable medium.\",\n \"The computer-readable medium includes any electronic, optical, magnetic, or other storage device capable of providing a processor with computer-readable instructions or other program code.\",\n \"Non-limiting examples of a computer-readable medium include a magnetic disk, memory chip, ROM, RAM, an ASIC, a configured processor, optical storage, magnetic tape or other magnetic storage, or any other medium from which a computer processor can read instructions.\",\n \"The instructions include processor-specific instructions generated by a compiler and/or an interpreter from code written in any suitable computer-programming language, including, for example, C, C++, C#, Visual Basic, Java, Python, Perl, JavaScript, and ActionScript.\",\n \"The physician computing device 110 also comprises a number of external or internal devices such as input or output devices.\",\n \"For example, the physician computing device 110 is shown with an input/output (“I/O”) interface 1008 that receives input from input devices or provide output to output devices.\",\n \"A bus 1006 is also included in the physician computing device 110.The bus 1006 communicatively couples one or more components of the physician computing device 110.The physician computing device 110 executes program code that configures the processor 1002 to perform one or more of the operations described above.\",\n \"The program code includes one or more of the patient feedback interface 111 or the physician interface application 112.The program code is resident in the memory 1004 or any suitable computer-readable medium and is executed by the processor 1002 or any other suitable processor.\",\n \"In additional or alternative embodiments, one or more modules are resident in a memory that is accessible via a data network, such as a memory accessible to a cloud service.\",\n \"The physician computing device 110 also includes a communication interface 1010.The communication interface 1010 includes any device or group of devices suitable for establishing a wired or wireless data connection to one or more data networks 115.Non-limiting examples of the communication interface 1010 include an Ethernet network adapter, a modem, and/or the like.\",\n \"The physician computing device 110 transmits messages as electronic or optical signals via the communication interface 1010.Similar to the physician computing device 110, the patient computing device 120 also includes a processor 1102, I/O interface 1108, communication interface 1110, and memory 1104 communicatively coupled via a bus 1106.The memory 1104 includes non-transitory computer-readable memory as described above and stores program code defining operations of the patient computing device 120.The processor 1102 executes the computer-executable program code and/or accesses information stored in the memory 1104.For example, the patient computing device 120 includes memory 1104 that stores program code for the physician interface application 121 and the patient interface application 122.The following paragraphs describe further illustrative embodiments for the pain therapy device 100.There may be provided a pain therapy device that is useful in treating various physiological conditions.\",\n \"The device may include a controller, sensors and an applicator.\",\n \"The applicator generally features a plurality of transducers that produce electrical, heat, cold and ultrasound energies respectively.\",\n \"The controller provides the required electronics to control energies produced by the transducers.\",\n \"The controller is configured to modify the intensity, timing, or duration of the different energies, which are applied over the treatment area (skin) over the feedback control signal obtained from the sensors.\",\n \"Both the controller and the applicator may be cooperate either by wired communication or can communicate wirelessly.\",\n \"They may be integrated into a single product.\",\n \"The pain therapy for use herein can carry out therapeutic treatment using the lowest possible energy intensities in order to achieve a therapeutic effect.\",\n \"One or more of a combination of electric stimulation (electroceuticals), thermal stimulation (thermoceuticals via application of heat, cold) or ultrasound (pulsed or continuous), when applied to the treatment area in a systematic manner, has been demonstrated to show synergistic effect leading to better and faster therapeutic relief Superficially applied heat follows a top-down heating mechanism through conduction and heat may not get transferred beyond top 1 cm to 2 cm depth of the tissue (note that skin and tissue beneath it are poor thermal conductors).\",\n \"On the other hand, ultrasonic energy can heat up both surface and deep tissue (from 1 cm to 5 cm) easily as the acoustic energy absorbed by the tissue gets converted into thermal energy.\",\n \"Because of these fundamentally distinct modes of heating (conductive heating vs. converted heating), use of ultrasound and superficial heat combination rapidly creates a thermal gradient across the treated tissue leading to significantly higher blood flow rates quickly unlike conventional single form of thermal energy based therapies.\",\n \"Therefore, it is possible to provide improved oxygen supply to injured body part for sustained periods of time, and flush out unwanted inflammation causing chemicals to provide rapid and sustained pain relief Cold also follows a top-down thermal conduction, where cooling of the dermal and sub-dermal layers (top 1 cm to 2 cm) shows several beneficial effects with regard to treating acute injuries.\",\n \"Cold can decrease cellular metabolism and causes vasoconstriction of the blood vessels in the area and decreases the inflammation in the area and thus the associated pain and swelling.\",\n \"In combination with ultrasound, cold may provide an additive effect.\",\n \"For example, combination of cold and ultrasound energies together can create an inverse thermal gradient for improved blood flow, that is, the surface temperatures of the top most tissue layer will be below body temperature, while the deep tissue temperatures will be above body temperature.\",\n \"Indeed, such an inverse thermal gradient, which is practically impossible to accomplish from conventional thermal therapies may be extremely useful for safely heating deep tissue to 45-70° C. rapidly for shorter time periods for face lifting and cosmetic applications.\",\n \"Providing these energies in a controlled pulsatile manner can help reduce the risk of adverse effects, while still achieving the desired therapeutic effect.\",\n \"Because a larger volume of dermal and sub-dermal tissues can be exposed to the energies when used in combination, especially thermal energy and ultrasound, there may be increased blood flow around the treatment area providing fresh oxygen and nutrients, and increasing subsequent tissue metabolism.\",\n \"Similarly, the combination of electric stimulation (e.g., TENS) and thermal stimulation may offer synergetic benefits both in terms of improving local blood flow and efficiently masking pain signals.\",\n \"Therefore, combination therapies not only account for individual patient related physiologies, but also provide an opportunity to precisely fine tune or titrate body reflexes across the deep tissue to provide rapid pain relief and other related therapeutic benefits (e.g., faster tissue regeneration giving relief from pain, wound healing, blocking pain sensation reducing pain, inflammation, spasms, and other side effects).\",\n \"In one example, pulsed heating may be synchronized with pulses of pressure waves such that both pulses reach the target simultaneously.\",\n \"In another example, pulsed cooling may be synchronized with pulses of pressure waves such that both pulses reach the target simultaneously.\",\n \"In another example, pulsed heating is followed by pulsed cooling and both are synchronized with pulses of pressure waves such that both pulses reach the target simultaneously.\",\n \"In another example, TENS, ultrasound and surface heating can be synergistically applied to treat the entire cross section of the tissue.\",\n \"In another example, TENS, ultrasound and cold could be synergistically applied to accomplish targeted goals.\",\n \"The recent scientific advances made in medicine us realize that personalizing the medication or therapies is critical for achieving efficacious therapeutic benefits across the diverse population.\",\n \"The current approaches of using physical medicine indiscriminately across the various patient population leads to application of inconsistent therapies, and dosages and results in inefficient or inferior therapies, which may be randomly successful or unsuccessful.\",\n \"For example, the tissue thickness of a 300 pound person is different from 100 pound person, and so is the composition of the tissue, but if one applies electroceuticals or thermoceuticals identically to both these weight groups, the results may not be identical—after all, the applied energies are identical, but not the injured body parts.\",\n \"Further, the pathophysiology of each individual is different, and it is difficult to provide universal medicine for pain without personalizing it, especially physical medicines that do not cause adverse side effects.\",\n \"One more complex problem associated with pain is that patients' opinions/perceptions regarding pain are subjective and cannot be measured independently/objectively.\",\n \"Patients' perceptions about pain (especially chronic pain) may dynamically change; their response to a particular therapy may also change either positively or negatively over a period of time.\",\n \"Therefore, personalization of precisely dosed combination therapies accounting patient feedback provides an unprecedented opportunity to treat pain safely and efficiently.\",\n \"FIG.\",\n \"7 shows a schematic block diagram of an exemplary pain therapy device.\",\n \"This device may be used with the treatment methods described herein.\",\n \"The device includes a controller and applicator.\",\n \"The power is provided by a battery or capacitor of a suitable power supply unit.\",\n \"The controller includes a microprocessor unit and controls a plurality of electronic circuit modules for the generation of different energy, such as thermal energy (0 to 70° C., more specifically from about 0-50 ° C.) and ultrasound (0.2 to 20 MHz, or in other examples from about 0.1 to about 10 MHz).\",\n \"Alternatively, or in addition, the controller may deliver electro stimulation to the body in a post or continuously in the frequency range of about 1-200 Hz, pulse amplitude in the range of 0 mA to 500 mA, pulse width in that 1 micro second to millisecond range.\",\n \"The controller may be programmed for the duration, switching sequence and intensity of each of these energies.\",\n \"The applicator may include transducers capable of delivering heat, cold and ultrasound and/or electro stimulation to the skin/treatment area.\",\n \"The applicator also features a plurality of sensors for the purpose of feedback and control.\",\n \"The sequencing of the various layers could be altered and does not necessarily have to be in the order as shown in figures.\",\n \"FIGS.\",\n \"8A and 8B show the schematic cross sections of different possible pain therapy device designs.\",\n \"Controller (1) comprises of electronic circuitry (3), rechargeable battery (4), on/off switch (6) and an LED indicator (5).\",\n \"FIG.\",\n \"8A illustrates the integrated design where both the controller and applicator makes a single unit.\",\n \"Whereas FIG.\",\n \"8B illustrates the two piece design in which both the controller and applicator are two separate entities and are connected through a wire/wireless.\",\n \"FIGS.\",\n \"9A to 9C, FIGS.\",\n \"10A and 10B, FIGS.\",\n \"11A and 11B, FIGS.\",\n \"12A and 12B, and FIGS.\",\n \"13A and 13B illustrate schematic cross sections of different exemplary applicator designs.\",\n \"The applicator generally includes an ultrasound transducer (8), heat/cold transducer (10), insulation layer (9), temperature sensors/PCB (11), top cover (7) and bottom cover.\",\n \"In some embodiments, applicator may also include internal PCB, multiple sensors, and electrodes.\",\n \"In some of the embodiments this also includes side support (13).\",\n \"In some embodiments the ultrasonic energy from applicator is transferred into the body through conducting media.\",\n \"U.S. Pat.\",\n \"No.\",\n \"9,710,607 provides more detail about these devices, the entire disclosure of which is incorporated herein by reference.\",\n \"In one example, the power source used to operate the device can be a rechargeable battery, an AC power adapter and/or a capacitor.\",\n \"The input power unit may be configured for delivering current of range 0.1 mA to 4000 mA and delivering potential of range 2V to 120V to deliver multiple therapies at different currents or voltages.\",\n \"For example, the current and voltages used for accomplishing, heat, cold, ultrasonic and TENS (or IFT, interferential therapy) energies may be different.\",\n \"The device can include a plurality of circuit blocks configured and connected to various transducers for converting the input energy to heat, cold and ultrasound.\",\n \"This section may have a switch to keep the device in on/off/standby mode to conserve energy when not in use.\",\n \"The standby function is optionally automated based on the program in the controller.\",\n \"A controller can be provided for containing the required software for operation.\",\n \"The controller also interfaces with the detecting transducers for the required computation for quantifying the detected values.\",\n \"When various forms of energy are supplied to the treatment area via a combination effect of control signals, the controller and the transducer can supply pulses with a minimum duration of 1 millisecond or more.\",\n \"The controller may be further configured/programmed for altering the outputs on the basis of the feedback signals provided by the sensors disposed over the said applicator.\",\n \"Based on the settings and the program running in the controller, the exact temperature and duration of application of heat or cold or electric treatment or ultrasound can be precisely controlled by this circuit block.\",\n \"Various durations of temperature and frequencies are possible.\",\n \"The applicator can have an ultrasound sound transducer and heat and/or cold transducers or TENS (IFT) electrodes along with sensors that gather key diagnostic and therapy related information.\",\n \"As shown in FIGS.\",\n \"9A to 9C, 10A, 10B, 11A, 11B, 12A, 12B, 13A and 13B illustrate, these transducers may be aligned one above the other.\",\n \"In one example, the ultrasound transducer may be positioned above the heat/cold transducer, or the ultrasound transducer can surround the heat/cold transducer and vice versa, or the transducers can be side by side, or the design may be an irregular design to utilize the produced energies efficiently and treat the physiological condition very effectively.\",\n \"The applicator may also have temperature sensors placed on or around the heating/cooling element to measure the temperatures and send the information to the controller through feedback loop mechanism to maintain constant exposure temperatures.\",\n \"The sensors can be configured for feedback control of the device.\",\n \"For example, the sensors can provide control signals to the controller for the optimized and efficient use of the different energies to be applied over the treatment area.\",\n \"The sensors (which may include ultrasonic transducers that have dual function as sensor and therapeutic agent) can provide additional information regarding blood flow, tissue thickness, tissue composition, tissue image, bone strength, callus stiffness, blood oxygen levels, pain-pressure sensitivity, applicator contact with body and so on.\",\n \"This can reduce the power usage of the power source/battery and allow for prolonged use without repeated charging.\",\n \"In use, a gel or other material may be positioned on a patient's skin.\",\n \"This may help the ultrasound, electrical stimulation and any other form of physical medicine that needs an efficient conductive media to transfer energy into the body.\",\n \"For example, thermal energy from ultrasound can only be transferred efficiently through a conductive (electrically or thermally or acoustically) gel, while thermal energy from superficial heating may be transferred directly into the body without including any additional conducting medium.\",\n \"The electrical stimulation also requires conductive gel pads to pass electric current into the body and in between the electrodes.\",\n \"Further the applicator may also require an adhesive tape to attach it to the body.\",\n \"It is also possible that the adhesive pads could act as conductive elements, or vice versa.\",\n \"The gel could be applied in the form of liquid, semi-solid, solid, suspension or slurry.\",\n \"The applicators can also be attached to the body through strap mechanism.\",\n \"Therefore, the applicator may come in direct contact with the body partially or fully through an additional conducting medium as required or applicator may come in contact with skin without any conductive medium, if applied therapy do not require such a medium.\",\n \"In an exemplary embodiment, the method can include directing ultrasound waves at a tissue and heating the tissue with thermal energy.\",\n \"The thermal energy pulses may be synchronized to arrive at the tissue simultaneously with the ultrasound waves within a preset range, and the heat of each thermal energy pulse can be dissipated in an environment that includes the tissue before a subsequent thermal energy pulse arrives at the tissue.\",\n \"The deposited heat energy per pulse, the number of pulses, and the repetition rate of the pulses may be determined by a processor according to the temperature and the heat dissipation capability of the tissue.\",\n \"The electrical energy can be delivered continuously or in pulses at low frequency (2-20 Hz) or high frequency (20 Hz to 200 Hz) in combination with pulsed or continuous thermoceuticals.\",\n \"Therefore, the above-described intelligent pain management computer systems and methods for managing pain therapy may be implemented using a variety of pain therapy devices or physical medicine delivery systems described herein.\",\n \"Additionally or alternatively, the method can include directing electro stimulation at the tissue as well.\",\n \"The compact design of the disclosed device can give a patient the freedom to use the device on the move and/or at home, reducing the clinic visits.\",\n \"The device can be used/placed on any part of the body and also for any ailment that will respond to these energies.\",\n \"To provide further explanation, the following examples are provided as additional illustrative embodiments and use cases for the computer-implemented pain management system disclosed herein.\",\n \"The present disclosure provides, in one aspect, a pain therapy device for delivering at least one form of physical medicine having a microprocessor and wired/wireless networking capability that communicates with mobile or smart phones or computers either through physical connectivity or remotely (e.g., via Bluetooth or wife) and enables users to manage and track therapeutic treatments (e.g., pain therapy).\",\n \"In one implementation, the application includes software that is stored on a memory of the mobile therapeutic device and is executed by the processor.\",\n \"The present disclosure also provides a solution for efficiently managing pain without drugs and invasive procedures, by delivering one or more forms of physical therapies either individually, sequentially or in combination.\",\n \"The physical therapies are compliant and can be self-administered conveniently, safely and cost effectively.\",\n \"Further, the present disclosure provides a method for connecting patients with the health care providers.\",\n \"In some examples, it enables them to communicate the progression or regression of the therapy as they experience it along with measurable feedback, compliance data, sensor data, if any.\",\n \"It also allows them to receive a safe, compliant and efficient therapy.\",\n \"The present disclosure also provides a method employing an intelligent means for delivering physical medicine to a plurality of patients, with an option from a remote location, comprising the steps of: (i) providing each of the patients with a personal pain therapy device(s) capable of providing one or more forms of physical medicine to patients on demand (at home or at doctor's office); (ii) providing a microprocessor associated with therapy device capable of controlling physical medicine delivery and simultaneously send and receive the information over network(s) to suggest or carry out preferred prescription(s), monitoring and compliance related activities; (iii) providing the usage information, sensing information and compiling the status report of the said therapy device(s) via a network(s); (iv) providing a quantified patient response measurement after each compliance of prescription that is transmitted to the remote computing system for a report; and (v) providing an analysis algorithm on the local or remote computing system for processing the data collected or monitored from the device, sensors, and patients for formulating an automated prescription, modifying a prescription, and assessing the therapy compliance and thereof In a sense, the most efficacious therapy is identified akin to clinical trials, by comparing and contrasting and conducting statistical analysis of various therapy related parameters.\",\n \"In one embodiment of the present disclosure, a repository database gathers and stores the information regarding individual or collective patient profiles, demographics, disease symptoms, diagnosis, prescription, sensing data, physiological data, device usage/compliance and quantified response from patient and/or health care provider manually, semi-automatically, or automatically over the network.\",\n \"If the prescribed therapy does not lead to satisfactory results in a given time frame as indicated by the patient feedback, an analytical algorithm recommends alternate therapies involving same physical medicine with different dosages or alternate physical medicine or combination of physical therapies as defined by the rules for providing various physical therapies until the patient experiences most efficacious therapy as indicated by his/her feedback.\",\n \"Further, the algorithm with access to wider patient database comprising above information, can have the ability to compare the pain symptoms or diagnosis or profile or demographics of the patient to be treated with those in the database and thereby identify the best possible prescription(s) or dosage of physical medicine such that the therapy administered can lead to efficacious therapy.\",\n \"In another embodiment of the present disclosure, the pain therapy device provided is a wearable pain therapy device that is compact, convenient, and is capable of providing a combination of physical medicine for efficacious and sustainable pain relief.\",\n \"In another embodiment of the present disclosure, the disclosed system intelligently personalizes pain therapy by electronically connecting the pain therapy device to a physician computing device, enabling the health care provider to receive and view the feedback from the patient seamlessly and search a network-based database comprising data on numerous pain patients along with their patient profiles (i.e.\",\n \"indicating patient demographic and other information), physiological responses to the therapies, and pain relief scores received in response to the various physical medicine therapies administered.\",\n \"The disclosed system thereby allows the physician to identify data/statistics driven preferred therapeutic options for personalizing the pain therapy.\",\n \"The system provides reports and/or graphs of the recorded data such that the compliance and progression of the therapy is monitored, trends are identified, prescription rules are framed or the outcome of the therapy is correlated with the therapy or therapies administered in conjunction with multiple patient profiles with related symptoms, therapies, patient feedback, diagnosis and/or sensing data such as vital signs, tissue temperature, blood flow in painful part of the body etc.\",\n \"for further evaluation.\",\n \"In another embodiment, the present disclosure provides a software application (e.g., a mobile application or other program that is executable by a portable device having a processor) that includes a therapy tracking feature that enables patients to record and review various parameter data related to applied pain management therapies.\",\n \"The parameters may include testable and quantitatively measureable aspects of certain symptoms associated with the therapy.\",\n \"For example, a symptom of pain may be recorded on a recurring basis (e.g., daily) by the patient ranking the extent of the pain on a fixed scale, such as 0 (for no pain) to 10 (severe pain) or 0 (no pain) to 5 (severe pain) as defined (one could also use painful and smiley faces as a graphical user interface to quantify the pain).\",\n \"The disclosed software application can provide reports and/or graphs of the recorded data such that trends may be identified, or such that the outcome of the therapy is correlated with the therapy or therapies administered in conjunction with the patient profile and/or physiological data such as vital signs, tissue temperature, blood flow, blood oxygen level, tissue thickness, tissue imaging etc.\",\n \"for further evaluation.\",\n \"Some of the parametric values graphed/tabulated or stored include, level of compliance, progression/regression of the therapy, patient profile, demographics, physical modality/dosage administered, and physiological data captured from sensors.\",\n \"The progression or regression of the pain management therapy may be tracked in response to the historical data being requested; such tracking may include retrieving at least one of the parameters from the repository, and displaying the retrieved parameter in a tabular and/or graphical format.\",\n \"The tracking of pain management therapy progress and on demand/automated prescription or suggestion options can be tailored (e.g., made compliant with any governing law).\",\n \"In some embodiments, the patient can request the prescription and the history related to his/her treatment can also be revealed/shared with the patient.\",\n \"In another embodiment of the present disclosure, the software application includes a calendar/timing feature for scheduling administrations of the pain management therapy treatments and/or appointments, or ensuring the compliance of the prescription provided.\",\n \"For example, if treatment involves administration of a pain management therapy on a recurring basis, and the calendar feature allows the patient to schedule such administrations and may include reminders.\",\n \"Similarly, if the patient does not follow the prescription or misses a dosage, the event can be recorded and evaluated as part of the comprehensive therapy review by the physician.\",\n \"In another embodiment of the present disclosure, the software application provides information related to the pain management therapy and/or ongoing treatments, which is viewable on the communicating device.\",\n \"The information may include news, company alerts, and/or the parameters related to the therapy outcome.\",\n \"In some embodiments, the information is received on demand remotely or stored in the memory.\",\n \"For example, each of the news items may include a news story and/or a company alert.\",\n \"The said method may also include communicating, through the network interface, one or more messages between the patient and a case manager.\",\n \"Any one of the messages may be an address change notification, an insurance notification, and/or a vacation notification.\",\n \"In yet another embodiment of the present disclosure, the software application provides a support feature that enables the user to communicate with, for example, a health care provider, a physician or care manager or head nurse.\",\n \"In other examples, the user may use the support feature to select a care manager from a list of service providers to ask questions related to the pain management therapy, and/or to request scheduling appointments and other support services.\",\n \"According to another embodiment of the present disclosure, a system for managing therapeutic treatment of a disease of a patient by a user is provided, including a communicating device having a processor and a memory coupled to the processor.\",\n \"The said communicating device is constructed and adapted to communicate with at least one server.\",\n \"A software application is stored on the memory.\",\n \"The software application is executable by the processor and comprises a physiological data collection engine for collecting physiological data, a data storage module for storing one or more parameters related to the treatment, a tracking module for tracking the parameters, a therapy analysis engine for determining a personalized pain management therapy, and a server system interface engine for communicating information related to the treatment with a health physician, a company, and/or a case manager.\",\n \"In some embodiments, the communicating device may be a smart phone having a wireless network device, or a personal digital assistant having a wireless network device or a computer.\",\n \"The information may include news, company alerts, and/or the parameters related to therapy outcome.\",\n \"The parameters and/or the information are optionally displayed to the user in an interface of the computing device.\",\n \"The software application may also include a calendar module for scheduling treatment administrations and/or appointments.\",\n \"The information may include the treatment administrations and/or the appointments.\",\n \"The parameters may further include parameter data acquired from a medical test and diagnosis of the patient.\",\n \"The parameters may include a parameter type, a parameter value, and/or a test date.\",\n \"The parameter type may involve various types of pain symptom such as somatic pain, neuropathic pain, musculoskeletal pains of various body parts, back pain, arthritis (rheumatoid or osteo), elbow pain, bursitis, tendonitis, migraine, headaches, fibromyalgia, post-operative pain, joint pain, tunnel syndrome, tendon or ligament pain, acute injuries; extensibility of collagen tissue, skin lift, skin rejuvenation, facial tightening, decreases in joint stiffness, improvement in range of motion, relief in muscle spasms, increase in global and local blood flow, global and local blood oxygen levels, body/skin temperature, tissue temperature, heart rate, tenderness of the tissue (as measured by algometry), skin pH, vital signs such as blood pressure, body temperature, local metabolism, nerve conduction velocities and so on.\",\n \"In another embodiment of the present disclosure, the repository database in a server system stores patient profile.\",\n \"The patient profile may include patient information comprising a patient name, demographics, vital signs, patient street address, a patient telephone number, time and date of therapy administration, therapy compliance, and/or a patient e-mail address.\",\n \"The server system may generate the messages based on the patient profile, the case manager, and/or a message type.\",\n \"The message type may be an address change notification, an insurance notification, and/or a vacation notification.\",\n \"In another embodiment of the present disclosure, the repository database at the server system stores various physical therapies administered, the dosage, such as electric stimulation applied (voltage, current, pulsing time, duration), ultrasound (frequency, intensity, duty cycle, duration), heat (temperature [e,g, 25-60° C., in some examples, 25-50° C.], duration, pulsing), cold (0-25° C., duration, pulsing), and combinations involving simultaneous and sequential applications of aforementioned physical therapies with the corresponding parameters that define the physical medicine dosage, exposure intensity, therapy duration.\",\n \"In another embodiment of the present disclosure, a system and method are provided that enable entry of the patient profile, pain symptom, and prescription for physical medicine to be administered.\",\n \"The entered information is stored in a database for immediate or future reference to personalize the therapy.\",\n \"In another embodiment of the present disclosure, a system and method are provided which enable a single device with the capability of delivering more than one physical medicine or modalities or combination of medical devices to deliver multiple physical modalities to targeted tissue such as temperature (heat or cold), ultrasound (e.g., 0.5 to 3 MHz) and electrical stimulation (e.g., TENS or IFT) to a targeted live tissue to provide optimum therapeutic benefits.\",\n \"Further, the system may have the capability collect non-invasive sensing information of patient such as vital signs, tissue thickness, tissue images, tissue temperature at different depths, blood flow rates in the skin or in the tissue, blood oxygen levels, pressure point depth or pressure-pain threshold, and skin pH, if required.\",\n \"In addition, the system may be configured for retrieving and storing treatment information (including day and time), subject information, sensing information, demographics, billing information and outcome of the therapy session as defined by the subject on a given pain relief score from unsatisfactory to fully satisfied and further capable of communicating with a database located on a server either locally or in cloud.\",\n \"In another embodiment of the present disclosure, a system and method are provided which are configured to perform analysis of the compiled or stored data to determine whether the prescribed treatment is compliant, progressing or regressing or needs alteration.\",\n \"The system and method may be designed in such a way that it conducts comprehensive analytics regularly on ever increasing data being gathered and intelligently refines its recommendation for prescription or automatically titrates the physical medicine delivery/prescription.\",\n \"It may normalize the pain relief score from multitude of patients and may make recommendations for personalized physical medicine, i.e., individual or combination modalities, method, dosage and therapy duration, for individuals or a group or section of demographics and may generate automatic messages regarding pain therapy status.\",\n \"In another embodiment of the present disclosure, a graphical user interface for the entry of data (i.e., prior to the treatment) is provided, such as patient profile, demographics, symptoms, diagnosis, pre-existing condition.\",\n \"Further, the interface may display information correlating pertinent entry data in a graphical manner, to show the relationship between individual (or a group of) patient profile(s) or demographics, with regard to physical medicine(s) administered and the outcome of the therapy, risk and benefit ratios with respect to any type of clinical application or therapy as warranted to make the therapy safe, personable and efficient.\",\n \"The disclosed graphical user interface can also display the population exposures and outcomes, costs and benefits, antecedents and outcomes, causes and effects, and comorbidities of any number of health care scenarios.\",\n \"The graphical user interface can provide a graphical representation of the relationship between any such information or events.\",\n \"In another embodiment of the present disclosure, a computer readable medium is provided for storing executable instructions for execution by a computer having memory, where medium stores instructions for inputting contact information into a data storage device, transmitting an electronic message based on the contact information, receiving a response, storing the response and a timestamp into the data storage device, storing a time and date of receipt of the response into the data storage device, and querying the database for trends based on the response.\",\n \"In some embodiments, the ever increasing amount of information stored in the database with regard to patient profiles, pain symptoms, physical therapies administered, outcomes measured, sensing data gathered, compliance levels monitored would be collectively and intelligently evaluated to propose/recommend a preferred prescription either automatically or upon request to personalize the pain therapy for an individual or classified group.\",\n \"The disclosed system is capable of self-correcting/fine tuning the prescription recommendation or optimizing the physical medicine delivery as the data sampling size increases from a broad spectrum of the society.\",\n \"In another embodiment of the present disclosure, a medical device is provided which is capable of delivering multiple modes of physical medicine (e.g., electric stimulation, ultrasound, heat and cold either individually or in combination), collecting non-invasive sensing information relevant to assessing the progression or regression of the therapy, connects wirelessly to a database, and transmits the entry data, therapy data, sensing data and the patient feedback, conducts analytics, identifies the trends/correlations, and thereby intelligently recommends the prescription or automatically administers the therapy.\",\n \"In another embodiment, a portable and versatile pain therapy device is presented that provides an applicator, a plurality of sensors and an electronic controller powered by a rechargeable battery/power source.\",\n \"The said device is capable of producing and applying different forms of energies when placed on the treatment area (the skin).\",\n \"The generated energies penetrate through the skin into the deeper layers to produce soothing and palliative effects to give the sense of relief In another embodiment, disclosed is provided a pain therapy device, comprising: an applicator and a controller wherein the applicator is configured for accepting at least one electrical input; a controller configured for providing the intensity, sequence, nature, and timing information for the different energies supplied to the said applicator; and the applicator comprising of plurality of transducers configured for converting input electrical energy to different forms of output energies that are transmitted to the dermal and sub-dermal layers; and a plurality of sensors disposed over the applicator configured for providing a feedback control signal to the controller.\",\n \"Further herein disclosed is a method for performing electronic therapy using a portable electronic device comprising the steps of: attaching the device to the skin of the subject; inputting electrical energy from a power source; controlling the electrical energy power input using a controller; converting the electrical energy to different forms of output energy using a plurality of configured circuit blocks; and providing the intensity, sequence, nature, and timing signals for activating therapy using different energies or at least one energy through an applicator; and modifying the intensity, sequence, nature, and timing signals as per the feedback control signals from a plurality of sensors.\",\n \"In a further embodiment of the present invention there is provided a feedback control mechanism enabled by a plurality of sensors disposed over the applicator, which provides further control over the application of the different energies to the treatment area.\",\n \"The sensors can collect and send the data to the feedback control mechanism of the controller to control various parameters such as temperature, frequency, intensity, input power, time, or any other parameters.\",\n \"The data collected can be sent to the feedback loop of the controller.\",\n \"In another example, the data collected can be delivered as outlined above with respect to the intelligent pain management system described.\",\n \"The device/platform disclosed herein may also be used for intelligent and personalized fracture healing.\",\n \"The device may be used to offer low intensity pulsed ultrasound (LIPUS) combination therapies.\",\n \"Deliver of LIPUS in combination with thermoceuticals, electroceuticals and bone healing rate determining sensors provides an opportunity for personalizing faster bone healing therapies.\",\n \"The disclosed device/software platform can allow easy selection of the appropriate therapy with feedback loop mechanisms, which may involve (automatic) selection of dosage, duration, and any other appropriate features.\",\n \"Use of the device in combination with the intelligent data systems described herein can allow a doctor to monitor therapy compliance by a patient.\",\n \"The sensor feedback can automatically measure the tissue temperature and the rate of bone healing in response to applied therapy.\",\n \"FIG.\",\n \"14 illustrates a flow chart that illustrates various patient profile data, sensor data related to physiological parameters, tissue and bone, therapy data and the bone fracture type to be treated.\",\n \"This data collected on hundreds/thousands or even millions of patients can be mined to provide personalized treatment for faster/efficient bone healing.\",\n \"Disclosed herein is a portable therapy device configured to drive inputs to one or more switches controlling combination treatments comprising a combination of at least one thermoceutical, electroceutical, and ultrasound therapy while measuring physiological, musculoskeletal characteristics related parameters via sensors.\",\n \"The device may include one or more applicators.\",\n \"It is possible to provide three separate applicators for the therapies.\",\n \"It is possible to provide one or more therapies combined into one applicator.\",\n \"In a specific example, heat/cold therapy (thermoceuticals) and ultrasound therapy may be provided in a single applicator.\",\n \"In another example, heat/cold therapy (thermoceuticals), ultrasound, and electrical stimulation (electroceuticals) may be provided in a single application.\",\n \"In one example, an applicator is coupled to the one or more switches and configured to deliver ultrasonic energy in a pulsed or continuous mode, wherein ultrasound frequency ranges from about 0.1 MHz to about 10 MHZ, and wherein intensities range from about 0.01 W/cm2 to about 3.0 W/cm2 in various combinations.\",\n \"The same or an additional applicator coupled to the one or more switches and configured to deliver thermoceutical energy in a pulsed or continuous mode, wherein thermal energy ranges from about 0 ° C. to about 50° C. The same or an additional applicator comprising electrodes coupled to the one or more switches and configured to deliver electroceutical energy in a pulsed or continuous in the frequency range from about 1-200 Hz; pulse amplitude 0 mA to 500 mA.\",\n \"It is understood that any of the proposed or defined parameters can operate with±20% error margin.\",\n \"The device may also feature at least one or more sensors integrated into the same or additional applicators and coupled to a processing device to measure at least one physiological parameter or musculoskeletal characteristics related parameter comprising body temperature, tissue temperature, local blood flow, local blood oxygen levels, local tissue thickness, local tissue composition/structure, bone strength, bone fracture type, callus stiffness, and velocity and attenuation properties of sound waves in tissue or bone.\",\n \"The device may be used to treat arthritis, joint pain, bursitis, muscle pain or injuries, muscle spasm or strain, soft tissue injuries, musculoskeletal injuries, back pain, joint stiffness, cold hands, rheumatism, neuralgia, inflammation, edema, ischemia, spasm, to stimulate enzyme activity and immune system, bone healing, tendon healing, or wound healing.\",\n \"In other examples, it may be used to stimulate or accelerate fractured bone or tissue healing.\",\n \"The device may be used for faster healing of damaged or fractured bones, and for monitoring bone healing progress through sensor feedback.\",\n \"Other embodiments provide a medical device for the application of a therapy, comprising: a processing device configured to drive inputs for one or more switches controlling characteristics of treatments comprising thermoceuticals, electroceuticals, ultrasound, or a combination thereof, the characteristics of the treatments corresponding to the therapy; an applicator, coupled to the one or more switches, the applicator configured to apply the treatments or a combination thereof based on the inputs to the one or more switches; one or more sensors coupled to the processing device, the one or more sensors configured to 1) detect physiological parameters responsive to the application of the treatments or combination thereof and 2) provide the physiological parameters to the processing device; and a patient feedback interface communicatively coupled to the processing device, the patient feedback interface configured to receive user inputs indicating patient feedback information responsive to the application of the treatments or combination thereof.\",\n \"The characteristics of the treatments or the combination thereof may include intensity levels and time durations.\",\n \"The physiological parameters may comprise one or more of body temperature, tissue temperature, local blood flow, local blood oxygen levels, local tissue thickness, local tissue composition/structure, local tissue imaging, local tissue bone strength, bone fracture type, callus stiffness, and velocity and attenuation properties of sound waves in tissue or bone.\",\n \"In other embodiments, there is disclosed a method for delivering a bone healing treatment, comprising: receiving patient information comprising patient data and symptoms; comparing the received patient information with bone healing analytics data compiled on a plurality of individuals to determine a personalized bone healing therapy; applying the personalized bone healing therapy to deliver one or more of thermoceuticals, electroceuticals, or ultrasound, in various combinations; receiving updated patient information in response to the applied personalized bone healing therapy; and storing the updated patient information and the personalized pain management therapy in a database to add to the bone healing analytics data compiled on the plurality of individuals.\",\n \"It is possible to adjust, in response to the updated patient information, the personalized bone healing therapy by adjusting the combination of thermoceuticals, electroceuticals, or ultrasound; and store the adjusted personalized bone healing therapy in the database to add to the bone healing analytics data.\",\n \"The patient data and the updated patient information may further comprise patient physiological data including one or more of patient vital signs, body or tissue temperature, blood flow rate, blood oxygen levels, or body tissue thickness or density.\",\n \"The patient data and the updated patient information may be received at a bone healing therapy device, and wherein the personalized bone healing therapy is applied by transmitting electronic signals to an applicator to deliver the thermoceuticals, electroceuticals, ultrasound, or combination thereof via one or more applicators.\",\n \"The patient data and the bone healing analytics data may be stored in a memory of the bone healing therapy device or in a remotely connected database, and the bone healing analytics data may include correlated patient information and patient feedback regarding bone healing therapy outcomes on the plurality of individuals.\",\n \"Comparing the received patient information with bone healing analytics data to determine the personalized bone healing therapy may comprises: identifying a subset of individuals from the plurality of individuals that have similar characteristics as the patient as indicated in the patient information; and identifying, from the bone healing analytics data on the subset of individuals, a stored applied therapy associated with a stored therapy outcome indicating enhanced bone healing symptoms, wherein the identified stored applied therapy corresponds to the personalized bone healing therapy.\",\n \"It is possible for the patient data and the updated patient information to be received by one or more sensors communicatively coupled to a bone healing therapy device or by user inputs received at a patient feedback interface.\",\n \"The personalized bone healing therapy may comprise a combination therapy of: delivering thermoceuticals comprising heat in a temperature range of about 0-50° C.; and delivering ultrasonic energy at ultrasound frequency ranges of from about 0.1 MHz to about 10 MHZ and intensities from about 0.01 W/cm2 to about 3.0 W/cm2, wherein the delivery of thermoceuticals and ultrasonic energy may be in a pulsed or continuous mode and in various combinations of duration and intensities.\",\n \"Numerous specific details are set forth herein to provide a thorough understanding of the claimed subject matter.\",\n \"However, those skilled in the art will understand that the claimed subject matter may be practiced without these specific details.\",\n \"In other instances, methods, apparatuses, or systems that would be known by one of ordinary skill have not been described in detail so as not to obscure claimed subject matter.\",\n \"Unless specifically stated otherwise, it is appreciated that throughout this specification discussions utilizing terms such as “processing,” “computing,” “calculating,” “determining,” and “identifying” or the like refer to actions or processes of a computing device, such as one or more computers or a similar electronic computing device or devices, that manipulate or transform data represented as physical electronic or magnetic quantities within memories, registers, or other information storage devices, transmission devices, or display devices of the computing platform.\",\n \"The system or systems discussed herein are not limited to any particular hardware architecture or configuration.\",\n \"A computing device can include any suitable arrangement of components that provides a result conditioned on one or more inputs.\",\n \"Suitable computing devices include multipurpose microprocessor-based computer systems accessing stored software that programs or configures the computing system from a general purpose computing apparatus to a specialized computing apparatus implementing one or more embodiments of the present subject matter.\",\n \"Any suitable programming, scripting, or other type of language or combinations of languages may be used to implement the teachings contained herein in software to be used in programming or configuring a computing device.\",\n \"Embodiments of the methods disclosed herein may be performed in the operation of such computing devices.\",\n \"The order of the blocks presented in the examples above can be varied—for example, blocks can be re-ordered, combined, and/or broken into sub-blocks.\",\n \"Certain blocks or processes can be performed in parallel.\",\n \"The use of “adapted to” or “configured to” herein is meant as open and inclusive language that does not foreclose devices adapted to or configured to perform additional tasks or steps.\",\n \"Additionally, the use of “based on” is meant to be open and inclusive, in that a process, step, calculation, or other action “based on” one or more recited conditions or values may, in practice, be based on additional conditions or values beyond those recited.\",\n \"Headings, lists, and numbering included herein are for ease of explanation only and are not meant to be limiting.\",\n \"While the present subject matter has been described in detail with respect to specific embodiments thereof, it will be appreciated that those skilled in the art, upon attaining an understanding of the foregoing, may readily produce alterations to, variations of, and equivalents to such embodiments.\",\n \"Accordingly, it should be understood that the present disclosure has been presented for purposes of example rather than limitation, and does not preclude inclusion of such modifications, variations, and/or additions to the present subject matter as would be readily apparent to one of ordinary skill in the art.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875743"}}},{"rowIdx":4494962,"cells":{"text":{"kind":"list like","value":[["IMAGE-FORMING APPARATUS PROVIDED WITH URGING MEMBER FOR URGING PROCESS CARTRIDGE","An image-forming apparatus includes: a main body; a toner cartridge having a first opening; a process cartridge having a photosensitive drum and a second opening; a positioning part; a transfer unit; and an urging member.","The toner cartridge and process cartridge are attachable to and detachable from the main body in an axial direction of the photosensitive drum.","The positioning part and transfer unit are positioned above the process cartridge attached to the main body.","The positioning part fixes the attached process cartridge in position relative to the main body.","The urging member urges the attached process cartridge toward the positioning part and urges the process cartridge such that such that the toner can be supplied from the toner cartridge to the process cartridge through the first opening and the second opening when the toner cartridge and the process cartridge are attached to the main body."],["1.An image-forming apparatus configured to form an image on a sheet, the image-forming apparatus comprising: a main body comprising: an upper wall having a tray that is recessed downward for catching the sheet; a first wall having a first access opening; and a second wall having a second access opening; a toner cartridge attachable to the main body in a first direction through the first access opening, the toner cartridge accommodating toner and having a first opening; a waste toner container attachable to the main body in a second direction perpendicular to the first direction through the second access opening; a process cartridge including a photosensitive drum, the process cartridge being attachable to the main body in an axial direction along an axis of the photosensitive drum, the process cartridge having a second opening, the process cartridge further comprising: a cleaning member configured to remove toner from the photosensitive drum; and a discharge tube having a third opening, the discharge tube being configured to discharge the toner removed by the cleaning member toward the waste toner container through the third opening; a positioning part positioned above the process cartridge in a state where the process cartridge is attached to the main body, the positioning part being configured to fix the process cartridge in position relative to the main body in the state where the process cartridge is attached to the main body; and a transfer belt positioned above the process cartridge in the state where the process cartridge is attached to the main body.","2.The image-forming apparatus according to claim 1, further comprising an urging member for urging the process cartridge toward the positioning part in the state where the process cartridge is attached to the main body, the urging member being configured to urge the process cartridge to allow the second opening of the process cartridge to communicate with the first opening of the toner cartridge in a state where the toner cartridge is attached to the main body and in the state where the process cartridge is attached to the main body, wherein the process cartridge includes: a drum unit including the photosensitive drum; and a developing unit including a developing roller, wherein the drum unit includes a first side plate and a second side plate apart from the first side plate in the axial direction, the photosensitive drum being supported by the first side plate and the second side plate, and wherein the second side plate includes a surface, the urging member urging the surface of the process cartridge toward the positioning part in the state where the process cartridge is attached to the main body.","3.The image-forming apparatus according to claim 2, wherein the main body includes a coupling, wherein the second side plate of the drum unit includes a support part including a cylindrical part having a general cylindrical shape, the cylindrical part protruding from an outer surface of the second side plate and supporting an end of the photosensitive drum, the end of the photosensitive drum having a coupling recess, and the coupling of the main body being inserted into the coupling recess in the state where the process cartridge is attached to the main body, and wherein the support part of the drum unit includes the surface, the surface being positioned below the coupling recess.","4.The image-forming apparatus according to claim 2, wherein the developing unit is movable about a rotational shaft extending in the axial direction relative to the drum unit.","5.The image-forming apparatus as claimed in claim 1, further comprising an urging member for urging the process cartridge toward the positioning part in the state where the process cartridge is attached to the main body, the urging member being configured to urge the process cartridge to allow the second opening of the process cartridge to communicate with the first opening of the toner cartridge in a state where the toner cartridge is attached to the main body and in the state where the process cartridge is attached to the main body, wherein the process cartridge includes a surface that contacts the urging member in the state where the process cartridge is attached to the main body, the surface of the process cartridge being positioned between the second opening of the process cartridge and the third opening of the discharge tube in a direction perpendicular to the axial direction and a vertical direction.","6.The image-forming apparatus according to claim 1, wherein the main body includes: a coupling; a third access opening, the process cartridge being attachable to the main body through the third access opening; and a cover movable between a closed position where the cover closes the third access opening and an open position where the cover opens the third access opening, and wherein the main body includes a side plate, the process cartridge being positioned between the cover and the side plate of the main body in the axial direction in the state where process cartridge is attached to the main body, the coupling being disposed on the side plate of the main body.","7.The image-forming apparatus according to claim 1, wherein the positioning part comprises a first positioning part and a second positioning part, the transfer belt being positioned between the first positioning part and the second positioning part in the axial direction in the state where the process cartridge is attached to the main body, wherein the main body includes: a third access opening; and a cover movable between a closed position where the cover closes the third access opening and an open position where the cover opens the third access opening, the second positioning part being positioned between the cover and the first positioning part in the axial direction, wherein the waste toner container is positioned between the second positioning part and the cover in the axial direction.","8.The image-forming apparatus according to claim 1, further comprising an urging member for urging the process cartridge toward the positioning part in the state where the process cartridge is attached to the main body, the urging member being configured to urge the process cartridge to allow the second opening of the process cartridge to communicate with the first opening of the toner cartridge in a state where the toner cartridge is attached to the main body and in the state where the process cartridge is attached to the main body, wherein the urging member has an engaging surface, the process cartridge moving from an outside position where the process cartridge is outside the main body to an inside position where the process cartridge is inside the main body in the axial direction during attachment of the process cartridge to the main body, and wherein the engaging surface contacts the process cartridge during attachment of the process cartridge to the main body, the engaging surface sloping upward toward downstream in a direction in which the process cartridge moves from the outside position to the inside position.","9.The image-forming apparatus according to claim 8, wherein the urging member includes a tension spring.","10.The image-forming apparatus according to claim 1, wherein the toner cartridge is positioned above the process cartridge in the state where the toner cartridge is attached to the main body and in the state where the process cartridge is attached to the main body.","11.The image-forming apparatus according to claim 10, wherein the main body includes a receiving part receiving the toner cartridge in the state where the toner cartridge is attached to the main body, the receiving part including a bottom wall having a fourth opening communicating with the toner cartridge in the state where the toner cartridge is attached to the main body, and wherein the main body includes an input tube, the input tube including a top end communicating with the fourth opening of the receiving part and a bottom end having a fifth opening, the fifth opening communicating with the second opening of the process cartridge in the state where the process cartridge is attached to the main body.","12.The image-forming apparatus according to claim 1, further comprising: a sheet tray attachable to the main body in a direction perpendicular to the axial direction, the sheet tray being positioned below the process cartridge in the state where the process cartridge is attached to the main body and in a state where the sheet tray is attached to the main body, the sheet tray moving from an inside position where the sheet tray is inside the main body to an outside position where the sheet tray is outside the main body in the direction perpendicular to the axial direction during detachment of the sheet tray from the main body; a secondary transfer roller; a first roller configured to convey a sheet from the sheet tray toward a position between the transfer belt and the secondary transfer roller; and a discharge roller configured to discharge the sheet conveyed from the position between the transfer belt and the secondary transfer roller toward the tray in a direction in which the sheet tray moves from the inside position to the outside position.","13.The image-forming apparatus according to claim 1, further comprising an image-reading unit configured to read image data on an original document, the image-reading unit being positioned above the main body.","14.The image-forming apparatus according to claim 13, wherein the image-reading unit includes: a platen on which the original document is to be placed; and a pressure cover supported to the platen, the pressure cover being pivotally movable with respect to the platen.","15.An image-forming apparatus configured to form an image on a sheet, the image-forming apparatus comprising: a main body comprising: an upper wall having a tray that is recessed downward for catching the sheet; and a first wall having an access opening; a first toner cartridge attachable to the main body in a first direction, the first toner cartridge accommodating first toner and having a first toner opening; a second toner cartridge attachable to the main body in the first direction, the second toner cartridge accommodating second toner and having a second toner opening; a waste toner container attachable to the main body in a second direction perpendicular to the first direction through the access opening; a process cartridge including a photosensitive drum, the process cartridge being attachable to the main body in an axial direction along an axis of the photosensitive drum, the process cartridge having a second opening, the process cartridge further comprising: a cleaning member configured to remove toner from the photosensitive drum; and a discharge tube having a third opening, the discharge tube being configured to discharge the toner removed by the cleaning member toward the waste toner container through the third opening; and a transfer belt positioned above the process cartridge in a state where the process cartridge is attached to the main body.","16.The image-forming apparatus according to claim 15, wherein the first toner cartridge is disposed between the first wall and the second toner cartridge in a state where the first toner cartridge and the second toner cartridge are attached to the main body.","17.The image-forming apparatus according to claim 15, further comprising: a sheet tray attachable to the main body in a direction perpendicular to the axial direction, the sheet tray being positioned below the process cartridge in the state where the process cartridge is attached to the main body and in a state where the sheet tray is attached to the main body, the sheet tray moving from an inside position where the sheet tray is inside the main body to an outside position where the sheet tray is outside the main body in the direction perpendicular to the axial direction during detachment of the sheet tray from the main body; a secondary transfer roller; a first roller configured to convey a sheet from the sheet tray toward a position between the transfer belt and the secondary transfer roller; and a discharge roller configured to discharge the sheet conveyed from the position between the transfer belt and the secondary transfer roller toward the tray in a direction in which the sheet tray moves from the inside position to the outside position."],["<SOH> BACKGROUND <EOH>There has been known an image-forming apparatus provided with a process cartridge to be attached to and detached from a main housing.","Japanese Patent Application Publication No.","2008-170944 discloses an image-forming apparatus provided with a process cartridge including a drum unit and a developing unit.","The drum unit includes a photosensitive drum, and the developing unit is positioned to oppose the drum unit.","The process cartridge is attachable to and detachable from a main housing with respect to an axial direction of the photosensitive drum."],["<SOH> SUMMARY <EOH>In view of the foregoing, it is an object of the present disclosure to provide an improved image-forming apparatus.","In order to attain the above and other objects, the disclosure provides an image-forming apparatus including a main body, a toner cartridge, a process cartridge, a positioning part, a transfer unit and an urging member.","The toner cartridge is attachable to and detachable from the main body, the toner cartridge accommodating toner therein and having a first opening.","The process cartridge includes a photosensitive drum configured to carry a toner image thereon, the photosensitive drum defining an axis extending in an axial direction, the process cartridge being attachable to and detachable from the main body in the axial direction, the process cartridge having a second opening.","The positioning part is positioned above the process cartridge attached to the main body, the positioning part being configured to fix the process cartridge in position relative to the main body when the process cartridge is attached to the main body.","The transfer unit is positioned above the process cartridge attached to the main body, the toner image on the photosensitive drum being configured to be transferred to the transfer unit when the process cartridge is attached to the main body.","The urging member is configured to urge the process cartridge toward the positioning part when the process cartridge is attached to the main body, the urging member being configured to urge the process cartridge such that the toner can be supplied from the toner cartridge to the process cartridge through the first opening and the second opening when the toner cartridge and the process cartridge are attached to the main body."],["CROSS REFERENCE TO RELATED APPLICATION This application is a continuation of prior U.S. application Ser.","No.","15/589,267, filed May 8, 2017, which is a continuation of prior U.S. application Ser.","No.","15/065,967, filed Mar.","10, 2016 (now U.S. Pat.","No.","9,678,470 issued Jun.","13, 2017), which claims priority from Japanese Patent Application No.","2015-070127 filed Mar.","30, 2015.The entire content of the priority application is incorporated herein by reference.","TECHNICAL FIELD The present disclosure relates to an electro-photographic type image-forming apparatus.","BACKGROUND There has been known an image-forming apparatus provided with a process cartridge to be attached to and detached from a main housing.","Japanese Patent Application Publication No.","2008-170944 discloses an image-forming apparatus provided with a process cartridge including a drum unit and a developing unit.","The drum unit includes a photosensitive drum, and the developing unit is positioned to oppose the drum unit.","The process cartridge is attachable to and detachable from a main housing with respect to an axial direction of the photosensitive drum.","SUMMARY In view of the foregoing, it is an object of the present disclosure to provide an improved image-forming apparatus.","In order to attain the above and other objects, the disclosure provides an image-forming apparatus including a main body, a toner cartridge, a process cartridge, a positioning part, a transfer unit and an urging member.","The toner cartridge is attachable to and detachable from the main body, the toner cartridge accommodating toner therein and having a first opening.","The process cartridge includes a photosensitive drum configured to carry a toner image thereon, the photosensitive drum defining an axis extending in an axial direction, the process cartridge being attachable to and detachable from the main body in the axial direction, the process cartridge having a second opening.","The positioning part is positioned above the process cartridge attached to the main body, the positioning part being configured to fix the process cartridge in position relative to the main body when the process cartridge is attached to the main body.","The transfer unit is positioned above the process cartridge attached to the main body, the toner image on the photosensitive drum being configured to be transferred to the transfer unit when the process cartridge is attached to the main body.","The urging member is configured to urge the process cartridge toward the positioning part when the process cartridge is attached to the main body, the urging member being configured to urge the process cartridge such that the toner can be supplied from the toner cartridge to the process cartridge through the first opening and the second opening when the toner cartridge and the process cartridge are attached to the main body.","BRIEF DESCRIPTION OF THE DRAWINGS The particular features and advantages of the disclosure as well as other objects will become apparent from the following description taken in connection with the accompanying drawings, in which: FIG.","1 is a central cross-sectional view of a printer as an example of an image-forming apparatus according to a first embodiment; FIG.","2 is a cross-sectional view of the printer according to the first embodiment taken along a line A-A of FIG.","6; FIG.","3 is a perspective view of a process cartridge shown in FIG.","2 in the printer according to the first embodiment; FIG.","4A is a perspective view of a left end portion of the process cartridge shown in FIG.","3; FIG.","4B is a right side view of the process cartridge shown in FIG.","3; FIG.","5 is a perspective view of an urging member shown in FIG.","3; FIG.","6 is a cross-sectional view of the printer according to the first embodiment taken along a line B-B shown in FIG.","1, and showing a state where the process cartridge is at its first position and a connector tube is at its communication position; FIG.","7 is a cross-sectional view of the printer according to the first embodiment taken along the line B-B shown in FIG.","1, and showing a state where the process cartridge is at the first position and the connector tube is at a non-communication position; FIG.","8 is a cross-sectional view of the printer according to the first embodiment taken along the line B-B shown in FIG.","1, and showing a state where the process cartridge is at its second position and the connector tube is at the non-communication position; FIG.","9 is a cross-sectional view of a printer according to a second embodiment and taken along a line corresponding to the line B-B of FIG.","1, and showing a state where a process cartridge is at its first position and the connector tube is at the communication position; and FIG.","10 is a cross-sectional view of the printer according to the second embodiment and taken along the line corresponding to the line B-B of FIG.","1, and showing a state where the process cartridge is at its second position and the connector tube is at the non-communication position.","DETAILED DESCRIPTION 1.Overall Structure of the Printer A printer 1 as an example of an image-forming apparatus according to a first embodiment will be described while referring to FIGS.","1 through 8.As shown in FIG.","1, the printer 1 includes a main casing 2, a sheet-supplying unit 11 for supplying a sheet, an image-forming unit 3 for forming an image on the sheet, a sheet-discharging unit 4 for discharging the image-formed sheet, and an image-reading unit 5 for reading image data on an original document.","The main casing 2 is generally box-shaped, and includes an outer frame 50 and an inner frame 51 provided within the outer frame 50, as shown in FIG.","6.The outer frame 50 includes a front wall, a rear wall, an upper wall, a right wall and a left wall which constitute a front wall, a rear wall, an upper wall, a right wall and a left wall of the main casing 2.The front wall of the outer frame 50 is formed with an access opening 7 and another access opening 63 for allowing communication between the inside and the outside of the main casing 2 in a front-rear direction.","Structures of the outer frame 50 and inner frame 51 will be described later in greater detail.","The sheet-supplying unit 11 includes a first sheet tray 9, a first pick-up roller 12, a second sheet tray 10, and a second pick-up roller 13.The first sheet tray 9 is positioned at a lower end portion of an interior of the main casing 2.The first sheet tray 9 is generally box shaped having an upper open end, and is detachably attachable to the main casing 2.The first sheet tray 9 is configured to accommodate sheets.","The first pick-up roller 12 is positioned above a rear end portion of the first sheet tray 9.The first pick-up roller 12 is generally cylindrical extending in a left-right direction, and is rotatably supported to the main casing 2.The second sheet tray 10 is provided at the front wall of the main casing 2 (i.e., outer frame 50).","The second sheet tray 10 is a flat plate-like shape having a generally rectangular shape in a front view.","The second sheet tray 10 has a lower end pivotally connected to the front wall, so that the second sheet tray 10 is pivotally movable about the lower end between a closed position closing the access opening 7 (shown by a sloid line in FIG.","1) and an open position opening the access opening 7 (shown by a phantom line in FIG.","1).","When placed at the open position, the second sheet tray 10 serves as a sheet receiving tray on which sheets for manual insertion are placed.","The second pick-up roller 13 is positioned rearward of the second sheet tray 10 and at a generally center portion of the main casing 2 in the front-rear direction.","The second pick-up roller 13 has a generally cylindrical shape extending in the left-right direction.","The second pick-up roller 13 is rotatably supported to the main casing 2.The sheet-supplying unit 11 also includes: a first sheet-feeding path 181 along which a sheet is configured to be fed by the first pick-up roller 12 from the first sheet tray 9; and a second sheet-feeding path 182 along which a sheet is configured to be fed by the second pick-up roller 13 from the second sheet tray 10.As shown in FIGS.","1 and 2, the image-forming unit 3 includes toner cartridges 16Y, 16M, 16C and 16K, process cartridges 17Y, 17M, 17C and 17K, a scanner unit 15, a transfer unit 18, and a fixing unit 19.In the following description Y, M, C and K represent toners of yellow, magenta, cyan, and black, respectively.","Further, in the drawings, reference characters of Y, M, C and K are added only for typical components, for explanatory purpose.","As shown in FIG.","6, the toner cartridges 16Y, 16M, 16C and 16K are positioned at right upper end portion of the interior of the main casing 2.As shown in FIG.","2, the toner cartridges 16Y, 16M, 16C and 16K are arrayed and spaced apart from one another in a diagonal direction from an upper front portion toward a lower rear portion of the main casing 2.The toner cartridges 16Y, 16M, 16C and 16K are detachably attached to the main casing 2, and contain therein toners of different colors of yellow, magenta, cyan, and black, respectively.","The toner cartridges 16Y, 16M, 16C and 16K have the same structures as one another.","As shown in FIG.","1, the process cartridges 17Y, 17M, 17C and 17K are positioned at a generally center in the main casing 2.The process cartridges 17Y, 17M, 17C and 17K are arrayed in the diagonal direction from the upper front upper to the lower rear with a space between neighboring cartridges.","The process cartridges 17Y, 17M, 17C and 17K are attached to and detached from the main casing 2 with respect to the left-right direction.","Specifically, the process cartridges 17Y, 17M, 17C and 17K are attached to the main casing 2 in a leftward direction (from the right to the left), while being detached from the main casing 2 in a rightward direction (from the left to the right).","The leftward direction is an example of an attaching direction.","As shown in FIGS.","2 and 6, each of the process cartridges 17Y, 17M, 17C and 17K is positioned leftward and downward of the corresponding one of the toner cartridges 16Y, 16M, 16C and 16K when mounted in the main casing 2.Incidentally, the process cartridges 17Y, 17M, 17C and 17K have identical structures to each other.","Therefore, in the following, the structure of the process cartridge 17K will only be described.","As shown in FIG.","1, the process cartridge 17K includes a drum unit 21K and a developing unit 22K.","The drum unit 21K includes a photosensitive drum 24K and a charging roller 25K.","The photosensitive drum 24K is provided in an upper end portion of the drum unit 21K.","The photosensitive drum 24K is generally cylindrical and extends in the left-right direction.","The photosensitive drum 24K is rotatably supported to a drum-unit frame 23K (described later) of the drum unit 21K.","The photosensitive drum 24K defines an axis extending in the left-right direction about which the photosensitive drum 24K is rotatable.","The charging roller 25K is positioned downward of the photosensitive drum 21K, and is generally cylindrical shaped extending in the left-right direction.","The charging roller 25K is rotatably supported to the drum-unit frame 23 (described later) of the drum unit 21K.","The developing unit 22K includes a developing roller 27K, a supply roller 28K, and a thickness-regulating blade 29K.","The developing roller 27K is rotatably provided in an upper end portion of the developing unit 22K.","The developing roller 27K is generally cylindrical extending in the left-right direction.","The developing roller 27K is rotatably supported to a developing-unit frame 26 (described later) of the developing unit 22K, and is in contact with a front end portion of the photosensitive drum 24K.","The supply roller 28K is positioned frontward and downward of the developing roller 27K.","The supply roller 22 has a generally cylindrical shape extending in the left-right direction.","The supply roller 28K is rotatably supported to the developing-unit frame 26 (described later) of the developing unit 22K.","The supply roller 28K has an upper end portion in contact with a lower front end portion of the developing roller 21.The thickness-regulating blade 29K is positioned rearward and downward of the developing roller 27K.","The thickness-regulating blade 29K has a plate-like configuration extending in the left-right direction.","The thickness-regulating blade 29K is in contact with a lower rear end portion of the developing roller 27K.","The scanner unit 15 is positioned downward of the respective process cartridges 17Y, 17M, 17C and 17K.","More specifically, the scanner unit 15 is positioned between the process cartridges 17Y, 17M, 17C and 17K and the second pick-up roller 13 in a vertical direction.","The scanner unit 15 is configured to irradiate laser beams to the respective photosensitive drums 24Y, 24M, 24C and 24K based on image data to expose the respective photosensitive drums 24Y, 24M, 24C and 24K to light.","The transfer unit 18 is positioned upward of the respective process cartridges 17Y, 17M, 17C and 17K.","The transfer unit 18 includes a belt unit 31, a secondary transfer roller 32, and a belt cleaning unit 150.The belt unit 31 generally extends in the front-rear direction.","The belt unit 31 includes a first roller 33, a second roller 34, a third roller 35, an intermediate transfer belt 36, and primary transfer rollers 37Y, 37M, 37C and 37K.","The first roller 33 is positioned at a rear end portion of the belt unit 31, and is generally cylindrical shaped extending in the left-right direction.","The second roller 34 is positioned at a front end portion of the belt unit 31, and is generally cylindrical shaped extending in the left-right direction.","The third roller 35 is positioned at a lower rear portion of the belt unit 31, and is positioned frontward and downward of the first roller 33.The third roller 35 is generally cylindrical shaped extending in the left-right direction.","The intermediate transfer belt 36 is looped over the first roller 33, the second roller 34, and the third roller 35 under tension.","The intermediate transfer belt 36 has a lower portion in contact with the photosensitive drums 24Y, 24M, 24C and 24K of the process cartridges 17Y, 17M, 17C and 17K attached to the main casing 2.The intermediate transfer belt 36 is circularly movable such that the lower portion thereof moves rearward.","The primary transfer rollers 37Y, 37M, 37C and 37K are arrayed between the second roller 34 and the third roller 35 in the front-rear direction with a space between neighboring rollers.","Each of the primary transfer rollers 37Y, 37M, 37C and 37K is positioned upward of and in confrontation with corresponding one of the attached photosensitive drums 24Y, 24M, 24C and 24K via the intermediate transfer belt 36.The primary transfer rollers 37Y, 37M, 37C and 37K have a generally cylindrical shape extending in the left-right direction.","The secondary transfer roller 32 is positioned rearward of the first roller 33 such that the intermediate transfer belt 36 is nipped between the secondary transfer roller 32 and first roller 33.The secondary transfer roller 32 is generally cylindrical shaped extending in the left-right direction.","The belt cleaning unit 150 includes a belt-cleaning frame 151, a belt-cleaning blade 152, and a belt-cleaning screw 153.The belt-cleaning frame 151 is generally box shaped extending in the left-right direction.","The belt-cleaning frame 151 has an upper rear end portion in which an opening 106 is formed to penetrate the upper rear end portion of the belt-cleaning frame 151 in the front-rear direction.","The belt-cleaning blade 152 is positioned at a rear end portion of the belt-cleaning frame 151.The belt-cleaning blade 152 has a generally flat plate shape extending in the left-right direction.","The belt-cleaning blade 152 has an upper end portion in contact with a front end portion of the intermediate transfer belt 36.The belt-cleaning blade 152 faces the opening 106.The belt-cleaning screw 153 is provided in a lower end portion of the belt-cleaning frame 151 and extends in the left-right direction.","The belt-cleaning screw 153 has a right end rotatably supported by a right wall constituting a first conveying tube 161 (FIG.","2) described later.","The fixing unit 19 is positioned upward of the secondary transfer roller 32.The fixing unit 19 includes a heat roller 41 and a pressure roller 42 in pressure contact with a rear end portion of the heat roller 41.The sheet-discharging unit 4 includes a discharge tray 43, discharge rollers 48, reverse rollers 44, and a guide 45.The discharge tray 43 is formed in the upper wall of the main casing 2 and is recessed downward.","The discharge rollers 48 are positioned rearward and upward of the discharge tray 43.The discharge rollers 48 are generally cylindrical shaped and extend in the left-right direction.","The reverse rollers 44 are positioned upward of the fixing unit 19.The reverse rollers 44 have a generally cylindrical shape and extend in the left-right direction.","The guide 45 is positioned above the fixing unit 19.The guide 45 is movable between a discharge position indicated by a solid line in FIG.","1 and a reverse position indicated by a phantom line in FIG.","1.As shown in FIG.","1, in the discharge position, the guide 45 extends generally in the vertical direction in a side view and has an upper end portion pivotally movably supported to the main casing 2.In the discharge position, a lower end portion of the guide 45 is rearward relative to the upper end portion thereof so that the sheet can be directed toward the discharge rollers 48.In the reverse position, the lower end portion of the guide 45 is positioned frontward than that at the discharge position, so that the sheet can be directed toward the reverse rollers 44.The sheet-discharging unit 4 further includes a first conveying path 183 and a second conveying path 184.The sheet from the fixing unit 19 is conveyed toward the discharge rollers 48 along the first conveying path 183 when the guide 45 is at the discharge position.","The sheet is conveyed from the fixing unit 19 to the reverse rollers 44 along the second conveying path 184 when the guide 45 is at the reverse position.","The sheet nipped by the reverse rollers 44 is configured to be conveyed downward while passing rearward of the fixing unit 19 by reverse rotations of the reverse rollers 44, and is then turned upward in a U-shaped fashion toward a position between the intermediate transfer belt 36 and the secondary transfer roller 32.The image-reading unit 5 is positioned upward of the main casing 2 so as to cover the discharge tray 43 from above.","The image-reading unit 5 includes a platen 46 on which an original document is to be placed, and a pressure cover 47 pivotally movably supported to the platen 46.2.Detailed Structure of the Main Casing The main casing 2 includes the outer frame 50 and the inner frame 51, as described earlier.","As shown in FIG.","6, the outer frame 50 has a box-like shape and is formed of a resin material.","The right wall of the outer frame 50 is formed with an opening 6 as an example of a sixth opening for allowing communication between an inside and an outside of the main casing 2 in the left-right direction.","The outer frame 50 also includes a cover 8 pivotally movable between a closed position for closing the opening 6 (FIG.","6) and an open position for opening the opening 6 (FIG.","7).","The outer frame 50 further includes: mounting units 53Y, 53M, 53C, and 53K having respective openings 59Y, 59M, 59C, and 59K; covers 60Y, 60M, 60C, and 60K capable of opening and closing over the openings 59Y, 59M, 59C, and 59K; and a cover 64 (see FIG.","2) that opens and closes over the access opening 63 formed in the front wall.","The mounting units 53Y, 53M, 53C and 53K are respectively disposed on the upper-right sides of the corresponding process cartridges 17Y, 17M, 17C and 17K.","The mounting units 53Y, 53M, 53C and 53K are arranged at intervals in the front-rear direction.","The openings 59Y, 59M, 59C and 59K provide communication between the interior of the corresponding mounting units 53Y, 53M, 53C and 53K and the exterior of the outer frame 50 in the left-right direction.","In the first embodiment, the mounting units 53Y, 53M, 53C and 53K all have the same construction.","Therefore, only the mounting unit 53M will be described below as a representative example.","Similarly, the covers 60Y, 60M, 60C and 60K all have the same construction and, therefore, only the cover 60M will be described below.","The mounting unit 53M includes a receiving part 65M, and an input tube 66M.","The receiving part 65M has a box-like shape with an open top.","As shown in FIG.","2, the receiving part 65M has a bottom portion having a rounded W-shape in a side view.","An opening 67M (see FIG.","2) is formed in a front end portion of the bottom portion of the receiving part 65M to penetrate the same vertically.","The input tube 66M extends downward from the front end portion of the receiving part 65M.","The input tube 66M has a general cylindrical shape that is elongated vertically.","The input tube 66M has a top end that is in vertical communication with the opening 67M of the receiving part 65M.","The input tube 66M has a bottom end portion that slopes downward toward the left.","The bottom end portion is formed with an opening 68M, as an example of a third opening.","That is, the opening 68 occupies a plane that slopes downward toward the left.","The input tube 66M is provided with a seal 69M on its bottom end.","The seal 69M is formed of an elastic material and has a frame-like structure that is generally rectangular in a plan view.","The seal 69M is arranged around the opening 68M.","The cover 60M is pivotably movably supported to a bottom edge on the right wall of the mounting unit 53M.","The cover 60 can pivot pivot between a closed position for covering the opening 59M and an open position (see FIG.","7) for exposing the opening 59M.","The cover 64 has a plate-like shape that is generally rectangular in a front view.","The cover 64 is pivotably movably supported to a bottom edge on the front wall of the main casing 2 (outer frame 50).","The cover 64 can pivot between a closed position for covering the access opening 63 and an open position for exposing the access opening 63.The cover 8 is provided with detectors 110Y, 110M, 110C, and 110K.","Since the detectors 110Y, 110M, 110C and 110K all have the same construction, only the detector 110K will be described below as a representative example.","As shown in FIG.","4B, the detector 110K includes a light-emitting element 111K, and a light-receiving element 112K.","The light-emitting element 111K is disposed on the cover 8 at a position to the lower-front side of a second conveying tube 98K described later.","The light-receiving element 112K is disposed on the cover 8 at a position on the upper-rear side of the second conveying tube 98K described later.","The light-receiving element 112K is configured to receive light emitted from the light-emitting element 111K.","The inner frame 51 is formed of a metallic material.","As shown in FIGS.","2 and 6, the inner frame 51 includes a first side plate 54 having openings 58 and 107 formed therein, a second side plate 55, a bottom plate 56 supporting the scanning unit 15, a top plate 57 connected to the first side plate 54 and second side plate 55, a center plate 52, a first positioning part 61, and a second positioning part 62.The first side plate 54 constitutes a right end of the inner frame 51.The first side plate 54 has a flat plate shape that is generally rectangular in a side view and elongated vertically.","The opening 58 is formed in a vertical center region of the first side plate 54.The opening 58 has a general rectangular shape in a side view.","As shown in FIG.","2, the opening 58 has a front-rear dimension that is larger than a size of the process cartridges 17Y, 17M, 17C, and 17K juxtaposed in the front-rear direction.","The opening 58 penetrates the first side plate 54 in the left-right direction.","As shown in FIG.","2, the opening 107 is formed in a front end region of the first side plate 54.The opening 107 is positioned frontward of the opening 58 and has a circular shape in a side view.","The opening 107 penetrates the first side plate 54 in the left-right direction.","The second side plate 55 constitutes a left end of the inner frame 51.The second side plate 55 is disposed leftward of and apart from the first side plate 54.The second side plate 55 has a flat plate shape that is generally rectangular in a side view and elongated vertically.","Coupling gears 132 and couplings 133 are disposed on a left surface of the second side plate 55.The coupling gears 132 are rotatably supported on the second side plate 55.The couplings 133 are supported on the corresponding coupling gears 132 so as to be capable of moving relative to the same.","Each of the couplings 133 has a right end that protrudes rightward from the second side plate 55.The couplings 133 can move in the left-right direction.","Springs (not shown) constantly urge the couplings 133 rightward.","The bottom plate 56 is disposed beneath the scanning unit 15 to support the same.","The bottom plate 56 has a flat plate shape that is generally rectangular in a plan view and elongated in the left-right direction.","The bottom plate 56 is connected to the first side plate 54 and second side plate 55.The top plate 57 is disposed above the belt unit 31.The top plate 57 has a flat plate shape that is generally rectangular in a plan view and elongated in the left-right direction.","The center plate 52 is disposed beneath the process cartridges 17Y, 17M, 17C, and 17K and above the scanning unit 15.The center plate 52 has a flat plate shape that is generally rectangular in a plan view and elongated in the left-right direction.","The center plate 52 is formed of a resin material.","The center plate 52 has a right end that extends rightward beyond a bottom edge defining the opening 58.The first positioning part 61 is disposed beneath a right end portion of the top plate 57 and between the first side plate 54 and belt unit 31 in the left-right direction.","The first positioning part 61 is positioned above the process cartridges 17Y, 17M, 17C, and 17K.","The first positioning part 61 is a plate-shaped member that is generally rectangular in a side view and L-shaped in a front view.","The first positioning part 61 has a top end portion connected to the right end portion of the top plate 57.The first positioning part 61 has a bottom end portion that extends downward to approximately the same position as the bottom end of the belt unit 31 in the vertical direction.","The first positioning part 61 includes first positioning grooves 135Y, 135M, 135C, and 135K.","The first positioning grooves 135Y, 135M, 135C, and 135K are formed in a bottom edge of the first positioning part 61.The first positioning grooves 135Y, 135M, 135C, and 135K are spaced at intervals from each other in the diagonal direction from the upper front to the lower rear.","The first positioning grooves 135Y, 135M, 135C, and 135K are recessed upward from the bottom edge of the first positioning part 61.The second positioning part 62 is disposed below a left end portion of the top plate 57 and between the second side plate 55 and the belt unit 31 in the left-right direction.","The second positioning part 62 is a plate-shaped member that is generally rectangular in a side view and L-shaped in a front view.","The second positioning part 62 has a top end portion connected to the left end portion of the top plate 57; and a bottom end portion that extends to approximately the same vertical position as the bottom end of the belt unit 31.The second positioning part 62 includes second positioning grooves 136Y, 136M, 136C, and 136K.","The second positioning grooves 136Y, 136M, 136C, and 136K are formed in a bottom edge of the second positioning part 62 and are spaced at intervals from each other in the diagonal direction from the upper front to the lower rear.","The second positioning grooves 136Y, 136M, 136C, and 136K are recessed upward from the bottom edge of the second positioning part 62.In a left-right projection, the second positioning grooves 136Y, 136M, 136C, and 136K are respectively aligned with the first positioning grooves 135Y, 135M, 135C, and 135K.","3.Detailed Description of the Toner Cartridges Referring to FIG.","2, the toner cartridge 16K includes a cartridge frame 71K having an opening 72K formed therein, a first agitator 141K, and a second agitator 142K.","The cartridge frame 71K has a box-like shape and is elongated in the left-right direction.","The cartridge frame 71K has a bottom wall that has a general rounded W-shape in a side view.","The cartridge frame 71K includes a partitioning plate 137K.","The partitioning plate 137K extends diagonally downward and rearward from an inner peripheral surface of a front wall constituting the cartridge frame 71K.","The partitioning plate 137K partitions the cartridge frame 71K into a large accommodating chamber 138K disposed constituting a rear portion of the cartridge frame 71K, and a small accommodating chamber 139K constituting a front portion of the cartridge frame 71K.","The large accommodating chamber 138K is larger than the small accommodating chamber 139K.","The first agitator 141K is accommodated in the large accommodating chamber 138K.","The first agitator 141 is rotatably supported by the cartridge frame 71K.","The second agitator 142K is accommodated in the small accommodating chamber 139K and is rotatably supported by the cartridge frame 71K.","The opening 72K is formed in a lower-front end portion of the cartridge frame 71K.","The opening 72K vertically penetrates a bottom wall constituting the small accommodating chamber 139K.","The opening 72K is an example of a first opening.","4.Detailed Description of the Process Cartridges (1) Drum Unit As shown in FIG.","3, the drum unit 21K includes the drum-unit frame 23K.","The drum-unit frame 23K has a box-like shape that is elongated in the left-right direction and open on the top side.","The drum-unit frame 23K includes a first side plate 75K, a second side plate 76K, a first conveying tube 77K having an opening 70K as an example of a second opening, and a drum cleaning unit 73K.","As shown in FIGS.","3 and 4B, the first side plate 75K constitutes a right end portion of the drum-unit frame 23K.","The first side plate 75K has a flat plate shape that is generally rectangular in a side view.","The first side plate 75K includes a first support part 78K.","The first support part 78K is disposed in a front-rear center region of the first side plate 75K to protrude rightward therefrom.","The first support part 78K includes a first cylindrical part 79K, and a first engagement part 80K.","The first cylindrical part 79K has a general cylindrical shape that is elongated in the left-right direction.","The first cylindrical part 79K protrudes rightward from a right surface of the first side plate 75K.","Also, as shown in FIGS.","2 and 4B, the first cylindrical part 79K has an upper end portion that protrudes upward from an upper edge of the first side plate 75K.","The first cylindrical part 79K thus has a top surface positioned higher than a top surface of the first side plate 75K.","The first cylindrical part 79K rotatably supports a right end of the photosensitive drum 24K.","The first engagement part 80K protrudes upward from a top edge of the first cylindrical part 79K.","The first engagement part 80K is positioned between the opening 70K formed in the first conveying tube 77K and an opening 102K formed in a discharge tube 100K described later in the front-rear direction.","The first engagement part 80K includes a first plate part 81K having an opening 83K formed therein, a first bar part 82K, and a first protruding part 144K.","The first plate part 81K has a flat plate shape that extends upward from the first cylindrical part 79K.","The opening 83K is formed in an upper end portion of the first plate part 81K.","The opening 83K has a general circular shape in a side view and penetrates the upper end portion of the first plate part 81K in the left-right direction.","The first bar part 82K protrudes rearward from the upper end portion of the first plate part 81K.","The first protruding part 144K protrudes leftward from a rear end of the first bar part 82K.","The first protruding part 144K includes a first sloped surface 84K.","The first sloped surface 84K constitutes a bottom surface of the first protruding part 144K.","The first sloped surface 84K slopes upward toward the left side.","As shown in FIG.","4A, the second side plate 76K constitutes a left end portion of the drum-unit frame 23K and is positioned leftward and apart from the first side plate 75K.","The second side plate 76K has a flat plate shape that is generally rectangular in a side view.","The second side plate 76K is separated leftward from the opening 70K by a greater distance than the first side plate 75K is.","The second side plate 76K includes a second support part 85K.","The second support part 85K is provided in a front-rear center region of the second side plate 76K and protrudes leftward from the same.","The second support part 85K includes a second cylindrical part 86K, and a second engagement part 87K.","The second cylindrical part 86K has a general cylindrical shape that is elongated in the left-right direction.","The second cylindrical part 86K protrudes leftward from the left surface of the second side plate 76K.","Also, the second cylindrical part 86K has an upper end portion that protrudes upward from an upper edge of the second side plate 76K.","The second cylindrical part 86K thus has a top surface positioned higher than a top surface of the second side plate 76K.","The second cylindrical part 86K rotatably supports a left end of the photosensitive drum 24K.","Here, the left end of the photosensitive drum 24K has a coupling recess 145K for engaging with the coupling 133K.","The second engagement part 87K protrudes downward from a bottom edge of the second cylindrical part 86K.","The second engagement part 87K includes a second plate part 88K having an opening 90K formed therein, a second bar part 89K, and a second protruding part 146K.","The second plate part 88K has a flat plate shape that extends downward from the second cylindrical part 86K.","The opening 90K is formed in a bottom end portion of the second plate part 88K.","The opening 90K has a general circular shape in a side view and penetrates the bottom end portion of the second plate part 88K in the left-right direction.","The second bar part 89K protrudes rearward from the bottom end portion of the second plate part 88K.","The second protruding part 146K protrudes leftward from a rear end of the second bar part 89K.","The second protruding part 146K includes a second sloped surface 91K.","The second sloped surface 91K constitutes a bottom surface of the second protruding part 146K.","The second sloped surface 91K slopes upward toward the left side.","As shown in FIG.","3, the first conveying tube 77K is assembled to the first side plate 75K through a fixing part 93K that protrudes rightward from the right surface of the first side plate 75K.","The first conveying tube 77K has a general square cylindrical shape that is elongated vertically.","The first conveying tube 77 has a top wall that slopes downward toward the left.","The opening 70 is formed in the top wall of the first conveying tube 77.Accordingly, the opening 70K also occupies a plane that slopes downward toward the left.","The opening 70K can be in vertical communication with the opening 68K formed in the input tube 66K.","As shown in FIG.","6, the opening 70K in the first conveying tube 77K is arranged to the right of the first positioning part 61.The first conveying tube 77K is provided with a seal 92K on its upper end.","The seal 92K is formed of an elastic material in a frame-like shape that is rectangular in a plan view.","The seal 92K is arranged around the opening 70K.","When the process cartridge 17K is mounted in the main casing 2, the seal 92K contacts the seal 69K of the input tube 66K.","As shown in FIGS.","1 and 3, the drum cleaning unit 73K is provided on rearward of the photosensitive drum 24K.","The drum cleaning unit 73K includes a drum cleaning frame 95K having an opening 105K formed therein, a drum cleaning blade 96K as an example of a cleaning member, a drum cleaning screw 97K, and the discharge tube 100K having the opening 102K as an example of a fourth opening.","The drum cleaning frame 95K has a box-like shape and is elongated in the left-right direction.","The drum cleaning frame 95K has a right end supported on the first side plate 75K, and a left end supported on the second side plate 76K.","As shown in FIG.","1, the opening 105K is formed in an upper-front portion of the drum cleaning frame 95K and penetrates the same in the front-rear direction.","The drum cleaning blade 96K is arranged on a front portion of the drum cleaning frame 95K.","The drum cleaning blade 96K has a flat plate shape and is elongated in the left-right direction.","The drum cleaning blade 96K has a top end portion positioned in confrontation with the opening 105K in the front-rear direction and in contact with a rear end portion on a circumferential surface of the photosensitive drum 24K.","The drum cleaning screw 97K is disposed in a bottom portion of the drum cleaning frame 95K and is oriented in the left-right direction.","The drum cleaning screw 97K has a left end that is rotatably supported by the second side plate 76K.","The drum cleaning screw 97K has a right end that is positioned inside the discharge tube 100K.","As shown in FIG.","3, the discharge tube 100K has a general cylindrical shape and extends rightward from a right end portion of the drum cleaning frame 95K, and then bends and extends downward.","The opening 102K is formed in a bottom end of the discharge tube 100K.","The discharge tube 100 has a right wall that rotatably supports the right end of the drum cleaning screw 97K.","The discharge tube 100K is provided with a seal 101K on its bottom end.","As shown in FIG.","6, the opening 102K formed in the discharge tube 100K is positioned farther rightward than the opening 70K formed in the first conveying tube 77K.","Further, the opening 102K in the discharge tube 100K is disposed rightward of the first positioning part 61K.","The seal 101K is formed of an elastic material in a frame-like shape that is rectangular in a plan view.","The seal 101K is arranged around the opening 102K on the bottom end of the discharge tube 100K.","(2) Developing Unit As shown in FIG.","3, the developing unit 22K is positioned between the front end portions of the first side plate 75K and second side plate 76K constituting the drum-unit frame 23K.","The developing unit 22K further includes the developing-unit frame 26K, and a unit screw 30K (see FIG.","1).","The developing-unit frame 26K has a box-like shape that is elongated in the left-right direction and open on the top side.","The developing-unit frame 26K includes a rotational shaft 74K, and the second conveying tube 98K.","The rotational shaft 74K protrudes rightward from a right wall constituting the developing-unit frame 26K.","The rotational shaft 74K has a general columnar shape and is elongated in the left-right direction.","The rotational shaft 74K is rotatably supported in a bottom end portion of the first side plate 75K.","The rotational shaft 74K also protrudes leftward from a left wall of the developing-unit frame 26K.","The protruding portion (left end portion) of the rotational shaft 74K is rotatably supported in a bottom end portion of the second side plate 76K.","In this way, the developing-unit frame 26K can pivotally movable about the rotational shaft 74K relative to the drum-unit frame 23K.","More specifically, the developing-unit frame 26K can pivotally move between a contact position in which the developing roller 27K contacts the photosensitive drum 24K, and a separated position in which the developing roller 27K is separated from the photosensitive drum 24K.","The second conveying tube 98K is positioned rightward of the first side plate 75K constituting the drum-unit frame 23K.","The second conveying tube 98K has a general cylindrical shape that first extends rightward from the right end of the developing-unit frame 26K, and then bends and extends upward.","The second conveying tube 98K is configured of a light-permeable member, at least in a region in which the light-emitting element 111K and light-receiving element 112K confront each other.","Hence, if a sufficient amount of toner is present in the second conveying tube 98K, the light from the light-emitting element 111K is blocked by the toner and thus cannot be received by the light-receiving element 112K.","The second conveying tube 98K has a top end in communication with a bottom end of the first conveying tube 77K.","A connector 99K is provided to surround the junction of the second conveying tube 98K and first conveying tube 77K.","The connector 99K is formed of an elastic material, and specifically a sponge material in the present embodiment.","The connector 99 has a general cylindrical shape that is elongated vertically.","The connector 99K has a top end portion connected to the bottom end of the first conveying tube 77K, while a bottom end of the connector 99K is connected to the top end of the second conveying tube 98K.","In this way, the internal space of the first conveying tube 77K is in communication with the internal space in the second conveying tube 98K through the connector 99K.","Further, the first conveying tube 77K and second conveying tube 98K are joined on the right side of the first side plate 75K.","As shown in FIG.","1, the unit screw 30K is arranged in a bottom portion of the developing-unit frame 26K.","The unit screw 30K is positioned rearward of the supply roller 28K.","The right end of the unit screw 30K is rotatably supported in the right wall of the second conveying tube 98K (see FIG.","3), while the left end of the unit screw 30K is rotatably supported in the left wall of the developing-unit frame 26K.","5.Structure of the Urging Members As shown in FIGS.","2 and 6, urging members 120RY, 120RM, 120RC and 120RK and urging members 120LY, 120LM, 120LC, and 120LK are disposed in the main casing 2 on respective ends of the corresponding process cartridges 17Y, 17M, 17C, and 17K.","Other than being disposed beneath the left ends of the process cartridges 17 and to the left of the second positioning part 62, the urging members 120LY, 120LM, 120LC, and 120LK have the same structure and configuration as the urging members 120RY, 120RM, 120RC and 120RK.","Therefore, the urging members 120RY, 120RM, 120RC and 120RK will serve as a representative example in the following description.","Further, since the urging members 120RY, 120RM, 120RC and 120RK have the structure, the urging member 120RM will be used as a representative example in the following description.","As shown in FIG.","6, the urging member 120RM is disposed above the right end of the process cartridge 17M and overlaps the first conveying tube 77M in a front-rear projection.","The urging member 120RM is positioned to the right of the first positioning part 61 and to the left of the opening 70M.","As shown in FIG.","5, the urging member 120RM includes a pivoting part 121M having a center hole 129M formed therein, a contact part 122M, an engaging part 123M, and a tension spring 124M.","The pivoting part 121M has a general bar shape that is elongated in the front-rear direction.","The pivoting part 121M has a front end serving as an example of a first end, while a rear end thereof serves as an example of a second end.","The front-rear direction is an example of an orthogonal direction.","The center hole 129M is formed in the front end of the pivoting part 121M.","The center hole 129M has a general circular shape in a side view and penetrates the front end of the pivoting part 121M in the left-right direction.","The center hole 129M is engaged with a boss (not shown) provided on either the first side plate 54 or the second side plate 55.Through this engagement, the pivoting part 121M can pivot about a central axis of the center hole 129M.","The contact part 122M protrudes rightward from the rear end of the pivoting part 121M.","The contact part 122M has a general plate shape that is elongated in the left-right direction.","The contact part 122M includes an engaging surface 125M.","The engaging surface 125M constitutes a top surface on a right end portion of the contact part 122M.","The engaging surface 125M slopes upward toward the left.","The engaging part 123M protrudes rightward from a front-rear center portion of the pivoting part 121M.","The engaging part 123M includes a base part 126M, and a tip-end part 127M.","The base part 126M has a general columnar shape and is elongated in the left-right direction.","The base part 126M protrudes rightward from the front-rear center portion of the pivoting part 121M.","The tip-end part 127M protrudes rightward from a right end of the base part 126M.","The tip-end part 127M has a conical shape that tapers toward the right.","The tip-end part 127M has a peripheral surface that constitutes a sloped surface 128M.","That is, the sloped surface 128M has a top edge that slopes upward toward the left.","The tension spring 124M is a helical spring whose bottom end is engaged with the rear end of the pivoting part 121M.","More specifically, when viewed in the left-right direction, the bottom end of the tension spring 124M is disposed between the contact part 122M and the engaging part 123M.","In other words, the tension spring 124M is disposed closer to the rear end of the pivoting part 121M than the engaging part 123M is to the rear end of the pivoting part 121M.","As shown in FIG.","6, the urging member 120RM is pivotably movably supported on the first side plate 54 through the boss (not shown) thereof inserted through the center hole 129M.","Accordingly, the urging member 120RM can pivot about the central axis of the center hole 129M aligned in the left-right direction.","Further, the top end of the tension spring 124M is engaged with a first mounting part 130 provided on a right surface of the first side plate 54.With this arrangement, the rear end of the pivoting part 121M is constantly urged upward.","Note that the tension spring 124 in each of the urging members 120L is engaged with a second mounting part 131 provided on a right surface of the second side plate 55.6.Structures Related to Waste Toner Conveyance As shown in FIG.","2, the main casing 2 includes a first conveying tube 161, a second conveying tube 162, a conveying screw 164, a third conveying tube 165, and a waste toner container 166 having an opening 177.The first conveying tube 161 is disposed rightward of the front end portion of the first side plate 54.The first conveying tube 161 has a general cylindrical shape and is elongated vertically.","The first conveying tube 161 has a top end that is connected to the lower end portion of the belt-cleaning frame 151 of the belt cleaning unit 150 shown in FIG.","1 via the opening 107 formed in the first side plate 54.The right wall constituting the first conveying tube 161 rotatably supports the right end of the belt cleaning screw 153.The second conveying tube 162 is disposed below the first conveying tube 161 and extends in the diagonal direction from the upper front to the lower rear.","The second conveying tube 162 has a general cylindrical shape.","The second conveying tube 162 is fixed to the first side plate 54.The second conveying tube 162 has a front end connected to a bottom end of the first conveying tube 161.The second conveying tube 162 includes a waste toner conveying tube 163 therein.","The waste toner conveying tube 163 is disposed within the second conveying tube 162.The waste toner conveying tube 163 can rotate relative to the second conveying tube 162.The waste toner conveying tube 163 is connected to connector tubes 172 described later, and movement of the connector tubes 172 causes the waste toner conveying tube 163 to rotate relative to the second conveying tube 162, as will be described later.","The waste toner conveying tube 163 includes a conveying cylindrical part 171, and the connector tubes 172Y, 172M, 172C, and 172K having respective openings 175Y, 175M, 175C, and 175K.","The conveying cylindrical part 171 is disposed in the second conveying tube 162 and extends along the same direction of the second conveying tube 162 (i.e., in the diagonal direction).","The conveying cylindrical part 171 has a general cylindrical shape.","As shown in FIG.","2, the connector tubes 172Y, 172M, 172C, and 172K are arranged at intervals from each other in the diagonal direction in which the conveying cylindrical part 171 extends.","Since the connector tubes 172Y, 172M, 172C, and 172K all have the same construction, only the connector tube 172M will be described below as a representative example.","As shown in FIG.","6, the connector tube 172M has a general cylindrical shape that extends diagonally upward and rightward from the conveying cylindrical part 171, and then bends and extends upward.","The opening 175M is formed in a top end of the connector tube 172M.","The opening 175M is as an example of a fifth opening.","As shown in FIG.","6, the connector tube 172M includes a seal 173M, and an interlocking member 174M.","The opening 175M formed in the connector tube 172M is capable of communicating with the opening 102M of the discharge tube 100M, as will be described later.","The seal 173M is formed of an elastic material having a frame-like shape that is rectangular in a plan view.","The seal 173M is arranged around the opening 175M.","The seal 173M is in contact with the seal 101M of the discharge tube 100M.","The interlocking member 174M has a general bar shape.","One end of the interlocking member 174M is attached to the top end of the connector tube 172M so as to be capable of rotating relative thereto, while the other end is attached to the cover 8 and is capable of rotating relative thereto.","With this structure, the interlocking member 174M can move in conjunction with movement of the cover 8.Movement of the interlocking member 174M can in turn move the connector tube 172M between a communication position in which the connector tube 172M is communicated with the discharge tube 100, and a non-communication position in which such communication of the connector tube 172M to the discharge tube 100 is interrupted.","As shown in FIG.","2, the conveying screw 164 is disposed inside the conveying cylindrical part 171.The conveying screw 164 extends in the diagonal direction from the upper front to the lower rear.","The conveying screw 164 is rotatably supported in the conveying cylindrical part 171.The third conveying tube 165 extends downward from a rear end of the second conveying tube 162.The third conveying tube 165 has a general cylindrical shape that is elongated vertically.","The third conveying tube 165 has an opening 200 formed in a bottom end portion of the third conveying tube 165.A shutter 176 is movably disposed in the bottom end portion of the third conveying tube 165.The opening 200 is configured to be opened and closed through the movement of the shutter 176.The waste toner container 166 is disposed in a lower-right section of the main casing 2 to the rear of the access opening 63.The waste toner container 166 has a box-like shape that is elongated in the front-rear direction and can be mounted in and removed from the main casing 2 through the access opening 63.The waste toner container 166 has an opening 177 formed in an upper-rear corner portion of the waste toner container 166.The opening 177 penetrates a top wall constituting the waste toner container 166 vertically.","A shutter 178 is movably disposed on the top wall of the waste toner container 166 such that the opening 177 can be opened and closed through the movement of the shutter 178.When the waste toner container 166 is mounted in the main casing 2, the opening 177 is in communication with the opening 200 formed in the third conveying tube 165.Hence, the waste toner conveying tube 163 is connected to the waste toner container 166 through the third conveying tube 165.7.Operations for Mounting and Removing the Toner Cartridges In the following description for the mounting and removal of the toner cartridges 16 and process cartridges 17, operations for mounting and removing the toner cartridge 16M and process cartridge 17M will be described as representative examples.","For mounting the toner cartridge 16M in the main casing 2, the cover 60M is placed in its open position shown in FIG.","7.The toner cartridge 16M is then inserted into the receiving part 65M of the mounting unit 53M via the opening 59M.","When the toner cartridge 16M has been mounted on the receiving part 65M, the opening 72M of the toner cartridge 16M is in vertical communication with the opening 67M formed in the receiving part 65M of the mounting unit 53M.","To remove the toner cartridge 16M from the main casing 2, the cover 60M is again placed in its open position, and the toner cartridge 16M is extracted from the main casing 2 through the opening 59M.","8.Operations for Mounting and Removing the Process Cartridges To mount the process cartridge 17M in the main casing 2, the cover 8 is placed in its open position shown in FIG.","8.The process cartridge 17M is then inserted into the main casing 2 through the opening 6 and the opening 58, while slidingly moving along the center plate 52.At this time, the first sloped surface 84M of the first support part 78M in the process cartridge 17M contacts the engaging surface 125M of the urging member 120RM, as shown in solid lines in FIG.","8.Further, the second sloped surface 91M of the second support part 85M in the process cartridge 17M contacts the engaging surface 125M of the urging member 120LM.","As the process cartridge 17M is further moved leftward, the first sloped surface 84M slides diagonally upward and leftward along the engaging surface 125M of the urging member 120RM, and the second sloped surface 91M slides diagonally upward and leftward along the engaging surface 125M of the urging member 120LM.","Consequently, the process cartridge 17M moves diagonally upward and leftward.","As a result, the opening 83M in the first support part 78M of the process cartridge 17M becomes fitted around the right end of the engaging part 123M constituting the urging member 120RM, and the opening 90M formed in the second support part 85M of the process cartridge 17M becomes fitted around the right end of the engaging part 123M constituting the urging member 120LM.","As the process cartridge 17M moves farther leftward, the inner edge of the opening 83M defined in the first support part 78M contacts the sloped surface 128M of the urging member 120RM, while the inner edge of the opening 90M defined in the second support part 85M contacts the sloped surface 128M of the urging member 120LM.","As the process cartridge 17M continues to move leftward, the inner edge of the opening 83M defined in the first support part 78M slides diagonally upward and leftward along the sloped surface 128M of the urging member 120RM, while the inner edge of the opening 90M defined in the second support part 85M slides diagonally upward and leftward along the sloped surface 128M of the urging member 120LM.","Consequently, the process cartridge 17M moves diagonally upward and leftward.","At this time, the first sloped surface 84M separates from the engaging surface 125M formed on the urging member 120RM, and the second sloped surface 91M separates from the engaging surface 125M formed on the urging member 120LM.","As the process cartridge 17M continues to move leftward, the base part 126M of the urging member 120RM is inserted into the opening 83M formed in the first support part 78M.","Similarly, the base part 126M on the urging member 120LM is inserted into the opening 90M formed in the second support part 85M.","Next, the top surface of the first cylindrical part 79M in the process cartridge 17M becomes engaged in the first positioning groove 135M formed in the first positioning part 61.Similarly, the top surface of the second cylindrical part 86M becomes engaged in the second positioning groove 136M formed in the second positioning part 62.At this time, the process cartridge 17M is fixed in position in the main casing 2, as shown in FIG.","2.In addition, the coupling 133M is inserted into the coupling recess 145M formed in the left end of the photosensitive drum 24 supported by the drum-unit frame 23M.","At this time, the tension spring 124M of the urging member 120RM urges the first support part 78M upward through the base part 126M of the urging member 120RM.","Similarly, the tension spring 124M of the urging member 120LM urges the second support part 85M upward through the base part 126M of the urging member 120LM.","Due to the upward urging of the process cartridge 17M by the urging members 120RM and 120LM, the seal 92M of the first conveying tube 77M and the seal 69M on the input tube 66M of the mounting unit 53M contact each other with pressure.","At this time, the opening 70M formed in the first conveying tube 77M is in vertical communication with the opening 68M formed in the mounting unit 53M.","In this state, the process cartridge 17M is in the first position, as shown in FIG.","6.To remove the process cartridge 17M from the main casing 2, the cover 8 is first moved from its closed position to its open position shown in FIG.","7.At this time, the cover 8 pulls the interlocking member 174M downward and the interlocking member 174M in turn pulls the connector tube 172M downward, causing the waste toner conveying tube 163 to rotate counterclockwise in a rear view and the connector tube 172M to move into its non-communication position.","The connector tube 172M is configured to move from its communication position to its non-communication position by a distance L1 in the vertical direction, as shown in FIG.","7.From this state, an operator pulls the process cartridge 17M rightward.","Through this action, the opening 83M of the first support part 78M disengages from the base part 126M on the urging member 120RM, and the opening 90M formed in the second support part 85M disengages from the base part 126M on the urging member 120LM, as shown in FIG.","8.As the process cartridge 17M continues to move rightward, the inner edge of the opening 83M defined in the first support part 78M slides downward and rightward along the sloped surface 128M of the urging member 120RM, and the inner edge of the opening 90M defined in the second support part 85M slides downward and rightward along the sloped surface 128M of the urging member 120LM.","Consequently, the process cartridge 17M itself moves diagonally downward and rightward.","As the process cartridge 17M continues to move rightward, the first sloped surface 84M on the first support part 78M contacts the engaging surface 125M on the urging member 120RM, while the second sloped surface 91M on the second support part 85M contacts the engaging surface 125M on the urging member 120LM.","At this time, the inner edge of the opening 83M defined in the first support part 78M separates from the sloped surface 128M on the urging member 120RM, and the inner edge of the opening 90M defined in the second support part 85M separates from the sloped surface 128M on the urging member 120LM.","As the process cartridge 17M continues to move rightward, the first sloped surface 84M slides diagonally downward and rightward along the engaging surface 125M formed on the urging member 120RM, and the second sloped surface 91M slides diagonally downward and rightward along the engaging surface 125M formed on the urging member 120LM.","Consequently, the process cartridge 17M itself moves diagonally downward and rightward and is placed on the center plate 52.This action interrupts communication between the opening 70M formed in the first conveying tube 77M and the opening 68M formed in the mounting unit 53M.","At this time, the process cartridge 17M is in its second position, as shown in FIG.","8.The process cartridge 17M is configured to move between the first position and the second position by a distance L2 smaller than the distance L1 in the vertical direction.","From this state, the process cartridge 17M is extracted from the main casing 2 through the opening 6 and opening 58.9.Image-Forming Operation When the toner cartridges 16Y, 16M, 16C, and 16K and process cartridges 17Y, 17M, 17C, and 17K are mounted in the main casing 2, as shown in FIG.","2, and an image-forming operation is initiated on the printer 1, the charging rollers 25Y, 25M, 25C, and 25K is configured to apply a uniform positive charge to the surfaces of the corresponding photosensitive drums 24Y, 24M, 24C, and 24K, as illustrated in FIG.","1.Subsequently, the scanning unit 15 exposes the surfaces of the photosensitive drums 24Y, 24M, 24C, and 24K by irradiating laser beams with high-speed scanning, thereby forming electrostatic latent images based on image data on the surfaces of the corresponding photosensitive drums 24Y, 24M, 24C, and 24K.","Incidentally, in each of the toner cartridges 16Y, 16M, 16C, and 16K, when the light-receiving element 112 receives light from the corresponding light-emitting element 111 (that is, when the level of toner in the second conveying tube 98 has not yet reached up to a position detectable by the detector 110), the first agitator 141 in each toner cartridge 16 is configured to rotate to convey toner from the corresponding large accommodating chamber 138 into the corresponding small accommodating chamber 139, as illustrated in FIG.","2.The second agitator 142 in the corresponding small accommodating chamber 139 also rotates to introduce toner from the small accommodating chamber 139 into the input tube 66 via the corresponding openings 72 and 68.The toner introduced into the input tube 66 moves through the first conveying tube 77 and second conveying tube 98 of the corresponding process cartridge 17.When the light-receiving element 112 no longer receives light from the corresponding light-emitting element 111 (that is, when a sufficient amount of the toner has been introduced into the second conveying tube 98), the printer 1 stops driving the first agitator 141 and second agitator 142 of the corresponding toner cartridge 16.Thus, the toner can be maintained at a low level in the second conveying tubes 98Y, 98M, 98C, and 98K, and therefore the level of the toner can be prevented from rising higher to reach the openings 70Y, 70M, 70C, and 70K in the first conveying tubes 77Y, 77M, 77M and 77C.","As illustrated in FIG.","1, the unit screws 30Y, 30M, 30C, and 30K subsequently convey the toner from right to left in the developing-unit frames 26Y, 26M, 26C, and 26K while supplying the toner onto the supply rollers 28Y, 28M, 28C, and 28K.","The toner supplied to the supply rollers 28Y, 28M, 28C, and 28K is in turn supplied onto the developing rollers 27Y, 27M, 27C, and 27K, at which time the toner is positively tribocharged between the supply rollers 28Y, 28M, 28C, and 28K and the corresponding developing rollers 27Y, 27M, 27C, and 27K.","As the developing rollers 27Y, 27M, 27C, and 27K rotate, the thickness of the toner supplied onto the developing rollers 27Y, 27M, 27C, and 27K is regulated by the thickness-regulating blades 29Y, 29M, 29C, and 29K so that a toner layer of uniform thickness is carried on the surface of each of the developing rollers 27Y, 27M, 27C, and 27K.","The positively charged toner carried on the surfaces of the developing rollers 27Y, 27M, 27C, and 27K is subsequently supplied to the electrostatic latent images formed on the surfaces of the respective photosensitive drums 24Y, 24M, 24C, and 24K as the photosensitive drums 24Y, 24M, 24C, and 24K rotate.","In this way, toner images are formed through reverse development on the surfaces of the photosensitive drums 24Y, 24M, 24C, and 24K.","Next, while the intermediate transfer belt 36 circulates, the photosensitive drums 24Y, 24M, 24C, and 24K transfer the toner images in their corresponding colors onto the intermediate transfer belt 36 in a primary transfer process.","In the meantime, the first pick-up roller 12 picks up and separates the sheets accommodated in the first sheet tray 9 and conveys the sheets one at a time and at a prescribed timing along the first sheet-feeding path 181 to the position between the intermediate transfer belt 36 and the secondary transfer roller 32.As each sheet passes between the intermediate transfer belt 36 and the secondary transfer roller 32, the toner image carried on the intermediate transfer belt 36 is transferred onto the sheet in a secondary transfer process.","Thereafter, heat and pressure are applied to the sheet in the fixing unit 19 as the sheet passes between the heat roller 41 and the pressure roller 42, thereby thermally fixing the toner image to the sheet.","After the toner image has been thermally fixed to the sheet in the fixing unit 19, the sheet is guided by the guide 45 oriented in the discharge position and is discharged into the discharge tray 43.Here, if sheets have been loaded in the second sheet tray 10, the second pick-up roller 13 picks up and separates the sheets in the second sheet tray 10 and conveys the sheets one at a time and at a prescribed timing along the second sheet-feeding path 182 to the position between the intermediate transfer belt 36 and secondary transfer roller 32.Further, when images are being formed on both surfaces of the sheet, the sheet is guided along the guide 45 oriented in the reverse position after a toner image has been thermally fixed to one side of the sheet in the fixing unit 19, and the sheet enters between the reversing rollers 44.By reversing their rotation, the reversing rollers 44 convey the sheet back downward into the main casing 2 along a U-shaped path that guides the sheet back to the position between the intermediate transfer belt 36 and the secondary transfer roller 32 in order that an image can be formed on the back side of the sheet.","Once the image has been formed on the back side of the sheet and thermally fixed to the sheet in the fixing unit 19, the sheet is guided along the guide 45, now oriented in the discharging position, and is discharged into the discharge tray 43.10.Cleaning Operation In the meantime, the drum cleaning blades 96Y, 96M, 96C, and 96K scrape off waster toner remaining on the corresponding photosensitive drums 24Y, 24M, 24C, and 24K.","The waste toner is collected in the drum cleaning frames 95Y, 95M, 95C, and 95K.","The drum cleaning screws 97Y, 97M, 97C, and 97K convey this waste toner rightward in the drum cleaning frames 95Y, 95M, 95C, and 95K.","As shown in FIG.","2, the waste toner being conveyed through the drum cleaning frames 95Y, 95M, 95C, and 95K flows into the connector tubes 172Y, 172M, 172C, and 172K through the discharge tubes 100Y, 100M, 100C, and 100K.","Thereafter, the conveying screw 164 conveys the waste toner diagonally downward and rearward in the conveying cylindrical part 171 to the third conveying tube 165.The waste toner falls down through the third conveying tube 165 and is collected in the waste toner container 166.As shown in FIG.","1, the belt-cleaning blade 152 scrapes residual toner off the intermediate transfer belt 36 so that the toner drops into the belt-cleaning frame 151.The belt-cleaning screw 153 then conveys the waste toner rightward in the belt-cleaning frame 151.The waste toner being conveyed in the belt-cleaning frame 151 flows into the conveying cylindrical part 171 through the first conveying tube 161 shown in FIG.","2.The waste toner is subsequently conveyed diagonally downward and rearward in the conveying cylindrical part 171 by the conveying screw 164 and flows into the third conveying tube 165.The waste toner is discharged from the third conveying tube 165 and collected in the waste toner container 166.To remove the waste toner container 166 from the main casing 2, the operator places the cover 64 in the open position and pulls the waste toner container 166 out of the main casing 2 through the access opening 63.At this time, the shutter 178 closes the opening 177 formed in the waste toner container 166, and the shutter 176 closes the opening 200 at the bottom end of the third conveying tube 165.11.Operational and Technical Advantages of the First Embodiment (1) In the printer 1 of the embodiment described above, the toner cartridges 16Y, 16M, 16C, and 16K can be mounted in and removed from the main casing 2 in the left-right direction through the corresponding openings 59Y, 59M, 59C, and 59K, as shown in FIG.","7.Further, the process cartridges 17Y, 17M, 17C, and 17K can be mounted in and removed from the main casing 2 in the left-right direction through the openings 6 and 58, as shown in FIG.","8.Hence, the toner cartridges 16Y, 16M, 16C, and 16K and process cartridges 17Y, 17M, 17C, and 17K can be independently mounted in and removed from the main casing 2 in the left-right direction.","When the process cartridges 17Y, 17M, 17C, and 17K are mounted in the main casing 2, as shown in FIG.","6, the urging members 120RY, 120RM, 120RC and 120RK and the urging members 120LY, 120LM, 120LC, and 120LK urge the corresponding process cartridges 17Y, 17M, 17C, and 17K toward the first positioning part 61 and the second positioning part 62.Thus, the process cartridges 17Y, 17M, 17C, and 17K are positioned such that toner supplied from the toner cartridges 16Y, 16M, 16C, and 16K can be received through the corresponding openings 70Y, 70M, 70C, and 70K.","Therefore, the toner supplied from the toner cartridges 16Y, 16M, 16C, and 16K can be reliably supplied to and received in the process cartridges 17Y, 17M, 17C, and 17K.","(2) As shown in FIG.","6, the urging members 120RY, 120RM, 120RC and 120RK and the urging members 120LY, 120LM, 120LC, and 120LK are positioned to the left of the openings 70Y, 70M, 70C, and 70K formed in the first conveying tubes 77Y, 77M, 77C, and 77K.","Accordingly, this construction can prevent interference between the urging members 120RY, 120RM, 120RC and 120RK and urging members 120LY, 120LM, 120LC, and 120LK and the openings 70Y, 70M, 70C, and 70K during mounting and removal of the process cartridges 17Y, 17M, 17C, and 17K relative to the main casing 2.","(3) Further, the urging members 120RY, 120RM, 120RC and 120RK are disposed to the right of the first positioning part 61, as shown in FIG.","6.Accordingly, the space in the printer 1 is effectively utilized when laying out the urging members 120RY, 120RM, 120RC and 120RK.","(4) Further, as shown in FIG.","6, the first positioning part 61 and second positioning part 62 are arranged further leftward than the openings 70Y, 70M, 70C, and 70K formed in the first conveying tubes 77Y, 77M, 77C, and 77K.","This arrangement can prevent interference between the first positioning part 61 and second positioning part 62 and the openings 70Y, 70M, 70C, and 70K when the process cartridges 17Y, 17M, 17C, and 17K are mounted in or removed from the main casing 2.","(5) As shown in FIG.","3, the process cartridges 17Y, 17M, 17C, and 17K are respectively provided with the drum-unit frames 23Y, 23M, 23C, and 23K and developing-unit frames 26Y, 26M, 26C, and 26K.","Further, the openings 70Y, 70M, 70C, and 70K are respectively formed in the drum-unit frames 23Y, 23M, 23C, and 23K.","Accordingly, the openings 70Y, 70M, 70C, and 70K can be arranged in fixed positions, even when the developing-unit frames 26Y, 26M, 26C, and 26K pivot relative to the drum-unit frames 23Y, 23M, 23C, and 23K.","Thus, the toner supplied from the toner cartridges 16Y, 16M, 16C, and 16K can be reliably received through the openings 70Y, 70M, 70C, and 70K.","(6) As shown in FIG.","3, the first conveying tubes 77Y, 77M, 77C, and 77K are connected to the second conveying tubes 98Y, 98M, 98C, and 98K on the right side of the first side plates 75Y, 75M, 75C, and 75K.","In other words, the first conveying tubes 77Y, 77M, 77C, and 77K are connected to the second conveying tubes 98Y, 98M, 98C, and 98K respectively at positions opposite to the second side plates 76Y, 76M, 76C, and 76K with respect to the first side plates 75Y, 75M, 75C, and 75K in the left-right direction.","This configuration prevents the need to enlarge the process cartridges 17Y, 17M, 17C, and 17K in the front-rear and vertical directions.","(7) As shown in FIG.","6, the first conveying tubes 77Y, 77M, 77C, and 77K at least partially overlap the corresponding urging members 120RY, 120RM, 120RC and 120RK in a front-rear projection.","Accordingly, the space required for arranging the urging members 120RY, 120RM, 120RC and 120RK and the first conveying tubes 77Y, 77M, 77C, and 77K in the printer 1 can be reduced.","(8) As shown in FIG.","3, the developing-unit frames 26Y, 26M, 26C, and 26K can pivot about the rotational shaft 74K relative to the drum-unit frames 23Y, 23M, 23C, and 23K, respectively.","Hence, by pivoting the developing-unit frames 26Y, 26M, 26C, and 26K relative to the drum-unit frames 23Y, 23M, 23C, and 23K, the developing-unit frames 26Y, 26M, 26C, and 26K can be separated from the drum-unit frames 23Y, 23M, 23C, and 23K, and the developing rollers 27Y, 27M, 27C, and 27K can be separated from the photosensitive drums 24Y, 24M, 24C, and 24K.","(9) The connectors 99Y, 99M, 99C, and 99K that connect the first conveying tubes 77Y, 77M, 77C, and 77K to the second conveying tubes 98Y, 98M, 98C, and 98K shown in FIG.","3 are formed of an elastic material, and specifically a sponge.","Hence, the connectors 99Y, 99M, 99C, and 99K can flex appropriately when the developing-unit frames 26Y, 26M, 26C, and 26K pivot relative to the drum-unit frames 23Y, 23M, 23C, and 23K.","Accordingly, the connectors 99Y, 99M, 99C, and 99K can reliably connect the first conveying tubes 77Y, 77M, 77C, and 77K to the corresponding second conveying tubes 98Y, 98M, 98C, and 98K, even when the developing-unit frames 26Y, 26M, 26C, and 26K pivot relative to the drum-unit frames 23Y, 23M, 23C, and 23K.","(10) As shown in FIG.","4B, the printer 1 of the first embodiment is provided with the detectors 110Y, 110M, 110C, and 110K for detecting the quantity of toner in the respective second conveying tubes 98Y, 98M, 98C, and 98K.","Hence, the detectors 110Y, 110M, 110C, and 110K can detect whether toner is present in the respective second conveying tubes 98Y, 98M, 98C, and 98K.","(11) As shown in FIG.","5, the urging members 120RY, 120RM, 120RC and 120RK and the urging members 120LY, 120LM, 120LC, and 120LK are respectively provided with the engaging surfaces 125Y, 125M, 125C, and 125K.","The engaging surfaces 125Y, 125M, 125C, and 125K slope upward toward the left.","Therefore, when the process cartridges 17Y, 17M, 17C, and 17K are mounted in the main casing 2, the first support parts 78Y, 78M, 78C, 78K engage with the engaging surfaces 125Y, 125M, 125C, and 125K of the respective urging members 120RY, 120RM, 120RC and 120RK and the second support parts 85Y, 85M, 85C, and 85K engage with the engaging surfaces 125Y, 125M, 125C, and 125K of the respective urging members 120LY, 120LM, 120LC, and 120LK, and together move the process cartridges 17Y, 17M, 17C, and 17K upward.","Accordingly, the process cartridges 17Y, 17M, 17C, and 17K can be smoothly engaged with the respective urging members 120RY, 120RM, 120RC and 120RK and urging members 120LY, 120LM, 120LC, and 120LK during mounting of the process cartridges 17Y, 17M, 17C, and 17K in the main casing 2.","(12) As shown in FIG.","5, each of the urging members 120RY, 120RM, 120RC and 120RK and urging members 120LY, 120LM, 120LC, and 120LK is provided with respective pivoting parts 121 121Y, 121M, 121C, and 121K; engaging parts 123Y, 123M, 123C, and 123K; and tension springs 124Y, 124M, 124C, and 124K.","When the process cartridges 17Y, 17M, 17C, and 17K are mounted in the main casing 2, the tension springs 124Y, 124M, 124C, and 124K of the corresponding urging members 120RY, 120RM, 120RC and 120RK urge the first support parts 78Y, 78M, 78C, 78K upward through the base parts 126Y, 126M, 126C, and 126K of the corresponding urging members 120RY, 120RM, 120RC and 120RK.","Similarly, the tension springs 124Y, 124M, 124C, and 124K of the corresponding urging members 120LY, 120LM, 120LC, and 120LK urge the second support parts 85Y, 85M, 85C, and 85K upward through the base parts 126Y, 126M, 126C, and 126K of the corresponding urging members 120LY, 120LM, 120LC, and 120LK.","This configuration can reliably urge the process cartridges 17Y, 17M, 17C, and 17K upward.","(13) As shown in FIG.","6, the lower surfaces of the input tubes 66Y, 66M, 66C, 66Y of the respective mounting units 53Y, 53M, 53C, and 53K in which the openings 68Y, 68M, 68C, and 68K are formed slope downward toward the left.","As shown in FIG.","3, the top surfaces of the first conveying tubes 77Y, 77M, 77C, and 77K in which the openings 70Y, 70M, 70C, and 70K are formed also slope downward toward the left.","Thus, the openings 68Y, 68M, 68C, and 68K can be placed smoothly in communication with the openings 70Y, 70M, 70C, and 70K when the process cartridges 17Y, 17M, 17C, and 17K are mounted in the main casing 2.Further, the urging members 120RY, 120RM, 120RC and 120RK and urging members 120LY, 120LM, 120LC, and 120LK urge the process cartridges 17Y, 17M, 17C, and 17K toward the first positioning part 61 and second positioning part 62.In this way, the seals 92Y, 92M, 92C, and 92K provided on the first conveying tubes 77Y, 77M, 77C, and 77K are pressed against the corresponding seals 69Y, 69M, 69C, and 69K provided on the input tubes 66Y, 66M, 66C, and 66K.","This arrangement improves the tightness of the seal formed between the seals 92Y, 92M, 92C, and 92K and the corresponding seals 69Y, 69M, 69C, and 69K.","(14) As shown in FIG.","6, the openings 102Y, 102M, 102C, and 102K formed in the discharge tubes 100Y, 100M, 100C, and 100K are arranged to the right of the openings 70Y, 70M, 70C, and 70K formed in the first conveying tubes 77Y, 77M, 77C, and 77K.","In this way, the openings 102Y, 102M, 102C, and 102K and the openings 70Y, 70M, 70C, and 70K can be arranged with good balance in the main casing 2.","(15) As shown in FIG.","6, the openings 102Y, 102M, 102C, and 102K formed in the discharge tubes 100Y, 100M, 100C, and 100K are arranged to the right of the first positioning part 61.Accordingly, this arrangement prevents interference between the openings 102Y, 102M, 102C, and 102K and the first positioning part 61 when the process cartridges 17Y, 17M, 17C, and 17K are mounted in or removed from the main casing 2.","(16) As shown in FIG.","3, the first sloped surfaces 84Y, 84M, 84C, and 84K formed on the first support parts 78Y, 78M, 78C, 78K in the process cartridges 17Y, 17M, 17C, and 17K are arranged between the corresponding openings 70Y, 70M, 70C, and 70K and openings 102Y, 102M, 102C, and 102K in the front-rear direction.","This arrangement reduces the space required in the printer 1 for arranging the openings 70Y, 70M, 70C, and 70K; openings 102Y, 102M, 102C, and 102K; and urging members 120RY, 120RM, 120RC and 120RK.","(17) As shown in FIGS.","6 and 7, the connector tubes 172Y, 172M, 172C, and 172K can be moved between the communication position and the non-communication position.","With this configuration, the connector tubes 172Y, 172M, 172C, and 172K can be placed in the non-communication position when the process cartridges 17Y, 17M, 17C, and 17K are being mounted in or removed from the main casing 2, thereby preventing the connector tubes 172Y, 172M, 172C, and 172K from interfering with the process cartridges 17Y, 17M, 17C, and 17K.","(18) As shown in FIGS.","7 and 8, the vertical distance L1 by which the connector tubes 172Y, 172M, 172C, and 172K moves between the communication position and the non-communication position is greater than the vertical distance L2 by which the process cartridges 17Y, 17M, 17C, and 17K move between the first position and the second position.","This arrangement can prevent interference between the connector tubes 172Y, 172M, 172C, and 172K and the process cartridges 17Y, 17M, 17C, and 17K by moving the process cartridges 17Y, 17M, 17C, and 17K from their first position to their second position after moving the connector tubes 172Y, 172M, 172C, and 172K from the communication position to the non-communication position.","(19) As shown in FIG.","7, the connector tubes 172Y, 172M, 172C, and 172K are in their communication position when the cover 8 is in its closed position, and the connector tubes 172Y, 172M, 172C, and 172K are in their non-communication position when the cover 8 is in its open position.","Accordingly, the connector tubes 172Y, 172M, 172C, and 172K can be reliably placed at the non-communication position when mounting or removing the process cartridges 17Y, 17M, 17C, and 17K relative to the main casing 2.12.Second Embodiment Next, a printer 1A according to a second embodiment will be described with reference to FIGS.","9 and 10, wherein like parts and components are designated with the same reference numerals to avoid duplicating description.","In the first embodiment described above, the process cartridges 17Y, 17M, 17C, and 17K are urged toward the first positioning part 61 and second positioning part 62 by the urging members 120RY, 120RM, 120RC and 120RK and urging members 120LY, 120LM, 120LC, and 120LK.","In the second embodiment shown in FIG.","9, the main casing 2 is provided with a linkage 250 that can urge the process cartridges 17Y, 17M, 17C, and 17K toward the first positioning part 61 and second positioning part 62.The linkage 250 specifically includes a plate 251, a first linking member 252, a second linking member 253, a first spring 261, and a second spring 262.The plate 251 is disposed above the center plate 52.The plate 251 has a flat plate shape that is generally rectangular in a plan view and elongated in the left-right direction.","The plate 251 has a right edge engageable with the left surface of the cover 8.The plate 251 has a left edge engageable with the right surface of the second side plate 55.The process cartridges 17Y, 17M, 17C, and 17K are supported on the plate 251.The first linking member 252 is disposed below a right end portion of the plate 251.The first linking member 252 has a general bar shape, with one end of the first linking member 252 attached to the right end portion of the plate 251 so as to be capable of rotating relative thereto, and the other end attached to a right end portion of the center plate 52 so as to be capable of rotating relative thereto.","The second linking member 253 is disposed below a left end portion of the plate 251.The second linking member 253 has a general bar shape, with one end of the second linking member 253 attached to the left end portion of the plate 251 so as to be capable of rotating relative thereto, and the other end attached to a left end portion of the center plate 52 so as to be capable of rotating relative thereto.","The first spring 261 is disposed above the right end portion of the plate 251.The first spring 261 is configured of a helical spring, with its bottom end engaged in the plate 251.The second spring 262 is disposed above the left end portion of the plate 251.The second spring 262 is configured of a helical spring, with its bottom end engaged in the plate 251.When mounted in the main casing 2, the process cartridges 17Y, 17M, 17C, and 17K are positioned above the plate 251.At this time, the right ends of the process cartridges 17Y, 17M, 17C, and 17K are urged toward the first positioning part 61 by the first spring 261, and the left ends of the process cartridges 17Y, 17M, 17C, and 17K are urged toward the second positioning part 62 by the second spring 262.When the cover 8 is moved to its open position while the process cartridges 17Y, 17M, 17C, and 17K are mounted in the main casing 2, the weight of the process cartridges 17Y, 17M, 17C, and 17K causes the first linking member 252 and second linking member 253 to pivot counterclockwise in FIG.","10 so that the plate 251 moves diagonally downward and rightward.","As a result, the process cartridges 17Y, 17M, 17C, and 17K move from their first position to their second position.","Conversely, when the cover 8 is moved from this state to its closed position, the left surface of the cover 8 pushes the right end portion of the plate 251 leftward, as illustrated in FIG.","9.Accordingly, the first linking member 252 and the second linking member 253 pivot clockwise in FIG.","9, and the plate 251 moves diagonally upward and leftward.","The printer 1A according to the second embodiment can obtain the same operational and technical advantages as those described in the first embodiment.","Further, with the printer 1A according to the second embodiment, the linkage 250 can associate the opening and closing operations of the cover 8 with the operations for moving the process cartridges 17Y, 17M, 17C, and 17K between the first position and second position, as shown in FIGS.","9 and 10.Accordingly, the process cartridges 17Y, 17M, 17C, and 17K can be reliably placed in their second position when the cover 8 is placed in its open position.","13.Variations of the Embodiments In the embodiments described above, the printer 1(1A) is provided with the drum cleaning blades 96Y, 96M, 96C, and 96K as an example of the cleaning member.","However, in place of the drum cleaning blades 96Y, 96M, 96C, and 96K, the printer 1(1A) may be provided with cleaning rollers or cleaning brushes that contact the photosensitive drums 24Y, 24M, 24C, and 24K.","While the description has been made in detail with reference to specific embodiments thereof, it would be apparent to those skilled in the art that various changes and modifications may be made therein without departing from the scope of the above described embodiments."]],"string":"[\n [\n \"IMAGE-FORMING APPARATUS PROVIDED WITH URGING MEMBER FOR URGING PROCESS CARTRIDGE\",\n \"An image-forming apparatus includes: a main body; a toner cartridge having a first opening; a process cartridge having a photosensitive drum and a second opening; a positioning part; a transfer unit; and an urging member.\",\n \"The toner cartridge and process cartridge are attachable to and detachable from the main body in an axial direction of the photosensitive drum.\",\n \"The positioning part and transfer unit are positioned above the process cartridge attached to the main body.\",\n \"The positioning part fixes the attached process cartridge in position relative to the main body.\",\n \"The urging member urges the attached process cartridge toward the positioning part and urges the process cartridge such that such that the toner can be supplied from the toner cartridge to the process cartridge through the first opening and the second opening when the toner cartridge and the process cartridge are attached to the main body.\"\n ],\n [\n \"1.An image-forming apparatus configured to form an image on a sheet, the image-forming apparatus comprising: a main body comprising: an upper wall having a tray that is recessed downward for catching the sheet; a first wall having a first access opening; and a second wall having a second access opening; a toner cartridge attachable to the main body in a first direction through the first access opening, the toner cartridge accommodating toner and having a first opening; a waste toner container attachable to the main body in a second direction perpendicular to the first direction through the second access opening; a process cartridge including a photosensitive drum, the process cartridge being attachable to the main body in an axial direction along an axis of the photosensitive drum, the process cartridge having a second opening, the process cartridge further comprising: a cleaning member configured to remove toner from the photosensitive drum; and a discharge tube having a third opening, the discharge tube being configured to discharge the toner removed by the cleaning member toward the waste toner container through the third opening; a positioning part positioned above the process cartridge in a state where the process cartridge is attached to the main body, the positioning part being configured to fix the process cartridge in position relative to the main body in the state where the process cartridge is attached to the main body; and a transfer belt positioned above the process cartridge in the state where the process cartridge is attached to the main body.\",\n \"2.The image-forming apparatus according to claim 1, further comprising an urging member for urging the process cartridge toward the positioning part in the state where the process cartridge is attached to the main body, the urging member being configured to urge the process cartridge to allow the second opening of the process cartridge to communicate with the first opening of the toner cartridge in a state where the toner cartridge is attached to the main body and in the state where the process cartridge is attached to the main body, wherein the process cartridge includes: a drum unit including the photosensitive drum; and a developing unit including a developing roller, wherein the drum unit includes a first side plate and a second side plate apart from the first side plate in the axial direction, the photosensitive drum being supported by the first side plate and the second side plate, and wherein the second side plate includes a surface, the urging member urging the surface of the process cartridge toward the positioning part in the state where the process cartridge is attached to the main body.\",\n \"3.The image-forming apparatus according to claim 2, wherein the main body includes a coupling, wherein the second side plate of the drum unit includes a support part including a cylindrical part having a general cylindrical shape, the cylindrical part protruding from an outer surface of the second side plate and supporting an end of the photosensitive drum, the end of the photosensitive drum having a coupling recess, and the coupling of the main body being inserted into the coupling recess in the state where the process cartridge is attached to the main body, and wherein the support part of the drum unit includes the surface, the surface being positioned below the coupling recess.\",\n \"4.The image-forming apparatus according to claim 2, wherein the developing unit is movable about a rotational shaft extending in the axial direction relative to the drum unit.\",\n \"5.The image-forming apparatus as claimed in claim 1, further comprising an urging member for urging the process cartridge toward the positioning part in the state where the process cartridge is attached to the main body, the urging member being configured to urge the process cartridge to allow the second opening of the process cartridge to communicate with the first opening of the toner cartridge in a state where the toner cartridge is attached to the main body and in the state where the process cartridge is attached to the main body, wherein the process cartridge includes a surface that contacts the urging member in the state where the process cartridge is attached to the main body, the surface of the process cartridge being positioned between the second opening of the process cartridge and the third opening of the discharge tube in a direction perpendicular to the axial direction and a vertical direction.\",\n \"6.The image-forming apparatus according to claim 1, wherein the main body includes: a coupling; a third access opening, the process cartridge being attachable to the main body through the third access opening; and a cover movable between a closed position where the cover closes the third access opening and an open position where the cover opens the third access opening, and wherein the main body includes a side plate, the process cartridge being positioned between the cover and the side plate of the main body in the axial direction in the state where process cartridge is attached to the main body, the coupling being disposed on the side plate of the main body.\",\n \"7.The image-forming apparatus according to claim 1, wherein the positioning part comprises a first positioning part and a second positioning part, the transfer belt being positioned between the first positioning part and the second positioning part in the axial direction in the state where the process cartridge is attached to the main body, wherein the main body includes: a third access opening; and a cover movable between a closed position where the cover closes the third access opening and an open position where the cover opens the third access opening, the second positioning part being positioned between the cover and the first positioning part in the axial direction, wherein the waste toner container is positioned between the second positioning part and the cover in the axial direction.\",\n \"8.The image-forming apparatus according to claim 1, further comprising an urging member for urging the process cartridge toward the positioning part in the state where the process cartridge is attached to the main body, the urging member being configured to urge the process cartridge to allow the second opening of the process cartridge to communicate with the first opening of the toner cartridge in a state where the toner cartridge is attached to the main body and in the state where the process cartridge is attached to the main body, wherein the urging member has an engaging surface, the process cartridge moving from an outside position where the process cartridge is outside the main body to an inside position where the process cartridge is inside the main body in the axial direction during attachment of the process cartridge to the main body, and wherein the engaging surface contacts the process cartridge during attachment of the process cartridge to the main body, the engaging surface sloping upward toward downstream in a direction in which the process cartridge moves from the outside position to the inside position.\",\n \"9.The image-forming apparatus according to claim 8, wherein the urging member includes a tension spring.\",\n \"10.The image-forming apparatus according to claim 1, wherein the toner cartridge is positioned above the process cartridge in the state where the toner cartridge is attached to the main body and in the state where the process cartridge is attached to the main body.\",\n \"11.The image-forming apparatus according to claim 10, wherein the main body includes a receiving part receiving the toner cartridge in the state where the toner cartridge is attached to the main body, the receiving part including a bottom wall having a fourth opening communicating with the toner cartridge in the state where the toner cartridge is attached to the main body, and wherein the main body includes an input tube, the input tube including a top end communicating with the fourth opening of the receiving part and a bottom end having a fifth opening, the fifth opening communicating with the second opening of the process cartridge in the state where the process cartridge is attached to the main body.\",\n \"12.The image-forming apparatus according to claim 1, further comprising: a sheet tray attachable to the main body in a direction perpendicular to the axial direction, the sheet tray being positioned below the process cartridge in the state where the process cartridge is attached to the main body and in a state where the sheet tray is attached to the main body, the sheet tray moving from an inside position where the sheet tray is inside the main body to an outside position where the sheet tray is outside the main body in the direction perpendicular to the axial direction during detachment of the sheet tray from the main body; a secondary transfer roller; a first roller configured to convey a sheet from the sheet tray toward a position between the transfer belt and the secondary transfer roller; and a discharge roller configured to discharge the sheet conveyed from the position between the transfer belt and the secondary transfer roller toward the tray in a direction in which the sheet tray moves from the inside position to the outside position.\",\n \"13.The image-forming apparatus according to claim 1, further comprising an image-reading unit configured to read image data on an original document, the image-reading unit being positioned above the main body.\",\n \"14.The image-forming apparatus according to claim 13, wherein the image-reading unit includes: a platen on which the original document is to be placed; and a pressure cover supported to the platen, the pressure cover being pivotally movable with respect to the platen.\",\n \"15.An image-forming apparatus configured to form an image on a sheet, the image-forming apparatus comprising: a main body comprising: an upper wall having a tray that is recessed downward for catching the sheet; and a first wall having an access opening; a first toner cartridge attachable to the main body in a first direction, the first toner cartridge accommodating first toner and having a first toner opening; a second toner cartridge attachable to the main body in the first direction, the second toner cartridge accommodating second toner and having a second toner opening; a waste toner container attachable to the main body in a second direction perpendicular to the first direction through the access opening; a process cartridge including a photosensitive drum, the process cartridge being attachable to the main body in an axial direction along an axis of the photosensitive drum, the process cartridge having a second opening, the process cartridge further comprising: a cleaning member configured to remove toner from the photosensitive drum; and a discharge tube having a third opening, the discharge tube being configured to discharge the toner removed by the cleaning member toward the waste toner container through the third opening; and a transfer belt positioned above the process cartridge in a state where the process cartridge is attached to the main body.\",\n \"16.The image-forming apparatus according to claim 15, wherein the first toner cartridge is disposed between the first wall and the second toner cartridge in a state where the first toner cartridge and the second toner cartridge are attached to the main body.\",\n \"17.The image-forming apparatus according to claim 15, further comprising: a sheet tray attachable to the main body in a direction perpendicular to the axial direction, the sheet tray being positioned below the process cartridge in the state where the process cartridge is attached to the main body and in a state where the sheet tray is attached to the main body, the sheet tray moving from an inside position where the sheet tray is inside the main body to an outside position where the sheet tray is outside the main body in the direction perpendicular to the axial direction during detachment of the sheet tray from the main body; a secondary transfer roller; a first roller configured to convey a sheet from the sheet tray toward a position between the transfer belt and the secondary transfer roller; and a discharge roller configured to discharge the sheet conveyed from the position between the transfer belt and the secondary transfer roller toward the tray in a direction in which the sheet tray moves from the inside position to the outside position.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>There has been known an image-forming apparatus provided with a process cartridge to be attached to and detached from a main housing.\",\n \"Japanese Patent Application Publication No.\",\n \"2008-170944 discloses an image-forming apparatus provided with a process cartridge including a drum unit and a developing unit.\",\n \"The drum unit includes a photosensitive drum, and the developing unit is positioned to oppose the drum unit.\",\n \"The process cartridge is attachable to and detachable from a main housing with respect to an axial direction of the photosensitive drum.\"\n ],\n [\n \"<SOH> SUMMARY <EOH>In view of the foregoing, it is an object of the present disclosure to provide an improved image-forming apparatus.\",\n \"In order to attain the above and other objects, the disclosure provides an image-forming apparatus including a main body, a toner cartridge, a process cartridge, a positioning part, a transfer unit and an urging member.\",\n \"The toner cartridge is attachable to and detachable from the main body, the toner cartridge accommodating toner therein and having a first opening.\",\n \"The process cartridge includes a photosensitive drum configured to carry a toner image thereon, the photosensitive drum defining an axis extending in an axial direction, the process cartridge being attachable to and detachable from the main body in the axial direction, the process cartridge having a second opening.\",\n \"The positioning part is positioned above the process cartridge attached to the main body, the positioning part being configured to fix the process cartridge in position relative to the main body when the process cartridge is attached to the main body.\",\n \"The transfer unit is positioned above the process cartridge attached to the main body, the toner image on the photosensitive drum being configured to be transferred to the transfer unit when the process cartridge is attached to the main body.\",\n \"The urging member is configured to urge the process cartridge toward the positioning part when the process cartridge is attached to the main body, the urging member being configured to urge the process cartridge such that the toner can be supplied from the toner cartridge to the process cartridge through the first opening and the second opening when the toner cartridge and the process cartridge are attached to the main body.\"\n ],\n [\n \"CROSS REFERENCE TO RELATED APPLICATION This application is a continuation of prior U.S. application Ser.\",\n \"No.\",\n \"15/589,267, filed May 8, 2017, which is a continuation of prior U.S. application Ser.\",\n \"No.\",\n \"15/065,967, filed Mar.\",\n \"10, 2016 (now U.S. Pat.\",\n \"No.\",\n \"9,678,470 issued Jun.\",\n \"13, 2017), which claims priority from Japanese Patent Application No.\",\n \"2015-070127 filed Mar.\",\n \"30, 2015.The entire content of the priority application is incorporated herein by reference.\",\n \"TECHNICAL FIELD The present disclosure relates to an electro-photographic type image-forming apparatus.\",\n \"BACKGROUND There has been known an image-forming apparatus provided with a process cartridge to be attached to and detached from a main housing.\",\n \"Japanese Patent Application Publication No.\",\n \"2008-170944 discloses an image-forming apparatus provided with a process cartridge including a drum unit and a developing unit.\",\n \"The drum unit includes a photosensitive drum, and the developing unit is positioned to oppose the drum unit.\",\n \"The process cartridge is attachable to and detachable from a main housing with respect to an axial direction of the photosensitive drum.\",\n \"SUMMARY In view of the foregoing, it is an object of the present disclosure to provide an improved image-forming apparatus.\",\n \"In order to attain the above and other objects, the disclosure provides an image-forming apparatus including a main body, a toner cartridge, a process cartridge, a positioning part, a transfer unit and an urging member.\",\n \"The toner cartridge is attachable to and detachable from the main body, the toner cartridge accommodating toner therein and having a first opening.\",\n \"The process cartridge includes a photosensitive drum configured to carry a toner image thereon, the photosensitive drum defining an axis extending in an axial direction, the process cartridge being attachable to and detachable from the main body in the axial direction, the process cartridge having a second opening.\",\n \"The positioning part is positioned above the process cartridge attached to the main body, the positioning part being configured to fix the process cartridge in position relative to the main body when the process cartridge is attached to the main body.\",\n \"The transfer unit is positioned above the process cartridge attached to the main body, the toner image on the photosensitive drum being configured to be transferred to the transfer unit when the process cartridge is attached to the main body.\",\n \"The urging member is configured to urge the process cartridge toward the positioning part when the process cartridge is attached to the main body, the urging member being configured to urge the process cartridge such that the toner can be supplied from the toner cartridge to the process cartridge through the first opening and the second opening when the toner cartridge and the process cartridge are attached to the main body.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS The particular features and advantages of the disclosure as well as other objects will become apparent from the following description taken in connection with the accompanying drawings, in which: FIG.\",\n \"1 is a central cross-sectional view of a printer as an example of an image-forming apparatus according to a first embodiment; FIG.\",\n \"2 is a cross-sectional view of the printer according to the first embodiment taken along a line A-A of FIG.\",\n \"6; FIG.\",\n \"3 is a perspective view of a process cartridge shown in FIG.\",\n \"2 in the printer according to the first embodiment; FIG.\",\n \"4A is a perspective view of a left end portion of the process cartridge shown in FIG.\",\n \"3; FIG.\",\n \"4B is a right side view of the process cartridge shown in FIG.\",\n \"3; FIG.\",\n \"5 is a perspective view of an urging member shown in FIG.\",\n \"3; FIG.\",\n \"6 is a cross-sectional view of the printer according to the first embodiment taken along a line B-B shown in FIG.\",\n \"1, and showing a state where the process cartridge is at its first position and a connector tube is at its communication position; FIG.\",\n \"7 is a cross-sectional view of the printer according to the first embodiment taken along the line B-B shown in FIG.\",\n \"1, and showing a state where the process cartridge is at the first position and the connector tube is at a non-communication position; FIG.\",\n \"8 is a cross-sectional view of the printer according to the first embodiment taken along the line B-B shown in FIG.\",\n \"1, and showing a state where the process cartridge is at its second position and the connector tube is at the non-communication position; FIG.\",\n \"9 is a cross-sectional view of a printer according to a second embodiment and taken along a line corresponding to the line B-B of FIG.\",\n \"1, and showing a state where a process cartridge is at its first position and the connector tube is at the communication position; and FIG.\",\n \"10 is a cross-sectional view of the printer according to the second embodiment and taken along the line corresponding to the line B-B of FIG.\",\n \"1, and showing a state where the process cartridge is at its second position and the connector tube is at the non-communication position.\",\n \"DETAILED DESCRIPTION 1.Overall Structure of the Printer A printer 1 as an example of an image-forming apparatus according to a first embodiment will be described while referring to FIGS.\",\n \"1 through 8.As shown in FIG.\",\n \"1, the printer 1 includes a main casing 2, a sheet-supplying unit 11 for supplying a sheet, an image-forming unit 3 for forming an image on the sheet, a sheet-discharging unit 4 for discharging the image-formed sheet, and an image-reading unit 5 for reading image data on an original document.\",\n \"The main casing 2 is generally box-shaped, and includes an outer frame 50 and an inner frame 51 provided within the outer frame 50, as shown in FIG.\",\n \"6.The outer frame 50 includes a front wall, a rear wall, an upper wall, a right wall and a left wall which constitute a front wall, a rear wall, an upper wall, a right wall and a left wall of the main casing 2.The front wall of the outer frame 50 is formed with an access opening 7 and another access opening 63 for allowing communication between the inside and the outside of the main casing 2 in a front-rear direction.\",\n \"Structures of the outer frame 50 and inner frame 51 will be described later in greater detail.\",\n \"The sheet-supplying unit 11 includes a first sheet tray 9, a first pick-up roller 12, a second sheet tray 10, and a second pick-up roller 13.The first sheet tray 9 is positioned at a lower end portion of an interior of the main casing 2.The first sheet tray 9 is generally box shaped having an upper open end, and is detachably attachable to the main casing 2.The first sheet tray 9 is configured to accommodate sheets.\",\n \"The first pick-up roller 12 is positioned above a rear end portion of the first sheet tray 9.The first pick-up roller 12 is generally cylindrical extending in a left-right direction, and is rotatably supported to the main casing 2.The second sheet tray 10 is provided at the front wall of the main casing 2 (i.e., outer frame 50).\",\n \"The second sheet tray 10 is a flat plate-like shape having a generally rectangular shape in a front view.\",\n \"The second sheet tray 10 has a lower end pivotally connected to the front wall, so that the second sheet tray 10 is pivotally movable about the lower end between a closed position closing the access opening 7 (shown by a sloid line in FIG.\",\n \"1) and an open position opening the access opening 7 (shown by a phantom line in FIG.\",\n \"1).\",\n \"When placed at the open position, the second sheet tray 10 serves as a sheet receiving tray on which sheets for manual insertion are placed.\",\n \"The second pick-up roller 13 is positioned rearward of the second sheet tray 10 and at a generally center portion of the main casing 2 in the front-rear direction.\",\n \"The second pick-up roller 13 has a generally cylindrical shape extending in the left-right direction.\",\n \"The second pick-up roller 13 is rotatably supported to the main casing 2.The sheet-supplying unit 11 also includes: a first sheet-feeding path 181 along which a sheet is configured to be fed by the first pick-up roller 12 from the first sheet tray 9; and a second sheet-feeding path 182 along which a sheet is configured to be fed by the second pick-up roller 13 from the second sheet tray 10.As shown in FIGS.\",\n \"1 and 2, the image-forming unit 3 includes toner cartridges 16Y, 16M, 16C and 16K, process cartridges 17Y, 17M, 17C and 17K, a scanner unit 15, a transfer unit 18, and a fixing unit 19.In the following description Y, M, C and K represent toners of yellow, magenta, cyan, and black, respectively.\",\n \"Further, in the drawings, reference characters of Y, M, C and K are added only for typical components, for explanatory purpose.\",\n \"As shown in FIG.\",\n \"6, the toner cartridges 16Y, 16M, 16C and 16K are positioned at right upper end portion of the interior of the main casing 2.As shown in FIG.\",\n \"2, the toner cartridges 16Y, 16M, 16C and 16K are arrayed and spaced apart from one another in a diagonal direction from an upper front portion toward a lower rear portion of the main casing 2.The toner cartridges 16Y, 16M, 16C and 16K are detachably attached to the main casing 2, and contain therein toners of different colors of yellow, magenta, cyan, and black, respectively.\",\n \"The toner cartridges 16Y, 16M, 16C and 16K have the same structures as one another.\",\n \"As shown in FIG.\",\n \"1, the process cartridges 17Y, 17M, 17C and 17K are positioned at a generally center in the main casing 2.The process cartridges 17Y, 17M, 17C and 17K are arrayed in the diagonal direction from the upper front upper to the lower rear with a space between neighboring cartridges.\",\n \"The process cartridges 17Y, 17M, 17C and 17K are attached to and detached from the main casing 2 with respect to the left-right direction.\",\n \"Specifically, the process cartridges 17Y, 17M, 17C and 17K are attached to the main casing 2 in a leftward direction (from the right to the left), while being detached from the main casing 2 in a rightward direction (from the left to the right).\",\n \"The leftward direction is an example of an attaching direction.\",\n \"As shown in FIGS.\",\n \"2 and 6, each of the process cartridges 17Y, 17M, 17C and 17K is positioned leftward and downward of the corresponding one of the toner cartridges 16Y, 16M, 16C and 16K when mounted in the main casing 2.Incidentally, the process cartridges 17Y, 17M, 17C and 17K have identical structures to each other.\",\n \"Therefore, in the following, the structure of the process cartridge 17K will only be described.\",\n \"As shown in FIG.\",\n \"1, the process cartridge 17K includes a drum unit 21K and a developing unit 22K.\",\n \"The drum unit 21K includes a photosensitive drum 24K and a charging roller 25K.\",\n \"The photosensitive drum 24K is provided in an upper end portion of the drum unit 21K.\",\n \"The photosensitive drum 24K is generally cylindrical and extends in the left-right direction.\",\n \"The photosensitive drum 24K is rotatably supported to a drum-unit frame 23K (described later) of the drum unit 21K.\",\n \"The photosensitive drum 24K defines an axis extending in the left-right direction about which the photosensitive drum 24K is rotatable.\",\n \"The charging roller 25K is positioned downward of the photosensitive drum 21K, and is generally cylindrical shaped extending in the left-right direction.\",\n \"The charging roller 25K is rotatably supported to the drum-unit frame 23 (described later) of the drum unit 21K.\",\n \"The developing unit 22K includes a developing roller 27K, a supply roller 28K, and a thickness-regulating blade 29K.\",\n \"The developing roller 27K is rotatably provided in an upper end portion of the developing unit 22K.\",\n \"The developing roller 27K is generally cylindrical extending in the left-right direction.\",\n \"The developing roller 27K is rotatably supported to a developing-unit frame 26 (described later) of the developing unit 22K, and is in contact with a front end portion of the photosensitive drum 24K.\",\n \"The supply roller 28K is positioned frontward and downward of the developing roller 27K.\",\n \"The supply roller 22 has a generally cylindrical shape extending in the left-right direction.\",\n \"The supply roller 28K is rotatably supported to the developing-unit frame 26 (described later) of the developing unit 22K.\",\n \"The supply roller 28K has an upper end portion in contact with a lower front end portion of the developing roller 21.The thickness-regulating blade 29K is positioned rearward and downward of the developing roller 27K.\",\n \"The thickness-regulating blade 29K has a plate-like configuration extending in the left-right direction.\",\n \"The thickness-regulating blade 29K is in contact with a lower rear end portion of the developing roller 27K.\",\n \"The scanner unit 15 is positioned downward of the respective process cartridges 17Y, 17M, 17C and 17K.\",\n \"More specifically, the scanner unit 15 is positioned between the process cartridges 17Y, 17M, 17C and 17K and the second pick-up roller 13 in a vertical direction.\",\n \"The scanner unit 15 is configured to irradiate laser beams to the respective photosensitive drums 24Y, 24M, 24C and 24K based on image data to expose the respective photosensitive drums 24Y, 24M, 24C and 24K to light.\",\n \"The transfer unit 18 is positioned upward of the respective process cartridges 17Y, 17M, 17C and 17K.\",\n \"The transfer unit 18 includes a belt unit 31, a secondary transfer roller 32, and a belt cleaning unit 150.The belt unit 31 generally extends in the front-rear direction.\",\n \"The belt unit 31 includes a first roller 33, a second roller 34, a third roller 35, an intermediate transfer belt 36, and primary transfer rollers 37Y, 37M, 37C and 37K.\",\n \"The first roller 33 is positioned at a rear end portion of the belt unit 31, and is generally cylindrical shaped extending in the left-right direction.\",\n \"The second roller 34 is positioned at a front end portion of the belt unit 31, and is generally cylindrical shaped extending in the left-right direction.\",\n \"The third roller 35 is positioned at a lower rear portion of the belt unit 31, and is positioned frontward and downward of the first roller 33.The third roller 35 is generally cylindrical shaped extending in the left-right direction.\",\n \"The intermediate transfer belt 36 is looped over the first roller 33, the second roller 34, and the third roller 35 under tension.\",\n \"The intermediate transfer belt 36 has a lower portion in contact with the photosensitive drums 24Y, 24M, 24C and 24K of the process cartridges 17Y, 17M, 17C and 17K attached to the main casing 2.The intermediate transfer belt 36 is circularly movable such that the lower portion thereof moves rearward.\",\n \"The primary transfer rollers 37Y, 37M, 37C and 37K are arrayed between the second roller 34 and the third roller 35 in the front-rear direction with a space between neighboring rollers.\",\n \"Each of the primary transfer rollers 37Y, 37M, 37C and 37K is positioned upward of and in confrontation with corresponding one of the attached photosensitive drums 24Y, 24M, 24C and 24K via the intermediate transfer belt 36.The primary transfer rollers 37Y, 37M, 37C and 37K have a generally cylindrical shape extending in the left-right direction.\",\n \"The secondary transfer roller 32 is positioned rearward of the first roller 33 such that the intermediate transfer belt 36 is nipped between the secondary transfer roller 32 and first roller 33.The secondary transfer roller 32 is generally cylindrical shaped extending in the left-right direction.\",\n \"The belt cleaning unit 150 includes a belt-cleaning frame 151, a belt-cleaning blade 152, and a belt-cleaning screw 153.The belt-cleaning frame 151 is generally box shaped extending in the left-right direction.\",\n \"The belt-cleaning frame 151 has an upper rear end portion in which an opening 106 is formed to penetrate the upper rear end portion of the belt-cleaning frame 151 in the front-rear direction.\",\n \"The belt-cleaning blade 152 is positioned at a rear end portion of the belt-cleaning frame 151.The belt-cleaning blade 152 has a generally flat plate shape extending in the left-right direction.\",\n \"The belt-cleaning blade 152 has an upper end portion in contact with a front end portion of the intermediate transfer belt 36.The belt-cleaning blade 152 faces the opening 106.The belt-cleaning screw 153 is provided in a lower end portion of the belt-cleaning frame 151 and extends in the left-right direction.\",\n \"The belt-cleaning screw 153 has a right end rotatably supported by a right wall constituting a first conveying tube 161 (FIG.\",\n \"2) described later.\",\n \"The fixing unit 19 is positioned upward of the secondary transfer roller 32.The fixing unit 19 includes a heat roller 41 and a pressure roller 42 in pressure contact with a rear end portion of the heat roller 41.The sheet-discharging unit 4 includes a discharge tray 43, discharge rollers 48, reverse rollers 44, and a guide 45.The discharge tray 43 is formed in the upper wall of the main casing 2 and is recessed downward.\",\n \"The discharge rollers 48 are positioned rearward and upward of the discharge tray 43.The discharge rollers 48 are generally cylindrical shaped and extend in the left-right direction.\",\n \"The reverse rollers 44 are positioned upward of the fixing unit 19.The reverse rollers 44 have a generally cylindrical shape and extend in the left-right direction.\",\n \"The guide 45 is positioned above the fixing unit 19.The guide 45 is movable between a discharge position indicated by a solid line in FIG.\",\n \"1 and a reverse position indicated by a phantom line in FIG.\",\n \"1.As shown in FIG.\",\n \"1, in the discharge position, the guide 45 extends generally in the vertical direction in a side view and has an upper end portion pivotally movably supported to the main casing 2.In the discharge position, a lower end portion of the guide 45 is rearward relative to the upper end portion thereof so that the sheet can be directed toward the discharge rollers 48.In the reverse position, the lower end portion of the guide 45 is positioned frontward than that at the discharge position, so that the sheet can be directed toward the reverse rollers 44.The sheet-discharging unit 4 further includes a first conveying path 183 and a second conveying path 184.The sheet from the fixing unit 19 is conveyed toward the discharge rollers 48 along the first conveying path 183 when the guide 45 is at the discharge position.\",\n \"The sheet is conveyed from the fixing unit 19 to the reverse rollers 44 along the second conveying path 184 when the guide 45 is at the reverse position.\",\n \"The sheet nipped by the reverse rollers 44 is configured to be conveyed downward while passing rearward of the fixing unit 19 by reverse rotations of the reverse rollers 44, and is then turned upward in a U-shaped fashion toward a position between the intermediate transfer belt 36 and the secondary transfer roller 32.The image-reading unit 5 is positioned upward of the main casing 2 so as to cover the discharge tray 43 from above.\",\n \"The image-reading unit 5 includes a platen 46 on which an original document is to be placed, and a pressure cover 47 pivotally movably supported to the platen 46.2.Detailed Structure of the Main Casing The main casing 2 includes the outer frame 50 and the inner frame 51, as described earlier.\",\n \"As shown in FIG.\",\n \"6, the outer frame 50 has a box-like shape and is formed of a resin material.\",\n \"The right wall of the outer frame 50 is formed with an opening 6 as an example of a sixth opening for allowing communication between an inside and an outside of the main casing 2 in the left-right direction.\",\n \"The outer frame 50 also includes a cover 8 pivotally movable between a closed position for closing the opening 6 (FIG.\",\n \"6) and an open position for opening the opening 6 (FIG.\",\n \"7).\",\n \"The outer frame 50 further includes: mounting units 53Y, 53M, 53C, and 53K having respective openings 59Y, 59M, 59C, and 59K; covers 60Y, 60M, 60C, and 60K capable of opening and closing over the openings 59Y, 59M, 59C, and 59K; and a cover 64 (see FIG.\",\n \"2) that opens and closes over the access opening 63 formed in the front wall.\",\n \"The mounting units 53Y, 53M, 53C and 53K are respectively disposed on the upper-right sides of the corresponding process cartridges 17Y, 17M, 17C and 17K.\",\n \"The mounting units 53Y, 53M, 53C and 53K are arranged at intervals in the front-rear direction.\",\n \"The openings 59Y, 59M, 59C and 59K provide communication between the interior of the corresponding mounting units 53Y, 53M, 53C and 53K and the exterior of the outer frame 50 in the left-right direction.\",\n \"In the first embodiment, the mounting units 53Y, 53M, 53C and 53K all have the same construction.\",\n \"Therefore, only the mounting unit 53M will be described below as a representative example.\",\n \"Similarly, the covers 60Y, 60M, 60C and 60K all have the same construction and, therefore, only the cover 60M will be described below.\",\n \"The mounting unit 53M includes a receiving part 65M, and an input tube 66M.\",\n \"The receiving part 65M has a box-like shape with an open top.\",\n \"As shown in FIG.\",\n \"2, the receiving part 65M has a bottom portion having a rounded W-shape in a side view.\",\n \"An opening 67M (see FIG.\",\n \"2) is formed in a front end portion of the bottom portion of the receiving part 65M to penetrate the same vertically.\",\n \"The input tube 66M extends downward from the front end portion of the receiving part 65M.\",\n \"The input tube 66M has a general cylindrical shape that is elongated vertically.\",\n \"The input tube 66M has a top end that is in vertical communication with the opening 67M of the receiving part 65M.\",\n \"The input tube 66M has a bottom end portion that slopes downward toward the left.\",\n \"The bottom end portion is formed with an opening 68M, as an example of a third opening.\",\n \"That is, the opening 68 occupies a plane that slopes downward toward the left.\",\n \"The input tube 66M is provided with a seal 69M on its bottom end.\",\n \"The seal 69M is formed of an elastic material and has a frame-like structure that is generally rectangular in a plan view.\",\n \"The seal 69M is arranged around the opening 68M.\",\n \"The cover 60M is pivotably movably supported to a bottom edge on the right wall of the mounting unit 53M.\",\n \"The cover 60 can pivot pivot between a closed position for covering the opening 59M and an open position (see FIG.\",\n \"7) for exposing the opening 59M.\",\n \"The cover 64 has a plate-like shape that is generally rectangular in a front view.\",\n \"The cover 64 is pivotably movably supported to a bottom edge on the front wall of the main casing 2 (outer frame 50).\",\n \"The cover 64 can pivot between a closed position for covering the access opening 63 and an open position for exposing the access opening 63.The cover 8 is provided with detectors 110Y, 110M, 110C, and 110K.\",\n \"Since the detectors 110Y, 110M, 110C and 110K all have the same construction, only the detector 110K will be described below as a representative example.\",\n \"As shown in FIG.\",\n \"4B, the detector 110K includes a light-emitting element 111K, and a light-receiving element 112K.\",\n \"The light-emitting element 111K is disposed on the cover 8 at a position to the lower-front side of a second conveying tube 98K described later.\",\n \"The light-receiving element 112K is disposed on the cover 8 at a position on the upper-rear side of the second conveying tube 98K described later.\",\n \"The light-receiving element 112K is configured to receive light emitted from the light-emitting element 111K.\",\n \"The inner frame 51 is formed of a metallic material.\",\n \"As shown in FIGS.\",\n \"2 and 6, the inner frame 51 includes a first side plate 54 having openings 58 and 107 formed therein, a second side plate 55, a bottom plate 56 supporting the scanning unit 15, a top plate 57 connected to the first side plate 54 and second side plate 55, a center plate 52, a first positioning part 61, and a second positioning part 62.The first side plate 54 constitutes a right end of the inner frame 51.The first side plate 54 has a flat plate shape that is generally rectangular in a side view and elongated vertically.\",\n \"The opening 58 is formed in a vertical center region of the first side plate 54.The opening 58 has a general rectangular shape in a side view.\",\n \"As shown in FIG.\",\n \"2, the opening 58 has a front-rear dimension that is larger than a size of the process cartridges 17Y, 17M, 17C, and 17K juxtaposed in the front-rear direction.\",\n \"The opening 58 penetrates the first side plate 54 in the left-right direction.\",\n \"As shown in FIG.\",\n \"2, the opening 107 is formed in a front end region of the first side plate 54.The opening 107 is positioned frontward of the opening 58 and has a circular shape in a side view.\",\n \"The opening 107 penetrates the first side plate 54 in the left-right direction.\",\n \"The second side plate 55 constitutes a left end of the inner frame 51.The second side plate 55 is disposed leftward of and apart from the first side plate 54.The second side plate 55 has a flat plate shape that is generally rectangular in a side view and elongated vertically.\",\n \"Coupling gears 132 and couplings 133 are disposed on a left surface of the second side plate 55.The coupling gears 132 are rotatably supported on the second side plate 55.The couplings 133 are supported on the corresponding coupling gears 132 so as to be capable of moving relative to the same.\",\n \"Each of the couplings 133 has a right end that protrudes rightward from the second side plate 55.The couplings 133 can move in the left-right direction.\",\n \"Springs (not shown) constantly urge the couplings 133 rightward.\",\n \"The bottom plate 56 is disposed beneath the scanning unit 15 to support the same.\",\n \"The bottom plate 56 has a flat plate shape that is generally rectangular in a plan view and elongated in the left-right direction.\",\n \"The bottom plate 56 is connected to the first side plate 54 and second side plate 55.The top plate 57 is disposed above the belt unit 31.The top plate 57 has a flat plate shape that is generally rectangular in a plan view and elongated in the left-right direction.\",\n \"The center plate 52 is disposed beneath the process cartridges 17Y, 17M, 17C, and 17K and above the scanning unit 15.The center plate 52 has a flat plate shape that is generally rectangular in a plan view and elongated in the left-right direction.\",\n \"The center plate 52 is formed of a resin material.\",\n \"The center plate 52 has a right end that extends rightward beyond a bottom edge defining the opening 58.The first positioning part 61 is disposed beneath a right end portion of the top plate 57 and between the first side plate 54 and belt unit 31 in the left-right direction.\",\n \"The first positioning part 61 is positioned above the process cartridges 17Y, 17M, 17C, and 17K.\",\n \"The first positioning part 61 is a plate-shaped member that is generally rectangular in a side view and L-shaped in a front view.\",\n \"The first positioning part 61 has a top end portion connected to the right end portion of the top plate 57.The first positioning part 61 has a bottom end portion that extends downward to approximately the same position as the bottom end of the belt unit 31 in the vertical direction.\",\n \"The first positioning part 61 includes first positioning grooves 135Y, 135M, 135C, and 135K.\",\n \"The first positioning grooves 135Y, 135M, 135C, and 135K are formed in a bottom edge of the first positioning part 61.The first positioning grooves 135Y, 135M, 135C, and 135K are spaced at intervals from each other in the diagonal direction from the upper front to the lower rear.\",\n \"The first positioning grooves 135Y, 135M, 135C, and 135K are recessed upward from the bottom edge of the first positioning part 61.The second positioning part 62 is disposed below a left end portion of the top plate 57 and between the second side plate 55 and the belt unit 31 in the left-right direction.\",\n \"The second positioning part 62 is a plate-shaped member that is generally rectangular in a side view and L-shaped in a front view.\",\n \"The second positioning part 62 has a top end portion connected to the left end portion of the top plate 57; and a bottom end portion that extends to approximately the same vertical position as the bottom end of the belt unit 31.The second positioning part 62 includes second positioning grooves 136Y, 136M, 136C, and 136K.\",\n \"The second positioning grooves 136Y, 136M, 136C, and 136K are formed in a bottom edge of the second positioning part 62 and are spaced at intervals from each other in the diagonal direction from the upper front to the lower rear.\",\n \"The second positioning grooves 136Y, 136M, 136C, and 136K are recessed upward from the bottom edge of the second positioning part 62.In a left-right projection, the second positioning grooves 136Y, 136M, 136C, and 136K are respectively aligned with the first positioning grooves 135Y, 135M, 135C, and 135K.\",\n \"3.Detailed Description of the Toner Cartridges Referring to FIG.\",\n \"2, the toner cartridge 16K includes a cartridge frame 71K having an opening 72K formed therein, a first agitator 141K, and a second agitator 142K.\",\n \"The cartridge frame 71K has a box-like shape and is elongated in the left-right direction.\",\n \"The cartridge frame 71K has a bottom wall that has a general rounded W-shape in a side view.\",\n \"The cartridge frame 71K includes a partitioning plate 137K.\",\n \"The partitioning plate 137K extends diagonally downward and rearward from an inner peripheral surface of a front wall constituting the cartridge frame 71K.\",\n \"The partitioning plate 137K partitions the cartridge frame 71K into a large accommodating chamber 138K disposed constituting a rear portion of the cartridge frame 71K, and a small accommodating chamber 139K constituting a front portion of the cartridge frame 71K.\",\n \"The large accommodating chamber 138K is larger than the small accommodating chamber 139K.\",\n \"The first agitator 141K is accommodated in the large accommodating chamber 138K.\",\n \"The first agitator 141 is rotatably supported by the cartridge frame 71K.\",\n \"The second agitator 142K is accommodated in the small accommodating chamber 139K and is rotatably supported by the cartridge frame 71K.\",\n \"The opening 72K is formed in a lower-front end portion of the cartridge frame 71K.\",\n \"The opening 72K vertically penetrates a bottom wall constituting the small accommodating chamber 139K.\",\n \"The opening 72K is an example of a first opening.\",\n \"4.Detailed Description of the Process Cartridges (1) Drum Unit As shown in FIG.\",\n \"3, the drum unit 21K includes the drum-unit frame 23K.\",\n \"The drum-unit frame 23K has a box-like shape that is elongated in the left-right direction and open on the top side.\",\n \"The drum-unit frame 23K includes a first side plate 75K, a second side plate 76K, a first conveying tube 77K having an opening 70K as an example of a second opening, and a drum cleaning unit 73K.\",\n \"As shown in FIGS.\",\n \"3 and 4B, the first side plate 75K constitutes a right end portion of the drum-unit frame 23K.\",\n \"The first side plate 75K has a flat plate shape that is generally rectangular in a side view.\",\n \"The first side plate 75K includes a first support part 78K.\",\n \"The first support part 78K is disposed in a front-rear center region of the first side plate 75K to protrude rightward therefrom.\",\n \"The first support part 78K includes a first cylindrical part 79K, and a first engagement part 80K.\",\n \"The first cylindrical part 79K has a general cylindrical shape that is elongated in the left-right direction.\",\n \"The first cylindrical part 79K protrudes rightward from a right surface of the first side plate 75K.\",\n \"Also, as shown in FIGS.\",\n \"2 and 4B, the first cylindrical part 79K has an upper end portion that protrudes upward from an upper edge of the first side plate 75K.\",\n \"The first cylindrical part 79K thus has a top surface positioned higher than a top surface of the first side plate 75K.\",\n \"The first cylindrical part 79K rotatably supports a right end of the photosensitive drum 24K.\",\n \"The first engagement part 80K protrudes upward from a top edge of the first cylindrical part 79K.\",\n \"The first engagement part 80K is positioned between the opening 70K formed in the first conveying tube 77K and an opening 102K formed in a discharge tube 100K described later in the front-rear direction.\",\n \"The first engagement part 80K includes a first plate part 81K having an opening 83K formed therein, a first bar part 82K, and a first protruding part 144K.\",\n \"The first plate part 81K has a flat plate shape that extends upward from the first cylindrical part 79K.\",\n \"The opening 83K is formed in an upper end portion of the first plate part 81K.\",\n \"The opening 83K has a general circular shape in a side view and penetrates the upper end portion of the first plate part 81K in the left-right direction.\",\n \"The first bar part 82K protrudes rearward from the upper end portion of the first plate part 81K.\",\n \"The first protruding part 144K protrudes leftward from a rear end of the first bar part 82K.\",\n \"The first protruding part 144K includes a first sloped surface 84K.\",\n \"The first sloped surface 84K constitutes a bottom surface of the first protruding part 144K.\",\n \"The first sloped surface 84K slopes upward toward the left side.\",\n \"As shown in FIG.\",\n \"4A, the second side plate 76K constitutes a left end portion of the drum-unit frame 23K and is positioned leftward and apart from the first side plate 75K.\",\n \"The second side plate 76K has a flat plate shape that is generally rectangular in a side view.\",\n \"The second side plate 76K is separated leftward from the opening 70K by a greater distance than the first side plate 75K is.\",\n \"The second side plate 76K includes a second support part 85K.\",\n \"The second support part 85K is provided in a front-rear center region of the second side plate 76K and protrudes leftward from the same.\",\n \"The second support part 85K includes a second cylindrical part 86K, and a second engagement part 87K.\",\n \"The second cylindrical part 86K has a general cylindrical shape that is elongated in the left-right direction.\",\n \"The second cylindrical part 86K protrudes leftward from the left surface of the second side plate 76K.\",\n \"Also, the second cylindrical part 86K has an upper end portion that protrudes upward from an upper edge of the second side plate 76K.\",\n \"The second cylindrical part 86K thus has a top surface positioned higher than a top surface of the second side plate 76K.\",\n \"The second cylindrical part 86K rotatably supports a left end of the photosensitive drum 24K.\",\n \"Here, the left end of the photosensitive drum 24K has a coupling recess 145K for engaging with the coupling 133K.\",\n \"The second engagement part 87K protrudes downward from a bottom edge of the second cylindrical part 86K.\",\n \"The second engagement part 87K includes a second plate part 88K having an opening 90K formed therein, a second bar part 89K, and a second protruding part 146K.\",\n \"The second plate part 88K has a flat plate shape that extends downward from the second cylindrical part 86K.\",\n \"The opening 90K is formed in a bottom end portion of the second plate part 88K.\",\n \"The opening 90K has a general circular shape in a side view and penetrates the bottom end portion of the second plate part 88K in the left-right direction.\",\n \"The second bar part 89K protrudes rearward from the bottom end portion of the second plate part 88K.\",\n \"The second protruding part 146K protrudes leftward from a rear end of the second bar part 89K.\",\n \"The second protruding part 146K includes a second sloped surface 91K.\",\n \"The second sloped surface 91K constitutes a bottom surface of the second protruding part 146K.\",\n \"The second sloped surface 91K slopes upward toward the left side.\",\n \"As shown in FIG.\",\n \"3, the first conveying tube 77K is assembled to the first side plate 75K through a fixing part 93K that protrudes rightward from the right surface of the first side plate 75K.\",\n \"The first conveying tube 77K has a general square cylindrical shape that is elongated vertically.\",\n \"The first conveying tube 77 has a top wall that slopes downward toward the left.\",\n \"The opening 70 is formed in the top wall of the first conveying tube 77.Accordingly, the opening 70K also occupies a plane that slopes downward toward the left.\",\n \"The opening 70K can be in vertical communication with the opening 68K formed in the input tube 66K.\",\n \"As shown in FIG.\",\n \"6, the opening 70K in the first conveying tube 77K is arranged to the right of the first positioning part 61.The first conveying tube 77K is provided with a seal 92K on its upper end.\",\n \"The seal 92K is formed of an elastic material in a frame-like shape that is rectangular in a plan view.\",\n \"The seal 92K is arranged around the opening 70K.\",\n \"When the process cartridge 17K is mounted in the main casing 2, the seal 92K contacts the seal 69K of the input tube 66K.\",\n \"As shown in FIGS.\",\n \"1 and 3, the drum cleaning unit 73K is provided on rearward of the photosensitive drum 24K.\",\n \"The drum cleaning unit 73K includes a drum cleaning frame 95K having an opening 105K formed therein, a drum cleaning blade 96K as an example of a cleaning member, a drum cleaning screw 97K, and the discharge tube 100K having the opening 102K as an example of a fourth opening.\",\n \"The drum cleaning frame 95K has a box-like shape and is elongated in the left-right direction.\",\n \"The drum cleaning frame 95K has a right end supported on the first side plate 75K, and a left end supported on the second side plate 76K.\",\n \"As shown in FIG.\",\n \"1, the opening 105K is formed in an upper-front portion of the drum cleaning frame 95K and penetrates the same in the front-rear direction.\",\n \"The drum cleaning blade 96K is arranged on a front portion of the drum cleaning frame 95K.\",\n \"The drum cleaning blade 96K has a flat plate shape and is elongated in the left-right direction.\",\n \"The drum cleaning blade 96K has a top end portion positioned in confrontation with the opening 105K in the front-rear direction and in contact with a rear end portion on a circumferential surface of the photosensitive drum 24K.\",\n \"The drum cleaning screw 97K is disposed in a bottom portion of the drum cleaning frame 95K and is oriented in the left-right direction.\",\n \"The drum cleaning screw 97K has a left end that is rotatably supported by the second side plate 76K.\",\n \"The drum cleaning screw 97K has a right end that is positioned inside the discharge tube 100K.\",\n \"As shown in FIG.\",\n \"3, the discharge tube 100K has a general cylindrical shape and extends rightward from a right end portion of the drum cleaning frame 95K, and then bends and extends downward.\",\n \"The opening 102K is formed in a bottom end of the discharge tube 100K.\",\n \"The discharge tube 100 has a right wall that rotatably supports the right end of the drum cleaning screw 97K.\",\n \"The discharge tube 100K is provided with a seal 101K on its bottom end.\",\n \"As shown in FIG.\",\n \"6, the opening 102K formed in the discharge tube 100K is positioned farther rightward than the opening 70K formed in the first conveying tube 77K.\",\n \"Further, the opening 102K in the discharge tube 100K is disposed rightward of the first positioning part 61K.\",\n \"The seal 101K is formed of an elastic material in a frame-like shape that is rectangular in a plan view.\",\n \"The seal 101K is arranged around the opening 102K on the bottom end of the discharge tube 100K.\",\n \"(2) Developing Unit As shown in FIG.\",\n \"3, the developing unit 22K is positioned between the front end portions of the first side plate 75K and second side plate 76K constituting the drum-unit frame 23K.\",\n \"The developing unit 22K further includes the developing-unit frame 26K, and a unit screw 30K (see FIG.\",\n \"1).\",\n \"The developing-unit frame 26K has a box-like shape that is elongated in the left-right direction and open on the top side.\",\n \"The developing-unit frame 26K includes a rotational shaft 74K, and the second conveying tube 98K.\",\n \"The rotational shaft 74K protrudes rightward from a right wall constituting the developing-unit frame 26K.\",\n \"The rotational shaft 74K has a general columnar shape and is elongated in the left-right direction.\",\n \"The rotational shaft 74K is rotatably supported in a bottom end portion of the first side plate 75K.\",\n \"The rotational shaft 74K also protrudes leftward from a left wall of the developing-unit frame 26K.\",\n \"The protruding portion (left end portion) of the rotational shaft 74K is rotatably supported in a bottom end portion of the second side plate 76K.\",\n \"In this way, the developing-unit frame 26K can pivotally movable about the rotational shaft 74K relative to the drum-unit frame 23K.\",\n \"More specifically, the developing-unit frame 26K can pivotally move between a contact position in which the developing roller 27K contacts the photosensitive drum 24K, and a separated position in which the developing roller 27K is separated from the photosensitive drum 24K.\",\n \"The second conveying tube 98K is positioned rightward of the first side plate 75K constituting the drum-unit frame 23K.\",\n \"The second conveying tube 98K has a general cylindrical shape that first extends rightward from the right end of the developing-unit frame 26K, and then bends and extends upward.\",\n \"The second conveying tube 98K is configured of a light-permeable member, at least in a region in which the light-emitting element 111K and light-receiving element 112K confront each other.\",\n \"Hence, if a sufficient amount of toner is present in the second conveying tube 98K, the light from the light-emitting element 111K is blocked by the toner and thus cannot be received by the light-receiving element 112K.\",\n \"The second conveying tube 98K has a top end in communication with a bottom end of the first conveying tube 77K.\",\n \"A connector 99K is provided to surround the junction of the second conveying tube 98K and first conveying tube 77K.\",\n \"The connector 99K is formed of an elastic material, and specifically a sponge material in the present embodiment.\",\n \"The connector 99 has a general cylindrical shape that is elongated vertically.\",\n \"The connector 99K has a top end portion connected to the bottom end of the first conveying tube 77K, while a bottom end of the connector 99K is connected to the top end of the second conveying tube 98K.\",\n \"In this way, the internal space of the first conveying tube 77K is in communication with the internal space in the second conveying tube 98K through the connector 99K.\",\n \"Further, the first conveying tube 77K and second conveying tube 98K are joined on the right side of the first side plate 75K.\",\n \"As shown in FIG.\",\n \"1, the unit screw 30K is arranged in a bottom portion of the developing-unit frame 26K.\",\n \"The unit screw 30K is positioned rearward of the supply roller 28K.\",\n \"The right end of the unit screw 30K is rotatably supported in the right wall of the second conveying tube 98K (see FIG.\",\n \"3), while the left end of the unit screw 30K is rotatably supported in the left wall of the developing-unit frame 26K.\",\n \"5.Structure of the Urging Members As shown in FIGS.\",\n \"2 and 6, urging members 120RY, 120RM, 120RC and 120RK and urging members 120LY, 120LM, 120LC, and 120LK are disposed in the main casing 2 on respective ends of the corresponding process cartridges 17Y, 17M, 17C, and 17K.\",\n \"Other than being disposed beneath the left ends of the process cartridges 17 and to the left of the second positioning part 62, the urging members 120LY, 120LM, 120LC, and 120LK have the same structure and configuration as the urging members 120RY, 120RM, 120RC and 120RK.\",\n \"Therefore, the urging members 120RY, 120RM, 120RC and 120RK will serve as a representative example in the following description.\",\n \"Further, since the urging members 120RY, 120RM, 120RC and 120RK have the structure, the urging member 120RM will be used as a representative example in the following description.\",\n \"As shown in FIG.\",\n \"6, the urging member 120RM is disposed above the right end of the process cartridge 17M and overlaps the first conveying tube 77M in a front-rear projection.\",\n \"The urging member 120RM is positioned to the right of the first positioning part 61 and to the left of the opening 70M.\",\n \"As shown in FIG.\",\n \"5, the urging member 120RM includes a pivoting part 121M having a center hole 129M formed therein, a contact part 122M, an engaging part 123M, and a tension spring 124M.\",\n \"The pivoting part 121M has a general bar shape that is elongated in the front-rear direction.\",\n \"The pivoting part 121M has a front end serving as an example of a first end, while a rear end thereof serves as an example of a second end.\",\n \"The front-rear direction is an example of an orthogonal direction.\",\n \"The center hole 129M is formed in the front end of the pivoting part 121M.\",\n \"The center hole 129M has a general circular shape in a side view and penetrates the front end of the pivoting part 121M in the left-right direction.\",\n \"The center hole 129M is engaged with a boss (not shown) provided on either the first side plate 54 or the second side plate 55.Through this engagement, the pivoting part 121M can pivot about a central axis of the center hole 129M.\",\n \"The contact part 122M protrudes rightward from the rear end of the pivoting part 121M.\",\n \"The contact part 122M has a general plate shape that is elongated in the left-right direction.\",\n \"The contact part 122M includes an engaging surface 125M.\",\n \"The engaging surface 125M constitutes a top surface on a right end portion of the contact part 122M.\",\n \"The engaging surface 125M slopes upward toward the left.\",\n \"The engaging part 123M protrudes rightward from a front-rear center portion of the pivoting part 121M.\",\n \"The engaging part 123M includes a base part 126M, and a tip-end part 127M.\",\n \"The base part 126M has a general columnar shape and is elongated in the left-right direction.\",\n \"The base part 126M protrudes rightward from the front-rear center portion of the pivoting part 121M.\",\n \"The tip-end part 127M protrudes rightward from a right end of the base part 126M.\",\n \"The tip-end part 127M has a conical shape that tapers toward the right.\",\n \"The tip-end part 127M has a peripheral surface that constitutes a sloped surface 128M.\",\n \"That is, the sloped surface 128M has a top edge that slopes upward toward the left.\",\n \"The tension spring 124M is a helical spring whose bottom end is engaged with the rear end of the pivoting part 121M.\",\n \"More specifically, when viewed in the left-right direction, the bottom end of the tension spring 124M is disposed between the contact part 122M and the engaging part 123M.\",\n \"In other words, the tension spring 124M is disposed closer to the rear end of the pivoting part 121M than the engaging part 123M is to the rear end of the pivoting part 121M.\",\n \"As shown in FIG.\",\n \"6, the urging member 120RM is pivotably movably supported on the first side plate 54 through the boss (not shown) thereof inserted through the center hole 129M.\",\n \"Accordingly, the urging member 120RM can pivot about the central axis of the center hole 129M aligned in the left-right direction.\",\n \"Further, the top end of the tension spring 124M is engaged with a first mounting part 130 provided on a right surface of the first side plate 54.With this arrangement, the rear end of the pivoting part 121M is constantly urged upward.\",\n \"Note that the tension spring 124 in each of the urging members 120L is engaged with a second mounting part 131 provided on a right surface of the second side plate 55.6.Structures Related to Waste Toner Conveyance As shown in FIG.\",\n \"2, the main casing 2 includes a first conveying tube 161, a second conveying tube 162, a conveying screw 164, a third conveying tube 165, and a waste toner container 166 having an opening 177.The first conveying tube 161 is disposed rightward of the front end portion of the first side plate 54.The first conveying tube 161 has a general cylindrical shape and is elongated vertically.\",\n \"The first conveying tube 161 has a top end that is connected to the lower end portion of the belt-cleaning frame 151 of the belt cleaning unit 150 shown in FIG.\",\n \"1 via the opening 107 formed in the first side plate 54.The right wall constituting the first conveying tube 161 rotatably supports the right end of the belt cleaning screw 153.The second conveying tube 162 is disposed below the first conveying tube 161 and extends in the diagonal direction from the upper front to the lower rear.\",\n \"The second conveying tube 162 has a general cylindrical shape.\",\n \"The second conveying tube 162 is fixed to the first side plate 54.The second conveying tube 162 has a front end connected to a bottom end of the first conveying tube 161.The second conveying tube 162 includes a waste toner conveying tube 163 therein.\",\n \"The waste toner conveying tube 163 is disposed within the second conveying tube 162.The waste toner conveying tube 163 can rotate relative to the second conveying tube 162.The waste toner conveying tube 163 is connected to connector tubes 172 described later, and movement of the connector tubes 172 causes the waste toner conveying tube 163 to rotate relative to the second conveying tube 162, as will be described later.\",\n \"The waste toner conveying tube 163 includes a conveying cylindrical part 171, and the connector tubes 172Y, 172M, 172C, and 172K having respective openings 175Y, 175M, 175C, and 175K.\",\n \"The conveying cylindrical part 171 is disposed in the second conveying tube 162 and extends along the same direction of the second conveying tube 162 (i.e., in the diagonal direction).\",\n \"The conveying cylindrical part 171 has a general cylindrical shape.\",\n \"As shown in FIG.\",\n \"2, the connector tubes 172Y, 172M, 172C, and 172K are arranged at intervals from each other in the diagonal direction in which the conveying cylindrical part 171 extends.\",\n \"Since the connector tubes 172Y, 172M, 172C, and 172K all have the same construction, only the connector tube 172M will be described below as a representative example.\",\n \"As shown in FIG.\",\n \"6, the connector tube 172M has a general cylindrical shape that extends diagonally upward and rightward from the conveying cylindrical part 171, and then bends and extends upward.\",\n \"The opening 175M is formed in a top end of the connector tube 172M.\",\n \"The opening 175M is as an example of a fifth opening.\",\n \"As shown in FIG.\",\n \"6, the connector tube 172M includes a seal 173M, and an interlocking member 174M.\",\n \"The opening 175M formed in the connector tube 172M is capable of communicating with the opening 102M of the discharge tube 100M, as will be described later.\",\n \"The seal 173M is formed of an elastic material having a frame-like shape that is rectangular in a plan view.\",\n \"The seal 173M is arranged around the opening 175M.\",\n \"The seal 173M is in contact with the seal 101M of the discharge tube 100M.\",\n \"The interlocking member 174M has a general bar shape.\",\n \"One end of the interlocking member 174M is attached to the top end of the connector tube 172M so as to be capable of rotating relative thereto, while the other end is attached to the cover 8 and is capable of rotating relative thereto.\",\n \"With this structure, the interlocking member 174M can move in conjunction with movement of the cover 8.Movement of the interlocking member 174M can in turn move the connector tube 172M between a communication position in which the connector tube 172M is communicated with the discharge tube 100, and a non-communication position in which such communication of the connector tube 172M to the discharge tube 100 is interrupted.\",\n \"As shown in FIG.\",\n \"2, the conveying screw 164 is disposed inside the conveying cylindrical part 171.The conveying screw 164 extends in the diagonal direction from the upper front to the lower rear.\",\n \"The conveying screw 164 is rotatably supported in the conveying cylindrical part 171.The third conveying tube 165 extends downward from a rear end of the second conveying tube 162.The third conveying tube 165 has a general cylindrical shape that is elongated vertically.\",\n \"The third conveying tube 165 has an opening 200 formed in a bottom end portion of the third conveying tube 165.A shutter 176 is movably disposed in the bottom end portion of the third conveying tube 165.The opening 200 is configured to be opened and closed through the movement of the shutter 176.The waste toner container 166 is disposed in a lower-right section of the main casing 2 to the rear of the access opening 63.The waste toner container 166 has a box-like shape that is elongated in the front-rear direction and can be mounted in and removed from the main casing 2 through the access opening 63.The waste toner container 166 has an opening 177 formed in an upper-rear corner portion of the waste toner container 166.The opening 177 penetrates a top wall constituting the waste toner container 166 vertically.\",\n \"A shutter 178 is movably disposed on the top wall of the waste toner container 166 such that the opening 177 can be opened and closed through the movement of the shutter 178.When the waste toner container 166 is mounted in the main casing 2, the opening 177 is in communication with the opening 200 formed in the third conveying tube 165.Hence, the waste toner conveying tube 163 is connected to the waste toner container 166 through the third conveying tube 165.7.Operations for Mounting and Removing the Toner Cartridges In the following description for the mounting and removal of the toner cartridges 16 and process cartridges 17, operations for mounting and removing the toner cartridge 16M and process cartridge 17M will be described as representative examples.\",\n \"For mounting the toner cartridge 16M in the main casing 2, the cover 60M is placed in its open position shown in FIG.\",\n \"7.The toner cartridge 16M is then inserted into the receiving part 65M of the mounting unit 53M via the opening 59M.\",\n \"When the toner cartridge 16M has been mounted on the receiving part 65M, the opening 72M of the toner cartridge 16M is in vertical communication with the opening 67M formed in the receiving part 65M of the mounting unit 53M.\",\n \"To remove the toner cartridge 16M from the main casing 2, the cover 60M is again placed in its open position, and the toner cartridge 16M is extracted from the main casing 2 through the opening 59M.\",\n \"8.Operations for Mounting and Removing the Process Cartridges To mount the process cartridge 17M in the main casing 2, the cover 8 is placed in its open position shown in FIG.\",\n \"8.The process cartridge 17M is then inserted into the main casing 2 through the opening 6 and the opening 58, while slidingly moving along the center plate 52.At this time, the first sloped surface 84M of the first support part 78M in the process cartridge 17M contacts the engaging surface 125M of the urging member 120RM, as shown in solid lines in FIG.\",\n \"8.Further, the second sloped surface 91M of the second support part 85M in the process cartridge 17M contacts the engaging surface 125M of the urging member 120LM.\",\n \"As the process cartridge 17M is further moved leftward, the first sloped surface 84M slides diagonally upward and leftward along the engaging surface 125M of the urging member 120RM, and the second sloped surface 91M slides diagonally upward and leftward along the engaging surface 125M of the urging member 120LM.\",\n \"Consequently, the process cartridge 17M moves diagonally upward and leftward.\",\n \"As a result, the opening 83M in the first support part 78M of the process cartridge 17M becomes fitted around the right end of the engaging part 123M constituting the urging member 120RM, and the opening 90M formed in the second support part 85M of the process cartridge 17M becomes fitted around the right end of the engaging part 123M constituting the urging member 120LM.\",\n \"As the process cartridge 17M moves farther leftward, the inner edge of the opening 83M defined in the first support part 78M contacts the sloped surface 128M of the urging member 120RM, while the inner edge of the opening 90M defined in the second support part 85M contacts the sloped surface 128M of the urging member 120LM.\",\n \"As the process cartridge 17M continues to move leftward, the inner edge of the opening 83M defined in the first support part 78M slides diagonally upward and leftward along the sloped surface 128M of the urging member 120RM, while the inner edge of the opening 90M defined in the second support part 85M slides diagonally upward and leftward along the sloped surface 128M of the urging member 120LM.\",\n \"Consequently, the process cartridge 17M moves diagonally upward and leftward.\",\n \"At this time, the first sloped surface 84M separates from the engaging surface 125M formed on the urging member 120RM, and the second sloped surface 91M separates from the engaging surface 125M formed on the urging member 120LM.\",\n \"As the process cartridge 17M continues to move leftward, the base part 126M of the urging member 120RM is inserted into the opening 83M formed in the first support part 78M.\",\n \"Similarly, the base part 126M on the urging member 120LM is inserted into the opening 90M formed in the second support part 85M.\",\n \"Next, the top surface of the first cylindrical part 79M in the process cartridge 17M becomes engaged in the first positioning groove 135M formed in the first positioning part 61.Similarly, the top surface of the second cylindrical part 86M becomes engaged in the second positioning groove 136M formed in the second positioning part 62.At this time, the process cartridge 17M is fixed in position in the main casing 2, as shown in FIG.\",\n \"2.In addition, the coupling 133M is inserted into the coupling recess 145M formed in the left end of the photosensitive drum 24 supported by the drum-unit frame 23M.\",\n \"At this time, the tension spring 124M of the urging member 120RM urges the first support part 78M upward through the base part 126M of the urging member 120RM.\",\n \"Similarly, the tension spring 124M of the urging member 120LM urges the second support part 85M upward through the base part 126M of the urging member 120LM.\",\n \"Due to the upward urging of the process cartridge 17M by the urging members 120RM and 120LM, the seal 92M of the first conveying tube 77M and the seal 69M on the input tube 66M of the mounting unit 53M contact each other with pressure.\",\n \"At this time, the opening 70M formed in the first conveying tube 77M is in vertical communication with the opening 68M formed in the mounting unit 53M.\",\n \"In this state, the process cartridge 17M is in the first position, as shown in FIG.\",\n \"6.To remove the process cartridge 17M from the main casing 2, the cover 8 is first moved from its closed position to its open position shown in FIG.\",\n \"7.At this time, the cover 8 pulls the interlocking member 174M downward and the interlocking member 174M in turn pulls the connector tube 172M downward, causing the waste toner conveying tube 163 to rotate counterclockwise in a rear view and the connector tube 172M to move into its non-communication position.\",\n \"The connector tube 172M is configured to move from its communication position to its non-communication position by a distance L1 in the vertical direction, as shown in FIG.\",\n \"7.From this state, an operator pulls the process cartridge 17M rightward.\",\n \"Through this action, the opening 83M of the first support part 78M disengages from the base part 126M on the urging member 120RM, and the opening 90M formed in the second support part 85M disengages from the base part 126M on the urging member 120LM, as shown in FIG.\",\n \"8.As the process cartridge 17M continues to move rightward, the inner edge of the opening 83M defined in the first support part 78M slides downward and rightward along the sloped surface 128M of the urging member 120RM, and the inner edge of the opening 90M defined in the second support part 85M slides downward and rightward along the sloped surface 128M of the urging member 120LM.\",\n \"Consequently, the process cartridge 17M itself moves diagonally downward and rightward.\",\n \"As the process cartridge 17M continues to move rightward, the first sloped surface 84M on the first support part 78M contacts the engaging surface 125M on the urging member 120RM, while the second sloped surface 91M on the second support part 85M contacts the engaging surface 125M on the urging member 120LM.\",\n \"At this time, the inner edge of the opening 83M defined in the first support part 78M separates from the sloped surface 128M on the urging member 120RM, and the inner edge of the opening 90M defined in the second support part 85M separates from the sloped surface 128M on the urging member 120LM.\",\n \"As the process cartridge 17M continues to move rightward, the first sloped surface 84M slides diagonally downward and rightward along the engaging surface 125M formed on the urging member 120RM, and the second sloped surface 91M slides diagonally downward and rightward along the engaging surface 125M formed on the urging member 120LM.\",\n \"Consequently, the process cartridge 17M itself moves diagonally downward and rightward and is placed on the center plate 52.This action interrupts communication between the opening 70M formed in the first conveying tube 77M and the opening 68M formed in the mounting unit 53M.\",\n \"At this time, the process cartridge 17M is in its second position, as shown in FIG.\",\n \"8.The process cartridge 17M is configured to move between the first position and the second position by a distance L2 smaller than the distance L1 in the vertical direction.\",\n \"From this state, the process cartridge 17M is extracted from the main casing 2 through the opening 6 and opening 58.9.Image-Forming Operation When the toner cartridges 16Y, 16M, 16C, and 16K and process cartridges 17Y, 17M, 17C, and 17K are mounted in the main casing 2, as shown in FIG.\",\n \"2, and an image-forming operation is initiated on the printer 1, the charging rollers 25Y, 25M, 25C, and 25K is configured to apply a uniform positive charge to the surfaces of the corresponding photosensitive drums 24Y, 24M, 24C, and 24K, as illustrated in FIG.\",\n \"1.Subsequently, the scanning unit 15 exposes the surfaces of the photosensitive drums 24Y, 24M, 24C, and 24K by irradiating laser beams with high-speed scanning, thereby forming electrostatic latent images based on image data on the surfaces of the corresponding photosensitive drums 24Y, 24M, 24C, and 24K.\",\n \"Incidentally, in each of the toner cartridges 16Y, 16M, 16C, and 16K, when the light-receiving element 112 receives light from the corresponding light-emitting element 111 (that is, when the level of toner in the second conveying tube 98 has not yet reached up to a position detectable by the detector 110), the first agitator 141 in each toner cartridge 16 is configured to rotate to convey toner from the corresponding large accommodating chamber 138 into the corresponding small accommodating chamber 139, as illustrated in FIG.\",\n \"2.The second agitator 142 in the corresponding small accommodating chamber 139 also rotates to introduce toner from the small accommodating chamber 139 into the input tube 66 via the corresponding openings 72 and 68.The toner introduced into the input tube 66 moves through the first conveying tube 77 and second conveying tube 98 of the corresponding process cartridge 17.When the light-receiving element 112 no longer receives light from the corresponding light-emitting element 111 (that is, when a sufficient amount of the toner has been introduced into the second conveying tube 98), the printer 1 stops driving the first agitator 141 and second agitator 142 of the corresponding toner cartridge 16.Thus, the toner can be maintained at a low level in the second conveying tubes 98Y, 98M, 98C, and 98K, and therefore the level of the toner can be prevented from rising higher to reach the openings 70Y, 70M, 70C, and 70K in the first conveying tubes 77Y, 77M, 77M and 77C.\",\n \"As illustrated in FIG.\",\n \"1, the unit screws 30Y, 30M, 30C, and 30K subsequently convey the toner from right to left in the developing-unit frames 26Y, 26M, 26C, and 26K while supplying the toner onto the supply rollers 28Y, 28M, 28C, and 28K.\",\n \"The toner supplied to the supply rollers 28Y, 28M, 28C, and 28K is in turn supplied onto the developing rollers 27Y, 27M, 27C, and 27K, at which time the toner is positively tribocharged between the supply rollers 28Y, 28M, 28C, and 28K and the corresponding developing rollers 27Y, 27M, 27C, and 27K.\",\n \"As the developing rollers 27Y, 27M, 27C, and 27K rotate, the thickness of the toner supplied onto the developing rollers 27Y, 27M, 27C, and 27K is regulated by the thickness-regulating blades 29Y, 29M, 29C, and 29K so that a toner layer of uniform thickness is carried on the surface of each of the developing rollers 27Y, 27M, 27C, and 27K.\",\n \"The positively charged toner carried on the surfaces of the developing rollers 27Y, 27M, 27C, and 27K is subsequently supplied to the electrostatic latent images formed on the surfaces of the respective photosensitive drums 24Y, 24M, 24C, and 24K as the photosensitive drums 24Y, 24M, 24C, and 24K rotate.\",\n \"In this way, toner images are formed through reverse development on the surfaces of the photosensitive drums 24Y, 24M, 24C, and 24K.\",\n \"Next, while the intermediate transfer belt 36 circulates, the photosensitive drums 24Y, 24M, 24C, and 24K transfer the toner images in their corresponding colors onto the intermediate transfer belt 36 in a primary transfer process.\",\n \"In the meantime, the first pick-up roller 12 picks up and separates the sheets accommodated in the first sheet tray 9 and conveys the sheets one at a time and at a prescribed timing along the first sheet-feeding path 181 to the position between the intermediate transfer belt 36 and the secondary transfer roller 32.As each sheet passes between the intermediate transfer belt 36 and the secondary transfer roller 32, the toner image carried on the intermediate transfer belt 36 is transferred onto the sheet in a secondary transfer process.\",\n \"Thereafter, heat and pressure are applied to the sheet in the fixing unit 19 as the sheet passes between the heat roller 41 and the pressure roller 42, thereby thermally fixing the toner image to the sheet.\",\n \"After the toner image has been thermally fixed to the sheet in the fixing unit 19, the sheet is guided by the guide 45 oriented in the discharge position and is discharged into the discharge tray 43.Here, if sheets have been loaded in the second sheet tray 10, the second pick-up roller 13 picks up and separates the sheets in the second sheet tray 10 and conveys the sheets one at a time and at a prescribed timing along the second sheet-feeding path 182 to the position between the intermediate transfer belt 36 and secondary transfer roller 32.Further, when images are being formed on both surfaces of the sheet, the sheet is guided along the guide 45 oriented in the reverse position after a toner image has been thermally fixed to one side of the sheet in the fixing unit 19, and the sheet enters between the reversing rollers 44.By reversing their rotation, the reversing rollers 44 convey the sheet back downward into the main casing 2 along a U-shaped path that guides the sheet back to the position between the intermediate transfer belt 36 and the secondary transfer roller 32 in order that an image can be formed on the back side of the sheet.\",\n \"Once the image has been formed on the back side of the sheet and thermally fixed to the sheet in the fixing unit 19, the sheet is guided along the guide 45, now oriented in the discharging position, and is discharged into the discharge tray 43.10.Cleaning Operation In the meantime, the drum cleaning blades 96Y, 96M, 96C, and 96K scrape off waster toner remaining on the corresponding photosensitive drums 24Y, 24M, 24C, and 24K.\",\n \"The waste toner is collected in the drum cleaning frames 95Y, 95M, 95C, and 95K.\",\n \"The drum cleaning screws 97Y, 97M, 97C, and 97K convey this waste toner rightward in the drum cleaning frames 95Y, 95M, 95C, and 95K.\",\n \"As shown in FIG.\",\n \"2, the waste toner being conveyed through the drum cleaning frames 95Y, 95M, 95C, and 95K flows into the connector tubes 172Y, 172M, 172C, and 172K through the discharge tubes 100Y, 100M, 100C, and 100K.\",\n \"Thereafter, the conveying screw 164 conveys the waste toner diagonally downward and rearward in the conveying cylindrical part 171 to the third conveying tube 165.The waste toner falls down through the third conveying tube 165 and is collected in the waste toner container 166.As shown in FIG.\",\n \"1, the belt-cleaning blade 152 scrapes residual toner off the intermediate transfer belt 36 so that the toner drops into the belt-cleaning frame 151.The belt-cleaning screw 153 then conveys the waste toner rightward in the belt-cleaning frame 151.The waste toner being conveyed in the belt-cleaning frame 151 flows into the conveying cylindrical part 171 through the first conveying tube 161 shown in FIG.\",\n \"2.The waste toner is subsequently conveyed diagonally downward and rearward in the conveying cylindrical part 171 by the conveying screw 164 and flows into the third conveying tube 165.The waste toner is discharged from the third conveying tube 165 and collected in the waste toner container 166.To remove the waste toner container 166 from the main casing 2, the operator places the cover 64 in the open position and pulls the waste toner container 166 out of the main casing 2 through the access opening 63.At this time, the shutter 178 closes the opening 177 formed in the waste toner container 166, and the shutter 176 closes the opening 200 at the bottom end of the third conveying tube 165.11.Operational and Technical Advantages of the First Embodiment (1) In the printer 1 of the embodiment described above, the toner cartridges 16Y, 16M, 16C, and 16K can be mounted in and removed from the main casing 2 in the left-right direction through the corresponding openings 59Y, 59M, 59C, and 59K, as shown in FIG.\",\n \"7.Further, the process cartridges 17Y, 17M, 17C, and 17K can be mounted in and removed from the main casing 2 in the left-right direction through the openings 6 and 58, as shown in FIG.\",\n \"8.Hence, the toner cartridges 16Y, 16M, 16C, and 16K and process cartridges 17Y, 17M, 17C, and 17K can be independently mounted in and removed from the main casing 2 in the left-right direction.\",\n \"When the process cartridges 17Y, 17M, 17C, and 17K are mounted in the main casing 2, as shown in FIG.\",\n \"6, the urging members 120RY, 120RM, 120RC and 120RK and the urging members 120LY, 120LM, 120LC, and 120LK urge the corresponding process cartridges 17Y, 17M, 17C, and 17K toward the first positioning part 61 and the second positioning part 62.Thus, the process cartridges 17Y, 17M, 17C, and 17K are positioned such that toner supplied from the toner cartridges 16Y, 16M, 16C, and 16K can be received through the corresponding openings 70Y, 70M, 70C, and 70K.\",\n \"Therefore, the toner supplied from the toner cartridges 16Y, 16M, 16C, and 16K can be reliably supplied to and received in the process cartridges 17Y, 17M, 17C, and 17K.\",\n \"(2) As shown in FIG.\",\n \"6, the urging members 120RY, 120RM, 120RC and 120RK and the urging members 120LY, 120LM, 120LC, and 120LK are positioned to the left of the openings 70Y, 70M, 70C, and 70K formed in the first conveying tubes 77Y, 77M, 77C, and 77K.\",\n \"Accordingly, this construction can prevent interference between the urging members 120RY, 120RM, 120RC and 120RK and urging members 120LY, 120LM, 120LC, and 120LK and the openings 70Y, 70M, 70C, and 70K during mounting and removal of the process cartridges 17Y, 17M, 17C, and 17K relative to the main casing 2.\",\n \"(3) Further, the urging members 120RY, 120RM, 120RC and 120RK are disposed to the right of the first positioning part 61, as shown in FIG.\",\n \"6.Accordingly, the space in the printer 1 is effectively utilized when laying out the urging members 120RY, 120RM, 120RC and 120RK.\",\n \"(4) Further, as shown in FIG.\",\n \"6, the first positioning part 61 and second positioning part 62 are arranged further leftward than the openings 70Y, 70M, 70C, and 70K formed in the first conveying tubes 77Y, 77M, 77C, and 77K.\",\n \"This arrangement can prevent interference between the first positioning part 61 and second positioning part 62 and the openings 70Y, 70M, 70C, and 70K when the process cartridges 17Y, 17M, 17C, and 17K are mounted in or removed from the main casing 2.\",\n \"(5) As shown in FIG.\",\n \"3, the process cartridges 17Y, 17M, 17C, and 17K are respectively provided with the drum-unit frames 23Y, 23M, 23C, and 23K and developing-unit frames 26Y, 26M, 26C, and 26K.\",\n \"Further, the openings 70Y, 70M, 70C, and 70K are respectively formed in the drum-unit frames 23Y, 23M, 23C, and 23K.\",\n \"Accordingly, the openings 70Y, 70M, 70C, and 70K can be arranged in fixed positions, even when the developing-unit frames 26Y, 26M, 26C, and 26K pivot relative to the drum-unit frames 23Y, 23M, 23C, and 23K.\",\n \"Thus, the toner supplied from the toner cartridges 16Y, 16M, 16C, and 16K can be reliably received through the openings 70Y, 70M, 70C, and 70K.\",\n \"(6) As shown in FIG.\",\n \"3, the first conveying tubes 77Y, 77M, 77C, and 77K are connected to the second conveying tubes 98Y, 98M, 98C, and 98K on the right side of the first side plates 75Y, 75M, 75C, and 75K.\",\n \"In other words, the first conveying tubes 77Y, 77M, 77C, and 77K are connected to the second conveying tubes 98Y, 98M, 98C, and 98K respectively at positions opposite to the second side plates 76Y, 76M, 76C, and 76K with respect to the first side plates 75Y, 75M, 75C, and 75K in the left-right direction.\",\n \"This configuration prevents the need to enlarge the process cartridges 17Y, 17M, 17C, and 17K in the front-rear and vertical directions.\",\n \"(7) As shown in FIG.\",\n \"6, the first conveying tubes 77Y, 77M, 77C, and 77K at least partially overlap the corresponding urging members 120RY, 120RM, 120RC and 120RK in a front-rear projection.\",\n \"Accordingly, the space required for arranging the urging members 120RY, 120RM, 120RC and 120RK and the first conveying tubes 77Y, 77M, 77C, and 77K in the printer 1 can be reduced.\",\n \"(8) As shown in FIG.\",\n \"3, the developing-unit frames 26Y, 26M, 26C, and 26K can pivot about the rotational shaft 74K relative to the drum-unit frames 23Y, 23M, 23C, and 23K, respectively.\",\n \"Hence, by pivoting the developing-unit frames 26Y, 26M, 26C, and 26K relative to the drum-unit frames 23Y, 23M, 23C, and 23K, the developing-unit frames 26Y, 26M, 26C, and 26K can be separated from the drum-unit frames 23Y, 23M, 23C, and 23K, and the developing rollers 27Y, 27M, 27C, and 27K can be separated from the photosensitive drums 24Y, 24M, 24C, and 24K.\",\n \"(9) The connectors 99Y, 99M, 99C, and 99K that connect the first conveying tubes 77Y, 77M, 77C, and 77K to the second conveying tubes 98Y, 98M, 98C, and 98K shown in FIG.\",\n \"3 are formed of an elastic material, and specifically a sponge.\",\n \"Hence, the connectors 99Y, 99M, 99C, and 99K can flex appropriately when the developing-unit frames 26Y, 26M, 26C, and 26K pivot relative to the drum-unit frames 23Y, 23M, 23C, and 23K.\",\n \"Accordingly, the connectors 99Y, 99M, 99C, and 99K can reliably connect the first conveying tubes 77Y, 77M, 77C, and 77K to the corresponding second conveying tubes 98Y, 98M, 98C, and 98K, even when the developing-unit frames 26Y, 26M, 26C, and 26K pivot relative to the drum-unit frames 23Y, 23M, 23C, and 23K.\",\n \"(10) As shown in FIG.\",\n \"4B, the printer 1 of the first embodiment is provided with the detectors 110Y, 110M, 110C, and 110K for detecting the quantity of toner in the respective second conveying tubes 98Y, 98M, 98C, and 98K.\",\n \"Hence, the detectors 110Y, 110M, 110C, and 110K can detect whether toner is present in the respective second conveying tubes 98Y, 98M, 98C, and 98K.\",\n \"(11) As shown in FIG.\",\n \"5, the urging members 120RY, 120RM, 120RC and 120RK and the urging members 120LY, 120LM, 120LC, and 120LK are respectively provided with the engaging surfaces 125Y, 125M, 125C, and 125K.\",\n \"The engaging surfaces 125Y, 125M, 125C, and 125K slope upward toward the left.\",\n \"Therefore, when the process cartridges 17Y, 17M, 17C, and 17K are mounted in the main casing 2, the first support parts 78Y, 78M, 78C, 78K engage with the engaging surfaces 125Y, 125M, 125C, and 125K of the respective urging members 120RY, 120RM, 120RC and 120RK and the second support parts 85Y, 85M, 85C, and 85K engage with the engaging surfaces 125Y, 125M, 125C, and 125K of the respective urging members 120LY, 120LM, 120LC, and 120LK, and together move the process cartridges 17Y, 17M, 17C, and 17K upward.\",\n \"Accordingly, the process cartridges 17Y, 17M, 17C, and 17K can be smoothly engaged with the respective urging members 120RY, 120RM, 120RC and 120RK and urging members 120LY, 120LM, 120LC, and 120LK during mounting of the process cartridges 17Y, 17M, 17C, and 17K in the main casing 2.\",\n \"(12) As shown in FIG.\",\n \"5, each of the urging members 120RY, 120RM, 120RC and 120RK and urging members 120LY, 120LM, 120LC, and 120LK is provided with respective pivoting parts 121 121Y, 121M, 121C, and 121K; engaging parts 123Y, 123M, 123C, and 123K; and tension springs 124Y, 124M, 124C, and 124K.\",\n \"When the process cartridges 17Y, 17M, 17C, and 17K are mounted in the main casing 2, the tension springs 124Y, 124M, 124C, and 124K of the corresponding urging members 120RY, 120RM, 120RC and 120RK urge the first support parts 78Y, 78M, 78C, 78K upward through the base parts 126Y, 126M, 126C, and 126K of the corresponding urging members 120RY, 120RM, 120RC and 120RK.\",\n \"Similarly, the tension springs 124Y, 124M, 124C, and 124K of the corresponding urging members 120LY, 120LM, 120LC, and 120LK urge the second support parts 85Y, 85M, 85C, and 85K upward through the base parts 126Y, 126M, 126C, and 126K of the corresponding urging members 120LY, 120LM, 120LC, and 120LK.\",\n \"This configuration can reliably urge the process cartridges 17Y, 17M, 17C, and 17K upward.\",\n \"(13) As shown in FIG.\",\n \"6, the lower surfaces of the input tubes 66Y, 66M, 66C, 66Y of the respective mounting units 53Y, 53M, 53C, and 53K in which the openings 68Y, 68M, 68C, and 68K are formed slope downward toward the left.\",\n \"As shown in FIG.\",\n \"3, the top surfaces of the first conveying tubes 77Y, 77M, 77C, and 77K in which the openings 70Y, 70M, 70C, and 70K are formed also slope downward toward the left.\",\n \"Thus, the openings 68Y, 68M, 68C, and 68K can be placed smoothly in communication with the openings 70Y, 70M, 70C, and 70K when the process cartridges 17Y, 17M, 17C, and 17K are mounted in the main casing 2.Further, the urging members 120RY, 120RM, 120RC and 120RK and urging members 120LY, 120LM, 120LC, and 120LK urge the process cartridges 17Y, 17M, 17C, and 17K toward the first positioning part 61 and second positioning part 62.In this way, the seals 92Y, 92M, 92C, and 92K provided on the first conveying tubes 77Y, 77M, 77C, and 77K are pressed against the corresponding seals 69Y, 69M, 69C, and 69K provided on the input tubes 66Y, 66M, 66C, and 66K.\",\n \"This arrangement improves the tightness of the seal formed between the seals 92Y, 92M, 92C, and 92K and the corresponding seals 69Y, 69M, 69C, and 69K.\",\n \"(14) As shown in FIG.\",\n \"6, the openings 102Y, 102M, 102C, and 102K formed in the discharge tubes 100Y, 100M, 100C, and 100K are arranged to the right of the openings 70Y, 70M, 70C, and 70K formed in the first conveying tubes 77Y, 77M, 77C, and 77K.\",\n \"In this way, the openings 102Y, 102M, 102C, and 102K and the openings 70Y, 70M, 70C, and 70K can be arranged with good balance in the main casing 2.\",\n \"(15) As shown in FIG.\",\n \"6, the openings 102Y, 102M, 102C, and 102K formed in the discharge tubes 100Y, 100M, 100C, and 100K are arranged to the right of the first positioning part 61.Accordingly, this arrangement prevents interference between the openings 102Y, 102M, 102C, and 102K and the first positioning part 61 when the process cartridges 17Y, 17M, 17C, and 17K are mounted in or removed from the main casing 2.\",\n \"(16) As shown in FIG.\",\n \"3, the first sloped surfaces 84Y, 84M, 84C, and 84K formed on the first support parts 78Y, 78M, 78C, 78K in the process cartridges 17Y, 17M, 17C, and 17K are arranged between the corresponding openings 70Y, 70M, 70C, and 70K and openings 102Y, 102M, 102C, and 102K in the front-rear direction.\",\n \"This arrangement reduces the space required in the printer 1 for arranging the openings 70Y, 70M, 70C, and 70K; openings 102Y, 102M, 102C, and 102K; and urging members 120RY, 120RM, 120RC and 120RK.\",\n \"(17) As shown in FIGS.\",\n \"6 and 7, the connector tubes 172Y, 172M, 172C, and 172K can be moved between the communication position and the non-communication position.\",\n \"With this configuration, the connector tubes 172Y, 172M, 172C, and 172K can be placed in the non-communication position when the process cartridges 17Y, 17M, 17C, and 17K are being mounted in or removed from the main casing 2, thereby preventing the connector tubes 172Y, 172M, 172C, and 172K from interfering with the process cartridges 17Y, 17M, 17C, and 17K.\",\n \"(18) As shown in FIGS.\",\n \"7 and 8, the vertical distance L1 by which the connector tubes 172Y, 172M, 172C, and 172K moves between the communication position and the non-communication position is greater than the vertical distance L2 by which the process cartridges 17Y, 17M, 17C, and 17K move between the first position and the second position.\",\n \"This arrangement can prevent interference between the connector tubes 172Y, 172M, 172C, and 172K and the process cartridges 17Y, 17M, 17C, and 17K by moving the process cartridges 17Y, 17M, 17C, and 17K from their first position to their second position after moving the connector tubes 172Y, 172M, 172C, and 172K from the communication position to the non-communication position.\",\n \"(19) As shown in FIG.\",\n \"7, the connector tubes 172Y, 172M, 172C, and 172K are in their communication position when the cover 8 is in its closed position, and the connector tubes 172Y, 172M, 172C, and 172K are in their non-communication position when the cover 8 is in its open position.\",\n \"Accordingly, the connector tubes 172Y, 172M, 172C, and 172K can be reliably placed at the non-communication position when mounting or removing the process cartridges 17Y, 17M, 17C, and 17K relative to the main casing 2.12.Second Embodiment Next, a printer 1A according to a second embodiment will be described with reference to FIGS.\",\n \"9 and 10, wherein like parts and components are designated with the same reference numerals to avoid duplicating description.\",\n \"In the first embodiment described above, the process cartridges 17Y, 17M, 17C, and 17K are urged toward the first positioning part 61 and second positioning part 62 by the urging members 120RY, 120RM, 120RC and 120RK and urging members 120LY, 120LM, 120LC, and 120LK.\",\n \"In the second embodiment shown in FIG.\",\n \"9, the main casing 2 is provided with a linkage 250 that can urge the process cartridges 17Y, 17M, 17C, and 17K toward the first positioning part 61 and second positioning part 62.The linkage 250 specifically includes a plate 251, a first linking member 252, a second linking member 253, a first spring 261, and a second spring 262.The plate 251 is disposed above the center plate 52.The plate 251 has a flat plate shape that is generally rectangular in a plan view and elongated in the left-right direction.\",\n \"The plate 251 has a right edge engageable with the left surface of the cover 8.The plate 251 has a left edge engageable with the right surface of the second side plate 55.The process cartridges 17Y, 17M, 17C, and 17K are supported on the plate 251.The first linking member 252 is disposed below a right end portion of the plate 251.The first linking member 252 has a general bar shape, with one end of the first linking member 252 attached to the right end portion of the plate 251 so as to be capable of rotating relative thereto, and the other end attached to a right end portion of the center plate 52 so as to be capable of rotating relative thereto.\",\n \"The second linking member 253 is disposed below a left end portion of the plate 251.The second linking member 253 has a general bar shape, with one end of the second linking member 253 attached to the left end portion of the plate 251 so as to be capable of rotating relative thereto, and the other end attached to a left end portion of the center plate 52 so as to be capable of rotating relative thereto.\",\n \"The first spring 261 is disposed above the right end portion of the plate 251.The first spring 261 is configured of a helical spring, with its bottom end engaged in the plate 251.The second spring 262 is disposed above the left end portion of the plate 251.The second spring 262 is configured of a helical spring, with its bottom end engaged in the plate 251.When mounted in the main casing 2, the process cartridges 17Y, 17M, 17C, and 17K are positioned above the plate 251.At this time, the right ends of the process cartridges 17Y, 17M, 17C, and 17K are urged toward the first positioning part 61 by the first spring 261, and the left ends of the process cartridges 17Y, 17M, 17C, and 17K are urged toward the second positioning part 62 by the second spring 262.When the cover 8 is moved to its open position while the process cartridges 17Y, 17M, 17C, and 17K are mounted in the main casing 2, the weight of the process cartridges 17Y, 17M, 17C, and 17K causes the first linking member 252 and second linking member 253 to pivot counterclockwise in FIG.\",\n \"10 so that the plate 251 moves diagonally downward and rightward.\",\n \"As a result, the process cartridges 17Y, 17M, 17C, and 17K move from their first position to their second position.\",\n \"Conversely, when the cover 8 is moved from this state to its closed position, the left surface of the cover 8 pushes the right end portion of the plate 251 leftward, as illustrated in FIG.\",\n \"9.Accordingly, the first linking member 252 and the second linking member 253 pivot clockwise in FIG.\",\n \"9, and the plate 251 moves diagonally upward and leftward.\",\n \"The printer 1A according to the second embodiment can obtain the same operational and technical advantages as those described in the first embodiment.\",\n \"Further, with the printer 1A according to the second embodiment, the linkage 250 can associate the opening and closing operations of the cover 8 with the operations for moving the process cartridges 17Y, 17M, 17C, and 17K between the first position and second position, as shown in FIGS.\",\n \"9 and 10.Accordingly, the process cartridges 17Y, 17M, 17C, and 17K can be reliably placed in their second position when the cover 8 is placed in its open position.\",\n \"13.Variations of the Embodiments In the embodiments described above, the printer 1(1A) is provided with the drum cleaning blades 96Y, 96M, 96C, and 96K as an example of the cleaning member.\",\n \"However, in place of the drum cleaning blades 96Y, 96M, 96C, and 96K, the printer 1(1A) may be provided with cleaning rollers or cleaning brushes that contact the photosensitive drums 24Y, 24M, 24C, and 24K.\",\n \"While the description has been made in detail with reference to specific embodiments thereof, it would be apparent to those skilled in the art that various changes and modifications may be made therein without departing from the scope of the above described embodiments.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875746"}}},{"rowIdx":4494963,"cells":{"text":{"kind":"list like","value":[["PROJECTION EXPOSURE METHODS AND SYSTEMS","Projection exposure methods, systems, sub-systems and components are disclosed.","Methods can include performing a first exposure to image a first sub-pattern of the pattern, where the first sub-pattern includes a plurality of first features extending in a first direction and spaced apart essentially periodically at a predominant periodicity length P in a second direction perpendicular to the first direction.","The first exposure can be performed using a multipolar illumination mode that includes at least one substantially dipolar intensity distribution having two illumination poles positioned on a pole orientation axis substantially parallel to the second direction and spaced apart from each other."],["1.-25.","(canceled) 26.An illumination system, comprising: a plurality of optical elements constructed and arranged to receive primary radiation emitted from a light source and to generate illumination radiation incident on a mask bearing a pattern, a pupil shaping unit configured to generate a defined multipolar intensity distribution corresponding to a selected illumination mode in a pupil surface of the illumination system during use, wherein: the multipolar intensity distribution comprises a quadrupolar intensity distribution having four illumination poles positioned on two pole orientation axes and spaced apart from one another; and the poles of the quadrupolar intensity distribution each have a lenticular pole shape defined by an overlapping zone of two circles with equal unit radius having a distance between the centers of the circles.","27.The illumination system according to claim 26, wherein the poles of the quadrupolar intensity distribution each have a pole dimension ratio PDR=PH/PW between a pole height PH and a pole width PW according to PDROPT−20%≤PDR≤PDROPT+20% where PDROPT=sin (α)/(1−cos(α)), α is a half pole angle, the pole width PW is measured between an inner pole edge and an outer pole edge in a direction parallel to the pole orientation axis, and the pole height is measured between pole edges in a direction perpendicular to the pole orientation axis.","28.The illumination system of claim 26, wherein the pupil-shaping unit comprises an array of individual elements.","29.The illumination system of claim 28, wherein the individual elements comprise diffraction gratings.","30.The illumination system of claim 28, wherein the individual elements comprise mirrors.","31.The illumination system of claim 26, wherein the pupil-shaping unit comprises an optical modulation device configured to controllably change an angular distribution of radiation incident on the optical modulation device such that a desired intensity distribution is obtained in the pupil surface of the illumination system.","32.The illumination system of claim 31, wherein the optical modulation device has an array of individual elements configured to be driven individually to change the angular distribution of radiation incident on the individual elements.","33.The illumination system of claim 32, wherein the individual elements comprise mirrors.","34.The illumination system of claim 32, wherein the individual elements comprise diffractive optical elements or acousto-optical elements.","35.The illumination system according to claim 26, further comprising a blocking device arranged at or close to the pupil surface of the illumination system where the basic intensity distribution is generated, or at or close to a pupil surface optically conjugate thereto; and the blocking device is designed to block areas of the basic intensity distribution which lie outside the region desired for the pole shape.","36.The illumination system according to claim 26, wherein the pupil shaping unit further comprises a zoom lens group configured to provide a continuously variable magnification during use.","37.The illumination system according to claim 26, wherein the pupil shaping unit further comprises a pair of axicon elements having axicon surfaces, one concave and one convex, wherein at least one of the axicon elements is movable along an optical axis of the illumination system to allow adjusting a distance between the axicon surfaces.","38.An apparatus, comprising: an illumination system configured so that during use the illumination system guides radiation along an illumination path to generate illumination radiation incident on a mask bearing a pattern; and a projection objective configured so that during use the projection objective projects an image of the pattern onto a radiation-sensitive substrate with projection radiation guided along a projection path, wherein the apparatus is a projection exposure apparatus, and the illumination system is configured according to claim 26.39.An illumination system, comprising: a plurality of optical elements constructed and arranged to receive primary radiation emitted from a light source and to generate illumination radiation incident on a mask bearing a pattern, a pupil shaping unit configured to generate a defined multipolar intensity distribution corresponding to a selected illumination mode in a pupil surface of the illumination system during use, wherein: the pattern comprises features spaced apart periodically at a predominant periodicity length P where the condition 0.7λ/NA<P<λ/NA holds; the multipolar intensity distribution comprises a dipolar intensity distribution having two illumination poles positioned on a pole orientation axis and spaced apart from each other at a distance d<λ/(P*NA), where λ is a nominal operation wavelength of radiation used, and NA is an image-side numerical aperture of a projection optical system used; and the poles of the dipolar intensity distribution each have a pole shape selected from the group consisting of: a generally biconvex pole shape with a pole dimension ratio PDR=PH/PW>1 between a pole height PH and a pole width PW, where the pole width PW is measured between an inner edge and an outer pole edge in a direction parallel to the pole orientation axis, and the pole height PH is measured between inner and outer pole edges in a direction perpendicular to the pole orientation axis; and a substantially lenticular pole shape defined by two convexly curved edges having opposite sense of curvature and centres of curvature essentially on a line parallel to the pole orientation axis; and the poles of the dipolar intensity distribution each have a pole dimension ratio PDR=PH/PW according to PDROPT−20%≤PDR≤PDROPT+20% where PDROPT=sin (α)/(1−cos(α)), α is a half pole angle, PW is measured between an inner pole edge and an outer pole edge in a direction parallel to the pole orientation axis, and PH is measured between pole edges in a direction perpendicular to the pole orientation axis.","40.The illumination system of claim 39, wherein the pupil-shaping unit comprises an array of individual elements.","41.The illumination system of claim 40, wherein the individual elements comprise diffraction gratings.","42.The illumination system of claim 40, wherein the individual elements comprise mirrors.","43.The illumination system of claim 40, wherein the individual elements are configured to be controlled individually in order to change an angular distribution of radiation influenced by the individual elements.","44.The illumination system of claim 40, wherein during use: the array of individual elements is configured to generate a basic intensity distribution including areas of the poles of the dipolar intensity distribution and extending beyond the areas of the poles; the illumination system further comprises a blocking device arranged at or close to the pupil surface of the illumination system where the basic intensity distribution is generated, or at or close to a pupil surface optically conjugate thereto; and the blocking device is designed to block areas of the basic intensity distribution which lie outside the region desired for the pole shape.","45.The illumination system of claim 39, wherein the pupil shaping unit further comprises a zoom lens group configured to provide a continuously variable magnification during use.","46.The illumination system of claim 45, wherein the zoom lens group is arranged between the array of individual elements and the pupil surface of the illumination system.","47.The illumination system of claim 39, wherein the pupil shaping unit further comprises a pair of axicon elements having axicon surfaces, one concave and one convex, wherein at least one of the axicon elements is movable along an optical axis of the illumination system to allow adjusting a distance between the axicon surfaces.","48.The illumination system of claim 47, wherein the axicon group is arranged between the array of individual elements and the pupil surface of the illumination system.","49.An apparatus, comprising: an illumination system configured so that during use the illumination system guides radiation along an illumination path to generate illumination radiation incident on a mask bearing a pattern; and a projection objective configured so that during use the projection objective projects an image of the pattern onto a radiation-sensitive substrate with projection radiation guided along a projection path, wherein the apparatus is a projection exposure apparatus, and the illumination system is configured according to claim 39."],["<SOH> BACKGROUND <EOH>Microlithographic projection exposure methods are used for fabricating semiconductor components and other finely structured components.","Use is made of masks (reticles) that bear the pattern of a structure to be imaged, for example a line pattern of a layer of a semiconductor component, such as an integrated circuit (IC).","A mask is positioned in a projection exposure system between an illumination system and projection objective in the region of the object surface of the projection objective, and illuminated with illumination radiation provided by the illumination system.","The radiation varied by the mask and the pattern forms projection radiation propagating through the projection objective, which images the pattern of the mask onto the substrate to be exposed, which normally bears a radiation-sensitive layer (photoresist).","In some cases, the pattern of the mask is illuminated with radiation from an effective source having an intensity distribution at a pupil plane of the illumination system corresponding to a particular illumination mode.","An image of the illuminated mask is projected onto a resist-coated semiconductor wafer."],["<SOH> SUMMARY <EOH>In some embodiments, the disclosure provides projection exposure methods and systems that can provide improved long-term stability of optical performance when multipole illumination, such as dipole illumination, is used.","In certain embodiments, the disclosure provides projection exposure methods and systems that can allow imaging of patterns having predominant periodic features running in a first direction at high contrast, while at the same time other sub-patterns including features running at an angle to the first direction may still be imaged with sufficient detail.","In one aspect, the disclosure generally provides a method of imaging a pattern onto a substrate provided with a layer of a radiation-sensitive material.","The method includes performing an exposure to image a first sub-pattern of the pattern, where the first sub-pattern includes a plurality of first features extending in a first direction and spaced apart essentially periodically at a predominant periodicity length P in a second direction perpendicular to the first direction.","The exposure is performed using a multipolar illumination mode that includes at least one a substantially dipolar intensity distribution having two illumination poles positioned on a pole orientation axis substantially parallel to the second direction and spaced apart from each other.","The poles of the dipolar intensity distribution each have an azimuthal width defined by a pole angle θ, and a pole area A POLE according to: in-line-formulae description=\"In-line Formulae\" end=\"lead\"?","0.6< A POLE /A OPT <1.1 in-line-formulae description=\"In-line Formulae\" end=\"tail\"?","where A OPT =θ−sin (θ) and where cos(θ/2)=λ/(2*P*NA), where λ is a nominal operation wavelength of radiation used for the first exposure and NA is an image-side numerical aperture of a projection optical system used for the first exposure.","The spatial intensity distribution at a pupil plane of the illumination system representing the effective source of radiation incident on the mask pattern can be optimized considering at least two different criteria.","A first criterion relates to the angles of incidence (or illumination directions) provided by the effective source in view of the particular sub-pattern to be exposed, which is characterized by first features extending in a first direction and spaced apart essentially periodically at the predominant periodicity length P in the second direction.","Under these conditions, an optimized illumination (optimized for contrast in an appropriate focus range determined by the depth of focus (DOF)) would generally provide only those illumination directions which could contribute to the imaging process for the detail of interest, which is characterized by periodicity length P. Where two-beam interference beyond the coherent resolution limit is desired to optimize resolution, the illumination directions allowing high contrast two-beam interference correspond to certain areas in the pupil of the illumination system.","Those areas including all useful illumination directions (to obtain maximum contrast) generally define areas in the pupil surface having a lenticular shape resulting from an overlapping zone of two circles with equal unit radius having a distance d between the centers of the circles.","Illumination directions corresponding to pupil locations outside these useful lens-shaped areas generally do not contribute to the desired two-beam interference and might in fact blur a resulting image.","Those lenticular useful areas including all illumination directions contributing constructively to two-beam interference may be characterized by their size and correspond to a pole area (e.g., an optimum pole area) A OPT in a conjugated exit pupil of the projection optical system used for the exposure method.","The second criterion regards the illumination angles actually used in an exposure process.","It has been found that known systems employing dipole illumination typically use only a small fraction of the illumination angles which might theoretically be used to form a high-contrast image with two-beam interference.","For example, small poles with circular shape or poles having the shape of a segment of an annulus have been used.","Whereas those small poles of dipole illumination may be acceptable from a contrast point of view if only “useful” illumination directions are used, drawbacks in respect to overall performance may result if light energy is concentrated on correspondingly small areas on optical surfaces at or close to a pupil surface within the exposure system.","Those local energy concentrations may cause or contribute to “lens heating” and associated time-dependent fluctuations of performance of the exposure system.","Such issues can be addressed and at least partly avoided by providing illumination modes including at least one substantially dipolar intensity distribution with poles having optimized pole size and pole shape such that the pole area of such poles and/or the shape of the poles is close to the pole area and/or the pole shape.","Where the condition 0.6<A POLE /A OPT <1.1 is fulfilled for a pole area, light energy within a pupil surface may be distributed over relatively large area fractions of the pupil essentially without trade-off between attainable contrast and intensity.","Distributing light energy over larger local areas instead of smaller local areas has been found to significantly reduce detrimental effects of lens heating and associated effects on the performance.","Where the pole area becomes significantly smaller than the lower limit a concentration of radiation energy in a relatively small area may result, which may cause problems associated with inhomogenous lens heating.","Where the pole area becomes significantly larger than the upper limit, a corresponding distribution of illumination directions may include larger fractions of illumination direction not constructively contributing to a desired contrast, which may be undesirable.","In some embodiments, the poles of the dipolar intensity distribution have a generally biconvex shape with a pole dimension ratio PDR=PH/PW>1 between a pole height PH and a pole width PW, where the pole width PW is measured between an inner and an outer pole edge in a direction parallel to the pole orientation axis and the pole height PH is measured between pole edges in a direction perpendicular to the pole orientation axis.","At least one of the conditions PDR>1.2, PDR>1.4, PDR>1.6, PDR>1.8, PDR>2.0, PDR>3.0 and PDR>3.5 may be fulfilled.","For example, a generally biconvex shape may be defined by a convex polygon having four or more sides, at least some of the sides including angles significantly larger than 90°, for example 120° or more.","In certain embodiments, the poles of the dipolar intensity distribution have a substantially lenticular pole shape.","The shape of a “planar circular two-angle” may be well approximated by a lenticular pole shape.","A planar circular two-angle may be bound by two segments of a circle with opposite sense of curvature, where the segments intersect at intersection points forming the two “corners” of a “two-angle”.","The segments of the circle delimiting the pole shape may have the same radius of curvature.","In some embodiments, the poles of the dipolar intensity distribution have a parallelogram pole shape.","A pole defined by two pairs of mutually parallel sides including non-rectangular angles may be optimized to fit closely to the shape of a pole area.","The pole shape may be the shape of a rhombus (or rhomb), which is a quadrilateral in which all of the sides are of equal length (equilateral quadrangle).","The shape may be described as a diamond or lozenge.","In certain embodiments, the poles of the dipolar intensity distribution each have a pole dimension ratio PDR=PH/PW between a pole height PH and a pole width PW according to in-line-formulae description=\"In-line Formulae\" end=\"lead\"?","PDR OPT −20%≤PDR≤PDR OPT +20% in-line-formulae description=\"In-line Formulae\" end=\"tail\"?","where PDR OPT =sin (α)/(2*(1−cos(α)) and where the pole width PW is measured between an inner and an outer pole edge in a direction parallel to the pole orientation axis and the pole height PH is measured between pole edges in a direction perpendicular to the pole orientation axis.","If this condition is fulfilled, a desirable balance may be obtained between a high contrast and a relatively large area where incident radiation energy is distributed at optical elements relatively close to a pupil surface.","The disclosure also relates to an illumination system configured to generate and use the large pole illumination settings described above, and to a projection exposure apparatus including such an illumination system.","In some embodiments, the disclosure provides an illumination system that includes a plurality of optical elements constructed and arranged to receive primary radiation emitted from a primary light source and to generate illumination radiation incident on a mask bearing a pattern.","A number of the optical elements form a pupil shaping unit configured to generate a defined spatial intensity distribution corresponding to a selected illumination mode in a pupil surface of the illumination system.","The spatial intensity distribution being a multipolar intensity distribution includes at least one substantially dipolar intensity distribution having two illumination poles positioned on a pole orientation axis and spaced apart from each other.","The poles of the dipolar intensity distribution each have have a pole shape selected from: a generally biconvex pole shape with a pole dimension ratio PDR=PH/PW>1 between a pole height PH and a pole width PW, where the pole width PW is measured between an inner and an outer pole edge in a direction parallel to the pole orientation axis and the pole height PH is measured between pole edges in a direction perpendicular to the pole orientation axis; a generally biconvex pole shape defined by a convex polygon having four or more sides, where some of the sides include angles larger than 90°; a parallelogram pole shape defined by a non-rectangular parallelogram having a shorter diagonal and a longer diagonal, where the shorter diagonal extends substantially parallel to a line parallel to the pole orientation axis; and a substantially lenticular pole shape defined by two convexly curved edges having opposite sense of curvature and centres of curvature essentially on a line parallel to the pole orientation axis.","While reference is made to the use of the projection exposure method and apparatus in the manufacture of integrated circuits, more generally the method and apparatus may also be used in other applications, such as in the manufacture of integrated optical systems, guidance and detection patterns for magnetic domain memories, liquid-crystal display panels, thin-film magnetic heads, etc.","The individual features may be implemented either alone or in combination as embodiments, or may be implemented in other fields of application.","Further, they may represent advantageous embodiments that are protectable in their own right, for which protection is claimed in the application as filed or for which protection will be claimed during pendency of the application."],["CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of, and claims benefit under 35 USC 120 to, U.S. application Ser.","No.","14/556,432, filed Dec. 1, 2014, now U.S. Pat.","No.","9,885,958, which is a continuation of, and claims benefit under 35 USC 120 to, U.S. application Ser.","No.","12/483,733, filed Jun.","12, 2009, now U.S. Pat.","No.","8,917,379, which is a continuation of, and claims benefit under 35 USC 120 to, international application PCT/EP2007/001574, filed Feb. 23, 2007, which claims benefit of European Application No.","07000731.5, filed Jan. 16, 2007 and U.S. Ser.","No.","60/880,447, filed Jan. 16, 2007.U.S.","application Ser.","Nos.","14/556,432, 12/483,733 and international application PCT/EP2007/001574 are hereby incorporated by reference in their entirety.","FIELD The disclosure relates to projection exposure methods, systems, sub-systems and components.","BACKGROUND Microlithographic projection exposure methods are used for fabricating semiconductor components and other finely structured components.","Use is made of masks (reticles) that bear the pattern of a structure to be imaged, for example a line pattern of a layer of a semiconductor component, such as an integrated circuit (IC).","A mask is positioned in a projection exposure system between an illumination system and projection objective in the region of the object surface of the projection objective, and illuminated with illumination radiation provided by the illumination system.","The radiation varied by the mask and the pattern forms projection radiation propagating through the projection objective, which images the pattern of the mask onto the substrate to be exposed, which normally bears a radiation-sensitive layer (photoresist).","In some cases, the pattern of the mask is illuminated with radiation from an effective source having an intensity distribution at a pupil plane of the illumination system corresponding to a particular illumination mode.","An image of the illuminated mask is projected onto a resist-coated semiconductor wafer.","SUMMARY In some embodiments, the disclosure provides projection exposure methods and systems that can provide improved long-term stability of optical performance when multipole illumination, such as dipole illumination, is used.","In certain embodiments, the disclosure provides projection exposure methods and systems that can allow imaging of patterns having predominant periodic features running in a first direction at high contrast, while at the same time other sub-patterns including features running at an angle to the first direction may still be imaged with sufficient detail.","In one aspect, the disclosure generally provides a method of imaging a pattern onto a substrate provided with a layer of a radiation-sensitive material.","The method includes performing an exposure to image a first sub-pattern of the pattern, where the first sub-pattern includes a plurality of first features extending in a first direction and spaced apart essentially periodically at a predominant periodicity length P in a second direction perpendicular to the first direction.","The exposure is performed using a multipolar illumination mode that includes at least one a substantially dipolar intensity distribution having two illumination poles positioned on a pole orientation axis substantially parallel to the second direction and spaced apart from each other.","The poles of the dipolar intensity distribution each have an azimuthal width defined by a pole angle θ, and a pole area APOLE according to: 0.6<APOLE/AOPT<1.1 where AOPT=θ−sin (θ) and where cos(θ/2)=λ/(2*P*NA), where λ is a nominal operation wavelength of radiation used for the first exposure and NA is an image-side numerical aperture of a projection optical system used for the first exposure.","The spatial intensity distribution at a pupil plane of the illumination system representing the effective source of radiation incident on the mask pattern can be optimized considering at least two different criteria.","A first criterion relates to the angles of incidence (or illumination directions) provided by the effective source in view of the particular sub-pattern to be exposed, which is characterized by first features extending in a first direction and spaced apart essentially periodically at the predominant periodicity length P in the second direction.","Under these conditions, an optimized illumination (optimized for contrast in an appropriate focus range determined by the depth of focus (DOF)) would generally provide only those illumination directions which could contribute to the imaging process for the detail of interest, which is characterized by periodicity length P. Where two-beam interference beyond the coherent resolution limit is desired to optimize resolution, the illumination directions allowing high contrast two-beam interference correspond to certain areas in the pupil of the illumination system.","Those areas including all useful illumination directions (to obtain maximum contrast) generally define areas in the pupil surface having a lenticular shape resulting from an overlapping zone of two circles with equal unit radius having a distance d between the centers of the circles.","Illumination directions corresponding to pupil locations outside these useful lens-shaped areas generally do not contribute to the desired two-beam interference and might in fact blur a resulting image.","Those lenticular useful areas including all illumination directions contributing constructively to two-beam interference may be characterized by their size and correspond to a pole area (e.g., an optimum pole area) AOPT in a conjugated exit pupil of the projection optical system used for the exposure method.","The second criterion regards the illumination angles actually used in an exposure process.","It has been found that known systems employing dipole illumination typically use only a small fraction of the illumination angles which might theoretically be used to form a high-contrast image with two-beam interference.","For example, small poles with circular shape or poles having the shape of a segment of an annulus have been used.","Whereas those small poles of dipole illumination may be acceptable from a contrast point of view if only “useful” illumination directions are used, drawbacks in respect to overall performance may result if light energy is concentrated on correspondingly small areas on optical surfaces at or close to a pupil surface within the exposure system.","Those local energy concentrations may cause or contribute to “lens heating” and associated time-dependent fluctuations of performance of the exposure system.","Such issues can be addressed and at least partly avoided by providing illumination modes including at least one substantially dipolar intensity distribution with poles having optimized pole size and pole shape such that the pole area of such poles and/or the shape of the poles is close to the pole area and/or the pole shape.","Where the condition 0.6<APOLE/AOPT<1.1 is fulfilled for a pole area, light energy within a pupil surface may be distributed over relatively large area fractions of the pupil essentially without trade-off between attainable contrast and intensity.","Distributing light energy over larger local areas instead of smaller local areas has been found to significantly reduce detrimental effects of lens heating and associated effects on the performance.","Where the pole area becomes significantly smaller than the lower limit a concentration of radiation energy in a relatively small area may result, which may cause problems associated with inhomogenous lens heating.","Where the pole area becomes significantly larger than the upper limit, a corresponding distribution of illumination directions may include larger fractions of illumination direction not constructively contributing to a desired contrast, which may be undesirable.","In some embodiments, the poles of the dipolar intensity distribution have a generally biconvex shape with a pole dimension ratio PDR=PH/PW>1 between a pole height PH and a pole width PW, where the pole width PW is measured between an inner and an outer pole edge in a direction parallel to the pole orientation axis and the pole height PH is measured between pole edges in a direction perpendicular to the pole orientation axis.","At least one of the conditions PDR>1.2, PDR>1.4, PDR>1.6, PDR>1.8, PDR>2.0, PDR>3.0 and PDR>3.5 may be fulfilled.","For example, a generally biconvex shape may be defined by a convex polygon having four or more sides, at least some of the sides including angles significantly larger than 90°, for example 120° or more.","In certain embodiments, the poles of the dipolar intensity distribution have a substantially lenticular pole shape.","The shape of a “planar circular two-angle” may be well approximated by a lenticular pole shape.","A planar circular two-angle may be bound by two segments of a circle with opposite sense of curvature, where the segments intersect at intersection points forming the two “corners” of a “two-angle”.","The segments of the circle delimiting the pole shape may have the same radius of curvature.","In some embodiments, the poles of the dipolar intensity distribution have a parallelogram pole shape.","A pole defined by two pairs of mutually parallel sides including non-rectangular angles may be optimized to fit closely to the shape of a pole area.","The pole shape may be the shape of a rhombus (or rhomb), which is a quadrilateral in which all of the sides are of equal length (equilateral quadrangle).","The shape may be described as a diamond or lozenge.","In certain embodiments, the poles of the dipolar intensity distribution each have a pole dimension ratio PDR=PH/PW between a pole height PH and a pole width PW according to PDROPT−20%≤PDR≤PDROPT+20% where PDROPT=sin (α)/(2*(1−cos(α)) and where the pole width PW is measured between an inner and an outer pole edge in a direction parallel to the pole orientation axis and the pole height PH is measured between pole edges in a direction perpendicular to the pole orientation axis.","If this condition is fulfilled, a desirable balance may be obtained between a high contrast and a relatively large area where incident radiation energy is distributed at optical elements relatively close to a pupil surface.","The disclosure also relates to an illumination system configured to generate and use the large pole illumination settings described above, and to a projection exposure apparatus including such an illumination system.","In some embodiments, the disclosure provides an illumination system that includes a plurality of optical elements constructed and arranged to receive primary radiation emitted from a primary light source and to generate illumination radiation incident on a mask bearing a pattern.","A number of the optical elements form a pupil shaping unit configured to generate a defined spatial intensity distribution corresponding to a selected illumination mode in a pupil surface of the illumination system.","The spatial intensity distribution being a multipolar intensity distribution includes at least one substantially dipolar intensity distribution having two illumination poles positioned on a pole orientation axis and spaced apart from each other.","The poles of the dipolar intensity distribution each have have a pole shape selected from: a generally biconvex pole shape with a pole dimension ratio PDR=PH/PW>1 between a pole height PH and a pole width PW, where the pole width PW is measured between an inner and an outer pole edge in a direction parallel to the pole orientation axis and the pole height PH is measured between pole edges in a direction perpendicular to the pole orientation axis; a generally biconvex pole shape defined by a convex polygon having four or more sides, where some of the sides include angles larger than 90°; a parallelogram pole shape defined by a non-rectangular parallelogram having a shorter diagonal and a longer diagonal, where the shorter diagonal extends substantially parallel to a line parallel to the pole orientation axis; and a substantially lenticular pole shape defined by two convexly curved edges having opposite sense of curvature and centres of curvature essentially on a line parallel to the pole orientation axis.","While reference is made to the use of the projection exposure method and apparatus in the manufacture of integrated circuits, more generally the method and apparatus may also be used in other applications, such as in the manufacture of integrated optical systems, guidance and detection patterns for magnetic domain memories, liquid-crystal display panels, thin-film magnetic heads, etc.","The individual features may be implemented either alone or in combination as embodiments, or may be implemented in other fields of application.","Further, they may represent advantageous embodiments that are protectable in their own right, for which protection is claimed in the application as filed or for which protection will be claimed during pendency of the application.","BRIEF DESCRIPTION OF THE DRAWINGS FIG.","1 illustrates schematically the principle of symmetric off-axis illumination; FIGS.","2A-2D show schematically various illumination modes; FIG.","3 illustrates schematically a projection exposure system configured for dipole illumination mode with lenticular poles; FIG.","4 illustrates schematically a circular pupil of a projection objective at imaging conditions beyond the coherent resolution limit using symmetric two-beam interference imaging conditions; FIGS.","5A-5C illustrate where the poles of the dipolar intensity distribution each have a lenticular pole shape; FIGS.","6A-6B illustrate schematically the use of a mask to generate biconvex, lenticular illumination poles in a modified conventional illumination system; FIGS.","7A-7B show poles of a dipolar intensity distribution having a parallelogram pole shape; FIG.","8 shows a meridional section of an illumination system configured to generate large polses in a projection exposure step-and-scan apparatus; FIGS.","9A-9B show schematically a detail of a first raster element configured to generate a substantially dipolar intensity distribution having two illumination poles each having a diamond shape as shown in FIG.","7; FIGS.","10A-10B show diagrams illustrating improvements on lens heating induced wavefront phase errors obtained by illuminating with large poles; and FIG.","11 shows dipole illumination with lenticular poles used for double patterning.","FIG.","12 shows illumination.","DETAILED DESCRIPTION In the following description, similar or identical features shown in different figures are designated with the same reference identifications, where appropriate.","In optical lithography it is known to use off-axis illumination, which enables smaller features to be faithfully imaged.","With this technique, a mask providing the patterned structure (pattern) is illuminated at oblique (non-perpendicular) angles such that process latitude is improved by increasing the depth of focus and/or such that contrast is improved.","FIG.","1 illustrates this principle in which a beam B of radiation is incident on a mask M carrying a pattern PAT at an opening angle γ inclined to the optical axis OA, which is conventionally vertical.","The incident beam B is diffracted by features of the pattern PAT on the mask M, which are to be imaged onto the wafer W coated by a layer of photoresist RES.","The zeroth and two first-order-diffracted beams (0, ±1) are shown in FIG.","1.Improved performance can be achieved when, for example, at least part of the zeroth order and one of the first orders, which are coherent, are captured by the projection objective PO and used to form the image on the wafer W. The smaller the pitch P (or periodicity length) of features of the pattern on the mask M, the larger the diffraction angle β will be according to β=λ/P, where λ is the nominal operating wavelength of radiation in beam B.","If the size of the features decreases and/or their density increases too much, there will come a point at which the pupil of the projection objective PO can no longer capture more than one diffracted order.","In practical systems there will be a range of opening angles γ which determines the partial coherence of the light source and thus is important to the figures of merit of the exposure process, such as exposure latitude, depth of focus and proximity effects.","The distribution of opening angles γ can be visualized by considering the intensity distribution of the effective radiation source (effective source) or equivalently the intensity distribution in the plane of a pupil of the projection objective.","FIGS.","2A-2D show representative examples.","FIG.","2A illustrates a simple on-axis illumination mode characterized by the parameter σ shown by an arrow in the figure.","Values of σ (often referred to as coherence factor) are conventionally quoted as the ratio of the radius of the illumination intensity disc (hatched) to the radius of the pupil and therefore take a value between 0 and 1.FIG.","2B shows an annular illumination mode in which the intensity distribution of the source is confined to an annulus to limit the range of angles of incidence of the off-axis illumination, considering that the spatial intensity distribution at the pupil plane is related to the angular distribution at the mask plane, which is a Fourier transform plane to the pupil plane.","The annulus may be characterized by the values σi and σo, which are the ratios of its inner and outer radii to the radius of the pupil.","FIG.","2C illustrates the intensity distribution of the quadrupole illumination mode, the use of which sometimes gives improved imaging results to the use of annular or coherent modes.","Conventionally, in using such a quadrupole configuration, it is assumed that the patterned structure of the mask to be projected includes sub-patterns of orthogonal lines along x and y axes and the illumination is oriented such that each of the four poles is situated in a respective one of the four quadrants defined by these x and y axes and at their point of intersection.","In specific applications it has been found that superior performance can be obtained using dipolar illumination modes.","FIG.","2D shows an example of the dipolar illumination intensity distribution for a dipole mode.","The two poles POLE1, POLE2 of this mode are located off the optical axis OA of the imaging system.","For illustrative purposes, the two poles illustrated in FIG.","2D are said to lie along the x axis (second direction) and may be optimal for imaging lines extending parallel to the y axis (first direction), i.e.","perpendicular to the pole orientation axis POA joining the two poles.","Sometimes the x and y axis are referred to as horizontal and vertical, respectively, but these terms typically do not bear any relation to the orientation of the machine.","As illustrated in FIG.","2D the pole shape of the poles POLE1, POLE2 in conventional systems may correspond to an azimuthal section of an annulus.","Due to the desire that the first diffraction order should pass completely through the aperture of the projection objective to obtain maximum contrast, limitations result for the radial width Δσ=σo−σi of the poles and for the azimuthal width (width in circumferential direction) of the poles defined by the pole angle Θ.","With dipole illumination, the effective light source is confined to two poles, in order to create the conditions for two-beam imaging with theoretical ideal contrast.","FIG.","3 illustrates schematically a projection exposure system configured for dipole illumination mode.","Primary radiation provided by a primary light source LS is transformed by an illumination system ILL to provide illumination radiation incident on a mask M bearing a pattern PAT.","The radiation is diffracted by pattern PAT and forms projection radiation propagating through the projection objective PO, which images the pattern of the mask onto the substrate, which is a wafer W coated with a resist layer RES in the exemplary embodiment.","The illumination system ILL includes a pupil shaping unit PSU to create an effective source ES formed by a predefined intensity distribution at a pupil plane PILL of the illumination system, where the predefined intensity distribution is a dipole illumination characterized by two lenticular poles POLE1 and POLE2.The pupil plane PILL, where the effective source ES is formed, is a Fourier transform surface with respect to the object surface of the projection objective PO, where the mask M is situated.","Therefore, the spatial distribution of light intensity of the effective source ES determines an angular distribution of illumination radiation incident on the mask M. A condenser system CS is provided to perform the Fourier transformation.","The pupil surface PPO of the projection objective is optically conjugated to the pupil surface PILL of the illumination system.","Therefore, in the absence of a mask, a spatial intensity distribution equivalent to the intensity distribution at the effective source ES may be formed in the pupil surface PPO of the projection objective.","Where a mask bearing a pattern is inserted between the illumination system and the projection objective, the intensity distribution in the pupil plane PPO of the projection objective also contains diffraction information corresponding to the properties of the mask pattern PAT.","FIG.","4 illustrates schematically a circular pupil PPO of a projection objective having unit radius (length=1) corresponding to the utilized image-side numerical aperture NA at imaging conditions beyond the coherent resolution limit of a periodic pattern of mutually parallel lines running in a first direction (y direction) having periodicity length (pitch) P in a second direction (x direction).","A symmetric two-beam interference imaging condition is assumed, where a first diffraction order (+1 or −1) coincides with the zeroth order (0).","In this representation, all illumination directions which contribute constructively to two-beam interference correspond to pupil positions lying within the lenticular (lens-shaped) regions LR at opposite edges of the pupil in the x direction.","Those lenticular regions (also denoted as “planar circular two-angles” result from a partial overlap of circles of equal size corresponding to neighbouring diffraction orders.","A distance d between the centers of the lenticular regions is determined by d=λ/(P*NA).","The angular width of the lenticular area (width in circumferential direction) may be defined by a pole angle θ between the opposing corners of the area in the y direction, where pole angle θ is twice the pole half angle α (i.e.","θ=2*α).","The size of the lenticular area, i.e.","the area AOPT of the hatched lenticular region LR in FIG.","4, may be calculated as AOPT=θ−sin(θ) with cos(α)=d/2=λ/(2*P*NA).","It is contemplated that a maximum contrast is possible if all illumination directions corresponding to pupil positions within the lenticular regions LR are used.","The size AOPT of the lenticular regions may be calculated based on the following considerations explained now in connection with FIG.","4.The area AOPT is four times the difference between the area AS of the circular sector with sector angle α, and the area AABC of triangle ABC indicated in FIG.","4.The difference area AS-AABC is hatched darkly in FIG.","4.Calculating the angles in radians, the sector area AS is calculated as follows: AS=(α/2π)·π·r2, where r=1 is the unit radius of the pupil.","Therefore, AS=(α/2π)·π=α/2.With distance A−C=cos (α) and distance B−C=sin (α) the area AABC of the triangle calculate as: AABC=(sin (α)·cos (α))/2.Further considering that 2·sin (α)·cos (α)=sin (2·α), the area AOPT of the lenticular region LR calculates as follows: A OPT = 4 · ( A S - A ABC ) = 4 · ( α / 2 - ( sin ( α ) · cos ( α ) ) / 2 ) = 2 · α - sin ( 2 · α ) = θ - sin ( θ ) An illumination pole having the size and shape of a desirable (e.g., optimum) lenticular region LR may be characterized by a pole width PW measured between an inner and an outer pole edge in a direction parallel to the pole orientation axis POA, and a pole height PH measured between pole edges in a direction perpendicular to the pole orientation axis, i.e.","in y direction (see FIG.","5A).","Defining a pole dimension ratio PDR as the aspect ratio between pole PH height and pole width PW according to PDR=PH/PW, for the lenticular regions PDROPT=sin(α)/(1−cos(α)).","In conventional systems, only a fraction of those illumination directions is normally used.","For illustration purposes, FIG.","4 shows conventional poles CP having a shape corresponding to an azimuthal section of an annulus within the lenticular regions LR.","Limitations regarding radial width Δσ and pole angle result from the desire that the first diffraction order should fall completely within the aperture of the objective to obtain maximum contrast.","As evident from FIG.","4, the area of the conventional poles CP is significantly smaller than the area AOPT of the lenticular zones which could be used for the imaging process at good (e.g., optimum) contrast.","For example, the size of the conventional poles may be 50% or less of the area AOPT.","The pole dimension ratio PDR of a conventional pole usually differs significantly from the pole dimension ratio PDROPT defined above.","For example, a circular pole would correspond to PDR=1.The annular segment shaped conventional poles CP depicted schematically in FIG.","4 may have varying pole dimension ratio depending on the selected values for Δσ and pole angle.","Generally, as the pole height increases, the pole width will decrease, and vice versa.","Now consider a lens or another optical element having an optical surface at or close to the pupil surface of the projection objective, where light intensity is concentrated at the edge of the lens surface in regions corresponding to the poles of the dipole illumination.","Studies have shown that effects of lens heating may cause characteristic deformations of wavefronts passing the projection objective due to local deformation of the lenses and/or due to localized radiation-induced changes of refractive index.","For example, where a dipolar intensity distribution is used, the local deformation of lenses or other optical elements and associated wavefront deformations may be dominated by astigmatic contributions.","In the following a number of embodiments are described where a multipolar illumination mode includes at least one substantially dipolar intensity distribution having two illumination poles, where the pole area APOLE of poles is selected to be very close to or equal to the pole area AOPT defined above.","Negative effects caused by localized lens heating may be reduced significantly when compared to using conventional poles.","FIGS.","5A-5C illustrate where the poles POLE 1 and POLE 2 of the dipolar intensity distribution each have a lenticular pole shape defined by two convexly curved edges having opposite sense of curvature and centers of curvature essentially on a line parallel to the pole orientation axis POA.","In FIG.","5A the size and shape of the poles is adjusted such that the poles exactly fit the lenticular region LR corresponding to the given pitch P of the sub-pattern to be printed.","The conditions APOLE=AOPT and PDRPOLE=PDROPT hold for the pole area and pole dimension ratio, respectively.","FIG.","5B shows an example where all light intensity is concentrated in poles POLE1, POLE2 slightly smaller than the lenticular area by about 10%.","Although not all illumination directions theoretically contributing to constructive interference are used in this setting, the intensity of the poles is still distributed over a relatively large area on optical surfaces near pupil surfaces to eliminate or alleviate lens heating problems.","In FIG.","5C the size of the poles POLE1, POLE2 is slightly larger than the pole area AOPT of poles such that a small fraction of illumination directions falls outside the pupil, thereby not contributing to imaging, and some illumination angles smaller than the lowest limit of the optimum angular distribution according to FIG.","4 are also present.","As light energy is distributed over relatively large areas around the poles, lens heating problems may be smallest in FIG.","5C with potential trade-offs in attainable contrast.","Optimum compromise settings may be evaluated by simulation or test exposures.","FIGS.","6A-6B illustrate schematically one option to generate biconvex, lenticular (lens-shaped shaped) illumination poles as described above in a modified conventional illumination system configured to generate illumination poles having the shape of a segment of an annulus.","Illumination systems as described e. g. in U.S. Pat.","No.","6,452,662 B2 may be used and modified for that purpose.","The disclosure of U.S. Pat.","No.","6,452,662 B2 and U.S. Pat.","No.","6,855,486 B1 regarding constructive details of illumination systems capable of generating segment shaped pairs of poles are incorporated herein by reference.","The adjustable optical elements of the pupil shaping unit of the illumination system are first set to generate, in a pupil surface of the illumination system, a dipolar intensity distribution having two basic poles BP1 and BP2, each having the shape of a segment of an annulus where the outer radius is set to σO=1 and the width of the annular segment is adjusted such that Δσ corresponds to the desired pole width PW of the desired lenticular pole.","The pole angle θ is set to correspond to the desired pole angle θ of the lenticular pole (FIG.","6A).","It is to be noted that conventional systems may need to be modified with respect to the variation width of adjustable elements to allow for those dimensions of the annular segment shaped poles, which may be larger than poles in the conventional system in both the circumferential and the radial direction.","The illumination system includes a blocking device BD (FIG.","6B) at or close to the pupil surface of the illumination system where the effective source is generated, or at or close to a pupil surface optically conjugate thereto.","The blocking device in this embodiment is designed to block those areas at the inner edge of the annulus segment shaped poles which lie outside the lenticular region desired for the pole shape.","For that purpose, the blocking device may take the general butterfly shape schematically shown in FIG.","6B having “wings” extending in azimuthal direction over an angle θ corresponding to the pole angle, and comprising outer edges concavely curved inwards towards the center of the blocking device to define the inner edge of the lenticular pole.","Those areas actually blocked by the blocking device are drawn with diagonal hatching in FIG.","6A.","When the blocking device is inserted into the appropriate position, the resulting effective light source includes two lenticular poles POLE1 and POLE2 having the pole area AOPT or a slight variation therefrom as described above.","An exchanging device allowing to exchange blocking devices having different layout may be provided to allow variation of dimensions of the lenticular poles.","Also, a blocking device may be designed to be variable, for example by providing a number of smaller blades arranged in the manner of a fan to allow varying the pole angle θ as desired.","The blocking device may also be formed by an opaque coating on a transparent optical element, such as a plate, which may be exchangeable.","In FIGS.","7A-7B the poles of the dipolar intensity distribution have a parallelogram pole shape defined by a non-rectangular parallelogram having a shorter diagonal D2 and a longer diagonal D1, the shorter diagonal extending substantially parallel to a line parallel to the pole orientation axis POA.","FIGS.","7A and 7B each show the lenticular regions LR corresponding to the optimum size and shape of poles adapted to a sub-pattern having predominant pitch P. In FIG.","7A, each of the poles POLE1 and POLE2 of the dipolar intensity distribution has the shape of a rhombus, i. e. the shape of an equilateral quadrangle arranged mirror symmetric to the pole orientation axis POA.","The biconvex, diamond shaped poles are fit into the optimum sized lenticular region LR such that their longer diagonal D1 (extending in y-direction) defines the pole height PH, whereas the shorter diagonal D2 extending between the inner and outer edge of the pole in the second direction (x-direction) corresponds to the pole width PW.","The area of each of the rhombohedral poles POLE1, POLE2 is APOLE=(D1*D2)/2, which is smaller than the area AOPT of the optimum sized lenticular region.","The difference in area, ΔA, may be calculated according to ΔA=2*α·sin (2*α)−4*sin (α)*(1−cos (α)).","As exemplified in FIG.","7B, it is not necessary to fit the diamond shaped poles exactly into the optimum lenticular region LR.","For example, the rhombohedral poles may be slightly larger such that tips of the rhombohedron in the first direction and/or in the second direction may extend beyond the outer limits of the ideal lenticular region LR.","Also, the pole dimension ration PH/PW may deviate from the optimum value, thereby resulting in slightly narrower or wider diamond shaped poles.","The deviation may be up to about 10%, for example.","Although some loss of contrast might occur, the oversizing of the rhombohedral poles allows to distribute light energy over larger areas at the edges of optical elements near to a pupil, thereby eliminating or decreasing problems associated with localized lens heating.","FIG.","8 shows a meridional section of an illumination system ILL configured to be used in a projection exposure step-and-scan apparatus.","The illumination system includes a plurality of optical elements constructed and arranged to receive primary radiation emitted from a primary light source LS and to generate illumination radiation incident on a mask M bearing a pattern.","In the embodiment, the light source LS is an excimer laser emitting primary radiation having a nominal operation wavelength in the deep ultraviolet (DUV) spectral range, for example 193 nm.","Primary radiation exciting the light source LS forms a coherent radiation bundle having a small cross-section and low divergence, which corresponds to a small value of geometrical optical flux (etendue).","A number of optical elements following the light source LS form a variable pupil shaping unit PSU configured to generate a defined spatial intensity distribution corresponding to a selected illumination mode in a pupil surface PILL of the illumination system.","A partial system PS following the pupil surface PILL includes a number of optical elements configured to transform the two-dimensional intensity distribution present in the pupil surface PILL into a corresponding angular distribution of illumination radiation incident on the mask M. The partial system PS includes elements to homogenize the radiation and to sharply define the edges of an illumination field in the exit surface EX of the illumination system, which coincides with the object surface of a subsequent projection objective (see FIG.","3).","The pupil shaping unit PSU comprises, at an entry side thereof, a beam expansion unit EXP which expands the coherent radiation bundle received from the light source LS.","The beam expansion unit includes a number of refractive optical elements diverting the radiation such that the cross-section of the bundle is increased without altering the geometrical optical flux of the bundle.","After passing through the beam expansion unit EXP the projection radiation bundle impinges on a first optical raster element RE1 structured to increase divergence of the radiation bundle by introducing propagation angles according to a desired illumination mode.","In FIG.","8 this is schematically illustrated for an axial ray that is split into two diverging rays R1, R2 after the raster element RE1.The first raster element RE1 modifies the angular distribution of the radiation bundle and also increases the geometrical optical flux thereof.","The first raster element RE1 may be formed by a diffractive optical element (DOE) or by a refractive optical element (ROE), for example.","Various kinds of optical raster elements are possible, for example a micro-lens array in which micro-lenses are formed by Fresnel zone plates.","The first raster element RE1 may be a reflective raster element including an array of mirror segments oriented at different angles (multi-mirror array).","First raster element RE1 is arranged in a front focal plane FFP of a zoom/axicon module ZA which includes a zoom lens group Z providing a continuously variable magnification, and an axicon group AX comprising a pair of axicons AX1, AX2, one concave and one convex, whose separation can be varied continuously to allow adjusting a distance between the axicon surfaces between zero distance (contact between axicon surfaces) and preselected finite values.","The entire zoom/axicon module ZA is configured as a focal length optical system transforming an angular distribution of radiation in the front focal plane FFP into a desired two-dimensional (spatial) intensity distribution in the rear focal plane RFP, which coincides with the pupil surface PILL of the illumination system.","A field defining arrangement FD is positioned in the rear focal plane RFP of the zoom/axicon module ZA.","The field defining arrangement is configured to further introduce divergence into the radiation beam, thereby further enlarging the geometrical flux of the radiation beam.","The divergence introduced by the field defining arrangement FD is schematically represented by divergent rays downstream of the field defining arrangement.","Embodiments of field defining arrangements suitable for this purpose are disclosed, for example, in applicant's international application published as WO 2005/078522 A2, which is incorporated herein by reference in its entirety.","The diverging rays exiting the field defining arrangement FD enter an objective OB represented by a single condenser lens.","The objective OB is arranged within the illumination systems such that an entrance pupil plane of the objective OB coincides with the exit pupil surface of the zoom/axicon module.","The image plane of objective OB, which is a Fourier transform plane to the pupil PILL of the illumination system, is a field plane FP within the illumination system.","A reticle masking unit REMA acting as an adjustable field stop is positioned in the field plane FP to define the edges of the illumination field.","Details of embodiments may be taken, for example from WO 2005/078522 A2.An imaging objective RO is arranged between the field plane FP and the exit surface ES of the illumination system, where the mask M may be positioned and allows to image the intensity distribution present in the field plane FP onto the mask pattern.","FIGS.","9A-9b show schematically a detail of a first raster element RE1 configured to generate a substantially dipolar intensity distribution having two illumination poles each having the diamond shape discussed in context of FIG.","7.The raster element RE1 is formed by an array of raster segments RS arranged side by side in a mosaic arrangement to cover without interspaces the complete illuminated surface of the raster element RE1.Such arrangement allows to generate the dipolar intensity distribution essentially without blocking any parts of the beam so that there is no intensity loss involved in the generation of the dipolar intensity distribution.","The raster element RE1 can be formed by an array of refractive lens segments.","Each raster segment RS may be formed by a segment of a lens or a prism where an entry-side surface and an exit-side surface of the raster segment are oriented such that a desired redirection of radiation is caused by refraction at the segment surfaces as the radiation passes through the raster segment.","The rhombohedral shape of the raster segments RS determines the shape of the poles in the pupil surface PILL.","In FIG.","9A the raster segments are numbered “1” and “2” to illustrate which raster segments contribute to the illumination intensity in the two poles POLE1 and POLE2 shown in FIG.","9B.","The structure of the raster segments is adjusted to redirect at least a major portion of impinging radiation to the two poles.","As illustrated by dashed lines in some raster segments of FIG.","9A, the raster elements may also be segmented into other shapes, such as triangular raster segments, where the size and shape of the triangles are adapted to define, in combination, a rhombohedral area corresponding to the desired pole shape.","In some embodiments, the raster element RE1 may be designed as a diffractive computer generated hologram (CGH) assigning to each of the raster segments RS a diffractive structure effective to redirect light intensity present in a partial beam impinging on the raster segment into the associated pole.","The raster segments may have a shape differing from the shape of the desired poles, e.g.","a rectangular shape.","The diffractive structure may be formed on the surface of a transparent substrate, such as a plane plate made of fused silica or calcium fluoride.","The raster segments may also be formed of grooves etched into the surface to provide segments of a Fresnel lenses.","The depth and width of the grooves may be in the order of micrometers, for example.","Each raster segment may be in the order of millimeters in size and the entire array forming the raster element may have typical dimensions of one or a few centimeters.","The basic distribution of angles introduced by the raster element RE1 may be modified within the pupil shaping unit by setting the elements of the variable zoom lens group Z and/or the variable axicon group AX accordingly.","In one configuration, the separation between the axicon elements AX1 and AX2 is set to zero (contact between axicon surfaces) such that no radial redirection of light intensity is effected by the axicon group AX.","In other configurations, a defined separation may be set, which generally causes a central symmetric dilatation of the radiation intensity distribution, which may be useful in some cases.","Adjusting the magnification of the zoom lens group Z allows to adapt the illumination intensity distribution in the pupil surface PILL of the illumination system to different NA values in a homomorphous imaging step.","It is to be noted that the conditions for the pole area APOLE, pole height PH and pole width PW as defined above remain unchanged as long as P*NA=2 k1*λ=const.","Therefore, the area of the poles as well as the pole height and pole width may be considered as a function of parameter k1 alone, where k1<1 is a process dependent parameter that incorporates everything in a lithography process that is not wavelength or numerical aperture.","Generally, any process or system modification that allows improvements in resolution effectively reduces the k1 factor.","Diffraction-limited values are 0.25 for incoherent and 0.5 for coherent illumination, for example.","Where k1 stays essentially constant, sub-patterns with different predominant periodicity values P (pitches) may be illuminated using one and the same raster element RE1 by simply adjusting the appropriate NA value using the zoom lens group Z.","With other words: one type of raster element with fixed configuration, such as a diffractive optical element, may be sufficient for different processes defined by one particular k1 value (or a small variation of k1).","Different values for APOLE, PW and/or PH and different pole patterns may also be obtained by providing several different, interchangeable first raster elements.","An automatic changer may be used to exchange raster elements of different configuration in the illumination system.","In general, the pupil-shaping unit may include at least one optical modulation device configured to controllably change an angular distribution of radiation incident on the optical modulation device such that a desired intensity distribution is obtained in the pupil surface of the illumination system.","Although the optical modulation device may have a fixed configuration to obtain only one type of intensity distribution (which may be changeable by additional variable optical elements), it is possible that the optical modulation device has an array of individual elements configured to be driven individually to change the angular distribution of radiation incident on the individual elements.","The optical modulation device may include a controllable micro-mirror array, for example.","Various optical modulation devices which may be used when modified for that purpose are disclosed in applicant's international patent application published as WO 2005/026843 A2.The disclosure of this application is incorporated herein by reference.","FIGS.","10A-10B show diagrams illustrating, for an exemplary projection exposure systems, improvements that may be obtained if an optimized dipole setting is used instead of a conventional setting.","In the diagrams, pupil coordinates in terms of image-side numerical aperture NA are drawn in the abscissa.","The ordinates show values for the phase error value of the overall wavefront aberration.","The value “0” corresponding to the optical axis.","Each diagram shows an “x-cut” parallel to the x-axis (second direction) and an “y-cut” perpendicular thereto in the first direction.","An x-dipole (orientation of pole orientation axis along x-direction) is used for all experiments.","A dipole setting having poles with the shape of a segment of an annulus (compare e.g.","FIG.","2B) was used for the reference example of a conventional dipole setting CONV shown in FIG.","10A.","An x-dipole setting with lenticular poles with APOLE=AOPT was used for the experiment illustrated in FIG.","10B.","The x-cut in both experiments illustrates that the localized heating in the region of the poles generally aligned along the x-direction leads to relatively strong wavefront aberrations close to the outer edge of the pupil where the energetic centriods of the poles are positioned.","In contrast, essentially no wavefront aberration is caused on and close to the optical axis in the center of the pupil.","In the y-direction a relatively large variation of wavefront aberrations occurs superimposed onto a slight gradient from the upper edge to the lower edge of the pupil in this specific type of projection objective used for the experiment.","The general characteristics of the local distribution of wavefront aberrations caused by lens heating are quite similar in the experiment according to FIG.","10B.","Note, however, that the absolute amount of wavefront aberration caused by lens heating is reduced by about a factor two, i.e.","reduced to about 50% of the value for the conventional setting in the x-direction (different scales in the ordinates in FIG.","10A, in FIG.","10B).","This significant improvement is attributed to the fact that radiant energy present within the projection beam is distributed over larger areas at the position of the poles, whereby the energy distribution in smeared out over a larger area, thereby reducing associated lens heating effects on wavefront aberrations.","The effect is less pronounced in the y-direction.","In some embodiments, the multipolar illumination is a pure dipole illumination, where the intensity distribution in the pupil surface of the illumination system is formed by one substantially dipolar intensity distribution having exactly two illumination poles.","Such dipole illumination may be used, for example, to print periodic patterns with features essentially aligned in one direction only.","As a practical example, a layer of a highly integrated flash memory device may be strongly dominated by lines running in direction only.","Due to the relatively large pole height PH of the optimized pole areas those dipole illuminations are also useful to improve contrast of sub-patterns not running at the predominant direction, but at an angle thereto since the dipolar intensity distribution includes illumination directions significantly deviating from the direction defined by the pole orientation axis.","The multipolar illumination mode may include two substantially dipolar intensity distributions (“dipoles”) superimposed on each other, where the pole orientation axes of the dipoles are rotated relatively to each other, for example by 90°.","FIG.","11 depicts schematically the intensity distribution in the illumination pupil for a quadrupole illumination having two pairs of lenticular poles relatively rotated by 90° around the optical axis to form four lenticular poles, POLE1, POLE2, POLE3, POLE 4, where the pole orientation axis POAx of the first dipolar intensity distribution (forming poles POLE1 and POLE2) is oriented along the x-direction, whereas the pole orientation axis POAy of the second dipolar intensity distribution (forming poles POLE3 and POLE4) is oriented perpendicular thereto in the y-direction.","A bi-directional pattern having periodic features in x- and y-direction may be printed with high contrast for both directions.","The area of each of the poles corresponds approximately to the optimum area AOPT in this example.","As illustrated schematically in FIG.","12, the method and apparatus may also be used in exposure processes which do not exploit the full resolution potential of the projection exposure apparatus.","For example, a multi-polar illumination mode may be set for a pattern or sub-pattern having features spaced apart periodically at a predominant periodicity length P where the condition 0.7*λ/NA<P<λ/NA holds.","Those conditions are sometimes used in processes known as “double patterning” where a final structure with very fine pitch is formed by subsequent exposures of coarser pattern relatively shifted to each other by one half of the periodicity length.","The corresponding illumination mode may be characterized by two poles POLE1, POLE2 positioned between the edge of the pupil (corresponding to full NA) and the optical axis and defining a distance d<λ/(P*NA).","The poles may have a lenticular or a biconvex polygonal shape, for example.","The disclosure has been given by way of example.","From this information, those skilled in the art will not only understand the disclosure and its attendant advantages, but will also find apparent various changes and modifications to the structures and methods disclosed.","The applicant seeks, therefore, to cover all such changes and modifications as fall within the spirit and scope of defined by the appended claims, and equivalents thereof.","The contents of the claims are incorporated by reference into the description."]],"string":"[\n [\n \"PROJECTION EXPOSURE METHODS AND SYSTEMS\",\n \"Projection exposure methods, systems, sub-systems and components are disclosed.\",\n \"Methods can include performing a first exposure to image a first sub-pattern of the pattern, where the first sub-pattern includes a plurality of first features extending in a first direction and spaced apart essentially periodically at a predominant periodicity length P in a second direction perpendicular to the first direction.\",\n \"The first exposure can be performed using a multipolar illumination mode that includes at least one substantially dipolar intensity distribution having two illumination poles positioned on a pole orientation axis substantially parallel to the second direction and spaced apart from each other.\"\n ],\n [\n \"1.-25.\",\n \"(canceled) 26.An illumination system, comprising: a plurality of optical elements constructed and arranged to receive primary radiation emitted from a light source and to generate illumination radiation incident on a mask bearing a pattern, a pupil shaping unit configured to generate a defined multipolar intensity distribution corresponding to a selected illumination mode in a pupil surface of the illumination system during use, wherein: the multipolar intensity distribution comprises a quadrupolar intensity distribution having four illumination poles positioned on two pole orientation axes and spaced apart from one another; and the poles of the quadrupolar intensity distribution each have a lenticular pole shape defined by an overlapping zone of two circles with equal unit radius having a distance between the centers of the circles.\",\n \"27.The illumination system according to claim 26, wherein the poles of the quadrupolar intensity distribution each have a pole dimension ratio PDR=PH/PW between a pole height PH and a pole width PW according to PDROPT−20%≤PDR≤PDROPT+20% where PDROPT=sin (α)/(1−cos(α)), α is a half pole angle, the pole width PW is measured between an inner pole edge and an outer pole edge in a direction parallel to the pole orientation axis, and the pole height is measured between pole edges in a direction perpendicular to the pole orientation axis.\",\n \"28.The illumination system of claim 26, wherein the pupil-shaping unit comprises an array of individual elements.\",\n \"29.The illumination system of claim 28, wherein the individual elements comprise diffraction gratings.\",\n \"30.The illumination system of claim 28, wherein the individual elements comprise mirrors.\",\n \"31.The illumination system of claim 26, wherein the pupil-shaping unit comprises an optical modulation device configured to controllably change an angular distribution of radiation incident on the optical modulation device such that a desired intensity distribution is obtained in the pupil surface of the illumination system.\",\n \"32.The illumination system of claim 31, wherein the optical modulation device has an array of individual elements configured to be driven individually to change the angular distribution of radiation incident on the individual elements.\",\n \"33.The illumination system of claim 32, wherein the individual elements comprise mirrors.\",\n \"34.The illumination system of claim 32, wherein the individual elements comprise diffractive optical elements or acousto-optical elements.\",\n \"35.The illumination system according to claim 26, further comprising a blocking device arranged at or close to the pupil surface of the illumination system where the basic intensity distribution is generated, or at or close to a pupil surface optically conjugate thereto; and the blocking device is designed to block areas of the basic intensity distribution which lie outside the region desired for the pole shape.\",\n \"36.The illumination system according to claim 26, wherein the pupil shaping unit further comprises a zoom lens group configured to provide a continuously variable magnification during use.\",\n \"37.The illumination system according to claim 26, wherein the pupil shaping unit further comprises a pair of axicon elements having axicon surfaces, one concave and one convex, wherein at least one of the axicon elements is movable along an optical axis of the illumination system to allow adjusting a distance between the axicon surfaces.\",\n \"38.An apparatus, comprising: an illumination system configured so that during use the illumination system guides radiation along an illumination path to generate illumination radiation incident on a mask bearing a pattern; and a projection objective configured so that during use the projection objective projects an image of the pattern onto a radiation-sensitive substrate with projection radiation guided along a projection path, wherein the apparatus is a projection exposure apparatus, and the illumination system is configured according to claim 26.39.An illumination system, comprising: a plurality of optical elements constructed and arranged to receive primary radiation emitted from a light source and to generate illumination radiation incident on a mask bearing a pattern, a pupil shaping unit configured to generate a defined multipolar intensity distribution corresponding to a selected illumination mode in a pupil surface of the illumination system during use, wherein: the pattern comprises features spaced apart periodically at a predominant periodicity length P where the condition 0.7λ/NA<P<λ/NA holds; the multipolar intensity distribution comprises a dipolar intensity distribution having two illumination poles positioned on a pole orientation axis and spaced apart from each other at a distance d<λ/(P*NA), where λ is a nominal operation wavelength of radiation used, and NA is an image-side numerical aperture of a projection optical system used; and the poles of the dipolar intensity distribution each have a pole shape selected from the group consisting of: a generally biconvex pole shape with a pole dimension ratio PDR=PH/PW>1 between a pole height PH and a pole width PW, where the pole width PW is measured between an inner edge and an outer pole edge in a direction parallel to the pole orientation axis, and the pole height PH is measured between inner and outer pole edges in a direction perpendicular to the pole orientation axis; and a substantially lenticular pole shape defined by two convexly curved edges having opposite sense of curvature and centres of curvature essentially on a line parallel to the pole orientation axis; and the poles of the dipolar intensity distribution each have a pole dimension ratio PDR=PH/PW according to PDROPT−20%≤PDR≤PDROPT+20% where PDROPT=sin (α)/(1−cos(α)), α is a half pole angle, PW is measured between an inner pole edge and an outer pole edge in a direction parallel to the pole orientation axis, and PH is measured between pole edges in a direction perpendicular to the pole orientation axis.\",\n \"40.The illumination system of claim 39, wherein the pupil-shaping unit comprises an array of individual elements.\",\n \"41.The illumination system of claim 40, wherein the individual elements comprise diffraction gratings.\",\n \"42.The illumination system of claim 40, wherein the individual elements comprise mirrors.\",\n \"43.The illumination system of claim 40, wherein the individual elements are configured to be controlled individually in order to change an angular distribution of radiation influenced by the individual elements.\",\n \"44.The illumination system of claim 40, wherein during use: the array of individual elements is configured to generate a basic intensity distribution including areas of the poles of the dipolar intensity distribution and extending beyond the areas of the poles; the illumination system further comprises a blocking device arranged at or close to the pupil surface of the illumination system where the basic intensity distribution is generated, or at or close to a pupil surface optically conjugate thereto; and the blocking device is designed to block areas of the basic intensity distribution which lie outside the region desired for the pole shape.\",\n \"45.The illumination system of claim 39, wherein the pupil shaping unit further comprises a zoom lens group configured to provide a continuously variable magnification during use.\",\n \"46.The illumination system of claim 45, wherein the zoom lens group is arranged between the array of individual elements and the pupil surface of the illumination system.\",\n \"47.The illumination system of claim 39, wherein the pupil shaping unit further comprises a pair of axicon elements having axicon surfaces, one concave and one convex, wherein at least one of the axicon elements is movable along an optical axis of the illumination system to allow adjusting a distance between the axicon surfaces.\",\n \"48.The illumination system of claim 47, wherein the axicon group is arranged between the array of individual elements and the pupil surface of the illumination system.\",\n \"49.An apparatus, comprising: an illumination system configured so that during use the illumination system guides radiation along an illumination path to generate illumination radiation incident on a mask bearing a pattern; and a projection objective configured so that during use the projection objective projects an image of the pattern onto a radiation-sensitive substrate with projection radiation guided along a projection path, wherein the apparatus is a projection exposure apparatus, and the illumination system is configured according to claim 39.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>Microlithographic projection exposure methods are used for fabricating semiconductor components and other finely structured components.\",\n \"Use is made of masks (reticles) that bear the pattern of a structure to be imaged, for example a line pattern of a layer of a semiconductor component, such as an integrated circuit (IC).\",\n \"A mask is positioned in a projection exposure system between an illumination system and projection objective in the region of the object surface of the projection objective, and illuminated with illumination radiation provided by the illumination system.\",\n \"The radiation varied by the mask and the pattern forms projection radiation propagating through the projection objective, which images the pattern of the mask onto the substrate to be exposed, which normally bears a radiation-sensitive layer (photoresist).\",\n \"In some cases, the pattern of the mask is illuminated with radiation from an effective source having an intensity distribution at a pupil plane of the illumination system corresponding to a particular illumination mode.\",\n \"An image of the illuminated mask is projected onto a resist-coated semiconductor wafer.\"\n ],\n [\n \"<SOH> SUMMARY <EOH>In some embodiments, the disclosure provides projection exposure methods and systems that can provide improved long-term stability of optical performance when multipole illumination, such as dipole illumination, is used.\",\n \"In certain embodiments, the disclosure provides projection exposure methods and systems that can allow imaging of patterns having predominant periodic features running in a first direction at high contrast, while at the same time other sub-patterns including features running at an angle to the first direction may still be imaged with sufficient detail.\",\n \"In one aspect, the disclosure generally provides a method of imaging a pattern onto a substrate provided with a layer of a radiation-sensitive material.\",\n \"The method includes performing an exposure to image a first sub-pattern of the pattern, where the first sub-pattern includes a plurality of first features extending in a first direction and spaced apart essentially periodically at a predominant periodicity length P in a second direction perpendicular to the first direction.\",\n \"The exposure is performed using a multipolar illumination mode that includes at least one a substantially dipolar intensity distribution having two illumination poles positioned on a pole orientation axis substantially parallel to the second direction and spaced apart from each other.\",\n \"The poles of the dipolar intensity distribution each have an azimuthal width defined by a pole angle θ, and a pole area A POLE according to: in-line-formulae description=\\\"In-line Formulae\\\" end=\\\"lead\\\"?\",\n \"0.6< A POLE /A OPT <1.1 in-line-formulae description=\\\"In-line Formulae\\\" end=\\\"tail\\\"?\",\n \"where A OPT =θ−sin (θ) and where cos(θ/2)=λ/(2*P*NA), where λ is a nominal operation wavelength of radiation used for the first exposure and NA is an image-side numerical aperture of a projection optical system used for the first exposure.\",\n \"The spatial intensity distribution at a pupil plane of the illumination system representing the effective source of radiation incident on the mask pattern can be optimized considering at least two different criteria.\",\n \"A first criterion relates to the angles of incidence (or illumination directions) provided by the effective source in view of the particular sub-pattern to be exposed, which is characterized by first features extending in a first direction and spaced apart essentially periodically at the predominant periodicity length P in the second direction.\",\n \"Under these conditions, an optimized illumination (optimized for contrast in an appropriate focus range determined by the depth of focus (DOF)) would generally provide only those illumination directions which could contribute to the imaging process for the detail of interest, which is characterized by periodicity length P. Where two-beam interference beyond the coherent resolution limit is desired to optimize resolution, the illumination directions allowing high contrast two-beam interference correspond to certain areas in the pupil of the illumination system.\",\n \"Those areas including all useful illumination directions (to obtain maximum contrast) generally define areas in the pupil surface having a lenticular shape resulting from an overlapping zone of two circles with equal unit radius having a distance d between the centers of the circles.\",\n \"Illumination directions corresponding to pupil locations outside these useful lens-shaped areas generally do not contribute to the desired two-beam interference and might in fact blur a resulting image.\",\n \"Those lenticular useful areas including all illumination directions contributing constructively to two-beam interference may be characterized by their size and correspond to a pole area (e.g., an optimum pole area) A OPT in a conjugated exit pupil of the projection optical system used for the exposure method.\",\n \"The second criterion regards the illumination angles actually used in an exposure process.\",\n \"It has been found that known systems employing dipole illumination typically use only a small fraction of the illumination angles which might theoretically be used to form a high-contrast image with two-beam interference.\",\n \"For example, small poles with circular shape or poles having the shape of a segment of an annulus have been used.\",\n \"Whereas those small poles of dipole illumination may be acceptable from a contrast point of view if only “useful” illumination directions are used, drawbacks in respect to overall performance may result if light energy is concentrated on correspondingly small areas on optical surfaces at or close to a pupil surface within the exposure system.\",\n \"Those local energy concentrations may cause or contribute to “lens heating” and associated time-dependent fluctuations of performance of the exposure system.\",\n \"Such issues can be addressed and at least partly avoided by providing illumination modes including at least one substantially dipolar intensity distribution with poles having optimized pole size and pole shape such that the pole area of such poles and/or the shape of the poles is close to the pole area and/or the pole shape.\",\n \"Where the condition 0.6<A POLE /A OPT <1.1 is fulfilled for a pole area, light energy within a pupil surface may be distributed over relatively large area fractions of the pupil essentially without trade-off between attainable contrast and intensity.\",\n \"Distributing light energy over larger local areas instead of smaller local areas has been found to significantly reduce detrimental effects of lens heating and associated effects on the performance.\",\n \"Where the pole area becomes significantly smaller than the lower limit a concentration of radiation energy in a relatively small area may result, which may cause problems associated with inhomogenous lens heating.\",\n \"Where the pole area becomes significantly larger than the upper limit, a corresponding distribution of illumination directions may include larger fractions of illumination direction not constructively contributing to a desired contrast, which may be undesirable.\",\n \"In some embodiments, the poles of the dipolar intensity distribution have a generally biconvex shape with a pole dimension ratio PDR=PH/PW>1 between a pole height PH and a pole width PW, where the pole width PW is measured between an inner and an outer pole edge in a direction parallel to the pole orientation axis and the pole height PH is measured between pole edges in a direction perpendicular to the pole orientation axis.\",\n \"At least one of the conditions PDR>1.2, PDR>1.4, PDR>1.6, PDR>1.8, PDR>2.0, PDR>3.0 and PDR>3.5 may be fulfilled.\",\n \"For example, a generally biconvex shape may be defined by a convex polygon having four or more sides, at least some of the sides including angles significantly larger than 90°, for example 120° or more.\",\n \"In certain embodiments, the poles of the dipolar intensity distribution have a substantially lenticular pole shape.\",\n \"The shape of a “planar circular two-angle” may be well approximated by a lenticular pole shape.\",\n \"A planar circular two-angle may be bound by two segments of a circle with opposite sense of curvature, where the segments intersect at intersection points forming the two “corners” of a “two-angle”.\",\n \"The segments of the circle delimiting the pole shape may have the same radius of curvature.\",\n \"In some embodiments, the poles of the dipolar intensity distribution have a parallelogram pole shape.\",\n \"A pole defined by two pairs of mutually parallel sides including non-rectangular angles may be optimized to fit closely to the shape of a pole area.\",\n \"The pole shape may be the shape of a rhombus (or rhomb), which is a quadrilateral in which all of the sides are of equal length (equilateral quadrangle).\",\n \"The shape may be described as a diamond or lozenge.\",\n \"In certain embodiments, the poles of the dipolar intensity distribution each have a pole dimension ratio PDR=PH/PW between a pole height PH and a pole width PW according to in-line-formulae description=\\\"In-line Formulae\\\" end=\\\"lead\\\"?\",\n \"PDR OPT −20%≤PDR≤PDR OPT +20% in-line-formulae description=\\\"In-line Formulae\\\" end=\\\"tail\\\"?\",\n \"where PDR OPT =sin (α)/(2*(1−cos(α)) and where the pole width PW is measured between an inner and an outer pole edge in a direction parallel to the pole orientation axis and the pole height PH is measured between pole edges in a direction perpendicular to the pole orientation axis.\",\n \"If this condition is fulfilled, a desirable balance may be obtained between a high contrast and a relatively large area where incident radiation energy is distributed at optical elements relatively close to a pupil surface.\",\n \"The disclosure also relates to an illumination system configured to generate and use the large pole illumination settings described above, and to a projection exposure apparatus including such an illumination system.\",\n \"In some embodiments, the disclosure provides an illumination system that includes a plurality of optical elements constructed and arranged to receive primary radiation emitted from a primary light source and to generate illumination radiation incident on a mask bearing a pattern.\",\n \"A number of the optical elements form a pupil shaping unit configured to generate a defined spatial intensity distribution corresponding to a selected illumination mode in a pupil surface of the illumination system.\",\n \"The spatial intensity distribution being a multipolar intensity distribution includes at least one substantially dipolar intensity distribution having two illumination poles positioned on a pole orientation axis and spaced apart from each other.\",\n \"The poles of the dipolar intensity distribution each have have a pole shape selected from: a generally biconvex pole shape with a pole dimension ratio PDR=PH/PW>1 between a pole height PH and a pole width PW, where the pole width PW is measured between an inner and an outer pole edge in a direction parallel to the pole orientation axis and the pole height PH is measured between pole edges in a direction perpendicular to the pole orientation axis; a generally biconvex pole shape defined by a convex polygon having four or more sides, where some of the sides include angles larger than 90°; a parallelogram pole shape defined by a non-rectangular parallelogram having a shorter diagonal and a longer diagonal, where the shorter diagonal extends substantially parallel to a line parallel to the pole orientation axis; and a substantially lenticular pole shape defined by two convexly curved edges having opposite sense of curvature and centres of curvature essentially on a line parallel to the pole orientation axis.\",\n \"While reference is made to the use of the projection exposure method and apparatus in the manufacture of integrated circuits, more generally the method and apparatus may also be used in other applications, such as in the manufacture of integrated optical systems, guidance and detection patterns for magnetic domain memories, liquid-crystal display panels, thin-film magnetic heads, etc.\",\n \"The individual features may be implemented either alone or in combination as embodiments, or may be implemented in other fields of application.\",\n \"Further, they may represent advantageous embodiments that are protectable in their own right, for which protection is claimed in the application as filed or for which protection will be claimed during pendency of the application.\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of, and claims benefit under 35 USC 120 to, U.S. application Ser.\",\n \"No.\",\n \"14/556,432, filed Dec. 1, 2014, now U.S. Pat.\",\n \"No.\",\n \"9,885,958, which is a continuation of, and claims benefit under 35 USC 120 to, U.S. application Ser.\",\n \"No.\",\n \"12/483,733, filed Jun.\",\n \"12, 2009, now U.S. Pat.\",\n \"No.\",\n \"8,917,379, which is a continuation of, and claims benefit under 35 USC 120 to, international application PCT/EP2007/001574, filed Feb. 23, 2007, which claims benefit of European Application No.\",\n \"07000731.5, filed Jan. 16, 2007 and U.S. Ser.\",\n \"No.\",\n \"60/880,447, filed Jan. 16, 2007.U.S.\",\n \"application Ser.\",\n \"Nos.\",\n \"14/556,432, 12/483,733 and international application PCT/EP2007/001574 are hereby incorporated by reference in their entirety.\",\n \"FIELD The disclosure relates to projection exposure methods, systems, sub-systems and components.\",\n \"BACKGROUND Microlithographic projection exposure methods are used for fabricating semiconductor components and other finely structured components.\",\n \"Use is made of masks (reticles) that bear the pattern of a structure to be imaged, for example a line pattern of a layer of a semiconductor component, such as an integrated circuit (IC).\",\n \"A mask is positioned in a projection exposure system between an illumination system and projection objective in the region of the object surface of the projection objective, and illuminated with illumination radiation provided by the illumination system.\",\n \"The radiation varied by the mask and the pattern forms projection radiation propagating through the projection objective, which images the pattern of the mask onto the substrate to be exposed, which normally bears a radiation-sensitive layer (photoresist).\",\n \"In some cases, the pattern of the mask is illuminated with radiation from an effective source having an intensity distribution at a pupil plane of the illumination system corresponding to a particular illumination mode.\",\n \"An image of the illuminated mask is projected onto a resist-coated semiconductor wafer.\",\n \"SUMMARY In some embodiments, the disclosure provides projection exposure methods and systems that can provide improved long-term stability of optical performance when multipole illumination, such as dipole illumination, is used.\",\n \"In certain embodiments, the disclosure provides projection exposure methods and systems that can allow imaging of patterns having predominant periodic features running in a first direction at high contrast, while at the same time other sub-patterns including features running at an angle to the first direction may still be imaged with sufficient detail.\",\n \"In one aspect, the disclosure generally provides a method of imaging a pattern onto a substrate provided with a layer of a radiation-sensitive material.\",\n \"The method includes performing an exposure to image a first sub-pattern of the pattern, where the first sub-pattern includes a plurality of first features extending in a first direction and spaced apart essentially periodically at a predominant periodicity length P in a second direction perpendicular to the first direction.\",\n \"The exposure is performed using a multipolar illumination mode that includes at least one a substantially dipolar intensity distribution having two illumination poles positioned on a pole orientation axis substantially parallel to the second direction and spaced apart from each other.\",\n \"The poles of the dipolar intensity distribution each have an azimuthal width defined by a pole angle θ, and a pole area APOLE according to: 0.6<APOLE/AOPT<1.1 where AOPT=θ−sin (θ) and where cos(θ/2)=λ/(2*P*NA), where λ is a nominal operation wavelength of radiation used for the first exposure and NA is an image-side numerical aperture of a projection optical system used for the first exposure.\",\n \"The spatial intensity distribution at a pupil plane of the illumination system representing the effective source of radiation incident on the mask pattern can be optimized considering at least two different criteria.\",\n \"A first criterion relates to the angles of incidence (or illumination directions) provided by the effective source in view of the particular sub-pattern to be exposed, which is characterized by first features extending in a first direction and spaced apart essentially periodically at the predominant periodicity length P in the second direction.\",\n \"Under these conditions, an optimized illumination (optimized for contrast in an appropriate focus range determined by the depth of focus (DOF)) would generally provide only those illumination directions which could contribute to the imaging process for the detail of interest, which is characterized by periodicity length P. Where two-beam interference beyond the coherent resolution limit is desired to optimize resolution, the illumination directions allowing high contrast two-beam interference correspond to certain areas in the pupil of the illumination system.\",\n \"Those areas including all useful illumination directions (to obtain maximum contrast) generally define areas in the pupil surface having a lenticular shape resulting from an overlapping zone of two circles with equal unit radius having a distance d between the centers of the circles.\",\n \"Illumination directions corresponding to pupil locations outside these useful lens-shaped areas generally do not contribute to the desired two-beam interference and might in fact blur a resulting image.\",\n \"Those lenticular useful areas including all illumination directions contributing constructively to two-beam interference may be characterized by their size and correspond to a pole area (e.g., an optimum pole area) AOPT in a conjugated exit pupil of the projection optical system used for the exposure method.\",\n \"The second criterion regards the illumination angles actually used in an exposure process.\",\n \"It has been found that known systems employing dipole illumination typically use only a small fraction of the illumination angles which might theoretically be used to form a high-contrast image with two-beam interference.\",\n \"For example, small poles with circular shape or poles having the shape of a segment of an annulus have been used.\",\n \"Whereas those small poles of dipole illumination may be acceptable from a contrast point of view if only “useful” illumination directions are used, drawbacks in respect to overall performance may result if light energy is concentrated on correspondingly small areas on optical surfaces at or close to a pupil surface within the exposure system.\",\n \"Those local energy concentrations may cause or contribute to “lens heating” and associated time-dependent fluctuations of performance of the exposure system.\",\n \"Such issues can be addressed and at least partly avoided by providing illumination modes including at least one substantially dipolar intensity distribution with poles having optimized pole size and pole shape such that the pole area of such poles and/or the shape of the poles is close to the pole area and/or the pole shape.\",\n \"Where the condition 0.6<APOLE/AOPT<1.1 is fulfilled for a pole area, light energy within a pupil surface may be distributed over relatively large area fractions of the pupil essentially without trade-off between attainable contrast and intensity.\",\n \"Distributing light energy over larger local areas instead of smaller local areas has been found to significantly reduce detrimental effects of lens heating and associated effects on the performance.\",\n \"Where the pole area becomes significantly smaller than the lower limit a concentration of radiation energy in a relatively small area may result, which may cause problems associated with inhomogenous lens heating.\",\n \"Where the pole area becomes significantly larger than the upper limit, a corresponding distribution of illumination directions may include larger fractions of illumination direction not constructively contributing to a desired contrast, which may be undesirable.\",\n \"In some embodiments, the poles of the dipolar intensity distribution have a generally biconvex shape with a pole dimension ratio PDR=PH/PW>1 between a pole height PH and a pole width PW, where the pole width PW is measured between an inner and an outer pole edge in a direction parallel to the pole orientation axis and the pole height PH is measured between pole edges in a direction perpendicular to the pole orientation axis.\",\n \"At least one of the conditions PDR>1.2, PDR>1.4, PDR>1.6, PDR>1.8, PDR>2.0, PDR>3.0 and PDR>3.5 may be fulfilled.\",\n \"For example, a generally biconvex shape may be defined by a convex polygon having four or more sides, at least some of the sides including angles significantly larger than 90°, for example 120° or more.\",\n \"In certain embodiments, the poles of the dipolar intensity distribution have a substantially lenticular pole shape.\",\n \"The shape of a “planar circular two-angle” may be well approximated by a lenticular pole shape.\",\n \"A planar circular two-angle may be bound by two segments of a circle with opposite sense of curvature, where the segments intersect at intersection points forming the two “corners” of a “two-angle”.\",\n \"The segments of the circle delimiting the pole shape may have the same radius of curvature.\",\n \"In some embodiments, the poles of the dipolar intensity distribution have a parallelogram pole shape.\",\n \"A pole defined by two pairs of mutually parallel sides including non-rectangular angles may be optimized to fit closely to the shape of a pole area.\",\n \"The pole shape may be the shape of a rhombus (or rhomb), which is a quadrilateral in which all of the sides are of equal length (equilateral quadrangle).\",\n \"The shape may be described as a diamond or lozenge.\",\n \"In certain embodiments, the poles of the dipolar intensity distribution each have a pole dimension ratio PDR=PH/PW between a pole height PH and a pole width PW according to PDROPT−20%≤PDR≤PDROPT+20% where PDROPT=sin (α)/(2*(1−cos(α)) and where the pole width PW is measured between an inner and an outer pole edge in a direction parallel to the pole orientation axis and the pole height PH is measured between pole edges in a direction perpendicular to the pole orientation axis.\",\n \"If this condition is fulfilled, a desirable balance may be obtained between a high contrast and a relatively large area where incident radiation energy is distributed at optical elements relatively close to a pupil surface.\",\n \"The disclosure also relates to an illumination system configured to generate and use the large pole illumination settings described above, and to a projection exposure apparatus including such an illumination system.\",\n \"In some embodiments, the disclosure provides an illumination system that includes a plurality of optical elements constructed and arranged to receive primary radiation emitted from a primary light source and to generate illumination radiation incident on a mask bearing a pattern.\",\n \"A number of the optical elements form a pupil shaping unit configured to generate a defined spatial intensity distribution corresponding to a selected illumination mode in a pupil surface of the illumination system.\",\n \"The spatial intensity distribution being a multipolar intensity distribution includes at least one substantially dipolar intensity distribution having two illumination poles positioned on a pole orientation axis and spaced apart from each other.\",\n \"The poles of the dipolar intensity distribution each have have a pole shape selected from: a generally biconvex pole shape with a pole dimension ratio PDR=PH/PW>1 between a pole height PH and a pole width PW, where the pole width PW is measured between an inner and an outer pole edge in a direction parallel to the pole orientation axis and the pole height PH is measured between pole edges in a direction perpendicular to the pole orientation axis; a generally biconvex pole shape defined by a convex polygon having four or more sides, where some of the sides include angles larger than 90°; a parallelogram pole shape defined by a non-rectangular parallelogram having a shorter diagonal and a longer diagonal, where the shorter diagonal extends substantially parallel to a line parallel to the pole orientation axis; and a substantially lenticular pole shape defined by two convexly curved edges having opposite sense of curvature and centres of curvature essentially on a line parallel to the pole orientation axis.\",\n \"While reference is made to the use of the projection exposure method and apparatus in the manufacture of integrated circuits, more generally the method and apparatus may also be used in other applications, such as in the manufacture of integrated optical systems, guidance and detection patterns for magnetic domain memories, liquid-crystal display panels, thin-film magnetic heads, etc.\",\n \"The individual features may be implemented either alone or in combination as embodiments, or may be implemented in other fields of application.\",\n \"Further, they may represent advantageous embodiments that are protectable in their own right, for which protection is claimed in the application as filed or for which protection will be claimed during pendency of the application.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS FIG.\",\n \"1 illustrates schematically the principle of symmetric off-axis illumination; FIGS.\",\n \"2A-2D show schematically various illumination modes; FIG.\",\n \"3 illustrates schematically a projection exposure system configured for dipole illumination mode with lenticular poles; FIG.\",\n \"4 illustrates schematically a circular pupil of a projection objective at imaging conditions beyond the coherent resolution limit using symmetric two-beam interference imaging conditions; FIGS.\",\n \"5A-5C illustrate where the poles of the dipolar intensity distribution each have a lenticular pole shape; FIGS.\",\n \"6A-6B illustrate schematically the use of a mask to generate biconvex, lenticular illumination poles in a modified conventional illumination system; FIGS.\",\n \"7A-7B show poles of a dipolar intensity distribution having a parallelogram pole shape; FIG.\",\n \"8 shows a meridional section of an illumination system configured to generate large polses in a projection exposure step-and-scan apparatus; FIGS.\",\n \"9A-9B show schematically a detail of a first raster element configured to generate a substantially dipolar intensity distribution having two illumination poles each having a diamond shape as shown in FIG.\",\n \"7; FIGS.\",\n \"10A-10B show diagrams illustrating improvements on lens heating induced wavefront phase errors obtained by illuminating with large poles; and FIG.\",\n \"11 shows dipole illumination with lenticular poles used for double patterning.\",\n \"FIG.\",\n \"12 shows illumination.\",\n \"DETAILED DESCRIPTION In the following description, similar or identical features shown in different figures are designated with the same reference identifications, where appropriate.\",\n \"In optical lithography it is known to use off-axis illumination, which enables smaller features to be faithfully imaged.\",\n \"With this technique, a mask providing the patterned structure (pattern) is illuminated at oblique (non-perpendicular) angles such that process latitude is improved by increasing the depth of focus and/or such that contrast is improved.\",\n \"FIG.\",\n \"1 illustrates this principle in which a beam B of radiation is incident on a mask M carrying a pattern PAT at an opening angle γ inclined to the optical axis OA, which is conventionally vertical.\",\n \"The incident beam B is diffracted by features of the pattern PAT on the mask M, which are to be imaged onto the wafer W coated by a layer of photoresist RES.\",\n \"The zeroth and two first-order-diffracted beams (0, ±1) are shown in FIG.\",\n \"1.Improved performance can be achieved when, for example, at least part of the zeroth order and one of the first orders, which are coherent, are captured by the projection objective PO and used to form the image on the wafer W. The smaller the pitch P (or periodicity length) of features of the pattern on the mask M, the larger the diffraction angle β will be according to β=λ/P, where λ is the nominal operating wavelength of radiation in beam B.\",\n \"If the size of the features decreases and/or their density increases too much, there will come a point at which the pupil of the projection objective PO can no longer capture more than one diffracted order.\",\n \"In practical systems there will be a range of opening angles γ which determines the partial coherence of the light source and thus is important to the figures of merit of the exposure process, such as exposure latitude, depth of focus and proximity effects.\",\n \"The distribution of opening angles γ can be visualized by considering the intensity distribution of the effective radiation source (effective source) or equivalently the intensity distribution in the plane of a pupil of the projection objective.\",\n \"FIGS.\",\n \"2A-2D show representative examples.\",\n \"FIG.\",\n \"2A illustrates a simple on-axis illumination mode characterized by the parameter σ shown by an arrow in the figure.\",\n \"Values of σ (often referred to as coherence factor) are conventionally quoted as the ratio of the radius of the illumination intensity disc (hatched) to the radius of the pupil and therefore take a value between 0 and 1.FIG.\",\n \"2B shows an annular illumination mode in which the intensity distribution of the source is confined to an annulus to limit the range of angles of incidence of the off-axis illumination, considering that the spatial intensity distribution at the pupil plane is related to the angular distribution at the mask plane, which is a Fourier transform plane to the pupil plane.\",\n \"The annulus may be characterized by the values σi and σo, which are the ratios of its inner and outer radii to the radius of the pupil.\",\n \"FIG.\",\n \"2C illustrates the intensity distribution of the quadrupole illumination mode, the use of which sometimes gives improved imaging results to the use of annular or coherent modes.\",\n \"Conventionally, in using such a quadrupole configuration, it is assumed that the patterned structure of the mask to be projected includes sub-patterns of orthogonal lines along x and y axes and the illumination is oriented such that each of the four poles is situated in a respective one of the four quadrants defined by these x and y axes and at their point of intersection.\",\n \"In specific applications it has been found that superior performance can be obtained using dipolar illumination modes.\",\n \"FIG.\",\n \"2D shows an example of the dipolar illumination intensity distribution for a dipole mode.\",\n \"The two poles POLE1, POLE2 of this mode are located off the optical axis OA of the imaging system.\",\n \"For illustrative purposes, the two poles illustrated in FIG.\",\n \"2D are said to lie along the x axis (second direction) and may be optimal for imaging lines extending parallel to the y axis (first direction), i.e.\",\n \"perpendicular to the pole orientation axis POA joining the two poles.\",\n \"Sometimes the x and y axis are referred to as horizontal and vertical, respectively, but these terms typically do not bear any relation to the orientation of the machine.\",\n \"As illustrated in FIG.\",\n \"2D the pole shape of the poles POLE1, POLE2 in conventional systems may correspond to an azimuthal section of an annulus.\",\n \"Due to the desire that the first diffraction order should pass completely through the aperture of the projection objective to obtain maximum contrast, limitations result for the radial width Δσ=σo−σi of the poles and for the azimuthal width (width in circumferential direction) of the poles defined by the pole angle Θ.\",\n \"With dipole illumination, the effective light source is confined to two poles, in order to create the conditions for two-beam imaging with theoretical ideal contrast.\",\n \"FIG.\",\n \"3 illustrates schematically a projection exposure system configured for dipole illumination mode.\",\n \"Primary radiation provided by a primary light source LS is transformed by an illumination system ILL to provide illumination radiation incident on a mask M bearing a pattern PAT.\",\n \"The radiation is diffracted by pattern PAT and forms projection radiation propagating through the projection objective PO, which images the pattern of the mask onto the substrate, which is a wafer W coated with a resist layer RES in the exemplary embodiment.\",\n \"The illumination system ILL includes a pupil shaping unit PSU to create an effective source ES formed by a predefined intensity distribution at a pupil plane PILL of the illumination system, where the predefined intensity distribution is a dipole illumination characterized by two lenticular poles POLE1 and POLE2.The pupil plane PILL, where the effective source ES is formed, is a Fourier transform surface with respect to the object surface of the projection objective PO, where the mask M is situated.\",\n \"Therefore, the spatial distribution of light intensity of the effective source ES determines an angular distribution of illumination radiation incident on the mask M. A condenser system CS is provided to perform the Fourier transformation.\",\n \"The pupil surface PPO of the projection objective is optically conjugated to the pupil surface PILL of the illumination system.\",\n \"Therefore, in the absence of a mask, a spatial intensity distribution equivalent to the intensity distribution at the effective source ES may be formed in the pupil surface PPO of the projection objective.\",\n \"Where a mask bearing a pattern is inserted between the illumination system and the projection objective, the intensity distribution in the pupil plane PPO of the projection objective also contains diffraction information corresponding to the properties of the mask pattern PAT.\",\n \"FIG.\",\n \"4 illustrates schematically a circular pupil PPO of a projection objective having unit radius (length=1) corresponding to the utilized image-side numerical aperture NA at imaging conditions beyond the coherent resolution limit of a periodic pattern of mutually parallel lines running in a first direction (y direction) having periodicity length (pitch) P in a second direction (x direction).\",\n \"A symmetric two-beam interference imaging condition is assumed, where a first diffraction order (+1 or −1) coincides with the zeroth order (0).\",\n \"In this representation, all illumination directions which contribute constructively to two-beam interference correspond to pupil positions lying within the lenticular (lens-shaped) regions LR at opposite edges of the pupil in the x direction.\",\n \"Those lenticular regions (also denoted as “planar circular two-angles” result from a partial overlap of circles of equal size corresponding to neighbouring diffraction orders.\",\n \"A distance d between the centers of the lenticular regions is determined by d=λ/(P*NA).\",\n \"The angular width of the lenticular area (width in circumferential direction) may be defined by a pole angle θ between the opposing corners of the area in the y direction, where pole angle θ is twice the pole half angle α (i.e.\",\n \"θ=2*α).\",\n \"The size of the lenticular area, i.e.\",\n \"the area AOPT of the hatched lenticular region LR in FIG.\",\n \"4, may be calculated as AOPT=θ−sin(θ) with cos(α)=d/2=λ/(2*P*NA).\",\n \"It is contemplated that a maximum contrast is possible if all illumination directions corresponding to pupil positions within the lenticular regions LR are used.\",\n \"The size AOPT of the lenticular regions may be calculated based on the following considerations explained now in connection with FIG.\",\n \"4.The area AOPT is four times the difference between the area AS of the circular sector with sector angle α, and the area AABC of triangle ABC indicated in FIG.\",\n \"4.The difference area AS-AABC is hatched darkly in FIG.\",\n \"4.Calculating the angles in radians, the sector area AS is calculated as follows: AS=(α/2π)·π·r2, where r=1 is the unit radius of the pupil.\",\n \"Therefore, AS=(α/2π)·π=α/2.With distance A−C=cos (α) and distance B−C=sin (α) the area AABC of the triangle calculate as: AABC=(sin (α)·cos (α))/2.Further considering that 2·sin (α)·cos (α)=sin (2·α), the area AOPT of the lenticular region LR calculates as follows: A OPT = 4 · ( A S - A ABC ) = 4 · ( α / 2 - ( sin ( α ) · cos ( α ) ) / 2 ) = 2 · α - sin ( 2 · α ) = θ - sin ( θ ) An illumination pole having the size and shape of a desirable (e.g., optimum) lenticular region LR may be characterized by a pole width PW measured between an inner and an outer pole edge in a direction parallel to the pole orientation axis POA, and a pole height PH measured between pole edges in a direction perpendicular to the pole orientation axis, i.e.\",\n \"in y direction (see FIG.\",\n \"5A).\",\n \"Defining a pole dimension ratio PDR as the aspect ratio between pole PH height and pole width PW according to PDR=PH/PW, for the lenticular regions PDROPT=sin(α)/(1−cos(α)).\",\n \"In conventional systems, only a fraction of those illumination directions is normally used.\",\n \"For illustration purposes, FIG.\",\n \"4 shows conventional poles CP having a shape corresponding to an azimuthal section of an annulus within the lenticular regions LR.\",\n \"Limitations regarding radial width Δσ and pole angle result from the desire that the first diffraction order should fall completely within the aperture of the objective to obtain maximum contrast.\",\n \"As evident from FIG.\",\n \"4, the area of the conventional poles CP is significantly smaller than the area AOPT of the lenticular zones which could be used for the imaging process at good (e.g., optimum) contrast.\",\n \"For example, the size of the conventional poles may be 50% or less of the area AOPT.\",\n \"The pole dimension ratio PDR of a conventional pole usually differs significantly from the pole dimension ratio PDROPT defined above.\",\n \"For example, a circular pole would correspond to PDR=1.The annular segment shaped conventional poles CP depicted schematically in FIG.\",\n \"4 may have varying pole dimension ratio depending on the selected values for Δσ and pole angle.\",\n \"Generally, as the pole height increases, the pole width will decrease, and vice versa.\",\n \"Now consider a lens or another optical element having an optical surface at or close to the pupil surface of the projection objective, where light intensity is concentrated at the edge of the lens surface in regions corresponding to the poles of the dipole illumination.\",\n \"Studies have shown that effects of lens heating may cause characteristic deformations of wavefronts passing the projection objective due to local deformation of the lenses and/or due to localized radiation-induced changes of refractive index.\",\n \"For example, where a dipolar intensity distribution is used, the local deformation of lenses or other optical elements and associated wavefront deformations may be dominated by astigmatic contributions.\",\n \"In the following a number of embodiments are described where a multipolar illumination mode includes at least one substantially dipolar intensity distribution having two illumination poles, where the pole area APOLE of poles is selected to be very close to or equal to the pole area AOPT defined above.\",\n \"Negative effects caused by localized lens heating may be reduced significantly when compared to using conventional poles.\",\n \"FIGS.\",\n \"5A-5C illustrate where the poles POLE 1 and POLE 2 of the dipolar intensity distribution each have a lenticular pole shape defined by two convexly curved edges having opposite sense of curvature and centers of curvature essentially on a line parallel to the pole orientation axis POA.\",\n \"In FIG.\",\n \"5A the size and shape of the poles is adjusted such that the poles exactly fit the lenticular region LR corresponding to the given pitch P of the sub-pattern to be printed.\",\n \"The conditions APOLE=AOPT and PDRPOLE=PDROPT hold for the pole area and pole dimension ratio, respectively.\",\n \"FIG.\",\n \"5B shows an example where all light intensity is concentrated in poles POLE1, POLE2 slightly smaller than the lenticular area by about 10%.\",\n \"Although not all illumination directions theoretically contributing to constructive interference are used in this setting, the intensity of the poles is still distributed over a relatively large area on optical surfaces near pupil surfaces to eliminate or alleviate lens heating problems.\",\n \"In FIG.\",\n \"5C the size of the poles POLE1, POLE2 is slightly larger than the pole area AOPT of poles such that a small fraction of illumination directions falls outside the pupil, thereby not contributing to imaging, and some illumination angles smaller than the lowest limit of the optimum angular distribution according to FIG.\",\n \"4 are also present.\",\n \"As light energy is distributed over relatively large areas around the poles, lens heating problems may be smallest in FIG.\",\n \"5C with potential trade-offs in attainable contrast.\",\n \"Optimum compromise settings may be evaluated by simulation or test exposures.\",\n \"FIGS.\",\n \"6A-6B illustrate schematically one option to generate biconvex, lenticular (lens-shaped shaped) illumination poles as described above in a modified conventional illumination system configured to generate illumination poles having the shape of a segment of an annulus.\",\n \"Illumination systems as described e. g. in U.S. Pat.\",\n \"No.\",\n \"6,452,662 B2 may be used and modified for that purpose.\",\n \"The disclosure of U.S. Pat.\",\n \"No.\",\n \"6,452,662 B2 and U.S. Pat.\",\n \"No.\",\n \"6,855,486 B1 regarding constructive details of illumination systems capable of generating segment shaped pairs of poles are incorporated herein by reference.\",\n \"The adjustable optical elements of the pupil shaping unit of the illumination system are first set to generate, in a pupil surface of the illumination system, a dipolar intensity distribution having two basic poles BP1 and BP2, each having the shape of a segment of an annulus where the outer radius is set to σO=1 and the width of the annular segment is adjusted such that Δσ corresponds to the desired pole width PW of the desired lenticular pole.\",\n \"The pole angle θ is set to correspond to the desired pole angle θ of the lenticular pole (FIG.\",\n \"6A).\",\n \"It is to be noted that conventional systems may need to be modified with respect to the variation width of adjustable elements to allow for those dimensions of the annular segment shaped poles, which may be larger than poles in the conventional system in both the circumferential and the radial direction.\",\n \"The illumination system includes a blocking device BD (FIG.\",\n \"6B) at or close to the pupil surface of the illumination system where the effective source is generated, or at or close to a pupil surface optically conjugate thereto.\",\n \"The blocking device in this embodiment is designed to block those areas at the inner edge of the annulus segment shaped poles which lie outside the lenticular region desired for the pole shape.\",\n \"For that purpose, the blocking device may take the general butterfly shape schematically shown in FIG.\",\n \"6B having “wings” extending in azimuthal direction over an angle θ corresponding to the pole angle, and comprising outer edges concavely curved inwards towards the center of the blocking device to define the inner edge of the lenticular pole.\",\n \"Those areas actually blocked by the blocking device are drawn with diagonal hatching in FIG.\",\n \"6A.\",\n \"When the blocking device is inserted into the appropriate position, the resulting effective light source includes two lenticular poles POLE1 and POLE2 having the pole area AOPT or a slight variation therefrom as described above.\",\n \"An exchanging device allowing to exchange blocking devices having different layout may be provided to allow variation of dimensions of the lenticular poles.\",\n \"Also, a blocking device may be designed to be variable, for example by providing a number of smaller blades arranged in the manner of a fan to allow varying the pole angle θ as desired.\",\n \"The blocking device may also be formed by an opaque coating on a transparent optical element, such as a plate, which may be exchangeable.\",\n \"In FIGS.\",\n \"7A-7B the poles of the dipolar intensity distribution have a parallelogram pole shape defined by a non-rectangular parallelogram having a shorter diagonal D2 and a longer diagonal D1, the shorter diagonal extending substantially parallel to a line parallel to the pole orientation axis POA.\",\n \"FIGS.\",\n \"7A and 7B each show the lenticular regions LR corresponding to the optimum size and shape of poles adapted to a sub-pattern having predominant pitch P. In FIG.\",\n \"7A, each of the poles POLE1 and POLE2 of the dipolar intensity distribution has the shape of a rhombus, i. e. the shape of an equilateral quadrangle arranged mirror symmetric to the pole orientation axis POA.\",\n \"The biconvex, diamond shaped poles are fit into the optimum sized lenticular region LR such that their longer diagonal D1 (extending in y-direction) defines the pole height PH, whereas the shorter diagonal D2 extending between the inner and outer edge of the pole in the second direction (x-direction) corresponds to the pole width PW.\",\n \"The area of each of the rhombohedral poles POLE1, POLE2 is APOLE=(D1*D2)/2, which is smaller than the area AOPT of the optimum sized lenticular region.\",\n \"The difference in area, ΔA, may be calculated according to ΔA=2*α·sin (2*α)−4*sin (α)*(1−cos (α)).\",\n \"As exemplified in FIG.\",\n \"7B, it is not necessary to fit the diamond shaped poles exactly into the optimum lenticular region LR.\",\n \"For example, the rhombohedral poles may be slightly larger such that tips of the rhombohedron in the first direction and/or in the second direction may extend beyond the outer limits of the ideal lenticular region LR.\",\n \"Also, the pole dimension ration PH/PW may deviate from the optimum value, thereby resulting in slightly narrower or wider diamond shaped poles.\",\n \"The deviation may be up to about 10%, for example.\",\n \"Although some loss of contrast might occur, the oversizing of the rhombohedral poles allows to distribute light energy over larger areas at the edges of optical elements near to a pupil, thereby eliminating or decreasing problems associated with localized lens heating.\",\n \"FIG.\",\n \"8 shows a meridional section of an illumination system ILL configured to be used in a projection exposure step-and-scan apparatus.\",\n \"The illumination system includes a plurality of optical elements constructed and arranged to receive primary radiation emitted from a primary light source LS and to generate illumination radiation incident on a mask M bearing a pattern.\",\n \"In the embodiment, the light source LS is an excimer laser emitting primary radiation having a nominal operation wavelength in the deep ultraviolet (DUV) spectral range, for example 193 nm.\",\n \"Primary radiation exciting the light source LS forms a coherent radiation bundle having a small cross-section and low divergence, which corresponds to a small value of geometrical optical flux (etendue).\",\n \"A number of optical elements following the light source LS form a variable pupil shaping unit PSU configured to generate a defined spatial intensity distribution corresponding to a selected illumination mode in a pupil surface PILL of the illumination system.\",\n \"A partial system PS following the pupil surface PILL includes a number of optical elements configured to transform the two-dimensional intensity distribution present in the pupil surface PILL into a corresponding angular distribution of illumination radiation incident on the mask M. The partial system PS includes elements to homogenize the radiation and to sharply define the edges of an illumination field in the exit surface EX of the illumination system, which coincides with the object surface of a subsequent projection objective (see FIG.\",\n \"3).\",\n \"The pupil shaping unit PSU comprises, at an entry side thereof, a beam expansion unit EXP which expands the coherent radiation bundle received from the light source LS.\",\n \"The beam expansion unit includes a number of refractive optical elements diverting the radiation such that the cross-section of the bundle is increased without altering the geometrical optical flux of the bundle.\",\n \"After passing through the beam expansion unit EXP the projection radiation bundle impinges on a first optical raster element RE1 structured to increase divergence of the radiation bundle by introducing propagation angles according to a desired illumination mode.\",\n \"In FIG.\",\n \"8 this is schematically illustrated for an axial ray that is split into two diverging rays R1, R2 after the raster element RE1.The first raster element RE1 modifies the angular distribution of the radiation bundle and also increases the geometrical optical flux thereof.\",\n \"The first raster element RE1 may be formed by a diffractive optical element (DOE) or by a refractive optical element (ROE), for example.\",\n \"Various kinds of optical raster elements are possible, for example a micro-lens array in which micro-lenses are formed by Fresnel zone plates.\",\n \"The first raster element RE1 may be a reflective raster element including an array of mirror segments oriented at different angles (multi-mirror array).\",\n \"First raster element RE1 is arranged in a front focal plane FFP of a zoom/axicon module ZA which includes a zoom lens group Z providing a continuously variable magnification, and an axicon group AX comprising a pair of axicons AX1, AX2, one concave and one convex, whose separation can be varied continuously to allow adjusting a distance between the axicon surfaces between zero distance (contact between axicon surfaces) and preselected finite values.\",\n \"The entire zoom/axicon module ZA is configured as a focal length optical system transforming an angular distribution of radiation in the front focal plane FFP into a desired two-dimensional (spatial) intensity distribution in the rear focal plane RFP, which coincides with the pupil surface PILL of the illumination system.\",\n \"A field defining arrangement FD is positioned in the rear focal plane RFP of the zoom/axicon module ZA.\",\n \"The field defining arrangement is configured to further introduce divergence into the radiation beam, thereby further enlarging the geometrical flux of the radiation beam.\",\n \"The divergence introduced by the field defining arrangement FD is schematically represented by divergent rays downstream of the field defining arrangement.\",\n \"Embodiments of field defining arrangements suitable for this purpose are disclosed, for example, in applicant's international application published as WO 2005/078522 A2, which is incorporated herein by reference in its entirety.\",\n \"The diverging rays exiting the field defining arrangement FD enter an objective OB represented by a single condenser lens.\",\n \"The objective OB is arranged within the illumination systems such that an entrance pupil plane of the objective OB coincides with the exit pupil surface of the zoom/axicon module.\",\n \"The image plane of objective OB, which is a Fourier transform plane to the pupil PILL of the illumination system, is a field plane FP within the illumination system.\",\n \"A reticle masking unit REMA acting as an adjustable field stop is positioned in the field plane FP to define the edges of the illumination field.\",\n \"Details of embodiments may be taken, for example from WO 2005/078522 A2.An imaging objective RO is arranged between the field plane FP and the exit surface ES of the illumination system, where the mask M may be positioned and allows to image the intensity distribution present in the field plane FP onto the mask pattern.\",\n \"FIGS.\",\n \"9A-9b show schematically a detail of a first raster element RE1 configured to generate a substantially dipolar intensity distribution having two illumination poles each having the diamond shape discussed in context of FIG.\",\n \"7.The raster element RE1 is formed by an array of raster segments RS arranged side by side in a mosaic arrangement to cover without interspaces the complete illuminated surface of the raster element RE1.Such arrangement allows to generate the dipolar intensity distribution essentially without blocking any parts of the beam so that there is no intensity loss involved in the generation of the dipolar intensity distribution.\",\n \"The raster element RE1 can be formed by an array of refractive lens segments.\",\n \"Each raster segment RS may be formed by a segment of a lens or a prism where an entry-side surface and an exit-side surface of the raster segment are oriented such that a desired redirection of radiation is caused by refraction at the segment surfaces as the radiation passes through the raster segment.\",\n \"The rhombohedral shape of the raster segments RS determines the shape of the poles in the pupil surface PILL.\",\n \"In FIG.\",\n \"9A the raster segments are numbered “1” and “2” to illustrate which raster segments contribute to the illumination intensity in the two poles POLE1 and POLE2 shown in FIG.\",\n \"9B.\",\n \"The structure of the raster segments is adjusted to redirect at least a major portion of impinging radiation to the two poles.\",\n \"As illustrated by dashed lines in some raster segments of FIG.\",\n \"9A, the raster elements may also be segmented into other shapes, such as triangular raster segments, where the size and shape of the triangles are adapted to define, in combination, a rhombohedral area corresponding to the desired pole shape.\",\n \"In some embodiments, the raster element RE1 may be designed as a diffractive computer generated hologram (CGH) assigning to each of the raster segments RS a diffractive structure effective to redirect light intensity present in a partial beam impinging on the raster segment into the associated pole.\",\n \"The raster segments may have a shape differing from the shape of the desired poles, e.g.\",\n \"a rectangular shape.\",\n \"The diffractive structure may be formed on the surface of a transparent substrate, such as a plane plate made of fused silica or calcium fluoride.\",\n \"The raster segments may also be formed of grooves etched into the surface to provide segments of a Fresnel lenses.\",\n \"The depth and width of the grooves may be in the order of micrometers, for example.\",\n \"Each raster segment may be in the order of millimeters in size and the entire array forming the raster element may have typical dimensions of one or a few centimeters.\",\n \"The basic distribution of angles introduced by the raster element RE1 may be modified within the pupil shaping unit by setting the elements of the variable zoom lens group Z and/or the variable axicon group AX accordingly.\",\n \"In one configuration, the separation between the axicon elements AX1 and AX2 is set to zero (contact between axicon surfaces) such that no radial redirection of light intensity is effected by the axicon group AX.\",\n \"In other configurations, a defined separation may be set, which generally causes a central symmetric dilatation of the radiation intensity distribution, which may be useful in some cases.\",\n \"Adjusting the magnification of the zoom lens group Z allows to adapt the illumination intensity distribution in the pupil surface PILL of the illumination system to different NA values in a homomorphous imaging step.\",\n \"It is to be noted that the conditions for the pole area APOLE, pole height PH and pole width PW as defined above remain unchanged as long as P*NA=2 k1*λ=const.\",\n \"Therefore, the area of the poles as well as the pole height and pole width may be considered as a function of parameter k1 alone, where k1<1 is a process dependent parameter that incorporates everything in a lithography process that is not wavelength or numerical aperture.\",\n \"Generally, any process or system modification that allows improvements in resolution effectively reduces the k1 factor.\",\n \"Diffraction-limited values are 0.25 for incoherent and 0.5 for coherent illumination, for example.\",\n \"Where k1 stays essentially constant, sub-patterns with different predominant periodicity values P (pitches) may be illuminated using one and the same raster element RE1 by simply adjusting the appropriate NA value using the zoom lens group Z.\",\n \"With other words: one type of raster element with fixed configuration, such as a diffractive optical element, may be sufficient for different processes defined by one particular k1 value (or a small variation of k1).\",\n \"Different values for APOLE, PW and/or PH and different pole patterns may also be obtained by providing several different, interchangeable first raster elements.\",\n \"An automatic changer may be used to exchange raster elements of different configuration in the illumination system.\",\n \"In general, the pupil-shaping unit may include at least one optical modulation device configured to controllably change an angular distribution of radiation incident on the optical modulation device such that a desired intensity distribution is obtained in the pupil surface of the illumination system.\",\n \"Although the optical modulation device may have a fixed configuration to obtain only one type of intensity distribution (which may be changeable by additional variable optical elements), it is possible that the optical modulation device has an array of individual elements configured to be driven individually to change the angular distribution of radiation incident on the individual elements.\",\n \"The optical modulation device may include a controllable micro-mirror array, for example.\",\n \"Various optical modulation devices which may be used when modified for that purpose are disclosed in applicant's international patent application published as WO 2005/026843 A2.The disclosure of this application is incorporated herein by reference.\",\n \"FIGS.\",\n \"10A-10B show diagrams illustrating, for an exemplary projection exposure systems, improvements that may be obtained if an optimized dipole setting is used instead of a conventional setting.\",\n \"In the diagrams, pupil coordinates in terms of image-side numerical aperture NA are drawn in the abscissa.\",\n \"The ordinates show values for the phase error value of the overall wavefront aberration.\",\n \"The value “0” corresponding to the optical axis.\",\n \"Each diagram shows an “x-cut” parallel to the x-axis (second direction) and an “y-cut” perpendicular thereto in the first direction.\",\n \"An x-dipole (orientation of pole orientation axis along x-direction) is used for all experiments.\",\n \"A dipole setting having poles with the shape of a segment of an annulus (compare e.g.\",\n \"FIG.\",\n \"2B) was used for the reference example of a conventional dipole setting CONV shown in FIG.\",\n \"10A.\",\n \"An x-dipole setting with lenticular poles with APOLE=AOPT was used for the experiment illustrated in FIG.\",\n \"10B.\",\n \"The x-cut in both experiments illustrates that the localized heating in the region of the poles generally aligned along the x-direction leads to relatively strong wavefront aberrations close to the outer edge of the pupil where the energetic centriods of the poles are positioned.\",\n \"In contrast, essentially no wavefront aberration is caused on and close to the optical axis in the center of the pupil.\",\n \"In the y-direction a relatively large variation of wavefront aberrations occurs superimposed onto a slight gradient from the upper edge to the lower edge of the pupil in this specific type of projection objective used for the experiment.\",\n \"The general characteristics of the local distribution of wavefront aberrations caused by lens heating are quite similar in the experiment according to FIG.\",\n \"10B.\",\n \"Note, however, that the absolute amount of wavefront aberration caused by lens heating is reduced by about a factor two, i.e.\",\n \"reduced to about 50% of the value for the conventional setting in the x-direction (different scales in the ordinates in FIG.\",\n \"10A, in FIG.\",\n \"10B).\",\n \"This significant improvement is attributed to the fact that radiant energy present within the projection beam is distributed over larger areas at the position of the poles, whereby the energy distribution in smeared out over a larger area, thereby reducing associated lens heating effects on wavefront aberrations.\",\n \"The effect is less pronounced in the y-direction.\",\n \"In some embodiments, the multipolar illumination is a pure dipole illumination, where the intensity distribution in the pupil surface of the illumination system is formed by one substantially dipolar intensity distribution having exactly two illumination poles.\",\n \"Such dipole illumination may be used, for example, to print periodic patterns with features essentially aligned in one direction only.\",\n \"As a practical example, a layer of a highly integrated flash memory device may be strongly dominated by lines running in direction only.\",\n \"Due to the relatively large pole height PH of the optimized pole areas those dipole illuminations are also useful to improve contrast of sub-patterns not running at the predominant direction, but at an angle thereto since the dipolar intensity distribution includes illumination directions significantly deviating from the direction defined by the pole orientation axis.\",\n \"The multipolar illumination mode may include two substantially dipolar intensity distributions (“dipoles”) superimposed on each other, where the pole orientation axes of the dipoles are rotated relatively to each other, for example by 90°.\",\n \"FIG.\",\n \"11 depicts schematically the intensity distribution in the illumination pupil for a quadrupole illumination having two pairs of lenticular poles relatively rotated by 90° around the optical axis to form four lenticular poles, POLE1, POLE2, POLE3, POLE 4, where the pole orientation axis POAx of the first dipolar intensity distribution (forming poles POLE1 and POLE2) is oriented along the x-direction, whereas the pole orientation axis POAy of the second dipolar intensity distribution (forming poles POLE3 and POLE4) is oriented perpendicular thereto in the y-direction.\",\n \"A bi-directional pattern having periodic features in x- and y-direction may be printed with high contrast for both directions.\",\n \"The area of each of the poles corresponds approximately to the optimum area AOPT in this example.\",\n \"As illustrated schematically in FIG.\",\n \"12, the method and apparatus may also be used in exposure processes which do not exploit the full resolution potential of the projection exposure apparatus.\",\n \"For example, a multi-polar illumination mode may be set for a pattern or sub-pattern having features spaced apart periodically at a predominant periodicity length P where the condition 0.7*λ/NA<P<λ/NA holds.\",\n \"Those conditions are sometimes used in processes known as “double patterning” where a final structure with very fine pitch is formed by subsequent exposures of coarser pattern relatively shifted to each other by one half of the periodicity length.\",\n \"The corresponding illumination mode may be characterized by two poles POLE1, POLE2 positioned between the edge of the pupil (corresponding to full NA) and the optical axis and defining a distance d<λ/(P*NA).\",\n \"The poles may have a lenticular or a biconvex polygonal shape, for example.\",\n \"The disclosure has been given by way of example.\",\n \"From this information, those skilled in the art will not only understand the disclosure and its attendant advantages, but will also find apparent various changes and modifications to the structures and methods disclosed.\",\n \"The applicant seeks, therefore, to cover all such changes and modifications as fall within the spirit and scope of defined by the appended claims, and equivalents thereof.\",\n \"The contents of the claims are incorporated by reference into the description.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875752"}}},{"rowIdx":4494964,"cells":{"text":{"kind":"list like","value":[["SYSTEM AND METHOD FOR IDENTIFYING, INDEXING, AND NAVIGATING TO DEEP STATES OF MOBILE APPLICATIONS","A mobile application development system includes a developer portal that receives an application from a developer and provides a routing library to the developer to augment the application.","An offline analysis system analyzes the application to (i) determine a set of activities that a handler within the application is programmed to resume in response to respective resumption requests from a host operating system and (ii) determine parameters for each of the activities.","The offline analysis system generates a set of links that each corresponds to a respective one of the activities.","The routing library, installed as part of the augmented application onto a user device, receives a link, from the user device's operating system, that identifies a first activity.","The routing library includes instructions for generating a first resumption request based on parameters corresponding to the first activity and transmitting the first resumption request to the augmented application's handler."],["1.An electronic device comprising: a processor; and a memory electrically connected to the processor, wherein the memory stores instructions which, when executed, direct the processor to install a first application on the electronic device, the first application comprising: a routing library configured to register a link scheme with an operating system of the electronic device, and a handler configured to resume an activity of the first application in response to a request from the routing library.","2.The electronic device of claim 1, wherein the link scheme comprises a scheme providing access to an internal state of the first application.","3.The electronic device of claim 1, wherein the routing library is further configured to: install a business rule specifying a state of the first application that is to be accessible by the handler.","4.The electronic device of claim 3, wherein the routing library is further configured to: install a user interface (UI) event sequence to reach the specified state of the first application that is to be accessible by the handler.","5.The electronic device of claim 4, wherein the routing library is further configured to: download one or more UI event sequences each time the first application is opened.","6.The electronic device of claim 4, wherein the routing library is further configured to: download one or more UI event sequences at predetermined intervals.","7.The electronic device of claim 1, wherein the routing library is further configured to: receive a link from the operating system, wherein the link identifies a first activity; generate a first resumption request based on parameters corresponding to the first activity; and transmit the first resumption request to the handler.","8.The electronic device of claim 5, wherein the link is received as a part of a search result from a second application of the electronic device.","9.The electronic device of claim 8, wherein the link allows a user of the second application access to an internal state of the first application in response to selection of the search result.","10.The electronic device of claim 1, wherein registering the link scheme with the operating system comprises registering a uniform resource identifier (URI) template with the operating system upon installation of the first application.","11.A method providing access to a state of an application on an electronic device, comprising: installing, using at least one processor of the electronic device, a first application on the electronic device; registering, using a routing library of the first application executed by the at least one processor, a link scheme with an operating system of the electronic device; and resuming, using a handler of the first application, an activity of the first application in response to a request from the routing library.","12.The method of claim 11, wherein the link scheme comprises a scheme providing access to an internal state of the first application.","13.The method of claim 11, wherein the method further comprises: installing a business rule specifying a state of the first application that is to be accessible by the handler.","14.The method of claim 13, wherein the method further comprises: installing a user interface (UI) event sequence to reach the specified state of the application that is to be accessible by the handler.","15.The method of claim 14, wherein the method further comprises: downloading one or more UI event sequences each time the first application is opened.","16.The method of claim 14, wherein the method further comprises: downloading one or more UI event sequences at predetermined intervals.","17.The method of claim 11, wherein the method further comprises: receiving a link from the operating system, wherein the link identifies a first activity; generating a first resumption request based on parameters corresponding to the first activity; and transmitting the first resumption request to the handler.","18.The method of claim 17, wherein the link is received as a part of a search result from a second application of the electronic device.","19.The method of claim 11, wherein the registering of the link scheme with the operating system comprises registering a uniform resource identifier (URI) template with the operating system upon installation of the first application.","20.A non-transitory computer readable recording medium having a program recorded thereon, the program implementing a method comprising: installing a first application on an electronic device; registering, using a routing library of the first application, a link scheme with an operating system of the electronic device; and resuming, using a handler of the first application, an activity of the first application in response to a request from the routing library."],["<SOH> BACKGROUND <EOH>This section provides background information related to the present disclosure and is not necessarily prior art.","An application (referred to interchangeably in this disclosure as an “app”), such as a mobile app, may contain multiple deep states.","For example, in an app that rates the quality of restaurants based on social media opinion data, the detail page for each restaurant would be considered a deep state.","Deep states are reachable from within the app through a sequence of user actions that can involve navigating through multiple menu screens (or, views) as well as interactions with user interface elements.","Each of these menu screens and user interface elements can be mediated by a unique view controller associated with that displayed screen.","Usually, these deep states are accessible only from within the app itself web search engines operating outside the app, for example, cannot reach the deep states within the app.","This means that when a user conducts a conventional web search for restaurants and wants to explore one of the returned choices in a specialized restaurant rating app, the user would have to manually copy and paste the name of the selected search result into the search field of the restaurant rating app and command the restaurant ranking app to access its internal deep state corresponding to the selected restaurant.","This represents undesirable additional interaction required of the user.","If deep states of apps could be exposed to external apps and computer processes, the user could enjoy additional functionality and convenience.","For example, the user could begin a search for a suitable restaurant using an Internet-based search server and then, by selecting one of the results of that search, be automatically led to the appropriate deep linked page of a specialized restaurant ranking app.","However, implementing such functionality requires developer effort and requires deep linking expertise that the developer may not possess.","When app development is limited by time, budget, or expertise, deep link functionality for some or even all of the states of an app may not be a high enough priority to get implemented.","Mobile operating systems, such as the iOS operating system from Apple Inc. and the Android operating system from Google Inc., may allow a developer to provide data to the operating system for indexing.","In the iOS operating system, this may take the form of a CSSearchableItem (where the CS stands for Core Spotlight) object.","The developer may implement code that bookmarks certain states of an app by providing information about those states to the operating system.","In the iOS operating system, this may take the form of an NSUserActivity object (where NS stands for NeXTSTEP).","Then, users can perform a search through the operating system, where relevant data or states from the developer's app are identified.","If a user selects one of those activities from an operating system interface, such as a search dialogue or a recent tasks menu, the developer's code can restore the app to the state corresponding to the bookmarked activity.","A bookmarked activity on a first device may even be continued on a different device (assuming the app is also installed on the other device).","Via inter-device communication, the operating system of the first device notifies the operating system of the other device what state the user was most recently interacting with.","In addition, the developer may specify that certain types of data, such as telephone numbers and names from a contact database maintained by the app, be indexed by the operating system.","When a user indicates to the operating system that one of those data objects (for example, a certain contact) is of interest, the developer's code can transition to a state of the app that presents that data object for viewing or editing.","In order to take advantage of these operating system capabilities, the developer may implement code that can restore the app to a state based on indicated activity or data object.","However, these activities and data objects may be known only to the operating system or to search systems maintained by a developer of the operating system.","In other words, third party apps and search services may be unable to access this data and navigate directly to the states or data objects within the app.","Further, developing code to display data objects, index data objects, bookmark activities, and continue activities requires developer effort and may not be accomplished for any of an app's states much less for all of the app's states.","As a result, these enhanced operating system capabilities may not be available for a variety of states of an app and may also not be accessible to third party apps and search systems.","In FIG.","1 , the enhanced operating system functionality is graphically depicted.","On a user device, an operating system 100 executes a first app (referred to as “App A”) 104 .","App A 104 includes a representative set of views, View A 108 - 1 , View B 108 - 2 , View C 108 - 3 , View D 108 - 4 , and View E 108 - 5 (collectively, views 108 ).","The views 108 may be managed by one or more view controllers, which may be developed according to the model-view-controller (MVC) software architecture pattern.","As an example only, App A 104 is a restaurant information app, View A 108 - 1 is a home (or, default) state of App A 104 from which restaurant searches by cuisine, geography, etc.","can be performed.","Continuing the example, View B 108 - 2 is a two-dimensional app interface showing restaurant locations, View C 108 - 3 is a restaurant detail view, View D 108 - 4 is a list of restaurants by cuisine, and View E 108 - 5 is a list of recently-reviewed restaurants.","In various implementations, including this example, a single view may be a template populated with entity-specific data.","For example, View C 108 - 3 may have a visual layout for a restaurant specifying where a photo of the restaurant will be located, the location, size, and font face of the restaurant's name, how reviews will be summarized, etc.","The visual layout view will be instantiated with data corresponding to a specific restaurant from a data store.","App A 104 selects and provides data objects to the operating system 100 for indexing.","For example, App A 104 may provide the names of each of the specific cuisines encompassed by App A 104 .","The operating system 100 can then provide results to users who are searching by that cuisine name.","App A 104 includes an activity handler 112 that receives a continue user activity signal from the operating system 100 .","For example, the continue user activity signal may specify that a certain cuisine type was of interest to a user.","The activity handler 112 then invokes View D 108 - 4 and populates View D 108 - 4 with results corresponding to the specified cuisine.","App A 104 may be selective regarding which cuisines to provide to the operating system 100 for indexing because providing too many data objects may lead to a decrease in their average relevance.","This may cause the operating system 100 to down-rank or even remove indexed objects from search results that do not appear to have high relevance.","App A 104 may, therefore, include programming that indexes a list of the most popular cuisines or cuisines whose names are more likely to be unique to cuisines.","For example, while “American” may be a cuisine name, there is a high false positive rate because this term applies to many other searches than simply cuisine.","However, if a user indicates interest in a cuisine, such as by reviewing the restaurant listings for a certain cuisine one or more times, App A 104 may add that cuisine name to the list of objects to index by the operating system 100 .","In addition, App A 104 may indicate to the operating system 100 , using an activity object, that a user is currently viewing restaurant results for a particular cuisine.","This allows the operating system 100 to maintain essentially a history of activities performed by the user within App A 104 .","In addition, the most recent activity engaged in by the user can be shared with another device, allowing a hand-off of user interaction with that activity from one device to another.","Submitting an activity object to the operating system, allowing later resumption of the activity on the same or another device, is referred to in this disclosure as bookmarking the activity.","Activity objects may be sent to the operating system 100 when the user enters View B 108 - 2 to view restaurant results in a map display.","For example, the activity object sent to the operating system 100 may include a latitude and longitude at a center of the map.","If the user adjusts the center of the map, App A 104 may provide an updated activity object to the operating system 100 indicating the new center point.","App A 104 may further include in the activity object additional data such as filters.","For example, the user may have restricted the displayed results to only those restaurants that are currently open.","This filter may be identified in the activity object provided to the operating system 100 .","The activity handler 112 may receive a continue user activity signal from the operating system 100 indicating that the user is interested in continuing a map view of restaurants at a certain center point with a certain set of filters.","For example only, in the iOS operating system, this may take the form of a continueUserActivity call to the app delegate of the app.","The activity handler 112 then invokes View B 108 - 2 with the provided parameters and presents the user with the desired map view.","The continue user activity signal may have been received from another device on which the user was previously viewing that map display.","As shown in FIG.","1 , the activity handler 112 is programmed to invoke View B 108 - 2 , View D 108 - 4 , and View E 108 - 5 , but not View A 108 - 1 or View C 108 - 3 .","In the operating system 100 , a search index 120 receives data objects from App A 104 .","The search index 120 also receives data objects from other apps and, in some implementations, from the operating system 100 itself, such as the names of frequently-accessed device settings.","For example only, in the iOS operating system, the search index 120 may be referred to as Spotlight and the data objects provided to the search index 120 may take the form of CSSearchableItem objects.","The search index 120 may also receive activity metadata from an activity tracker 124 .","The activity tracker 124 receives activity objects, including from App A 104 .","An activity object may take the form of an NSUserActivity object.","An activity object received by the activity tracker 124 may include metadata similar to that of a data object.","The metadata can be indexed by the search index 120 .","The metadata may take the form of a CSSearchableItemAttributeSet object, which may be the same form used in CSSearchableItem objects.","Activities indicated as public may be shared with a cloud index maintained by the developer of the operating system 100 .","A cloud index interface 128 provides the public activities to the cloud index.","These public activities are selectively indexed by the cloud index, allowing other users to search for and find activities generated by App A 104 even when App A 104 is not installed on their devices.","A handoff controller 132 shares the latest activity with other devices.","In various implementations, the other devices have been authenticated to the handoff controller 132 to indicate that they have permission to receive the latest activities from the present device.","These other devices can, therefore, allow a user to begin an activity on the device where the operating system 100 is executed and resume the activity on another device.","A search interface 136 allows a user to perform a search, such as by entering a text query.","The search index 120 provides relevant search results to the search interface 136 and, upon a user selection, the user-selected result is provided to the activity tracker 124 .","The activity tracker 124 identifies which app corresponds to the user-selected result and sends a continue user activity signal to the relevant app.","The continue user activity signal may include an indicator whether the continue user activity signal pertains to a data object or an activity object."],["<SOH> SUMMARY <EOH>A mobile application development system includes a developer portal and an offline analysis system.","The developer portal is configured to receive a copy of a first application from a first developer and provide a routing library to the first developer for incorporation into the first application prior to the first developer distributing an augmented application via a digital distribution platform.","The routing library is incorporated into the first application to form the augmented application.","The offline analysis system is configured to analyze the first application to (i) determine a set of activities that a handler within the first application is programmed to resume in response to respective resumption requests from a host operating system and (ii) determine parameters for each activity of the set of activities.","The offline analysis system is configured to generate a set of links.","Each link of the set of links corresponds to a respective activity of the set of activities.","The routing library includes instructions configured to, subsequent to installation of the augmented application from the digital distribution platform onto a user device, receive a link from an operating system of the user device.","The link identifies a first activity.","The routing library includes instructions configured to generate a first resumption request based on parameters corresponding to the first activity and transmit the first resumption request to the handler of the augmented application.","In other features, the parameters corresponding to the first activity include an activity type and an activity title.","In other features, the first resumption request is transmitted by a continueUserActivity call to an app delegate of the augmented application.","In other features, the first activity includes an NSUserActivity object.","In other features, the offline analysis system is configured to (i) analyze the first application to determine a set of data objects that the handler within the first application is programmed to access in response to respective resumption requests from the host operating system, (ii) determine parameters for each data object of the set of data objects, and (iii) generate a second set of links.","Each link of the second set of links corresponds to a respective data object of the set of data objects.","The routing library includes instructions configured to, subsequent to installation of the augmented application in the user device, receive a second link from an operating system of the user device.","The second link identifies a first data object.","The instructions are further configured to generate a second resumption request based on parameters corresponding to the first data object and transmit the second resumption request to the handler of the augmented application.","In other features, the first data object is a CSSearchableItem object.","In other features, by incorporating the routing library, the augmented application is configured to register a first uniform resource identifier (URI) template with the operating system upon installation.","The link conforms to the first URI template.","In other features, the first URI template specifies a scheme includes a text string ending with a colon and two forward slashes.","The scheme is unique to the augmented application.","The text string is a concatenation of a text identifier associated with the developer portal and a name of the first application.","The link begins with the scheme.","In other features, the offline analysis system is configured to execute the first application and, during execution, monitor a sequence of user interface (UI) events initiated by an operator starting from an initial state and proceeding to a first state.","The offline analysis system is configured to store the sequence of UI events as a first data structure corresponding to the first state.","The routing library includes instructions configured to, in response to a user of the user device encountering the first state while using the augmented application, transmitting a bookmark to the operating system.","The instructions are configured to, in response to receiving a resumption request indicating the first state from the operating system, replay the sequence of UI events from the first data structure.","In other features, the offline analysis system is configured to execute the first application and, during execution, monitor a sequence of user interface (UI) events initiated by an operator starting from an initial state and proceeding to a first state corresponding to a first data object.","The offline analysis system is configured to store the sequence of UI events as a first data structure corresponding to the first data object.","The routing library includes instructions configured to, in response to execution of the augmented application, selectively transmit the first data object to the operating system.","The instructions are configured to, in response to receiving a resumption request indicating the first data object from the operating system, replay the sequence of UI events from the first data structure.","In other features, the link selectively includes serialized data.","The routing library includes instructions configured to decode the parameters corresponding to the first activity from the serialized data within the link.","In other features, the link selectively includes a unique identifier.","The routing library includes instructions configured to retrieve the parameters corresponding to the first activity based on the unique identifier.","In other features, the mobile application development system includes a data server configured to store a plurality of parameters corresponding to activities determined by the offline analysis system.","The routing library includes instructions configured to, upon the first execution of the augmented application, download the parameters corresponding to at least the first activity from the data server for storage in a data store local to the routing library.","The routing library includes instructions configured to retrieve the parameters corresponding to the first activity from the data store in response to the unique identifier.","A system includes the above mobile application development system and a search system configured to return results to the user device in response to a search commissioned by a user of the user device.","A first result of the returned results includes the link.","In response to selection of the first result by the user, the link is transmitted to the routing library by the operating system.","A method of operating a mobile application development system includes receiving a copy of a first application from a first developer.","The method includes providing a routing library to the first developer for incorporation into the first application prior to the first developer distributing an augmented application via a digital distribution platform.","The routing library is incorporated into the first application to form the augmented application.","The method includes analyzing the first application to (i) determine a set of activities that a handler within the first application is programmed to resume in response to respective resumption requests from a host operating system and (ii) determine parameters for each activity of the set of activities.","The method includes generating a set of links.","Each link of the set of links corresponds to a respective activity of the set of activities.","The routing library includes instructions configured to, subsequent to installation of the augmented application from the digital distribution platform onto a user device.","The instructions are further configured to receive a link from an operating system of the user device.","The link identifies a first activity.","The instructions are further configured to generate a first resumption request based on parameters corresponding to the first activity.","The instructions are further configured to transmit the first resumption request to the handler of the augmented application.","In other features, the parameters corresponding to the first activity include an activity type and an activity title.","In other features, the first resumption request is transmitted by a continueUserActivity call to an app delegate of the augmented application.","In other features, the method includes analyzing the first application to determine a set of data objects that the handler within the first application is programmed to access in response to respective resumption requests from the host operating system.","The method includes determining parameters for each data object of the set of data objects.","The method includes generating a second set of links.","Each link of the second set of links corresponds to a respective data object of the set of data objects.","The routing library includes instructions configured to, subsequent to installation of the augmented application in the user device.","The instructions are further configured to receive a second link from an operating system of the user device.","The second link identifies a first data object.","The instructions are further configured to generate a second resumption request based on parameters corresponding to the first data object.","The instructions are further configured to transmit the second resumption request to the handler of the augmented application.","In other features, the first data object is a CSSearchableItem object.","In other features, by incorporating the routing library, the augmented application is configured to register a first uniform resource identifier (URI) template with the operating system upon installation.","The link conforms to the first URI template.","In other features, the method includes executing the first application and, during execution, monitoring a sequence of user interface (UI) events initiated by an operator starting from an initial state and proceeding to a first state.","The method includes storing the sequence of UI events as a first data structure corresponding to the first state.","The routing library includes instructions configured to, in response to a user of the user device encountering the first state while using the augmented application, transmitting a bookmark to the operating system.","The instructions are further configured to, in response to receiving a resumption request indicating the first state from the operating system, replay the sequence of UI events from the first data structure.","In other features, the method includes executing the first application and, during execution, monitor a sequence of user interface (UI) events initiated by an operator starting from an initial state and proceeding to a first state corresponding to a first data object.","The method includes storing the sequence of UI events as a first data structure corresponding to the first data object.","The routing library includes instructions configured to, in response to execution of the augmented application, selectively transmit the first data object to the operating system.","The instructions are further configured to, in response to receiving a resumption request indicating the first data object from the operating system, replay the sequence of UI events from the first data structure.","In other features, the link selectively includes serialized data.","The routing library includes instructions configured to decode the parameters corresponding to the first activity from the serialized data within the link.","In other features, the link selectively includes a unique identifier.","The routing library includes instructions configured to retrieve the parameters corresponding to the first activity based on the unique identifier.","In other features, the method includes storing, in a data store, a plurality of parameters corresponding to the determined set of activities.","The routing library includes instructions configured to, upon first execution of the augmented application, download the parameters corresponding to at least the first activity from the data store for storage in a data store local to the routing library.","The routing library includes instructions configured to retrieve the parameters corresponding to the first activity from the data store in response to the unique identifier.","Further areas of applicability of the present disclosure will become apparent from the detailed description, the claims, and the drawings.","The detailed description and specific examples are intended for purposes of illustration only and are not intended to limit the scope of the disclosure."],["CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation application of prior application Ser.","No.","15/236,140, filed on Aug. 12, 2016, which claimed the benefit of U.S.","Provisional Application No.","62/274,152, filed Dec. 31, 2015, U.S.","Provisional Application No.","62/252,357, filed Nov. 6, 2015, and U.S.","Provisional Application No.","62/204,960, filed Aug. 13, 2015.The entire disclosures of the applications referenced above are incorporated by reference.","FIELD The present disclosure relates generally to mobile application development and more specifically to deep linking to specific states of mobile applications.","BACKGROUND This section provides background information related to the present disclosure and is not necessarily prior art.","An application (referred to interchangeably in this disclosure as an “app”), such as a mobile app, may contain multiple deep states.","For example, in an app that rates the quality of restaurants based on social media opinion data, the detail page for each restaurant would be considered a deep state.","Deep states are reachable from within the app through a sequence of user actions that can involve navigating through multiple menu screens (or, views) as well as interactions with user interface elements.","Each of these menu screens and user interface elements can be mediated by a unique view controller associated with that displayed screen.","Usually, these deep states are accessible only from within the app itself web search engines operating outside the app, for example, cannot reach the deep states within the app.","This means that when a user conducts a conventional web search for restaurants and wants to explore one of the returned choices in a specialized restaurant rating app, the user would have to manually copy and paste the name of the selected search result into the search field of the restaurant rating app and command the restaurant ranking app to access its internal deep state corresponding to the selected restaurant.","This represents undesirable additional interaction required of the user.","If deep states of apps could be exposed to external apps and computer processes, the user could enjoy additional functionality and convenience.","For example, the user could begin a search for a suitable restaurant using an Internet-based search server and then, by selecting one of the results of that search, be automatically led to the appropriate deep linked page of a specialized restaurant ranking app.","However, implementing such functionality requires developer effort and requires deep linking expertise that the developer may not possess.","When app development is limited by time, budget, or expertise, deep link functionality for some or even all of the states of an app may not be a high enough priority to get implemented.","Mobile operating systems, such as the iOS operating system from Apple Inc. and the Android operating system from Google Inc., may allow a developer to provide data to the operating system for indexing.","In the iOS operating system, this may take the form of a CSSearchableItem (where the CS stands for Core Spotlight) object.","The developer may implement code that bookmarks certain states of an app by providing information about those states to the operating system.","In the iOS operating system, this may take the form of an NSUserActivity object (where NS stands for NeXTSTEP).","Then, users can perform a search through the operating system, where relevant data or states from the developer's app are identified.","If a user selects one of those activities from an operating system interface, such as a search dialogue or a recent tasks menu, the developer's code can restore the app to the state corresponding to the bookmarked activity.","A bookmarked activity on a first device may even be continued on a different device (assuming the app is also installed on the other device).","Via inter-device communication, the operating system of the first device notifies the operating system of the other device what state the user was most recently interacting with.","In addition, the developer may specify that certain types of data, such as telephone numbers and names from a contact database maintained by the app, be indexed by the operating system.","When a user indicates to the operating system that one of those data objects (for example, a certain contact) is of interest, the developer's code can transition to a state of the app that presents that data object for viewing or editing.","In order to take advantage of these operating system capabilities, the developer may implement code that can restore the app to a state based on indicated activity or data object.","However, these activities and data objects may be known only to the operating system or to search systems maintained by a developer of the operating system.","In other words, third party apps and search services may be unable to access this data and navigate directly to the states or data objects within the app.","Further, developing code to display data objects, index data objects, bookmark activities, and continue activities requires developer effort and may not be accomplished for any of an app's states much less for all of the app's states.","As a result, these enhanced operating system capabilities may not be available for a variety of states of an app and may also not be accessible to third party apps and search systems.","In FIG.","1, the enhanced operating system functionality is graphically depicted.","On a user device, an operating system 100 executes a first app (referred to as “App A”) 104.App A 104 includes a representative set of views, View A 108-1, View B 108-2, View C 108-3, View D 108-4, and View E 108-5 (collectively, views 108).","The views 108 may be managed by one or more view controllers, which may be developed according to the model-view-controller (MVC) software architecture pattern.","As an example only, App A 104 is a restaurant information app, View A 108-1 is a home (or, default) state of App A 104 from which restaurant searches by cuisine, geography, etc.","can be performed.","Continuing the example, View B 108-2 is a two-dimensional app interface showing restaurant locations, View C 108-3 is a restaurant detail view, View D 108-4 is a list of restaurants by cuisine, and View E 108-5 is a list of recently-reviewed restaurants.","In various implementations, including this example, a single view may be a template populated with entity-specific data.","For example, View C 108-3 may have a visual layout for a restaurant specifying where a photo of the restaurant will be located, the location, size, and font face of the restaurant's name, how reviews will be summarized, etc.","The visual layout view will be instantiated with data corresponding to a specific restaurant from a data store.","App A 104 selects and provides data objects to the operating system 100 for indexing.","For example, App A 104 may provide the names of each of the specific cuisines encompassed by App A 104.The operating system 100 can then provide results to users who are searching by that cuisine name.","App A 104 includes an activity handler 112 that receives a continue user activity signal from the operating system 100.For example, the continue user activity signal may specify that a certain cuisine type was of interest to a user.","The activity handler 112 then invokes View D 108-4 and populates View D 108-4 with results corresponding to the specified cuisine.","App A 104 may be selective regarding which cuisines to provide to the operating system 100 for indexing because providing too many data objects may lead to a decrease in their average relevance.","This may cause the operating system 100 to down-rank or even remove indexed objects from search results that do not appear to have high relevance.","App A 104 may, therefore, include programming that indexes a list of the most popular cuisines or cuisines whose names are more likely to be unique to cuisines.","For example, while “American” may be a cuisine name, there is a high false positive rate because this term applies to many other searches than simply cuisine.","However, if a user indicates interest in a cuisine, such as by reviewing the restaurant listings for a certain cuisine one or more times, App A 104 may add that cuisine name to the list of objects to index by the operating system 100.In addition, App A 104 may indicate to the operating system 100, using an activity object, that a user is currently viewing restaurant results for a particular cuisine.","This allows the operating system 100 to maintain essentially a history of activities performed by the user within App A 104.In addition, the most recent activity engaged in by the user can be shared with another device, allowing a hand-off of user interaction with that activity from one device to another.","Submitting an activity object to the operating system, allowing later resumption of the activity on the same or another device, is referred to in this disclosure as bookmarking the activity.","Activity objects may be sent to the operating system 100 when the user enters View B 108-2 to view restaurant results in a map display.","For example, the activity object sent to the operating system 100 may include a latitude and longitude at a center of the map.","If the user adjusts the center of the map, App A 104 may provide an updated activity object to the operating system 100 indicating the new center point.","App A 104 may further include in the activity object additional data such as filters.","For example, the user may have restricted the displayed results to only those restaurants that are currently open.","This filter may be identified in the activity object provided to the operating system 100.The activity handler 112 may receive a continue user activity signal from the operating system 100 indicating that the user is interested in continuing a map view of restaurants at a certain center point with a certain set of filters.","For example only, in the iOS operating system, this may take the form of a continueUserActivity call to the app delegate of the app.","The activity handler 112 then invokes View B 108-2 with the provided parameters and presents the user with the desired map view.","The continue user activity signal may have been received from another device on which the user was previously viewing that map display.","As shown in FIG.","1, the activity handler 112 is programmed to invoke View B 108-2, View D 108-4, and View E 108-5, but not View A 108-1 or View C 108-3.In the operating system 100, a search index 120 receives data objects from App A 104.The search index 120 also receives data objects from other apps and, in some implementations, from the operating system 100 itself, such as the names of frequently-accessed device settings.","For example only, in the iOS operating system, the search index 120 may be referred to as Spotlight and the data objects provided to the search index 120 may take the form of CSSearchableItem objects.","The search index 120 may also receive activity metadata from an activity tracker 124.The activity tracker 124 receives activity objects, including from App A 104.An activity object may take the form of an NSUserActivity object.","An activity object received by the activity tracker 124 may include metadata similar to that of a data object.","The metadata can be indexed by the search index 120.The metadata may take the form of a CSSearchableItemAttributeSet object, which may be the same form used in CSSearchableItem objects.","Activities indicated as public may be shared with a cloud index maintained by the developer of the operating system 100.A cloud index interface 128 provides the public activities to the cloud index.","These public activities are selectively indexed by the cloud index, allowing other users to search for and find activities generated by App A 104 even when App A 104 is not installed on their devices.","A handoff controller 132 shares the latest activity with other devices.","In various implementations, the other devices have been authenticated to the handoff controller 132 to indicate that they have permission to receive the latest activities from the present device.","These other devices can, therefore, allow a user to begin an activity on the device where the operating system 100 is executed and resume the activity on another device.","A search interface 136 allows a user to perform a search, such as by entering a text query.","The search index 120 provides relevant search results to the search interface 136 and, upon a user selection, the user-selected result is provided to the activity tracker 124.The activity tracker 124 identifies which app corresponds to the user-selected result and sends a continue user activity signal to the relevant app.","The continue user activity signal may include an indicator whether the continue user activity signal pertains to a data object or an activity object.","SUMMARY A mobile application development system includes a developer portal and an offline analysis system.","The developer portal is configured to receive a copy of a first application from a first developer and provide a routing library to the first developer for incorporation into the first application prior to the first developer distributing an augmented application via a digital distribution platform.","The routing library is incorporated into the first application to form the augmented application.","The offline analysis system is configured to analyze the first application to (i) determine a set of activities that a handler within the first application is programmed to resume in response to respective resumption requests from a host operating system and (ii) determine parameters for each activity of the set of activities.","The offline analysis system is configured to generate a set of links.","Each link of the set of links corresponds to a respective activity of the set of activities.","The routing library includes instructions configured to, subsequent to installation of the augmented application from the digital distribution platform onto a user device, receive a link from an operating system of the user device.","The link identifies a first activity.","The routing library includes instructions configured to generate a first resumption request based on parameters corresponding to the first activity and transmit the first resumption request to the handler of the augmented application.","In other features, the parameters corresponding to the first activity include an activity type and an activity title.","In other features, the first resumption request is transmitted by a continueUserActivity call to an app delegate of the augmented application.","In other features, the first activity includes an NSUserActivity object.","In other features, the offline analysis system is configured to (i) analyze the first application to determine a set of data objects that the handler within the first application is programmed to access in response to respective resumption requests from the host operating system, (ii) determine parameters for each data object of the set of data objects, and (iii) generate a second set of links.","Each link of the second set of links corresponds to a respective data object of the set of data objects.","The routing library includes instructions configured to, subsequent to installation of the augmented application in the user device, receive a second link from an operating system of the user device.","The second link identifies a first data object.","The instructions are further configured to generate a second resumption request based on parameters corresponding to the first data object and transmit the second resumption request to the handler of the augmented application.","In other features, the first data object is a CSSearchableItem object.","In other features, by incorporating the routing library, the augmented application is configured to register a first uniform resource identifier (URI) template with the operating system upon installation.","The link conforms to the first URI template.","In other features, the first URI template specifies a scheme includes a text string ending with a colon and two forward slashes.","The scheme is unique to the augmented application.","The text string is a concatenation of a text identifier associated with the developer portal and a name of the first application.","The link begins with the scheme.","In other features, the offline analysis system is configured to execute the first application and, during execution, monitor a sequence of user interface (UI) events initiated by an operator starting from an initial state and proceeding to a first state.","The offline analysis system is configured to store the sequence of UI events as a first data structure corresponding to the first state.","The routing library includes instructions configured to, in response to a user of the user device encountering the first state while using the augmented application, transmitting a bookmark to the operating system.","The instructions are configured to, in response to receiving a resumption request indicating the first state from the operating system, replay the sequence of UI events from the first data structure.","In other features, the offline analysis system is configured to execute the first application and, during execution, monitor a sequence of user interface (UI) events initiated by an operator starting from an initial state and proceeding to a first state corresponding to a first data object.","The offline analysis system is configured to store the sequence of UI events as a first data structure corresponding to the first data object.","The routing library includes instructions configured to, in response to execution of the augmented application, selectively transmit the first data object to the operating system.","The instructions are configured to, in response to receiving a resumption request indicating the first data object from the operating system, replay the sequence of UI events from the first data structure.","In other features, the link selectively includes serialized data.","The routing library includes instructions configured to decode the parameters corresponding to the first activity from the serialized data within the link.","In other features, the link selectively includes a unique identifier.","The routing library includes instructions configured to retrieve the parameters corresponding to the first activity based on the unique identifier.","In other features, the mobile application development system includes a data server configured to store a plurality of parameters corresponding to activities determined by the offline analysis system.","The routing library includes instructions configured to, upon the first execution of the augmented application, download the parameters corresponding to at least the first activity from the data server for storage in a data store local to the routing library.","The routing library includes instructions configured to retrieve the parameters corresponding to the first activity from the data store in response to the unique identifier.","A system includes the above mobile application development system and a search system configured to return results to the user device in response to a search commissioned by a user of the user device.","A first result of the returned results includes the link.","In response to selection of the first result by the user, the link is transmitted to the routing library by the operating system.","A method of operating a mobile application development system includes receiving a copy of a first application from a first developer.","The method includes providing a routing library to the first developer for incorporation into the first application prior to the first developer distributing an augmented application via a digital distribution platform.","The routing library is incorporated into the first application to form the augmented application.","The method includes analyzing the first application to (i) determine a set of activities that a handler within the first application is programmed to resume in response to respective resumption requests from a host operating system and (ii) determine parameters for each activity of the set of activities.","The method includes generating a set of links.","Each link of the set of links corresponds to a respective activity of the set of activities.","The routing library includes instructions configured to, subsequent to installation of the augmented application from the digital distribution platform onto a user device.","The instructions are further configured to receive a link from an operating system of the user device.","The link identifies a first activity.","The instructions are further configured to generate a first resumption request based on parameters corresponding to the first activity.","The instructions are further configured to transmit the first resumption request to the handler of the augmented application.","In other features, the parameters corresponding to the first activity include an activity type and an activity title.","In other features, the first resumption request is transmitted by a continueUserActivity call to an app delegate of the augmented application.","In other features, the method includes analyzing the first application to determine a set of data objects that the handler within the first application is programmed to access in response to respective resumption requests from the host operating system.","The method includes determining parameters for each data object of the set of data objects.","The method includes generating a second set of links.","Each link of the second set of links corresponds to a respective data object of the set of data objects.","The routing library includes instructions configured to, subsequent to installation of the augmented application in the user device.","The instructions are further configured to receive a second link from an operating system of the user device.","The second link identifies a first data object.","The instructions are further configured to generate a second resumption request based on parameters corresponding to the first data object.","The instructions are further configured to transmit the second resumption request to the handler of the augmented application.","In other features, the first data object is a CSSearchableItem object.","In other features, by incorporating the routing library, the augmented application is configured to register a first uniform resource identifier (URI) template with the operating system upon installation.","The link conforms to the first URI template.","In other features, the method includes executing the first application and, during execution, monitoring a sequence of user interface (UI) events initiated by an operator starting from an initial state and proceeding to a first state.","The method includes storing the sequence of UI events as a first data structure corresponding to the first state.","The routing library includes instructions configured to, in response to a user of the user device encountering the first state while using the augmented application, transmitting a bookmark to the operating system.","The instructions are further configured to, in response to receiving a resumption request indicating the first state from the operating system, replay the sequence of UI events from the first data structure.","In other features, the method includes executing the first application and, during execution, monitor a sequence of user interface (UI) events initiated by an operator starting from an initial state and proceeding to a first state corresponding to a first data object.","The method includes storing the sequence of UI events as a first data structure corresponding to the first data object.","The routing library includes instructions configured to, in response to execution of the augmented application, selectively transmit the first data object to the operating system.","The instructions are further configured to, in response to receiving a resumption request indicating the first data object from the operating system, replay the sequence of UI events from the first data structure.","In other features, the link selectively includes serialized data.","The routing library includes instructions configured to decode the parameters corresponding to the first activity from the serialized data within the link.","In other features, the link selectively includes a unique identifier.","The routing library includes instructions configured to retrieve the parameters corresponding to the first activity based on the unique identifier.","In other features, the method includes storing, in a data store, a plurality of parameters corresponding to the determined set of activities.","The routing library includes instructions configured to, upon first execution of the augmented application, download the parameters corresponding to at least the first activity from the data store for storage in a data store local to the routing library.","The routing library includes instructions configured to retrieve the parameters corresponding to the first activity from the data store in response to the unique identifier.","Further areas of applicability of the present disclosure will become apparent from the detailed description, the claims, and the drawings.","The detailed description and specific examples are intended for purposes of illustration only and are not intended to limit the scope of the disclosure.","DRAWINGS The drawings described herein are for illustrative purposes only of selected embodiments and not all possible implementations and are not intended to limit the scope of the present disclosure.","FIG.","1 is a graphical illustration and functional block diagram of an example app interacting with operating system app indexing functionality.","FIG.","2 is a high-level functional block diagram of a mobile application environment according to the principles of the present disclosure.","FIG.","3A is a functional block diagram of an example implementation of integration of a routing library with an example app.","FIG.","3B is a functional block diagram of an example integration of routing library with another example app.","FIG.","4 is a functional block diagram of an example implementation of a routing library.","FIG.","5 is a flowchart of example overall operation of a mobile application ecosystem according to the principles of the present disclosure.","FIG.","6 is a flowchart of example operation of a routing library.","FIG.","7 is a flowchart of example operation of activity and link handling within a routing library.","FIG.","8 is a flowchart of example traversal of a breadcrumb to reach a specified state.","FIG.","9 is a functional block diagram of an example implementation of the search system of FIG.","2.FIG.","10 is a flowchart of example operation of deep link creation and provision to user devices according to the principles of the present disclosure.","FIG.","11 is a functional block diagram of an example implementation of an offline analysis system.","FIG.","12 is a flowchart of example operation of breadcrumb creation for an app as part of offline analysis.","FIG.","13 is a flowchart of extrapolation as part of offline analysis to identify additional states of interest.","Corresponding reference numerals indicate corresponding parts throughout the several views of the drawings.","DETAILED DESCRIPTION Introduction A developer of an app may write code to take advantage of operating system (OS) functionality that allows, in one example, an activity within the app to be bookmarked for the user to return to later or for the activity to be resumed on another of the user's devices.","The developer may also write code that submits data to the OS for indexing so that the OS can surface the data, such as in response to an OS-wide search.","In order to implement this functionality, the developer writes code that allows the app to resume to an activity indicated by the OS or to a state that interacts with a data object specified by the OS.","In some implementations, the activity object received from the OS fully specifies the activity for the app to resume, even if this particular copy of the app has not performed that activity previously.","Meanwhile, for data objects, some apps may be able to show a state of the app corresponding to a certain data object only if that data object has been stored by the present copy of the app.","In other implementations, or for certain apps, certain data objects may fully specify the state to which the app should return to view that data object.","This generally means that the data for the data object is either known by the app, accessible to the app, or provided to the app from the OS within the continue user activity request.","For data objects that do not fully specify the state of an app, these data objects may be specific to the app where they were created, and cannot be accessed by other copies of the app.","Even though the developer may have implemented, for some or all states and for some or all data objects, the ability to resume that activity or navigate to that data object, there may be no provision for third parties, such as search services or other apps, to directly link to those activities or data objects within the app.","The present disclosure identifies activities implemented by the developer and provides a library that, when presented with an appropriate deep link, can invoke the internal activity handling of the app.","This allows the developer's efforts in interacting with the OS to be leveraged to provide deep link access to third parties.","For some apps, the developer may not have implemented OS search functionality for some states and for some data.","For some apps, the developer may not have implemented that functionality for any states or any data.","The present disclosure, therefore, describes how the developer can specify which states of an app should have this functionality enabled.","The present disclosure describes how the application can be supplemented to enable this functionality for the app, such as by recording sequences of user interface events that can be replayed to reach deep states of the app.","When a routing library according to the principles of the present disclosure is used to enable activity bookmarking and data indexing, the configuration of the routing library may be specified by the developer.","In various implementations, an agent of the developer may be able to make configuration decisions, such as which states to bookmark and which data to index, and those configuration decisions are relayed to the routing library.","In various implementations, the routing library may periodically update this configuration so that the developer can change the configuration even for apps already installed on devices.","A developer portal may allow even non-programmers working with the developer to specify business rules.","For example, a marketing or user experience professional at the developer may specify what data to submit to the OS for indexing in order to optimize the search relevancy of the app for a given OS.","A developer portal according to the present disclosure provides a routing library to the developer for integration into an app, and that routing library implements the above functionality.","For example, based on configuration data, the routing library may bookmark certain activities with the OS and may submit certain data objects for indexing to the OS.","The configuration data may be generated at the time of onboarding the app, and may be generated manually, with artificial intelligence, or with operator-supplemented artificial intelligence.","In addition, the routing library may service continuing activity requests from the OS, such as by executing a series of user interface events to return to the selective activity or to display the selected data.","The routing library may also handle incoming links, such as from other apps or from browser instances.","The routing library may take the form of a dynamic link library (DLL), a dylib, or a software development kit (SDK).","The routing library may be downloaded by the developer and imported into the integrated development environment (IDE) of the developer, such as the Xcode IDE from Apple Inc.","In some implementations, the routing library is either already compiled or includes make files and other configuration files allowing the routing library to be compiled.","The developer may integrate the routing library simply by instructing the IDE to add the routing library to their app's project, such as by adding the routing library to an import list or to a list of included code modules.","The developer may also need to update a configuration file to indicate that the routing library will handle certain uniform resource identifiers (URIs) or activity types.","The configuration file may take the form of an information property list (Info.plist) file.","In various implementations, a script may be provided along with the routing library that performs the configuration file update as well as the import of the routing library into the current IDE project.","Meanwhile, the developer portal supplies the app to an offline analysis system that determines how to access states of interest.","The states of interest may be specified by the app developer or determined by the developer portal.","In brief, an offline analysis system of the developer portal determines what sequence of user interface (UI) actions a user would take to reach a state of interest.","That UI action sequence can be replayed by the routing library within an app on a user's device to arrive at the state of interest.","In other words, the routing library simulates the UI actions users would themselves perform to reach a deep state.","By simulating the UI actions, the routing library avoids the user having to perform each UI action and will generally be far faster than a user manually performing the sequence of UI actions.","The user may not even see some of the intermediate states when the routing library is navigating to the deep state of interest, or these intermediate states may only be visible briefly.","The UI action sequences for the deep states of an app may be integrated into the app along with the routing library, or may be downloaded by the routing library once the app is installed.","In some implementations, a UI action sequence can be encoded as part of a link designating the app and serviced by the routing library.","Without further effort from the developer, the app now has deep link functionality that can be accessed from external sources.","For example, a search system could provide results that lead directly to deep states of the app.","Or a third party app could easily direct users to deep states of the app.","This may increase the visibility of the app and allow for tighter integration and better overall user experience with the app.","In addition, now that the developer portal is responsible for deep linking, deep links can be added or modified without requiring assistance from the developer's software programmers, who may be working on other projects and have other priorities.","In other words, a business person, such as an advertising or marketing professional working for an app developer, may use the developer portal to identify which states of the app should be deep-linkable.","The business person could even remove states from the list of deep-linked states, all without requiring the assistance of a software programmer.","Block Diagram In FIG.","2, additional details are presented.","As noted above, a developer 204 provides an app (referred to as “App A”) to a developer portal 208.The developer portal 208 provides a copy of a routing library to the developer 204 for incorporation into App A, creating an augmented version of App A.","The developer 204 provides the augmented App A, which is still referred to below as App A for simplicity, to a digital distribution platform 212 for distribution to end users.","The digital distribution platform 212 provides native apps to user devices and may be specific to an OS.","Example digital distribution platforms include the GOOGLE PLAY digital distribution platform by Google, Inc., the APP STORE digital distribution platform by Apple, Inc., and the WINDOWS PHONE digital distribution platform by Microsoft Corp.","If the developer 204 had already provided App A to the digital distribution platform 212 before augmentation with the routing library, the developer 204 can release the augmented App A as a new version of App A.","The user of a user device 220 installs App A (as augmented) from the digital distribution platform 212.In the user device 220, one or more processors (which may encompass general purpose processors as well as additional co-processors, such as physical sensor processors and graphics processors) execute instructions from memory.","Some of these instructions correspond to an operating system 224, a browser 228, an installed copy of App A (referred to as App A 232), and a third party app (App B 236).","The operating system 224 includes an installed app registry 240 and a link router 244.The link router 244 receives links, such as URLs (uniform resource locators) and URIs (uniform resource identifiers), and determines how to handle those links.","Generally, the link router 244 handles a link by forwarding it to a registered receiver.","The link router 244 checks the installed app registry 240 to determine whether an app has claimed a particular scheme, domain, or other filter that matches the link.","If not, the link may be passed to the browser 228, which may have registered a set of schemes for protocols such as HTTP (hypertext transfer protocol), HTTPS (HTTP secure), FTP (file transfer protocol), Telnet, and Gopher.","In some implementations, when the link specifies a web server address, the link router 244 may contact the web server to obtain a list of authorized apps.","In this way, the link router 244 verifies that an app that has registered a certain domain is authorized by that domain to handle links.","This prevents apps from commandeering links to which they're not eligible.","If an app that has registered a domain is authorized by the web server host of that domain, the link router 244 can provide the link to the registered app.","Routing library 260, received from the developer portal 208, causes App A 232 to register a specific scheme or domain with the installed app registry 240.The scheme may be based on an identifier of the developer portal 208 as well as an identifier of App A.","For example, a test string associated with the developer portal 208 (such as “portal”) may be concatenated with a text string corresponding to App A (such as “appa”).","As a specific example, the scheme registered by App A 232 may be “portal-appa://”.","In other implementations, the text string associated with the developer portal 208 may not be human-readable.","When the link router 244 receives a link, such as from the browser 228, where the scheme matches “portal-appa://”, the link router 244 forwards that link to App A 232, where the link is received and handled by the routing library 260.The routing library 260 parses the link and navigates to a deep state indicated by the link.","For illustration only, in FIG.","2, View A 268-1, View B 268-2, and View C 268-3 (collectively, views 268) are shown.","In many apps, more than three views will be present.","In various implementations, multiple or all views may be controlled by a single view controller.","In other implementations, each view may be controlled by a separate view controller.","For illustration only, the routing library 260 is shown simulating events from a predetermined UI event sequence identified by an example link.","The link is received by the routing library 260 and corresponds to a deep state, specifically View C 268-3.The UI event sequence includes a first UI event, causing App A 232 to transition from View A 268-1 to View B 268-2, a second UI event, in which App A remains in View B 268-2, and then a third UI event, causing App A 232 to transition from View B 268-2 to View C 268-3.The routing library 260 would simulate these UI events in series.","A search system 272 of the operating system 224 receives data and activity objects from the routing library 260.The routing library 260 provides the data objects for indexing and the activity objects for bookmarking.","The search system 272 allows a user to search for data and/or activities from App A 232.When the user selects an activity corresponding to App A 232, the search system 272 sends an indication of a selected activity to the routing library 260.The search system 272 is shown in more detail in FIG.","3A and FIG.","3B.","In parallel with providing the routing library from the developer portal 208 to the developer 204, the developer portal 208 provides App A to an offline analysis system 280.The copy of App A provided to the developer portal 208 may be a standard release build, such as an iOS App Store Package (ipa file).","In other implementations, the copy of App A provided to the developer portal 208 may be a special build that allows App A to be run in a simulator, and may include symbols, debugging info, and/or source code that would not ordinarily be present in an app distributed by the digital distribution platform 212.This may allow the offline analysis system 280 to more efficiently or accurately analyze App A.","For example, the copy of App A may be a debug build designed to run in the Simulator application from Apple, Inc. on the OS X operating system.","By contrast, the version of App A distributed by the digital distribution platform 212 is a standard release build.","The offline analysis system 280, as described in more detail below, determines UI event sequences that can be used by the routing library 260 to reach specific views of App A 232.A UI event sequence may be referred to as a breadcrumb trail composed of an ordered sequence of individual breadcrumbs (that is, UI events).","For simplicity, in the remainder of this disclosure, the term breadcrumb will be used to refer to a breadcrumb trail.","The offline analysis system 280 may provide the determined breadcrumbs to a data server 284.The data server 284 includes a data store, such as a relational database, that stores breadcrumbs for each app processed by the offline analysis system 280.Each deep state of an app is associated with a corresponding breadcrumb.","In some implementations, the data server 284 may be implemented as a cloud-based block storage service, such as the S3 (Simple Storage Service) service available from Amazon Web Services.","Access mechanisms define how deep states can be reached for such purposes as display advertisements and deep search results.","For example, a search result may correspond to a specific deep state of an app.","The search result may be a deep view card (DVC, see below) with a link including or indicating a breadcrumb corresponding to that deep state.","Other potential access mechanisms for the search result may include a native deep link prepared by the app developer itself, or a standard URL pointing to a web edition of the app.","One of the available access mechanisms may be selected by a search system and provided along with the search result to a search client.","In other implementations, multiple access mechanisms may be provided within the search result, and the search client determines which access mechanism to use in response to user selection of the search result.","For example, a breadcrumb-based access mechanism may be chosen over a web-based access mechanism when business rules indicate a preference for results to render in native apps instead of in web editions of those apps.","The breadcrumb-based access mechanism, however, may only be available when the app is already installed.","In some implementations, the search client may incorporate, or receive as part of the search result, code that scripts downloading and installing of the app, followed by actuation of a deep link.","The deep link may be actuated by sending a breadcrumb-based URI to the newly-installed app.","The data server 284 may also store configuration settings, such as which deep states to allow links to, which deep states to bookmark as activities, and which data to index.","This configuration may be specified by the developer 204 using the developer portal 208.The data server 284 may also receive index items from the routing library 260.For example, the routing library 260 may report activity objects back to the data server 284.The data server 284 can then analyze user interaction with App A 232 and generate information about how to provide more relevant search results.","In addition, data from the data server 284 may be provided back to the developer 204, essentially providing an easy way to instrument App A 232 to analyze user engagement.","The data server 284 may correlate user activity across multiple apps on the user device 220, thereby further improving search results.","Routing Library Integration with Application In FIG.","3A, an example of App A 232 includes the routing library 260 and also includes an App A handler 300, which was created by the developer of App A 232.As seen in the example of FIG.","3A, the App A handler 300 is able to continue user activities relating to View B 268-2, View D-268-4, and View E-268-5.The App A handler 300 cooperates with an activity creator 304, which updates the search system 272 with activity objects indicating activities the user is performing with App A 232.In various implementations, the search system 272 may include elements similar to those shown in the operating system 100 in FIG.","1.The activity creator 304 may send activity objects to the search system 272 based on user activities associated with View B 268-2, View D 268-4, and View E 268-5.The App A handler 300 also interfaces with a data indexer 308, which may provide data objects to the search system 272 related to View B 268-2, View D 268-4, and View E 268-5.The routing library 260 is able to invoke View A 268-1 and View C 268-3 if the developer of App A 232 has requested that functionality through a developer portal.","The routing library 260 may be able to access View A 268-1 and View C 268-3 by invoking respective view controllers, as described in more detail in U.S. patent application Ser.","No.","15/235,650, filed Aug. 12, 2016, titled “Monitoring and Actuation of View Controller Parameters to Reach Deep States Without Manual Intervention,” with first-named inventor Kalyan Desineni, and having attorney docket no.","17100-000029-US.","The entire disclosure of this application is incorporated by reference.","In other implementations, the routing library 260 may access View A 268-1 and View C 268-3 by replaying sequences of user interface events that are determined in an offline process.","For more information, see U.S. patent application Ser.","No.","15/235,859, filed Aug. 12, 2016, titled “Deep Linking to Mobile Application States Through Programmatic Replay of User Interface Events,” with first-named inventor Kalyan Desineni, and having attorney docket no.","17100-000032-US.","The entire disclosure of this application is incorporated by reference.","While the activity creator 304 developed by the developer of App A 232 provides activity objects for some of the views 268 to the activity tracker 124, the routing library 260 is able to provide activity objects from others of the views 268.For example, the activity creator 304 may create an NSUserActivity object and invoke the becomeCurrent( ) method to provide the activity object to the activity tracker 124.It may be irrelevant to the activity tracker 124 whether the routing library or the App A handler 300 sent the activity object.","When the activity tracker 124 sends a continue user activity signal to App A 232, the routing library 260 traps (such as by overloading, overriding, or swizzling the continue user activity method) the continue user activity signal.","If the continue user activity signal is relevant to the App A handler 300, the continue user activity signal is passed through to the App A handler 300.Otherwise, the routing library 260 handles the continue user activity signal.","Similarly, the routing library 260 and the data indexer 308 developed by the developer of App A 232 may each create CSSearchableItem objects and introduce them to the search index 120, such as by using the indexSearchableItems method.","When the activity tracker 124 provides a continue user activity signal to the routing library 260 related to a data object, the routing library 260 either instantiates a view based on the selected data object or passes the continue user activity signal through to the App A handler 300.The NSUserActivity object may include a unique identifier (such as a title) and an activity type.","In a continue user activity signal, the activity type may differentiate an NSUseractivity object from a CSSearchableItem object.","The NSUserActivity object may also include a list of text keywords to allow the object to be indexed.","The NSUserActivity object may also include a set of metadata, such as a CSSearchableItemAttributeSet, which may include an image and other information.","The set of metadata for an object may be displayed when the object is included in a set of search results and gives the user information about whether the object satisfies their query.","The CSSearchableItem object includes a unique identifier and a set of metadata, which may take the form of a CSSearchableItemAttributeSet.","The CSSearchableItem object may also include an expiration date beyond which the object will be automatically de-indexed by the operating system.","Further, the CSSearchableItem object may include a domain identifier to group related objects.","In various implementations, the routing library 260 and the App A handler 300 may both be able to instantiate one or more of the views 268.For example, the App A handler 300 may be programmed to instruct the activity creator 304 to bookmark activities with respect to View B 268-2.Meanwhile, the routing library 260 may be programmed to submit data for indexing from View B 268-2.When a continue user activity signal is received by the routing library 260, if the continue user activity signal is related to a bookmarked activity, the routing library 260 passes through the continue user activity signal to the App A handler 300.Meanwhile, if the continue user activity signal for View B 268-2 is related to a data object, the routing library 260 itself navigates to View B 268-2 in order to display data related to the data object.","Although not shown in FIG.","3A, App A 232 may include an internal link router that receives deep links and instantiates views based on those deep links.","For links including a scheme registered by the routing library 260, which is different than the scheme registered by the internal link router of App A 232, the routing library 260 receives the deep link and instantiates one of the views 268 based on the link.","For example, the link may specify a breadcrumb to follow in order to arrive at the desired state.","The routing library 260 may override methods invoked by the activity creator 304 and the data indexer 308 to pass activity objects and data objects to the search system 272.In this way, the routing library 260 can first inspect the activity objects and data objects before then passing the activity objects data objects to the search system 272.The routing library 260 will then be aware of which activity objects have been created by the activity creator 304, and can, therefore, service deep links related to those activity objects.","Similarly, the routing library 260 will know which data objects have been indexed by the data indexer 308, and can then service deep links related to those data objects.","In order to allow third party Apps and services to access App A 232 using those deep links, the routing library 260 may upload information from the activity objects and the data objects to a remote server.","In order to service a deep link related to the activity objects from the activity creator 304 and the data objects from the data indexer 308, the routing library 260 can generate a continue user activity signal and send that signal to the App A handler 300.The App A handler 300 may be unaware that the continue user activity signal was received from the routing library 260 instead of from the search system 272.The App A handler 300 can then resume the activity or instantiate a review related to the index data as if the request came directly from the search system 272.In FIG.","3B, another example app, App B 360, is shown.","In App B 360, views 364-1, 364-2, 364-3, 364-4, and 364-5 (collectively, views 364) are shown for illustration.","App B 360 does not include a built-in handler similar to the App A handler 300 of FIG.","3A.","As a result, in order to access any of the views 364, the routing library 260 includes mechanisms (such as breadcrumbs) to access each of the views 364.Further, the routing library 260 is solely responsible for generating activity objects and data objects to send to the search system 272.When a continue user activity signal is received by the routing library 260, the routing library 260 cannot pass the continue user activity signal through and instead is responsible for handling the resumption of an activity or a creation of a view related to a data object.","Routing Library In FIG.","4, an example implementation of the routing library 260 includes registration data 404.The registration data 404 indicates to the operating system that the routing library 260 will handle links having a scheme relating to the routing library 260 and will also handle continue user activity signals relating to the app in which the routing library 260 is incorporated.","In various implementations, the registration data 404 is included in a configuration file of the app into which the routing library 260 is incorporated.","A URI (uniform resource identifier) processor 408 receives a link from the operating system.","For example, the link may have originated from a browser or from a third-party app.","The URI processor 408 extracts a unique ID from the link, which may simply be the text within the URI to the right of the pair of forward slashes following the scheme.","An internal router 412 consults an index data store 416 to determine whether the unique ID from the URI corresponds to a breadcrumb or corresponds to an activity call that will be made to the App A handler 300.In other words, the internal router 412 decides whether a breadcrumb exists to reach the state indicated by the unique ID or whether an activity call should be made to the App A handler 300 to reach the state indicated by the unique ID.","When the internal router 412 determines the unique ID corresponds to a breadcrumb, the internal router 412 sends a breadcrumb ID to a state machine 420.In various implementations, the breadcrumb ID may be the same as the unique ID or may be different as defined by a mapping from the index data store 416.As described in more detail below, the state machine 420 retrieves a breadcrumb from a breadcrumb data store 424 and executes each user interface action within the breadcrumb using a UI replay actuator 428.The state machine 420 may monitor the state of App A 232 to ensure that each user interface event is processed by App A 232 before moving to the next UI event.","If the internal router 412 determines that the unique ID from the URI processor 408 corresponds to an activity or data object handled by the App A handler 300, a signal is sent to an activity call creator 432.The activity call creator 432 creates a continue user activity signal specifying the activity or data object related to the link.","The parameters required for creating the continue user activity signal may be obtained from the index data store 416.The continue user activity signal is passed to the App A handler 300 via a handler interface 436, which may send a continue user activity signal to the App A handler 300 as if the App A handler 300 was receiving that signal directly from the operating system.","As mentioned above, the routing library 260 traps the method called by the operating system to provide a continue user activity signal to the app.","An activity handler 440 of the routing library 260 then receives the continue user activity signal.","The activity handler 440 determines whether the continue user activity signal should be handled by the App A handler 300 already implemented by the developer.","This determination may be based on the index data store 416.In such cases, the activity handler 440 provides the continue user activity as a pass through to the App A handler 300 via the handler interface 436.In apps where the developer has not coded a handler such as the App A handler 300, the activity handler 440 may never transmit pass through activities and the activity call creator 432 and the handler interface 436 may be dormant.","If the activity handler 440 determines that the continue user activity signal, according to the index data store 416, can be resumed using a stored breadcrumb, the breadcrumb ID is provided to the state machine 420 for execution.","So far, the aspects of the routing library 260 related to incoming deep links, whether in the form of a link or a continue user activity signal from the operating system, have been described.","The routing library 260 may also implement functionality that sends activity objects and data objects to the operating system.","This allows the operating system to return search results from the app.","A data indexer 460 determines which data objects of the app to index based on rules from a business rules data store 464.For example only, the data indexer 460 may respond to an app loaded signal to execute upon the app successfully running on the device.","The data indexer 460 may, upon the first execution of the app, send a predetermined set of data objects to the operating system via an operating system interface 468.For example only, with respect to data objects, the operating system interface 468 may simply be an invocation of the indexSearchableItems( )method.","On subsequent loading of the app, the data indexer 460 may update the index data objects based on their continued relevancy, based on data changes made to the app, or based on rule changes from the business rules data store 464.For example, if cuisine names are being indexed, as new cuisine names are added to the app, the data indexer 460 may add the additional cuisine names to the operating system index.","Meanwhile, if the business rules data store 464 is updated to indicate that cuisine names should no longer be indexed, the data indexer 460 may delete the corresponding data objects from the operating system index.","A data store updater 472 is responsible for updating one or more data stores, including the breadcrumb data store 424, the index data store 416, and the business rules data store 464.The data store updater 472 contacts the data server 284 of FIG.","2 via a network interface 476.The network interface 476 may handle authentication and encryption so that the validity of data store updates can be confirmed.","The data store updater 472 may operate when the app incorporating the routing library 260 is first opened on a device and at subsequent periodic intervals.","In addition, the data store updater 472 may perform additional updates in response to data needs, such as if a breadcrumb ID is not present in the breadcrumb data store 424.An activity creator 480 creates activity objects to bookmark activities with the operating system.","The operating system interface 468 may bookmark an activity by calling the becomeCurrent( )method on a created activity object.","The activity creator 480 may respond to a view appearing, such as the viewDidAppear signal, or to some other event, such as the view loading or being about to appear.","The activity creator 480 may update activity objects as interactions with a view occur.","The activity creator 480 may, therefore, trap additional methods that provide user input to a view so that the corresponding activity object can be updated.","For example, as the user edits a textbox, the activity creator 480 may update the activity object after each keystroke.","In addition to creating an activity object, the activity creator 480 may indicate to the data indexer 460 that certain data objects should be indexed.","These decisions may be based on rules from the business rules data store 464.For example, the activity creator 480 may create an activity object based on the user viewing a list of restaurants for a particular cuisine.","Whether this activity object is created is determined by the business rules data store 464.The business rules data store 464 may also dictate that the activity creator 480 signal to the data indexer 460 that the top one or more results from a search should be indexed.","For example, if the user is viewing a set of Thai restaurants and the most relevant result is the Amarin Thai restaurant, the user may later wish to search for Amarin Thai.","By indexing the Amarin Thai data object, the operating system can provide a result directly to the app for Amarin Thai.","In addition, depending on how the operating system index identifies search results, a user searching within the operating system for “Thai” may see both the activity for the app related to a list of Thai restaurants as well as the specific Amarin Thai data object.","When the operating system sends a continue user activity signal related to one of the activity objects from the activity creator 480 or the data objects from the data indexer 460, a corresponding breadcrumb will be present in the breadcrumb data store 424 to reach these activity objects or data objects since the app itself was not programmed by the developer to accommodate them.","The activity objects and data objects created by the activity creator 480 and the data indexer 460 respectively are provided to the index data store 416 so that the index data store 416 is aware of which activity objects and data objects can be handled by the routing library 260 instead of being passed through the App A handler 300.A remote indexer 484 may be instructed by the business rules data store 464 to mirror activity objects and/or data objects from the index data store 416 to a remote index.","This remote index may be maintained by the provider of the routing library 260 or by a search service.","Activity objects and data objects may be marked with a private identifier (or assumed private unless marked with a public identifier).","This private identifier may prevent the object from being uploaded to the remote index or may prevent the object from being exposed by the remote index in public search results.","This privacy indication may be provided by the developer as part of the onboarding process of the app to the developer portal and may be updated by the developer over time.","A search system 288 receives access mechanisms from the data server 284 incorporating identifiers of breadcrumbs or the breadcrumbs themselves.","The search system 288 may already have information about states of interest of App A and then can associate the access mechanisms with the respective states.","In other implementations, the search system 288 may crawl and scrape App A to obtain metadata for states of interest, and may follow the access mechanisms to find the content of the states.","In one use model, the user of the user device 220 performs a search for certain functionality and/or for a certain entity, such as reviews for a restaurant of interest.","The user may perform this search with a standalone search app or, as shown in FIG.","2, a web search performed via the browser 228.The search system 288, as described in more detail below, provides search results to the browser 228.These results may include a result corresponding to App A 232, and may include a link indicating a specific deep state in App A 232.If the user selects the link corresponding to App A 232, the link is forwarded to the link router 244 and then passed to the routing library 260 of App A 232.App A 232 is then controlled by the routing library 260 to display the indicated deep state using the corresponding breadcrumb.","In various implementations, the routing library 260 receives the contents of the breadcrumb from parameters encoded within the link itself.","For example, the link (in this case, a URI) may include the scheme (“portal-appa://”) followed by a serialized encoding of each UI event of the breadcrumb in series leading to the desired view.","For example, the breadcrumb may be specified in a JSON (JavaScript Object Notation) data structure encoded using Base64.The search system 288 is, therefore, able to provide a link that will take the user directly to relevant content within App A 232.The search system 288 may provide search results to others apps.","For example, a hotels app may query the search system 288 for restaurants near the user's selected hotel and the search system 288 may provide restaurant search results to the hotels app.","In the case where App A 232 is a restaurant review app, the hotels app can link directly into a deep state of App A 232 corresponding to the restaurant of interest.","The search system 288 may provide the search results in the form of DVCs.","A DVC for an app or a state of an app shows additional information, beyond just the identification of the app or app state.","For example, the information may include a title of the app state or a description of the app state, which may be a snippet of text from the app state.","Other metadata may be provided from the app state, including images, location, number of reviews, average review, and status indicators.","For example, a status indicator of “open now” or “closed” may be applied to a business depending on whether the current time is within the operating hours of the business.","Some DVCs may emphasize information that led to the DVC being selected as a search result.","For example, text within the DVC that matches a user's query may be shown in bold or italics.","The DVC may also incorporate elements that allow direct actions, such as the ability to immediately call an establishment or to transition directly to a mapping app to get navigation directions to the establishment.","Other interactions with the DVC (such as tapping or clicking any other area of the DVC) may take the user to the indicated state or app.","As described in more detail below, this may be accomplished by opening the relevant app or, if the app is not installed, opening a website related to the desired app state.","In other implementations, an app that is not installed may be downloaded, installed, and then executed in order to reach the desired app state.","In other words, a DVC includes identifying information for the app or state as well as additional content from the app or state itself.","The additional content allows the user to make a more informed choice about which result to choose, and may even allow the user to directly perform an action without having to navigate to the app state.","If the action the user wants to take is to obtain information, in some circumstances the DVC itself may provide the necessary information to accomplish such action.","In various implementations, the routing library may be identical for each app with the only exception being the name of the custom scheme that the routing library will register upon installation.","The scheme may be formed by concatenating text of the developer portal with the text of the app name, and may include a separator such as a hyphen or an underscore.","The name of the app may change over time, but the scheme may be fixed after first being set to provide backward compatibility with older versions of the app whose routing library may only recognize the original scheme.","In various implementations, the routing library may be updated with security updates, bug fixes, and feature additions while maintaining backward compatibility.","Developers, such as the developer 204, may download and incorporate the newest version of the routing library each time they release a new version of their app to the digital distribution platform 212.In some implementations, the build/compile process may automatically download the latest version of the routing library when resolving linker dependencies.","The offline analysis system 280 may need to be invoked each time the developer 204 prepares a new version of App A for the digital distribution platform 212.In addition, as the developer 204 adds more content to App A, the offline analysis system 280 may be invoked to determine the breadcrumbs needed to access that added content.","Invocation of the offline analysis system 280 may be performed at the request of the developer 204 or may be performed on a periodic basis.","Any updates or additions to the breadcrumbs are stored by the data server 284 and can be provided to the search system 288 so that links within search results have the most up-to-date access mechanisms.","In some implementations, the breadcrumbs may be communicated to the routing library 260 using a mechanism other than direct inclusion in the URI.","For example, this may be necessary when a maximum-length link is shorter than the number of characters an encoded breadcrumb may require.","The routing library 260 may, therefore, in some implementations, download a package of breadcrumbs from the data server 284.Search results from the search system 288 or other links may then reference a unique identifier, which the routing library 260 maps to a breadcrumb.","For example only, the unique identifier may be formed from a function and an entity, such as “restaurant_reviews” and “Amarin_Thai”.","In one specific example, the URI “portal-appa://restaurant_reviews/Amarin_Thai” may be resolved by the routing library 260 to a breadcrumb that reaches the restaurant reviews state for the Amarin Thai restaurant from a default state of App A 232.However, there is no requirement that the unique identifier be human-readable.","In other implementations, the routing library 260 may consult the data server 284 in response to receiving a deep link.","By providing the unique identifier, the routing library 260 can download the necessary breadcrumb from the data server 284.In such implementations, the routing library 260 may cache breadcrumbs so that a network access isn't required to resolve deep links visited recently.","Pre-caching of some or all breadcrumbs may also be performed, such as when App A 232 first executes on the user device 220.Pre-caching may happen even earlier, such as when the developer 204 is preparing App A for distribution.","In other words, the full set or a subset of the breadcrumbs may be included along with App A so that when a unique identifier is received via a link, the appropriate breadcrumb can be chosen by the routing library 260 without delay.","Pre-caching may be combined with periodic verification of the breadcrumbs by the routing library 260, such as by checking a version number of the package of breadcrumbs at a periodic calendar interval, such as once a month.","In other implementations, the data server 284 may send a push notification to the routing library 260 indicating that new breadcrumbs are available.","To the extent that the developer 204 had implemented some deep links within App A, a developer-implemented router (not shown) in App A 232 would receive links from the link router 244.The developer's routing code would not have registered “portal-appa://” but instead a scheme independent of the developer portal 208, such as “appa.com://”.","In various implementations, the developer-specified URIs may not be publicly available or may only be available to companies with an established relationship with the developer 204.Some operating systems, including the iOS operating system, have a sandbox infrastructure to limit the extent to which an app can access resources or areas of memory beyond what has been specifically allocated to the app.","Sandboxing enhances security, making it more difficult for malicious software to compromise a user system.","Because the routing library 260 executes within the context of App A 232, the sandbox should pose no difficulty for interactions between the routing library 260 and the view controllers responsible for the views 268.High-Level Flowchart In FIG.","5, an overview of the operation of the present disclosure with respect to one developer and one app begins at 504.The developer first develops the app (referred to here as “App A”).","App A may not have functionality that can expose deep links to all of its states.","In addition, App A may not have indexing functionality or activity resumption functionality for some or all states.","Further, any deep linking or search functionality that App A possesses may require programmer intervention to modify.","As a result, the developer could benefit from the routing library described by the present invention.","At 508, the developer provides a copy of App A to the developer portal.","This may be a standard build, such as what would be provided to a digital distribution platform.","In fact, if App A has already been released to a digital distribution platform, the developer portal may acquire the copy of App A from the digital distribution platform.","While the standard build is generally restricted to running on emulators or hardware devices, the developer could instead provide a special build of App A, such as a build tailored to a simulation environment.","The simulation environment may even run on a different architecture (such as an x86 architecture) compared to the app (which may run on user device hardware based on the ARM architecture).","At 512, control begins offline analysis of App A. Offline analysis may include determining states for which deep links are already present in App A. Offline analysis may also include determining which activities can be resumed within App A in which data can be indexed by App A based on code written by the developer.","For example only, offline analysis may include static and dynamic analysis of App A, which is described in more detail in U.S. application Ser.","No.","14/984,642, filed Dec. 30, 2015, titled “Static Analysis and Reconstruction of Deep Link Handling and Compiled Applications,” with first-named inventor Kalyan Desineni, and having attorney docket no.","17100-000030-US.","The entire disclosure of this application is incorporated by reference.","At 516, the developer specifies business rules for App A.","For example, the developer specifies to the developer portal which states of App A to provide deep link functionality for, which activities of App A to bookmark, and what data to index.","The developer may navigate a copy of App A in order to specify which states to provide deep links for.","For example, the developer may interact with App A in a simulator, while the offline analysis platform monitors the user interface events for later replay.","The developer may simply be asked to navigate to states of interest, without needing to understand that the user interface events are being recorded for deep linking purposes.","For each state the developer navigates to, the developer may specify whether one or more activities being performed in that state should be bookmarked and may identify one or more pieces of data to index from that state.","The developer may specify what metadata to include with the data being indexed, and may flag activities or data as public or private.","At 520, in parallel with offline analysis, control provides a copy of the routing library from the developer portal to the developer.","At 524, the developer integrates the routing library into App A.","For example, this may include adding references in a configuration file to the scheme handled by the linking capability of the routing library as well as adding the types of activities that the routing library will recognize.","In some implementations, the activities recognized by the routing library will be redundant with activities already recognized by App A, such as when App A already allows for some activity resumption or data indexing.","The developer also links the binary to the App A project within the integrated development environment.","In various implementations, a script may be provided to the developer to perform the incorporation actions of 524.At 528, the developer compiles App A, which now includes the routing library, and provides App A to one or more digital distribution platforms.","At 532, a user of a user device installs App A from a digital distribution platform.","At 536, as part of installation, the routing library of App A registers a custom link scheme handled by the routing library as well as activity types handled by the routing library.","For example, this registration may be performed by the operating system based on a configuration file, such as Info.plist.","At 540, the routing library of the now-installed application updates access mechanisms and business rules.","For example, the access mechanisms may be breadcrumbs to reach certain states.","The business rules identify which states should be accessed, which activities should be bookmarked, and which data should be indexed.","When the application is first run, the routing library may download a full set of access mechanisms and business rules so that no access latency is incurred when an access mechanism or business rule is needed.","In other implementations, upon first being run, the routing library only downloads a subset of the access mechanisms, such as access mechanisms for the most popular states.","The updates at 540 may be performed each time the app is opened or at predetermined intervals.","In addition, the routing library may update access mechanisms and/or business rules if a required access mechanism (for example, a breadcrumb) is missing or if the access mechanism appears to not be working.","At 544, the routing library indexes data indicated by the developer according to the business rules.","For example, when the app first loads, the routing library may index a set of data indicated by the developer.","Then, as data is modified in App A, the routing library may update the operating system index based on the updated data.","At 548, the routing library bookmarks selected activities engaged by the user.","For example, when the user performs a search, the search criteria and filters may be bookmarked as an activity that the user can resume on that device or handoff to another device.","At 552, the routing library in App A handles proprietary App A links (indicated by the registered scheme) provided to the routing library from the operating system.","At 556, the routing library handles activities sent by the operating system, including continue user activity signals.","These activities may refer to bookmarked activities or to indexed data.","Control then returns to 540.Although 540, 544, 548, 552, and 556 are displayed in series, they may run asynchronously and in parallel.","Routing Library Operation In FIG.","6, example operation of the routing library is shown.","At 604, during installation of App A onto a device, the proprietary App A URI scheme and activity types in the routing library are registered.","This may be performed by the operating system from a configuration file (also known as a manifest file) as part of the installation process.","At 608, control requests breadcrumbs and configuration data from the data server.","This may be performed upon the first execution of App A on the user device.","At 612, control determines whether an activity or a proprietary App A URI has been received from the operating system.","If so, control transfers to 616; otherwise, control transfers to 620.At 616, control invokes a handler for the activity or proprietary App A URI.","For example, the handler may be implemented as shown in FIG.","7.For example only, the handler may respond to an openURL( ) call received by the operating system or from a continue user activity signal generated by the operating system.","After handling the activity or proprietary App A URI, control returns to 612.At 620, control determines whether an activity trigger event has occurred.","If so, control transfers to 624; otherwise, control transfers to 628.An activity trigger event may be the loading of a state or an action performed within a state.","The developer may specify which event qualifies as an activity trigger.","The developer may establish business rules dictating that some states trigger an activity when the state is entered while for other states an activity is bookmarked upon some further action being performed, such as user input.","At 624, control determines whether a breadcrumb is available to return to that activity.","If so, control transfers to 632; otherwise, control transfers to 636.If a breadcrumb that returns to that activity is not available, the routing library may not be able to resume that activity when requested by the operating system and therefore will not bookmark that activity.","At 632, the breadcrumb is available and therefore control sends an activity object to the operating system to bookmark the activity.","At 636, control determines whether the activity has been indicated by the developers as being public.","If so, control transfers to 640; otherwise, control continues at 628.At 640, the activity has been indicated as public and therefore control uploads the activity to a remote index.","Control then continues at 628.In other implementations, control may upload the activity to the remote index regardless of whether the activity has been indicated as public, and instead uses the public indicator to determine whether to reveal that activity to any users of the remote index.","At 628, control determines whether data should be indexed according to business rules established by the developer.","If so, control transfers to 644; otherwise, control transfers to 648.For example, when first running App A, there may be a predetermined set of data objects that the developer desires to index.","Then, after certain states have been accessed, the developer may have specified that data related to those states should be indexed.","For example, in a music streaming app, if the user has viewed a list of artists in a particular genre, data objects corresponding to each of the artists may be added to the operating system index.","At 644, if a breadcrumb is available for a data object the developer has indicated should be indexed, control transfers to 652; otherwise, control continues at 648.At 652, the breadcrumb to reach a state that can access that data object is available and therefore the data object is sent to the operating system.","If the breadcrumb were not available, the routing library would not be able to service a request from the operating system to display the data object to a user.","While FIG.","6 shows operation of the routing library, the developer may have implemented logic within App A that will index data objects and bookmark activities, separate from the routing library.","This indexing and bookmarking is not precluded by the operation of the routing library.","Therefore, even when the routing library does not index the data object or bookmarking activity, App A itself may be performing that task.","In order for App A to then resume the activity when instructed by the operating system, App A will have logic implemented by the developer to reach the appropriate states.","This logic may include direct actuation of view controllers or may include a user interface breadcrumb similar to that used by the routing library.","Control continues from 652 to 656, where if the data object is indicated as public, control transfers to 660; otherwise, control continues at 648.At 660, control uploads the data object to the remote index and continues at 648.Again, the public identifier may be ignored at the time of uploading the data object to the remote index and instead be taken into account when determining whether to reveal the data objects to other users.","At 648, control determines whether the last data update of breadcrumbs and configuration data is more than a predetermined time in the past.","If so, control transfers to 664 to update this data; otherwise, control returns to 612.Although shown as a predetermined amount of time, data updating may be performed dynamically based on how often the app is used, how often breadcrumbs or configuration data historically has changed, and/or may be based on a push signal from the data server indicating that data should be updated.","Activity/URI Handling In FIG.","7, example routing library operation for handling activities and proprietary URIs is shown.","In various implementations, the process of FIG.","7 may be called by 616 of FIG.","6.Control begins at 704, where if a proprietary App A URI has been received, control transfers to 708; otherwise, control transfers to 712.At 708, control determines whether the URI corresponds to a preexisting data object—that is, a data object that App A was able to index and display independent of the routing library.","If the URI corresponds to such a preexisting data object, control continues at 716; otherwise, control transfers to 720.At 716, the routing library will be able to use the preexisting access mechanism within App A to display a state relevant to that data object.","To accomplish this, control may prepare an activity request that is similar or identical to the activity request the operating system would provide to App A in order to display a state related to that data object.","Control then continues at 724, where the prepared activity request is passed to a preexisting App A handler that was written by the developer independent of the routing library.","Control then continues at 712.At 720, control determines whether the URI corresponds to a preexisting activity—that is, an activity that App A could bookmark and resume independent of the routing library.","If so, control transfers to 728; otherwise, control transfers to 732.At 728, control prepares an activity request identifying that preexisting activity.","The activity request may be similar or identical to a request that the operating system would provide to App A in order to resume the bookmarked activity.","The control then continues at 724.At 732, control determines whether the URI corresponds to a breadcrumb.","If so, control transfers to 736; otherwise, control transfers to 740.Although referred to as a breadcrumb, the access mechanism can be another mechanism the routing library uses to navigate to a certain state.","For example, the routing library may be programmed with a set of parameters allowing a specific view controller to be invoked with particular input parameters to arrive at a certain state.","At 736, control replays the breadcrumb, such as using a process shown in FIG.","8.Control then continues at 712.At 740, the proprietary App A URI cannot be passed to the preexisting App A handler and an access mechanism (such as a breadcrumb) does not exist.","As a result, error handling is performed.","For example, the error handling may include displaying a message to the user indicating that the link failed and directing the user to a default state of the app.","Before displaying the message, control may refresh downloaded breadcrumbs to ensure that the latest breadcrumbs are available.","As another example, control may attempt to find and then traverse a comparable URI, such as by querying a mapping of obsolete URIs to active URIs.","Control then continues at 712.At 712, if an activity request (such as a continue user activity method call) is received by App A (for example, by the App delegate of App A), control transfers to 744; otherwise, control transfers to 748.At 744, control determines whether the activity should be handled by the routing library.","If so, control transfers to 752; otherwise, control transfers to 756.At 752, the activity is handled by the routing library because the routing library bookmarked the corresponding activity or indexed the corresponding data object.","The activity may be resumed by replaying a breadcrumb corresponding to the state identified by the activity request.","For example, this may be performed as shown in FIG.","8.Control then returns to FIG.","6.At 756, if the routing library is aware that App A handles at least some activity requests, control continues at 760.Otherwise, if the routing library is confident that App A is otherwise unable to handle any activities, control transfers to 764 where error handling is performed.","For example, the error handling may include displaying an error message that the activity request cannot be met.","At 760, the activity request is passed through to the preexisting App A handler in the hope that the App A handler can handle the activity request.","Control then returns from FIG.","7.At 748, error handling is performed because neither a proprietary App A URI has been received or an activity request has been received.","Control may not be aware of what was received other than an activity request or a proprietary App A URI and therefore may not display anything to the user, instead simply taking the user to a default state of the app.","Control then returns from FIG.","7.Breadcrumb Traversal In FIG.","8, example operation of the routing library when traversing a breadcrumb is shown.","Control begins at 804, where if the breadcrumb is embedded in the URI, control transfers to 808; otherwise, control transfers to 812.As described above, breadcrumbs that allow the routing library to navigate to certain deep states may be received in links or may be indicated by unique ID in the link.","When indicated by a unique ID, the routing library may have to request the breadcrumb from a data server.","In some implementations, the routing library will therefore pre-cache some or all breadcrumbs.","This operation may be omitted if breadcrumbs will always be received within links.","In some implementations, certain breadcrumbs when encoded are longer than a maximum permitted length of a link.","This maximum length may be dictated by a browser, by an operating system, or by some other technological or business restriction.","These breadcrumbs may therefore be obtained from the data server, while shorter breadcrumbs are contained within URIs.","In this way, the generator of the URI (such as a search system) prepares the URI including the breadcrumb data itself when the maximum link length will not be exceeded, while otherwise including only a unique identifier of the breadcrumb.","At 808, control decodes a data structure holding the breadcrumb from the URI and control continues at 816.At 812, since the breadcrumb was not included in the URI, control determines whether the breadcrumb is already stored in the breadcrumb data store.","If so, control uses the breadcrumb from the breadcrumb data store and continues at 816; otherwise, control transfers to 820.At 820, control requests the breadcrumb from the data server, and when the breadcrumb is returned, control continues at 816.In various implementations, the routing library acquires an initial set of breadcrumbs before one of the breadcrumbs would be indicated by a URI.","For example, the routing library may be pre-packaged with the initial set of breadcrumbs or the routing library may download the initial set of breadcrumbs upon installation or first execution on the user device.","The routing library may periodically (for example, via a background process) receive new breadcrumbs to supplement functionality.","In some implementations, an improved user experience may result from breadcrumbs always being obtained from the data store and never retrieved from the data server.","This minimizes delays in response resulting from obtaining breadcrumbs from the data server and avoids availability issues from network connectivity problems.","At 816, control selects the first UI event in the sequence specified by the breadcrumb.","At 824, control replays the selected UI event from the breadcrumb.","At 828, control determines whether replaying the selected UI event successfully led to the next view or updated the current view as expected.","In various implementations, control may wait for a predetermined period of time before checking for success.","This predetermined period of time allows the app to respond to the UI event.","In various implementations, the breadcrumb data structure may include a specified wait time, which may apply to all UI events, or may have a separate wait time for each UI event.","As part of the breadcrumb determination process, the offline analysis system may detect that certain UI events take longer for an app to respond to.","In such cases, the offline analysis system may indicate that additional delay periods should be implemented before replaying another UI event.","At 828, success may instead be identified when the routing library detects that a method has been called with certain parameters corresponding to the replayed event.","In other words, as part of the offline analysis, the expected response to the app to a UI event may be recorded.","When this expected response is seen, success may be inferred.","If, at 828, the UI event appears to have been processed successfully, control transfers to 832; otherwise, control transfers to 836.At 836, control waits for another predetermined period of time.","This additional period of time may allow for unexpectedly slow response to a UI event.","Control continues at 840, where control once again attempts to verify that replaying the selected UI event has successfully led to the expected behavior.","If so, control continues at 832; otherwise, control transfers to 844.At 844, if the selected UI event has been replayed twice in an attempt to obtain a successful response, control transfers to 848.At 848, an error is declared.","For example, error handling may cause the app to revert to a home state and display a notification message to the user that the deep link was unsuccessful.","In addition, a message may be sent to the data server indicating that the deep link was unsuccessful.","Control then returns from FIG.","8.At 844, if the selected UI event has only been replayed a single time, there has not yet been a second failure, and therefore control returns to 824 to attempt to replay the selected UI event a second time.","In various implementations, success is not evaluated, and the UI events are replayed in series with the expectation that in most circumstances, the desired deep link will be reached.","As a result, elements 828, 836, 840, 844, and 848 may be replaced with a simple wait step.","The wait step may wait for a predetermined delay that has been empirically determined to allow the app to respond to user input.","The wait step may be used in systems where UI events cannot be processed by the app as quickly as they can be replayed by the routing library.","In other implementations, the wait step may involve watching for a method call resulting from the UI event.","Once response of the app to the UI event has been detected, such as by watching certain method calls, control may allow the following UI event to be replayed.","At 832, if there are additional UI events, control transfers to 852; otherwise, control returns from FIG.","8.At 852, control selects the next UI in the breadcrumb and returns to 824.Search System In FIG.","9, an example implementation of the search system 288 includes a search module 900.The search module 900 includes a query analysis module 904 that receives a query wrapper, which may take the form of a query string within a URL transmitted by the browser 228 of FIG.","2.The query analysis module 904 analyzes the text query from the query wrapper.","For example, the query analysis module 904 may tokenize the query text, filter the query text, and perform word stemming, synonymization, and stop word removal.","The query analysis module 904 may also analyze additional data stored within the query wrapper.","The query analysis module 904 provides the tokenized query to a set generation module 908.The set generation module 908 identifies a consideration set of application state records from a search data store 910 based on the query tokens.","Application (equivalently, app) state records correspond to specific states of apps.","In various implementations, the search data store 910 may also include app records.","In various implementations, an app record may be stored as an app state record that simply has a predetermined value, such as null, for the specific state of the app.","App state records in the search data store 910 may be generated by crawling and scraping apps according to the principles of the present disclosure.","Some or all of the contents of the records of the search data store 910 may be indexed in inverted indices.","In some implementations, the set generation module 908 uses the APACHE LUCENE software library by the Apache Software Foundation to identify records from the inverted indices.","The set generation module 908 may search the inverted indices to identify records containing one or more query tokens.","As the set generation module 908 identifies matching records, the set generation module 908 can include the unique ID of each identified record in the consideration set.","For example, the set generation module 908 may compare query terms to an app state name and app attributes (such as a text description and user reviews) of an app state record.","Further, in some implementations, the set generation module 908 may determine an initial score of the record with respect to the search query.","The initial score may indicate how well the contents of the record matched the query.","For example, the initial score may be a function of term frequency-inverse document frequency (TF-IDF) values of the respective query terms.","A set processing module 912 receives unique IDs of app state records identified by the set generation module 908 and determines a result score for some or all of the IDs.","A result score indicates the relevance of an app state with respect to the tokenized query and context parameters.","In various implementations, a higher score indicates a greater perceived relevance.","For example, other items in the query wrapper may act as context parameters.","Geolocation data may limit the score of (or simply remove altogether) apps that are not pertinent to the location of the user device.","A blacklist in the query wrapper may cause the set processing module 912 to remove app records and/or app state records from the consideration set that match the criteria in the blacklist, or to set their score to a null value, such as zero.","The set processing module 912 may generate a result score based on one or more scoring features, such as record scoring features, query scoring features, and record-query scoring features.","Example record scoring features may be based on measurements associated with the record, such as how often the record is retrieved during searches and how often links generated based on the record are selected by a user.","Query scoring features may include, but are not limited to, the number of words in the search query, the popularity of the search query, and the expected frequency of the words in the search query.","Record-query scoring features may include parameters that indicate how well the terms of the search query match the terms of the record indicated by the corresponding ID.","The set processing module 912 may include one or more machine-learned models (such as a supervised learning model) configured to receive one or more scoring features.","The one or more machine-learned models may generate result scores based on at least one of the record scoring features, the query scoring features, and the record-query scoring features.","For example, the set processing module 912 may pair the search query with each app state ID and calculate a vector of features for each {query, ID} pair.","The vector of features may include one or more record scoring features, one or more query scoring features, and one or more record-query scoring features.","In some implementations, the set processing module 912 normalizes the scoring features in the feature vector.","The set processing module 912 can set non-pertinent features to a null value or zero.","The set processing module 912 may then input the feature vector for one of the app state IDs into a machine-learned regression model to calculate a result score for the ID.","In some examples, the machine-learned regression model may include a set of decision trees (such as gradient-boosted decision trees).","Additionally or alternatively, the machine-learned regression model may include a logistic probability formula.","In some implementations, the machine-learned task can be framed as a semi-supervised learning task, where a minority of the training data is labeled with human-curated scores and the rest are used without human labels.","The machine-learned model outputs a result score of the ID.","The set processing module 912 can calculate result scores for each of the IDs that the set processing module 912 receives.","The set processing module 912 associates the result scores with the respective IDs and outputs the most relevant scored IDs.","A results generation module 924 may choose specific access mechanisms from the application records and app state records chosen by the set processing module 912.The results generation module 924 then prepares a results set to return to the user device.","Although called “app state results” here, some of the access mechanisms may correspond to a default state (such as a home page) of an app—these may be a special case of an app state record or may be an app record.","The results generation module 924 may select an access mechanism for an app state record based on whether the app is installed on the device.","If the app is installed, an access mechanism that opens the app directly to the specified state is selected.","Meanwhile, if the app is not installed, a selected access mechanism first downloads and installs the app, such as via a script, before opening the app to the specified state.","Opening the app to the specified state may include a single command or data structure (such as an intent in the ANDROID operating system) that directly actuates the specified state.","For other apps, a script or other sequence may be used to open the app to a certain state (such as a home, or default, state) and then navigate to the specified state.","The results generation module 924 may generate or modify access mechanisms based on the operating system identity and version for the user device to which the results are being transmitted.","For example, a script to download, install, open, and navigate to a designated state may be fully formed for a specific operating system by the results generation module 924.If the results generation module 924 determines that none of the native access mechanisms are likely to be compatible with the user device, the search module 900 may send a web access mechanism to the user device.","If no web access mechanism is available, or would be incompatible with the user device for some reason (for example, if the web access mechanism relies on the JAVA programming language, which is not installed on the user device), the results generation module 924 may omit the result.","Server-Side Control In FIG.","10, operation of server-side components may be performed within a single device or may be performed across the developer portal 208, the offline analysis system 280, the data server 284, and the search system 288 of FIG.","2.In various implementations, the developer portal 208, the data server 284, and the search system 288 may be under the control of the same entity.","The offline analysis system 280 may employ operators that facilitate static analysis and/or dynamic analysis to ensure that accurate and complete parameters are extracted from each app.","Control begins at 1002, where the routing library is made available to app developers.","Over time, the routing library may be updated, and the most up-to-date version may be the only one available to app developers.","At 1004, if a request for a breadcrumb has been received, control transfers to 1006; otherwise, control transfers to 1008.At 1006, control determines a subset of the breadcrumbs that has changed since the last request was received from the requester.","This subset can then be provided at 1010 to bring the data up-to-date at the source of the request.","Control then returns to 1004.At 1008, if offline processing of an app has been initiated, control transfers to 1012; otherwise, control transfers to 1016.At 1016, if a search query has been received from a search system, control transfers to 1020; otherwise, control returns to 1004.At 1020, control determines a consideration set of results corresponding to the search query.","This consideration set may include apps that are open to the search query as well as specific states (deep states) of apps that are relevant to the search query.","At 1024, control scores the elements in the consideration set based on how closely they match the understood intent of the search query.","The scored results can then be ranked from most relevant to least relevant.","At 1028, the highest-ranked results are formatted as deep view cards associated with deep links to the specific states within the results.","At 1032, control returns the deep view cards to the requestor of the query.","The deep view cards may not be fully rendered, and instead include images, text, and instructions on how to render the deep view cards for particular screen sizes, orientations, and other requirements of the requesting application or operating system.","For apps where the deep links are serviced by a routing library according to the principles of the present disclosure, an access mechanism returned along with the corresponding search result may include a URI with an encoded data structure.","The encoded data structure may include the breadcrumb necessary to invoke that specific state from within the app.","The URI, being a string, includes a serialized version of that data structure and is prefixed with a scheme.","The scheme, such as “portal-appa://”, will cause the URI to be forwarded to and recognized by the routing library of the app.","Control then returns to 1004.At 1012, control runs App A, such as in a simulator.","While App A is running, control monitors UI events resulting from the operator's usage of App A.","At 1036, control allows an operator to interact with App A to reach a deep state of interest, recording each UI interaction to form a breadcrumb.","In various implementations, control may monitor how long it takes App A to respond to certain UI events.","These response times, or delays based on the response times, may be encoded in the breadcrumb along with the corresponding UI events.","For example, some operations may require App A to obtain data from a server, incurring network communication delays.","When replaying the UI events in the breadcrumb, there should be a longer delay after the UI event leading to network access before the next UI event is replayed.","At 1040, if there are additional deep states of interest, control returns to 1036; otherwise, control continues at 1044.At 1044, control determines states that are parallel to the states identified by the operator.","For example, if the operator selects a link from a list of similar-looking items, and the selected link leads to a state of interest, control may assume that the other items in the list are also of interest.","These parallel states, and the breadcrumbs used to reach them (in the list example, the breadcrumbs would differ only in the last UI event), are added to the list of deep-linkable states.","In various implementations, App A may be exercised using a crawling algorithm to reach some or all deep states of App A.","For additional information regarding crawling, see U.S. patent application Ser.","No.","14/849,540, filed Sep. 9, 2015, titled “Unguided Application Crawling Architecture,” with first-named inventor Kalyan Desineni, and having Attorney Docket No.","17100-000006-US-01.The entire disclosure of this application is incorporated by reference.","At 1048, control provides a list of deep-linkable states to a search system for indexing.","At 1052, for each deep-linkable state, control provides a data structure containing the breadcrumb to the data server to be used in a URI as an access mechanism to access the deep state.","Control then returns to 1004.At 1012, an operator interacts with a copy of the app, such as in a simulator, to navigate to states of interest.","In some implementations, the operator navigates to states of interest designated by the developer; in other implementations, the developer herself navigates to states of interest.","User interface events required to reach various states are recorded such as described in FIG.","12.Control continues at 1040, where control may extrapolate additional states of interest from the operator-identified states of interest.","Example operation for extrapolation is shown in FIG.","13.At 1012, while the operator is identifying states of interest, the operator may also be tagging states as activities to be bookmarked and may be identifying data within the states as data objects to index.","Control continues at 1056, where configuration parameters established by the operator are transmitted to the data server.","For example, configuration parameters may be business rules specifying which states should be deep linked which states should be bookmarked as activities, and what data should be indexed.","Offline Analysis In FIG.","11, an example implementation of the offline analysis system 280 includes a guide creation system 1100 that allows for operator interaction with an app of interest (such as App A).","The guide creation system 1100 allows an operator to specify which states of an app should be deep-linkable and may use input from the operator to determine how to reach those deep states.","In various implementations, the operator is an administrator of the offline analysis system 280, acting on standard operating procedures for offline processing of an app or on instructions from a developer of the app.","Additionally or alternatively, an agent of the app developer may act as the operator.","The agent may specify which states or types of states should be made accessible as deep states.","After the initial offline analysis, the agent may use the developer portal 208 to request that additional states of the app be added as deep states and request that existing deep-linked states be removed.","This may be done via the developer portal 208 with no need for the agent to modify code of the app or even request assistance from the app's software developers.","In other words, marketing personnel or user experience designers may themselves control the scope of the deep linking within the app, without even releasing a new version of the app.","For added states, the offline analysis system 280 will re-process the app to determine the breadcrumbs to the added states.","For an app being processed by the offline analysis system 280, the operator controls a copy of the app of interest executing within a simulator 1104.In various other implementations, the app of interest may be installed on a physical device or executed in an emulation environment.","In various implementations, the simulator 1104 may be instantiated at a cloud hosting operator that may provide compute facilities within which to execute emulator/simulator code or that may directly provide emulators or simulators for one or more mobile device operating systems.","For more information, see U.S. patent application Ser.","No.","14/868,294, filed Sep. 28, 2015, titled “Operator-Guided Application Crawling Architecture,” with first-named inventor Kalyan Desineni, and having Attorney Docket No.","17100-000006-US-02.The entire disclosure of this application is incorporated by reference.","In some implementations, a physical device running the operating system may be used instead of the simulator 1104, such as for an operating system that does not have a suitable simulator or emulator.","The physical device may be connected to the guide creation system 1100 using a wireless or wired interface, such as USB (universal serial bus).","A root-level control application may be installed on the physical device to track user input.","Installing the root-level application may require bypassing security limitations of the firmware or operating system regarding privileges of installed apps and may require that the device be jailbroken.","Jailbreaking involves bypassing or removing various software restrictions imposed by the operating system and/or device firmware, and may be accomplished using a privilege escalation technique.","The jailbroken device may be further modified with pre-installed and specific settings that enable the techniques of the present disclosure, such as recording UI interactions.","The simulator 1104 is essentially already jailbroken.","However, the simulator 1104 may also be modified to allow for better control, such as to more easily allow recording UI interactions.","The operator's interaction with the app may be recorded to form a guide indicating how a state is reached.","This guide defines the breadcrumb used to reach the end state, and subsets of the guide define the breadcrumbs for intermediate states.","The guide may also be used to infer other states of interest and determine breadcrumbs leading to those states.","Each UI event may be associated with a specific UI element, identified according to a predetermined rubric by a unique ID.","For example, the unique ID may be dictated by how the UI elements are programmatically created when rendering the view.","In other implementations, the unique ID may be dictated by how the UI elements are actually seen, with the UI elements numbered in increasing order from left to right and top to bottom.","In other implementations, x-y coordinates may be used to identify the location of the user interaction, or the boundaries of the UI element actuated, or a center of the UI element actuated even if the operator's action was off-center.","In various implementations, static analysis may be used to analyze the UI elements of various states of the app.","Static analysis involves analyzing the code of the app without making observations of the app being executed.","In some implementations, a static analyzer (not shown) may identify the UI elements of each view and assign unique identifiers to each UI element within a view.","Then, dynamic analysis would have a predetermined nomenclature when referring to user interactions with any UI elements.","For example, static analysis may be performed with a disassembler and debugger implemented by the IDA Pro software from Hex-Rays SA.","Additionally or alternatively, the static analyzer may analyze the methods and views of an app to determine how best to instrument the app.","With this information, the dynamic analyzer can hook to the correct methods and listen for the correct events to accurately track user interaction with the app and discard method calls unrelated to user interaction.","For more information on static analysis, see U.S. patent application Ser.","No.","14/843,929, filed Sep. 2, 2015, titled “Static Analysis-Assisted Dynamic Application Crawling Architecture,” with first-named inventor Kalyan Desineni, and having Attorney Docket No.","17100-000006-US.","The entire disclosure of this application is incorporated by reference.","While the app is running in the simulator 1104, the guide creation system 1100 may monitor the messaging queue of the simulator 1104 (or of the actual operating system when executing in an emulator or physical device), listening for messages indicative of user manipulation of the app.","Such manipulation includes, for example, clicking, pressing, pinching, or swiping of the user interface.","In addition to capturing a unique identifier for each UI element the operator interacts with, the guide creation system 1100 may also extract the type of each element according to the defined types specified by the operating system, and further extract the identity of the associated view controller.","For example, the following methods may be hooked, such as by using method swizzling: (void)sendEvent:(UIEvent *)event method in the UIApplication class (void)sendAction:(SEL)action to:(id)target forEvent:(UIEvent *)event in UIControl class (void)viewDidAppear:(BOOL)animated for all the controllers that were loaded A handler may be implemented to record each type of UI element.","As an example, code for recording a button press can be implemented as follows: -(void)sendEvent:(UIEvent *)event { for (UITouch *touch in event.allTouches) { if (touch.phase == UITouchPhaseBegan) { if ([touch.view isKindOfClass:[UIButton class]]) { NSLog(@“UIButton:id:{%@}”, [((UIButton *)touch.view) currentTitle]); } } } } Other types of UI elements may be recorded by similar handler code.","In various implementations, after hooking the objc_msgSend function, a guide tracker 1108 may listen to the AppDelegate class and the (BOOL) application:(id)application ˜didFinishLaunchingWith Options: ˜(NSDictionary *)launchOptions method.","Further, the guide tracker 1108 may dynamically create listeners for controllers.","Instead of trying to exhaustively discover every state of an app through an unguided crawl of the app, the operator can help focus the analysis on the states for which deep links are desired—generally, the most interesting or important states.","The operator may begin at a home state of the app and progress to one state of interest for each category of states for which deep linking is desired.","The offline analysis system 280 may then extrapolate to find similar/parallel actions, each of which may correspond to another state of interest.","These parallel states can be added to a state list that defines which states will have corresponding breadcrumbs stored.","For example, if the app includes information about restaurants, the operator may browse to a state that lists restaurants, and then select one of the restaurants.","The operator may stop after finding a state that shows details about a first restaurant.","Based on the series of actions taken by the operator during browsing, the offline analysis system 280 can find other restaurant detail states that could have been reached in a similar way.","For example, after selecting a restaurant item with a certain layout and certain properties (e.g.","an image with property X next to a text box with property Y) from a list, the offline analysis system 280 may detect multiple additional restaurant items (that have the same layout and/or properties) within that view, which the operator could have selected.","It may then predict that selecting the other restaurant listings will result in finding additional restaurant info states.","For additional information about extrapolation, see U.S. patent application Ser.","No.","14/869,127, filed Sep. 29, 2015, titled “State Extrapolation for Automated and Semi-Automated Crawling Architecture,” with first-named inventor Kalyan Desineni, and having Attorney Docket No.","17100-000006-US-03.The entire disclosure of this application is incorporated by reference.","Within the guide creation system 1100, the guide tracker 1108 records operator interaction with the app in the simulator 1104 to create operator-specified guides.","For example, a guide may include each user interface interaction performed by the operator, beginning at the home (or, default) state of the app.","In various implementations, a target state tracker 1112 may allow the operator to flag a state currently visible in the simulator 1104 as a state of interest.","For example, the target state tracker 1112 may provide a user interface element (such as a button) within the simulator 1104 or as part of software through which the operator controls the simulator 1104.For each state of interest, a link extraction controller 1116 generates a breadcrumb specifying a sequence of UI events that leads to the state of interest.","The link extraction controller 1116 is aware of states that are of interest to the operator, either explicitly (such as via the target state tracker 1112) or implicitly (such as via the guide tracker 1108).","The link extraction controller 1116 may attempt to identify similar states—for example, states that are reached using similar UI (user interface) elements.","Target states may be explicitly identified by the operator using the target state tracker 1112.If target states are not specified by the operator, the link extraction controller 1116 may assume that the final state reached when an operator is creating a guide is the target state.","Alternatively, the link extraction controller 1116 may make the assumption that every state the operator navigated to should be a target state.","A deduplication procedure may be used to detect when the operator has browsed in a loop, thus avoiding recording duplicative and/or non-shortest-path guides.","Deduplication may be less necessary if the operator is explicitly marking target states.","The link extraction controller 1116 operates a simulator 1120, which, as described above, could instead be an emulator or a physical device.","For scale, multiple emulators, simulators, and/or physical devices may be controlled by the link extraction controller 1116 to analyze the same or different applications.","As an example only, a bank of physical smailphones may all be connected via USB to an interface card that is controlled by the link extraction controller 1116.Simply for ease of illustration, a single simulator (the simulator 1120) is shown in FIG.","4.In various implementations, the simulator 1120 and the simulator 1104 may be a single simulator shared by the guide creation system 1100 and the link extraction controller 1116.The application of interest is executed within the simulator 1120.In various implementations, the app executed by the simulator 1120 may be supplemented with a routing library, such as is described in FIG.","3A or FIG.","3B.","With the routing library, the link extraction controller 1116 can cause the app in the simulator 1120 to replay UI events to follow guides and identify additional states of interest.","In other implementations, because the app in the simulator 1120 does not need to be a publicly-distributed version of the app, an accessibility or automation framework may be used to perform UI control.","The routing library may be reserved for the version of the app that is publicly distributed.","The link extraction controller 1116 identifies states of interest corresponding to each of the guides specified by the guide tracker 1108.In order to reach a state within the app, the link extraction controller 1116 sends the shortest path specified by the guide tracker 1108 to the simulator 1120 to be replayed.","The link extraction controller 1116 identifies states of interest corresponding to each of the guides specified by the guide tracker 1108.In various implementations, the offline analysis system 280 may include a scraper (not shown) that extracts content from each state of interest.","The content may include text, images, and metadata, such as location, formatting, interface hints, etc.","This content may be used by the search system 288 of FIG.","2 to determine which deep states of the app are relevant to a search query.","In other implementations, the search system 288 may crawl and scrape the app separately, but may use the breadcrumbs from the offline analysis system 280 to navigate to the various states.","If there are UI fields into which text needs to be entered, the operator may identify to the guide creation system 1100 what types of textual input need to be entered.","The types could be, for example, city names, cuisine names, etc.","The link extraction controller 1116 then consults a knowledge base to get a list of possible values of such types (for cities, the list might include “Seattle,” “San Jose,” etc.)","and then replay each one of these values into the textual input field.","The link extraction controller 1116 may detect that a potential state of interest has already been reached by following a different breadcrumb.","The link extraction controller 1116 may then select one of the breadcrumbs to associate with that state.","For example, the breadcrumb having the fewest number of UI events may be selected.","Alternatively, the breadcrumb having the fewest view changes may be selected, and total number of UI events may be used as a tiebreaker.","To identify that a state has already been reached, the link extraction controller 1116 may store a fingerprint for each state along with the breadcrumb.","The fingerprint may be a reduced representation of the components of a state.","For example, a representation of visible objects may be created, such as by enumerating the objects in an XML data structure and then computing a mathematical hash (such as with MD5) of the data structure.","The hash is then the fingerprint, and if the hash of a new state matches a hash of an existing state, the states are considered to be the same.","As the link extraction controller 1116 assembles the set of states of interest, the link extraction controller 1116 may store an identifier of the state into a configuration data store 1124.For each state of interest, the link extraction controller 1116 determines a breadcrumb to reach that state and stores the breadcrumb in the configuration data store 1124.In addition, content or a fingerprint from states is stored in the configuration data store 1124.Data from the configuration data store 1124 may be provided to the search system 288 of FIG.","2.Breadcrumb Creation In FIG.","12, example operation of breadcrumb creation by an operator begins at 1204, where control opens the subject app in an emulator or simulator to the home state of the app.","At 1208, control begins tracking user interaction with the app, including tracking the user interface elements with which the operator interacts.","At 1212, if the operator marks the current state as a deep link target, control transfers to 1216; otherwise, control transfers to 1220.At 1216, the state is added to a list of target states and control continues at 1224.At 1224, control stores the operator interaction leading to the present state as a breadcrumb.","Control continues at 1220.At 1220, if the operator marks the state as an activity for bookmarking purposes, control transfers to 1228; otherwise, control transfers to 1232.At 1228, control adds the state to the rules for activity bookmarking so that when the state is encountered by a user, an activity corresponding to that state is bookmarked by sending an activity object to the operating system.","Control continues at 1236, where the operator interaction leading to the present state is stored as a breadcrumb.","If the breadcrumb was already stored at 1224 for the present state, an additional copy of the breadcrumb may be omitted from storage.","Control continues at 1232.At 1232, control continues tracking operator interaction with the app.","At 1240, control determines whether the operator has instructed the app to reset to a home state of the app.","If so, control transfers to 1244; otherwise, control returns to 1212.Resetting the home state may be accomplished by a user interface element belonging to the simulator within which the app is operating.","In other limitations, the app itself may have a mechanism for returning to the home state and this is recognized by 1240 as well.","By resetting to the home state, the operator indicates that a new set of user interface events should be tracked to lead to another state of interest.","At 1244, if the present state was not already marked as a deep link target, control stores the operator interaction leading to the present state as a breadcrumb and adds the present state to the list of target states.","Control continues at 1248, where if the operator is done, control ends.","Otherwise, control returns to 1208.Breadcrumb Extrapolation Referring to FIG.","13, the operator may have established a series of breadcrumbs but not labeled any particular states as target states.","For example, in some implementations, the operator may not be presented with an option to designate target states.","However, operator-created breadcrumbs generally begin at a home state and end at a terminal (or, final) state.","This final state may be assumed to be the state of interest for deep-linking.","In other words, only terminal states are assumed to be target states.","In other implementations, each state encountered along a breadcrumb is assumed to be a target state.","For example, when an operator is creating breadcrumbs for a restaurant review application, the operator may create one breadcrumb by navigating from the home state to a state containing restaurant information and reviews.","This would be assumed to be a desired target state, and the link extraction controller would attempt to find additional states that have similar data for scraping.","Control begins at 1304, where a first breadcrumb from a list of operator-created breadcrumbs is selected.","At 1308, control opens the app to a home state in an emulator.","At 1312, control follows the selected breadcrumb, stopping in the state immediately before the final state.","At 1316, control performs extrapolation to identify states similar to the final state.","For example, control identifies UI widgets parallel to the UI widget that, when followed according to the selected breadcrumb, will reach the final state.","At 1320, control adds the final state, as well as states reached from UI widgets identified as parallel, to a state list.","Each of the added states is annotated with a breadcrumb based on the selected breadcrumb.","The breadcrumb for the states other than the final state will diverge from the breadcrumb for the final state at the final UI event of each breadcrumb.","At 1324, control determines whether additional breadcrumbs are present in the list of breadcrumbs.","If so, control transfers to 1328; otherwise, control ends.","At 1328, control selects the next breadcrumb from the list of breadcrumbs and returns to 1308.CONCLUSION The foregoing description is merely illustrative in nature and is in no way intended to limit the disclosure, its application, or uses.","The broad teachings of the disclosure can be implemented in a variety of forms.","Therefore, while this disclosure includes particular examples, the true scope of the disclosure should not be so limited since other modifications will become apparent upon a study of the drawings, the specification, and the following claims.","It should be understood that one or more steps within a method may be executed in different order (or concurrently) without altering the principles of the present disclosure.","Further, although each of the embodiments is described above as having certain features, any one or more of those features described with respect to any embodiment of the disclosure can be implemented in and/or combined with features of any of the other embodiments, even if that combination is not explicitly described.","In other words, the described embodiments are not mutually exclusive, and permutations of one or more embodiments with one another remain within the scope of this disclosure.","Spatial and functional relationships between elements (for example, between modules) are described using various terms, including “connected,” “engaged,” “interfaced,” and “coupled.” Unless explicitly described as being “direct,” when a relationship between first and second elements is described in the above disclosure, that relationship encompasses a direct relationship where no other intervening elements are present between the first and second elements, and also an indirect relationship where one or more intervening elements are present (either spatially or functionally) between the first and second elements.","As used herein, the phrase at least one of A, B, and C should be construed to mean a logical (A OR B OR C), using a non-exclusive logical OR, and should not be construed to mean “at least one of A, at least one of B, and at least one of C.” In this application, including the definitions below, the term ‘module’ or the term ‘controller’ may be replaced with the term ‘circuit.’ The term ‘module’ may refer to, be part of, or include processor hardware (shared, dedicated, or group) that executes code and memory hardware (shared, dedicated, or group) that stores code executed by the processor hardware.","The module may include one or more interface circuits.","In some examples, the interface circuits may include wired or wireless interfaces that are connected to a local area network (LAN), the Internet, a wide area network (WAN), or combinations thereof.","The functionality of any given module of the present disclosure may be distributed among multiple modules that are connected via interface circuits.","For example, multiple modules may allow load balancing.","In a further example, a server (also known as remote, or cloud) module may accomplish some functionality on behalf of a client module.","The term code, as used above, may include software, firmware, and/or microcode, and may refer to programs, routines, functions, classes, data structures, and/or objects.","Shared processor hardware encompasses a single microprocessor that executes some or all code from multiple modules.","Group processor hardware encompasses a microprocessor that, in combination with additional microprocessors, executes some or all code from one or more modules.","References to multiple microprocessors encompass multiple microprocessors on discrete dies, multiple microprocessors on a single die, multiple cores of a single microprocessor, multiple threads of a single microprocessor, or a combination of the above.","Shared memory hardware encompasses a single memory device that stores some or all code from multiple modules.","Group memory hardware encompasses a memory device that, in combination with other memory devices, stores some or all code from one or more modules.","The term memory hardware is a subset of the term computer-readable medium.","The term computer-readable medium, as used herein, does not encompass transitory electrical or electromagnetic signals propagating through a medium (such as on a carrier wave); the term computer-readable medium is therefore considered tangible and non-transitory.","Non-limiting examples of a non-transitory computer-readable medium are nonvolatile memory devices (such as a flash memory device, an erasable programmable read-only memory device, or a mask read-only memory device), volatile memory devices (such as a static random access memory device or a dynamic random access memory device), magnetic storage media (such as an analog or digital magnetic tape or a hard disk drive), and optical storage media (such as a CD, a DVD, or a Blu-ray Disc).","The apparatuses and methods described in this application may be partially or fully implemented by a special purpose computer created by configuring a general purpose computer to execute one or more particular functions embodied in computer programs.","The functional blocks and flowchart elements described above serve as software specifications, which can be translated into the computer programs by the routine work of a skilled technician or programmer.","The computer programs include processor-executable instructions that are stored on at least one non-transitory computer-readable medium.","The computer programs may also include or rely on stored data.","The computer programs may encompass a basic input/output system (BIOS) that interacts with hardware of the special purpose computer, device drivers that interact with particular devices of the special purpose computer, one or more operating systems, user applications, background services, background applications, etc.","The computer programs may include: (i) descriptive text to be parsed, such as HTML (hypertext markup language) or XML (extensible markup language), (ii) assembly code, (iii) object code generated from source code by a compiler, (iv) source code for execution by an interpreter, (v) source code for compilation and execution by a just-in-time compiler, etc.","As examples only, source code may be written using syntax from languages including C, C++, C#, Objective-C, Swift, Haskell, Go, SQL, R, Lisp, Java®, Fortran, Perl, Pascal, Curl, OCaml, Javascript®, HTML5 (Hypertext Markup Language 5th revision), Ada, ASP (Active Server Pages), PHP (PHP: Hypertext Preprocessor), Scala, Eiffel, Smalltalk, Erlang, Ruby, Flash®, Visual Basic®, Lua, MATLAB, SIMULINK, and Python®.","None of the elements recited in the claims are intended to be a means-plus-function element within the meaning of 35 U.S.C.","§ 112(f) unless an element is expressly recited using the phrase “means for” or, in the case of a method claim, using the phrases “operation for” or “step for.”"]],"string":"[\n [\n \"SYSTEM AND METHOD FOR IDENTIFYING, INDEXING, AND NAVIGATING TO DEEP STATES OF MOBILE APPLICATIONS\",\n \"A mobile application development system includes a developer portal that receives an application from a developer and provides a routing library to the developer to augment the application.\",\n \"An offline analysis system analyzes the application to (i) determine a set of activities that a handler within the application is programmed to resume in response to respective resumption requests from a host operating system and (ii) determine parameters for each of the activities.\",\n \"The offline analysis system generates a set of links that each corresponds to a respective one of the activities.\",\n \"The routing library, installed as part of the augmented application onto a user device, receives a link, from the user device's operating system, that identifies a first activity.\",\n \"The routing library includes instructions for generating a first resumption request based on parameters corresponding to the first activity and transmitting the first resumption request to the augmented application's handler.\"\n ],\n [\n \"1.An electronic device comprising: a processor; and a memory electrically connected to the processor, wherein the memory stores instructions which, when executed, direct the processor to install a first application on the electronic device, the first application comprising: a routing library configured to register a link scheme with an operating system of the electronic device, and a handler configured to resume an activity of the first application in response to a request from the routing library.\",\n \"2.The electronic device of claim 1, wherein the link scheme comprises a scheme providing access to an internal state of the first application.\",\n \"3.The electronic device of claim 1, wherein the routing library is further configured to: install a business rule specifying a state of the first application that is to be accessible by the handler.\",\n \"4.The electronic device of claim 3, wherein the routing library is further configured to: install a user interface (UI) event sequence to reach the specified state of the first application that is to be accessible by the handler.\",\n \"5.The electronic device of claim 4, wherein the routing library is further configured to: download one or more UI event sequences each time the first application is opened.\",\n \"6.The electronic device of claim 4, wherein the routing library is further configured to: download one or more UI event sequences at predetermined intervals.\",\n \"7.The electronic device of claim 1, wherein the routing library is further configured to: receive a link from the operating system, wherein the link identifies a first activity; generate a first resumption request based on parameters corresponding to the first activity; and transmit the first resumption request to the handler.\",\n \"8.The electronic device of claim 5, wherein the link is received as a part of a search result from a second application of the electronic device.\",\n \"9.The electronic device of claim 8, wherein the link allows a user of the second application access to an internal state of the first application in response to selection of the search result.\",\n \"10.The electronic device of claim 1, wherein registering the link scheme with the operating system comprises registering a uniform resource identifier (URI) template with the operating system upon installation of the first application.\",\n \"11.A method providing access to a state of an application on an electronic device, comprising: installing, using at least one processor of the electronic device, a first application on the electronic device; registering, using a routing library of the first application executed by the at least one processor, a link scheme with an operating system of the electronic device; and resuming, using a handler of the first application, an activity of the first application in response to a request from the routing library.\",\n \"12.The method of claim 11, wherein the link scheme comprises a scheme providing access to an internal state of the first application.\",\n \"13.The method of claim 11, wherein the method further comprises: installing a business rule specifying a state of the first application that is to be accessible by the handler.\",\n \"14.The method of claim 13, wherein the method further comprises: installing a user interface (UI) event sequence to reach the specified state of the application that is to be accessible by the handler.\",\n \"15.The method of claim 14, wherein the method further comprises: downloading one or more UI event sequences each time the first application is opened.\",\n \"16.The method of claim 14, wherein the method further comprises: downloading one or more UI event sequences at predetermined intervals.\",\n \"17.The method of claim 11, wherein the method further comprises: receiving a link from the operating system, wherein the link identifies a first activity; generating a first resumption request based on parameters corresponding to the first activity; and transmitting the first resumption request to the handler.\",\n \"18.The method of claim 17, wherein the link is received as a part of a search result from a second application of the electronic device.\",\n \"19.The method of claim 11, wherein the registering of the link scheme with the operating system comprises registering a uniform resource identifier (URI) template with the operating system upon installation of the first application.\",\n \"20.A non-transitory computer readable recording medium having a program recorded thereon, the program implementing a method comprising: installing a first application on an electronic device; registering, using a routing library of the first application, a link scheme with an operating system of the electronic device; and resuming, using a handler of the first application, an activity of the first application in response to a request from the routing library.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>This section provides background information related to the present disclosure and is not necessarily prior art.\",\n \"An application (referred to interchangeably in this disclosure as an “app”), such as a mobile app, may contain multiple deep states.\",\n \"For example, in an app that rates the quality of restaurants based on social media opinion data, the detail page for each restaurant would be considered a deep state.\",\n \"Deep states are reachable from within the app through a sequence of user actions that can involve navigating through multiple menu screens (or, views) as well as interactions with user interface elements.\",\n \"Each of these menu screens and user interface elements can be mediated by a unique view controller associated with that displayed screen.\",\n \"Usually, these deep states are accessible only from within the app itself web search engines operating outside the app, for example, cannot reach the deep states within the app.\",\n \"This means that when a user conducts a conventional web search for restaurants and wants to explore one of the returned choices in a specialized restaurant rating app, the user would have to manually copy and paste the name of the selected search result into the search field of the restaurant rating app and command the restaurant ranking app to access its internal deep state corresponding to the selected restaurant.\",\n \"This represents undesirable additional interaction required of the user.\",\n \"If deep states of apps could be exposed to external apps and computer processes, the user could enjoy additional functionality and convenience.\",\n \"For example, the user could begin a search for a suitable restaurant using an Internet-based search server and then, by selecting one of the results of that search, be automatically led to the appropriate deep linked page of a specialized restaurant ranking app.\",\n \"However, implementing such functionality requires developer effort and requires deep linking expertise that the developer may not possess.\",\n \"When app development is limited by time, budget, or expertise, deep link functionality for some or even all of the states of an app may not be a high enough priority to get implemented.\",\n \"Mobile operating systems, such as the iOS operating system from Apple Inc. and the Android operating system from Google Inc., may allow a developer to provide data to the operating system for indexing.\",\n \"In the iOS operating system, this may take the form of a CSSearchableItem (where the CS stands for Core Spotlight) object.\",\n \"The developer may implement code that bookmarks certain states of an app by providing information about those states to the operating system.\",\n \"In the iOS operating system, this may take the form of an NSUserActivity object (where NS stands for NeXTSTEP).\",\n \"Then, users can perform a search through the operating system, where relevant data or states from the developer's app are identified.\",\n \"If a user selects one of those activities from an operating system interface, such as a search dialogue or a recent tasks menu, the developer's code can restore the app to the state corresponding to the bookmarked activity.\",\n \"A bookmarked activity on a first device may even be continued on a different device (assuming the app is also installed on the other device).\",\n \"Via inter-device communication, the operating system of the first device notifies the operating system of the other device what state the user was most recently interacting with.\",\n \"In addition, the developer may specify that certain types of data, such as telephone numbers and names from a contact database maintained by the app, be indexed by the operating system.\",\n \"When a user indicates to the operating system that one of those data objects (for example, a certain contact) is of interest, the developer's code can transition to a state of the app that presents that data object for viewing or editing.\",\n \"In order to take advantage of these operating system capabilities, the developer may implement code that can restore the app to a state based on indicated activity or data object.\",\n \"However, these activities and data objects may be known only to the operating system or to search systems maintained by a developer of the operating system.\",\n \"In other words, third party apps and search services may be unable to access this data and navigate directly to the states or data objects within the app.\",\n \"Further, developing code to display data objects, index data objects, bookmark activities, and continue activities requires developer effort and may not be accomplished for any of an app's states much less for all of the app's states.\",\n \"As a result, these enhanced operating system capabilities may not be available for a variety of states of an app and may also not be accessible to third party apps and search systems.\",\n \"In FIG.\",\n \"1 , the enhanced operating system functionality is graphically depicted.\",\n \"On a user device, an operating system 100 executes a first app (referred to as “App A”) 104 .\",\n \"App A 104 includes a representative set of views, View A 108 - 1 , View B 108 - 2 , View C 108 - 3 , View D 108 - 4 , and View E 108 - 5 (collectively, views 108 ).\",\n \"The views 108 may be managed by one or more view controllers, which may be developed according to the model-view-controller (MVC) software architecture pattern.\",\n \"As an example only, App A 104 is a restaurant information app, View A 108 - 1 is a home (or, default) state of App A 104 from which restaurant searches by cuisine, geography, etc.\",\n \"can be performed.\",\n \"Continuing the example, View B 108 - 2 is a two-dimensional app interface showing restaurant locations, View C 108 - 3 is a restaurant detail view, View D 108 - 4 is a list of restaurants by cuisine, and View E 108 - 5 is a list of recently-reviewed restaurants.\",\n \"In various implementations, including this example, a single view may be a template populated with entity-specific data.\",\n \"For example, View C 108 - 3 may have a visual layout for a restaurant specifying where a photo of the restaurant will be located, the location, size, and font face of the restaurant's name, how reviews will be summarized, etc.\",\n \"The visual layout view will be instantiated with data corresponding to a specific restaurant from a data store.\",\n \"App A 104 selects and provides data objects to the operating system 100 for indexing.\",\n \"For example, App A 104 may provide the names of each of the specific cuisines encompassed by App A 104 .\",\n \"The operating system 100 can then provide results to users who are searching by that cuisine name.\",\n \"App A 104 includes an activity handler 112 that receives a continue user activity signal from the operating system 100 .\",\n \"For example, the continue user activity signal may specify that a certain cuisine type was of interest to a user.\",\n \"The activity handler 112 then invokes View D 108 - 4 and populates View D 108 - 4 with results corresponding to the specified cuisine.\",\n \"App A 104 may be selective regarding which cuisines to provide to the operating system 100 for indexing because providing too many data objects may lead to a decrease in their average relevance.\",\n \"This may cause the operating system 100 to down-rank or even remove indexed objects from search results that do not appear to have high relevance.\",\n \"App A 104 may, therefore, include programming that indexes a list of the most popular cuisines or cuisines whose names are more likely to be unique to cuisines.\",\n \"For example, while “American” may be a cuisine name, there is a high false positive rate because this term applies to many other searches than simply cuisine.\",\n \"However, if a user indicates interest in a cuisine, such as by reviewing the restaurant listings for a certain cuisine one or more times, App A 104 may add that cuisine name to the list of objects to index by the operating system 100 .\",\n \"In addition, App A 104 may indicate to the operating system 100 , using an activity object, that a user is currently viewing restaurant results for a particular cuisine.\",\n \"This allows the operating system 100 to maintain essentially a history of activities performed by the user within App A 104 .\",\n \"In addition, the most recent activity engaged in by the user can be shared with another device, allowing a hand-off of user interaction with that activity from one device to another.\",\n \"Submitting an activity object to the operating system, allowing later resumption of the activity on the same or another device, is referred to in this disclosure as bookmarking the activity.\",\n \"Activity objects may be sent to the operating system 100 when the user enters View B 108 - 2 to view restaurant results in a map display.\",\n \"For example, the activity object sent to the operating system 100 may include a latitude and longitude at a center of the map.\",\n \"If the user adjusts the center of the map, App A 104 may provide an updated activity object to the operating system 100 indicating the new center point.\",\n \"App A 104 may further include in the activity object additional data such as filters.\",\n \"For example, the user may have restricted the displayed results to only those restaurants that are currently open.\",\n \"This filter may be identified in the activity object provided to the operating system 100 .\",\n \"The activity handler 112 may receive a continue user activity signal from the operating system 100 indicating that the user is interested in continuing a map view of restaurants at a certain center point with a certain set of filters.\",\n \"For example only, in the iOS operating system, this may take the form of a continueUserActivity call to the app delegate of the app.\",\n \"The activity handler 112 then invokes View B 108 - 2 with the provided parameters and presents the user with the desired map view.\",\n \"The continue user activity signal may have been received from another device on which the user was previously viewing that map display.\",\n \"As shown in FIG.\",\n \"1 , the activity handler 112 is programmed to invoke View B 108 - 2 , View D 108 - 4 , and View E 108 - 5 , but not View A 108 - 1 or View C 108 - 3 .\",\n \"In the operating system 100 , a search index 120 receives data objects from App A 104 .\",\n \"The search index 120 also receives data objects from other apps and, in some implementations, from the operating system 100 itself, such as the names of frequently-accessed device settings.\",\n \"For example only, in the iOS operating system, the search index 120 may be referred to as Spotlight and the data objects provided to the search index 120 may take the form of CSSearchableItem objects.\",\n \"The search index 120 may also receive activity metadata from an activity tracker 124 .\",\n \"The activity tracker 124 receives activity objects, including from App A 104 .\",\n \"An activity object may take the form of an NSUserActivity object.\",\n \"An activity object received by the activity tracker 124 may include metadata similar to that of a data object.\",\n \"The metadata can be indexed by the search index 120 .\",\n \"The metadata may take the form of a CSSearchableItemAttributeSet object, which may be the same form used in CSSearchableItem objects.\",\n \"Activities indicated as public may be shared with a cloud index maintained by the developer of the operating system 100 .\",\n \"A cloud index interface 128 provides the public activities to the cloud index.\",\n \"These public activities are selectively indexed by the cloud index, allowing other users to search for and find activities generated by App A 104 even when App A 104 is not installed on their devices.\",\n \"A handoff controller 132 shares the latest activity with other devices.\",\n \"In various implementations, the other devices have been authenticated to the handoff controller 132 to indicate that they have permission to receive the latest activities from the present device.\",\n \"These other devices can, therefore, allow a user to begin an activity on the device where the operating system 100 is executed and resume the activity on another device.\",\n \"A search interface 136 allows a user to perform a search, such as by entering a text query.\",\n \"The search index 120 provides relevant search results to the search interface 136 and, upon a user selection, the user-selected result is provided to the activity tracker 124 .\",\n \"The activity tracker 124 identifies which app corresponds to the user-selected result and sends a continue user activity signal to the relevant app.\",\n \"The continue user activity signal may include an indicator whether the continue user activity signal pertains to a data object or an activity object.\"\n ],\n [\n \"<SOH> SUMMARY <EOH>A mobile application development system includes a developer portal and an offline analysis system.\",\n \"The developer portal is configured to receive a copy of a first application from a first developer and provide a routing library to the first developer for incorporation into the first application prior to the first developer distributing an augmented application via a digital distribution platform.\",\n \"The routing library is incorporated into the first application to form the augmented application.\",\n \"The offline analysis system is configured to analyze the first application to (i) determine a set of activities that a handler within the first application is programmed to resume in response to respective resumption requests from a host operating system and (ii) determine parameters for each activity of the set of activities.\",\n \"The offline analysis system is configured to generate a set of links.\",\n \"Each link of the set of links corresponds to a respective activity of the set of activities.\",\n \"The routing library includes instructions configured to, subsequent to installation of the augmented application from the digital distribution platform onto a user device, receive a link from an operating system of the user device.\",\n \"The link identifies a first activity.\",\n \"The routing library includes instructions configured to generate a first resumption request based on parameters corresponding to the first activity and transmit the first resumption request to the handler of the augmented application.\",\n \"In other features, the parameters corresponding to the first activity include an activity type and an activity title.\",\n \"In other features, the first resumption request is transmitted by a continueUserActivity call to an app delegate of the augmented application.\",\n \"In other features, the first activity includes an NSUserActivity object.\",\n \"In other features, the offline analysis system is configured to (i) analyze the first application to determine a set of data objects that the handler within the first application is programmed to access in response to respective resumption requests from the host operating system, (ii) determine parameters for each data object of the set of data objects, and (iii) generate a second set of links.\",\n \"Each link of the second set of links corresponds to a respective data object of the set of data objects.\",\n \"The routing library includes instructions configured to, subsequent to installation of the augmented application in the user device, receive a second link from an operating system of the user device.\",\n \"The second link identifies a first data object.\",\n \"The instructions are further configured to generate a second resumption request based on parameters corresponding to the first data object and transmit the second resumption request to the handler of the augmented application.\",\n \"In other features, the first data object is a CSSearchableItem object.\",\n \"In other features, by incorporating the routing library, the augmented application is configured to register a first uniform resource identifier (URI) template with the operating system upon installation.\",\n \"The link conforms to the first URI template.\",\n \"In other features, the first URI template specifies a scheme includes a text string ending with a colon and two forward slashes.\",\n \"The scheme is unique to the augmented application.\",\n \"The text string is a concatenation of a text identifier associated with the developer portal and a name of the first application.\",\n \"The link begins with the scheme.\",\n \"In other features, the offline analysis system is configured to execute the first application and, during execution, monitor a sequence of user interface (UI) events initiated by an operator starting from an initial state and proceeding to a first state.\",\n \"The offline analysis system is configured to store the sequence of UI events as a first data structure corresponding to the first state.\",\n \"The routing library includes instructions configured to, in response to a user of the user device encountering the first state while using the augmented application, transmitting a bookmark to the operating system.\",\n \"The instructions are configured to, in response to receiving a resumption request indicating the first state from the operating system, replay the sequence of UI events from the first data structure.\",\n \"In other features, the offline analysis system is configured to execute the first application and, during execution, monitor a sequence of user interface (UI) events initiated by an operator starting from an initial state and proceeding to a first state corresponding to a first data object.\",\n \"The offline analysis system is configured to store the sequence of UI events as a first data structure corresponding to the first data object.\",\n \"The routing library includes instructions configured to, in response to execution of the augmented application, selectively transmit the first data object to the operating system.\",\n \"The instructions are configured to, in response to receiving a resumption request indicating the first data object from the operating system, replay the sequence of UI events from the first data structure.\",\n \"In other features, the link selectively includes serialized data.\",\n \"The routing library includes instructions configured to decode the parameters corresponding to the first activity from the serialized data within the link.\",\n \"In other features, the link selectively includes a unique identifier.\",\n \"The routing library includes instructions configured to retrieve the parameters corresponding to the first activity based on the unique identifier.\",\n \"In other features, the mobile application development system includes a data server configured to store a plurality of parameters corresponding to activities determined by the offline analysis system.\",\n \"The routing library includes instructions configured to, upon the first execution of the augmented application, download the parameters corresponding to at least the first activity from the data server for storage in a data store local to the routing library.\",\n \"The routing library includes instructions configured to retrieve the parameters corresponding to the first activity from the data store in response to the unique identifier.\",\n \"A system includes the above mobile application development system and a search system configured to return results to the user device in response to a search commissioned by a user of the user device.\",\n \"A first result of the returned results includes the link.\",\n \"In response to selection of the first result by the user, the link is transmitted to the routing library by the operating system.\",\n \"A method of operating a mobile application development system includes receiving a copy of a first application from a first developer.\",\n \"The method includes providing a routing library to the first developer for incorporation into the first application prior to the first developer distributing an augmented application via a digital distribution platform.\",\n \"The routing library is incorporated into the first application to form the augmented application.\",\n \"The method includes analyzing the first application to (i) determine a set of activities that a handler within the first application is programmed to resume in response to respective resumption requests from a host operating system and (ii) determine parameters for each activity of the set of activities.\",\n \"The method includes generating a set of links.\",\n \"Each link of the set of links corresponds to a respective activity of the set of activities.\",\n \"The routing library includes instructions configured to, subsequent to installation of the augmented application from the digital distribution platform onto a user device.\",\n \"The instructions are further configured to receive a link from an operating system of the user device.\",\n \"The link identifies a first activity.\",\n \"The instructions are further configured to generate a first resumption request based on parameters corresponding to the first activity.\",\n \"The instructions are further configured to transmit the first resumption request to the handler of the augmented application.\",\n \"In other features, the parameters corresponding to the first activity include an activity type and an activity title.\",\n \"In other features, the first resumption request is transmitted by a continueUserActivity call to an app delegate of the augmented application.\",\n \"In other features, the method includes analyzing the first application to determine a set of data objects that the handler within the first application is programmed to access in response to respective resumption requests from the host operating system.\",\n \"The method includes determining parameters for each data object of the set of data objects.\",\n \"The method includes generating a second set of links.\",\n \"Each link of the second set of links corresponds to a respective data object of the set of data objects.\",\n \"The routing library includes instructions configured to, subsequent to installation of the augmented application in the user device.\",\n \"The instructions are further configured to receive a second link from an operating system of the user device.\",\n \"The second link identifies a first data object.\",\n \"The instructions are further configured to generate a second resumption request based on parameters corresponding to the first data object.\",\n \"The instructions are further configured to transmit the second resumption request to the handler of the augmented application.\",\n \"In other features, the first data object is a CSSearchableItem object.\",\n \"In other features, by incorporating the routing library, the augmented application is configured to register a first uniform resource identifier (URI) template with the operating system upon installation.\",\n \"The link conforms to the first URI template.\",\n \"In other features, the method includes executing the first application and, during execution, monitoring a sequence of user interface (UI) events initiated by an operator starting from an initial state and proceeding to a first state.\",\n \"The method includes storing the sequence of UI events as a first data structure corresponding to the first state.\",\n \"The routing library includes instructions configured to, in response to a user of the user device encountering the first state while using the augmented application, transmitting a bookmark to the operating system.\",\n \"The instructions are further configured to, in response to receiving a resumption request indicating the first state from the operating system, replay the sequence of UI events from the first data structure.\",\n \"In other features, the method includes executing the first application and, during execution, monitor a sequence of user interface (UI) events initiated by an operator starting from an initial state and proceeding to a first state corresponding to a first data object.\",\n \"The method includes storing the sequence of UI events as a first data structure corresponding to the first data object.\",\n \"The routing library includes instructions configured to, in response to execution of the augmented application, selectively transmit the first data object to the operating system.\",\n \"The instructions are further configured to, in response to receiving a resumption request indicating the first data object from the operating system, replay the sequence of UI events from the first data structure.\",\n \"In other features, the link selectively includes serialized data.\",\n \"The routing library includes instructions configured to decode the parameters corresponding to the first activity from the serialized data within the link.\",\n \"In other features, the link selectively includes a unique identifier.\",\n \"The routing library includes instructions configured to retrieve the parameters corresponding to the first activity based on the unique identifier.\",\n \"In other features, the method includes storing, in a data store, a plurality of parameters corresponding to the determined set of activities.\",\n \"The routing library includes instructions configured to, upon first execution of the augmented application, download the parameters corresponding to at least the first activity from the data store for storage in a data store local to the routing library.\",\n \"The routing library includes instructions configured to retrieve the parameters corresponding to the first activity from the data store in response to the unique identifier.\",\n \"Further areas of applicability of the present disclosure will become apparent from the detailed description, the claims, and the drawings.\",\n \"The detailed description and specific examples are intended for purposes of illustration only and are not intended to limit the scope of the disclosure.\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation application of prior application Ser.\",\n \"No.\",\n \"15/236,140, filed on Aug. 12, 2016, which claimed the benefit of U.S.\",\n \"Provisional Application No.\",\n \"62/274,152, filed Dec. 31, 2015, U.S.\",\n \"Provisional Application No.\",\n \"62/252,357, filed Nov. 6, 2015, and U.S.\",\n \"Provisional Application No.\",\n \"62/204,960, filed Aug. 13, 2015.The entire disclosures of the applications referenced above are incorporated by reference.\",\n \"FIELD The present disclosure relates generally to mobile application development and more specifically to deep linking to specific states of mobile applications.\",\n \"BACKGROUND This section provides background information related to the present disclosure and is not necessarily prior art.\",\n \"An application (referred to interchangeably in this disclosure as an “app”), such as a mobile app, may contain multiple deep states.\",\n \"For example, in an app that rates the quality of restaurants based on social media opinion data, the detail page for each restaurant would be considered a deep state.\",\n \"Deep states are reachable from within the app through a sequence of user actions that can involve navigating through multiple menu screens (or, views) as well as interactions with user interface elements.\",\n \"Each of these menu screens and user interface elements can be mediated by a unique view controller associated with that displayed screen.\",\n \"Usually, these deep states are accessible only from within the app itself web search engines operating outside the app, for example, cannot reach the deep states within the app.\",\n \"This means that when a user conducts a conventional web search for restaurants and wants to explore one of the returned choices in a specialized restaurant rating app, the user would have to manually copy and paste the name of the selected search result into the search field of the restaurant rating app and command the restaurant ranking app to access its internal deep state corresponding to the selected restaurant.\",\n \"This represents undesirable additional interaction required of the user.\",\n \"If deep states of apps could be exposed to external apps and computer processes, the user could enjoy additional functionality and convenience.\",\n \"For example, the user could begin a search for a suitable restaurant using an Internet-based search server and then, by selecting one of the results of that search, be automatically led to the appropriate deep linked page of a specialized restaurant ranking app.\",\n \"However, implementing such functionality requires developer effort and requires deep linking expertise that the developer may not possess.\",\n \"When app development is limited by time, budget, or expertise, deep link functionality for some or even all of the states of an app may not be a high enough priority to get implemented.\",\n \"Mobile operating systems, such as the iOS operating system from Apple Inc. and the Android operating system from Google Inc., may allow a developer to provide data to the operating system for indexing.\",\n \"In the iOS operating system, this may take the form of a CSSearchableItem (where the CS stands for Core Spotlight) object.\",\n \"The developer may implement code that bookmarks certain states of an app by providing information about those states to the operating system.\",\n \"In the iOS operating system, this may take the form of an NSUserActivity object (where NS stands for NeXTSTEP).\",\n \"Then, users can perform a search through the operating system, where relevant data or states from the developer's app are identified.\",\n \"If a user selects one of those activities from an operating system interface, such as a search dialogue or a recent tasks menu, the developer's code can restore the app to the state corresponding to the bookmarked activity.\",\n \"A bookmarked activity on a first device may even be continued on a different device (assuming the app is also installed on the other device).\",\n \"Via inter-device communication, the operating system of the first device notifies the operating system of the other device what state the user was most recently interacting with.\",\n \"In addition, the developer may specify that certain types of data, such as telephone numbers and names from a contact database maintained by the app, be indexed by the operating system.\",\n \"When a user indicates to the operating system that one of those data objects (for example, a certain contact) is of interest, the developer's code can transition to a state of the app that presents that data object for viewing or editing.\",\n \"In order to take advantage of these operating system capabilities, the developer may implement code that can restore the app to a state based on indicated activity or data object.\",\n \"However, these activities and data objects may be known only to the operating system or to search systems maintained by a developer of the operating system.\",\n \"In other words, third party apps and search services may be unable to access this data and navigate directly to the states or data objects within the app.\",\n \"Further, developing code to display data objects, index data objects, bookmark activities, and continue activities requires developer effort and may not be accomplished for any of an app's states much less for all of the app's states.\",\n \"As a result, these enhanced operating system capabilities may not be available for a variety of states of an app and may also not be accessible to third party apps and search systems.\",\n \"In FIG.\",\n \"1, the enhanced operating system functionality is graphically depicted.\",\n \"On a user device, an operating system 100 executes a first app (referred to as “App A”) 104.App A 104 includes a representative set of views, View A 108-1, View B 108-2, View C 108-3, View D 108-4, and View E 108-5 (collectively, views 108).\",\n \"The views 108 may be managed by one or more view controllers, which may be developed according to the model-view-controller (MVC) software architecture pattern.\",\n \"As an example only, App A 104 is a restaurant information app, View A 108-1 is a home (or, default) state of App A 104 from which restaurant searches by cuisine, geography, etc.\",\n \"can be performed.\",\n \"Continuing the example, View B 108-2 is a two-dimensional app interface showing restaurant locations, View C 108-3 is a restaurant detail view, View D 108-4 is a list of restaurants by cuisine, and View E 108-5 is a list of recently-reviewed restaurants.\",\n \"In various implementations, including this example, a single view may be a template populated with entity-specific data.\",\n \"For example, View C 108-3 may have a visual layout for a restaurant specifying where a photo of the restaurant will be located, the location, size, and font face of the restaurant's name, how reviews will be summarized, etc.\",\n \"The visual layout view will be instantiated with data corresponding to a specific restaurant from a data store.\",\n \"App A 104 selects and provides data objects to the operating system 100 for indexing.\",\n \"For example, App A 104 may provide the names of each of the specific cuisines encompassed by App A 104.The operating system 100 can then provide results to users who are searching by that cuisine name.\",\n \"App A 104 includes an activity handler 112 that receives a continue user activity signal from the operating system 100.For example, the continue user activity signal may specify that a certain cuisine type was of interest to a user.\",\n \"The activity handler 112 then invokes View D 108-4 and populates View D 108-4 with results corresponding to the specified cuisine.\",\n \"App A 104 may be selective regarding which cuisines to provide to the operating system 100 for indexing because providing too many data objects may lead to a decrease in their average relevance.\",\n \"This may cause the operating system 100 to down-rank or even remove indexed objects from search results that do not appear to have high relevance.\",\n \"App A 104 may, therefore, include programming that indexes a list of the most popular cuisines or cuisines whose names are more likely to be unique to cuisines.\",\n \"For example, while “American” may be a cuisine name, there is a high false positive rate because this term applies to many other searches than simply cuisine.\",\n \"However, if a user indicates interest in a cuisine, such as by reviewing the restaurant listings for a certain cuisine one or more times, App A 104 may add that cuisine name to the list of objects to index by the operating system 100.In addition, App A 104 may indicate to the operating system 100, using an activity object, that a user is currently viewing restaurant results for a particular cuisine.\",\n \"This allows the operating system 100 to maintain essentially a history of activities performed by the user within App A 104.In addition, the most recent activity engaged in by the user can be shared with another device, allowing a hand-off of user interaction with that activity from one device to another.\",\n \"Submitting an activity object to the operating system, allowing later resumption of the activity on the same or another device, is referred to in this disclosure as bookmarking the activity.\",\n \"Activity objects may be sent to the operating system 100 when the user enters View B 108-2 to view restaurant results in a map display.\",\n \"For example, the activity object sent to the operating system 100 may include a latitude and longitude at a center of the map.\",\n \"If the user adjusts the center of the map, App A 104 may provide an updated activity object to the operating system 100 indicating the new center point.\",\n \"App A 104 may further include in the activity object additional data such as filters.\",\n \"For example, the user may have restricted the displayed results to only those restaurants that are currently open.\",\n \"This filter may be identified in the activity object provided to the operating system 100.The activity handler 112 may receive a continue user activity signal from the operating system 100 indicating that the user is interested in continuing a map view of restaurants at a certain center point with a certain set of filters.\",\n \"For example only, in the iOS operating system, this may take the form of a continueUserActivity call to the app delegate of the app.\",\n \"The activity handler 112 then invokes View B 108-2 with the provided parameters and presents the user with the desired map view.\",\n \"The continue user activity signal may have been received from another device on which the user was previously viewing that map display.\",\n \"As shown in FIG.\",\n \"1, the activity handler 112 is programmed to invoke View B 108-2, View D 108-4, and View E 108-5, but not View A 108-1 or View C 108-3.In the operating system 100, a search index 120 receives data objects from App A 104.The search index 120 also receives data objects from other apps and, in some implementations, from the operating system 100 itself, such as the names of frequently-accessed device settings.\",\n \"For example only, in the iOS operating system, the search index 120 may be referred to as Spotlight and the data objects provided to the search index 120 may take the form of CSSearchableItem objects.\",\n \"The search index 120 may also receive activity metadata from an activity tracker 124.The activity tracker 124 receives activity objects, including from App A 104.An activity object may take the form of an NSUserActivity object.\",\n \"An activity object received by the activity tracker 124 may include metadata similar to that of a data object.\",\n \"The metadata can be indexed by the search index 120.The metadata may take the form of a CSSearchableItemAttributeSet object, which may be the same form used in CSSearchableItem objects.\",\n \"Activities indicated as public may be shared with a cloud index maintained by the developer of the operating system 100.A cloud index interface 128 provides the public activities to the cloud index.\",\n \"These public activities are selectively indexed by the cloud index, allowing other users to search for and find activities generated by App A 104 even when App A 104 is not installed on their devices.\",\n \"A handoff controller 132 shares the latest activity with other devices.\",\n \"In various implementations, the other devices have been authenticated to the handoff controller 132 to indicate that they have permission to receive the latest activities from the present device.\",\n \"These other devices can, therefore, allow a user to begin an activity on the device where the operating system 100 is executed and resume the activity on another device.\",\n \"A search interface 136 allows a user to perform a search, such as by entering a text query.\",\n \"The search index 120 provides relevant search results to the search interface 136 and, upon a user selection, the user-selected result is provided to the activity tracker 124.The activity tracker 124 identifies which app corresponds to the user-selected result and sends a continue user activity signal to the relevant app.\",\n \"The continue user activity signal may include an indicator whether the continue user activity signal pertains to a data object or an activity object.\",\n \"SUMMARY A mobile application development system includes a developer portal and an offline analysis system.\",\n \"The developer portal is configured to receive a copy of a first application from a first developer and provide a routing library to the first developer for incorporation into the first application prior to the first developer distributing an augmented application via a digital distribution platform.\",\n \"The routing library is incorporated into the first application to form the augmented application.\",\n \"The offline analysis system is configured to analyze the first application to (i) determine a set of activities that a handler within the first application is programmed to resume in response to respective resumption requests from a host operating system and (ii) determine parameters for each activity of the set of activities.\",\n \"The offline analysis system is configured to generate a set of links.\",\n \"Each link of the set of links corresponds to a respective activity of the set of activities.\",\n \"The routing library includes instructions configured to, subsequent to installation of the augmented application from the digital distribution platform onto a user device, receive a link from an operating system of the user device.\",\n \"The link identifies a first activity.\",\n \"The routing library includes instructions configured to generate a first resumption request based on parameters corresponding to the first activity and transmit the first resumption request to the handler of the augmented application.\",\n \"In other features, the parameters corresponding to the first activity include an activity type and an activity title.\",\n \"In other features, the first resumption request is transmitted by a continueUserActivity call to an app delegate of the augmented application.\",\n \"In other features, the first activity includes an NSUserActivity object.\",\n \"In other features, the offline analysis system is configured to (i) analyze the first application to determine a set of data objects that the handler within the first application is programmed to access in response to respective resumption requests from the host operating system, (ii) determine parameters for each data object of the set of data objects, and (iii) generate a second set of links.\",\n \"Each link of the second set of links corresponds to a respective data object of the set of data objects.\",\n \"The routing library includes instructions configured to, subsequent to installation of the augmented application in the user device, receive a second link from an operating system of the user device.\",\n \"The second link identifies a first data object.\",\n \"The instructions are further configured to generate a second resumption request based on parameters corresponding to the first data object and transmit the second resumption request to the handler of the augmented application.\",\n \"In other features, the first data object is a CSSearchableItem object.\",\n \"In other features, by incorporating the routing library, the augmented application is configured to register a first uniform resource identifier (URI) template with the operating system upon installation.\",\n \"The link conforms to the first URI template.\",\n \"In other features, the first URI template specifies a scheme includes a text string ending with a colon and two forward slashes.\",\n \"The scheme is unique to the augmented application.\",\n \"The text string is a concatenation of a text identifier associated with the developer portal and a name of the first application.\",\n \"The link begins with the scheme.\",\n \"In other features, the offline analysis system is configured to execute the first application and, during execution, monitor a sequence of user interface (UI) events initiated by an operator starting from an initial state and proceeding to a first state.\",\n \"The offline analysis system is configured to store the sequence of UI events as a first data structure corresponding to the first state.\",\n \"The routing library includes instructions configured to, in response to a user of the user device encountering the first state while using the augmented application, transmitting a bookmark to the operating system.\",\n \"The instructions are configured to, in response to receiving a resumption request indicating the first state from the operating system, replay the sequence of UI events from the first data structure.\",\n \"In other features, the offline analysis system is configured to execute the first application and, during execution, monitor a sequence of user interface (UI) events initiated by an operator starting from an initial state and proceeding to a first state corresponding to a first data object.\",\n \"The offline analysis system is configured to store the sequence of UI events as a first data structure corresponding to the first data object.\",\n \"The routing library includes instructions configured to, in response to execution of the augmented application, selectively transmit the first data object to the operating system.\",\n \"The instructions are configured to, in response to receiving a resumption request indicating the first data object from the operating system, replay the sequence of UI events from the first data structure.\",\n \"In other features, the link selectively includes serialized data.\",\n \"The routing library includes instructions configured to decode the parameters corresponding to the first activity from the serialized data within the link.\",\n \"In other features, the link selectively includes a unique identifier.\",\n \"The routing library includes instructions configured to retrieve the parameters corresponding to the first activity based on the unique identifier.\",\n \"In other features, the mobile application development system includes a data server configured to store a plurality of parameters corresponding to activities determined by the offline analysis system.\",\n \"The routing library includes instructions configured to, upon the first execution of the augmented application, download the parameters corresponding to at least the first activity from the data server for storage in a data store local to the routing library.\",\n \"The routing library includes instructions configured to retrieve the parameters corresponding to the first activity from the data store in response to the unique identifier.\",\n \"A system includes the above mobile application development system and a search system configured to return results to the user device in response to a search commissioned by a user of the user device.\",\n \"A first result of the returned results includes the link.\",\n \"In response to selection of the first result by the user, the link is transmitted to the routing library by the operating system.\",\n \"A method of operating a mobile application development system includes receiving a copy of a first application from a first developer.\",\n \"The method includes providing a routing library to the first developer for incorporation into the first application prior to the first developer distributing an augmented application via a digital distribution platform.\",\n \"The routing library is incorporated into the first application to form the augmented application.\",\n \"The method includes analyzing the first application to (i) determine a set of activities that a handler within the first application is programmed to resume in response to respective resumption requests from a host operating system and (ii) determine parameters for each activity of the set of activities.\",\n \"The method includes generating a set of links.\",\n \"Each link of the set of links corresponds to a respective activity of the set of activities.\",\n \"The routing library includes instructions configured to, subsequent to installation of the augmented application from the digital distribution platform onto a user device.\",\n \"The instructions are further configured to receive a link from an operating system of the user device.\",\n \"The link identifies a first activity.\",\n \"The instructions are further configured to generate a first resumption request based on parameters corresponding to the first activity.\",\n \"The instructions are further configured to transmit the first resumption request to the handler of the augmented application.\",\n \"In other features, the parameters corresponding to the first activity include an activity type and an activity title.\",\n \"In other features, the first resumption request is transmitted by a continueUserActivity call to an app delegate of the augmented application.\",\n \"In other features, the method includes analyzing the first application to determine a set of data objects that the handler within the first application is programmed to access in response to respective resumption requests from the host operating system.\",\n \"The method includes determining parameters for each data object of the set of data objects.\",\n \"The method includes generating a second set of links.\",\n \"Each link of the second set of links corresponds to a respective data object of the set of data objects.\",\n \"The routing library includes instructions configured to, subsequent to installation of the augmented application in the user device.\",\n \"The instructions are further configured to receive a second link from an operating system of the user device.\",\n \"The second link identifies a first data object.\",\n \"The instructions are further configured to generate a second resumption request based on parameters corresponding to the first data object.\",\n \"The instructions are further configured to transmit the second resumption request to the handler of the augmented application.\",\n \"In other features, the first data object is a CSSearchableItem object.\",\n \"In other features, by incorporating the routing library, the augmented application is configured to register a first uniform resource identifier (URI) template with the operating system upon installation.\",\n \"The link conforms to the first URI template.\",\n \"In other features, the method includes executing the first application and, during execution, monitoring a sequence of user interface (UI) events initiated by an operator starting from an initial state and proceeding to a first state.\",\n \"The method includes storing the sequence of UI events as a first data structure corresponding to the first state.\",\n \"The routing library includes instructions configured to, in response to a user of the user device encountering the first state while using the augmented application, transmitting a bookmark to the operating system.\",\n \"The instructions are further configured to, in response to receiving a resumption request indicating the first state from the operating system, replay the sequence of UI events from the first data structure.\",\n \"In other features, the method includes executing the first application and, during execution, monitor a sequence of user interface (UI) events initiated by an operator starting from an initial state and proceeding to a first state corresponding to a first data object.\",\n \"The method includes storing the sequence of UI events as a first data structure corresponding to the first data object.\",\n \"The routing library includes instructions configured to, in response to execution of the augmented application, selectively transmit the first data object to the operating system.\",\n \"The instructions are further configured to, in response to receiving a resumption request indicating the first data object from the operating system, replay the sequence of UI events from the first data structure.\",\n \"In other features, the link selectively includes serialized data.\",\n \"The routing library includes instructions configured to decode the parameters corresponding to the first activity from the serialized data within the link.\",\n \"In other features, the link selectively includes a unique identifier.\",\n \"The routing library includes instructions configured to retrieve the parameters corresponding to the first activity based on the unique identifier.\",\n \"In other features, the method includes storing, in a data store, a plurality of parameters corresponding to the determined set of activities.\",\n \"The routing library includes instructions configured to, upon first execution of the augmented application, download the parameters corresponding to at least the first activity from the data store for storage in a data store local to the routing library.\",\n \"The routing library includes instructions configured to retrieve the parameters corresponding to the first activity from the data store in response to the unique identifier.\",\n \"Further areas of applicability of the present disclosure will become apparent from the detailed description, the claims, and the drawings.\",\n \"The detailed description and specific examples are intended for purposes of illustration only and are not intended to limit the scope of the disclosure.\",\n \"DRAWINGS The drawings described herein are for illustrative purposes only of selected embodiments and not all possible implementations and are not intended to limit the scope of the present disclosure.\",\n \"FIG.\",\n \"1 is a graphical illustration and functional block diagram of an example app interacting with operating system app indexing functionality.\",\n \"FIG.\",\n \"2 is a high-level functional block diagram of a mobile application environment according to the principles of the present disclosure.\",\n \"FIG.\",\n \"3A is a functional block diagram of an example implementation of integration of a routing library with an example app.\",\n \"FIG.\",\n \"3B is a functional block diagram of an example integration of routing library with another example app.\",\n \"FIG.\",\n \"4 is a functional block diagram of an example implementation of a routing library.\",\n \"FIG.\",\n \"5 is a flowchart of example overall operation of a mobile application ecosystem according to the principles of the present disclosure.\",\n \"FIG.\",\n \"6 is a flowchart of example operation of a routing library.\",\n \"FIG.\",\n \"7 is a flowchart of example operation of activity and link handling within a routing library.\",\n \"FIG.\",\n \"8 is a flowchart of example traversal of a breadcrumb to reach a specified state.\",\n \"FIG.\",\n \"9 is a functional block diagram of an example implementation of the search system of FIG.\",\n \"2.FIG.\",\n \"10 is a flowchart of example operation of deep link creation and provision to user devices according to the principles of the present disclosure.\",\n \"FIG.\",\n \"11 is a functional block diagram of an example implementation of an offline analysis system.\",\n \"FIG.\",\n \"12 is a flowchart of example operation of breadcrumb creation for an app as part of offline analysis.\",\n \"FIG.\",\n \"13 is a flowchart of extrapolation as part of offline analysis to identify additional states of interest.\",\n \"Corresponding reference numerals indicate corresponding parts throughout the several views of the drawings.\",\n \"DETAILED DESCRIPTION Introduction A developer of an app may write code to take advantage of operating system (OS) functionality that allows, in one example, an activity within the app to be bookmarked for the user to return to later or for the activity to be resumed on another of the user's devices.\",\n \"The developer may also write code that submits data to the OS for indexing so that the OS can surface the data, such as in response to an OS-wide search.\",\n \"In order to implement this functionality, the developer writes code that allows the app to resume to an activity indicated by the OS or to a state that interacts with a data object specified by the OS.\",\n \"In some implementations, the activity object received from the OS fully specifies the activity for the app to resume, even if this particular copy of the app has not performed that activity previously.\",\n \"Meanwhile, for data objects, some apps may be able to show a state of the app corresponding to a certain data object only if that data object has been stored by the present copy of the app.\",\n \"In other implementations, or for certain apps, certain data objects may fully specify the state to which the app should return to view that data object.\",\n \"This generally means that the data for the data object is either known by the app, accessible to the app, or provided to the app from the OS within the continue user activity request.\",\n \"For data objects that do not fully specify the state of an app, these data objects may be specific to the app where they were created, and cannot be accessed by other copies of the app.\",\n \"Even though the developer may have implemented, for some or all states and for some or all data objects, the ability to resume that activity or navigate to that data object, there may be no provision for third parties, such as search services or other apps, to directly link to those activities or data objects within the app.\",\n \"The present disclosure identifies activities implemented by the developer and provides a library that, when presented with an appropriate deep link, can invoke the internal activity handling of the app.\",\n \"This allows the developer's efforts in interacting with the OS to be leveraged to provide deep link access to third parties.\",\n \"For some apps, the developer may not have implemented OS search functionality for some states and for some data.\",\n \"For some apps, the developer may not have implemented that functionality for any states or any data.\",\n \"The present disclosure, therefore, describes how the developer can specify which states of an app should have this functionality enabled.\",\n \"The present disclosure describes how the application can be supplemented to enable this functionality for the app, such as by recording sequences of user interface events that can be replayed to reach deep states of the app.\",\n \"When a routing library according to the principles of the present disclosure is used to enable activity bookmarking and data indexing, the configuration of the routing library may be specified by the developer.\",\n \"In various implementations, an agent of the developer may be able to make configuration decisions, such as which states to bookmark and which data to index, and those configuration decisions are relayed to the routing library.\",\n \"In various implementations, the routing library may periodically update this configuration so that the developer can change the configuration even for apps already installed on devices.\",\n \"A developer portal may allow even non-programmers working with the developer to specify business rules.\",\n \"For example, a marketing or user experience professional at the developer may specify what data to submit to the OS for indexing in order to optimize the search relevancy of the app for a given OS.\",\n \"A developer portal according to the present disclosure provides a routing library to the developer for integration into an app, and that routing library implements the above functionality.\",\n \"For example, based on configuration data, the routing library may bookmark certain activities with the OS and may submit certain data objects for indexing to the OS.\",\n \"The configuration data may be generated at the time of onboarding the app, and may be generated manually, with artificial intelligence, or with operator-supplemented artificial intelligence.\",\n \"In addition, the routing library may service continuing activity requests from the OS, such as by executing a series of user interface events to return to the selective activity or to display the selected data.\",\n \"The routing library may also handle incoming links, such as from other apps or from browser instances.\",\n \"The routing library may take the form of a dynamic link library (DLL), a dylib, or a software development kit (SDK).\",\n \"The routing library may be downloaded by the developer and imported into the integrated development environment (IDE) of the developer, such as the Xcode IDE from Apple Inc.\",\n \"In some implementations, the routing library is either already compiled or includes make files and other configuration files allowing the routing library to be compiled.\",\n \"The developer may integrate the routing library simply by instructing the IDE to add the routing library to their app's project, such as by adding the routing library to an import list or to a list of included code modules.\",\n \"The developer may also need to update a configuration file to indicate that the routing library will handle certain uniform resource identifiers (URIs) or activity types.\",\n \"The configuration file may take the form of an information property list (Info.plist) file.\",\n \"In various implementations, a script may be provided along with the routing library that performs the configuration file update as well as the import of the routing library into the current IDE project.\",\n \"Meanwhile, the developer portal supplies the app to an offline analysis system that determines how to access states of interest.\",\n \"The states of interest may be specified by the app developer or determined by the developer portal.\",\n \"In brief, an offline analysis system of the developer portal determines what sequence of user interface (UI) actions a user would take to reach a state of interest.\",\n \"That UI action sequence can be replayed by the routing library within an app on a user's device to arrive at the state of interest.\",\n \"In other words, the routing library simulates the UI actions users would themselves perform to reach a deep state.\",\n \"By simulating the UI actions, the routing library avoids the user having to perform each UI action and will generally be far faster than a user manually performing the sequence of UI actions.\",\n \"The user may not even see some of the intermediate states when the routing library is navigating to the deep state of interest, or these intermediate states may only be visible briefly.\",\n \"The UI action sequences for the deep states of an app may be integrated into the app along with the routing library, or may be downloaded by the routing library once the app is installed.\",\n \"In some implementations, a UI action sequence can be encoded as part of a link designating the app and serviced by the routing library.\",\n \"Without further effort from the developer, the app now has deep link functionality that can be accessed from external sources.\",\n \"For example, a search system could provide results that lead directly to deep states of the app.\",\n \"Or a third party app could easily direct users to deep states of the app.\",\n \"This may increase the visibility of the app and allow for tighter integration and better overall user experience with the app.\",\n \"In addition, now that the developer portal is responsible for deep linking, deep links can be added or modified without requiring assistance from the developer's software programmers, who may be working on other projects and have other priorities.\",\n \"In other words, a business person, such as an advertising or marketing professional working for an app developer, may use the developer portal to identify which states of the app should be deep-linkable.\",\n \"The business person could even remove states from the list of deep-linked states, all without requiring the assistance of a software programmer.\",\n \"Block Diagram In FIG.\",\n \"2, additional details are presented.\",\n \"As noted above, a developer 204 provides an app (referred to as “App A”) to a developer portal 208.The developer portal 208 provides a copy of a routing library to the developer 204 for incorporation into App A, creating an augmented version of App A.\",\n \"The developer 204 provides the augmented App A, which is still referred to below as App A for simplicity, to a digital distribution platform 212 for distribution to end users.\",\n \"The digital distribution platform 212 provides native apps to user devices and may be specific to an OS.\",\n \"Example digital distribution platforms include the GOOGLE PLAY digital distribution platform by Google, Inc., the APP STORE digital distribution platform by Apple, Inc., and the WINDOWS PHONE digital distribution platform by Microsoft Corp.\",\n \"If the developer 204 had already provided App A to the digital distribution platform 212 before augmentation with the routing library, the developer 204 can release the augmented App A as a new version of App A.\",\n \"The user of a user device 220 installs App A (as augmented) from the digital distribution platform 212.In the user device 220, one or more processors (which may encompass general purpose processors as well as additional co-processors, such as physical sensor processors and graphics processors) execute instructions from memory.\",\n \"Some of these instructions correspond to an operating system 224, a browser 228, an installed copy of App A (referred to as App A 232), and a third party app (App B 236).\",\n \"The operating system 224 includes an installed app registry 240 and a link router 244.The link router 244 receives links, such as URLs (uniform resource locators) and URIs (uniform resource identifiers), and determines how to handle those links.\",\n \"Generally, the link router 244 handles a link by forwarding it to a registered receiver.\",\n \"The link router 244 checks the installed app registry 240 to determine whether an app has claimed a particular scheme, domain, or other filter that matches the link.\",\n \"If not, the link may be passed to the browser 228, which may have registered a set of schemes for protocols such as HTTP (hypertext transfer protocol), HTTPS (HTTP secure), FTP (file transfer protocol), Telnet, and Gopher.\",\n \"In some implementations, when the link specifies a web server address, the link router 244 may contact the web server to obtain a list of authorized apps.\",\n \"In this way, the link router 244 verifies that an app that has registered a certain domain is authorized by that domain to handle links.\",\n \"This prevents apps from commandeering links to which they're not eligible.\",\n \"If an app that has registered a domain is authorized by the web server host of that domain, the link router 244 can provide the link to the registered app.\",\n \"Routing library 260, received from the developer portal 208, causes App A 232 to register a specific scheme or domain with the installed app registry 240.The scheme may be based on an identifier of the developer portal 208 as well as an identifier of App A.\",\n \"For example, a test string associated with the developer portal 208 (such as “portal”) may be concatenated with a text string corresponding to App A (such as “appa”).\",\n \"As a specific example, the scheme registered by App A 232 may be “portal-appa://”.\",\n \"In other implementations, the text string associated with the developer portal 208 may not be human-readable.\",\n \"When the link router 244 receives a link, such as from the browser 228, where the scheme matches “portal-appa://”, the link router 244 forwards that link to App A 232, where the link is received and handled by the routing library 260.The routing library 260 parses the link and navigates to a deep state indicated by the link.\",\n \"For illustration only, in FIG.\",\n \"2, View A 268-1, View B 268-2, and View C 268-3 (collectively, views 268) are shown.\",\n \"In many apps, more than three views will be present.\",\n \"In various implementations, multiple or all views may be controlled by a single view controller.\",\n \"In other implementations, each view may be controlled by a separate view controller.\",\n \"For illustration only, the routing library 260 is shown simulating events from a predetermined UI event sequence identified by an example link.\",\n \"The link is received by the routing library 260 and corresponds to a deep state, specifically View C 268-3.The UI event sequence includes a first UI event, causing App A 232 to transition from View A 268-1 to View B 268-2, a second UI event, in which App A remains in View B 268-2, and then a third UI event, causing App A 232 to transition from View B 268-2 to View C 268-3.The routing library 260 would simulate these UI events in series.\",\n \"A search system 272 of the operating system 224 receives data and activity objects from the routing library 260.The routing library 260 provides the data objects for indexing and the activity objects for bookmarking.\",\n \"The search system 272 allows a user to search for data and/or activities from App A 232.When the user selects an activity corresponding to App A 232, the search system 272 sends an indication of a selected activity to the routing library 260.The search system 272 is shown in more detail in FIG.\",\n \"3A and FIG.\",\n \"3B.\",\n \"In parallel with providing the routing library from the developer portal 208 to the developer 204, the developer portal 208 provides App A to an offline analysis system 280.The copy of App A provided to the developer portal 208 may be a standard release build, such as an iOS App Store Package (ipa file).\",\n \"In other implementations, the copy of App A provided to the developer portal 208 may be a special build that allows App A to be run in a simulator, and may include symbols, debugging info, and/or source code that would not ordinarily be present in an app distributed by the digital distribution platform 212.This may allow the offline analysis system 280 to more efficiently or accurately analyze App A.\",\n \"For example, the copy of App A may be a debug build designed to run in the Simulator application from Apple, Inc. on the OS X operating system.\",\n \"By contrast, the version of App A distributed by the digital distribution platform 212 is a standard release build.\",\n \"The offline analysis system 280, as described in more detail below, determines UI event sequences that can be used by the routing library 260 to reach specific views of App A 232.A UI event sequence may be referred to as a breadcrumb trail composed of an ordered sequence of individual breadcrumbs (that is, UI events).\",\n \"For simplicity, in the remainder of this disclosure, the term breadcrumb will be used to refer to a breadcrumb trail.\",\n \"The offline analysis system 280 may provide the determined breadcrumbs to a data server 284.The data server 284 includes a data store, such as a relational database, that stores breadcrumbs for each app processed by the offline analysis system 280.Each deep state of an app is associated with a corresponding breadcrumb.\",\n \"In some implementations, the data server 284 may be implemented as a cloud-based block storage service, such as the S3 (Simple Storage Service) service available from Amazon Web Services.\",\n \"Access mechanisms define how deep states can be reached for such purposes as display advertisements and deep search results.\",\n \"For example, a search result may correspond to a specific deep state of an app.\",\n \"The search result may be a deep view card (DVC, see below) with a link including or indicating a breadcrumb corresponding to that deep state.\",\n \"Other potential access mechanisms for the search result may include a native deep link prepared by the app developer itself, or a standard URL pointing to a web edition of the app.\",\n \"One of the available access mechanisms may be selected by a search system and provided along with the search result to a search client.\",\n \"In other implementations, multiple access mechanisms may be provided within the search result, and the search client determines which access mechanism to use in response to user selection of the search result.\",\n \"For example, a breadcrumb-based access mechanism may be chosen over a web-based access mechanism when business rules indicate a preference for results to render in native apps instead of in web editions of those apps.\",\n \"The breadcrumb-based access mechanism, however, may only be available when the app is already installed.\",\n \"In some implementations, the search client may incorporate, or receive as part of the search result, code that scripts downloading and installing of the app, followed by actuation of a deep link.\",\n \"The deep link may be actuated by sending a breadcrumb-based URI to the newly-installed app.\",\n \"The data server 284 may also store configuration settings, such as which deep states to allow links to, which deep states to bookmark as activities, and which data to index.\",\n \"This configuration may be specified by the developer 204 using the developer portal 208.The data server 284 may also receive index items from the routing library 260.For example, the routing library 260 may report activity objects back to the data server 284.The data server 284 can then analyze user interaction with App A 232 and generate information about how to provide more relevant search results.\",\n \"In addition, data from the data server 284 may be provided back to the developer 204, essentially providing an easy way to instrument App A 232 to analyze user engagement.\",\n \"The data server 284 may correlate user activity across multiple apps on the user device 220, thereby further improving search results.\",\n \"Routing Library Integration with Application In FIG.\",\n \"3A, an example of App A 232 includes the routing library 260 and also includes an App A handler 300, which was created by the developer of App A 232.As seen in the example of FIG.\",\n \"3A, the App A handler 300 is able to continue user activities relating to View B 268-2, View D-268-4, and View E-268-5.The App A handler 300 cooperates with an activity creator 304, which updates the search system 272 with activity objects indicating activities the user is performing with App A 232.In various implementations, the search system 272 may include elements similar to those shown in the operating system 100 in FIG.\",\n \"1.The activity creator 304 may send activity objects to the search system 272 based on user activities associated with View B 268-2, View D 268-4, and View E 268-5.The App A handler 300 also interfaces with a data indexer 308, which may provide data objects to the search system 272 related to View B 268-2, View D 268-4, and View E 268-5.The routing library 260 is able to invoke View A 268-1 and View C 268-3 if the developer of App A 232 has requested that functionality through a developer portal.\",\n \"The routing library 260 may be able to access View A 268-1 and View C 268-3 by invoking respective view controllers, as described in more detail in U.S. patent application Ser.\",\n \"No.\",\n \"15/235,650, filed Aug. 12, 2016, titled “Monitoring and Actuation of View Controller Parameters to Reach Deep States Without Manual Intervention,” with first-named inventor Kalyan Desineni, and having attorney docket no.\",\n \"17100-000029-US.\",\n \"The entire disclosure of this application is incorporated by reference.\",\n \"In other implementations, the routing library 260 may access View A 268-1 and View C 268-3 by replaying sequences of user interface events that are determined in an offline process.\",\n \"For more information, see U.S. patent application Ser.\",\n \"No.\",\n \"15/235,859, filed Aug. 12, 2016, titled “Deep Linking to Mobile Application States Through Programmatic Replay of User Interface Events,” with first-named inventor Kalyan Desineni, and having attorney docket no.\",\n \"17100-000032-US.\",\n \"The entire disclosure of this application is incorporated by reference.\",\n \"While the activity creator 304 developed by the developer of App A 232 provides activity objects for some of the views 268 to the activity tracker 124, the routing library 260 is able to provide activity objects from others of the views 268.For example, the activity creator 304 may create an NSUserActivity object and invoke the becomeCurrent( ) method to provide the activity object to the activity tracker 124.It may be irrelevant to the activity tracker 124 whether the routing library or the App A handler 300 sent the activity object.\",\n \"When the activity tracker 124 sends a continue user activity signal to App A 232, the routing library 260 traps (such as by overloading, overriding, or swizzling the continue user activity method) the continue user activity signal.\",\n \"If the continue user activity signal is relevant to the App A handler 300, the continue user activity signal is passed through to the App A handler 300.Otherwise, the routing library 260 handles the continue user activity signal.\",\n \"Similarly, the routing library 260 and the data indexer 308 developed by the developer of App A 232 may each create CSSearchableItem objects and introduce them to the search index 120, such as by using the indexSearchableItems method.\",\n \"When the activity tracker 124 provides a continue user activity signal to the routing library 260 related to a data object, the routing library 260 either instantiates a view based on the selected data object or passes the continue user activity signal through to the App A handler 300.The NSUserActivity object may include a unique identifier (such as a title) and an activity type.\",\n \"In a continue user activity signal, the activity type may differentiate an NSUseractivity object from a CSSearchableItem object.\",\n \"The NSUserActivity object may also include a list of text keywords to allow the object to be indexed.\",\n \"The NSUserActivity object may also include a set of metadata, such as a CSSearchableItemAttributeSet, which may include an image and other information.\",\n \"The set of metadata for an object may be displayed when the object is included in a set of search results and gives the user information about whether the object satisfies their query.\",\n \"The CSSearchableItem object includes a unique identifier and a set of metadata, which may take the form of a CSSearchableItemAttributeSet.\",\n \"The CSSearchableItem object may also include an expiration date beyond which the object will be automatically de-indexed by the operating system.\",\n \"Further, the CSSearchableItem object may include a domain identifier to group related objects.\",\n \"In various implementations, the routing library 260 and the App A handler 300 may both be able to instantiate one or more of the views 268.For example, the App A handler 300 may be programmed to instruct the activity creator 304 to bookmark activities with respect to View B 268-2.Meanwhile, the routing library 260 may be programmed to submit data for indexing from View B 268-2.When a continue user activity signal is received by the routing library 260, if the continue user activity signal is related to a bookmarked activity, the routing library 260 passes through the continue user activity signal to the App A handler 300.Meanwhile, if the continue user activity signal for View B 268-2 is related to a data object, the routing library 260 itself navigates to View B 268-2 in order to display data related to the data object.\",\n \"Although not shown in FIG.\",\n \"3A, App A 232 may include an internal link router that receives deep links and instantiates views based on those deep links.\",\n \"For links including a scheme registered by the routing library 260, which is different than the scheme registered by the internal link router of App A 232, the routing library 260 receives the deep link and instantiates one of the views 268 based on the link.\",\n \"For example, the link may specify a breadcrumb to follow in order to arrive at the desired state.\",\n \"The routing library 260 may override methods invoked by the activity creator 304 and the data indexer 308 to pass activity objects and data objects to the search system 272.In this way, the routing library 260 can first inspect the activity objects and data objects before then passing the activity objects data objects to the search system 272.The routing library 260 will then be aware of which activity objects have been created by the activity creator 304, and can, therefore, service deep links related to those activity objects.\",\n \"Similarly, the routing library 260 will know which data objects have been indexed by the data indexer 308, and can then service deep links related to those data objects.\",\n \"In order to allow third party Apps and services to access App A 232 using those deep links, the routing library 260 may upload information from the activity objects and the data objects to a remote server.\",\n \"In order to service a deep link related to the activity objects from the activity creator 304 and the data objects from the data indexer 308, the routing library 260 can generate a continue user activity signal and send that signal to the App A handler 300.The App A handler 300 may be unaware that the continue user activity signal was received from the routing library 260 instead of from the search system 272.The App A handler 300 can then resume the activity or instantiate a review related to the index data as if the request came directly from the search system 272.In FIG.\",\n \"3B, another example app, App B 360, is shown.\",\n \"In App B 360, views 364-1, 364-2, 364-3, 364-4, and 364-5 (collectively, views 364) are shown for illustration.\",\n \"App B 360 does not include a built-in handler similar to the App A handler 300 of FIG.\",\n \"3A.\",\n \"As a result, in order to access any of the views 364, the routing library 260 includes mechanisms (such as breadcrumbs) to access each of the views 364.Further, the routing library 260 is solely responsible for generating activity objects and data objects to send to the search system 272.When a continue user activity signal is received by the routing library 260, the routing library 260 cannot pass the continue user activity signal through and instead is responsible for handling the resumption of an activity or a creation of a view related to a data object.\",\n \"Routing Library In FIG.\",\n \"4, an example implementation of the routing library 260 includes registration data 404.The registration data 404 indicates to the operating system that the routing library 260 will handle links having a scheme relating to the routing library 260 and will also handle continue user activity signals relating to the app in which the routing library 260 is incorporated.\",\n \"In various implementations, the registration data 404 is included in a configuration file of the app into which the routing library 260 is incorporated.\",\n \"A URI (uniform resource identifier) processor 408 receives a link from the operating system.\",\n \"For example, the link may have originated from a browser or from a third-party app.\",\n \"The URI processor 408 extracts a unique ID from the link, which may simply be the text within the URI to the right of the pair of forward slashes following the scheme.\",\n \"An internal router 412 consults an index data store 416 to determine whether the unique ID from the URI corresponds to a breadcrumb or corresponds to an activity call that will be made to the App A handler 300.In other words, the internal router 412 decides whether a breadcrumb exists to reach the state indicated by the unique ID or whether an activity call should be made to the App A handler 300 to reach the state indicated by the unique ID.\",\n \"When the internal router 412 determines the unique ID corresponds to a breadcrumb, the internal router 412 sends a breadcrumb ID to a state machine 420.In various implementations, the breadcrumb ID may be the same as the unique ID or may be different as defined by a mapping from the index data store 416.As described in more detail below, the state machine 420 retrieves a breadcrumb from a breadcrumb data store 424 and executes each user interface action within the breadcrumb using a UI replay actuator 428.The state machine 420 may monitor the state of App A 232 to ensure that each user interface event is processed by App A 232 before moving to the next UI event.\",\n \"If the internal router 412 determines that the unique ID from the URI processor 408 corresponds to an activity or data object handled by the App A handler 300, a signal is sent to an activity call creator 432.The activity call creator 432 creates a continue user activity signal specifying the activity or data object related to the link.\",\n \"The parameters required for creating the continue user activity signal may be obtained from the index data store 416.The continue user activity signal is passed to the App A handler 300 via a handler interface 436, which may send a continue user activity signal to the App A handler 300 as if the App A handler 300 was receiving that signal directly from the operating system.\",\n \"As mentioned above, the routing library 260 traps the method called by the operating system to provide a continue user activity signal to the app.\",\n \"An activity handler 440 of the routing library 260 then receives the continue user activity signal.\",\n \"The activity handler 440 determines whether the continue user activity signal should be handled by the App A handler 300 already implemented by the developer.\",\n \"This determination may be based on the index data store 416.In such cases, the activity handler 440 provides the continue user activity as a pass through to the App A handler 300 via the handler interface 436.In apps where the developer has not coded a handler such as the App A handler 300, the activity handler 440 may never transmit pass through activities and the activity call creator 432 and the handler interface 436 may be dormant.\",\n \"If the activity handler 440 determines that the continue user activity signal, according to the index data store 416, can be resumed using a stored breadcrumb, the breadcrumb ID is provided to the state machine 420 for execution.\",\n \"So far, the aspects of the routing library 260 related to incoming deep links, whether in the form of a link or a continue user activity signal from the operating system, have been described.\",\n \"The routing library 260 may also implement functionality that sends activity objects and data objects to the operating system.\",\n \"This allows the operating system to return search results from the app.\",\n \"A data indexer 460 determines which data objects of the app to index based on rules from a business rules data store 464.For example only, the data indexer 460 may respond to an app loaded signal to execute upon the app successfully running on the device.\",\n \"The data indexer 460 may, upon the first execution of the app, send a predetermined set of data objects to the operating system via an operating system interface 468.For example only, with respect to data objects, the operating system interface 468 may simply be an invocation of the indexSearchableItems( )method.\",\n \"On subsequent loading of the app, the data indexer 460 may update the index data objects based on their continued relevancy, based on data changes made to the app, or based on rule changes from the business rules data store 464.For example, if cuisine names are being indexed, as new cuisine names are added to the app, the data indexer 460 may add the additional cuisine names to the operating system index.\",\n \"Meanwhile, if the business rules data store 464 is updated to indicate that cuisine names should no longer be indexed, the data indexer 460 may delete the corresponding data objects from the operating system index.\",\n \"A data store updater 472 is responsible for updating one or more data stores, including the breadcrumb data store 424, the index data store 416, and the business rules data store 464.The data store updater 472 contacts the data server 284 of FIG.\",\n \"2 via a network interface 476.The network interface 476 may handle authentication and encryption so that the validity of data store updates can be confirmed.\",\n \"The data store updater 472 may operate when the app incorporating the routing library 260 is first opened on a device and at subsequent periodic intervals.\",\n \"In addition, the data store updater 472 may perform additional updates in response to data needs, such as if a breadcrumb ID is not present in the breadcrumb data store 424.An activity creator 480 creates activity objects to bookmark activities with the operating system.\",\n \"The operating system interface 468 may bookmark an activity by calling the becomeCurrent( )method on a created activity object.\",\n \"The activity creator 480 may respond to a view appearing, such as the viewDidAppear signal, or to some other event, such as the view loading or being about to appear.\",\n \"The activity creator 480 may update activity objects as interactions with a view occur.\",\n \"The activity creator 480 may, therefore, trap additional methods that provide user input to a view so that the corresponding activity object can be updated.\",\n \"For example, as the user edits a textbox, the activity creator 480 may update the activity object after each keystroke.\",\n \"In addition to creating an activity object, the activity creator 480 may indicate to the data indexer 460 that certain data objects should be indexed.\",\n \"These decisions may be based on rules from the business rules data store 464.For example, the activity creator 480 may create an activity object based on the user viewing a list of restaurants for a particular cuisine.\",\n \"Whether this activity object is created is determined by the business rules data store 464.The business rules data store 464 may also dictate that the activity creator 480 signal to the data indexer 460 that the top one or more results from a search should be indexed.\",\n \"For example, if the user is viewing a set of Thai restaurants and the most relevant result is the Amarin Thai restaurant, the user may later wish to search for Amarin Thai.\",\n \"By indexing the Amarin Thai data object, the operating system can provide a result directly to the app for Amarin Thai.\",\n \"In addition, depending on how the operating system index identifies search results, a user searching within the operating system for “Thai” may see both the activity for the app related to a list of Thai restaurants as well as the specific Amarin Thai data object.\",\n \"When the operating system sends a continue user activity signal related to one of the activity objects from the activity creator 480 or the data objects from the data indexer 460, a corresponding breadcrumb will be present in the breadcrumb data store 424 to reach these activity objects or data objects since the app itself was not programmed by the developer to accommodate them.\",\n \"The activity objects and data objects created by the activity creator 480 and the data indexer 460 respectively are provided to the index data store 416 so that the index data store 416 is aware of which activity objects and data objects can be handled by the routing library 260 instead of being passed through the App A handler 300.A remote indexer 484 may be instructed by the business rules data store 464 to mirror activity objects and/or data objects from the index data store 416 to a remote index.\",\n \"This remote index may be maintained by the provider of the routing library 260 or by a search service.\",\n \"Activity objects and data objects may be marked with a private identifier (or assumed private unless marked with a public identifier).\",\n \"This private identifier may prevent the object from being uploaded to the remote index or may prevent the object from being exposed by the remote index in public search results.\",\n \"This privacy indication may be provided by the developer as part of the onboarding process of the app to the developer portal and may be updated by the developer over time.\",\n \"A search system 288 receives access mechanisms from the data server 284 incorporating identifiers of breadcrumbs or the breadcrumbs themselves.\",\n \"The search system 288 may already have information about states of interest of App A and then can associate the access mechanisms with the respective states.\",\n \"In other implementations, the search system 288 may crawl and scrape App A to obtain metadata for states of interest, and may follow the access mechanisms to find the content of the states.\",\n \"In one use model, the user of the user device 220 performs a search for certain functionality and/or for a certain entity, such as reviews for a restaurant of interest.\",\n \"The user may perform this search with a standalone search app or, as shown in FIG.\",\n \"2, a web search performed via the browser 228.The search system 288, as described in more detail below, provides search results to the browser 228.These results may include a result corresponding to App A 232, and may include a link indicating a specific deep state in App A 232.If the user selects the link corresponding to App A 232, the link is forwarded to the link router 244 and then passed to the routing library 260 of App A 232.App A 232 is then controlled by the routing library 260 to display the indicated deep state using the corresponding breadcrumb.\",\n \"In various implementations, the routing library 260 receives the contents of the breadcrumb from parameters encoded within the link itself.\",\n \"For example, the link (in this case, a URI) may include the scheme (“portal-appa://”) followed by a serialized encoding of each UI event of the breadcrumb in series leading to the desired view.\",\n \"For example, the breadcrumb may be specified in a JSON (JavaScript Object Notation) data structure encoded using Base64.The search system 288 is, therefore, able to provide a link that will take the user directly to relevant content within App A 232.The search system 288 may provide search results to others apps.\",\n \"For example, a hotels app may query the search system 288 for restaurants near the user's selected hotel and the search system 288 may provide restaurant search results to the hotels app.\",\n \"In the case where App A 232 is a restaurant review app, the hotels app can link directly into a deep state of App A 232 corresponding to the restaurant of interest.\",\n \"The search system 288 may provide the search results in the form of DVCs.\",\n \"A DVC for an app or a state of an app shows additional information, beyond just the identification of the app or app state.\",\n \"For example, the information may include a title of the app state or a description of the app state, which may be a snippet of text from the app state.\",\n \"Other metadata may be provided from the app state, including images, location, number of reviews, average review, and status indicators.\",\n \"For example, a status indicator of “open now” or “closed” may be applied to a business depending on whether the current time is within the operating hours of the business.\",\n \"Some DVCs may emphasize information that led to the DVC being selected as a search result.\",\n \"For example, text within the DVC that matches a user's query may be shown in bold or italics.\",\n \"The DVC may also incorporate elements that allow direct actions, such as the ability to immediately call an establishment or to transition directly to a mapping app to get navigation directions to the establishment.\",\n \"Other interactions with the DVC (such as tapping or clicking any other area of the DVC) may take the user to the indicated state or app.\",\n \"As described in more detail below, this may be accomplished by opening the relevant app or, if the app is not installed, opening a website related to the desired app state.\",\n \"In other implementations, an app that is not installed may be downloaded, installed, and then executed in order to reach the desired app state.\",\n \"In other words, a DVC includes identifying information for the app or state as well as additional content from the app or state itself.\",\n \"The additional content allows the user to make a more informed choice about which result to choose, and may even allow the user to directly perform an action without having to navigate to the app state.\",\n \"If the action the user wants to take is to obtain information, in some circumstances the DVC itself may provide the necessary information to accomplish such action.\",\n \"In various implementations, the routing library may be identical for each app with the only exception being the name of the custom scheme that the routing library will register upon installation.\",\n \"The scheme may be formed by concatenating text of the developer portal with the text of the app name, and may include a separator such as a hyphen or an underscore.\",\n \"The name of the app may change over time, but the scheme may be fixed after first being set to provide backward compatibility with older versions of the app whose routing library may only recognize the original scheme.\",\n \"In various implementations, the routing library may be updated with security updates, bug fixes, and feature additions while maintaining backward compatibility.\",\n \"Developers, such as the developer 204, may download and incorporate the newest version of the routing library each time they release a new version of their app to the digital distribution platform 212.In some implementations, the build/compile process may automatically download the latest version of the routing library when resolving linker dependencies.\",\n \"The offline analysis system 280 may need to be invoked each time the developer 204 prepares a new version of App A for the digital distribution platform 212.In addition, as the developer 204 adds more content to App A, the offline analysis system 280 may be invoked to determine the breadcrumbs needed to access that added content.\",\n \"Invocation of the offline analysis system 280 may be performed at the request of the developer 204 or may be performed on a periodic basis.\",\n \"Any updates or additions to the breadcrumbs are stored by the data server 284 and can be provided to the search system 288 so that links within search results have the most up-to-date access mechanisms.\",\n \"In some implementations, the breadcrumbs may be communicated to the routing library 260 using a mechanism other than direct inclusion in the URI.\",\n \"For example, this may be necessary when a maximum-length link is shorter than the number of characters an encoded breadcrumb may require.\",\n \"The routing library 260 may, therefore, in some implementations, download a package of breadcrumbs from the data server 284.Search results from the search system 288 or other links may then reference a unique identifier, which the routing library 260 maps to a breadcrumb.\",\n \"For example only, the unique identifier may be formed from a function and an entity, such as “restaurant_reviews” and “Amarin_Thai”.\",\n \"In one specific example, the URI “portal-appa://restaurant_reviews/Amarin_Thai” may be resolved by the routing library 260 to a breadcrumb that reaches the restaurant reviews state for the Amarin Thai restaurant from a default state of App A 232.However, there is no requirement that the unique identifier be human-readable.\",\n \"In other implementations, the routing library 260 may consult the data server 284 in response to receiving a deep link.\",\n \"By providing the unique identifier, the routing library 260 can download the necessary breadcrumb from the data server 284.In such implementations, the routing library 260 may cache breadcrumbs so that a network access isn't required to resolve deep links visited recently.\",\n \"Pre-caching of some or all breadcrumbs may also be performed, such as when App A 232 first executes on the user device 220.Pre-caching may happen even earlier, such as when the developer 204 is preparing App A for distribution.\",\n \"In other words, the full set or a subset of the breadcrumbs may be included along with App A so that when a unique identifier is received via a link, the appropriate breadcrumb can be chosen by the routing library 260 without delay.\",\n \"Pre-caching may be combined with periodic verification of the breadcrumbs by the routing library 260, such as by checking a version number of the package of breadcrumbs at a periodic calendar interval, such as once a month.\",\n \"In other implementations, the data server 284 may send a push notification to the routing library 260 indicating that new breadcrumbs are available.\",\n \"To the extent that the developer 204 had implemented some deep links within App A, a developer-implemented router (not shown) in App A 232 would receive links from the link router 244.The developer's routing code would not have registered “portal-appa://” but instead a scheme independent of the developer portal 208, such as “appa.com://”.\",\n \"In various implementations, the developer-specified URIs may not be publicly available or may only be available to companies with an established relationship with the developer 204.Some operating systems, including the iOS operating system, have a sandbox infrastructure to limit the extent to which an app can access resources or areas of memory beyond what has been specifically allocated to the app.\",\n \"Sandboxing enhances security, making it more difficult for malicious software to compromise a user system.\",\n \"Because the routing library 260 executes within the context of App A 232, the sandbox should pose no difficulty for interactions between the routing library 260 and the view controllers responsible for the views 268.High-Level Flowchart In FIG.\",\n \"5, an overview of the operation of the present disclosure with respect to one developer and one app begins at 504.The developer first develops the app (referred to here as “App A”).\",\n \"App A may not have functionality that can expose deep links to all of its states.\",\n \"In addition, App A may not have indexing functionality or activity resumption functionality for some or all states.\",\n \"Further, any deep linking or search functionality that App A possesses may require programmer intervention to modify.\",\n \"As a result, the developer could benefit from the routing library described by the present invention.\",\n \"At 508, the developer provides a copy of App A to the developer portal.\",\n \"This may be a standard build, such as what would be provided to a digital distribution platform.\",\n \"In fact, if App A has already been released to a digital distribution platform, the developer portal may acquire the copy of App A from the digital distribution platform.\",\n \"While the standard build is generally restricted to running on emulators or hardware devices, the developer could instead provide a special build of App A, such as a build tailored to a simulation environment.\",\n \"The simulation environment may even run on a different architecture (such as an x86 architecture) compared to the app (which may run on user device hardware based on the ARM architecture).\",\n \"At 512, control begins offline analysis of App A. Offline analysis may include determining states for which deep links are already present in App A. Offline analysis may also include determining which activities can be resumed within App A in which data can be indexed by App A based on code written by the developer.\",\n \"For example only, offline analysis may include static and dynamic analysis of App A, which is described in more detail in U.S. application Ser.\",\n \"No.\",\n \"14/984,642, filed Dec. 30, 2015, titled “Static Analysis and Reconstruction of Deep Link Handling and Compiled Applications,” with first-named inventor Kalyan Desineni, and having attorney docket no.\",\n \"17100-000030-US.\",\n \"The entire disclosure of this application is incorporated by reference.\",\n \"At 516, the developer specifies business rules for App A.\",\n \"For example, the developer specifies to the developer portal which states of App A to provide deep link functionality for, which activities of App A to bookmark, and what data to index.\",\n \"The developer may navigate a copy of App A in order to specify which states to provide deep links for.\",\n \"For example, the developer may interact with App A in a simulator, while the offline analysis platform monitors the user interface events for later replay.\",\n \"The developer may simply be asked to navigate to states of interest, without needing to understand that the user interface events are being recorded for deep linking purposes.\",\n \"For each state the developer navigates to, the developer may specify whether one or more activities being performed in that state should be bookmarked and may identify one or more pieces of data to index from that state.\",\n \"The developer may specify what metadata to include with the data being indexed, and may flag activities or data as public or private.\",\n \"At 520, in parallel with offline analysis, control provides a copy of the routing library from the developer portal to the developer.\",\n \"At 524, the developer integrates the routing library into App A.\",\n \"For example, this may include adding references in a configuration file to the scheme handled by the linking capability of the routing library as well as adding the types of activities that the routing library will recognize.\",\n \"In some implementations, the activities recognized by the routing library will be redundant with activities already recognized by App A, such as when App A already allows for some activity resumption or data indexing.\",\n \"The developer also links the binary to the App A project within the integrated development environment.\",\n \"In various implementations, a script may be provided to the developer to perform the incorporation actions of 524.At 528, the developer compiles App A, which now includes the routing library, and provides App A to one or more digital distribution platforms.\",\n \"At 532, a user of a user device installs App A from a digital distribution platform.\",\n \"At 536, as part of installation, the routing library of App A registers a custom link scheme handled by the routing library as well as activity types handled by the routing library.\",\n \"For example, this registration may be performed by the operating system based on a configuration file, such as Info.plist.\",\n \"At 540, the routing library of the now-installed application updates access mechanisms and business rules.\",\n \"For example, the access mechanisms may be breadcrumbs to reach certain states.\",\n \"The business rules identify which states should be accessed, which activities should be bookmarked, and which data should be indexed.\",\n \"When the application is first run, the routing library may download a full set of access mechanisms and business rules so that no access latency is incurred when an access mechanism or business rule is needed.\",\n \"In other implementations, upon first being run, the routing library only downloads a subset of the access mechanisms, such as access mechanisms for the most popular states.\",\n \"The updates at 540 may be performed each time the app is opened or at predetermined intervals.\",\n \"In addition, the routing library may update access mechanisms and/or business rules if a required access mechanism (for example, a breadcrumb) is missing or if the access mechanism appears to not be working.\",\n \"At 544, the routing library indexes data indicated by the developer according to the business rules.\",\n \"For example, when the app first loads, the routing library may index a set of data indicated by the developer.\",\n \"Then, as data is modified in App A, the routing library may update the operating system index based on the updated data.\",\n \"At 548, the routing library bookmarks selected activities engaged by the user.\",\n \"For example, when the user performs a search, the search criteria and filters may be bookmarked as an activity that the user can resume on that device or handoff to another device.\",\n \"At 552, the routing library in App A handles proprietary App A links (indicated by the registered scheme) provided to the routing library from the operating system.\",\n \"At 556, the routing library handles activities sent by the operating system, including continue user activity signals.\",\n \"These activities may refer to bookmarked activities or to indexed data.\",\n \"Control then returns to 540.Although 540, 544, 548, 552, and 556 are displayed in series, they may run asynchronously and in parallel.\",\n \"Routing Library Operation In FIG.\",\n \"6, example operation of the routing library is shown.\",\n \"At 604, during installation of App A onto a device, the proprietary App A URI scheme and activity types in the routing library are registered.\",\n \"This may be performed by the operating system from a configuration file (also known as a manifest file) as part of the installation process.\",\n \"At 608, control requests breadcrumbs and configuration data from the data server.\",\n \"This may be performed upon the first execution of App A on the user device.\",\n \"At 612, control determines whether an activity or a proprietary App A URI has been received from the operating system.\",\n \"If so, control transfers to 616; otherwise, control transfers to 620.At 616, control invokes a handler for the activity or proprietary App A URI.\",\n \"For example, the handler may be implemented as shown in FIG.\",\n \"7.For example only, the handler may respond to an openURL( ) call received by the operating system or from a continue user activity signal generated by the operating system.\",\n \"After handling the activity or proprietary App A URI, control returns to 612.At 620, control determines whether an activity trigger event has occurred.\",\n \"If so, control transfers to 624; otherwise, control transfers to 628.An activity trigger event may be the loading of a state or an action performed within a state.\",\n \"The developer may specify which event qualifies as an activity trigger.\",\n \"The developer may establish business rules dictating that some states trigger an activity when the state is entered while for other states an activity is bookmarked upon some further action being performed, such as user input.\",\n \"At 624, control determines whether a breadcrumb is available to return to that activity.\",\n \"If so, control transfers to 632; otherwise, control transfers to 636.If a breadcrumb that returns to that activity is not available, the routing library may not be able to resume that activity when requested by the operating system and therefore will not bookmark that activity.\",\n \"At 632, the breadcrumb is available and therefore control sends an activity object to the operating system to bookmark the activity.\",\n \"At 636, control determines whether the activity has been indicated by the developers as being public.\",\n \"If so, control transfers to 640; otherwise, control continues at 628.At 640, the activity has been indicated as public and therefore control uploads the activity to a remote index.\",\n \"Control then continues at 628.In other implementations, control may upload the activity to the remote index regardless of whether the activity has been indicated as public, and instead uses the public indicator to determine whether to reveal that activity to any users of the remote index.\",\n \"At 628, control determines whether data should be indexed according to business rules established by the developer.\",\n \"If so, control transfers to 644; otherwise, control transfers to 648.For example, when first running App A, there may be a predetermined set of data objects that the developer desires to index.\",\n \"Then, after certain states have been accessed, the developer may have specified that data related to those states should be indexed.\",\n \"For example, in a music streaming app, if the user has viewed a list of artists in a particular genre, data objects corresponding to each of the artists may be added to the operating system index.\",\n \"At 644, if a breadcrumb is available for a data object the developer has indicated should be indexed, control transfers to 652; otherwise, control continues at 648.At 652, the breadcrumb to reach a state that can access that data object is available and therefore the data object is sent to the operating system.\",\n \"If the breadcrumb were not available, the routing library would not be able to service a request from the operating system to display the data object to a user.\",\n \"While FIG.\",\n \"6 shows operation of the routing library, the developer may have implemented logic within App A that will index data objects and bookmark activities, separate from the routing library.\",\n \"This indexing and bookmarking is not precluded by the operation of the routing library.\",\n \"Therefore, even when the routing library does not index the data object or bookmarking activity, App A itself may be performing that task.\",\n \"In order for App A to then resume the activity when instructed by the operating system, App A will have logic implemented by the developer to reach the appropriate states.\",\n \"This logic may include direct actuation of view controllers or may include a user interface breadcrumb similar to that used by the routing library.\",\n \"Control continues from 652 to 656, where if the data object is indicated as public, control transfers to 660; otherwise, control continues at 648.At 660, control uploads the data object to the remote index and continues at 648.Again, the public identifier may be ignored at the time of uploading the data object to the remote index and instead be taken into account when determining whether to reveal the data objects to other users.\",\n \"At 648, control determines whether the last data update of breadcrumbs and configuration data is more than a predetermined time in the past.\",\n \"If so, control transfers to 664 to update this data; otherwise, control returns to 612.Although shown as a predetermined amount of time, data updating may be performed dynamically based on how often the app is used, how often breadcrumbs or configuration data historically has changed, and/or may be based on a push signal from the data server indicating that data should be updated.\",\n \"Activity/URI Handling In FIG.\",\n \"7, example routing library operation for handling activities and proprietary URIs is shown.\",\n \"In various implementations, the process of FIG.\",\n \"7 may be called by 616 of FIG.\",\n \"6.Control begins at 704, where if a proprietary App A URI has been received, control transfers to 708; otherwise, control transfers to 712.At 708, control determines whether the URI corresponds to a preexisting data object—that is, a data object that App A was able to index and display independent of the routing library.\",\n \"If the URI corresponds to such a preexisting data object, control continues at 716; otherwise, control transfers to 720.At 716, the routing library will be able to use the preexisting access mechanism within App A to display a state relevant to that data object.\",\n \"To accomplish this, control may prepare an activity request that is similar or identical to the activity request the operating system would provide to App A in order to display a state related to that data object.\",\n \"Control then continues at 724, where the prepared activity request is passed to a preexisting App A handler that was written by the developer independent of the routing library.\",\n \"Control then continues at 712.At 720, control determines whether the URI corresponds to a preexisting activity—that is, an activity that App A could bookmark and resume independent of the routing library.\",\n \"If so, control transfers to 728; otherwise, control transfers to 732.At 728, control prepares an activity request identifying that preexisting activity.\",\n \"The activity request may be similar or identical to a request that the operating system would provide to App A in order to resume the bookmarked activity.\",\n \"The control then continues at 724.At 732, control determines whether the URI corresponds to a breadcrumb.\",\n \"If so, control transfers to 736; otherwise, control transfers to 740.Although referred to as a breadcrumb, the access mechanism can be another mechanism the routing library uses to navigate to a certain state.\",\n \"For example, the routing library may be programmed with a set of parameters allowing a specific view controller to be invoked with particular input parameters to arrive at a certain state.\",\n \"At 736, control replays the breadcrumb, such as using a process shown in FIG.\",\n \"8.Control then continues at 712.At 740, the proprietary App A URI cannot be passed to the preexisting App A handler and an access mechanism (such as a breadcrumb) does not exist.\",\n \"As a result, error handling is performed.\",\n \"For example, the error handling may include displaying a message to the user indicating that the link failed and directing the user to a default state of the app.\",\n \"Before displaying the message, control may refresh downloaded breadcrumbs to ensure that the latest breadcrumbs are available.\",\n \"As another example, control may attempt to find and then traverse a comparable URI, such as by querying a mapping of obsolete URIs to active URIs.\",\n \"Control then continues at 712.At 712, if an activity request (such as a continue user activity method call) is received by App A (for example, by the App delegate of App A), control transfers to 744; otherwise, control transfers to 748.At 744, control determines whether the activity should be handled by the routing library.\",\n \"If so, control transfers to 752; otherwise, control transfers to 756.At 752, the activity is handled by the routing library because the routing library bookmarked the corresponding activity or indexed the corresponding data object.\",\n \"The activity may be resumed by replaying a breadcrumb corresponding to the state identified by the activity request.\",\n \"For example, this may be performed as shown in FIG.\",\n \"8.Control then returns to FIG.\",\n \"6.At 756, if the routing library is aware that App A handles at least some activity requests, control continues at 760.Otherwise, if the routing library is confident that App A is otherwise unable to handle any activities, control transfers to 764 where error handling is performed.\",\n \"For example, the error handling may include displaying an error message that the activity request cannot be met.\",\n \"At 760, the activity request is passed through to the preexisting App A handler in the hope that the App A handler can handle the activity request.\",\n \"Control then returns from FIG.\",\n \"7.At 748, error handling is performed because neither a proprietary App A URI has been received or an activity request has been received.\",\n \"Control may not be aware of what was received other than an activity request or a proprietary App A URI and therefore may not display anything to the user, instead simply taking the user to a default state of the app.\",\n \"Control then returns from FIG.\",\n \"7.Breadcrumb Traversal In FIG.\",\n \"8, example operation of the routing library when traversing a breadcrumb is shown.\",\n \"Control begins at 804, where if the breadcrumb is embedded in the URI, control transfers to 808; otherwise, control transfers to 812.As described above, breadcrumbs that allow the routing library to navigate to certain deep states may be received in links or may be indicated by unique ID in the link.\",\n \"When indicated by a unique ID, the routing library may have to request the breadcrumb from a data server.\",\n \"In some implementations, the routing library will therefore pre-cache some or all breadcrumbs.\",\n \"This operation may be omitted if breadcrumbs will always be received within links.\",\n \"In some implementations, certain breadcrumbs when encoded are longer than a maximum permitted length of a link.\",\n \"This maximum length may be dictated by a browser, by an operating system, or by some other technological or business restriction.\",\n \"These breadcrumbs may therefore be obtained from the data server, while shorter breadcrumbs are contained within URIs.\",\n \"In this way, the generator of the URI (such as a search system) prepares the URI including the breadcrumb data itself when the maximum link length will not be exceeded, while otherwise including only a unique identifier of the breadcrumb.\",\n \"At 808, control decodes a data structure holding the breadcrumb from the URI and control continues at 816.At 812, since the breadcrumb was not included in the URI, control determines whether the breadcrumb is already stored in the breadcrumb data store.\",\n \"If so, control uses the breadcrumb from the breadcrumb data store and continues at 816; otherwise, control transfers to 820.At 820, control requests the breadcrumb from the data server, and when the breadcrumb is returned, control continues at 816.In various implementations, the routing library acquires an initial set of breadcrumbs before one of the breadcrumbs would be indicated by a URI.\",\n \"For example, the routing library may be pre-packaged with the initial set of breadcrumbs or the routing library may download the initial set of breadcrumbs upon installation or first execution on the user device.\",\n \"The routing library may periodically (for example, via a background process) receive new breadcrumbs to supplement functionality.\",\n \"In some implementations, an improved user experience may result from breadcrumbs always being obtained from the data store and never retrieved from the data server.\",\n \"This minimizes delays in response resulting from obtaining breadcrumbs from the data server and avoids availability issues from network connectivity problems.\",\n \"At 816, control selects the first UI event in the sequence specified by the breadcrumb.\",\n \"At 824, control replays the selected UI event from the breadcrumb.\",\n \"At 828, control determines whether replaying the selected UI event successfully led to the next view or updated the current view as expected.\",\n \"In various implementations, control may wait for a predetermined period of time before checking for success.\",\n \"This predetermined period of time allows the app to respond to the UI event.\",\n \"In various implementations, the breadcrumb data structure may include a specified wait time, which may apply to all UI events, or may have a separate wait time for each UI event.\",\n \"As part of the breadcrumb determination process, the offline analysis system may detect that certain UI events take longer for an app to respond to.\",\n \"In such cases, the offline analysis system may indicate that additional delay periods should be implemented before replaying another UI event.\",\n \"At 828, success may instead be identified when the routing library detects that a method has been called with certain parameters corresponding to the replayed event.\",\n \"In other words, as part of the offline analysis, the expected response to the app to a UI event may be recorded.\",\n \"When this expected response is seen, success may be inferred.\",\n \"If, at 828, the UI event appears to have been processed successfully, control transfers to 832; otherwise, control transfers to 836.At 836, control waits for another predetermined period of time.\",\n \"This additional period of time may allow for unexpectedly slow response to a UI event.\",\n \"Control continues at 840, where control once again attempts to verify that replaying the selected UI event has successfully led to the expected behavior.\",\n \"If so, control continues at 832; otherwise, control transfers to 844.At 844, if the selected UI event has been replayed twice in an attempt to obtain a successful response, control transfers to 848.At 848, an error is declared.\",\n \"For example, error handling may cause the app to revert to a home state and display a notification message to the user that the deep link was unsuccessful.\",\n \"In addition, a message may be sent to the data server indicating that the deep link was unsuccessful.\",\n \"Control then returns from FIG.\",\n \"8.At 844, if the selected UI event has only been replayed a single time, there has not yet been a second failure, and therefore control returns to 824 to attempt to replay the selected UI event a second time.\",\n \"In various implementations, success is not evaluated, and the UI events are replayed in series with the expectation that in most circumstances, the desired deep link will be reached.\",\n \"As a result, elements 828, 836, 840, 844, and 848 may be replaced with a simple wait step.\",\n \"The wait step may wait for a predetermined delay that has been empirically determined to allow the app to respond to user input.\",\n \"The wait step may be used in systems where UI events cannot be processed by the app as quickly as they can be replayed by the routing library.\",\n \"In other implementations, the wait step may involve watching for a method call resulting from the UI event.\",\n \"Once response of the app to the UI event has been detected, such as by watching certain method calls, control may allow the following UI event to be replayed.\",\n \"At 832, if there are additional UI events, control transfers to 852; otherwise, control returns from FIG.\",\n \"8.At 852, control selects the next UI in the breadcrumb and returns to 824.Search System In FIG.\",\n \"9, an example implementation of the search system 288 includes a search module 900.The search module 900 includes a query analysis module 904 that receives a query wrapper, which may take the form of a query string within a URL transmitted by the browser 228 of FIG.\",\n \"2.The query analysis module 904 analyzes the text query from the query wrapper.\",\n \"For example, the query analysis module 904 may tokenize the query text, filter the query text, and perform word stemming, synonymization, and stop word removal.\",\n \"The query analysis module 904 may also analyze additional data stored within the query wrapper.\",\n \"The query analysis module 904 provides the tokenized query to a set generation module 908.The set generation module 908 identifies a consideration set of application state records from a search data store 910 based on the query tokens.\",\n \"Application (equivalently, app) state records correspond to specific states of apps.\",\n \"In various implementations, the search data store 910 may also include app records.\",\n \"In various implementations, an app record may be stored as an app state record that simply has a predetermined value, such as null, for the specific state of the app.\",\n \"App state records in the search data store 910 may be generated by crawling and scraping apps according to the principles of the present disclosure.\",\n \"Some or all of the contents of the records of the search data store 910 may be indexed in inverted indices.\",\n \"In some implementations, the set generation module 908 uses the APACHE LUCENE software library by the Apache Software Foundation to identify records from the inverted indices.\",\n \"The set generation module 908 may search the inverted indices to identify records containing one or more query tokens.\",\n \"As the set generation module 908 identifies matching records, the set generation module 908 can include the unique ID of each identified record in the consideration set.\",\n \"For example, the set generation module 908 may compare query terms to an app state name and app attributes (such as a text description and user reviews) of an app state record.\",\n \"Further, in some implementations, the set generation module 908 may determine an initial score of the record with respect to the search query.\",\n \"The initial score may indicate how well the contents of the record matched the query.\",\n \"For example, the initial score may be a function of term frequency-inverse document frequency (TF-IDF) values of the respective query terms.\",\n \"A set processing module 912 receives unique IDs of app state records identified by the set generation module 908 and determines a result score for some or all of the IDs.\",\n \"A result score indicates the relevance of an app state with respect to the tokenized query and context parameters.\",\n \"In various implementations, a higher score indicates a greater perceived relevance.\",\n \"For example, other items in the query wrapper may act as context parameters.\",\n \"Geolocation data may limit the score of (or simply remove altogether) apps that are not pertinent to the location of the user device.\",\n \"A blacklist in the query wrapper may cause the set processing module 912 to remove app records and/or app state records from the consideration set that match the criteria in the blacklist, or to set their score to a null value, such as zero.\",\n \"The set processing module 912 may generate a result score based on one or more scoring features, such as record scoring features, query scoring features, and record-query scoring features.\",\n \"Example record scoring features may be based on measurements associated with the record, such as how often the record is retrieved during searches and how often links generated based on the record are selected by a user.\",\n \"Query scoring features may include, but are not limited to, the number of words in the search query, the popularity of the search query, and the expected frequency of the words in the search query.\",\n \"Record-query scoring features may include parameters that indicate how well the terms of the search query match the terms of the record indicated by the corresponding ID.\",\n \"The set processing module 912 may include one or more machine-learned models (such as a supervised learning model) configured to receive one or more scoring features.\",\n \"The one or more machine-learned models may generate result scores based on at least one of the record scoring features, the query scoring features, and the record-query scoring features.\",\n \"For example, the set processing module 912 may pair the search query with each app state ID and calculate a vector of features for each {query, ID} pair.\",\n \"The vector of features may include one or more record scoring features, one or more query scoring features, and one or more record-query scoring features.\",\n \"In some implementations, the set processing module 912 normalizes the scoring features in the feature vector.\",\n \"The set processing module 912 can set non-pertinent features to a null value or zero.\",\n \"The set processing module 912 may then input the feature vector for one of the app state IDs into a machine-learned regression model to calculate a result score for the ID.\",\n \"In some examples, the machine-learned regression model may include a set of decision trees (such as gradient-boosted decision trees).\",\n \"Additionally or alternatively, the machine-learned regression model may include a logistic probability formula.\",\n \"In some implementations, the machine-learned task can be framed as a semi-supervised learning task, where a minority of the training data is labeled with human-curated scores and the rest are used without human labels.\",\n \"The machine-learned model outputs a result score of the ID.\",\n \"The set processing module 912 can calculate result scores for each of the IDs that the set processing module 912 receives.\",\n \"The set processing module 912 associates the result scores with the respective IDs and outputs the most relevant scored IDs.\",\n \"A results generation module 924 may choose specific access mechanisms from the application records and app state records chosen by the set processing module 912.The results generation module 924 then prepares a results set to return to the user device.\",\n \"Although called “app state results” here, some of the access mechanisms may correspond to a default state (such as a home page) of an app—these may be a special case of an app state record or may be an app record.\",\n \"The results generation module 924 may select an access mechanism for an app state record based on whether the app is installed on the device.\",\n \"If the app is installed, an access mechanism that opens the app directly to the specified state is selected.\",\n \"Meanwhile, if the app is not installed, a selected access mechanism first downloads and installs the app, such as via a script, before opening the app to the specified state.\",\n \"Opening the app to the specified state may include a single command or data structure (such as an intent in the ANDROID operating system) that directly actuates the specified state.\",\n \"For other apps, a script or other sequence may be used to open the app to a certain state (such as a home, or default, state) and then navigate to the specified state.\",\n \"The results generation module 924 may generate or modify access mechanisms based on the operating system identity and version for the user device to which the results are being transmitted.\",\n \"For example, a script to download, install, open, and navigate to a designated state may be fully formed for a specific operating system by the results generation module 924.If the results generation module 924 determines that none of the native access mechanisms are likely to be compatible with the user device, the search module 900 may send a web access mechanism to the user device.\",\n \"If no web access mechanism is available, or would be incompatible with the user device for some reason (for example, if the web access mechanism relies on the JAVA programming language, which is not installed on the user device), the results generation module 924 may omit the result.\",\n \"Server-Side Control In FIG.\",\n \"10, operation of server-side components may be performed within a single device or may be performed across the developer portal 208, the offline analysis system 280, the data server 284, and the search system 288 of FIG.\",\n \"2.In various implementations, the developer portal 208, the data server 284, and the search system 288 may be under the control of the same entity.\",\n \"The offline analysis system 280 may employ operators that facilitate static analysis and/or dynamic analysis to ensure that accurate and complete parameters are extracted from each app.\",\n \"Control begins at 1002, where the routing library is made available to app developers.\",\n \"Over time, the routing library may be updated, and the most up-to-date version may be the only one available to app developers.\",\n \"At 1004, if a request for a breadcrumb has been received, control transfers to 1006; otherwise, control transfers to 1008.At 1006, control determines a subset of the breadcrumbs that has changed since the last request was received from the requester.\",\n \"This subset can then be provided at 1010 to bring the data up-to-date at the source of the request.\",\n \"Control then returns to 1004.At 1008, if offline processing of an app has been initiated, control transfers to 1012; otherwise, control transfers to 1016.At 1016, if a search query has been received from a search system, control transfers to 1020; otherwise, control returns to 1004.At 1020, control determines a consideration set of results corresponding to the search query.\",\n \"This consideration set may include apps that are open to the search query as well as specific states (deep states) of apps that are relevant to the search query.\",\n \"At 1024, control scores the elements in the consideration set based on how closely they match the understood intent of the search query.\",\n \"The scored results can then be ranked from most relevant to least relevant.\",\n \"At 1028, the highest-ranked results are formatted as deep view cards associated with deep links to the specific states within the results.\",\n \"At 1032, control returns the deep view cards to the requestor of the query.\",\n \"The deep view cards may not be fully rendered, and instead include images, text, and instructions on how to render the deep view cards for particular screen sizes, orientations, and other requirements of the requesting application or operating system.\",\n \"For apps where the deep links are serviced by a routing library according to the principles of the present disclosure, an access mechanism returned along with the corresponding search result may include a URI with an encoded data structure.\",\n \"The encoded data structure may include the breadcrumb necessary to invoke that specific state from within the app.\",\n \"The URI, being a string, includes a serialized version of that data structure and is prefixed with a scheme.\",\n \"The scheme, such as “portal-appa://”, will cause the URI to be forwarded to and recognized by the routing library of the app.\",\n \"Control then returns to 1004.At 1012, control runs App A, such as in a simulator.\",\n \"While App A is running, control monitors UI events resulting from the operator's usage of App A.\",\n \"At 1036, control allows an operator to interact with App A to reach a deep state of interest, recording each UI interaction to form a breadcrumb.\",\n \"In various implementations, control may monitor how long it takes App A to respond to certain UI events.\",\n \"These response times, or delays based on the response times, may be encoded in the breadcrumb along with the corresponding UI events.\",\n \"For example, some operations may require App A to obtain data from a server, incurring network communication delays.\",\n \"When replaying the UI events in the breadcrumb, there should be a longer delay after the UI event leading to network access before the next UI event is replayed.\",\n \"At 1040, if there are additional deep states of interest, control returns to 1036; otherwise, control continues at 1044.At 1044, control determines states that are parallel to the states identified by the operator.\",\n \"For example, if the operator selects a link from a list of similar-looking items, and the selected link leads to a state of interest, control may assume that the other items in the list are also of interest.\",\n \"These parallel states, and the breadcrumbs used to reach them (in the list example, the breadcrumbs would differ only in the last UI event), are added to the list of deep-linkable states.\",\n \"In various implementations, App A may be exercised using a crawling algorithm to reach some or all deep states of App A.\",\n \"For additional information regarding crawling, see U.S. patent application Ser.\",\n \"No.\",\n \"14/849,540, filed Sep. 9, 2015, titled “Unguided Application Crawling Architecture,” with first-named inventor Kalyan Desineni, and having Attorney Docket No.\",\n \"17100-000006-US-01.The entire disclosure of this application is incorporated by reference.\",\n \"At 1048, control provides a list of deep-linkable states to a search system for indexing.\",\n \"At 1052, for each deep-linkable state, control provides a data structure containing the breadcrumb to the data server to be used in a URI as an access mechanism to access the deep state.\",\n \"Control then returns to 1004.At 1012, an operator interacts with a copy of the app, such as in a simulator, to navigate to states of interest.\",\n \"In some implementations, the operator navigates to states of interest designated by the developer; in other implementations, the developer herself navigates to states of interest.\",\n \"User interface events required to reach various states are recorded such as described in FIG.\",\n \"12.Control continues at 1040, where control may extrapolate additional states of interest from the operator-identified states of interest.\",\n \"Example operation for extrapolation is shown in FIG.\",\n \"13.At 1012, while the operator is identifying states of interest, the operator may also be tagging states as activities to be bookmarked and may be identifying data within the states as data objects to index.\",\n \"Control continues at 1056, where configuration parameters established by the operator are transmitted to the data server.\",\n \"For example, configuration parameters may be business rules specifying which states should be deep linked which states should be bookmarked as activities, and what data should be indexed.\",\n \"Offline Analysis In FIG.\",\n \"11, an example implementation of the offline analysis system 280 includes a guide creation system 1100 that allows for operator interaction with an app of interest (such as App A).\",\n \"The guide creation system 1100 allows an operator to specify which states of an app should be deep-linkable and may use input from the operator to determine how to reach those deep states.\",\n \"In various implementations, the operator is an administrator of the offline analysis system 280, acting on standard operating procedures for offline processing of an app or on instructions from a developer of the app.\",\n \"Additionally or alternatively, an agent of the app developer may act as the operator.\",\n \"The agent may specify which states or types of states should be made accessible as deep states.\",\n \"After the initial offline analysis, the agent may use the developer portal 208 to request that additional states of the app be added as deep states and request that existing deep-linked states be removed.\",\n \"This may be done via the developer portal 208 with no need for the agent to modify code of the app or even request assistance from the app's software developers.\",\n \"In other words, marketing personnel or user experience designers may themselves control the scope of the deep linking within the app, without even releasing a new version of the app.\",\n \"For added states, the offline analysis system 280 will re-process the app to determine the breadcrumbs to the added states.\",\n \"For an app being processed by the offline analysis system 280, the operator controls a copy of the app of interest executing within a simulator 1104.In various other implementations, the app of interest may be installed on a physical device or executed in an emulation environment.\",\n \"In various implementations, the simulator 1104 may be instantiated at a cloud hosting operator that may provide compute facilities within which to execute emulator/simulator code or that may directly provide emulators or simulators for one or more mobile device operating systems.\",\n \"For more information, see U.S. patent application Ser.\",\n \"No.\",\n \"14/868,294, filed Sep. 28, 2015, titled “Operator-Guided Application Crawling Architecture,” with first-named inventor Kalyan Desineni, and having Attorney Docket No.\",\n \"17100-000006-US-02.The entire disclosure of this application is incorporated by reference.\",\n \"In some implementations, a physical device running the operating system may be used instead of the simulator 1104, such as for an operating system that does not have a suitable simulator or emulator.\",\n \"The physical device may be connected to the guide creation system 1100 using a wireless or wired interface, such as USB (universal serial bus).\",\n \"A root-level control application may be installed on the physical device to track user input.\",\n \"Installing the root-level application may require bypassing security limitations of the firmware or operating system regarding privileges of installed apps and may require that the device be jailbroken.\",\n \"Jailbreaking involves bypassing or removing various software restrictions imposed by the operating system and/or device firmware, and may be accomplished using a privilege escalation technique.\",\n \"The jailbroken device may be further modified with pre-installed and specific settings that enable the techniques of the present disclosure, such as recording UI interactions.\",\n \"The simulator 1104 is essentially already jailbroken.\",\n \"However, the simulator 1104 may also be modified to allow for better control, such as to more easily allow recording UI interactions.\",\n \"The operator's interaction with the app may be recorded to form a guide indicating how a state is reached.\",\n \"This guide defines the breadcrumb used to reach the end state, and subsets of the guide define the breadcrumbs for intermediate states.\",\n \"The guide may also be used to infer other states of interest and determine breadcrumbs leading to those states.\",\n \"Each UI event may be associated with a specific UI element, identified according to a predetermined rubric by a unique ID.\",\n \"For example, the unique ID may be dictated by how the UI elements are programmatically created when rendering the view.\",\n \"In other implementations, the unique ID may be dictated by how the UI elements are actually seen, with the UI elements numbered in increasing order from left to right and top to bottom.\",\n \"In other implementations, x-y coordinates may be used to identify the location of the user interaction, or the boundaries of the UI element actuated, or a center of the UI element actuated even if the operator's action was off-center.\",\n \"In various implementations, static analysis may be used to analyze the UI elements of various states of the app.\",\n \"Static analysis involves analyzing the code of the app without making observations of the app being executed.\",\n \"In some implementations, a static analyzer (not shown) may identify the UI elements of each view and assign unique identifiers to each UI element within a view.\",\n \"Then, dynamic analysis would have a predetermined nomenclature when referring to user interactions with any UI elements.\",\n \"For example, static analysis may be performed with a disassembler and debugger implemented by the IDA Pro software from Hex-Rays SA.\",\n \"Additionally or alternatively, the static analyzer may analyze the methods and views of an app to determine how best to instrument the app.\",\n \"With this information, the dynamic analyzer can hook to the correct methods and listen for the correct events to accurately track user interaction with the app and discard method calls unrelated to user interaction.\",\n \"For more information on static analysis, see U.S. patent application Ser.\",\n \"No.\",\n \"14/843,929, filed Sep. 2, 2015, titled “Static Analysis-Assisted Dynamic Application Crawling Architecture,” with first-named inventor Kalyan Desineni, and having Attorney Docket No.\",\n \"17100-000006-US.\",\n \"The entire disclosure of this application is incorporated by reference.\",\n \"While the app is running in the simulator 1104, the guide creation system 1100 may monitor the messaging queue of the simulator 1104 (or of the actual operating system when executing in an emulator or physical device), listening for messages indicative of user manipulation of the app.\",\n \"Such manipulation includes, for example, clicking, pressing, pinching, or swiping of the user interface.\",\n \"In addition to capturing a unique identifier for each UI element the operator interacts with, the guide creation system 1100 may also extract the type of each element according to the defined types specified by the operating system, and further extract the identity of the associated view controller.\",\n \"For example, the following methods may be hooked, such as by using method swizzling: (void)sendEvent:(UIEvent *)event method in the UIApplication class (void)sendAction:(SEL)action to:(id)target forEvent:(UIEvent *)event in UIControl class (void)viewDidAppear:(BOOL)animated for all the controllers that were loaded A handler may be implemented to record each type of UI element.\",\n \"As an example, code for recording a button press can be implemented as follows: -(void)sendEvent:(UIEvent *)event { for (UITouch *touch in event.allTouches) { if (touch.phase == UITouchPhaseBegan) { if ([touch.view isKindOfClass:[UIButton class]]) { NSLog(@“UIButton:id:{%@}”, [((UIButton *)touch.view) currentTitle]); } } } } Other types of UI elements may be recorded by similar handler code.\",\n \"In various implementations, after hooking the objc_msgSend function, a guide tracker 1108 may listen to the AppDelegate class and the (BOOL) application:(id)application ˜didFinishLaunchingWith Options: ˜(NSDictionary *)launchOptions method.\",\n \"Further, the guide tracker 1108 may dynamically create listeners for controllers.\",\n \"Instead of trying to exhaustively discover every state of an app through an unguided crawl of the app, the operator can help focus the analysis on the states for which deep links are desired—generally, the most interesting or important states.\",\n \"The operator may begin at a home state of the app and progress to one state of interest for each category of states for which deep linking is desired.\",\n \"The offline analysis system 280 may then extrapolate to find similar/parallel actions, each of which may correspond to another state of interest.\",\n \"These parallel states can be added to a state list that defines which states will have corresponding breadcrumbs stored.\",\n \"For example, if the app includes information about restaurants, the operator may browse to a state that lists restaurants, and then select one of the restaurants.\",\n \"The operator may stop after finding a state that shows details about a first restaurant.\",\n \"Based on the series of actions taken by the operator during browsing, the offline analysis system 280 can find other restaurant detail states that could have been reached in a similar way.\",\n \"For example, after selecting a restaurant item with a certain layout and certain properties (e.g.\",\n \"an image with property X next to a text box with property Y) from a list, the offline analysis system 280 may detect multiple additional restaurant items (that have the same layout and/or properties) within that view, which the operator could have selected.\",\n \"It may then predict that selecting the other restaurant listings will result in finding additional restaurant info states.\",\n \"For additional information about extrapolation, see U.S. patent application Ser.\",\n \"No.\",\n \"14/869,127, filed Sep. 29, 2015, titled “State Extrapolation for Automated and Semi-Automated Crawling Architecture,” with first-named inventor Kalyan Desineni, and having Attorney Docket No.\",\n \"17100-000006-US-03.The entire disclosure of this application is incorporated by reference.\",\n \"Within the guide creation system 1100, the guide tracker 1108 records operator interaction with the app in the simulator 1104 to create operator-specified guides.\",\n \"For example, a guide may include each user interface interaction performed by the operator, beginning at the home (or, default) state of the app.\",\n \"In various implementations, a target state tracker 1112 may allow the operator to flag a state currently visible in the simulator 1104 as a state of interest.\",\n \"For example, the target state tracker 1112 may provide a user interface element (such as a button) within the simulator 1104 or as part of software through which the operator controls the simulator 1104.For each state of interest, a link extraction controller 1116 generates a breadcrumb specifying a sequence of UI events that leads to the state of interest.\",\n \"The link extraction controller 1116 is aware of states that are of interest to the operator, either explicitly (such as via the target state tracker 1112) or implicitly (such as via the guide tracker 1108).\",\n \"The link extraction controller 1116 may attempt to identify similar states—for example, states that are reached using similar UI (user interface) elements.\",\n \"Target states may be explicitly identified by the operator using the target state tracker 1112.If target states are not specified by the operator, the link extraction controller 1116 may assume that the final state reached when an operator is creating a guide is the target state.\",\n \"Alternatively, the link extraction controller 1116 may make the assumption that every state the operator navigated to should be a target state.\",\n \"A deduplication procedure may be used to detect when the operator has browsed in a loop, thus avoiding recording duplicative and/or non-shortest-path guides.\",\n \"Deduplication may be less necessary if the operator is explicitly marking target states.\",\n \"The link extraction controller 1116 operates a simulator 1120, which, as described above, could instead be an emulator or a physical device.\",\n \"For scale, multiple emulators, simulators, and/or physical devices may be controlled by the link extraction controller 1116 to analyze the same or different applications.\",\n \"As an example only, a bank of physical smailphones may all be connected via USB to an interface card that is controlled by the link extraction controller 1116.Simply for ease of illustration, a single simulator (the simulator 1120) is shown in FIG.\",\n \"4.In various implementations, the simulator 1120 and the simulator 1104 may be a single simulator shared by the guide creation system 1100 and the link extraction controller 1116.The application of interest is executed within the simulator 1120.In various implementations, the app executed by the simulator 1120 may be supplemented with a routing library, such as is described in FIG.\",\n \"3A or FIG.\",\n \"3B.\",\n \"With the routing library, the link extraction controller 1116 can cause the app in the simulator 1120 to replay UI events to follow guides and identify additional states of interest.\",\n \"In other implementations, because the app in the simulator 1120 does not need to be a publicly-distributed version of the app, an accessibility or automation framework may be used to perform UI control.\",\n \"The routing library may be reserved for the version of the app that is publicly distributed.\",\n \"The link extraction controller 1116 identifies states of interest corresponding to each of the guides specified by the guide tracker 1108.In order to reach a state within the app, the link extraction controller 1116 sends the shortest path specified by the guide tracker 1108 to the simulator 1120 to be replayed.\",\n \"The link extraction controller 1116 identifies states of interest corresponding to each of the guides specified by the guide tracker 1108.In various implementations, the offline analysis system 280 may include a scraper (not shown) that extracts content from each state of interest.\",\n \"The content may include text, images, and metadata, such as location, formatting, interface hints, etc.\",\n \"This content may be used by the search system 288 of FIG.\",\n \"2 to determine which deep states of the app are relevant to a search query.\",\n \"In other implementations, the search system 288 may crawl and scrape the app separately, but may use the breadcrumbs from the offline analysis system 280 to navigate to the various states.\",\n \"If there are UI fields into which text needs to be entered, the operator may identify to the guide creation system 1100 what types of textual input need to be entered.\",\n \"The types could be, for example, city names, cuisine names, etc.\",\n \"The link extraction controller 1116 then consults a knowledge base to get a list of possible values of such types (for cities, the list might include “Seattle,” “San Jose,” etc.)\",\n \"and then replay each one of these values into the textual input field.\",\n \"The link extraction controller 1116 may detect that a potential state of interest has already been reached by following a different breadcrumb.\",\n \"The link extraction controller 1116 may then select one of the breadcrumbs to associate with that state.\",\n \"For example, the breadcrumb having the fewest number of UI events may be selected.\",\n \"Alternatively, the breadcrumb having the fewest view changes may be selected, and total number of UI events may be used as a tiebreaker.\",\n \"To identify that a state has already been reached, the link extraction controller 1116 may store a fingerprint for each state along with the breadcrumb.\",\n \"The fingerprint may be a reduced representation of the components of a state.\",\n \"For example, a representation of visible objects may be created, such as by enumerating the objects in an XML data structure and then computing a mathematical hash (such as with MD5) of the data structure.\",\n \"The hash is then the fingerprint, and if the hash of a new state matches a hash of an existing state, the states are considered to be the same.\",\n \"As the link extraction controller 1116 assembles the set of states of interest, the link extraction controller 1116 may store an identifier of the state into a configuration data store 1124.For each state of interest, the link extraction controller 1116 determines a breadcrumb to reach that state and stores the breadcrumb in the configuration data store 1124.In addition, content or a fingerprint from states is stored in the configuration data store 1124.Data from the configuration data store 1124 may be provided to the search system 288 of FIG.\",\n \"2.Breadcrumb Creation In FIG.\",\n \"12, example operation of breadcrumb creation by an operator begins at 1204, where control opens the subject app in an emulator or simulator to the home state of the app.\",\n \"At 1208, control begins tracking user interaction with the app, including tracking the user interface elements with which the operator interacts.\",\n \"At 1212, if the operator marks the current state as a deep link target, control transfers to 1216; otherwise, control transfers to 1220.At 1216, the state is added to a list of target states and control continues at 1224.At 1224, control stores the operator interaction leading to the present state as a breadcrumb.\",\n \"Control continues at 1220.At 1220, if the operator marks the state as an activity for bookmarking purposes, control transfers to 1228; otherwise, control transfers to 1232.At 1228, control adds the state to the rules for activity bookmarking so that when the state is encountered by a user, an activity corresponding to that state is bookmarked by sending an activity object to the operating system.\",\n \"Control continues at 1236, where the operator interaction leading to the present state is stored as a breadcrumb.\",\n \"If the breadcrumb was already stored at 1224 for the present state, an additional copy of the breadcrumb may be omitted from storage.\",\n \"Control continues at 1232.At 1232, control continues tracking operator interaction with the app.\",\n \"At 1240, control determines whether the operator has instructed the app to reset to a home state of the app.\",\n \"If so, control transfers to 1244; otherwise, control returns to 1212.Resetting the home state may be accomplished by a user interface element belonging to the simulator within which the app is operating.\",\n \"In other limitations, the app itself may have a mechanism for returning to the home state and this is recognized by 1240 as well.\",\n \"By resetting to the home state, the operator indicates that a new set of user interface events should be tracked to lead to another state of interest.\",\n \"At 1244, if the present state was not already marked as a deep link target, control stores the operator interaction leading to the present state as a breadcrumb and adds the present state to the list of target states.\",\n \"Control continues at 1248, where if the operator is done, control ends.\",\n \"Otherwise, control returns to 1208.Breadcrumb Extrapolation Referring to FIG.\",\n \"13, the operator may have established a series of breadcrumbs but not labeled any particular states as target states.\",\n \"For example, in some implementations, the operator may not be presented with an option to designate target states.\",\n \"However, operator-created breadcrumbs generally begin at a home state and end at a terminal (or, final) state.\",\n \"This final state may be assumed to be the state of interest for deep-linking.\",\n \"In other words, only terminal states are assumed to be target states.\",\n \"In other implementations, each state encountered along a breadcrumb is assumed to be a target state.\",\n \"For example, when an operator is creating breadcrumbs for a restaurant review application, the operator may create one breadcrumb by navigating from the home state to a state containing restaurant information and reviews.\",\n \"This would be assumed to be a desired target state, and the link extraction controller would attempt to find additional states that have similar data for scraping.\",\n \"Control begins at 1304, where a first breadcrumb from a list of operator-created breadcrumbs is selected.\",\n \"At 1308, control opens the app to a home state in an emulator.\",\n \"At 1312, control follows the selected breadcrumb, stopping in the state immediately before the final state.\",\n \"At 1316, control performs extrapolation to identify states similar to the final state.\",\n \"For example, control identifies UI widgets parallel to the UI widget that, when followed according to the selected breadcrumb, will reach the final state.\",\n \"At 1320, control adds the final state, as well as states reached from UI widgets identified as parallel, to a state list.\",\n \"Each of the added states is annotated with a breadcrumb based on the selected breadcrumb.\",\n \"The breadcrumb for the states other than the final state will diverge from the breadcrumb for the final state at the final UI event of each breadcrumb.\",\n \"At 1324, control determines whether additional breadcrumbs are present in the list of breadcrumbs.\",\n \"If so, control transfers to 1328; otherwise, control ends.\",\n \"At 1328, control selects the next breadcrumb from the list of breadcrumbs and returns to 1308.CONCLUSION The foregoing description is merely illustrative in nature and is in no way intended to limit the disclosure, its application, or uses.\",\n \"The broad teachings of the disclosure can be implemented in a variety of forms.\",\n \"Therefore, while this disclosure includes particular examples, the true scope of the disclosure should not be so limited since other modifications will become apparent upon a study of the drawings, the specification, and the following claims.\",\n \"It should be understood that one or more steps within a method may be executed in different order (or concurrently) without altering the principles of the present disclosure.\",\n \"Further, although each of the embodiments is described above as having certain features, any one or more of those features described with respect to any embodiment of the disclosure can be implemented in and/or combined with features of any of the other embodiments, even if that combination is not explicitly described.\",\n \"In other words, the described embodiments are not mutually exclusive, and permutations of one or more embodiments with one another remain within the scope of this disclosure.\",\n \"Spatial and functional relationships between elements (for example, between modules) are described using various terms, including “connected,” “engaged,” “interfaced,” and “coupled.” Unless explicitly described as being “direct,” when a relationship between first and second elements is described in the above disclosure, that relationship encompasses a direct relationship where no other intervening elements are present between the first and second elements, and also an indirect relationship where one or more intervening elements are present (either spatially or functionally) between the first and second elements.\",\n \"As used herein, the phrase at least one of A, B, and C should be construed to mean a logical (A OR B OR C), using a non-exclusive logical OR, and should not be construed to mean “at least one of A, at least one of B, and at least one of C.” In this application, including the definitions below, the term ‘module’ or the term ‘controller’ may be replaced with the term ‘circuit.’ The term ‘module’ may refer to, be part of, or include processor hardware (shared, dedicated, or group) that executes code and memory hardware (shared, dedicated, or group) that stores code executed by the processor hardware.\",\n \"The module may include one or more interface circuits.\",\n \"In some examples, the interface circuits may include wired or wireless interfaces that are connected to a local area network (LAN), the Internet, a wide area network (WAN), or combinations thereof.\",\n \"The functionality of any given module of the present disclosure may be distributed among multiple modules that are connected via interface circuits.\",\n \"For example, multiple modules may allow load balancing.\",\n \"In a further example, a server (also known as remote, or cloud) module may accomplish some functionality on behalf of a client module.\",\n \"The term code, as used above, may include software, firmware, and/or microcode, and may refer to programs, routines, functions, classes, data structures, and/or objects.\",\n \"Shared processor hardware encompasses a single microprocessor that executes some or all code from multiple modules.\",\n \"Group processor hardware encompasses a microprocessor that, in combination with additional microprocessors, executes some or all code from one or more modules.\",\n \"References to multiple microprocessors encompass multiple microprocessors on discrete dies, multiple microprocessors on a single die, multiple cores of a single microprocessor, multiple threads of a single microprocessor, or a combination of the above.\",\n \"Shared memory hardware encompasses a single memory device that stores some or all code from multiple modules.\",\n \"Group memory hardware encompasses a memory device that, in combination with other memory devices, stores some or all code from one or more modules.\",\n \"The term memory hardware is a subset of the term computer-readable medium.\",\n \"The term computer-readable medium, as used herein, does not encompass transitory electrical or electromagnetic signals propagating through a medium (such as on a carrier wave); the term computer-readable medium is therefore considered tangible and non-transitory.\",\n \"Non-limiting examples of a non-transitory computer-readable medium are nonvolatile memory devices (such as a flash memory device, an erasable programmable read-only memory device, or a mask read-only memory device), volatile memory devices (such as a static random access memory device or a dynamic random access memory device), magnetic storage media (such as an analog or digital magnetic tape or a hard disk drive), and optical storage media (such as a CD, a DVD, or a Blu-ray Disc).\",\n \"The apparatuses and methods described in this application may be partially or fully implemented by a special purpose computer created by configuring a general purpose computer to execute one or more particular functions embodied in computer programs.\",\n \"The functional blocks and flowchart elements described above serve as software specifications, which can be translated into the computer programs by the routine work of a skilled technician or programmer.\",\n \"The computer programs include processor-executable instructions that are stored on at least one non-transitory computer-readable medium.\",\n \"The computer programs may also include or rely on stored data.\",\n \"The computer programs may encompass a basic input/output system (BIOS) that interacts with hardware of the special purpose computer, device drivers that interact with particular devices of the special purpose computer, one or more operating systems, user applications, background services, background applications, etc.\",\n \"The computer programs may include: (i) descriptive text to be parsed, such as HTML (hypertext markup language) or XML (extensible markup language), (ii) assembly code, (iii) object code generated from source code by a compiler, (iv) source code for execution by an interpreter, (v) source code for compilation and execution by a just-in-time compiler, etc.\",\n \"As examples only, source code may be written using syntax from languages including C, C++, C#, Objective-C, Swift, Haskell, Go, SQL, R, Lisp, Java®, Fortran, Perl, Pascal, Curl, OCaml, Javascript®, HTML5 (Hypertext Markup Language 5th revision), Ada, ASP (Active Server Pages), PHP (PHP: Hypertext Preprocessor), Scala, Eiffel, Smalltalk, Erlang, Ruby, Flash®, Visual Basic®, Lua, MATLAB, SIMULINK, and Python®.\",\n \"None of the elements recited in the claims are intended to be a means-plus-function element within the meaning of 35 U.S.C.\",\n \"§ 112(f) unless an element is expressly recited using the phrase “means for” or, in the case of a method claim, using the phrases “operation for” or “step for.”\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875753"}}},{"rowIdx":4494965,"cells":{"text":{"kind":"list like","value":[["EMBEDDING DEBUGGING INFORMATION VIA WATERMARKS","Debugging information for content rendered for display on a client device can be included in one or more watermarks inserted into the content.","Performance, state, configuration, debugging, and other information can be encoded into a watermark and placed in rendered content in such a way that the information is imperceptible to most users.","When a user reports a potential issue or problem, the user (or another source) can provide a version of the image frame corresponding to the issue, which enables the watermark to be located and the data extracted.","A checksum or other value can be used to ensure that a complete and valid watermark was obtained.","The data extracted from the watermark can then be used to attempt to identify and/or diagnose the potential issue without having to have access to the client device or communication with the user."],["1.","(canceled) 2.A computer-implemented method, comprising: analyzing a first image frame representing rendered content on a client device; identifying first watermark data represented in the first image frame, the first watermark data corresponding to at least a first portion of a watermark containing debugging data; analyzing a second image frame representing the rendered content; identifying second watermark data represented in the second image frame, the second watermark data corresponding to at least a portion of the watermark containing debugging data; and utilizing the debugging data from the watermark to attempt to determine a cause of an issue with the rendered content.","3.The computer-implemented method of claim 2, further comprising: causing the debugging data to be encoded at pixel locations proximate edges of objects represented in the rendered content.","4.The computer-implemented method of claim 2, further comprising: determining at least one parameter from the watermark corresponding to a checksum, a hash, or a length identifier; and verifying the watermark data using the at least one parameter.","5.The computer-implemented method of claim 2, further comprising: storing additional debugging data to a log data store; correlating the additional data to identifier information from the watermark; and accessing the log data store to obtain the additional debugging data.","6.The computer-implemented method of claim 2, further comprising: embedding the debugging data into a second watermark; and positioning the second watermark in a different location than the watermark.","7.The computer-implemented method of claim 2, further comprising: determining a quality associated with an image file comprising the first and second image frames; determining the quality is below a threshold amount, the threshold indicating where data is lost; and encoding at least a portion of the debugging data at a different encoding level to prevent data loss.","8.A computer-implemented method, comprising: obtaining content for rendering on a client device; determining debugging data relevant to the content; determining verification data relevant to the content or client device; generating watermark data including at least the debugging data and the verification data; and encoding the watermark data into the content.","9.The computer-implemented method of claim 8, further comprising: providing the content for the presentation via the client device.","10.The computer-implemented method of claim 8, further comprising: determining at least one parameter from the watermark data corresponding to a checksum, a hash, or a length identifier; and verifying the watermark data using the at least one parameter.","11.The computer-implemented method of claim 8, wherein the debugging data includes at least one of state information, frame information, timestamp information, content selection information, content layout information, user information, application information, rendering time data, processing data, sample data, failure occurrence record data, or breakpoint information.","12.The computer-implemented method of claim 8, wherein encoding the watermark data comprises using at least one of a quantization type watermarking algorithm, a spread-spectrum watermarking algorithm, or an amplitude modulation watermarking algorithm.","13.The computer-implemented method of claim 8, further comprising: encoding a first portion of the watermark data into the content using a first watermarking algorithm and a second portion of the watermark data into the content using a second watermarking algorithm.","14.The computer-implemented method of claim 8, further comprising: receiving a notification indicating a potential issue with a presentation of the content via the client device; extracting the watermark data from the content; and utilizing the debugging data, contained within the watermark data, to attempt to determine a cause of the potential issue.","15.The computer-implemented method of claim 8, wherein the content is rendered content comprising an image frame, the computer-implemented method further comprising: receiving the image frame captured from the client device, the image frame being captured as displayed on the client device; identifying the watermark data from the image frame; and verifying the content of the watermark data.","16.The computer-implemented method of claim 8, further comprising: receiving a first image frame from the user device, the first image frame representative of content rendered on the client device; locating watermark data within the first image frame; determining the watermark data is incomplete; evaluating a second image frame from the user device, the second image frame representative of content rendered on the client device; and extracting the watermark data from a different location within the second image frame.","17.A system, comprising: at least one processor; and memory including instructions that, when executed by the at least one processor, cause the system to: obtain content for rendering on a client device; determine debugging data relevant to the content; determine verification data relevant to the content or client device; generate watermark data including at least the debugging data and the verification data; and encode the watermark data into the content.","18.The system of claim 17, wherein the instructions when executed further cause the system to: encode a first portion of the watermark data into the content using a first watermarking algorithm and a second portion of the watermark data into the content using a second watermarking algorithm.","19.The system of claim 17, wherein the instructions when executed further cause the system to: determine at least one parameter from the watermark data corresponding to a checksum, a hash, or a length identifier; and verify the watermark data using the at least one parameter.","20.The system of claim 17, wherein the instructions when executed further cause the system to: receiving a notification indicating a potential issue with a presentation of the content via the client device; extracting the watermark data from the content; and utilizing the debugging data, contained within the watermark data, to attempt to determine a cause of the potential issue.","21.The system of claim 17, wherein the instructions when executed further cause the system to: store additional debugging data in a log data store; correlate the additional data to the verification data from the watermark; and access the log data store to obtain the additional debugging data."],["<SOH> BACKGROUND <EOH>Users are increasingly utilizing electronic devices to perform various tasks.","These tasks can be performed in various ways, such as by using Web content displayed through a Web browser or content accessed using an application (or “app”) executing on a client device.","Users using a variety of different applications accessing a variety of different content will occasionally experience issues with the intended functionality.","A user can report these issues, but a developer will want to determine contextual information in an attempt to determine a potential cause of the reported issue.","In some instances, this also involves attempting to recreate the issue.","In order to perform these tasks, a developer needs to obtain the contextual information from the user or another source.","Users may be unwilling to provide contextual information, or may not know how to provide the appropriate information.","Further, various engines and protocols do not provide for the capturing of robust debugging information, particularly from client or third party devices."],["<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>Various embodiments in accordance with the present disclosure will be described with reference to the drawings, in which: FIGS.","1A, 1B, 1C, 1D, and 1E illustrate example approaches to embedding information in an image through watermarking that can be utilized in accordance with various embodiments.","FIG.","2 illustrates an example environment for embedding debugging data in image content that can be utilized in accordance with various embodiments.","FIG.","3 illustrates an example process for embedding debugging data in image content that can be utilized in accordance with various embodiments.","FIG.","4 illustrates an example process for extracting debugging data from image content that can be utilized in accordance with various embodiments.","FIG.","5 illustrates an example display of content wherein a portion of a watermark may be occluded by content rendered from an embedded engine that can be processed in accordance with various embodiments.","FIG.","6 illustrates an example device that can be used to implement aspects of the various embodiments.","FIG.","7 illustrates example components of a client device such as that illustrated in FIG.","6 .","FIG.","8 illustrates an environment in which various embodiments can be implemented.","detailed-description description=\"Detailed Description\" end=\"lead\"?"],["CROSS-REFERENCE TO RELATED APPLICATIONS This is a continuation application of U.S. patent application Ser.","No.","14/970,131, filed on Dec. 15, 2015, entitled “EMBEDDING DEBUGGING INFORMATION VIA WATERMARKS,” which is hereby incorporated by reference in its entirety.","BACKGROUND Users are increasingly utilizing electronic devices to perform various tasks.","These tasks can be performed in various ways, such as by using Web content displayed through a Web browser or content accessed using an application (or “app”) executing on a client device.","Users using a variety of different applications accessing a variety of different content will occasionally experience issues with the intended functionality.","A user can report these issues, but a developer will want to determine contextual information in an attempt to determine a potential cause of the reported issue.","In some instances, this also involves attempting to recreate the issue.","In order to perform these tasks, a developer needs to obtain the contextual information from the user or another source.","Users may be unwilling to provide contextual information, or may not know how to provide the appropriate information.","Further, various engines and protocols do not provide for the capturing of robust debugging information, particularly from client or third party devices.","BRIEF DESCRIPTION OF THE DRAWINGS Various embodiments in accordance with the present disclosure will be described with reference to the drawings, in which: FIGS.","1A, 1B, 1C, 1D, and 1E illustrate example approaches to embedding information in an image through watermarking that can be utilized in accordance with various embodiments.","FIG.","2 illustrates an example environment for embedding debugging data in image content that can be utilized in accordance with various embodiments.","FIG.","3 illustrates an example process for embedding debugging data in image content that can be utilized in accordance with various embodiments.","FIG.","4 illustrates an example process for extracting debugging data from image content that can be utilized in accordance with various embodiments.","FIG.","5 illustrates an example display of content wherein a portion of a watermark may be occluded by content rendered from an embedded engine that can be processed in accordance with various embodiments.","FIG.","6 illustrates an example device that can be used to implement aspects of the various embodiments.","FIG.","7 illustrates example components of a client device such as that illustrated in FIG.","6.FIG.","8 illustrates an environment in which various embodiments can be implemented.","DETAILED DESCRIPTION Systems and methods in accordance with various embodiments of the present disclosure overcome one or more of the above-referenced and other deficiencies in conventional approaches to obtaining operational information in an electronic device.","In particular, various embodiments provide for the obtaining of debugging information through the inclusion of watermarks in rendered content.","Performance, state, configuration, debugging, and other information can be encoded into a watermark and placed in rendered content in such a way that the information is imperceptible to most users.","When a user reports a potential issue or problem, the user (or another source) can provide an image frame corresponding to the issue, which enables the watermark to be located and the data extracted.","A checksum or other value can be used to ensure that a complete and valid watermark was obtained.","The data extracted from the watermark can then be used to attempt to identify and/or diagnose the potential issue.","Various other functions and advantages are described and suggested below as may be provided in accordance with the various embodiments.","FIG.","1 illustrates an example situation 100 in which a page of content 104 is displayed on a computing device 102.Although a portable computing device is illustrated, it should be understood that any appropriate device can be used to present content in accordance with the various embodiments, as may include notebook computers, personal data assistants, e-book readers, cellular phones, video gaming consoles or controllers, smart televisions, set top boxes, a wearable computer (e.g., a smart watch or glasses), and portable media players, among others.","In this example, the content displayed includes image and text content, as may be rendered on the computing device 102 or by a remote rendering engine, among other such options.","The content can be Web content displayed through a browser application, content rendered by an application from a content provider or third party application provider, among other types of content.","In this example, the displayed content relates to furniture placed in a virtual room that enables a user to view collections of furniture in realistic environments.","There might be any of a number of issues with such a display or presentation of content, however.","In this example, the size of a lamp 112 displayed in the image is too large relative to the other content displayed.","Accordingly, a customer experiencing the issue might generate a notification to be sent to a provider of the content and/or application in order to report the alleged problem.","An entity receiving the notification may then want to be able to determine sufficient information to identify the type of problem or issue that was alleged to have been experienced on the device.","The entity might also attempt to determine contextual information in order for the entity to be able to recreate the situation and/or problem.","This can include information such as the content being displayed, the display settings, information about the device used to display the content, a time at which the content was displayed, a frame number if the problem occurred with a specific frame or set of frames, or other such information that may be known to one of ordinary skill in the art for debugging applications or content that would be apparent in light of the teachings and suggestions contained herein.","Problems can arise, however, when the entity attempting to diagnose the problem is unable to obtain the appropriate information.","For example, a rendering engine might have only limited capability with respect to the generating and/or outputting of metadata, state, or debugging data, among other such types of information.","If a rendering engine is not able to fully utilize a component such as an embedded view component or sandboxed renderer process, for example, retrieving debugging data might require implementing an additional interface or performing security exceptions, which might not be available or may not be implemented as needed, such as where a software author using cloud-based rendering chooses not to implement any auxiliary interfaces.","The choice to not implement such interfaces may be a valid choice due to the burden of implementing the interfaces as well as introducing security or other such issues.","In some embodiments a debugging process might not be allowed to send debugging data during normal rendering due bandwidth or security constraints, among other such issues.","It thus can be difficult for a developer to obtain debugging information such as program state information (i.e., the state of variables and calls made), timestamp information, subroutines executed, types or constants defined, frame information, processing data, sample data, failure occurrence record data, breakpoints met, and the like.","The types and amount of information can further depend upon the complexity of the content or application, the type of issue experienced, and other such factors.","Accordingly, approaches in accordance with various embodiments attempt to provide for the availability of debugging information by embedding the debugging information in the content (e.g., image, video, or audio content) presented using a computing device.","In particular, the debugging information can be inserted into an image frame as a watermark that is barely perceptible to the average user.","In this way, the debugging information can be available regardless of the type of application or device used to display the content, and can avoid various bandwidth, security, and other such concerns mentioned elsewhere herein.","A user experiencing a problem can provide a copy of the image with the notification, such as by capturing a screenshot or selecting an option that automatically captures and sends a copy of the image to a remote debugging service or other such location.","In other embodiments, a debugging tool can analyze the image on the client device in order to extract the debugging information and then provide the debugging information to the debugging service.","Various other approaches can be used as well as discussed and suggested elsewhere herein.","Various types of watermarks can be utilized in accordance with various embodiments.","A digital watermark can be embedded in noise-tolerant content, such as an image, audio, or video content.","Digital watermarks can be perceptible under certain conditions, such as under examination by a watermark extraction algorithm, but imperceptible under other conditions, such as upon viewing by a human user.","A watermark can be added to an image in some embodiments by adjusting the values of certain pixels of the image by amounts determined by a particular encoding engine.","The amount of adjusting should be such that the visible changes to the pixels are minimal, in order to reduce the impact and detectability by a user.","Further, the encoding can be performed using pixel locations that are likely to be less perceptible to a user.","In some embodiments, an encoding bit rate can be varied based on the underlying content and a rate of content change.","For example, when scrolling down quickly, a higher bit rate can be used to encode more information into each frame, as human eyes are unable to focus and differentiate the “artificial noise” from faster moving/changing content.","The visual complexity for choosing the amount of data to encode can be approximated by monitoring how much CPU time content rasterization requires and/or monitoring the kind of drawing instructions that were executed to generate a piece of content, such as a tile.","Bitrate change can be gradual or “modulated” near tile boundaries, to avoid regular-shaped changes in noise patterns, which could be more easily seen by humans.","As an example, FIG.","1B illustrates a subset of pixels corresponding to a region 108 of the image in FIG.","1A that is substantially represented by a single color value or pixel value.","If the encoding were to be placed using pixels in such a region, as illustrated in the encoded region 120 of FIG.","1C, the changes would be relatively noticeable to a user viewing the image content.","A lower bit rate can be used to encode information in these areas, but it might be desirable in at least some embodiments to use portions of the image, where available, that allow for the use of higher bit rates.","If the encoding were instead placed at locations such as the edges of letters or objects, which typically demonstrate some amount of blurring or antialiasing, the encoding may be less perceptible.","For example, FIG.","1D illustrates an example region 110 from the image of FIG.","1A that includes a portion of a letter represented in the image.","As illustrated, there are pixels of varying color around the edges of the letter.","If the encoding is positioned in such locations, such as near the edges of the letter where some amount of color gradation is expected by the user, the user may not be able to perceive the difference.","For example, FIG.","1E illustrates one such encoded region 140 where the encoding affects pixels near the edges of the letter.","While a side by side comparison would enable a user to discern the differences, a user just viewing FIG.","1E by itself would generally not perceive that any encoding had taken place.","While the encoding of the example of FIG.","1C might be perceptible to a user due in part to its placement, the placement in FIG.","1E can help to hide the encoding from a user.","This is not necessarily to attempt to hide the presence of the debugging information from the user, but can instead enable the information to be provided without negatively impacting the user experience.","For example, using the approach discussed with respect to FIG.","1E a user might not perceive any degradation or change in image quality through the inclusion of such information.","As mentioned, there can be various watermarking algorithms used to determine the encoding and placement of the debugging data in rendered image content.","These can include, for example, quantization type watermarking algorithms, spread-spectrum watermarking algorithms, or amplitude modulation watermarking algorithms, among others.","A watermarking process might utilize one or more different algorithms at different times, such as may depend at least in part upon a type of content, a type or amount of information to be embedded, a security level of the information, and the like.","It at least some embodiments the watermark encoded into an image can include a checksum, or multiple checksums, as it can be difficult in at least some embodiments to determine the presence of a valid watermark, as well as to ensure that the entire watermark has been located.","This is particularly true when the placement depends upon the location of objects represented in the content, and an image with a different portion, contrast, intensity, aspect ratio, resolution, or other such factor may result in an algorithm selecting different locations to place the encoding.","For multiple checksums, one might be included for each record/chunk as opposed to the entire watermark, where one or more of the records with checksums can be used to verify all the data was decoded.","Thus, if content is rendered with encoded information at determined locations using an algorithm, a screen shot from a user that includes additional or less information might result in that algorithm picking different places to look in the image.","Thus, a checksum, hash, watermark length identifier, or other such data included in the watermark can be useful in ensuring that a valid and complete watermark has been identified.","The data extracted can then be used to attempt to debug the problem, using any of a number of different debugging approaches as might be used for similar data obtained from conventional sources.","FIG.","2 illustrates an example environment 200 in which aspects of the various embodiments can be implemented.","In this example, content is to be rendered on a client device 202.The content can originate from a content provider network 208, for example, as may be received over a least one network 206, such as the Internet, an intranet, a local area network, a cellular network, or another appropriate wired and/or wireless network.","The content can be rendered using a rendering engine 204 on the client device and/or a rendering engine 214 in the resource provider environment 208, among other such options.","In this example, at least some of the content can be pulled from a content repository 216 and rendered by a rendering engine 214 before being provided to the client device 202 by at least one content server 212.A request for the content can be received to a network interface layer 210, which can include one or more interfaces such as application programming interfaces (APIs) for receiving requests, as well as various other network components such as routers, load balancers, and the like.","In at least some embodiments the content server 212 or another appropriate component can cause data to be written to at least one log 218, as may include information regarding the content served.","The content can be delivered across the at least one network 206 to the client device 202.As mentioned, at least some rendering can be performed by a rendering engine 204 on the client device.","For example, a rendering engine for a Web browser might take markup language content such as HTML and formatting information to render Web content to be displayed on the client device 202 that can be formatted to fit the display and the current zoom level, etc.","Various other components such as layout or placement engines can be used as well within the scope of the various embodiments.","These engines can render data once the data is received, or may begin rendering as the data is received, among other such options.","Further, a rendering engine might render only that portion of the content that will be visible, or may render some additional amount that can reduce the likelihood of chunking or delayed rendering in response to a navigation or zoom action, among other such possibilities.","As mentioned the client device can display the content, and if a user (or application or other source) detects a potential issue or problem with the content, software, or device, the user can cause the image information to be provided to the content provider network 208.As mentioned, this can be accomplished by a user capturing a screenshot of the content, taking a picture using a digital camera, or selecting an option in an executing application or console that causes image data to be captured, among other such options.","In some embodiments the image can be processed on the client device 202, while in other embodiments the image can be provided to the content provider network 208, wherein the image can be directed to a debugging engine 220 or other such system or service.","The debugging engine can have access (directly or indirectly) to a watermarking algorithm that can be used to analyze the image to attempt to locate and extract the watermark from the image.","The content of the watermark can be analyzed to verify the accuracy, validity, and completeness of the watermark, such as by analyzing a checksum, hash, or length identifier of the watermark data and ensuring that the content of the watermark is as expected.","If not, the image data can be re-analyzed using a different algorithm or different values for the same algorithm to attempt to determine the appropriate watermark.","In some instances there might be multiple watermarks, with one being embedded in the original content or otherwise provided, which might prevent a single watermark from being accurately detected.","In the event that a watermark cannot be properly identified, conventional approaches to locating debugging information can be used, among other such options.","It should be mentioned that, as discussed elsewhere herein, a debugging engine 224 can also be included on the client device 202 in order to embed watermark data to content rendered and/or displayed on the client.","In some embodiments a debugging engine 226 might be offered as a third party service and/or service outside the resource provider environment, whereby content from a provider can have debugging information added if the debugging service has access to the appropriate data to be included in the watermark.","If the watermark can be verified, the data included in the watermark can be analyzed and used to attempt to determine the source of the reported issue.","As mentioned, this can include attempting to recreate the situation using the information provided.","The watermark data, as discussed elsewhere herein, can include various types of data useful for debugging, as may include timestamp data, state data, frame data, configuration data, identifiers for external logs (additional logged information), serialized data structures that cause or are related to a failure, and the like.","This information can be compared, using a debugging engine 220 or other such component or service, to information stored in a log data store 218 or other such location, which might contain additional information for the image frame.","The amount of data that can be included in a watermark is limited, at least in keeping the perceptibility of the watermark low, such that additional information for the rendering might also be stored to a log data store.","By using identifier information (frame, timestamp, client, etc.)","from the watermark, the information from the watermark can be correlated with information in the log for purposes of obtaining additional information for debugging.","Similarly, the debugging engine can use the debugging information from the watermark to check for similar data in a debugging data store 222, or other such location, do determine whether similar issues previously arose for similar circumstances, which can help point to a solution if one was previously determined.","Once the appropriate information is obtained, any appropriate debugging process can be used to attempt to identify and rectify any potential issues, as would be apparent to one of ordinary skill in the art in light of the teachings and suggestions contained herein.","A rendering engine in some embodiments can employ an error-correction (ECC, parity bits), compression (such as Lempel-Ziv-Markov chain, arithmetic coding) and/or encryption scheme before watermarking, which can be separate from any such schemes in the watermarking algorithm itself.","This can enable the use of multiple different available watermarking libraries and/or algorithms, and can help to secure any private user data or prevent malicious third parties from feeding incorrect information.","An example rendering engine can provide a callback interface to the embedding application for adding additional debugging data, and another callback interface to the embedding application for notifying when it has added its changes to the output frame (i.e., finalized it), allowing a rendering engine to use application's output surface area.","The latter callback can contain a frame buffer texture handle (or equivalent) as a parameter.","When multiple layers of content are composited (i.e., flattened) into a final output image, a read-back phase may be used to retrieve the final frame texture and modify it directly.","In some embodiments, a translucent layer containing the watermark data can be composited (i.e., merged) to the output frame.","A watermarking algorithm might add actual noise to the image (not containing any data or containing dummy records) in some embodiments in order to make the output more pleasing to the human eye, such as when there's not enough data to cover the entire image area or tile.","The same debugging data can also be repeated multiple times, as discussed elsewhere herein, to increase the chances of the data surviving in the event that some portion of the image is lost or otherwise not provided.","In some embodiments there may be a queue of pending records, from which records can be encoded opportunistically to fill in any remaining unused watermark capacity after higher priority data has been encoded.","In some embodiments a rendering engine may keep collecting information (up to a limit, discarding lowest importance data) and keep a list of data records to be encoded, but only do the encoding when a screenshot function is activated, encoding as many as possible of the pending records into one frame.","When an application using a rendering engine encounters a problem, such as violating an internal check for correctness, the rendering engine may temporarily use an algorithm with a higher bit rate and/or higher complexity than for normal output frames, in order to encode more information or increase the probability of the encoded data surviving any future quality degradation, possibly causing skipping small number of output frames.","FIG.","3 illustrates an example process 300 for embedding debugging data in a watermark that can be utilized in accordance with various embodiments.","It should be understood that there can be additional, fewer, or alternative steps performed in similar or alternative orders, or in parallel, within the scope of the various embodiments unless otherwise stated.","In this example, content to be rendered for a frame can be obtained 302 from an appropriate source, such as from a content provider network or third party provider.","In some embodiments, the content can include webpage content (e.g., HTML) to be rendered that may include content from other providers, among other such content.","In addition, debugging data relevant to a frame (or set of frames) of content to be rendered can be determined.","This can include, for example, state data, frame number data, a time stamp, a client or customer identifier, and other such information.","Watermark data that includes the debugging data and some verification data can be generated 306 that is to be inserted into the frame after, or at the time, the frame is rendered.","As mentioned, the verification data can include a checksum, hash, or other mechanism that can be used to determine a completeness and validity of the watermark data.","The watermark data can also be encoded such that the data can be distributed across an image in such a way that the data can be extracted but is generally imperceptible to a user viewing the image.","The frame of content can then be rendered 308 and the watermark included.","The watermark can be included at the time of rendering, or can be added as a separate step after the initial rendering, among other such options.","As mentioned, portions of the watermark can be positioned near the edges of objects represented in the image that would typically demonstrate some amount of anti-aliasing, blending, blurring, or smoothing, such that a slight variation in pixel value will not be unexpected or even noticeable to a user.","The watermark in at least some embodiments is encoded into the bitmap written into the frame buffer for the content to be displayed.","The image can then be caused to be displayed 310, or otherwise presented, with the embedded watermark.","If the watermark is instead in audio data, for example, then the audio with the watermark can be provided to be played through one or more speakers, among other such options.","The capturing or saving of at least a portion of the rendered image is then enabled 312 in the event of an issue or potential problem, whereby the image can be provided to a debugging engine, service, or provider in order to enable that entity to extract the debugging information from the image, which can help to diagnose and/or re-create the identified issue.","FIG.","4 illustrates an example process 400 for extracting debugging data from a watermark that can be utilized in accordance with various embodiments.","In this example, an image (or image frame) is received 402 that correspond to a reported issue with the content, the rendering of the content, an application or device rendering the content, etc.","As mentioned, this image can be captured by a user using a screenshot function or digital camera, or can be captured by a console or application executing on the client device, among other such options.","The image can be processed 404 with a watermark extraction algorithm that can analyze some, or all, of the image to attempt to recognize the watermark.","Since this process will often be performed offline, the algorithm(s) can analyze the entire image using multiple passes with different parameters as needed to identify the watermark.","If a watermark cannot be located 406, a different approach can be attempted 408, such as to adjust one or more search parameters or utilize a different extraction algorithm.","Other data sources also can be used if a watermark cannot be located, such as those that would be used to obtain debugging data using conventional approaches.","Once located, the content of the watermark can be verified 410 using a checksum, hash, length value, or other parameter included in the watermark.","The data from the watermark can also be checked to ensure that the data corresponds to a valid watermark, includes appropriate debugging data, etc.","If the watermark is determined 412 to not be valid, another approach can be used as discussed above to attempt to locate a complete watermark or use other data sources, among other such options.","If the watermark is determined to be complete and valid, the debugging data or other appropriate information can be extracted 414 from the watermark and utilized 416 to attempt to determine contextual information for the reported issue.","As mentioned, this can include information such as a state of the device, a state of the content, a frame sequence number, a timestamp of the reported issue, performance data for the time of the issue, intentionally placed debugging data, a rendering time for the frame, a list of assumptions, a set of state flags, and other such information.","In some embodiments, a debugging tool can process a series of images to attempt to determine commonalities among images, analyze trends, or generate statistics, among other such features.","For example, statistics can be generated as to the frequency of types of watermarks, the frequency of invalid or incomplete watermarks detected, the percentage of images containing a certain flag or debugging data value, etc.","An advantage to processing several images using a debugging tool or service is that incomplete information may be able to be obtained by utilizing information obtained from other images.","For example, the display 500 of content in FIG.","5 illustrates the display of FIG.","1, except that here an embedded application or other source has caused other content to be displayed as an overlay 502 that obscures or occludes a portion of the displayed image.","In such a situation, at least a portion of the watermark embedded in the image may not be able to be determined from an image or screenshot.","If information from other images is available, which may also be sourced from content rendered for other clients, the information might be able to be completed or at least partially recovered in order to enable at least some of the debugging information to be determined for the corresponding situation.","Another advantage to embedding the debugging information in the image data is that a third party developer or content author can diagnose problems even if that party may not otherwise be able to obtain access to the appropriate data.","For example, a user posting a screenshot of the issue on a social networking site can be sufficient for an entity to analyze the screenshot and determine debugging information for the issue, without having to obtain the information from the user in some other way, such as through the submission of log files or the implementation of a listener interface to collect data, among other such options.","Such an approach also enables the party to debug the problem even if the identity of the poster is unknown or access is otherwise problematic.","Another advantage is that performance can be diagnosed and issues debugged using the data without the third party developer or author even being aware of the inclusion of the data in some embodiments, and where such modification is permitted and authorized.","In some embodiments, a web crawler can be used to “scrape” known discussion forums or support web sites to automatically identify any images containing watermarks, and retrieve production debugging data without end-users having to provide the images to the original software author.","Such an approach is also useful for developers of applications, or apps, that might be purchased through an application store provided by another provider.","The app developer thus might have no direct relationship with the customer.","The ability to embed debugging information in a watermark, however, enables the app developer to determine the debugging information as long as the appropriate watermarked portion is somehow available to the developer.","In some embodiments multiple instances of a watermark might be placed in an image frame, enabling the discovery of debugging data even if only a portion of the frame is visible.","In some embodiments, such as where there are multiple frames in a sequence, the watermark data might also be displayed over several frames such that a video clip would be necessary to obtain all the appropriate watermark data.","The watermark data can also be split over audio, video, and image encoding in some embodiments.","The watermark can include other information as well, such as state or content of a portion of a page that is not visible but currently rendered.","If an example screen includes around two million pixels and each pixel in this example can accept 32 bits of information, then there are around 8 megabytes of data available in a single image frame.","In such a frame, there can be tens of kilobytes of information added without becoming visible to the human eye using certain watermarking algorithms.","In some instances certain types of images might affect the quality of the encoding.","For example, an image that is saved to a JPEG format or compressed might lose some detail from the encoding that might make the watermark data unusable.","In some embodiments there might be different levels of encoding, some of which being more likely to survive such a change.","For example, a limited amount of high priority information might be encoded using a level or type of encoding that is more likely to survive a change, while lower priority information might be encoded using an approach that may be higher frequency and allow for a greater amount of information, but might be more likely to disappear in the event that the image is modified in some way.","FIG.","6 illustrates an example electronic user device 600 that can be used in accordance with various embodiments.","Although a portable computing device (e.g., an electronic book reader or tablet computer) is shown, it should be understood that any electronic device capable of receiving, determining, and/or processing input can be used in accordance with various embodiments discussed herein, where the devices can include, for example, desktop computers, notebook computers, personal data assistants, smart phones, video gaming consoles, television set top boxes, and portable media players.","In this example, the computing device 600 has a display screen 602 on the front side, which under normal operation will display information to a user facing the display screen (e.g., on the same side of the computing device as the display screen).","The computing device in this example includes at least one camera 604 or other imaging element for capturing still or video image information over at least a field of view of the at least one camera.","In some embodiments, the computing device might only contain one imaging element, and in other embodiments the computing device might contain several imaging elements.","Each image capture element may be, for example, a camera, a charge-coupled device (CCD), a motion detection sensor, or an infrared sensor, among many other possibilities.","If there are multiple image capture elements on the computing device, the image capture elements may be of different types.","In some embodiments, at least one imaging element can include at least one wide-angle optical element, such as a fish eye lens, that enables the camera to capture images over a wide range of angles, such as 180 degrees or more.","Further, each image capture element can comprise a digital still camera, configured to capture subsequent frames in rapid succession, or a video camera able to capture streaming video.","The example computing device 600 also includes at least one microphone 606 or other audio capture device capable of capturing audio data, such as words or commands spoken by a user of the device.","In this example, a microphone 606 is placed on the same side of the device as the display screen 602, such that the microphone will typically be better able to capture words spoken by a user of the device.","In at least some embodiments, a microphone can be a directional microphone that captures sound information from substantially directly in front of the microphone, and picks up only a limited amount of sound from other directions.","It should be understood that a microphone might be located on any appropriate surface of any region, face, or edge of the device in different embodiments, and that multiple microphones can be used for audio recording and filtering purposes, etc.","The example computing device 600 also includes at least one orientation sensor 608, such as a position and/or movement-determining element.","Such a sensor can include, for example, an accelerometer or gyroscope operable to detect an orientation and/or change in orientation of the computing device, as well as small movements of the device.","An orientation sensor also can include an electronic or digital compass, which can indicate a direction (e.g., north or south) in which the device is determined to be pointing (e.g., with respect to a primary axis or other such aspect).","An orientation sensor also can include or comprise a global positioning system (GPS) or similar positioning element operable to determine relative coordinates for a position of the computing device, as well as information about relatively large movements of the device.","Various embodiments can include one or more such elements in any appropriate combination.","As should be understood, the algorithms or mechanisms used for determining relative position, orientation, and/or movement can depend at least in part upon the selection of elements available to the device.","FIG.","7 illustrates a logical arrangement of a set of general components of an example computing device 700 such as the device 600 described with respect to FIG.","6.In this example, the device includes a processor 702 for executing instructions that can be stored in a memory device or element 704.As would be apparent to one of ordinary skill in the art, the device can include many types of memory, data storage, or non-transitory computer-readable storage media, such as a first data storage for program instructions for execution by the processor 702, a separate storage for images or data, a removable memory for sharing information with other devices, etc.","The device typically will include some type of display element 706, such as a touch screen or liquid crystal display (LCD), although devices such as portable media players might convey information via other means, such as through audio speakers.","As discussed, the device in many embodiments will include at least one image capture element 708 such as a camera or infrared sensor that is able to image projected images or other objects in the vicinity of the device.","Methods for capturing images or video using a camera element with a computing device are well known in the art and will not be discussed herein in detail.","It should be understood that image capture can be performed using a single image, multiple images, periodic imaging, continuous image capturing, image streaming, etc.","Further, a device can include the ability to start and/or stop image capture, such as when receiving a command from a user, application, or other device.","The example device similarly includes at least one audio capture component, such as a mono or stereo microphone or microphone array, operable to capture audio information from at least one primary direction.","A microphone can be a uni-or omni-directional microphone as known for such devices.","In some embodiments, the computing device 700 of FIG.","7 can include one or more communication elements (not shown), such as a Wi-Fi, Bluetooth, RF, wired, or wireless communication system.","The device in many embodiments can communicate with a network, such as the Internet, and may be able to communicate with other such devices.","In some embodiments the device can include at least one additional input component 712 able to receive conventional input from a user.","This conventional input can include, for example, a push button, touch pad, touch screen, wheel, joystick, keyboard, mouse, keypad, or any other such device or element whereby a user can input a command to the device.","In some embodiments, however, such a device might not include any buttons at all, and might be controlled only through a combination of visual and audio commands, such that a user can control the device without having to be in contact with the device.","The device 700 also can include at least one orientation or motion sensor or component 710.As discussed, such a sensor can include an accelerometer or gyroscope operable to detect an orientation and/or change in orientation, or an electronic or digital compass, which can indicate a direction in which the device is determined to be facing.","The mechanism(s) also (or alternatively) can include or comprise a global positioning system (GPS) or similar positioning element operable to determine relative coordinates for a position of the computing device, as well as information about relatively large movements of the device.","The device can include other elements as well, such as may enable location determinations through triangulation or another such approach.","These mechanisms can communicate with the processor 702, whereby the device can perform any of a number of actions described or suggested herein.","As an example, a computing device such as that described with respect to FIG.","6 can capture and/or track various information for a user over time.","This information can include any appropriate information, such as location, actions (e.g., sending a message or creating a document), user behavior (e.g., how often a user performs a task, the amount of time a user spends on a task, the ways in which a user navigates through an interface, etc.","), user preferences (e.g., how a user likes to receive information), open applications, submitted requests, received calls, and the like.","As discussed above, the information can be stored in such a way that the information is linked or otherwise associated whereby a user can access the information using any appropriate dimension or group of dimensions.","As discussed, different approaches can be implemented in various environments in accordance with the described embodiments.","For example, FIG.","8 illustrates an example of an environment 800 for implementing aspects in accordance with various embodiments.","As will be appreciated, although a Web-based environment is used for purposes of explanation, different environments may be used, as appropriate, to implement various embodiments.","The system includes an electronic client device 802, which can include any appropriate device operable to send and receive requests, messages or information over an appropriate network 804 and convey information back to a user of the device.","Examples of such client devices include personal computers, cell phones, handheld messaging devices, laptop computers, set-top boxes, personal data assistants, electronic book readers and the like.","The network can include any appropriate network, including an intranet, the Internet, a cellular network, a local area network or any other such network or combination thereof.","Components used for such a system can depend at least in part upon the type of network and/or environment selected.","Protocols and components for communicating via such a network are well known and will not be discussed herein in detail.","Communication over the network can be enabled via wired or wireless connections and combinations thereof.","In this example, the network includes the Internet, as the environment includes a Web server 806 for receiving requests and serving content in response thereto, although for other networks an alternative device serving a similar purpose could be used, as would be apparent to one of ordinary skill in the art.","The illustrative environment includes at least one application server 808 and a data store 810.It should be understood that there can be several application servers, layers or other elements, processes or components, which may be chained or otherwise configured, which can interact to perform tasks such as obtaining data from an appropriate data store.","As used herein the term “data store” refers to any device or combination of devices capable of storing, accessing and retrieving data, which may include any combination and number of data servers, databases, data storage devices and data storage media, in any standard, distributed or clustered environment.","The application server can include any appropriate hardware and software for integrating with the data store as needed to execute aspects of one or more applications for the client device and handling a majority of the data access and business logic for an application.","The application server provides access control services in cooperation with the data store and is able to generate content such as text, graphics, audio and/or video to be transferred to the user, which may be served to the user by the Web server in the form of HTML, XML or another appropriate structured language in this example.","The handling of all requests and responses, as well as the delivery of content between the client device 802 and the application server 808, can be handled by the Web server 806.It should be understood that the Web and application servers are not required and are merely example components, as structured code discussed herein can be executed on any appropriate device or host machine as discussed elsewhere herein.","The data store 810 can include several separate data tables, databases or other data storage mechanisms and media for storing data relating to a particular aspect.","For example, the data store illustrated includes mechanisms for storing production data 812 and user information 816, which can be used to serve content for the production side.","The data store also is shown to include a mechanism for storing log or session data 814.It should be understood that there can be many other aspects that may need to be stored in the data store, such as page image information and access rights information, which can be stored in any of the above listed mechanisms as appropriate or in additional mechanisms in the data store 810.The data store 810 is operable, through logic associated therewith, to receive instructions from the application server 808 and obtain, update or otherwise process data in response thereto.","In one example, a user might submit a search request for a certain type of element.","In this case, the data store might access the user information to verify the identity of the user and can access the catalog detail information to obtain information about elements of that type.","The information can then be returned to the user, such as in a results listing on a Web page that the user is able to view via a browser on the user device 802.Information for a particular element of interest can be viewed in a dedicated page or window of the browser.","Each server typically will include an operating system that provides executable program instructions for the general administration and operation of that server and typically will include computer-readable medium storing instructions that, when executed by a processor of the server, allow the server to perform its intended functions.","Suitable implementations for the operating system and general functionality of the servers are known or commercially available and are readily implemented by persons having ordinary skill in the art, particularly in light of the disclosure herein.","The environment in one embodiment is a distributed computing environment utilizing several computer systems and components that are interconnected via communication links, using one or more computer networks or direct connections.","However, it will be appreciated by those of ordinary skill in the art that such a system could operate equally well in a system having fewer or a greater number of components than are illustrated in FIG.","8.Thus, the depiction of the system 800 in FIG.","8 should be taken as being illustrative in nature and not limiting to the scope of the disclosure.","As discussed above, the various embodiments can be implemented in a wide variety of operating environments, which in some cases can include one or more user computers, computing devices, or processing devices which can be used to operate any of a number of applications.","User or client devices can include any of a number of general purpose personal computers, such as desktop or laptop computers running a standard operating system, as well as cellular, wireless, and handheld devices running mobile software and capable of supporting a number of networking and messaging protocols.","Such a system also can include a number of workstations running any of a variety of commercially-available operating systems and other known applications for purposes such as development and database management.","These devices also can include other electronic devices, such as dummy terminals, thin-clients, gaming systems, and other devices capable of communicating via a network.","Various aspects also can be implemented as part of at least one service or Web service, such as may be part of a service-oriented architecture.","Services such as Web services can communicate using any appropriate type of messaging, such as by using messages in extensible markup language (XML) format and exchanged using an appropriate protocol such as SOAP (derived from the “Simple Object Access Protocol”).","Processes provided or executed by such services can be written in any appropriate language, such as the Web Services Description Language (WSDL).","Using a language such as WSDL allows for functionality such as the automated generation of client-side code in various SOAP frameworks.","Most embodiments utilize at least one network that would be familiar to those skilled in the art for supporting communications using any of a variety of commercially-available protocols, such as TCP/IP, FTP, UPnP, NFS, and CIFS.","The network can be, for example, a local area network, a wide-area network, a virtual private network, the Internet, an intranet, an extranet, a public switched telephone network, an infrared network, a wireless network, and any combination thereof.","In embodiments utilizing a Web server, the Web server can run any of a variety of server or mid-tier applications, including HTTP servers, FTP servers, CGI servers, data servers, Java servers, and business application servers.","The server(s) also may be capable of executing programs or scripts in response requests from user devices, such as by executing one or more Web applications that may be implemented as one or more scripts or programs written in any programming language, such as Java®, C, C# or C++, or any scripting language, such as Perl, Python, or TCL, as well as combinations thereof.","The server(s) may also include database servers, including without limitation those commercially available from Oracle®, Microsoft®, Sybase®, and IBM®.","The environment can include a variety of data stores and other memory and storage media as discussed above.","These can reside in a variety of locations, such as on a storage medium local to (and/or resident in) one or more of the computers or remote from any or all of the computers across the network.","In a particular set of embodiments, the information may reside in a storage-area network (“SAN”) familiar to those skilled in the art Similarly, any necessary files for performing the functions attributed to the computers, servers, or other network devices may be stored locally and/or remotely, as appropriate.","Where a system includes computerized devices, each such device can include hardware elements that may be electrically coupled via a bus, the elements including, for example, at least one central processing unit (CPU), at least one input device (e.g., a mouse, keyboard, controller, touch screen, or keypad), and at least one output device (e.g., a display device, printer, or speaker).","Such a system may also include one or more storage devices, such as disk drives, optical storage devices, and solid-state storage devices such as random access memory (“RAM”) or read-only memory (“ROM”), as well as removable media devices, memory cards, flash cards, etc.","Such devices also can include a computer-readable storage media reader, a communications device (e.g., a modem, a network card (wireless or wired), an infrared communication device, etc.","), and working memory as described above.","The computer-readable storage media reader can be connected with, or configured to receive, a computer-readable storage medium, representing remote, local, fixed, and/or removable storage devices as well as storage media for temporarily and/or more permanently containing, storing, transmitting, and retrieving computer-readable information.","The system and various devices also typically will include a number of software applications, modules, services, or other elements located within at least one working memory device, including an operating system and application programs, such as a client application or Web browser.","It should be appreciated that alternate embodiments may have numerous variations from that described above.","For example, customized hardware might also be used and/or particular elements might be implemented in hardware, software (including portable software, such as applets), or both.","Further, connection to other computing devices such as network input/output devices may be employed.","Storage media and computer-readable media for containing code, or portions of code, can include any appropriate media known or used in the art, including non-transitory computer-readable storage media, such as but not limited to volatile and non-volatile, removable and non-removable media implemented in any method or technology for storage of information such as computer readable instructions, data structures, program modules, or other data, including RAM, ROM, EEPROM, flash memory or other memory technology, CD-ROM, digital versatile disk (DVD) or other optical storage, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices, or any other medium which can be used to store the desired information and which can be accessed by the a system device.","Based on the disclosure and teachings provided herein, a person of ordinary skill in the art will appreciate other ways and/or methods to implement the various embodiments.","The specification and drawings are, accordingly, to be regarded in an illustrative rather than a restrictive sense.","It will, however, be evident that various modifications and changes may be made thereunto without departing from the broader spirit and scope of the invention as set forth in the claims."]],"string":"[\n [\n \"EMBEDDING DEBUGGING INFORMATION VIA WATERMARKS\",\n \"Debugging information for content rendered for display on a client device can be included in one or more watermarks inserted into the content.\",\n \"Performance, state, configuration, debugging, and other information can be encoded into a watermark and placed in rendered content in such a way that the information is imperceptible to most users.\",\n \"When a user reports a potential issue or problem, the user (or another source) can provide a version of the image frame corresponding to the issue, which enables the watermark to be located and the data extracted.\",\n \"A checksum or other value can be used to ensure that a complete and valid watermark was obtained.\",\n \"The data extracted from the watermark can then be used to attempt to identify and/or diagnose the potential issue without having to have access to the client device or communication with the user.\"\n ],\n [\n \"1.\",\n \"(canceled) 2.A computer-implemented method, comprising: analyzing a first image frame representing rendered content on a client device; identifying first watermark data represented in the first image frame, the first watermark data corresponding to at least a first portion of a watermark containing debugging data; analyzing a second image frame representing the rendered content; identifying second watermark data represented in the second image frame, the second watermark data corresponding to at least a portion of the watermark containing debugging data; and utilizing the debugging data from the watermark to attempt to determine a cause of an issue with the rendered content.\",\n \"3.The computer-implemented method of claim 2, further comprising: causing the debugging data to be encoded at pixel locations proximate edges of objects represented in the rendered content.\",\n \"4.The computer-implemented method of claim 2, further comprising: determining at least one parameter from the watermark corresponding to a checksum, a hash, or a length identifier; and verifying the watermark data using the at least one parameter.\",\n \"5.The computer-implemented method of claim 2, further comprising: storing additional debugging data to a log data store; correlating the additional data to identifier information from the watermark; and accessing the log data store to obtain the additional debugging data.\",\n \"6.The computer-implemented method of claim 2, further comprising: embedding the debugging data into a second watermark; and positioning the second watermark in a different location than the watermark.\",\n \"7.The computer-implemented method of claim 2, further comprising: determining a quality associated with an image file comprising the first and second image frames; determining the quality is below a threshold amount, the threshold indicating where data is lost; and encoding at least a portion of the debugging data at a different encoding level to prevent data loss.\",\n \"8.A computer-implemented method, comprising: obtaining content for rendering on a client device; determining debugging data relevant to the content; determining verification data relevant to the content or client device; generating watermark data including at least the debugging data and the verification data; and encoding the watermark data into the content.\",\n \"9.The computer-implemented method of claim 8, further comprising: providing the content for the presentation via the client device.\",\n \"10.The computer-implemented method of claim 8, further comprising: determining at least one parameter from the watermark data corresponding to a checksum, a hash, or a length identifier; and verifying the watermark data using the at least one parameter.\",\n \"11.The computer-implemented method of claim 8, wherein the debugging data includes at least one of state information, frame information, timestamp information, content selection information, content layout information, user information, application information, rendering time data, processing data, sample data, failure occurrence record data, or breakpoint information.\",\n \"12.The computer-implemented method of claim 8, wherein encoding the watermark data comprises using at least one of a quantization type watermarking algorithm, a spread-spectrum watermarking algorithm, or an amplitude modulation watermarking algorithm.\",\n \"13.The computer-implemented method of claim 8, further comprising: encoding a first portion of the watermark data into the content using a first watermarking algorithm and a second portion of the watermark data into the content using a second watermarking algorithm.\",\n \"14.The computer-implemented method of claim 8, further comprising: receiving a notification indicating a potential issue with a presentation of the content via the client device; extracting the watermark data from the content; and utilizing the debugging data, contained within the watermark data, to attempt to determine a cause of the potential issue.\",\n \"15.The computer-implemented method of claim 8, wherein the content is rendered content comprising an image frame, the computer-implemented method further comprising: receiving the image frame captured from the client device, the image frame being captured as displayed on the client device; identifying the watermark data from the image frame; and verifying the content of the watermark data.\",\n \"16.The computer-implemented method of claim 8, further comprising: receiving a first image frame from the user device, the first image frame representative of content rendered on the client device; locating watermark data within the first image frame; determining the watermark data is incomplete; evaluating a second image frame from the user device, the second image frame representative of content rendered on the client device; and extracting the watermark data from a different location within the second image frame.\",\n \"17.A system, comprising: at least one processor; and memory including instructions that, when executed by the at least one processor, cause the system to: obtain content for rendering on a client device; determine debugging data relevant to the content; determine verification data relevant to the content or client device; generate watermark data including at least the debugging data and the verification data; and encode the watermark data into the content.\",\n \"18.The system of claim 17, wherein the instructions when executed further cause the system to: encode a first portion of the watermark data into the content using a first watermarking algorithm and a second portion of the watermark data into the content using a second watermarking algorithm.\",\n \"19.The system of claim 17, wherein the instructions when executed further cause the system to: determine at least one parameter from the watermark data corresponding to a checksum, a hash, or a length identifier; and verify the watermark data using the at least one parameter.\",\n \"20.The system of claim 17, wherein the instructions when executed further cause the system to: receiving a notification indicating a potential issue with a presentation of the content via the client device; extracting the watermark data from the content; and utilizing the debugging data, contained within the watermark data, to attempt to determine a cause of the potential issue.\",\n \"21.The system of claim 17, wherein the instructions when executed further cause the system to: store additional debugging data in a log data store; correlate the additional data to the verification data from the watermark; and access the log data store to obtain the additional debugging data.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>Users are increasingly utilizing electronic devices to perform various tasks.\",\n \"These tasks can be performed in various ways, such as by using Web content displayed through a Web browser or content accessed using an application (or “app”) executing on a client device.\",\n \"Users using a variety of different applications accessing a variety of different content will occasionally experience issues with the intended functionality.\",\n \"A user can report these issues, but a developer will want to determine contextual information in an attempt to determine a potential cause of the reported issue.\",\n \"In some instances, this also involves attempting to recreate the issue.\",\n \"In order to perform these tasks, a developer needs to obtain the contextual information from the user or another source.\",\n \"Users may be unwilling to provide contextual information, or may not know how to provide the appropriate information.\",\n \"Further, various engines and protocols do not provide for the capturing of robust debugging information, particularly from client or third party devices.\"\n ],\n [\n \"<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>Various embodiments in accordance with the present disclosure will be described with reference to the drawings, in which: FIGS.\",\n \"1A, 1B, 1C, 1D, and 1E illustrate example approaches to embedding information in an image through watermarking that can be utilized in accordance with various embodiments.\",\n \"FIG.\",\n \"2 illustrates an example environment for embedding debugging data in image content that can be utilized in accordance with various embodiments.\",\n \"FIG.\",\n \"3 illustrates an example process for embedding debugging data in image content that can be utilized in accordance with various embodiments.\",\n \"FIG.\",\n \"4 illustrates an example process for extracting debugging data from image content that can be utilized in accordance with various embodiments.\",\n \"FIG.\",\n \"5 illustrates an example display of content wherein a portion of a watermark may be occluded by content rendered from an embedded engine that can be processed in accordance with various embodiments.\",\n \"FIG.\",\n \"6 illustrates an example device that can be used to implement aspects of the various embodiments.\",\n \"FIG.\",\n \"7 illustrates example components of a client device such as that illustrated in FIG.\",\n \"6 .\",\n \"FIG.\",\n \"8 illustrates an environment in which various embodiments can be implemented.\",\n \"detailed-description description=\\\"Detailed Description\\\" end=\\\"lead\\\"?\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATIONS This is a continuation application of U.S. patent application Ser.\",\n \"No.\",\n \"14/970,131, filed on Dec. 15, 2015, entitled “EMBEDDING DEBUGGING INFORMATION VIA WATERMARKS,” which is hereby incorporated by reference in its entirety.\",\n \"BACKGROUND Users are increasingly utilizing electronic devices to perform various tasks.\",\n \"These tasks can be performed in various ways, such as by using Web content displayed through a Web browser or content accessed using an application (or “app”) executing on a client device.\",\n \"Users using a variety of different applications accessing a variety of different content will occasionally experience issues with the intended functionality.\",\n \"A user can report these issues, but a developer will want to determine contextual information in an attempt to determine a potential cause of the reported issue.\",\n \"In some instances, this also involves attempting to recreate the issue.\",\n \"In order to perform these tasks, a developer needs to obtain the contextual information from the user or another source.\",\n \"Users may be unwilling to provide contextual information, or may not know how to provide the appropriate information.\",\n \"Further, various engines and protocols do not provide for the capturing of robust debugging information, particularly from client or third party devices.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS Various embodiments in accordance with the present disclosure will be described with reference to the drawings, in which: FIGS.\",\n \"1A, 1B, 1C, 1D, and 1E illustrate example approaches to embedding information in an image through watermarking that can be utilized in accordance with various embodiments.\",\n \"FIG.\",\n \"2 illustrates an example environment for embedding debugging data in image content that can be utilized in accordance with various embodiments.\",\n \"FIG.\",\n \"3 illustrates an example process for embedding debugging data in image content that can be utilized in accordance with various embodiments.\",\n \"FIG.\",\n \"4 illustrates an example process for extracting debugging data from image content that can be utilized in accordance with various embodiments.\",\n \"FIG.\",\n \"5 illustrates an example display of content wherein a portion of a watermark may be occluded by content rendered from an embedded engine that can be processed in accordance with various embodiments.\",\n \"FIG.\",\n \"6 illustrates an example device that can be used to implement aspects of the various embodiments.\",\n \"FIG.\",\n \"7 illustrates example components of a client device such as that illustrated in FIG.\",\n \"6.FIG.\",\n \"8 illustrates an environment in which various embodiments can be implemented.\",\n \"DETAILED DESCRIPTION Systems and methods in accordance with various embodiments of the present disclosure overcome one or more of the above-referenced and other deficiencies in conventional approaches to obtaining operational information in an electronic device.\",\n \"In particular, various embodiments provide for the obtaining of debugging information through the inclusion of watermarks in rendered content.\",\n \"Performance, state, configuration, debugging, and other information can be encoded into a watermark and placed in rendered content in such a way that the information is imperceptible to most users.\",\n \"When a user reports a potential issue or problem, the user (or another source) can provide an image frame corresponding to the issue, which enables the watermark to be located and the data extracted.\",\n \"A checksum or other value can be used to ensure that a complete and valid watermark was obtained.\",\n \"The data extracted from the watermark can then be used to attempt to identify and/or diagnose the potential issue.\",\n \"Various other functions and advantages are described and suggested below as may be provided in accordance with the various embodiments.\",\n \"FIG.\",\n \"1 illustrates an example situation 100 in which a page of content 104 is displayed on a computing device 102.Although a portable computing device is illustrated, it should be understood that any appropriate device can be used to present content in accordance with the various embodiments, as may include notebook computers, personal data assistants, e-book readers, cellular phones, video gaming consoles or controllers, smart televisions, set top boxes, a wearable computer (e.g., a smart watch or glasses), and portable media players, among others.\",\n \"In this example, the content displayed includes image and text content, as may be rendered on the computing device 102 or by a remote rendering engine, among other such options.\",\n \"The content can be Web content displayed through a browser application, content rendered by an application from a content provider or third party application provider, among other types of content.\",\n \"In this example, the displayed content relates to furniture placed in a virtual room that enables a user to view collections of furniture in realistic environments.\",\n \"There might be any of a number of issues with such a display or presentation of content, however.\",\n \"In this example, the size of a lamp 112 displayed in the image is too large relative to the other content displayed.\",\n \"Accordingly, a customer experiencing the issue might generate a notification to be sent to a provider of the content and/or application in order to report the alleged problem.\",\n \"An entity receiving the notification may then want to be able to determine sufficient information to identify the type of problem or issue that was alleged to have been experienced on the device.\",\n \"The entity might also attempt to determine contextual information in order for the entity to be able to recreate the situation and/or problem.\",\n \"This can include information such as the content being displayed, the display settings, information about the device used to display the content, a time at which the content was displayed, a frame number if the problem occurred with a specific frame or set of frames, or other such information that may be known to one of ordinary skill in the art for debugging applications or content that would be apparent in light of the teachings and suggestions contained herein.\",\n \"Problems can arise, however, when the entity attempting to diagnose the problem is unable to obtain the appropriate information.\",\n \"For example, a rendering engine might have only limited capability with respect to the generating and/or outputting of metadata, state, or debugging data, among other such types of information.\",\n \"If a rendering engine is not able to fully utilize a component such as an embedded view component or sandboxed renderer process, for example, retrieving debugging data might require implementing an additional interface or performing security exceptions, which might not be available or may not be implemented as needed, such as where a software author using cloud-based rendering chooses not to implement any auxiliary interfaces.\",\n \"The choice to not implement such interfaces may be a valid choice due to the burden of implementing the interfaces as well as introducing security or other such issues.\",\n \"In some embodiments a debugging process might not be allowed to send debugging data during normal rendering due bandwidth or security constraints, among other such issues.\",\n \"It thus can be difficult for a developer to obtain debugging information such as program state information (i.e., the state of variables and calls made), timestamp information, subroutines executed, types or constants defined, frame information, processing data, sample data, failure occurrence record data, breakpoints met, and the like.\",\n \"The types and amount of information can further depend upon the complexity of the content or application, the type of issue experienced, and other such factors.\",\n \"Accordingly, approaches in accordance with various embodiments attempt to provide for the availability of debugging information by embedding the debugging information in the content (e.g., image, video, or audio content) presented using a computing device.\",\n \"In particular, the debugging information can be inserted into an image frame as a watermark that is barely perceptible to the average user.\",\n \"In this way, the debugging information can be available regardless of the type of application or device used to display the content, and can avoid various bandwidth, security, and other such concerns mentioned elsewhere herein.\",\n \"A user experiencing a problem can provide a copy of the image with the notification, such as by capturing a screenshot or selecting an option that automatically captures and sends a copy of the image to a remote debugging service or other such location.\",\n \"In other embodiments, a debugging tool can analyze the image on the client device in order to extract the debugging information and then provide the debugging information to the debugging service.\",\n \"Various other approaches can be used as well as discussed and suggested elsewhere herein.\",\n \"Various types of watermarks can be utilized in accordance with various embodiments.\",\n \"A digital watermark can be embedded in noise-tolerant content, such as an image, audio, or video content.\",\n \"Digital watermarks can be perceptible under certain conditions, such as under examination by a watermark extraction algorithm, but imperceptible under other conditions, such as upon viewing by a human user.\",\n \"A watermark can be added to an image in some embodiments by adjusting the values of certain pixels of the image by amounts determined by a particular encoding engine.\",\n \"The amount of adjusting should be such that the visible changes to the pixels are minimal, in order to reduce the impact and detectability by a user.\",\n \"Further, the encoding can be performed using pixel locations that are likely to be less perceptible to a user.\",\n \"In some embodiments, an encoding bit rate can be varied based on the underlying content and a rate of content change.\",\n \"For example, when scrolling down quickly, a higher bit rate can be used to encode more information into each frame, as human eyes are unable to focus and differentiate the “artificial noise” from faster moving/changing content.\",\n \"The visual complexity for choosing the amount of data to encode can be approximated by monitoring how much CPU time content rasterization requires and/or monitoring the kind of drawing instructions that were executed to generate a piece of content, such as a tile.\",\n \"Bitrate change can be gradual or “modulated” near tile boundaries, to avoid regular-shaped changes in noise patterns, which could be more easily seen by humans.\",\n \"As an example, FIG.\",\n \"1B illustrates a subset of pixels corresponding to a region 108 of the image in FIG.\",\n \"1A that is substantially represented by a single color value or pixel value.\",\n \"If the encoding were to be placed using pixels in such a region, as illustrated in the encoded region 120 of FIG.\",\n \"1C, the changes would be relatively noticeable to a user viewing the image content.\",\n \"A lower bit rate can be used to encode information in these areas, but it might be desirable in at least some embodiments to use portions of the image, where available, that allow for the use of higher bit rates.\",\n \"If the encoding were instead placed at locations such as the edges of letters or objects, which typically demonstrate some amount of blurring or antialiasing, the encoding may be less perceptible.\",\n \"For example, FIG.\",\n \"1D illustrates an example region 110 from the image of FIG.\",\n \"1A that includes a portion of a letter represented in the image.\",\n \"As illustrated, there are pixels of varying color around the edges of the letter.\",\n \"If the encoding is positioned in such locations, such as near the edges of the letter where some amount of color gradation is expected by the user, the user may not be able to perceive the difference.\",\n \"For example, FIG.\",\n \"1E illustrates one such encoded region 140 where the encoding affects pixels near the edges of the letter.\",\n \"While a side by side comparison would enable a user to discern the differences, a user just viewing FIG.\",\n \"1E by itself would generally not perceive that any encoding had taken place.\",\n \"While the encoding of the example of FIG.\",\n \"1C might be perceptible to a user due in part to its placement, the placement in FIG.\",\n \"1E can help to hide the encoding from a user.\",\n \"This is not necessarily to attempt to hide the presence of the debugging information from the user, but can instead enable the information to be provided without negatively impacting the user experience.\",\n \"For example, using the approach discussed with respect to FIG.\",\n \"1E a user might not perceive any degradation or change in image quality through the inclusion of such information.\",\n \"As mentioned, there can be various watermarking algorithms used to determine the encoding and placement of the debugging data in rendered image content.\",\n \"These can include, for example, quantization type watermarking algorithms, spread-spectrum watermarking algorithms, or amplitude modulation watermarking algorithms, among others.\",\n \"A watermarking process might utilize one or more different algorithms at different times, such as may depend at least in part upon a type of content, a type or amount of information to be embedded, a security level of the information, and the like.\",\n \"It at least some embodiments the watermark encoded into an image can include a checksum, or multiple checksums, as it can be difficult in at least some embodiments to determine the presence of a valid watermark, as well as to ensure that the entire watermark has been located.\",\n \"This is particularly true when the placement depends upon the location of objects represented in the content, and an image with a different portion, contrast, intensity, aspect ratio, resolution, or other such factor may result in an algorithm selecting different locations to place the encoding.\",\n \"For multiple checksums, one might be included for each record/chunk as opposed to the entire watermark, where one or more of the records with checksums can be used to verify all the data was decoded.\",\n \"Thus, if content is rendered with encoded information at determined locations using an algorithm, a screen shot from a user that includes additional or less information might result in that algorithm picking different places to look in the image.\",\n \"Thus, a checksum, hash, watermark length identifier, or other such data included in the watermark can be useful in ensuring that a valid and complete watermark has been identified.\",\n \"The data extracted can then be used to attempt to debug the problem, using any of a number of different debugging approaches as might be used for similar data obtained from conventional sources.\",\n \"FIG.\",\n \"2 illustrates an example environment 200 in which aspects of the various embodiments can be implemented.\",\n \"In this example, content is to be rendered on a client device 202.The content can originate from a content provider network 208, for example, as may be received over a least one network 206, such as the Internet, an intranet, a local area network, a cellular network, or another appropriate wired and/or wireless network.\",\n \"The content can be rendered using a rendering engine 204 on the client device and/or a rendering engine 214 in the resource provider environment 208, among other such options.\",\n \"In this example, at least some of the content can be pulled from a content repository 216 and rendered by a rendering engine 214 before being provided to the client device 202 by at least one content server 212.A request for the content can be received to a network interface layer 210, which can include one or more interfaces such as application programming interfaces (APIs) for receiving requests, as well as various other network components such as routers, load balancers, and the like.\",\n \"In at least some embodiments the content server 212 or another appropriate component can cause data to be written to at least one log 218, as may include information regarding the content served.\",\n \"The content can be delivered across the at least one network 206 to the client device 202.As mentioned, at least some rendering can be performed by a rendering engine 204 on the client device.\",\n \"For example, a rendering engine for a Web browser might take markup language content such as HTML and formatting information to render Web content to be displayed on the client device 202 that can be formatted to fit the display and the current zoom level, etc.\",\n \"Various other components such as layout or placement engines can be used as well within the scope of the various embodiments.\",\n \"These engines can render data once the data is received, or may begin rendering as the data is received, among other such options.\",\n \"Further, a rendering engine might render only that portion of the content that will be visible, or may render some additional amount that can reduce the likelihood of chunking or delayed rendering in response to a navigation or zoom action, among other such possibilities.\",\n \"As mentioned the client device can display the content, and if a user (or application or other source) detects a potential issue or problem with the content, software, or device, the user can cause the image information to be provided to the content provider network 208.As mentioned, this can be accomplished by a user capturing a screenshot of the content, taking a picture using a digital camera, or selecting an option in an executing application or console that causes image data to be captured, among other such options.\",\n \"In some embodiments the image can be processed on the client device 202, while in other embodiments the image can be provided to the content provider network 208, wherein the image can be directed to a debugging engine 220 or other such system or service.\",\n \"The debugging engine can have access (directly or indirectly) to a watermarking algorithm that can be used to analyze the image to attempt to locate and extract the watermark from the image.\",\n \"The content of the watermark can be analyzed to verify the accuracy, validity, and completeness of the watermark, such as by analyzing a checksum, hash, or length identifier of the watermark data and ensuring that the content of the watermark is as expected.\",\n \"If not, the image data can be re-analyzed using a different algorithm or different values for the same algorithm to attempt to determine the appropriate watermark.\",\n \"In some instances there might be multiple watermarks, with one being embedded in the original content or otherwise provided, which might prevent a single watermark from being accurately detected.\",\n \"In the event that a watermark cannot be properly identified, conventional approaches to locating debugging information can be used, among other such options.\",\n \"It should be mentioned that, as discussed elsewhere herein, a debugging engine 224 can also be included on the client device 202 in order to embed watermark data to content rendered and/or displayed on the client.\",\n \"In some embodiments a debugging engine 226 might be offered as a third party service and/or service outside the resource provider environment, whereby content from a provider can have debugging information added if the debugging service has access to the appropriate data to be included in the watermark.\",\n \"If the watermark can be verified, the data included in the watermark can be analyzed and used to attempt to determine the source of the reported issue.\",\n \"As mentioned, this can include attempting to recreate the situation using the information provided.\",\n \"The watermark data, as discussed elsewhere herein, can include various types of data useful for debugging, as may include timestamp data, state data, frame data, configuration data, identifiers for external logs (additional logged information), serialized data structures that cause or are related to a failure, and the like.\",\n \"This information can be compared, using a debugging engine 220 or other such component or service, to information stored in a log data store 218 or other such location, which might contain additional information for the image frame.\",\n \"The amount of data that can be included in a watermark is limited, at least in keeping the perceptibility of the watermark low, such that additional information for the rendering might also be stored to a log data store.\",\n \"By using identifier information (frame, timestamp, client, etc.)\",\n \"from the watermark, the information from the watermark can be correlated with information in the log for purposes of obtaining additional information for debugging.\",\n \"Similarly, the debugging engine can use the debugging information from the watermark to check for similar data in a debugging data store 222, or other such location, do determine whether similar issues previously arose for similar circumstances, which can help point to a solution if one was previously determined.\",\n \"Once the appropriate information is obtained, any appropriate debugging process can be used to attempt to identify and rectify any potential issues, as would be apparent to one of ordinary skill in the art in light of the teachings and suggestions contained herein.\",\n \"A rendering engine in some embodiments can employ an error-correction (ECC, parity bits), compression (such as Lempel-Ziv-Markov chain, arithmetic coding) and/or encryption scheme before watermarking, which can be separate from any such schemes in the watermarking algorithm itself.\",\n \"This can enable the use of multiple different available watermarking libraries and/or algorithms, and can help to secure any private user data or prevent malicious third parties from feeding incorrect information.\",\n \"An example rendering engine can provide a callback interface to the embedding application for adding additional debugging data, and another callback interface to the embedding application for notifying when it has added its changes to the output frame (i.e., finalized it), allowing a rendering engine to use application's output surface area.\",\n \"The latter callback can contain a frame buffer texture handle (or equivalent) as a parameter.\",\n \"When multiple layers of content are composited (i.e., flattened) into a final output image, a read-back phase may be used to retrieve the final frame texture and modify it directly.\",\n \"In some embodiments, a translucent layer containing the watermark data can be composited (i.e., merged) to the output frame.\",\n \"A watermarking algorithm might add actual noise to the image (not containing any data or containing dummy records) in some embodiments in order to make the output more pleasing to the human eye, such as when there's not enough data to cover the entire image area or tile.\",\n \"The same debugging data can also be repeated multiple times, as discussed elsewhere herein, to increase the chances of the data surviving in the event that some portion of the image is lost or otherwise not provided.\",\n \"In some embodiments there may be a queue of pending records, from which records can be encoded opportunistically to fill in any remaining unused watermark capacity after higher priority data has been encoded.\",\n \"In some embodiments a rendering engine may keep collecting information (up to a limit, discarding lowest importance data) and keep a list of data records to be encoded, but only do the encoding when a screenshot function is activated, encoding as many as possible of the pending records into one frame.\",\n \"When an application using a rendering engine encounters a problem, such as violating an internal check for correctness, the rendering engine may temporarily use an algorithm with a higher bit rate and/or higher complexity than for normal output frames, in order to encode more information or increase the probability of the encoded data surviving any future quality degradation, possibly causing skipping small number of output frames.\",\n \"FIG.\",\n \"3 illustrates an example process 300 for embedding debugging data in a watermark that can be utilized in accordance with various embodiments.\",\n \"It should be understood that there can be additional, fewer, or alternative steps performed in similar or alternative orders, or in parallel, within the scope of the various embodiments unless otherwise stated.\",\n \"In this example, content to be rendered for a frame can be obtained 302 from an appropriate source, such as from a content provider network or third party provider.\",\n \"In some embodiments, the content can include webpage content (e.g., HTML) to be rendered that may include content from other providers, among other such content.\",\n \"In addition, debugging data relevant to a frame (or set of frames) of content to be rendered can be determined.\",\n \"This can include, for example, state data, frame number data, a time stamp, a client or customer identifier, and other such information.\",\n \"Watermark data that includes the debugging data and some verification data can be generated 306 that is to be inserted into the frame after, or at the time, the frame is rendered.\",\n \"As mentioned, the verification data can include a checksum, hash, or other mechanism that can be used to determine a completeness and validity of the watermark data.\",\n \"The watermark data can also be encoded such that the data can be distributed across an image in such a way that the data can be extracted but is generally imperceptible to a user viewing the image.\",\n \"The frame of content can then be rendered 308 and the watermark included.\",\n \"The watermark can be included at the time of rendering, or can be added as a separate step after the initial rendering, among other such options.\",\n \"As mentioned, portions of the watermark can be positioned near the edges of objects represented in the image that would typically demonstrate some amount of anti-aliasing, blending, blurring, or smoothing, such that a slight variation in pixel value will not be unexpected or even noticeable to a user.\",\n \"The watermark in at least some embodiments is encoded into the bitmap written into the frame buffer for the content to be displayed.\",\n \"The image can then be caused to be displayed 310, or otherwise presented, with the embedded watermark.\",\n \"If the watermark is instead in audio data, for example, then the audio with the watermark can be provided to be played through one or more speakers, among other such options.\",\n \"The capturing or saving of at least a portion of the rendered image is then enabled 312 in the event of an issue or potential problem, whereby the image can be provided to a debugging engine, service, or provider in order to enable that entity to extract the debugging information from the image, which can help to diagnose and/or re-create the identified issue.\",\n \"FIG.\",\n \"4 illustrates an example process 400 for extracting debugging data from a watermark that can be utilized in accordance with various embodiments.\",\n \"In this example, an image (or image frame) is received 402 that correspond to a reported issue with the content, the rendering of the content, an application or device rendering the content, etc.\",\n \"As mentioned, this image can be captured by a user using a screenshot function or digital camera, or can be captured by a console or application executing on the client device, among other such options.\",\n \"The image can be processed 404 with a watermark extraction algorithm that can analyze some, or all, of the image to attempt to recognize the watermark.\",\n \"Since this process will often be performed offline, the algorithm(s) can analyze the entire image using multiple passes with different parameters as needed to identify the watermark.\",\n \"If a watermark cannot be located 406, a different approach can be attempted 408, such as to adjust one or more search parameters or utilize a different extraction algorithm.\",\n \"Other data sources also can be used if a watermark cannot be located, such as those that would be used to obtain debugging data using conventional approaches.\",\n \"Once located, the content of the watermark can be verified 410 using a checksum, hash, length value, or other parameter included in the watermark.\",\n \"The data from the watermark can also be checked to ensure that the data corresponds to a valid watermark, includes appropriate debugging data, etc.\",\n \"If the watermark is determined 412 to not be valid, another approach can be used as discussed above to attempt to locate a complete watermark or use other data sources, among other such options.\",\n \"If the watermark is determined to be complete and valid, the debugging data or other appropriate information can be extracted 414 from the watermark and utilized 416 to attempt to determine contextual information for the reported issue.\",\n \"As mentioned, this can include information such as a state of the device, a state of the content, a frame sequence number, a timestamp of the reported issue, performance data for the time of the issue, intentionally placed debugging data, a rendering time for the frame, a list of assumptions, a set of state flags, and other such information.\",\n \"In some embodiments, a debugging tool can process a series of images to attempt to determine commonalities among images, analyze trends, or generate statistics, among other such features.\",\n \"For example, statistics can be generated as to the frequency of types of watermarks, the frequency of invalid or incomplete watermarks detected, the percentage of images containing a certain flag or debugging data value, etc.\",\n \"An advantage to processing several images using a debugging tool or service is that incomplete information may be able to be obtained by utilizing information obtained from other images.\",\n \"For example, the display 500 of content in FIG.\",\n \"5 illustrates the display of FIG.\",\n \"1, except that here an embedded application or other source has caused other content to be displayed as an overlay 502 that obscures or occludes a portion of the displayed image.\",\n \"In such a situation, at least a portion of the watermark embedded in the image may not be able to be determined from an image or screenshot.\",\n \"If information from other images is available, which may also be sourced from content rendered for other clients, the information might be able to be completed or at least partially recovered in order to enable at least some of the debugging information to be determined for the corresponding situation.\",\n \"Another advantage to embedding the debugging information in the image data is that a third party developer or content author can diagnose problems even if that party may not otherwise be able to obtain access to the appropriate data.\",\n \"For example, a user posting a screenshot of the issue on a social networking site can be sufficient for an entity to analyze the screenshot and determine debugging information for the issue, without having to obtain the information from the user in some other way, such as through the submission of log files or the implementation of a listener interface to collect data, among other such options.\",\n \"Such an approach also enables the party to debug the problem even if the identity of the poster is unknown or access is otherwise problematic.\",\n \"Another advantage is that performance can be diagnosed and issues debugged using the data without the third party developer or author even being aware of the inclusion of the data in some embodiments, and where such modification is permitted and authorized.\",\n \"In some embodiments, a web crawler can be used to “scrape” known discussion forums or support web sites to automatically identify any images containing watermarks, and retrieve production debugging data without end-users having to provide the images to the original software author.\",\n \"Such an approach is also useful for developers of applications, or apps, that might be purchased through an application store provided by another provider.\",\n \"The app developer thus might have no direct relationship with the customer.\",\n \"The ability to embed debugging information in a watermark, however, enables the app developer to determine the debugging information as long as the appropriate watermarked portion is somehow available to the developer.\",\n \"In some embodiments multiple instances of a watermark might be placed in an image frame, enabling the discovery of debugging data even if only a portion of the frame is visible.\",\n \"In some embodiments, such as where there are multiple frames in a sequence, the watermark data might also be displayed over several frames such that a video clip would be necessary to obtain all the appropriate watermark data.\",\n \"The watermark data can also be split over audio, video, and image encoding in some embodiments.\",\n \"The watermark can include other information as well, such as state or content of a portion of a page that is not visible but currently rendered.\",\n \"If an example screen includes around two million pixels and each pixel in this example can accept 32 bits of information, then there are around 8 megabytes of data available in a single image frame.\",\n \"In such a frame, there can be tens of kilobytes of information added without becoming visible to the human eye using certain watermarking algorithms.\",\n \"In some instances certain types of images might affect the quality of the encoding.\",\n \"For example, an image that is saved to a JPEG format or compressed might lose some detail from the encoding that might make the watermark data unusable.\",\n \"In some embodiments there might be different levels of encoding, some of which being more likely to survive such a change.\",\n \"For example, a limited amount of high priority information might be encoded using a level or type of encoding that is more likely to survive a change, while lower priority information might be encoded using an approach that may be higher frequency and allow for a greater amount of information, but might be more likely to disappear in the event that the image is modified in some way.\",\n \"FIG.\",\n \"6 illustrates an example electronic user device 600 that can be used in accordance with various embodiments.\",\n \"Although a portable computing device (e.g., an electronic book reader or tablet computer) is shown, it should be understood that any electronic device capable of receiving, determining, and/or processing input can be used in accordance with various embodiments discussed herein, where the devices can include, for example, desktop computers, notebook computers, personal data assistants, smart phones, video gaming consoles, television set top boxes, and portable media players.\",\n \"In this example, the computing device 600 has a display screen 602 on the front side, which under normal operation will display information to a user facing the display screen (e.g., on the same side of the computing device as the display screen).\",\n \"The computing device in this example includes at least one camera 604 or other imaging element for capturing still or video image information over at least a field of view of the at least one camera.\",\n \"In some embodiments, the computing device might only contain one imaging element, and in other embodiments the computing device might contain several imaging elements.\",\n \"Each image capture element may be, for example, a camera, a charge-coupled device (CCD), a motion detection sensor, or an infrared sensor, among many other possibilities.\",\n \"If there are multiple image capture elements on the computing device, the image capture elements may be of different types.\",\n \"In some embodiments, at least one imaging element can include at least one wide-angle optical element, such as a fish eye lens, that enables the camera to capture images over a wide range of angles, such as 180 degrees or more.\",\n \"Further, each image capture element can comprise a digital still camera, configured to capture subsequent frames in rapid succession, or a video camera able to capture streaming video.\",\n \"The example computing device 600 also includes at least one microphone 606 or other audio capture device capable of capturing audio data, such as words or commands spoken by a user of the device.\",\n \"In this example, a microphone 606 is placed on the same side of the device as the display screen 602, such that the microphone will typically be better able to capture words spoken by a user of the device.\",\n \"In at least some embodiments, a microphone can be a directional microphone that captures sound information from substantially directly in front of the microphone, and picks up only a limited amount of sound from other directions.\",\n \"It should be understood that a microphone might be located on any appropriate surface of any region, face, or edge of the device in different embodiments, and that multiple microphones can be used for audio recording and filtering purposes, etc.\",\n \"The example computing device 600 also includes at least one orientation sensor 608, such as a position and/or movement-determining element.\",\n \"Such a sensor can include, for example, an accelerometer or gyroscope operable to detect an orientation and/or change in orientation of the computing device, as well as small movements of the device.\",\n \"An orientation sensor also can include an electronic or digital compass, which can indicate a direction (e.g., north or south) in which the device is determined to be pointing (e.g., with respect to a primary axis or other such aspect).\",\n \"An orientation sensor also can include or comprise a global positioning system (GPS) or similar positioning element operable to determine relative coordinates for a position of the computing device, as well as information about relatively large movements of the device.\",\n \"Various embodiments can include one or more such elements in any appropriate combination.\",\n \"As should be understood, the algorithms or mechanisms used for determining relative position, orientation, and/or movement can depend at least in part upon the selection of elements available to the device.\",\n \"FIG.\",\n \"7 illustrates a logical arrangement of a set of general components of an example computing device 700 such as the device 600 described with respect to FIG.\",\n \"6.In this example, the device includes a processor 702 for executing instructions that can be stored in a memory device or element 704.As would be apparent to one of ordinary skill in the art, the device can include many types of memory, data storage, or non-transitory computer-readable storage media, such as a first data storage for program instructions for execution by the processor 702, a separate storage for images or data, a removable memory for sharing information with other devices, etc.\",\n \"The device typically will include some type of display element 706, such as a touch screen or liquid crystal display (LCD), although devices such as portable media players might convey information via other means, such as through audio speakers.\",\n \"As discussed, the device in many embodiments will include at least one image capture element 708 such as a camera or infrared sensor that is able to image projected images or other objects in the vicinity of the device.\",\n \"Methods for capturing images or video using a camera element with a computing device are well known in the art and will not be discussed herein in detail.\",\n \"It should be understood that image capture can be performed using a single image, multiple images, periodic imaging, continuous image capturing, image streaming, etc.\",\n \"Further, a device can include the ability to start and/or stop image capture, such as when receiving a command from a user, application, or other device.\",\n \"The example device similarly includes at least one audio capture component, such as a mono or stereo microphone or microphone array, operable to capture audio information from at least one primary direction.\",\n \"A microphone can be a uni-or omni-directional microphone as known for such devices.\",\n \"In some embodiments, the computing device 700 of FIG.\",\n \"7 can include one or more communication elements (not shown), such as a Wi-Fi, Bluetooth, RF, wired, or wireless communication system.\",\n \"The device in many embodiments can communicate with a network, such as the Internet, and may be able to communicate with other such devices.\",\n \"In some embodiments the device can include at least one additional input component 712 able to receive conventional input from a user.\",\n \"This conventional input can include, for example, a push button, touch pad, touch screen, wheel, joystick, keyboard, mouse, keypad, or any other such device or element whereby a user can input a command to the device.\",\n \"In some embodiments, however, such a device might not include any buttons at all, and might be controlled only through a combination of visual and audio commands, such that a user can control the device without having to be in contact with the device.\",\n \"The device 700 also can include at least one orientation or motion sensor or component 710.As discussed, such a sensor can include an accelerometer or gyroscope operable to detect an orientation and/or change in orientation, or an electronic or digital compass, which can indicate a direction in which the device is determined to be facing.\",\n \"The mechanism(s) also (or alternatively) can include or comprise a global positioning system (GPS) or similar positioning element operable to determine relative coordinates for a position of the computing device, as well as information about relatively large movements of the device.\",\n \"The device can include other elements as well, such as may enable location determinations through triangulation or another such approach.\",\n \"These mechanisms can communicate with the processor 702, whereby the device can perform any of a number of actions described or suggested herein.\",\n \"As an example, a computing device such as that described with respect to FIG.\",\n \"6 can capture and/or track various information for a user over time.\",\n \"This information can include any appropriate information, such as location, actions (e.g., sending a message or creating a document), user behavior (e.g., how often a user performs a task, the amount of time a user spends on a task, the ways in which a user navigates through an interface, etc.\",\n \"), user preferences (e.g., how a user likes to receive information), open applications, submitted requests, received calls, and the like.\",\n \"As discussed above, the information can be stored in such a way that the information is linked or otherwise associated whereby a user can access the information using any appropriate dimension or group of dimensions.\",\n \"As discussed, different approaches can be implemented in various environments in accordance with the described embodiments.\",\n \"For example, FIG.\",\n \"8 illustrates an example of an environment 800 for implementing aspects in accordance with various embodiments.\",\n \"As will be appreciated, although a Web-based environment is used for purposes of explanation, different environments may be used, as appropriate, to implement various embodiments.\",\n \"The system includes an electronic client device 802, which can include any appropriate device operable to send and receive requests, messages or information over an appropriate network 804 and convey information back to a user of the device.\",\n \"Examples of such client devices include personal computers, cell phones, handheld messaging devices, laptop computers, set-top boxes, personal data assistants, electronic book readers and the like.\",\n \"The network can include any appropriate network, including an intranet, the Internet, a cellular network, a local area network or any other such network or combination thereof.\",\n \"Components used for such a system can depend at least in part upon the type of network and/or environment selected.\",\n \"Protocols and components for communicating via such a network are well known and will not be discussed herein in detail.\",\n \"Communication over the network can be enabled via wired or wireless connections and combinations thereof.\",\n \"In this example, the network includes the Internet, as the environment includes a Web server 806 for receiving requests and serving content in response thereto, although for other networks an alternative device serving a similar purpose could be used, as would be apparent to one of ordinary skill in the art.\",\n \"The illustrative environment includes at least one application server 808 and a data store 810.It should be understood that there can be several application servers, layers or other elements, processes or components, which may be chained or otherwise configured, which can interact to perform tasks such as obtaining data from an appropriate data store.\",\n \"As used herein the term “data store” refers to any device or combination of devices capable of storing, accessing and retrieving data, which may include any combination and number of data servers, databases, data storage devices and data storage media, in any standard, distributed or clustered environment.\",\n \"The application server can include any appropriate hardware and software for integrating with the data store as needed to execute aspects of one or more applications for the client device and handling a majority of the data access and business logic for an application.\",\n \"The application server provides access control services in cooperation with the data store and is able to generate content such as text, graphics, audio and/or video to be transferred to the user, which may be served to the user by the Web server in the form of HTML, XML or another appropriate structured language in this example.\",\n \"The handling of all requests and responses, as well as the delivery of content between the client device 802 and the application server 808, can be handled by the Web server 806.It should be understood that the Web and application servers are not required and are merely example components, as structured code discussed herein can be executed on any appropriate device or host machine as discussed elsewhere herein.\",\n \"The data store 810 can include several separate data tables, databases or other data storage mechanisms and media for storing data relating to a particular aspect.\",\n \"For example, the data store illustrated includes mechanisms for storing production data 812 and user information 816, which can be used to serve content for the production side.\",\n \"The data store also is shown to include a mechanism for storing log or session data 814.It should be understood that there can be many other aspects that may need to be stored in the data store, such as page image information and access rights information, which can be stored in any of the above listed mechanisms as appropriate or in additional mechanisms in the data store 810.The data store 810 is operable, through logic associated therewith, to receive instructions from the application server 808 and obtain, update or otherwise process data in response thereto.\",\n \"In one example, a user might submit a search request for a certain type of element.\",\n \"In this case, the data store might access the user information to verify the identity of the user and can access the catalog detail information to obtain information about elements of that type.\",\n \"The information can then be returned to the user, such as in a results listing on a Web page that the user is able to view via a browser on the user device 802.Information for a particular element of interest can be viewed in a dedicated page or window of the browser.\",\n \"Each server typically will include an operating system that provides executable program instructions for the general administration and operation of that server and typically will include computer-readable medium storing instructions that, when executed by a processor of the server, allow the server to perform its intended functions.\",\n \"Suitable implementations for the operating system and general functionality of the servers are known or commercially available and are readily implemented by persons having ordinary skill in the art, particularly in light of the disclosure herein.\",\n \"The environment in one embodiment is a distributed computing environment utilizing several computer systems and components that are interconnected via communication links, using one or more computer networks or direct connections.\",\n \"However, it will be appreciated by those of ordinary skill in the art that such a system could operate equally well in a system having fewer or a greater number of components than are illustrated in FIG.\",\n \"8.Thus, the depiction of the system 800 in FIG.\",\n \"8 should be taken as being illustrative in nature and not limiting to the scope of the disclosure.\",\n \"As discussed above, the various embodiments can be implemented in a wide variety of operating environments, which in some cases can include one or more user computers, computing devices, or processing devices which can be used to operate any of a number of applications.\",\n \"User or client devices can include any of a number of general purpose personal computers, such as desktop or laptop computers running a standard operating system, as well as cellular, wireless, and handheld devices running mobile software and capable of supporting a number of networking and messaging protocols.\",\n \"Such a system also can include a number of workstations running any of a variety of commercially-available operating systems and other known applications for purposes such as development and database management.\",\n \"These devices also can include other electronic devices, such as dummy terminals, thin-clients, gaming systems, and other devices capable of communicating via a network.\",\n \"Various aspects also can be implemented as part of at least one service or Web service, such as may be part of a service-oriented architecture.\",\n \"Services such as Web services can communicate using any appropriate type of messaging, such as by using messages in extensible markup language (XML) format and exchanged using an appropriate protocol such as SOAP (derived from the “Simple Object Access Protocol”).\",\n \"Processes provided or executed by such services can be written in any appropriate language, such as the Web Services Description Language (WSDL).\",\n \"Using a language such as WSDL allows for functionality such as the automated generation of client-side code in various SOAP frameworks.\",\n \"Most embodiments utilize at least one network that would be familiar to those skilled in the art for supporting communications using any of a variety of commercially-available protocols, such as TCP/IP, FTP, UPnP, NFS, and CIFS.\",\n \"The network can be, for example, a local area network, a wide-area network, a virtual private network, the Internet, an intranet, an extranet, a public switched telephone network, an infrared network, a wireless network, and any combination thereof.\",\n \"In embodiments utilizing a Web server, the Web server can run any of a variety of server or mid-tier applications, including HTTP servers, FTP servers, CGI servers, data servers, Java servers, and business application servers.\",\n \"The server(s) also may be capable of executing programs or scripts in response requests from user devices, such as by executing one or more Web applications that may be implemented as one or more scripts or programs written in any programming language, such as Java®, C, C# or C++, or any scripting language, such as Perl, Python, or TCL, as well as combinations thereof.\",\n \"The server(s) may also include database servers, including without limitation those commercially available from Oracle®, Microsoft®, Sybase®, and IBM®.\",\n \"The environment can include a variety of data stores and other memory and storage media as discussed above.\",\n \"These can reside in a variety of locations, such as on a storage medium local to (and/or resident in) one or more of the computers or remote from any or all of the computers across the network.\",\n \"In a particular set of embodiments, the information may reside in a storage-area network (“SAN”) familiar to those skilled in the art Similarly, any necessary files for performing the functions attributed to the computers, servers, or other network devices may be stored locally and/or remotely, as appropriate.\",\n \"Where a system includes computerized devices, each such device can include hardware elements that may be electrically coupled via a bus, the elements including, for example, at least one central processing unit (CPU), at least one input device (e.g., a mouse, keyboard, controller, touch screen, or keypad), and at least one output device (e.g., a display device, printer, or speaker).\",\n \"Such a system may also include one or more storage devices, such as disk drives, optical storage devices, and solid-state storage devices such as random access memory (“RAM”) or read-only memory (“ROM”), as well as removable media devices, memory cards, flash cards, etc.\",\n \"Such devices also can include a computer-readable storage media reader, a communications device (e.g., a modem, a network card (wireless or wired), an infrared communication device, etc.\",\n \"), and working memory as described above.\",\n \"The computer-readable storage media reader can be connected with, or configured to receive, a computer-readable storage medium, representing remote, local, fixed, and/or removable storage devices as well as storage media for temporarily and/or more permanently containing, storing, transmitting, and retrieving computer-readable information.\",\n \"The system and various devices also typically will include a number of software applications, modules, services, or other elements located within at least one working memory device, including an operating system and application programs, such as a client application or Web browser.\",\n \"It should be appreciated that alternate embodiments may have numerous variations from that described above.\",\n \"For example, customized hardware might also be used and/or particular elements might be implemented in hardware, software (including portable software, such as applets), or both.\",\n \"Further, connection to other computing devices such as network input/output devices may be employed.\",\n \"Storage media and computer-readable media for containing code, or portions of code, can include any appropriate media known or used in the art, including non-transitory computer-readable storage media, such as but not limited to volatile and non-volatile, removable and non-removable media implemented in any method or technology for storage of information such as computer readable instructions, data structures, program modules, or other data, including RAM, ROM, EEPROM, flash memory or other memory technology, CD-ROM, digital versatile disk (DVD) or other optical storage, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices, or any other medium which can be used to store the desired information and which can be accessed by the a system device.\",\n \"Based on the disclosure and teachings provided herein, a person of ordinary skill in the art will appreciate other ways and/or methods to implement the various embodiments.\",\n \"The specification and drawings are, accordingly, to be regarded in an illustrative rather than a restrictive sense.\",\n \"It will, however, be evident that various modifications and changes may be made thereunto without departing from the broader spirit and scope of the invention as set forth in the claims.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875754"}}},{"rowIdx":4494966,"cells":{"text":{"kind":"list like","value":[["FIBER TERMINATION ENCLOSURE WITH MODULAR PLATE ASSEMBLIES","Certain types of fiber termination enclosures include an enclosure and at least one of a plurality of plate module mounting assemblies.","Example plate module mounting assemblies include a termination panel plate assembly; a splice tray plate assembly; a cable spool plate assembly; and a drop-in plate assembly.","Example cable spool plate assemblies include a cable spool arrangement rotationally coupled to a mounting plate, which fixedly mounts within the enclosure housing.","A stand-off mount element may be disposed on the front of the cable spool arrangement to rotate in unison with the cable spool arrangement.","The stand-off mount element may include one or more termination adapters."],["1.An enclosure system comprising: a housing having opposite sidewalls extending between a top and a bottom and between a rear wall and a front to define an interior, the front of the housing defining a front opening providing access to the interior, the bottom of the housing defining an aperture; a plurality of subassemblies configured to be selectively and interchangeably mounted to the rear wall within the housing interior through the front opening, the plurality of subassemblies including: a first subassembly including a rotatable spool that rotates relative to the housing when mounted therein to allow a cable to be paid off from the spool, the first subassembly further including a mounting plate that carries the rotatable spool, the mounting plate mounting to the rear wall of the housing, the first subassembly also including a fiber optic connector terminating one end of the cable, the fiber optic connector rotating with the spool when the cable is paid off; and a second subassembly including cable splice mounts and a row of fiber optic adapters; and a cable port module disposed at the aperture in the bottom of the housing, the cable port module including a plate defining a cable port extending therethrough, the plate covering the aperture when mounted to the bottom of the housing.","2.The enclosure system of claim 1, wherein the cable port module includes a plurality of cable ports extending through the plate.","3.The enclosure system of claim 1, wherein the bottom of the housing defines a plurality of apertures; and wherein the cable port module is one of a plurality of cable port modules, each cable port module including a respective plate sized to cover one of the apertures, each of the plates defining at least one cable port extending through the respective plate.","4.The enclosure system of claim 1, wherein the cable port module is one type of a plurality of cable port module types that can be selected to interchangeably mount at the bottom of the housing to cover the aperture, each of the cable port module types having a different configuration of cable ports from others of the cable port module types.","5.The enclosure system of claim 1, wherein the fiber optic connector is a first fiber optic connector; wherein a second fiber optic connector terminates an opposite end of the cable from the first fiber optic connector; and wherein the second fiber optic connector is external of the housing.","6.The enclosure system of claim 1, wherein the first subassembly includes a second row of fiber optic adapters.","7.The enclosure system of claim 6, wherein each of the fiber optic adapters on the first subassembly defines first and second aligned ports, wherein insertion axes of the first and second ports extend perpendicular to a rotation axis of the spool.","8.The enclosure system of claim 6, wherein the adapters on the first subassembly are carried by the spool so that the adapters rotate with the spool relative to the housing when the cable is paid off.","9.The enclosure system of claim 1, wherein the fiber optic connector is fixed in a position relative to the spool so that the connector does not move relative to the spool when cable is paid off the spool.","10.The enclosure system of claim 1, wherein the spool extends across a majority of a width of the mounting plate.","11.The enclosure system of claim 1, wherein the spool of the first subassembly includes a manual lock.","12.The enclosure system of claim 1, wherein the cable is a multi-fiber cable; and wherein a fanout is carried by the spool so that the fanout rotates with the spool relative to the housing when the cable is paid off, the fanout separating out optical fibers of the multi-fiber cable.","13.The enclosure system of claim 1, wherein the spool includes a flange and a drum, the flange being spaced from the mounting plate by the drum.","14.The enclosure system of claim 13, wherein the flange defines an aperture through which a fastener can be inserted to rotationally fix the spool relative to the housing.","15.The enclosure system of claim 1, wherein the first subassembly includes a fiber management arrangement including a radius limiter.","16.The enclosure system of claim 15, wherein the fiber management arrangement includes a plurality of radius limiters.","17.The enclosure system of claim 15, wherein the fiber management arrangement includes a management plate at which the radius limiter is disposed, the management plate being mounted to the spool.","18.An enclosure system comprising: a housing defining an interior and a front opening providing access to the interior, the housing including a back wall partially defining the interior, the back wall having a front surface accessible through the front opening; a fiber deployment module loaded into the housing through the front opening and disposed within the housing interior, the fiber deployment module including a mounting plate that mounts to the front surface of the back wall of the housing, the fiber deployment module including a spool that rotates relative to the mounting plate, the spool extending across a majority of a width of the mounting plate, the mounting plate having at least a portion that extends beyond a perimeter of the spool, the spool including a drum extending outwardly from the mounting plate and a flange disposed at an opposite side of the drum from the mounting plate, the flange having a front axial face; and a multi-fiber cable coiled around the drum of the spool between the mounting plate and the flange, the multi-fiber cable being paid off the drum when the spool is rotated relative to the housing, the multi-fiber cable extending between a first end and a second end, the first end being carried with and rotating in unison with the spool when the cable is paid out by pulling the second end from the housing, the first end of the multi-fiber cable including a fan-out at which fibers of the multi-fiber cable are separated out into a plurality of pigtails, each of the plurality of pigtails having an end connectorized by a fiber optic connector that rotates in unison with the spool when the multi-fiber cable is paid out.","19.The enclosure system of claim 18, wherein the fiber deployment module further includes a plurality of fiber optic adapters having ports in which fiber optic connectors at the ends of the pigtails are loaded, and wherein the fiber optic adapters are disposed in a row.","20.The enclosure system of claim 19, wherein the plurality of fiber optic adapters are rotatable with the spool when the cable is paid out.","21.The enclosure system of claim 18, wherein the fiber deployment module includes a plate that carries a plurality of fiber optic adapters, the fiber deployment module also including a plurality of radius limiters, wherein each of the plurality of fiber optic adapters defines first and second aligned ports, wherein insertion axes of the first and second aligned ports extend perpendicular to a rotation axis of the spool.","22.The enclosure system of claim 18, wherein excess length of the pigtails is stored in a coil that is not wound around the drum, the coil being accessible from the front axial face of the flange.","23.The enclosure system of claim 22, wherein the coil extends around an axis of rotation of the spool."],["<SOH> BACKGROUND <EOH>As demand for the telecommunication services increases, fiber optic networks are being extended in more and more areas (e.g., multiple dwelling units, apartments, condominiums, businesses, distributed antenna systems, cell towers, rural areas, single family residences).","This growth has been particularly notable in the area of wireless communications, e.g., cellular, personal communication services (PCS) and other mobile radio systems.","To efficiently distribute fiber optic services to these various different subscribers, system design flexibility is significant.","System design flexibility can include the ability to efficiently provide different varying fiber optic cable lengths and the ability to efficiently provide fiber optic enclosures having interior components customized to meet a given customer's needs."],["<SOH> SUMMARY <EOH>An aspect of the present disclosure relates to a fiber optic enclosure assembly.","The fiber optic enclosure includes an enclosure housing that is adapted to optically connect incoming fibers to outgoing fibers.","One or more modular plate assemblies may be mounted within an interior of the enclosure to customize the fiber optic enclosure.","In accordance with some aspects of the disclosure, certain types of modular plate assemblies include termination adapter arrangements.","In accordance with some aspects of the disclosure, certain types of modular plate assemblies include splice trays arrangements.","In accordance with some aspects of the disclosure, certain types of modular plate assemblies include cable spool arrangements.","In accordance with some aspects of the disclosure, modular cable port arrangements may be disposed at the enclosure housing.","In some implementations, various types of modular cable port arrangements can be selectively mounted at the enclosure housing.","In accordance with certain aspects of the disclosure, a cable spool arrangement is connected to an interior of the enclosure to rotate relative to the enclosure.","One or more fiber cables may be paid out from the enclosure by pulling one end of the fiber cable through a cable port to unwind the fiber cable from the cable spool arrangement.","In certain implementations, one or more adapters may be disposed on the cable spool arrangement to rotate in unison with the cable spool arrangement.","In certain implementations, the termination adapters are disposed on a stand-off mount element that is spaced from the cable spool arrangement, but configured to rotate in unison with the cable spool arrangement.","A variety of additional aspects will be set forth in the description that follows.","These aspects can relate to individual features and to combinations of features.","It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the broad concepts upon which the embodiments disclosed herein are based."],["CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser.","No.","15/615,999, filed Jun.","7, 2017, which is a continuation of U.S. application Ser.","No.","15/243,143, filed Aug. 22, 2016, now U.S. Pat.","No.","9,678,293, which is a continuation of U.S. application Ser.","No.","14/979,803, filed Dec. 28, 2015, now U.S. Pat.","No.","9,423,584, which is a continuation of U.S. application Ser.","No.14/127,851, filed Feb. 12, 2014, now U.S. Pat.","No.","9,223,106, which is a National Stage of PCT/US2012/043827, filed Jun.","22, 2012, which claims the benefit of U.S.","Application Nos.","61/500,769, filed Jun.","24, 2011, and titled “Fiber Termination Enclosure with Internal Cable Spool Assembly;” 61/500,764, filed Jun.","24, 2011, and titled “Fiber Termination Enclosure with Modular Plate Assemblies;” 61/507,263, filed Jul.","13, 2011, and titled “Fiber Termination Enclosure with Internal Cable Spool Assembly,” and 61/507,270, filed Jul.","13, 2011, and titled “Fiber Termination Enclosure with Modular Plate Assemblies;” the disclosures of which are hereby incorporated herein by reference.","TECHNICAL FIELD The present disclosure relates to fiber optic enclosure, and more particularly, to a fiber optic enclosure with cable payout.","BACKGROUND As demand for the telecommunication services increases, fiber optic networks are being extended in more and more areas (e.g., multiple dwelling units, apartments, condominiums, businesses, distributed antenna systems, cell towers, rural areas, single family residences).","This growth has been particularly notable in the area of wireless communications, e.g., cellular, personal communication services (PCS) and other mobile radio systems.","To efficiently distribute fiber optic services to these various different subscribers, system design flexibility is significant.","System design flexibility can include the ability to efficiently provide different varying fiber optic cable lengths and the ability to efficiently provide fiber optic enclosures having interior components customized to meet a given customer's needs.","SUMMARY An aspect of the present disclosure relates to a fiber optic enclosure assembly.","The fiber optic enclosure includes an enclosure housing that is adapted to optically connect incoming fibers to outgoing fibers.","One or more modular plate assemblies may be mounted within an interior of the enclosure to customize the fiber optic enclosure.","In accordance with some aspects of the disclosure, certain types of modular plate assemblies include termination adapter arrangements.","In accordance with some aspects of the disclosure, certain types of modular plate assemblies include splice trays arrangements.","In accordance with some aspects of the disclosure, certain types of modular plate assemblies include cable spool arrangements.","In accordance with some aspects of the disclosure, modular cable port arrangements may be disposed at the enclosure housing.","In some implementations, various types of modular cable port arrangements can be selectively mounted at the enclosure housing.","In accordance with certain aspects of the disclosure, a cable spool arrangement is connected to an interior of the enclosure to rotate relative to the enclosure.","One or more fiber cables may be paid out from the enclosure by pulling one end of the fiber cable through a cable port to unwind the fiber cable from the cable spool arrangement.","In certain implementations, one or more adapters may be disposed on the cable spool arrangement to rotate in unison with the cable spool arrangement.","In certain implementations, the termination adapters are disposed on a stand-off mount element that is spaced from the cable spool arrangement, but configured to rotate in unison with the cable spool arrangement.","A variety of additional aspects will be set forth in the description that follows.","These aspects can relate to individual features and to combinations of features.","It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the broad concepts upon which the embodiments disclosed herein are based.","BRIEF DESCRIPTION OF THE DRAWINGS FIG.","1 is a schematic diagram of a fiber termination enclosure having an example mounting assembly disposed therein in accordance with the principles of the present disclosure; FIG.","2 is a front, top perspective view of an example fiber termination enclosure including an enclosure configured in accordance with the principles of the present disclosure and shown with a door in a closed position; FIG.","3 is a front, bottom perspective view of the example fiber termination enclosure of FIG.","2 in which two cable port modules are visible; FIG.","4 is a front, top perspective view of the example fiber termination enclosure of FIG.","2 shown with the door in the open position and a cable spool mounting assembly exploded from the interior of the enclosure; FIG.","5 is a schematic diagram of the fiber termination enclosure of FIG.","4 configured in accordance with the principles of the present disclosure; FIG.","6 is a front, top perspective view of the example fiber termination enclosure of FIG.","4 in which with the cable spool mounting assembly is exploded to show various example components of the cable spool mounting assembly including a mounting plate, a cable spool arrangement, and a stand-off mount element; FIG.","7 is a front, top perspective view of the example fiber termination enclosure of FIG.","6 shown with the cable spool mounting assembly installed within the interior of the enclosure housing; FIG.","8 is a front, top perspective view of the example fiber termination enclosure of FIG.","2 shown with an example splice tray reel mounting assembly installed within the interior of the enclosure housing; FIG.","9 is a front, top perspective view of the example fiber termination enclosure of FIG.","2 shown with an example termination panel mounting assembly installed within the interior of the enclosure housing; FIG.","10 is a front, top perspective view of the example fiber termination enclosure of FIG.","9 shown with an example cover disposed over the cable spool mounting assembly; FIG.","11 is a front, top perspective view of the example fiber termination enclosure of FIG.","2 shown with the door in the open position, an example sliding adapter mounting assembly disposed within the interior of the enclosure, and an example drop-in plate mounting assembly exploded from the interior of the enclosure; FIG.","12 is a front, top perspective view of the example fiber termination enclosure of FIG.","11 shown with the example drop-in plate mounting assembly disposed within the interior of the enclosure and partially cabled; FIG.","13 is a front, top perspective view of the example fiber termination enclosure of FIG.","12 shown with cabling extending between the example drop-in plate mounting assembly and the example sliding adapter mounting assembly; FIG.","14 is a front, top perspective view of the example fiber termination enclosure of FIG.","2 shown with an example splice tray mounting assembly and an example sliding adapter mounting assembly disposed within the interior of the enclosure housing; FIG.","15 is a front, top perspective view of the example fiber termination enclosure of FIG.","14 shown with an example cover disposed over the splice tray mounting assembly; and FIG.","16 is a schematic representation of a telecommunications network having exemplary features of aspects in accordance with the principles of the present disclosure.","DETAILED DESCRIPTION Reference will now be made in detail to the exemplary aspects of the present disclosure that are illustrated in the accompanying drawings.","Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like structure.","FIG.","1 is a schematic diagram of an example fiber optic enclosure 100.The fiber optic enclosure 100 includes a housing, generally designated 110, at which telecommunications cables (e.g., optical and/or electrical cables) can be optically coupled and/or stored.","One or more modular plate assemblies 120 may be mounted within the interior of the enclosure housing 110.Each modular plate assembly 120 includes a mounting plate 121 that is configured to mount to the enclosure housing 110 in a stationary configuration.","Each modular plate assembly 120 includes a coupling arrangement 170 at which one or more optical fibers 182 of at least a first fiber cable 180 are optically coupled to optical fibers 192 of at least a second fiber cable 190.The fiber cables 180, 190 enter the enclosure housing 110 through cable ports 101.In use, the enclosure housing 110 is deployed by securing the enclosure housing 110 to a mounting location (e.g., a wall, a pole, etc.).","In some implementations, the enclosure housing 110 has brackets disposed on the top and bottom walls 111, 112.In other implementations, the enclosure housing 110 may have brackets disposed on other walls to secure the enclosure housing 110 to the mounting location.","In still other implementations, the enclosure housing 110 is adapted to be otherwise secured to a mounting location.","FIGS.","2-4 illustrate one example enclosure housing 110 having a top wall 111, a bottom wall 112 (FIG.","3), a first side wall 113, a second side wall 114 (FIG.","4), and a rear wall 115 (FIG.","4) defining an interior.","The enclosure housing 110 also defines an open front 116 that provides access to the interior of the enclosure housing 110 (see FIG.","4).","At least one cover 118 is coupled to the enclosure housing 110 to selectively close the open front 116 of the enclosure housing 110.The cover 118 is pivotally coupled to the enclosure housing 110 using one or more hinges 103 disposed on one of the side walls 113, 114 (see FIG.","4).","The hinge 103 allows the cover 118 to selectively pivot between a closed position (shown in FIG.","2) and an open position (shown in FIG.","4).","The cover 118 can be held closed using locking flanges 117, 119 (FIG.","4).","In one implementation, the enclosure housing 110 is molded from a plastic material.","In one implementation, the enclosure housing 110 is molded from a plastic material.","In another implementation, the enclosure housing 110 is molded from a metal material.","In some implementations, the enclosure housing 110 defines one or more cable ports 101 (FIG.","1) at which cables 180, 190 may enter and exit the interior of the enclosure housing 110.In certain implementations, the cable ports 101 are disposed at the bottom wall 112 of the enclosure housing 110.In other implementations, however, the cable ports 101 may be disposed elsewhere on the enclosure housing 110, such as at the top wall 111, the rear wall 115, or one of the side walls 113, 114.In some implementations, the enclosure housing 110 is configured to receive one or more cable port modules 150 at the cable ports 101 (e.g., see FIGS.","3 and 4).","For example, the cable ports 101 may define openings 155 (FIG.","4) in one or more walls 111-115 of the enclosure housing 110 at which the cable port modules 150 may be received.","Each cable port module 150 receives one or more cables 180, 190.In some implementations, a first cable port module 150 may receive one or more service cables and a second cable port module 150 may receive one or more subscriber cables.","In other implementations, the same cable port module 150 may receive both service cables and subscriber cables.","In still other implementations, the enclosure housing 110 may receive an even greater number of cable port modules 150, each of which may receive service cables and/or subscriber cables.","In certain implementations, a variety of cable port modules 150 may be configured to fit at the same opening 155, thereby enabling a user to select which of the cable port modules 150 to mount at the opening 155.In certain implementations, the cable port modules 150 may be removably mounted to the enclosure housing at the openings 155, thereby enabling a user to switch which cable port modules 150 are mounted at any particular enclosure housing 110.Two example implementations of cable port modules 150, 150′ are shown in FIGS.","3 and 4.Each of the cable port modules 150, 150′ includes a port panel 151 configured to be mounted at an opening 155 defined in an enclosure housing 110.For example, the port panel 151 may define one or more openings 152 through which fasteners (e.g., screws, bolts, etc.)","may extend to secure the port panel 151 to one of the walls 111-115 of the enclosure housing 110.One or more grommets extend through the port panel 151.Each grommet enables one or more cables 180, 190 or fibers to enter the enclosure housing 110 while inhibiting the ingress of environmental contaminants, such as water, dirt, and rodents.","A first example cable port module 150 includes a first type of grommet 153 and a second type of grommet 154.The second type of grommet 154 is larger than the first type of grommet 153.In the example shown, a cable 180 to be dispensed extends through the smaller grommet 153.A second example cable port module 150′ includes only the second type of grommet 154 extending through the port panel 151.Other implementations may include still other types of cable port modules, each having its own configuration of grommets.","Referring to FIGS.","4-15, the mounting plates 121 of the modular plate assemblies 120 are adapted and configured to be mounted to the rear wall 115 of the enclosure housing 110.In some implementations, the rear wall 115 defines one or more openings through which fasteners may extend to secure a mounting plate 121 to the rear wall 115.In other implementations, the rear wall 115 may include one or more pegs over which the mounting plate 121 may be pressed.","In other implementations, one or more panel fastening structures can be attached, secured, or mounted to the rear wall 115.In still other implementations, the rear wall 115 may include one or more pems 104 that are pressed into the rear wall 115 (see FIG.","4).","The pems 104 are sized and configured to be inserted through openings 122 defined in the mounting plate 121.The pems 104 define threaded passages that are configured to receive fasteners that secure the mounting plate 121 to the rear wall 115, or can be exterior threaded shanks.","In accordance with some aspects, the mounting plates 121 of the modular plate assemblies 120 extend over a majority of the area of the rear wall 115.In some implementations, a mounting plate 121 has a rectangular shape (e.g., see FIG.","4).","In other implementations, a mounting plate 121 may define one or more cutouts 129 or otherwise have a non-rectangular shape (e.g., see FIGS.","9-12).","In accordance with other aspects, the mounting plates 121 of the modular plate assemblies 120 may extend over only a portion of the area of the rear wall 115.For example, some implementations, of the mounting plates 121 may be configured to extend over about half of the area of the rear wall 115 (e.g., see FIGS.","11-14).","FIGS.","4-7 illustrate a first implementation of a modular plate assembly 120 that includes a cable spool arrangement 130 (FIG.","6) that is rotationally mounted to the modular plate assembly 120.As shown in FIG.","5, the cable spool arrangement 130 includes a first storage area 102, a second storage area 104, and a termination region 108.In some implementations, the termination region 108 is spaced from the second storage area 104, which is spaced from the first storage area 102.In certain implementations, the termination region 108 is spaced forwardly of the second storage region 104, which is spaced forwardly of the first storage region 102 (e.g., see FIG.","4).","In certain implementations, the second storage area 104 forms part of a protected fiber management region 106 at which optical fibers can be separated out from optical cables.","At least a first fiber cable (e.g., distribution cable) 180 and at least a second cable (e.g., subscriber cable) 190 enter the housing 110 through cable ports 101.Fibers 192 of the second fiber cable 190 are routed to the termination region 108.The first fiber cable 180 is routed to the first storage area 102 of the cable spool arrangement 130.From the first storage area 102, the first fiber cable 180 is routed to the second storage area 104.The first fiber cable 180 is broken out into individual optical fibers 182 at the protected fiber management region 106.The fibers 182 are routed to the termination region 108 at which the optical fibers 184 are connected to optical fibers 192 of the second fiber cable 190.The fiber optic enclosure 100 provides an enclosure from which lengths of a cable (e.g., a distribution cable) 180 can be dispensed following the mounting of the fiber optic enclosure 100 to a mounting location.","The distribution cable 180 is dispensed from the fiber optic enclosure 100 by pulling on an end (e.g., a connectorized end) 185 of the cable 180 (see FIGS.","4 and 7).","As the distribution cable 180 is dispensed, the cable spool arrangement 130 rotates about an axis relative to the stationary mounting plate 121 of the fiber optic enclosure 100.In the event that there is a residual length of distribution cable 180 that is not dispensed during the cable payout, the fiber optic enclosure 100 can store this residual length.","As shown in FIG.","6, the cable spool mounting assembly 120 includes a mounting plate 121 and a cable spool arrangement 130.The mounting plate 121 includes a first side 124 and an opposite second side 123.The mounting plate 121 is adapted for stationary mounting to the rear wall 115 of the housing enclosure.","In certain implementations, the second side 123 of the mounting plate 121 is configured to be mounted to an interior surface of the rear wall 115 so that the mounting plate 121 is disposed within the interior of the housing enclosure 110.For example, in certain implementations, the mounting plate 121 defines one or more fastener openings 122 that are disposed to align with fastener openings provided on the rear wall 115 of the housing enclosure 110.Certain types of mounting plates 121 extend along substantially the entire rear wall 115 of the enclosure housing 110.The cable spool arrangement 130 includes a drum 131 extending between first and second support flanges 132, 133 to form a first cable spool 134.The first cable spool 134 defines the first storage region 102 (FIG.","5).","In some implementations, the cable spool arrangement 130 also includes a termination region 108 (FIG.","5).","In certain implementations, a protected fiber management region 106 (FIG.","5) is defined between the first storage region 102 and the termination region 108.For example, in certain implementations, in FIG.","6, the cable spool arrangement 130 includes a stand-off mounting assembly 140, at which the termination region 108 (FIG.","5) is disposed as will be described in more detail herein.","The protected fiber management region 106 (FIG.","5) is defined between the stand-off mounting assembly 140 and one of the first cable spool 134 (e.g., see FIG.","4).","In certain implementations, the drum portion 131 of the first cable spool 134 is generally cylindrical in shape.","The drum portion 131 includes a first end portion that couples to the first support flange 132 and an oppositely disposed second end portion that couples to the second support flange 133.The support flanges 132, 133, which are generally parallel to each other, are configured to rotate with the drum 131.An outer surface of the drum 131 and inner surfaces of the support flanges 132, 133 define the first storage region 102 (FIG.","5) within which optical fibers or cables (e.g., distribution cable 180) may be coiled.","The drum portion 131 has a sufficient diameter to provide bend radius protection to optical fibers wound around the fiber spool 134.The drum portion 131 defines a central bore that extends through the drum portion 131.In the subject embodiment, the central bore is adapted to receive a spindle 129 (FIG.","6).","In certain implementations, the spindle 129 extends through the bore in the drum 131 and secures to the second side 123 of the mounting plate 121.For example, in certain implementations, the mounting plate 121 defines openings 125 at which the spindle 129 is fastened to the mounting plate 121.The first cable spool 134 is configured to rotate about the spindle 129 relative to the mounting plate 121.The support flanges 132, 133 are sized and shaped to retain the optical fibers wound around the drum 131 in the first storage region 102.In some implementations, the support flanges 132, 133 are generally circular.","In certain implementations, the support flanges 132, 133 have a sufficient diameter to cover a majority of a surface area of the mounting plate 121.In other implementations, however, one or both of the support flanges 132, 133 may have a smaller diameter.","In some implementations, the cable spool arrangement 130 is configured to be releasably locked in a rotationally fixed position relative to the mounting plate 121.For example, in certain implementations, the mounting plate 121 includes a forwardly extending flange 126 that is configured to extend past the support flanges 132, 133 of the drum 131 to interact with the front of the cable spool arrangement 130 (see FIG.","6).","The forwardly extending flange 126 defines an opening 127.The second flange 133 of the cable spool 134 defines an opening 136 that is disposed to align with the opening 127 of the forwardly extending flange 126 when the cable spool arrangement 130 is disposed in one rotational position.","In certain implementations, the opening 136 is defined in a tab 135 that extends outwardly from the generally annular circumference of the second support flange 133.A fastener 128 may be inserted through the openings 136, 127 to lock the cable spool arrangement 130 in the rotationally fixed position.","In some implementations, the second support flange 133 of the cable spool 134 defines an aperture 139 through which optical fibers or cables (e.g., distribution cable 180) may pass between the first storage area 102 and the front of the cable spool 134.In certain implementations, the cables pass through aperture 139 from the first storage region 102 to the protected fiber management region 106.For example, in certain implementations, the aperture 139 is located directly adjacent to the protected fiber management region 106 and allows cables from inside the first storage region 102 of the spool to be routed from the drum surface 131 to the protected storage region 106.The protected fiber management region 106 (FIG.","5) provides a mounting location for a fan out arrangement.","The fan out arrangement includes one or more fan outs 138 disposed between the back side of the stand-off 140 and the front side of the cable spool 134 (see FIG.","4).","For example, the fan outs 138 may be disposed on the front side of the second support flange 133 of the cable spool 134.Accordingly, the fan outs 138 rotate with the cable spool 134.The cable 180 wrapped around the supplemental spool region 104 can be routed to one of the fan outs 138 where individual optical fiber are broken out to form individual fiber optic pigtails 182.The pigtails 182 have ends connectorized by fiber optic connectors that are inserted into the fiber optic adapters 147 at the termination field 108 (see FIG.","4).","Fiber optic connectors corresponding to fibers 192 of subscriber cables 190 also may be inserted into the adapters 147 to provide optical connections between the subscriber cables 190 and the cables 180 routed from the first cable spool 134.The protected fiber management region 106 also can include bend radius protectors 137 attached to the front spool flange 133 (FIG.","6).","The bend radius protector 137 can form a supplemental spooling region 104 where cables routed from drum 131 through aperture 139 can be wrapped/spooled to provide cable storage and cable management.","The pigtails 182 also may be wrapped/spooled around the bend radius limiters 137.In some implementations, the supplemental spooling region 104 provides strain relief to the cables (e.g., distribution cables) 180.Axial loads applied to the outside end 185 of the cables 180 will be transferred through the cable 180 to the wrapped portions of the cable 180.However, the axial loads will not be transferred to the connectorized ends of the pigtails 182.Accordingly, pulling on the first cable end 185 will not detach the connectorized pigtails 182 from the adapters 147 at the termination region 108.Still referring to FIGS.","4-7, a stand-off mount element 140 may be coupled to the front of the first cable spool 134.For example, the stand-off mount element 140 may be secured to the second support flange 133 of the first cable spool 134 so that the stand-off mount element 140 unitarily rotates with the first cable spool 134.The stand-off mount element 140 provides a front plate 141 where optical components (e.g., fiber optic adapters, splitters, splice trays, spools, bend radius protector, etc.)","can be mounted.","For example, fiber optic adapters 147 may form a termination region 108 on the front plate 141.Cable management structures (e.g., bend radius limiters, spools, etc.)","148 also may be provided on the stand-off plate 141.In the example shown, two opposing bend radius limiters 148 form a fiber spool on the stand-off plate 141.In certain implementations, one or more legs 142 extend rearwardly from the stand-off plate 141 of the stand-off mount element 140.Each leg 142 defines an opening 143 configured to receive a peg 145 or fastener to secure the feet 143 to the front support flange 133 of the cable spool 134.In the example shown, the stand-off mount element 140 includes four legs 142.In other implementations, however, the stand-off mount element 140 may include greater or fewer legs 142.In still other implementations, the legs 142 may be unitary with the cable spool 134 and secure to the stand-off plate 141.The stand-off plate 141 is forwardly offset from the front side of the spool flange 133, thereby forming the protected fiber management region 106 between the front side of the first cable spool 134 and back side of the stand-off mount element 140 (e.g., see FIG.","4).","The separated fibers 184 in the protected fiber management region 106 are routed around the bend radius limiters 137 or other management structures on the front of the cable spool 134 to the stand-off mount element 140.In the example shown, the separated fibers 184 have connectorized ends that plug into first ports of termination adapters 147 disposed at the stand-off plate 141.Components disposed on the stand-off mount element 140 are spaced forwardly of the cable spool 134.Accordingly, the fiber optic adapters 147 are disposed on a different layer or plane than the fan outs 138, which are disposed on a different layer or plane than the first cable spool 134.In certain implementations, the fan outs 138 are disposed on the same layer or plane as the bend radius limiters 137.The spacing between the cable spool layer and the stand-off layer enhances slack storage of optical fibers routed through the protected fiber management region 106.In some implementations, the spacing between the cable spool layer and the stand-off layer inhibits over-bending of the fibers when routed between the fan out arrangements 138 and the fiber optic adapters 147.In certain implementations, the termination adapters 147 are included in one or more termination modules 146.In certain implementations, the adapter modules 146 are sliding adapter modules.","Similar sliding adapter modules have been described in commonly owned U.S. Pat.","Nos.","5,497,444; 5,717,810; 6,591,051; and 7,416,349, the disclosures of which are hereby incorporated by reference.","In the example shown, the stand-off mount element 140 includes six sliding adapter modules 146, each holding four fiber optic adapters 147.In other implementations, the stand-off mount element 140 may include greater or fewer sliding adapter modules 146 holding greater or fewer termination adapters 147.In certain implementations, sufficient slack length of the separated fibers 182 is left between the fan out arrangement 138 and the adapters 147 to accommodate the sliding movement of the sliding adapter modules 146.In some implementations, the cable spool arrangement 130 may be precabled at the factory or manufacturing center with one or more optical fibers or cables 180.For example, one or more multi-fiber cables 180 may be wound around the storage area 102 of the cable spool 134.In certain implementations, the multi-fiber cables 180 may be precabled to pass through the aperture 139 to the fan out arrangement 138 disposed in the protected fiber management region 106 (e.g., see FIGS.","4 and 7).","The fan out arrangement 138 separates the cables 180 into pigtails 182.In certain implementations, the fan out arrangement 138 also upjackets the fibers 182.In other implementations, however, the cable spool arrangement 130 may be cabled with the one or more multi-fiber cables 180 after the enclosure housing 110 is deployed.","The precabled cable spool mounting assembly 120 is mounted within the enclosure housing 110.For example, the mounting plate 121 is secured to a rear wall 115 of the enclosure housing 110.When the mounting assembly 120 is installed in the enclosure housing 110, the second ends of the multi-fiber cables 180 may be routed through one of the cable ports so that the second ends are disposed outside of the enclosure housing 110.In some implementations, the second ends of the one or more precabled multi-fiber cables 180 may be terminated at one or more multi-fiber connectors 185.In other implementations, the second end of a precabled multi-fiber cable 180 is separated into two or more connectorized optical fibers (jacketed or unjacketed).","In still other implementations, the second ends of the multi-fiber cables 180 are configured to be spliced to one or more optical fiber cables.","A user may pull on the second ends to dispense the stored length of cable 180 from the cable spool arrangement 130.For example, a user may pull a second end of a cable 180 to a fiber distribution hub, drop terminal, or other network connection.","Because the adapters 147 rotate in unison with the cable spool arrangement 130, the second end of each multi-fiber cable 180 may be paid out without interfering with the cabling of the first ends of the multi-fiber cable 180.When the second ends 185 of the one or more multi-fiber cables 180 are each connected to the network, the fastener 128 may be inserted through aligned openings 135, 128 to secure the cable spool arrangement 130 in a fixed rotational position relative to the mounting plate 121.When the cable spool arrangement 130 is secured in a rotationally fixed position, additional optical fiber cables may be routed into the enclosure housing 110 to secure to second ports of the termination adapters 147.For example, the additional optical fiber cables may be routed into the enclosure through one or more cable ports defined in the enclosure housing 110.The termination adapters 147 are configured to align and optically couple connectors terminating the additional optical cables with the connectorized ends of the multi-fiber cable 180 plugged into the first ports of the adapters 147.FIG.","8 illustrates a second example modular plate assembly 220 implemented as a second example cable spool mounting assembly 120 for mounting within the enclosure housing 110.The second cable spool mounting assembly 220 includes a rectangular mounting plate 221 that extends over a majority of the rear wall 115.A cable spool arrangement 241 is disposed on the mounting plate 221 and is configured to rotate relative to the mounting plate 221 (e.g., about a spindle).","Since the mounting plate 221 is configured to remain stationary on the rear wall 115, the cable spool arrangement 241 is configured to rotate relative to the enclosure housing 110.The cable spool arrangement 241 defines a storage area including a drum about which optical fibers or cables (e.g.","of a multi-fiber distribution cable 180) may be coiled.","The drum has a sufficient diameter to provide bend radius protection to optical fibers wound around the fiber spool arrangement 241.Rotating the cable spool arrangement 241 dispenses or retracts the optical fibers or cables wound around the drum.","In some implementations, the cable spool arrangement 241 may be locked in a rotational orientation relative to the mounting plate 221.In certain implementations, one or more splice trays 242 are disposed on the cable spool arrangement 241.Each splice tray 242 is configured to optically couple together two or more optical fibers.","For example, each splice tray 242 may optically couple together at least one optical fiber of the distribution cable 180 and at least one optical fiber of a subscriber cable 190 (FIG.","1).","Certain types of splice tray 242 may be pivoted between open and closed positions to provide access to the splices contained therein.","In certain implementations, the splice trays 242 are stacked upon each other so that a bottom of the stack extends over the cable spool arrangement 241 and a top of the stack faces the open front 116 of the enclosure housing 110.One or more fiber management structures may be disposed on the cable spool arrangement 241.For example, in certain implementations, one or more bend radius limiters 243 are disposed on a front of the cable spool arrangement 241.In the example shown, four bend radius limiters are disposed at a top, bottom, and sides of the cable spool arrangement 241.The cable spool arrangement 241 also defines one or more channels 244 through which optical fibers or cables can pass between the storage area of the cable spool arrangement 241 and the splice trays 242.In the example shown, the cable spool arrangement 241 defines four openings 244 spaced between the bend radius limiters 243.In some implementations, the second cable spool mounting assembly 220 may be precabled at the factory or manufacturing center with one or more distribution cables 180.The one or more distribution cables 180 may be wound around the drum in the storage area of the second cable spool arrangement 241.In certain implementations, the first end of each distribution cable fiber may be routed through one of the openings 244 in the cable spool arrangement 241, around one or more of the bend radius limiters 243, and into one of the splice trays 242 disposed at a front of the cable spool arrangement 241 (e.g., see FIG.","8).","The precabled second cable spool mounting assembly 220 is mounted within the enclosure housing 110 to deploy the one or more distribution cables 180.For example, the mounting plate 221 is secured to the rear wall 115 of the enclosure housing 110 as described above.","The second ends 185 of the distribution cables 180 may be routed out of the housing 110 through one of the cable port modules 101 so that the second ends 185 are disposed outside of the enclosure housing 110 (e.g., see FIG.","8).","Additional optical fiber cables (e.g., subscriber cables 190 of FIG.","1) may be routed into the enclosure housing 110 (e.g., through the same or other port modules 101).","Unconnectorized ends of the subscriber cable fibers may be optically coupled to the first ends of the service cable fibers at the splice trays 242.For example, each subscriber cable fiber may be routed from the respective cable port module 101 to the respective splice tray 242 (e.g., either directly or after being wound around some of the bend radius limiters 243 of the second cable spool mounting assembly 220.FIGS.","9 and 10 illustrate a third example modular plate assembly 120 implemented as a termination panel mounting assembly 320.The termination panel mounting assembly 320 includes a mounting plate 321 that is sized to extend over a majority of the rear wall 115 of the enclosure housing 110.In particular, the mounting plate 321 has a height that extends over a majority of a height of the rear wall 115 and the mounting plate 321 has a width that extends over a majority of a width of the rear wall 115.The mounting plate 321 defines one or more apertures 322 or pems that facilitate connection to the rear wall 115.Certain types of mounting plates 321 define one or more cutouts 329.In the example shown in FIG.","9, the mounting plate 321 defines a cutout 329 at an upper, right corner of the mounting plate 321, thereby resulting in an L-shaped mounting panel 321.In other implementations, the mounting plate 321 may have other configurations.","A termination plate 351 is coupled to the mounting plate 321.In some implementations, the termination plate 351 is a bent portion of the mounting plate 321.In other implementations, the termination plate 351 is a separate piece that attaches to the mounting plate 321 (e.g., via snap-fit connection, latches, fasteners, etc.).","In the example shown, the termination plate 351 extends vertically with a first side facing the first side wall 113 and a second side facing he second side wall 114 of the enclosure housing 110.In other implementations, the termination plate 351 has a first side that faces the rear wall 115 and a second side that faces the open front 116 of the enclosure housing 110.One or more termination adapters 352 are disposed on the termination plate 351.Each termination adapter 352 has a first port and a second port.","In the example shown, the first port faces the first side wall 113 and the second port faces the second side wall 114 of the enclosure housing 110.In other implementations, the adapter ports may face the rear wall 115 and open front 116 of the enclosure housing 110.In still other implementations, the adapters 352 and the termination plate 351 may be oriented at any desired angle relative to the mounting plate 321.In certain implementations, adapter dust caps 353 may be provided at the adapter ports.","In certain implementations, one or more cable management structures may be provided on the termination plate 351 or mounting plate 321.In the example shown, four bend radius limiters 354 are disposed on a front of the mounting plate 321.The bend radius limiters 354 are configured to form two fiber spools.","In certain implementations, the bend radius limiters 354 form a first fiber spool located between the termination plate 351 and the first side wall 113 of the housing 110 and a second fiber spool located between the termination plate 351 and the second side wall 114 of the housing 110.In certain implementations, the bend radius limiters 354 are located substantially below the termination plate 351.In other implementations, the same or other types of cable management structures may be disposed in different configurations.","During deployment of the termination panel mounting assembly 350, one or more optical fiber cables (e.g., distribution cables 180) may be routed into the enclosure housing 110 (e.g., through one or more port modules 101).","Connectorized ends of the distribution cables may be secured to the first ports of the termination adapters 352.Additional optical fiber cables (e.g., subscriber cables 190) also may be routed into the enclosure housing 110 (e.g., through the same or other port modules 101).","Connectorized ends of the subscriber cables may be secured to the second ports of the termination adapters 352, which align and optically couple together the connectorized ends of the subscriber cables with the connectorized ends of the service cables.","In certain implementations, a cover 330 may be positioned within the enclosure housing 110 to enclose or otherwise inhibit access to at least a portion of the optical components location within the enclosure housing 110 (see FIG.","10).","In some implementations, the cover 330 extends from one of the side walls 113, 114 to the termination plate 351 to block access to at least some of the fiber connectors plugged into one side of the termination adapters 352.In the example shown, the cover 330 extends from the second side wall 114 to the termination plate 351 to block access to any cables (e.g., service cables) entering the enclosure housing 110 through the left cable ports 101, while allowing access to the cables (e.g., subscriber cables) entering the enclosure housing 110 through the right cable ports 101.In other implementations, the cover 330 may extend across the entire termination panel mounting assembly 320.In the example shown, the cover 330 includes a front plate 366 and a side plate 367 forming an L-shaped flange.","The front plate 366 extends from the second side wall 114 of the enclosure to the termination plate 351, thereby covering the bend radius limiters 354 located to the left of the termination plate 351.The front plate 366 also blocks access to the second ports of the adapters 352 from the open front 116 of the enclosure housing 110.The side plate 367 extends downwardly from the termination plate 351 to inhibit access to the second side of the termination plate 351 from the right side of the enclosure housing interior.","In other implementations, the cover 330 may include two side plates and be located at a central portion of the enclosure interior.","In still other implementations, the cover 330 may include a planar panel that extends across the open front 116 of the enclosure housing 110.In some implementations, the cover 330 defines one or more finger holes 368 by which the cover 330 may be installed and/or removed from the enclosure housing 110.For example, in one implementation, the front plate 366 of the cover 330 defines two finger holes 368.In other implementations, the cover 330 may include a handle or other structure to facilitate manipulation of the cover 330.In certain implementations, the cover 330 may be secured in place by a lock arrangement 369.FIGS.","11-13 illustrate fourth and fifth example modular plate assemblies 120 implemented as an example drop-in plate mounting assembly 400 and an example sliding adapter mounting assembly 450, respectively.","The fourth and fifth modular plate assemblies 400, 450 each extend over only a portion of the rear wall 115.For example, each of the fourth and fifth modular plate assemblies 400, 450 includes a mounting plate 401, 451 that has a height that extends substantially over a height of the rear wall 115 and a width that extends over less than half of the rear wall 115.In some implementations, the mounting plate 401, 451 is rectangular.","In other implementations, the mounting plate 401, 451 is generally rectangular with notched corners.","The mounting plate 401, 451 defines one or more apertures 402, 452 through which fasteners extend to secure the mount plate 401, 451 to the enclosure housing 110.The drop-in plate assembly 400 includes a drop-in plate 411 defining one or more holes 412 at which adapters 413 may be secured.","In some implementations, the drop-in plate 411 is formed from a bent portion of the mounting plate 401.In other implementations, the drop-in plate 411 is attached to the mounting plate 401.In some implementations, the drop-in plate 411 extends generally horizontally (i.e., parallel with the top wall 111 and bottom wall 112 of the enclosure housing 110).","In other implementations, the drop-in plate 411 may be angled relative to the top and bottom walls 111, 112.In certain implementations, the adapters 413 are snap-fit or press-fit into the holes 412 of the drop-in plate 411.In some implementations, the adapters 413 are configured to receive and align multi-fiber (MPO) connectors.","A description of example MPO connectors can be found in U.S. Pat.","No.","5,214,730, the disclosure of which is hereby incorporated herein by reference.","In certain implementations, the adapters 413 are configured to receive and align hardened multi-fiber adapters (HMFOCs).","A description of example HIVIFOCs can be found in U.S. Pat.","No.","6,648,520, the disclosure of which is hereby incorporated herein by reference.","In other implementations, the adapters 413 are configured to receive and align single optical connectors (e.g., LC-connectors, SC-connectors, ST-connectors, FC-connectors, etc.).","In certain implementations, the drop-in plate assembly 400 includes fiber management structures to facilitate routing optical fibers or cable between the adapters 413 and other components within the enclosure housing 110.For example, the drop-in plate assembly 400 may include bend radius limiters extending forwardly from the mounting plate 401.In the example shown, smaller bend radius limiters 414 are disposed above the drop-in plate 411 and larger bend radius limiters 415 are disposed below the drop-in plate 411.The larger bend radius limiters 415 form a slack storage spool.","The example sliding adapter mounting assembly 450 includes at least one sliding adapter module 461.Each sliding adapter module 461 includes a plurality of adapters that are slideably mounted to rails.","In the example shown, each sliding adapter module 461 includes a row of six adapters.","In the example shown, the example sliding adapter mounting assembly 450 includes a first group of two sliding adapter modules 461 spaced from another group of two sliding adapter modules 461.In other implementations, however, the example sliding adapter mounting assembly 450 may greater or fewer groups each having greater or fewer sliding adapter modules 461.In some implementations, the sliding adapter modules 461 are configured to slide generally horizontally in a forward-rearward direction relative to the enclosure housing 110.In certain implementations, the sliding adapter modules 461 slide at an angle (e.g., at least partially in an upward-downward direction).","In the example shown, the adapter modules 461 are oriented so that ports of the adapter modules 461 face towards the upper and lower walls 111, 112 of the enclosure housing 110.In other implementations, the adapter modules 461 may be oriented to face the side walls 113, 114 of the enclosure housing 110.As noted above, additional details pertaining to example sliding adapter modules are provided in commonly owned U.S. Pat.","Nos.","5,497,444; 5,717,810; 6,591,051; and 7,416,349, the disclosures of which are incorporated above.","The example sliding adapter mounting assembly 450 also includes a fanout arrangement 462 including one or more fanouts.","Each fanout separates optical fibers from a multi-fiber cable.","In the example shown, the fanout arrangement 462 is disposed between the two groups of adapter modules 461.In other implementations, the fanout arrangement 462 may be disposed elsewhere on the mounting panel 401.In certain implementations, two or more fanouts are stacked together so that a bottom of the stack abuts the mounting panel 401 and a top of the stack faces the open front 116 of the enclosure housing 110.The example sliding adapter mounting assembly 450 also includes fiber management structures to facilitate routing optical fibers or cables from the sliding adapter modules 461 to other components within the enclosure housing 110.In certain implementations, the sliding adapter mounting assembly 450 may include one or more bend radius limiters 463 (FIG.","11).","In the example shown, each group of adapter modules 461 has two corresponding bend radius limiters 463 at a bottom of the mounting panel 401 and at least one bend radius limiter 463 at a top of the mounting panel 401.In certain implementations, the mounting panel 401 also may include guide flanges 464 (FIG.","11) that facilitates retaining optical fibers or cables within the area of the mounting panel 401.In some implementations, the mounting panel 401 defines a guide flange 464 on each side of the mounting panel 401.In the example shown in FIG.","11, each guide flange 464 is bent forwardly from the mounting panel 401.In other implementations, each guide flange 464 may be a separately attached piece.","In the example shown, each guide flange 464 extends vertically to inhibit the fibers from spilling into the rest of the enclosure interior.","In the example shown in FIG.","13, the mounting panel 401 includes retaining flanges 465 defining a guide channel through which one or more fibers or cables may be routed.","The retaining flanges 465 include a first portion extending forwardly of the mounting plate and a second portion that extends across the fibers disposed in the channel.","For example, each retaining flange 465 may have an L-shaped cross-section.","The mounting panel 401 of FIG.","13 also includes another type of guide flange 466 is T-shaped.","The guide flange 466 is disposed between the two groups of sliding adapter modules 461.In some implementations, the sliding adapter mounting assembly 450 may be precabled at the factory or manufacturing center with one or more intermediate fibers 467.Some example intermediate fibers 467 each include a single optical fiber.","First ends of the intermediate fibers 467 are connectorized and plugged into first ports of the sliding adapter modules 461.Second ends of the intermediate fibers 467 are joined at a fanout arrangement 462 to form one or more multi-fiber cables 417.In certain implementations, the second ends of the multi-fiber cables 417 are connectorized (e.g., see optical connectors 418 of FIG.","13).","In other implementations, the second ends of the multi-fiber cables 417 are unconnectorized.","The separate intermediate fibers 467 are routed around from the sliding adapter modules 461 and around the fiber management structures (e.g., bend radius limiters 463 and/or any of flanges 464-466).","In certain implementations, sufficient slack length of the separated fibers 467 is left between the fanout arrangement 462 and the adapter modules 461 to accommodate the sliding movement of the sliding adapter modules 461.In other implementations, however, the sliding adapter mounting assembly 450 may be cabled after the enclosure housing 110 is deployed.","As shown in FIG.","13, the connectors 418 terminating the multi-fiber cables 417 may be plugged into the first ports of the adapters 418 of the drop-in plate assembly 400 when both the drop-in plate assembly 400 and the sliding adapter mounting assembly 450 are disposed within the enclosure housing 110.A first set of additional optical fiber cables (e.g., distribution cables 180) may be routed into the enclosure housing 110 (e.g., through one or more ports 101).","Connectorized ends of the first set of optical fiber cables 180 may be plugged into the second ports of the adapters 413 at the drop-in plate assembly 400.A second set of additional optical fiber cables (e.g., subscriber cables 190) may be routed into the enclosure housing 110 (e.g., through the same or other port modules 101).","Connectorized ends of the second set of optical fiber cables 190 may be secured to second ports of the sliding adapter modules 461.Accordingly, optical signals carried by the first group of optical fibers 182 may be passed to the multi-fiber cables 417 via the drop-in adapters 413 and then to the second group of optical fibers 192 via the sliding adapter modules 461.FIG.","14 illustrates a sixth example modular plate assemblies 120 implemented as an example splice tray mounting assembly 500.In the example shown, the splice tray mounting assembly 500 extends over only a portion of the rear wall 115.For example, the splice tray mounting assembly 500 includes a mounting plate 501 that has a height that extends substantially over a height of the rear wall 115 and a width that extends over less than half of the rear wall 115.In some implementations, the mounting plate 501 is rectangular.","In other implementations, the mounting plate 501 is generally rectangular with notched corners.","In still other implementations, the mounting plate 501 has notched sides.","The mounting plate 501 defines one or more apertures 502 through which fasteners extend to secure the mount plate 501 to the enclosure housing 110.In certain implementations, one or more splice trays 511 are disposed on the mounting plate 501.Each splice tray 511 is configured to optically couple together two or more optical fibers.","For example, each splice tray 511 may optically couple together at least one optical fiber of a service cable and at least one optical fiber of a subscriber cable or an intermediate fiber.","Certain types of splice trays 511 may be pivoted between open and closed positions to provide access to the splices contained therein.","In certain implementations, the splice trays 511 are stacked upon each other so that a bottom of the stack extends over the mounting plate 501 and a top of the stack faces the open front 116 of the enclosure housing 110.One or more support members 503 may aid in securing the splice tray 511 to the mounting plate 501.In FIG.","14, a support member 503 is illustrated as at least one flange bent forwardly from the mounting late 501 at one side of the splice tray 511.One or more fiber management structures may be disposed on the mounting plate 501 about the splice tray arrangement 511.For example, in certain implementations, one or more bend radius limiters 512 are disposed on a front of the mounting plate 501.In the example shown, four bend radius limiters 512 are disposed at four corners of the splice tray arrangement 511.In other implementations, greater or fewer bend radius limiters 512 may be disposed in other configurations.","When the splice tray mounting assembly 500 is installed within the interior of the enclosure housing 110, two or more optical fibers may be spliced at the splice trays 511.In some implementations, one or more optical fiber cables (e.g., service cables) may be routed into the enclosure housing 110 through one or more modular cable ports 101.One or more additional optical fiber cables (e.g., subscriber cables) also may be routed into the enclosure housing 110 through the same or other modular cable ports 101.In some implementations, unconnectorized ends of both groups of optical fiber cables are coupled together at the splice trays 511.In other implementations, the splice tray mounting assembly 500 is disposed within the enclosure housing 110 with the sliding adapter mounting assembly 450.In such implementations, the splice trays 511 are configured to optically couple together unconnectorized ends of a first group of optical fibers (e.g., from one or more service cables) to unconnectorized ends of intermediate fibers 467 plugged into the sliding adapter modules 461 of the sliding adapter mounting assembly 450.As shown in FIG.","15, an example cover 600 may be positioned within the enclosure housing 110 to enclose or otherwise inhibit access to at least a portion of the optical components location within the enclosure housing 110.In some implementations, the cover 600 extends from one of the side walls 113, 114 to an intermediate portion of the enclosure interior to block access to at least some of the fiber optical connectors disposed within the enclosure interior.","In the example shown, the cover 600 extends from the second side wall 114 to cover the drop-in mounting assembly 400.Accordingly, the cover 600 blocks access to the drop-in adapters 413 and to any fiber optic connectors plugged into the drop-in adapters 413.In other implementations, the cover 600 may extend across both the drop-in mounting assembly 400 and the sliding adapter module assembly 450.In still other implementations, the cover 600 may extend across the splice tray mounting assembly 500.In the example shown, the cover 600 includes a front plate 601 and a side plate 602 forming a generally L-shaped flange.","The front plate 601 extends from one side of the mounting plate 401 of the drop-in mounting assembly 400 (or plate 501 of splice tray assembly 500) to the opposite side of the mounting plate 401.The front plate 601 also extends a majority of the distance between the top wall 111 and the bottom wall 112.The side plate 602 extends from the front plate 601 to the rear wall 115 of the enclosure housing 110.In certain implementations, the side plate 602 defines an opening, cutout, or other routing channel 603 through which optical fibers may be routed between the interior spaced enclosed by the cover 600 and the interior space accessible through the open front 116 of the enclosure housing 110.In other implementations, the cover 600 may include two side plates and be located at a central portion of the enclosure interior.","In still other implementations, the cover 600 may include a planar panel that extends across the open front 116 of the enclosure housing 110.In some implementations, the cover 600 defines one or more finger holes 604 by which the cover 600 may be installed and/or removed from the enclosure housing 110.For example, in one implementation, the front panel 601 of the cover 600 defines two finger holes 604.In other implementations, the cover 600 may include a handle or other structure to facilitate manipulation of the cover 600.In certain implementations, the cover 600 may be secured in place by a lock arrangement 605.In some implementations, implementations of the fiber termination enclosure 100 disclosed above may be used in cell site applications.","For example, certain implementations 992 of the fiber termination enclosure 100 may be mounted to a top of a cellular tower or in a hut at a base of a cellular tower.","FIG.","16 is a schematic representation of one example telecommunications network 910 utilizing such a cell site application.","In the depicted embodiment, the telecommunications network 910 is a cellular network 910.The cellular network 910 includes a cell site 912, a demarcation point 914, a backhaul 916 and a core network 918.The cell site 912 creates an area of telecommunications coverage (i.e., a cell) in the cellular network 910.In one embodiment, the cell site 912 includes a tower or mast 920 and a hut 922 that is in communication with the tower 920.In another embodiment, the cell site 912 includes a hut 922 that is in communication with an antenna or a plurality of antenna.","The tower 920 includes a base portion 924 and an oppositely disposed top portion 926.In the depicted embodiment, the base portion 924 is rigidly fixed at a mounting location.","In one embodiment, the top portion 926 of the tower 920 may include an antenna.","The remote transceiver 928 may be integrated into the antenna.","The top portion 926 includes a remote transceiver 928 (e.g., a remote radio head).","The remote transceiver 928 is adapted to transmit and receive signals to and from devices (e.g., mobile phones, smart-phones, devices with wireless internet connectivity, etc.)","of subscribers to the cellular network 910.In certain implementations, the top portion 926 of the tower 920 includes multiple remote transceivers.","In certain implementations, some of the remote transceivers are backup remote transceivers.","The top portion 926 of the tower 920 further includes a multi-service terminal 930.Terminal that are suitable for use as the multi-service terminal 930 of the present disclosure have been described in U.S. Pat.","Nos.","7,292,763 and 7,512,304, the disclosures of which are hereby incorporated by reference in their entirety.","The fiber optic cable 952 from the multi-service terminal 930 is routed to an enclosure 992 at the hut 922.The fiber optic cable 952 includes a first end 962 and an oppositely disposed second end 964.The first end 962 includes a plurality of connectors that are engaged to the inner ports of the fiber optic adapters of the multi-service terminal 930.The second end 964 includes a multi-fiber connector that is adapted for engagement to one of the first and second multi-fiber connectors of the enclosure 992.A jumper cable 966 provides communication between the enclosure 992 and the base transceiver station 990.The jumper cable 966 includes a first end 968 and an oppositely disposed second end 970.The first end 968 is connected to the enclosure 992 while the second end 970 is connected to the base transceiver station 990.In one embodiment, the first end 968 includes a plurality of connectors that are engaged with the second side 924 of the fiber optic adapters 920 of the enclosure 992.In one embodiment, the second end 970 of the jumper cable 966 includes a multi-fiber connector that is engaged to the base transceiver station 990.In another embodiment, the second end 970 includes a plurality of connectors that is engaged to the base transceiver station 990.The base transceiver station 990 is in communication with a telecommunications equipment rack 980 through a multi-fiber patch cable 982.The telecommunications equipment rack 980 is disposed in the hut 922.In one embodiment, the telecommunications equipment rack 980 includes any one or more of a power distribution unit, a fiber distribution unit, a transport switch, a mobile router, a media converter, an Ethernet panel, a DSX panel, protection and a battery.","The telecommunications equipment rack 980 is in communication with the demarcation point 914.The demarcation point 914 is in communication with the backhaul 916, which is in communication with the core network 918.Further details on such a telecommunications network 910 may be found in U.S. patent application Ser.","No.","13/087,022, filed Apr.","14, 2011, and titled “Fiber to the Antenna,” the disclosure of which is hereby incorporated herein by reference.","In other implementations, the fiber termination enclosure disclosed above may be used with other applications.","For example, some fiber termination enclosures may be installed at facilities, such as multiple dwelling units, apartments, condominiums, businesses, etc., to provide a subscriber access point to the fiber optic network.","Other fiber termination enclosures may be installed on towers located on top of high rise buildings or other tall structures.","Various implementations of fiber termination enclosures may be installed at walls, H-frame racks, and poles.","Having described the preferred aspects and implementations of the present disclosure, modifications and equivalents of the disclosed concepts may readily occur to one skilled in the art.","For example, one or more pass-through connections may be provided with any of the above-described types of modular plate assemblies 120.However, it is intended that such modifications and equivalents be included within the scope of the claims which are appended hereto."]],"string":"[\n [\n \"FIBER TERMINATION ENCLOSURE WITH MODULAR PLATE ASSEMBLIES\",\n \"Certain types of fiber termination enclosures include an enclosure and at least one of a plurality of plate module mounting assemblies.\",\n \"Example plate module mounting assemblies include a termination panel plate assembly; a splice tray plate assembly; a cable spool plate assembly; and a drop-in plate assembly.\",\n \"Example cable spool plate assemblies include a cable spool arrangement rotationally coupled to a mounting plate, which fixedly mounts within the enclosure housing.\",\n \"A stand-off mount element may be disposed on the front of the cable spool arrangement to rotate in unison with the cable spool arrangement.\",\n \"The stand-off mount element may include one or more termination adapters.\"\n ],\n [\n \"1.An enclosure system comprising: a housing having opposite sidewalls extending between a top and a bottom and between a rear wall and a front to define an interior, the front of the housing defining a front opening providing access to the interior, the bottom of the housing defining an aperture; a plurality of subassemblies configured to be selectively and interchangeably mounted to the rear wall within the housing interior through the front opening, the plurality of subassemblies including: a first subassembly including a rotatable spool that rotates relative to the housing when mounted therein to allow a cable to be paid off from the spool, the first subassembly further including a mounting plate that carries the rotatable spool, the mounting plate mounting to the rear wall of the housing, the first subassembly also including a fiber optic connector terminating one end of the cable, the fiber optic connector rotating with the spool when the cable is paid off; and a second subassembly including cable splice mounts and a row of fiber optic adapters; and a cable port module disposed at the aperture in the bottom of the housing, the cable port module including a plate defining a cable port extending therethrough, the plate covering the aperture when mounted to the bottom of the housing.\",\n \"2.The enclosure system of claim 1, wherein the cable port module includes a plurality of cable ports extending through the plate.\",\n \"3.The enclosure system of claim 1, wherein the bottom of the housing defines a plurality of apertures; and wherein the cable port module is one of a plurality of cable port modules, each cable port module including a respective plate sized to cover one of the apertures, each of the plates defining at least one cable port extending through the respective plate.\",\n \"4.The enclosure system of claim 1, wherein the cable port module is one type of a plurality of cable port module types that can be selected to interchangeably mount at the bottom of the housing to cover the aperture, each of the cable port module types having a different configuration of cable ports from others of the cable port module types.\",\n \"5.The enclosure system of claim 1, wherein the fiber optic connector is a first fiber optic connector; wherein a second fiber optic connector terminates an opposite end of the cable from the first fiber optic connector; and wherein the second fiber optic connector is external of the housing.\",\n \"6.The enclosure system of claim 1, wherein the first subassembly includes a second row of fiber optic adapters.\",\n \"7.The enclosure system of claim 6, wherein each of the fiber optic adapters on the first subassembly defines first and second aligned ports, wherein insertion axes of the first and second ports extend perpendicular to a rotation axis of the spool.\",\n \"8.The enclosure system of claim 6, wherein the adapters on the first subassembly are carried by the spool so that the adapters rotate with the spool relative to the housing when the cable is paid off.\",\n \"9.The enclosure system of claim 1, wherein the fiber optic connector is fixed in a position relative to the spool so that the connector does not move relative to the spool when cable is paid off the spool.\",\n \"10.The enclosure system of claim 1, wherein the spool extends across a majority of a width of the mounting plate.\",\n \"11.The enclosure system of claim 1, wherein the spool of the first subassembly includes a manual lock.\",\n \"12.The enclosure system of claim 1, wherein the cable is a multi-fiber cable; and wherein a fanout is carried by the spool so that the fanout rotates with the spool relative to the housing when the cable is paid off, the fanout separating out optical fibers of the multi-fiber cable.\",\n \"13.The enclosure system of claim 1, wherein the spool includes a flange and a drum, the flange being spaced from the mounting plate by the drum.\",\n \"14.The enclosure system of claim 13, wherein the flange defines an aperture through which a fastener can be inserted to rotationally fix the spool relative to the housing.\",\n \"15.The enclosure system of claim 1, wherein the first subassembly includes a fiber management arrangement including a radius limiter.\",\n \"16.The enclosure system of claim 15, wherein the fiber management arrangement includes a plurality of radius limiters.\",\n \"17.The enclosure system of claim 15, wherein the fiber management arrangement includes a management plate at which the radius limiter is disposed, the management plate being mounted to the spool.\",\n \"18.An enclosure system comprising: a housing defining an interior and a front opening providing access to the interior, the housing including a back wall partially defining the interior, the back wall having a front surface accessible through the front opening; a fiber deployment module loaded into the housing through the front opening and disposed within the housing interior, the fiber deployment module including a mounting plate that mounts to the front surface of the back wall of the housing, the fiber deployment module including a spool that rotates relative to the mounting plate, the spool extending across a majority of a width of the mounting plate, the mounting plate having at least a portion that extends beyond a perimeter of the spool, the spool including a drum extending outwardly from the mounting plate and a flange disposed at an opposite side of the drum from the mounting plate, the flange having a front axial face; and a multi-fiber cable coiled around the drum of the spool between the mounting plate and the flange, the multi-fiber cable being paid off the drum when the spool is rotated relative to the housing, the multi-fiber cable extending between a first end and a second end, the first end being carried with and rotating in unison with the spool when the cable is paid out by pulling the second end from the housing, the first end of the multi-fiber cable including a fan-out at which fibers of the multi-fiber cable are separated out into a plurality of pigtails, each of the plurality of pigtails having an end connectorized by a fiber optic connector that rotates in unison with the spool when the multi-fiber cable is paid out.\",\n \"19.The enclosure system of claim 18, wherein the fiber deployment module further includes a plurality of fiber optic adapters having ports in which fiber optic connectors at the ends of the pigtails are loaded, and wherein the fiber optic adapters are disposed in a row.\",\n \"20.The enclosure system of claim 19, wherein the plurality of fiber optic adapters are rotatable with the spool when the cable is paid out.\",\n \"21.The enclosure system of claim 18, wherein the fiber deployment module includes a plate that carries a plurality of fiber optic adapters, the fiber deployment module also including a plurality of radius limiters, wherein each of the plurality of fiber optic adapters defines first and second aligned ports, wherein insertion axes of the first and second aligned ports extend perpendicular to a rotation axis of the spool.\",\n \"22.The enclosure system of claim 18, wherein excess length of the pigtails is stored in a coil that is not wound around the drum, the coil being accessible from the front axial face of the flange.\",\n \"23.The enclosure system of claim 22, wherein the coil extends around an axis of rotation of the spool.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>As demand for the telecommunication services increases, fiber optic networks are being extended in more and more areas (e.g., multiple dwelling units, apartments, condominiums, businesses, distributed antenna systems, cell towers, rural areas, single family residences).\",\n \"This growth has been particularly notable in the area of wireless communications, e.g., cellular, personal communication services (PCS) and other mobile radio systems.\",\n \"To efficiently distribute fiber optic services to these various different subscribers, system design flexibility is significant.\",\n \"System design flexibility can include the ability to efficiently provide different varying fiber optic cable lengths and the ability to efficiently provide fiber optic enclosures having interior components customized to meet a given customer's needs.\"\n ],\n [\n \"<SOH> SUMMARY <EOH>An aspect of the present disclosure relates to a fiber optic enclosure assembly.\",\n \"The fiber optic enclosure includes an enclosure housing that is adapted to optically connect incoming fibers to outgoing fibers.\",\n \"One or more modular plate assemblies may be mounted within an interior of the enclosure to customize the fiber optic enclosure.\",\n \"In accordance with some aspects of the disclosure, certain types of modular plate assemblies include termination adapter arrangements.\",\n \"In accordance with some aspects of the disclosure, certain types of modular plate assemblies include splice trays arrangements.\",\n \"In accordance with some aspects of the disclosure, certain types of modular plate assemblies include cable spool arrangements.\",\n \"In accordance with some aspects of the disclosure, modular cable port arrangements may be disposed at the enclosure housing.\",\n \"In some implementations, various types of modular cable port arrangements can be selectively mounted at the enclosure housing.\",\n \"In accordance with certain aspects of the disclosure, a cable spool arrangement is connected to an interior of the enclosure to rotate relative to the enclosure.\",\n \"One or more fiber cables may be paid out from the enclosure by pulling one end of the fiber cable through a cable port to unwind the fiber cable from the cable spool arrangement.\",\n \"In certain implementations, one or more adapters may be disposed on the cable spool arrangement to rotate in unison with the cable spool arrangement.\",\n \"In certain implementations, the termination adapters are disposed on a stand-off mount element that is spaced from the cable spool arrangement, but configured to rotate in unison with the cable spool arrangement.\",\n \"A variety of additional aspects will be set forth in the description that follows.\",\n \"These aspects can relate to individual features and to combinations of features.\",\n \"It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the broad concepts upon which the embodiments disclosed herein are based.\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser.\",\n \"No.\",\n \"15/615,999, filed Jun.\",\n \"7, 2017, which is a continuation of U.S. application Ser.\",\n \"No.\",\n \"15/243,143, filed Aug. 22, 2016, now U.S. Pat.\",\n \"No.\",\n \"9,678,293, which is a continuation of U.S. application Ser.\",\n \"No.\",\n \"14/979,803, filed Dec. 28, 2015, now U.S. Pat.\",\n \"No.\",\n \"9,423,584, which is a continuation of U.S. application Ser.\",\n \"No.14/127,851, filed Feb. 12, 2014, now U.S. Pat.\",\n \"No.\",\n \"9,223,106, which is a National Stage of PCT/US2012/043827, filed Jun.\",\n \"22, 2012, which claims the benefit of U.S.\",\n \"Application Nos.\",\n \"61/500,769, filed Jun.\",\n \"24, 2011, and titled “Fiber Termination Enclosure with Internal Cable Spool Assembly;” 61/500,764, filed Jun.\",\n \"24, 2011, and titled “Fiber Termination Enclosure with Modular Plate Assemblies;” 61/507,263, filed Jul.\",\n \"13, 2011, and titled “Fiber Termination Enclosure with Internal Cable Spool Assembly,” and 61/507,270, filed Jul.\",\n \"13, 2011, and titled “Fiber Termination Enclosure with Modular Plate Assemblies;” the disclosures of which are hereby incorporated herein by reference.\",\n \"TECHNICAL FIELD The present disclosure relates to fiber optic enclosure, and more particularly, to a fiber optic enclosure with cable payout.\",\n \"BACKGROUND As demand for the telecommunication services increases, fiber optic networks are being extended in more and more areas (e.g., multiple dwelling units, apartments, condominiums, businesses, distributed antenna systems, cell towers, rural areas, single family residences).\",\n \"This growth has been particularly notable in the area of wireless communications, e.g., cellular, personal communication services (PCS) and other mobile radio systems.\",\n \"To efficiently distribute fiber optic services to these various different subscribers, system design flexibility is significant.\",\n \"System design flexibility can include the ability to efficiently provide different varying fiber optic cable lengths and the ability to efficiently provide fiber optic enclosures having interior components customized to meet a given customer's needs.\",\n \"SUMMARY An aspect of the present disclosure relates to a fiber optic enclosure assembly.\",\n \"The fiber optic enclosure includes an enclosure housing that is adapted to optically connect incoming fibers to outgoing fibers.\",\n \"One or more modular plate assemblies may be mounted within an interior of the enclosure to customize the fiber optic enclosure.\",\n \"In accordance with some aspects of the disclosure, certain types of modular plate assemblies include termination adapter arrangements.\",\n \"In accordance with some aspects of the disclosure, certain types of modular plate assemblies include splice trays arrangements.\",\n \"In accordance with some aspects of the disclosure, certain types of modular plate assemblies include cable spool arrangements.\",\n \"In accordance with some aspects of the disclosure, modular cable port arrangements may be disposed at the enclosure housing.\",\n \"In some implementations, various types of modular cable port arrangements can be selectively mounted at the enclosure housing.\",\n \"In accordance with certain aspects of the disclosure, a cable spool arrangement is connected to an interior of the enclosure to rotate relative to the enclosure.\",\n \"One or more fiber cables may be paid out from the enclosure by pulling one end of the fiber cable through a cable port to unwind the fiber cable from the cable spool arrangement.\",\n \"In certain implementations, one or more adapters may be disposed on the cable spool arrangement to rotate in unison with the cable spool arrangement.\",\n \"In certain implementations, the termination adapters are disposed on a stand-off mount element that is spaced from the cable spool arrangement, but configured to rotate in unison with the cable spool arrangement.\",\n \"A variety of additional aspects will be set forth in the description that follows.\",\n \"These aspects can relate to individual features and to combinations of features.\",\n \"It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the broad concepts upon which the embodiments disclosed herein are based.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS FIG.\",\n \"1 is a schematic diagram of a fiber termination enclosure having an example mounting assembly disposed therein in accordance with the principles of the present disclosure; FIG.\",\n \"2 is a front, top perspective view of an example fiber termination enclosure including an enclosure configured in accordance with the principles of the present disclosure and shown with a door in a closed position; FIG.\",\n \"3 is a front, bottom perspective view of the example fiber termination enclosure of FIG.\",\n \"2 in which two cable port modules are visible; FIG.\",\n \"4 is a front, top perspective view of the example fiber termination enclosure of FIG.\",\n \"2 shown with the door in the open position and a cable spool mounting assembly exploded from the interior of the enclosure; FIG.\",\n \"5 is a schematic diagram of the fiber termination enclosure of FIG.\",\n \"4 configured in accordance with the principles of the present disclosure; FIG.\",\n \"6 is a front, top perspective view of the example fiber termination enclosure of FIG.\",\n \"4 in which with the cable spool mounting assembly is exploded to show various example components of the cable spool mounting assembly including a mounting plate, a cable spool arrangement, and a stand-off mount element; FIG.\",\n \"7 is a front, top perspective view of the example fiber termination enclosure of FIG.\",\n \"6 shown with the cable spool mounting assembly installed within the interior of the enclosure housing; FIG.\",\n \"8 is a front, top perspective view of the example fiber termination enclosure of FIG.\",\n \"2 shown with an example splice tray reel mounting assembly installed within the interior of the enclosure housing; FIG.\",\n \"9 is a front, top perspective view of the example fiber termination enclosure of FIG.\",\n \"2 shown with an example termination panel mounting assembly installed within the interior of the enclosure housing; FIG.\",\n \"10 is a front, top perspective view of the example fiber termination enclosure of FIG.\",\n \"9 shown with an example cover disposed over the cable spool mounting assembly; FIG.\",\n \"11 is a front, top perspective view of the example fiber termination enclosure of FIG.\",\n \"2 shown with the door in the open position, an example sliding adapter mounting assembly disposed within the interior of the enclosure, and an example drop-in plate mounting assembly exploded from the interior of the enclosure; FIG.\",\n \"12 is a front, top perspective view of the example fiber termination enclosure of FIG.\",\n \"11 shown with the example drop-in plate mounting assembly disposed within the interior of the enclosure and partially cabled; FIG.\",\n \"13 is a front, top perspective view of the example fiber termination enclosure of FIG.\",\n \"12 shown with cabling extending between the example drop-in plate mounting assembly and the example sliding adapter mounting assembly; FIG.\",\n \"14 is a front, top perspective view of the example fiber termination enclosure of FIG.\",\n \"2 shown with an example splice tray mounting assembly and an example sliding adapter mounting assembly disposed within the interior of the enclosure housing; FIG.\",\n \"15 is a front, top perspective view of the example fiber termination enclosure of FIG.\",\n \"14 shown with an example cover disposed over the splice tray mounting assembly; and FIG.\",\n \"16 is a schematic representation of a telecommunications network having exemplary features of aspects in accordance with the principles of the present disclosure.\",\n \"DETAILED DESCRIPTION Reference will now be made in detail to the exemplary aspects of the present disclosure that are illustrated in the accompanying drawings.\",\n \"Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like structure.\",\n \"FIG.\",\n \"1 is a schematic diagram of an example fiber optic enclosure 100.The fiber optic enclosure 100 includes a housing, generally designated 110, at which telecommunications cables (e.g., optical and/or electrical cables) can be optically coupled and/or stored.\",\n \"One or more modular plate assemblies 120 may be mounted within the interior of the enclosure housing 110.Each modular plate assembly 120 includes a mounting plate 121 that is configured to mount to the enclosure housing 110 in a stationary configuration.\",\n \"Each modular plate assembly 120 includes a coupling arrangement 170 at which one or more optical fibers 182 of at least a first fiber cable 180 are optically coupled to optical fibers 192 of at least a second fiber cable 190.The fiber cables 180, 190 enter the enclosure housing 110 through cable ports 101.In use, the enclosure housing 110 is deployed by securing the enclosure housing 110 to a mounting location (e.g., a wall, a pole, etc.).\",\n \"In some implementations, the enclosure housing 110 has brackets disposed on the top and bottom walls 111, 112.In other implementations, the enclosure housing 110 may have brackets disposed on other walls to secure the enclosure housing 110 to the mounting location.\",\n \"In still other implementations, the enclosure housing 110 is adapted to be otherwise secured to a mounting location.\",\n \"FIGS.\",\n \"2-4 illustrate one example enclosure housing 110 having a top wall 111, a bottom wall 112 (FIG.\",\n \"3), a first side wall 113, a second side wall 114 (FIG.\",\n \"4), and a rear wall 115 (FIG.\",\n \"4) defining an interior.\",\n \"The enclosure housing 110 also defines an open front 116 that provides access to the interior of the enclosure housing 110 (see FIG.\",\n \"4).\",\n \"At least one cover 118 is coupled to the enclosure housing 110 to selectively close the open front 116 of the enclosure housing 110.The cover 118 is pivotally coupled to the enclosure housing 110 using one or more hinges 103 disposed on one of the side walls 113, 114 (see FIG.\",\n \"4).\",\n \"The hinge 103 allows the cover 118 to selectively pivot between a closed position (shown in FIG.\",\n \"2) and an open position (shown in FIG.\",\n \"4).\",\n \"The cover 118 can be held closed using locking flanges 117, 119 (FIG.\",\n \"4).\",\n \"In one implementation, the enclosure housing 110 is molded from a plastic material.\",\n \"In one implementation, the enclosure housing 110 is molded from a plastic material.\",\n \"In another implementation, the enclosure housing 110 is molded from a metal material.\",\n \"In some implementations, the enclosure housing 110 defines one or more cable ports 101 (FIG.\",\n \"1) at which cables 180, 190 may enter and exit the interior of the enclosure housing 110.In certain implementations, the cable ports 101 are disposed at the bottom wall 112 of the enclosure housing 110.In other implementations, however, the cable ports 101 may be disposed elsewhere on the enclosure housing 110, such as at the top wall 111, the rear wall 115, or one of the side walls 113, 114.In some implementations, the enclosure housing 110 is configured to receive one or more cable port modules 150 at the cable ports 101 (e.g., see FIGS.\",\n \"3 and 4).\",\n \"For example, the cable ports 101 may define openings 155 (FIG.\",\n \"4) in one or more walls 111-115 of the enclosure housing 110 at which the cable port modules 150 may be received.\",\n \"Each cable port module 150 receives one or more cables 180, 190.In some implementations, a first cable port module 150 may receive one or more service cables and a second cable port module 150 may receive one or more subscriber cables.\",\n \"In other implementations, the same cable port module 150 may receive both service cables and subscriber cables.\",\n \"In still other implementations, the enclosure housing 110 may receive an even greater number of cable port modules 150, each of which may receive service cables and/or subscriber cables.\",\n \"In certain implementations, a variety of cable port modules 150 may be configured to fit at the same opening 155, thereby enabling a user to select which of the cable port modules 150 to mount at the opening 155.In certain implementations, the cable port modules 150 may be removably mounted to the enclosure housing at the openings 155, thereby enabling a user to switch which cable port modules 150 are mounted at any particular enclosure housing 110.Two example implementations of cable port modules 150, 150′ are shown in FIGS.\",\n \"3 and 4.Each of the cable port modules 150, 150′ includes a port panel 151 configured to be mounted at an opening 155 defined in an enclosure housing 110.For example, the port panel 151 may define one or more openings 152 through which fasteners (e.g., screws, bolts, etc.)\",\n \"may extend to secure the port panel 151 to one of the walls 111-115 of the enclosure housing 110.One or more grommets extend through the port panel 151.Each grommet enables one or more cables 180, 190 or fibers to enter the enclosure housing 110 while inhibiting the ingress of environmental contaminants, such as water, dirt, and rodents.\",\n \"A first example cable port module 150 includes a first type of grommet 153 and a second type of grommet 154.The second type of grommet 154 is larger than the first type of grommet 153.In the example shown, a cable 180 to be dispensed extends through the smaller grommet 153.A second example cable port module 150′ includes only the second type of grommet 154 extending through the port panel 151.Other implementations may include still other types of cable port modules, each having its own configuration of grommets.\",\n \"Referring to FIGS.\",\n \"4-15, the mounting plates 121 of the modular plate assemblies 120 are adapted and configured to be mounted to the rear wall 115 of the enclosure housing 110.In some implementations, the rear wall 115 defines one or more openings through which fasteners may extend to secure a mounting plate 121 to the rear wall 115.In other implementations, the rear wall 115 may include one or more pegs over which the mounting plate 121 may be pressed.\",\n \"In other implementations, one or more panel fastening structures can be attached, secured, or mounted to the rear wall 115.In still other implementations, the rear wall 115 may include one or more pems 104 that are pressed into the rear wall 115 (see FIG.\",\n \"4).\",\n \"The pems 104 are sized and configured to be inserted through openings 122 defined in the mounting plate 121.The pems 104 define threaded passages that are configured to receive fasteners that secure the mounting plate 121 to the rear wall 115, or can be exterior threaded shanks.\",\n \"In accordance with some aspects, the mounting plates 121 of the modular plate assemblies 120 extend over a majority of the area of the rear wall 115.In some implementations, a mounting plate 121 has a rectangular shape (e.g., see FIG.\",\n \"4).\",\n \"In other implementations, a mounting plate 121 may define one or more cutouts 129 or otherwise have a non-rectangular shape (e.g., see FIGS.\",\n \"9-12).\",\n \"In accordance with other aspects, the mounting plates 121 of the modular plate assemblies 120 may extend over only a portion of the area of the rear wall 115.For example, some implementations, of the mounting plates 121 may be configured to extend over about half of the area of the rear wall 115 (e.g., see FIGS.\",\n \"11-14).\",\n \"FIGS.\",\n \"4-7 illustrate a first implementation of a modular plate assembly 120 that includes a cable spool arrangement 130 (FIG.\",\n \"6) that is rotationally mounted to the modular plate assembly 120.As shown in FIG.\",\n \"5, the cable spool arrangement 130 includes a first storage area 102, a second storage area 104, and a termination region 108.In some implementations, the termination region 108 is spaced from the second storage area 104, which is spaced from the first storage area 102.In certain implementations, the termination region 108 is spaced forwardly of the second storage region 104, which is spaced forwardly of the first storage region 102 (e.g., see FIG.\",\n \"4).\",\n \"In certain implementations, the second storage area 104 forms part of a protected fiber management region 106 at which optical fibers can be separated out from optical cables.\",\n \"At least a first fiber cable (e.g., distribution cable) 180 and at least a second cable (e.g., subscriber cable) 190 enter the housing 110 through cable ports 101.Fibers 192 of the second fiber cable 190 are routed to the termination region 108.The first fiber cable 180 is routed to the first storage area 102 of the cable spool arrangement 130.From the first storage area 102, the first fiber cable 180 is routed to the second storage area 104.The first fiber cable 180 is broken out into individual optical fibers 182 at the protected fiber management region 106.The fibers 182 are routed to the termination region 108 at which the optical fibers 184 are connected to optical fibers 192 of the second fiber cable 190.The fiber optic enclosure 100 provides an enclosure from which lengths of a cable (e.g., a distribution cable) 180 can be dispensed following the mounting of the fiber optic enclosure 100 to a mounting location.\",\n \"The distribution cable 180 is dispensed from the fiber optic enclosure 100 by pulling on an end (e.g., a connectorized end) 185 of the cable 180 (see FIGS.\",\n \"4 and 7).\",\n \"As the distribution cable 180 is dispensed, the cable spool arrangement 130 rotates about an axis relative to the stationary mounting plate 121 of the fiber optic enclosure 100.In the event that there is a residual length of distribution cable 180 that is not dispensed during the cable payout, the fiber optic enclosure 100 can store this residual length.\",\n \"As shown in FIG.\",\n \"6, the cable spool mounting assembly 120 includes a mounting plate 121 and a cable spool arrangement 130.The mounting plate 121 includes a first side 124 and an opposite second side 123.The mounting plate 121 is adapted for stationary mounting to the rear wall 115 of the housing enclosure.\",\n \"In certain implementations, the second side 123 of the mounting plate 121 is configured to be mounted to an interior surface of the rear wall 115 so that the mounting plate 121 is disposed within the interior of the housing enclosure 110.For example, in certain implementations, the mounting plate 121 defines one or more fastener openings 122 that are disposed to align with fastener openings provided on the rear wall 115 of the housing enclosure 110.Certain types of mounting plates 121 extend along substantially the entire rear wall 115 of the enclosure housing 110.The cable spool arrangement 130 includes a drum 131 extending between first and second support flanges 132, 133 to form a first cable spool 134.The first cable spool 134 defines the first storage region 102 (FIG.\",\n \"5).\",\n \"In some implementations, the cable spool arrangement 130 also includes a termination region 108 (FIG.\",\n \"5).\",\n \"In certain implementations, a protected fiber management region 106 (FIG.\",\n \"5) is defined between the first storage region 102 and the termination region 108.For example, in certain implementations, in FIG.\",\n \"6, the cable spool arrangement 130 includes a stand-off mounting assembly 140, at which the termination region 108 (FIG.\",\n \"5) is disposed as will be described in more detail herein.\",\n \"The protected fiber management region 106 (FIG.\",\n \"5) is defined between the stand-off mounting assembly 140 and one of the first cable spool 134 (e.g., see FIG.\",\n \"4).\",\n \"In certain implementations, the drum portion 131 of the first cable spool 134 is generally cylindrical in shape.\",\n \"The drum portion 131 includes a first end portion that couples to the first support flange 132 and an oppositely disposed second end portion that couples to the second support flange 133.The support flanges 132, 133, which are generally parallel to each other, are configured to rotate with the drum 131.An outer surface of the drum 131 and inner surfaces of the support flanges 132, 133 define the first storage region 102 (FIG.\",\n \"5) within which optical fibers or cables (e.g., distribution cable 180) may be coiled.\",\n \"The drum portion 131 has a sufficient diameter to provide bend radius protection to optical fibers wound around the fiber spool 134.The drum portion 131 defines a central bore that extends through the drum portion 131.In the subject embodiment, the central bore is adapted to receive a spindle 129 (FIG.\",\n \"6).\",\n \"In certain implementations, the spindle 129 extends through the bore in the drum 131 and secures to the second side 123 of the mounting plate 121.For example, in certain implementations, the mounting plate 121 defines openings 125 at which the spindle 129 is fastened to the mounting plate 121.The first cable spool 134 is configured to rotate about the spindle 129 relative to the mounting plate 121.The support flanges 132, 133 are sized and shaped to retain the optical fibers wound around the drum 131 in the first storage region 102.In some implementations, the support flanges 132, 133 are generally circular.\",\n \"In certain implementations, the support flanges 132, 133 have a sufficient diameter to cover a majority of a surface area of the mounting plate 121.In other implementations, however, one or both of the support flanges 132, 133 may have a smaller diameter.\",\n \"In some implementations, the cable spool arrangement 130 is configured to be releasably locked in a rotationally fixed position relative to the mounting plate 121.For example, in certain implementations, the mounting plate 121 includes a forwardly extending flange 126 that is configured to extend past the support flanges 132, 133 of the drum 131 to interact with the front of the cable spool arrangement 130 (see FIG.\",\n \"6).\",\n \"The forwardly extending flange 126 defines an opening 127.The second flange 133 of the cable spool 134 defines an opening 136 that is disposed to align with the opening 127 of the forwardly extending flange 126 when the cable spool arrangement 130 is disposed in one rotational position.\",\n \"In certain implementations, the opening 136 is defined in a tab 135 that extends outwardly from the generally annular circumference of the second support flange 133.A fastener 128 may be inserted through the openings 136, 127 to lock the cable spool arrangement 130 in the rotationally fixed position.\",\n \"In some implementations, the second support flange 133 of the cable spool 134 defines an aperture 139 through which optical fibers or cables (e.g., distribution cable 180) may pass between the first storage area 102 and the front of the cable spool 134.In certain implementations, the cables pass through aperture 139 from the first storage region 102 to the protected fiber management region 106.For example, in certain implementations, the aperture 139 is located directly adjacent to the protected fiber management region 106 and allows cables from inside the first storage region 102 of the spool to be routed from the drum surface 131 to the protected storage region 106.The protected fiber management region 106 (FIG.\",\n \"5) provides a mounting location for a fan out arrangement.\",\n \"The fan out arrangement includes one or more fan outs 138 disposed between the back side of the stand-off 140 and the front side of the cable spool 134 (see FIG.\",\n \"4).\",\n \"For example, the fan outs 138 may be disposed on the front side of the second support flange 133 of the cable spool 134.Accordingly, the fan outs 138 rotate with the cable spool 134.The cable 180 wrapped around the supplemental spool region 104 can be routed to one of the fan outs 138 where individual optical fiber are broken out to form individual fiber optic pigtails 182.The pigtails 182 have ends connectorized by fiber optic connectors that are inserted into the fiber optic adapters 147 at the termination field 108 (see FIG.\",\n \"4).\",\n \"Fiber optic connectors corresponding to fibers 192 of subscriber cables 190 also may be inserted into the adapters 147 to provide optical connections between the subscriber cables 190 and the cables 180 routed from the first cable spool 134.The protected fiber management region 106 also can include bend radius protectors 137 attached to the front spool flange 133 (FIG.\",\n \"6).\",\n \"The bend radius protector 137 can form a supplemental spooling region 104 where cables routed from drum 131 through aperture 139 can be wrapped/spooled to provide cable storage and cable management.\",\n \"The pigtails 182 also may be wrapped/spooled around the bend radius limiters 137.In some implementations, the supplemental spooling region 104 provides strain relief to the cables (e.g., distribution cables) 180.Axial loads applied to the outside end 185 of the cables 180 will be transferred through the cable 180 to the wrapped portions of the cable 180.However, the axial loads will not be transferred to the connectorized ends of the pigtails 182.Accordingly, pulling on the first cable end 185 will not detach the connectorized pigtails 182 from the adapters 147 at the termination region 108.Still referring to FIGS.\",\n \"4-7, a stand-off mount element 140 may be coupled to the front of the first cable spool 134.For example, the stand-off mount element 140 may be secured to the second support flange 133 of the first cable spool 134 so that the stand-off mount element 140 unitarily rotates with the first cable spool 134.The stand-off mount element 140 provides a front plate 141 where optical components (e.g., fiber optic adapters, splitters, splice trays, spools, bend radius protector, etc.)\",\n \"can be mounted.\",\n \"For example, fiber optic adapters 147 may form a termination region 108 on the front plate 141.Cable management structures (e.g., bend radius limiters, spools, etc.)\",\n \"148 also may be provided on the stand-off plate 141.In the example shown, two opposing bend radius limiters 148 form a fiber spool on the stand-off plate 141.In certain implementations, one or more legs 142 extend rearwardly from the stand-off plate 141 of the stand-off mount element 140.Each leg 142 defines an opening 143 configured to receive a peg 145 or fastener to secure the feet 143 to the front support flange 133 of the cable spool 134.In the example shown, the stand-off mount element 140 includes four legs 142.In other implementations, however, the stand-off mount element 140 may include greater or fewer legs 142.In still other implementations, the legs 142 may be unitary with the cable spool 134 and secure to the stand-off plate 141.The stand-off plate 141 is forwardly offset from the front side of the spool flange 133, thereby forming the protected fiber management region 106 between the front side of the first cable spool 134 and back side of the stand-off mount element 140 (e.g., see FIG.\",\n \"4).\",\n \"The separated fibers 184 in the protected fiber management region 106 are routed around the bend radius limiters 137 or other management structures on the front of the cable spool 134 to the stand-off mount element 140.In the example shown, the separated fibers 184 have connectorized ends that plug into first ports of termination adapters 147 disposed at the stand-off plate 141.Components disposed on the stand-off mount element 140 are spaced forwardly of the cable spool 134.Accordingly, the fiber optic adapters 147 are disposed on a different layer or plane than the fan outs 138, which are disposed on a different layer or plane than the first cable spool 134.In certain implementations, the fan outs 138 are disposed on the same layer or plane as the bend radius limiters 137.The spacing between the cable spool layer and the stand-off layer enhances slack storage of optical fibers routed through the protected fiber management region 106.In some implementations, the spacing between the cable spool layer and the stand-off layer inhibits over-bending of the fibers when routed between the fan out arrangements 138 and the fiber optic adapters 147.In certain implementations, the termination adapters 147 are included in one or more termination modules 146.In certain implementations, the adapter modules 146 are sliding adapter modules.\",\n \"Similar sliding adapter modules have been described in commonly owned U.S. Pat.\",\n \"Nos.\",\n \"5,497,444; 5,717,810; 6,591,051; and 7,416,349, the disclosures of which are hereby incorporated by reference.\",\n \"In the example shown, the stand-off mount element 140 includes six sliding adapter modules 146, each holding four fiber optic adapters 147.In other implementations, the stand-off mount element 140 may include greater or fewer sliding adapter modules 146 holding greater or fewer termination adapters 147.In certain implementations, sufficient slack length of the separated fibers 182 is left between the fan out arrangement 138 and the adapters 147 to accommodate the sliding movement of the sliding adapter modules 146.In some implementations, the cable spool arrangement 130 may be precabled at the factory or manufacturing center with one or more optical fibers or cables 180.For example, one or more multi-fiber cables 180 may be wound around the storage area 102 of the cable spool 134.In certain implementations, the multi-fiber cables 180 may be precabled to pass through the aperture 139 to the fan out arrangement 138 disposed in the protected fiber management region 106 (e.g., see FIGS.\",\n \"4 and 7).\",\n \"The fan out arrangement 138 separates the cables 180 into pigtails 182.In certain implementations, the fan out arrangement 138 also upjackets the fibers 182.In other implementations, however, the cable spool arrangement 130 may be cabled with the one or more multi-fiber cables 180 after the enclosure housing 110 is deployed.\",\n \"The precabled cable spool mounting assembly 120 is mounted within the enclosure housing 110.For example, the mounting plate 121 is secured to a rear wall 115 of the enclosure housing 110.When the mounting assembly 120 is installed in the enclosure housing 110, the second ends of the multi-fiber cables 180 may be routed through one of the cable ports so that the second ends are disposed outside of the enclosure housing 110.In some implementations, the second ends of the one or more precabled multi-fiber cables 180 may be terminated at one or more multi-fiber connectors 185.In other implementations, the second end of a precabled multi-fiber cable 180 is separated into two or more connectorized optical fibers (jacketed or unjacketed).\",\n \"In still other implementations, the second ends of the multi-fiber cables 180 are configured to be spliced to one or more optical fiber cables.\",\n \"A user may pull on the second ends to dispense the stored length of cable 180 from the cable spool arrangement 130.For example, a user may pull a second end of a cable 180 to a fiber distribution hub, drop terminal, or other network connection.\",\n \"Because the adapters 147 rotate in unison with the cable spool arrangement 130, the second end of each multi-fiber cable 180 may be paid out without interfering with the cabling of the first ends of the multi-fiber cable 180.When the second ends 185 of the one or more multi-fiber cables 180 are each connected to the network, the fastener 128 may be inserted through aligned openings 135, 128 to secure the cable spool arrangement 130 in a fixed rotational position relative to the mounting plate 121.When the cable spool arrangement 130 is secured in a rotationally fixed position, additional optical fiber cables may be routed into the enclosure housing 110 to secure to second ports of the termination adapters 147.For example, the additional optical fiber cables may be routed into the enclosure through one or more cable ports defined in the enclosure housing 110.The termination adapters 147 are configured to align and optically couple connectors terminating the additional optical cables with the connectorized ends of the multi-fiber cable 180 plugged into the first ports of the adapters 147.FIG.\",\n \"8 illustrates a second example modular plate assembly 220 implemented as a second example cable spool mounting assembly 120 for mounting within the enclosure housing 110.The second cable spool mounting assembly 220 includes a rectangular mounting plate 221 that extends over a majority of the rear wall 115.A cable spool arrangement 241 is disposed on the mounting plate 221 and is configured to rotate relative to the mounting plate 221 (e.g., about a spindle).\",\n \"Since the mounting plate 221 is configured to remain stationary on the rear wall 115, the cable spool arrangement 241 is configured to rotate relative to the enclosure housing 110.The cable spool arrangement 241 defines a storage area including a drum about which optical fibers or cables (e.g.\",\n \"of a multi-fiber distribution cable 180) may be coiled.\",\n \"The drum has a sufficient diameter to provide bend radius protection to optical fibers wound around the fiber spool arrangement 241.Rotating the cable spool arrangement 241 dispenses or retracts the optical fibers or cables wound around the drum.\",\n \"In some implementations, the cable spool arrangement 241 may be locked in a rotational orientation relative to the mounting plate 221.In certain implementations, one or more splice trays 242 are disposed on the cable spool arrangement 241.Each splice tray 242 is configured to optically couple together two or more optical fibers.\",\n \"For example, each splice tray 242 may optically couple together at least one optical fiber of the distribution cable 180 and at least one optical fiber of a subscriber cable 190 (FIG.\",\n \"1).\",\n \"Certain types of splice tray 242 may be pivoted between open and closed positions to provide access to the splices contained therein.\",\n \"In certain implementations, the splice trays 242 are stacked upon each other so that a bottom of the stack extends over the cable spool arrangement 241 and a top of the stack faces the open front 116 of the enclosure housing 110.One or more fiber management structures may be disposed on the cable spool arrangement 241.For example, in certain implementations, one or more bend radius limiters 243 are disposed on a front of the cable spool arrangement 241.In the example shown, four bend radius limiters are disposed at a top, bottom, and sides of the cable spool arrangement 241.The cable spool arrangement 241 also defines one or more channels 244 through which optical fibers or cables can pass between the storage area of the cable spool arrangement 241 and the splice trays 242.In the example shown, the cable spool arrangement 241 defines four openings 244 spaced between the bend radius limiters 243.In some implementations, the second cable spool mounting assembly 220 may be precabled at the factory or manufacturing center with one or more distribution cables 180.The one or more distribution cables 180 may be wound around the drum in the storage area of the second cable spool arrangement 241.In certain implementations, the first end of each distribution cable fiber may be routed through one of the openings 244 in the cable spool arrangement 241, around one or more of the bend radius limiters 243, and into one of the splice trays 242 disposed at a front of the cable spool arrangement 241 (e.g., see FIG.\",\n \"8).\",\n \"The precabled second cable spool mounting assembly 220 is mounted within the enclosure housing 110 to deploy the one or more distribution cables 180.For example, the mounting plate 221 is secured to the rear wall 115 of the enclosure housing 110 as described above.\",\n \"The second ends 185 of the distribution cables 180 may be routed out of the housing 110 through one of the cable port modules 101 so that the second ends 185 are disposed outside of the enclosure housing 110 (e.g., see FIG.\",\n \"8).\",\n \"Additional optical fiber cables (e.g., subscriber cables 190 of FIG.\",\n \"1) may be routed into the enclosure housing 110 (e.g., through the same or other port modules 101).\",\n \"Unconnectorized ends of the subscriber cable fibers may be optically coupled to the first ends of the service cable fibers at the splice trays 242.For example, each subscriber cable fiber may be routed from the respective cable port module 101 to the respective splice tray 242 (e.g., either directly or after being wound around some of the bend radius limiters 243 of the second cable spool mounting assembly 220.FIGS.\",\n \"9 and 10 illustrate a third example modular plate assembly 120 implemented as a termination panel mounting assembly 320.The termination panel mounting assembly 320 includes a mounting plate 321 that is sized to extend over a majority of the rear wall 115 of the enclosure housing 110.In particular, the mounting plate 321 has a height that extends over a majority of a height of the rear wall 115 and the mounting plate 321 has a width that extends over a majority of a width of the rear wall 115.The mounting plate 321 defines one or more apertures 322 or pems that facilitate connection to the rear wall 115.Certain types of mounting plates 321 define one or more cutouts 329.In the example shown in FIG.\",\n \"9, the mounting plate 321 defines a cutout 329 at an upper, right corner of the mounting plate 321, thereby resulting in an L-shaped mounting panel 321.In other implementations, the mounting plate 321 may have other configurations.\",\n \"A termination plate 351 is coupled to the mounting plate 321.In some implementations, the termination plate 351 is a bent portion of the mounting plate 321.In other implementations, the termination plate 351 is a separate piece that attaches to the mounting plate 321 (e.g., via snap-fit connection, latches, fasteners, etc.).\",\n \"In the example shown, the termination plate 351 extends vertically with a first side facing the first side wall 113 and a second side facing he second side wall 114 of the enclosure housing 110.In other implementations, the termination plate 351 has a first side that faces the rear wall 115 and a second side that faces the open front 116 of the enclosure housing 110.One or more termination adapters 352 are disposed on the termination plate 351.Each termination adapter 352 has a first port and a second port.\",\n \"In the example shown, the first port faces the first side wall 113 and the second port faces the second side wall 114 of the enclosure housing 110.In other implementations, the adapter ports may face the rear wall 115 and open front 116 of the enclosure housing 110.In still other implementations, the adapters 352 and the termination plate 351 may be oriented at any desired angle relative to the mounting plate 321.In certain implementations, adapter dust caps 353 may be provided at the adapter ports.\",\n \"In certain implementations, one or more cable management structures may be provided on the termination plate 351 or mounting plate 321.In the example shown, four bend radius limiters 354 are disposed on a front of the mounting plate 321.The bend radius limiters 354 are configured to form two fiber spools.\",\n \"In certain implementations, the bend radius limiters 354 form a first fiber spool located between the termination plate 351 and the first side wall 113 of the housing 110 and a second fiber spool located between the termination plate 351 and the second side wall 114 of the housing 110.In certain implementations, the bend radius limiters 354 are located substantially below the termination plate 351.In other implementations, the same or other types of cable management structures may be disposed in different configurations.\",\n \"During deployment of the termination panel mounting assembly 350, one or more optical fiber cables (e.g., distribution cables 180) may be routed into the enclosure housing 110 (e.g., through one or more port modules 101).\",\n \"Connectorized ends of the distribution cables may be secured to the first ports of the termination adapters 352.Additional optical fiber cables (e.g., subscriber cables 190) also may be routed into the enclosure housing 110 (e.g., through the same or other port modules 101).\",\n \"Connectorized ends of the subscriber cables may be secured to the second ports of the termination adapters 352, which align and optically couple together the connectorized ends of the subscriber cables with the connectorized ends of the service cables.\",\n \"In certain implementations, a cover 330 may be positioned within the enclosure housing 110 to enclose or otherwise inhibit access to at least a portion of the optical components location within the enclosure housing 110 (see FIG.\",\n \"10).\",\n \"In some implementations, the cover 330 extends from one of the side walls 113, 114 to the termination plate 351 to block access to at least some of the fiber connectors plugged into one side of the termination adapters 352.In the example shown, the cover 330 extends from the second side wall 114 to the termination plate 351 to block access to any cables (e.g., service cables) entering the enclosure housing 110 through the left cable ports 101, while allowing access to the cables (e.g., subscriber cables) entering the enclosure housing 110 through the right cable ports 101.In other implementations, the cover 330 may extend across the entire termination panel mounting assembly 320.In the example shown, the cover 330 includes a front plate 366 and a side plate 367 forming an L-shaped flange.\",\n \"The front plate 366 extends from the second side wall 114 of the enclosure to the termination plate 351, thereby covering the bend radius limiters 354 located to the left of the termination plate 351.The front plate 366 also blocks access to the second ports of the adapters 352 from the open front 116 of the enclosure housing 110.The side plate 367 extends downwardly from the termination plate 351 to inhibit access to the second side of the termination plate 351 from the right side of the enclosure housing interior.\",\n \"In other implementations, the cover 330 may include two side plates and be located at a central portion of the enclosure interior.\",\n \"In still other implementations, the cover 330 may include a planar panel that extends across the open front 116 of the enclosure housing 110.In some implementations, the cover 330 defines one or more finger holes 368 by which the cover 330 may be installed and/or removed from the enclosure housing 110.For example, in one implementation, the front plate 366 of the cover 330 defines two finger holes 368.In other implementations, the cover 330 may include a handle or other structure to facilitate manipulation of the cover 330.In certain implementations, the cover 330 may be secured in place by a lock arrangement 369.FIGS.\",\n \"11-13 illustrate fourth and fifth example modular plate assemblies 120 implemented as an example drop-in plate mounting assembly 400 and an example sliding adapter mounting assembly 450, respectively.\",\n \"The fourth and fifth modular plate assemblies 400, 450 each extend over only a portion of the rear wall 115.For example, each of the fourth and fifth modular plate assemblies 400, 450 includes a mounting plate 401, 451 that has a height that extends substantially over a height of the rear wall 115 and a width that extends over less than half of the rear wall 115.In some implementations, the mounting plate 401, 451 is rectangular.\",\n \"In other implementations, the mounting plate 401, 451 is generally rectangular with notched corners.\",\n \"The mounting plate 401, 451 defines one or more apertures 402, 452 through which fasteners extend to secure the mount plate 401, 451 to the enclosure housing 110.The drop-in plate assembly 400 includes a drop-in plate 411 defining one or more holes 412 at which adapters 413 may be secured.\",\n \"In some implementations, the drop-in plate 411 is formed from a bent portion of the mounting plate 401.In other implementations, the drop-in plate 411 is attached to the mounting plate 401.In some implementations, the drop-in plate 411 extends generally horizontally (i.e., parallel with the top wall 111 and bottom wall 112 of the enclosure housing 110).\",\n \"In other implementations, the drop-in plate 411 may be angled relative to the top and bottom walls 111, 112.In certain implementations, the adapters 413 are snap-fit or press-fit into the holes 412 of the drop-in plate 411.In some implementations, the adapters 413 are configured to receive and align multi-fiber (MPO) connectors.\",\n \"A description of example MPO connectors can be found in U.S. Pat.\",\n \"No.\",\n \"5,214,730, the disclosure of which is hereby incorporated herein by reference.\",\n \"In certain implementations, the adapters 413 are configured to receive and align hardened multi-fiber adapters (HMFOCs).\",\n \"A description of example HIVIFOCs can be found in U.S. Pat.\",\n \"No.\",\n \"6,648,520, the disclosure of which is hereby incorporated herein by reference.\",\n \"In other implementations, the adapters 413 are configured to receive and align single optical connectors (e.g., LC-connectors, SC-connectors, ST-connectors, FC-connectors, etc.).\",\n \"In certain implementations, the drop-in plate assembly 400 includes fiber management structures to facilitate routing optical fibers or cable between the adapters 413 and other components within the enclosure housing 110.For example, the drop-in plate assembly 400 may include bend radius limiters extending forwardly from the mounting plate 401.In the example shown, smaller bend radius limiters 414 are disposed above the drop-in plate 411 and larger bend radius limiters 415 are disposed below the drop-in plate 411.The larger bend radius limiters 415 form a slack storage spool.\",\n \"The example sliding adapter mounting assembly 450 includes at least one sliding adapter module 461.Each sliding adapter module 461 includes a plurality of adapters that are slideably mounted to rails.\",\n \"In the example shown, each sliding adapter module 461 includes a row of six adapters.\",\n \"In the example shown, the example sliding adapter mounting assembly 450 includes a first group of two sliding adapter modules 461 spaced from another group of two sliding adapter modules 461.In other implementations, however, the example sliding adapter mounting assembly 450 may greater or fewer groups each having greater or fewer sliding adapter modules 461.In some implementations, the sliding adapter modules 461 are configured to slide generally horizontally in a forward-rearward direction relative to the enclosure housing 110.In certain implementations, the sliding adapter modules 461 slide at an angle (e.g., at least partially in an upward-downward direction).\",\n \"In the example shown, the adapter modules 461 are oriented so that ports of the adapter modules 461 face towards the upper and lower walls 111, 112 of the enclosure housing 110.In other implementations, the adapter modules 461 may be oriented to face the side walls 113, 114 of the enclosure housing 110.As noted above, additional details pertaining to example sliding adapter modules are provided in commonly owned U.S. Pat.\",\n \"Nos.\",\n \"5,497,444; 5,717,810; 6,591,051; and 7,416,349, the disclosures of which are incorporated above.\",\n \"The example sliding adapter mounting assembly 450 also includes a fanout arrangement 462 including one or more fanouts.\",\n \"Each fanout separates optical fibers from a multi-fiber cable.\",\n \"In the example shown, the fanout arrangement 462 is disposed between the two groups of adapter modules 461.In other implementations, the fanout arrangement 462 may be disposed elsewhere on the mounting panel 401.In certain implementations, two or more fanouts are stacked together so that a bottom of the stack abuts the mounting panel 401 and a top of the stack faces the open front 116 of the enclosure housing 110.The example sliding adapter mounting assembly 450 also includes fiber management structures to facilitate routing optical fibers or cables from the sliding adapter modules 461 to other components within the enclosure housing 110.In certain implementations, the sliding adapter mounting assembly 450 may include one or more bend radius limiters 463 (FIG.\",\n \"11).\",\n \"In the example shown, each group of adapter modules 461 has two corresponding bend radius limiters 463 at a bottom of the mounting panel 401 and at least one bend radius limiter 463 at a top of the mounting panel 401.In certain implementations, the mounting panel 401 also may include guide flanges 464 (FIG.\",\n \"11) that facilitates retaining optical fibers or cables within the area of the mounting panel 401.In some implementations, the mounting panel 401 defines a guide flange 464 on each side of the mounting panel 401.In the example shown in FIG.\",\n \"11, each guide flange 464 is bent forwardly from the mounting panel 401.In other implementations, each guide flange 464 may be a separately attached piece.\",\n \"In the example shown, each guide flange 464 extends vertically to inhibit the fibers from spilling into the rest of the enclosure interior.\",\n \"In the example shown in FIG.\",\n \"13, the mounting panel 401 includes retaining flanges 465 defining a guide channel through which one or more fibers or cables may be routed.\",\n \"The retaining flanges 465 include a first portion extending forwardly of the mounting plate and a second portion that extends across the fibers disposed in the channel.\",\n \"For example, each retaining flange 465 may have an L-shaped cross-section.\",\n \"The mounting panel 401 of FIG.\",\n \"13 also includes another type of guide flange 466 is T-shaped.\",\n \"The guide flange 466 is disposed between the two groups of sliding adapter modules 461.In some implementations, the sliding adapter mounting assembly 450 may be precabled at the factory or manufacturing center with one or more intermediate fibers 467.Some example intermediate fibers 467 each include a single optical fiber.\",\n \"First ends of the intermediate fibers 467 are connectorized and plugged into first ports of the sliding adapter modules 461.Second ends of the intermediate fibers 467 are joined at a fanout arrangement 462 to form one or more multi-fiber cables 417.In certain implementations, the second ends of the multi-fiber cables 417 are connectorized (e.g., see optical connectors 418 of FIG.\",\n \"13).\",\n \"In other implementations, the second ends of the multi-fiber cables 417 are unconnectorized.\",\n \"The separate intermediate fibers 467 are routed around from the sliding adapter modules 461 and around the fiber management structures (e.g., bend radius limiters 463 and/or any of flanges 464-466).\",\n \"In certain implementations, sufficient slack length of the separated fibers 467 is left between the fanout arrangement 462 and the adapter modules 461 to accommodate the sliding movement of the sliding adapter modules 461.In other implementations, however, the sliding adapter mounting assembly 450 may be cabled after the enclosure housing 110 is deployed.\",\n \"As shown in FIG.\",\n \"13, the connectors 418 terminating the multi-fiber cables 417 may be plugged into the first ports of the adapters 418 of the drop-in plate assembly 400 when both the drop-in plate assembly 400 and the sliding adapter mounting assembly 450 are disposed within the enclosure housing 110.A first set of additional optical fiber cables (e.g., distribution cables 180) may be routed into the enclosure housing 110 (e.g., through one or more ports 101).\",\n \"Connectorized ends of the first set of optical fiber cables 180 may be plugged into the second ports of the adapters 413 at the drop-in plate assembly 400.A second set of additional optical fiber cables (e.g., subscriber cables 190) may be routed into the enclosure housing 110 (e.g., through the same or other port modules 101).\",\n \"Connectorized ends of the second set of optical fiber cables 190 may be secured to second ports of the sliding adapter modules 461.Accordingly, optical signals carried by the first group of optical fibers 182 may be passed to the multi-fiber cables 417 via the drop-in adapters 413 and then to the second group of optical fibers 192 via the sliding adapter modules 461.FIG.\",\n \"14 illustrates a sixth example modular plate assemblies 120 implemented as an example splice tray mounting assembly 500.In the example shown, the splice tray mounting assembly 500 extends over only a portion of the rear wall 115.For example, the splice tray mounting assembly 500 includes a mounting plate 501 that has a height that extends substantially over a height of the rear wall 115 and a width that extends over less than half of the rear wall 115.In some implementations, the mounting plate 501 is rectangular.\",\n \"In other implementations, the mounting plate 501 is generally rectangular with notched corners.\",\n \"In still other implementations, the mounting plate 501 has notched sides.\",\n \"The mounting plate 501 defines one or more apertures 502 through which fasteners extend to secure the mount plate 501 to the enclosure housing 110.In certain implementations, one or more splice trays 511 are disposed on the mounting plate 501.Each splice tray 511 is configured to optically couple together two or more optical fibers.\",\n \"For example, each splice tray 511 may optically couple together at least one optical fiber of a service cable and at least one optical fiber of a subscriber cable or an intermediate fiber.\",\n \"Certain types of splice trays 511 may be pivoted between open and closed positions to provide access to the splices contained therein.\",\n \"In certain implementations, the splice trays 511 are stacked upon each other so that a bottom of the stack extends over the mounting plate 501 and a top of the stack faces the open front 116 of the enclosure housing 110.One or more support members 503 may aid in securing the splice tray 511 to the mounting plate 501.In FIG.\",\n \"14, a support member 503 is illustrated as at least one flange bent forwardly from the mounting late 501 at one side of the splice tray 511.One or more fiber management structures may be disposed on the mounting plate 501 about the splice tray arrangement 511.For example, in certain implementations, one or more bend radius limiters 512 are disposed on a front of the mounting plate 501.In the example shown, four bend radius limiters 512 are disposed at four corners of the splice tray arrangement 511.In other implementations, greater or fewer bend radius limiters 512 may be disposed in other configurations.\",\n \"When the splice tray mounting assembly 500 is installed within the interior of the enclosure housing 110, two or more optical fibers may be spliced at the splice trays 511.In some implementations, one or more optical fiber cables (e.g., service cables) may be routed into the enclosure housing 110 through one or more modular cable ports 101.One or more additional optical fiber cables (e.g., subscriber cables) also may be routed into the enclosure housing 110 through the same or other modular cable ports 101.In some implementations, unconnectorized ends of both groups of optical fiber cables are coupled together at the splice trays 511.In other implementations, the splice tray mounting assembly 500 is disposed within the enclosure housing 110 with the sliding adapter mounting assembly 450.In such implementations, the splice trays 511 are configured to optically couple together unconnectorized ends of a first group of optical fibers (e.g., from one or more service cables) to unconnectorized ends of intermediate fibers 467 plugged into the sliding adapter modules 461 of the sliding adapter mounting assembly 450.As shown in FIG.\",\n \"15, an example cover 600 may be positioned within the enclosure housing 110 to enclose or otherwise inhibit access to at least a portion of the optical components location within the enclosure housing 110.In some implementations, the cover 600 extends from one of the side walls 113, 114 to an intermediate portion of the enclosure interior to block access to at least some of the fiber optical connectors disposed within the enclosure interior.\",\n \"In the example shown, the cover 600 extends from the second side wall 114 to cover the drop-in mounting assembly 400.Accordingly, the cover 600 blocks access to the drop-in adapters 413 and to any fiber optic connectors plugged into the drop-in adapters 413.In other implementations, the cover 600 may extend across both the drop-in mounting assembly 400 and the sliding adapter module assembly 450.In still other implementations, the cover 600 may extend across the splice tray mounting assembly 500.In the example shown, the cover 600 includes a front plate 601 and a side plate 602 forming a generally L-shaped flange.\",\n \"The front plate 601 extends from one side of the mounting plate 401 of the drop-in mounting assembly 400 (or plate 501 of splice tray assembly 500) to the opposite side of the mounting plate 401.The front plate 601 also extends a majority of the distance between the top wall 111 and the bottom wall 112.The side plate 602 extends from the front plate 601 to the rear wall 115 of the enclosure housing 110.In certain implementations, the side plate 602 defines an opening, cutout, or other routing channel 603 through which optical fibers may be routed between the interior spaced enclosed by the cover 600 and the interior space accessible through the open front 116 of the enclosure housing 110.In other implementations, the cover 600 may include two side plates and be located at a central portion of the enclosure interior.\",\n \"In still other implementations, the cover 600 may include a planar panel that extends across the open front 116 of the enclosure housing 110.In some implementations, the cover 600 defines one or more finger holes 604 by which the cover 600 may be installed and/or removed from the enclosure housing 110.For example, in one implementation, the front panel 601 of the cover 600 defines two finger holes 604.In other implementations, the cover 600 may include a handle or other structure to facilitate manipulation of the cover 600.In certain implementations, the cover 600 may be secured in place by a lock arrangement 605.In some implementations, implementations of the fiber termination enclosure 100 disclosed above may be used in cell site applications.\",\n \"For example, certain implementations 992 of the fiber termination enclosure 100 may be mounted to a top of a cellular tower or in a hut at a base of a cellular tower.\",\n \"FIG.\",\n \"16 is a schematic representation of one example telecommunications network 910 utilizing such a cell site application.\",\n \"In the depicted embodiment, the telecommunications network 910 is a cellular network 910.The cellular network 910 includes a cell site 912, a demarcation point 914, a backhaul 916 and a core network 918.The cell site 912 creates an area of telecommunications coverage (i.e., a cell) in the cellular network 910.In one embodiment, the cell site 912 includes a tower or mast 920 and a hut 922 that is in communication with the tower 920.In another embodiment, the cell site 912 includes a hut 922 that is in communication with an antenna or a plurality of antenna.\",\n \"The tower 920 includes a base portion 924 and an oppositely disposed top portion 926.In the depicted embodiment, the base portion 924 is rigidly fixed at a mounting location.\",\n \"In one embodiment, the top portion 926 of the tower 920 may include an antenna.\",\n \"The remote transceiver 928 may be integrated into the antenna.\",\n \"The top portion 926 includes a remote transceiver 928 (e.g., a remote radio head).\",\n \"The remote transceiver 928 is adapted to transmit and receive signals to and from devices (e.g., mobile phones, smart-phones, devices with wireless internet connectivity, etc.)\",\n \"of subscribers to the cellular network 910.In certain implementations, the top portion 926 of the tower 920 includes multiple remote transceivers.\",\n \"In certain implementations, some of the remote transceivers are backup remote transceivers.\",\n \"The top portion 926 of the tower 920 further includes a multi-service terminal 930.Terminal that are suitable for use as the multi-service terminal 930 of the present disclosure have been described in U.S. Pat.\",\n \"Nos.\",\n \"7,292,763 and 7,512,304, the disclosures of which are hereby incorporated by reference in their entirety.\",\n \"The fiber optic cable 952 from the multi-service terminal 930 is routed to an enclosure 992 at the hut 922.The fiber optic cable 952 includes a first end 962 and an oppositely disposed second end 964.The first end 962 includes a plurality of connectors that are engaged to the inner ports of the fiber optic adapters of the multi-service terminal 930.The second end 964 includes a multi-fiber connector that is adapted for engagement to one of the first and second multi-fiber connectors of the enclosure 992.A jumper cable 966 provides communication between the enclosure 992 and the base transceiver station 990.The jumper cable 966 includes a first end 968 and an oppositely disposed second end 970.The first end 968 is connected to the enclosure 992 while the second end 970 is connected to the base transceiver station 990.In one embodiment, the first end 968 includes a plurality of connectors that are engaged with the second side 924 of the fiber optic adapters 920 of the enclosure 992.In one embodiment, the second end 970 of the jumper cable 966 includes a multi-fiber connector that is engaged to the base transceiver station 990.In another embodiment, the second end 970 includes a plurality of connectors that is engaged to the base transceiver station 990.The base transceiver station 990 is in communication with a telecommunications equipment rack 980 through a multi-fiber patch cable 982.The telecommunications equipment rack 980 is disposed in the hut 922.In one embodiment, the telecommunications equipment rack 980 includes any one or more of a power distribution unit, a fiber distribution unit, a transport switch, a mobile router, a media converter, an Ethernet panel, a DSX panel, protection and a battery.\",\n \"The telecommunications equipment rack 980 is in communication with the demarcation point 914.The demarcation point 914 is in communication with the backhaul 916, which is in communication with the core network 918.Further details on such a telecommunications network 910 may be found in U.S. patent application Ser.\",\n \"No.\",\n \"13/087,022, filed Apr.\",\n \"14, 2011, and titled “Fiber to the Antenna,” the disclosure of which is hereby incorporated herein by reference.\",\n \"In other implementations, the fiber termination enclosure disclosed above may be used with other applications.\",\n \"For example, some fiber termination enclosures may be installed at facilities, such as multiple dwelling units, apartments, condominiums, businesses, etc., to provide a subscriber access point to the fiber optic network.\",\n \"Other fiber termination enclosures may be installed on towers located on top of high rise buildings or other tall structures.\",\n \"Various implementations of fiber termination enclosures may be installed at walls, H-frame racks, and poles.\",\n \"Having described the preferred aspects and implementations of the present disclosure, modifications and equivalents of the disclosed concepts may readily occur to one skilled in the art.\",\n \"For example, one or more pass-through connections may be provided with any of the above-described types of modular plate assemblies 120.However, it is intended that such modifications and equivalents be included within the scope of the claims which are appended hereto.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875756"}}},{"rowIdx":4494967,"cells":{"text":{"kind":"list like","value":[["OUT OF STOCK ITEM TRACKING AT RETAIL SALES FACILITIES","In some embodiments, methods and systems of locating overstock items at a retail sales facility include receiving an indication that a product at the retail sales facility is out of stock and determining whether the product is located on a sales floor or in the stock room at the retail sales facility; then, in response to a determination that the product is not located on the sales floor or in the stock room, tracking a location of the product based on at least one inventory management factor associated with the retail sales facility and at least one worker task event associated with the product; and outputting to a worker at the retail sales facility, based on the tracking of the location of the at least one product, an indication of a perceived location of the least one product."],["1.A method for assisting in the locating of out of stock products at a retail sales facility, the method comprising: providing an inventory management database storing electronic data indicating at least one product that is offered for sale to consumers at a display location on a sales floor of the retail sales facility; receiving, an indication that at least one product is out of stock on the sales floor of the retail sales facility; determining, via an inventory management electronic device including a processor, and in response to querying the inventory management database via the inventory management electronic device to obtain inventory management data associated with the at least one product, that the inventory management data obtained via the inventory management electronic device from the inventory management database indicates that the at least one product is not located at the display location on the sales floor of the retail sales facility and is not located in a stock room of the retail sales facility; tracking, via the inventory management electronic device and the inventory management database, a location of the at least one product at the retail sales facility other than the display location and other than the stock room, based on analyzing, via the inventory management electronic device, at least one inventory management factor associated with the retail sales facility and at least one worker task event associated with the at least one product, the at least one management factor and the worker task event being stored in the inventory management database; and outputting, based on the tracking step and via the inventory management electronic device, an indication of a predicted location of the least one product at the retail sales facility other than the display location and other than the stock room, to a worker at the retail sales facility; wherein the at least one inventory management factor includes at least one of: mis-rings, shipping error, sales floor quantity versus shelf cap, change in on-hand inventory at the retail sales facility, bin accuracy, perpetual inventory accuracy, modular integrity, shrink, replenishment method, and pick completion; and wherein the at least one worker task event includes at least one of: time stamp of last sale of the at least one product, time stamp of last customer return of the at least one product, time stamp of last customer claim for the at least one product, time stamp of last binning or unbinning of the at least one product, time stamp of last feature set or unset of the at least one product, time stamp of last delivery of the at least one product, time stamp of last scan of the at least one product, time stamp of last price change of the at least one product, and time stamp of pick of the at least one product.","2.The method of claim 1, wherein the receiving step includes inputting identifying information for the at least one product into the inventory management database and receiving a signal from the inventory database indicating that the at least one product is out of stock at the retail sales facility.","3.The method of claim 2, wherein the display location is a shelf on the sales floor of the retail sales facility where the at least one product is regularly offered for sale.","4.The method of claim 1, wherein the tracking step is performed via a control circuit including the processor in communication with the at least one inventory management database.","5.The method of claim 1, further comprising monitoring, via the inventory management electronic device, whether the at least one worker task event entered into the inventory management database as being completed was physically completed, generating in the inventory management database at least one data point indicating whether the at least one worker task event entered into the inventory management database as being completed was physically completed, and generating, via the inventory management electronic device, a report including the at least one data point over a predetermined period of the monitoring.","6.The method of claim 1, wherein the outputting step further comprises indicating, via the inventory management electronic device, to the user, based on the tracking step, to look for the at least one product in a location at the retail sales facility including at least one of: truck unload area, to be stocked area, unworked freight area, unbinned area, returns area, claims area, pick cart in stock room, area near shelf on the sales floor of the retail sales facility, last known bin location, and feature product display.","7.The method of claim 1, wherein the outputting step further comprises indicating, via the inventory management electronic device, to the worker and based on the tracking step, that the at least one product is not present on hand at the retail sales facility.","8.A system for tracking out of stock products at a retail sales facility, the system comprising: at least one inventory management database storing electronic data indicating at least one product that is offered for sale to consumers at a display location on a sales floor of at the retail sales facility; and a control circuit including a processor in communication with the at least one inventory management database, the control circuit configured to: receive electronic data from the at least one inventory management database that indicates that the at least one product is not located at the display location on the sales floor of the retail sales facility y and is not located in a stock room of the retail sales facility; track a location of the at least one product at the retail sales facility other than the display location and other than the stock room of the retail sales facility, based on an analysis, by the control circuit, of at least one inventory management factor associated with the retail sales facility and at least one worker task event associated with the at least one product, the at least one management factor and the worker task event being stored in the inventory management database; and output to a worker at the retail sales facility, based on the tracked location of the at least one product, an indication of a predicted location of the least one product at the retail sales facility other than the display location and other than the stock room of the retail sales facility; wherein the at least one inventory management factor includes at least one of: mis-rings, shipping error, sales floor quantity versus shelf cap, change in on-hand inventory at the retail sales facility, bin accuracy, perpetual inventory accuracy, modular integrity, shrink, replenishment method, and pick completion; and wherein the at least one worker task event includes at least one of: time stamp of last sale of the at least one product, time stamp of last customer return of the at least one product, time stamp of last customer claim for the at least one product, time stamp of last binning or unbinning of the at least one product, time stamp of last feature set or unset of the at least one product, time stamp of last delivery of the at least one product, time stamp of last scan of the at least one product, time stamp of last price change of the at least one product, and time stamp of pick of the at least one product.","9.The system of claim 8, wherein the control circuit is configured to send a signal including identifying information for the at least one product to the at least one inventory management database and receive a signal from the inventory database indicating that the at least one product is out of stock at the retail sales facility.","10.The system of claim 9, wherein the display location is a shelf on the sales floor of the retail sales facility where the at least one product is regularly offered for sale.","11.The system of claim 8, wherein the control circuit is configured to: monitor whether the at least one worker task event entered into the at least one inventory management database as being completed was physically completed; generate in the at least one inventory management database at least one data point indicating whether the at least one worker task event entered into the at least one inventory management database as being completed was physically completed; and generate a report including the at least one data point over a predetermined period of monitoring by the server.","12.The system of claim 8, wherein the control circuit is configured to indicate to the user, based on the tracked location of the at least one product, to look for the at least one product at a location at the retail sales facility including at least one of: truck unload area, to be stocked area, unworked freight area, unbinned area, returns area, claims area, pick cart in stock room, area near shelf on the sales floor of the retail sales facility, last known bin location, and feature item display.","13.The system of claim 8, wherein the control circuit is configured to indicate to the worker, based on the tracked location of the at least one product, that the at least one product is not present at the retail sales facility.","14.A system for tracking out of stock items at a retail sales facility, the system comprising: at least one storage means storing electronic data indicating at least one product that is offered for sale to consumers at a display location on a sales floor of at the retail sales facility; and a control means including a processor in communication with the at least one inventory management database, the control means configured to: receive electronic data from the at least one storage means that indicates that the at least one product is not located at the display location on the sales floor of the retail sales facility and is not located in a stock room of the retail sales facility; track a location of the at least one product at the retail sales facility other than the display location and other than the stock room of the retail sales facility based on at least one inventory management factor associated with the retail sales facility and at least one worker task event associated with the at least one product, the at least one management factor and the worker task event being stored in the storage means; and output to a worker at the retail sales facility, based on the tracked location of the at least one product, an indication of a predicted location of the least one product at the retail sales facility other than the display location and other than the stock room of the retail sales facility; wherein the at least one inventory management factor includes at least one of: mis-rings, shipping error, sales floor quantity versus shelf cap, change in on-hand inventory at the retail sales facility, bin accuracy, perpetual inventory accuracy, modular integrity, shrink, replenishment method, and pick completion; and wherein the at least one worker task event includes at least one of: time stamp of last sale of the at least one product, time stamp of last customer return of the at least one product, time stamp of last customer claim for the at least one product, time stamp of last binning or unbinning of the at least one product, time stamp of last feature set or unset of the at least one product, time stamp of last delivery of the at least one product, time stamp of last scan of the at least one product, time stamp of last price change of the at least one product, and time stamp of pick of the at least one product."],["<SOH> BACKGROUND <EOH>Retail sales facilities often permit consumers to determine whether a product offered for sale at the retail sales facility is in stock by scanning the product.","Also, consumers often request sales associates and/or managers at the retail sales facility to check whether a product of interest is in stock at the retail sales facility.","Having to perform a large number of scans for low inventory and/or out of stock items often takes up a large portion of time from department managers and/or sales associates at the retail sales facility.","When a product is determined to be out of stock at the retail sales facility via a scan by the consumer or sales or stocking associate, the consumer is typically informed either that the product is not available, or that the sales or stocking associate will go to the stock room to check whether the product indicated to be out of stock may be nevertheless present in the stock room.","However, since the conventional inventory management systems do not provide the sales or stocking associate with possible locations where additional units of the product indicated to be out of stock may be present at the retail sales facility, the sales or stocking associates are often forced to physically check multiple locations at the retail sales facility to look for possible additional units of the out of stock product, which is time consuming and inefficient."],["<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>Disclosed herein are embodiments of systems, apparatuses and methods pertaining to methods and systems for sorting overstock inventory.","This description includes drawings, wherein: FIG.","1 is a diagram of a retail sales facility overstock tracking system in accordance with some embodiments.","FIG.","2 is a functional diagram of an inventory management electronic device in accordance with several embodiments.","FIG.","3 is a flow chart diagram of a process of tracking out of stock items at a retail sales location in accordance with some embodiments.","FIG.","4 is a flow chart diagram of a method of tracking out of stock products at a retail sales facility in accordance with several embodiments.","detailed-description description=\"Detailed Description\" end=\"lead\"?","Elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale.","For example, the dimensions and/or relative positioning of some of the elements in the figures may be exaggerated relative to other elements to help to improve understanding of various embodiments of the present invention.","Also, common but well-understood elements that are useful or necessary in a commercially feasible embodiment are often not depicted in order to facilitate a less obstructed view of these various embodiments of the present invention.","Certain actions and/or steps may be described or depicted in a particular order of occurrence while those skilled in the art will understand that such specificity with respect to sequence is not actually required.","The terms and expressions used herein have the ordinary technical meaning as is accorded to such terms and expressions by persons skilled in the technical field as set forth above except where different specific meanings have otherwise been set forth herein."],["CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation of U.S. application Ser.","No.","15/202,897, filed Jul.","6, 2016, which claims the benefit of U.S.","Provisional Application No.","62/200,431, filed Aug. 3, 2015, which are incorporated herein by reference in their entireties.","TECHNICAL FIELD This invention relates generally to managing inventory at retail sales facilities and, in particular, to systems and methods for tracking out of stock items at retail sales facilities.","BACKGROUND Retail sales facilities often permit consumers to determine whether a product offered for sale at the retail sales facility is in stock by scanning the product.","Also, consumers often request sales associates and/or managers at the retail sales facility to check whether a product of interest is in stock at the retail sales facility.","Having to perform a large number of scans for low inventory and/or out of stock items often takes up a large portion of time from department managers and/or sales associates at the retail sales facility.","When a product is determined to be out of stock at the retail sales facility via a scan by the consumer or sales or stocking associate, the consumer is typically informed either that the product is not available, or that the sales or stocking associate will go to the stock room to check whether the product indicated to be out of stock may be nevertheless present in the stock room.","However, since the conventional inventory management systems do not provide the sales or stocking associate with possible locations where additional units of the product indicated to be out of stock may be present at the retail sales facility, the sales or stocking associates are often forced to physically check multiple locations at the retail sales facility to look for possible additional units of the out of stock product, which is time consuming and inefficient.","BRIEF DESCRIPTION OF THE DRAWINGS Disclosed herein are embodiments of systems, apparatuses and methods pertaining to methods and systems for sorting overstock inventory.","This description includes drawings, wherein: FIG.","1 is a diagram of a retail sales facility overstock tracking system in accordance with some embodiments.","FIG.","2 is a functional diagram of an inventory management electronic device in accordance with several embodiments.","FIG.","3 is a flow chart diagram of a process of tracking out of stock items at a retail sales location in accordance with some embodiments.","FIG.","4 is a flow chart diagram of a method of tracking out of stock products at a retail sales facility in accordance with several embodiments.","Elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale.","For example, the dimensions and/or relative positioning of some of the elements in the figures may be exaggerated relative to other elements to help to improve understanding of various embodiments of the present invention.","Also, common but well-understood elements that are useful or necessary in a commercially feasible embodiment are often not depicted in order to facilitate a less obstructed view of these various embodiments of the present invention.","Certain actions and/or steps may be described or depicted in a particular order of occurrence while those skilled in the art will understand that such specificity with respect to sequence is not actually required.","The terms and expressions used herein have the ordinary technical meaning as is accorded to such terms and expressions by persons skilled in the technical field as set forth above except where different specific meanings have otherwise been set forth herein.","DETAILED DESCRIPTION Generally speaking, this application describes systems and methods for tracking out of stock items at retail sales facilities.","In some embodiments, the systems and methods described herein include one or more electronic devices configured to receive an indication that a product at a retail sales facility is out of stock and determine a location of the product at the retail sales facility based on at least one inventory management factor associated with the retail sales facility and/or at least one worker task event associated with the at least one product.","In one embodiment, a method for assisting in the locating of out of stock items at a retail sales facility includes: receiving, an indication that at least one product at the retail sales facility is out of stock on a sales floor at the retail sales facility; determining, via an inventory management electronic device including a processor, that inventory management data indicates that the at least one product is not located on the sales floor and is not located in a stock room of the retail sales facility; tracking, via the inventory management electronic device, a location of the at least one product based on at least one inventory management factor associated with the retail sales facility and at least one worker task event associated with the at least one product; and outputting, based on the tracking step and via the inventory management electronic device, an indication of a predicted location of the least one product to a user at the retail sales facility.","A system for tracking out of stock items at a retail sales facility according to one embodiment includes at least one inventory management database including inventory management data regarding at least one product at the retail sales facility; and a control circuit including a processor in communication with the at least one inventory management database.","The control circuit is configured to: receive inventory management data that indicates that the at least one product is not located on the sales floor and is not located in a stock room of the retail sales facility; track a location of the at least one product based on at least one inventory management factor associated with the retail sales facility and at least one worker task event associated with the at least one product; and output to a user at the retail sales facility, based on the tracking of the location of the at least one product, an indication of a predicted location of the least one product.","According to one embodiment, a system for tracking out of stock items at a retail sales facility includes at least one storage means including inventory management data regarding at least one product at the retail sales facility and a control means including a processor in communication with the at least one inventory management database.","The control means is configured to: receive inventory management data that indicates that the at least one product is not located on the sales floor and is not located in a stock room of the retail sales facility; track a location of the at least one product based on at least one inventory management factor associated with the retail sales facility and at least one worker task event associated with the at least one product; and output to a user at the retail sales facility, based on the tracking of the location of the at least one product, an indication of a predicted location of the least one product.","Referring to FIG.","1, one embodiment of a system 100 for tracking and/or locating out of stock products at a retail sales facility 110 is shown.","The retail sales facility 110 may be any place of business such as a store or warehouse where consumer products are stocked and/or sold.","The system 100 includes an inventory management electronic device 120 configured to manage product inventory at the retail sales facility 110.The inventory management electronic device 120 illustrated in FIG.","1 may be a stationary, portable, or hand-held electronic device, for example, a desktop computer, a laptop computer, a tablet, a mobile phone, or any other electronic, processor-based device that may be configured for data entry and communication with another electronic, processor-based device located at the retail sales facility 110, or at a location remote to the retail sales facility 110 (e.g., a regional or central server configured for two-way communication with multiple retail sales facilities 110).","The exemplary inventory management electronic device 120 shown in FIG.","1 includes an inventory management database 140 configured to store information regarding the items 90 present at the retail sales facility 110.The inventory management database 140 may be stored, for example, on non-volatile storage media (e.g., a hard drive, flash drive, or removable optical disk) internal or external relative to the inventory management electronic device 120 or internal to computing devices (e.g., remote server) separate and distinct from the inventory management electronic device 120.The information regarding the items 90 stored on the inventory management database 140 may include various historical/statistical inventory management factors pertaining to the retail sales facility 110 and worker task events pertaining to the items 90, which are shown in FIG.","4, and will be discussed in more detail below.","FIG.","1 schematically shows (via dotted lines 155, 165, and 175) that the inventory management database 140 contains information regarding the items 90 present in the product delivery area 160, stock room 170, sales floor 180, and product sale/return/claim areas 190 of the retail sales facility 110, but it will be appreciated that the inventory management database 140 may contain information regarding any items 90 present in any other area of the retail sales facility 110 and may include information relating to tasks performed by workers in any other area of the retail sales facility 110 with respect to the items 90.The items 90 may be identified in the inventory management database 140 by way of stock keeping unit (SKU) numbers or any other unique identifiers.","It will be appreciated that the inventory management database 140 does not have to be incorporated into the inventory management electronic device 120 local to the retail sales facility 110, but may be stored on a remote (e.g., central) server in communication with the inventory management electronic device 120.An exemplary inventory management electronic device 120 depicted in FIG.","2 is a computer-based device and includes a control circuit 210 including a processor (for example, a microprocessor or a microcontroller) electrically coupled via a connection 215 to a memory 220 and via a connection 225 to a power supply 230.The control circuit 210 can comprise a fixed-purpose hard-wired platform or can comprise a partially or wholly programmable platform, such as a microcontroller, an application specification integrated circuit, a field programmable gate array, and so on.","These architectural options are well known and understood in the art and require no further description here.","This control circuit 210 can be configured (for example, by using corresponding programming stored in the memory 220 as will be well understood by those skilled in the art) to carry out one or more of the steps, actions, and/or functions described herein.","In some embodiments, the memory 220 may be integral to the control circuit 210 or can be physically discrete (in whole or in part) from the control circuit 210 and is a non-volatile data storage media such as a hard drive configured to store the inventory management database 140.The memory 220 can be configured non-transitorily store the computer instructions that, when executed by the control circuit 210, cause the control circuit 210 to behave as described herein.","(As used herein, this reference to “non-transitorily” will be understood to refer to a non-ephemeral state for the stored contents (and hence excludes when the stored contents merely constitute signals or waves) rather than volatility of the storage media itself and hence includes both non-volatile memory (such as read-only memory (ROM)) as well as volatile memory (such as an erasable programmable read-only memory (EPROM)).)","The control circuit 210 of the electronic device 120 is also electrically coupled via a connection 235 to an input/output 240 that can receive signals from and send signals (via a wired or wireless connection) to (e.g., commands, inventory database information) devices local to the retail sales facility 110, or one or more servers remote to the retail sales facility 110.In the embodiment shown in FIG.","2, the control circuit 210 of the electronic device 120 is electrically coupled via a connection 245 to a user interface 250, which may include a visual display or display screen 260 (e.g., LED screen) and/or button input 270 that provide the user interface 250 with the ability to permit a user such as a stock room or sales floor associate at the retail sales facility 110 to manually control the inventory management electronic device 120 by inputting commands, for example, via touch-screen and/or button operation or voice commands.","The display screen 260 can also permit the user to see various menus, options, and/or alerts displayed by the inventory management electronic device 120.The user interface 250 of the inventory management electronic device 120 may also include a speaker 280 that may provide audible feedback (e.g., alerts) to the user.","With reference to FIGS.","1-3, one method 300 of operation of the system 100 to track and located out of stock products 90 at a retail sales facility 110 will now be described.","For exemplary purposes, the method is described in the context of the system of FIG.","1, but it is understood that embodiments of the method may be implemented in this or other systems.","Generally, as shown in FIG.","3, the method 300 includes receiving, an indication that a product 90 at the retail sales facility 110 is out of stock (step 310).","Such an indication may be received as a result of a customer approaching a sales or stocking associate at the retail sales location 110 to inform the sales or stocking associate that the product 90 is not present on a shelf on the sales floor 180 where this product 90 is normally stocked.","Alternatively, the consumer may inform the sales or stocking associate that the product 90 is out of stock after entering an SKU or an item identifier into an inventory management device available to consumers (e.g., by scanning a floor sample of the product 90 using an inventory management scanner) and receiving an indication that the product 90 is out of stock at the retail sales location 110.Alternatively, the out of stock indication may come as a result of a sales or stocking associate either scanning the floor sample of the product 90 or otherwise entering information identifying the product 90 into the inventory management database 140 (e.g., using the inventory management electronic device 120) and receiving an alert that the product 90 is out of stock.","In the embodiment shown in FIG.","3, the method 300 further includes determining whether the product 90 is located on a sales floor 180 at the retail sales facility 110 (step 320).","This determination may be made as a result of the stocking associate at the retail sales facility 110 entering identifying information regarding the out of stock item 90 into the inventory management electronic device 120, in response to which the processor of the control circuit 210 of the inventory management electronic device 120 may be programmed to send an appropriate query or signal to the inventory management database 140 internal to the inventory management electronic device 120, or to a remote inventory management database via the input/output 240.In one embodiment, the inventory management database 140, upon receiving such a query or signal including data identifying the item 90 can retrieve information regarding the current location of the item 90 at the retail sales facility 110, and more specifically, regarding whether the item 90 is presently located on a shelf on the sales floor 180 where the item 90 is normally stocked for display and sale to consumers.","In some embodiments, if the information retrieved from the inventory management database 140 indicates that the item 90 is present on a shelf on the sales floor 180 of the retail sales facility 110, the processor of the control circuit 210 is programmed to send a signal to the display 260 and/or speaker 280 of the inventory management electronic device 120 to generate a visible alert (e.g., via the on-screen menu) or an audible alert (e.g., beep or voice command) to inform the user (e.g., stocking associate) that the item 90 is present on the shelf on the sales floor 180.It will be appreciated that instead of retrieving information related to the present location of the item 90 at the retail sales facility 110 from the inventory management database 140, such information may be retrieved by the inventory management electronic device 120 from an inventory management database remote to the retail sales facility 110.In one embodiment shown in FIG.","3, in response to a determination by the processor of the control circuit 210 of the inventory management electronic device 120 that the product 90 is not located on the sales floor 180 at the retail sales facility 110, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to determine whether the product 90 is located in the stock room 170 at the retail sales facility 110 (step 330).","As described above, this determination may be made as a result of the stocking associate at the retail sales facility 110 entering identifying information regarding the out of stock item 90 into the inventory management electronic device 120, in response to which the processor of the control circuit 210 of the inventory management electronic device 120 may be programmed to send an appropriate query or signal to the inventory management database 140, and the inventory management database 140, upon receiving such a query or signal including data identifying the item 90 can retrieve information regarding the current location of the item 90 at the retail sales facility 110, and more specifically, regarding whether the item 90 is presently located in the stock room 170.If the information retrieved from the inventory management database 140 indicates that the item 90 is in the stock room 170 of the retail sales facility 110, the processor of the control circuit 210 of the inventory management electronic device 120 may be programmed to send a signal to the display 260 or speaker 280 of the inventory management electronic device 120 to generate a visible alert (e.g., via the on-screen menu) or an audible alert (e.g., beep or voice command) to inform the user (e.g., stocking associate) that the item 90 is in the stock room 170.In one embodiment shown in FIG.","3, in response to a determination by the processor of the control circuit 210 of the inventory management electronic device 120 that the product 90 is not located on the sales floor 180 or in the stock room 170 at the retail sales facility 110, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to track the location of the out of stock product 90 at the retail sales facility 110 based on at least one inventory management factor associated with the retail sales facility 110 and/or at least one worker task event associated with the product 90 (step 340).","The inventory management factors and worker task events that the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to analyze in tracking the location of the product 90 at the retail sales facility 110 are depicted in FIG.","4 and discussed in more detail below.","Based on the tracking analysis by the processor of the control circuit 210 of the inventory management electronic device 120, which will be described in more detail below, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to output an indication of a perceived or predicted location of the product 90 (step 350).","The perceived location may be a physical location at the retail sales facility 110 such as the stock room 170, sales floor 180 or any other location at the retail sales facility 110 determined by the processor of the control circuit 210 of the inventory management electronic device 120 to contain the product 90.Alternatively, the output of the tracking analysis may be an indication that the product 90 is not present at the retail sales facility 110.For example, based on the tracking analysis, the processor of the control circuit 210 of the inventory management electronic device 120 may be programmed to send signal to the display 260 or speaker 280 of the inventory management electronic device 120 to generate a visible alert (e.g., via the on-screen menu) or an audible alert (e.g., beep or voice command) to inform the user (e.g., stocking associate) that the item 90 is perceived to be in the stock room 170, on the sales floor 180, or not present at the retail sales facility 110.Such an alert would signal to the stocking associate to take appropriate action (e.g., retrieve the item 90 from the perceived location for the consumer) or inform the consumer seeking the item 90 at the retail sales facility 110 that the item 90 is not present at the retail sales facility 110.In one embodiment, when the inventory management electronic device 120 indicates (e.g., via a visual or audible alert), based on tracking the item 90, to the stocking associate that the item 90 may be stocked on a shelf on the sales floor 180 or in the stock room 170, the inventory management electronic device 120 presents the associate with an option to acknowledge the alert, for example, by pressing on the display screen 260 or on one of the inputs 270 of the inventory management electronic device 120.When the stocking associate physically confirms whether the perceived location (i.e., based on the tracking analysis) of the item 90 is correct by walking to the perceived location and attempting to retrieve the item 90 and responds to the alert by indicating (e.g., via using the inputs 270 of the inventory management electronic device 120) whether the perceived location of the item 90 is correct or incorrect, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to designate the product 90 as being located in the location perceived based on the tracking analysis, or as being in an unidentified location at the retail sales facility 110, or as being not present at the retail sales facility 110.For example, the processor of the control circuit 210 may be programmed to send a signal to the inventory management database 140 or, via the input/output 240, to an inventory management database on a remote server, to indicate the actual physical location of the item 90 at the retail sales facility 110.As such, the location of the item 90 at the retail sales facility 110 may be updated in the inventory management database 140 or remote inventory management database for the retail sales facility 110, which enables the inventory management database 140 and/or a remote database to systematically store updated information regarding the location of items 90 indicated to be out of stock at the retail sales facility 110 and to permit the associates to efficiently retrieve such items and provide them to consumers seeking to buy these items 90.An exemplary method 400 of managing and stocking of products 90 at the retail sales facility 110 will now be described with reference to FIGS.","1 and 4.As shown generally in step 410, when a stocking associate wishes to identify the location of a product 90 indicated to the customer or the stocking associate to be out of stock (step 410), the inventory management electronic device 120 may be initially operated by the stocking associate to determine, as described above, whether the item 90 (indicated to be out of stock) is present in a primary location at the retail sales facility 110 (step 420).","The primary location may be, for example, a shelf on the sales floor 180 at the retail sales facility 110 where the item 90 is normally offered for sale to the customers.","If the inventory management electronic device 120 indicates (e.g., via a displayed message, beep, or spoken words as discussed above) to the stocking associate that the item 90 is present in the primary location (step 425), the tracking process ends (step 430), enabling the stocking associate to physically check the primary location in an attempt to find the item 90 and provide it to the customer.","Alternatively, if the inventory management electronic device 120 indicates (e.g., via a displayed message, beep, or spoken words as discussed above) to the stocking associate that the item 90 is not present in the primary location (step 435), the stocking associate may then operate the inventory management electronic device 120 to determine, as described above, whether the item 90 indicated to be out of stock is present in a secondary location at the retail sales facility 110 (step 440).","The secondary location may be a location on the sales floor 180 other than the shelf where the item 90 is normally offered for sale to the customers, such as, for example, a feature, seasonal, or discount display on the sales floor 180.In yet another alternative, instead of relying on the inventory management electronic device 120 for a determination of whether the item 90 is present in the primary location, the stocking associate may walk to the primary location of the item 90 on the sales floor and visually inspect the primary location of the item 90 on the sales floor 180 to determine whether the item 90 indicated to be out of stock is present at the primary location.","Upon the visual inspection, the stocking associate may then enter information into the inventory management system 100 using the inventory management electronic device 120 to indicate whether the item 90 is or is not present at the primary location at the retail sales facility 110.If the inventory management electronic device 120 indicates (e.g., via a displayed message, beep, or spoken words as discussed above) to the stocking associate that the item 90 is present in the secondary location (step 445), the tracking process ends (step 450), enabling the stocking associate to physically check the secondary location in an attempt to find the item 90 and provide it to the customer.","Alternatively, if the inventory management electronic device 120 indicates (e.g., via a displayed message, beep, or spoken words as discussed above) to the stocking associate that the item 90 is not present in the secondary location (step 455), the stocking associate may then operate the inventory management electronic device 120 to determine, as described above, whether the item 90 indicated to be out of stock is present in the back room or stock room 170 at the retail sales facility 110 (step 460).","If the inventory management electronic device 120 indicates (e.g., via a displayed message, beep, or spoken words as discussed above) to the stocking associate that the item 90 is present in the stock room 170 (step 465), the tracking process ends (step 470), enabling the stocking associate to physically check the stock room 170 in an attempt to find the item 90 and provide it to the customer.","Alternatively, if the inventory management electronic device 120 indicates (e.g., via a displayed message, beep, or spoken words as discussed above) to the stocking associate that the item 90 is not present in the stock room 170 (step 475), the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to track the location of the item 90 at the retail sales facility 110 using predetermined inventory management factors 480 associated with the retail sales facility 110, as shown in FIG.","4.It will be appreciated that the ten inventory management factors depicted in FIG.","4 are shown by way of example only, and the processor of the control circuit 210 of the inventory management electronic device 120 may be programmed to analyze any one or more of these inventory management factors (or additional inventory management factors) to determine a predicted location of an out of stock item 90 at the retail sales facility 110.It will appreciated that the tracking of the out of stock items 90 at the retail sales facility 110 may be performed without requiring any calculation or analysis by the processor of the control circuit 210 of the inventory management electronic device 120, and that the system 100 may be configured such that the tracking of the out of stock items 90 may be performed by an inventory management computing device remote to the retail sales facility 110 and in communication with the inventory management electronic device 120.In such embodiments, the tracking analysis of the out of stock item 90 may be performed by the inventory management computing device remote to the grocery location 110 (based on data stored in the inventory management database 140 or a remote inventory management database), and may be stored at the remote inventory management database or in the inventory management database 140 until a time when a user uses the electronic computing device 120 to request and retrieve the perceived location of the out of stock item 90 from the remote inventory management database or the inventory management database 140, as appropriate.","With reference to FIG.","4, the exemplary inventory management factors that may be used for the tracking of the out of stock items 90 are: (1) mis-rings; (2) shipping error; (3) sales floor quantity versus shelf cap; (4) change in on-hand inventory at the retail sales facility; (5) bin accuracy; (6) perpetual inventory accuracy; (7) modular integrity; (8) shrink; (9) replenishment method; and (10) pick completion.","Each factor is discussed in more detail below.","Factor 1, Mis-Rings, refers to the data stored in the inventory management database 140 indicating that a cashier at a cash register did not correctly scan an item 90 (or did not for some reason scan all of the items 90) during a sale or return of the item 90.In some embodiments, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to interpret a higher value of Mis-Rings at the retail sales facility 110 as representing a higher likelihood that the system-indicated location/status of the item 90 is incorrect, and that the item 90 may be out of stock and not present at the retail sales facility 110.Factor 2, Shipping Error, refers to the data stored in the inventory management database 140 indicating that the number of items 90 indicated in shipping slips or in the system inventory database as being shipped to the retail sales facility 110 was incorrect.","For example, a shipping error may be generated when the system indicates that 1000 items 90 were shipped to the retail sales facility 110 when in fact it was determined that only 980 or 990 items 90 were shipped to the retail sales facility 110.In some embodiments, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to interpret a higher value of Shipping Error at the retail sales facility 110 as representing a higher likelihood that the system-indicated location/status of the item 90 is incorrect, and that the item 90 may be out of stock and not present at the retail sales facility 110.Factor 3, SF>SC (sales floor quantity greater than shelf cap), refers to the data stored in the inventory management database 140 indicating that the number of items 90 indicated to be on the sales floor 180 at the retail sales facility 110 is greater than the shelf space where the items 90 are typically stored.","In some embodiments, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to interpret a higher number of SF>SC occurrences at the retail sales facility 110 as representing a higher likelihood that the system-indicated location of the item 90 as being out of stock is incorrect, and that the item 90 may be elsewhere on the sales floor 180 or in another area of the retail sales facility 110.Factor 4, OH Delta (on-hand change), refers to the data stored in the inventory management database 140 indicating a change in the total number of items 90 in stock (i.e., on-hand) at the retail sales facility 110.In some embodiments, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to interpret a higher OH Delta value as representing a higher likelihood that the system-indicated location of the item 90 as being on the sales floor 180 of the retail sales facility 110 is incorrect, and that the item 90 is may be out of stock at the retail sales facility 110.Factor 5, Bin Accuracy, refers to the data stored in the inventory management database 140 reflecting the accuracy of the systematic indication of the location of an item 90 by the stocking associates at the retail sales facility 110.For example, if the number of items 90 entered into the system as being present in a storage bin by a stocking associate corresponds to actual number of items 90 in the storage bin when physically checked, or when the system indicates that the item 90 is not present in a storage bin and the item 90 is actually not present in the storage bin when physically checked, the bin accuracy value would be high for the retail sales facility 110, and vice versa.","In some embodiments, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to interpret a lower Bin Accuracy value as representing a higher likelihood that the system-indicated location and status of the item 90 at the retail sales facility 110 is incorrect and vice versa.","Factor 6, PI Accuracy (or perpetual accuracy), refers to the data stored in the inventory management database 140 reflecting the accuracy of the inventory location designation by the stocking associates at the retail sales facility 110.This factor generally indicates whether the items 90 are generally located where the system indicates they are located.","In some embodiments, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to interpret a lower PI Accuracy value as representing a higher likelihood that the system-indicated location and status of the item 90 at the retail sales facility 110 is incorrect and vice versa.","Factor 7, Mod Integrity (or modular planogram integrity), refers to the data stored in the inventory management database 140 indicating how correctly the stocking associates at the retail sales facility 110 stock the shelf on the sales floor 180 with the items 90 and/or how correctly the shelf on the sales floor 180 is set up for the items 90.This factor generally indicates whether the actual layout of the items 90 on the sales floor of the retail sales facility 110 corresponds to the layout of the items 90 according to the inventory management system 10.In some embodiments, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to interpret a lower PI Accuracy value as representing a higher likelihood that the system-indicated location and status of the item 90 at the retail sales facility 110 is incorrect and vice versa.","Factor 8, shrink, indicates how often items 90 go missing or unaccounted for at the retail sales facility 110 (e.g., as a result of theft, supplier mistakes, or other paperwork errors).","In some embodiments, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to interpret a higher shrink value as representing a higher likelihood that the item 90 is not present at the retail sales facility 110 and vice versa.","Factor 9, Replen Method (or replenishment method) indicates whether the item 90 moves quickly or slowly and is replenished quickly or slowly at the retail sales facility 110.The replenishment method may be indicated as a high velocity distribution center (HVDC) or a regional distribution center (RDC).","If the replenishment method is indicated as HVDC, the item 90 is replenished quickly and has high turnover, while an RDC replenishment method is indicative of items 90 that have low turnover and move slowly.","Accordingly, in some embodiments, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to interpret an HVDC replenishment method as generally indicating a higher likelihood that the system-indicated location or status of the item 90 at the retail sales facility 110 is incorrect, and to interpret the RDC replenishment method as generally indicating a higher likelihood that the system-indicated location or status of the item 90 at the retail sales facility 110 is correct.","Factor 10, Pick Completion, indicates how often when the system indicates to an associate to pick an item 90 (e.g., from a storage bin) that the associate actually completes the pick.","For instance, a low pick completion percentage may indicate that a stocking associate is not operating efficiently but likely honestly; an average pick completion may indicate that a stocking associate is operating within the norm of expected efficiency and honesty; a high pick completion may indicate that an associate may be entering into the system that the associate picked an item while the associate is not physically picking the item.","Thus, in some embodiments, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to interpret a high pick completion percentage at the retail sales facility 110 as indicative of a higher likelihood that the system-indicated location or status of the item 90 at the retail sales facility 110 is incorrect.","In the exemplary embodiment illustrated in FIG.","4, in addition to the ten exemplary inventory management factors discussed above based on which a perceived location of the out of stock item 90 may be tracked at the retail sales facility 110, the processor of the control circuit 210 of the inventory management electronic device 120 may be programmed to track the location of the item 90 at the retail sales facility 110 using predetermined worker task events 490 associated with the product 90.It will be appreciated that the nine worker task events 490 depicted in FIG.","4 are shown by way of example only, and any one or more of these worker task events 490 (or additional worker task events) may be analyzed by the processor of the control circuit 210 of the inventory management electronic device 120 to determine a perceived location of an out of stock item 90 at the retail sales facility 110.The exemplary worker task events are identified in FIG.","4 by numbers that continue the numbering from the last inventory management factor and are as follows: (11) time stamp of last sale of the item 90 to a customer; (12) time stamp of last customer return of the item 90; (13) time stamp of last customer claim for the item 90 (i.e., product indicated as not sellable); (14) time stamp of last binning or unbinning of the item 90; (15) time stamp of last feature set or unset of the item 90 (i.e., product is displayed as a featured item on the sales floor 180); (16) time stamp of last delivery of the item 90; (17) time stamp of last scan of the item 90; (18 ) time stamp of last price change of the item 90; and (19) time stamp of pick of the item 90.In one embodiment, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to track the location of the item 90 at the retail sales facility 110 using the inventory management factors 480 and the worker task events 490 described above and output a perceived location of the item 90 at the retail sales facility 110 based on the tracking analysis.","Some exemplary output of the processor of the control circuit 210 of the inventory management electronic device 120 based on the above-discussed inventory management factors (F1, F2, F3, etc.)","and worker task events (T11, T12, T13, etc.)","are discussed below.","It will be appreciated that output of the processor of the control circuit 210 of the inventory management electronic device 120 regarding the perceived location of an out of stock item 90 at the retail sales facility 110 may be based on many different combinations of one or more of the above-discussed inventory management factors 480 and/or worker task events 490, or may be based on combinations including additional inventory management factors 480 and additional worker task events 490 suitable for tracking a location of the out of stock item 90 at the retail sales facility 110.For example, the processor of the control circuit 210 of the inventory management electronic device 120 may be programmed to output that the item 90 is not present (i.e., out of stock) at the retail sales facility 110 if at least one of the following eight conditions is met during the tracking analysis: (1) if bin accuracy (F5) or perpetual accuracy (F6) or modular planogram integrity (F7) or pick completion percentage (F10) are low, and shrink (F8) or shipping error (F2) or mis-rings (F1) are high; (2) if time stamp of last delivery (T16) is newest and then the time stamp of last sale (T11) is newest, and on-hand delta (F4) is low; (3) if shrink (F8) is high; (4) if time stamp of last scan is newest (T17), and then timestamp of last sale is newest (T11), and then time stamp of last delivery (T16) is newest; (5) if the replenishment method (F9) is RDC assembly; (6) if on-hand delta (F4) is high and/or perpetual accuracy (F6) is low; (7) if time stamp of last price change newest (T18) and on-hand delta (F4) is high and/or perpetual accuracy (F6) is low; and (8) if the answer is “no” on all worker task events.","Some other exemplary outputs of the control circuit 210 of the inventory management electronic device 120 and the inventory management factors 480 and worker task events 490 contributing to such outputs are described below.","If SF>SC (F3) and time stamp of last delivery is newest (T16), and then time stamp of last pick is newest (T19), or time stamp of last sale is newest (T11), or time stamp of last claim is newest (T13), or time stamp of last bin or unbin is newest (T14), or time stamp of last return is newest (T12), or time stamp of last scan is newest (T17), then the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to output an indication to a stocking associate to look for the item 90 in the unworked freight.","If the replenishment method (F9) is determined to be HVDC, then the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to output an indication to a stocking associate to look for the item 90 in unbinned locations or previous binned area of the retail sales facility 110.If the time stamp of last claim is newest (T13), then the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to output an indication to a stocking associate to look for the item 90 in the claims area of the retail sales facility 110.If the time stamp of last return is newest (T12), then the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to output an indication to a stocking associate to look for the item 90 in the claims or returns area of the retail sales facility 110.If the time stamp of last pick is newest (T19) and pick completion (F10) is high, then the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to output an indication to a stocking associate to look for the item 90 in the pick carts in the stock room 170 of the retail sales facility 110.If modular planogram integrity (F7) is low, then the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to output an indication to a stocking associate to look for the item 90 in an area near the primary location on the sales floor 180 of the retail sales facility 110.If the time stamp of last pick is newest (T19) and pick completion (F10) or bin accuracy (F5) are low, then the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to output an indication to a stocking associate to look for the item 90 in the bin where the item 90 was indicated to be previously stored at the retail sales facility 110.If the time stamp of last bin or unbin is newest (T14) and pick completion (F10) or bin accuracy (F5) are low, then the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to output an indication to a stocking associate to look for the item 90 in the bin where the item 90 was indicated to be previously stored at the retail sales facility 110.If the time stamp of last feature set newest (T15), then the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to output an indication to a stocking associate to look for the item 90 in feature locations on the sales floor 180 or unbinned in the stock room 170 of the retail sales facility 110.In one approach, the processor of the control circuit 210 of the inventory management device 120 is programmed to monitor whether one or more worker task events 490 entered into the inventory management database 140 as being completed was in fact physically completed.","Based on this monitoring, the processor of the control circuit 210 of the inventory management device 120 is programmed to generate in the inventory management database 140 at least one data point indicating whether the one or more worker task event entered into the inventory management database 140 as being completed was physically completed.","In addition, the processor of the control circuit 210 of the inventory management device 120 is programmed to generate a report including at least one data point over a predetermined period of the monitoring.","The processor of the control circuit 210 of the inventory management device 120 is programmed to use such data points to generate an alert for items 90 for which a worker task was entered into the inventory management database 140 as being completed but was in fact not completed.","In addition, such data points can be used to determine a metric for the quality of stocking work by the inventory management associates at the retail sales facility 110.As described herein, the system and methods described herein provide for easy and efficient tracking and retrieval of out of stock inventory at a retail sales facility.","As discussed above, in a response to an indication that an item is out of stock at the retail sales facility, the methods and systems described herein can track the location of the out of stock item using one or more inventory management factors and worker task events described above and output an accurate perceived location of the item at the retail sales facility based on the tracking analysis.","This advantageously improves the efficiency of associates in determining whether items indicated to be out of stock are present at the retail sales facility, and if so, facilitates the stocking associates in tracking down and retrieving the items sought by the consumers and providing the retrieved items to the consumers.","Those skilled in the art will recognize that a wide variety of other modifications, alterations, and combinations can also be made with respect to the above described embodiments without departing from the scope of the invention, and that such modifications, alterations, and combinations are to be viewed as being within the ambit of the inventive concept."]],"string":"[\n [\n \"OUT OF STOCK ITEM TRACKING AT RETAIL SALES FACILITIES\",\n \"In some embodiments, methods and systems of locating overstock items at a retail sales facility include receiving an indication that a product at the retail sales facility is out of stock and determining whether the product is located on a sales floor or in the stock room at the retail sales facility; then, in response to a determination that the product is not located on the sales floor or in the stock room, tracking a location of the product based on at least one inventory management factor associated with the retail sales facility and at least one worker task event associated with the product; and outputting to a worker at the retail sales facility, based on the tracking of the location of the at least one product, an indication of a perceived location of the least one product.\"\n ],\n [\n \"1.A method for assisting in the locating of out of stock products at a retail sales facility, the method comprising: providing an inventory management database storing electronic data indicating at least one product that is offered for sale to consumers at a display location on a sales floor of the retail sales facility; receiving, an indication that at least one product is out of stock on the sales floor of the retail sales facility; determining, via an inventory management electronic device including a processor, and in response to querying the inventory management database via the inventory management electronic device to obtain inventory management data associated with the at least one product, that the inventory management data obtained via the inventory management electronic device from the inventory management database indicates that the at least one product is not located at the display location on the sales floor of the retail sales facility and is not located in a stock room of the retail sales facility; tracking, via the inventory management electronic device and the inventory management database, a location of the at least one product at the retail sales facility other than the display location and other than the stock room, based on analyzing, via the inventory management electronic device, at least one inventory management factor associated with the retail sales facility and at least one worker task event associated with the at least one product, the at least one management factor and the worker task event being stored in the inventory management database; and outputting, based on the tracking step and via the inventory management electronic device, an indication of a predicted location of the least one product at the retail sales facility other than the display location and other than the stock room, to a worker at the retail sales facility; wherein the at least one inventory management factor includes at least one of: mis-rings, shipping error, sales floor quantity versus shelf cap, change in on-hand inventory at the retail sales facility, bin accuracy, perpetual inventory accuracy, modular integrity, shrink, replenishment method, and pick completion; and wherein the at least one worker task event includes at least one of: time stamp of last sale of the at least one product, time stamp of last customer return of the at least one product, time stamp of last customer claim for the at least one product, time stamp of last binning or unbinning of the at least one product, time stamp of last feature set or unset of the at least one product, time stamp of last delivery of the at least one product, time stamp of last scan of the at least one product, time stamp of last price change of the at least one product, and time stamp of pick of the at least one product.\",\n \"2.The method of claim 1, wherein the receiving step includes inputting identifying information for the at least one product into the inventory management database and receiving a signal from the inventory database indicating that the at least one product is out of stock at the retail sales facility.\",\n \"3.The method of claim 2, wherein the display location is a shelf on the sales floor of the retail sales facility where the at least one product is regularly offered for sale.\",\n \"4.The method of claim 1, wherein the tracking step is performed via a control circuit including the processor in communication with the at least one inventory management database.\",\n \"5.The method of claim 1, further comprising monitoring, via the inventory management electronic device, whether the at least one worker task event entered into the inventory management database as being completed was physically completed, generating in the inventory management database at least one data point indicating whether the at least one worker task event entered into the inventory management database as being completed was physically completed, and generating, via the inventory management electronic device, a report including the at least one data point over a predetermined period of the monitoring.\",\n \"6.The method of claim 1, wherein the outputting step further comprises indicating, via the inventory management electronic device, to the user, based on the tracking step, to look for the at least one product in a location at the retail sales facility including at least one of: truck unload area, to be stocked area, unworked freight area, unbinned area, returns area, claims area, pick cart in stock room, area near shelf on the sales floor of the retail sales facility, last known bin location, and feature product display.\",\n \"7.The method of claim 1, wherein the outputting step further comprises indicating, via the inventory management electronic device, to the worker and based on the tracking step, that the at least one product is not present on hand at the retail sales facility.\",\n \"8.A system for tracking out of stock products at a retail sales facility, the system comprising: at least one inventory management database storing electronic data indicating at least one product that is offered for sale to consumers at a display location on a sales floor of at the retail sales facility; and a control circuit including a processor in communication with the at least one inventory management database, the control circuit configured to: receive electronic data from the at least one inventory management database that indicates that the at least one product is not located at the display location on the sales floor of the retail sales facility y and is not located in a stock room of the retail sales facility; track a location of the at least one product at the retail sales facility other than the display location and other than the stock room of the retail sales facility, based on an analysis, by the control circuit, of at least one inventory management factor associated with the retail sales facility and at least one worker task event associated with the at least one product, the at least one management factor and the worker task event being stored in the inventory management database; and output to a worker at the retail sales facility, based on the tracked location of the at least one product, an indication of a predicted location of the least one product at the retail sales facility other than the display location and other than the stock room of the retail sales facility; wherein the at least one inventory management factor includes at least one of: mis-rings, shipping error, sales floor quantity versus shelf cap, change in on-hand inventory at the retail sales facility, bin accuracy, perpetual inventory accuracy, modular integrity, shrink, replenishment method, and pick completion; and wherein the at least one worker task event includes at least one of: time stamp of last sale of the at least one product, time stamp of last customer return of the at least one product, time stamp of last customer claim for the at least one product, time stamp of last binning or unbinning of the at least one product, time stamp of last feature set or unset of the at least one product, time stamp of last delivery of the at least one product, time stamp of last scan of the at least one product, time stamp of last price change of the at least one product, and time stamp of pick of the at least one product.\",\n \"9.The system of claim 8, wherein the control circuit is configured to send a signal including identifying information for the at least one product to the at least one inventory management database and receive a signal from the inventory database indicating that the at least one product is out of stock at the retail sales facility.\",\n \"10.The system of claim 9, wherein the display location is a shelf on the sales floor of the retail sales facility where the at least one product is regularly offered for sale.\",\n \"11.The system of claim 8, wherein the control circuit is configured to: monitor whether the at least one worker task event entered into the at least one inventory management database as being completed was physically completed; generate in the at least one inventory management database at least one data point indicating whether the at least one worker task event entered into the at least one inventory management database as being completed was physically completed; and generate a report including the at least one data point over a predetermined period of monitoring by the server.\",\n \"12.The system of claim 8, wherein the control circuit is configured to indicate to the user, based on the tracked location of the at least one product, to look for the at least one product at a location at the retail sales facility including at least one of: truck unload area, to be stocked area, unworked freight area, unbinned area, returns area, claims area, pick cart in stock room, area near shelf on the sales floor of the retail sales facility, last known bin location, and feature item display.\",\n \"13.The system of claim 8, wherein the control circuit is configured to indicate to the worker, based on the tracked location of the at least one product, that the at least one product is not present at the retail sales facility.\",\n \"14.A system for tracking out of stock items at a retail sales facility, the system comprising: at least one storage means storing electronic data indicating at least one product that is offered for sale to consumers at a display location on a sales floor of at the retail sales facility; and a control means including a processor in communication with the at least one inventory management database, the control means configured to: receive electronic data from the at least one storage means that indicates that the at least one product is not located at the display location on the sales floor of the retail sales facility and is not located in a stock room of the retail sales facility; track a location of the at least one product at the retail sales facility other than the display location and other than the stock room of the retail sales facility based on at least one inventory management factor associated with the retail sales facility and at least one worker task event associated with the at least one product, the at least one management factor and the worker task event being stored in the storage means; and output to a worker at the retail sales facility, based on the tracked location of the at least one product, an indication of a predicted location of the least one product at the retail sales facility other than the display location and other than the stock room of the retail sales facility; wherein the at least one inventory management factor includes at least one of: mis-rings, shipping error, sales floor quantity versus shelf cap, change in on-hand inventory at the retail sales facility, bin accuracy, perpetual inventory accuracy, modular integrity, shrink, replenishment method, and pick completion; and wherein the at least one worker task event includes at least one of: time stamp of last sale of the at least one product, time stamp of last customer return of the at least one product, time stamp of last customer claim for the at least one product, time stamp of last binning or unbinning of the at least one product, time stamp of last feature set or unset of the at least one product, time stamp of last delivery of the at least one product, time stamp of last scan of the at least one product, time stamp of last price change of the at least one product, and time stamp of pick of the at least one product.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>Retail sales facilities often permit consumers to determine whether a product offered for sale at the retail sales facility is in stock by scanning the product.\",\n \"Also, consumers often request sales associates and/or managers at the retail sales facility to check whether a product of interest is in stock at the retail sales facility.\",\n \"Having to perform a large number of scans for low inventory and/or out of stock items often takes up a large portion of time from department managers and/or sales associates at the retail sales facility.\",\n \"When a product is determined to be out of stock at the retail sales facility via a scan by the consumer or sales or stocking associate, the consumer is typically informed either that the product is not available, or that the sales or stocking associate will go to the stock room to check whether the product indicated to be out of stock may be nevertheless present in the stock room.\",\n \"However, since the conventional inventory management systems do not provide the sales or stocking associate with possible locations where additional units of the product indicated to be out of stock may be present at the retail sales facility, the sales or stocking associates are often forced to physically check multiple locations at the retail sales facility to look for possible additional units of the out of stock product, which is time consuming and inefficient.\"\n ],\n [\n \"<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>Disclosed herein are embodiments of systems, apparatuses and methods pertaining to methods and systems for sorting overstock inventory.\",\n \"This description includes drawings, wherein: FIG.\",\n \"1 is a diagram of a retail sales facility overstock tracking system in accordance with some embodiments.\",\n \"FIG.\",\n \"2 is a functional diagram of an inventory management electronic device in accordance with several embodiments.\",\n \"FIG.\",\n \"3 is a flow chart diagram of a process of tracking out of stock items at a retail sales location in accordance with some embodiments.\",\n \"FIG.\",\n \"4 is a flow chart diagram of a method of tracking out of stock products at a retail sales facility in accordance with several embodiments.\",\n \"detailed-description description=\\\"Detailed Description\\\" end=\\\"lead\\\"?\",\n \"Elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale.\",\n \"For example, the dimensions and/or relative positioning of some of the elements in the figures may be exaggerated relative to other elements to help to improve understanding of various embodiments of the present invention.\",\n \"Also, common but well-understood elements that are useful or necessary in a commercially feasible embodiment are often not depicted in order to facilitate a less obstructed view of these various embodiments of the present invention.\",\n \"Certain actions and/or steps may be described or depicted in a particular order of occurrence while those skilled in the art will understand that such specificity with respect to sequence is not actually required.\",\n \"The terms and expressions used herein have the ordinary technical meaning as is accorded to such terms and expressions by persons skilled in the technical field as set forth above except where different specific meanings have otherwise been set forth herein.\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation of U.S. application Ser.\",\n \"No.\",\n \"15/202,897, filed Jul.\",\n \"6, 2016, which claims the benefit of U.S.\",\n \"Provisional Application No.\",\n \"62/200,431, filed Aug. 3, 2015, which are incorporated herein by reference in their entireties.\",\n \"TECHNICAL FIELD This invention relates generally to managing inventory at retail sales facilities and, in particular, to systems and methods for tracking out of stock items at retail sales facilities.\",\n \"BACKGROUND Retail sales facilities often permit consumers to determine whether a product offered for sale at the retail sales facility is in stock by scanning the product.\",\n \"Also, consumers often request sales associates and/or managers at the retail sales facility to check whether a product of interest is in stock at the retail sales facility.\",\n \"Having to perform a large number of scans for low inventory and/or out of stock items often takes up a large portion of time from department managers and/or sales associates at the retail sales facility.\",\n \"When a product is determined to be out of stock at the retail sales facility via a scan by the consumer or sales or stocking associate, the consumer is typically informed either that the product is not available, or that the sales or stocking associate will go to the stock room to check whether the product indicated to be out of stock may be nevertheless present in the stock room.\",\n \"However, since the conventional inventory management systems do not provide the sales or stocking associate with possible locations where additional units of the product indicated to be out of stock may be present at the retail sales facility, the sales or stocking associates are often forced to physically check multiple locations at the retail sales facility to look for possible additional units of the out of stock product, which is time consuming and inefficient.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS Disclosed herein are embodiments of systems, apparatuses and methods pertaining to methods and systems for sorting overstock inventory.\",\n \"This description includes drawings, wherein: FIG.\",\n \"1 is a diagram of a retail sales facility overstock tracking system in accordance with some embodiments.\",\n \"FIG.\",\n \"2 is a functional diagram of an inventory management electronic device in accordance with several embodiments.\",\n \"FIG.\",\n \"3 is a flow chart diagram of a process of tracking out of stock items at a retail sales location in accordance with some embodiments.\",\n \"FIG.\",\n \"4 is a flow chart diagram of a method of tracking out of stock products at a retail sales facility in accordance with several embodiments.\",\n \"Elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale.\",\n \"For example, the dimensions and/or relative positioning of some of the elements in the figures may be exaggerated relative to other elements to help to improve understanding of various embodiments of the present invention.\",\n \"Also, common but well-understood elements that are useful or necessary in a commercially feasible embodiment are often not depicted in order to facilitate a less obstructed view of these various embodiments of the present invention.\",\n \"Certain actions and/or steps may be described or depicted in a particular order of occurrence while those skilled in the art will understand that such specificity with respect to sequence is not actually required.\",\n \"The terms and expressions used herein have the ordinary technical meaning as is accorded to such terms and expressions by persons skilled in the technical field as set forth above except where different specific meanings have otherwise been set forth herein.\",\n \"DETAILED DESCRIPTION Generally speaking, this application describes systems and methods for tracking out of stock items at retail sales facilities.\",\n \"In some embodiments, the systems and methods described herein include one or more electronic devices configured to receive an indication that a product at a retail sales facility is out of stock and determine a location of the product at the retail sales facility based on at least one inventory management factor associated with the retail sales facility and/or at least one worker task event associated with the at least one product.\",\n \"In one embodiment, a method for assisting in the locating of out of stock items at a retail sales facility includes: receiving, an indication that at least one product at the retail sales facility is out of stock on a sales floor at the retail sales facility; determining, via an inventory management electronic device including a processor, that inventory management data indicates that the at least one product is not located on the sales floor and is not located in a stock room of the retail sales facility; tracking, via the inventory management electronic device, a location of the at least one product based on at least one inventory management factor associated with the retail sales facility and at least one worker task event associated with the at least one product; and outputting, based on the tracking step and via the inventory management electronic device, an indication of a predicted location of the least one product to a user at the retail sales facility.\",\n \"A system for tracking out of stock items at a retail sales facility according to one embodiment includes at least one inventory management database including inventory management data regarding at least one product at the retail sales facility; and a control circuit including a processor in communication with the at least one inventory management database.\",\n \"The control circuit is configured to: receive inventory management data that indicates that the at least one product is not located on the sales floor and is not located in a stock room of the retail sales facility; track a location of the at least one product based on at least one inventory management factor associated with the retail sales facility and at least one worker task event associated with the at least one product; and output to a user at the retail sales facility, based on the tracking of the location of the at least one product, an indication of a predicted location of the least one product.\",\n \"According to one embodiment, a system for tracking out of stock items at a retail sales facility includes at least one storage means including inventory management data regarding at least one product at the retail sales facility and a control means including a processor in communication with the at least one inventory management database.\",\n \"The control means is configured to: receive inventory management data that indicates that the at least one product is not located on the sales floor and is not located in a stock room of the retail sales facility; track a location of the at least one product based on at least one inventory management factor associated with the retail sales facility and at least one worker task event associated with the at least one product; and output to a user at the retail sales facility, based on the tracking of the location of the at least one product, an indication of a predicted location of the least one product.\",\n \"Referring to FIG.\",\n \"1, one embodiment of a system 100 for tracking and/or locating out of stock products at a retail sales facility 110 is shown.\",\n \"The retail sales facility 110 may be any place of business such as a store or warehouse where consumer products are stocked and/or sold.\",\n \"The system 100 includes an inventory management electronic device 120 configured to manage product inventory at the retail sales facility 110.The inventory management electronic device 120 illustrated in FIG.\",\n \"1 may be a stationary, portable, or hand-held electronic device, for example, a desktop computer, a laptop computer, a tablet, a mobile phone, or any other electronic, processor-based device that may be configured for data entry and communication with another electronic, processor-based device located at the retail sales facility 110, or at a location remote to the retail sales facility 110 (e.g., a regional or central server configured for two-way communication with multiple retail sales facilities 110).\",\n \"The exemplary inventory management electronic device 120 shown in FIG.\",\n \"1 includes an inventory management database 140 configured to store information regarding the items 90 present at the retail sales facility 110.The inventory management database 140 may be stored, for example, on non-volatile storage media (e.g., a hard drive, flash drive, or removable optical disk) internal or external relative to the inventory management electronic device 120 or internal to computing devices (e.g., remote server) separate and distinct from the inventory management electronic device 120.The information regarding the items 90 stored on the inventory management database 140 may include various historical/statistical inventory management factors pertaining to the retail sales facility 110 and worker task events pertaining to the items 90, which are shown in FIG.\",\n \"4, and will be discussed in more detail below.\",\n \"FIG.\",\n \"1 schematically shows (via dotted lines 155, 165, and 175) that the inventory management database 140 contains information regarding the items 90 present in the product delivery area 160, stock room 170, sales floor 180, and product sale/return/claim areas 190 of the retail sales facility 110, but it will be appreciated that the inventory management database 140 may contain information regarding any items 90 present in any other area of the retail sales facility 110 and may include information relating to tasks performed by workers in any other area of the retail sales facility 110 with respect to the items 90.The items 90 may be identified in the inventory management database 140 by way of stock keeping unit (SKU) numbers or any other unique identifiers.\",\n \"It will be appreciated that the inventory management database 140 does not have to be incorporated into the inventory management electronic device 120 local to the retail sales facility 110, but may be stored on a remote (e.g., central) server in communication with the inventory management electronic device 120.An exemplary inventory management electronic device 120 depicted in FIG.\",\n \"2 is a computer-based device and includes a control circuit 210 including a processor (for example, a microprocessor or a microcontroller) electrically coupled via a connection 215 to a memory 220 and via a connection 225 to a power supply 230.The control circuit 210 can comprise a fixed-purpose hard-wired platform or can comprise a partially or wholly programmable platform, such as a microcontroller, an application specification integrated circuit, a field programmable gate array, and so on.\",\n \"These architectural options are well known and understood in the art and require no further description here.\",\n \"This control circuit 210 can be configured (for example, by using corresponding programming stored in the memory 220 as will be well understood by those skilled in the art) to carry out one or more of the steps, actions, and/or functions described herein.\",\n \"In some embodiments, the memory 220 may be integral to the control circuit 210 or can be physically discrete (in whole or in part) from the control circuit 210 and is a non-volatile data storage media such as a hard drive configured to store the inventory management database 140.The memory 220 can be configured non-transitorily store the computer instructions that, when executed by the control circuit 210, cause the control circuit 210 to behave as described herein.\",\n \"(As used herein, this reference to “non-transitorily” will be understood to refer to a non-ephemeral state for the stored contents (and hence excludes when the stored contents merely constitute signals or waves) rather than volatility of the storage media itself and hence includes both non-volatile memory (such as read-only memory (ROM)) as well as volatile memory (such as an erasable programmable read-only memory (EPROM)).)\",\n \"The control circuit 210 of the electronic device 120 is also electrically coupled via a connection 235 to an input/output 240 that can receive signals from and send signals (via a wired or wireless connection) to (e.g., commands, inventory database information) devices local to the retail sales facility 110, or one or more servers remote to the retail sales facility 110.In the embodiment shown in FIG.\",\n \"2, the control circuit 210 of the electronic device 120 is electrically coupled via a connection 245 to a user interface 250, which may include a visual display or display screen 260 (e.g., LED screen) and/or button input 270 that provide the user interface 250 with the ability to permit a user such as a stock room or sales floor associate at the retail sales facility 110 to manually control the inventory management electronic device 120 by inputting commands, for example, via touch-screen and/or button operation or voice commands.\",\n \"The display screen 260 can also permit the user to see various menus, options, and/or alerts displayed by the inventory management electronic device 120.The user interface 250 of the inventory management electronic device 120 may also include a speaker 280 that may provide audible feedback (e.g., alerts) to the user.\",\n \"With reference to FIGS.\",\n \"1-3, one method 300 of operation of the system 100 to track and located out of stock products 90 at a retail sales facility 110 will now be described.\",\n \"For exemplary purposes, the method is described in the context of the system of FIG.\",\n \"1, but it is understood that embodiments of the method may be implemented in this or other systems.\",\n \"Generally, as shown in FIG.\",\n \"3, the method 300 includes receiving, an indication that a product 90 at the retail sales facility 110 is out of stock (step 310).\",\n \"Such an indication may be received as a result of a customer approaching a sales or stocking associate at the retail sales location 110 to inform the sales or stocking associate that the product 90 is not present on a shelf on the sales floor 180 where this product 90 is normally stocked.\",\n \"Alternatively, the consumer may inform the sales or stocking associate that the product 90 is out of stock after entering an SKU or an item identifier into an inventory management device available to consumers (e.g., by scanning a floor sample of the product 90 using an inventory management scanner) and receiving an indication that the product 90 is out of stock at the retail sales location 110.Alternatively, the out of stock indication may come as a result of a sales or stocking associate either scanning the floor sample of the product 90 or otherwise entering information identifying the product 90 into the inventory management database 140 (e.g., using the inventory management electronic device 120) and receiving an alert that the product 90 is out of stock.\",\n \"In the embodiment shown in FIG.\",\n \"3, the method 300 further includes determining whether the product 90 is located on a sales floor 180 at the retail sales facility 110 (step 320).\",\n \"This determination may be made as a result of the stocking associate at the retail sales facility 110 entering identifying information regarding the out of stock item 90 into the inventory management electronic device 120, in response to which the processor of the control circuit 210 of the inventory management electronic device 120 may be programmed to send an appropriate query or signal to the inventory management database 140 internal to the inventory management electronic device 120, or to a remote inventory management database via the input/output 240.In one embodiment, the inventory management database 140, upon receiving such a query or signal including data identifying the item 90 can retrieve information regarding the current location of the item 90 at the retail sales facility 110, and more specifically, regarding whether the item 90 is presently located on a shelf on the sales floor 180 where the item 90 is normally stocked for display and sale to consumers.\",\n \"In some embodiments, if the information retrieved from the inventory management database 140 indicates that the item 90 is present on a shelf on the sales floor 180 of the retail sales facility 110, the processor of the control circuit 210 is programmed to send a signal to the display 260 and/or speaker 280 of the inventory management electronic device 120 to generate a visible alert (e.g., via the on-screen menu) or an audible alert (e.g., beep or voice command) to inform the user (e.g., stocking associate) that the item 90 is present on the shelf on the sales floor 180.It will be appreciated that instead of retrieving information related to the present location of the item 90 at the retail sales facility 110 from the inventory management database 140, such information may be retrieved by the inventory management electronic device 120 from an inventory management database remote to the retail sales facility 110.In one embodiment shown in FIG.\",\n \"3, in response to a determination by the processor of the control circuit 210 of the inventory management electronic device 120 that the product 90 is not located on the sales floor 180 at the retail sales facility 110, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to determine whether the product 90 is located in the stock room 170 at the retail sales facility 110 (step 330).\",\n \"As described above, this determination may be made as a result of the stocking associate at the retail sales facility 110 entering identifying information regarding the out of stock item 90 into the inventory management electronic device 120, in response to which the processor of the control circuit 210 of the inventory management electronic device 120 may be programmed to send an appropriate query or signal to the inventory management database 140, and the inventory management database 140, upon receiving such a query or signal including data identifying the item 90 can retrieve information regarding the current location of the item 90 at the retail sales facility 110, and more specifically, regarding whether the item 90 is presently located in the stock room 170.If the information retrieved from the inventory management database 140 indicates that the item 90 is in the stock room 170 of the retail sales facility 110, the processor of the control circuit 210 of the inventory management electronic device 120 may be programmed to send a signal to the display 260 or speaker 280 of the inventory management electronic device 120 to generate a visible alert (e.g., via the on-screen menu) or an audible alert (e.g., beep or voice command) to inform the user (e.g., stocking associate) that the item 90 is in the stock room 170.In one embodiment shown in FIG.\",\n \"3, in response to a determination by the processor of the control circuit 210 of the inventory management electronic device 120 that the product 90 is not located on the sales floor 180 or in the stock room 170 at the retail sales facility 110, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to track the location of the out of stock product 90 at the retail sales facility 110 based on at least one inventory management factor associated with the retail sales facility 110 and/or at least one worker task event associated with the product 90 (step 340).\",\n \"The inventory management factors and worker task events that the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to analyze in tracking the location of the product 90 at the retail sales facility 110 are depicted in FIG.\",\n \"4 and discussed in more detail below.\",\n \"Based on the tracking analysis by the processor of the control circuit 210 of the inventory management electronic device 120, which will be described in more detail below, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to output an indication of a perceived or predicted location of the product 90 (step 350).\",\n \"The perceived location may be a physical location at the retail sales facility 110 such as the stock room 170, sales floor 180 or any other location at the retail sales facility 110 determined by the processor of the control circuit 210 of the inventory management electronic device 120 to contain the product 90.Alternatively, the output of the tracking analysis may be an indication that the product 90 is not present at the retail sales facility 110.For example, based on the tracking analysis, the processor of the control circuit 210 of the inventory management electronic device 120 may be programmed to send signal to the display 260 or speaker 280 of the inventory management electronic device 120 to generate a visible alert (e.g., via the on-screen menu) or an audible alert (e.g., beep or voice command) to inform the user (e.g., stocking associate) that the item 90 is perceived to be in the stock room 170, on the sales floor 180, or not present at the retail sales facility 110.Such an alert would signal to the stocking associate to take appropriate action (e.g., retrieve the item 90 from the perceived location for the consumer) or inform the consumer seeking the item 90 at the retail sales facility 110 that the item 90 is not present at the retail sales facility 110.In one embodiment, when the inventory management electronic device 120 indicates (e.g., via a visual or audible alert), based on tracking the item 90, to the stocking associate that the item 90 may be stocked on a shelf on the sales floor 180 or in the stock room 170, the inventory management electronic device 120 presents the associate with an option to acknowledge the alert, for example, by pressing on the display screen 260 or on one of the inputs 270 of the inventory management electronic device 120.When the stocking associate physically confirms whether the perceived location (i.e., based on the tracking analysis) of the item 90 is correct by walking to the perceived location and attempting to retrieve the item 90 and responds to the alert by indicating (e.g., via using the inputs 270 of the inventory management electronic device 120) whether the perceived location of the item 90 is correct or incorrect, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to designate the product 90 as being located in the location perceived based on the tracking analysis, or as being in an unidentified location at the retail sales facility 110, or as being not present at the retail sales facility 110.For example, the processor of the control circuit 210 may be programmed to send a signal to the inventory management database 140 or, via the input/output 240, to an inventory management database on a remote server, to indicate the actual physical location of the item 90 at the retail sales facility 110.As such, the location of the item 90 at the retail sales facility 110 may be updated in the inventory management database 140 or remote inventory management database for the retail sales facility 110, which enables the inventory management database 140 and/or a remote database to systematically store updated information regarding the location of items 90 indicated to be out of stock at the retail sales facility 110 and to permit the associates to efficiently retrieve such items and provide them to consumers seeking to buy these items 90.An exemplary method 400 of managing and stocking of products 90 at the retail sales facility 110 will now be described with reference to FIGS.\",\n \"1 and 4.As shown generally in step 410, when a stocking associate wishes to identify the location of a product 90 indicated to the customer or the stocking associate to be out of stock (step 410), the inventory management electronic device 120 may be initially operated by the stocking associate to determine, as described above, whether the item 90 (indicated to be out of stock) is present in a primary location at the retail sales facility 110 (step 420).\",\n \"The primary location may be, for example, a shelf on the sales floor 180 at the retail sales facility 110 where the item 90 is normally offered for sale to the customers.\",\n \"If the inventory management electronic device 120 indicates (e.g., via a displayed message, beep, or spoken words as discussed above) to the stocking associate that the item 90 is present in the primary location (step 425), the tracking process ends (step 430), enabling the stocking associate to physically check the primary location in an attempt to find the item 90 and provide it to the customer.\",\n \"Alternatively, if the inventory management electronic device 120 indicates (e.g., via a displayed message, beep, or spoken words as discussed above) to the stocking associate that the item 90 is not present in the primary location (step 435), the stocking associate may then operate the inventory management electronic device 120 to determine, as described above, whether the item 90 indicated to be out of stock is present in a secondary location at the retail sales facility 110 (step 440).\",\n \"The secondary location may be a location on the sales floor 180 other than the shelf where the item 90 is normally offered for sale to the customers, such as, for example, a feature, seasonal, or discount display on the sales floor 180.In yet another alternative, instead of relying on the inventory management electronic device 120 for a determination of whether the item 90 is present in the primary location, the stocking associate may walk to the primary location of the item 90 on the sales floor and visually inspect the primary location of the item 90 on the sales floor 180 to determine whether the item 90 indicated to be out of stock is present at the primary location.\",\n \"Upon the visual inspection, the stocking associate may then enter information into the inventory management system 100 using the inventory management electronic device 120 to indicate whether the item 90 is or is not present at the primary location at the retail sales facility 110.If the inventory management electronic device 120 indicates (e.g., via a displayed message, beep, or spoken words as discussed above) to the stocking associate that the item 90 is present in the secondary location (step 445), the tracking process ends (step 450), enabling the stocking associate to physically check the secondary location in an attempt to find the item 90 and provide it to the customer.\",\n \"Alternatively, if the inventory management electronic device 120 indicates (e.g., via a displayed message, beep, or spoken words as discussed above) to the stocking associate that the item 90 is not present in the secondary location (step 455), the stocking associate may then operate the inventory management electronic device 120 to determine, as described above, whether the item 90 indicated to be out of stock is present in the back room or stock room 170 at the retail sales facility 110 (step 460).\",\n \"If the inventory management electronic device 120 indicates (e.g., via a displayed message, beep, or spoken words as discussed above) to the stocking associate that the item 90 is present in the stock room 170 (step 465), the tracking process ends (step 470), enabling the stocking associate to physically check the stock room 170 in an attempt to find the item 90 and provide it to the customer.\",\n \"Alternatively, if the inventory management electronic device 120 indicates (e.g., via a displayed message, beep, or spoken words as discussed above) to the stocking associate that the item 90 is not present in the stock room 170 (step 475), the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to track the location of the item 90 at the retail sales facility 110 using predetermined inventory management factors 480 associated with the retail sales facility 110, as shown in FIG.\",\n \"4.It will be appreciated that the ten inventory management factors depicted in FIG.\",\n \"4 are shown by way of example only, and the processor of the control circuit 210 of the inventory management electronic device 120 may be programmed to analyze any one or more of these inventory management factors (or additional inventory management factors) to determine a predicted location of an out of stock item 90 at the retail sales facility 110.It will appreciated that the tracking of the out of stock items 90 at the retail sales facility 110 may be performed without requiring any calculation or analysis by the processor of the control circuit 210 of the inventory management electronic device 120, and that the system 100 may be configured such that the tracking of the out of stock items 90 may be performed by an inventory management computing device remote to the retail sales facility 110 and in communication with the inventory management electronic device 120.In such embodiments, the tracking analysis of the out of stock item 90 may be performed by the inventory management computing device remote to the grocery location 110 (based on data stored in the inventory management database 140 or a remote inventory management database), and may be stored at the remote inventory management database or in the inventory management database 140 until a time when a user uses the electronic computing device 120 to request and retrieve the perceived location of the out of stock item 90 from the remote inventory management database or the inventory management database 140, as appropriate.\",\n \"With reference to FIG.\",\n \"4, the exemplary inventory management factors that may be used for the tracking of the out of stock items 90 are: (1) mis-rings; (2) shipping error; (3) sales floor quantity versus shelf cap; (4) change in on-hand inventory at the retail sales facility; (5) bin accuracy; (6) perpetual inventory accuracy; (7) modular integrity; (8) shrink; (9) replenishment method; and (10) pick completion.\",\n \"Each factor is discussed in more detail below.\",\n \"Factor 1, Mis-Rings, refers to the data stored in the inventory management database 140 indicating that a cashier at a cash register did not correctly scan an item 90 (or did not for some reason scan all of the items 90) during a sale or return of the item 90.In some embodiments, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to interpret a higher value of Mis-Rings at the retail sales facility 110 as representing a higher likelihood that the system-indicated location/status of the item 90 is incorrect, and that the item 90 may be out of stock and not present at the retail sales facility 110.Factor 2, Shipping Error, refers to the data stored in the inventory management database 140 indicating that the number of items 90 indicated in shipping slips or in the system inventory database as being shipped to the retail sales facility 110 was incorrect.\",\n \"For example, a shipping error may be generated when the system indicates that 1000 items 90 were shipped to the retail sales facility 110 when in fact it was determined that only 980 or 990 items 90 were shipped to the retail sales facility 110.In some embodiments, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to interpret a higher value of Shipping Error at the retail sales facility 110 as representing a higher likelihood that the system-indicated location/status of the item 90 is incorrect, and that the item 90 may be out of stock and not present at the retail sales facility 110.Factor 3, SF>SC (sales floor quantity greater than shelf cap), refers to the data stored in the inventory management database 140 indicating that the number of items 90 indicated to be on the sales floor 180 at the retail sales facility 110 is greater than the shelf space where the items 90 are typically stored.\",\n \"In some embodiments, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to interpret a higher number of SF>SC occurrences at the retail sales facility 110 as representing a higher likelihood that the system-indicated location of the item 90 as being out of stock is incorrect, and that the item 90 may be elsewhere on the sales floor 180 or in another area of the retail sales facility 110.Factor 4, OH Delta (on-hand change), refers to the data stored in the inventory management database 140 indicating a change in the total number of items 90 in stock (i.e., on-hand) at the retail sales facility 110.In some embodiments, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to interpret a higher OH Delta value as representing a higher likelihood that the system-indicated location of the item 90 as being on the sales floor 180 of the retail sales facility 110 is incorrect, and that the item 90 is may be out of stock at the retail sales facility 110.Factor 5, Bin Accuracy, refers to the data stored in the inventory management database 140 reflecting the accuracy of the systematic indication of the location of an item 90 by the stocking associates at the retail sales facility 110.For example, if the number of items 90 entered into the system as being present in a storage bin by a stocking associate corresponds to actual number of items 90 in the storage bin when physically checked, or when the system indicates that the item 90 is not present in a storage bin and the item 90 is actually not present in the storage bin when physically checked, the bin accuracy value would be high for the retail sales facility 110, and vice versa.\",\n \"In some embodiments, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to interpret a lower Bin Accuracy value as representing a higher likelihood that the system-indicated location and status of the item 90 at the retail sales facility 110 is incorrect and vice versa.\",\n \"Factor 6, PI Accuracy (or perpetual accuracy), refers to the data stored in the inventory management database 140 reflecting the accuracy of the inventory location designation by the stocking associates at the retail sales facility 110.This factor generally indicates whether the items 90 are generally located where the system indicates they are located.\",\n \"In some embodiments, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to interpret a lower PI Accuracy value as representing a higher likelihood that the system-indicated location and status of the item 90 at the retail sales facility 110 is incorrect and vice versa.\",\n \"Factor 7, Mod Integrity (or modular planogram integrity), refers to the data stored in the inventory management database 140 indicating how correctly the stocking associates at the retail sales facility 110 stock the shelf on the sales floor 180 with the items 90 and/or how correctly the shelf on the sales floor 180 is set up for the items 90.This factor generally indicates whether the actual layout of the items 90 on the sales floor of the retail sales facility 110 corresponds to the layout of the items 90 according to the inventory management system 10.In some embodiments, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to interpret a lower PI Accuracy value as representing a higher likelihood that the system-indicated location and status of the item 90 at the retail sales facility 110 is incorrect and vice versa.\",\n \"Factor 8, shrink, indicates how often items 90 go missing or unaccounted for at the retail sales facility 110 (e.g., as a result of theft, supplier mistakes, or other paperwork errors).\",\n \"In some embodiments, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to interpret a higher shrink value as representing a higher likelihood that the item 90 is not present at the retail sales facility 110 and vice versa.\",\n \"Factor 9, Replen Method (or replenishment method) indicates whether the item 90 moves quickly or slowly and is replenished quickly or slowly at the retail sales facility 110.The replenishment method may be indicated as a high velocity distribution center (HVDC) or a regional distribution center (RDC).\",\n \"If the replenishment method is indicated as HVDC, the item 90 is replenished quickly and has high turnover, while an RDC replenishment method is indicative of items 90 that have low turnover and move slowly.\",\n \"Accordingly, in some embodiments, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to interpret an HVDC replenishment method as generally indicating a higher likelihood that the system-indicated location or status of the item 90 at the retail sales facility 110 is incorrect, and to interpret the RDC replenishment method as generally indicating a higher likelihood that the system-indicated location or status of the item 90 at the retail sales facility 110 is correct.\",\n \"Factor 10, Pick Completion, indicates how often when the system indicates to an associate to pick an item 90 (e.g., from a storage bin) that the associate actually completes the pick.\",\n \"For instance, a low pick completion percentage may indicate that a stocking associate is not operating efficiently but likely honestly; an average pick completion may indicate that a stocking associate is operating within the norm of expected efficiency and honesty; a high pick completion may indicate that an associate may be entering into the system that the associate picked an item while the associate is not physically picking the item.\",\n \"Thus, in some embodiments, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to interpret a high pick completion percentage at the retail sales facility 110 as indicative of a higher likelihood that the system-indicated location or status of the item 90 at the retail sales facility 110 is incorrect.\",\n \"In the exemplary embodiment illustrated in FIG.\",\n \"4, in addition to the ten exemplary inventory management factors discussed above based on which a perceived location of the out of stock item 90 may be tracked at the retail sales facility 110, the processor of the control circuit 210 of the inventory management electronic device 120 may be programmed to track the location of the item 90 at the retail sales facility 110 using predetermined worker task events 490 associated with the product 90.It will be appreciated that the nine worker task events 490 depicted in FIG.\",\n \"4 are shown by way of example only, and any one or more of these worker task events 490 (or additional worker task events) may be analyzed by the processor of the control circuit 210 of the inventory management electronic device 120 to determine a perceived location of an out of stock item 90 at the retail sales facility 110.The exemplary worker task events are identified in FIG.\",\n \"4 by numbers that continue the numbering from the last inventory management factor and are as follows: (11) time stamp of last sale of the item 90 to a customer; (12) time stamp of last customer return of the item 90; (13) time stamp of last customer claim for the item 90 (i.e., product indicated as not sellable); (14) time stamp of last binning or unbinning of the item 90; (15) time stamp of last feature set or unset of the item 90 (i.e., product is displayed as a featured item on the sales floor 180); (16) time stamp of last delivery of the item 90; (17) time stamp of last scan of the item 90; (18 ) time stamp of last price change of the item 90; and (19) time stamp of pick of the item 90.In one embodiment, the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to track the location of the item 90 at the retail sales facility 110 using the inventory management factors 480 and the worker task events 490 described above and output a perceived location of the item 90 at the retail sales facility 110 based on the tracking analysis.\",\n \"Some exemplary output of the processor of the control circuit 210 of the inventory management electronic device 120 based on the above-discussed inventory management factors (F1, F2, F3, etc.)\",\n \"and worker task events (T11, T12, T13, etc.)\",\n \"are discussed below.\",\n \"It will be appreciated that output of the processor of the control circuit 210 of the inventory management electronic device 120 regarding the perceived location of an out of stock item 90 at the retail sales facility 110 may be based on many different combinations of one or more of the above-discussed inventory management factors 480 and/or worker task events 490, or may be based on combinations including additional inventory management factors 480 and additional worker task events 490 suitable for tracking a location of the out of stock item 90 at the retail sales facility 110.For example, the processor of the control circuit 210 of the inventory management electronic device 120 may be programmed to output that the item 90 is not present (i.e., out of stock) at the retail sales facility 110 if at least one of the following eight conditions is met during the tracking analysis: (1) if bin accuracy (F5) or perpetual accuracy (F6) or modular planogram integrity (F7) or pick completion percentage (F10) are low, and shrink (F8) or shipping error (F2) or mis-rings (F1) are high; (2) if time stamp of last delivery (T16) is newest and then the time stamp of last sale (T11) is newest, and on-hand delta (F4) is low; (3) if shrink (F8) is high; (4) if time stamp of last scan is newest (T17), and then timestamp of last sale is newest (T11), and then time stamp of last delivery (T16) is newest; (5) if the replenishment method (F9) is RDC assembly; (6) if on-hand delta (F4) is high and/or perpetual accuracy (F6) is low; (7) if time stamp of last price change newest (T18) and on-hand delta (F4) is high and/or perpetual accuracy (F6) is low; and (8) if the answer is “no” on all worker task events.\",\n \"Some other exemplary outputs of the control circuit 210 of the inventory management electronic device 120 and the inventory management factors 480 and worker task events 490 contributing to such outputs are described below.\",\n \"If SF>SC (F3) and time stamp of last delivery is newest (T16), and then time stamp of last pick is newest (T19), or time stamp of last sale is newest (T11), or time stamp of last claim is newest (T13), or time stamp of last bin or unbin is newest (T14), or time stamp of last return is newest (T12), or time stamp of last scan is newest (T17), then the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to output an indication to a stocking associate to look for the item 90 in the unworked freight.\",\n \"If the replenishment method (F9) is determined to be HVDC, then the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to output an indication to a stocking associate to look for the item 90 in unbinned locations or previous binned area of the retail sales facility 110.If the time stamp of last claim is newest (T13), then the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to output an indication to a stocking associate to look for the item 90 in the claims area of the retail sales facility 110.If the time stamp of last return is newest (T12), then the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to output an indication to a stocking associate to look for the item 90 in the claims or returns area of the retail sales facility 110.If the time stamp of last pick is newest (T19) and pick completion (F10) is high, then the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to output an indication to a stocking associate to look for the item 90 in the pick carts in the stock room 170 of the retail sales facility 110.If modular planogram integrity (F7) is low, then the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to output an indication to a stocking associate to look for the item 90 in an area near the primary location on the sales floor 180 of the retail sales facility 110.If the time stamp of last pick is newest (T19) and pick completion (F10) or bin accuracy (F5) are low, then the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to output an indication to a stocking associate to look for the item 90 in the bin where the item 90 was indicated to be previously stored at the retail sales facility 110.If the time stamp of last bin or unbin is newest (T14) and pick completion (F10) or bin accuracy (F5) are low, then the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to output an indication to a stocking associate to look for the item 90 in the bin where the item 90 was indicated to be previously stored at the retail sales facility 110.If the time stamp of last feature set newest (T15), then the processor of the control circuit 210 of the inventory management electronic device 120 is programmed to output an indication to a stocking associate to look for the item 90 in feature locations on the sales floor 180 or unbinned in the stock room 170 of the retail sales facility 110.In one approach, the processor of the control circuit 210 of the inventory management device 120 is programmed to monitor whether one or more worker task events 490 entered into the inventory management database 140 as being completed was in fact physically completed.\",\n \"Based on this monitoring, the processor of the control circuit 210 of the inventory management device 120 is programmed to generate in the inventory management database 140 at least one data point indicating whether the one or more worker task event entered into the inventory management database 140 as being completed was physically completed.\",\n \"In addition, the processor of the control circuit 210 of the inventory management device 120 is programmed to generate a report including at least one data point over a predetermined period of the monitoring.\",\n \"The processor of the control circuit 210 of the inventory management device 120 is programmed to use such data points to generate an alert for items 90 for which a worker task was entered into the inventory management database 140 as being completed but was in fact not completed.\",\n \"In addition, such data points can be used to determine a metric for the quality of stocking work by the inventory management associates at the retail sales facility 110.As described herein, the system and methods described herein provide for easy and efficient tracking and retrieval of out of stock inventory at a retail sales facility.\",\n \"As discussed above, in a response to an indication that an item is out of stock at the retail sales facility, the methods and systems described herein can track the location of the out of stock item using one or more inventory management factors and worker task events described above and output an accurate perceived location of the item at the retail sales facility based on the tracking analysis.\",\n \"This advantageously improves the efficiency of associates in determining whether items indicated to be out of stock are present at the retail sales facility, and if so, facilitates the stocking associates in tracking down and retrieving the items sought by the consumers and providing the retrieved items to the consumers.\",\n \"Those skilled in the art will recognize that a wide variety of other modifications, alterations, and combinations can also be made with respect to the above described embodiments without departing from the scope of the invention, and that such modifications, alterations, and combinations are to be viewed as being within the ambit of the inventive concept.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875760"}}},{"rowIdx":4494968,"cells":{"text":{"kind":"list like","value":[["Electronic Method and System that Improves Efficiencies for Rendering Diagnosis of Radiology Procedures","An electronic method and system for improving radiologists' efficiencies when viewing radiology procedures and rendering diagnosis in a manner that emulates current methods and apparatus.","The method of the present invention includes reviewing electronic radiology images and reports contained in a patient's digital master folder (an information object invented to manage the patient's radiology information), comparing images from the current procedure to specific images from prior procedures in a specified order, and dictating the procedure's diagnosis into the digital master folder.","The apparatus of the present invention includes a flat panel monitor for the viewing and manipulation of digital master folders, a dictation trackball device for manual and voice enabled operation and navigation of the system, and multiple high-resolution computer monitors functioning as a “light-box” for the viewing of radiology images."],["1.An electronic method of improving the efficiency of a radiologist, comprising the steps of: a) providing a system that includes a computer and a plurality of monitors interfaced with the computer, each monitor for displaying an image; b) using at least one of the monitors to display electronic radiology images; c) using at least one of the monitors to simulate a digital graphical representation of a patient's manual master folder comprising the steps of: (i) generating by a software application the digital graphical representation of the patient's manual master folder as an image on the monitor designed for use as a graphical user interface by the radiologist; (ii) generating data fields on the digital graphical representation including patient information, medical procedures information and radiologist information regarding radiology procedures associated with such patient stored in an information database; (iii) providing information and hyperlinks to radiology reports and images in a default electronic layout conforming to the layout of the patient's manual master folder and tailored to a user; and (iv) including hyperlinks within at least one data field to view additional information or images relating to a patient's medical records when clicked; d) using a hyperlink to open the folder displayed in step “c” to display information contained in the folder; and e) using a hyperlink that accesses the folder to display a radiology image from a radiology procedure to permit diagnosis.","2.The method of claim 1 wherein in step “d” a voice activated command is used to open the patient's master folder.","3.The method of claim 1 wherein in step “d” an input device is used to open the patient's master folder.","4.The method of claim 1 further comprising the step of providing a combination dictation and input device, and wherein in step “d” a user can selectively use either a voice activated command or the input device to open the patient's master folder.","5.The method of claim 1 further comprising the step of using the computer to interface the monitors and the hyperlink.","6.The method of claim 4 further comprising the step of using the computer to interface the monitors and the combination dictation and input device.","7.The method of claim 1 wherein there are two monitors in step “c” that are used to display electronic radiology images.","8.The method of claim 1 wherein the monitor in step “c” that is used to display electronic radiology images is a high resolution monitor.","9.The method of claim 7 wherein the monitors in step “c” that are used to display electronic radiology images is a high resolution monitor.","10.The method of claim 1 wherein in step “b” the image viewed is an ultrasound image.","11.The method of claim 1 wherein in step “b” the image viewed is a magnetic resonance image.","12.The method of claim 1 wherein in step “b” the image viewed is a computer tomography image.","13.The method of claim 1 wherein in step “b” the image viewed is a digital image.","14.The method of claim 1 wherein in step “b” the image viewed is a nuclear medicine image.","15.A method for reviewing electronic radiology information including patient demographics, radiology procedures, radiology reports and radiology images, comprising the steps of: a) loading the radiology information associated with a selected group of patients that are assigned to a selected radiologist into a computer memory; b) generating by a software application an image of a radiology manual master folder on an area of a computer display for use as a graphical user interface by the radiologist; c) generating data fields associated with a digital master folder on the image of a patient's manual master folder including patient's name, medical record number, date of birth, sex, and information regarding procedures associated with such patient stored in an information database including date, type of procedure, report, and radiologist, the digital master folder designed for use by a radiologist; d) displaying the information associated with the patient from computer memory in data fields on the computer display in a default electronic layout conforming to the layout of the patient's manual master folder; e) providing hyperlinks within the procedure and report data fields to view additional information or images relating to a patient's medical records when clicked, the information and images displayed in electronic formats and configurations tailored to a radiology practice; f) clicking on the report field, displays a new window that contains the text of the report and a link to the digitally recorded dictation of the report, that when clicked will play the recording; g) placing a cursor over the report field on the digital master folder, to display summary information of the report; h) clicking on the procedure field to send a command to a viewing portal to load the procedures and images that meet the criteria of the radiologist's file; i) viewing the radiology images from radiology procedures; j) generating a searchable and selectable list of patients that have procedures assigned to the radiologist on the computer display; and k) providing commands that navigate through the stack of master folders, displaying information associated with a new patient in a data field on the computer display from computer memory.","16.An apparatus to access, store, and distribute electronic radiology information including patient demographics, radiology procedures, radiology reports and radiology images comprising: a) an information database including patient demographics, radiology identification number, procedures, images, reports, orders and appointments; b) means for transmitting and receiving the information between computers connected to a computer network via extensible markup language (XML); c) means for searching for a plurality of user specified types of information contained in the information database; d) means for generating by a software application a digital master folder representation of a patient's manual master folder for displaying the specified types of information over a monitor of a computer connected to the computer network, the digital master folder representation designed for use as a graphical user interface by a radiologist; e) means for generating data fields on the digital master folder representation including radiology reports and images information regarding radiology procedures associated with such patient stored in the information database; f) means for viewing radiology images from a radiology procedure; g) means for displaying the radiology reports and images in an electronic layout conforming to the layout of the patient's manual master folder and tailored to a user; and h) means for providing hyperlinks within at least one data field to view additional information or images relating to a patient's medical records when clicked.","17.A multi-monitor radiology image viewing system comprising: a) a plurality of monitors; b) a combination dictation and input device that includes a hyperlink to view a patients' information and medical images on separate monitors comprising: c) a radiology portal that includes a monitor and a computer for the searching and that includes viewing medical information, the medical information displayed over the monitor by generating by a software application a digital master folder representation of a patient's manual master folder, the digital master folder representation designed for use as a graphical user interface by a radiologist; d) said digital master folder representation providing data fields included within the digital master folder representation providing information and links to radiology reports and images regarding radiology procedures associated with such patient stored in an information database in an electronic layout conforming to the layout of the patient's manual master folder and tailored to a user, such links providing for the viewing of additional information or images relating to a patient's medical records when clicked; e) said viewing portal consisting of at least two monitors designed for the viewing of a plurality of radiology images including digital images, computer tomography, ultrasound, nuclear medicine, and magnetic resonance images; and f) said combination dictation and input device including a voice component that issues operational and navigational commands to the radiology portal and viewing portal by providing speech recognition for the creation of dictated radiology reports.","18.The system of claim 17, wherein the radiology portal consists of a monitor and computer for the searching and viewing of medical information stored internal and external to the system.","19.The system of claim 17, wherein the radiology portal consists of a touch screen monitor and computer for searching and viewing of medical information stored internal and external to the system.","20.The system of claim 17, wherein the radiology portal consists of a flat panel monitor and computer for searching and viewing of medical information stored internal and external to the system.","21.The system of claim 17, wherein the radiology portal consists of a touch screen flat panel monitor and computer for searching and viewing of medical information stored internal and external to the system.","22.The system of claim 17, wherein the viewing portal consists of a single high-resolution monitor designed for the viewing of a plurality of radiology images including digital images, computer tomography, ultrasound, nuclear medicine, and magnetic resonance images.","23.The system of claim 17, wherein the viewing portal consists of a single high-resolution computer monitor.","24.The system of claim 17, wherein the viewing portal consists of two high-resolution computer monitors.","25.The system of claim 17, wherein the viewing portal consists of four high-resolution monitors designed for the viewing of a plurality of radiology images including digital images, computer radiology, computer tomography, ultrasound, nuclear medicine, and magnetic resonance images.","26.The system of claim 17, wherein the viewing portal includes six high-resolution monitors for the viewing of a plurality of radiology images including digital images, computer tomography, ultrasound, nuclear medicine, and magnetic resonance images.","27.The system of claim 17, wherein the viewing portal consists of eight high-resolution monitors designed for the viewing of a plurality of radiology images including digital images, computer tomography, ultrasound, nuclear medicine, and magnetic resonance images.","28.The system of claim 17, wherein the combination dictation and input device includes a separate mouse and microphone."],["<SOH> BACKGROUND OF THE INVENTION <EOH>"],["<SOH> BRIEF SUMMARY OF THE INVENTION <EOH>The present invention provides an electronic method of improving the efficiency of a radiologist and of a radiology department.","With the present invention, a plurality of computer monitors are provided for displaying various images.","At least one of the monitors simulates a radiology “light box”, roto viewer, or like device for displaying electronic radiology images.","At least one of the monitors is used to display a digital graphical representation of a patient's folder, namely a digital master folder.","A hyperlink is used to open the report and to open different “pages” of the patient's master folder.","In one embodiment, a voice activated command can be used to open the patient's master folder or to open “pages” of the patient's folder.","In another embodiment, a track ball device such as a computer mouse can be used to open the patient's master folder or “pages” contained within the folder.","In another embodiment, the radiologist/user is provided with a combination microphone/track ball device that enables the radiologist or user to open the patient's master folder or components thereof using either voice activated commands or the track ball device.","A touch screen device hyperlink can also be used to open a patient's folder or report."],["CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of and claims the benefit of U.S. Non-Provisional patent application Ser.","No.","14/703,362 filed May 4, 2015, which is a continuation of and claims the benefit of U.S. Non-Provisional patent application Ser.","No.","14/208,864 filed Mar.","13, 2014, which is a continuation of and claims the benefit of U.S. Non-Provisional patent application Ser.","No.","13/954,310 filed Jul.","30, 2013, which is a continuation of and claims the benefit of U.S. Non-Provisional patent application Ser.","No.","13/527,924 filed Jun.","20, 2012, which is a continuation of and claims the benefit of U.S. Non-Provisional patent application Ser.","No.","12/684,289 filed Jan. 8, 2010, which is a continuation of and claims the benefit of U.S. Non-Provisional patent application Ser.","No.","12/069,468 filed Feb. 11, 2008, which is a continuation of and claims the benefit of Non-Provisional patent application Ser.","No.","09/726,475 filed Nov. 30, 2000, which further claims the benefit of U.S.","Provisional Application No.","60/168,106 filed Nov. 30, 1999.The subject matter of those applications is incorporated by this reference.","STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT Not applicable REFERENCE TO A “MICROFICHE APPENDIX” Not applicable BACKGROUND OF THE INVENTION 1.Field of the Invention The present invention relates to a method and apparatus for improving radiologists' efficiencies when viewing radiology procedures and rendering diagnosis.","2.General Background of the Invention Typically, every radiology office uses a dictating machine for the preparation of reports, a stack of master folders that contain patient information, and a light box, roto viewer, or like device for viewing radiology images.","These images can include for example x-rays, ultrasound, magnetic resonance imaging (MRI), computer tomography, nuclear medicine images and the like.","The manual file folder system employed by radiologists and radiology departments is inefficient and cumbersome.","BRIEF SUMMARY OF THE INVENTION The present invention provides an electronic method of improving the efficiency of a radiologist and of a radiology department.","With the present invention, a plurality of computer monitors are provided for displaying various images.","At least one of the monitors simulates a radiology “light box”, roto viewer, or like device for displaying electronic radiology images.","At least one of the monitors is used to display a digital graphical representation of a patient's folder, namely a digital master folder.","A hyperlink is used to open the report and to open different “pages” of the patient's master folder.","In one embodiment, a voice activated command can be used to open the patient's master folder or to open “pages” of the patient's folder.","In another embodiment, a track ball device such as a computer mouse can be used to open the patient's master folder or “pages” contained within the folder.","In another embodiment, the radiologist/user is provided with a combination microphone/track ball device that enables the radiologist or user to open the patient's master folder or components thereof using either voice activated commands or the track ball device.","A touch screen device hyperlink can also be used to open a patient's folder or report.","BRIEF DESCRIPTION OF THE DRAWINGS For a further understanding of the nature, objects, and advantages of the present invention, reference should be had to the following detailed description, read in conjunction with the following drawings, wherein like reference numerals denote like elements and wherein: FIG.","1 is a screen capture image showing a patient's radiology master folder that displays basic patient information including name, number, and study date; FIG.","2 is a screen capture image showing the report, displayed by double clicking on the report hyperlink; FIG.","3 is a screen capture image showing the audio graphical display generated by the audio hyperlink 15; FIG.","4 is a screen capture image showing a modality subfolder generated by double clicking on the ultrasound header 17; FIG.","5 is a screen capture image that shows radiology images in twelve up format; FIG.","6 is a screen capture image that shows radiology images in four up format; FIG.","7 is a screen capture image that shows radiology images in cine mode; FIG.","8 is a screen capture image that shows a cine set display; FIG.","9 is a screen capture image that shows radiographic images, showing current chest x-rays views, on the two high resolution monitors with the roto viewer window displayed; FIG.","10 is a screen capture image that shows chest x-ray views current and most recent with the roto viewer window displayed; FIG.","11 is a screen capture image that shows radiographic images demonstrating picture zoom; FIG.","12 is a screen capture image showing radiographic images without the roto viewer; and FIG.","13 is a screen capture image showing multiple images using the roto viewer.","DETAILED DESCRIPTION OF THE INVENTION FIG.","1 shows a digital representation of a patient folder designated generally by the numeral 10.Patient folder 10 shows two hyperlinks 11, 12.At the top center of the folder 10, a header 17 indicates that this folder can, for example, relate to an ultrasound.","The folder could relate to their radiology procedures.","By clicking on the ultrasound hyperlink, the window shown in FIG.","1 is opened providing a report display area 13 to be filled with the report information in text form as dictated by a radiologist.","When a radiologist double clicks on the report hyperlink 12 in FIG.","1, the screen in FIG.","2 is displayed which is the report screen 14 containing patient information and the substance of the report.","Audio hyperlink 15 can be double clicked using the computer mouse in order to actually hear the report.","When a user double clicks on the hyperlink 15 in FIG.","2, the display in FIG.","3 is shown on the screen having a graphical display for the audio.","When the radiologist double clicks on the ultrasound header 17 in FIG.","1, the screen provided in FIG.","4 has a modality subfolder 18 having a hyperlink 19.When the radiologist uses the computer mouse to double click on the exam hyperlink in FIG.","4, actual radiology images as shown in FIG.","5 are displayed.","In FIG.","5, a left computer monitor 20 and a right computer monitor 21 are shown.","In FIG.","5, a “twelve up” configuration is shown in each of the monitors 20, 21.In FIG.","6, a “four up” configuration is shown in each of the monitors 20, 21.In FIG.","7, a cine mode is shown for each of the monitors 20, 21.In the cine mode, sets of images are grouped and maintained in that grouping on a selected screen 20 or 21.FIG.","8 is a screen capture image that shows a cine set display.","FIGS.","9-12 show the use of the method and apparatus of the present invention to display full size radiology images, namely one image per screen 20, 21.In FIG.","9, as an example, image 31 is a left image, current PA for a patient.","The right image in FIG.","9 is an image that is a current lateral for the patient.","To the left hand side in the screen capture of FIG.","9, a roto viewer 22 is also shown.","The roto viewer in FIG.","9 is comprised of two columns of boxes, each column containing a set of windows, each window can be designated by the numeral 25.The windows 25 can be scrolled to display various radiology images as further shown in FIGS.","9 and 10.In FIGS.","9 and 10, the upper left window box of roto viewer 22 is designated by the numeral 23.The upper right window box is designated by the numeral 24.The screen captures of FIGS.","9 and 10 illustrate examples of radiology images that can be displayed using the method and apparatus of the present invention.","As shown in FIG.","10, the roto viewer 22 can include different groups of images in each of the window boxes 23, 24, 25 or 26.In FIG.","10, the window 23 contains those images which are displayed in the left hand computer monitor 20.The window box 24 of roto viewer 22 contains images which are displayed in the right hand monitor 21 in FIG.","10.Other images can be contained in other window boxes of the roto viewer 22 as shown in FIG.","10, just below window boxes 23, 24.Each of these images 33, 34 appear in the roto viewer window boxes 23, 24.The roto viewer 22 can be moved about the screen by dragging it.","In FIG.","11, the zoom feature of the present invention is illustrated.","Each of the screens 20, 21 display a zoomed image.","The monitor 20 displays image 36.The monitor 21 displays image 39.At the lower left hand corner of each of the screens 20, 21, there is provided a picture in a picture display.","This picture in a picture display includes the smaller picture 35 showing a chest x-ray as an example.","The viewing area 37 represents that portion of the chest x-ray 35 that is to be displayed in zoom format as image 36 in FIG.","11.Similarly, the monitor 21 displays at its lower left hand corner a picture in picture 38 having viewing area 40 that designates the zoom area of the chest x-ray 38.The image 39 is that portion of the image contained within viewing area 40 and which has been enlarged to fill substantially all of screen 21.FIG.","12 illustrates monitors 20, 21 with the roto viewer 22 removed.","In FIG.","13, the group of windows 27, 28, 29 and 30 represent different cine sets or groups of images that have been purposely grouped together by the radiologist.","Each of the windows 27-30 can be moved about within the roto viewer to move the displayed images around the screens 20, 21.PARTS LIST Part No.","Description 10 folder 11 hyperlink (ultrasound) 12 hyperlink (report) 13 report display area 14 report 15 audio hyperlink 16 graphical display - audio 17 ultrasound header 18 modality subfolder 19 hyperlink 20 left monitor 21 right monitor 22 roto viewer 23 left window box 24 right window box 25 windows/roto viewer 26 windows/roto viewer 27 windows group 28 windows group 29 windows group 30 windows group 31 left image/current PA 32 right image/current lateral 33 left image/current PA 34 right image/most recent lateral 35 picture in picture 36 image - zoom 37 view area 38 picture in picture 39 image - zoom 40 view area The foregoing embodiments are presented by way of example only; the scope of the present invention is to be limited only by the following claims."]],"string":"[\n [\n \"Electronic Method and System that Improves Efficiencies for Rendering Diagnosis of Radiology Procedures\",\n \"An electronic method and system for improving radiologists' efficiencies when viewing radiology procedures and rendering diagnosis in a manner that emulates current methods and apparatus.\",\n \"The method of the present invention includes reviewing electronic radiology images and reports contained in a patient's digital master folder (an information object invented to manage the patient's radiology information), comparing images from the current procedure to specific images from prior procedures in a specified order, and dictating the procedure's diagnosis into the digital master folder.\",\n \"The apparatus of the present invention includes a flat panel monitor for the viewing and manipulation of digital master folders, a dictation trackball device for manual and voice enabled operation and navigation of the system, and multiple high-resolution computer monitors functioning as a “light-box” for the viewing of radiology images.\"\n ],\n [\n \"1.An electronic method of improving the efficiency of a radiologist, comprising the steps of: a) providing a system that includes a computer and a plurality of monitors interfaced with the computer, each monitor for displaying an image; b) using at least one of the monitors to display electronic radiology images; c) using at least one of the monitors to simulate a digital graphical representation of a patient's manual master folder comprising the steps of: (i) generating by a software application the digital graphical representation of the patient's manual master folder as an image on the monitor designed for use as a graphical user interface by the radiologist; (ii) generating data fields on the digital graphical representation including patient information, medical procedures information and radiologist information regarding radiology procedures associated with such patient stored in an information database; (iii) providing information and hyperlinks to radiology reports and images in a default electronic layout conforming to the layout of the patient's manual master folder and tailored to a user; and (iv) including hyperlinks within at least one data field to view additional information or images relating to a patient's medical records when clicked; d) using a hyperlink to open the folder displayed in step “c” to display information contained in the folder; and e) using a hyperlink that accesses the folder to display a radiology image from a radiology procedure to permit diagnosis.\",\n \"2.The method of claim 1 wherein in step “d” a voice activated command is used to open the patient's master folder.\",\n \"3.The method of claim 1 wherein in step “d” an input device is used to open the patient's master folder.\",\n \"4.The method of claim 1 further comprising the step of providing a combination dictation and input device, and wherein in step “d” a user can selectively use either a voice activated command or the input device to open the patient's master folder.\",\n \"5.The method of claim 1 further comprising the step of using the computer to interface the monitors and the hyperlink.\",\n \"6.The method of claim 4 further comprising the step of using the computer to interface the monitors and the combination dictation and input device.\",\n \"7.The method of claim 1 wherein there are two monitors in step “c” that are used to display electronic radiology images.\",\n \"8.The method of claim 1 wherein the monitor in step “c” that is used to display electronic radiology images is a high resolution monitor.\",\n \"9.The method of claim 7 wherein the monitors in step “c” that are used to display electronic radiology images is a high resolution monitor.\",\n \"10.The method of claim 1 wherein in step “b” the image viewed is an ultrasound image.\",\n \"11.The method of claim 1 wherein in step “b” the image viewed is a magnetic resonance image.\",\n \"12.The method of claim 1 wherein in step “b” the image viewed is a computer tomography image.\",\n \"13.The method of claim 1 wherein in step “b” the image viewed is a digital image.\",\n \"14.The method of claim 1 wherein in step “b” the image viewed is a nuclear medicine image.\",\n \"15.A method for reviewing electronic radiology information including patient demographics, radiology procedures, radiology reports and radiology images, comprising the steps of: a) loading the radiology information associated with a selected group of patients that are assigned to a selected radiologist into a computer memory; b) generating by a software application an image of a radiology manual master folder on an area of a computer display for use as a graphical user interface by the radiologist; c) generating data fields associated with a digital master folder on the image of a patient's manual master folder including patient's name, medical record number, date of birth, sex, and information regarding procedures associated with such patient stored in an information database including date, type of procedure, report, and radiologist, the digital master folder designed for use by a radiologist; d) displaying the information associated with the patient from computer memory in data fields on the computer display in a default electronic layout conforming to the layout of the patient's manual master folder; e) providing hyperlinks within the procedure and report data fields to view additional information or images relating to a patient's medical records when clicked, the information and images displayed in electronic formats and configurations tailored to a radiology practice; f) clicking on the report field, displays a new window that contains the text of the report and a link to the digitally recorded dictation of the report, that when clicked will play the recording; g) placing a cursor over the report field on the digital master folder, to display summary information of the report; h) clicking on the procedure field to send a command to a viewing portal to load the procedures and images that meet the criteria of the radiologist's file; i) viewing the radiology images from radiology procedures; j) generating a searchable and selectable list of patients that have procedures assigned to the radiologist on the computer display; and k) providing commands that navigate through the stack of master folders, displaying information associated with a new patient in a data field on the computer display from computer memory.\",\n \"16.An apparatus to access, store, and distribute electronic radiology information including patient demographics, radiology procedures, radiology reports and radiology images comprising: a) an information database including patient demographics, radiology identification number, procedures, images, reports, orders and appointments; b) means for transmitting and receiving the information between computers connected to a computer network via extensible markup language (XML); c) means for searching for a plurality of user specified types of information contained in the information database; d) means for generating by a software application a digital master folder representation of a patient's manual master folder for displaying the specified types of information over a monitor of a computer connected to the computer network, the digital master folder representation designed for use as a graphical user interface by a radiologist; e) means for generating data fields on the digital master folder representation including radiology reports and images information regarding radiology procedures associated with such patient stored in the information database; f) means for viewing radiology images from a radiology procedure; g) means for displaying the radiology reports and images in an electronic layout conforming to the layout of the patient's manual master folder and tailored to a user; and h) means for providing hyperlinks within at least one data field to view additional information or images relating to a patient's medical records when clicked.\",\n \"17.A multi-monitor radiology image viewing system comprising: a) a plurality of monitors; b) a combination dictation and input device that includes a hyperlink to view a patients' information and medical images on separate monitors comprising: c) a radiology portal that includes a monitor and a computer for the searching and that includes viewing medical information, the medical information displayed over the monitor by generating by a software application a digital master folder representation of a patient's manual master folder, the digital master folder representation designed for use as a graphical user interface by a radiologist; d) said digital master folder representation providing data fields included within the digital master folder representation providing information and links to radiology reports and images regarding radiology procedures associated with such patient stored in an information database in an electronic layout conforming to the layout of the patient's manual master folder and tailored to a user, such links providing for the viewing of additional information or images relating to a patient's medical records when clicked; e) said viewing portal consisting of at least two monitors designed for the viewing of a plurality of radiology images including digital images, computer tomography, ultrasound, nuclear medicine, and magnetic resonance images; and f) said combination dictation and input device including a voice component that issues operational and navigational commands to the radiology portal and viewing portal by providing speech recognition for the creation of dictated radiology reports.\",\n \"18.The system of claim 17, wherein the radiology portal consists of a monitor and computer for the searching and viewing of medical information stored internal and external to the system.\",\n \"19.The system of claim 17, wherein the radiology portal consists of a touch screen monitor and computer for searching and viewing of medical information stored internal and external to the system.\",\n \"20.The system of claim 17, wherein the radiology portal consists of a flat panel monitor and computer for searching and viewing of medical information stored internal and external to the system.\",\n \"21.The system of claim 17, wherein the radiology portal consists of a touch screen flat panel monitor and computer for searching and viewing of medical information stored internal and external to the system.\",\n \"22.The system of claim 17, wherein the viewing portal consists of a single high-resolution monitor designed for the viewing of a plurality of radiology images including digital images, computer tomography, ultrasound, nuclear medicine, and magnetic resonance images.\",\n \"23.The system of claim 17, wherein the viewing portal consists of a single high-resolution computer monitor.\",\n \"24.The system of claim 17, wherein the viewing portal consists of two high-resolution computer monitors.\",\n \"25.The system of claim 17, wherein the viewing portal consists of four high-resolution monitors designed for the viewing of a plurality of radiology images including digital images, computer radiology, computer tomography, ultrasound, nuclear medicine, and magnetic resonance images.\",\n \"26.The system of claim 17, wherein the viewing portal includes six high-resolution monitors for the viewing of a plurality of radiology images including digital images, computer tomography, ultrasound, nuclear medicine, and magnetic resonance images.\",\n \"27.The system of claim 17, wherein the viewing portal consists of eight high-resolution monitors designed for the viewing of a plurality of radiology images including digital images, computer tomography, ultrasound, nuclear medicine, and magnetic resonance images.\",\n \"28.The system of claim 17, wherein the combination dictation and input device includes a separate mouse and microphone.\"\n ],\n [\n \"<SOH> BACKGROUND OF THE INVENTION <EOH>\"\n ],\n [\n \"<SOH> BRIEF SUMMARY OF THE INVENTION <EOH>The present invention provides an electronic method of improving the efficiency of a radiologist and of a radiology department.\",\n \"With the present invention, a plurality of computer monitors are provided for displaying various images.\",\n \"At least one of the monitors simulates a radiology “light box”, roto viewer, or like device for displaying electronic radiology images.\",\n \"At least one of the monitors is used to display a digital graphical representation of a patient's folder, namely a digital master folder.\",\n \"A hyperlink is used to open the report and to open different “pages” of the patient's master folder.\",\n \"In one embodiment, a voice activated command can be used to open the patient's master folder or to open “pages” of the patient's folder.\",\n \"In another embodiment, a track ball device such as a computer mouse can be used to open the patient's master folder or “pages” contained within the folder.\",\n \"In another embodiment, the radiologist/user is provided with a combination microphone/track ball device that enables the radiologist or user to open the patient's master folder or components thereof using either voice activated commands or the track ball device.\",\n \"A touch screen device hyperlink can also be used to open a patient's folder or report.\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of and claims the benefit of U.S. Non-Provisional patent application Ser.\",\n \"No.\",\n \"14/703,362 filed May 4, 2015, which is a continuation of and claims the benefit of U.S. Non-Provisional patent application Ser.\",\n \"No.\",\n \"14/208,864 filed Mar.\",\n \"13, 2014, which is a continuation of and claims the benefit of U.S. Non-Provisional patent application Ser.\",\n \"No.\",\n \"13/954,310 filed Jul.\",\n \"30, 2013, which is a continuation of and claims the benefit of U.S. Non-Provisional patent application Ser.\",\n \"No.\",\n \"13/527,924 filed Jun.\",\n \"20, 2012, which is a continuation of and claims the benefit of U.S. Non-Provisional patent application Ser.\",\n \"No.\",\n \"12/684,289 filed Jan. 8, 2010, which is a continuation of and claims the benefit of U.S. Non-Provisional patent application Ser.\",\n \"No.\",\n \"12/069,468 filed Feb. 11, 2008, which is a continuation of and claims the benefit of Non-Provisional patent application Ser.\",\n \"No.\",\n \"09/726,475 filed Nov. 30, 2000, which further claims the benefit of U.S.\",\n \"Provisional Application No.\",\n \"60/168,106 filed Nov. 30, 1999.The subject matter of those applications is incorporated by this reference.\",\n \"STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT Not applicable REFERENCE TO A “MICROFICHE APPENDIX” Not applicable BACKGROUND OF THE INVENTION 1.Field of the Invention The present invention relates to a method and apparatus for improving radiologists' efficiencies when viewing radiology procedures and rendering diagnosis.\",\n \"2.General Background of the Invention Typically, every radiology office uses a dictating machine for the preparation of reports, a stack of master folders that contain patient information, and a light box, roto viewer, or like device for viewing radiology images.\",\n \"These images can include for example x-rays, ultrasound, magnetic resonance imaging (MRI), computer tomography, nuclear medicine images and the like.\",\n \"The manual file folder system employed by radiologists and radiology departments is inefficient and cumbersome.\",\n \"BRIEF SUMMARY OF THE INVENTION The present invention provides an electronic method of improving the efficiency of a radiologist and of a radiology department.\",\n \"With the present invention, a plurality of computer monitors are provided for displaying various images.\",\n \"At least one of the monitors simulates a radiology “light box”, roto viewer, or like device for displaying electronic radiology images.\",\n \"At least one of the monitors is used to display a digital graphical representation of a patient's folder, namely a digital master folder.\",\n \"A hyperlink is used to open the report and to open different “pages” of the patient's master folder.\",\n \"In one embodiment, a voice activated command can be used to open the patient's master folder or to open “pages” of the patient's folder.\",\n \"In another embodiment, a track ball device such as a computer mouse can be used to open the patient's master folder or “pages” contained within the folder.\",\n \"In another embodiment, the radiologist/user is provided with a combination microphone/track ball device that enables the radiologist or user to open the patient's master folder or components thereof using either voice activated commands or the track ball device.\",\n \"A touch screen device hyperlink can also be used to open a patient's folder or report.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS For a further understanding of the nature, objects, and advantages of the present invention, reference should be had to the following detailed description, read in conjunction with the following drawings, wherein like reference numerals denote like elements and wherein: FIG.\",\n \"1 is a screen capture image showing a patient's radiology master folder that displays basic patient information including name, number, and study date; FIG.\",\n \"2 is a screen capture image showing the report, displayed by double clicking on the report hyperlink; FIG.\",\n \"3 is a screen capture image showing the audio graphical display generated by the audio hyperlink 15; FIG.\",\n \"4 is a screen capture image showing a modality subfolder generated by double clicking on the ultrasound header 17; FIG.\",\n \"5 is a screen capture image that shows radiology images in twelve up format; FIG.\",\n \"6 is a screen capture image that shows radiology images in four up format; FIG.\",\n \"7 is a screen capture image that shows radiology images in cine mode; FIG.\",\n \"8 is a screen capture image that shows a cine set display; FIG.\",\n \"9 is a screen capture image that shows radiographic images, showing current chest x-rays views, on the two high resolution monitors with the roto viewer window displayed; FIG.\",\n \"10 is a screen capture image that shows chest x-ray views current and most recent with the roto viewer window displayed; FIG.\",\n \"11 is a screen capture image that shows radiographic images demonstrating picture zoom; FIG.\",\n \"12 is a screen capture image showing radiographic images without the roto viewer; and FIG.\",\n \"13 is a screen capture image showing multiple images using the roto viewer.\",\n \"DETAILED DESCRIPTION OF THE INVENTION FIG.\",\n \"1 shows a digital representation of a patient folder designated generally by the numeral 10.Patient folder 10 shows two hyperlinks 11, 12.At the top center of the folder 10, a header 17 indicates that this folder can, for example, relate to an ultrasound.\",\n \"The folder could relate to their radiology procedures.\",\n \"By clicking on the ultrasound hyperlink, the window shown in FIG.\",\n \"1 is opened providing a report display area 13 to be filled with the report information in text form as dictated by a radiologist.\",\n \"When a radiologist double clicks on the report hyperlink 12 in FIG.\",\n \"1, the screen in FIG.\",\n \"2 is displayed which is the report screen 14 containing patient information and the substance of the report.\",\n \"Audio hyperlink 15 can be double clicked using the computer mouse in order to actually hear the report.\",\n \"When a user double clicks on the hyperlink 15 in FIG.\",\n \"2, the display in FIG.\",\n \"3 is shown on the screen having a graphical display for the audio.\",\n \"When the radiologist double clicks on the ultrasound header 17 in FIG.\",\n \"1, the screen provided in FIG.\",\n \"4 has a modality subfolder 18 having a hyperlink 19.When the radiologist uses the computer mouse to double click on the exam hyperlink in FIG.\",\n \"4, actual radiology images as shown in FIG.\",\n \"5 are displayed.\",\n \"In FIG.\",\n \"5, a left computer monitor 20 and a right computer monitor 21 are shown.\",\n \"In FIG.\",\n \"5, a “twelve up” configuration is shown in each of the monitors 20, 21.In FIG.\",\n \"6, a “four up” configuration is shown in each of the monitors 20, 21.In FIG.\",\n \"7, a cine mode is shown for each of the monitors 20, 21.In the cine mode, sets of images are grouped and maintained in that grouping on a selected screen 20 or 21.FIG.\",\n \"8 is a screen capture image that shows a cine set display.\",\n \"FIGS.\",\n \"9-12 show the use of the method and apparatus of the present invention to display full size radiology images, namely one image per screen 20, 21.In FIG.\",\n \"9, as an example, image 31 is a left image, current PA for a patient.\",\n \"The right image in FIG.\",\n \"9 is an image that is a current lateral for the patient.\",\n \"To the left hand side in the screen capture of FIG.\",\n \"9, a roto viewer 22 is also shown.\",\n \"The roto viewer in FIG.\",\n \"9 is comprised of two columns of boxes, each column containing a set of windows, each window can be designated by the numeral 25.The windows 25 can be scrolled to display various radiology images as further shown in FIGS.\",\n \"9 and 10.In FIGS.\",\n \"9 and 10, the upper left window box of roto viewer 22 is designated by the numeral 23.The upper right window box is designated by the numeral 24.The screen captures of FIGS.\",\n \"9 and 10 illustrate examples of radiology images that can be displayed using the method and apparatus of the present invention.\",\n \"As shown in FIG.\",\n \"10, the roto viewer 22 can include different groups of images in each of the window boxes 23, 24, 25 or 26.In FIG.\",\n \"10, the window 23 contains those images which are displayed in the left hand computer monitor 20.The window box 24 of roto viewer 22 contains images which are displayed in the right hand monitor 21 in FIG.\",\n \"10.Other images can be contained in other window boxes of the roto viewer 22 as shown in FIG.\",\n \"10, just below window boxes 23, 24.Each of these images 33, 34 appear in the roto viewer window boxes 23, 24.The roto viewer 22 can be moved about the screen by dragging it.\",\n \"In FIG.\",\n \"11, the zoom feature of the present invention is illustrated.\",\n \"Each of the screens 20, 21 display a zoomed image.\",\n \"The monitor 20 displays image 36.The monitor 21 displays image 39.At the lower left hand corner of each of the screens 20, 21, there is provided a picture in a picture display.\",\n \"This picture in a picture display includes the smaller picture 35 showing a chest x-ray as an example.\",\n \"The viewing area 37 represents that portion of the chest x-ray 35 that is to be displayed in zoom format as image 36 in FIG.\",\n \"11.Similarly, the monitor 21 displays at its lower left hand corner a picture in picture 38 having viewing area 40 that designates the zoom area of the chest x-ray 38.The image 39 is that portion of the image contained within viewing area 40 and which has been enlarged to fill substantially all of screen 21.FIG.\",\n \"12 illustrates monitors 20, 21 with the roto viewer 22 removed.\",\n \"In FIG.\",\n \"13, the group of windows 27, 28, 29 and 30 represent different cine sets or groups of images that have been purposely grouped together by the radiologist.\",\n \"Each of the windows 27-30 can be moved about within the roto viewer to move the displayed images around the screens 20, 21.PARTS LIST Part No.\",\n \"Description 10 folder 11 hyperlink (ultrasound) 12 hyperlink (report) 13 report display area 14 report 15 audio hyperlink 16 graphical display - audio 17 ultrasound header 18 modality subfolder 19 hyperlink 20 left monitor 21 right monitor 22 roto viewer 23 left window box 24 right window box 25 windows/roto viewer 26 windows/roto viewer 27 windows group 28 windows group 29 windows group 30 windows group 31 left image/current PA 32 right image/current lateral 33 left image/current PA 34 right image/most recent lateral 35 picture in picture 36 image - zoom 37 view area 38 picture in picture 39 image - zoom 40 view area The foregoing embodiments are presented by way of example only; the scope of the present invention is to be limited only by the following claims.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875763"}}},{"rowIdx":4494969,"cells":{"text":{"kind":"list like","value":[["ELECTRICALLY HEATED GARMENT","An article of clothing including a garment body and a heating system coupled to the garment body.","The heating system includes a plurality of heating zones configured to heat different portions of the garment body.","A battery pack supplies power to the heating system.","A controller selectively provides power from the battery pack to the multiple heating zones.","A user input member is provided for selecting a mode of the controller."],["1.An article of clothing comprising: a garment body; a heating system coupled to the garment body, the heating system including a plurality of heating zones configured to heat different portions of the garment body; a power tool battery pack for supplying power to the heating system and operable to power a power tool, the power tool battery pack having a nominal voltage of at least about 10.8 volts, the power tool battery pack including at least three cells, each cell having a nominal voltage of between about 3.6 volts and about 4.2 volts, and each cell having a capacity rating of at least 1.2 Ah; a controller for selectively providing power from the battery pack to the heating zones; and a user input member for selecting a mode of the controller.","2.The article of clothing of claim 1, wherein the user input member includes a first zone control button and a second zone control button to selectively control a respective first heating zone and a second heating zone of the multiple heating zones, wherein the first zone control button selectively switches the first heating zone between an on mode and an off mode, wherein the on mode includes a plurality of selectable thermal output levels.","3.The article of clothing of claim 1, wherein the user input member includes a display portion, wherein the display portion is illuminated, wherein the illumination indicates a control mode of each heating zone, and wherein illumination indicates a thermal output level of each heating zone.","4.The article of clothing of claim 1, wherein the controller is configured to monitor a condition of each heating zone, wherein each heating zone is defined by at least one heater array, and wherein a first heater array is disposed in both a left portion and a right portion of a torso body of the garment body, and a second heater array is disposed in a back portion of the garment body.","5.The article of clothing of claim 1, wherein each of the cells has a capacity rating of about 3.0 Ah.","6.The article of clothing of claim 1, wherein the power tool battery pack has a nominal voltage of about 12 volts.","7.An article of clothing comprising: a garment body; a heater coupled to the garment body; a battery holder separate and removable from the garment body and providing a support and a battery terminal, the battery holder being selectively electrically and mechanically disconnectable from the heater; a rechargeable power tool battery pack including a latching arrangement, the rechargeable power tool battery pack being operable to power a power tool, the rechargeable power tool battery pack being supportable by the support for electrical connection to the battery terminal and detachably coupled to the battery holder, the rechargeable power tool battery pack having a nominal voltage of at least 10.8 volts, the power tool battery pack including a plurality of cells, each of the cells having a nominal voltage between about 3.6 and 4.2 volts, and each of the cells having a capacity rating of at least about 1.2 Ah; a controller selectively providing power from the rechargeable power tool battery pack to the heater; and a user input member coupled to the garment body, the user input member for selecting a mode of the controller.","8.The article of clothing of claim 7, wherein the heater includes a plurality of heating zones configured to heat different portions of the garment body, wherein the user input member includes an illuminated display portion, and wherein illumination of the display portion indicates a thermal output level of each heating zone.","9.The article of clothing of claim 7, wherein the heater includes a plurality of heating zones configured to heat different portions of the garment body, wherein each heating zone is defined by at least one heater array, and wherein a first heater array is disposed in both a left portion and a right portion of a torso body of the garment body, and a second heater array is disposed in a back portion of the garment body.","10.The article of clothing of claim 7, wherein each of the cells has a capacity rating of about 3.0 Ah.","11.The article of clothing of claim 7, wherein the plurality of cells may be made up of at least three cells.","12.An article of clothing comprising: a garment body; a heater coupled to the garment body; a cord electrically connected to the heater and including a cord connector terminal; a battery holder comprising a unit separate and removable from the garment body defining a receptacle and a battery terminal, the battery holder including a holder connector terminal, the battery holder being electrically coupled to the heater via electrical connection of the cord connector terminal and the holder connector terminal; a rechargeable power tool battery pack slidably received by the receptacle and including a latch arrangement, the rechargeable power tool battery pack being operable to power a power tool, the rechargeable power tool battery pack being electrically connected to the battery terminal and detachably coupled to the battery holder, the rechargeable power tool battery pack having a nominal voltage of at least about 10.8 volts, the power tool battery pack including a plurality of cells, each cell having a nominal voltage of between about 3.6 volts and about 4.2 volts, and each cell having a capacity rating of at least 1.2 Ah; a user input member coupled to the garment body; and a controller for selectively providing power from the rechargeable power tool battery pack to the heater in response to control signals from the user input member, the controller causing the heater to enter a first mode in response to a first signal from the user input member, and selectively switching the heater to a second mode in response to a second signal from the user input member.","13.The article of clothing of claim 12, wherein the heater includes a plurality of heating zones configured to heat different portions of the garment body, wherein the user input member includes an illuminated display portion, and wherein illumination of the display portion indicates a thermal output level of each heating zone.","14.The article of clothing of claim 12, wherein the heater includes a plurality of heating zones configured to heat different portions of the garment body, wherein each heating zone is defined by at least one heater array, and wherein a first heater array is disposed in both a left portion and a right portion of a torso body of the garment body, and a second heater array is disposed in a back portion of the garment body.","15.The article of clothing of claim 12, wherein the rechargeable power tool battery pack has a nominal voltage of no more than about 14.4 volts.","16.The article of clothing of claim 12, wherein the rechargeable power tool battery pack has a nominal voltage of about 12 volts.","17.The article of clothing of claim 12, wherein the plurality of cells may be made up of at least three cells.","18.The article of clothing of claim 12, wherein each of the cells has a capacity rating of about 3.0 Ah."],["<SOH> BACKGROUND OF INVENTION <EOH>The present invention relates to garments, and in particular, to an electrically heated jacket for providing heat to a user wearing the jacket.","Garments, especially outwear such as jackets and parkas, may be insulated to protect a user from the cold.","Insulated jackets rely on the user's own body heat to keep the user warm.","If the insulation is too thin, the user may be cold.","If the insulation is too thick, the user may overheat."],["<SOH> SUMMARY OF THE INVENTION <EOH>In one embodiment, the invention provides an article of clothing including a garment body and a heating system coupled to the garment body.","The heating system includes a plurality of heating zones configured to heat different portions of the garment body.","A battery pack supplies power to the heating system.","A controller selectively provides power from the battery pack to the multiple heating zones.","A user input member is provided for selecting a mode of the controller.","In another embodiment, the invention provides a method of operating a garment heated by a first electric heater and a second electric heater, powered by a battery pack, and controlled by a controller via a first user input and a second user input.","The first user input is actuated to cause the first electric heater to enter a first thermal output mode.","The second user input is actuated to cause the second electric heater to enter a second thermal output mode.","The first user input is illuminated in response to entering the first thermal output mode.","The second user input is illuminated in response to entering the second thermal output mode.","The first user input is actuated to cause the first electric heater to enter an off mode.","The second user input is actuated to cause the second electric heater to enter an off mode.","Other aspects of the invention will become apparent by consideration of the detailed description and accompanying drawings."],["CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation of U.S. patent application Ser.","No.","14/733,503, filed Jun.","8, 2015, which is a continuation of U.S. patent application Ser.","No.","13/588,692, filed Aug. 17, 2012, which claims priority to U.S.","Provisional Patent Application No.","61/525,549, filed Aug. 19, 2011, and to U.S.","Provisional Patent Application No.","61/658,662, filed Jun.","12, 2012, and which is a continuation-in-part of U.S. patent application Ser.","No.","12/940,429, filed Nov. 5, 2010, which claims priority to U.S.","Provisional Patent Application No.","61/258,714, filed Nov. 6, 2009.The entire contents of these applications are incorporated herein by reference.","BACKGROUND OF INVENTION The present invention relates to garments, and in particular, to an electrically heated jacket for providing heat to a user wearing the jacket.","Garments, especially outwear such as jackets and parkas, may be insulated to protect a user from the cold.","Insulated jackets rely on the user's own body heat to keep the user warm.","If the insulation is too thin, the user may be cold.","If the insulation is too thick, the user may overheat.","SUMMARY OF THE INVENTION In one embodiment, the invention provides an article of clothing including a garment body and a heating system coupled to the garment body.","The heating system includes a plurality of heating zones configured to heat different portions of the garment body.","A battery pack supplies power to the heating system.","A controller selectively provides power from the battery pack to the multiple heating zones.","A user input member is provided for selecting a mode of the controller.","In another embodiment, the invention provides a method of operating a garment heated by a first electric heater and a second electric heater, powered by a battery pack, and controlled by a controller via a first user input and a second user input.","The first user input is actuated to cause the first electric heater to enter a first thermal output mode.","The second user input is actuated to cause the second electric heater to enter a second thermal output mode.","The first user input is illuminated in response to entering the first thermal output mode.","The second user input is illuminated in response to entering the second thermal output mode.","The first user input is actuated to cause the first electric heater to enter an off mode.","The second user input is actuated to cause the second electric heater to enter an off mode.","Other aspects of the invention will become apparent by consideration of the detailed description and accompanying drawings.","BRIEF DESCRIPTION OF THE DRAWINGS FIG.","1 is a front view of a jacket according to one embodiment of the invention.","FIG.","2 is a rear view of the jacket of FIG.","1.FIG.","3 is a detailed view of a rear compartment of the jacket of FIG.","2, and taken along line 3-3 of FIG.","2.FIG.","4 is a perspective view of a battery holder according to one embodiment of the invention.","FIG.","5 is a perspective view of a battery pack for use with the battery holder of FIG.","4.FIG.","6 is an exploded view of the battery pack of FIG.","5.FIG.","7 is an electrical block diagram for the jacket of FIG.","1.FIG.","8 is an image of a heated jacket including a heating module according to another embodiment of the invention.","FIG.","9 is an enlarged view of the heated jacket including the heating module of FIG.","8.FIG.","10 is a top perspective view of a portion the heating module of FIG.","8.FIG.","11 is a bottom perspective view of the portion of the heating module of FIG.","10.FIG.","12 is a front view of a display for positioning in an aperture of the heating module of FIG.","10.FIG.","13 is a perspective view of tools and devices usable with the battery pack of FIG.","5.FIG.","14 is a front view of a jacket according to one embodiment of the invention.","FIG.","15 is a rear view of the jacket of FIG.","14.FIG.","16A is a detailed view of a control input of the jacket of FIG.","14, and taken along line 16A-16A of FIG.","14.FIG.","16B is a detailed view of a rear compartment of the jacket of FIG.","15, and taken along line 16B-16B of FIG.","15 FIG.","17 is a perspective view of a battery holder according to one embodiment of the invention.","FIG.","18 is a perspective view of a battery pack for use with the battery holder of FIG.","17.FIG.","19 is an exploded view of the battery pack of FIG.","18.FIG.","20 is an electrical block diagram for the jacket of FIG.","14.FIG.","21 is an image of a heated jacket including a heating module according to another embodiment of the invention.","FIG.","22 is an enlarged view of the heated jacket including the heating module of FIG.","21.FIG.","23 is a top perspective view of a portion the heating module of FIG.","21.FIG.","24 is a bottom perspective view of the portion of the heating module of FIG.","23.FIG.","25 is a front view of a display for positioning in an aperture of the heating module of FIG.","23.FIG.","26 is a perspective view of tools and devices usable with the battery pack of FIG.","18.FIG.","27 is a perspective view of a jacket according to another embodiment of the invention.","FIG.","28 is a front view of a control input of the jacket of FIG.","27.FIG.","29 is a diagram of a printed circuit board of the control input of FIG.","28.FIG.","30 is a circuit diagram for the jacket of FIG.","27.FIG.","31 is a block diagram of an alternative construction of the jacket of FIG.","27.FIG.","32 is a perspective view of a battery receptacle module.","FIG.","33 is another perspective view of the battery receptacle module of FIG.","32.FIG.","34 is a perspective view of a battery and battery receptacle module according to another aspect of the invention.","FIG.","35 illustrates a power source adapter for use with the jacket of FIG.","27.FIG.","36 illustrates an electrically heated glove coupled to an accessory port of a heated jacket.","FIG.","37 illustrates the electrically heated glove of FIG.","36.FIG.","38 illustrates a pocket, including wire routing features, of the jacket of FIG.","14.FIG.","39 illustrates wire routing features on a lining of the jacket of FIG.","27.FIG.","40 also illustrates the wire routing features of FIG.","39.FIG.","41 also illustrates the wire routing features of FIG.","39.FIG.","42 illustrates a front of a jacket with visibility features.","FIG.","43 illustrates a back of a jacket with visibility features.","Before any embodiments of the invention are explained in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the following drawings.","The invention is capable of other embodiments and of being practiced or of being carried out in various ways.","DETAILED DESCRIPTION FIG.","1 illustrates a heated jacket 10 according to one embodiment of the invention.","The jacket 10 may be constructed in various sizes to fit a variety of users.","The jacket 10 includes typical jacket features such as a torso body 12, arms 14, a collar 16, and front pockets 18.A front surface 20 of the jacket 10 includes a control input.","In the illustrated embodiment, the control input is a button 22 that may be actuated by user.","As explained in greater detail below, the button 22 includes a display portion 24 to indicate a status of the heated jacket 10.As illustrated in cutaway portions of FIGS.","1 and 2, the jacket 10 includes a heater array 26.The heater array 26 is disposed in both a left portion 28 and a right portion 30 of the torso body 12.In some embodiments, the heater array 26 may extend into the arms 14 and/or collar 16.In other embodiments the jacket may include a first heater array and second heater array arranged as an upper module and a lower module, respectively.","In the illustrated embodiment, the heater array 26 is controlled via the button 22 shown in FIG.","1.In other embodiments, multiple heater arrays may be controlled individually via a single control input or multiple control inputs.","The heating array 26 may include resistive heating coils formed of carbon fibers, high density carbon fibers, or other heating devices.","The heated jacket 10 is capable of maintaining a temperature of up to 110 degrees Fahrenheit, although in further embodiments lower or greater temperatures are possible depending upon the heat source.","As illustrated in FIG.","2, the heated jacket 10 includes a compartment 32 located on a lower portion of the back torso body.","The compartment 32 houses an electrical component, such as a battery pack and battery holder.","As illustrated in FIG.","3, the compartment 32 includes a zipper 34, providing selective access by a user to the compartment 32 in order to access the battery pack and other electrical components.","FIG.","4 illustrates one example of a battery holder 36.The battery holder 36 is configured to receive a battery pack 38, such as the battery pack illustrated in FIG.","5.Referring to FIG.","5, the battery pack 38 is a lithium-based, rechargeable battery pack.","The battery pack 38 is removably and interchangeably connected to the battery holder 36 to provide power to the jacket 10 during operation and to facilitate recharging of the battery pack 38 when not in use.","In some embodiments, the battery pack 38 may be used with other types of cordless, battery-powered tools or devices.","FIG.","13, discussed below, illustrates exemplary tools and devices with which the battery pack 38 may be used.","The battery pack 38 also may be used with other power tools or sensing devices not specifically discussed herein.","As illustrated in FIGS.","5 and 6, the battery pack 38 includes a casing 40, an outer housing 42 coupled to the casing 40, and a plurality of battery cells 44 positioned within the casing 40.The casing 40 is shaped and sized to fit within a cavity 46 of the battery holder 36 illustrated in FIG.","4, or alternatively, in a power tool or non-motorized sensing device to connect the battery pack 38 to the tool or device.","The casing 40 includes an end cap 48 to substantially enclose the battery cells 44 within the casing 40.The illustrated end cap 48 includes two power terminals 50 configured to mate with corresponding power terminals 60 (FIG.","7) extending within the cavity 46 of the battery holder 36.In other embodiments, the end cap 48 may also include sense or communication terminals that are configured to mate with corresponding terminals within the battery holder or a tool.","The outer housing 42 includes a latching arrangement 52 for positively engaging the battery pack 38 with the battery holder 36.The latching arrangement 52 includes latching tabs 54 and resilient actuating portions 56.The latching tabs 54 are configured to engage corresponding recesses within the cavity 46 of the battery holder 36.The resilient actuating portions 56 are coupled to the latching tabs 54 and are configured for a user to selectively disengage the latching tabs 54 from the battery holder 36.As shown in FIG.","6, the battery pack 38 includes three battery cells 44 positioned within the casing 40 and electrically coupled to the terminals 50.The battery cells provide operational power (e.g., DC power) to the jacket 10 or other device.","In the illustrated embodiment, the battery cells 44 are arranged in series, and each battery cell has a nominal voltage of approximately four-volts (4.0V), such that the battery pack 38 has a nominal voltage of approximately twelve-volts (12V).","The cells 44 also have a capacity rating of approximately 1.4 Ah.","In other embodiments, the battery pack 38 may include more or fewer battery cells 44, and the cells 44 can be arranged in series, parallel, or a serial and parallel combination.","For example, the battery pack 38 can include a total of six battery cells in a parallel arrangement of two sets of three series-connected cells.","The series-parallel combination of battery cells creates a battery pack having a nominal voltage of approximately 12V and a capacity rating of approximately 2.8 Ah.","In other embodiments, the battery cells 44 may have different nominal voltages, such as, for example, 3.6V, 3.8V, 4.2V, etc., and/or may have different capacity ratings, such as, for example, 1.2 Ah, 1.3 Ah, 2.0 Ah, 2.4 Ah, 2.6 Ah, 3.0 Ah, etc.","In other embodiments, the battery pack 38 can have a different nominal voltage, such as, for example, 10.8V, 14.4V, etc.","In the illustrated embodiment, the battery cells 44 are lithium-ion battery cells having a chemistry of, for example, lithium-cobalt (Li—Co), lithium-manganese (Li—Mn), or Li—Mn spinel.","In other embodiments, the battery cells 44 may have other suitable lithium or lithium-based chemistries.","The heated jacket 10 includes control circuitry for the heater array 26 and battery pack 38.FIG.","7 is a block diagram of the heated jacket 10.A battery controller 58 receives electricity from the battery pack 38 via battery terminals 60 (disposed within the battery holder 36).","The battery controller 58 may be configured to monitor a state of charge of the battery pack 38 and, if necessary, shutdown the heater array 26.A heater controller 62 receives inputs from the control button 22 and selectively powers the heater array 26 depending upon the selected thermal output.","The display portion 24 is selectively illuminated based upon the selected thermal output setting.","The heater controller 62 may be configured to monitor a plurality of conditions of the jacket 10 including, but not limited to, an amount of current drawn by the heater array 26.The controllers 58, 62 are, for example, microprocessors, microcontrollers, or the like, and are configured to communicate with one another.","In the illustrated embodiment, the battery controller 58 provides information to the heater controller 62 related to a battery pack temperature or voltage level.","The heater controller 62 and the battery controller 58 also include low voltage monitors and state-of-charge monitors.","The monitors are used to determine whether the battery pack 38 is experiencing a low voltage condition, which may prevent proper operation of the heater array 26, or if the battery pack 38 is in a state-of-charge that makes the battery pack 38 susceptible to being damaged.","If such a low voltage condition or state-of-charge exists, the heater array 26 is shut down or the battery pack 38 is otherwise prevented from further discharging current to prevent the battery pack from becoming further depleted.","The heated jacket 10 illustrated in FIGS.","1 and 2 may be operated as follows.","To turn on the heated jacket 10, a user presses and holds the control button 22 for a first period (e.g., three seconds).","When first turned on, the heater controller 62 causes the heated jacket 10 to enter pre-heat mode.","The heated jacket 10 remains in a pre-heat mode for a period (e.g., five minutes) and then the heater controller 62 switches the heater array 26 to a medium thermal output setting.","The user may adjust the thermal output setting by actuating the control button 22.Each press of the control button 22 will cycle the heater controller 62 through one of a sequence of thermal output settings (e.g., low, medium, high).","In order to turn off the heated jacket 10 (or de-energize the heater array 26), the user presses and holds the control button 22 for a third period (e.g., three seconds).","As mentioned previously, the control button 22 includes an illuminated display portion 24 to indicate a status of the heaters.","The display portion may be, for example, one or more LEDs.","In the pre-heat mode, the display portion 24 flashes red.","At a low thermal output setting, the display portion 24 glows blue.","At a medium thermal output setting, the display portion 24 glows white.","At a high thermal output setting, the display portion glows red.","Other embodiments may use various other colors or light patterns to indicate thermal output settings.","Still other embodiments may indicate a state of charge of the battery pack 38.FIG.","8 illustrates a heated jacket 110 according to another embodiment of the invention.","The heated jacket 110 may be constructed in various sizes to fit a variety of users.","FIG.","9 is an enlarged view of a heating module 164, which is coupled to an outside surface of the jacket 110 by way of a strap 166.Alternatively, the heating module 164 may be coupled to an inner surface of the jacket 110 or disposed inside of an inner pocket of the jacket 110.The heating module 164 includes a battery pack holder 136 (FIGS.","10 and 11) and a battery pack 38 (FIG.","5).","The heating module 164 is electrically coupled to one or more heating coils (not shown) positioned within the jacket 110 to heat the jacket and provide heat to a user wearing the jacket.","In the illustrated embodiment, multiple heating coils are employed and positioned in various locations, or zones, within the jacket.","For example, separate heating coils may be positioned in an upper torso area and a lower torso area, and may be separately controllable by the user.","In further embodiments, a single heating coil may be used, or the heating coils may be positioned at other locations within the jacket, (e.g., the back, arms, etc.).","FIGS.","10 and 11 illustrate the battery holder 136 of the heating module 164 in greater detail.","With reference to FIG.","11, the battery holder 136 includes an aperture 168 for receiving an end of a cord (not shown), the cord being connected to the one or more heating coils and including a male connector terminal.","A female connector (not shown) is positioned within the battery holder 136 adjacent the aperture 168 to receive the male connector and form an electrical connection between the heating coils and the battery pack 38.The battery holder 136 also includes a hook 170 for securing the cord disposed between the connector and the jacket 110.With further reference to FIG.","10, the battery holder 136 includes a housing portion 172 for electrical components, including a circuit board (not shown).","The housing portion 172 includes a first button 174, a second button 176 and a display 178.The first button 174 and the second button 176 are capable of communicating with the electrical components.","In the illustrated embodiment, the first button 174 is pressed by a user to increase the temperature of the heating coils, and the second button 176 is pressed by a user for lowering the temperature of the heating coils.","In the illustrated embodiment of FIG.","12, the display 178 is a seven segment display for representing a heating level indicative of the temperature of the heating coils.","With reference to FIG.","11, the battery holder 136 includes a power indicator 182, such as a light emitting diode (LED) that displays to the user when lit that the battery is connected, the heating coils are on, or the like.","A portion of the battery holder 136 defines a battery cavity 184 for receiving the battery pack 38 (FIG.","5).","In other embodiments, the battery holder 136 includes an on/off switch (such as the control button 22 discussed above), a fuel gauge that displays the amount of battery power remaining, and a user interface including heat zone controls to individually control the heating coils if multiple heating coils are employed.","FIG.","13 illustrates exemplary power tools and sensing devices with which the battery pack 38 may be usable.","The battery pack 38 may be usable with power tools such as a drill 202, a pipe cutter 204, an impact driver 206, and a reciprocating saw 208.The battery pack 38 may also be usable with non-motorized sensing devices such as a visual inspection camera 212, an infrared sensor 214 (such as a thermometer or thermal imaging camera), a clamp-type multimeter 216, and a wall scanner 218 (such as a “stud finder”).","FIGS.","14 and 15 illustrate a heated jacket 310 according to one embodiment of the invention.","The jacket 310 may be constructed in various sizes to fit a variety of users.","The heated jacket 310 is capable of maintaining a temperature of up to 110 degrees Fahrenheit, although in further embodiments lower or greater temperatures are possible depending upon the heat source.","The jacket 310 includes typical jacket features such as a torso body 312, arms 314, a back 315, a collar 316, and front pockets 318.The jacket 310 further includes a heating system having multiple heating zones.","A front face 320 of the jacket 310 includes a control input 321 that is itself sealed or has a sealed connection to the jacket, such that the control input 321 is protected from environmental conditions.","In the illustrated embodiment, the control input 321 is configured to be actuated by a user to direct the control of the jacket heating system and heating zones.","As illustrated in FIG.","16A and explained in greater detail below, the control input 321 includes three zone control buttons 322a, 322b, and 322c and an on/off button 323.Further, each of the zone control buttons 322a, 322b, 322c and the on/off button 323 include a display portion 324a, 324b, 324c, 324d (FIG.","20; e.g., a LED or other type of illumination embedded into each of the above buttons), respectively, to indicate the status of the jacket based on the inputs associated with pressing these buttons.","In other embodiments, the display portion 324 may be configured as a single display panel or display lights/illumination separate from the above buttons.","Further, the control input 321 may be configured at different locations on the outside or the inside of the jacket, may be configured with different orientations for the buttons, and may be separated into multiple control inputs at different locations on the jacket.","As illustrated in cutaway portions of FIGS.","14 and 15, the jacket 310 includes a heating system made up of a first heater array 326 and a second heater array 327.The first heater array 326 is disposed in both a left portion 328 and a right portion 330 of the torso body 312.The second heater array 327 is disposed in the back 315.The heating system is further made up of a third heater array 329 (FIG.","20) disposed in the front pockets 318.The heating arrays may include resistive heating coils formed of carbon fibers, high density carbon fibers, or other heating devices.","In other embodiments, the heating system may include a fourth heater array (not shown) disposed in the arms 314 and/or a fifth heat array (not shown) disposed in the collar 16, and/or additional heater arrays, and may further have different configurations of the heater arrays, as the different heater arrays may be alternatively configured to extend into or be removed from other parts of the jacket 310.As illustrated in FIG.","15, the heated jacket 310 includes a compartment 332 located on a lower portion of the back torso body 315.The compartment 332 houses an electrical component, such as a battery pack 338 and a battery holder 336.As illustrated in FIG.","16B, the compartment 332 includes a zipper 334, providing selective access by a user to the compartment 332 in order to access the battery pack 338 and other electrical components.","FIG.","17 illustrates one example of a battery holder 336.The battery holder 336 is configured to receive the battery pack 338, such as the battery pack 338 illustrated in FIG.","18.The battery holder 336 also includes a USB-type port 337 for communicating with and charging other devices, such as a digital media player, an iPOD®, or similar device Referring to FIG.","18, the battery pack 338 is a lithium-based, rechargeable battery pack.","The battery pack 338 is removably and interchangeably connected to the battery holder 336 to provide power to the jacket 310 during operation and to facilitate recharging of the battery pack 338 when not in use.","In some embodiments, the battery pack 338 may be used with other types of cordless, battery-powered tools or devices.","For example, the battery pack 338 may be usable with a drill, a PVC pipe cutter, an impact driver, and a metal pipe cutter, or other tools.","The battery pack 338 may also be usable with a non-motorized sensing device such as a thermal imaging camera, a micro-inspection camera, a wall scanner, a digital multimeter, a thermometer, and a gas detector.","A variety of such tools and devices are illustrated in FIG.","26.Furthermore, the battery pack 338 may be used with other power tools or sensing devices not specifically discussed herein.","As illustrated in FIGS.","18 and 19, the battery pack 338 includes a casing 340, an outer housing 342 coupled to the casing 340, and a plurality of battery cells 344 positioned within the casing 340.The casing 340 is shaped and sized to fit within a cavity 346 of the battery holder 336 illustrated in FIG.","17, or alternatively, in a power tool or non-motorized sensing device to connect the battery pack 338 to the tool or device.","The casing 340 includes an end cap 348 to substantially enclose the battery cells 344 within the casing 340.The illustrated end cap 348 includes two power terminals 350 configured to mate with corresponding power terminals 360 (FIG.","20) extending within the cavity 346 of the battery holder 336.In other embodiments, the end cap 348 may also include sense or communication terminals that are configured to mate with corresponding terminals within the battery holder or a tool.","The outer housing 342 includes a latching arrangement 352 for positively engaging the battery pack 338 with the battery holder 336.The latching arrangement 352 includes latching tabs 354 and resilient actuating portions 356.The latching tabs 354 are configured to engage corresponding recesses within the cavity 346 of the battery holder 336.The resilient actuating portions 356 are coupled to the latching tabs 354 and are configured for a user to selectively disengage the latching tabs 354 from the battery holder 336.As shown in FIG.","19, the battery pack 338 includes three battery cells 344 positioned within the casing 340 and electrically coupled to the terminals 350.The battery cells provide operational power (e.g., DC power) to the jacket 310 or other device.","In the illustrated embodiment, the battery cells 344 are arranged in series, and each battery cell has a nominal voltage of approximately four-volts (4.0V), such that the battery pack 338 has a nominal voltage of approximately twelve-volts (12V).","The cells 344 also have a capacity rating of approximately 1.4 Ah.","In other embodiments, the battery pack 338 may include more or fewer battery cells 344, and the cells 344 can be arranged in series, parallel, or a serial and parallel combination.","For example, the battery pack 338 can include a total of six battery cells in a parallel arrangement of two sets of three series-connected cells.","The series-parallel combination of battery cells creates a battery pack having a nominal voltage of approximately 12V and a capacity rating of approximately 2.8 Ah.","In other embodiments, the battery cells 344 may have different nominal voltages, such as, for example, 3.6V, 3.8V, 4.2V, etc., and/or may have different capacity ratings, such as, for example, 1.2 Ah, 1.3 Ah, 2.0 Ah, 2.4 Ah, 2.6 Ah, 3.0 Ah, etc.","In other embodiments, the battery pack 338 can have a different nominal voltage, such as, for example, 10.8V, 14.4V, etc.","In the illustrated embodiment, the battery cells 344 are lithium-ion battery cells having a chemistry of, for example, lithium-cobalt (Li—Co), lithium-manganese (Li—Mn), or Li—Mn spinel.","In other embodiments, the battery cells 344 may have other suitable lithium or lithium-based chemistries.","The heated jacket 310 includes control circuitry for the heating system having multiple heating zones.","FIG.","20 is an electrical block diagram of the heated jacket 310.A battery controller 358 receives electricity from the battery pack 338 via battery terminals 360 (disposed within the battery holder 336).","The battery controller 358 may be configured to monitor a state of charge of the battery pack 338 and, if necessary, shutdown the heater array 326.As shown in FIG.","20, a heater controller 362 receives inputs from the control input 321 and selectively powers the heater arrays 326, 327, 329 depending upon a desired thermal output.","The display portion 324a, 324b, 324c, 324d, associated with the particular control input button described above, is illuminated based upon the current status of that input button.","The heater controller 362 may be configured to monitor a plurality of conditions of the jacket 310 including, but not limited to, an amount of current drawn by the heater arrays 326, 327, 329.The controllers 358, 362 are, for example, microprocessors, microcontrollers, or the like, and are configured to communicate with one another.","In the illustrated embodiment, the battery controller 358 provides information to the heater controller 362 related to a battery pack temperature or voltage level.","The heater controller 362 and the battery controller 358 also include low voltage monitors and state-of-charge monitors.","The monitors are used to determine whether the battery pack 338 is experiencing a low voltage condition, which may prevent proper operation of the heater arrays 326, 327, 329 or if the battery pack 338 is in a state-of-charge that makes the battery pack 338 susceptible to being damaged.","If such a low voltage condition or state-of-charge exists, the heater arrays 326, 327, 329 are shut down or the battery pack 338 is otherwise prevented from further discharging current to prevent the battery pack from becoming further depleted.","In the illustrated embodiment, the heating system and heating arrays 326, 327, 329 are configured to be actuated via the control input 321 (FIG.","14).","The on/off button 323 is configured to turn the heating system on and off and also is configured to change thermal output setting of the heating system, including a high thermal output setting, a medium thermal output setting, and low thermal output setting.","More specifically, the on/off button is configured to turn the heating system on after being pressed and held for a designated period of time (e.g., 1.5 seconds), such that all heating arrays 326, 327, 329 are turned on and automatically set to an initial predetermined thermal output setting.","Subsequent presses of the on/off button change the thermal output setting according to sequence, such that the next press of the on/off button changes the heating system to the high thermal output setting.","A further press of the on/off button changes the heating system to the medium thermal output setting.","A further press of the on/off button changes the heating system to the low thermal output setting.","A further press of the on/off changes the heating system back to the high thermal output setting to complete the sequence of high, medium, low, high, medium, low, and so on.","The heating system is on, if any of the heating arrays 326, 327, 329 are on.","The on/off button is configured to turn the heating system off after being pressed and held for designated period of time (e.g., 1.5 seconds).","In other embodiments, it is conceivable that the number of thermal output settings, the initial thermal output setting, and the sequence of thermal output settings could vary.","While the heating system is on, the zone control buttons 322a, 322b, 322c are each configured to turn a particular heater array on and off.","More specifically, zone control button 322a is configured to turn the first heater array 326 on and off, zone control button 322b is configured to turn the second heater array 327 on and off, and zone control button 322c is configured to turn the third heater array 329 on and off.","Subsequent presses of any one of the zone control buttons switches alternate the associated heating array between on and off.","In other embodiments, it is conceivable that multiple heater arrays may be controlled individually via a single control input button or multiple control input buttons.","The heated jacket 310 illustrated in FIGS.","14 and 15 may be operated as follows.","To turn on the heated jacket 310, a user presses and holds the on/off button 323 for a designated period of time (e.g., 1.5 seconds).","When first turned on, the heater controller 362 causes the heated jacket 310 to enter pre-heat mode.","The heated jacket 310 remains in a pre-heat mode for a period (e.g., five minutes) and then the heater controller 362 switches the heater arrays 326, 327, 329 to a medium thermal output setting.","The user may adjust the thermal output setting by actuating the on/off button 323, as discussed above.","Each press of the on/off button 323 will cycle the heater controller 362 through one of a sequence of thermal output settings (e.g., high, medium, low).","In order to turn off the heated jacket 10, the user presses and holds the on/off button for a designated period of time (e.g., 1.5 seconds).","As mentioned previously, the control input buttons 322a, 322b, 322c, 323 each include an illuminated display portion 324a, 324b, 324c, 324d to indicate a status of the heating system.","As discussed above, the display portion may be, for example, one or more LEDs.","The display portions 324a, 324b, 324c illuminate to indicate that their associated heating arrays are on.","In the pre-heat mode, the display portion 324d on the on/off button 323 flashes red.","At a low thermal output setting, the display portion 324d glows blue.","At a medium thermal output setting, the display portion 324d glows white.","At a high thermal output setting, the display portion 324d glows red.","Other embodiments may use various other colors or light patterns to indicate thermal output settings.","Still other embodiments may indicate a state of charge of the battery pack 338.Various modifications of the control method or sequence are possible.","For example, in other embodiments, the user may select a desired temperature rather than a thermal output setting.","FIG.","21 illustrates a heated jacket 410 according to another embodiment of the invention.","The heated jacket 410 may be constructed in various sizes to fit a variety of users.","FIG.","22 is an enlarged view of a heating module 464, which is coupled to an outside surface of the jacket 410 by way of a strap 466.Alternatively, the heating module 464 may be coupled to an inner surface of the jacket 410 or disposed inside of an inner pocket of the jacket 410.The heating module 464 includes a battery pack holder 436 (FIGS.","23 and 24) and a battery pack 338 (FIG.","18).","The heating module 464 is electrically coupled to one or more heating coils (not shown) positioned within the jacket 410 to heat the jacket and provide heat to a user wearing the jacket.","In the illustrated embodiment, multiple heating coils are employed and positioned in various locations, or zones, within the jacket.","For example, separate heating coils may be positioned in an upper torso area and a lower torso area, in a back area, and in front pockets, and may be separately controllable by the user.","In further embodiments, a single heating coil may be used, or the heating coils may be positioned at other locations within the jacket, (e.g., the back, arms, etc.).","FIGS.","23 and 24 illustrate the battery holder 436 of the heating module 464 in greater detail.","With reference to FIG.","23, the battery holder 436 includes an aperture 468 for receiving an end of a cord (not shown), the cord being connected to the one or more heating coils and including a male connector terminal.","A female connector (not shown) is positioned within the battery holder 436 adjacent the aperture 468 to receive the male connector and form an electrical connection between the heating coils and the battery pack 338.The battery holder 436 also includes a hook 470 for securing the cord disposed between the connector and the jacket 410, and a USB port 475 for communicating with and charging other devices, such as a digital media player, an iPOD®, or similar device.","With further reference to FIG.","23, the battery holder 436 includes a housing portion 472 for electrical components, including a circuit board (not shown).","The housing portion 472 includes a first on/off button 474, three zone control buttons 476a, 476b, 476c, and a display 478.The first button 174 and the zone buttons 476a, 476b, 476c are capable of communicating with the electrical components.","In the illustrated embodiment, the on/off button 474 and zone control buttons 476a, 476b, 476c are configured and operate similarly to the above control input buttons 322a, 322b, 322c, 323.In the illustrated embodiment of FIG.","25, the display 478 is a seven segment display for representing a heating level indicative of the temperature of the heating coils.","With reference to FIG.","24, the battery holder 436 includes a power indicator 482, such as a light emitting diode (LED) that displays to the user when lit that the battery is connected, the heating coils are on, or the like.","A portion of the battery holder 436 defines a battery port 484 for receiving the battery pack 338 (FIG.","18).","In other embodiments, the battery holder 436 includes a fuel gauge that displays the amount of battery power remaining.","FIG.","27 illustrates a heated jacket 488 according to another embodiment of the invention.","The jacket 188 includes an outer shell 492 with left and right front pockets 496 and 498, and a chest pocket 502.FIG.","38 illustrates a rear compartment 506 of the jacket 488.Referring to FIG.","30, the heated jacket 488 includes a heating system 510 including a core heater array 514 and a pocket heater array 518.The core heater array 514 includes a right chest heating module 522, a left chest heating module 526, and a back heating module 530.The pocket heater array 518 includes a right pocket heating module 534 and a left pocket heating module 538.The heater arrays 514 and 518 may include resistive heating coils formed of carbon fibers, high density carbon fibers, or other heating devices.","The core heater array 514 and pocket heater array 518 are controlled via a heater control module 542.The heater control module 542 is coupled to a chest portion 546 of the jacket 488 (FIG.","27).","Referring to FIG.","28 an external surface 550 of the heater control module 542 provides access to a first heater control button 554 and a second heater control button 558.The first heater control button 554 may be, for example a control input for the core heater array 514 (FIG.","30), while the second heater control button 558 may be, for example, a control input for the pocket heater array 518.Referring to FIG.","29, the first heater control button 554 and the second heater control button 558 are coupled to a printed circuit board (PCB) 562 of the heater control module 542.Each of the first control button 554 and the second control button 558 has an array of light emitting diodes (LEDs) 566 associate with it.","More specifically, each button has associated with it a first pair of LEDs (e.g., red LEDs) 570, a second pair of LEDs (e.g., white LEDs) 574, and a third pair of LEDs (e.g., blue LEDs) 578.The LEDs 566 illuminate the external surface 550 of the heater control module 542 (FIG.","28) to provide indication of a control mode of the core heater array 514 (as selected by the first button 554) or the pocket heater array 518 (as selected by the second button 558).","For example, illumination of the red LEDs 570 may indicate a high thermal output setting, illumination of the white LEDs 574 may indicate a medium thermal output setting, and illumination of the blue LEDs 578 may indicate a low thermal output setting.","The heater arrays 514 and 518 are indicated as being off when no LED is illuminated.","To turn on either of the heater arrays 514 or 518, a heater control button 554 or 558, respectively, is pressed by the user and held for a period of, for example, 0.5-2.5 seconds.","A temperature setting (e.g., high, medium, or low) of the core heater array 514 or pocket heater array 518 may be selected by again pressing the respective first heater control button 554 or the second heater control button 558.The heater arrays 514, 518 may be turned off by pressing and holding the respective heater control buttons 554, 558 for a period of 0.5 to 2.5 seconds.","FIG.","31 is an electrical block diagram of the heated jacket 488.A battery receptacle 482 receives electricity from a battery pack (e.g., the battery pack 338 of FIG.","5) and supplies electricity to the heater control module 542 for distribution to the heater arrays 514, 518.FIG.","32 illustrates the battery receptacle 582 according to a first configuration.","The battery receptacle 582 is configured to receive the 12 volt lithium-ion battery pack 338 (FIG.","18).","A heater supply cable 586 from the heater control module 542 is detachably coupled the battery receptacle 582.The battery receptacle 582 also includes an accessory port 590.The accessory port 590 may be in the form of a USB outlet for receiving a USB cable 594.The USB cable may, in turn, be coupled to an accessory device such as smart phone or MP3 player.","Referring to FIG.","33, the battery receptacle 582 includes a battery state-of-charge indicator 598.A state-of-charge may be indicated by the illumination of one or more LEDs.","FIG.","34 illustrates a battery receptacle 602 according to another configuration.","The battery receptacle 602 is configured to receive, for example, an 18 volt lithium-ion battery pack 606.FIG.","35 illustrates an adapter 610 that may be used with the heated jacket in place of a battery and battery receptacle.","The adapter 610 includes an input plug 614 for mating with a 12V outlet cigarette lighter-type socket of a motor vehicle.","An output plug 618 connects to heated jacket 488.Referring to FIG.","31, the heater control module 542 may also interface with a heated accessory device 622.When a heated accessory device 622 is coupled to the jacket 488 and detected by the heater control module 542, the heater control module 542 deactivates the pocket heater array 518 and selective provides power to the heated accessory device 622.The second heater control button 558 may then be used to control a thermal output setting of the accessory device 622 in a manner similar to that used to control the pocket heater array 518.FIG.","36 illustrates an exemplary heated accessory device 622, in the form of an electrically heated glove 622.Each glove 622 includes a resistive heating element.","A power cord 626 is coupled to the heating element.","The power cord 626 includes a connector 630 for connecting to the electrical system of the heated jacket 488.FIG.","37 illustrates the heated gloves 622 connected to a left sleeve portion 634 and a right sleeve portion 638 of a heated jacket.","An accessory power port 642 is coupled to each sleeve portion 634, 638.The accessory power ports 642 include a body 646 that is coupled to an outer surface 650 of the sleeves 634, 638 by sewing, rivets, adhesives or other attachment means.","The body 646 defines a power receptacle.","The power receptacle is in electrical communication with the heater control module 542 (FIG.","31).","Each power receptacle is configured to receive the connector 630 of the power cord 626 of a heated accessory device 322, such that the device is selectively powered by the heater control module 542.FIGS.","38-41 illustrate accessory wire routing features that may be incorporated into a heated jacket, such as the heated jacket 488 of FIG.","27.Referring to FIG.","38, the rear compartment 506 may serve, for example, to hold and secure the battery receptacle 582 (FIG.","32) and battery 338 (FIG.","18).","Grommets 650 are coupled to the jacket shell 492 inside the rear compartment 506.The grommets 650 surround openings through the jacket shell.","FIGS.","39-41 illustrate a liner 654 of the jacket 488.The jacket 488 defines an open space between the outer shell 492 (FIG.","38) and the liner 654 (FIGS.","39-41).","Grommets 650 are coupled to the liner 654 and surround openings through the liner 654.The grommets 650 facilitate the passage of accessory wires from the liner 654, through the open space, and through the outer shell 492 to the rear compartment 506.For example, a USB-type wire 594 of a device may be coupled to the accessory port 590 of a battery receptacle 582 (FIGS.","32-33) that is stored in the rear compartment (FIG.","38) 506.Referring to FIGS.","39-41, additional wire routing features are coupled to the jacket liner 654.These additional features include wire routing tabs 658 and wire routing channels 662.The wire routing tabs 658 include a cloth tab member 664 that is sewn to the liner 654 along a tab seam 666.Opposite the tab seam 666, hook and loop fasteners 670 are coupled to the tab members 662 and jacket liner 654, to facilitate capturing a section of wire (e.g., 594) between the liner 654 and the tab member 664.The wire routing channels 662 include a cloth channel member 674 that is sewn to the liner 654 along a channel seam 678.Opposite the channel seam 678, hook and loop fasteners 670 are coupled to the channel member 674 and the jacket liner 654, to facilitate capturing a section of wire 594 between the liner 654 and the channel member 674.In other embodiments, the hook and loop fasteners 670 of the wire routing tabs 658 and wire routing channels 662 may be replaced with buttons, snaps, or other types of fasteners.","FIGS.","42 and 43 illustrate a jacket 682 according to another embodiment of the invention.","The jacket 682 may incorporate heater and heater control features similar to those described with respect to the jacket 310 (FIG.","14) or the jacket 488 (FIG.","27), or various combinations thereof.","Reflective strips 686 are coupled to an outer shell 690 of the jacket 682.The reflective strips 686 may be sewn onto the outer shell 690 of the jacket 682, or they may be adhesively bonded to the outer shell 690.In still other embodiments, the reflective strips 686 may be painted onto the outer shell 690 of the jacket.","Although the invention has been described in detail with reference to certain preferred embodiments, variations and modifications exist within the scope and spirit of one or more independent aspects of the invention as described."]],"string":"[\n [\n \"ELECTRICALLY HEATED GARMENT\",\n \"An article of clothing including a garment body and a heating system coupled to the garment body.\",\n \"The heating system includes a plurality of heating zones configured to heat different portions of the garment body.\",\n \"A battery pack supplies power to the heating system.\",\n \"A controller selectively provides power from the battery pack to the multiple heating zones.\",\n \"A user input member is provided for selecting a mode of the controller.\"\n ],\n [\n \"1.An article of clothing comprising: a garment body; a heating system coupled to the garment body, the heating system including a plurality of heating zones configured to heat different portions of the garment body; a power tool battery pack for supplying power to the heating system and operable to power a power tool, the power tool battery pack having a nominal voltage of at least about 10.8 volts, the power tool battery pack including at least three cells, each cell having a nominal voltage of between about 3.6 volts and about 4.2 volts, and each cell having a capacity rating of at least 1.2 Ah; a controller for selectively providing power from the battery pack to the heating zones; and a user input member for selecting a mode of the controller.\",\n \"2.The article of clothing of claim 1, wherein the user input member includes a first zone control button and a second zone control button to selectively control a respective first heating zone and a second heating zone of the multiple heating zones, wherein the first zone control button selectively switches the first heating zone between an on mode and an off mode, wherein the on mode includes a plurality of selectable thermal output levels.\",\n \"3.The article of clothing of claim 1, wherein the user input member includes a display portion, wherein the display portion is illuminated, wherein the illumination indicates a control mode of each heating zone, and wherein illumination indicates a thermal output level of each heating zone.\",\n \"4.The article of clothing of claim 1, wherein the controller is configured to monitor a condition of each heating zone, wherein each heating zone is defined by at least one heater array, and wherein a first heater array is disposed in both a left portion and a right portion of a torso body of the garment body, and a second heater array is disposed in a back portion of the garment body.\",\n \"5.The article of clothing of claim 1, wherein each of the cells has a capacity rating of about 3.0 Ah.\",\n \"6.The article of clothing of claim 1, wherein the power tool battery pack has a nominal voltage of about 12 volts.\",\n \"7.An article of clothing comprising: a garment body; a heater coupled to the garment body; a battery holder separate and removable from the garment body and providing a support and a battery terminal, the battery holder being selectively electrically and mechanically disconnectable from the heater; a rechargeable power tool battery pack including a latching arrangement, the rechargeable power tool battery pack being operable to power a power tool, the rechargeable power tool battery pack being supportable by the support for electrical connection to the battery terminal and detachably coupled to the battery holder, the rechargeable power tool battery pack having a nominal voltage of at least 10.8 volts, the power tool battery pack including a plurality of cells, each of the cells having a nominal voltage between about 3.6 and 4.2 volts, and each of the cells having a capacity rating of at least about 1.2 Ah; a controller selectively providing power from the rechargeable power tool battery pack to the heater; and a user input member coupled to the garment body, the user input member for selecting a mode of the controller.\",\n \"8.The article of clothing of claim 7, wherein the heater includes a plurality of heating zones configured to heat different portions of the garment body, wherein the user input member includes an illuminated display portion, and wherein illumination of the display portion indicates a thermal output level of each heating zone.\",\n \"9.The article of clothing of claim 7, wherein the heater includes a plurality of heating zones configured to heat different portions of the garment body, wherein each heating zone is defined by at least one heater array, and wherein a first heater array is disposed in both a left portion and a right portion of a torso body of the garment body, and a second heater array is disposed in a back portion of the garment body.\",\n \"10.The article of clothing of claim 7, wherein each of the cells has a capacity rating of about 3.0 Ah.\",\n \"11.The article of clothing of claim 7, wherein the plurality of cells may be made up of at least three cells.\",\n \"12.An article of clothing comprising: a garment body; a heater coupled to the garment body; a cord electrically connected to the heater and including a cord connector terminal; a battery holder comprising a unit separate and removable from the garment body defining a receptacle and a battery terminal, the battery holder including a holder connector terminal, the battery holder being electrically coupled to the heater via electrical connection of the cord connector terminal and the holder connector terminal; a rechargeable power tool battery pack slidably received by the receptacle and including a latch arrangement, the rechargeable power tool battery pack being operable to power a power tool, the rechargeable power tool battery pack being electrically connected to the battery terminal and detachably coupled to the battery holder, the rechargeable power tool battery pack having a nominal voltage of at least about 10.8 volts, the power tool battery pack including a plurality of cells, each cell having a nominal voltage of between about 3.6 volts and about 4.2 volts, and each cell having a capacity rating of at least 1.2 Ah; a user input member coupled to the garment body; and a controller for selectively providing power from the rechargeable power tool battery pack to the heater in response to control signals from the user input member, the controller causing the heater to enter a first mode in response to a first signal from the user input member, and selectively switching the heater to a second mode in response to a second signal from the user input member.\",\n \"13.The article of clothing of claim 12, wherein the heater includes a plurality of heating zones configured to heat different portions of the garment body, wherein the user input member includes an illuminated display portion, and wherein illumination of the display portion indicates a thermal output level of each heating zone.\",\n \"14.The article of clothing of claim 12, wherein the heater includes a plurality of heating zones configured to heat different portions of the garment body, wherein each heating zone is defined by at least one heater array, and wherein a first heater array is disposed in both a left portion and a right portion of a torso body of the garment body, and a second heater array is disposed in a back portion of the garment body.\",\n \"15.The article of clothing of claim 12, wherein the rechargeable power tool battery pack has a nominal voltage of no more than about 14.4 volts.\",\n \"16.The article of clothing of claim 12, wherein the rechargeable power tool battery pack has a nominal voltage of about 12 volts.\",\n \"17.The article of clothing of claim 12, wherein the plurality of cells may be made up of at least three cells.\",\n \"18.The article of clothing of claim 12, wherein each of the cells has a capacity rating of about 3.0 Ah.\"\n ],\n [\n \"<SOH> BACKGROUND OF INVENTION <EOH>The present invention relates to garments, and in particular, to an electrically heated jacket for providing heat to a user wearing the jacket.\",\n \"Garments, especially outwear such as jackets and parkas, may be insulated to protect a user from the cold.\",\n \"Insulated jackets rely on the user's own body heat to keep the user warm.\",\n \"If the insulation is too thin, the user may be cold.\",\n \"If the insulation is too thick, the user may overheat.\"\n ],\n [\n \"<SOH> SUMMARY OF THE INVENTION <EOH>In one embodiment, the invention provides an article of clothing including a garment body and a heating system coupled to the garment body.\",\n \"The heating system includes a plurality of heating zones configured to heat different portions of the garment body.\",\n \"A battery pack supplies power to the heating system.\",\n \"A controller selectively provides power from the battery pack to the multiple heating zones.\",\n \"A user input member is provided for selecting a mode of the controller.\",\n \"In another embodiment, the invention provides a method of operating a garment heated by a first electric heater and a second electric heater, powered by a battery pack, and controlled by a controller via a first user input and a second user input.\",\n \"The first user input is actuated to cause the first electric heater to enter a first thermal output mode.\",\n \"The second user input is actuated to cause the second electric heater to enter a second thermal output mode.\",\n \"The first user input is illuminated in response to entering the first thermal output mode.\",\n \"The second user input is illuminated in response to entering the second thermal output mode.\",\n \"The first user input is actuated to cause the first electric heater to enter an off mode.\",\n \"The second user input is actuated to cause the second electric heater to enter an off mode.\",\n \"Other aspects of the invention will become apparent by consideration of the detailed description and accompanying drawings.\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation of U.S. patent application Ser.\",\n \"No.\",\n \"14/733,503, filed Jun.\",\n \"8, 2015, which is a continuation of U.S. patent application Ser.\",\n \"No.\",\n \"13/588,692, filed Aug. 17, 2012, which claims priority to U.S.\",\n \"Provisional Patent Application No.\",\n \"61/525,549, filed Aug. 19, 2011, and to U.S.\",\n \"Provisional Patent Application No.\",\n \"61/658,662, filed Jun.\",\n \"12, 2012, and which is a continuation-in-part of U.S. patent application Ser.\",\n \"No.\",\n \"12/940,429, filed Nov. 5, 2010, which claims priority to U.S.\",\n \"Provisional Patent Application No.\",\n \"61/258,714, filed Nov. 6, 2009.The entire contents of these applications are incorporated herein by reference.\",\n \"BACKGROUND OF INVENTION The present invention relates to garments, and in particular, to an electrically heated jacket for providing heat to a user wearing the jacket.\",\n \"Garments, especially outwear such as jackets and parkas, may be insulated to protect a user from the cold.\",\n \"Insulated jackets rely on the user's own body heat to keep the user warm.\",\n \"If the insulation is too thin, the user may be cold.\",\n \"If the insulation is too thick, the user may overheat.\",\n \"SUMMARY OF THE INVENTION In one embodiment, the invention provides an article of clothing including a garment body and a heating system coupled to the garment body.\",\n \"The heating system includes a plurality of heating zones configured to heat different portions of the garment body.\",\n \"A battery pack supplies power to the heating system.\",\n \"A controller selectively provides power from the battery pack to the multiple heating zones.\",\n \"A user input member is provided for selecting a mode of the controller.\",\n \"In another embodiment, the invention provides a method of operating a garment heated by a first electric heater and a second electric heater, powered by a battery pack, and controlled by a controller via a first user input and a second user input.\",\n \"The first user input is actuated to cause the first electric heater to enter a first thermal output mode.\",\n \"The second user input is actuated to cause the second electric heater to enter a second thermal output mode.\",\n \"The first user input is illuminated in response to entering the first thermal output mode.\",\n \"The second user input is illuminated in response to entering the second thermal output mode.\",\n \"The first user input is actuated to cause the first electric heater to enter an off mode.\",\n \"The second user input is actuated to cause the second electric heater to enter an off mode.\",\n \"Other aspects of the invention will become apparent by consideration of the detailed description and accompanying drawings.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS FIG.\",\n \"1 is a front view of a jacket according to one embodiment of the invention.\",\n \"FIG.\",\n \"2 is a rear view of the jacket of FIG.\",\n \"1.FIG.\",\n \"3 is a detailed view of a rear compartment of the jacket of FIG.\",\n \"2, and taken along line 3-3 of FIG.\",\n \"2.FIG.\",\n \"4 is a perspective view of a battery holder according to one embodiment of the invention.\",\n \"FIG.\",\n \"5 is a perspective view of a battery pack for use with the battery holder of FIG.\",\n \"4.FIG.\",\n \"6 is an exploded view of the battery pack of FIG.\",\n \"5.FIG.\",\n \"7 is an electrical block diagram for the jacket of FIG.\",\n \"1.FIG.\",\n \"8 is an image of a heated jacket including a heating module according to another embodiment of the invention.\",\n \"FIG.\",\n \"9 is an enlarged view of the heated jacket including the heating module of FIG.\",\n \"8.FIG.\",\n \"10 is a top perspective view of a portion the heating module of FIG.\",\n \"8.FIG.\",\n \"11 is a bottom perspective view of the portion of the heating module of FIG.\",\n \"10.FIG.\",\n \"12 is a front view of a display for positioning in an aperture of the heating module of FIG.\",\n \"10.FIG.\",\n \"13 is a perspective view of tools and devices usable with the battery pack of FIG.\",\n \"5.FIG.\",\n \"14 is a front view of a jacket according to one embodiment of the invention.\",\n \"FIG.\",\n \"15 is a rear view of the jacket of FIG.\",\n \"14.FIG.\",\n \"16A is a detailed view of a control input of the jacket of FIG.\",\n \"14, and taken along line 16A-16A of FIG.\",\n \"14.FIG.\",\n \"16B is a detailed view of a rear compartment of the jacket of FIG.\",\n \"15, and taken along line 16B-16B of FIG.\",\n \"15 FIG.\",\n \"17 is a perspective view of a battery holder according to one embodiment of the invention.\",\n \"FIG.\",\n \"18 is a perspective view of a battery pack for use with the battery holder of FIG.\",\n \"17.FIG.\",\n \"19 is an exploded view of the battery pack of FIG.\",\n \"18.FIG.\",\n \"20 is an electrical block diagram for the jacket of FIG.\",\n \"14.FIG.\",\n \"21 is an image of a heated jacket including a heating module according to another embodiment of the invention.\",\n \"FIG.\",\n \"22 is an enlarged view of the heated jacket including the heating module of FIG.\",\n \"21.FIG.\",\n \"23 is a top perspective view of a portion the heating module of FIG.\",\n \"21.FIG.\",\n \"24 is a bottom perspective view of the portion of the heating module of FIG.\",\n \"23.FIG.\",\n \"25 is a front view of a display for positioning in an aperture of the heating module of FIG.\",\n \"23.FIG.\",\n \"26 is a perspective view of tools and devices usable with the battery pack of FIG.\",\n \"18.FIG.\",\n \"27 is a perspective view of a jacket according to another embodiment of the invention.\",\n \"FIG.\",\n \"28 is a front view of a control input of the jacket of FIG.\",\n \"27.FIG.\",\n \"29 is a diagram of a printed circuit board of the control input of FIG.\",\n \"28.FIG.\",\n \"30 is a circuit diagram for the jacket of FIG.\",\n \"27.FIG.\",\n \"31 is a block diagram of an alternative construction of the jacket of FIG.\",\n \"27.FIG.\",\n \"32 is a perspective view of a battery receptacle module.\",\n \"FIG.\",\n \"33 is another perspective view of the battery receptacle module of FIG.\",\n \"32.FIG.\",\n \"34 is a perspective view of a battery and battery receptacle module according to another aspect of the invention.\",\n \"FIG.\",\n \"35 illustrates a power source adapter for use with the jacket of FIG.\",\n \"27.FIG.\",\n \"36 illustrates an electrically heated glove coupled to an accessory port of a heated jacket.\",\n \"FIG.\",\n \"37 illustrates the electrically heated glove of FIG.\",\n \"36.FIG.\",\n \"38 illustrates a pocket, including wire routing features, of the jacket of FIG.\",\n \"14.FIG.\",\n \"39 illustrates wire routing features on a lining of the jacket of FIG.\",\n \"27.FIG.\",\n \"40 also illustrates the wire routing features of FIG.\",\n \"39.FIG.\",\n \"41 also illustrates the wire routing features of FIG.\",\n \"39.FIG.\",\n \"42 illustrates a front of a jacket with visibility features.\",\n \"FIG.\",\n \"43 illustrates a back of a jacket with visibility features.\",\n \"Before any embodiments of the invention are explained in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the following drawings.\",\n \"The invention is capable of other embodiments and of being practiced or of being carried out in various ways.\",\n \"DETAILED DESCRIPTION FIG.\",\n \"1 illustrates a heated jacket 10 according to one embodiment of the invention.\",\n \"The jacket 10 may be constructed in various sizes to fit a variety of users.\",\n \"The jacket 10 includes typical jacket features such as a torso body 12, arms 14, a collar 16, and front pockets 18.A front surface 20 of the jacket 10 includes a control input.\",\n \"In the illustrated embodiment, the control input is a button 22 that may be actuated by user.\",\n \"As explained in greater detail below, the button 22 includes a display portion 24 to indicate a status of the heated jacket 10.As illustrated in cutaway portions of FIGS.\",\n \"1 and 2, the jacket 10 includes a heater array 26.The heater array 26 is disposed in both a left portion 28 and a right portion 30 of the torso body 12.In some embodiments, the heater array 26 may extend into the arms 14 and/or collar 16.In other embodiments the jacket may include a first heater array and second heater array arranged as an upper module and a lower module, respectively.\",\n \"In the illustrated embodiment, the heater array 26 is controlled via the button 22 shown in FIG.\",\n \"1.In other embodiments, multiple heater arrays may be controlled individually via a single control input or multiple control inputs.\",\n \"The heating array 26 may include resistive heating coils formed of carbon fibers, high density carbon fibers, or other heating devices.\",\n \"The heated jacket 10 is capable of maintaining a temperature of up to 110 degrees Fahrenheit, although in further embodiments lower or greater temperatures are possible depending upon the heat source.\",\n \"As illustrated in FIG.\",\n \"2, the heated jacket 10 includes a compartment 32 located on a lower portion of the back torso body.\",\n \"The compartment 32 houses an electrical component, such as a battery pack and battery holder.\",\n \"As illustrated in FIG.\",\n \"3, the compartment 32 includes a zipper 34, providing selective access by a user to the compartment 32 in order to access the battery pack and other electrical components.\",\n \"FIG.\",\n \"4 illustrates one example of a battery holder 36.The battery holder 36 is configured to receive a battery pack 38, such as the battery pack illustrated in FIG.\",\n \"5.Referring to FIG.\",\n \"5, the battery pack 38 is a lithium-based, rechargeable battery pack.\",\n \"The battery pack 38 is removably and interchangeably connected to the battery holder 36 to provide power to the jacket 10 during operation and to facilitate recharging of the battery pack 38 when not in use.\",\n \"In some embodiments, the battery pack 38 may be used with other types of cordless, battery-powered tools or devices.\",\n \"FIG.\",\n \"13, discussed below, illustrates exemplary tools and devices with which the battery pack 38 may be used.\",\n \"The battery pack 38 also may be used with other power tools or sensing devices not specifically discussed herein.\",\n \"As illustrated in FIGS.\",\n \"5 and 6, the battery pack 38 includes a casing 40, an outer housing 42 coupled to the casing 40, and a plurality of battery cells 44 positioned within the casing 40.The casing 40 is shaped and sized to fit within a cavity 46 of the battery holder 36 illustrated in FIG.\",\n \"4, or alternatively, in a power tool or non-motorized sensing device to connect the battery pack 38 to the tool or device.\",\n \"The casing 40 includes an end cap 48 to substantially enclose the battery cells 44 within the casing 40.The illustrated end cap 48 includes two power terminals 50 configured to mate with corresponding power terminals 60 (FIG.\",\n \"7) extending within the cavity 46 of the battery holder 36.In other embodiments, the end cap 48 may also include sense or communication terminals that are configured to mate with corresponding terminals within the battery holder or a tool.\",\n \"The outer housing 42 includes a latching arrangement 52 for positively engaging the battery pack 38 with the battery holder 36.The latching arrangement 52 includes latching tabs 54 and resilient actuating portions 56.The latching tabs 54 are configured to engage corresponding recesses within the cavity 46 of the battery holder 36.The resilient actuating portions 56 are coupled to the latching tabs 54 and are configured for a user to selectively disengage the latching tabs 54 from the battery holder 36.As shown in FIG.\",\n \"6, the battery pack 38 includes three battery cells 44 positioned within the casing 40 and electrically coupled to the terminals 50.The battery cells provide operational power (e.g., DC power) to the jacket 10 or other device.\",\n \"In the illustrated embodiment, the battery cells 44 are arranged in series, and each battery cell has a nominal voltage of approximately four-volts (4.0V), such that the battery pack 38 has a nominal voltage of approximately twelve-volts (12V).\",\n \"The cells 44 also have a capacity rating of approximately 1.4 Ah.\",\n \"In other embodiments, the battery pack 38 may include more or fewer battery cells 44, and the cells 44 can be arranged in series, parallel, or a serial and parallel combination.\",\n \"For example, the battery pack 38 can include a total of six battery cells in a parallel arrangement of two sets of three series-connected cells.\",\n \"The series-parallel combination of battery cells creates a battery pack having a nominal voltage of approximately 12V and a capacity rating of approximately 2.8 Ah.\",\n \"In other embodiments, the battery cells 44 may have different nominal voltages, such as, for example, 3.6V, 3.8V, 4.2V, etc., and/or may have different capacity ratings, such as, for example, 1.2 Ah, 1.3 Ah, 2.0 Ah, 2.4 Ah, 2.6 Ah, 3.0 Ah, etc.\",\n \"In other embodiments, the battery pack 38 can have a different nominal voltage, such as, for example, 10.8V, 14.4V, etc.\",\n \"In the illustrated embodiment, the battery cells 44 are lithium-ion battery cells having a chemistry of, for example, lithium-cobalt (Li—Co), lithium-manganese (Li—Mn), or Li—Mn spinel.\",\n \"In other embodiments, the battery cells 44 may have other suitable lithium or lithium-based chemistries.\",\n \"The heated jacket 10 includes control circuitry for the heater array 26 and battery pack 38.FIG.\",\n \"7 is a block diagram of the heated jacket 10.A battery controller 58 receives electricity from the battery pack 38 via battery terminals 60 (disposed within the battery holder 36).\",\n \"The battery controller 58 may be configured to monitor a state of charge of the battery pack 38 and, if necessary, shutdown the heater array 26.A heater controller 62 receives inputs from the control button 22 and selectively powers the heater array 26 depending upon the selected thermal output.\",\n \"The display portion 24 is selectively illuminated based upon the selected thermal output setting.\",\n \"The heater controller 62 may be configured to monitor a plurality of conditions of the jacket 10 including, but not limited to, an amount of current drawn by the heater array 26.The controllers 58, 62 are, for example, microprocessors, microcontrollers, or the like, and are configured to communicate with one another.\",\n \"In the illustrated embodiment, the battery controller 58 provides information to the heater controller 62 related to a battery pack temperature or voltage level.\",\n \"The heater controller 62 and the battery controller 58 also include low voltage monitors and state-of-charge monitors.\",\n \"The monitors are used to determine whether the battery pack 38 is experiencing a low voltage condition, which may prevent proper operation of the heater array 26, or if the battery pack 38 is in a state-of-charge that makes the battery pack 38 susceptible to being damaged.\",\n \"If such a low voltage condition or state-of-charge exists, the heater array 26 is shut down or the battery pack 38 is otherwise prevented from further discharging current to prevent the battery pack from becoming further depleted.\",\n \"The heated jacket 10 illustrated in FIGS.\",\n \"1 and 2 may be operated as follows.\",\n \"To turn on the heated jacket 10, a user presses and holds the control button 22 for a first period (e.g., three seconds).\",\n \"When first turned on, the heater controller 62 causes the heated jacket 10 to enter pre-heat mode.\",\n \"The heated jacket 10 remains in a pre-heat mode for a period (e.g., five minutes) and then the heater controller 62 switches the heater array 26 to a medium thermal output setting.\",\n \"The user may adjust the thermal output setting by actuating the control button 22.Each press of the control button 22 will cycle the heater controller 62 through one of a sequence of thermal output settings (e.g., low, medium, high).\",\n \"In order to turn off the heated jacket 10 (or de-energize the heater array 26), the user presses and holds the control button 22 for a third period (e.g., three seconds).\",\n \"As mentioned previously, the control button 22 includes an illuminated display portion 24 to indicate a status of the heaters.\",\n \"The display portion may be, for example, one or more LEDs.\",\n \"In the pre-heat mode, the display portion 24 flashes red.\",\n \"At a low thermal output setting, the display portion 24 glows blue.\",\n \"At a medium thermal output setting, the display portion 24 glows white.\",\n \"At a high thermal output setting, the display portion glows red.\",\n \"Other embodiments may use various other colors or light patterns to indicate thermal output settings.\",\n \"Still other embodiments may indicate a state of charge of the battery pack 38.FIG.\",\n \"8 illustrates a heated jacket 110 according to another embodiment of the invention.\",\n \"The heated jacket 110 may be constructed in various sizes to fit a variety of users.\",\n \"FIG.\",\n \"9 is an enlarged view of a heating module 164, which is coupled to an outside surface of the jacket 110 by way of a strap 166.Alternatively, the heating module 164 may be coupled to an inner surface of the jacket 110 or disposed inside of an inner pocket of the jacket 110.The heating module 164 includes a battery pack holder 136 (FIGS.\",\n \"10 and 11) and a battery pack 38 (FIG.\",\n \"5).\",\n \"The heating module 164 is electrically coupled to one or more heating coils (not shown) positioned within the jacket 110 to heat the jacket and provide heat to a user wearing the jacket.\",\n \"In the illustrated embodiment, multiple heating coils are employed and positioned in various locations, or zones, within the jacket.\",\n \"For example, separate heating coils may be positioned in an upper torso area and a lower torso area, and may be separately controllable by the user.\",\n \"In further embodiments, a single heating coil may be used, or the heating coils may be positioned at other locations within the jacket, (e.g., the back, arms, etc.).\",\n \"FIGS.\",\n \"10 and 11 illustrate the battery holder 136 of the heating module 164 in greater detail.\",\n \"With reference to FIG.\",\n \"11, the battery holder 136 includes an aperture 168 for receiving an end of a cord (not shown), the cord being connected to the one or more heating coils and including a male connector terminal.\",\n \"A female connector (not shown) is positioned within the battery holder 136 adjacent the aperture 168 to receive the male connector and form an electrical connection between the heating coils and the battery pack 38.The battery holder 136 also includes a hook 170 for securing the cord disposed between the connector and the jacket 110.With further reference to FIG.\",\n \"10, the battery holder 136 includes a housing portion 172 for electrical components, including a circuit board (not shown).\",\n \"The housing portion 172 includes a first button 174, a second button 176 and a display 178.The first button 174 and the second button 176 are capable of communicating with the electrical components.\",\n \"In the illustrated embodiment, the first button 174 is pressed by a user to increase the temperature of the heating coils, and the second button 176 is pressed by a user for lowering the temperature of the heating coils.\",\n \"In the illustrated embodiment of FIG.\",\n \"12, the display 178 is a seven segment display for representing a heating level indicative of the temperature of the heating coils.\",\n \"With reference to FIG.\",\n \"11, the battery holder 136 includes a power indicator 182, such as a light emitting diode (LED) that displays to the user when lit that the battery is connected, the heating coils are on, or the like.\",\n \"A portion of the battery holder 136 defines a battery cavity 184 for receiving the battery pack 38 (FIG.\",\n \"5).\",\n \"In other embodiments, the battery holder 136 includes an on/off switch (such as the control button 22 discussed above), a fuel gauge that displays the amount of battery power remaining, and a user interface including heat zone controls to individually control the heating coils if multiple heating coils are employed.\",\n \"FIG.\",\n \"13 illustrates exemplary power tools and sensing devices with which the battery pack 38 may be usable.\",\n \"The battery pack 38 may be usable with power tools such as a drill 202, a pipe cutter 204, an impact driver 206, and a reciprocating saw 208.The battery pack 38 may also be usable with non-motorized sensing devices such as a visual inspection camera 212, an infrared sensor 214 (such as a thermometer or thermal imaging camera), a clamp-type multimeter 216, and a wall scanner 218 (such as a “stud finder”).\",\n \"FIGS.\",\n \"14 and 15 illustrate a heated jacket 310 according to one embodiment of the invention.\",\n \"The jacket 310 may be constructed in various sizes to fit a variety of users.\",\n \"The heated jacket 310 is capable of maintaining a temperature of up to 110 degrees Fahrenheit, although in further embodiments lower or greater temperatures are possible depending upon the heat source.\",\n \"The jacket 310 includes typical jacket features such as a torso body 312, arms 314, a back 315, a collar 316, and front pockets 318.The jacket 310 further includes a heating system having multiple heating zones.\",\n \"A front face 320 of the jacket 310 includes a control input 321 that is itself sealed or has a sealed connection to the jacket, such that the control input 321 is protected from environmental conditions.\",\n \"In the illustrated embodiment, the control input 321 is configured to be actuated by a user to direct the control of the jacket heating system and heating zones.\",\n \"As illustrated in FIG.\",\n \"16A and explained in greater detail below, the control input 321 includes three zone control buttons 322a, 322b, and 322c and an on/off button 323.Further, each of the zone control buttons 322a, 322b, 322c and the on/off button 323 include a display portion 324a, 324b, 324c, 324d (FIG.\",\n \"20; e.g., a LED or other type of illumination embedded into each of the above buttons), respectively, to indicate the status of the jacket based on the inputs associated with pressing these buttons.\",\n \"In other embodiments, the display portion 324 may be configured as a single display panel or display lights/illumination separate from the above buttons.\",\n \"Further, the control input 321 may be configured at different locations on the outside or the inside of the jacket, may be configured with different orientations for the buttons, and may be separated into multiple control inputs at different locations on the jacket.\",\n \"As illustrated in cutaway portions of FIGS.\",\n \"14 and 15, the jacket 310 includes a heating system made up of a first heater array 326 and a second heater array 327.The first heater array 326 is disposed in both a left portion 328 and a right portion 330 of the torso body 312.The second heater array 327 is disposed in the back 315.The heating system is further made up of a third heater array 329 (FIG.\",\n \"20) disposed in the front pockets 318.The heating arrays may include resistive heating coils formed of carbon fibers, high density carbon fibers, or other heating devices.\",\n \"In other embodiments, the heating system may include a fourth heater array (not shown) disposed in the arms 314 and/or a fifth heat array (not shown) disposed in the collar 16, and/or additional heater arrays, and may further have different configurations of the heater arrays, as the different heater arrays may be alternatively configured to extend into or be removed from other parts of the jacket 310.As illustrated in FIG.\",\n \"15, the heated jacket 310 includes a compartment 332 located on a lower portion of the back torso body 315.The compartment 332 houses an electrical component, such as a battery pack 338 and a battery holder 336.As illustrated in FIG.\",\n \"16B, the compartment 332 includes a zipper 334, providing selective access by a user to the compartment 332 in order to access the battery pack 338 and other electrical components.\",\n \"FIG.\",\n \"17 illustrates one example of a battery holder 336.The battery holder 336 is configured to receive the battery pack 338, such as the battery pack 338 illustrated in FIG.\",\n \"18.The battery holder 336 also includes a USB-type port 337 for communicating with and charging other devices, such as a digital media player, an iPOD®, or similar device Referring to FIG.\",\n \"18, the battery pack 338 is a lithium-based, rechargeable battery pack.\",\n \"The battery pack 338 is removably and interchangeably connected to the battery holder 336 to provide power to the jacket 310 during operation and to facilitate recharging of the battery pack 338 when not in use.\",\n \"In some embodiments, the battery pack 338 may be used with other types of cordless, battery-powered tools or devices.\",\n \"For example, the battery pack 338 may be usable with a drill, a PVC pipe cutter, an impact driver, and a metal pipe cutter, or other tools.\",\n \"The battery pack 338 may also be usable with a non-motorized sensing device such as a thermal imaging camera, a micro-inspection camera, a wall scanner, a digital multimeter, a thermometer, and a gas detector.\",\n \"A variety of such tools and devices are illustrated in FIG.\",\n \"26.Furthermore, the battery pack 338 may be used with other power tools or sensing devices not specifically discussed herein.\",\n \"As illustrated in FIGS.\",\n \"18 and 19, the battery pack 338 includes a casing 340, an outer housing 342 coupled to the casing 340, and a plurality of battery cells 344 positioned within the casing 340.The casing 340 is shaped and sized to fit within a cavity 346 of the battery holder 336 illustrated in FIG.\",\n \"17, or alternatively, in a power tool or non-motorized sensing device to connect the battery pack 338 to the tool or device.\",\n \"The casing 340 includes an end cap 348 to substantially enclose the battery cells 344 within the casing 340.The illustrated end cap 348 includes two power terminals 350 configured to mate with corresponding power terminals 360 (FIG.\",\n \"20) extending within the cavity 346 of the battery holder 336.In other embodiments, the end cap 348 may also include sense or communication terminals that are configured to mate with corresponding terminals within the battery holder or a tool.\",\n \"The outer housing 342 includes a latching arrangement 352 for positively engaging the battery pack 338 with the battery holder 336.The latching arrangement 352 includes latching tabs 354 and resilient actuating portions 356.The latching tabs 354 are configured to engage corresponding recesses within the cavity 346 of the battery holder 336.The resilient actuating portions 356 are coupled to the latching tabs 354 and are configured for a user to selectively disengage the latching tabs 354 from the battery holder 336.As shown in FIG.\",\n \"19, the battery pack 338 includes three battery cells 344 positioned within the casing 340 and electrically coupled to the terminals 350.The battery cells provide operational power (e.g., DC power) to the jacket 310 or other device.\",\n \"In the illustrated embodiment, the battery cells 344 are arranged in series, and each battery cell has a nominal voltage of approximately four-volts (4.0V), such that the battery pack 338 has a nominal voltage of approximately twelve-volts (12V).\",\n \"The cells 344 also have a capacity rating of approximately 1.4 Ah.\",\n \"In other embodiments, the battery pack 338 may include more or fewer battery cells 344, and the cells 344 can be arranged in series, parallel, or a serial and parallel combination.\",\n \"For example, the battery pack 338 can include a total of six battery cells in a parallel arrangement of two sets of three series-connected cells.\",\n \"The series-parallel combination of battery cells creates a battery pack having a nominal voltage of approximately 12V and a capacity rating of approximately 2.8 Ah.\",\n \"In other embodiments, the battery cells 344 may have different nominal voltages, such as, for example, 3.6V, 3.8V, 4.2V, etc., and/or may have different capacity ratings, such as, for example, 1.2 Ah, 1.3 Ah, 2.0 Ah, 2.4 Ah, 2.6 Ah, 3.0 Ah, etc.\",\n \"In other embodiments, the battery pack 338 can have a different nominal voltage, such as, for example, 10.8V, 14.4V, etc.\",\n \"In the illustrated embodiment, the battery cells 344 are lithium-ion battery cells having a chemistry of, for example, lithium-cobalt (Li—Co), lithium-manganese (Li—Mn), or Li—Mn spinel.\",\n \"In other embodiments, the battery cells 344 may have other suitable lithium or lithium-based chemistries.\",\n \"The heated jacket 310 includes control circuitry for the heating system having multiple heating zones.\",\n \"FIG.\",\n \"20 is an electrical block diagram of the heated jacket 310.A battery controller 358 receives electricity from the battery pack 338 via battery terminals 360 (disposed within the battery holder 336).\",\n \"The battery controller 358 may be configured to monitor a state of charge of the battery pack 338 and, if necessary, shutdown the heater array 326.As shown in FIG.\",\n \"20, a heater controller 362 receives inputs from the control input 321 and selectively powers the heater arrays 326, 327, 329 depending upon a desired thermal output.\",\n \"The display portion 324a, 324b, 324c, 324d, associated with the particular control input button described above, is illuminated based upon the current status of that input button.\",\n \"The heater controller 362 may be configured to monitor a plurality of conditions of the jacket 310 including, but not limited to, an amount of current drawn by the heater arrays 326, 327, 329.The controllers 358, 362 are, for example, microprocessors, microcontrollers, or the like, and are configured to communicate with one another.\",\n \"In the illustrated embodiment, the battery controller 358 provides information to the heater controller 362 related to a battery pack temperature or voltage level.\",\n \"The heater controller 362 and the battery controller 358 also include low voltage monitors and state-of-charge monitors.\",\n \"The monitors are used to determine whether the battery pack 338 is experiencing a low voltage condition, which may prevent proper operation of the heater arrays 326, 327, 329 or if the battery pack 338 is in a state-of-charge that makes the battery pack 338 susceptible to being damaged.\",\n \"If such a low voltage condition or state-of-charge exists, the heater arrays 326, 327, 329 are shut down or the battery pack 338 is otherwise prevented from further discharging current to prevent the battery pack from becoming further depleted.\",\n \"In the illustrated embodiment, the heating system and heating arrays 326, 327, 329 are configured to be actuated via the control input 321 (FIG.\",\n \"14).\",\n \"The on/off button 323 is configured to turn the heating system on and off and also is configured to change thermal output setting of the heating system, including a high thermal output setting, a medium thermal output setting, and low thermal output setting.\",\n \"More specifically, the on/off button is configured to turn the heating system on after being pressed and held for a designated period of time (e.g., 1.5 seconds), such that all heating arrays 326, 327, 329 are turned on and automatically set to an initial predetermined thermal output setting.\",\n \"Subsequent presses of the on/off button change the thermal output setting according to sequence, such that the next press of the on/off button changes the heating system to the high thermal output setting.\",\n \"A further press of the on/off button changes the heating system to the medium thermal output setting.\",\n \"A further press of the on/off button changes the heating system to the low thermal output setting.\",\n \"A further press of the on/off changes the heating system back to the high thermal output setting to complete the sequence of high, medium, low, high, medium, low, and so on.\",\n \"The heating system is on, if any of the heating arrays 326, 327, 329 are on.\",\n \"The on/off button is configured to turn the heating system off after being pressed and held for designated period of time (e.g., 1.5 seconds).\",\n \"In other embodiments, it is conceivable that the number of thermal output settings, the initial thermal output setting, and the sequence of thermal output settings could vary.\",\n \"While the heating system is on, the zone control buttons 322a, 322b, 322c are each configured to turn a particular heater array on and off.\",\n \"More specifically, zone control button 322a is configured to turn the first heater array 326 on and off, zone control button 322b is configured to turn the second heater array 327 on and off, and zone control button 322c is configured to turn the third heater array 329 on and off.\",\n \"Subsequent presses of any one of the zone control buttons switches alternate the associated heating array between on and off.\",\n \"In other embodiments, it is conceivable that multiple heater arrays may be controlled individually via a single control input button or multiple control input buttons.\",\n \"The heated jacket 310 illustrated in FIGS.\",\n \"14 and 15 may be operated as follows.\",\n \"To turn on the heated jacket 310, a user presses and holds the on/off button 323 for a designated period of time (e.g., 1.5 seconds).\",\n \"When first turned on, the heater controller 362 causes the heated jacket 310 to enter pre-heat mode.\",\n \"The heated jacket 310 remains in a pre-heat mode for a period (e.g., five minutes) and then the heater controller 362 switches the heater arrays 326, 327, 329 to a medium thermal output setting.\",\n \"The user may adjust the thermal output setting by actuating the on/off button 323, as discussed above.\",\n \"Each press of the on/off button 323 will cycle the heater controller 362 through one of a sequence of thermal output settings (e.g., high, medium, low).\",\n \"In order to turn off the heated jacket 10, the user presses and holds the on/off button for a designated period of time (e.g., 1.5 seconds).\",\n \"As mentioned previously, the control input buttons 322a, 322b, 322c, 323 each include an illuminated display portion 324a, 324b, 324c, 324d to indicate a status of the heating system.\",\n \"As discussed above, the display portion may be, for example, one or more LEDs.\",\n \"The display portions 324a, 324b, 324c illuminate to indicate that their associated heating arrays are on.\",\n \"In the pre-heat mode, the display portion 324d on the on/off button 323 flashes red.\",\n \"At a low thermal output setting, the display portion 324d glows blue.\",\n \"At a medium thermal output setting, the display portion 324d glows white.\",\n \"At a high thermal output setting, the display portion 324d glows red.\",\n \"Other embodiments may use various other colors or light patterns to indicate thermal output settings.\",\n \"Still other embodiments may indicate a state of charge of the battery pack 338.Various modifications of the control method or sequence are possible.\",\n \"For example, in other embodiments, the user may select a desired temperature rather than a thermal output setting.\",\n \"FIG.\",\n \"21 illustrates a heated jacket 410 according to another embodiment of the invention.\",\n \"The heated jacket 410 may be constructed in various sizes to fit a variety of users.\",\n \"FIG.\",\n \"22 is an enlarged view of a heating module 464, which is coupled to an outside surface of the jacket 410 by way of a strap 466.Alternatively, the heating module 464 may be coupled to an inner surface of the jacket 410 or disposed inside of an inner pocket of the jacket 410.The heating module 464 includes a battery pack holder 436 (FIGS.\",\n \"23 and 24) and a battery pack 338 (FIG.\",\n \"18).\",\n \"The heating module 464 is electrically coupled to one or more heating coils (not shown) positioned within the jacket 410 to heat the jacket and provide heat to a user wearing the jacket.\",\n \"In the illustrated embodiment, multiple heating coils are employed and positioned in various locations, or zones, within the jacket.\",\n \"For example, separate heating coils may be positioned in an upper torso area and a lower torso area, in a back area, and in front pockets, and may be separately controllable by the user.\",\n \"In further embodiments, a single heating coil may be used, or the heating coils may be positioned at other locations within the jacket, (e.g., the back, arms, etc.).\",\n \"FIGS.\",\n \"23 and 24 illustrate the battery holder 436 of the heating module 464 in greater detail.\",\n \"With reference to FIG.\",\n \"23, the battery holder 436 includes an aperture 468 for receiving an end of a cord (not shown), the cord being connected to the one or more heating coils and including a male connector terminal.\",\n \"A female connector (not shown) is positioned within the battery holder 436 adjacent the aperture 468 to receive the male connector and form an electrical connection between the heating coils and the battery pack 338.The battery holder 436 also includes a hook 470 for securing the cord disposed between the connector and the jacket 410, and a USB port 475 for communicating with and charging other devices, such as a digital media player, an iPOD®, or similar device.\",\n \"With further reference to FIG.\",\n \"23, the battery holder 436 includes a housing portion 472 for electrical components, including a circuit board (not shown).\",\n \"The housing portion 472 includes a first on/off button 474, three zone control buttons 476a, 476b, 476c, and a display 478.The first button 174 and the zone buttons 476a, 476b, 476c are capable of communicating with the electrical components.\",\n \"In the illustrated embodiment, the on/off button 474 and zone control buttons 476a, 476b, 476c are configured and operate similarly to the above control input buttons 322a, 322b, 322c, 323.In the illustrated embodiment of FIG.\",\n \"25, the display 478 is a seven segment display for representing a heating level indicative of the temperature of the heating coils.\",\n \"With reference to FIG.\",\n \"24, the battery holder 436 includes a power indicator 482, such as a light emitting diode (LED) that displays to the user when lit that the battery is connected, the heating coils are on, or the like.\",\n \"A portion of the battery holder 436 defines a battery port 484 for receiving the battery pack 338 (FIG.\",\n \"18).\",\n \"In other embodiments, the battery holder 436 includes a fuel gauge that displays the amount of battery power remaining.\",\n \"FIG.\",\n \"27 illustrates a heated jacket 488 according to another embodiment of the invention.\",\n \"The jacket 188 includes an outer shell 492 with left and right front pockets 496 and 498, and a chest pocket 502.FIG.\",\n \"38 illustrates a rear compartment 506 of the jacket 488.Referring to FIG.\",\n \"30, the heated jacket 488 includes a heating system 510 including a core heater array 514 and a pocket heater array 518.The core heater array 514 includes a right chest heating module 522, a left chest heating module 526, and a back heating module 530.The pocket heater array 518 includes a right pocket heating module 534 and a left pocket heating module 538.The heater arrays 514 and 518 may include resistive heating coils formed of carbon fibers, high density carbon fibers, or other heating devices.\",\n \"The core heater array 514 and pocket heater array 518 are controlled via a heater control module 542.The heater control module 542 is coupled to a chest portion 546 of the jacket 488 (FIG.\",\n \"27).\",\n \"Referring to FIG.\",\n \"28 an external surface 550 of the heater control module 542 provides access to a first heater control button 554 and a second heater control button 558.The first heater control button 554 may be, for example a control input for the core heater array 514 (FIG.\",\n \"30), while the second heater control button 558 may be, for example, a control input for the pocket heater array 518.Referring to FIG.\",\n \"29, the first heater control button 554 and the second heater control button 558 are coupled to a printed circuit board (PCB) 562 of the heater control module 542.Each of the first control button 554 and the second control button 558 has an array of light emitting diodes (LEDs) 566 associate with it.\",\n \"More specifically, each button has associated with it a first pair of LEDs (e.g., red LEDs) 570, a second pair of LEDs (e.g., white LEDs) 574, and a third pair of LEDs (e.g., blue LEDs) 578.The LEDs 566 illuminate the external surface 550 of the heater control module 542 (FIG.\",\n \"28) to provide indication of a control mode of the core heater array 514 (as selected by the first button 554) or the pocket heater array 518 (as selected by the second button 558).\",\n \"For example, illumination of the red LEDs 570 may indicate a high thermal output setting, illumination of the white LEDs 574 may indicate a medium thermal output setting, and illumination of the blue LEDs 578 may indicate a low thermal output setting.\",\n \"The heater arrays 514 and 518 are indicated as being off when no LED is illuminated.\",\n \"To turn on either of the heater arrays 514 or 518, a heater control button 554 or 558, respectively, is pressed by the user and held for a period of, for example, 0.5-2.5 seconds.\",\n \"A temperature setting (e.g., high, medium, or low) of the core heater array 514 or pocket heater array 518 may be selected by again pressing the respective first heater control button 554 or the second heater control button 558.The heater arrays 514, 518 may be turned off by pressing and holding the respective heater control buttons 554, 558 for a period of 0.5 to 2.5 seconds.\",\n \"FIG.\",\n \"31 is an electrical block diagram of the heated jacket 488.A battery receptacle 482 receives electricity from a battery pack (e.g., the battery pack 338 of FIG.\",\n \"5) and supplies electricity to the heater control module 542 for distribution to the heater arrays 514, 518.FIG.\",\n \"32 illustrates the battery receptacle 582 according to a first configuration.\",\n \"The battery receptacle 582 is configured to receive the 12 volt lithium-ion battery pack 338 (FIG.\",\n \"18).\",\n \"A heater supply cable 586 from the heater control module 542 is detachably coupled the battery receptacle 582.The battery receptacle 582 also includes an accessory port 590.The accessory port 590 may be in the form of a USB outlet for receiving a USB cable 594.The USB cable may, in turn, be coupled to an accessory device such as smart phone or MP3 player.\",\n \"Referring to FIG.\",\n \"33, the battery receptacle 582 includes a battery state-of-charge indicator 598.A state-of-charge may be indicated by the illumination of one or more LEDs.\",\n \"FIG.\",\n \"34 illustrates a battery receptacle 602 according to another configuration.\",\n \"The battery receptacle 602 is configured to receive, for example, an 18 volt lithium-ion battery pack 606.FIG.\",\n \"35 illustrates an adapter 610 that may be used with the heated jacket in place of a battery and battery receptacle.\",\n \"The adapter 610 includes an input plug 614 for mating with a 12V outlet cigarette lighter-type socket of a motor vehicle.\",\n \"An output plug 618 connects to heated jacket 488.Referring to FIG.\",\n \"31, the heater control module 542 may also interface with a heated accessory device 622.When a heated accessory device 622 is coupled to the jacket 488 and detected by the heater control module 542, the heater control module 542 deactivates the pocket heater array 518 and selective provides power to the heated accessory device 622.The second heater control button 558 may then be used to control a thermal output setting of the accessory device 622 in a manner similar to that used to control the pocket heater array 518.FIG.\",\n \"36 illustrates an exemplary heated accessory device 622, in the form of an electrically heated glove 622.Each glove 622 includes a resistive heating element.\",\n \"A power cord 626 is coupled to the heating element.\",\n \"The power cord 626 includes a connector 630 for connecting to the electrical system of the heated jacket 488.FIG.\",\n \"37 illustrates the heated gloves 622 connected to a left sleeve portion 634 and a right sleeve portion 638 of a heated jacket.\",\n \"An accessory power port 642 is coupled to each sleeve portion 634, 638.The accessory power ports 642 include a body 646 that is coupled to an outer surface 650 of the sleeves 634, 638 by sewing, rivets, adhesives or other attachment means.\",\n \"The body 646 defines a power receptacle.\",\n \"The power receptacle is in electrical communication with the heater control module 542 (FIG.\",\n \"31).\",\n \"Each power receptacle is configured to receive the connector 630 of the power cord 626 of a heated accessory device 322, such that the device is selectively powered by the heater control module 542.FIGS.\",\n \"38-41 illustrate accessory wire routing features that may be incorporated into a heated jacket, such as the heated jacket 488 of FIG.\",\n \"27.Referring to FIG.\",\n \"38, the rear compartment 506 may serve, for example, to hold and secure the battery receptacle 582 (FIG.\",\n \"32) and battery 338 (FIG.\",\n \"18).\",\n \"Grommets 650 are coupled to the jacket shell 492 inside the rear compartment 506.The grommets 650 surround openings through the jacket shell.\",\n \"FIGS.\",\n \"39-41 illustrate a liner 654 of the jacket 488.The jacket 488 defines an open space between the outer shell 492 (FIG.\",\n \"38) and the liner 654 (FIGS.\",\n \"39-41).\",\n \"Grommets 650 are coupled to the liner 654 and surround openings through the liner 654.The grommets 650 facilitate the passage of accessory wires from the liner 654, through the open space, and through the outer shell 492 to the rear compartment 506.For example, a USB-type wire 594 of a device may be coupled to the accessory port 590 of a battery receptacle 582 (FIGS.\",\n \"32-33) that is stored in the rear compartment (FIG.\",\n \"38) 506.Referring to FIGS.\",\n \"39-41, additional wire routing features are coupled to the jacket liner 654.These additional features include wire routing tabs 658 and wire routing channels 662.The wire routing tabs 658 include a cloth tab member 664 that is sewn to the liner 654 along a tab seam 666.Opposite the tab seam 666, hook and loop fasteners 670 are coupled to the tab members 662 and jacket liner 654, to facilitate capturing a section of wire (e.g., 594) between the liner 654 and the tab member 664.The wire routing channels 662 include a cloth channel member 674 that is sewn to the liner 654 along a channel seam 678.Opposite the channel seam 678, hook and loop fasteners 670 are coupled to the channel member 674 and the jacket liner 654, to facilitate capturing a section of wire 594 between the liner 654 and the channel member 674.In other embodiments, the hook and loop fasteners 670 of the wire routing tabs 658 and wire routing channels 662 may be replaced with buttons, snaps, or other types of fasteners.\",\n \"FIGS.\",\n \"42 and 43 illustrate a jacket 682 according to another embodiment of the invention.\",\n \"The jacket 682 may incorporate heater and heater control features similar to those described with respect to the jacket 310 (FIG.\",\n \"14) or the jacket 488 (FIG.\",\n \"27), or various combinations thereof.\",\n \"Reflective strips 686 are coupled to an outer shell 690 of the jacket 682.The reflective strips 686 may be sewn onto the outer shell 690 of the jacket 682, or they may be adhesively bonded to the outer shell 690.In still other embodiments, the reflective strips 686 may be painted onto the outer shell 690 of the jacket.\",\n \"Although the invention has been described in detail with reference to certain preferred embodiments, variations and modifications exist within the scope and spirit of one or more independent aspects of the invention as described.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875768"}}},{"rowIdx":4494970,"cells":{"text":{"kind":"list like","value":[["REAL-TIME OR JUST-IN-TIME ONLINE ASSISTANCE FOR INDIVIDUALS TO HELP THEM IN ACHIEVING PERSONALIZED HEALTH GOALS","A method and a system for providing real-time assistance to users in achieving their personalized health goals through a mobile phone with an integrated software application by uploading the photographs to a secured database of the software application of the mobile phone provided with specific text comments or requests placed in appropriately classified input queues for assigning to a qualified nutritionist or an Artificial Intelligence (AI) Program for analyzing the uploaded photographs and generating specific modifications to the food items on the photograph of a meal by applying the user-specific weight-loss/meal modification rules, displaying the analysis information and the specific modifications on the food items to the user on the mobile phone screen.","The system and method also comprises a container, a partition plate, a closable lid for storing the food items that are rejected by the nutritionist or the AI and a placemat printed with colored squares patterns."],["1.A method for providing real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user obtains assistance in neutralizing a food craving comprising the steps of: initiating a craving help request in dealing with food cravings at any time by the registered user; setting up other users as helpers or groups along with their contact numbers and other information to whom the craving help request is sent; specifying the helpers or groups to whom the request should be sent; broadcasting the craving request to the specified helpers or groups and notify the registered users, helpers or groups individually; responding and attempting to distract the requesting registered user from the craving by calling, texting, sending video clips, links or other means by the registered/unregistered helpers; and maintaining the craving help request open for a specified duration and automatically closing it after receiving at least one response; wherein the AI automatically responds to the craving request to distract the registered user from the craving at typical snack-craving times or at anytime or if there is no response from any helper or group after a set duration.","2.The method according to claim 1, wherein the AI automatically engages different friends when having different kinds of cravings by mapping specific cravings to a given friend's profile.","3.The method according to claim 1, wherein the AI automatically sends a reminder or a notification to a specially-designated friend to proactively distract a specific registered user from a craving.","4.The method according to claim 1, wherein the AI analyzes patterns of craving to predict the next time of day when a registered user might get a craving and proactively suggests or engages a friend to respond to the craving."],["<SOH> BACKGROUND <EOH>The burden of being overweight or obese, in terms of health problems and expenditures, is well known.","Numerous weight loss approaches exist that require substantial changes to diets and exercise routines, sustained tracking and detailed numeric analysis of ingredients, caloric values, fat content, etc.","Individuals are unable to adhere to and maintain these requirements, which typically leads to temporary weight loss, but the lost weight is regained, sometimes repeatedly.","Weight loss approaches based on diet plans require individuals to first remember to follow the plans, and second, to do a good job of actually following the plans.","Individuals often have difficulty remembering their respective list of foods to avoid or reduce.","Tools are available to analyze the content of foods, and many individuals try to adjust their eating to comply with their respective diet plans.","Users packed with busy work schedules and under social pressure to join others in the act of eating find it very difficult to sustain over time.","Pre-packaged diets packages help in this regard, but they are expensive and individuals can get tired of eating the same items over and over, which leads to non-adherence.","Further, deprivation of certain favorite food items results in frustration and can lead to abandonment.","Other approaches provide detailed information regarding the calories, fat, sodium, etc., content of foods, and rely on the diligence of the individual to check, analyze and modify their eating habits in order to stay within their dietary plans or guidelines.","Again, adherence eventually breaks down because of the amount of detailed effort involved, and only the most diligent individuals continue for the longer term.","Many systems or methods or devices have been introduced globally to adopt good dietary habits to build healthier lifestyle.","Since it has become impractical for most individuals to exercise for more than an hour or two a day, modifying their food intake is more effective than exercise.","U.S. Pat.","No.","6,478,736 discloses a health management system for a person, in which the person's resting metabolic rate (RMR) is determined at intervals using an indirect calorimeter.","RMR values are used in setting and revising goals in, for example, a weight control program.","The effects of a weight control program on RMR can hence be compensated for, which enables an improved weight control program to be developed.","In one embodiment, the person is provided with a portable electronic device, for use as a caloric intake calculator, caloric expenditure calculator, and caloric balance calculator.","This user needs to carry the system whenever he or she wishes to consume food, which is not feasible all the time.","U.S. Pat.","No.","7,959,567 relates to an apparatus for detecting at least one of human physiological and contextual information from the body of a wearer that includes a sensor device adapted to be worn on the body having one or more sensors selected from the group consisting of physiological sensors and contextual sensors and an I/O device in electronic communication with said sensor device.","The I/O device includes means for displaying information and a dial, the dial being supported for rotational movement about an external surface of the I/O device.","The dial enables the wearer to enter information into the I/O device.","The I/O device may further include at least one button that also enables the wearer to enter information into the I/O device.","The task of entering information relating to type and quantity of meals sometimes results in inaccurate estimation of caloric content if a user is not sure about the relative size of the meal.","U.S. Pat.","No.","5,454,721 discloses a system intended to teach individuals the relationship between the visual size and a few nutritional characteristics of portions of food by using either a life size image of, or the corporeal finger of the individual, as a scale against images of different sized portions of different kinds of food, while showing a few nutritional characteristics of such portions.","The system proposed is minimal when compared to the present invention's features.","This system does not evaluate the user's ability to visually estimate macro and micronutrient content of meals nor does it permit analysis of an individual's dietary pro-activities.","US20070179359 discloses a receiving a caloric request and a resting metabolic rate, computing an expended number of calories based on the user's resting metabolic rate and physical activity performed by the user, computing a consumed number of calories based on food the user consumes, determining a status for the user based on whether the user is to consume calories or expend calories, and sending an alert to the user.","This method calculates the estimated calories based on the physical activity performed by the user and resting metabolic rate.","Performing physical activity is not feasible for every user at every time with respect to their busy schedule.","However, these techniques can sometimes be difficult to employ.","As an example, during a busy day, people may forget to exercise or count caloric intake.","As another example, people who are traveling may be unable to easily locate activity centers or food sources that help them to manage their health.","Often, people lack the motivation to live healthy lives.","The advent of smart phones with built-in cameras makes it possible to provide real-time assistance in the form of suggestions or comments on meals about to be consumed.","Therefore, there is a need to provide a method and system operable by a software application integrated with a smart mobile phone to maintain a healthy lifestyle by a user attaining real-time assistance in estimating nutritional attributes in a meal, modifying the meal and encouraging them to maintain health for a longer duration."],["<SOH> SUMMARY OF THE INVENTION <EOH>The invention comprises a method for providing real-time assistance to users in achieving their personalized health goals through a mobile phone comprising steps of: installing a software application in the user's mobile phone; registering with the said software application by providing personalized profile parameters, personalized health goals, other health goals of a user; providing a secured database to store photographs of food items/meals to be consumed by a user; analyzing the profile parameters of each user and generating specific ranked weight-loss rules/meal modification rules applicable to that particular user; generating specific modifications to the food items on the photograph of a meal by applying the user-specific weight-loss/meal modification rules; displaying the analysis information and the specific modifications on the food items to the user on the mobile phone screen; tracking the status/modification stage of the image by providing a speed indicator, and displaying a timeline of previously uploaded photographs of meals consumed, modifications, and other information, along with the means to rate the quality of the modifications and the level of adherence by the user.","A feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing.","Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the food items by a nutritionist/Artificial Intelligence (AI) for providing suggested modifications.","Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the food items by a nutritionist/Artificial Intelligence (AI) and providing adherence/evaluation by the registered user.","Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user obtains assistance in neutralizing a food craving.","Yet another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the unconsumed food items stored in a container or a device or a plate.","A further feature of this invention comprises a system for providing real-time assistance to users in achieving their personalized health goals through a mobile phone comprising of: a mobile phone integrated with a software application; one or more secured databases to store the photographs of the food items/meals, generated ranked weight-loss rules/meal modification rules, suggested modifications; a processor for performing analysis of nutritional information; wherein comprises a container or a device provided with a closable lid and a knob for categorizing the food items for consuming placed on a plate, wherein creates a partition of the plate into which the rejected food items are placed using the device, and wherein comprises a placemat printed with colored squares of standard size for providing size reference for estimating size and/or quantity of food items on the plate that is placed on top of the placemat.","Another feature of this system is to generate reports depicting past trends, current status and future predictions and displays the reports at the time of analyzing."],["FIELD OF INVENTION The present invention relates to providing an individual a real-time or an online assistance in achieving personalized health and wellness goals such as weight loss, adherence to various types of diets, prevention of heart disease or cancer, proper medication-taking, etc.","Further, the present invention provides a smart-phone application with facilities for individuals to upload a picture of a meal they are about to consume and receive a real-time or just-in-time modification to the meal generated by a qualified nutritionist or an artificial intelligence (AI) program.","Specifically, the present invention eliminates the need for individuals to remember dietary plans or guidelines or analyze any detailed information about the meal, and makes it very easy for individuals to maintain health.","BACKGROUND The burden of being overweight or obese, in terms of health problems and expenditures, is well known.","Numerous weight loss approaches exist that require substantial changes to diets and exercise routines, sustained tracking and detailed numeric analysis of ingredients, caloric values, fat content, etc.","Individuals are unable to adhere to and maintain these requirements, which typically leads to temporary weight loss, but the lost weight is regained, sometimes repeatedly.","Weight loss approaches based on diet plans require individuals to first remember to follow the plans, and second, to do a good job of actually following the plans.","Individuals often have difficulty remembering their respective list of foods to avoid or reduce.","Tools are available to analyze the content of foods, and many individuals try to adjust their eating to comply with their respective diet plans.","Users packed with busy work schedules and under social pressure to join others in the act of eating find it very difficult to sustain over time.","Pre-packaged diets packages help in this regard, but they are expensive and individuals can get tired of eating the same items over and over, which leads to non-adherence.","Further, deprivation of certain favorite food items results in frustration and can lead to abandonment.","Other approaches provide detailed information regarding the calories, fat, sodium, etc., content of foods, and rely on the diligence of the individual to check, analyze and modify their eating habits in order to stay within their dietary plans or guidelines.","Again, adherence eventually breaks down because of the amount of detailed effort involved, and only the most diligent individuals continue for the longer term.","Many systems or methods or devices have been introduced globally to adopt good dietary habits to build healthier lifestyle.","Since it has become impractical for most individuals to exercise for more than an hour or two a day, modifying their food intake is more effective than exercise.","U.S. Pat.","No.","6,478,736 discloses a health management system for a person, in which the person's resting metabolic rate (RMR) is determined at intervals using an indirect calorimeter.","RMR values are used in setting and revising goals in, for example, a weight control program.","The effects of a weight control program on RMR can hence be compensated for, which enables an improved weight control program to be developed.","In one embodiment, the person is provided with a portable electronic device, for use as a caloric intake calculator, caloric expenditure calculator, and caloric balance calculator.","This user needs to carry the system whenever he or she wishes to consume food, which is not feasible all the time.","U.S. Pat.","No.","7,959,567 relates to an apparatus for detecting at least one of human physiological and contextual information from the body of a wearer that includes a sensor device adapted to be worn on the body having one or more sensors selected from the group consisting of physiological sensors and contextual sensors and an I/O device in electronic communication with said sensor device.","The I/O device includes means for displaying information and a dial, the dial being supported for rotational movement about an external surface of the I/O device.","The dial enables the wearer to enter information into the I/O device.","The I/O device may further include at least one button that also enables the wearer to enter information into the I/O device.","The task of entering information relating to type and quantity of meals sometimes results in inaccurate estimation of caloric content if a user is not sure about the relative size of the meal.","U.S. Pat.","No.","5,454,721 discloses a system intended to teach individuals the relationship between the visual size and a few nutritional characteristics of portions of food by using either a life size image of, or the corporeal finger of the individual, as a scale against images of different sized portions of different kinds of food, while showing a few nutritional characteristics of such portions.","The system proposed is minimal when compared to the present invention's features.","This system does not evaluate the user's ability to visually estimate macro and micronutrient content of meals nor does it permit analysis of an individual's dietary pro-activities.","US20070179359 discloses a receiving a caloric request and a resting metabolic rate, computing an expended number of calories based on the user's resting metabolic rate and physical activity performed by the user, computing a consumed number of calories based on food the user consumes, determining a status for the user based on whether the user is to consume calories or expend calories, and sending an alert to the user.","This method calculates the estimated calories based on the physical activity performed by the user and resting metabolic rate.","Performing physical activity is not feasible for every user at every time with respect to their busy schedule.","However, these techniques can sometimes be difficult to employ.","As an example, during a busy day, people may forget to exercise or count caloric intake.","As another example, people who are traveling may be unable to easily locate activity centers or food sources that help them to manage their health.","Often, people lack the motivation to live healthy lives.","The advent of smart phones with built-in cameras makes it possible to provide real-time assistance in the form of suggestions or comments on meals about to be consumed.","Therefore, there is a need to provide a method and system operable by a software application integrated with a smart mobile phone to maintain a healthy lifestyle by a user attaining real-time assistance in estimating nutritional attributes in a meal, modifying the meal and encouraging them to maintain health for a longer duration.","SUMMARY OF THE INVENTION The invention comprises a method for providing real-time assistance to users in achieving their personalized health goals through a mobile phone comprising steps of: installing a software application in the user's mobile phone; registering with the said software application by providing personalized profile parameters, personalized health goals, other health goals of a user; providing a secured database to store photographs of food items/meals to be consumed by a user; analyzing the profile parameters of each user and generating specific ranked weight-loss rules/meal modification rules applicable to that particular user; generating specific modifications to the food items on the photograph of a meal by applying the user-specific weight-loss/meal modification rules; displaying the analysis information and the specific modifications on the food items to the user on the mobile phone screen; tracking the status/modification stage of the image by providing a speed indicator, and displaying a timeline of previously uploaded photographs of meals consumed, modifications, and other information, along with the means to rate the quality of the modifications and the level of adherence by the user.","A feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing.","Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the food items by a nutritionist/Artificial Intelligence (AI) for providing suggested modifications.","Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the food items by a nutritionist/Artificial Intelligence (AI) and providing adherence/evaluation by the registered user.","Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user obtains assistance in neutralizing a food craving.","Yet another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the unconsumed food items stored in a container or a device or a plate.","A further feature of this invention comprises a system for providing real-time assistance to users in achieving their personalized health goals through a mobile phone comprising of: a mobile phone integrated with a software application; one or more secured databases to store the photographs of the food items/meals, generated ranked weight-loss rules/meal modification rules, suggested modifications; a processor for performing analysis of nutritional information; wherein comprises a container or a device provided with a closable lid and a knob for categorizing the food items for consuming placed on a plate, wherein creates a partition of the plate into which the rejected food items are placed using the device, and wherein comprises a placemat printed with colored squares of standard size for providing size reference for estimating size and/or quantity of food items on the plate that is placed on top of the placemat.","Another feature of this system is to generate reports depicting past trends, current status and future predictions and displays the reports at the time of analyzing.","BRIEF DESCRIPTION OF DRAWINGS FIG.","1a: illustrates the process flow for downloading and registering with the mobile phone application according to the preferred embodiment.","FIG.","1b: illustrates the process flow for generation of user-specific ranked weight-loss rules according to the preferred embodiment.","FIG.","2: illustrates the process flow for sending a meal-time reminder to the registered user according to the preferred embodiment.","FIG.","3: illustrates the process flow for storing the uploaded photographs in a secured database and queuing of the photographs according to the preferred embodiment.","FIG.","4a: illustrates the process flow for nutritionists to access the system for providing modifications according to the preferred embodiment.","FIG.","4b: illustrates the process flow for the AI Program to provide modifications according to the preferred embodiment.","FIG.","5: illustrates the process flow for notifying the users regarding the suggested modifications and sending the appropriate data according to the preferred embodiment.","FIG.","6: illustrates the process flow for escalating exceptions for further handling by experts according to the preferred embodiment.","FIG.","7: illustrates the process flow for viewing a timeline of their past meal photographs, modifications and comments and indicating their adherence to the modifications according to the preferred embodiment.","FIG.","8: illustrates the process flow for setting up ‘Help Groups’ for assistance according to the preferred embodiment.","FIG.","9: illustrates the process flow assisting the ‘Help Groups’ dealing with food cravings at any time according to the preferred embodiment.","FIG.","10: illustrates the process flow for requesting assistance from a nutritionist, dietician or other professional at any time according to the preferred embodiment.","FIG.","11: illustrates the process flow for calculating the modification quality ratings by nutritionist and user's adherence to it according to the preferred embodiment.","FIG.","12a-b: illustrates a container into which rejected food items as part of the nutritionist's modification are placed according to the preferred embodiment.","FIG.","12c: illustrates a device for creating a partition on a plate into which rejected food items are placed according to the preferred embodiment.","FIG.","12d: illustrates a pouch-like device into which rejected food items are placed according to the preferred embodiment.","FIG.","13a: illustrates a processed image of a plate with food items that have been color-coded based on their dominant nutritional attribute value according to the preferred embodiment.","FIG.","13b: illustrates a processed image of a plate with food items that are superimposed, pie-charts or other like representations indicating the relative proportions of various nutritional attributes of each food item according to the preferred embodiment.","FIG.","14a: illustrates a placemat printed with grey and white squares of one-inch size to provide a sizing reference with the plate placed on top of the placemat according to the preferred embodiment.","FIG.","14b: illustrates a placemat printed with colored squares of one-inch size to provide color and sizing reference with the plate placed on top of the placemat according to the preferred embodiment.","FIG.","15: illustrates a plate partition as shown in FIG.","12c printed with standard sized colored squares that serve as reference in identifying and estimating the food items on the plate according to the preferred embodiment.","FIG.","16: illustrates the process flow for estimating the nutritional values of the food items for either a plate of food or the food items set aside as the modification and report generation according to the preferred embodiment.","FIG.","17: illustrates the process flow for predicting a user's craving times and responding to it according to the preferred embodiment.","FIG.","18: illustrates the process flow for monitoring the user's eating patterns and flag issues raised by the user according to the preferred embodiment.","FIG.","19: illustrates the process flow for providing coaching to a user through two-way rich media according to the preferred embodiment.","DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS A preferred embodiment of the present invention addresses the needs of individuals desiring to lose weight by modifying their food intake by analyzing the content of foods and assisting the individuals to adjust their eating to comply with their respective diet plans.","The preferred embodiment provides a smart mobile phone application provided with facilities for individuals to upload a picture of a plate of food items or meals they are about to consume and receive a real-time or just-in-time modification to the meal generated by a nutritionist or an artificial intelligence (AI) program.","The modification is generated based on the individual's personalized profile parameters, personalized weight-loss goals and the meal to be consumed as well as the history of meals previously consumed.","Since the modification is generated at the point of consumption, the individual does not need to remember any dietary plans or guidelines or analyze any detailed information about the meal in order to make practical decisions about what to eat.","The individual uploads a picture of the meal, receives a real time modification and eats the meal according to the modification.","In the mobile application, individuals register as users and enter certain required profile parameters, and use the smart-phone camera to take photographs of meals and upload them to a secured database.","Authorized nutritionists, dieticians or professionals examine the uploaded photographs and related information and compose specific modifications to the meals based on the individuals' respective profile parameters and their personalized weight-loss goals.","The user receives a customized modification to the uploaded photograph by a qualified nutritionist.","This greatly simplifies the weight-loss regimen.","Nutritionists or dieticians edit or add pre-configured clarifying text, graphics, audio or video to the uploaded photographs in order to indicate the specific modifications.","This embodiment also envisions the use of artificial intelligence techniques to algorithmically select uploaded photographs, apply user-specific weight-loss rules, generate and compose suitable modifications for the associated users.","In cases where the photographs are not readable, the nutritionist or the artificial intelligence program marks them as exceptions and sets up a queue for further handling by more skilled human experts.","Once the modifications are composed, push notifications are automatically sent to the respective users to view the modifications.","The time of elapse of tracking for each photograph is monitored, and if it is elapsed beyond certain threshold limits delay notifications, tips and other information are automatically sent.","The mobile application also displays a timeline of past photographs, modifications and comments, so the user may scroll back and forth to examine them at any time, zoom in to a specific past photograph, indicate actual adherence to the modifications and rate their quality, timeliness and effectiveness.","The preferred embodiment also enables users to get answers to weight-loss or other health-related questions at any time by initiating a help request and directing it to a nutritionist or a dietician or other health professional, or an artificial intelligence program.","Also, the users to get assistance in dealing with food cravings at any time by initiating a craving help request to assigned helper or friend groups, who may respond and attempt to distract the requesting user.","A further provision aggregates, for a particular user, the nutritional values of the food ingested on a particular day, and suggest what items may be eaten at the end of the day to ensure that the user's specific daily dietary limits are not exceeded.","This also provides information regarding nearby restaurant menus or grocery store items in the vicinity of the user's current location and suggests consuming the food items available in the restaurant menus or grocery stores.","The present invention also provides a separate container or plate separator device for placing food items that are flagged as ‘do not eat at this meal’ or rejected as part of the nutritionist's modification, for ingestion by the user, a different person or animal, or for disposal, at a later time.","In addition to this, the present invention also provides a placemat printed with grey and white or color patterned squares of standard size to provide a sizing and color reference, as assistance for estimating the nature, size and/or quantity of food items on a plate that is placed on top of the placemat.","Referring now to FIG.","1a, illustrates a process flow for downloading and registering with the mobile phone application by an individual user.","An individual can locate and download the mobile application from play store or from a website and to activate the application by installing in the mobile phone [2].","The application prompts the individual to enter the mobile phone number and receives a verification code and sends an authentication code as one-time-password to the mobile phone number for verification.","The application then allows the user to enter the one-time-password [6].","The system verifies the entered code and permits the user for further data entry [8] that includes personalized profile parameters, personalized health goal, other health goals, personalized weight-loss goals, etc.","[10].","The user's personalized profile parameters include age, gender, body shape, current weight & height, target weight, blood pressure, cholesterol, blood sugar, etc.","The personalized health goals include target amount of weight to reduce, target amount of blood pressure or blood sugar to be attained, etc.","Further, the user then accepts the terms and conditions of the system to attain the assistance of the application and completes the registration [12].","The system stores the selected user data in the mobile phone application and in the secured server [14] with respective databases as secured server user database [16] and secured mobile app user database [18].","Where, the user can be a person or a parent or a caregiver or a pet-owner seeking real-time assistance.","FIG.","1b, illustrates the process flow for generation of user-specific ranked weight-loss rules based on user-profile parameters and other user data from the secured server database.","The system reads the user data and parameters [14] from the secured server user database [16].","These user personalized profile parameters and other parameters such as recent meal history serve as inputs to the algorithms for generating the user specific ranked weight-loss rules.","The ranked weight-loss rules also include meal modification rules that are generated by various algorithms for different health goals that are assigned based on the specific user's profile data and/or health goals.","The system generates the user specific ranked rules for weight-loss [20] and stores the generated rules in a database of user specific ranked rules for weight loss [22].","FIG.","2, illustrates the process flow for sending a meal-time reminder to the registered user by prompting the user to activate the mobile application.","The application runs a typical ‘Meal-Time Monitor’ routine [24] in the background that detects the occurrence of a ‘typical meal-time’, based on past history of meals and other relevant data entered by a registered user that is stored in the secured mobile application user database [18].","When an impending meal-time is detected, the application displays a Meal-Time Reminder as a notification [26] that is displayed on the mobile phone screen.","Simultaneously, the application also activates the camera and displays the camera icon for the user to capture a photograph of the next meal [28].","The users can also use 2D or a 3D camera affixed to their eyeglass or other means to capture photographs of the food item/meals to be consumed.","Further, the users are allowed to capture photographs of the food items at a grocery store to attain personalized instructions on their suitability, based on personalized health profile and other health goals.","The registered user can also capture and upload additional or sequential photographs representing additional servings at a particular meal.","The user captures multiple photographs of the meal [30], views them, and selects the best photograph with respect to clarity and uploads it [32] by clicking on the ‘upload’ button.","Before uploading, the user is allowed to add specific graphical modifications or text comments or audio comments or requests and/or other related information to the captured photographs.","These comments also include specific queries with respect to their weight-loss or health goals.","Further, means are provided for the registered users to add annotations by clicking or touching on the mobile phone screen on certain food items in the modified image to indicate respective food item names and to provide specific requests to the nutritionist.","Additionally, means are provided for the registered user to seek advice from the nutritionist or AI on what to eat for dessert at the end of the meal, given the meal that has just been consumed and receive a response; on what to eat for dinner at the end of the day, given all the meals that have been consumed thus far and receive a response and to seek advice on food item or recipe swaps to improve the quality of their nutritional intake.","FIG.","3, illustrates the process flow for storing the uploaded photographs in a secured database and queuing of the photographs to initiate further action.","After uploading the best photographs by the registered users, the uploaded photographs are received, identified, time-stamped &associated with other user data [34], and stored in a secured database of uploaded photographs.","All the data received from multiple users is stored in a secured database of meal photographs, time stamps and other user data [36].","The system then sorts the data using pre-defined criteria and generates an input queue of photographs and associated data for further action by nutritionists, dieticians and other professionals [38].","The System also generates an input queue of photographs for input to an Artificial Intelligence (AI) Program [40] and the further process is depicted in FIG.","4b.","The input queues are classified based on the specific text comments or requests attached to the uploaded photographs for assigning to a particular nutritionist or an AI.","This classification is attained by providing specific filters that include by user, by associated nutritionist, by artificial intelligence program or the like for assigning the uploaded photographs.","Additional filters are also provided based on meal modification rules or other criteria to further classify the input queues, thereby presenting an input queue of uploaded photographs to which same rules or criteria are to be applied.","FIG.","4a illustrates the process flow for nutritionists to access the system for providing modifications on the uploaded photographs of the food items.","Nutritionists log in to the system to view the input queues of uploaded photographs, compose and save meal modifications.","In the customary manner, nutritionists, dieticians or other authorized professionals log in to the system [44] after their authentication.","Further, the system displays sorted input queues of photographs and associated information based on their respective authorizations [46].","As new photographs are continuously uploaded by users, the system continuously refreshes the sorted input queues [48].","A particular nutritionist, dietician or professional with proper authorizations, who has accessed his or her respective sorted queue, views thumbnails of the uploaded photographs and associated data and selects a particular photograph [50].","The System then displays a larger version of the selected photograph along with the applicable Ranked Weight-loss Rules for the Particular User [60].","The rules are generated using the Database of User-Specific Diet Rules [62] and the Database of User-Specific Ranked Rules for Weight Loss [22] according to the present embodiment.","In other embodiments, the user-specific ranked rules may reflect other health objectives such as waist-reduction, heart-healthy, cancer-prevention, diabetes management, etc., or rules that enforce adherence to certain diets, e.g.","DASH (Dietary Approaches to Stop Hypertension) Diet, etc.","The Nutritionist analyzes the selected photograph and categorizes the food items in the meal [52].","The nutritionist then applies the user's respective weight-loss rules to compose specific Meal Modifications and Comments by using web-based applications or mobile phone applications or tablet-based applications, and saves those [54] to the Secured Output Queue [66].","The composed meal modifications and comments by the nutritionist include text based or graphic based comments or modifications on the photographs and also estimates of the nutritional attributes and their corresponding values of the food items or meals to be consumed or rejected by a user.","The text based comments include generic eating instructions, personalized eating instructions, pre-configured textual comments and textual indicators on the modifications to indicate the increase or decrease in the quantity of the food to be consumed.","The graphic based comments include free-form line drawings, visual effects for increasing/decreasing the appearance of the food items, pre-configured clarifying graphics, pre-configured graphical indicators to indicate the increase or decrease in the quantity of the food to be consumed, magnification/de-magnification of specific food items indicating consumption levels.","Means are provided for vocal comments and video comments to be attached.","These comments are stored in the secured database as a data set associated with a specific image or from a specific registered user.","All these Photographs, modifications and associated data are also stored in the Secured Database of Food Items, Values, Modifications and Rules as an archive [56].","If the nutritionist is unable to recognize or categorize the food items in any photograph, then the nutritionist generates an exception for that particular photograph [58].","The nutritionist makes suggestions to reduce one item or to increase other items to compensate for nutritional values based on the specific user goals.","Also, the nutritionist manually composes specific modifications to photographs based on the user's past meal history or user's specific dietary restrictions, profile parameters, personalized weight-loss goals or personalized diet plans.","In one embodiment, there exists a means on the mobile phone to view a suggested eating sequence for eating food items in the photograph which is automatically projected by the registered user by clicking on the said means include an icon or the like.","This suggested eating sequence can be an unconventional sequence projected as a numbered list.","The exception marked photographs [58] are reverted back to the respective registered user, thereby enabling the user to modify or add clarifying comments to that particular food item and re-upload the photograph.","In one embodiment, the nutritionist provides appropriate observations, or asks questions to a particular user depending on their diet; determines the consumable calories by a particular user based on the target amount of calories to be reduced, and determine the quantity of food items to be reduced/increased; uses pre-configured or free graphical/alphanumeric editing tools to indicate the food items to be modified and also sends encouraging or congratulatory comments when the plate of food needs no suggestions.","In all embodiments, the nutritionist may be a dietician or a veterinarian or other professional, providing assistance to individual adults, parents on behalf of children, adults on behalf of their parents, pet-owners and so on.","FIG.","4b illustrates the process flow for the AI Program to provide modifications on the uploaded photographs of the food items.","The automated programs using artificial intelligence (AI) techniques access input queues of uploaded photographs and associated data, select a photograph, access the associated data and user-specific weight-loss rules to generate and compose modifications and comments.","The AI program selects a photograph in the input queue [72] to apply known exception rules from the database Known Exception Rules Database [76] on the selected photograph [74].","If exception rules apply, the AI Program generates an exception immediately [82] and assigning an exception mark to that particular image if unrecognizable or not clear to be properly analyzed or if the program is unable to generate modifications.","The AI program sets up an exception queue for queuing of photographs marked with exceptions and automatically send notifications to an expert panel or agent for further processing and selects the next photograph from the input queue.","The AI program analyzes the selected photograph, categorizes the food Items and applies user rules [78] to compose meal modifications [80] and saves them to a Secured Output Queue [66].","All Photographs, modifications and associated data are also stored in the Secured Database of Food Items, Values, Modifications and Rules as an archive [56].","The user-specific diet and weight-loss rules [78] are generated using the database of User-Specific Diet Rules [62] and the database of user-specific weight-loss rules based on their respective profile data [64] stored in the database of User-Specific Ranked Weight Loss Rules [22].","The AI program also displays a timeline of past photographs, modifications and comments to the registered user for examination and sends automated reminders or notifications including tips related to health, weight-loss, meal-time reminders or the like.","In one embodiment, the AI program suggests modifications to reduce one item or to increase another item to compensate nutritional values based on specific user goals and overlays color shading within the food item borders to indicate each item's respective dominant nutritional attribute thereby assisting the nutritionist to recognize the items need to be modified.","The AI program automatically edits the uploaded image by inserting text icons and graphics to convey the suggested modifications for approval by the nutritionist.","In one embodiment, the AI directs the nutritionist to estimate the nutritional attributes of the food items after identifying the respective food items, and by intimating the particular user's amount of nutritional attributes consumed on a particular day, enables the nutritionist to recommend the items to be eaten by the end of that day to maintain the user's specific daily dietary limits.","In another embodiment, the AI determines the current physical location of a user from the mobile phone to provide information relating to restaurants, menu items, grocery stores, and other places where meals or food items are available in the vicinity of the user's current location and intimates a particular user the amount of nutritional attributes consumed on a particular day and recommends the items that are available in restaurants, grocery stores, etc., in the vicinity of the user's current location to be eaten by the end of that day to maintain the user's specific daily dietary limits.","In yet another embodiment, the AI intimates the user on the amount of nutritional values to be consumed on a meal by meal, daily, weekly or other time period basis.","In one embodiment, the AI automatically generates and displays personalized/opening messages along with a calorie or other nutritional attribute value to be consumed for that day or to be consumed for lunch or to be consumed for dinner; automatically generates and displays personalized/opening messages with recommendations for the next meal as specific food items or recipe modifications or restaurant menu choices or products available in store shelves with modifications.","In another embodiment, the AI monitors and analyzes the user's eating patterns and flags serious issues that prevent achievement of user objectives, and initiates or recommends a counseling session with an adviser or different AI program to provide personalized or general advice.","FIG.","5 illustrates the process flow for notifying the users regarding the suggested modifications and sending the appropriate data to them.","The system notifies the users that a modification is ready to be viewed and enables the user to view the modification and comments.","The System continuously scans the Secured Output Queue [66], Selects the next available item, reads the user bandwidth setting from the user profile parameters [84] stored in the Secured Server User Database [16].","Each image in the output queue is consolidated with the its respective identifiers, time-stamps, modifications, comments and other associated information to save the entire data set in the secured server database.","Based on the user bandwidth setting, the system either composes the full dataset [86], including the uploaded photograph, modifications, comments, and other associated information that is to be sent to the respective mobile phone, or the system composes a subset that excludes the uploaded photograph [88].The system then identifies the user's mobile number and sends a push notification with the full data set [90], or the data subset [96].","The sub-data set consists of modifications, comments and associated information, but not the image uploaded by the registered user.","The user upon seeing the push notification opens it [92], and the mobile application automatically displays the full dataset, including the photograph, modifications and comments [94] or overlays the data subset on the photograph in the mobile application database, and then displays the photograph, modifications and comments [98].","FIG.","6 illustrates the process flow for escalating exceptions for further handling by experts.","An exception is manually generated by a nutritionist if he or she is unable to recognize or categorize items in an uploaded photograph [58].","Similarly, the AI Program generates an immediate exception if known exception rules applied to a particular uploaded photograph [82].","In both cases, the subject photographs and associated data are flagged as exceptions and transferred to an exception queue [100].","An expert nutritionist selects a particular photograph from the exception queue [102], analyzes the selected photograph and categorizes the food items [104] to compose the modification [110] by applying the weight-loss rules for the particular user [60] and save these modifications to the Secured Output Queue [66].","If the expert nutritionist is unable to analyze the Photograph, he or she appends an ‘Apology’ customer service type message [106] and saves it to the Secured Output Queue [66].","FIG.","7 illustrates the user process flow for viewing a timeline of their past meal photographs, modifications and comments and indicating their adherence to the modifications by providing rating on the quality of the modifications.","The registered user activates the mobile application [112], opens the Timeline view and scrolls through the photographs [114].","The user then selects a particular photograph and views it, the modifications and comments in more detail [116].","In one embodiment, means are provided in the Timeline view for the user to enter health information such as weight, waist circumference, blood pressure, blood sugar, etc.","manually/automatically by importing from various devices.","While viewing the photograph, modifications and comments, user may evaluate and rate the quality and effectiveness of the modifications [118], by selecting the appropriate graphical or other indicators provided in the display.","The evaluation is also attained by providing comments, star-rating on a scale representing the quality of the modifications or by dragging on the timeline by holding a slider.","The user rating is stored in the Modification Rating Database [120].","The user may also enter his or her adherence to the modifications by selecting the provided indicators [122], for example, whether he or she implemented the modifications fully or partially by uploading a second image depicting the actual post-consumption left-over's or unconsumed food items set aside.","Adherence indications are stored in the User Adherence Database [124].","FIG.","8 illustrates the process flow for setting up ‘help groups’ for assistance by selecting individuals from their known contacts as well as from other users of the mobile application.","The user may call upon any of the groups for assistance in dealing with a food craving, at any time of day.","Any individual or individuals from the called-upon group may respond via any means available and try to distract or dissuade the user from succumbing to the craving.","It is not necessary for ‘Help Friend’ Group members to be registered users of the application or services.","The user activates the app in the usual manner [112], and uses the app function to set up at least one named ‘Help Friend’ groups [130].","Multiple such groups can be set up.","The user then selects certain personal contacts in order to invite them to join that particular group [132].","The system immediately sends Pre-Configured Text Message (SMS) invitation to the invitees [134], and resends the invitation one more time if any invitee does not respond after a set period [136].","If an invitee responds in the affirmative [138], then the system registers that invitee as a member of the user's named ‘Help Friend’ group [140].","If an invitee responds in the negative [142], the system does not register that invitee as a member of the user's named ‘Help Friend’ group and notifies the user that the invitation has been declined [144].","FIG.","9 illustrates the process flow assisting the ‘Help Groups’ dealing with food cravings at any time of the day.","The user activates the app in the usual manner [112].","Assuming at least one named ‘Help Friend’ group with at least one contact has been set-up.","The user can request assistance in dealing with a food craving at any time by selecting a particular named ‘Help Friend’ group [146].","The system immediately dispatches ‘Help’ push notifications to the members of the selected named group [148].","Any member of the named group, regardless of whether or not they are registered users, responds by any available means to help the user [150], including SMS (text messaging), chats, phone call, sending information (e.g.","jokes, cartoons, videos, links, etc.)","and attempts to distract the requesting registered user from the craving.","Craving help requests are maintained open for a specified duration and are automatically closed after receiving at least one response, or at the end of the duration, whichever occurs first.","Alternatively, the AI automatically responds to the craving request to distract the registered user from the craving at typical snack-craving times or at anytime or if there is no response from any helper or group after a set duration.","This AI automatically engages different friends when having different kinds of cravings by mapping specific cravings to a given friend's profile, sends a reminder or a notification to a specially-designated friend to proactively distract a specific registered user from a craving and analyzes patterns of craving to predict the next time of day when a registered user might get a craving and proactively suggests or engages a friend to respond to the craving.","FIG.","10 illustrates the process flow for requesting assistance from a helper, nutritionist, dietician or other professional (‘Expert’) at any time.","The user may have a diet related question, may have taken a photograph of a meal and want a modification, or may want a modification to a recipe before cooking, or may be at a restaurant and want a menu item modification, etc.","The user activates the app in the usual manner [112].","Assuming at least one ‘Expert’ with his or her contact information has been set up, the user can request help with any relevant subject matter as described above.","The user composes a help request [152] by adding textual data and attaching photographs or other documents to the request.","The user then selects at least one expert contact to send the request [154].","The system immediately sends a push notification to the selected expert [156].","The expert views the help request [158] and responds [160] by any available means to help the user, including SMS (text messaging), chats, phone call, or sending information (e.g.","jokes, cartoons, videos, links, etc.","), or suggest modifications using textual and graphical tools.","FIG.","11 illustrates the process flow for calculating the modification quality ratings by nutritionist and user's adherence to it and stored in their respective databases.","The system reads the modification quality ratings in the modification rating database [120], sorts the data by nutritionist and calculates an overall quality rating that is, for example, an average of user ratings for a particular nutritionist over a set time period [162].","It then stores the nutritionist-respective ratings in the database of modification quality ratings by nutritionist [164].","Similarly, the system reads the user adherence database [124] sorts the data by user and calculates the user adherence indicator for each user [166].","It then stores the user-respective indicators in the database of user adherence to modifications by user [168].","FIG.","12a-b illustrates a container into which rejected food items as part of the nutritionist's modification are placed.","The container [170] accommodates food items that are flagged as ‘not for eating at this meal’ representing rejected food items as part of the nutritionist modification, for disposal or ingestion at a later time.","In one embodiment, the container [172] is inbuilt into a plate [174] equipped with a separate lid [176] for accommodating food items that are flagged as ‘not for eating at this meal’ representing rejected as part of the nutritionist modification as shown in FIG.","12b.","FIG.","12c illustrates a device for creating a partition on the plate into which rejected food items are placed.","The device [178] that creates a partition on the plate [174] into which food items flagged as ‘not for eating at this meal’, representing rejected as part of the nutritionist's modification for consumption or disposal at later stage.","FIG.","12d illustrates a pouch-like device into which rejected food items are placed.","The pouch-like device into which food items flagged as ‘not for eating at this meal’ as part of the nutritionist's modification for consumption or disposal at a later stage.","FIG.","13a illustrates a processed image of a plate with food items that have been color-coded based on their dominant nutritional attribute value depicting white for food items that are mostly carbohydrate, like rice, red for protein-dominant items or green for vegetable/fiber-dominant items.","FIG.","13b illustrates a processed image of a plate with food items on which are superimposed, pie-charts or other like representations indicating the relative proportions of various nutritional attributes of each food item such as, for example, a pie chart on a rice-based item showing a majority of carbohydrate ‘C’, followed by fiber ‘F’, protein ‘P’ and sodium ‘S’.","FIG.","14a a placemat printed with grey and white squares of one-inch or standard size to provide a sizing reference as an aid for estimating the size and/or quantity of the food items on a plate that is placed on top of the placemat.","FIG.","14b illustrates a placemat printed with colored squares of one-inch or standard size to provide color and sizing reference as an aid for identifying the food items and estimating their size and/or quantity on a plate that is placed on top of the placemat.","FIG.","15 shows a plate partition device shown in FIG.","12c printed with standard sized colored squares that serve as reference in identifying and estimating food items on the plate.","FIG.","16 illustrates the process flow for estimating the nutritional values of the food items for either a plate of food or the food items set aside or rejected as the modification, and report generation.","The photograph of a plate of food or modification is analyzed [251] for individual food items, identified and labeled [252], and their respective number or quantities are estimated [253].The total nutritional attribute values such as carbohydrate, protein, fiber, etc.","of each food item in the photograph are calculated [255], by taking the product of the quantity or number of a specific food item and its respective nutritional attribute values from a database [254] of such values for a large number of food items.","The calculated values are displayed [259] in tabular form and each item is labeled by its predominant nutritional attribute [260].","These calculations are stored in a database [258], and personalized reports are generated [261] for individual users.","These reports also depict past trends, current status and future predictions and display them at the time of analyzing.","FIG.","17 illustrates the process flow for predicting a user's craving times and generating proactive distractions to it.","Snacking adds unnecessary calories, carbs, sodium, fats etc., to the daily intake and can thwart weight-loss.","A user may get a craving at some time of day for a snack; these cravings typically last several minutes and by distracting the person, attention is diverted and the craving passes.","The ‘Buzz’ function is a means to request ‘distractions’ from friends or others.","When a user has a craving and uses the ‘Buzz’ function [271], the use is time-stamped [272], and the buzz requests are stored in a database [273].","These requests are analyzed and typical craving times of day are computed [274], for that particular user and stored in a database [275].","At a typical craving time [276], the system checks if the user has already used the Buzz function [277].","If the user has not used the Buzz function, the system automatically sends a proactive Buzz request to the user's friends [279].","If the user has already used the Buzz function, no action is taken and any automated buzz is suspended [278].","After a predetermined delay, the system automatically sends a buzz response to the user [281], drawing from a database of automatic buzz responses [280].","All buzzes and responses are recorded [282] and stored in a database [283].","FIG.","18 illustrates the process flow for monitoring the user's eating patterns and flag issues raised by the user and providing personalized advice.","At any preset time, e.g.","end of day [293], the AI, nutritionists or other staff analyze the user-uploaded images [294], from the database of user-uploaded images [295], applying issue-analysis criteria [292].","The criteria may include ‘eating the same food items 3 days in a row’, ‘eating more than 5 servings of carbohydrates’, etc.","The findings from the analysis are stored in a database [296].","A nutritionist or other staff professional views the findings for a particular user and manually composes personalized tips [297] that are stored in a database of personalized tips [300].","At some convenient time of day, the system automatically sends the personalized tips to the respective user [301].","Alternatively, an artificial intelligence (AI) program [298] may compose such personalized tips.","An artificial intelligence program [299] also flags issues that may be detrimental to achievement of user objectives (such as eating too many calories, which would not help achieve a weight-loss objective) and store such issues in a database [302].","This database may be used by a counselor to provide advice to the user on flagged issues [303].","The artificial intelligence program [304] would use the database [302] to compose and send personalized messages to advise the user about their respective flagged issues.","FIG.","19 illustrates the process flow for providing coaching to a user through two-way rich media.","The registered user's questions are received [311] by the system and stored in a database [312].","An authorized or user-assigned nutritionist [313] selects a question and views associated user information [314], which may be in the forms of text, images, graphics, voice, etc.","stored in a database [315].","Based on analysis of the questions and associated information, the nutritionist or other professional manually composes a multi-media response [317], selecting and attaching appropriate content from the database [316] and storing the response in a database [319].","Alternatively, an artificial intelligence program [318] may compose and store the response.","The system sends the response to the user [320].","The user may view the response and enter further clarifying questions or comments [321].","Such two-way interactions continue until the user concludes the interaction.","Various modifications and adaptations on the described preferred embodiments can be configured without departing from the scope and spirit of the invention.","Therefore, it is to be understood that within the scope of the appended claims, the invention may be practiced other than as specifically described herein."]],"string":"[\n [\n \"REAL-TIME OR JUST-IN-TIME ONLINE ASSISTANCE FOR INDIVIDUALS TO HELP THEM IN ACHIEVING PERSONALIZED HEALTH GOALS\",\n \"A method and a system for providing real-time assistance to users in achieving their personalized health goals through a mobile phone with an integrated software application by uploading the photographs to a secured database of the software application of the mobile phone provided with specific text comments or requests placed in appropriately classified input queues for assigning to a qualified nutritionist or an Artificial Intelligence (AI) Program for analyzing the uploaded photographs and generating specific modifications to the food items on the photograph of a meal by applying the user-specific weight-loss/meal modification rules, displaying the analysis information and the specific modifications on the food items to the user on the mobile phone screen.\",\n \"The system and method also comprises a container, a partition plate, a closable lid for storing the food items that are rejected by the nutritionist or the AI and a placemat printed with colored squares patterns.\"\n ],\n [\n \"1.A method for providing real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user obtains assistance in neutralizing a food craving comprising the steps of: initiating a craving help request in dealing with food cravings at any time by the registered user; setting up other users as helpers or groups along with their contact numbers and other information to whom the craving help request is sent; specifying the helpers or groups to whom the request should be sent; broadcasting the craving request to the specified helpers or groups and notify the registered users, helpers or groups individually; responding and attempting to distract the requesting registered user from the craving by calling, texting, sending video clips, links or other means by the registered/unregistered helpers; and maintaining the craving help request open for a specified duration and automatically closing it after receiving at least one response; wherein the AI automatically responds to the craving request to distract the registered user from the craving at typical snack-craving times or at anytime or if there is no response from any helper or group after a set duration.\",\n \"2.The method according to claim 1, wherein the AI automatically engages different friends when having different kinds of cravings by mapping specific cravings to a given friend's profile.\",\n \"3.The method according to claim 1, wherein the AI automatically sends a reminder or a notification to a specially-designated friend to proactively distract a specific registered user from a craving.\",\n \"4.The method according to claim 1, wherein the AI analyzes patterns of craving to predict the next time of day when a registered user might get a craving and proactively suggests or engages a friend to respond to the craving.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>The burden of being overweight or obese, in terms of health problems and expenditures, is well known.\",\n \"Numerous weight loss approaches exist that require substantial changes to diets and exercise routines, sustained tracking and detailed numeric analysis of ingredients, caloric values, fat content, etc.\",\n \"Individuals are unable to adhere to and maintain these requirements, which typically leads to temporary weight loss, but the lost weight is regained, sometimes repeatedly.\",\n \"Weight loss approaches based on diet plans require individuals to first remember to follow the plans, and second, to do a good job of actually following the plans.\",\n \"Individuals often have difficulty remembering their respective list of foods to avoid or reduce.\",\n \"Tools are available to analyze the content of foods, and many individuals try to adjust their eating to comply with their respective diet plans.\",\n \"Users packed with busy work schedules and under social pressure to join others in the act of eating find it very difficult to sustain over time.\",\n \"Pre-packaged diets packages help in this regard, but they are expensive and individuals can get tired of eating the same items over and over, which leads to non-adherence.\",\n \"Further, deprivation of certain favorite food items results in frustration and can lead to abandonment.\",\n \"Other approaches provide detailed information regarding the calories, fat, sodium, etc., content of foods, and rely on the diligence of the individual to check, analyze and modify their eating habits in order to stay within their dietary plans or guidelines.\",\n \"Again, adherence eventually breaks down because of the amount of detailed effort involved, and only the most diligent individuals continue for the longer term.\",\n \"Many systems or methods or devices have been introduced globally to adopt good dietary habits to build healthier lifestyle.\",\n \"Since it has become impractical for most individuals to exercise for more than an hour or two a day, modifying their food intake is more effective than exercise.\",\n \"U.S. Pat.\",\n \"No.\",\n \"6,478,736 discloses a health management system for a person, in which the person's resting metabolic rate (RMR) is determined at intervals using an indirect calorimeter.\",\n \"RMR values are used in setting and revising goals in, for example, a weight control program.\",\n \"The effects of a weight control program on RMR can hence be compensated for, which enables an improved weight control program to be developed.\",\n \"In one embodiment, the person is provided with a portable electronic device, for use as a caloric intake calculator, caloric expenditure calculator, and caloric balance calculator.\",\n \"This user needs to carry the system whenever he or she wishes to consume food, which is not feasible all the time.\",\n \"U.S. Pat.\",\n \"No.\",\n \"7,959,567 relates to an apparatus for detecting at least one of human physiological and contextual information from the body of a wearer that includes a sensor device adapted to be worn on the body having one or more sensors selected from the group consisting of physiological sensors and contextual sensors and an I/O device in electronic communication with said sensor device.\",\n \"The I/O device includes means for displaying information and a dial, the dial being supported for rotational movement about an external surface of the I/O device.\",\n \"The dial enables the wearer to enter information into the I/O device.\",\n \"The I/O device may further include at least one button that also enables the wearer to enter information into the I/O device.\",\n \"The task of entering information relating to type and quantity of meals sometimes results in inaccurate estimation of caloric content if a user is not sure about the relative size of the meal.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,454,721 discloses a system intended to teach individuals the relationship between the visual size and a few nutritional characteristics of portions of food by using either a life size image of, or the corporeal finger of the individual, as a scale against images of different sized portions of different kinds of food, while showing a few nutritional characteristics of such portions.\",\n \"The system proposed is minimal when compared to the present invention's features.\",\n \"This system does not evaluate the user's ability to visually estimate macro and micronutrient content of meals nor does it permit analysis of an individual's dietary pro-activities.\",\n \"US20070179359 discloses a receiving a caloric request and a resting metabolic rate, computing an expended number of calories based on the user's resting metabolic rate and physical activity performed by the user, computing a consumed number of calories based on food the user consumes, determining a status for the user based on whether the user is to consume calories or expend calories, and sending an alert to the user.\",\n \"This method calculates the estimated calories based on the physical activity performed by the user and resting metabolic rate.\",\n \"Performing physical activity is not feasible for every user at every time with respect to their busy schedule.\",\n \"However, these techniques can sometimes be difficult to employ.\",\n \"As an example, during a busy day, people may forget to exercise or count caloric intake.\",\n \"As another example, people who are traveling may be unable to easily locate activity centers or food sources that help them to manage their health.\",\n \"Often, people lack the motivation to live healthy lives.\",\n \"The advent of smart phones with built-in cameras makes it possible to provide real-time assistance in the form of suggestions or comments on meals about to be consumed.\",\n \"Therefore, there is a need to provide a method and system operable by a software application integrated with a smart mobile phone to maintain a healthy lifestyle by a user attaining real-time assistance in estimating nutritional attributes in a meal, modifying the meal and encouraging them to maintain health for a longer duration.\"\n ],\n [\n \"<SOH> SUMMARY OF THE INVENTION <EOH>The invention comprises a method for providing real-time assistance to users in achieving their personalized health goals through a mobile phone comprising steps of: installing a software application in the user's mobile phone; registering with the said software application by providing personalized profile parameters, personalized health goals, other health goals of a user; providing a secured database to store photographs of food items/meals to be consumed by a user; analyzing the profile parameters of each user and generating specific ranked weight-loss rules/meal modification rules applicable to that particular user; generating specific modifications to the food items on the photograph of a meal by applying the user-specific weight-loss/meal modification rules; displaying the analysis information and the specific modifications on the food items to the user on the mobile phone screen; tracking the status/modification stage of the image by providing a speed indicator, and displaying a timeline of previously uploaded photographs of meals consumed, modifications, and other information, along with the means to rate the quality of the modifications and the level of adherence by the user.\",\n \"A feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing.\",\n \"Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the food items by a nutritionist/Artificial Intelligence (AI) for providing suggested modifications.\",\n \"Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the food items by a nutritionist/Artificial Intelligence (AI) and providing adherence/evaluation by the registered user.\",\n \"Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user obtains assistance in neutralizing a food craving.\",\n \"Yet another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the unconsumed food items stored in a container or a device or a plate.\",\n \"A further feature of this invention comprises a system for providing real-time assistance to users in achieving their personalized health goals through a mobile phone comprising of: a mobile phone integrated with a software application; one or more secured databases to store the photographs of the food items/meals, generated ranked weight-loss rules/meal modification rules, suggested modifications; a processor for performing analysis of nutritional information; wherein comprises a container or a device provided with a closable lid and a knob for categorizing the food items for consuming placed on a plate, wherein creates a partition of the plate into which the rejected food items are placed using the device, and wherein comprises a placemat printed with colored squares of standard size for providing size reference for estimating size and/or quantity of food items on the plate that is placed on top of the placemat.\",\n \"Another feature of this system is to generate reports depicting past trends, current status and future predictions and displays the reports at the time of analyzing.\"\n ],\n [\n \"FIELD OF INVENTION The present invention relates to providing an individual a real-time or an online assistance in achieving personalized health and wellness goals such as weight loss, adherence to various types of diets, prevention of heart disease or cancer, proper medication-taking, etc.\",\n \"Further, the present invention provides a smart-phone application with facilities for individuals to upload a picture of a meal they are about to consume and receive a real-time or just-in-time modification to the meal generated by a qualified nutritionist or an artificial intelligence (AI) program.\",\n \"Specifically, the present invention eliminates the need for individuals to remember dietary plans or guidelines or analyze any detailed information about the meal, and makes it very easy for individuals to maintain health.\",\n \"BACKGROUND The burden of being overweight or obese, in terms of health problems and expenditures, is well known.\",\n \"Numerous weight loss approaches exist that require substantial changes to diets and exercise routines, sustained tracking and detailed numeric analysis of ingredients, caloric values, fat content, etc.\",\n \"Individuals are unable to adhere to and maintain these requirements, which typically leads to temporary weight loss, but the lost weight is regained, sometimes repeatedly.\",\n \"Weight loss approaches based on diet plans require individuals to first remember to follow the plans, and second, to do a good job of actually following the plans.\",\n \"Individuals often have difficulty remembering their respective list of foods to avoid or reduce.\",\n \"Tools are available to analyze the content of foods, and many individuals try to adjust their eating to comply with their respective diet plans.\",\n \"Users packed with busy work schedules and under social pressure to join others in the act of eating find it very difficult to sustain over time.\",\n \"Pre-packaged diets packages help in this regard, but they are expensive and individuals can get tired of eating the same items over and over, which leads to non-adherence.\",\n \"Further, deprivation of certain favorite food items results in frustration and can lead to abandonment.\",\n \"Other approaches provide detailed information regarding the calories, fat, sodium, etc., content of foods, and rely on the diligence of the individual to check, analyze and modify their eating habits in order to stay within their dietary plans or guidelines.\",\n \"Again, adherence eventually breaks down because of the amount of detailed effort involved, and only the most diligent individuals continue for the longer term.\",\n \"Many systems or methods or devices have been introduced globally to adopt good dietary habits to build healthier lifestyle.\",\n \"Since it has become impractical for most individuals to exercise for more than an hour or two a day, modifying their food intake is more effective than exercise.\",\n \"U.S. Pat.\",\n \"No.\",\n \"6,478,736 discloses a health management system for a person, in which the person's resting metabolic rate (RMR) is determined at intervals using an indirect calorimeter.\",\n \"RMR values are used in setting and revising goals in, for example, a weight control program.\",\n \"The effects of a weight control program on RMR can hence be compensated for, which enables an improved weight control program to be developed.\",\n \"In one embodiment, the person is provided with a portable electronic device, for use as a caloric intake calculator, caloric expenditure calculator, and caloric balance calculator.\",\n \"This user needs to carry the system whenever he or she wishes to consume food, which is not feasible all the time.\",\n \"U.S. Pat.\",\n \"No.\",\n \"7,959,567 relates to an apparatus for detecting at least one of human physiological and contextual information from the body of a wearer that includes a sensor device adapted to be worn on the body having one or more sensors selected from the group consisting of physiological sensors and contextual sensors and an I/O device in electronic communication with said sensor device.\",\n \"The I/O device includes means for displaying information and a dial, the dial being supported for rotational movement about an external surface of the I/O device.\",\n \"The dial enables the wearer to enter information into the I/O device.\",\n \"The I/O device may further include at least one button that also enables the wearer to enter information into the I/O device.\",\n \"The task of entering information relating to type and quantity of meals sometimes results in inaccurate estimation of caloric content if a user is not sure about the relative size of the meal.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,454,721 discloses a system intended to teach individuals the relationship between the visual size and a few nutritional characteristics of portions of food by using either a life size image of, or the corporeal finger of the individual, as a scale against images of different sized portions of different kinds of food, while showing a few nutritional characteristics of such portions.\",\n \"The system proposed is minimal when compared to the present invention's features.\",\n \"This system does not evaluate the user's ability to visually estimate macro and micronutrient content of meals nor does it permit analysis of an individual's dietary pro-activities.\",\n \"US20070179359 discloses a receiving a caloric request and a resting metabolic rate, computing an expended number of calories based on the user's resting metabolic rate and physical activity performed by the user, computing a consumed number of calories based on food the user consumes, determining a status for the user based on whether the user is to consume calories or expend calories, and sending an alert to the user.\",\n \"This method calculates the estimated calories based on the physical activity performed by the user and resting metabolic rate.\",\n \"Performing physical activity is not feasible for every user at every time with respect to their busy schedule.\",\n \"However, these techniques can sometimes be difficult to employ.\",\n \"As an example, during a busy day, people may forget to exercise or count caloric intake.\",\n \"As another example, people who are traveling may be unable to easily locate activity centers or food sources that help them to manage their health.\",\n \"Often, people lack the motivation to live healthy lives.\",\n \"The advent of smart phones with built-in cameras makes it possible to provide real-time assistance in the form of suggestions or comments on meals about to be consumed.\",\n \"Therefore, there is a need to provide a method and system operable by a software application integrated with a smart mobile phone to maintain a healthy lifestyle by a user attaining real-time assistance in estimating nutritional attributes in a meal, modifying the meal and encouraging them to maintain health for a longer duration.\",\n \"SUMMARY OF THE INVENTION The invention comprises a method for providing real-time assistance to users in achieving their personalized health goals through a mobile phone comprising steps of: installing a software application in the user's mobile phone; registering with the said software application by providing personalized profile parameters, personalized health goals, other health goals of a user; providing a secured database to store photographs of food items/meals to be consumed by a user; analyzing the profile parameters of each user and generating specific ranked weight-loss rules/meal modification rules applicable to that particular user; generating specific modifications to the food items on the photograph of a meal by applying the user-specific weight-loss/meal modification rules; displaying the analysis information and the specific modifications on the food items to the user on the mobile phone screen; tracking the status/modification stage of the image by providing a speed indicator, and displaying a timeline of previously uploaded photographs of meals consumed, modifications, and other information, along with the means to rate the quality of the modifications and the level of adherence by the user.\",\n \"A feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing.\",\n \"Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the food items by a nutritionist/Artificial Intelligence (AI) for providing suggested modifications.\",\n \"Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the food items by a nutritionist/Artificial Intelligence (AI) and providing adherence/evaluation by the registered user.\",\n \"Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user obtains assistance in neutralizing a food craving.\",\n \"Yet another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the unconsumed food items stored in a container or a device or a plate.\",\n \"A further feature of this invention comprises a system for providing real-time assistance to users in achieving their personalized health goals through a mobile phone comprising of: a mobile phone integrated with a software application; one or more secured databases to store the photographs of the food items/meals, generated ranked weight-loss rules/meal modification rules, suggested modifications; a processor for performing analysis of nutritional information; wherein comprises a container or a device provided with a closable lid and a knob for categorizing the food items for consuming placed on a plate, wherein creates a partition of the plate into which the rejected food items are placed using the device, and wherein comprises a placemat printed with colored squares of standard size for providing size reference for estimating size and/or quantity of food items on the plate that is placed on top of the placemat.\",\n \"Another feature of this system is to generate reports depicting past trends, current status and future predictions and displays the reports at the time of analyzing.\",\n \"BRIEF DESCRIPTION OF DRAWINGS FIG.\",\n \"1a: illustrates the process flow for downloading and registering with the mobile phone application according to the preferred embodiment.\",\n \"FIG.\",\n \"1b: illustrates the process flow for generation of user-specific ranked weight-loss rules according to the preferred embodiment.\",\n \"FIG.\",\n \"2: illustrates the process flow for sending a meal-time reminder to the registered user according to the preferred embodiment.\",\n \"FIG.\",\n \"3: illustrates the process flow for storing the uploaded photographs in a secured database and queuing of the photographs according to the preferred embodiment.\",\n \"FIG.\",\n \"4a: illustrates the process flow for nutritionists to access the system for providing modifications according to the preferred embodiment.\",\n \"FIG.\",\n \"4b: illustrates the process flow for the AI Program to provide modifications according to the preferred embodiment.\",\n \"FIG.\",\n \"5: illustrates the process flow for notifying the users regarding the suggested modifications and sending the appropriate data according to the preferred embodiment.\",\n \"FIG.\",\n \"6: illustrates the process flow for escalating exceptions for further handling by experts according to the preferred embodiment.\",\n \"FIG.\",\n \"7: illustrates the process flow for viewing a timeline of their past meal photographs, modifications and comments and indicating their adherence to the modifications according to the preferred embodiment.\",\n \"FIG.\",\n \"8: illustrates the process flow for setting up ‘Help Groups’ for assistance according to the preferred embodiment.\",\n \"FIG.\",\n \"9: illustrates the process flow assisting the ‘Help Groups’ dealing with food cravings at any time according to the preferred embodiment.\",\n \"FIG.\",\n \"10: illustrates the process flow for requesting assistance from a nutritionist, dietician or other professional at any time according to the preferred embodiment.\",\n \"FIG.\",\n \"11: illustrates the process flow for calculating the modification quality ratings by nutritionist and user's adherence to it according to the preferred embodiment.\",\n \"FIG.\",\n \"12a-b: illustrates a container into which rejected food items as part of the nutritionist's modification are placed according to the preferred embodiment.\",\n \"FIG.\",\n \"12c: illustrates a device for creating a partition on a plate into which rejected food items are placed according to the preferred embodiment.\",\n \"FIG.\",\n \"12d: illustrates a pouch-like device into which rejected food items are placed according to the preferred embodiment.\",\n \"FIG.\",\n \"13a: illustrates a processed image of a plate with food items that have been color-coded based on their dominant nutritional attribute value according to the preferred embodiment.\",\n \"FIG.\",\n \"13b: illustrates a processed image of a plate with food items that are superimposed, pie-charts or other like representations indicating the relative proportions of various nutritional attributes of each food item according to the preferred embodiment.\",\n \"FIG.\",\n \"14a: illustrates a placemat printed with grey and white squares of one-inch size to provide a sizing reference with the plate placed on top of the placemat according to the preferred embodiment.\",\n \"FIG.\",\n \"14b: illustrates a placemat printed with colored squares of one-inch size to provide color and sizing reference with the plate placed on top of the placemat according to the preferred embodiment.\",\n \"FIG.\",\n \"15: illustrates a plate partition as shown in FIG.\",\n \"12c printed with standard sized colored squares that serve as reference in identifying and estimating the food items on the plate according to the preferred embodiment.\",\n \"FIG.\",\n \"16: illustrates the process flow for estimating the nutritional values of the food items for either a plate of food or the food items set aside as the modification and report generation according to the preferred embodiment.\",\n \"FIG.\",\n \"17: illustrates the process flow for predicting a user's craving times and responding to it according to the preferred embodiment.\",\n \"FIG.\",\n \"18: illustrates the process flow for monitoring the user's eating patterns and flag issues raised by the user according to the preferred embodiment.\",\n \"FIG.\",\n \"19: illustrates the process flow for providing coaching to a user through two-way rich media according to the preferred embodiment.\",\n \"DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS A preferred embodiment of the present invention addresses the needs of individuals desiring to lose weight by modifying their food intake by analyzing the content of foods and assisting the individuals to adjust their eating to comply with their respective diet plans.\",\n \"The preferred embodiment provides a smart mobile phone application provided with facilities for individuals to upload a picture of a plate of food items or meals they are about to consume and receive a real-time or just-in-time modification to the meal generated by a nutritionist or an artificial intelligence (AI) program.\",\n \"The modification is generated based on the individual's personalized profile parameters, personalized weight-loss goals and the meal to be consumed as well as the history of meals previously consumed.\",\n \"Since the modification is generated at the point of consumption, the individual does not need to remember any dietary plans or guidelines or analyze any detailed information about the meal in order to make practical decisions about what to eat.\",\n \"The individual uploads a picture of the meal, receives a real time modification and eats the meal according to the modification.\",\n \"In the mobile application, individuals register as users and enter certain required profile parameters, and use the smart-phone camera to take photographs of meals and upload them to a secured database.\",\n \"Authorized nutritionists, dieticians or professionals examine the uploaded photographs and related information and compose specific modifications to the meals based on the individuals' respective profile parameters and their personalized weight-loss goals.\",\n \"The user receives a customized modification to the uploaded photograph by a qualified nutritionist.\",\n \"This greatly simplifies the weight-loss regimen.\",\n \"Nutritionists or dieticians edit or add pre-configured clarifying text, graphics, audio or video to the uploaded photographs in order to indicate the specific modifications.\",\n \"This embodiment also envisions the use of artificial intelligence techniques to algorithmically select uploaded photographs, apply user-specific weight-loss rules, generate and compose suitable modifications for the associated users.\",\n \"In cases where the photographs are not readable, the nutritionist or the artificial intelligence program marks them as exceptions and sets up a queue for further handling by more skilled human experts.\",\n \"Once the modifications are composed, push notifications are automatically sent to the respective users to view the modifications.\",\n \"The time of elapse of tracking for each photograph is monitored, and if it is elapsed beyond certain threshold limits delay notifications, tips and other information are automatically sent.\",\n \"The mobile application also displays a timeline of past photographs, modifications and comments, so the user may scroll back and forth to examine them at any time, zoom in to a specific past photograph, indicate actual adherence to the modifications and rate their quality, timeliness and effectiveness.\",\n \"The preferred embodiment also enables users to get answers to weight-loss or other health-related questions at any time by initiating a help request and directing it to a nutritionist or a dietician or other health professional, or an artificial intelligence program.\",\n \"Also, the users to get assistance in dealing with food cravings at any time by initiating a craving help request to assigned helper or friend groups, who may respond and attempt to distract the requesting user.\",\n \"A further provision aggregates, for a particular user, the nutritional values of the food ingested on a particular day, and suggest what items may be eaten at the end of the day to ensure that the user's specific daily dietary limits are not exceeded.\",\n \"This also provides information regarding nearby restaurant menus or grocery store items in the vicinity of the user's current location and suggests consuming the food items available in the restaurant menus or grocery stores.\",\n \"The present invention also provides a separate container or plate separator device for placing food items that are flagged as ‘do not eat at this meal’ or rejected as part of the nutritionist's modification, for ingestion by the user, a different person or animal, or for disposal, at a later time.\",\n \"In addition to this, the present invention also provides a placemat printed with grey and white or color patterned squares of standard size to provide a sizing and color reference, as assistance for estimating the nature, size and/or quantity of food items on a plate that is placed on top of the placemat.\",\n \"Referring now to FIG.\",\n \"1a, illustrates a process flow for downloading and registering with the mobile phone application by an individual user.\",\n \"An individual can locate and download the mobile application from play store or from a website and to activate the application by installing in the mobile phone [2].\",\n \"The application prompts the individual to enter the mobile phone number and receives a verification code and sends an authentication code as one-time-password to the mobile phone number for verification.\",\n \"The application then allows the user to enter the one-time-password [6].\",\n \"The system verifies the entered code and permits the user for further data entry [8] that includes personalized profile parameters, personalized health goal, other health goals, personalized weight-loss goals, etc.\",\n \"[10].\",\n \"The user's personalized profile parameters include age, gender, body shape, current weight & height, target weight, blood pressure, cholesterol, blood sugar, etc.\",\n \"The personalized health goals include target amount of weight to reduce, target amount of blood pressure or blood sugar to be attained, etc.\",\n \"Further, the user then accepts the terms and conditions of the system to attain the assistance of the application and completes the registration [12].\",\n \"The system stores the selected user data in the mobile phone application and in the secured server [14] with respective databases as secured server user database [16] and secured mobile app user database [18].\",\n \"Where, the user can be a person or a parent or a caregiver or a pet-owner seeking real-time assistance.\",\n \"FIG.\",\n \"1b, illustrates the process flow for generation of user-specific ranked weight-loss rules based on user-profile parameters and other user data from the secured server database.\",\n \"The system reads the user data and parameters [14] from the secured server user database [16].\",\n \"These user personalized profile parameters and other parameters such as recent meal history serve as inputs to the algorithms for generating the user specific ranked weight-loss rules.\",\n \"The ranked weight-loss rules also include meal modification rules that are generated by various algorithms for different health goals that are assigned based on the specific user's profile data and/or health goals.\",\n \"The system generates the user specific ranked rules for weight-loss [20] and stores the generated rules in a database of user specific ranked rules for weight loss [22].\",\n \"FIG.\",\n \"2, illustrates the process flow for sending a meal-time reminder to the registered user by prompting the user to activate the mobile application.\",\n \"The application runs a typical ‘Meal-Time Monitor’ routine [24] in the background that detects the occurrence of a ‘typical meal-time’, based on past history of meals and other relevant data entered by a registered user that is stored in the secured mobile application user database [18].\",\n \"When an impending meal-time is detected, the application displays a Meal-Time Reminder as a notification [26] that is displayed on the mobile phone screen.\",\n \"Simultaneously, the application also activates the camera and displays the camera icon for the user to capture a photograph of the next meal [28].\",\n \"The users can also use 2D or a 3D camera affixed to their eyeglass or other means to capture photographs of the food item/meals to be consumed.\",\n \"Further, the users are allowed to capture photographs of the food items at a grocery store to attain personalized instructions on their suitability, based on personalized health profile and other health goals.\",\n \"The registered user can also capture and upload additional or sequential photographs representing additional servings at a particular meal.\",\n \"The user captures multiple photographs of the meal [30], views them, and selects the best photograph with respect to clarity and uploads it [32] by clicking on the ‘upload’ button.\",\n \"Before uploading, the user is allowed to add specific graphical modifications or text comments or audio comments or requests and/or other related information to the captured photographs.\",\n \"These comments also include specific queries with respect to their weight-loss or health goals.\",\n \"Further, means are provided for the registered users to add annotations by clicking or touching on the mobile phone screen on certain food items in the modified image to indicate respective food item names and to provide specific requests to the nutritionist.\",\n \"Additionally, means are provided for the registered user to seek advice from the nutritionist or AI on what to eat for dessert at the end of the meal, given the meal that has just been consumed and receive a response; on what to eat for dinner at the end of the day, given all the meals that have been consumed thus far and receive a response and to seek advice on food item or recipe swaps to improve the quality of their nutritional intake.\",\n \"FIG.\",\n \"3, illustrates the process flow for storing the uploaded photographs in a secured database and queuing of the photographs to initiate further action.\",\n \"After uploading the best photographs by the registered users, the uploaded photographs are received, identified, time-stamped &associated with other user data [34], and stored in a secured database of uploaded photographs.\",\n \"All the data received from multiple users is stored in a secured database of meal photographs, time stamps and other user data [36].\",\n \"The system then sorts the data using pre-defined criteria and generates an input queue of photographs and associated data for further action by nutritionists, dieticians and other professionals [38].\",\n \"The System also generates an input queue of photographs for input to an Artificial Intelligence (AI) Program [40] and the further process is depicted in FIG.\",\n \"4b.\",\n \"The input queues are classified based on the specific text comments or requests attached to the uploaded photographs for assigning to a particular nutritionist or an AI.\",\n \"This classification is attained by providing specific filters that include by user, by associated nutritionist, by artificial intelligence program or the like for assigning the uploaded photographs.\",\n \"Additional filters are also provided based on meal modification rules or other criteria to further classify the input queues, thereby presenting an input queue of uploaded photographs to which same rules or criteria are to be applied.\",\n \"FIG.\",\n \"4a illustrates the process flow for nutritionists to access the system for providing modifications on the uploaded photographs of the food items.\",\n \"Nutritionists log in to the system to view the input queues of uploaded photographs, compose and save meal modifications.\",\n \"In the customary manner, nutritionists, dieticians or other authorized professionals log in to the system [44] after their authentication.\",\n \"Further, the system displays sorted input queues of photographs and associated information based on their respective authorizations [46].\",\n \"As new photographs are continuously uploaded by users, the system continuously refreshes the sorted input queues [48].\",\n \"A particular nutritionist, dietician or professional with proper authorizations, who has accessed his or her respective sorted queue, views thumbnails of the uploaded photographs and associated data and selects a particular photograph [50].\",\n \"The System then displays a larger version of the selected photograph along with the applicable Ranked Weight-loss Rules for the Particular User [60].\",\n \"The rules are generated using the Database of User-Specific Diet Rules [62] and the Database of User-Specific Ranked Rules for Weight Loss [22] according to the present embodiment.\",\n \"In other embodiments, the user-specific ranked rules may reflect other health objectives such as waist-reduction, heart-healthy, cancer-prevention, diabetes management, etc., or rules that enforce adherence to certain diets, e.g.\",\n \"DASH (Dietary Approaches to Stop Hypertension) Diet, etc.\",\n \"The Nutritionist analyzes the selected photograph and categorizes the food items in the meal [52].\",\n \"The nutritionist then applies the user's respective weight-loss rules to compose specific Meal Modifications and Comments by using web-based applications or mobile phone applications or tablet-based applications, and saves those [54] to the Secured Output Queue [66].\",\n \"The composed meal modifications and comments by the nutritionist include text based or graphic based comments or modifications on the photographs and also estimates of the nutritional attributes and their corresponding values of the food items or meals to be consumed or rejected by a user.\",\n \"The text based comments include generic eating instructions, personalized eating instructions, pre-configured textual comments and textual indicators on the modifications to indicate the increase or decrease in the quantity of the food to be consumed.\",\n \"The graphic based comments include free-form line drawings, visual effects for increasing/decreasing the appearance of the food items, pre-configured clarifying graphics, pre-configured graphical indicators to indicate the increase or decrease in the quantity of the food to be consumed, magnification/de-magnification of specific food items indicating consumption levels.\",\n \"Means are provided for vocal comments and video comments to be attached.\",\n \"These comments are stored in the secured database as a data set associated with a specific image or from a specific registered user.\",\n \"All these Photographs, modifications and associated data are also stored in the Secured Database of Food Items, Values, Modifications and Rules as an archive [56].\",\n \"If the nutritionist is unable to recognize or categorize the food items in any photograph, then the nutritionist generates an exception for that particular photograph [58].\",\n \"The nutritionist makes suggestions to reduce one item or to increase other items to compensate for nutritional values based on the specific user goals.\",\n \"Also, the nutritionist manually composes specific modifications to photographs based on the user's past meal history or user's specific dietary restrictions, profile parameters, personalized weight-loss goals or personalized diet plans.\",\n \"In one embodiment, there exists a means on the mobile phone to view a suggested eating sequence for eating food items in the photograph which is automatically projected by the registered user by clicking on the said means include an icon or the like.\",\n \"This suggested eating sequence can be an unconventional sequence projected as a numbered list.\",\n \"The exception marked photographs [58] are reverted back to the respective registered user, thereby enabling the user to modify or add clarifying comments to that particular food item and re-upload the photograph.\",\n \"In one embodiment, the nutritionist provides appropriate observations, or asks questions to a particular user depending on their diet; determines the consumable calories by a particular user based on the target amount of calories to be reduced, and determine the quantity of food items to be reduced/increased; uses pre-configured or free graphical/alphanumeric editing tools to indicate the food items to be modified and also sends encouraging or congratulatory comments when the plate of food needs no suggestions.\",\n \"In all embodiments, the nutritionist may be a dietician or a veterinarian or other professional, providing assistance to individual adults, parents on behalf of children, adults on behalf of their parents, pet-owners and so on.\",\n \"FIG.\",\n \"4b illustrates the process flow for the AI Program to provide modifications on the uploaded photographs of the food items.\",\n \"The automated programs using artificial intelligence (AI) techniques access input queues of uploaded photographs and associated data, select a photograph, access the associated data and user-specific weight-loss rules to generate and compose modifications and comments.\",\n \"The AI program selects a photograph in the input queue [72] to apply known exception rules from the database Known Exception Rules Database [76] on the selected photograph [74].\",\n \"If exception rules apply, the AI Program generates an exception immediately [82] and assigning an exception mark to that particular image if unrecognizable or not clear to be properly analyzed or if the program is unable to generate modifications.\",\n \"The AI program sets up an exception queue for queuing of photographs marked with exceptions and automatically send notifications to an expert panel or agent for further processing and selects the next photograph from the input queue.\",\n \"The AI program analyzes the selected photograph, categorizes the food Items and applies user rules [78] to compose meal modifications [80] and saves them to a Secured Output Queue [66].\",\n \"All Photographs, modifications and associated data are also stored in the Secured Database of Food Items, Values, Modifications and Rules as an archive [56].\",\n \"The user-specific diet and weight-loss rules [78] are generated using the database of User-Specific Diet Rules [62] and the database of user-specific weight-loss rules based on their respective profile data [64] stored in the database of User-Specific Ranked Weight Loss Rules [22].\",\n \"The AI program also displays a timeline of past photographs, modifications and comments to the registered user for examination and sends automated reminders or notifications including tips related to health, weight-loss, meal-time reminders or the like.\",\n \"In one embodiment, the AI program suggests modifications to reduce one item or to increase another item to compensate nutritional values based on specific user goals and overlays color shading within the food item borders to indicate each item's respective dominant nutritional attribute thereby assisting the nutritionist to recognize the items need to be modified.\",\n \"The AI program automatically edits the uploaded image by inserting text icons and graphics to convey the suggested modifications for approval by the nutritionist.\",\n \"In one embodiment, the AI directs the nutritionist to estimate the nutritional attributes of the food items after identifying the respective food items, and by intimating the particular user's amount of nutritional attributes consumed on a particular day, enables the nutritionist to recommend the items to be eaten by the end of that day to maintain the user's specific daily dietary limits.\",\n \"In another embodiment, the AI determines the current physical location of a user from the mobile phone to provide information relating to restaurants, menu items, grocery stores, and other places where meals or food items are available in the vicinity of the user's current location and intimates a particular user the amount of nutritional attributes consumed on a particular day and recommends the items that are available in restaurants, grocery stores, etc., in the vicinity of the user's current location to be eaten by the end of that day to maintain the user's specific daily dietary limits.\",\n \"In yet another embodiment, the AI intimates the user on the amount of nutritional values to be consumed on a meal by meal, daily, weekly or other time period basis.\",\n \"In one embodiment, the AI automatically generates and displays personalized/opening messages along with a calorie or other nutritional attribute value to be consumed for that day or to be consumed for lunch or to be consumed for dinner; automatically generates and displays personalized/opening messages with recommendations for the next meal as specific food items or recipe modifications or restaurant menu choices or products available in store shelves with modifications.\",\n \"In another embodiment, the AI monitors and analyzes the user's eating patterns and flags serious issues that prevent achievement of user objectives, and initiates or recommends a counseling session with an adviser or different AI program to provide personalized or general advice.\",\n \"FIG.\",\n \"5 illustrates the process flow for notifying the users regarding the suggested modifications and sending the appropriate data to them.\",\n \"The system notifies the users that a modification is ready to be viewed and enables the user to view the modification and comments.\",\n \"The System continuously scans the Secured Output Queue [66], Selects the next available item, reads the user bandwidth setting from the user profile parameters [84] stored in the Secured Server User Database [16].\",\n \"Each image in the output queue is consolidated with the its respective identifiers, time-stamps, modifications, comments and other associated information to save the entire data set in the secured server database.\",\n \"Based on the user bandwidth setting, the system either composes the full dataset [86], including the uploaded photograph, modifications, comments, and other associated information that is to be sent to the respective mobile phone, or the system composes a subset that excludes the uploaded photograph [88].The system then identifies the user's mobile number and sends a push notification with the full data set [90], or the data subset [96].\",\n \"The sub-data set consists of modifications, comments and associated information, but not the image uploaded by the registered user.\",\n \"The user upon seeing the push notification opens it [92], and the mobile application automatically displays the full dataset, including the photograph, modifications and comments [94] or overlays the data subset on the photograph in the mobile application database, and then displays the photograph, modifications and comments [98].\",\n \"FIG.\",\n \"6 illustrates the process flow for escalating exceptions for further handling by experts.\",\n \"An exception is manually generated by a nutritionist if he or she is unable to recognize or categorize items in an uploaded photograph [58].\",\n \"Similarly, the AI Program generates an immediate exception if known exception rules applied to a particular uploaded photograph [82].\",\n \"In both cases, the subject photographs and associated data are flagged as exceptions and transferred to an exception queue [100].\",\n \"An expert nutritionist selects a particular photograph from the exception queue [102], analyzes the selected photograph and categorizes the food items [104] to compose the modification [110] by applying the weight-loss rules for the particular user [60] and save these modifications to the Secured Output Queue [66].\",\n \"If the expert nutritionist is unable to analyze the Photograph, he or she appends an ‘Apology’ customer service type message [106] and saves it to the Secured Output Queue [66].\",\n \"FIG.\",\n \"7 illustrates the user process flow for viewing a timeline of their past meal photographs, modifications and comments and indicating their adherence to the modifications by providing rating on the quality of the modifications.\",\n \"The registered user activates the mobile application [112], opens the Timeline view and scrolls through the photographs [114].\",\n \"The user then selects a particular photograph and views it, the modifications and comments in more detail [116].\",\n \"In one embodiment, means are provided in the Timeline view for the user to enter health information such as weight, waist circumference, blood pressure, blood sugar, etc.\",\n \"manually/automatically by importing from various devices.\",\n \"While viewing the photograph, modifications and comments, user may evaluate and rate the quality and effectiveness of the modifications [118], by selecting the appropriate graphical or other indicators provided in the display.\",\n \"The evaluation is also attained by providing comments, star-rating on a scale representing the quality of the modifications or by dragging on the timeline by holding a slider.\",\n \"The user rating is stored in the Modification Rating Database [120].\",\n \"The user may also enter his or her adherence to the modifications by selecting the provided indicators [122], for example, whether he or she implemented the modifications fully or partially by uploading a second image depicting the actual post-consumption left-over's or unconsumed food items set aside.\",\n \"Adherence indications are stored in the User Adherence Database [124].\",\n \"FIG.\",\n \"8 illustrates the process flow for setting up ‘help groups’ for assistance by selecting individuals from their known contacts as well as from other users of the mobile application.\",\n \"The user may call upon any of the groups for assistance in dealing with a food craving, at any time of day.\",\n \"Any individual or individuals from the called-upon group may respond via any means available and try to distract or dissuade the user from succumbing to the craving.\",\n \"It is not necessary for ‘Help Friend’ Group members to be registered users of the application or services.\",\n \"The user activates the app in the usual manner [112], and uses the app function to set up at least one named ‘Help Friend’ groups [130].\",\n \"Multiple such groups can be set up.\",\n \"The user then selects certain personal contacts in order to invite them to join that particular group [132].\",\n \"The system immediately sends Pre-Configured Text Message (SMS) invitation to the invitees [134], and resends the invitation one more time if any invitee does not respond after a set period [136].\",\n \"If an invitee responds in the affirmative [138], then the system registers that invitee as a member of the user's named ‘Help Friend’ group [140].\",\n \"If an invitee responds in the negative [142], the system does not register that invitee as a member of the user's named ‘Help Friend’ group and notifies the user that the invitation has been declined [144].\",\n \"FIG.\",\n \"9 illustrates the process flow assisting the ‘Help Groups’ dealing with food cravings at any time of the day.\",\n \"The user activates the app in the usual manner [112].\",\n \"Assuming at least one named ‘Help Friend’ group with at least one contact has been set-up.\",\n \"The user can request assistance in dealing with a food craving at any time by selecting a particular named ‘Help Friend’ group [146].\",\n \"The system immediately dispatches ‘Help’ push notifications to the members of the selected named group [148].\",\n \"Any member of the named group, regardless of whether or not they are registered users, responds by any available means to help the user [150], including SMS (text messaging), chats, phone call, sending information (e.g.\",\n \"jokes, cartoons, videos, links, etc.)\",\n \"and attempts to distract the requesting registered user from the craving.\",\n \"Craving help requests are maintained open for a specified duration and are automatically closed after receiving at least one response, or at the end of the duration, whichever occurs first.\",\n \"Alternatively, the AI automatically responds to the craving request to distract the registered user from the craving at typical snack-craving times or at anytime or if there is no response from any helper or group after a set duration.\",\n \"This AI automatically engages different friends when having different kinds of cravings by mapping specific cravings to a given friend's profile, sends a reminder or a notification to a specially-designated friend to proactively distract a specific registered user from a craving and analyzes patterns of craving to predict the next time of day when a registered user might get a craving and proactively suggests or engages a friend to respond to the craving.\",\n \"FIG.\",\n \"10 illustrates the process flow for requesting assistance from a helper, nutritionist, dietician or other professional (‘Expert’) at any time.\",\n \"The user may have a diet related question, may have taken a photograph of a meal and want a modification, or may want a modification to a recipe before cooking, or may be at a restaurant and want a menu item modification, etc.\",\n \"The user activates the app in the usual manner [112].\",\n \"Assuming at least one ‘Expert’ with his or her contact information has been set up, the user can request help with any relevant subject matter as described above.\",\n \"The user composes a help request [152] by adding textual data and attaching photographs or other documents to the request.\",\n \"The user then selects at least one expert contact to send the request [154].\",\n \"The system immediately sends a push notification to the selected expert [156].\",\n \"The expert views the help request [158] and responds [160] by any available means to help the user, including SMS (text messaging), chats, phone call, or sending information (e.g.\",\n \"jokes, cartoons, videos, links, etc.\",\n \"), or suggest modifications using textual and graphical tools.\",\n \"FIG.\",\n \"11 illustrates the process flow for calculating the modification quality ratings by nutritionist and user's adherence to it and stored in their respective databases.\",\n \"The system reads the modification quality ratings in the modification rating database [120], sorts the data by nutritionist and calculates an overall quality rating that is, for example, an average of user ratings for a particular nutritionist over a set time period [162].\",\n \"It then stores the nutritionist-respective ratings in the database of modification quality ratings by nutritionist [164].\",\n \"Similarly, the system reads the user adherence database [124] sorts the data by user and calculates the user adherence indicator for each user [166].\",\n \"It then stores the user-respective indicators in the database of user adherence to modifications by user [168].\",\n \"FIG.\",\n \"12a-b illustrates a container into which rejected food items as part of the nutritionist's modification are placed.\",\n \"The container [170] accommodates food items that are flagged as ‘not for eating at this meal’ representing rejected food items as part of the nutritionist modification, for disposal or ingestion at a later time.\",\n \"In one embodiment, the container [172] is inbuilt into a plate [174] equipped with a separate lid [176] for accommodating food items that are flagged as ‘not for eating at this meal’ representing rejected as part of the nutritionist modification as shown in FIG.\",\n \"12b.\",\n \"FIG.\",\n \"12c illustrates a device for creating a partition on the plate into which rejected food items are placed.\",\n \"The device [178] that creates a partition on the plate [174] into which food items flagged as ‘not for eating at this meal’, representing rejected as part of the nutritionist's modification for consumption or disposal at later stage.\",\n \"FIG.\",\n \"12d illustrates a pouch-like device into which rejected food items are placed.\",\n \"The pouch-like device into which food items flagged as ‘not for eating at this meal’ as part of the nutritionist's modification for consumption or disposal at a later stage.\",\n \"FIG.\",\n \"13a illustrates a processed image of a plate with food items that have been color-coded based on their dominant nutritional attribute value depicting white for food items that are mostly carbohydrate, like rice, red for protein-dominant items or green for vegetable/fiber-dominant items.\",\n \"FIG.\",\n \"13b illustrates a processed image of a plate with food items on which are superimposed, pie-charts or other like representations indicating the relative proportions of various nutritional attributes of each food item such as, for example, a pie chart on a rice-based item showing a majority of carbohydrate ‘C’, followed by fiber ‘F’, protein ‘P’ and sodium ‘S’.\",\n \"FIG.\",\n \"14a a placemat printed with grey and white squares of one-inch or standard size to provide a sizing reference as an aid for estimating the size and/or quantity of the food items on a plate that is placed on top of the placemat.\",\n \"FIG.\",\n \"14b illustrates a placemat printed with colored squares of one-inch or standard size to provide color and sizing reference as an aid for identifying the food items and estimating their size and/or quantity on a plate that is placed on top of the placemat.\",\n \"FIG.\",\n \"15 shows a plate partition device shown in FIG.\",\n \"12c printed with standard sized colored squares that serve as reference in identifying and estimating food items on the plate.\",\n \"FIG.\",\n \"16 illustrates the process flow for estimating the nutritional values of the food items for either a plate of food or the food items set aside or rejected as the modification, and report generation.\",\n \"The photograph of a plate of food or modification is analyzed [251] for individual food items, identified and labeled [252], and their respective number or quantities are estimated [253].The total nutritional attribute values such as carbohydrate, protein, fiber, etc.\",\n \"of each food item in the photograph are calculated [255], by taking the product of the quantity or number of a specific food item and its respective nutritional attribute values from a database [254] of such values for a large number of food items.\",\n \"The calculated values are displayed [259] in tabular form and each item is labeled by its predominant nutritional attribute [260].\",\n \"These calculations are stored in a database [258], and personalized reports are generated [261] for individual users.\",\n \"These reports also depict past trends, current status and future predictions and display them at the time of analyzing.\",\n \"FIG.\",\n \"17 illustrates the process flow for predicting a user's craving times and generating proactive distractions to it.\",\n \"Snacking adds unnecessary calories, carbs, sodium, fats etc., to the daily intake and can thwart weight-loss.\",\n \"A user may get a craving at some time of day for a snack; these cravings typically last several minutes and by distracting the person, attention is diverted and the craving passes.\",\n \"The ‘Buzz’ function is a means to request ‘distractions’ from friends or others.\",\n \"When a user has a craving and uses the ‘Buzz’ function [271], the use is time-stamped [272], and the buzz requests are stored in a database [273].\",\n \"These requests are analyzed and typical craving times of day are computed [274], for that particular user and stored in a database [275].\",\n \"At a typical craving time [276], the system checks if the user has already used the Buzz function [277].\",\n \"If the user has not used the Buzz function, the system automatically sends a proactive Buzz request to the user's friends [279].\",\n \"If the user has already used the Buzz function, no action is taken and any automated buzz is suspended [278].\",\n \"After a predetermined delay, the system automatically sends a buzz response to the user [281], drawing from a database of automatic buzz responses [280].\",\n \"All buzzes and responses are recorded [282] and stored in a database [283].\",\n \"FIG.\",\n \"18 illustrates the process flow for monitoring the user's eating patterns and flag issues raised by the user and providing personalized advice.\",\n \"At any preset time, e.g.\",\n \"end of day [293], the AI, nutritionists or other staff analyze the user-uploaded images [294], from the database of user-uploaded images [295], applying issue-analysis criteria [292].\",\n \"The criteria may include ‘eating the same food items 3 days in a row’, ‘eating more than 5 servings of carbohydrates’, etc.\",\n \"The findings from the analysis are stored in a database [296].\",\n \"A nutritionist or other staff professional views the findings for a particular user and manually composes personalized tips [297] that are stored in a database of personalized tips [300].\",\n \"At some convenient time of day, the system automatically sends the personalized tips to the respective user [301].\",\n \"Alternatively, an artificial intelligence (AI) program [298] may compose such personalized tips.\",\n \"An artificial intelligence program [299] also flags issues that may be detrimental to achievement of user objectives (such as eating too many calories, which would not help achieve a weight-loss objective) and store such issues in a database [302].\",\n \"This database may be used by a counselor to provide advice to the user on flagged issues [303].\",\n \"The artificial intelligence program [304] would use the database [302] to compose and send personalized messages to advise the user about their respective flagged issues.\",\n \"FIG.\",\n \"19 illustrates the process flow for providing coaching to a user through two-way rich media.\",\n \"The registered user's questions are received [311] by the system and stored in a database [312].\",\n \"An authorized or user-assigned nutritionist [313] selects a question and views associated user information [314], which may be in the forms of text, images, graphics, voice, etc.\",\n \"stored in a database [315].\",\n \"Based on analysis of the questions and associated information, the nutritionist or other professional manually composes a multi-media response [317], selecting and attaching appropriate content from the database [316] and storing the response in a database [319].\",\n \"Alternatively, an artificial intelligence program [318] may compose and store the response.\",\n \"The system sends the response to the user [320].\",\n \"The user may view the response and enter further clarifying questions or comments [321].\",\n \"Such two-way interactions continue until the user concludes the interaction.\",\n \"Various modifications and adaptations on the described preferred embodiments can be configured without departing from the scope and spirit of the invention.\",\n \"Therefore, it is to be understood that within the scope of the appended claims, the invention may be practiced other than as specifically described herein.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875771"}}},{"rowIdx":4494971,"cells":{"text":{"kind":"list like","value":[["COATED COMPRESSIVE SUBPAD FOR CHEMICAL MECHANICAL POLISHING","Coated compressive subpads for polishing pad stacks and methods of fabricating coated compressive subpads for polishing pad stacks are described.","In an example, a polishing pad stack for polishing a substrate includes a polishing pad having a polishing surface and a back surface.","The polishing pad stack also includes a compressive subpad with a first surface having a first pressure sensitive adhesive layer coated thereon.","The first surface of the compressive subpad is coupled directly to the back surface of the polishing pad by the first pressure sensitive adhesive layer."],["1.A method of fabricating a polishing pad stack for polishing a substrate, the method comprising: coating a first pressure sensitive adhesive layer on a first surface of a compressive subpad material; coating a second pressure sensitive adhesive layer on a second, opposite, surface of the compressive subpad material; and adhering the first surface of the compressive subpad material directly to a back surface of a polishing pad by the first pressure sensitive adhesive layer.","2.The method of claim 1, coating the first pressure sensitive adhesive layer comprises coating a permanent pressure sensitive adhesive layer, and wherein coating the second pressure sensitive adhesive layer comprises coating a removable pressure sensitive adhesive layer.","3.The method of claim 1, wherein coating the first pressure sensitive adhesive layer comprises dispensing and then spreading a first solvent-based adhesive formulation on the first surface of the compressive subpad material, and wherein coating the second pressure sensitive adhesive layer comprises dispensing and then spreading a second solvent-based adhesive formulation on the second surface of the compressive subpad material.","4.The method of claim 3, wherein dispensing and then spreading the first solvent-based adhesive formulation on the first surface of the compressive subpad material is performed prior to dispensing and then spreading the second solvent-based adhesive formulation on the second surface of the compressive subpad material.","5.The method of claim 3, wherein dispensing and then spreading the first solvent-based adhesive formulation on the first surface of the compressive subpad material is performed subsequent to dispensing and then spreading the second solvent-based adhesive formulation on the second surface of the compressive subpad material.","6.The method of claim 3, the method further comprising: subsequent to dispensing and then spreading the first solvent-based adhesive formulation on the first surface of the compressive subpad material and dispensing and then spreading the second solvent-based adhesive formulation on the second surface of the compressive subpad material, drying the first and second solvent-based adhesive formulations to remove substantially all solvent from the first and second solvent-based adhesive formulations.","7.The method of claim 3, wherein the compressive subpad is a compressive foam subpad, the method further comprising: prior to coating the first and second pressure sensitive adhesive layers, treating at least one of the first or second surfaces of the compressive foam subpad material with a process selected from the group consisting of a corona discharge treatment, a plasma treatment, and a flame treatment.","8.The method of claim 1, wherein coating the first pressure sensitive adhesive layer comprises applying a first solvent-based adhesive formulation on the first surface of the compressive subpad material at a temperature less than approximately 50 degrees Celsius and, subsequently, drying the first solvent-based adhesive formulation in an air dryer at a temperature less than approximately 50 degrees Celsius.","9.The method of claim 1, further comprising: applying a release liner to the second pressure sensitive adhesive layer.","10.The method of claim 1, wherein coating the second pressure sensitive adhesive layer on the second, opposite, surface of the compressive subpad material comprises applying the second pressure sensitive adhesive layer to a release liner and then applying the second pressure sensitive adhesive layer to the second, opposite, surface of the compressive subpad by the release liner.","11.The method of claim 1, wherein adhering the first surface of the compressive subpad material directly to the back surface of the polishing pad comprises adhering the first surface of the compressive subpad material directly to the back surface of a thermoset polyurethane polishing pad.","12.A subpad for a polishing pad stack, the subpad comprising: a compressive subpad material having a first surface and a second, opposite, surface; a first pressure sensitive adhesive layer coated on the first surface of the compressive subpad material, and a first release liner disposed on the first pressure sensitive adhesive layer; and a second pressure sensitive adhesive layer coated on the second surface of the compressive subpad material.","13.The subpad of claim 12, further comprising: a second release liner disposed on the second pressure sensitive adhesive layer.","14.The subpad of claim 12, wherein the first pressure sensitive adhesive layer is a removable pressure sensitive adhesive layer, and wherein the second pressure sensitive adhesive layer is a permanent pressure sensitive adhesive layer.","15.The subpad of claim 14, wherein the permanent pressure sensitive adhesive layer is for coupling to a back surface of a polishing pad, and wherein the removable pressure sensitive adhesive layer is for coupling the subpad to a platen of a chemical mechanical polishing apparatus.","16.The subpad of claim 12, wherein the second pressure sensitive adhesive layer has a peel strength of greater than approximately 4.5 pounds per inch at 25 degrees Celsius, and wherein the first pressure sensitive adhesive layer has a peel strength of less than approximately 4 pounds per inch at 25 degrees Celsius.","17.The subpad of claim 12, wherein the compressive subpad material is a compressive foam subpad material comprising a material selected from the group consisting of an ethylene vinyl acetate closed cell foam material, a polyethylene closed cell foam material, and a polyurethane mostly closed cell foam material.","18.The subpad of claim 12, the compressive subpad material is a compressive foam subpad material, and wherein the first and second surfaces of the compressive foam subpad material each have a surface energy approximately in the range of 30-40 dyne/cm2.19.The subpad of claim 9, wherein the compressive subpad material has a thickness approximately in the range of 10 mils to 40 mils.","20.The subpad of claim 12, wherein the second pressure sensitive adhesive layer comprises a first material selected from the group consisting of an acrylic material, a rubber, ethylene vinyl acetate, a silicone material, and a block co-polymer, and wherein the first pressure sensitive adhesive layer comprises a second material selected from the group consisting of an acrylic material, a rubber, ethylene vinyl acetate, a silicone material, and a block co-polymer.","21.The subpad of claim 12, wherein the first surface of the compressive subpad material has a surface roughness of at least 3 microns and has a total surface area, and the first pressure sensitive adhesive layer is in direct contact with at least 90% of the total surface area of the first surface of the compressive subpad material.","22.The subpad of claim 21, wherein the second surface of the compressive subpad material has a surface roughness of at least 3 microns and has a total surface area, and the second pressure sensitive adhesive layer is in direct contact with at least 90% of the total surface area of the second surface of the compressive subpad material."],["<SOH> BACKGROUND <EOH>Chemical-mechanical planarization or chemical-mechanical polishing, commonly abbreviated CMP, is a technique used in semiconductor fabrication for planarizing a semiconductor wafer or other substrate.","The process uses an abrasive and/or corrosive chemical slurry (commonly a colloid) in conjunction with a polishing pad and retaining ring, typically of a greater diameter than the wafer.","The polishing pad and wafer are pressed together by a dynamic polishing head and held in place by a plastic retaining ring.","The dynamic polishing head is rotated during polishing.","This approach aids in removal of material and tends to even out any irregular topography, making the wafer flat or planar.","This may be necessary in order to set up the wafer for the formation of additional circuit elements.","For example, this might be necessary in order to bring the entire surface within the depth of field of a photolithography system, or to selectively remove material based on its position.","Typical depth-of-field requirements are down to Angstrom levels for the latest sub-50 nanometer technology nodes.","The process of material removal is not simply that of abrasive scraping, like sandpaper on wood.","The chemicals in the slurry also react with and/or weaken the material to be removed.","The abrasive accelerates this weakening process and the polishing pad helps to wipe the reacted materials from the surface.","In addition to advances in slurry technology, the polishing pad plays a significant role in increasingly complex CMP operations.","However, additional improvements are needed in the evolution of CMP pad technology."],["<SOH> SUMMARY <EOH>Embodiments of the present invention include coated compressive subpads for polishing pad stacks and methods of fabricating coated compressive subpads for polishing pad stacks.","In an embodiment, a polishing pad stack for polishing a substrate includes a polishing pad having a polishing surface and a back surface.","The polishing pad stack also includes a compressive subpad with a first surface having a first pressure sensitive adhesive layer coated thereon.","The first surface of the compressive subpad is coupled directly to the back surface of the polishing pad by the first pressure sensitive adhesive layer.","In another embodiment, a method of fabricating a polishing pad stack for polishing a substrate involves coating a first pressure sensitive adhesive layer on a first surface of a compressive subpad material.","The method also involves coating a second pressure sensitive adhesive layer on a second, opposite, surface of the compressive subpad material.","The method also involves adhering the first surface of the compressive subpad material directly to a back surface of a polishing pad by the first pressure sensitive adhesive layer.","In another embodiment, a subpad for a polishing pad stack includes a compressive subpad material having a first surface and a second, opposite, surface.","A first pressure sensitive adhesive layer is coated on the first surface of the compressive subpad material.","A first release liner is disposed on the first pressure sensitive adhesive layer.","A second pressure sensitive adhesive layer is coated on the second surface of the compressive subpad material."],["CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisional of co-pending application Ser.","No.","14/635,973, filed on Mar.","2, 2015, which claims the benefit of U.S.","Provisional Application No.","62/083,101, filed on Nov. 21, 2014, the entire contents of which are hereby incorporated by reference herein.","TECHNICAL FIELD Embodiments of the present invention are in the field of chemical mechanical polishing (CMP) and, in particular, coated compressive subpads for polishing pad stacks and methods of fabricating coated compressive subpads for polishing pad stacks.","BACKGROUND Chemical-mechanical planarization or chemical-mechanical polishing, commonly abbreviated CMP, is a technique used in semiconductor fabrication for planarizing a semiconductor wafer or other substrate.","The process uses an abrasive and/or corrosive chemical slurry (commonly a colloid) in conjunction with a polishing pad and retaining ring, typically of a greater diameter than the wafer.","The polishing pad and wafer are pressed together by a dynamic polishing head and held in place by a plastic retaining ring.","The dynamic polishing head is rotated during polishing.","This approach aids in removal of material and tends to even out any irregular topography, making the wafer flat or planar.","This may be necessary in order to set up the wafer for the formation of additional circuit elements.","For example, this might be necessary in order to bring the entire surface within the depth of field of a photolithography system, or to selectively remove material based on its position.","Typical depth-of-field requirements are down to Angstrom levels for the latest sub-50 nanometer technology nodes.","The process of material removal is not simply that of abrasive scraping, like sandpaper on wood.","The chemicals in the slurry also react with and/or weaken the material to be removed.","The abrasive accelerates this weakening process and the polishing pad helps to wipe the reacted materials from the surface.","In addition to advances in slurry technology, the polishing pad plays a significant role in increasingly complex CMP operations.","However, additional improvements are needed in the evolution of CMP pad technology.","SUMMARY Embodiments of the present invention include coated compressive subpads for polishing pad stacks and methods of fabricating coated compressive subpads for polishing pad stacks.","In an embodiment, a polishing pad stack for polishing a substrate includes a polishing pad having a polishing surface and a back surface.","The polishing pad stack also includes a compressive subpad with a first surface having a first pressure sensitive adhesive layer coated thereon.","The first surface of the compressive subpad is coupled directly to the back surface of the polishing pad by the first pressure sensitive adhesive layer.","In another embodiment, a method of fabricating a polishing pad stack for polishing a substrate involves coating a first pressure sensitive adhesive layer on a first surface of a compressive subpad material.","The method also involves coating a second pressure sensitive adhesive layer on a second, opposite, surface of the compressive subpad material.","The method also involves adhering the first surface of the compressive subpad material directly to a back surface of a polishing pad by the first pressure sensitive adhesive layer.","In another embodiment, a subpad for a polishing pad stack includes a compressive subpad material having a first surface and a second, opposite, surface.","A first pressure sensitive adhesive layer is coated on the first surface of the compressive subpad material.","A first release liner is disposed on the first pressure sensitive adhesive layer.","A second pressure sensitive adhesive layer is coated on the second surface of the compressive subpad material.","BRIEF DESCRIPTION OF THE DRAWINGS FIG.","1 illustrates a cross-sectional view of a state of the art polishing pad and subpad pairing.","FIG.","2 illustrates a cross-sectional view of a polishing pad and subpad pairing, in accordance with an embodiment of the present invention.","FIG.","3A is cross-sectional scanning electron microscope (SEM) image of an exemplary compressive foam subpad, in accordance with an embodiment of the present invention.","FIG.","3B is cross-sectional scanning electron microscope (SEM) image of another exemplary compressive foam subpad, in accordance with another embodiment of the present invention.","FIG.","4A illustrates a cross-sectional view of a state of the art subpad having an adhesive film laminated thereon.","FIG.","4B illustrates a cross-sectional view of a subpad having a pressure sensitive adhesive layer coated thereon, in accordance with an embodiment of the present invention.","FIG.","5 illustrates a cross-sectional view of a polishing pad and subpad pairing where the polishing pad includes a polishing layer and a foundation layer, in accordance with an embodiment of the present invention.","FIG.","6 illustrates a state of the art four step lamination pass pad/subpad fabrication process.","FIG.","7 illustrates a subpad fabrication process involving coating of pressure sensitive adhesive layers onto the subpad material, in accordance with an embodiment of the present invention.","FIG.","8 illustrates coating of a pressure sensitive adhesive layer onto a subpad material using a Meyer bar, in accordance with an embodiment of the present invention.","FIG.","9 illustrates an apparatus for performing a Corona discharge treatment of a compressive foam subpad surface prior to coating an adhesive layer thereon, in accordance with an embodiment of the present invention.","FIG.","10 illustrates an isometric side-on view of a polishing apparatus compatible with a polishing pad/subpad polishing pad stack, in accordance with an embodiment of the present invention.","DETAILED DESCRIPTION Coated compressive subpads for polishing pad stacks and methods of fabricating coated compressive subpads for polishing pad stacks are described herein.","In the following description, numerous specific details are set forth, such as specific polishing pad and subpad compositions and designs, in order to provide a thorough understanding of embodiments of the present invention.","It will be apparent to one skilled in the art that embodiments of the present invention may be practiced without these specific details.","In other instances, well-known processing techniques, such as details concerning the combination of a slurry with a polishing pad to perform CMP of a semiconductor substrate, are not described in detail in order to not unnecessarily obscure embodiments of the present invention.","Furthermore, it is to be understood that the various embodiments shown in the figures are illustrative representations and are not necessarily drawn to scale.","Polishing pads for CMP operations may have trade-offs in performance such as a trade-off between across-wafer polishing uniformity versus within die polishing uniformity.","For example, hard polishing pads may exhibit good die-level planarization, but poor across-wafer uniformity.","A compressible subpad can be included with a polishing pad or layer to improve the global non-uniformity performance of the overlying polishing pad or layer.","In accordance with one or more embodiments herein, double coated subpads are described, such as double coated foam subpads.","For example, an adhesive coated foam can be used as a foundation (subpad) layer for CMP polishing pads.","The adhesive coated foam may be made using one or combination of the following features: (1) the adhesive may be directly coated onto one surface of the subpad material, (2) the adhesive can be directly coated onto both surfaces of the subpad material, (3) one adhesive can be a removable adhesive to enable application of a subpad/polishing layer pairing to a platen, and/or (4) one adhesive can be a permanent adhesive to promote strong bonding of the subpad to the back side of the polishing pad or layer.","To provide context, state of the art for subpad coupling to a polishing pad or layer involves use of a two-sided tape (such as a pressure sensitive adhesive, PSA, two-sided tape) to bond the subpad to the polishing pad.","A second two-sided tape is laminated to the side of the subpad that will ultimately be coupled to a platen of a CMP apparatus.","For example, fabrication of a polishing pad stack can involve laminating a PSA two-sided tape to both of the subpad faces.","FIG.","1 illustrates a cross-sectional view of a state of the art polishing pad and subpad pairing.","Referring to FIG.","1, a polishing pad 100 (top pad or polishing layer) is coupled to a subpad 102.The face of the subpad 102 proximate to the top pad 100 is coupled to the top pad 100 by a first PSA two-sided tape 104.The first PSA two-sided tape 104 may include a carrier film 104A (such as a polyethylene terephthalate, PET, film) which has a first permanent PSA layer 104B and a second permanent PSA layer 104C thereon.","The face of the subpad 102 distal from the top pad 100 has a second PSA two-sided tape 106 thereon.","The second PSA two-sided tape 106 may include a carrier film 106A (such as a PET film) which has a first permanent PSA layer 106B and a second permanent PSA layer 106C thereon.","The second PSA two-sided tape 106 may be further coupled to a third PSA two-sided tape 108.The third PSA two-sided tape 108 may include a carrier film 108A (such as a PET film) which has a first permanent PSA layer 108B and a second removable PSA layer 108C thereon.","The third PSA two-sided tape 108 may be suitable for removably coupling the top pad 100/subpad 102 polishing pad stack to a platen 110 of a CMP polishing apparatus, as is depicted in FIG.","1.There may be disadvantages associated with the type of polishing pad stack depicted in FIG.","1, as described below.","In contrast to the polishing pad stack of FIG.","1, FIG.","2 illustrates a cross-sectional view of a polishing pad and subpad pairing, in accordance with an embodiment of the present invention.","Referring to FIG.","2, a polishing pad stack for polishing a substrate includes a polishing pad 200 (top pad or polishing layer) coupled to a subpad 202, which may be a compressive subpad.","The polishing pad 200 has a polishing surface distal from the subpad 202, and a back surface proximate to the subpad 202.A first (upper) surface of the subpad 202 has a first pressure sensitive adhesive layer 204 coated thereon.","The upper surface of the subpad 202 is coupled directly to the back surface of the polishing pad 200 by the first pressure sensitive adhesive layer 204.Referring again to FIG.","2, in an embodiment, the polishing pad stack further includes a second pressure sensitive adhesive layer 206 coated on a second (lower) surface of the compressive subpad 202.In one such embodiment, the first pressure sensitive adhesive layer 204 is a permanent pressure sensitive adhesive layer for strong adhesion to the polishing pad 200.The second pressure sensitive adhesive layer 206 is a removable pressure sensitive adhesive layer and is for removably coupling the polishing pad stack to a platen 210 of a chemical mechanical polishing apparatus.","Although depicted in FIG.","2 as already coupled to a platen, in an embodiment, the polishing pad stack of FIG.","2 may include a release liner on the second pressure sensitive adhesive layer 206.Such a release liner may be used for transport and storage of a polishing pad stack, and may be removed to expose the second pressure sensitive adhesive layer 206 prior to coupling the polishing pad stack to a platen.","Advantages of the polishing pad stack of FIG.","2 over the polishing pad stack of FIG.","1 may be realized from the non-interrupted subpad construction achieved with the polishing pad stack type of FIG.","2.In particular, the number of interfaces is limited for adhesion failure.","Additionally, there may be less processing of the adhesive layers of the polishing pad stack of FIG.","2, as is described in greater detail below.","In an embodiment, direct coating of an adhesive onto a compressive subpad surface aids in sealing foam pores in the case of a compressive foam subpad.","Furthermore, the overall pad thickness may be reduced since there are no carrier films associated with the pressure sensitive adhesive layers, and the number of layers in the composite material is limited.","In an embodiment, direct adhesive coating offers superior adhesive anchorage to low surface energy foam that would otherwise be difficult when laminating a PSA two-sided tape to the surface of the subpad.","Finally, the number of manufacturing operations may be reduced from four to as low as one lamination operation (the lamination a coated subpad to a polishing pad), as is described in greater detail below.","Such a reduction in lamination operations and the achieved simplicity of construction of the polishing pad stack can result in potential reductions in manufacturing cost of the polishing pad stack.","Referring again to FIG.","2, a pressure sensitive adhesive layer, such as permanent pressure sensitive adhesive layer 204 or removable adhesive layer 206, requires only light to moderate pressure to adhere to a workpiece (such as light to moderate pressure to adhere a subpad 202 having a pressure sensitive adhesive layer coated thereon to a polishing pad 200).","A pressure sensitive adhesive layer is not a glue layer which would otherwise require some level of curing.","A pressure sensitive adhesive layer is also not a hot melt layer which otherwise requires heat for the adhesion to a workpiece.","A pressure sensitive adhesive layer, as defined herein, also does not require the addition of water to activate the adhesion to a workpiece.","Referring again to FIG.","2, in an embodiment, the permanent pressure sensitive adhesive layer 204 has a peel strength of greater than approximately 4.5 pounds per inch at 25 degrees Celsius.","The removable pressure sensitive adhesive layer 206 has a peel strength of less than approximately 4 pounds per inch at 25 degrees Celsius.","In a particular embodiment, the removable pressure sensitive adhesive layer 206 has a peel strength of less than approximately 2.5 pounds per inch at 25 degrees Celsius.","As used herein, peel strength is defined as strength at maximum adhesion of the pressure sensitive layer, where the test method use is defined in ASTM D3330.In an embodiment, the permanent pressure sensitive adhesive layer 204 or the removable pressure sensitive adhesive layer 206, or both, is a layer of material such as, but not limited to, an acrylic material, a rubber, ethylene vinyl acetate, a silicone material, or a block co-polymer.","The layer often incudes a tackifying resin in the formulation.","In an embodiment, the permanent pressure sensitive adhesive layer 204 or the removable pressure sensitive adhesive layer 206, or both, has a thickness of approximately 2 mils.","As mentioned briefly above, in an embodiment, the compressive subpad 202 is a compressive foam subpad.","In one such embodiment, the compressive foam subpad is post processed foam material (e.g., processed using a Corona treatment, as described in greater detail below) that provides improved thickness uniformity or improved surface energetics, or both.","In an embodiment, the compressive foam subpad is composed of a material such as, but not limited to, an ethylene vinyl acetate closed cell foam material, a polyethylene closed cell foam material, or a polyurethane mostly closed cell foam material.","In an embodiment, one or both of the surface of the compressive subpad (i.e., the surface that is coupled to a polishing pad or the surface for coupling to a platen) has a surface energy approximately in the range of 30-40 dyne/cm2 (as measured prior to any post processing such as a Corona treatment).","In an embodiment, the compressive subpad has a thickness approximately in the range of 10 mils to 40 mils.","FIGS.","3A and 3B are cross-sectional scanning electron microscope (SEM) images of exemplary compressive foam subpads, in accordance with an embodiment of the present invention.","Referring to SEM image 300A of FIG.","3A, a closed cell ethyl vinyl acetate (EVA) foam subpad is shown magnified at 100× magnification.","Referring to SEM image 300B of FIG.","3B, a closed cell polyethylene (PE) foam subpad is shown magnified at 100× magnification.","Referring again to FIGS.","3A and 3B, in an embodiment, the subpad foam layer is an EVA foam or polyethylene foam having low surface energy, typically 30-35 dyne/cm2.The surface energy is typically measured with an Accu Dyne pen that applies a simple solution using ASTM standard Test Method D 2578.The most common solution used includes ethyl cellosolve, formamide and a dye to make it easier to detect with the naked eye.","The variation in concentration of the ethyl cellosolve % vs. the formamide % results in different dyne level solutions with each pen.","Referring again to FIG.","2, the permanent pressure sensitive adhesive layer 204 is coated on the surface of the subpad 202 proximate to the polishing pad 200.The removable pressure sensitive adhesive layer 206 is coated on the surface of the subpad 202 distal to the polishing pad 200.Use of the term “coated” is used to distinguish embodiments of the present invention from situations where a PSA such as a PSA two-sided tape is laminated on the surface of a subpad for ultimate coupling of the subpad to a polishing pad or to a platen (depending on the side of the subpad having the PSA laminated thereon).","The term “coated” is also used to distinguish embodiments of the present invention from situations where a PSA such as a PSA two-sided tape is first laminated on the back surface of a polishing pad and subsequently used to adhere the polishing pad to the subpad through another lamination process.","By contrast, in accordance with embodiments described herein, an adhesive layer is coated on a surface of a subpad as a “wet” layer by a process such as, but not limited to, a dipping process, a rolling process, or a spreading process.","The coated layer is then dried to remove any carrier solvents used to apply the adhesive material on the surface of the subpad.","The dried layer coated on a subpad surface is the pressure sensitive adhesive layer (either permanent or removable, depending on which side of the subpad is referenced).","As an exemplary advantage of a coated adhesive layer as opposed to a laminated adhesive film on the surface of a subpad, embodiments of the present invention provide a pressure sensitive adhesive layer on the surface of a subpad where the surface area contact between the pressure sensitive adhesive layer and the surface of the subpad is greater than approximately 90%, and in some embodiments greater than approximately 95%.","FIG.","4A illustrates a cross-sectional view of a state of the art subpad having an adhesive film laminated thereon.","FIG.","4B illustrates a cross-sectional view of a subpad having a pressure sensitive adhesive layer coated thereon, in accordance with an embodiment of the present invention.","Referring to FIG.","4A, a conventional laminated adhesive sheet 400 may not have substantial surface area contact between the laminated sheet 400 and a topographical surface 402 of a closed cell sub pad 404.As shown in FIG.","4A, the laminated adhesive sheet 400 does not substantially fill surface voids/topography 402 of a surface of the subpad 404.It is to be appreciated that the same scenario may occur for the other (bottom) surface of the subpad 404.By contrast, in accordance with an embodiment of the present invention, referring to FIG.","4B, a coated pressure sensitive adhesion layer 450 substantially fills surface voids/topography 452 of a surface of a subpad 454.The result can be an ultimate increase in adhesion strength between the pressure sensitive adhesion layer 450 and the subpad 454.It is to be appreciated that the same scenario may occur for the other (bottom) surface of the subpad 454.In an exemplary embodiment, the surface 452 of the compressive subpad 454 has a surface roughness of at least 3 microns and has a total surface area.","The coated pressure sensitive adhesive layer 450 is in direct contact with at least 90% of the total surface area of the surface 452 of the compressive subpad 454.In some embodiment, the coated pressure sensitive adhesive layer 450 is in direct contact with greater than approximately 95% of the total surface area of the surface 452 of the compressive subpad 454.Referring again to FIG.","2, in an embodiment, the polishing pad 200 coupled to the subpad 202 is a homogeneous or single layer polishing pad, as is depicted in FIG.","2.In one such embodiment, the polishing pad 200 is composed of a thermoset polyurethane material, as described in greater detail below.","In another embodiment, however, the polishing pad 200 is a composite polishing pad.","In one such embodiment, the polishing pad 200 includes a polishing layer and a foundation layer that together define the polishing pad 200.As an example of the latter scenario, FIG.","5 illustrates a cross-sectional view of a polishing pad and subpad pairing where the polishing pad includes a polishing layer and a foundation layer, in accordance with an embodiment of the present invention.","Referring to FIG.","5, a polishing pad stack includes a polishing pad 500.The polishing pad includes a polishing layer 508 coupled to a foundation layer 502.As such, the back surface of the polishing pad 500 is a surface of the foundation layer 502.The front surface 504 of the foundation layer 502 is bonded to a surface polishing layer 508.In an embodiment, the polishing surface layer 508 includes a continuous layer portion 508A with a plurality of polishing features 508B protruding there from, as depicted in FIG.","5.It is the continuous layer portion 508A that is bonded with the foundation layer 502.In an embodiment, the foundation layer 502 is composed of a polycarbonate material, and the polishing surface layer 508 is a polyurethane material.","In a specific such embodiment, the polishing surface layer 508 is covalently bonded to the foundation layer 502.The term “covalently bonded” refers to arrangements where atoms from a first material (e.g., the material of a polishing surface layer) are cross-linked or share electrons with atoms from a second material (e.g., the material of a foundation layer) to effect actual chemical bonding.","Covalent bonding is distinguished from mechanical bonding, such as bonding through screws, nails, glues, or other adhesives.","In another specific embodiment, the polishing surface layer 508 is not covalently bonded, but is rather only electrostatically bonded (yet still directly bonded), to the foundation layer 502.Such electrostatic bonding may involve van der Waals type interactions between the foundation layer 502 and the polishing surface layer 508.Referring again to FIG.","5, the polishing pad stack includes subpad 550, which may be a compressive closed cell foam subpad.","A first (upper) surface of the subpad 550 has a first pressure sensitive adhesive layer 552 coated thereon.","The upper surface of the subpad 550 is coupled directly to the back surface of the foundation layer 502 of the polishing pad 500 by the first pressure sensitive adhesive layer 552.In an embodiment, a second pressure sensitive adhesive layer 554 is coated on a second (lower) surface of the compressive subpad 550.In one such embodiment, the first pressure sensitive adhesive layer 552 is a permanent pressure sensitive adhesive layer for strong adhesion to the polishing pad 500.The second pressure sensitive adhesive layer 554 is a removable pressure sensitive adhesive layer and is for removably coupling the polishing pad stack to a platen 556 of a chemical mechanical polishing apparatus.","Although depicted in FIG.","5 as already coupled to a platen, in an embodiment, the polishing pad stack of FIG.","5 may include a release liner on the second pressure sensitive adhesive layer 554.Such a release liner may be used for transport and storage of a polishing pad stack, and may be removed to expose the second pressure sensitive adhesive layer 554 prior to coupling the polishing pad stack to a platen.","As mentioned briefly above, polishing pad stacks including subpads such as those described herein may be fabricated using a reduced number of lamination processes than are otherwise used for state of the art pad stack fabrication.","As a comparative example, FIG.","6 illustrates a state of the art four step lamination pass pad/subpad fabrication process.","Referring to FIG.","6, a first lamination pass (Lamination Pass 1) involves lamination of a permanent PSA two-sided tape 602 on the back side of a polishing pad (top pad) 600.Excess of the permanent PSA two-sided tape is then trimmed off.","A second lamination pass (Lamination Pass 2) involves lamination of a subpad foam material 604 onto the permanent PSA two-sided tape 602 on the back up the polishing pad 600.Excess of the foam material is then trimmed off.","A third lamination pass (Lamination Pass 3) involves lamination of a second permanent PSA two-sided tape 606 onto the subpad foam material 604.Excess of the second permanent PSA two-sided tape is then trimmed off.","A fourth lamination pass (Lamination Pass 4) involves lamination of a removable PSA two-sided tape 608 onto the second permanent PSA two-sided tape 606.Excess of the removable PSA two-sided tape is then trimmed off.","A laminator 650 may be used where the polishing pad 652 is laminated with a roll 654 of the permanent PSA two-sided tape 602, the subpad foam material 604, the second permanent PSA two-sided tape 606 or the removable PSA two-sided tape 608, depending on which lamination pass is being performed.","The resulting pad stack may be one such as described in association with FIG.","1.In contrast to the above described multi-lamination process, FIG.","7 illustrates a subpad fabrication process involving coating of pressure sensitive adhesive layers onto the subpad material, in accordance with an embodiment of the present invention.","Referring to FIG.","7, a subpad foam material 702 is used as a carrier film for a coating process.","The subpad foam material 702 is fed into application rollers 704 and 706 which apply a first pressure sensitive adhesive material 708 onto a first side 710 of the subpad foam material 702.A spreader bar or Meyer bar 712 is used to remove excess of and to evenly distribute the first pressure sensitive adhesive material 708 on the first side 710 of the subpad foam material 702.Referring again to FIG.","7, the subpad foam material 702 is then fed into application rollers 724 and 726 which apply a second pressure sensitive adhesive material 728 onto a second side 730 of the subpad foam material 702.A spreader bar or Meyer bar 732 is used to remove excess of and to evenly distribute the second pressure sensitive adhesive material 728 on the second side 730 of the subpad foam material 702.Referring again to FIG.","7, the doubly coated subpad foam material 702 is then directed to a dryer 740.The drying provides a foam material 702 having a first surface 710 with a first pressure sensitive adhesive layer 746 coated thereon, and having a second surface 730 with a second pressure sensitive adhesive layer 748 coated thereon.","Once transported through the dryer 740, further processing of the foam material 702 having the first 746 and second 748 pressure sensitive adhesive layers thereon may be performed, as described in greater detail below.","Referring generally to FIG.","7, in an embodiment, a method of fabricating a polishing pad stack for polishing a substrate involves coating a first pressure sensitive adhesive layer 708 on a first surface 710 of a compressive subpad material 702.The method also involves coating a second pressure sensitive adhesive layer 728 on a second, opposite, surface 730 of the compressive subpad material 702.In an embodiment, the first pressure sensitive adhesive layer 708 is a permanent pressure sensitive adhesive layer, and the second pressure sensitive adhesive layer 728 is a removable pressure sensitive adhesive layer.","In another embodiment, the first pressure sensitive adhesive layer 708 is a removable pressure sensitive adhesive layer, and the second pressure sensitive adhesive layer 728 is a permanent pressure sensitive adhesive layer.","In either case, in an embodiment, for the removable pressure sensitive adhesive layer, a primer is applied to the associated side of the subpad material for increasing the adhesion of the removable pressure sensitive adhesive layer to the subpad material but retaining removability for the platen side of the removable pressure sensitive adhesive layer.","In an embodiment, coating of either the first or second pressure sensitive adhesive layer involves dispensing and then spreading a solvent-based adhesive formulation on a surface of the compressive subpad material.","In one such embodiment, subsequent to dispensing and then spreading a first solvent-based adhesive formulation on a first surface of the compressive subpad material and dispensing and then spreading a second solvent-based adhesive formulation on a second surface of the compressive subpad material, the first and second solvent-based adhesive formulations are dried (e.g., through dryer 740) to remove substantially all solvent from the first and second solvent-based adhesive formulations.","In an embodiment, a pressure sensitive adhesive layer is applied as a solvent-based adhesive formulation on a surface of the compressive subpad material at a temperature less than approximately 50 degrees Celsius.","Subsequently, the solvent-based adhesive formulation is dried in an air dryer at a temperature less than approximately 50 degrees Celsius.","Thus, referring generally to FIG.","7, providing PSA layers on a subpad material involves coating an adhesive/solvent solution onto the subpad material which acts a carrier film or a support layer in the fabrication process.","The viscosity of the adhesive formulation determines the coating method.","The adhesive formulation can be applied as an adhesive material carried in a solvent.","An exemplary coating method is a Meyer Rod Coating approach.","FIG.","8 illustrates coating of a pressure sensitive adhesive layer onto a subpad material using a Meyer bar, in accordance with an embodiment of the present invention.","Referring to FIG.","8, an applicator roll 802 delivers an adhesive formulation 804 to the surface of a subpad material 806 being coated.","In an embodiment, the adhesive formulation 804 is applied at a temperature less than approximately 50 degrees Celsius and, preferably less than approximately 40 degrees Celsius, and most preferably at room temperature or approximately 20-25 degrees Celsius.","In an embodiment, the temperature of the adhesive formulation 804 at the time of application is less than approximately 50 degrees Celsius and, preferably less than approximately 40 degrees Celsius, and most preferably at room temperature or approximately 20-25 degrees Celsius.","The applicator roll 802 delivers an excess of material 804.The excess is removed by a Meyer rod or bar 808 (an expanded view of which is depicted in box 810 of FIG.","8, which shows the rod wrapped with wire).","The amount of adhesive removed depends on the wire wrapping.","There may be multiple rods in series to produce smooth accurate coating thicknesses with tolerance at +/−0.001 inch.","The coated subpad material film is then directed 812 to an air dryer for solvent evaporation.","In an embodiment, the subpad having the adhesive coated thereon enters the dryer approximately 2-4 minutes after the adhesive is coated on the subpad.","In an embodiment, the subpad is dried in the air dryer for approximately 20 minutes.","Referring again to FIG.","7, a release liner 790 is then applied to one of the coated adhesive layers at the end of the coating process.","In one embodiment, the release liner 790 is added to the removable pressure sensitive adhesive layer after the removable pressure sensitive adhesive layer has been coated on the subpad material.","In other embodiments, however, the removable pressure sensitive adhesive layer is coated on the subpad material by first applying the removable pressure sensitive adhesive material to the release liner and then delivering the removable pressure sensitive adhesive material to the subpad material.","In either case, such a release liner may be removed prior to coupling the removable pressure sensitive adhesive layer to a platen.","In an embodiment, although not depicted, a second release liner is added to the permanent pressure sensitive adhesive layer.","Such a second release liner may be included for transporting or storage of a coated subpad, but removed prior to adhering the coated subpad to a polishing pad via the permanent pressure sensitive adhesive layer of the coated subpad.","In other embodiments, however, a roll of the subpad material is formed without a release liner being included on the side of the subpad material having the permanent pressure sensitive adhesive layer thereon.","Whether or not the second release liner is included, a polishing pad may be adhered to the coated permanent pressure sensitive adhesive layer of the subpad material by a lamination process (thus leaving a single lamination process in place of the four described in association with FIG.","6).","The subpad material may then be cut around the shape of the polishing pad material.","As described herein, a release liner is a paper or plastic based carrier web material, which has a release agent on one or both sides of the release liner.","The release agent provides a release effect against any type of a sticky material such as an adhesive.","Release of the release liner involves separation of the release liner from the pressure sensitive adhesive layer.","With reference again to the process of FIG.","7, in an embodiment, the foam material (such as EVA or PE foam material) of the subpad is post processed prior to adhesive coating to achieve a tight gage tolerance of +/−1 mil throughout the web.","Typically, the material is buffed on one or both sides.","Such foams can vary in thickness from 15 mils up to 60 mils and may be produced in a wide range of densities ranging from a few pounds up to 60 pound foam.","Typical gage tolerance is +/10% of the total thickness, which can be as much as +/−6 mils or a total of 12 mils throughout the web.","It is to be appreciated that, as the semiconductor market technologies become more and more demanding to reduce line width, the consumable set used to manufacture these technologies must also meet tighter material property tolerances.","Post processing of a foam and subsequent direct adhesive coating can, in an embodiment, reduce the thickness tolerance and provide improved adhesive anchorage.","Such factors in turn affect the foam compressibility of the subpad material.","Compressibility is defined as (thickness under a load minus initial thickness)/initial thickness.","In some embodiment, the desired compressibility is low, e.g., typically less than 10%.","As described briefly in association with FIG.","7, a corona 792A and 792B or like treatment may be applied to one or both sides of a subpad material prior to adhesive layer coating.","It is to be appreciated that surface energy properties are an important consideration with industrial coatings.","The surface energy dictates if an applied coating will be accepted by the surface; this is known as wetting.","The definition of wetting is the ability of a liquid to maintain contact with a solid surface, resulting from intermolecular interactions when the two are brought together.","The degree of wetting (wettability) is determined by a force balance between adhesive and cohesive forces.","For adhesive coatings, the surface tension of the adhesive must be lower than the surface energy of the surface to which they are applied.","In the case of a material such as an EVA foam, the surface energy of the substrate must be raised to ensure sufficient wet out of the applied liquid (pressure sensitive adhesive coating).","There are number of methods for such surface treatment such as, but not limited to corona discharge, flame treatment, or plasma treatment.","Such treatments may be implemented to increase the surface energy of an EVA or PE foam from 30 dyne/cm up to, e.g., 40-42 dynes/cm.","In one such embodiment, a corona discharge treatment is applied to a compressive foam subpad material just prior to the adhesive coating process, as is shown in FIG.","7.FIG.","9 illustrates an apparatus for performing a Corona discharge treatment of a compressive foam subpad surface prior to coating an adhesive layer thereon, in accordance with an embodiment of the present invention.","Referring to FIG.","9, a subpad material layer 902 (e.g., compressive foam material layer) is rolled on a tamper roll 904 having a dielectric 906 thereon.","The arrangement provides an electrode 908 above the subpad material layer 902 with an air gap 910 between the electrode 908 and the subpad material layer 902.A corona generator power supply 912 is coupled to the electrode 908.The corona treatment is a surface modification technique that uses a low temperature corona discharge plasma to impart changes in the properties of a surface of the subpad material layer 902.In an embodiment, referring again to FIGS.","2 and 5, the polishing pad 200 or the polishing surface layer 508 is a homogeneous polishing pad or polishing surface layer.","In one such embodiment, the homogeneous polishing pad or polishing surface layer is composed of a thermoset polyurethane material.","For example, in a specific embodiment, the homogeneous polishing pad or polishing surface layer is composed of a thermoset, closed cell polyurethane material.","In an embodiment, the term “homogeneous” is used to indicate that the composition of a thermoset, closed cell polyurethane material is consistent throughout the entire composition of the body.","For example, in an embodiment, the term “homogeneous” excludes polishing pad bodies composed of, e.g., impregnated felt or a composition (composite) of multiple layers of differing material.","In an embodiment, the term “thermoset” is used to indicate a polymer material that irreversibly cures, e.g., the precursor to the material changes irreversibly into an infusible, insoluble polymer network by curing.","For example, in an embodiment, the term “thermoset” excludes polishing pads composed of, e.g., “thermoplast” materials or “thermoplastics”—those materials composed of a polymer that turns to a liquid when heated and returns to a very glassy state when cooled sufficiently.","It is noted that polishing pads made from thermoset materials are typically fabricated from lower molecular weight precursors reacting to form a polymer in a chemical reaction, while pads made from thermoplastic materials are typically fabricated by heating a pre-existing polymer to cause a phase change so that a polishing pad is formed in a physical process.","Polyurethane thermoset polymers may be selected for fabricating polishing pads described herein based on their stable thermal and mechanical properties, resistance to the chemical environment, and tendency for wear resistance.","The materials of polishing pad 200 or polishing surface layer 508 may be molded.","The term “molded” may be used to indicate that the polishing surface layer is formed in a formation mold.","In an embodiment, the molded polishing pad 200 or polishing surface layer 508, upon conditioning and/or polishing, has a polishing surface roughness approximately in the range of 1-5 microns root mean square.","In one embodiment, the molded polishing pad 200 or polishing surface layer 508, upon conditioning and/or polishing, has a polishing surface roughness of approximately 2.35 microns root mean square.","In an embodiment, the molded polishing pad 200 or polishing surface layer 508 has a storage modulus at 25 degrees Celsius approximately in the range of 30-500 megaPascals (MPa).","In another embodiment, the molded polishing pad 200 or polishing surface layer 508 has a storage modulus at 25 degrees Celsius approximately less than 30 megaPascals (MPa).","The materials of polishing pad 200 or polishing surface layer 508 may include pore-forming features.","In an embodiment, the polishing surface layer 108 or 208 has a pore density of closed cell pores approximately in the range of 6%-50% total void volume.","In one embodiment, the plurality of closed cell pores is a plurality of porogens.","For example, the term “porogen” may be used to indicate micro- or nano-scale spherical or somewhat spherical particles with “hollow” centers.","The hollow centers are not filled with solid material, but may rather include a gaseous or liquid core.","In one embodiment, the plurality of closed cell pores is composed of pre-expanded and gas-filled EXPANCEL™ distributed throughout (e.g., as an additional component in) a polishing surface layer of a polishing pad.","In a specific embodiment, the EXPANCEL™ is filled with pentane.","In an embodiment, each of the plurality of closed cell pores has a diameter approximately in the range of 10-100 microns.","In an embodiment, the plurality of closed cell pores includes pores that are discrete from one another.","This is in contrast to open cell pores which may be connected to one another through tunnels, such as the case for the pores in a common sponge.","In one embodiment, each of the closed cell pores includes a physical shell, such as a shell of a porogen, as described above.","In another embodiment, however, each of the closed cell pores does not include a physical shell.","In an embodiment, the plurality of closed cell pores is distributed essentially evenly throughout a thermoset polyurethane material of a homogeneous polishing pad or polishing surface layer.","In an embodiment, polishing pad 200 or polishing surface layer 508 is opaque.","In one embodiment, the term “opaque” is used to indicate a material that allows approximately 10% or less visible light to pass.","In one embodiment, the polishing pad 200 or polishing surface layer 508 is opaque in most part, or due entirely to, the inclusion of an opacifying particle filler, such as a lubricant, throughout (e.g., as an additional component in) the polishing pad 200 or polishing surface layer 508.In a specific embodiment, the opacifying particle filler is a material such as, but not limited to boron nitride, cerium fluoride, graphite, graphite fluoride, molybdenum sulfide, niobium sulfide, talc, tantalum sulfide, tungsten disulfide, or Teflon®.","In another aspect, the polishing pad 200 or polishing surface layer 508 may have a pattern suitable for polishing during a CMP operation.","In a first general example, some embodiments of the present invention include a plurality of protrusions having a pattern of linear features.","In a second general example, some embodiments of the present invention include a plurality of protrusions having a pattern of discrete curved features.","In a specific such example, discrete arc-shaped protrusions are included.","Other specific such embodiments include, but are not limited to, a plurality of partial circumferential protrusions disposed on a substantially circular polishing pad.","In a third general example, some embodiments of the present invention include a plurality of protrusions having a pattern of discrete tiles.","In a specific such embodiment, discrete hexagonal tile protrusions are included.","Other specific such embodiments include, but are not limited to, pluralities of circular tiles, oval tiles, square tiles, rectangular tiles, or a combination thereof.","Although the above three general examples are defined in terms of protrusions (e.g., the highest points of a patterned polishing surface layer), the polishing surface layers may also or alternatively be defined in terms of grooves (e.g., the lowest points of a patterned polishing surface layer).","Individual grooves may be from about 4 to about 100 mils deep at any given point on each groove.","In some embodiments, the grooves are about 10 to about 50 mils deep at any given point on each groove.","The grooves may be of uniform depth, variable depth, or any combinations thereof.","In some embodiments, the grooves are all of uniform depth.","For example, the grooves of a groove pattern may all have the same depth.","In some embodiments, some of the grooves of a groove pattern may have a certain uniform depth while other grooves of the same pattern may have a different uniform depth.","For example, groove depth may increase with increasing distance from the center of the polishing pad.","In some embodiments, however, groove depth decreases with increasing distance from the center of the polishing pad.","In some embodiments, grooves of uniform depth alternate with grooves of variable depth.","Individual grooves may be from about 2 to about 100 mils wide at any given point on each groove.","In some embodiments, the grooves are about 15 to about 50 mils wide at any given point on each groove.","The grooves may be of uniform width, variable width, or any combinations thereof.","In some embodiments, the grooves of a groove pattern are all of uniform width.","In some embodiments, however, some of the grooves of a groove pattern have a certain uniform width, while other grooves of the same pattern have a different uniform width.","In some embodiments, groove width increases with increasing distance from the center of the polishing pad.","In some embodiments, groove width decreases with increasing distance from the center of the polishing pad.","In some embodiments, grooves of uniform width alternate with grooves of variable width.","In accordance with the previously described depth and width dimensions, individual grooves may be of uniform volume, variable volume, or any combinations thereof.","In some embodiments, the grooves are all of uniform volume.","In some embodiments, however, groove volume increases with increasing distance from the center of the polishing pad.","In some other embodiments, groove volume decreases with increasing distance from the center of the polishing pad.","In some embodiments, grooves of uniform volume alternate with grooves of variable volume.","Grooves of the groove patterns described herein may have a pitch from about 30 to about 1000 mils.","In some embodiments, the grooves have a pitch of about 125 mils.","For a circular polishing pad, groove pitch is measured along the radius of the circular polishing pad.","The grooves may be of uniform pitch, variable pitch, or in any combinations thereof.","In some embodiments, the grooves are all of uniform pitch.","In some embodiments, however, groove pitch increases with increasing distance from the center of the polishing pad.","In some other embodiments, groove pitch decreases with increasing distance from the center of the polishing pad.","In some embodiments, the pitch of the grooves in one sector varies with increasing distance from the center of the polishing pad while the pitch of the grooves in an adjacent sector remains uniform.","In some embodiments, the pitch of the grooves in one sector increases with increasing distance from the center of the polishing pad while the pitch of the grooves in an adjacent sector increases at a different rate.","In some embodiments, the pitch of the grooves in one sector increases with increasing distance from the center of the polishing pad while the pitch of the grooves in an adjacent sector decreases with increasing distance from the center of the polishing pad.","In some embodiments, grooves of uniform pitch alternate with grooves of variable pitch.","In some embodiments, sectors of grooves of uniform pitch alternate with sectors of grooves of variable pitch.","In an embodiment, polishing pad stacks described herein, such as the polishing pad stacks of FIGS.","2 and 5, are suitable for polishing substrates.","The substrate may be one used in the semiconductor manufacturing industry, such as a silicon substrate having device or other layers disposed thereon.","However, the substrate may be one such as, but not limited to, a substrates for MEMS devices, reticles, or solar modules.","Thus, reference to “a polishing pad for polishing a substrate,” as used herein, is intended to encompass these and related possibilities.","In an embodiment, a polishing pad stack has a diameter approximately in the range of 20 inches to 30.3 inches, e.g., approximately in the range of 50-77 centimeters, and possibly approximately in the range of 10 inches to 42 inches, e.g., approximately in the range of 25-107 centimeters.","Subpads described herein may be included with a polishing pad, as described above.","Such a combined polishing pad/subpad polishing pad stack may be suitable for use with a variety of chemical mechanical polishing apparatuses.","As an example, FIG.","10 illustrates an isometric side-on view of a polishing apparatus compatible with a polishing pad/subpad polishing pad stack, in accordance with an embodiment of the present invention.","Referring to FIG.","10, a polishing apparatus 1000 includes a platen 1004.The top surface 1002 of platen 1004 may be used to support a polishing pad/subpad polishing pad stack 1099.Platen 1004 may be configured to provide spindle rotation 1006.A sample carrier 1010 is used to hold, e.g., a semiconductor wafer 1011 in place during polishing of the semiconductor wafer with the polishing pad/subpad polishing pad stack 1099 and to provide slider oscillation 1008.Sample carrier 1010 is further supported by a suspension mechanism 1012.A slurry feed 1014 is included for providing slurry to a surface of the polishing pad/subpad polishing pad stack 1099 prior to and during polishing of the semiconductor wafer.","A conditioning unit 1090 may also be included and, in one embodiment, includes a diamond tip for conditioning the polishing pad of the polishing pad/subpad polishing pad stack 1099 combination.","In an embodiment, a relatively weaker adhesive coated adhesive layer on the subpad is used to mount the polishing pad/subpad polishing pad stack 1099 on the platen 1004.In an embodiment, a relatively stronger adhesive coated adhesive layer secures the subpad to the polishing pad.","Thus, coated compressive subpads for polishing pad stacks and methods of fabricating coated compressive subpads for polishing pad stacks have been disclosed."]],"string":"[\n [\n \"COATED COMPRESSIVE SUBPAD FOR CHEMICAL MECHANICAL POLISHING\",\n \"Coated compressive subpads for polishing pad stacks and methods of fabricating coated compressive subpads for polishing pad stacks are described.\",\n \"In an example, a polishing pad stack for polishing a substrate includes a polishing pad having a polishing surface and a back surface.\",\n \"The polishing pad stack also includes a compressive subpad with a first surface having a first pressure sensitive adhesive layer coated thereon.\",\n \"The first surface of the compressive subpad is coupled directly to the back surface of the polishing pad by the first pressure sensitive adhesive layer.\"\n ],\n [\n \"1.A method of fabricating a polishing pad stack for polishing a substrate, the method comprising: coating a first pressure sensitive adhesive layer on a first surface of a compressive subpad material; coating a second pressure sensitive adhesive layer on a second, opposite, surface of the compressive subpad material; and adhering the first surface of the compressive subpad material directly to a back surface of a polishing pad by the first pressure sensitive adhesive layer.\",\n \"2.The method of claim 1, coating the first pressure sensitive adhesive layer comprises coating a permanent pressure sensitive adhesive layer, and wherein coating the second pressure sensitive adhesive layer comprises coating a removable pressure sensitive adhesive layer.\",\n \"3.The method of claim 1, wherein coating the first pressure sensitive adhesive layer comprises dispensing and then spreading a first solvent-based adhesive formulation on the first surface of the compressive subpad material, and wherein coating the second pressure sensitive adhesive layer comprises dispensing and then spreading a second solvent-based adhesive formulation on the second surface of the compressive subpad material.\",\n \"4.The method of claim 3, wherein dispensing and then spreading the first solvent-based adhesive formulation on the first surface of the compressive subpad material is performed prior to dispensing and then spreading the second solvent-based adhesive formulation on the second surface of the compressive subpad material.\",\n \"5.The method of claim 3, wherein dispensing and then spreading the first solvent-based adhesive formulation on the first surface of the compressive subpad material is performed subsequent to dispensing and then spreading the second solvent-based adhesive formulation on the second surface of the compressive subpad material.\",\n \"6.The method of claim 3, the method further comprising: subsequent to dispensing and then spreading the first solvent-based adhesive formulation on the first surface of the compressive subpad material and dispensing and then spreading the second solvent-based adhesive formulation on the second surface of the compressive subpad material, drying the first and second solvent-based adhesive formulations to remove substantially all solvent from the first and second solvent-based adhesive formulations.\",\n \"7.The method of claim 3, wherein the compressive subpad is a compressive foam subpad, the method further comprising: prior to coating the first and second pressure sensitive adhesive layers, treating at least one of the first or second surfaces of the compressive foam subpad material with a process selected from the group consisting of a corona discharge treatment, a plasma treatment, and a flame treatment.\",\n \"8.The method of claim 1, wherein coating the first pressure sensitive adhesive layer comprises applying a first solvent-based adhesive formulation on the first surface of the compressive subpad material at a temperature less than approximately 50 degrees Celsius and, subsequently, drying the first solvent-based adhesive formulation in an air dryer at a temperature less than approximately 50 degrees Celsius.\",\n \"9.The method of claim 1, further comprising: applying a release liner to the second pressure sensitive adhesive layer.\",\n \"10.The method of claim 1, wherein coating the second pressure sensitive adhesive layer on the second, opposite, surface of the compressive subpad material comprises applying the second pressure sensitive adhesive layer to a release liner and then applying the second pressure sensitive adhesive layer to the second, opposite, surface of the compressive subpad by the release liner.\",\n \"11.The method of claim 1, wherein adhering the first surface of the compressive subpad material directly to the back surface of the polishing pad comprises adhering the first surface of the compressive subpad material directly to the back surface of a thermoset polyurethane polishing pad.\",\n \"12.A subpad for a polishing pad stack, the subpad comprising: a compressive subpad material having a first surface and a second, opposite, surface; a first pressure sensitive adhesive layer coated on the first surface of the compressive subpad material, and a first release liner disposed on the first pressure sensitive adhesive layer; and a second pressure sensitive adhesive layer coated on the second surface of the compressive subpad material.\",\n \"13.The subpad of claim 12, further comprising: a second release liner disposed on the second pressure sensitive adhesive layer.\",\n \"14.The subpad of claim 12, wherein the first pressure sensitive adhesive layer is a removable pressure sensitive adhesive layer, and wherein the second pressure sensitive adhesive layer is a permanent pressure sensitive adhesive layer.\",\n \"15.The subpad of claim 14, wherein the permanent pressure sensitive adhesive layer is for coupling to a back surface of a polishing pad, and wherein the removable pressure sensitive adhesive layer is for coupling the subpad to a platen of a chemical mechanical polishing apparatus.\",\n \"16.The subpad of claim 12, wherein the second pressure sensitive adhesive layer has a peel strength of greater than approximately 4.5 pounds per inch at 25 degrees Celsius, and wherein the first pressure sensitive adhesive layer has a peel strength of less than approximately 4 pounds per inch at 25 degrees Celsius.\",\n \"17.The subpad of claim 12, wherein the compressive subpad material is a compressive foam subpad material comprising a material selected from the group consisting of an ethylene vinyl acetate closed cell foam material, a polyethylene closed cell foam material, and a polyurethane mostly closed cell foam material.\",\n \"18.The subpad of claim 12, the compressive subpad material is a compressive foam subpad material, and wherein the first and second surfaces of the compressive foam subpad material each have a surface energy approximately in the range of 30-40 dyne/cm2.19.The subpad of claim 9, wherein the compressive subpad material has a thickness approximately in the range of 10 mils to 40 mils.\",\n \"20.The subpad of claim 12, wherein the second pressure sensitive adhesive layer comprises a first material selected from the group consisting of an acrylic material, a rubber, ethylene vinyl acetate, a silicone material, and a block co-polymer, and wherein the first pressure sensitive adhesive layer comprises a second material selected from the group consisting of an acrylic material, a rubber, ethylene vinyl acetate, a silicone material, and a block co-polymer.\",\n \"21.The subpad of claim 12, wherein the first surface of the compressive subpad material has a surface roughness of at least 3 microns and has a total surface area, and the first pressure sensitive adhesive layer is in direct contact with at least 90% of the total surface area of the first surface of the compressive subpad material.\",\n \"22.The subpad of claim 21, wherein the second surface of the compressive subpad material has a surface roughness of at least 3 microns and has a total surface area, and the second pressure sensitive adhesive layer is in direct contact with at least 90% of the total surface area of the second surface of the compressive subpad material.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>Chemical-mechanical planarization or chemical-mechanical polishing, commonly abbreviated CMP, is a technique used in semiconductor fabrication for planarizing a semiconductor wafer or other substrate.\",\n \"The process uses an abrasive and/or corrosive chemical slurry (commonly a colloid) in conjunction with a polishing pad and retaining ring, typically of a greater diameter than the wafer.\",\n \"The polishing pad and wafer are pressed together by a dynamic polishing head and held in place by a plastic retaining ring.\",\n \"The dynamic polishing head is rotated during polishing.\",\n \"This approach aids in removal of material and tends to even out any irregular topography, making the wafer flat or planar.\",\n \"This may be necessary in order to set up the wafer for the formation of additional circuit elements.\",\n \"For example, this might be necessary in order to bring the entire surface within the depth of field of a photolithography system, or to selectively remove material based on its position.\",\n \"Typical depth-of-field requirements are down to Angstrom levels for the latest sub-50 nanometer technology nodes.\",\n \"The process of material removal is not simply that of abrasive scraping, like sandpaper on wood.\",\n \"The chemicals in the slurry also react with and/or weaken the material to be removed.\",\n \"The abrasive accelerates this weakening process and the polishing pad helps to wipe the reacted materials from the surface.\",\n \"In addition to advances in slurry technology, the polishing pad plays a significant role in increasingly complex CMP operations.\",\n \"However, additional improvements are needed in the evolution of CMP pad technology.\"\n ],\n [\n \"<SOH> SUMMARY <EOH>Embodiments of the present invention include coated compressive subpads for polishing pad stacks and methods of fabricating coated compressive subpads for polishing pad stacks.\",\n \"In an embodiment, a polishing pad stack for polishing a substrate includes a polishing pad having a polishing surface and a back surface.\",\n \"The polishing pad stack also includes a compressive subpad with a first surface having a first pressure sensitive adhesive layer coated thereon.\",\n \"The first surface of the compressive subpad is coupled directly to the back surface of the polishing pad by the first pressure sensitive adhesive layer.\",\n \"In another embodiment, a method of fabricating a polishing pad stack for polishing a substrate involves coating a first pressure sensitive adhesive layer on a first surface of a compressive subpad material.\",\n \"The method also involves coating a second pressure sensitive adhesive layer on a second, opposite, surface of the compressive subpad material.\",\n \"The method also involves adhering the first surface of the compressive subpad material directly to a back surface of a polishing pad by the first pressure sensitive adhesive layer.\",\n \"In another embodiment, a subpad for a polishing pad stack includes a compressive subpad material having a first surface and a second, opposite, surface.\",\n \"A first pressure sensitive adhesive layer is coated on the first surface of the compressive subpad material.\",\n \"A first release liner is disposed on the first pressure sensitive adhesive layer.\",\n \"A second pressure sensitive adhesive layer is coated on the second surface of the compressive subpad material.\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATIONS This application is a divisional of co-pending application Ser.\",\n \"No.\",\n \"14/635,973, filed on Mar.\",\n \"2, 2015, which claims the benefit of U.S.\",\n \"Provisional Application No.\",\n \"62/083,101, filed on Nov. 21, 2014, the entire contents of which are hereby incorporated by reference herein.\",\n \"TECHNICAL FIELD Embodiments of the present invention are in the field of chemical mechanical polishing (CMP) and, in particular, coated compressive subpads for polishing pad stacks and methods of fabricating coated compressive subpads for polishing pad stacks.\",\n \"BACKGROUND Chemical-mechanical planarization or chemical-mechanical polishing, commonly abbreviated CMP, is a technique used in semiconductor fabrication for planarizing a semiconductor wafer or other substrate.\",\n \"The process uses an abrasive and/or corrosive chemical slurry (commonly a colloid) in conjunction with a polishing pad and retaining ring, typically of a greater diameter than the wafer.\",\n \"The polishing pad and wafer are pressed together by a dynamic polishing head and held in place by a plastic retaining ring.\",\n \"The dynamic polishing head is rotated during polishing.\",\n \"This approach aids in removal of material and tends to even out any irregular topography, making the wafer flat or planar.\",\n \"This may be necessary in order to set up the wafer for the formation of additional circuit elements.\",\n \"For example, this might be necessary in order to bring the entire surface within the depth of field of a photolithography system, or to selectively remove material based on its position.\",\n \"Typical depth-of-field requirements are down to Angstrom levels for the latest sub-50 nanometer technology nodes.\",\n \"The process of material removal is not simply that of abrasive scraping, like sandpaper on wood.\",\n \"The chemicals in the slurry also react with and/or weaken the material to be removed.\",\n \"The abrasive accelerates this weakening process and the polishing pad helps to wipe the reacted materials from the surface.\",\n \"In addition to advances in slurry technology, the polishing pad plays a significant role in increasingly complex CMP operations.\",\n \"However, additional improvements are needed in the evolution of CMP pad technology.\",\n \"SUMMARY Embodiments of the present invention include coated compressive subpads for polishing pad stacks and methods of fabricating coated compressive subpads for polishing pad stacks.\",\n \"In an embodiment, a polishing pad stack for polishing a substrate includes a polishing pad having a polishing surface and a back surface.\",\n \"The polishing pad stack also includes a compressive subpad with a first surface having a first pressure sensitive adhesive layer coated thereon.\",\n \"The first surface of the compressive subpad is coupled directly to the back surface of the polishing pad by the first pressure sensitive adhesive layer.\",\n \"In another embodiment, a method of fabricating a polishing pad stack for polishing a substrate involves coating a first pressure sensitive adhesive layer on a first surface of a compressive subpad material.\",\n \"The method also involves coating a second pressure sensitive adhesive layer on a second, opposite, surface of the compressive subpad material.\",\n \"The method also involves adhering the first surface of the compressive subpad material directly to a back surface of a polishing pad by the first pressure sensitive adhesive layer.\",\n \"In another embodiment, a subpad for a polishing pad stack includes a compressive subpad material having a first surface and a second, opposite, surface.\",\n \"A first pressure sensitive adhesive layer is coated on the first surface of the compressive subpad material.\",\n \"A first release liner is disposed on the first pressure sensitive adhesive layer.\",\n \"A second pressure sensitive adhesive layer is coated on the second surface of the compressive subpad material.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS FIG.\",\n \"1 illustrates a cross-sectional view of a state of the art polishing pad and subpad pairing.\",\n \"FIG.\",\n \"2 illustrates a cross-sectional view of a polishing pad and subpad pairing, in accordance with an embodiment of the present invention.\",\n \"FIG.\",\n \"3A is cross-sectional scanning electron microscope (SEM) image of an exemplary compressive foam subpad, in accordance with an embodiment of the present invention.\",\n \"FIG.\",\n \"3B is cross-sectional scanning electron microscope (SEM) image of another exemplary compressive foam subpad, in accordance with another embodiment of the present invention.\",\n \"FIG.\",\n \"4A illustrates a cross-sectional view of a state of the art subpad having an adhesive film laminated thereon.\",\n \"FIG.\",\n \"4B illustrates a cross-sectional view of a subpad having a pressure sensitive adhesive layer coated thereon, in accordance with an embodiment of the present invention.\",\n \"FIG.\",\n \"5 illustrates a cross-sectional view of a polishing pad and subpad pairing where the polishing pad includes a polishing layer and a foundation layer, in accordance with an embodiment of the present invention.\",\n \"FIG.\",\n \"6 illustrates a state of the art four step lamination pass pad/subpad fabrication process.\",\n \"FIG.\",\n \"7 illustrates a subpad fabrication process involving coating of pressure sensitive adhesive layers onto the subpad material, in accordance with an embodiment of the present invention.\",\n \"FIG.\",\n \"8 illustrates coating of a pressure sensitive adhesive layer onto a subpad material using a Meyer bar, in accordance with an embodiment of the present invention.\",\n \"FIG.\",\n \"9 illustrates an apparatus for performing a Corona discharge treatment of a compressive foam subpad surface prior to coating an adhesive layer thereon, in accordance with an embodiment of the present invention.\",\n \"FIG.\",\n \"10 illustrates an isometric side-on view of a polishing apparatus compatible with a polishing pad/subpad polishing pad stack, in accordance with an embodiment of the present invention.\",\n \"DETAILED DESCRIPTION Coated compressive subpads for polishing pad stacks and methods of fabricating coated compressive subpads for polishing pad stacks are described herein.\",\n \"In the following description, numerous specific details are set forth, such as specific polishing pad and subpad compositions and designs, in order to provide a thorough understanding of embodiments of the present invention.\",\n \"It will be apparent to one skilled in the art that embodiments of the present invention may be practiced without these specific details.\",\n \"In other instances, well-known processing techniques, such as details concerning the combination of a slurry with a polishing pad to perform CMP of a semiconductor substrate, are not described in detail in order to not unnecessarily obscure embodiments of the present invention.\",\n \"Furthermore, it is to be understood that the various embodiments shown in the figures are illustrative representations and are not necessarily drawn to scale.\",\n \"Polishing pads for CMP operations may have trade-offs in performance such as a trade-off between across-wafer polishing uniformity versus within die polishing uniformity.\",\n \"For example, hard polishing pads may exhibit good die-level planarization, but poor across-wafer uniformity.\",\n \"A compressible subpad can be included with a polishing pad or layer to improve the global non-uniformity performance of the overlying polishing pad or layer.\",\n \"In accordance with one or more embodiments herein, double coated subpads are described, such as double coated foam subpads.\",\n \"For example, an adhesive coated foam can be used as a foundation (subpad) layer for CMP polishing pads.\",\n \"The adhesive coated foam may be made using one or combination of the following features: (1) the adhesive may be directly coated onto one surface of the subpad material, (2) the adhesive can be directly coated onto both surfaces of the subpad material, (3) one adhesive can be a removable adhesive to enable application of a subpad/polishing layer pairing to a platen, and/or (4) one adhesive can be a permanent adhesive to promote strong bonding of the subpad to the back side of the polishing pad or layer.\",\n \"To provide context, state of the art for subpad coupling to a polishing pad or layer involves use of a two-sided tape (such as a pressure sensitive adhesive, PSA, two-sided tape) to bond the subpad to the polishing pad.\",\n \"A second two-sided tape is laminated to the side of the subpad that will ultimately be coupled to a platen of a CMP apparatus.\",\n \"For example, fabrication of a polishing pad stack can involve laminating a PSA two-sided tape to both of the subpad faces.\",\n \"FIG.\",\n \"1 illustrates a cross-sectional view of a state of the art polishing pad and subpad pairing.\",\n \"Referring to FIG.\",\n \"1, a polishing pad 100 (top pad or polishing layer) is coupled to a subpad 102.The face of the subpad 102 proximate to the top pad 100 is coupled to the top pad 100 by a first PSA two-sided tape 104.The first PSA two-sided tape 104 may include a carrier film 104A (such as a polyethylene terephthalate, PET, film) which has a first permanent PSA layer 104B and a second permanent PSA layer 104C thereon.\",\n \"The face of the subpad 102 distal from the top pad 100 has a second PSA two-sided tape 106 thereon.\",\n \"The second PSA two-sided tape 106 may include a carrier film 106A (such as a PET film) which has a first permanent PSA layer 106B and a second permanent PSA layer 106C thereon.\",\n \"The second PSA two-sided tape 106 may be further coupled to a third PSA two-sided tape 108.The third PSA two-sided tape 108 may include a carrier film 108A (such as a PET film) which has a first permanent PSA layer 108B and a second removable PSA layer 108C thereon.\",\n \"The third PSA two-sided tape 108 may be suitable for removably coupling the top pad 100/subpad 102 polishing pad stack to a platen 110 of a CMP polishing apparatus, as is depicted in FIG.\",\n \"1.There may be disadvantages associated with the type of polishing pad stack depicted in FIG.\",\n \"1, as described below.\",\n \"In contrast to the polishing pad stack of FIG.\",\n \"1, FIG.\",\n \"2 illustrates a cross-sectional view of a polishing pad and subpad pairing, in accordance with an embodiment of the present invention.\",\n \"Referring to FIG.\",\n \"2, a polishing pad stack for polishing a substrate includes a polishing pad 200 (top pad or polishing layer) coupled to a subpad 202, which may be a compressive subpad.\",\n \"The polishing pad 200 has a polishing surface distal from the subpad 202, and a back surface proximate to the subpad 202.A first (upper) surface of the subpad 202 has a first pressure sensitive adhesive layer 204 coated thereon.\",\n \"The upper surface of the subpad 202 is coupled directly to the back surface of the polishing pad 200 by the first pressure sensitive adhesive layer 204.Referring again to FIG.\",\n \"2, in an embodiment, the polishing pad stack further includes a second pressure sensitive adhesive layer 206 coated on a second (lower) surface of the compressive subpad 202.In one such embodiment, the first pressure sensitive adhesive layer 204 is a permanent pressure sensitive adhesive layer for strong adhesion to the polishing pad 200.The second pressure sensitive adhesive layer 206 is a removable pressure sensitive adhesive layer and is for removably coupling the polishing pad stack to a platen 210 of a chemical mechanical polishing apparatus.\",\n \"Although depicted in FIG.\",\n \"2 as already coupled to a platen, in an embodiment, the polishing pad stack of FIG.\",\n \"2 may include a release liner on the second pressure sensitive adhesive layer 206.Such a release liner may be used for transport and storage of a polishing pad stack, and may be removed to expose the second pressure sensitive adhesive layer 206 prior to coupling the polishing pad stack to a platen.\",\n \"Advantages of the polishing pad stack of FIG.\",\n \"2 over the polishing pad stack of FIG.\",\n \"1 may be realized from the non-interrupted subpad construction achieved with the polishing pad stack type of FIG.\",\n \"2.In particular, the number of interfaces is limited for adhesion failure.\",\n \"Additionally, there may be less processing of the adhesive layers of the polishing pad stack of FIG.\",\n \"2, as is described in greater detail below.\",\n \"In an embodiment, direct coating of an adhesive onto a compressive subpad surface aids in sealing foam pores in the case of a compressive foam subpad.\",\n \"Furthermore, the overall pad thickness may be reduced since there are no carrier films associated with the pressure sensitive adhesive layers, and the number of layers in the composite material is limited.\",\n \"In an embodiment, direct adhesive coating offers superior adhesive anchorage to low surface energy foam that would otherwise be difficult when laminating a PSA two-sided tape to the surface of the subpad.\",\n \"Finally, the number of manufacturing operations may be reduced from four to as low as one lamination operation (the lamination a coated subpad to a polishing pad), as is described in greater detail below.\",\n \"Such a reduction in lamination operations and the achieved simplicity of construction of the polishing pad stack can result in potential reductions in manufacturing cost of the polishing pad stack.\",\n \"Referring again to FIG.\",\n \"2, a pressure sensitive adhesive layer, such as permanent pressure sensitive adhesive layer 204 or removable adhesive layer 206, requires only light to moderate pressure to adhere to a workpiece (such as light to moderate pressure to adhere a subpad 202 having a pressure sensitive adhesive layer coated thereon to a polishing pad 200).\",\n \"A pressure sensitive adhesive layer is not a glue layer which would otherwise require some level of curing.\",\n \"A pressure sensitive adhesive layer is also not a hot melt layer which otherwise requires heat for the adhesion to a workpiece.\",\n \"A pressure sensitive adhesive layer, as defined herein, also does not require the addition of water to activate the adhesion to a workpiece.\",\n \"Referring again to FIG.\",\n \"2, in an embodiment, the permanent pressure sensitive adhesive layer 204 has a peel strength of greater than approximately 4.5 pounds per inch at 25 degrees Celsius.\",\n \"The removable pressure sensitive adhesive layer 206 has a peel strength of less than approximately 4 pounds per inch at 25 degrees Celsius.\",\n \"In a particular embodiment, the removable pressure sensitive adhesive layer 206 has a peel strength of less than approximately 2.5 pounds per inch at 25 degrees Celsius.\",\n \"As used herein, peel strength is defined as strength at maximum adhesion of the pressure sensitive layer, where the test method use is defined in ASTM D3330.In an embodiment, the permanent pressure sensitive adhesive layer 204 or the removable pressure sensitive adhesive layer 206, or both, is a layer of material such as, but not limited to, an acrylic material, a rubber, ethylene vinyl acetate, a silicone material, or a block co-polymer.\",\n \"The layer often incudes a tackifying resin in the formulation.\",\n \"In an embodiment, the permanent pressure sensitive adhesive layer 204 or the removable pressure sensitive adhesive layer 206, or both, has a thickness of approximately 2 mils.\",\n \"As mentioned briefly above, in an embodiment, the compressive subpad 202 is a compressive foam subpad.\",\n \"In one such embodiment, the compressive foam subpad is post processed foam material (e.g., processed using a Corona treatment, as described in greater detail below) that provides improved thickness uniformity or improved surface energetics, or both.\",\n \"In an embodiment, the compressive foam subpad is composed of a material such as, but not limited to, an ethylene vinyl acetate closed cell foam material, a polyethylene closed cell foam material, or a polyurethane mostly closed cell foam material.\",\n \"In an embodiment, one or both of the surface of the compressive subpad (i.e., the surface that is coupled to a polishing pad or the surface for coupling to a platen) has a surface energy approximately in the range of 30-40 dyne/cm2 (as measured prior to any post processing such as a Corona treatment).\",\n \"In an embodiment, the compressive subpad has a thickness approximately in the range of 10 mils to 40 mils.\",\n \"FIGS.\",\n \"3A and 3B are cross-sectional scanning electron microscope (SEM) images of exemplary compressive foam subpads, in accordance with an embodiment of the present invention.\",\n \"Referring to SEM image 300A of FIG.\",\n \"3A, a closed cell ethyl vinyl acetate (EVA) foam subpad is shown magnified at 100× magnification.\",\n \"Referring to SEM image 300B of FIG.\",\n \"3B, a closed cell polyethylene (PE) foam subpad is shown magnified at 100× magnification.\",\n \"Referring again to FIGS.\",\n \"3A and 3B, in an embodiment, the subpad foam layer is an EVA foam or polyethylene foam having low surface energy, typically 30-35 dyne/cm2.The surface energy is typically measured with an Accu Dyne pen that applies a simple solution using ASTM standard Test Method D 2578.The most common solution used includes ethyl cellosolve, formamide and a dye to make it easier to detect with the naked eye.\",\n \"The variation in concentration of the ethyl cellosolve % vs. the formamide % results in different dyne level solutions with each pen.\",\n \"Referring again to FIG.\",\n \"2, the permanent pressure sensitive adhesive layer 204 is coated on the surface of the subpad 202 proximate to the polishing pad 200.The removable pressure sensitive adhesive layer 206 is coated on the surface of the subpad 202 distal to the polishing pad 200.Use of the term “coated” is used to distinguish embodiments of the present invention from situations where a PSA such as a PSA two-sided tape is laminated on the surface of a subpad for ultimate coupling of the subpad to a polishing pad or to a platen (depending on the side of the subpad having the PSA laminated thereon).\",\n \"The term “coated” is also used to distinguish embodiments of the present invention from situations where a PSA such as a PSA two-sided tape is first laminated on the back surface of a polishing pad and subsequently used to adhere the polishing pad to the subpad through another lamination process.\",\n \"By contrast, in accordance with embodiments described herein, an adhesive layer is coated on a surface of a subpad as a “wet” layer by a process such as, but not limited to, a dipping process, a rolling process, or a spreading process.\",\n \"The coated layer is then dried to remove any carrier solvents used to apply the adhesive material on the surface of the subpad.\",\n \"The dried layer coated on a subpad surface is the pressure sensitive adhesive layer (either permanent or removable, depending on which side of the subpad is referenced).\",\n \"As an exemplary advantage of a coated adhesive layer as opposed to a laminated adhesive film on the surface of a subpad, embodiments of the present invention provide a pressure sensitive adhesive layer on the surface of a subpad where the surface area contact between the pressure sensitive adhesive layer and the surface of the subpad is greater than approximately 90%, and in some embodiments greater than approximately 95%.\",\n \"FIG.\",\n \"4A illustrates a cross-sectional view of a state of the art subpad having an adhesive film laminated thereon.\",\n \"FIG.\",\n \"4B illustrates a cross-sectional view of a subpad having a pressure sensitive adhesive layer coated thereon, in accordance with an embodiment of the present invention.\",\n \"Referring to FIG.\",\n \"4A, a conventional laminated adhesive sheet 400 may not have substantial surface area contact between the laminated sheet 400 and a topographical surface 402 of a closed cell sub pad 404.As shown in FIG.\",\n \"4A, the laminated adhesive sheet 400 does not substantially fill surface voids/topography 402 of a surface of the subpad 404.It is to be appreciated that the same scenario may occur for the other (bottom) surface of the subpad 404.By contrast, in accordance with an embodiment of the present invention, referring to FIG.\",\n \"4B, a coated pressure sensitive adhesion layer 450 substantially fills surface voids/topography 452 of a surface of a subpad 454.The result can be an ultimate increase in adhesion strength between the pressure sensitive adhesion layer 450 and the subpad 454.It is to be appreciated that the same scenario may occur for the other (bottom) surface of the subpad 454.In an exemplary embodiment, the surface 452 of the compressive subpad 454 has a surface roughness of at least 3 microns and has a total surface area.\",\n \"The coated pressure sensitive adhesive layer 450 is in direct contact with at least 90% of the total surface area of the surface 452 of the compressive subpad 454.In some embodiment, the coated pressure sensitive adhesive layer 450 is in direct contact with greater than approximately 95% of the total surface area of the surface 452 of the compressive subpad 454.Referring again to FIG.\",\n \"2, in an embodiment, the polishing pad 200 coupled to the subpad 202 is a homogeneous or single layer polishing pad, as is depicted in FIG.\",\n \"2.In one such embodiment, the polishing pad 200 is composed of a thermoset polyurethane material, as described in greater detail below.\",\n \"In another embodiment, however, the polishing pad 200 is a composite polishing pad.\",\n \"In one such embodiment, the polishing pad 200 includes a polishing layer and a foundation layer that together define the polishing pad 200.As an example of the latter scenario, FIG.\",\n \"5 illustrates a cross-sectional view of a polishing pad and subpad pairing where the polishing pad includes a polishing layer and a foundation layer, in accordance with an embodiment of the present invention.\",\n \"Referring to FIG.\",\n \"5, a polishing pad stack includes a polishing pad 500.The polishing pad includes a polishing layer 508 coupled to a foundation layer 502.As such, the back surface of the polishing pad 500 is a surface of the foundation layer 502.The front surface 504 of the foundation layer 502 is bonded to a surface polishing layer 508.In an embodiment, the polishing surface layer 508 includes a continuous layer portion 508A with a plurality of polishing features 508B protruding there from, as depicted in FIG.\",\n \"5.It is the continuous layer portion 508A that is bonded with the foundation layer 502.In an embodiment, the foundation layer 502 is composed of a polycarbonate material, and the polishing surface layer 508 is a polyurethane material.\",\n \"In a specific such embodiment, the polishing surface layer 508 is covalently bonded to the foundation layer 502.The term “covalently bonded” refers to arrangements where atoms from a first material (e.g., the material of a polishing surface layer) are cross-linked or share electrons with atoms from a second material (e.g., the material of a foundation layer) to effect actual chemical bonding.\",\n \"Covalent bonding is distinguished from mechanical bonding, such as bonding through screws, nails, glues, or other adhesives.\",\n \"In another specific embodiment, the polishing surface layer 508 is not covalently bonded, but is rather only electrostatically bonded (yet still directly bonded), to the foundation layer 502.Such electrostatic bonding may involve van der Waals type interactions between the foundation layer 502 and the polishing surface layer 508.Referring again to FIG.\",\n \"5, the polishing pad stack includes subpad 550, which may be a compressive closed cell foam subpad.\",\n \"A first (upper) surface of the subpad 550 has a first pressure sensitive adhesive layer 552 coated thereon.\",\n \"The upper surface of the subpad 550 is coupled directly to the back surface of the foundation layer 502 of the polishing pad 500 by the first pressure sensitive adhesive layer 552.In an embodiment, a second pressure sensitive adhesive layer 554 is coated on a second (lower) surface of the compressive subpad 550.In one such embodiment, the first pressure sensitive adhesive layer 552 is a permanent pressure sensitive adhesive layer for strong adhesion to the polishing pad 500.The second pressure sensitive adhesive layer 554 is a removable pressure sensitive adhesive layer and is for removably coupling the polishing pad stack to a platen 556 of a chemical mechanical polishing apparatus.\",\n \"Although depicted in FIG.\",\n \"5 as already coupled to a platen, in an embodiment, the polishing pad stack of FIG.\",\n \"5 may include a release liner on the second pressure sensitive adhesive layer 554.Such a release liner may be used for transport and storage of a polishing pad stack, and may be removed to expose the second pressure sensitive adhesive layer 554 prior to coupling the polishing pad stack to a platen.\",\n \"As mentioned briefly above, polishing pad stacks including subpads such as those described herein may be fabricated using a reduced number of lamination processes than are otherwise used for state of the art pad stack fabrication.\",\n \"As a comparative example, FIG.\",\n \"6 illustrates a state of the art four step lamination pass pad/subpad fabrication process.\",\n \"Referring to FIG.\",\n \"6, a first lamination pass (Lamination Pass 1) involves lamination of a permanent PSA two-sided tape 602 on the back side of a polishing pad (top pad) 600.Excess of the permanent PSA two-sided tape is then trimmed off.\",\n \"A second lamination pass (Lamination Pass 2) involves lamination of a subpad foam material 604 onto the permanent PSA two-sided tape 602 on the back up the polishing pad 600.Excess of the foam material is then trimmed off.\",\n \"A third lamination pass (Lamination Pass 3) involves lamination of a second permanent PSA two-sided tape 606 onto the subpad foam material 604.Excess of the second permanent PSA two-sided tape is then trimmed off.\",\n \"A fourth lamination pass (Lamination Pass 4) involves lamination of a removable PSA two-sided tape 608 onto the second permanent PSA two-sided tape 606.Excess of the removable PSA two-sided tape is then trimmed off.\",\n \"A laminator 650 may be used where the polishing pad 652 is laminated with a roll 654 of the permanent PSA two-sided tape 602, the subpad foam material 604, the second permanent PSA two-sided tape 606 or the removable PSA two-sided tape 608, depending on which lamination pass is being performed.\",\n \"The resulting pad stack may be one such as described in association with FIG.\",\n \"1.In contrast to the above described multi-lamination process, FIG.\",\n \"7 illustrates a subpad fabrication process involving coating of pressure sensitive adhesive layers onto the subpad material, in accordance with an embodiment of the present invention.\",\n \"Referring to FIG.\",\n \"7, a subpad foam material 702 is used as a carrier film for a coating process.\",\n \"The subpad foam material 702 is fed into application rollers 704 and 706 which apply a first pressure sensitive adhesive material 708 onto a first side 710 of the subpad foam material 702.A spreader bar or Meyer bar 712 is used to remove excess of and to evenly distribute the first pressure sensitive adhesive material 708 on the first side 710 of the subpad foam material 702.Referring again to FIG.\",\n \"7, the subpad foam material 702 is then fed into application rollers 724 and 726 which apply a second pressure sensitive adhesive material 728 onto a second side 730 of the subpad foam material 702.A spreader bar or Meyer bar 732 is used to remove excess of and to evenly distribute the second pressure sensitive adhesive material 728 on the second side 730 of the subpad foam material 702.Referring again to FIG.\",\n \"7, the doubly coated subpad foam material 702 is then directed to a dryer 740.The drying provides a foam material 702 having a first surface 710 with a first pressure sensitive adhesive layer 746 coated thereon, and having a second surface 730 with a second pressure sensitive adhesive layer 748 coated thereon.\",\n \"Once transported through the dryer 740, further processing of the foam material 702 having the first 746 and second 748 pressure sensitive adhesive layers thereon may be performed, as described in greater detail below.\",\n \"Referring generally to FIG.\",\n \"7, in an embodiment, a method of fabricating a polishing pad stack for polishing a substrate involves coating a first pressure sensitive adhesive layer 708 on a first surface 710 of a compressive subpad material 702.The method also involves coating a second pressure sensitive adhesive layer 728 on a second, opposite, surface 730 of the compressive subpad material 702.In an embodiment, the first pressure sensitive adhesive layer 708 is a permanent pressure sensitive adhesive layer, and the second pressure sensitive adhesive layer 728 is a removable pressure sensitive adhesive layer.\",\n \"In another embodiment, the first pressure sensitive adhesive layer 708 is a removable pressure sensitive adhesive layer, and the second pressure sensitive adhesive layer 728 is a permanent pressure sensitive adhesive layer.\",\n \"In either case, in an embodiment, for the removable pressure sensitive adhesive layer, a primer is applied to the associated side of the subpad material for increasing the adhesion of the removable pressure sensitive adhesive layer to the subpad material but retaining removability for the platen side of the removable pressure sensitive adhesive layer.\",\n \"In an embodiment, coating of either the first or second pressure sensitive adhesive layer involves dispensing and then spreading a solvent-based adhesive formulation on a surface of the compressive subpad material.\",\n \"In one such embodiment, subsequent to dispensing and then spreading a first solvent-based adhesive formulation on a first surface of the compressive subpad material and dispensing and then spreading a second solvent-based adhesive formulation on a second surface of the compressive subpad material, the first and second solvent-based adhesive formulations are dried (e.g., through dryer 740) to remove substantially all solvent from the first and second solvent-based adhesive formulations.\",\n \"In an embodiment, a pressure sensitive adhesive layer is applied as a solvent-based adhesive formulation on a surface of the compressive subpad material at a temperature less than approximately 50 degrees Celsius.\",\n \"Subsequently, the solvent-based adhesive formulation is dried in an air dryer at a temperature less than approximately 50 degrees Celsius.\",\n \"Thus, referring generally to FIG.\",\n \"7, providing PSA layers on a subpad material involves coating an adhesive/solvent solution onto the subpad material which acts a carrier film or a support layer in the fabrication process.\",\n \"The viscosity of the adhesive formulation determines the coating method.\",\n \"The adhesive formulation can be applied as an adhesive material carried in a solvent.\",\n \"An exemplary coating method is a Meyer Rod Coating approach.\",\n \"FIG.\",\n \"8 illustrates coating of a pressure sensitive adhesive layer onto a subpad material using a Meyer bar, in accordance with an embodiment of the present invention.\",\n \"Referring to FIG.\",\n \"8, an applicator roll 802 delivers an adhesive formulation 804 to the surface of a subpad material 806 being coated.\",\n \"In an embodiment, the adhesive formulation 804 is applied at a temperature less than approximately 50 degrees Celsius and, preferably less than approximately 40 degrees Celsius, and most preferably at room temperature or approximately 20-25 degrees Celsius.\",\n \"In an embodiment, the temperature of the adhesive formulation 804 at the time of application is less than approximately 50 degrees Celsius and, preferably less than approximately 40 degrees Celsius, and most preferably at room temperature or approximately 20-25 degrees Celsius.\",\n \"The applicator roll 802 delivers an excess of material 804.The excess is removed by a Meyer rod or bar 808 (an expanded view of which is depicted in box 810 of FIG.\",\n \"8, which shows the rod wrapped with wire).\",\n \"The amount of adhesive removed depends on the wire wrapping.\",\n \"There may be multiple rods in series to produce smooth accurate coating thicknesses with tolerance at +/−0.001 inch.\",\n \"The coated subpad material film is then directed 812 to an air dryer for solvent evaporation.\",\n \"In an embodiment, the subpad having the adhesive coated thereon enters the dryer approximately 2-4 minutes after the adhesive is coated on the subpad.\",\n \"In an embodiment, the subpad is dried in the air dryer for approximately 20 minutes.\",\n \"Referring again to FIG.\",\n \"7, a release liner 790 is then applied to one of the coated adhesive layers at the end of the coating process.\",\n \"In one embodiment, the release liner 790 is added to the removable pressure sensitive adhesive layer after the removable pressure sensitive adhesive layer has been coated on the subpad material.\",\n \"In other embodiments, however, the removable pressure sensitive adhesive layer is coated on the subpad material by first applying the removable pressure sensitive adhesive material to the release liner and then delivering the removable pressure sensitive adhesive material to the subpad material.\",\n \"In either case, such a release liner may be removed prior to coupling the removable pressure sensitive adhesive layer to a platen.\",\n \"In an embodiment, although not depicted, a second release liner is added to the permanent pressure sensitive adhesive layer.\",\n \"Such a second release liner may be included for transporting or storage of a coated subpad, but removed prior to adhering the coated subpad to a polishing pad via the permanent pressure sensitive adhesive layer of the coated subpad.\",\n \"In other embodiments, however, a roll of the subpad material is formed without a release liner being included on the side of the subpad material having the permanent pressure sensitive adhesive layer thereon.\",\n \"Whether or not the second release liner is included, a polishing pad may be adhered to the coated permanent pressure sensitive adhesive layer of the subpad material by a lamination process (thus leaving a single lamination process in place of the four described in association with FIG.\",\n \"6).\",\n \"The subpad material may then be cut around the shape of the polishing pad material.\",\n \"As described herein, a release liner is a paper or plastic based carrier web material, which has a release agent on one or both sides of the release liner.\",\n \"The release agent provides a release effect against any type of a sticky material such as an adhesive.\",\n \"Release of the release liner involves separation of the release liner from the pressure sensitive adhesive layer.\",\n \"With reference again to the process of FIG.\",\n \"7, in an embodiment, the foam material (such as EVA or PE foam material) of the subpad is post processed prior to adhesive coating to achieve a tight gage tolerance of +/−1 mil throughout the web.\",\n \"Typically, the material is buffed on one or both sides.\",\n \"Such foams can vary in thickness from 15 mils up to 60 mils and may be produced in a wide range of densities ranging from a few pounds up to 60 pound foam.\",\n \"Typical gage tolerance is +/10% of the total thickness, which can be as much as +/−6 mils or a total of 12 mils throughout the web.\",\n \"It is to be appreciated that, as the semiconductor market technologies become more and more demanding to reduce line width, the consumable set used to manufacture these technologies must also meet tighter material property tolerances.\",\n \"Post processing of a foam and subsequent direct adhesive coating can, in an embodiment, reduce the thickness tolerance and provide improved adhesive anchorage.\",\n \"Such factors in turn affect the foam compressibility of the subpad material.\",\n \"Compressibility is defined as (thickness under a load minus initial thickness)/initial thickness.\",\n \"In some embodiment, the desired compressibility is low, e.g., typically less than 10%.\",\n \"As described briefly in association with FIG.\",\n \"7, a corona 792A and 792B or like treatment may be applied to one or both sides of a subpad material prior to adhesive layer coating.\",\n \"It is to be appreciated that surface energy properties are an important consideration with industrial coatings.\",\n \"The surface energy dictates if an applied coating will be accepted by the surface; this is known as wetting.\",\n \"The definition of wetting is the ability of a liquid to maintain contact with a solid surface, resulting from intermolecular interactions when the two are brought together.\",\n \"The degree of wetting (wettability) is determined by a force balance between adhesive and cohesive forces.\",\n \"For adhesive coatings, the surface tension of the adhesive must be lower than the surface energy of the surface to which they are applied.\",\n \"In the case of a material such as an EVA foam, the surface energy of the substrate must be raised to ensure sufficient wet out of the applied liquid (pressure sensitive adhesive coating).\",\n \"There are number of methods for such surface treatment such as, but not limited to corona discharge, flame treatment, or plasma treatment.\",\n \"Such treatments may be implemented to increase the surface energy of an EVA or PE foam from 30 dyne/cm up to, e.g., 40-42 dynes/cm.\",\n \"In one such embodiment, a corona discharge treatment is applied to a compressive foam subpad material just prior to the adhesive coating process, as is shown in FIG.\",\n \"7.FIG.\",\n \"9 illustrates an apparatus for performing a Corona discharge treatment of a compressive foam subpad surface prior to coating an adhesive layer thereon, in accordance with an embodiment of the present invention.\",\n \"Referring to FIG.\",\n \"9, a subpad material layer 902 (e.g., compressive foam material layer) is rolled on a tamper roll 904 having a dielectric 906 thereon.\",\n \"The arrangement provides an electrode 908 above the subpad material layer 902 with an air gap 910 between the electrode 908 and the subpad material layer 902.A corona generator power supply 912 is coupled to the electrode 908.The corona treatment is a surface modification technique that uses a low temperature corona discharge plasma to impart changes in the properties of a surface of the subpad material layer 902.In an embodiment, referring again to FIGS.\",\n \"2 and 5, the polishing pad 200 or the polishing surface layer 508 is a homogeneous polishing pad or polishing surface layer.\",\n \"In one such embodiment, the homogeneous polishing pad or polishing surface layer is composed of a thermoset polyurethane material.\",\n \"For example, in a specific embodiment, the homogeneous polishing pad or polishing surface layer is composed of a thermoset, closed cell polyurethane material.\",\n \"In an embodiment, the term “homogeneous” is used to indicate that the composition of a thermoset, closed cell polyurethane material is consistent throughout the entire composition of the body.\",\n \"For example, in an embodiment, the term “homogeneous” excludes polishing pad bodies composed of, e.g., impregnated felt or a composition (composite) of multiple layers of differing material.\",\n \"In an embodiment, the term “thermoset” is used to indicate a polymer material that irreversibly cures, e.g., the precursor to the material changes irreversibly into an infusible, insoluble polymer network by curing.\",\n \"For example, in an embodiment, the term “thermoset” excludes polishing pads composed of, e.g., “thermoplast” materials or “thermoplastics”—those materials composed of a polymer that turns to a liquid when heated and returns to a very glassy state when cooled sufficiently.\",\n \"It is noted that polishing pads made from thermoset materials are typically fabricated from lower molecular weight precursors reacting to form a polymer in a chemical reaction, while pads made from thermoplastic materials are typically fabricated by heating a pre-existing polymer to cause a phase change so that a polishing pad is formed in a physical process.\",\n \"Polyurethane thermoset polymers may be selected for fabricating polishing pads described herein based on their stable thermal and mechanical properties, resistance to the chemical environment, and tendency for wear resistance.\",\n \"The materials of polishing pad 200 or polishing surface layer 508 may be molded.\",\n \"The term “molded” may be used to indicate that the polishing surface layer is formed in a formation mold.\",\n \"In an embodiment, the molded polishing pad 200 or polishing surface layer 508, upon conditioning and/or polishing, has a polishing surface roughness approximately in the range of 1-5 microns root mean square.\",\n \"In one embodiment, the molded polishing pad 200 or polishing surface layer 508, upon conditioning and/or polishing, has a polishing surface roughness of approximately 2.35 microns root mean square.\",\n \"In an embodiment, the molded polishing pad 200 or polishing surface layer 508 has a storage modulus at 25 degrees Celsius approximately in the range of 30-500 megaPascals (MPa).\",\n \"In another embodiment, the molded polishing pad 200 or polishing surface layer 508 has a storage modulus at 25 degrees Celsius approximately less than 30 megaPascals (MPa).\",\n \"The materials of polishing pad 200 or polishing surface layer 508 may include pore-forming features.\",\n \"In an embodiment, the polishing surface layer 108 or 208 has a pore density of closed cell pores approximately in the range of 6%-50% total void volume.\",\n \"In one embodiment, the plurality of closed cell pores is a plurality of porogens.\",\n \"For example, the term “porogen” may be used to indicate micro- or nano-scale spherical or somewhat spherical particles with “hollow” centers.\",\n \"The hollow centers are not filled with solid material, but may rather include a gaseous or liquid core.\",\n \"In one embodiment, the plurality of closed cell pores is composed of pre-expanded and gas-filled EXPANCEL™ distributed throughout (e.g., as an additional component in) a polishing surface layer of a polishing pad.\",\n \"In a specific embodiment, the EXPANCEL™ is filled with pentane.\",\n \"In an embodiment, each of the plurality of closed cell pores has a diameter approximately in the range of 10-100 microns.\",\n \"In an embodiment, the plurality of closed cell pores includes pores that are discrete from one another.\",\n \"This is in contrast to open cell pores which may be connected to one another through tunnels, such as the case for the pores in a common sponge.\",\n \"In one embodiment, each of the closed cell pores includes a physical shell, such as a shell of a porogen, as described above.\",\n \"In another embodiment, however, each of the closed cell pores does not include a physical shell.\",\n \"In an embodiment, the plurality of closed cell pores is distributed essentially evenly throughout a thermoset polyurethane material of a homogeneous polishing pad or polishing surface layer.\",\n \"In an embodiment, polishing pad 200 or polishing surface layer 508 is opaque.\",\n \"In one embodiment, the term “opaque” is used to indicate a material that allows approximately 10% or less visible light to pass.\",\n \"In one embodiment, the polishing pad 200 or polishing surface layer 508 is opaque in most part, or due entirely to, the inclusion of an opacifying particle filler, such as a lubricant, throughout (e.g., as an additional component in) the polishing pad 200 or polishing surface layer 508.In a specific embodiment, the opacifying particle filler is a material such as, but not limited to boron nitride, cerium fluoride, graphite, graphite fluoride, molybdenum sulfide, niobium sulfide, talc, tantalum sulfide, tungsten disulfide, or Teflon®.\",\n \"In another aspect, the polishing pad 200 or polishing surface layer 508 may have a pattern suitable for polishing during a CMP operation.\",\n \"In a first general example, some embodiments of the present invention include a plurality of protrusions having a pattern of linear features.\",\n \"In a second general example, some embodiments of the present invention include a plurality of protrusions having a pattern of discrete curved features.\",\n \"In a specific such example, discrete arc-shaped protrusions are included.\",\n \"Other specific such embodiments include, but are not limited to, a plurality of partial circumferential protrusions disposed on a substantially circular polishing pad.\",\n \"In a third general example, some embodiments of the present invention include a plurality of protrusions having a pattern of discrete tiles.\",\n \"In a specific such embodiment, discrete hexagonal tile protrusions are included.\",\n \"Other specific such embodiments include, but are not limited to, pluralities of circular tiles, oval tiles, square tiles, rectangular tiles, or a combination thereof.\",\n \"Although the above three general examples are defined in terms of protrusions (e.g., the highest points of a patterned polishing surface layer), the polishing surface layers may also or alternatively be defined in terms of grooves (e.g., the lowest points of a patterned polishing surface layer).\",\n \"Individual grooves may be from about 4 to about 100 mils deep at any given point on each groove.\",\n \"In some embodiments, the grooves are about 10 to about 50 mils deep at any given point on each groove.\",\n \"The grooves may be of uniform depth, variable depth, or any combinations thereof.\",\n \"In some embodiments, the grooves are all of uniform depth.\",\n \"For example, the grooves of a groove pattern may all have the same depth.\",\n \"In some embodiments, some of the grooves of a groove pattern may have a certain uniform depth while other grooves of the same pattern may have a different uniform depth.\",\n \"For example, groove depth may increase with increasing distance from the center of the polishing pad.\",\n \"In some embodiments, however, groove depth decreases with increasing distance from the center of the polishing pad.\",\n \"In some embodiments, grooves of uniform depth alternate with grooves of variable depth.\",\n \"Individual grooves may be from about 2 to about 100 mils wide at any given point on each groove.\",\n \"In some embodiments, the grooves are about 15 to about 50 mils wide at any given point on each groove.\",\n \"The grooves may be of uniform width, variable width, or any combinations thereof.\",\n \"In some embodiments, the grooves of a groove pattern are all of uniform width.\",\n \"In some embodiments, however, some of the grooves of a groove pattern have a certain uniform width, while other grooves of the same pattern have a different uniform width.\",\n \"In some embodiments, groove width increases with increasing distance from the center of the polishing pad.\",\n \"In some embodiments, groove width decreases with increasing distance from the center of the polishing pad.\",\n \"In some embodiments, grooves of uniform width alternate with grooves of variable width.\",\n \"In accordance with the previously described depth and width dimensions, individual grooves may be of uniform volume, variable volume, or any combinations thereof.\",\n \"In some embodiments, the grooves are all of uniform volume.\",\n \"In some embodiments, however, groove volume increases with increasing distance from the center of the polishing pad.\",\n \"In some other embodiments, groove volume decreases with increasing distance from the center of the polishing pad.\",\n \"In some embodiments, grooves of uniform volume alternate with grooves of variable volume.\",\n \"Grooves of the groove patterns described herein may have a pitch from about 30 to about 1000 mils.\",\n \"In some embodiments, the grooves have a pitch of about 125 mils.\",\n \"For a circular polishing pad, groove pitch is measured along the radius of the circular polishing pad.\",\n \"The grooves may be of uniform pitch, variable pitch, or in any combinations thereof.\",\n \"In some embodiments, the grooves are all of uniform pitch.\",\n \"In some embodiments, however, groove pitch increases with increasing distance from the center of the polishing pad.\",\n \"In some other embodiments, groove pitch decreases with increasing distance from the center of the polishing pad.\",\n \"In some embodiments, the pitch of the grooves in one sector varies with increasing distance from the center of the polishing pad while the pitch of the grooves in an adjacent sector remains uniform.\",\n \"In some embodiments, the pitch of the grooves in one sector increases with increasing distance from the center of the polishing pad while the pitch of the grooves in an adjacent sector increases at a different rate.\",\n \"In some embodiments, the pitch of the grooves in one sector increases with increasing distance from the center of the polishing pad while the pitch of the grooves in an adjacent sector decreases with increasing distance from the center of the polishing pad.\",\n \"In some embodiments, grooves of uniform pitch alternate with grooves of variable pitch.\",\n \"In some embodiments, sectors of grooves of uniform pitch alternate with sectors of grooves of variable pitch.\",\n \"In an embodiment, polishing pad stacks described herein, such as the polishing pad stacks of FIGS.\",\n \"2 and 5, are suitable for polishing substrates.\",\n \"The substrate may be one used in the semiconductor manufacturing industry, such as a silicon substrate having device or other layers disposed thereon.\",\n \"However, the substrate may be one such as, but not limited to, a substrates for MEMS devices, reticles, or solar modules.\",\n \"Thus, reference to “a polishing pad for polishing a substrate,” as used herein, is intended to encompass these and related possibilities.\",\n \"In an embodiment, a polishing pad stack has a diameter approximately in the range of 20 inches to 30.3 inches, e.g., approximately in the range of 50-77 centimeters, and possibly approximately in the range of 10 inches to 42 inches, e.g., approximately in the range of 25-107 centimeters.\",\n \"Subpads described herein may be included with a polishing pad, as described above.\",\n \"Such a combined polishing pad/subpad polishing pad stack may be suitable for use with a variety of chemical mechanical polishing apparatuses.\",\n \"As an example, FIG.\",\n \"10 illustrates an isometric side-on view of a polishing apparatus compatible with a polishing pad/subpad polishing pad stack, in accordance with an embodiment of the present invention.\",\n \"Referring to FIG.\",\n \"10, a polishing apparatus 1000 includes a platen 1004.The top surface 1002 of platen 1004 may be used to support a polishing pad/subpad polishing pad stack 1099.Platen 1004 may be configured to provide spindle rotation 1006.A sample carrier 1010 is used to hold, e.g., a semiconductor wafer 1011 in place during polishing of the semiconductor wafer with the polishing pad/subpad polishing pad stack 1099 and to provide slider oscillation 1008.Sample carrier 1010 is further supported by a suspension mechanism 1012.A slurry feed 1014 is included for providing slurry to a surface of the polishing pad/subpad polishing pad stack 1099 prior to and during polishing of the semiconductor wafer.\",\n \"A conditioning unit 1090 may also be included and, in one embodiment, includes a diamond tip for conditioning the polishing pad of the polishing pad/subpad polishing pad stack 1099 combination.\",\n \"In an embodiment, a relatively weaker adhesive coated adhesive layer on the subpad is used to mount the polishing pad/subpad polishing pad stack 1099 on the platen 1004.In an embodiment, a relatively stronger adhesive coated adhesive layer secures the subpad to the polishing pad.\",\n \"Thus, coated compressive subpads for polishing pad stacks and methods of fabricating coated compressive subpads for polishing pad stacks have been disclosed.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875773"}}},{"rowIdx":4494972,"cells":{"text":{"kind":"list like","value":[["BI-FOLD DOOR LATCH ASSEMBLY","A latch assembly connected to the drive unit of a bi-fold door retains the bi-fold door in engagement with upright columns of a building with elongated straps attached to the upright columns and rotatable latch drums mounted on a drive shaft of a drive unit.","Lift devices powered by the drive unit raise and lower the bi-fold door.","Latch assemblies include springs that maintain tension on the straps during the opening and closing of the bi-fold door."],["1.An apparatus for opening and closing a door opening with a bi-fold door mounted on a structure having the door opening and an upright column adjacent the door opening, the bi-fold door having an upper panel, a lower panel, and hinges connecting the upper panel and the lower panel to allow the upper and lower panels to move from a vertically aligned closed latched position to a folded side-by-side open position comprising: door lift devices operable to selectively open and close the bi-fold door, a door latch assembly operable to latch the bi-fold door into engagement with the upright columns when the bi-fold door is in the closed latched position, a reversible power unit connected to the door lift devices and the door latch assembly for operating the door lift devices and the door latch assembly whereby the door lift devices are operable to open and close the bi-fold door, the door latch assembly is operable to latch the bi-fold door into engagement with the upright column, a drive shaft operatively connected to the reversible power unit, each of the respective door lift devices having a door lift drum secured to the drive shaft, a first strap having a first end and a second end, the first end being connected to the door lift drum whereby the power unit selectively rotates the drive shaft and door lift drum to wind the first strap in overlapping relation on the door lift drum and unwind the first strap off the door lift drum, a first anchor mounted on one panel connected to the second end of the first strap, the door latch assembly having a door latch drum secured to the drive shaft, a second strap having a first end and a second end, the first end of the second strap being connected to the door latch drum whereby when the power unit rotates the drive shaft and the door latch drum to wind the second strap in overlapping relation opposite from the overlapping relation of the first strap on the door lift drum and unwind the second strap off the door latch drum, a second anchor mounted on the upright column connected to the second end of the second strap whereby the power unit rotates the drive shaft, the door lift drum and the door latch drum to wind the first strap on the door lift drum and unwind the second strap off the door latch drum to open the bi-fold door and the power unit rotates the door lift drum and the door latch drum to unwind the first strap off the door lift drum and wind the second strap on the door latch drum to close the bi-fold door and latch the bi-fold door into engagement with the upright column.","2.The apparatus of claim 1 wherein: the first and second straps are elongated generally flat members.","3.The apparatus of claim 1 wherein: the first and second straps are flexible and flat, plastic and fiber members.","4.The apparatus of claim 1 including: a roller assembly mounted on the structure adjacent the bi-fold door, the second strap extending from the door latch drum to the roller assembly and around the roller assembly to the second anchor.","5.The apparatus of claim 1 including: a device operative to bias the second strap to maintain tension on the second strap during the opening and closing of the door opening with the bi-fold door.","6.The apparatus of claim 1 including: a kick-out arm device having an arm pivotally connected to the structure, the arm having an eye-shaped outer end and accommodating the second strap, and a spring engaging the arm to bias the arm and the second strap away from the bi-fold door during opening and closing of the bi-fold door.","7.A combination of a bi-fold door and an apparatus for opening, closing and latching the bi-fold door to upright columns located adjacent opposite sides of a bi-fold door opening and building structure located above the bi-fold door opening comprising: a bi-fold door hinged to a header of the building structure located above the door opening, the bi-fold door having an upper panel, a lower panel and hinges pivotally connecting the upper and lower panels to allow the upper and lower panels to be moved from an aligned closed position to a folded generally side-by-side open position, bi-fold door lift devices operable to selectively move the upper and lower panels of the bi-fold door to the folded generally side-by-side open position and the aligned closed position, bi-fold door latch assemblies operable to retain the bi-fold door in engagement with the upright columns of the structure when the upper and lower panels of the bi-fold door are in the aligned closed position, a reversible power unit mounted on the building structure above the door opening and operatively connected to the bi-fold door lift devices and the door latch assemblies for operating the door lift devices and the door latch assemblies whereby the door lift devices open and close the bi-fold door and the bi-fold door latch assemblies latch the closed bi-fold door in engagement with the upright columns, each of the bi-fold door lift devices having a respective elongated flexible first strap having a first end and a second end, a respective rotatable first drum attached to the first end of the first strap operably connected to the power unit whereby on rotation of the first drum the first strap winds in overlapping relation around the first drum, a respective first anchor mounted on the lower panel connected to the second end of the first strap, each of the door latch assemblies has a respective elongated flexible second strap having a first end and a second end, a respective second rotatable drum attached to the first end of the second strap operatively connected to the power unit whereby on rotation of the second drum the second strap winds in overlapping relation around the second drum in a direction opposite from the overlapping relation of the first strap and the first drum, a respective second anchor secured to an upright column, the respective second end of the second strap being connected to a second anchor whereby when the power unit rotates the first and second rotatable drums to wind the first strap onto the first drum and unwind the second strap off the second drum the upper and lower panels move relative to each other to a side-by-side relationship to open the bi-fold door and when the power unit rotates the first and second drums to unwind the first strap off the first drum and wind the second strap onto the second drum the upper and lower panels move relative to each other to aligned relationship to close the bi-fold door and retain the bi-fold door in engagement with the upright columns of the structure.","8.The combination of claim 7 wherein: the first and second straps are flexible and flat, plastic and fiber members.","9.The combination of claim 7 including: a drive shaft, the reversible power unit is drivably connected to the drive shaft for selectively rotating the drive shaft in opposite directions, the first and second drums are mounted on the drive shaft whereby upon rotation of the drive shaft in one direction the first strap winds in overlapping relation around the first drum and the second strap unwinds off the second drum thereby moving the bi-fold door from a closed position to an open position and upon rotation of the drive shaft in a direction opposite the one direction the first strap unwinds off the first drum and the second strap winds in overlapping direction around the second drum whereby the bi-fold door moves from the open position to the closed position.","10.The combination of claim 7 including: a device operable to bias the second strap to maintain tension on the second strap during the opening and closing of the bi-fold door.","11.The combination of claim 7 including: a kick-out device having an arm, the arm having an eye-shaped outer end accommodating the second strap, and a spring engaging the arm to bias the arm and the second strap away from the bi-fold door.","12.The combination of claim 7 wherein: the respective second member includes a bracket fastened to one of the upright columns, a rotatable sleeve connected to the bracket, a device for holding the sleeve in a rotated selected position, the respective second end of the second strap being secured to the sleeve whereby rotation of the sleeve winds the respective second end of the strap on the sleeve, 13.The combination of claim 7 including: a frame secured to the building structure located above the door opening, the reversible power unit is mounted on the frame, a drive shaft rotatably mounted on the frame and operably connected to the reversible power unit whereby the reversible power unit operates to selectively rotate the drive shaft in opposite directions, and the first and second drums are mounted on the drive shaft whereby upon rotation of the drive shaft in one direction the first strap winds in overlapping relation around the first drum and the second strap unwinds off the second drum thereby moving the bi-fold door from a closed position to an open position and upon rotation of the drive shaft in a direction opposite the one direction the first strap unwinds off the first drum and the second strap winds in overlapping direction around the second drum whereby the bi-fold door moves from the open position to the closed position.","14.A door for closing a doorway in a building having a horizontal header, upright columns adjacent opposite sides of the doorway and building structure above the header comprising: a bi-fold door having an upper panel and a lower panel and hinges pivotally connecting the upper and lower panels to allow the upper and lower panels to move between an aligned upright position closing the doorway and folded generally side-by-side position opening the doorway, at least one hinge for connecting the upper panel to the header of the building, door lift devices operable to move the upper and lower panels between the upright position and the side-by-side position and allow the upper and lower panels to move from the open side-by-side position to the aligned upright position, door latch assemblies operable to retain the upper and lower panels in the upright position in engagement with the columns of the building, a power unit mounted on the building structure above the header operably connected to the door lift devices and door latch assemblies for operating the door lift devices and door latch assemblies whereby the door lift devices move the upper and lower panels between aligned upright and side-by-side positions and the door latch assemblies retain the upper and lower panels in the aligned upright position in engagement with the columns of the building, the power unit having a drive shaft and a motor operable to rotate the drive shaft, each of the door latch assemblies has a respective elongated flexible member having a first end and a second end, a respective latch drum attached to the drive shaft, the first end of the flexible member being connected to the latch drum, a respective anchor secured to an upright column adjacent one of the upper and lower panels, the second end of the flexible member being connected to the respective anchor, and a respective roller mounted on the one of the upper and lower panels adjacent the respective anchor, the flexible member extending from the latch drum and around the respective roller to the respective anchor whereby when the flexible member is wound on the latch drum the flexible member pulls the upper and lower panels to the aligned upright position and retains the upper and lower panels in the aligned upright position in engagement with the upright columns of the building closing the doorway, 15.The door of claim 14 wherein: the flexible member is an elongated flexible strap.","16.The door of claim 14 including: a biasing apparatus mounted on the one of the upper and lower panels for maintaining tension of the flexible member during the opening and closing of the upper and lower panels of the bi-fold door.","17.The door of claim 16 including: a kick-out device having an arm pivotally mounted on the headers, the arm having an eye-shaped outer end accommodating the second strap, and a biasing member engaging the arm to bias the arm and the second strap away from the bi-fold door.","18.The door of claim 17 wherein: the flexible member is an elongated flexible strap.","19.The door of claim 14 wherein: the respective anchor includes a bracket fastened to an upright column of the building, a rotatable sleeve connected to the bracket, a member for holding the sleeve on the bracket, and the respective second end of the flexible member being connected to the sleeve whereby on rotation of the drive shaft the flexible member winds around the respective latch drum and moves the upper and lower panels in aligned upright positions into engagement with the columns of the building.","20.A combination of a bi-fold door, bi-fold door lifts for selectively opening and closing the bi-fold door and door latches for holding the bi-fold door in a closed position relative to upright first and second columns located adjacent opposite sides of a bi-fold door opening and building structure including a header located above the bi-fold door opening comprising: a bi-fold door having a first panel, a second panel and hinges pivotally connecting the first and second panels to allow the first and second panels to be moved from an aligned position to close the bi-fold door opening and to a folded side-by-side position to open the bi-fold door opening, at least one hinge pivotally connecting the first panel to the header to support the bi-fold door on the header and allow the bi-fold door to move from the aligned position to the side-by-side position and moved from the folded generally side-by-side position to the aligned position, at least one bi-fold door lift device operable to selectively move the first and second panels of the bi-fold door between the aligned position to the folded side-by-side position and allow the first and second panels of the bi-fold door to move from the folded side-by-side position to the aligned position, a power unit mounted on the building structure above the header having a drive shaft rotatable in opposite directions, the bi-fold door lift device includes an elongated flexible first strap having a first end and a second end, a first drum attached to the drive shaft and connected to the first end of the first strap, a first anchor mounted on the second panel and connected to the second end of the first strap, a first bi-fold door latch operable to retain the bi-fold door in engagement with the upright first column when the bi-fold door is in the aligned position, the first bi-fold door latch includes an elongated flexible second strap having a first end and a second end, a second drum attached to the drive shaft and attached to the first end of the second strap, a second anchor mounted on the upright first column, a first connector securing the second end of the second strap to the second anchor, a second bi-fold door latch operable to retain the bi-fold door in engagement with the upright second column when the bi-fold door is in the aligned position, the second bi-fold door latch includes an elongated flexible third strap having a first end and a second end, a third drum attached to the drive shaft and first end of the third strap, a third anchor mounted on the upright second column, a second connector securing the second end of the third strap to the third anchor, whereby when the power unit rotates the drive shaft to wind the first strap on the first drum and unwind the second strap from the second drum and unwind the third strap from the third drum the first and second panels of the bi-fold door move relative to each other to a folded generally side-by-side position to open the bi-fold door opening and when the power unit rotates the drive shaft to unwind the first strap from the first drum and wind the second strap onto the second drum and wind the second strap onto the second drum and wind the third strap onto the third drum the first and second panels move relative to each other to the aligned position to close the bi-fold door opening and retain the first and second panels in engagement with the upright first and second columns.","21.The combination of claim 20 including: a frame secured to the building structure above the header, said power unit being operatively connected to the frame, and said drive shaft being rotatably mounted on the frame.","22.The combination of claim 20 including: a first kick-out device having a first arm pivotally connected to the header, including an eye-shaped member attached to the first arm accommodating the second strap, and a first spring engaging the first arm to bias the second strap away from the bi-fold door, a second kick-out device having a second arm pivotally connected to the header including an eye-shaped member attached to the second arm accommodating the third strap, and a second spring engaging the second arm to bias the third strap away from the bi-fold door.","23.The combination of claim 20 wherein: the first connector includes a rotatable first sleeve attached to the second anchor, a device for holding the first sleeve in a rotated selector position, the second end of the second strap being secured to the first sleeve whereby rotation of the first sleeve winds the second end of the second strap on the first sleeve, the second connector includes a rotatable second sleeve attached to the third anchor, a device for holding the second sleeve in a rotated selected position, and the second end of the third strap being secured to the second sleeve whereby rotation of the second sleeve winds the second end of the third strap on the second sleeve.","24.A door latch assembly for holding upper and lower panels of the bi-fold door in an aligned position in engagement with an upright column of a building comprising: an elongated flexible member having a first end and a second end, a rotatable latch drum located above the upper panel, a member connecting the first end of the flexible member to the latch drum whereby on rotation of the latch drum the flexible member winds around the latch drum, an anchor secured to a column of the building, a connector securing the second end of the flexible member to the anchor whereby on rotation of the latch drum to wind the flexible member on to the latch drum the flexible member moves the upper and lower panels of the bi-fold door into the aligned position in engagement with the upright column.","25.The door latch assembly of claim 24 wherein: the connector securing the second end of the flexible member to the anchor comprises a bracket attached to the anchor, a sleeve rotatably mounted on the bracket, a device for holding the sleeve in a rotated selected position, the second end of the flexible member being secured to the sleeve whereby rotation of the sleeve winds the second end of the flexible member on the sleeve.","26.The door latch assembly of claim 24 including: a roller mounted on one of the upper and lower panels of the bi-fold door adjacent the anchor, the flexible member engaging the roller to retain the upper and lower panels of the bi-fold door in the aligned position in engagement with the upright column.","27.The door latch assembly of claim 24 including: a kick-out device including an arm having an end, an eye-shaped member connected to the end of the arm accommodating the flexible member between the first and second ends of the flexible member, and a spring engaging the arm to bias the arm and the flexible member away from the bi-fold door.","28.A method of opening and closing a door opening located adjacent an upright column with a bi-fold door having a first panel pivotally connected to a second panel and holding the first and second panels in engagement with the upright column when the door opening is closed with the bi-fold door characterized by: locating the first and second panels in an aligned position adjacent the upright column to close the door opening, attaching a first end of a first strap to one of the first and second panels, attaching a second end of the first strap to a bi-fold door lift drum, attaching a first end of a second strap to the upright column, attaching a second end of the second strap to a bi-fold door latch drum, mounting the door lift drum and door latch drum on a shaft and connecting the shaft to a reversible drive unit operable to selectively rotate the shaft in opposite directions to wind and unwind the first strap onto and off the bi-fold door lift drum to open and close the door opening and to wind and unwind the second strap onto and off the bi-fold door latch drum to hold the first and second panels of the bi-fold door in engagement with an upright column when the first and second panels are in the aligned position closing the door opening and allow the first and second panels to move from the aligned position to a folded side-by-side position to open the door opening.","29.The method of claim 28 including: mounting the shaft for rotation on one of the first and second panels of the bi-fold door.","30.The method of claim 28 including: mounting the shaft for rotation on a frame located above the first and second panels of the bi-fold door.","31.The method of claim 28 including: biasing the second strap to maintain tension on the second strap during the opening and closing of the bi-fold door.","32.A method of opening and closing a door opening located between first and second upright columns with a bi-fold door having a first panel pivotally connected to a second panel and holding the first and second panels in engagement with the first and second upright columns when the door opening is closed with the bi-fold door characterized by: locating the first and second panels in an aligned position adjacent the first and second upright columns to close the door opening, attaching a first end of a first strap to one of the first and second panels, attaching a second end of the first strap to a bi-fold door lift drum, attaching a first end of a second strap to the first upright column, attaching a second end of the second strap to a first bi-fold door latch drum, attaching a first end of a third strap to the second upright column, attaching a second end of the third strap to a second bi-fold door latch drum, mounting the door lift drum and first and second bi-fold door latch drums on a shaft, and connecting the shaft to a reversible drive unit operable to selectively rotate the shaft in opposite directions to wind and unwind the first strap onto and off the bi-fold lift drum to open and close the door opening and to wind and unwind the second strap onto and off the first bi-fold door latch drum and to wind and unwind the third strap onto and off the second bi-fold door latch drum whereby the second strap holds the first and second panels in engagement with the first upright column and the third strap holds the first and second panels in engagement with the second upright column when the first and second panels are in the aligned position closing the door opening and allow the first and second panels to move from the aligned position to a folded side-by-side position to open the door opening.","33.The method of claim 32 including: mounting the shaft for rotation on one of the first and second panels of the bi-fold door.","34.The method of claim 32 including: mounting the shaft for rotation on a frame located above the first and second panels of the bi-fold door.","35.The method of claim 32 including: biasing the second strap and the third strap to maintain tension on the second strap and the third strap during the opening and closing of the bi-fold door."],["<SOH> BACKGROUND OF THE INVENTION <EOH>Buildings have large openings or doorways for accommodating vehicles, aircraft, watercraft and equipment which are moved into and out of the interior spaces in the buildings.","Common types of conventional doors used to open and close the doorways are horizontally sliding doors and two-piece center hinged doors known as bi-fold doors.","An example of an overhead bi-fold door is disclosed by M. L. Schweiss in U.S. Pat.","No.","6,866,080.The bi-fold doors have separate levers and mechanical latches operable to hold the doors in closed positions relative to the building structure.","C. E. McQueen et al.","in U.S. Pat.","No.","4,637,446 discloses a latch member that engages a catch plate to lock a bi-fold door in an upright closed position.","A spring connected to the latch member retains the latch member in locking engagement with the catch plate.","A lift cable connected to the latch member extending to a door opening mechanism is used to release the latch member from the catch plate to allow the bi-fold door to swing to an open folded position.","D. N. Keller in U.S. Pat.","No.","5,343,923 discloses a latching assembly operable to hold a bi-fold door in an upright closed position.","The latching assembly has an arm pivotally connected to the door frame that cooperates with a roller mounted on the adjacent door jamb.","An actuation assembly driven by an electric motor operates to open and close the bi-fold door.","The actuation assembly pulls a cable connected to the arm to pivot the arm into locking relationship with the roller on the door jamb to hold the bi-fold door in the upright closed position.","The latching assembly operates with a single electric motor that performs the latching and unlatching operations automatically in cooperation with the opening and closing of the bi-fold door."],["<SOH> SUMMARY OF THE INVENTION <EOH>The invention is a latch assembly cooperating with a door lift mechanism to secure a bi-fold door in an upright position closing a doorway of a building.","The bi-fold door has upper and lower panels hinged together to allow movement relative to each other between an upright closed position to a generally horizontal folded open position.","The upper panel is hinged to a header attached to upright columns or door jambs.","A lift mechanism comprising an electric motor driven shaft connect to lift drums accommodating flexible straps operates to move the door panels from upright closed positions to folded open positions to open the doorway to the interior of the building.","Latch assemblies operatively connected to one of the panels of the bi-fold door have latch drums connected to the shaft and latch straps joined to the latch drums and adjacent columns hold the bi-fold door in the closed upright position.","The lift mechanism straps wind on the lift drums and the latch straps unwind from the latch drums during movement of the bi-fold door from the upright closed position to the folded open position.","During closing of the bi-fold door the latch straps wind on the latch drums and retain the door panels in upright closed positions in engagement with the adjacent doorway columns."],["CROSS REFERENCE TO RELATED APPLICATION This application is a division of U.S. application Ser.","No.","15/067,431 filed Mar.","11, 2016.Application Ser.","No.","15/067,431 claims the priority of U.S.","Provisional Patent Application Ser.","No.","62/193,706 filed Jul.","17, 2015.FIELD OF THE INVENTION The latch assembly for a bi-fold door is in the art of apparatus for and methods of latching a bi-fold door in an upright position to close a doorway in a building.","BACKGROUND OF THE INVENTION Buildings have large openings or doorways for accommodating vehicles, aircraft, watercraft and equipment which are moved into and out of the interior spaces in the buildings.","Common types of conventional doors used to open and close the doorways are horizontally sliding doors and two-piece center hinged doors known as bi-fold doors.","An example of an overhead bi-fold door is disclosed by M. L. Schweiss in U.S. Pat.","No.","6,866,080.The bi-fold doors have separate levers and mechanical latches operable to hold the doors in closed positions relative to the building structure.","C. E. McQueen et al.","in U.S. Pat.","No.","4,637,446 discloses a latch member that engages a catch plate to lock a bi-fold door in an upright closed position.","A spring connected to the latch member retains the latch member in locking engagement with the catch plate.","A lift cable connected to the latch member extending to a door opening mechanism is used to release the latch member from the catch plate to allow the bi-fold door to swing to an open folded position.","D. N. Keller in U.S. Pat.","No.","5,343,923 discloses a latching assembly operable to hold a bi-fold door in an upright closed position.","The latching assembly has an arm pivotally connected to the door frame that cooperates with a roller mounted on the adjacent door jamb.","An actuation assembly driven by an electric motor operates to open and close the bi-fold door.","The actuation assembly pulls a cable connected to the arm to pivot the arm into locking relationship with the roller on the door jamb to hold the bi-fold door in the upright closed position.","The latching assembly operates with a single electric motor that performs the latching and unlatching operations automatically in cooperation with the opening and closing of the bi-fold door.","SUMMARY OF THE INVENTION The invention is a latch assembly cooperating with a door lift mechanism to secure a bi-fold door in an upright position closing a doorway of a building.","The bi-fold door has upper and lower panels hinged together to allow movement relative to each other between an upright closed position to a generally horizontal folded open position.","The upper panel is hinged to a header attached to upright columns or door jambs.","A lift mechanism comprising an electric motor driven shaft connect to lift drums accommodating flexible straps operates to move the door panels from upright closed positions to folded open positions to open the doorway to the interior of the building.","Latch assemblies operatively connected to one of the panels of the bi-fold door have latch drums connected to the shaft and latch straps joined to the latch drums and adjacent columns hold the bi-fold door in the closed upright position.","The lift mechanism straps wind on the lift drums and the latch straps unwind from the latch drums during movement of the bi-fold door from the upright closed position to the folded open position.","During closing of the bi-fold door the latch straps wind on the latch drums and retain the door panels in upright closed positions in engagement with the adjacent doorway columns.","DESCRIPTION OF THE DRAWING FIG.","1 is a perspective view of a bi-fold door closing a doorway of a building equipped with a door lift mechanism combined with automatic operated latch assemblies; FIG.","2 is a perspective view of the bi-fold door of FIG.","1 in a partly open position; FIG.","3 is an inside elevational view of a bi-fold door having a door lift mechanism combined with a latch assembly; FIG.","4 is a perspective view of the door lift strap assembly on a closed upright bi-fold door; FIG.","5 is an enlarged foreshortened sectional view taken along line 5-5 of FIG.","4; FIG.","6 is an end elevational view of the strap slack adjuster anchor for the strap of the door lift mechanism; FIG.","7 is an enlarged sectional view of the lift drum and strap taken along line 7-7 of FIG.","4; FIG.","8 is an enlarged perspective view of a section of the bi-fold door having a door lift mechanism combined with a latch assembly; FIG.","9 is an enlarged sectional view of a latch assembly for moving and holding the bi-fold door in the closed position; FIG.","10 is a sectional view taken along line 10-10 of FIG.","9; FIG.","11 is an enlarged elevational view, partly sectioned, of the upper end of the latch assembly shown in FIGS.","9 and 10; FIG.","12 is a sectional view taken along line 12-12 of FIG.","11; FIG.","13 is a perspective view of the strap ratchet and bracket assembly of the latch assembly; FIG.","14 is a perspective view of the lift drum and latch drum connected to a drive shaft accommodating lift and latch straps; FIG.","15 is a side elevational view showing the bi-fold door being moved to the folded open position; FIG.","16 is an inside elevational view of a bi-fold door and combined door lift mechanism and latch assemblies for locating the bi-fold door in an upright closed position; FIG.","17 is an elevational view of the combined door lift power drive apparatus rotating lift drums and latch drums; FIG.","18 is an enlarged sectional view taken along line 18-18 of FIG.","17; FIG.","19 is a perspective view of the lift drums and latch drums on the frame accommodating lift an latch straps; FIG.","20 is an enlarged elevational view of the latch strap roller assembly secured to a column of the building; FIG.","21 is a sectional view taken along line 21-21 of FIG.","20; and FIG.","22 is a perspective view of a latch strap ratchet anchor accommodating the latch strap.","DESCRIPTION OF THE BI-FOLD DOOR WITH LIFT MECHANISMS AND LATCH ASSEMBLIES In the following detailed descriptions of the bi-fold doors equipped with latch assemblies, reference is made to the accompanying drawing that form a part hereof, and in which are shown, by way of illustration, specific embodiments in which the invention may be practiced.","It is to be understood that other embodiments may be utilized and structure changes may be made or other method steps and sequence thereof may be used without departing from the scope of the present invention.","The latch assemblies are herein described as used in building environment.","The latch assemblies can have uses in other environments when securing doors used to close an opening is desired.","A building 20, shown in FIGS.","1 and 2, has a doorway 21 that is open and closed with a bi-fold door 22.Examples of building 20 include aviation hangers, automotive shops, farm shops, commercial buildings, warehouses and commercial plants.","Building 20 has a horizontal header 23 attached to upright end columns 24 and 26 located around doorway 21 open to the interior of building 20.Bi-fold door 22 has an upper panel 27 and a lower panel 28 movable between upright aligned positions to close doorway 21 and folded horizontal position to open doorway 21.Examples of bi-fold doors are disclosed in U.S. Pat.","Nos.","4,637,446; 5,168,914 and 6,199,617.Bi-fold door 22 has a metal frame 29 supporting upper and lower panels 27 and 28.Upper panel frame has top and bottom horizontal members 31 and 32 and a middle member 33 located between members 31 and 32.Upright end members 38 and 39 and upright middle members 41, 42, 43 and 44 are joined to horizontal members 31 and 32.Bottom panel 28 has top and bottom horizontal members 34 and 36 joined to end members 35.Frame members are elongated tubular beams welded to provide one-piece frames for panels 27 and 28.Sheathing 51 secured to frame 29 covers the outside of frame 29.A plurality of hinges 52 connected to frame members 32 and 34 pivotally join panels 27 and 28 for movement between an upright aligned closed position and a horizontal folded open position.","A plurality of hinges 53 connected to frame member 31 and header 23 pivotally mount door 22 on header 23 for swinging movement between an upright closed position and a generally horizontal folded open position.","A door lift mechanism 54 functions to lift door 22 from the upright closed position to the generally horizontal folded open position.","Lift mechanism 54 also retains door 22 in the open position.","When lift mechanism 54 releases door 22 the weight of door 22 and lift mechanism 54 returns door 22 to a nearly closed position.","Automatic latch assemblies 94 and 96 hereinafter described move panels 27 and 28 in upright aligned positions closing doorway 21 and retaining opposite sides of panels 27 and 28 in engagement with columns 24 and 26.Door lift mechanism 54 comprises a horizontal shaft 56 rotatably mounted on supports 57, 58, 59 and 60 secured to bottom member 36 of the lower panel frame.","Supports 57, 58, 59 and 60 have bearings accommodating shaft 56 for rotation about a generally horizontal axis.","A plurality of elongated flexible members, such as webs or straps 61, 62, 63 and 64 operatively connect shaft 56 to upper panel 27 whereby rotation of shaft 56 in one direction moves door 22 from the closed position to the open position and releases the automatic latch assemblies 94 and 96 and rotation of shaft 56 in an opposite direction to the one direction allows door 22 to move from the open position to the closed position and operating automatic latch assemblies 94 and 96 to retain panels 27 and 28 in upright aligned positions in engagement with columns 24 and 26 of building 20.As shown in FIG.","4, member 61 is an elongated flexible flat web or strap, such as a nylon or polyester web.","The upper section of member 61 is trained over a support 66 secured to upper frame member 31 and terminating on an anchor 67 secured to frame member 33.As shown in FIG.","5, support 66 has an inverted U-shaped bracket 68 secured with welds to the bottom of frame member 31.A roller or sleeve 69 is rotatably mounted on a bolt 71 attached to bracket 68.Strap 61 trained over roller 69 can move with roller 69 thereby reducing wear and strain on member 61.Anchor 67 has a U-shaped bracket 72 rotatably supporting a sleeve 73.Member 61 is wrapped around and secured to sleeve 73 to connect member 61 to sleeve 73 thereby anchoring member 61 to door frame 29.The slack or tension of strap 61 is adjusted with a ratchet ring 74 secured to sleeve 73.A holding panel 76 is held with a cotter pin 77 in engagement with the teeth on ring 74.Other devices can be used to adjust the slack or tension on strap 61.Flexible straps 62, 63 and 64 are trained over rollers operatively connected to frame member 31 and anchored to frame member 33 according to member 61 as shown in FIGS.","4, 5 and 6.The lower end of member 61 is connected to lift drum 78 secured to shaft 56.As shown in FIG.","7, disks 79 and 81 attached to opposite ends of drum 78 maintain member 61 in wrapping relation around drum 78 during winding of strap 61 of drum 78 and unwinding of member 61 from drum 78.A reversible electric motor 82 drives a power transmission 83 operable to transmit power through chain drives 84 and 86 coupled to sprockets 87 and 88 to shaft 56 whereby shaft 56 is selectively rotated in opposite directions to move bi-fold door 22 to a folded open position and allow door 22 to move to a closed position.","Shaft 56 is rotated in a counterclockwise direction, shown by arrow 89, to wind strap 61 around drum 78 to move door 22 to the open folded position.","Lift drums 91, 92 and 93, shown in FIG.","3, secured to shaft 56 accommodates flexible straps 62, 63 and 64 and concurrently wind and unwind flexible straps 62, 63 and 64 on drums 91, 92 and 93 as flexible straps 61 winds and unwinds on drum 78.Limit switches (not shown) associated with electric motor 82 and transmission 83 control the duration or timing of the operation of electric motor 82.Latch assemblies 94 and 96 mounted on opposite ends of frame 29 are operable to move panels 27 and 28 in upright or vertically aligned positions and retain panels 27 and 28 in engagement with columns 24 and 26 when door 22 is in the closed position.","As shown in FIGS.","8, 9 and 10, latch assembly 94 secured to door frame 29 adjacent column 24 comprises an upright U-shaped frame 97.Frame 97 is fastened with welds to frame member 38 and adjacent frame members.","Other types of fasteners can be used to attach frame 97 to door frame 29.A pair of horizontal rollers 98 and 99 are mounted on the upper end of frame 97.Rollers 98 and 99 are parallel and laterally spaced apart to accommodate a roller bracket assembly 101.As shown in FIG.","12, roller bracket assembly 101 has upright flat side members 102 and 103 connected to an upper pin or rod 104 and a lower pin or rod 106.A latch drum 109 located below frame 97 is rotatably mounted on supports 111 secured to door frame member 36.Shaft 56 is drivably connected to drum 109 to rotate drum 109 when driven by electric motor 82.Rotation of shaft 56 concurrently rotates lift drums 78, 91, 92 and 93 and latch drums 109 and 112 to move bi-fold door 22 to the upright closed position and retain bi-fold door 22 in the upright closed position.","A latch strap 113 attached to latch drum 109 extends upward into U-shaped frame 97 between a roller 114 and back wall of frame 97.The upper section of strap 113 extends horizontally over rollers 98 and 99 to a strap anchor 116.As shown in FIG.","13, anchor 116 has a bracket 117 secured with fasteners 118 to column 24.A U-shaped support 119 secured to bracket 117 rotatably accommodates a sleeve 121.Strap 113 is secured to sleeve 121 as shown in FIG.","11.Strap 113 is wound around sleeve 121 to adjust the effective length of strap 113 to retain bi-fold door 22 in the upright closed position.","A ratchet wheel 122 secured to sleeve 121 is used with a tool (not shown) to rotate sleeve 121 to wind strap 113 on sleeve 121.A pin 123 fixed to support 119 engages ratchet wheel 122 to hold ratchet wheel 122 and sleeve 121 in an adjusted position with strap 113 wound on sleeve 121.A tension spring 124 has a lower end connected to a bolt 126 extended through holes 127 in latch frame 97.As shown in FIG.","10, latch frame 97 has a plurality of vertically arranged holes 127 accommodating bolt 126 for adjusting the biasing force of spring 124 on strap 113, shown by arrow 127 in FIG.","11.The upper end of spring 124 is connected to pin 106 of roller bracket assembly 101.Pin 104 located on top of strap 113 between rollers 98 and 99 applies the biasing force of spring 124 to pull strap 113 down between rollers 98 and 99 to take up slack of strap 113 and maintain the tension on strap 113 during the opening and closing of bi-fold door 22.Latch assembly 96 mounted on the right end of door 22, as shown in FIG.","3, has the same structure and operation as latch assembly 96.Shaft 56 is drivably connected to latch drum 112 to rotate latch drum 112 whereby strap 128 is wound on and unwound from latch drum 112 during the opening and closing of bi-fold door 22 and the latching and unlatching functions of latch assembly 96.As shown in FIG.","14, when shaft 56 is rotated counterclockwise, shown by arrow 89, strap 61 is wound on drum 78.Straps 62, 63 and 64 are also wound on drums 91, 92 and 93.The combined straps 61, 62, 63 and 64 move down, shown by arrow 129, thereby moving bi-fold door 22 from the closed position to the folded open position.","During counterclockwise rotation of shaft 56 to latch drum 109 unwinds strap 113 from drum 109 whereby strap 113 moves upward releasing the horizontal force holding bi-fold door 22 in the closed position and allowing the bi-fold door to move upwardly to the open position, as shown by arrows 132 in FIG.","15.Strap 113 rides on roller 132 on the bottom of frame member 36 during movement of bi-fold door 22 between open and closed positions.","Spring 124 connected to roller bracket assembly 101 maintains a continuous biasing force on strap 113 during the opening and closing of bi-fold door 22.Shaft 56 is rotated in a clockwise direction by reversing the drive of electric motor 82.Straps 61, 62, 63 and 64 unwind from lift drums 78, 91, 92 and 93 allowing bi-fold door 22 to unfold from the open position to an upright closed position.","The weight of bi-fold door 22 caused by-fold door 22 to move down as straps 61-64 unwind from their respective drums.","Strap 113 as it winds onto drum 109 pulls bi-fold door 22 to an upright closed position, as shown in FIG.","10.When bi-fold door 22 is in the closed position, spring 124 acting on strap 113 biases bi-fold door 22 against column 24 and maintains bi-fold door 22 in the upright closed position.","An alternative embodiment of the bi-fold door having lift mechanism and automatic latch assemblies is shown in FIGS.","16 to 22.Bi-fold door 200 has an upper panel 221 and a lower panel 222 located in general vertical orientation closing doorway passage or opening in an exterior wall of building 20.Panels 221 and 222 are rectangular framed structures having exterior sheeting, such as wood, plastic, metal and the like.","Bi-fold door 200 has a plurality of center hinges 227 pivotally connecting adjacent horizontal frame members of panels 221 and 222 to allow panels 221 and 222 to fold upwardly, as shown in FIG.","2, to an open side-by-side position adjacent the top of the doorway opening.","Top frame member 228 of upper panel 221 is secured to a header 230 of the building wall with a plurality of hinges 229.As shown in FIG.","16, bi-fold door 200 is selectively moved to its open and closed positions with door lift devices indicated generally in FIG.","17 at 233, 234, 235 and 236 spaced along the length of bi-fold door 200.Door lift devices 233, 234, 235 and 236 have elongated flexible members, such as webs or straps 237, 238, 239 and 240 attached to anchors 241, 242, 243 and 244 mounted on bottom frame member 246 of lower panel 222 and lift drums 247, 248, 249 and 250 mounted on a frame member 253 of upper panel 221.Upper panel 221 and lower panel 222 of bi-fold door 200 are maintained in the vertically aligned closed position with door latch assemblies indicated generally at 271 and 272 located on opposite ends of bi-fold door 200.Door latch assemblies 271 and 272 have elongated flexible webs or straps 273 and 274 attached to anchors 276 and 277 mounted on the top portion of lower panel 222 and secured to latch drums 278 and 279 mounted on upper frame 253.Straps 273 and 274 are wrapped on latch drums 278 and 279 in an opposite direction from the direction straps 237-240 are wrapped on lift drums 247-250.Straps 237-240, 273 and 274 are elongated flexible, generally flat and substantially non-elastic members having a width between two and six inches and being made of plastic and fiber materials, such as nylon webs, polyester webs and the life.","Other types of materials can be used to make straps 237-240, 273 and 274.Straps 237-240, 273 and 274 can have other sizes and widths to accommodate different loads and latching requirements of bi-fold door 200.As shown in FIG.","17, a drive shaft 251 mounted on frame 253 is rotated with a power unit 252 to concurrently rotate lift drums 247-250 and latch drums 278 and 279 to wind straps 237-240 on lift drums 247-250 and allow straps 273 and 274 to unwind from latch drums 278 and 279 to unlatch and move bi-fold door 200 to is open position and wind straps 273 and 274 on latch drums 278 and 279 and allow straps 237-240 to unwind from lift drums 247-250 to move door 200 to its upright closed position and latch door 200 secure to the building columns.","Drive shaft 251 extends the length of frame 253.Latch drums 278 and 279 are mounted on opposite ends of frame 253 outwardly from lift drums 247 and 250.Frame 253 is attached to the building structure 250 and upright columns 245 and 255 above header 230.Door lift devices 231-236 are identical in structure and function.","The details of lift device 233, shown in FIGS.","17 to 22, are included in lift devices 234-237.The following description is directed to lift device 233.Power unit 252 mounted on frame 253, shown in FIGS.","16 and 18, includes a power transmission or gear box 266 driven with a reversible electric motor 269.An electric brake unit 267 locks gear box 266 when the electric power to motor 269 is turned off thereby preventing rotation of drive shaft 251.Motor 269 rotates drive shaft 251 connected to lift drums 247-250 and latch drums 278 and 279 to concurrently rotate lift drums 247-250 and latch drums 278 and 279 in opposite rotations directions to open and close bi-fold door 200 and latch bi-fold door 200 to the doorway columns.","Gear box 266 is drivably connected to drive shaft 251 to selectively rotate drive shaft 251 in clockwise and counterclockwise directions thereby concurrently rotating lift drums 247-250 and latch drums 278 and 279 in clockwise and counterclockwise directions to open bi-fold door 200 and close and latch bi-fold door 200 secure to the doorway columns.","A jack shaft chain and sprocket drive 268 is used to operatively connect gear box 266 with drive shaft 251.A manually operated switch (not shown) wired to motor 269 is used by an operator to control the electric power supplied to motor 269 and the opening, closing and latching of bi-fold door 200.As shown in FIG.","16, strap 237 extends downwardly from lift drum 247 to anchor 241 mounted on bottom frame member 246 of lower panel 222.The free end of strap 237 is attached to anchor 241.Anchor 241 can be adjusted to take up slack of strap 237 to adjust the operating or working length of strap 237 as needed.","As seen in FIG.","19, lift drum 247 is mounted on frame member 253.Lift drum 247 has a generally cylindrical outer surface providing a drum surface for strap 237.Door latch devices 271 and 272 are identical in structure and function.","The details of door latch device 271, shown in FIGS.","19 to 22, are included in door latch device 272.The following description is directed to door latch device 271.As shown in FIGS.","16 and 19, strap 273 extends downwardly from latch drum 278 through a kick out arm assembly 281 mounted on header 230.Kick out arm assembly 281 comprises a downward extending arm 286 having a lower end with a straight eye 287.Strap 273 extends through the opening of eye 287 downwardly to a roller 283, shown in FIGS.","20 and 21, mounted on support 285 attached to a bracket 288 secured to column 245 of the building.","Strap 273 is trained over roller 283 and extends laterally to anchor 276 mounted on the frame of lower panel 222.Returning to FIG.","19, arm assembly 281 has a spring member 289 that engages a horizontal bar member 291 to bias arm member 286 upwardly and inwardly away from the inside of bi-fold door 200, as shown by arrow 299 in FIG.","19, thereby maintaining tension on strap 273 during opening and closing of bi-fold door 200 and biasing the panels into engagement with the column 245 of the building.","As seen in FIG.","22, anchor 276 has a sleeve 292 mounted on a support 293 secured to lower panel 221.A ratchet wheel 294 and pawl 296 operate to hold sleeve 292 in a fixed position on support 293.In use, when bi-fold door 200 is moved from an open position to the closed latched position lift drums 247-250 are releasing straps 237-240 and latch drums 278 and 279 are taking up straps 273 and 274, as shown by arrows 301 and 302 in FIG.","17.When bi-fold door 200 is moved from the closed latched position to the open position latch drums 278 and 279 are releasing straps 273 and 274 and lift drums 247-250 are taking up straps 237-240.As bi-fold door 200 is moved from the closed latched position to the open position slack in straps 273 and 274 is taken up with kick out arm assemblies 281 and 282.When bi-fold door 200 is fully closed latch drums 278 and 279 are filled with straps 273 and 274 and lift drums 247-250 are left with a small amount of straps 237-240.Brake unit 267 locks gear box 266 when motor 269 is turned off whereby latch drums 278 and 279 are prevented from rotating and releasing straps 273 and 274 to maintain upper and lower panels 221 and 222 in a vertically aligned closed latched position in engagement with upright columns 245 and 255 of the building.","A bi-fold door 200 is unlatching and opening straps 237-240 are wrapped onto lift drums 247-250 while straps 273 and 274 are unwound off latch drums 278 and 279.Straps 273 and 274 add support to bi-fold door 200 preventing flipping of door 200 over the roof of the building in windy conditions.","The following drawing and description of the bi-fold door having latch assemblies is two embodiments of the invention.","Persons skilled in the art of bi-fold doors can make changes and modifications in structures and materials without departing from the invention defined in the claims."]],"string":"[\n [\n \"BI-FOLD DOOR LATCH ASSEMBLY\",\n \"A latch assembly connected to the drive unit of a bi-fold door retains the bi-fold door in engagement with upright columns of a building with elongated straps attached to the upright columns and rotatable latch drums mounted on a drive shaft of a drive unit.\",\n \"Lift devices powered by the drive unit raise and lower the bi-fold door.\",\n \"Latch assemblies include springs that maintain tension on the straps during the opening and closing of the bi-fold door.\"\n ],\n [\n \"1.An apparatus for opening and closing a door opening with a bi-fold door mounted on a structure having the door opening and an upright column adjacent the door opening, the bi-fold door having an upper panel, a lower panel, and hinges connecting the upper panel and the lower panel to allow the upper and lower panels to move from a vertically aligned closed latched position to a folded side-by-side open position comprising: door lift devices operable to selectively open and close the bi-fold door, a door latch assembly operable to latch the bi-fold door into engagement with the upright columns when the bi-fold door is in the closed latched position, a reversible power unit connected to the door lift devices and the door latch assembly for operating the door lift devices and the door latch assembly whereby the door lift devices are operable to open and close the bi-fold door, the door latch assembly is operable to latch the bi-fold door into engagement with the upright column, a drive shaft operatively connected to the reversible power unit, each of the respective door lift devices having a door lift drum secured to the drive shaft, a first strap having a first end and a second end, the first end being connected to the door lift drum whereby the power unit selectively rotates the drive shaft and door lift drum to wind the first strap in overlapping relation on the door lift drum and unwind the first strap off the door lift drum, a first anchor mounted on one panel connected to the second end of the first strap, the door latch assembly having a door latch drum secured to the drive shaft, a second strap having a first end and a second end, the first end of the second strap being connected to the door latch drum whereby when the power unit rotates the drive shaft and the door latch drum to wind the second strap in overlapping relation opposite from the overlapping relation of the first strap on the door lift drum and unwind the second strap off the door latch drum, a second anchor mounted on the upright column connected to the second end of the second strap whereby the power unit rotates the drive shaft, the door lift drum and the door latch drum to wind the first strap on the door lift drum and unwind the second strap off the door latch drum to open the bi-fold door and the power unit rotates the door lift drum and the door latch drum to unwind the first strap off the door lift drum and wind the second strap on the door latch drum to close the bi-fold door and latch the bi-fold door into engagement with the upright column.\",\n \"2.The apparatus of claim 1 wherein: the first and second straps are elongated generally flat members.\",\n \"3.The apparatus of claim 1 wherein: the first and second straps are flexible and flat, plastic and fiber members.\",\n \"4.The apparatus of claim 1 including: a roller assembly mounted on the structure adjacent the bi-fold door, the second strap extending from the door latch drum to the roller assembly and around the roller assembly to the second anchor.\",\n \"5.The apparatus of claim 1 including: a device operative to bias the second strap to maintain tension on the second strap during the opening and closing of the door opening with the bi-fold door.\",\n \"6.The apparatus of claim 1 including: a kick-out arm device having an arm pivotally connected to the structure, the arm having an eye-shaped outer end and accommodating the second strap, and a spring engaging the arm to bias the arm and the second strap away from the bi-fold door during opening and closing of the bi-fold door.\",\n \"7.A combination of a bi-fold door and an apparatus for opening, closing and latching the bi-fold door to upright columns located adjacent opposite sides of a bi-fold door opening and building structure located above the bi-fold door opening comprising: a bi-fold door hinged to a header of the building structure located above the door opening, the bi-fold door having an upper panel, a lower panel and hinges pivotally connecting the upper and lower panels to allow the upper and lower panels to be moved from an aligned closed position to a folded generally side-by-side open position, bi-fold door lift devices operable to selectively move the upper and lower panels of the bi-fold door to the folded generally side-by-side open position and the aligned closed position, bi-fold door latch assemblies operable to retain the bi-fold door in engagement with the upright columns of the structure when the upper and lower panels of the bi-fold door are in the aligned closed position, a reversible power unit mounted on the building structure above the door opening and operatively connected to the bi-fold door lift devices and the door latch assemblies for operating the door lift devices and the door latch assemblies whereby the door lift devices open and close the bi-fold door and the bi-fold door latch assemblies latch the closed bi-fold door in engagement with the upright columns, each of the bi-fold door lift devices having a respective elongated flexible first strap having a first end and a second end, a respective rotatable first drum attached to the first end of the first strap operably connected to the power unit whereby on rotation of the first drum the first strap winds in overlapping relation around the first drum, a respective first anchor mounted on the lower panel connected to the second end of the first strap, each of the door latch assemblies has a respective elongated flexible second strap having a first end and a second end, a respective second rotatable drum attached to the first end of the second strap operatively connected to the power unit whereby on rotation of the second drum the second strap winds in overlapping relation around the second drum in a direction opposite from the overlapping relation of the first strap and the first drum, a respective second anchor secured to an upright column, the respective second end of the second strap being connected to a second anchor whereby when the power unit rotates the first and second rotatable drums to wind the first strap onto the first drum and unwind the second strap off the second drum the upper and lower panels move relative to each other to a side-by-side relationship to open the bi-fold door and when the power unit rotates the first and second drums to unwind the first strap off the first drum and wind the second strap onto the second drum the upper and lower panels move relative to each other to aligned relationship to close the bi-fold door and retain the bi-fold door in engagement with the upright columns of the structure.\",\n \"8.The combination of claim 7 wherein: the first and second straps are flexible and flat, plastic and fiber members.\",\n \"9.The combination of claim 7 including: a drive shaft, the reversible power unit is drivably connected to the drive shaft for selectively rotating the drive shaft in opposite directions, the first and second drums are mounted on the drive shaft whereby upon rotation of the drive shaft in one direction the first strap winds in overlapping relation around the first drum and the second strap unwinds off the second drum thereby moving the bi-fold door from a closed position to an open position and upon rotation of the drive shaft in a direction opposite the one direction the first strap unwinds off the first drum and the second strap winds in overlapping direction around the second drum whereby the bi-fold door moves from the open position to the closed position.\",\n \"10.The combination of claim 7 including: a device operable to bias the second strap to maintain tension on the second strap during the opening and closing of the bi-fold door.\",\n \"11.The combination of claim 7 including: a kick-out device having an arm, the arm having an eye-shaped outer end accommodating the second strap, and a spring engaging the arm to bias the arm and the second strap away from the bi-fold door.\",\n \"12.The combination of claim 7 wherein: the respective second member includes a bracket fastened to one of the upright columns, a rotatable sleeve connected to the bracket, a device for holding the sleeve in a rotated selected position, the respective second end of the second strap being secured to the sleeve whereby rotation of the sleeve winds the respective second end of the strap on the sleeve, 13.The combination of claim 7 including: a frame secured to the building structure located above the door opening, the reversible power unit is mounted on the frame, a drive shaft rotatably mounted on the frame and operably connected to the reversible power unit whereby the reversible power unit operates to selectively rotate the drive shaft in opposite directions, and the first and second drums are mounted on the drive shaft whereby upon rotation of the drive shaft in one direction the first strap winds in overlapping relation around the first drum and the second strap unwinds off the second drum thereby moving the bi-fold door from a closed position to an open position and upon rotation of the drive shaft in a direction opposite the one direction the first strap unwinds off the first drum and the second strap winds in overlapping direction around the second drum whereby the bi-fold door moves from the open position to the closed position.\",\n \"14.A door for closing a doorway in a building having a horizontal header, upright columns adjacent opposite sides of the doorway and building structure above the header comprising: a bi-fold door having an upper panel and a lower panel and hinges pivotally connecting the upper and lower panels to allow the upper and lower panels to move between an aligned upright position closing the doorway and folded generally side-by-side position opening the doorway, at least one hinge for connecting the upper panel to the header of the building, door lift devices operable to move the upper and lower panels between the upright position and the side-by-side position and allow the upper and lower panels to move from the open side-by-side position to the aligned upright position, door latch assemblies operable to retain the upper and lower panels in the upright position in engagement with the columns of the building, a power unit mounted on the building structure above the header operably connected to the door lift devices and door latch assemblies for operating the door lift devices and door latch assemblies whereby the door lift devices move the upper and lower panels between aligned upright and side-by-side positions and the door latch assemblies retain the upper and lower panels in the aligned upright position in engagement with the columns of the building, the power unit having a drive shaft and a motor operable to rotate the drive shaft, each of the door latch assemblies has a respective elongated flexible member having a first end and a second end, a respective latch drum attached to the drive shaft, the first end of the flexible member being connected to the latch drum, a respective anchor secured to an upright column adjacent one of the upper and lower panels, the second end of the flexible member being connected to the respective anchor, and a respective roller mounted on the one of the upper and lower panels adjacent the respective anchor, the flexible member extending from the latch drum and around the respective roller to the respective anchor whereby when the flexible member is wound on the latch drum the flexible member pulls the upper and lower panels to the aligned upright position and retains the upper and lower panels in the aligned upright position in engagement with the upright columns of the building closing the doorway, 15.The door of claim 14 wherein: the flexible member is an elongated flexible strap.\",\n \"16.The door of claim 14 including: a biasing apparatus mounted on the one of the upper and lower panels for maintaining tension of the flexible member during the opening and closing of the upper and lower panels of the bi-fold door.\",\n \"17.The door of claim 16 including: a kick-out device having an arm pivotally mounted on the headers, the arm having an eye-shaped outer end accommodating the second strap, and a biasing member engaging the arm to bias the arm and the second strap away from the bi-fold door.\",\n \"18.The door of claim 17 wherein: the flexible member is an elongated flexible strap.\",\n \"19.The door of claim 14 wherein: the respective anchor includes a bracket fastened to an upright column of the building, a rotatable sleeve connected to the bracket, a member for holding the sleeve on the bracket, and the respective second end of the flexible member being connected to the sleeve whereby on rotation of the drive shaft the flexible member winds around the respective latch drum and moves the upper and lower panels in aligned upright positions into engagement with the columns of the building.\",\n \"20.A combination of a bi-fold door, bi-fold door lifts for selectively opening and closing the bi-fold door and door latches for holding the bi-fold door in a closed position relative to upright first and second columns located adjacent opposite sides of a bi-fold door opening and building structure including a header located above the bi-fold door opening comprising: a bi-fold door having a first panel, a second panel and hinges pivotally connecting the first and second panels to allow the first and second panels to be moved from an aligned position to close the bi-fold door opening and to a folded side-by-side position to open the bi-fold door opening, at least one hinge pivotally connecting the first panel to the header to support the bi-fold door on the header and allow the bi-fold door to move from the aligned position to the side-by-side position and moved from the folded generally side-by-side position to the aligned position, at least one bi-fold door lift device operable to selectively move the first and second panels of the bi-fold door between the aligned position to the folded side-by-side position and allow the first and second panels of the bi-fold door to move from the folded side-by-side position to the aligned position, a power unit mounted on the building structure above the header having a drive shaft rotatable in opposite directions, the bi-fold door lift device includes an elongated flexible first strap having a first end and a second end, a first drum attached to the drive shaft and connected to the first end of the first strap, a first anchor mounted on the second panel and connected to the second end of the first strap, a first bi-fold door latch operable to retain the bi-fold door in engagement with the upright first column when the bi-fold door is in the aligned position, the first bi-fold door latch includes an elongated flexible second strap having a first end and a second end, a second drum attached to the drive shaft and attached to the first end of the second strap, a second anchor mounted on the upright first column, a first connector securing the second end of the second strap to the second anchor, a second bi-fold door latch operable to retain the bi-fold door in engagement with the upright second column when the bi-fold door is in the aligned position, the second bi-fold door latch includes an elongated flexible third strap having a first end and a second end, a third drum attached to the drive shaft and first end of the third strap, a third anchor mounted on the upright second column, a second connector securing the second end of the third strap to the third anchor, whereby when the power unit rotates the drive shaft to wind the first strap on the first drum and unwind the second strap from the second drum and unwind the third strap from the third drum the first and second panels of the bi-fold door move relative to each other to a folded generally side-by-side position to open the bi-fold door opening and when the power unit rotates the drive shaft to unwind the first strap from the first drum and wind the second strap onto the second drum and wind the second strap onto the second drum and wind the third strap onto the third drum the first and second panels move relative to each other to the aligned position to close the bi-fold door opening and retain the first and second panels in engagement with the upright first and second columns.\",\n \"21.The combination of claim 20 including: a frame secured to the building structure above the header, said power unit being operatively connected to the frame, and said drive shaft being rotatably mounted on the frame.\",\n \"22.The combination of claim 20 including: a first kick-out device having a first arm pivotally connected to the header, including an eye-shaped member attached to the first arm accommodating the second strap, and a first spring engaging the first arm to bias the second strap away from the bi-fold door, a second kick-out device having a second arm pivotally connected to the header including an eye-shaped member attached to the second arm accommodating the third strap, and a second spring engaging the second arm to bias the third strap away from the bi-fold door.\",\n \"23.The combination of claim 20 wherein: the first connector includes a rotatable first sleeve attached to the second anchor, a device for holding the first sleeve in a rotated selector position, the second end of the second strap being secured to the first sleeve whereby rotation of the first sleeve winds the second end of the second strap on the first sleeve, the second connector includes a rotatable second sleeve attached to the third anchor, a device for holding the second sleeve in a rotated selected position, and the second end of the third strap being secured to the second sleeve whereby rotation of the second sleeve winds the second end of the third strap on the second sleeve.\",\n \"24.A door latch assembly for holding upper and lower panels of the bi-fold door in an aligned position in engagement with an upright column of a building comprising: an elongated flexible member having a first end and a second end, a rotatable latch drum located above the upper panel, a member connecting the first end of the flexible member to the latch drum whereby on rotation of the latch drum the flexible member winds around the latch drum, an anchor secured to a column of the building, a connector securing the second end of the flexible member to the anchor whereby on rotation of the latch drum to wind the flexible member on to the latch drum the flexible member moves the upper and lower panels of the bi-fold door into the aligned position in engagement with the upright column.\",\n \"25.The door latch assembly of claim 24 wherein: the connector securing the second end of the flexible member to the anchor comprises a bracket attached to the anchor, a sleeve rotatably mounted on the bracket, a device for holding the sleeve in a rotated selected position, the second end of the flexible member being secured to the sleeve whereby rotation of the sleeve winds the second end of the flexible member on the sleeve.\",\n \"26.The door latch assembly of claim 24 including: a roller mounted on one of the upper and lower panels of the bi-fold door adjacent the anchor, the flexible member engaging the roller to retain the upper and lower panels of the bi-fold door in the aligned position in engagement with the upright column.\",\n \"27.The door latch assembly of claim 24 including: a kick-out device including an arm having an end, an eye-shaped member connected to the end of the arm accommodating the flexible member between the first and second ends of the flexible member, and a spring engaging the arm to bias the arm and the flexible member away from the bi-fold door.\",\n \"28.A method of opening and closing a door opening located adjacent an upright column with a bi-fold door having a first panel pivotally connected to a second panel and holding the first and second panels in engagement with the upright column when the door opening is closed with the bi-fold door characterized by: locating the first and second panels in an aligned position adjacent the upright column to close the door opening, attaching a first end of a first strap to one of the first and second panels, attaching a second end of the first strap to a bi-fold door lift drum, attaching a first end of a second strap to the upright column, attaching a second end of the second strap to a bi-fold door latch drum, mounting the door lift drum and door latch drum on a shaft and connecting the shaft to a reversible drive unit operable to selectively rotate the shaft in opposite directions to wind and unwind the first strap onto and off the bi-fold door lift drum to open and close the door opening and to wind and unwind the second strap onto and off the bi-fold door latch drum to hold the first and second panels of the bi-fold door in engagement with an upright column when the first and second panels are in the aligned position closing the door opening and allow the first and second panels to move from the aligned position to a folded side-by-side position to open the door opening.\",\n \"29.The method of claim 28 including: mounting the shaft for rotation on one of the first and second panels of the bi-fold door.\",\n \"30.The method of claim 28 including: mounting the shaft for rotation on a frame located above the first and second panels of the bi-fold door.\",\n \"31.The method of claim 28 including: biasing the second strap to maintain tension on the second strap during the opening and closing of the bi-fold door.\",\n \"32.A method of opening and closing a door opening located between first and second upright columns with a bi-fold door having a first panel pivotally connected to a second panel and holding the first and second panels in engagement with the first and second upright columns when the door opening is closed with the bi-fold door characterized by: locating the first and second panels in an aligned position adjacent the first and second upright columns to close the door opening, attaching a first end of a first strap to one of the first and second panels, attaching a second end of the first strap to a bi-fold door lift drum, attaching a first end of a second strap to the first upright column, attaching a second end of the second strap to a first bi-fold door latch drum, attaching a first end of a third strap to the second upright column, attaching a second end of the third strap to a second bi-fold door latch drum, mounting the door lift drum and first and second bi-fold door latch drums on a shaft, and connecting the shaft to a reversible drive unit operable to selectively rotate the shaft in opposite directions to wind and unwind the first strap onto and off the bi-fold lift drum to open and close the door opening and to wind and unwind the second strap onto and off the first bi-fold door latch drum and to wind and unwind the third strap onto and off the second bi-fold door latch drum whereby the second strap holds the first and second panels in engagement with the first upright column and the third strap holds the first and second panels in engagement with the second upright column when the first and second panels are in the aligned position closing the door opening and allow the first and second panels to move from the aligned position to a folded side-by-side position to open the door opening.\",\n \"33.The method of claim 32 including: mounting the shaft for rotation on one of the first and second panels of the bi-fold door.\",\n \"34.The method of claim 32 including: mounting the shaft for rotation on a frame located above the first and second panels of the bi-fold door.\",\n \"35.The method of claim 32 including: biasing the second strap and the third strap to maintain tension on the second strap and the third strap during the opening and closing of the bi-fold door.\"\n ],\n [\n \"<SOH> BACKGROUND OF THE INVENTION <EOH>Buildings have large openings or doorways for accommodating vehicles, aircraft, watercraft and equipment which are moved into and out of the interior spaces in the buildings.\",\n \"Common types of conventional doors used to open and close the doorways are horizontally sliding doors and two-piece center hinged doors known as bi-fold doors.\",\n \"An example of an overhead bi-fold door is disclosed by M. L. Schweiss in U.S. Pat.\",\n \"No.\",\n \"6,866,080.The bi-fold doors have separate levers and mechanical latches operable to hold the doors in closed positions relative to the building structure.\",\n \"C. E. McQueen et al.\",\n \"in U.S. Pat.\",\n \"No.\",\n \"4,637,446 discloses a latch member that engages a catch plate to lock a bi-fold door in an upright closed position.\",\n \"A spring connected to the latch member retains the latch member in locking engagement with the catch plate.\",\n \"A lift cable connected to the latch member extending to a door opening mechanism is used to release the latch member from the catch plate to allow the bi-fold door to swing to an open folded position.\",\n \"D. N. Keller in U.S. Pat.\",\n \"No.\",\n \"5,343,923 discloses a latching assembly operable to hold a bi-fold door in an upright closed position.\",\n \"The latching assembly has an arm pivotally connected to the door frame that cooperates with a roller mounted on the adjacent door jamb.\",\n \"An actuation assembly driven by an electric motor operates to open and close the bi-fold door.\",\n \"The actuation assembly pulls a cable connected to the arm to pivot the arm into locking relationship with the roller on the door jamb to hold the bi-fold door in the upright closed position.\",\n \"The latching assembly operates with a single electric motor that performs the latching and unlatching operations automatically in cooperation with the opening and closing of the bi-fold door.\"\n ],\n [\n \"<SOH> SUMMARY OF THE INVENTION <EOH>The invention is a latch assembly cooperating with a door lift mechanism to secure a bi-fold door in an upright position closing a doorway of a building.\",\n \"The bi-fold door has upper and lower panels hinged together to allow movement relative to each other between an upright closed position to a generally horizontal folded open position.\",\n \"The upper panel is hinged to a header attached to upright columns or door jambs.\",\n \"A lift mechanism comprising an electric motor driven shaft connect to lift drums accommodating flexible straps operates to move the door panels from upright closed positions to folded open positions to open the doorway to the interior of the building.\",\n \"Latch assemblies operatively connected to one of the panels of the bi-fold door have latch drums connected to the shaft and latch straps joined to the latch drums and adjacent columns hold the bi-fold door in the closed upright position.\",\n \"The lift mechanism straps wind on the lift drums and the latch straps unwind from the latch drums during movement of the bi-fold door from the upright closed position to the folded open position.\",\n \"During closing of the bi-fold door the latch straps wind on the latch drums and retain the door panels in upright closed positions in engagement with the adjacent doorway columns.\"\n ],\n [\n \"CROSS REFERENCE TO RELATED APPLICATION This application is a division of U.S. application Ser.\",\n \"No.\",\n \"15/067,431 filed Mar.\",\n \"11, 2016.Application Ser.\",\n \"No.\",\n \"15/067,431 claims the priority of U.S.\",\n \"Provisional Patent Application Ser.\",\n \"No.\",\n \"62/193,706 filed Jul.\",\n \"17, 2015.FIELD OF THE INVENTION The latch assembly for a bi-fold door is in the art of apparatus for and methods of latching a bi-fold door in an upright position to close a doorway in a building.\",\n \"BACKGROUND OF THE INVENTION Buildings have large openings or doorways for accommodating vehicles, aircraft, watercraft and equipment which are moved into and out of the interior spaces in the buildings.\",\n \"Common types of conventional doors used to open and close the doorways are horizontally sliding doors and two-piece center hinged doors known as bi-fold doors.\",\n \"An example of an overhead bi-fold door is disclosed by M. L. Schweiss in U.S. Pat.\",\n \"No.\",\n \"6,866,080.The bi-fold doors have separate levers and mechanical latches operable to hold the doors in closed positions relative to the building structure.\",\n \"C. E. McQueen et al.\",\n \"in U.S. Pat.\",\n \"No.\",\n \"4,637,446 discloses a latch member that engages a catch plate to lock a bi-fold door in an upright closed position.\",\n \"A spring connected to the latch member retains the latch member in locking engagement with the catch plate.\",\n \"A lift cable connected to the latch member extending to a door opening mechanism is used to release the latch member from the catch plate to allow the bi-fold door to swing to an open folded position.\",\n \"D. N. Keller in U.S. Pat.\",\n \"No.\",\n \"5,343,923 discloses a latching assembly operable to hold a bi-fold door in an upright closed position.\",\n \"The latching assembly has an arm pivotally connected to the door frame that cooperates with a roller mounted on the adjacent door jamb.\",\n \"An actuation assembly driven by an electric motor operates to open and close the bi-fold door.\",\n \"The actuation assembly pulls a cable connected to the arm to pivot the arm into locking relationship with the roller on the door jamb to hold the bi-fold door in the upright closed position.\",\n \"The latching assembly operates with a single electric motor that performs the latching and unlatching operations automatically in cooperation with the opening and closing of the bi-fold door.\",\n \"SUMMARY OF THE INVENTION The invention is a latch assembly cooperating with a door lift mechanism to secure a bi-fold door in an upright position closing a doorway of a building.\",\n \"The bi-fold door has upper and lower panels hinged together to allow movement relative to each other between an upright closed position to a generally horizontal folded open position.\",\n \"The upper panel is hinged to a header attached to upright columns or door jambs.\",\n \"A lift mechanism comprising an electric motor driven shaft connect to lift drums accommodating flexible straps operates to move the door panels from upright closed positions to folded open positions to open the doorway to the interior of the building.\",\n \"Latch assemblies operatively connected to one of the panels of the bi-fold door have latch drums connected to the shaft and latch straps joined to the latch drums and adjacent columns hold the bi-fold door in the closed upright position.\",\n \"The lift mechanism straps wind on the lift drums and the latch straps unwind from the latch drums during movement of the bi-fold door from the upright closed position to the folded open position.\",\n \"During closing of the bi-fold door the latch straps wind on the latch drums and retain the door panels in upright closed positions in engagement with the adjacent doorway columns.\",\n \"DESCRIPTION OF THE DRAWING FIG.\",\n \"1 is a perspective view of a bi-fold door closing a doorway of a building equipped with a door lift mechanism combined with automatic operated latch assemblies; FIG.\",\n \"2 is a perspective view of the bi-fold door of FIG.\",\n \"1 in a partly open position; FIG.\",\n \"3 is an inside elevational view of a bi-fold door having a door lift mechanism combined with a latch assembly; FIG.\",\n \"4 is a perspective view of the door lift strap assembly on a closed upright bi-fold door; FIG.\",\n \"5 is an enlarged foreshortened sectional view taken along line 5-5 of FIG.\",\n \"4; FIG.\",\n \"6 is an end elevational view of the strap slack adjuster anchor for the strap of the door lift mechanism; FIG.\",\n \"7 is an enlarged sectional view of the lift drum and strap taken along line 7-7 of FIG.\",\n \"4; FIG.\",\n \"8 is an enlarged perspective view of a section of the bi-fold door having a door lift mechanism combined with a latch assembly; FIG.\",\n \"9 is an enlarged sectional view of a latch assembly for moving and holding the bi-fold door in the closed position; FIG.\",\n \"10 is a sectional view taken along line 10-10 of FIG.\",\n \"9; FIG.\",\n \"11 is an enlarged elevational view, partly sectioned, of the upper end of the latch assembly shown in FIGS.\",\n \"9 and 10; FIG.\",\n \"12 is a sectional view taken along line 12-12 of FIG.\",\n \"11; FIG.\",\n \"13 is a perspective view of the strap ratchet and bracket assembly of the latch assembly; FIG.\",\n \"14 is a perspective view of the lift drum and latch drum connected to a drive shaft accommodating lift and latch straps; FIG.\",\n \"15 is a side elevational view showing the bi-fold door being moved to the folded open position; FIG.\",\n \"16 is an inside elevational view of a bi-fold door and combined door lift mechanism and latch assemblies for locating the bi-fold door in an upright closed position; FIG.\",\n \"17 is an elevational view of the combined door lift power drive apparatus rotating lift drums and latch drums; FIG.\",\n \"18 is an enlarged sectional view taken along line 18-18 of FIG.\",\n \"17; FIG.\",\n \"19 is a perspective view of the lift drums and latch drums on the frame accommodating lift an latch straps; FIG.\",\n \"20 is an enlarged elevational view of the latch strap roller assembly secured to a column of the building; FIG.\",\n \"21 is a sectional view taken along line 21-21 of FIG.\",\n \"20; and FIG.\",\n \"22 is a perspective view of a latch strap ratchet anchor accommodating the latch strap.\",\n \"DESCRIPTION OF THE BI-FOLD DOOR WITH LIFT MECHANISMS AND LATCH ASSEMBLIES In the following detailed descriptions of the bi-fold doors equipped with latch assemblies, reference is made to the accompanying drawing that form a part hereof, and in which are shown, by way of illustration, specific embodiments in which the invention may be practiced.\",\n \"It is to be understood that other embodiments may be utilized and structure changes may be made or other method steps and sequence thereof may be used without departing from the scope of the present invention.\",\n \"The latch assemblies are herein described as used in building environment.\",\n \"The latch assemblies can have uses in other environments when securing doors used to close an opening is desired.\",\n \"A building 20, shown in FIGS.\",\n \"1 and 2, has a doorway 21 that is open and closed with a bi-fold door 22.Examples of building 20 include aviation hangers, automotive shops, farm shops, commercial buildings, warehouses and commercial plants.\",\n \"Building 20 has a horizontal header 23 attached to upright end columns 24 and 26 located around doorway 21 open to the interior of building 20.Bi-fold door 22 has an upper panel 27 and a lower panel 28 movable between upright aligned positions to close doorway 21 and folded horizontal position to open doorway 21.Examples of bi-fold doors are disclosed in U.S. Pat.\",\n \"Nos.\",\n \"4,637,446; 5,168,914 and 6,199,617.Bi-fold door 22 has a metal frame 29 supporting upper and lower panels 27 and 28.Upper panel frame has top and bottom horizontal members 31 and 32 and a middle member 33 located between members 31 and 32.Upright end members 38 and 39 and upright middle members 41, 42, 43 and 44 are joined to horizontal members 31 and 32.Bottom panel 28 has top and bottom horizontal members 34 and 36 joined to end members 35.Frame members are elongated tubular beams welded to provide one-piece frames for panels 27 and 28.Sheathing 51 secured to frame 29 covers the outside of frame 29.A plurality of hinges 52 connected to frame members 32 and 34 pivotally join panels 27 and 28 for movement between an upright aligned closed position and a horizontal folded open position.\",\n \"A plurality of hinges 53 connected to frame member 31 and header 23 pivotally mount door 22 on header 23 for swinging movement between an upright closed position and a generally horizontal folded open position.\",\n \"A door lift mechanism 54 functions to lift door 22 from the upright closed position to the generally horizontal folded open position.\",\n \"Lift mechanism 54 also retains door 22 in the open position.\",\n \"When lift mechanism 54 releases door 22 the weight of door 22 and lift mechanism 54 returns door 22 to a nearly closed position.\",\n \"Automatic latch assemblies 94 and 96 hereinafter described move panels 27 and 28 in upright aligned positions closing doorway 21 and retaining opposite sides of panels 27 and 28 in engagement with columns 24 and 26.Door lift mechanism 54 comprises a horizontal shaft 56 rotatably mounted on supports 57, 58, 59 and 60 secured to bottom member 36 of the lower panel frame.\",\n \"Supports 57, 58, 59 and 60 have bearings accommodating shaft 56 for rotation about a generally horizontal axis.\",\n \"A plurality of elongated flexible members, such as webs or straps 61, 62, 63 and 64 operatively connect shaft 56 to upper panel 27 whereby rotation of shaft 56 in one direction moves door 22 from the closed position to the open position and releases the automatic latch assemblies 94 and 96 and rotation of shaft 56 in an opposite direction to the one direction allows door 22 to move from the open position to the closed position and operating automatic latch assemblies 94 and 96 to retain panels 27 and 28 in upright aligned positions in engagement with columns 24 and 26 of building 20.As shown in FIG.\",\n \"4, member 61 is an elongated flexible flat web or strap, such as a nylon or polyester web.\",\n \"The upper section of member 61 is trained over a support 66 secured to upper frame member 31 and terminating on an anchor 67 secured to frame member 33.As shown in FIG.\",\n \"5, support 66 has an inverted U-shaped bracket 68 secured with welds to the bottom of frame member 31.A roller or sleeve 69 is rotatably mounted on a bolt 71 attached to bracket 68.Strap 61 trained over roller 69 can move with roller 69 thereby reducing wear and strain on member 61.Anchor 67 has a U-shaped bracket 72 rotatably supporting a sleeve 73.Member 61 is wrapped around and secured to sleeve 73 to connect member 61 to sleeve 73 thereby anchoring member 61 to door frame 29.The slack or tension of strap 61 is adjusted with a ratchet ring 74 secured to sleeve 73.A holding panel 76 is held with a cotter pin 77 in engagement with the teeth on ring 74.Other devices can be used to adjust the slack or tension on strap 61.Flexible straps 62, 63 and 64 are trained over rollers operatively connected to frame member 31 and anchored to frame member 33 according to member 61 as shown in FIGS.\",\n \"4, 5 and 6.The lower end of member 61 is connected to lift drum 78 secured to shaft 56.As shown in FIG.\",\n \"7, disks 79 and 81 attached to opposite ends of drum 78 maintain member 61 in wrapping relation around drum 78 during winding of strap 61 of drum 78 and unwinding of member 61 from drum 78.A reversible electric motor 82 drives a power transmission 83 operable to transmit power through chain drives 84 and 86 coupled to sprockets 87 and 88 to shaft 56 whereby shaft 56 is selectively rotated in opposite directions to move bi-fold door 22 to a folded open position and allow door 22 to move to a closed position.\",\n \"Shaft 56 is rotated in a counterclockwise direction, shown by arrow 89, to wind strap 61 around drum 78 to move door 22 to the open folded position.\",\n \"Lift drums 91, 92 and 93, shown in FIG.\",\n \"3, secured to shaft 56 accommodates flexible straps 62, 63 and 64 and concurrently wind and unwind flexible straps 62, 63 and 64 on drums 91, 92 and 93 as flexible straps 61 winds and unwinds on drum 78.Limit switches (not shown) associated with electric motor 82 and transmission 83 control the duration or timing of the operation of electric motor 82.Latch assemblies 94 and 96 mounted on opposite ends of frame 29 are operable to move panels 27 and 28 in upright or vertically aligned positions and retain panels 27 and 28 in engagement with columns 24 and 26 when door 22 is in the closed position.\",\n \"As shown in FIGS.\",\n \"8, 9 and 10, latch assembly 94 secured to door frame 29 adjacent column 24 comprises an upright U-shaped frame 97.Frame 97 is fastened with welds to frame member 38 and adjacent frame members.\",\n \"Other types of fasteners can be used to attach frame 97 to door frame 29.A pair of horizontal rollers 98 and 99 are mounted on the upper end of frame 97.Rollers 98 and 99 are parallel and laterally spaced apart to accommodate a roller bracket assembly 101.As shown in FIG.\",\n \"12, roller bracket assembly 101 has upright flat side members 102 and 103 connected to an upper pin or rod 104 and a lower pin or rod 106.A latch drum 109 located below frame 97 is rotatably mounted on supports 111 secured to door frame member 36.Shaft 56 is drivably connected to drum 109 to rotate drum 109 when driven by electric motor 82.Rotation of shaft 56 concurrently rotates lift drums 78, 91, 92 and 93 and latch drums 109 and 112 to move bi-fold door 22 to the upright closed position and retain bi-fold door 22 in the upright closed position.\",\n \"A latch strap 113 attached to latch drum 109 extends upward into U-shaped frame 97 between a roller 114 and back wall of frame 97.The upper section of strap 113 extends horizontally over rollers 98 and 99 to a strap anchor 116.As shown in FIG.\",\n \"13, anchor 116 has a bracket 117 secured with fasteners 118 to column 24.A U-shaped support 119 secured to bracket 117 rotatably accommodates a sleeve 121.Strap 113 is secured to sleeve 121 as shown in FIG.\",\n \"11.Strap 113 is wound around sleeve 121 to adjust the effective length of strap 113 to retain bi-fold door 22 in the upright closed position.\",\n \"A ratchet wheel 122 secured to sleeve 121 is used with a tool (not shown) to rotate sleeve 121 to wind strap 113 on sleeve 121.A pin 123 fixed to support 119 engages ratchet wheel 122 to hold ratchet wheel 122 and sleeve 121 in an adjusted position with strap 113 wound on sleeve 121.A tension spring 124 has a lower end connected to a bolt 126 extended through holes 127 in latch frame 97.As shown in FIG.\",\n \"10, latch frame 97 has a plurality of vertically arranged holes 127 accommodating bolt 126 for adjusting the biasing force of spring 124 on strap 113, shown by arrow 127 in FIG.\",\n \"11.The upper end of spring 124 is connected to pin 106 of roller bracket assembly 101.Pin 104 located on top of strap 113 between rollers 98 and 99 applies the biasing force of spring 124 to pull strap 113 down between rollers 98 and 99 to take up slack of strap 113 and maintain the tension on strap 113 during the opening and closing of bi-fold door 22.Latch assembly 96 mounted on the right end of door 22, as shown in FIG.\",\n \"3, has the same structure and operation as latch assembly 96.Shaft 56 is drivably connected to latch drum 112 to rotate latch drum 112 whereby strap 128 is wound on and unwound from latch drum 112 during the opening and closing of bi-fold door 22 and the latching and unlatching functions of latch assembly 96.As shown in FIG.\",\n \"14, when shaft 56 is rotated counterclockwise, shown by arrow 89, strap 61 is wound on drum 78.Straps 62, 63 and 64 are also wound on drums 91, 92 and 93.The combined straps 61, 62, 63 and 64 move down, shown by arrow 129, thereby moving bi-fold door 22 from the closed position to the folded open position.\",\n \"During counterclockwise rotation of shaft 56 to latch drum 109 unwinds strap 113 from drum 109 whereby strap 113 moves upward releasing the horizontal force holding bi-fold door 22 in the closed position and allowing the bi-fold door to move upwardly to the open position, as shown by arrows 132 in FIG.\",\n \"15.Strap 113 rides on roller 132 on the bottom of frame member 36 during movement of bi-fold door 22 between open and closed positions.\",\n \"Spring 124 connected to roller bracket assembly 101 maintains a continuous biasing force on strap 113 during the opening and closing of bi-fold door 22.Shaft 56 is rotated in a clockwise direction by reversing the drive of electric motor 82.Straps 61, 62, 63 and 64 unwind from lift drums 78, 91, 92 and 93 allowing bi-fold door 22 to unfold from the open position to an upright closed position.\",\n \"The weight of bi-fold door 22 caused by-fold door 22 to move down as straps 61-64 unwind from their respective drums.\",\n \"Strap 113 as it winds onto drum 109 pulls bi-fold door 22 to an upright closed position, as shown in FIG.\",\n \"10.When bi-fold door 22 is in the closed position, spring 124 acting on strap 113 biases bi-fold door 22 against column 24 and maintains bi-fold door 22 in the upright closed position.\",\n \"An alternative embodiment of the bi-fold door having lift mechanism and automatic latch assemblies is shown in FIGS.\",\n \"16 to 22.Bi-fold door 200 has an upper panel 221 and a lower panel 222 located in general vertical orientation closing doorway passage or opening in an exterior wall of building 20.Panels 221 and 222 are rectangular framed structures having exterior sheeting, such as wood, plastic, metal and the like.\",\n \"Bi-fold door 200 has a plurality of center hinges 227 pivotally connecting adjacent horizontal frame members of panels 221 and 222 to allow panels 221 and 222 to fold upwardly, as shown in FIG.\",\n \"2, to an open side-by-side position adjacent the top of the doorway opening.\",\n \"Top frame member 228 of upper panel 221 is secured to a header 230 of the building wall with a plurality of hinges 229.As shown in FIG.\",\n \"16, bi-fold door 200 is selectively moved to its open and closed positions with door lift devices indicated generally in FIG.\",\n \"17 at 233, 234, 235 and 236 spaced along the length of bi-fold door 200.Door lift devices 233, 234, 235 and 236 have elongated flexible members, such as webs or straps 237, 238, 239 and 240 attached to anchors 241, 242, 243 and 244 mounted on bottom frame member 246 of lower panel 222 and lift drums 247, 248, 249 and 250 mounted on a frame member 253 of upper panel 221.Upper panel 221 and lower panel 222 of bi-fold door 200 are maintained in the vertically aligned closed position with door latch assemblies indicated generally at 271 and 272 located on opposite ends of bi-fold door 200.Door latch assemblies 271 and 272 have elongated flexible webs or straps 273 and 274 attached to anchors 276 and 277 mounted on the top portion of lower panel 222 and secured to latch drums 278 and 279 mounted on upper frame 253.Straps 273 and 274 are wrapped on latch drums 278 and 279 in an opposite direction from the direction straps 237-240 are wrapped on lift drums 247-250.Straps 237-240, 273 and 274 are elongated flexible, generally flat and substantially non-elastic members having a width between two and six inches and being made of plastic and fiber materials, such as nylon webs, polyester webs and the life.\",\n \"Other types of materials can be used to make straps 237-240, 273 and 274.Straps 237-240, 273 and 274 can have other sizes and widths to accommodate different loads and latching requirements of bi-fold door 200.As shown in FIG.\",\n \"17, a drive shaft 251 mounted on frame 253 is rotated with a power unit 252 to concurrently rotate lift drums 247-250 and latch drums 278 and 279 to wind straps 237-240 on lift drums 247-250 and allow straps 273 and 274 to unwind from latch drums 278 and 279 to unlatch and move bi-fold door 200 to is open position and wind straps 273 and 274 on latch drums 278 and 279 and allow straps 237-240 to unwind from lift drums 247-250 to move door 200 to its upright closed position and latch door 200 secure to the building columns.\",\n \"Drive shaft 251 extends the length of frame 253.Latch drums 278 and 279 are mounted on opposite ends of frame 253 outwardly from lift drums 247 and 250.Frame 253 is attached to the building structure 250 and upright columns 245 and 255 above header 230.Door lift devices 231-236 are identical in structure and function.\",\n \"The details of lift device 233, shown in FIGS.\",\n \"17 to 22, are included in lift devices 234-237.The following description is directed to lift device 233.Power unit 252 mounted on frame 253, shown in FIGS.\",\n \"16 and 18, includes a power transmission or gear box 266 driven with a reversible electric motor 269.An electric brake unit 267 locks gear box 266 when the electric power to motor 269 is turned off thereby preventing rotation of drive shaft 251.Motor 269 rotates drive shaft 251 connected to lift drums 247-250 and latch drums 278 and 279 to concurrently rotate lift drums 247-250 and latch drums 278 and 279 in opposite rotations directions to open and close bi-fold door 200 and latch bi-fold door 200 to the doorway columns.\",\n \"Gear box 266 is drivably connected to drive shaft 251 to selectively rotate drive shaft 251 in clockwise and counterclockwise directions thereby concurrently rotating lift drums 247-250 and latch drums 278 and 279 in clockwise and counterclockwise directions to open bi-fold door 200 and close and latch bi-fold door 200 secure to the doorway columns.\",\n \"A jack shaft chain and sprocket drive 268 is used to operatively connect gear box 266 with drive shaft 251.A manually operated switch (not shown) wired to motor 269 is used by an operator to control the electric power supplied to motor 269 and the opening, closing and latching of bi-fold door 200.As shown in FIG.\",\n \"16, strap 237 extends downwardly from lift drum 247 to anchor 241 mounted on bottom frame member 246 of lower panel 222.The free end of strap 237 is attached to anchor 241.Anchor 241 can be adjusted to take up slack of strap 237 to adjust the operating or working length of strap 237 as needed.\",\n \"As seen in FIG.\",\n \"19, lift drum 247 is mounted on frame member 253.Lift drum 247 has a generally cylindrical outer surface providing a drum surface for strap 237.Door latch devices 271 and 272 are identical in structure and function.\",\n \"The details of door latch device 271, shown in FIGS.\",\n \"19 to 22, are included in door latch device 272.The following description is directed to door latch device 271.As shown in FIGS.\",\n \"16 and 19, strap 273 extends downwardly from latch drum 278 through a kick out arm assembly 281 mounted on header 230.Kick out arm assembly 281 comprises a downward extending arm 286 having a lower end with a straight eye 287.Strap 273 extends through the opening of eye 287 downwardly to a roller 283, shown in FIGS.\",\n \"20 and 21, mounted on support 285 attached to a bracket 288 secured to column 245 of the building.\",\n \"Strap 273 is trained over roller 283 and extends laterally to anchor 276 mounted on the frame of lower panel 222.Returning to FIG.\",\n \"19, arm assembly 281 has a spring member 289 that engages a horizontal bar member 291 to bias arm member 286 upwardly and inwardly away from the inside of bi-fold door 200, as shown by arrow 299 in FIG.\",\n \"19, thereby maintaining tension on strap 273 during opening and closing of bi-fold door 200 and biasing the panels into engagement with the column 245 of the building.\",\n \"As seen in FIG.\",\n \"22, anchor 276 has a sleeve 292 mounted on a support 293 secured to lower panel 221.A ratchet wheel 294 and pawl 296 operate to hold sleeve 292 in a fixed position on support 293.In use, when bi-fold door 200 is moved from an open position to the closed latched position lift drums 247-250 are releasing straps 237-240 and latch drums 278 and 279 are taking up straps 273 and 274, as shown by arrows 301 and 302 in FIG.\",\n \"17.When bi-fold door 200 is moved from the closed latched position to the open position latch drums 278 and 279 are releasing straps 273 and 274 and lift drums 247-250 are taking up straps 237-240.As bi-fold door 200 is moved from the closed latched position to the open position slack in straps 273 and 274 is taken up with kick out arm assemblies 281 and 282.When bi-fold door 200 is fully closed latch drums 278 and 279 are filled with straps 273 and 274 and lift drums 247-250 are left with a small amount of straps 237-240.Brake unit 267 locks gear box 266 when motor 269 is turned off whereby latch drums 278 and 279 are prevented from rotating and releasing straps 273 and 274 to maintain upper and lower panels 221 and 222 in a vertically aligned closed latched position in engagement with upright columns 245 and 255 of the building.\",\n \"A bi-fold door 200 is unlatching and opening straps 237-240 are wrapped onto lift drums 247-250 while straps 273 and 274 are unwound off latch drums 278 and 279.Straps 273 and 274 add support to bi-fold door 200 preventing flipping of door 200 over the roof of the building in windy conditions.\",\n \"The following drawing and description of the bi-fold door having latch assemblies is two embodiments of the invention.\",\n \"Persons skilled in the art of bi-fold doors can make changes and modifications in structures and materials without departing from the invention defined in the claims.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875776"}}},{"rowIdx":4494973,"cells":{"text":{"kind":"list like","value":[["GARDEN FOUNTAIN","The garden fountain includes a lower container, a middle container and an upper container.","A water pump positioned in the lower container pumps water up into the middle container.","The upper container rests in the middle container.","Using a combination of the water level in the middle container and the spacing of the bottom of the upper container with respect to the water level in the middle container, the user can accurately control the water flow to the upper container."],["1.A garden fountain comprising: a first container for retaining a first volume of water, the first container having a base portion configured for support on a stable surface; a second container disposed above the first container, the second container having an enclosed bottom configured to retain a second volume of water less than the first volume of water, the second container having waterspouts formed therein, wherein the waterspouts release water back into the first container; a third container supported on the enclosed bottom of the second container, the third container configured for retaining a third volume of water or material less than the first and second volumes, the third container further comprising inlets for passing water through a bottom thereof; and a pump disposed in the first container, the pump configured to pump water into the second container, wherein water pumped from the first container into the second container maintains a specific water level in the second container; wherein the third container further comprises at least one spacer configured to support the third container at a predetermined spacing above the enclosed bottom of the second container, wherein a water level in the second container determines an amount of water provided to the third container.","2.The garden fountain of claim 1, wherein the pump is battery-powered, and wherein the base portion further includes an openable battery compartment configured for retaining a battery for powering the pump.","3.The garden fountain of claim 2, wherein the battery is a rechargeable battery.","4.The garden fountain of claim 1, further comprising a timing system for controlling activation of the pump for predetermined time periods.","5.The garden fountain of claim 1, wherein the inlets comprise one or more openings through the bottom surface of the third container.","6.The garden fountain of claim 1, wherein the waterspouts are configured to return water to the first container only when the water level within the second container exceeds a predetermined level.","8.The garden fountain of claim 1, wherein the base portion comprises a pedestal.","9.The garden fountain of claim 1, further comprising a wireless speaker disposed within the base portion.","10.The garden fountain of claim 1, wherein the base portion further comprises a weight chamber configured to receive a weighting material."],["<SOH> BACKGROUND <EOH>Currently there are no known fountains that operate as both planters and fountains.","Such concept provides both functionality to a planter while also providing for an aesthetically pleasing landscape design element."],["<SOH> SUMMARY <EOH>According to one implementation, the garden fountain includes an upper bowl, a middle bowl and a lower bowl.","The upper bowl has a base configured to rest within the middle bowl.","A pump is disposed in the lower bowl and configured to pump water up into the middle bowl.","The water pumped from the lower bowl to the middle bowl maintains a specific water level in the middle bowl.","The upper bowl is configured to hold soil and an associated plant and includes means for passing water from a bottom thereof into the soil.","The positioning of the bottom of the upper bowl in the middle bowl and the water level in the middle bowl determines the amount of water provided to the soil of the upper bowl and associated plant.","According to another implementation, the garden fountain includes an upper bowl, a middle bowl having waterspouts, and a lower bowl.","The upper bowl has a base configured to rest within the middle bowl.","A base is configured to support the lower bowl on the ground or other stable surface, and includes a battery compartment contained therein.","A pump is disposed in the lower bowl and is configured to pump water up into the middle bowl.","Water pumped from the lower bowl to the middle bowl maintains a specific water level in the middle bowl.","The pump is electrically connected to the battery contained the base battery compartment.","The upper bowl is configured to hold soil and an associated plant, and includes means for passing water from a bottom thereof into the soil.","The position of the upper bowl in the middle bowl and the water level in the middle bowl determines the amount of water provided to the soil of the upper bowl and associated plant.","Other aspects and features of the present principles will become apparent from the following detailed description considered in conjunction with the accompanying drawings.","It is to be understood, however, that the drawings are designed solely for purposes of illustration and not as a definition of the limits of the present principles, for which reference should be made to the appended claims.","It should be further understood that the drawings are not necessarily drawn to scale and that, unless otherwise indicated, they are merely intended to conceptually illustrate the structures and procedures described herein."],["RELATED APPLICATIONS This is a continuation of application Ser.","No.","15/457,704, filed Mar.","13, 2017, issued as U.S. Pat.","No.","9,873,134, which is a continuation of application Ser.","No.","14/806,792, filed Jul.","23, 2015, issued as U.S. Pat.","No.","9,592,525, which is a continuation of application Ser.","No.","13/908,722, filed Jun.","3, 2013, issued as U.S. Pat.","No.","9,108,212, which claims the priority of U.S.","Provisional Application No.","61/655,334, filed Jun.","4, 2012, each of which is incorporated herein by reference.","FIELD OF THE INVENTION The present invention relates to fountains, and more particularly, to a garden fountain that is capable of containing and watering one or more plants.","BACKGROUND Currently there are no known fountains that operate as both planters and fountains.","Such concept provides both functionality to a planter while also providing for an aesthetically pleasing landscape design element.","SUMMARY According to one implementation, the garden fountain includes an upper bowl, a middle bowl and a lower bowl.","The upper bowl has a base configured to rest within the middle bowl.","A pump is disposed in the lower bowl and configured to pump water up into the middle bowl.","The water pumped from the lower bowl to the middle bowl maintains a specific water level in the middle bowl.","The upper bowl is configured to hold soil and an associated plant and includes means for passing water from a bottom thereof into the soil.","The positioning of the bottom of the upper bowl in the middle bowl and the water level in the middle bowl determines the amount of water provided to the soil of the upper bowl and associated plant.","According to another implementation, the garden fountain includes an upper bowl, a middle bowl having waterspouts, and a lower bowl.","The upper bowl has a base configured to rest within the middle bowl.","A base is configured to support the lower bowl on the ground or other stable surface, and includes a battery compartment contained therein.","A pump is disposed in the lower bowl and is configured to pump water up into the middle bowl.","Water pumped from the lower bowl to the middle bowl maintains a specific water level in the middle bowl.","The pump is electrically connected to the battery contained the base battery compartment.","The upper bowl is configured to hold soil and an associated plant, and includes means for passing water from a bottom thereof into the soil.","The position of the upper bowl in the middle bowl and the water level in the middle bowl determines the amount of water provided to the soil of the upper bowl and associated plant.","Other aspects and features of the present principles will become apparent from the following detailed description considered in conjunction with the accompanying drawings.","It is to be understood, however, that the drawings are designed solely for purposes of illustration and not as a definition of the limits of the present principles, for which reference should be made to the appended claims.","It should be further understood that the drawings are not necessarily drawn to scale and that, unless otherwise indicated, they are merely intended to conceptually illustrate the structures and procedures described herein.","BRIEF DESCRIPTION OF THE DRAWINGS In the drawings wherein like reference numerals denote similar components throughout the views: FIG.","1 is perspective view of the garden fountain according to an implementation of the present principles; FIG.","2A is a perspective view of the garden fountain showing the battery compartment in the base, according to an implementation of the present principles; FIG.","2B is an exploded view of the battery compartment shown in FIG.","2A; FIG.","3 is a perspective view of the garden fountain, shown partially in phantom, according to an implementation of the present principles; FIG.","4 is an exploded view of the planter portion of the garden fountain, according to an implementation of the present principles; FIG.","5 is a cross-sectional view of the taken down the center and showing the plant watering feed system, according to an implementation of the invention; FIGS.","6A and 6B are a cross-sectional view and perspective view, respectively, of the base of the garden fountain according to another implementation of the invention; FIGS.","7A and 7b is a perspective view and a cross-sectional view, respective, of the second water tier distribution system according to a further implementation of the invention; and FIG.","8 is perspective view of the base of the garden fountain according to yet a further implementation of the present principles.","DETAILED DESCRIPTION Referring to FIG.","1, there is shown a garden fountain 10 according to an implementation of the present principles.","The garden fountain 10 includes a base 12, a lower or reservoir bowl 24, a middle bowl 26 and an upper or planter bowl 28.The base 12 can be made up of one or more parts and is shown in the present example having a footing 14, a central shaft 16 and a bowl support 18.A power button 20 can be disposed in any suitable location and is shown here integrated into the bowl support 18.A battery compartment 22 is preferably disposed in the base of the central shaft 16, or the footing 14 (if of suitable size) The connection of the lower bowl to the footing can be achieved in any suitable known manner.","For example, a slot and groove mechanical engagement where the parts are fitted together and rotated to secure the connection could be used.","Such slot and groove configuration could also be used to connect the middle bowl 26 to the lower bowl 24.O-rings or other water sealing means can be used in any relevant application for the connection of the various parts of the fountain.","In addition, those of skill in the art will appreciated that each of the parts of the garden fountain 10 can be made of any suitable known material, which may include, but is not limited to, molded plastics.","FIGS.","2A and 2B show the battery compartment 22 having a battery 30 contained therein.","In this preferred implementation the battery is rechargeable and the battery compartment is preferably sealed from water such that the user may easily access the same without any concerns relating to the water contained within the lower and middle bowls.","Ideally, the battery compartment should have at least one opening to the outside air so as to prevent the formation of condensation in the compartment and thereby any negative effects to the battery as a result of the same.","Those of skill in the art will appreciate that the access panel for the battery compartment can be configured in any suitable manner, such as for example, a sliding panel, a hinged panel, and may also include a locking mechanism.","In one implementation, the rechargeable battery or batteries 30 can be recharged using a solar system (not shown), and/or using household electric power.","Alternatively, the batteries can be made to be disposable.","In addition to rechargeable power means, timing system 31 can be implemented where individual buttons are preset for predetermined time periods, or adjustable timing means are implemented.","In other implementations, the power source for the fountain can be solar powered, A/C powered using 110 v, 210 v and/or DC powered using a 12 v battery.","It is further contemplated that the garden fountain system may include a lighting system that provides accent lighting the fountain and/or the plant in the upper bowl planter.","The positioning of the lights cans be within or out of the water.","FIGS.","3 and 5 illustrate one example of the disposition of the pump 32 within the shaft 23 positioned within the lower/reservoir bowl 24 and configured to support the middle bowl 26.The pump 32 includes a power connection 34 which is connected to the battery 30 positioned in the base 16.The pump 32 sits in the bottom of the shaft 23 and is configured to draw water from the lower/reservoir bowl 24 and the pump feeds the same to the middle bowl 26 via a tube 36 connected to a water input connection 40 in the center of the middle bowl 26.Referring to FIGS.","3 and 4, the upper bowl 28, positioned siting within the middle bowl 26.In a preferred implementation, the upper bowl 28 is configured as planter.","As shown in FIG.","5, the upper bowl 28 includes a number of openings 42 at the bottom thereof.","The openings 42 allow the transfer of water from a middle bowl 26, into upper bowl 28 when the water level rises in bowl 26 to a predetermined level.","Bowl 26 has water introduced via a pump 32, (FIG.","3), drawing water from bottom of a lower bowl 24, (i.e., a reservoir bowl).","As shown in FIG.","3, the pump can be located in the lower reservoir bowl 24, and as shown in the present example, the pump 32 is positioned within the shaft supporting the middle bowl 26.Those of skill in the art will appreciate that any suitable known type of pump 32 with an appropriate water intake can be used.","According to one implementation, the pump 32 uses a 6-volt dc pump powered by the rechargeable battery 30 located in the base of the fountain.","When the pump is turned on, the water is pumped from lower bowl 24 into the middle bowl 26.The water continues to rise until the water level reaches the pour spouts 25 of middle bowl 26, at which point the water level 5 reaches its maximum height or level in middle bowl 26 and the water pours over back into lower bowl 24.","(See FIG.","5) As shown above, upper bowl 28 sits in middle bowl 26.The distance between the base of middle bowl 26 and base of bowl 28, specifically the water inlets 42 of upper bowl 28 are crucial to the operation.","The height of the water level in middle bowl 26 reaches at least to the bottom of the water inlets of upper bowl 28.Discs or spaces 43 can be added or subtracted to achieve the desired position of the base of the upper bowl 28 within the middle bowl 26.As will be evident from the above, height of the upper bowl 26 can be infinitely adjusted using the discs 43 depending on the water level desired/required for the plant in the upper bowl 28.According to one preferred implementation, a minimum height must at least reach the bottom of the water inlets 42 in upper bowl 28 in order for the soil 29 located in upper bowl 28 to be able to draw or wick the water up from middle bowl 26.Although shown in the form of openings, water inlets 42 can include a porous material 41 of any kind so as to prevent any soil from being undesirably being dispelled from the upper bowl 28 into middle bowl 26.As mentioned above, the height of upper bowl 28 in relation to middle bowl 26 will be adjustable.","The purpose of an adjustable height is such that you can raise or lower the water level in upper bowl 28.This is beneficial since plants require different amounts of water for growing.","In the current configuration one or more spacers 43 are used in between upper bowl 28 and middle bowl 26.Any number of or no spacers can be used.","In the configuration of FIG.","4, three (3) spacers 43 are shown.","This gives a total of four (4) water level settings.","The thickness of the spacers 43 can also be changed to accommodate other spacing options.","In one preferred implementation, no spacer present allows upper bowl 28 to sit at its lowest possible setting, providing the highest water level in upper bowl 28.As you add a spacer between the upper bowl 28 and middle bowl 26, bowl 28 will increase in height over middle bowl 26 thus raising upper bowl 28 proportionally higher above middle bowl 26 lowering the water level or line in upper bowl 28.As you add another spacer, this water level will continue to lower in bowl 28 until you can add spacer so that upper bowl 28 water inlets 42 can be completely above the water level in middle bowl 26.The above description is referring to the water level in the active or pump on mode.","This is when the water level is at its highest, but at no time does the water level rise above the maximum level provided by the waterspouts 25 in middle bowl 26.When in the active mode, or pump on mode and the maximum spacer 43 or height of upper bowl 28 is in use, the water level is raised in middle bowl 26 to the maximum height determined by the waterspouts 25.Upper bowl 28 being in its highest setting will only, when in active mode, have water coming in contact with the water inlets 42 in upper bowl.","When the fountain is inactive, pump off, the water level will lower to a point just below the maximum water level in middle bowl 26.At this point the water level is lower than the bottom of the water inlets 42 in upper bowl 28.This then provides an air gap necessary for healthy plant growth allowing the soil to aerate, from the bottom up.","In this same setting, when the fountain is in active mode, the water level in middle bowl 26 will rise to the maximum height provided by waterspouts 25 in bowl number 26.At such point, the water level will rise to allow the water inlets 42 in upper bowl 28 to come into contact with the water 5 in middle bowl 26.The resulting wicking effect allows the soil 29 in upper bowl 28 to wick the water up into bowl 28, providing water for the plant.","The water level in upper bowl 28 can be adjusted through raising and lowering the bowl in relation to middle bowl 26 with any number of methods, fixed and mechanical.","In addition, the water level in upper bowl 28 can be affected or adjusted to provide the proper amount of water to the plant in upper bowl 28 depending on if the fountain is active or inactive.","The above description relates to the adjusting of the water level in upper bowl 28 in the active mode.","If you adjust for the inactive mode, upper bowl 28 can be moved to, for example, the lowest setting.","This position will place the water inlets 42 of upper bowl 28 to below the maximum water level of middle bowl 26.If the fountain is first active and thus raising the water level in bowl 26 to the maximum level and then turned inactive, the water level will lower slightly to just below the spout level 25.However, upper bowl 28 water inlets 42 can be set so that they are lower than middle bowl 28's maximum level.","Therefore, the soil 29 in bowl 28 would continue to wick water up into bowl 28, even in the inactive mode.","This provides additional water for different type of plants or weather conditions.","This allows middle bowl 26 to act as a reservoir for upper bowl 28 until such time that the soil 29 in bowl 28 has wicked up the maximum amount of water it is capable of and or water has evaporated out of middle bowl 26.When either occurs, this will then lower the water level in middle bowl 26 to below the water inlets 42 in upper bowl 28, thus providing the necessary air gap 12 between upper bowl 28 and middle bowl number 26 to provide healthy conditions for good plant growth.","The shape of the bottom of upper bowl 28 and the bottom of middle bowl 26 is also critical for proper water flow.","Although there are numerous ways to introduce water into middle bowl 26, this description is for the current example being shown.","The outlet of a water distribution tube 40 coming from the pump 32 located, for example, in lower bowl number 24, in a preferred embodiment needs to be just slightly higher than the maximum water level provided by the waterspouts 25 in middle bowl 26.This prevents the water from middle bowl 26 from siphoning back into lower bowl 24, thus maintaining the inactive water level in middle bowl 26 once initially filled to maximum water level when active.","However, should the water siphon back into bowl 24, this can also be a benefit.","In the current embodiment, there is a fill chamber 46 located in the bottom of upper bowl 28, which is female in shape, which matches to the male water distribution pipe 40 in middle bowl 26.This allows the water distribution pipe 40 or tube to be higher than the maximum water level in middle bowl 26 while allowing the water inlet ports 42, located in the corresponding female shape of the bottom of upper bowl 28 to operate below the maximum water level in middle bowl 26.In a preferred embodiment, water is only introduced into upper bowl 28 through the water inlet ports 42.This allows for a non-pressurized or turbulent water introduction into the soil.","If the water from the distribution port in middle bowl 26 was directed straight directly into the soil 29 in upper bowl 28, it would erode the soil and causing excess soil to be introduced into the water system and erode the soil exposing the roots in the plant located in upper bowl 28.Although this system could have the water distributed to upper bowl 28 on in various manners, direct port from bowl number two into bowl number one.","Another is a water distribution pipe pouring water into the top of bowl 28 from bowl 24.The preferred embodiment is to wick the water from the bottom up from bowl number 26 into upper bowl 28 initially when in the active mode then also in the inactive mode as described above.","In the preferred embodiment, it has been found that the water distribution chamber 46 located in upper bowl 28, in relation to the air channels at the bottom of bowl 28, in relation to the water distribution port in middle bowl 26 can create a siphon effect after the fountain is inactive, thus siphoning all the water out of middle bowl 26 into lower bowl 24.This can be considered a positive effect if for example the plant in upper bowl 28 requires less water.","To reduce this effect if a small hole 48 is introduced into the top of the water distribution chamber 46, it has been found to break the effect of the siphon, allowing the water to maintain minimum or inactive water height in middle bowl 26.Those of skill in the art will appreciate that there are numerous ways to affect the siphon occurring between middle bowl 26 and lower bowl 24, this is just one of example of the same.","This anti-siphon hole 48 in the top of the water distribution chamber located in bowl 28 can also have a positive effect in providing water to the soil in bowl number one.","When in the active mode it can create a method of positive pressure water introduction into upper bowl 28.Although it is considered preferred to allow the water to wick up from bowl number 26 into bowl 28, it could be beneficial in certain situations in which more water is required for a specific plant and the addition water introduction into the soil has a positive effect.","However, as this positive pressure water inlet increases in size in relation the water flow or pressure created from the pump, located in bowl 24, it is possible to meter this flow by increasing or decreasing the diameter of this positive water pressure inlet.","FIGS.","6A and 6B show the base 12 of the fountain according to another implementation of the invention.","FIG.","6A shows the bottom 14 of the base being additionally, and adjustably, weighted with a suitable weighting material 68 (e.g., sand) Typical fountains made of stone, concrete, and any other heavy medium, do not require the ability have an adjustable weighted base as they very nature of their design is heavy.","However, with the recent use of polyresin as the construction medium for the fountain of the present invention, which allows them to be light weight enough to ship for mass merchandising and for easy installation by the end user, they are too light to withstand any type of weather and will fall over with small winds.","Simply making the fountain heavier is counter-productive since shipping costs will go up and the installation by the customer becomes more difficult.","According to the present design the fountain can ship in its lightweight format and the end user can then add sand or heavy material 68 to the bottom of the fountain to provide the weight necessary to withstand weather conditions.","In this embodiment (as described above), the battery location, combined with the weight chamber is unique.","By placing the battery 30 in the lowest possible location to establish a low center of gravity and then adding a chamber 67 below the battery compartment to be filled with a removable weighted material 68 will provide the best center of gravity for the fountain.","By placing the weighting material compartment 67 and battery compartment 22 close to each other, the issue or adding subtracting the weighted material becomes an issue for the end user and for methods of manufacturing.","First the method of manufacturing a poly resin fountain utilizes an outer shape for the exterior of the fountain and at the bottom base a panel is glued into place to seal the bottom of the fountain base to the outer shape thus providing rigidity to the outer structure and to finish the cosmetics of the bottom of the fountain.","This allows for a hollow inner structure which is both a cost and weight saving and the simplest method of manufacturing.","However, this method makes it difficult to make a separated chamber 67 to add material to since there is no inner structure to the fountain.","In the current design a male protrusion 66 which extends from the bottom base cap up into the inner body of the hollow fountain structure has been added.","The top of this protrusion 66 becomes the base in which the battery 30 can sit.","The diameter of the protrusion 66 is smaller than the inner diameter of the outer structure of the fountain.","The distance between the protrusion 66 and the outer structure provides for a conduit allowing the end user to add weighted material into the bottom of the fountain, the weight chamber.","The distance between the outer structure and the inner protrusion 66 is critical in that if it is too small it is difficult for the end user to add or remove weighted material and if it is too large, the base of the top of the protrusion 66 is not large enough to support the battery and any other object being stored in the battery compartment.","To help in providing the added room from the placement or removal of the weighted material 68, a small indent of any particular shape can be added the protrusion 66, thus maintaining adequate base area to support the battery while increasing the space between the outer structure and the protrusion 66 for ease of adding or removing the weighted material.","This method is preferred over other methods for adding or removing weight.","For example, an opening formed in the bottom base panel, with, for example, a plug to add or remove the weighted material, would require that the fountain be turned upside down to add the material.","This, in turn, would require that the hollow interior of the fountain have a separate panel molded and attached to the inner wall of the fountain.","This panel would have to be sealed to prevent the weighted material from leaking back into the body of the fountain when it is turned upside down to add the weighted material.","This added panel would significantly increase the manufacturing cost.","The battery base 16/compartment 22 is also unique to the poly resin fountains for manufacturing reasons as mentioned above, even without the ability to add weighted material.","By extending the outer edge of the battery base 16 to the inner dimension of the outer shape, which eliminates the ability to add weighted material, however provides a cost-effective method for production to establish a base for the battery.","FIG.","6B shows a clear view of the top 60 of the base 12.The top 60 includes a keyed slot 62 having keys 64.The keys 64 are configured to receive correspondingly shaped portions of the bottom of lower bowl 24 such that the same is received and rotated in the slot 62 and thereby secured to the top of the base during assembly.","FIGS.","7A and 7B show the configuration of the middle bowl 26 (2.sup.nd water tier) according to an implementation of the invention.","The 2.sup.nd water tier water distribution tube in a poly-resin fountain is typically fixed to a molded plastic or resin tube with is the union from the tube exiting the water pump located inside the fountain thru the wall of the resin allowing the water to be distributed to the exterior of the fountain.","This method does not allow for the ability to easily change or add new water features by the end user.","According to an implementation, the middle bowl 26 is molded with a large passageway 76 having an inner dimension configured to receive the water distribution plug 72 with hose 74 that can be inserted into the resin.","This removable plug 72 allows the end user to pull the tube 74 off of the water feature to be removed and re-attach a new water feature by pressing the water distribution plug in place on the new feature.","FIG.","8 shows another implementation of the base pedestal 16 having a wireless, e.g., Bluetooth®, speaker 80 positioned therein.","The speaker is connected to power source via plug 84 and wire 82.The power source connected to plug 82 can be any suitable battery source, and may, depending on the configuration, be connected to the water fountain's primary battery 30.Alternatively, a separate battery can be provided to power the wireless (Bluetooth®) speaker 80.As will be appreciated, the addition of the speaker 80 allows a user to wirelessly transmit audio content to the speaker via their own compatible Bluetooth® audio player or system.","The above description above is for a three-tier fountain.","This self-watering garden fountain can be constructed in various configurations.","It can have two tiers, with a reservoir located inside or in the base of the bottom tier.","Those of skill in the art will appreciate that the fountain of the present invention can be constructed with multiple tiers, with essentially no limit.","It can also be constructed with multiple planter bowls, in parallel to each other, vertically stacked to each other, and various other combinations and configurations.","While there have been shown, described and pointed out fundamental novel features of the present principles, it will be understood that various omissions, substitutions and changes in the form and details of the methods described and devices illustrated, and in their operation, may be made by those skilled in the art without departing from the spirit of the same.","For example, it is expressly intended that all combinations of those elements and/or method steps which perform substantially the same function in substantially the same way to achieve the same results are within the scope of the present principles.","Moreover, it should be recognized that structures and/or elements and/or method steps shown and/or described in connection with any disclosed form or implementation of the present principles may be incorporated in any other disclosed, described or suggested form or implementation as a general matter of design choice.","It is the intention, therefore, to be limited only as indicated by the scope of the claims appended hereto."]],"string":"[\n [\n \"GARDEN FOUNTAIN\",\n \"The garden fountain includes a lower container, a middle container and an upper container.\",\n \"A water pump positioned in the lower container pumps water up into the middle container.\",\n \"The upper container rests in the middle container.\",\n \"Using a combination of the water level in the middle container and the spacing of the bottom of the upper container with respect to the water level in the middle container, the user can accurately control the water flow to the upper container.\"\n ],\n [\n \"1.A garden fountain comprising: a first container for retaining a first volume of water, the first container having a base portion configured for support on a stable surface; a second container disposed above the first container, the second container having an enclosed bottom configured to retain a second volume of water less than the first volume of water, the second container having waterspouts formed therein, wherein the waterspouts release water back into the first container; a third container supported on the enclosed bottom of the second container, the third container configured for retaining a third volume of water or material less than the first and second volumes, the third container further comprising inlets for passing water through a bottom thereof; and a pump disposed in the first container, the pump configured to pump water into the second container, wherein water pumped from the first container into the second container maintains a specific water level in the second container; wherein the third container further comprises at least one spacer configured to support the third container at a predetermined spacing above the enclosed bottom of the second container, wherein a water level in the second container determines an amount of water provided to the third container.\",\n \"2.The garden fountain of claim 1, wherein the pump is battery-powered, and wherein the base portion further includes an openable battery compartment configured for retaining a battery for powering the pump.\",\n \"3.The garden fountain of claim 2, wherein the battery is a rechargeable battery.\",\n \"4.The garden fountain of claim 1, further comprising a timing system for controlling activation of the pump for predetermined time periods.\",\n \"5.The garden fountain of claim 1, wherein the inlets comprise one or more openings through the bottom surface of the third container.\",\n \"6.The garden fountain of claim 1, wherein the waterspouts are configured to return water to the first container only when the water level within the second container exceeds a predetermined level.\",\n \"8.The garden fountain of claim 1, wherein the base portion comprises a pedestal.\",\n \"9.The garden fountain of claim 1, further comprising a wireless speaker disposed within the base portion.\",\n \"10.The garden fountain of claim 1, wherein the base portion further comprises a weight chamber configured to receive a weighting material.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>Currently there are no known fountains that operate as both planters and fountains.\",\n \"Such concept provides both functionality to a planter while also providing for an aesthetically pleasing landscape design element.\"\n ],\n [\n \"<SOH> SUMMARY <EOH>According to one implementation, the garden fountain includes an upper bowl, a middle bowl and a lower bowl.\",\n \"The upper bowl has a base configured to rest within the middle bowl.\",\n \"A pump is disposed in the lower bowl and configured to pump water up into the middle bowl.\",\n \"The water pumped from the lower bowl to the middle bowl maintains a specific water level in the middle bowl.\",\n \"The upper bowl is configured to hold soil and an associated plant and includes means for passing water from a bottom thereof into the soil.\",\n \"The positioning of the bottom of the upper bowl in the middle bowl and the water level in the middle bowl determines the amount of water provided to the soil of the upper bowl and associated plant.\",\n \"According to another implementation, the garden fountain includes an upper bowl, a middle bowl having waterspouts, and a lower bowl.\",\n \"The upper bowl has a base configured to rest within the middle bowl.\",\n \"A base is configured to support the lower bowl on the ground or other stable surface, and includes a battery compartment contained therein.\",\n \"A pump is disposed in the lower bowl and is configured to pump water up into the middle bowl.\",\n \"Water pumped from the lower bowl to the middle bowl maintains a specific water level in the middle bowl.\",\n \"The pump is electrically connected to the battery contained the base battery compartment.\",\n \"The upper bowl is configured to hold soil and an associated plant, and includes means for passing water from a bottom thereof into the soil.\",\n \"The position of the upper bowl in the middle bowl and the water level in the middle bowl determines the amount of water provided to the soil of the upper bowl and associated plant.\",\n \"Other aspects and features of the present principles will become apparent from the following detailed description considered in conjunction with the accompanying drawings.\",\n \"It is to be understood, however, that the drawings are designed solely for purposes of illustration and not as a definition of the limits of the present principles, for which reference should be made to the appended claims.\",\n \"It should be further understood that the drawings are not necessarily drawn to scale and that, unless otherwise indicated, they are merely intended to conceptually illustrate the structures and procedures described herein.\"\n ],\n [\n \"RELATED APPLICATIONS This is a continuation of application Ser.\",\n \"No.\",\n \"15/457,704, filed Mar.\",\n \"13, 2017, issued as U.S. Pat.\",\n \"No.\",\n \"9,873,134, which is a continuation of application Ser.\",\n \"No.\",\n \"14/806,792, filed Jul.\",\n \"23, 2015, issued as U.S. Pat.\",\n \"No.\",\n \"9,592,525, which is a continuation of application Ser.\",\n \"No.\",\n \"13/908,722, filed Jun.\",\n \"3, 2013, issued as U.S. Pat.\",\n \"No.\",\n \"9,108,212, which claims the priority of U.S.\",\n \"Provisional Application No.\",\n \"61/655,334, filed Jun.\",\n \"4, 2012, each of which is incorporated herein by reference.\",\n \"FIELD OF THE INVENTION The present invention relates to fountains, and more particularly, to a garden fountain that is capable of containing and watering one or more plants.\",\n \"BACKGROUND Currently there are no known fountains that operate as both planters and fountains.\",\n \"Such concept provides both functionality to a planter while also providing for an aesthetically pleasing landscape design element.\",\n \"SUMMARY According to one implementation, the garden fountain includes an upper bowl, a middle bowl and a lower bowl.\",\n \"The upper bowl has a base configured to rest within the middle bowl.\",\n \"A pump is disposed in the lower bowl and configured to pump water up into the middle bowl.\",\n \"The water pumped from the lower bowl to the middle bowl maintains a specific water level in the middle bowl.\",\n \"The upper bowl is configured to hold soil and an associated plant and includes means for passing water from a bottom thereof into the soil.\",\n \"The positioning of the bottom of the upper bowl in the middle bowl and the water level in the middle bowl determines the amount of water provided to the soil of the upper bowl and associated plant.\",\n \"According to another implementation, the garden fountain includes an upper bowl, a middle bowl having waterspouts, and a lower bowl.\",\n \"The upper bowl has a base configured to rest within the middle bowl.\",\n \"A base is configured to support the lower bowl on the ground or other stable surface, and includes a battery compartment contained therein.\",\n \"A pump is disposed in the lower bowl and is configured to pump water up into the middle bowl.\",\n \"Water pumped from the lower bowl to the middle bowl maintains a specific water level in the middle bowl.\",\n \"The pump is electrically connected to the battery contained the base battery compartment.\",\n \"The upper bowl is configured to hold soil and an associated plant, and includes means for passing water from a bottom thereof into the soil.\",\n \"The position of the upper bowl in the middle bowl and the water level in the middle bowl determines the amount of water provided to the soil of the upper bowl and associated plant.\",\n \"Other aspects and features of the present principles will become apparent from the following detailed description considered in conjunction with the accompanying drawings.\",\n \"It is to be understood, however, that the drawings are designed solely for purposes of illustration and not as a definition of the limits of the present principles, for which reference should be made to the appended claims.\",\n \"It should be further understood that the drawings are not necessarily drawn to scale and that, unless otherwise indicated, they are merely intended to conceptually illustrate the structures and procedures described herein.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS In the drawings wherein like reference numerals denote similar components throughout the views: FIG.\",\n \"1 is perspective view of the garden fountain according to an implementation of the present principles; FIG.\",\n \"2A is a perspective view of the garden fountain showing the battery compartment in the base, according to an implementation of the present principles; FIG.\",\n \"2B is an exploded view of the battery compartment shown in FIG.\",\n \"2A; FIG.\",\n \"3 is a perspective view of the garden fountain, shown partially in phantom, according to an implementation of the present principles; FIG.\",\n \"4 is an exploded view of the planter portion of the garden fountain, according to an implementation of the present principles; FIG.\",\n \"5 is a cross-sectional view of the taken down the center and showing the plant watering feed system, according to an implementation of the invention; FIGS.\",\n \"6A and 6B are a cross-sectional view and perspective view, respectively, of the base of the garden fountain according to another implementation of the invention; FIGS.\",\n \"7A and 7b is a perspective view and a cross-sectional view, respective, of the second water tier distribution system according to a further implementation of the invention; and FIG.\",\n \"8 is perspective view of the base of the garden fountain according to yet a further implementation of the present principles.\",\n \"DETAILED DESCRIPTION Referring to FIG.\",\n \"1, there is shown a garden fountain 10 according to an implementation of the present principles.\",\n \"The garden fountain 10 includes a base 12, a lower or reservoir bowl 24, a middle bowl 26 and an upper or planter bowl 28.The base 12 can be made up of one or more parts and is shown in the present example having a footing 14, a central shaft 16 and a bowl support 18.A power button 20 can be disposed in any suitable location and is shown here integrated into the bowl support 18.A battery compartment 22 is preferably disposed in the base of the central shaft 16, or the footing 14 (if of suitable size) The connection of the lower bowl to the footing can be achieved in any suitable known manner.\",\n \"For example, a slot and groove mechanical engagement where the parts are fitted together and rotated to secure the connection could be used.\",\n \"Such slot and groove configuration could also be used to connect the middle bowl 26 to the lower bowl 24.O-rings or other water sealing means can be used in any relevant application for the connection of the various parts of the fountain.\",\n \"In addition, those of skill in the art will appreciated that each of the parts of the garden fountain 10 can be made of any suitable known material, which may include, but is not limited to, molded plastics.\",\n \"FIGS.\",\n \"2A and 2B show the battery compartment 22 having a battery 30 contained therein.\",\n \"In this preferred implementation the battery is rechargeable and the battery compartment is preferably sealed from water such that the user may easily access the same without any concerns relating to the water contained within the lower and middle bowls.\",\n \"Ideally, the battery compartment should have at least one opening to the outside air so as to prevent the formation of condensation in the compartment and thereby any negative effects to the battery as a result of the same.\",\n \"Those of skill in the art will appreciate that the access panel for the battery compartment can be configured in any suitable manner, such as for example, a sliding panel, a hinged panel, and may also include a locking mechanism.\",\n \"In one implementation, the rechargeable battery or batteries 30 can be recharged using a solar system (not shown), and/or using household electric power.\",\n \"Alternatively, the batteries can be made to be disposable.\",\n \"In addition to rechargeable power means, timing system 31 can be implemented where individual buttons are preset for predetermined time periods, or adjustable timing means are implemented.\",\n \"In other implementations, the power source for the fountain can be solar powered, A/C powered using 110 v, 210 v and/or DC powered using a 12 v battery.\",\n \"It is further contemplated that the garden fountain system may include a lighting system that provides accent lighting the fountain and/or the plant in the upper bowl planter.\",\n \"The positioning of the lights cans be within or out of the water.\",\n \"FIGS.\",\n \"3 and 5 illustrate one example of the disposition of the pump 32 within the shaft 23 positioned within the lower/reservoir bowl 24 and configured to support the middle bowl 26.The pump 32 includes a power connection 34 which is connected to the battery 30 positioned in the base 16.The pump 32 sits in the bottom of the shaft 23 and is configured to draw water from the lower/reservoir bowl 24 and the pump feeds the same to the middle bowl 26 via a tube 36 connected to a water input connection 40 in the center of the middle bowl 26.Referring to FIGS.\",\n \"3 and 4, the upper bowl 28, positioned siting within the middle bowl 26.In a preferred implementation, the upper bowl 28 is configured as planter.\",\n \"As shown in FIG.\",\n \"5, the upper bowl 28 includes a number of openings 42 at the bottom thereof.\",\n \"The openings 42 allow the transfer of water from a middle bowl 26, into upper bowl 28 when the water level rises in bowl 26 to a predetermined level.\",\n \"Bowl 26 has water introduced via a pump 32, (FIG.\",\n \"3), drawing water from bottom of a lower bowl 24, (i.e., a reservoir bowl).\",\n \"As shown in FIG.\",\n \"3, the pump can be located in the lower reservoir bowl 24, and as shown in the present example, the pump 32 is positioned within the shaft supporting the middle bowl 26.Those of skill in the art will appreciate that any suitable known type of pump 32 with an appropriate water intake can be used.\",\n \"According to one implementation, the pump 32 uses a 6-volt dc pump powered by the rechargeable battery 30 located in the base of the fountain.\",\n \"When the pump is turned on, the water is pumped from lower bowl 24 into the middle bowl 26.The water continues to rise until the water level reaches the pour spouts 25 of middle bowl 26, at which point the water level 5 reaches its maximum height or level in middle bowl 26 and the water pours over back into lower bowl 24.\",\n \"(See FIG.\",\n \"5) As shown above, upper bowl 28 sits in middle bowl 26.The distance between the base of middle bowl 26 and base of bowl 28, specifically the water inlets 42 of upper bowl 28 are crucial to the operation.\",\n \"The height of the water level in middle bowl 26 reaches at least to the bottom of the water inlets of upper bowl 28.Discs or spaces 43 can be added or subtracted to achieve the desired position of the base of the upper bowl 28 within the middle bowl 26.As will be evident from the above, height of the upper bowl 26 can be infinitely adjusted using the discs 43 depending on the water level desired/required for the plant in the upper bowl 28.According to one preferred implementation, a minimum height must at least reach the bottom of the water inlets 42 in upper bowl 28 in order for the soil 29 located in upper bowl 28 to be able to draw or wick the water up from middle bowl 26.Although shown in the form of openings, water inlets 42 can include a porous material 41 of any kind so as to prevent any soil from being undesirably being dispelled from the upper bowl 28 into middle bowl 26.As mentioned above, the height of upper bowl 28 in relation to middle bowl 26 will be adjustable.\",\n \"The purpose of an adjustable height is such that you can raise or lower the water level in upper bowl 28.This is beneficial since plants require different amounts of water for growing.\",\n \"In the current configuration one or more spacers 43 are used in between upper bowl 28 and middle bowl 26.Any number of or no spacers can be used.\",\n \"In the configuration of FIG.\",\n \"4, three (3) spacers 43 are shown.\",\n \"This gives a total of four (4) water level settings.\",\n \"The thickness of the spacers 43 can also be changed to accommodate other spacing options.\",\n \"In one preferred implementation, no spacer present allows upper bowl 28 to sit at its lowest possible setting, providing the highest water level in upper bowl 28.As you add a spacer between the upper bowl 28 and middle bowl 26, bowl 28 will increase in height over middle bowl 26 thus raising upper bowl 28 proportionally higher above middle bowl 26 lowering the water level or line in upper bowl 28.As you add another spacer, this water level will continue to lower in bowl 28 until you can add spacer so that upper bowl 28 water inlets 42 can be completely above the water level in middle bowl 26.The above description is referring to the water level in the active or pump on mode.\",\n \"This is when the water level is at its highest, but at no time does the water level rise above the maximum level provided by the waterspouts 25 in middle bowl 26.When in the active mode, or pump on mode and the maximum spacer 43 or height of upper bowl 28 is in use, the water level is raised in middle bowl 26 to the maximum height determined by the waterspouts 25.Upper bowl 28 being in its highest setting will only, when in active mode, have water coming in contact with the water inlets 42 in upper bowl.\",\n \"When the fountain is inactive, pump off, the water level will lower to a point just below the maximum water level in middle bowl 26.At this point the water level is lower than the bottom of the water inlets 42 in upper bowl 28.This then provides an air gap necessary for healthy plant growth allowing the soil to aerate, from the bottom up.\",\n \"In this same setting, when the fountain is in active mode, the water level in middle bowl 26 will rise to the maximum height provided by waterspouts 25 in bowl number 26.At such point, the water level will rise to allow the water inlets 42 in upper bowl 28 to come into contact with the water 5 in middle bowl 26.The resulting wicking effect allows the soil 29 in upper bowl 28 to wick the water up into bowl 28, providing water for the plant.\",\n \"The water level in upper bowl 28 can be adjusted through raising and lowering the bowl in relation to middle bowl 26 with any number of methods, fixed and mechanical.\",\n \"In addition, the water level in upper bowl 28 can be affected or adjusted to provide the proper amount of water to the plant in upper bowl 28 depending on if the fountain is active or inactive.\",\n \"The above description relates to the adjusting of the water level in upper bowl 28 in the active mode.\",\n \"If you adjust for the inactive mode, upper bowl 28 can be moved to, for example, the lowest setting.\",\n \"This position will place the water inlets 42 of upper bowl 28 to below the maximum water level of middle bowl 26.If the fountain is first active and thus raising the water level in bowl 26 to the maximum level and then turned inactive, the water level will lower slightly to just below the spout level 25.However, upper bowl 28 water inlets 42 can be set so that they are lower than middle bowl 28's maximum level.\",\n \"Therefore, the soil 29 in bowl 28 would continue to wick water up into bowl 28, even in the inactive mode.\",\n \"This provides additional water for different type of plants or weather conditions.\",\n \"This allows middle bowl 26 to act as a reservoir for upper bowl 28 until such time that the soil 29 in bowl 28 has wicked up the maximum amount of water it is capable of and or water has evaporated out of middle bowl 26.When either occurs, this will then lower the water level in middle bowl 26 to below the water inlets 42 in upper bowl 28, thus providing the necessary air gap 12 between upper bowl 28 and middle bowl number 26 to provide healthy conditions for good plant growth.\",\n \"The shape of the bottom of upper bowl 28 and the bottom of middle bowl 26 is also critical for proper water flow.\",\n \"Although there are numerous ways to introduce water into middle bowl 26, this description is for the current example being shown.\",\n \"The outlet of a water distribution tube 40 coming from the pump 32 located, for example, in lower bowl number 24, in a preferred embodiment needs to be just slightly higher than the maximum water level provided by the waterspouts 25 in middle bowl 26.This prevents the water from middle bowl 26 from siphoning back into lower bowl 24, thus maintaining the inactive water level in middle bowl 26 once initially filled to maximum water level when active.\",\n \"However, should the water siphon back into bowl 24, this can also be a benefit.\",\n \"In the current embodiment, there is a fill chamber 46 located in the bottom of upper bowl 28, which is female in shape, which matches to the male water distribution pipe 40 in middle bowl 26.This allows the water distribution pipe 40 or tube to be higher than the maximum water level in middle bowl 26 while allowing the water inlet ports 42, located in the corresponding female shape of the bottom of upper bowl 28 to operate below the maximum water level in middle bowl 26.In a preferred embodiment, water is only introduced into upper bowl 28 through the water inlet ports 42.This allows for a non-pressurized or turbulent water introduction into the soil.\",\n \"If the water from the distribution port in middle bowl 26 was directed straight directly into the soil 29 in upper bowl 28, it would erode the soil and causing excess soil to be introduced into the water system and erode the soil exposing the roots in the plant located in upper bowl 28.Although this system could have the water distributed to upper bowl 28 on in various manners, direct port from bowl number two into bowl number one.\",\n \"Another is a water distribution pipe pouring water into the top of bowl 28 from bowl 24.The preferred embodiment is to wick the water from the bottom up from bowl number 26 into upper bowl 28 initially when in the active mode then also in the inactive mode as described above.\",\n \"In the preferred embodiment, it has been found that the water distribution chamber 46 located in upper bowl 28, in relation to the air channels at the bottom of bowl 28, in relation to the water distribution port in middle bowl 26 can create a siphon effect after the fountain is inactive, thus siphoning all the water out of middle bowl 26 into lower bowl 24.This can be considered a positive effect if for example the plant in upper bowl 28 requires less water.\",\n \"To reduce this effect if a small hole 48 is introduced into the top of the water distribution chamber 46, it has been found to break the effect of the siphon, allowing the water to maintain minimum or inactive water height in middle bowl 26.Those of skill in the art will appreciate that there are numerous ways to affect the siphon occurring between middle bowl 26 and lower bowl 24, this is just one of example of the same.\",\n \"This anti-siphon hole 48 in the top of the water distribution chamber located in bowl 28 can also have a positive effect in providing water to the soil in bowl number one.\",\n \"When in the active mode it can create a method of positive pressure water introduction into upper bowl 28.Although it is considered preferred to allow the water to wick up from bowl number 26 into bowl 28, it could be beneficial in certain situations in which more water is required for a specific plant and the addition water introduction into the soil has a positive effect.\",\n \"However, as this positive pressure water inlet increases in size in relation the water flow or pressure created from the pump, located in bowl 24, it is possible to meter this flow by increasing or decreasing the diameter of this positive water pressure inlet.\",\n \"FIGS.\",\n \"6A and 6B show the base 12 of the fountain according to another implementation of the invention.\",\n \"FIG.\",\n \"6A shows the bottom 14 of the base being additionally, and adjustably, weighted with a suitable weighting material 68 (e.g., sand) Typical fountains made of stone, concrete, and any other heavy medium, do not require the ability have an adjustable weighted base as they very nature of their design is heavy.\",\n \"However, with the recent use of polyresin as the construction medium for the fountain of the present invention, which allows them to be light weight enough to ship for mass merchandising and for easy installation by the end user, they are too light to withstand any type of weather and will fall over with small winds.\",\n \"Simply making the fountain heavier is counter-productive since shipping costs will go up and the installation by the customer becomes more difficult.\",\n \"According to the present design the fountain can ship in its lightweight format and the end user can then add sand or heavy material 68 to the bottom of the fountain to provide the weight necessary to withstand weather conditions.\",\n \"In this embodiment (as described above), the battery location, combined with the weight chamber is unique.\",\n \"By placing the battery 30 in the lowest possible location to establish a low center of gravity and then adding a chamber 67 below the battery compartment to be filled with a removable weighted material 68 will provide the best center of gravity for the fountain.\",\n \"By placing the weighting material compartment 67 and battery compartment 22 close to each other, the issue or adding subtracting the weighted material becomes an issue for the end user and for methods of manufacturing.\",\n \"First the method of manufacturing a poly resin fountain utilizes an outer shape for the exterior of the fountain and at the bottom base a panel is glued into place to seal the bottom of the fountain base to the outer shape thus providing rigidity to the outer structure and to finish the cosmetics of the bottom of the fountain.\",\n \"This allows for a hollow inner structure which is both a cost and weight saving and the simplest method of manufacturing.\",\n \"However, this method makes it difficult to make a separated chamber 67 to add material to since there is no inner structure to the fountain.\",\n \"In the current design a male protrusion 66 which extends from the bottom base cap up into the inner body of the hollow fountain structure has been added.\",\n \"The top of this protrusion 66 becomes the base in which the battery 30 can sit.\",\n \"The diameter of the protrusion 66 is smaller than the inner diameter of the outer structure of the fountain.\",\n \"The distance between the protrusion 66 and the outer structure provides for a conduit allowing the end user to add weighted material into the bottom of the fountain, the weight chamber.\",\n \"The distance between the outer structure and the inner protrusion 66 is critical in that if it is too small it is difficult for the end user to add or remove weighted material and if it is too large, the base of the top of the protrusion 66 is not large enough to support the battery and any other object being stored in the battery compartment.\",\n \"To help in providing the added room from the placement or removal of the weighted material 68, a small indent of any particular shape can be added the protrusion 66, thus maintaining adequate base area to support the battery while increasing the space between the outer structure and the protrusion 66 for ease of adding or removing the weighted material.\",\n \"This method is preferred over other methods for adding or removing weight.\",\n \"For example, an opening formed in the bottom base panel, with, for example, a plug to add or remove the weighted material, would require that the fountain be turned upside down to add the material.\",\n \"This, in turn, would require that the hollow interior of the fountain have a separate panel molded and attached to the inner wall of the fountain.\",\n \"This panel would have to be sealed to prevent the weighted material from leaking back into the body of the fountain when it is turned upside down to add the weighted material.\",\n \"This added panel would significantly increase the manufacturing cost.\",\n \"The battery base 16/compartment 22 is also unique to the poly resin fountains for manufacturing reasons as mentioned above, even without the ability to add weighted material.\",\n \"By extending the outer edge of the battery base 16 to the inner dimension of the outer shape, which eliminates the ability to add weighted material, however provides a cost-effective method for production to establish a base for the battery.\",\n \"FIG.\",\n \"6B shows a clear view of the top 60 of the base 12.The top 60 includes a keyed slot 62 having keys 64.The keys 64 are configured to receive correspondingly shaped portions of the bottom of lower bowl 24 such that the same is received and rotated in the slot 62 and thereby secured to the top of the base during assembly.\",\n \"FIGS.\",\n \"7A and 7B show the configuration of the middle bowl 26 (2.sup.nd water tier) according to an implementation of the invention.\",\n \"The 2.sup.nd water tier water distribution tube in a poly-resin fountain is typically fixed to a molded plastic or resin tube with is the union from the tube exiting the water pump located inside the fountain thru the wall of the resin allowing the water to be distributed to the exterior of the fountain.\",\n \"This method does not allow for the ability to easily change or add new water features by the end user.\",\n \"According to an implementation, the middle bowl 26 is molded with a large passageway 76 having an inner dimension configured to receive the water distribution plug 72 with hose 74 that can be inserted into the resin.\",\n \"This removable plug 72 allows the end user to pull the tube 74 off of the water feature to be removed and re-attach a new water feature by pressing the water distribution plug in place on the new feature.\",\n \"FIG.\",\n \"8 shows another implementation of the base pedestal 16 having a wireless, e.g., Bluetooth®, speaker 80 positioned therein.\",\n \"The speaker is connected to power source via plug 84 and wire 82.The power source connected to plug 82 can be any suitable battery source, and may, depending on the configuration, be connected to the water fountain's primary battery 30.Alternatively, a separate battery can be provided to power the wireless (Bluetooth®) speaker 80.As will be appreciated, the addition of the speaker 80 allows a user to wirelessly transmit audio content to the speaker via their own compatible Bluetooth® audio player or system.\",\n \"The above description above is for a three-tier fountain.\",\n \"This self-watering garden fountain can be constructed in various configurations.\",\n \"It can have two tiers, with a reservoir located inside or in the base of the bottom tier.\",\n \"Those of skill in the art will appreciate that the fountain of the present invention can be constructed with multiple tiers, with essentially no limit.\",\n \"It can also be constructed with multiple planter bowls, in parallel to each other, vertically stacked to each other, and various other combinations and configurations.\",\n \"While there have been shown, described and pointed out fundamental novel features of the present principles, it will be understood that various omissions, substitutions and changes in the form and details of the methods described and devices illustrated, and in their operation, may be made by those skilled in the art without departing from the spirit of the same.\",\n \"For example, it is expressly intended that all combinations of those elements and/or method steps which perform substantially the same function in substantially the same way to achieve the same results are within the scope of the present principles.\",\n \"Moreover, it should be recognized that structures and/or elements and/or method steps shown and/or described in connection with any disclosed form or implementation of the present principles may be incorporated in any other disclosed, described or suggested form or implementation as a general matter of design choice.\",\n \"It is the intention, therefore, to be limited only as indicated by the scope of the claims appended hereto.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875778"}}},{"rowIdx":4494974,"cells":{"text":{"kind":"list like","value":[["METHODS AND DEVICES FOR STIMULATING CELL PROLIFERATION","Embodiments of the present disclosure are directed to devices and methods for stimulating cell proliferation.","In one implementation, a method for increasing cell proliferation is provided.","The method includes providing a vibrational dental device configured to vibrate at a frequency higher than about 60 Hz.","The method also includes mechanically stimulating, using the vibrational dental device, cells for a treatment period of less than about 10 to 20 minutes daily.","The method may further include generating a peak acceleration magnitude in the horizontal direction substantially greater than that in the vertical direction.","The number of the cells at the end of the period of time is increased.","The cells may include at least one of human osteoblasts and fibroblasts."],["1.A method for increasing periodontal cell proliferation, the method comprising: providing a vibrational dental device configured to vibrate at a frequency higher than about 60 Hz, wherein a peak acceleration magnitude generated by the vibrational dental device in the horizontal direction is substantially greater than that in the vertical direction; mechanically stimulating, using the vibrational dental device, periodontal cells, including at least one of human osteoblasts and fibroblasts, for a treatment period of less than about 10 minutes daily; and wherein the number of the periodontal cells at the end of the period of time is increased.","2.The method of claim 1, wherein the vibrational dental device is configured to vibrate at a total acceleration magnitude ranging between about 0.001 G and about 3 G. 3.The method of claim 1, wherein the peak acceleration magnitude produced by the vibrational dental device in the horizontal direction is about five times greater than that in the vertical direction.","4.The method of claim 1, further comprising mechanically stimulating the cells at a frequency between about 60 Hz and about 300 Hz.","5.The method of claim 1, further comprising mechanically stimulating the cells at a g-force between about 0.001 G and about 3 G. 6.The method of claim 1, wherein the vibrational dental device comprises a mouthpiece and a motor connected to and configured to vibrate the mouthpiece.","7.The method of claim 5, further comprising providing the mouthpiece between the occlusal surfaces of a user's teeth to be clamped by the user's teeth.","8.The method of claim 6, further comprising applying an axial vibratory force on the occlusal surfaces by the vibrational dental device.","9.The method of claim 1, further comprising detecting vibration characteristics of the mouthpiece produced by the vibrational dental device.","10.The method of claim 1, further comprising adjusting the frequency and/or g-force of the vibration of the vibrational dental device.","11.The method of claim 1, wherein the period of time ranges from a couple of days to a few months.","12.The method of claim 10, wherein the period of time ranges from a couple of days to a few days.","13.The method of claim 10, wherein the period of time ranges from a few days to couple of weeks.","14.The method of claim 10, wherein the period of time ranges from a month to a couple of months.","15.The method of claim 10, wherein the period of time ranges from a couple of months to a few months.","16.The method of claim 1, wherein the human osteoblasts comprise human osteoblasts in alveolar bone.","17.The method of claim 1, wherein the fibroblasts comprise periodontal ligament fibroblasts.","18.The method of claim 1, wherein the treatment period comprises one or more treatment sessions that range from about 1 minute to about 10 minutes.","19.A method for accelerating orthodontic tooth movement, the method comprising: providing a mouthpiece of a vibrational dental device to be clamped by the user's teeth; and mechanically stimulating, using the vibrational dental device, cells of the user, including at least one of osteoblasts in alveolar bone and periodontal ligament fibroblasts, for a treatment period of less than about 10 minutes daily at a frequency higher than about 60 Hz, wherein a peak acceleration magnitude of the mouthpiece in the horizontal direction is substantially greater than that in the vertical direction.","20.The method of claim 19, further comprising providing the mouthpiece between the occlusal surfaces of a user's teeth.","21.The method of claim 19, further comprising mechanically stimulating the cells of the user at a g-force between about 0.001 G and about 3 G. 22.The method of claim 18, further comprising mechanically stimulating the cells of the user at a frequency between about 60 Hz and about 300 Hz.","23.A dental device for increasing cell proliferation, the dental device comprising means for mechanically stimulating cells, including at least one of human osteoblasts and periodontal ligament fibroblasts, at a frequency higher than about 60 Hz for a treatment period of less than about 10 minutes daily, wherein a peak acceleration magnitude generated by the vibrational dental device in the horizontal direction is substantially greater than that in the vertical direction."],["<SOH> BACKGROUND <EOH>"],["<SOH> SUMMARY <EOH>The embodiments of the present disclosure include systems, devices, and methods for stimulating cell proliferation in periodontal tissues, including the alveolar processes and periodontal ligament.","Advantageously, the exemplary embodiments allow cells belonging to the connective-tissue cell family, such as human osteoblasts in alveolar bone and periodontal ligament fibroblasts, to proliferate after relatively short vibration treatments, thereby improving the efficiency and effectiveness of orthodontic treatments.","According to an exemplary embodiment of the present disclosure, a method for increasing cell proliferation is described.","The method includes providing a vibrational dental device that is capable of vibrating at a frequency higher than about 80 Hz.","The method also includes mechanically stimulating, using the vibrational dental device, cells for a treatment period of less than about 20 minutes daily over a period of time.","The treatment period can be, for example, less than about 20 minutes, 15 minutes, 10 minutes, 6 minutes, 5 minutes, 4 minutes, 2 minutes, 1 minute, or less.","It is contemplated that in other embodiments the treatment period could be any value within the range of about 1 minute and 19 minutes daily, and that the daily total treatment period could be formed of a plurality of treatment sessions contributing to the daily total treatment period.","In one exemplary embodiment, the daily total treatment period is about 5 minutes.","The cells may include human osteoblasts and/or human fibroblasts.","The method further includes increasing the number of the cells at the end of the period of time.","The vibration frequency can be less than about 300 Hz, for example, from about 60 Hz to about 300 Hz, from about 60 Hz to about 200 Hz, from about 60 Hz to about 130 Hz, from about 80 Hz to about 120 Hz, from about 110 Hz to about 120 Hz, from about 100 Hz to about 110 Hz, from about 90 Hz to about 100 Hz, or from about from about 80 Hz to about 90 Hz.","It is contemplated that in other embodiments the frequency could be any value within the range of about 80 Hz and about 120 Hz, and that the vibration frequency could be adjusted during a treatment period.","In one exemplary embodiment, the vibration frequency is about 100 Hz.","In some embodiments, the method further includes generating a peak acceleration magnitude in the horizontal direction substantially greater than that in the vertical direction.","For example, the peak acceleration magnitude of the vibration generated by the vibrational dental device in the horizontal direction can be about 1 to 5 times greater than that in the vertical direction.","In some embodiments, the peak acceleration magnitude of the vibration in the horizontal direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In some embodiments, the peak acceleration magnitude of the vibration in the vertical direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In other embodiments, the total peak acceleration magnitude of the vibration may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. According to a further exemplary embodiment of the present disclosure, a method for accelerating orthodontic tooth movement is described.","The method includes providing a mouthpiece of a vibrational dental device to be clamped by the user's teeth, for example, between the occlusal surfaces of a user's teeth.","The method further includes mechanically stimulating, using the vibrational dental device, cells of the user for a treatment period of less than about 20 minutes daily at a frequency higher than 80 Hz over a period of time.","The treatment period can be, for example, less than about 20 minutes, 15 minutes, 10 minutes, 6 minutes, 5 minutes, 4 minutes, 2 minutes, 1 minute, or less.","It is contemplated that in other embodiments the treatment period could be any value within the range of about 1 minute and 19 minutes daily, and that the daily total treatment period could be formed of a plurality of treatment sessions contributing to the daily total treatment period.","In one exemplary embodiment, the daily total treatment period is about 5 minutes.","The cells may include at least one of osteoblasts in alveolar bone and periodontal ligament fibroblasts.","The vibration frequency can be less than about 300 Hz, for example, from about 60 Hz to about 300 Hz, from about 60 Hz to about 200 Hz, from about 60 Hz to about 130 Hz, from about 80 Hz to about 120 Hz, from about 110 Hz to about 120 Hz, from about 100 Hz to about 110 Hz, from about 90 Hz to about 100 Hz, or from about from about 80 Hz to about 90 Hz.","It is contemplated that in other embodiments the frequency could be any value within the range of about 80 Hz and about 120 Hz, and that the vibration frequency could be adjusted during a treatment period.","In one exemplary embodiment, the vibration frequency is about 100 Hz.","In some embodiments, the method further includes producing a peak acceleration magnitude in the horizontal direction substantially greater than that in the vertical direction.","For example, the peak acceleration magnitude of the vibration generated by the vibrational dental device in the horizontal direction can be about 1 to 5 times greater than that in the vertical direction.","In some embodiments, the peak acceleration magnitude of the vibration in the horizontal direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In some embodiments, the peak acceleration magnitude of the vibration in the vertical direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In other embodiments, the total peak acceleration magnitude of the vibration may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. According to a yet further exemplary embodiment of the present disclosure, a dental device for increasing cell proliferation is described.","The dental device includes means for mechanically stimulating cells at a frequency higher than 80 Hz for a treatment period of less than about 20 minutes daily over a period of time, and further increasing the number of the cells at the end of the period of time.","The cells may include human osteoblasts and/or human fibroblasts.","The treatment period can be, for example, less than about 20 minutes, 15 minutes, 10 minutes, 6 minutes, 5 minutes, 4 minutes, 2 minutes, 1 minute, or less.","It is contemplated that in other embodiments the treatment period could be any value within the range of about 1 minute and 19 minutes daily, and that the daily total treatment period could be formed of a plurality of treatment sessions contributing to the daily total treatment period.","In one exemplary embodiment, the daily total treatment period is about 5 minutes.","The vibration frequency can be less than about 300 Hz, for example, from about 60 Hz to about 300 Hz, from about 60 Hz to about 200 Hz, from about 60 Hz to about 130 Hz, from about 80 Hz to about 120 Hz, from about 110 Hz to about 120 Hz, from about 100 Hz to about 110 Hz, from about 90 Hz to about 100 Hz, or from about from about 80 Hz to about 90 Hz.","It is contemplated that in other embodiments the frequency could be any value within the range of about 80 Hz and about 120 Hz, and that the vibration frequency could be adjusted during a treatment period.","In one exemplary embodiment, the vibration frequency is about 100 Hz.","In some embodiments, the dental device is capable of mechanically vibrating with a peak acceleration magnitude in the horizontal direction substantially greater than that in the vertical direction.","For example, the peak acceleration magnitude of the vibration generated by the dental device in the horizontal direction can be about 1 to 5 times greater than that in the vertical direction.","In some embodiments, the peak acceleration magnitude of the vibration in the horizontal direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In some embodiments, the peak acceleration magnitude of the vibration in the vertical direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In other embodiments, the total peak acceleration magnitude of the vibration may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. Additional features and advantages of the disclosed embodiments will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the disclosed embodiments.","The features and advantages of the disclosed embodiments will be realized and attained by the elements and combinations particularly pointed out in the appended claims.","It is to be understood that both the foregoing general description and the following detailed description are examples and explanatory only and are not restrictive of the disclosed embodiments as claimed.","The accompanying drawings constitute a part of this specification.","The drawings illustrate several embodiments of the present disclosure and, together with the description, serve to explain the principles of the disclosed embodiments as set forth in the accompanying claims."],["BACKGROUND Technical Field The present disclosure generally relates to dental devices and methods of use.","More particularly, and without limitation, the disclosed embodiments relate to systems, devices, and methods for stimulating cell proliferation in the region of the alveolar process of the maxilla and mandible, including the periodontal ligament, using vibration.","Background Description Mechanical vibration may enhance musculoskeletal properties.","For example, some studies suggested that low-intensity mechanical vibrations may stimulate bone formation or mitigate the degradation of the intervertebral disc in rats.","However, the biomolecular mechanisms for such enhancement effects have not yet been elucidated.","Some studies suggested that mechanical vibration may enhance differentiation of human bone marrow mesenchymal stem cells or periodontal ligament stem cells.","But discrepancies and unpredictability exist in literature as to the effects of mechanical vibration on cell proliferation.","For example, previous studies have demonstrated no effects or either increased or decreased proliferation after cyclic vibration treatment.","See Zhang, C., et al.","(2012).","Effects of mechanical vibration on proliferation and osteogenic differentiation of human periodontal ligament stem cells.","Archives of Oral Biology, 57(10), 1395-1407.The unpredictability in the art has manifested itself in the experimental data in the prior art.","Some studies have suggested vibrations at frequencies ranging from 15 Hz to 90 Hz may be more anabolic to bone formation.","See Zhang, C., et al.","(2012).","Most of the previous studies subjected cells or animals to vibration treatments for a certain number of vibration bouts per day, each bout lasting for a duration ranging from 15 minutes to 60 minutes.","See Judex, S., et al.","(2015).","Modulation of bone's sensitivity to low-intensity vibrations by acceleration magnitude, vibration duration, and number of bouts.","Osteoporosis International, 26(4), 1417-1428; see also Pongkitwitoon, S., et al.","(2016).","A recent study further suggested that increasing the bout duration to an even longer period (30 or 60 minutes) would positively influence bone formation rates in mice.","Cytoskeletal Configuration Modulates Mechanically Induced Changes in Mesenchymal Stem Cell Osteogenesis, Morphology, and Stiffness.","Scientific Reports, 6(1).","doi:10.1038/srep34791.It is recently hypothesized that mechanical vibration may promote periodontal regeneration and periodontal tissue remodeling during and following orthodontic tooth movement.","However, variables of mechanical vibration to be used for modulating bone biology so as to effectively accelerate orthodontic tooth movement remain to be determined.","SUMMARY The embodiments of the present disclosure include systems, devices, and methods for stimulating cell proliferation in periodontal tissues, including the alveolar processes and periodontal ligament.","Advantageously, the exemplary embodiments allow cells belonging to the connective-tissue cell family, such as human osteoblasts in alveolar bone and periodontal ligament fibroblasts, to proliferate after relatively short vibration treatments, thereby improving the efficiency and effectiveness of orthodontic treatments.","According to an exemplary embodiment of the present disclosure, a method for increasing cell proliferation is described.","The method includes providing a vibrational dental device that is capable of vibrating at a frequency higher than about 80 Hz.","The method also includes mechanically stimulating, using the vibrational dental device, cells for a treatment period of less than about 20 minutes daily over a period of time.","The treatment period can be, for example, less than about 20 minutes, 15 minutes, 10 minutes, 6 minutes, 5 minutes, 4 minutes, 2 minutes, 1 minute, or less.","It is contemplated that in other embodiments the treatment period could be any value within the range of about 1 minute and 19 minutes daily, and that the daily total treatment period could be formed of a plurality of treatment sessions contributing to the daily total treatment period.","In one exemplary embodiment, the daily total treatment period is about 5 minutes.","The cells may include human osteoblasts and/or human fibroblasts.","The method further includes increasing the number of the cells at the end of the period of time.","The vibration frequency can be less than about 300 Hz, for example, from about 60 Hz to about 300 Hz, from about 60 Hz to about 200 Hz, from about 60 Hz to about 130 Hz, from about 80 Hz to about 120 Hz, from about 110 Hz to about 120 Hz, from about 100 Hz to about 110 Hz, from about 90 Hz to about 100 Hz, or from about from about 80 Hz to about 90 Hz.","It is contemplated that in other embodiments the frequency could be any value within the range of about 80 Hz and about 120 Hz, and that the vibration frequency could be adjusted during a treatment period.","In one exemplary embodiment, the vibration frequency is about 100 Hz.","In some embodiments, the method further includes generating a peak acceleration magnitude in the horizontal direction substantially greater than that in the vertical direction.","For example, the peak acceleration magnitude of the vibration generated by the vibrational dental device in the horizontal direction can be about 1 to 5 times greater than that in the vertical direction.","In some embodiments, the peak acceleration magnitude of the vibration in the horizontal direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In some embodiments, the peak acceleration magnitude of the vibration in the vertical direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In other embodiments, the total peak acceleration magnitude of the vibration may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. According to a further exemplary embodiment of the present disclosure, a method for accelerating orthodontic tooth movement is described.","The method includes providing a mouthpiece of a vibrational dental device to be clamped by the user's teeth, for example, between the occlusal surfaces of a user's teeth.","The method further includes mechanically stimulating, using the vibrational dental device, cells of the user for a treatment period of less than about 20 minutes daily at a frequency higher than 80 Hz over a period of time.","The treatment period can be, for example, less than about 20 minutes, 15 minutes, 10 minutes, 6 minutes, 5 minutes, 4 minutes, 2 minutes, 1 minute, or less.","It is contemplated that in other embodiments the treatment period could be any value within the range of about 1 minute and 19 minutes daily, and that the daily total treatment period could be formed of a plurality of treatment sessions contributing to the daily total treatment period.","In one exemplary embodiment, the daily total treatment period is about 5 minutes.","The cells may include at least one of osteoblasts in alveolar bone and periodontal ligament fibroblasts.","The vibration frequency can be less than about 300 Hz, for example, from about 60 Hz to about 300 Hz, from about 60 Hz to about 200 Hz, from about 60 Hz to about 130 Hz, from about 80 Hz to about 120 Hz, from about 110 Hz to about 120 Hz, from about 100 Hz to about 110 Hz, from about 90 Hz to about 100 Hz, or from about from about 80 Hz to about 90 Hz.","It is contemplated that in other embodiments the frequency could be any value within the range of about 80 Hz and about 120 Hz, and that the vibration frequency could be adjusted during a treatment period.","In one exemplary embodiment, the vibration frequency is about 100 Hz.","In some embodiments, the method further includes producing a peak acceleration magnitude in the horizontal direction substantially greater than that in the vertical direction.","For example, the peak acceleration magnitude of the vibration generated by the vibrational dental device in the horizontal direction can be about 1 to 5 times greater than that in the vertical direction.","In some embodiments, the peak acceleration magnitude of the vibration in the horizontal direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In some embodiments, the peak acceleration magnitude of the vibration in the vertical direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In other embodiments, the total peak acceleration magnitude of the vibration may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. According to a yet further exemplary embodiment of the present disclosure, a dental device for increasing cell proliferation is described.","The dental device includes means for mechanically stimulating cells at a frequency higher than 80 Hz for a treatment period of less than about 20 minutes daily over a period of time, and further increasing the number of the cells at the end of the period of time.","The cells may include human osteoblasts and/or human fibroblasts.","The treatment period can be, for example, less than about 20 minutes, 15 minutes, 10 minutes, 6 minutes, 5 minutes, 4 minutes, 2 minutes, 1 minute, or less.","It is contemplated that in other embodiments the treatment period could be any value within the range of about 1 minute and 19 minutes daily, and that the daily total treatment period could be formed of a plurality of treatment sessions contributing to the daily total treatment period.","In one exemplary embodiment, the daily total treatment period is about 5 minutes.","The vibration frequency can be less than about 300 Hz, for example, from about 60 Hz to about 300 Hz, from about 60 Hz to about 200 Hz, from about 60 Hz to about 130 Hz, from about 80 Hz to about 120 Hz, from about 110 Hz to about 120 Hz, from about 100 Hz to about 110 Hz, from about 90 Hz to about 100 Hz, or from about from about 80 Hz to about 90 Hz.","It is contemplated that in other embodiments the frequency could be any value within the range of about 80 Hz and about 120 Hz, and that the vibration frequency could be adjusted during a treatment period.","In one exemplary embodiment, the vibration frequency is about 100 Hz.","In some embodiments, the dental device is capable of mechanically vibrating with a peak acceleration magnitude in the horizontal direction substantially greater than that in the vertical direction.","For example, the peak acceleration magnitude of the vibration generated by the dental device in the horizontal direction can be about 1 to 5 times greater than that in the vertical direction.","In some embodiments, the peak acceleration magnitude of the vibration in the horizontal direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In some embodiments, the peak acceleration magnitude of the vibration in the vertical direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In other embodiments, the total peak acceleration magnitude of the vibration may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. Additional features and advantages of the disclosed embodiments will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the disclosed embodiments.","The features and advantages of the disclosed embodiments will be realized and attained by the elements and combinations particularly pointed out in the appended claims.","It is to be understood that both the foregoing general description and the following detailed description are examples and explanatory only and are not restrictive of the disclosed embodiments as claimed.","The accompanying drawings constitute a part of this specification.","The drawings illustrate several embodiments of the present disclosure and, together with the description, serve to explain the principles of the disclosed embodiments as set forth in the accompanying claims.","BRIEF DESCRIPTION OF THE DRAWINGS FIG.","1A is a perspective view of an exemplary vibrational dental device, according to embodiments of the present disclosure.","FIG.","1B is a partial perspective view of the exemplary vibrational dental device of FIG.","1A, according to embodiments of the present disclosure.","FIG.","1C is a partial component view of the exemplary vibrational dental device of FIG.","1, according to embodiments of the present disclosure.","FIG.","2 illustrates the operation of the exemplary oral vibrational device of FIG.","1.FIGS.","3A-3P each show the measurement of vibration of an exemplary typodont subject to vibration treatment by the exemplary vibrational dental device of FIG.","1 under different testing conditions.","FIGS.","4A-4P each show the measurement of vibration of an exemplary typodont subject to vibration treatment by a commercially available dental device under different testing conditions.","FIG.","5A graphically compares g-force measurements of a typodont with an aligner subject to vibration treatment by the exemplary vibrational dental device of FIG.","1 and an exemplary commercially available dental device.","FIG.","5B graphically compares g-force measurements of a typodont without an aligner subject to vibration treatment by the exemplary vibrational dental device of FIG.","1 and an exemplary commercially available dental device.","FIG.","6 graphically compares peak acceleration magnitudes between the average peak acceleration magnitudes between an exemplary commercially available dental device and the exemplary vibrational dental device of FIG.","1.FIG.","7 graphically compares average total displacement of the vibratory motion produced by an exemplary commercially available dental device and by the exemplary vibrational dental device of FIG.","1.FIG.","8 graphically compares mean numbers of osteoblasts over three days of a control group, a first group subject to mechanical vibration by an exemplary commercially available dental device, and a second group subject to mechanical vibration by the exemplary vibrational dental device of FIG.","1.FIG.","9 graphically compares mean numbers of periodontal ligament fibroblasts over three days of a control group, a first group subject to mechanical vibration by an exemplary commercially available dental device, and a second group subject to mechanical vibration by the exemplary vibrational dental device of FIG.","1.FIG.","10 graphically compares mean activity of osteoclasts over three days of a control group, a first group subject to mechanical vibration by an exemplary commercially available dental device, and a second group subject to mechanical vibration by the exemplary vibrational dental device of FIG.","1.FIG.","11 is a flowchart of an exemplary method for increasing cell proliferation, according to embodiments of the present disclosure.","FIG.","12 is a flowchart of an exemplary method for accelerating orthodontic tooth movement, according to embodiments of the present disclosure.","DETAILED DESCRIPTION The disclosed embodiments relate to devices, systems, and methods for stimulating cell proliferation.","Advantageously, embodiments of the present disclosure can be implemented in an orthodontic treatment for accelerating orthodontic tooth movement.","Osteoblasts and fibroblasts are intimately involved in facilitating tooth movement and thus are typically targeted by techniques that aim at accelerating tooth movement in orthodontic treatments.","Different approaches, both pre-clinically and clinically, have been attempted to achieve quicker results, but there are still many uncertainties and undetermined variables towards most of these techniques.","For example, some commercially available dental devices, such as AcceleDent Aura™, developed by OrthoAccel® Technologies, Inc., are offered to accelerate orthodontic treatment.","Patients are advised to wear such dental devices that mechanically stimulate teeth and braces in the form of micro-vibrations at a frequency of 30 Hz for 20 min per day.","To get the maximum desired results of accelerated orthodontic treatment, further studies are still needed to identify the variables of mechanical vibrational stimulation, such as frequency, strength, and duration.","It was discovered that treating cells, such as human osteoblasts and fibroblasts, with mechanical vibration for less than about 20 minutes, for example for about 5 minutes, daily at a frequency higher than about 80 Hz and with anisotropic acceleration magnitudes increases the number of cells over a period of time.","That a marked improvement of cell proliferation over prior-art treatment methods using a shorter treatment interval is surprising and not suggested by the prior art.","Various aspects of the present disclosure are developed based on such discovery.","According to an aspect of the present disclosure, a vibrational dental device that vibrates at a frequency higher than about 80 Hz is provided.","The vibrational dental device includes a mouthpiece and a motor connected to the mouthpiece.","The mouthpiece is configured to be provided between the occlusal surfaces of a user's teeth so as to be clamped by the user's teeth.","The motor is configured to vibrate the mouthpiece at a frequency higher than about 80 Hz, such as at a frequency between about 100 Hz to about 120 Hz, and with an acceleration magnitude ranging between about 0.03 G and about 0.4 G. When the motor is in operation and when the mouthpiece is clamped between the occlusal surfaces of a user's teeth, the vibrational dental device applies an axial vibratory force on the occlusal surfaces.","Clamping the teeth onto the mouthpiece will apply a load to the vibrator, which may have the effect of lowering the vibrational frequency of the mouthpiece measured in free air, as described below.","In some embodiments, the vibrational dental device may further include a sensor configured to detect the vibration variables of the device, such as frequency and acceleration magnitude.","When the mouthpiece of the vibrational dental device is clamped between the occlusal surfaces of a user's teeth, the sensor may detect the vibration variables proximate to the occlusal surfaces of the user's teeth.","In some embodiments, the sensor is a piezoelectric sensor.","According to another aspect of the present disclosure, a method for increasing cell proliferation is provided.","The method includes mechanically stimulating, using an exemplary vibrational dental device, cells for less than about 20 minutes, for example for about 5 minutes, daily at a frequency higher than about 80 Hz over a period of time.","The cells may include at least one of human osteoblasts and fibroblasts.","The period of time may extend for a couple of days up to a number of months, at the end of which, the number of the cells increases.","As described herein, an increase of cell proliferation or an increase of the number of cells can be represented by an increase of cell density.","According to another aspect of the present disclosure, a method for accelerating orthodontic tooth movement is described.","The method includes providing the mouthpiece of the vibrational dental device between the occlusal surfaces of a user's teeth to be clamped by the user's teeth.","The method further includes mechanically stimulating, using the vibrational dental device, cells of the user, including at least one of osteoblasts in alveolar bone and periodontal ligament fibroblasts, for less than about 20 minutes, for example for about 5 minutes, at a frequency higher than 80 Hz daily over a period of time.","In some embodiments, the method further includes applying an axial vibratory force on the occlusal surfaces by the vibrational dental device.","In some embodiments, the vibrational frequency and/or the acceleration magnitude generated by the vibrational dental device may be adjusted.","Such adjustment may depend on one or more factors, such as the speed of tooth movement and/or user's reported comfort level.","Reference will now be made in detail to embodiments and aspects of the present disclosure, examples of which are illustrated in the accompanying drawings.","Where possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts.","FIG.","1A is a perspective view of an exemplary vibrational dental device 100.FIG.","1B is a partial perspective view of vibrational dental device 100.FIG.","1C is a partial component view of vibrational dental device 100.As shown in FIGS.","1A-1C, vibrational dental device 100 includes a mouthpiece 102, a base 104, and a motor 106.Mouthpiece 102 is removably attached to base 104.Mouthpiece 102 includes a biteplate 114 and a mouthpiece extension 110 configured to connect with base 104.In some embodiments, mouthpiece 102 and/or biteplate 114 can be configured to engage some or all of a user's teeth.","For example, in the exemplary embodiments shown in FIGS.","1A-2, mouthpiece 102 and/or biteplate 114 are shaped to engage some or all of a user's teeth.","As described herein, the shape of mouthpiece 102 and/or biteplate 114 shown in FIGS.","1A-2 is only exemplary.","Mouthpiece 102 and/or biteplate 114 may have a C-shape as depicted, or a customized shape suitable for safe application of vibrational treatment to all or some of a user's teeth.","The mouthpiece can be made to apply vibration directly to a user's teeth, or to aligners or other appliances applied to the teeth.","Extension 110 may further include contacts 108 that electrically connect base 104 with motor 106.As shown in FIGS.","1B and 1C, motor 106 is installed in extension 110 of mouthpiece 102.When mouthpiece 102 is attached to base 104, motor 106 resides in base 104.Base 104 further includes electronic circuitries (not shown), including a control circuitry and a power circuitry, for operating motor 106.Motor 106 may be any type of motor that can cause mouthpiece 102 or biteplate 114 to vibrate.","For example, motor 106 could be a vibration motor, piezoelectric motor, a linear motor, or an electromagnetic motor.","The frequency and/or strength of vibration caused by motor 106 can be adjusted by changing the voltage or current supplied to motor 106 by the electronic circuitries in base 104.For example, the voltage used for operating motor 106 may range from about 0.5 volt to about 4 volts.","The current supplied to an exemplary motor 106 may range from about 65 mA to about 100 mA.","Motor 106 may have any suitable mechanical configurations to cause mouthpiece 102 or biteplate 114 to vibrate axially.","FIG.","2 illustrates exemplary operation of vibrational dental device 100.As shown in FIG.","2, in one embodiment, motor 106 is a counter-weighted motor with a longitudinal axis parallel to the longitudinal axis of extension 110.Motor 106 may include a counterweight 212 that is off-axis from the longitudinal axis of motor 106.When the motor 106 rotates, as shown by the arrow 111 in FIG.","2, counterweight 212 moves up and down, causing the mouthpiece 102 to vibrate up and down, as shown by the arrows 113a-113d in FIG.","2.Accordingly, when the exemplary mouthpiece 102 is placed in a typodont or between a user's teeth, and when exemplary vibrational dental device 100 is turned on, the vibration of mouthpiece 102 will apply an axial vibratory force on the occlusal surfaces of the teeth.","For example, biteplate 114 of mouthpiece 102 may cyclically move axially between the occlusal surfaces of the teeth.","In some embodiments, vibrational dental device 100 may further include one or more sensors (not shown), such as piezoelectric sensors, configured to detect the acceleration magnitude and/or frequency of the vibration of mouthpiece 102.For example, sensors may be placed on the outside or the inside edge of biteplate 114, proximate to the occlusal surfaces of the teeth when mouthpiece 102 is clamped between the occlusal surfaces.","The sensors can be electrically connected to the electronic circuitries in base 104.Measurements of the sensors can be fed back to the control circuitry of motor 106 to adjust the acceleration magnitude and/or frequency of motor 106.For example, the detected acceleration magnitude and/or frequency may be compared to a desired acceleration magnitude and/or frequency, and the voltage and/or current supplied to motor 106 can be adjusted based on the comparison.","In some embodiments, motor 106 is configured to vibrate mouthpiece 102 at a frequency higher than about 80 Hz, such as at a frequency between about 100 Hz to about 120 Hz.","Motor 106 may be further configured to vibrate mouthpiece 102 at an acceleration magnitude ranging between about 0.03 G and about 0.2 G. As described herein, the vibrational frequency of mouthpiece 120 may vary from the rated “free-air” vibrational frequency of motor 106 due to the amount of biting force or load applied to mouthpiece 102, such as the force used to clamp vibrational dental device 100 in place.","For example, when motor 106 is configured to vibrate at a frequency of about 120 Hz, adding biting force or load to mouthpiece 102 may result in a lower vibrational frequency of mouthpiece 102 ranging from about 100 Hz to about 120 Hz.","Examples 1-11 described below illustrate the use of vibrational dental device 100 operating under these variables and its clinically relevant effects.","Example 1 A simulation was conducted to test and compare the vibration characteristics of a typodont caused by an exemplary embodiment of vibrational dental device 100 and a commercially available dental device, the AcceleDent Aura™.","In the simulation setup, the typodont was secured to a metal table.","The upper jaw of the typodont was hinged to the lower jaw and capable of opening and closing.","Each device was placed in the typodont (between the occlusal surfaces) and held in position by securely mounting a weight of about 0 to about 4 pounds on the upper jaw.","The weight simulates the biting force typically applied by a user to clamp the devices in place.","The simulation setup further included electronic instruments, including accelerometers, for measuring vibration characteristics of the typodont.","The accelerometers were placed directly on the devices and on the typodont.","FIGS.","3A-4P each show the measurement dataset of the accelerometer for two channels, channel 1 (“Ch1”) for detecting the vibration characteristics of the typodont and channel 2 (“Ch2”) for detecting the vibration characteristics of the device.","As shown in FIGS.","3A-4P, measurements of the accelerometers over the operation time of each device recorded increasing and decreasing accelerations of the devices and the typodont.","The measurement dataset of the accelerometers resembles a sinusoidal curve.","The distance from the bottom to the top of the sinusoidal curve is called the peak-to-peak G value or g-force (Gp-p).","In this simulation, the operation time of vibrational dental device 100 was about 5 minutes.","The operation time of AcceleDent Aura™ was about 20 minutes.","The maximum Gp-p values of the vibration of the typodont actuated by these two devices under different simulated biting forces (different weights) were measured using the accelerometers and other associated electronic instruments about one minute before the end of the operation time.","Therefore, measurement of the frequency and g-force for each channel was performed at the time point of about 4 minutes for vibrational dental device 100 and at the time point of about 19 minutes for AcceleDent Aura™.","The simulation was repeated for a second testing device of vibrational dental device 100 and a second testing device of AcceleDent Aura™.","Therefore, the first and second vibration dental devices 100 tested are shown as vibrational dental device 100 (1) and vibrational dental device 100 (2) respectively in FIGS.","3A-3P.","Also, the first and second AcceleDent Aura™ devices are shown as AcceleDent Aura™ (1) and AcceleDent Aura™ (2) respectively in FIGS.","4A-4P.","The simulation was also repeated where the typodont was installed with and without an aligner, as indicated in the captions of FIGS.","3A-4P.","All measurement data was summarized in Table 1 as shown below.","TABLE 1 G-force values (Gp-p) measured under different testing conditions.","g-force g-force on on Frequency typodont device Device Weight Aligner Time (Hz) (G) (G) AcceleDent Aura ™ (1) 4 Yes End-1 Min 29.8 0.002 0.074 AcceleDent Aura ™ (1) 4 No End-1 Min 30.46 0.002 0.072 Vibrational dental device 100 (1) 4 Yes End-1 Min 96.69 0.061 0.230 Vibrational dental device 100 (1) 4 No End-1 Min 98.02 0.048 0.210 AcceleDent Aura ™ (2) 4 Yes End-1 Min 29.8 0.002 0.054 AcceleDent Aura ™ (2) 4 No End-1 Min 29.8 0.002 0.061 Vibrational dental device 100 (2) 4 Yes End-1 Min 100 0.045 0.150 Vibrational dental device 100 (2) 4 No End-1 Min 98.02 0.025 0.210 AcceleDent Aura ™ (1) 2 Yes End-1 Min 29.8 0.016 0.084 AcceleDent Aura ™ (1) 2 No End-1 Min 29.8 0.016 0.076 Vibrational dental device 100 (1) 2 Yes End-1 Min 104 0.045 0.150 Vibrational dental device 100 (1) 2 No End-1 Min 112.6 0.081 0.150 AcceleDent Aura ™ (2) 2 Yes End-1 Min 29.8 0.011 0.082 AcceleDent Aura ™ (2) 2 No End-1 Min 29.8 0.014 0.079 Vibrational dental device 100 (2) 2 Yes End-1 Min 100.7 0.033 0.125 Vibrational dental device 100 (2) 2 No End-1 Min 111.3 0.046 0.118 AcceleDent Aura ™ (1) 1 Yes End-1 Min 29.8 0.008 0.094 AcceleDent Aura ™ (1) 1 No End-1 Min 29.8 0.031 0.086 Vibrational dental device 100 (1) 1 Yes End-1 Min 109.3 0.052 0.210 Vibrational dental device 100 (1) 1 No End-1 Min 109.9 0.175 0.120 AcceleDent Aura ™ (2) 1 Yes End-1 Min 29.8 0.014 0.084 AcceleDent Aura ™ (2) 1 No End-1 Min 29.8 0.038 0.092 Vibrational dental device 100 (2) 1 Yes End-1 Min 97.35 0.100 0.130 Vibrational dental device 100 (2) 1 No End-1 Min 106 0.126 0.108 In exemplary embodiments, the vibrational dental device can be configured to deliver g-forces above those found in prior art devices indicated for use with aligners or without aligners.","FIG.","5A and Table 2 show the measured g-force values (Gp-p) of the typodont mounted with different weights while subject to vibration by vibrational dental device 100 and by the AcceleDent Aura™ with the aligner.","FIG.","5B and Table 3 shows the measured g-force values (Gp-p) of the typodont mounted with different weights while subject to vibration by vibrational dental device 100 and by the AcceleDent Aura™ without the aligner.","As described herein, results shown in FIGS.","5A and 5B and Tables 1 and 2 were average values and standard deviations of the measured g-force values (Gp-p) on the typodont caused by the two testing devices of vibrational dental device 100 and the two testing devices of AcceleDent Aura™.","As shown in FIGS.","5A and 5B, vibrational dental device 100 produced greater acceleration than the AcceleDent Aura™ at various simulated biting forces (under various weights).","When the typodont was fitted an aligner (as shown in FIG.","5A and Table 1), depending on the simulated biting force, the AcceleDent Aura™ caused very low acceleration levels of the typodont with g-force values from less than 0.01 G to no greater than 0.02 G. In contrast, vibrational dental device 100 resulted in higher acceleration levels of the typodont with g-force values ranging from about 0.04 G to about 0.076 G. In particular, the two-pound and four-pound weights (or simulated biting force) caused the AcceleDent Aura™'s measured average g-force values to drop to very low levels of 0.0135 G and 0.002 G, respectively.","When the typodont was without an aligner (as shown in FIG.","5B and Table 2), depending on the simulated biting force, the AcceleDent Aura™ similarly caused very low acceleration levels with g-force values from less than 0.01 G to no greater than 0.04 G. Again, in contrast, vibrational dental device 100 resulted in multi-fold higher acceleration levels with g-force values ranging from about 0.04 G to about 0.15 G. These results suggest that vibrational dental device 100 can produce greater acceleration magnitude of the typodont under different simulated biting forces than the AcceleDent Aura™ with or without aligners.","TABLE 2 Average g-force values (Gp-p) of the typodont mounted with different weights while subject to vibration by vibrational dental device 100 and by the AcceleDent Aura ™ with the aligner.","4 lb 2 lb 1 lb Device Average SD Average SD Average SD AcceleDent 0.002 0.0000 0.0135 0.0035 0.011 0.0042 Aura ™ Vibrational 0.053 0.0113 0.0390 0.0085 0.076 0.0339 dental device 100 TABLE 3 Average g-force values (Gp-p) of the typodont mounted with different weights while subject to vibration by vibrational dental device 100 and by the AcceleDent Aura ™ without the aligner.","4 lb 2 lb 1 lb Device Average SD Average SD Average SD AcceleDent 0.0020 0.0000 0.0150 0.0014 0.0345 0.0049 Aura ™ Vibrational 0.0365 0.0163 0.0635 0.0247 0.1505 0.0346 dental device 100 Example 2 Vibrational dental device 100 and AcceleDent Aura™ produce distinct vibration frequencies, and accelerations, and are used for different treatment duration, but they produce about the same number of oscillations per treatment.","The different vibration variables of the AcceleDent Aura™ and vibrational dental device 100 may be perceived differently by cells residing in the alveolar bone and the periodontal tissue.","In this example, acceleration profiles of the two devices are quantified and compared, and the efficacy of the mechanical vibration generated by these two devices to stimulate cells, including osteoblasts, periodontal ligament fibroblasts, and osteoclasts was quantitatively evaluated and compared.","To measure the acceleration profiles of both vibrational dental device 100 and AcceleDent Aura™, an accelerometer Slamstick C (Mide Technology Corp, MA) was attached to the top surface of a mouthpiece and inserted into the mouth cavity of a volunteer as instructed by the manual of the manufacturer.","All data were recorded for 20 second intervals at a recording frequency of 800 Hz.","During recording, the mouthpiece was kept in the horizontal plane.","Fast Fourier Transform (FFT) was applied to determine the frequency content of the recordings.","For both vibrational dental device 100 and AcceleDent Aura™, three devices of each were tested and average peak acceleration magnitudes of the three devices in three orthogonal directions, including X-horizontal, Y-horizontal, and vertical dimensions were obtained.","Commercially available cells, including human osteoblasts, human periodontal ligament fibroblasts, and human osteoclasts (Lonza, Inc., Walkersville, Md.)","were cultured according to the manufacturer's instructions.","For all experiments, the cells were plated in multi-well tissue culture plates at a cell density of 7,500 cells/cm2 and placed in an incubator prior to vibration treatment.","The cells were taken out from the incubator immediately prior to vibration treatment.","The human osteoblasts, human periodontal ligament fibroblasts, and human osteoclasts samples were respectively separated into three groups, a first group subject to vibration treatment by AcceleDent Aura™, a second group subject to vibration treatment by an exemplary embodiment of vibrational dental device 100, and a control group handled identically to the other two groups but not subject to vibration treatment.","Vibration treatment was applied by placing the device between the cell culture plates and a plastic box.","The cell culture plates, the device, and the plastic box were securely fastened together by industrial elastic bands.","The plastic box and the industrial elastic bands isolated the vibrations generated by the devices from being transmitted to the experimental countertop.","A tri-axial accelerometer was directly attached to the top of the cell culture plates to verify the applied vibration frequency and acceleration magnitude.","Vibration treatment of the cells was applied daily at room temperature for a period of three days.","Each day, the first groups of osteoblasts, fibroblasts, and osteoclasts were subject to vibration treatment by AcceleDent Aura™ at a frequency of 30 Hz for 20 minutes.","The second groups of osteoblasts, fibroblasts, and osteoclasts were subject to vibration treatment by vibrational dental device 100 at a frequency from about 100 Hz to about 120 Hz for 5 minutes and subsequently left at room temperature for 15 minutes to match the 20 minutes room temperature exposure of the first groups.","The control groups were left at room temperate for 20 minutes without any vibration treatment.","For osteoblasts and periodontal ligament fibroblasts, cell proliferation or cell density (cells/cm2) over a three-day period was used as a marker for the cells' responsivity to the vibration stimuli.","A standard spectrophotometric MTS assay was used for determining cell density according to the manufacturer's instructions (XTT Assay, ATCC™).","The cell sample size for each group of osteoblasts and periodontal ligament fibroblasts was 5.Mean cell numbers of each group were calculated based on the measured cell densities of the cell samples of each group.","To quantify osteoclasts' responsivity to the vibration stimuli, TRAP optical density was measured over a three-day period.","The cell sample size for each group of osteoclast was 12.Datasets were presented as means and standard deviations.","The three groups were statistically compared to each other via Fisher tests.","A significance value of 0.05 was used for all datasets.","FIG.","6 and Table 4 show the average peak acceleration magnitudes of AcceleDent Aura™ and vibrational dental device 100 recorded with the accelerometer in three orthogonal directions.","As shown in FIG.","6 and Table 4, the average peak accelerations of the three sample devices of AcceleDent Aura™ were measured about 0.12 G in the medial-lateral or X-horizontal direction, about 0.15 G in the anterior-posterior or Y-horizontal direction, and about 0.15 G in the vertical direction.","The average peak accelerations of the three sample devices of vibrational dental device 100 were measured about 0.23 G in the medial-lateral or X-horizontal direction, about 0.33 G in the anterior-posterior Y-horizontal direction, and about 0.07 G in the vertical direction.","Combining the average acceleration magnitudes in the two horizontal directions resulted in an average peak acceleration in the horizontal dimension of about 0.18 G for the AcceleDent Aura™ devices and about 0.41 G for the vibrational dental devices 100.Combining the average acceleration magnitudes in all three directions resulted in an average Total Resultant acceleration magnitude of about 0.24 G for the AcceleDent Aura™ devices and about 0.41 G for the vibrational dental devices 100.As shown in FIG.","6, for both AcceleDent Aura™ and vibrational dental devices 100, variability across the three sample devices was low.","TABLE 4 Average peak acceleration magnitudes of vibrational dental device 100 and the AcceleDent Aura ™ AcceleDent Aura ™ Vibrational dental device 100 X 0.12 G 0.23 G Y 0.15 G 0.33 G Horizontal 0.18 G 0.41 G Vertical 0.15 G 0.07 G Total Resultant 0.24 G 0.41 G FIG.","7 graphically compares average total displacement of the vibratory motion produced by AcceleDent Aura™ and by vibrational dental device 100.As shown in FIG.","7, the average total displacement of the vibratory motion produced by AcceleDent Aura™ was about 140 μm and about 14 μm by vibrational dental device 100.Thus, as shown in FIGS.","6 and 7, vibrational dental device 100 achieved smaller displacements in spite of greater peak acceleration magnitudes by using a vibration frequency that is about four times greater than that of AcceleDent Aura™.","FIG.","8 shows mean cell numbers of three groups of osteoblasts.","FIG.","9 shows mean cell numbers of three groups of fibroblasts.","The cell numbers are presented in an arbitrary unit for the purpose of comparison.","FIG.","10 shows mean activity of three groups of osteoclasts presented in optical density (OD) measurements.","Daggers in FIGS.","8-10 mark statistically significant differences between control samples and samples subject to vibration treatment.","Asterisks mark statistically significant differences samples subject to vibration treatment AcceleDent Aura™ and samples subject to vibration treatment by vibrational dental device 100.Surprisingly, as shown in FIG.","8, the group of osteoblasts subject to vibration treatment by vibrational dental device 100 had significantly greater (p<0.05) cell proliferation than the group of osteoblasts subject to vibration treatment by AcceleDent Aura™ on day 2 and day 3.Similarly, as shown in FIG.","9, the group of fibroblasts subject to vibration treatment by vibrational dental device 100 had significantly greater (p<0.05) cell proliferation than the group of fibroblasts subject to vibration treatment by AcceleDent Aura™ on day 2 and day 3.As shown in FIG.","10, both AcceleDent Aura™ and vibrational dental device 100 were capable of moderately increasing the activity of osteoclasts as compared with the control group.","This example demonstrates the surprising results that vibration treatment by vibrational dental device 100 enhanced proliferation of human osteoblasts and periodontal ligament fibroblasts to a significantly greater level than AcceleDent Aura™ The in vitro experimental results presented in this example suggest that different cell types and tissues, such as the human osteoblasts and human periodontal ligament fibroblasts, can be more responsive to the vibration variables used by vibrational dental device 100.For example, vibrational dental device 100 produces vibratory motions at a frequency from about 100 Hz to about 120 Hz, about four times of that of AcceleDent Aura™, with greater peak acceleration magnitudes That superior results could be obtained in one-fourth the time required by the AcceleDent Aura™ could result in superior clinical results in orthodontics, as shorter treatment periods generally correlate to better user compliance and adherence.","Additionally, the difference in the peak acceleration magnitude produced by AcceleDent Aura™ and vibrational dental device 100 was significant.","As shown in Table 1, while AcceleDent Aura™ produced peak accelerations on the order of 0.15 G in all three directions, the peak accelerations produced by vibrational dental device 100 in the horizontal direction was about six times of that in the vertical direction.","This spatial anisotropy in acceleration magnitudes generated by vibrational dental device 100 may have directly contributed to the greater proliferation rates of the periodontal ligament fibroblast and osteoblast samples as cells may sense vibrations preferentially in the horizontal direction.","The Total Resultant peak acceleration magnitude of vibrational dental device 100 was about 70% greater than that of AcceleDent Aura™ As shown in FIGS.","6 and 7, the greater peak acceleration magnitude of vibrational dental device 100 was achieved via a greater vibration frequency and not a greater displacement magnitude.","In fact, as shown in FIG.","7, the displacement magnitude produced by vibrational dental device 100 was an order of magnitude smaller than that produced by AcceleDent Aura™.","This may be clinically important because small displacements induced by vibrations could reduce discomfort to the patients, thereby correlating with better user compliance.","Example 3 An exemplary embodiment of vibrational dental device 100 is used to subject periodontal cells for a period of vibrational treatment.","The periodontal cells include human osteoblasts in alveolar bone and periodontal ligament fibroblasts.","The periodontal cells are treated for less than about 20 minutes, for example for about 5 minutes, at a frequency higher than about 80 Hz, for example from about 100 Hz to about 120 Hz, daily over a period of time, which lasts for about a few days to a couple of weeks.","At the end of the period of time, the number of periodontal cells, including osteoblasts in alveolar bone and periodontal ligament fibroblasts, is increased.","Example 4 An exemplary embodiment of vibrational dental device 100 is used to subject periodontal cells for a period of vibrational treatment.","The periodontal cells include human osteoblasts in alveolar bone and periodontal ligament fibroblasts.","The periodontal cells are treated for less than about 20 minutes, for example for about 5 minutes, at a frequency higher than about 80 Hz, for example from about 100 Hz to about 120 Hz, daily over a period of time, which lasts for about a couple of weeks to about a month.","At the end of the period of time, the number of periodontal cells, including osteoblasts in alveolar bone and periodontal ligament fibroblasts, is increased.","Example 5 An exemplary embodiment of vibrational dental device 100 is used to subject periodontal cells for a period of vibrational treatment.","The periodontal cells include human osteoblasts in alveolar bone and periodontal ligament fibroblasts.","The periodontal cells are treated for less than about 20 minutes, for example for about 5 minutes, at a frequency higher than about 80 Hz, for example from about 100 Hz to about 120 Hz, daily over a period of time, which lasts for about a month to a couple of months.","At the end of the period of time, the number of periodontal cells, including osteoblasts in alveolar bone and periodontal ligament fibroblasts, is increased.","Example 6 An exemplary embodiment of vibrational dental device 100 is used to subject periodontal cells for a period of vibrational treatment.","The periodontal cells include human osteoblasts in alveolar bone and periodontal ligament fibroblasts.","The periodontal cells are treated for less than about 20 minutes, for example for about 5 minutes, at a frequency higher than about 80 Hz, for example from about 100 Hz to about 120 Hz, daily over a period of time, which lasts for about a couple of months to about a few months.","At the end of the period of time, the number of periodontal cells, including osteoblasts in alveolar bone and periodontal ligament fibroblasts, is increased.","Example 7 An exemplary embodiment of vibrational dental device 100 is provided to a user for a period of vibrational treatment.","While wearing an orthodontic aligner, the user uses vibrational dental device 100 by clamping the mouthpiece 102 between his or her teeth for less than about, for example about 5 minutes at a frequency higher than about 80 Hz, for example from about 100 Hz to about 120 Hz daily, during the period of vibrational treatment.","The period of vibrational treatment lasts for about 2 days to about a few days.","At the end of the period of vibrational treatment, the number of periodontal cells, including osteoblasts in alveolar bone and periodontal ligament fibroblasts, of the teeth that are subject to the vibrational treatment by vibrational dental device 100 is increased.","Additionally, a desired movement of all or some of the teeth subject to vibrational treatment by vibrational dental device 100 is achieved at the end of the period of vibrational treatment.","Example 8 An exemplary embodiment of vibrational dental device 100 is provided to a user for a period of vibrational treatment.","While wearing an orthodontic aligner, the user uses vibrational dental device 100 by clamping the mouthpiece 102 between his or her teeth for less than about 20 minutes, for example for about 5 minutes, at a frequency from higher than about 80 Hz, for example about 100 Hz to about 120 Hz, daily during the period of vibrational treatment.","The period of vibrational treatment lasts for about a few days to a couple of weeks.","At the end of the period of vibrational treatment, the number of periodontal cells, including osteoblasts in alveolar bone and periodontal ligament fibroblasts, of the teeth that are subject to the vibrational treatment by vibrational dental device 100 is increased.","Additionally, a desired movement of all or some of the teeth subject to vibrational treatment by vibrational dental device 100 is achieved at the end of the period of vibrational treatment.","Example 9 An exemplary embodiment of vibrational dental device 100 is provided to a user for a period of vibrational treatment.","While wearing an orthodontic aligner, the user uses vibrational dental device 100 by clamping the mouthpiece 102 between his or her teeth for less than about 80 Hz, for example for about 5 minutes, at a frequency higher than about 80 Hz, for example from about 100 Hz to about 120 Hz, daily during the period of vibrational treatment.","The period of vibrational treatment lasts for about a couple of weeks to about a month.","At the end of the period of vibrational treatment, the number of periodontal cells, including osteoblasts in alveolar bone and periodontal ligament fibroblasts, of the teeth that are subject to the vibrational treatment by vibrational dental device 100 is increased.","Additionally, a desired movement of all or some of the teeth subject to vibrational treatment by vibrational dental device 100 is achieved at the end of the period of vibrational treatment.","Example 10 An exemplary embodiment of vibrational dental device 100 is provided to a user for a period of vibrational treatment.","While wearing an orthodontic aligner, the user uses vibrational dental device 100 by clamping the mouthpiece 102 between his or her teeth for less than about 20 minutes, for example for about 5 minutes, at a frequency higher than about 80 Hz, for example from about 100 Hz daily to about 120 Hz during the period of vibrational treatment.","The period of vibrational treatment lasts for about a month to a couple of months.","At the end of the period of vibrational treatment, the number of periodontal cells, including osteoblasts in alveolar bone and periodontal ligament fibroblasts, of the teeth that are subject to the vibrational treatment by vibrational dental device 100 is increased.","Additionally, a desired movement of all or some of the teeth subject to vibrational treatment by vibrational dental device 100 is achieved at the end of the period of vibrational treatment.","Example 11 An exemplary embodiment of vibrational dental device 100 is provided to a user for a period of vibrational treatment.","While wearing an orthodontic aligner, the user uses vibrational dental device 100 by clamping the mouthpiece 102 between his or her teeth for less than about 20 minutes, for example for about 5 minutes, at a frequency higher than about 80 Hz, for example from about 100 Hz to about 120 Hz, daily during the period of vibrational treatment.","The period of vibrational treatment lasts for about a couple of months to a few months.","At the end of the period of vibrational treatment, the number of periodontal cells, including osteoblasts in alveolar bone and periodontal ligament fibroblasts, of the teeth that are subject to the vibrational treatment by vibrational dental device 100 is increased.","Additionally, a desired movement of all or some of the teeth subject to vibrational treatment by vibrational dental device 100 is achieved at the end of the period of vibrational treatment.","The above-described examples suggest that vibrational dental device 100 described herein may be utilized in a variety of procedures and methods for increasing cell proliferation.","An exemplary method 200 for increasing cell proliferation may use one or more features of the embodiments of vibrational dental device 100, described above in reference to FIGS.","1-5.Exemplary embodiments of method 200 are described below with reference to FIG.","8.As shown in FIG.","8, method 200 may include steps 210-230.Step 210 may include providing vibrational dental device 100.As described above, while in operation, vibrational dental device 100 can be configured to vibrate at a frequency higher than about 80 Hz and an acceleration magnitude ranging between about 0.03 G and about 0.2 G. For example, vibrational dental device 100 may vibrate at a frequency between about 100 Hz and about 120 Hz.","Step 220 may include mechanically stimulating, using vibrational dental device 100, cells for about less than 20 minutes, for example for about 5 minutes, daily over a period of time.","The cells may include one of human osteoblasts and fibroblasts.","As described herein, the period of time may last until a desirable result has achieved.","In some embodiments, the period of time may last for a couple of days up to a few months.","Step 230 may include increasing the number of the cells at the end of the period of time.","As described herein, an increase of the number of cells may be represented by an increase of the cell density, which indicates cell proliferation.","Step 230 may further include quantitatively evaluating the cell number and/or cell density daily.","As described herein, additional steps may be added to method 200.For example, method 200 may include increasing or decreasing the frequency and/or acceleration magnitude of vibrational dental device 100 based on the response of the cells to vibration treatment.","Method 200 may also include detecting characteristics of the vibration produced by vibrational dental device 100 and/or characteristics of the vibration applied to the cells by vibrational dental device 100.Also, some steps may be omitted or repeated, and/or may be performed simultaneously.","The above-described examples may further suggest that vibrational dental device 100 may stimulate more response of human osteoblasts and periodontal ligament fibroblasts during orthodontic treatment than AcceleDent Aura™.","Therefore, vibrational dental device 100 described herein may be utilized in a variety of procedures and methods for accelerating orthodontic tooth movement in orthodontic treatments.","An exemplary method 300 for accelerating orthodontic tooth movement may use one or more features of the embodiments of vibrational dental device 100, described above in reference to FIGS.","1-5.Exemplary embodiments of method 300 are described below with reference to FIG.","9.As shown in FIG.","9, method 300 may include steps 310 and 320.Step 310 may include providing a mouthpiece of vibrational dental device 100 between the occlusal surfaces of a user's teeth to be clamped by the user's teeth.","As described above, while in operation, vibrational dental device 100 is capable of vibrating at a frequency higher than about 80 Hz and an acceleration magnitude ranging between about 0.03 G and about 0.2 G. For example, vibrational dental device 100 may vibrate at a frequency between about 100 Hz and 120 Hz.","Step 320 may include mechanically stimulating, using vibrational dental device 100, cells of the user for less than about 20 minutes, for example for about 5 minutes, daily at a frequency higher than 80 Hz over a period of time.","The cells may include one of human osteoblasts and periodontal ligament fibroblasts.","As described herein, the period of time may last until a desirable result has been achieved, such as a desired amount of tooth movement.","In some embodiments, the period of time may last for a few of days up to a few months.","As described herein, additional steps may be added to method 300.For example, method 300 may include increasing or decreasing the frequency and/or acceleration magnitude of vibrational dental device 100 based on the response of vibration treatment, such as the speed or amount of tooth movement.","Method 300 may also include detecting characteristics of the vibration applied proximate to the occlusal surfaces, such as frequency and acceleration magnitude, by sensors of vibrational dental device 100.Also, some steps may be omitted or repeated, and/or may be performed simultaneously.","The foregoing description has been presented for purposes of illustration.","It is not exhaustive and is not limited to precise forms or embodiments disclosed.","Modifications and adaptations of the embodiments will be apparent from consideration of the specification and practice of the disclosed embodiments.","For example, the described implementations include hardware and software, but systems and methods consistent with the present disclosure can be implemented as hardware alone.","In addition, while certain components have been described as being coupled to one another, such components may be integrated with one another or distributed in any suitable fashion.","Moreover, while illustrative embodiments have been described herein, the scope includes any and all embodiments having equivalent elements, modifications, omissions, combinations (e.g., of aspects across various embodiments), adaptations and/or alterations based on the present disclosure.","The elements in the claims are to be interpreted broadly based on the language employed in the claims and not limited to examples described in the present specification or during the prosecution of the application, which examples are to be construed as nonexclusive.","Further, the steps of the disclosed methods can be modified in any manner, including reordering steps and/or inserting or deleting steps.","The features and advantages of the disclosure are apparent from the detailed specification, and thus, it is intended that the appended claims cover all systems and methods falling within the true spirit and scope of the disclosure.","As used herein, the indefinite articles “a” and “an” mean “one or more.” Similarly, the use of a plural term does not necessarily denote a plurality unless it is unambiguous in the given context.","Words such as “and” or “or” mean “and/or” unless specifically directed otherwise.","Further, since numerous modifications and variations will readily occur from studying the present disclosure, it is not desired to limit the disclosure to the exact construction and operation illustrated and described, and accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the disclosure.","Other embodiments will be apparent from consideration of the specification and practice of the embodiments disclosed herein.","It is intended that the specification and examples be considered as example only, with a true scope and spirit of the disclosed embodiments being indicated by the following claims."]],"string":"[\n [\n \"METHODS AND DEVICES FOR STIMULATING CELL PROLIFERATION\",\n \"Embodiments of the present disclosure are directed to devices and methods for stimulating cell proliferation.\",\n \"In one implementation, a method for increasing cell proliferation is provided.\",\n \"The method includes providing a vibrational dental device configured to vibrate at a frequency higher than about 60 Hz.\",\n \"The method also includes mechanically stimulating, using the vibrational dental device, cells for a treatment period of less than about 10 to 20 minutes daily.\",\n \"The method may further include generating a peak acceleration magnitude in the horizontal direction substantially greater than that in the vertical direction.\",\n \"The number of the cells at the end of the period of time is increased.\",\n \"The cells may include at least one of human osteoblasts and fibroblasts.\"\n ],\n [\n \"1.A method for increasing periodontal cell proliferation, the method comprising: providing a vibrational dental device configured to vibrate at a frequency higher than about 60 Hz, wherein a peak acceleration magnitude generated by the vibrational dental device in the horizontal direction is substantially greater than that in the vertical direction; mechanically stimulating, using the vibrational dental device, periodontal cells, including at least one of human osteoblasts and fibroblasts, for a treatment period of less than about 10 minutes daily; and wherein the number of the periodontal cells at the end of the period of time is increased.\",\n \"2.The method of claim 1, wherein the vibrational dental device is configured to vibrate at a total acceleration magnitude ranging between about 0.001 G and about 3 G. 3.The method of claim 1, wherein the peak acceleration magnitude produced by the vibrational dental device in the horizontal direction is about five times greater than that in the vertical direction.\",\n \"4.The method of claim 1, further comprising mechanically stimulating the cells at a frequency between about 60 Hz and about 300 Hz.\",\n \"5.The method of claim 1, further comprising mechanically stimulating the cells at a g-force between about 0.001 G and about 3 G. 6.The method of claim 1, wherein the vibrational dental device comprises a mouthpiece and a motor connected to and configured to vibrate the mouthpiece.\",\n \"7.The method of claim 5, further comprising providing the mouthpiece between the occlusal surfaces of a user's teeth to be clamped by the user's teeth.\",\n \"8.The method of claim 6, further comprising applying an axial vibratory force on the occlusal surfaces by the vibrational dental device.\",\n \"9.The method of claim 1, further comprising detecting vibration characteristics of the mouthpiece produced by the vibrational dental device.\",\n \"10.The method of claim 1, further comprising adjusting the frequency and/or g-force of the vibration of the vibrational dental device.\",\n \"11.The method of claim 1, wherein the period of time ranges from a couple of days to a few months.\",\n \"12.The method of claim 10, wherein the period of time ranges from a couple of days to a few days.\",\n \"13.The method of claim 10, wherein the period of time ranges from a few days to couple of weeks.\",\n \"14.The method of claim 10, wherein the period of time ranges from a month to a couple of months.\",\n \"15.The method of claim 10, wherein the period of time ranges from a couple of months to a few months.\",\n \"16.The method of claim 1, wherein the human osteoblasts comprise human osteoblasts in alveolar bone.\",\n \"17.The method of claim 1, wherein the fibroblasts comprise periodontal ligament fibroblasts.\",\n \"18.The method of claim 1, wherein the treatment period comprises one or more treatment sessions that range from about 1 minute to about 10 minutes.\",\n \"19.A method for accelerating orthodontic tooth movement, the method comprising: providing a mouthpiece of a vibrational dental device to be clamped by the user's teeth; and mechanically stimulating, using the vibrational dental device, cells of the user, including at least one of osteoblasts in alveolar bone and periodontal ligament fibroblasts, for a treatment period of less than about 10 minutes daily at a frequency higher than about 60 Hz, wherein a peak acceleration magnitude of the mouthpiece in the horizontal direction is substantially greater than that in the vertical direction.\",\n \"20.The method of claim 19, further comprising providing the mouthpiece between the occlusal surfaces of a user's teeth.\",\n \"21.The method of claim 19, further comprising mechanically stimulating the cells of the user at a g-force between about 0.001 G and about 3 G. 22.The method of claim 18, further comprising mechanically stimulating the cells of the user at a frequency between about 60 Hz and about 300 Hz.\",\n \"23.A dental device for increasing cell proliferation, the dental device comprising means for mechanically stimulating cells, including at least one of human osteoblasts and periodontal ligament fibroblasts, at a frequency higher than about 60 Hz for a treatment period of less than about 10 minutes daily, wherein a peak acceleration magnitude generated by the vibrational dental device in the horizontal direction is substantially greater than that in the vertical direction.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>\"\n ],\n [\n \"<SOH> SUMMARY <EOH>The embodiments of the present disclosure include systems, devices, and methods for stimulating cell proliferation in periodontal tissues, including the alveolar processes and periodontal ligament.\",\n \"Advantageously, the exemplary embodiments allow cells belonging to the connective-tissue cell family, such as human osteoblasts in alveolar bone and periodontal ligament fibroblasts, to proliferate after relatively short vibration treatments, thereby improving the efficiency and effectiveness of orthodontic treatments.\",\n \"According to an exemplary embodiment of the present disclosure, a method for increasing cell proliferation is described.\",\n \"The method includes providing a vibrational dental device that is capable of vibrating at a frequency higher than about 80 Hz.\",\n \"The method also includes mechanically stimulating, using the vibrational dental device, cells for a treatment period of less than about 20 minutes daily over a period of time.\",\n \"The treatment period can be, for example, less than about 20 minutes, 15 minutes, 10 minutes, 6 minutes, 5 minutes, 4 minutes, 2 minutes, 1 minute, or less.\",\n \"It is contemplated that in other embodiments the treatment period could be any value within the range of about 1 minute and 19 minutes daily, and that the daily total treatment period could be formed of a plurality of treatment sessions contributing to the daily total treatment period.\",\n \"In one exemplary embodiment, the daily total treatment period is about 5 minutes.\",\n \"The cells may include human osteoblasts and/or human fibroblasts.\",\n \"The method further includes increasing the number of the cells at the end of the period of time.\",\n \"The vibration frequency can be less than about 300 Hz, for example, from about 60 Hz to about 300 Hz, from about 60 Hz to about 200 Hz, from about 60 Hz to about 130 Hz, from about 80 Hz to about 120 Hz, from about 110 Hz to about 120 Hz, from about 100 Hz to about 110 Hz, from about 90 Hz to about 100 Hz, or from about from about 80 Hz to about 90 Hz.\",\n \"It is contemplated that in other embodiments the frequency could be any value within the range of about 80 Hz and about 120 Hz, and that the vibration frequency could be adjusted during a treatment period.\",\n \"In one exemplary embodiment, the vibration frequency is about 100 Hz.\",\n \"In some embodiments, the method further includes generating a peak acceleration magnitude in the horizontal direction substantially greater than that in the vertical direction.\",\n \"For example, the peak acceleration magnitude of the vibration generated by the vibrational dental device in the horizontal direction can be about 1 to 5 times greater than that in the vertical direction.\",\n \"In some embodiments, the peak acceleration magnitude of the vibration in the horizontal direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In some embodiments, the peak acceleration magnitude of the vibration in the vertical direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In other embodiments, the total peak acceleration magnitude of the vibration may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. According to a further exemplary embodiment of the present disclosure, a method for accelerating orthodontic tooth movement is described.\",\n \"The method includes providing a mouthpiece of a vibrational dental device to be clamped by the user's teeth, for example, between the occlusal surfaces of a user's teeth.\",\n \"The method further includes mechanically stimulating, using the vibrational dental device, cells of the user for a treatment period of less than about 20 minutes daily at a frequency higher than 80 Hz over a period of time.\",\n \"The treatment period can be, for example, less than about 20 minutes, 15 minutes, 10 minutes, 6 minutes, 5 minutes, 4 minutes, 2 minutes, 1 minute, or less.\",\n \"It is contemplated that in other embodiments the treatment period could be any value within the range of about 1 minute and 19 minutes daily, and that the daily total treatment period could be formed of a plurality of treatment sessions contributing to the daily total treatment period.\",\n \"In one exemplary embodiment, the daily total treatment period is about 5 minutes.\",\n \"The cells may include at least one of osteoblasts in alveolar bone and periodontal ligament fibroblasts.\",\n \"The vibration frequency can be less than about 300 Hz, for example, from about 60 Hz to about 300 Hz, from about 60 Hz to about 200 Hz, from about 60 Hz to about 130 Hz, from about 80 Hz to about 120 Hz, from about 110 Hz to about 120 Hz, from about 100 Hz to about 110 Hz, from about 90 Hz to about 100 Hz, or from about from about 80 Hz to about 90 Hz.\",\n \"It is contemplated that in other embodiments the frequency could be any value within the range of about 80 Hz and about 120 Hz, and that the vibration frequency could be adjusted during a treatment period.\",\n \"In one exemplary embodiment, the vibration frequency is about 100 Hz.\",\n \"In some embodiments, the method further includes producing a peak acceleration magnitude in the horizontal direction substantially greater than that in the vertical direction.\",\n \"For example, the peak acceleration magnitude of the vibration generated by the vibrational dental device in the horizontal direction can be about 1 to 5 times greater than that in the vertical direction.\",\n \"In some embodiments, the peak acceleration magnitude of the vibration in the horizontal direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In some embodiments, the peak acceleration magnitude of the vibration in the vertical direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In other embodiments, the total peak acceleration magnitude of the vibration may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. According to a yet further exemplary embodiment of the present disclosure, a dental device for increasing cell proliferation is described.\",\n \"The dental device includes means for mechanically stimulating cells at a frequency higher than 80 Hz for a treatment period of less than about 20 minutes daily over a period of time, and further increasing the number of the cells at the end of the period of time.\",\n \"The cells may include human osteoblasts and/or human fibroblasts.\",\n \"The treatment period can be, for example, less than about 20 minutes, 15 minutes, 10 minutes, 6 minutes, 5 minutes, 4 minutes, 2 minutes, 1 minute, or less.\",\n \"It is contemplated that in other embodiments the treatment period could be any value within the range of about 1 minute and 19 minutes daily, and that the daily total treatment period could be formed of a plurality of treatment sessions contributing to the daily total treatment period.\",\n \"In one exemplary embodiment, the daily total treatment period is about 5 minutes.\",\n \"The vibration frequency can be less than about 300 Hz, for example, from about 60 Hz to about 300 Hz, from about 60 Hz to about 200 Hz, from about 60 Hz to about 130 Hz, from about 80 Hz to about 120 Hz, from about 110 Hz to about 120 Hz, from about 100 Hz to about 110 Hz, from about 90 Hz to about 100 Hz, or from about from about 80 Hz to about 90 Hz.\",\n \"It is contemplated that in other embodiments the frequency could be any value within the range of about 80 Hz and about 120 Hz, and that the vibration frequency could be adjusted during a treatment period.\",\n \"In one exemplary embodiment, the vibration frequency is about 100 Hz.\",\n \"In some embodiments, the dental device is capable of mechanically vibrating with a peak acceleration magnitude in the horizontal direction substantially greater than that in the vertical direction.\",\n \"For example, the peak acceleration magnitude of the vibration generated by the dental device in the horizontal direction can be about 1 to 5 times greater than that in the vertical direction.\",\n \"In some embodiments, the peak acceleration magnitude of the vibration in the horizontal direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In some embodiments, the peak acceleration magnitude of the vibration in the vertical direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In other embodiments, the total peak acceleration magnitude of the vibration may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. Additional features and advantages of the disclosed embodiments will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the disclosed embodiments.\",\n \"The features and advantages of the disclosed embodiments will be realized and attained by the elements and combinations particularly pointed out in the appended claims.\",\n \"It is to be understood that both the foregoing general description and the following detailed description are examples and explanatory only and are not restrictive of the disclosed embodiments as claimed.\",\n \"The accompanying drawings constitute a part of this specification.\",\n \"The drawings illustrate several embodiments of the present disclosure and, together with the description, serve to explain the principles of the disclosed embodiments as set forth in the accompanying claims.\"\n ],\n [\n \"BACKGROUND Technical Field The present disclosure generally relates to dental devices and methods of use.\",\n \"More particularly, and without limitation, the disclosed embodiments relate to systems, devices, and methods for stimulating cell proliferation in the region of the alveolar process of the maxilla and mandible, including the periodontal ligament, using vibration.\",\n \"Background Description Mechanical vibration may enhance musculoskeletal properties.\",\n \"For example, some studies suggested that low-intensity mechanical vibrations may stimulate bone formation or mitigate the degradation of the intervertebral disc in rats.\",\n \"However, the biomolecular mechanisms for such enhancement effects have not yet been elucidated.\",\n \"Some studies suggested that mechanical vibration may enhance differentiation of human bone marrow mesenchymal stem cells or periodontal ligament stem cells.\",\n \"But discrepancies and unpredictability exist in literature as to the effects of mechanical vibration on cell proliferation.\",\n \"For example, previous studies have demonstrated no effects or either increased or decreased proliferation after cyclic vibration treatment.\",\n \"See Zhang, C., et al.\",\n \"(2012).\",\n \"Effects of mechanical vibration on proliferation and osteogenic differentiation of human periodontal ligament stem cells.\",\n \"Archives of Oral Biology, 57(10), 1395-1407.The unpredictability in the art has manifested itself in the experimental data in the prior art.\",\n \"Some studies have suggested vibrations at frequencies ranging from 15 Hz to 90 Hz may be more anabolic to bone formation.\",\n \"See Zhang, C., et al.\",\n \"(2012).\",\n \"Most of the previous studies subjected cells or animals to vibration treatments for a certain number of vibration bouts per day, each bout lasting for a duration ranging from 15 minutes to 60 minutes.\",\n \"See Judex, S., et al.\",\n \"(2015).\",\n \"Modulation of bone's sensitivity to low-intensity vibrations by acceleration magnitude, vibration duration, and number of bouts.\",\n \"Osteoporosis International, 26(4), 1417-1428; see also Pongkitwitoon, S., et al.\",\n \"(2016).\",\n \"A recent study further suggested that increasing the bout duration to an even longer period (30 or 60 minutes) would positively influence bone formation rates in mice.\",\n \"Cytoskeletal Configuration Modulates Mechanically Induced Changes in Mesenchymal Stem Cell Osteogenesis, Morphology, and Stiffness.\",\n \"Scientific Reports, 6(1).\",\n \"doi:10.1038/srep34791.It is recently hypothesized that mechanical vibration may promote periodontal regeneration and periodontal tissue remodeling during and following orthodontic tooth movement.\",\n \"However, variables of mechanical vibration to be used for modulating bone biology so as to effectively accelerate orthodontic tooth movement remain to be determined.\",\n \"SUMMARY The embodiments of the present disclosure include systems, devices, and methods for stimulating cell proliferation in periodontal tissues, including the alveolar processes and periodontal ligament.\",\n \"Advantageously, the exemplary embodiments allow cells belonging to the connective-tissue cell family, such as human osteoblasts in alveolar bone and periodontal ligament fibroblasts, to proliferate after relatively short vibration treatments, thereby improving the efficiency and effectiveness of orthodontic treatments.\",\n \"According to an exemplary embodiment of the present disclosure, a method for increasing cell proliferation is described.\",\n \"The method includes providing a vibrational dental device that is capable of vibrating at a frequency higher than about 80 Hz.\",\n \"The method also includes mechanically stimulating, using the vibrational dental device, cells for a treatment period of less than about 20 minutes daily over a period of time.\",\n \"The treatment period can be, for example, less than about 20 minutes, 15 minutes, 10 minutes, 6 minutes, 5 minutes, 4 minutes, 2 minutes, 1 minute, or less.\",\n \"It is contemplated that in other embodiments the treatment period could be any value within the range of about 1 minute and 19 minutes daily, and that the daily total treatment period could be formed of a plurality of treatment sessions contributing to the daily total treatment period.\",\n \"In one exemplary embodiment, the daily total treatment period is about 5 minutes.\",\n \"The cells may include human osteoblasts and/or human fibroblasts.\",\n \"The method further includes increasing the number of the cells at the end of the period of time.\",\n \"The vibration frequency can be less than about 300 Hz, for example, from about 60 Hz to about 300 Hz, from about 60 Hz to about 200 Hz, from about 60 Hz to about 130 Hz, from about 80 Hz to about 120 Hz, from about 110 Hz to about 120 Hz, from about 100 Hz to about 110 Hz, from about 90 Hz to about 100 Hz, or from about from about 80 Hz to about 90 Hz.\",\n \"It is contemplated that in other embodiments the frequency could be any value within the range of about 80 Hz and about 120 Hz, and that the vibration frequency could be adjusted during a treatment period.\",\n \"In one exemplary embodiment, the vibration frequency is about 100 Hz.\",\n \"In some embodiments, the method further includes generating a peak acceleration magnitude in the horizontal direction substantially greater than that in the vertical direction.\",\n \"For example, the peak acceleration magnitude of the vibration generated by the vibrational dental device in the horizontal direction can be about 1 to 5 times greater than that in the vertical direction.\",\n \"In some embodiments, the peak acceleration magnitude of the vibration in the horizontal direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In some embodiments, the peak acceleration magnitude of the vibration in the vertical direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In other embodiments, the total peak acceleration magnitude of the vibration may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. According to a further exemplary embodiment of the present disclosure, a method for accelerating orthodontic tooth movement is described.\",\n \"The method includes providing a mouthpiece of a vibrational dental device to be clamped by the user's teeth, for example, between the occlusal surfaces of a user's teeth.\",\n \"The method further includes mechanically stimulating, using the vibrational dental device, cells of the user for a treatment period of less than about 20 minutes daily at a frequency higher than 80 Hz over a period of time.\",\n \"The treatment period can be, for example, less than about 20 minutes, 15 minutes, 10 minutes, 6 minutes, 5 minutes, 4 minutes, 2 minutes, 1 minute, or less.\",\n \"It is contemplated that in other embodiments the treatment period could be any value within the range of about 1 minute and 19 minutes daily, and that the daily total treatment period could be formed of a plurality of treatment sessions contributing to the daily total treatment period.\",\n \"In one exemplary embodiment, the daily total treatment period is about 5 minutes.\",\n \"The cells may include at least one of osteoblasts in alveolar bone and periodontal ligament fibroblasts.\",\n \"The vibration frequency can be less than about 300 Hz, for example, from about 60 Hz to about 300 Hz, from about 60 Hz to about 200 Hz, from about 60 Hz to about 130 Hz, from about 80 Hz to about 120 Hz, from about 110 Hz to about 120 Hz, from about 100 Hz to about 110 Hz, from about 90 Hz to about 100 Hz, or from about from about 80 Hz to about 90 Hz.\",\n \"It is contemplated that in other embodiments the frequency could be any value within the range of about 80 Hz and about 120 Hz, and that the vibration frequency could be adjusted during a treatment period.\",\n \"In one exemplary embodiment, the vibration frequency is about 100 Hz.\",\n \"In some embodiments, the method further includes producing a peak acceleration magnitude in the horizontal direction substantially greater than that in the vertical direction.\",\n \"For example, the peak acceleration magnitude of the vibration generated by the vibrational dental device in the horizontal direction can be about 1 to 5 times greater than that in the vertical direction.\",\n \"In some embodiments, the peak acceleration magnitude of the vibration in the horizontal direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In some embodiments, the peak acceleration magnitude of the vibration in the vertical direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In other embodiments, the total peak acceleration magnitude of the vibration may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. According to a yet further exemplary embodiment of the present disclosure, a dental device for increasing cell proliferation is described.\",\n \"The dental device includes means for mechanically stimulating cells at a frequency higher than 80 Hz for a treatment period of less than about 20 minutes daily over a period of time, and further increasing the number of the cells at the end of the period of time.\",\n \"The cells may include human osteoblasts and/or human fibroblasts.\",\n \"The treatment period can be, for example, less than about 20 minutes, 15 minutes, 10 minutes, 6 minutes, 5 minutes, 4 minutes, 2 minutes, 1 minute, or less.\",\n \"It is contemplated that in other embodiments the treatment period could be any value within the range of about 1 minute and 19 minutes daily, and that the daily total treatment period could be formed of a plurality of treatment sessions contributing to the daily total treatment period.\",\n \"In one exemplary embodiment, the daily total treatment period is about 5 minutes.\",\n \"The vibration frequency can be less than about 300 Hz, for example, from about 60 Hz to about 300 Hz, from about 60 Hz to about 200 Hz, from about 60 Hz to about 130 Hz, from about 80 Hz to about 120 Hz, from about 110 Hz to about 120 Hz, from about 100 Hz to about 110 Hz, from about 90 Hz to about 100 Hz, or from about from about 80 Hz to about 90 Hz.\",\n \"It is contemplated that in other embodiments the frequency could be any value within the range of about 80 Hz and about 120 Hz, and that the vibration frequency could be adjusted during a treatment period.\",\n \"In one exemplary embodiment, the vibration frequency is about 100 Hz.\",\n \"In some embodiments, the dental device is capable of mechanically vibrating with a peak acceleration magnitude in the horizontal direction substantially greater than that in the vertical direction.\",\n \"For example, the peak acceleration magnitude of the vibration generated by the dental device in the horizontal direction can be about 1 to 5 times greater than that in the vertical direction.\",\n \"In some embodiments, the peak acceleration magnitude of the vibration in the horizontal direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In some embodiments, the peak acceleration magnitude of the vibration in the vertical direction may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. In other embodiments, the total peak acceleration magnitude of the vibration may range between about 0.001 G and about 3 G, such as between about 0.01 G and about 1 G. Additional features and advantages of the disclosed embodiments will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the disclosed embodiments.\",\n \"The features and advantages of the disclosed embodiments will be realized and attained by the elements and combinations particularly pointed out in the appended claims.\",\n \"It is to be understood that both the foregoing general description and the following detailed description are examples and explanatory only and are not restrictive of the disclosed embodiments as claimed.\",\n \"The accompanying drawings constitute a part of this specification.\",\n \"The drawings illustrate several embodiments of the present disclosure and, together with the description, serve to explain the principles of the disclosed embodiments as set forth in the accompanying claims.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS FIG.\",\n \"1A is a perspective view of an exemplary vibrational dental device, according to embodiments of the present disclosure.\",\n \"FIG.\",\n \"1B is a partial perspective view of the exemplary vibrational dental device of FIG.\",\n \"1A, according to embodiments of the present disclosure.\",\n \"FIG.\",\n \"1C is a partial component view of the exemplary vibrational dental device of FIG.\",\n \"1, according to embodiments of the present disclosure.\",\n \"FIG.\",\n \"2 illustrates the operation of the exemplary oral vibrational device of FIG.\",\n \"1.FIGS.\",\n \"3A-3P each show the measurement of vibration of an exemplary typodont subject to vibration treatment by the exemplary vibrational dental device of FIG.\",\n \"1 under different testing conditions.\",\n \"FIGS.\",\n \"4A-4P each show the measurement of vibration of an exemplary typodont subject to vibration treatment by a commercially available dental device under different testing conditions.\",\n \"FIG.\",\n \"5A graphically compares g-force measurements of a typodont with an aligner subject to vibration treatment by the exemplary vibrational dental device of FIG.\",\n \"1 and an exemplary commercially available dental device.\",\n \"FIG.\",\n \"5B graphically compares g-force measurements of a typodont without an aligner subject to vibration treatment by the exemplary vibrational dental device of FIG.\",\n \"1 and an exemplary commercially available dental device.\",\n \"FIG.\",\n \"6 graphically compares peak acceleration magnitudes between the average peak acceleration magnitudes between an exemplary commercially available dental device and the exemplary vibrational dental device of FIG.\",\n \"1.FIG.\",\n \"7 graphically compares average total displacement of the vibratory motion produced by an exemplary commercially available dental device and by the exemplary vibrational dental device of FIG.\",\n \"1.FIG.\",\n \"8 graphically compares mean numbers of osteoblasts over three days of a control group, a first group subject to mechanical vibration by an exemplary commercially available dental device, and a second group subject to mechanical vibration by the exemplary vibrational dental device of FIG.\",\n \"1.FIG.\",\n \"9 graphically compares mean numbers of periodontal ligament fibroblasts over three days of a control group, a first group subject to mechanical vibration by an exemplary commercially available dental device, and a second group subject to mechanical vibration by the exemplary vibrational dental device of FIG.\",\n \"1.FIG.\",\n \"10 graphically compares mean activity of osteoclasts over three days of a control group, a first group subject to mechanical vibration by an exemplary commercially available dental device, and a second group subject to mechanical vibration by the exemplary vibrational dental device of FIG.\",\n \"1.FIG.\",\n \"11 is a flowchart of an exemplary method for increasing cell proliferation, according to embodiments of the present disclosure.\",\n \"FIG.\",\n \"12 is a flowchart of an exemplary method for accelerating orthodontic tooth movement, according to embodiments of the present disclosure.\",\n \"DETAILED DESCRIPTION The disclosed embodiments relate to devices, systems, and methods for stimulating cell proliferation.\",\n \"Advantageously, embodiments of the present disclosure can be implemented in an orthodontic treatment for accelerating orthodontic tooth movement.\",\n \"Osteoblasts and fibroblasts are intimately involved in facilitating tooth movement and thus are typically targeted by techniques that aim at accelerating tooth movement in orthodontic treatments.\",\n \"Different approaches, both pre-clinically and clinically, have been attempted to achieve quicker results, but there are still many uncertainties and undetermined variables towards most of these techniques.\",\n \"For example, some commercially available dental devices, such as AcceleDent Aura™, developed by OrthoAccel® Technologies, Inc., are offered to accelerate orthodontic treatment.\",\n \"Patients are advised to wear such dental devices that mechanically stimulate teeth and braces in the form of micro-vibrations at a frequency of 30 Hz for 20 min per day.\",\n \"To get the maximum desired results of accelerated orthodontic treatment, further studies are still needed to identify the variables of mechanical vibrational stimulation, such as frequency, strength, and duration.\",\n \"It was discovered that treating cells, such as human osteoblasts and fibroblasts, with mechanical vibration for less than about 20 minutes, for example for about 5 minutes, daily at a frequency higher than about 80 Hz and with anisotropic acceleration magnitudes increases the number of cells over a period of time.\",\n \"That a marked improvement of cell proliferation over prior-art treatment methods using a shorter treatment interval is surprising and not suggested by the prior art.\",\n \"Various aspects of the present disclosure are developed based on such discovery.\",\n \"According to an aspect of the present disclosure, a vibrational dental device that vibrates at a frequency higher than about 80 Hz is provided.\",\n \"The vibrational dental device includes a mouthpiece and a motor connected to the mouthpiece.\",\n \"The mouthpiece is configured to be provided between the occlusal surfaces of a user's teeth so as to be clamped by the user's teeth.\",\n \"The motor is configured to vibrate the mouthpiece at a frequency higher than about 80 Hz, such as at a frequency between about 100 Hz to about 120 Hz, and with an acceleration magnitude ranging between about 0.03 G and about 0.4 G. When the motor is in operation and when the mouthpiece is clamped between the occlusal surfaces of a user's teeth, the vibrational dental device applies an axial vibratory force on the occlusal surfaces.\",\n \"Clamping the teeth onto the mouthpiece will apply a load to the vibrator, which may have the effect of lowering the vibrational frequency of the mouthpiece measured in free air, as described below.\",\n \"In some embodiments, the vibrational dental device may further include a sensor configured to detect the vibration variables of the device, such as frequency and acceleration magnitude.\",\n \"When the mouthpiece of the vibrational dental device is clamped between the occlusal surfaces of a user's teeth, the sensor may detect the vibration variables proximate to the occlusal surfaces of the user's teeth.\",\n \"In some embodiments, the sensor is a piezoelectric sensor.\",\n \"According to another aspect of the present disclosure, a method for increasing cell proliferation is provided.\",\n \"The method includes mechanically stimulating, using an exemplary vibrational dental device, cells for less than about 20 minutes, for example for about 5 minutes, daily at a frequency higher than about 80 Hz over a period of time.\",\n \"The cells may include at least one of human osteoblasts and fibroblasts.\",\n \"The period of time may extend for a couple of days up to a number of months, at the end of which, the number of the cells increases.\",\n \"As described herein, an increase of cell proliferation or an increase of the number of cells can be represented by an increase of cell density.\",\n \"According to another aspect of the present disclosure, a method for accelerating orthodontic tooth movement is described.\",\n \"The method includes providing the mouthpiece of the vibrational dental device between the occlusal surfaces of a user's teeth to be clamped by the user's teeth.\",\n \"The method further includes mechanically stimulating, using the vibrational dental device, cells of the user, including at least one of osteoblasts in alveolar bone and periodontal ligament fibroblasts, for less than about 20 minutes, for example for about 5 minutes, at a frequency higher than 80 Hz daily over a period of time.\",\n \"In some embodiments, the method further includes applying an axial vibratory force on the occlusal surfaces by the vibrational dental device.\",\n \"In some embodiments, the vibrational frequency and/or the acceleration magnitude generated by the vibrational dental device may be adjusted.\",\n \"Such adjustment may depend on one or more factors, such as the speed of tooth movement and/or user's reported comfort level.\",\n \"Reference will now be made in detail to embodiments and aspects of the present disclosure, examples of which are illustrated in the accompanying drawings.\",\n \"Where possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts.\",\n \"FIG.\",\n \"1A is a perspective view of an exemplary vibrational dental device 100.FIG.\",\n \"1B is a partial perspective view of vibrational dental device 100.FIG.\",\n \"1C is a partial component view of vibrational dental device 100.As shown in FIGS.\",\n \"1A-1C, vibrational dental device 100 includes a mouthpiece 102, a base 104, and a motor 106.Mouthpiece 102 is removably attached to base 104.Mouthpiece 102 includes a biteplate 114 and a mouthpiece extension 110 configured to connect with base 104.In some embodiments, mouthpiece 102 and/or biteplate 114 can be configured to engage some or all of a user's teeth.\",\n \"For example, in the exemplary embodiments shown in FIGS.\",\n \"1A-2, mouthpiece 102 and/or biteplate 114 are shaped to engage some or all of a user's teeth.\",\n \"As described herein, the shape of mouthpiece 102 and/or biteplate 114 shown in FIGS.\",\n \"1A-2 is only exemplary.\",\n \"Mouthpiece 102 and/or biteplate 114 may have a C-shape as depicted, or a customized shape suitable for safe application of vibrational treatment to all or some of a user's teeth.\",\n \"The mouthpiece can be made to apply vibration directly to a user's teeth, or to aligners or other appliances applied to the teeth.\",\n \"Extension 110 may further include contacts 108 that electrically connect base 104 with motor 106.As shown in FIGS.\",\n \"1B and 1C, motor 106 is installed in extension 110 of mouthpiece 102.When mouthpiece 102 is attached to base 104, motor 106 resides in base 104.Base 104 further includes electronic circuitries (not shown), including a control circuitry and a power circuitry, for operating motor 106.Motor 106 may be any type of motor that can cause mouthpiece 102 or biteplate 114 to vibrate.\",\n \"For example, motor 106 could be a vibration motor, piezoelectric motor, a linear motor, or an electromagnetic motor.\",\n \"The frequency and/or strength of vibration caused by motor 106 can be adjusted by changing the voltage or current supplied to motor 106 by the electronic circuitries in base 104.For example, the voltage used for operating motor 106 may range from about 0.5 volt to about 4 volts.\",\n \"The current supplied to an exemplary motor 106 may range from about 65 mA to about 100 mA.\",\n \"Motor 106 may have any suitable mechanical configurations to cause mouthpiece 102 or biteplate 114 to vibrate axially.\",\n \"FIG.\",\n \"2 illustrates exemplary operation of vibrational dental device 100.As shown in FIG.\",\n \"2, in one embodiment, motor 106 is a counter-weighted motor with a longitudinal axis parallel to the longitudinal axis of extension 110.Motor 106 may include a counterweight 212 that is off-axis from the longitudinal axis of motor 106.When the motor 106 rotates, as shown by the arrow 111 in FIG.\",\n \"2, counterweight 212 moves up and down, causing the mouthpiece 102 to vibrate up and down, as shown by the arrows 113a-113d in FIG.\",\n \"2.Accordingly, when the exemplary mouthpiece 102 is placed in a typodont or between a user's teeth, and when exemplary vibrational dental device 100 is turned on, the vibration of mouthpiece 102 will apply an axial vibratory force on the occlusal surfaces of the teeth.\",\n \"For example, biteplate 114 of mouthpiece 102 may cyclically move axially between the occlusal surfaces of the teeth.\",\n \"In some embodiments, vibrational dental device 100 may further include one or more sensors (not shown), such as piezoelectric sensors, configured to detect the acceleration magnitude and/or frequency of the vibration of mouthpiece 102.For example, sensors may be placed on the outside or the inside edge of biteplate 114, proximate to the occlusal surfaces of the teeth when mouthpiece 102 is clamped between the occlusal surfaces.\",\n \"The sensors can be electrically connected to the electronic circuitries in base 104.Measurements of the sensors can be fed back to the control circuitry of motor 106 to adjust the acceleration magnitude and/or frequency of motor 106.For example, the detected acceleration magnitude and/or frequency may be compared to a desired acceleration magnitude and/or frequency, and the voltage and/or current supplied to motor 106 can be adjusted based on the comparison.\",\n \"In some embodiments, motor 106 is configured to vibrate mouthpiece 102 at a frequency higher than about 80 Hz, such as at a frequency between about 100 Hz to about 120 Hz.\",\n \"Motor 106 may be further configured to vibrate mouthpiece 102 at an acceleration magnitude ranging between about 0.03 G and about 0.2 G. As described herein, the vibrational frequency of mouthpiece 120 may vary from the rated “free-air” vibrational frequency of motor 106 due to the amount of biting force or load applied to mouthpiece 102, such as the force used to clamp vibrational dental device 100 in place.\",\n \"For example, when motor 106 is configured to vibrate at a frequency of about 120 Hz, adding biting force or load to mouthpiece 102 may result in a lower vibrational frequency of mouthpiece 102 ranging from about 100 Hz to about 120 Hz.\",\n \"Examples 1-11 described below illustrate the use of vibrational dental device 100 operating under these variables and its clinically relevant effects.\",\n \"Example 1 A simulation was conducted to test and compare the vibration characteristics of a typodont caused by an exemplary embodiment of vibrational dental device 100 and a commercially available dental device, the AcceleDent Aura™.\",\n \"In the simulation setup, the typodont was secured to a metal table.\",\n \"The upper jaw of the typodont was hinged to the lower jaw and capable of opening and closing.\",\n \"Each device was placed in the typodont (between the occlusal surfaces) and held in position by securely mounting a weight of about 0 to about 4 pounds on the upper jaw.\",\n \"The weight simulates the biting force typically applied by a user to clamp the devices in place.\",\n \"The simulation setup further included electronic instruments, including accelerometers, for measuring vibration characteristics of the typodont.\",\n \"The accelerometers were placed directly on the devices and on the typodont.\",\n \"FIGS.\",\n \"3A-4P each show the measurement dataset of the accelerometer for two channels, channel 1 (“Ch1”) for detecting the vibration characteristics of the typodont and channel 2 (“Ch2”) for detecting the vibration characteristics of the device.\",\n \"As shown in FIGS.\",\n \"3A-4P, measurements of the accelerometers over the operation time of each device recorded increasing and decreasing accelerations of the devices and the typodont.\",\n \"The measurement dataset of the accelerometers resembles a sinusoidal curve.\",\n \"The distance from the bottom to the top of the sinusoidal curve is called the peak-to-peak G value or g-force (Gp-p).\",\n \"In this simulation, the operation time of vibrational dental device 100 was about 5 minutes.\",\n \"The operation time of AcceleDent Aura™ was about 20 minutes.\",\n \"The maximum Gp-p values of the vibration of the typodont actuated by these two devices under different simulated biting forces (different weights) were measured using the accelerometers and other associated electronic instruments about one minute before the end of the operation time.\",\n \"Therefore, measurement of the frequency and g-force for each channel was performed at the time point of about 4 minutes for vibrational dental device 100 and at the time point of about 19 minutes for AcceleDent Aura™.\",\n \"The simulation was repeated for a second testing device of vibrational dental device 100 and a second testing device of AcceleDent Aura™.\",\n \"Therefore, the first and second vibration dental devices 100 tested are shown as vibrational dental device 100 (1) and vibrational dental device 100 (2) respectively in FIGS.\",\n \"3A-3P.\",\n \"Also, the first and second AcceleDent Aura™ devices are shown as AcceleDent Aura™ (1) and AcceleDent Aura™ (2) respectively in FIGS.\",\n \"4A-4P.\",\n \"The simulation was also repeated where the typodont was installed with and without an aligner, as indicated in the captions of FIGS.\",\n \"3A-4P.\",\n \"All measurement data was summarized in Table 1 as shown below.\",\n \"TABLE 1 G-force values (Gp-p) measured under different testing conditions.\",\n \"g-force g-force on on Frequency typodont device Device Weight Aligner Time (Hz) (G) (G) AcceleDent Aura ™ (1) 4 Yes End-1 Min 29.8 0.002 0.074 AcceleDent Aura ™ (1) 4 No End-1 Min 30.46 0.002 0.072 Vibrational dental device 100 (1) 4 Yes End-1 Min 96.69 0.061 0.230 Vibrational dental device 100 (1) 4 No End-1 Min 98.02 0.048 0.210 AcceleDent Aura ™ (2) 4 Yes End-1 Min 29.8 0.002 0.054 AcceleDent Aura ™ (2) 4 No End-1 Min 29.8 0.002 0.061 Vibrational dental device 100 (2) 4 Yes End-1 Min 100 0.045 0.150 Vibrational dental device 100 (2) 4 No End-1 Min 98.02 0.025 0.210 AcceleDent Aura ™ (1) 2 Yes End-1 Min 29.8 0.016 0.084 AcceleDent Aura ™ (1) 2 No End-1 Min 29.8 0.016 0.076 Vibrational dental device 100 (1) 2 Yes End-1 Min 104 0.045 0.150 Vibrational dental device 100 (1) 2 No End-1 Min 112.6 0.081 0.150 AcceleDent Aura ™ (2) 2 Yes End-1 Min 29.8 0.011 0.082 AcceleDent Aura ™ (2) 2 No End-1 Min 29.8 0.014 0.079 Vibrational dental device 100 (2) 2 Yes End-1 Min 100.7 0.033 0.125 Vibrational dental device 100 (2) 2 No End-1 Min 111.3 0.046 0.118 AcceleDent Aura ™ (1) 1 Yes End-1 Min 29.8 0.008 0.094 AcceleDent Aura ™ (1) 1 No End-1 Min 29.8 0.031 0.086 Vibrational dental device 100 (1) 1 Yes End-1 Min 109.3 0.052 0.210 Vibrational dental device 100 (1) 1 No End-1 Min 109.9 0.175 0.120 AcceleDent Aura ™ (2) 1 Yes End-1 Min 29.8 0.014 0.084 AcceleDent Aura ™ (2) 1 No End-1 Min 29.8 0.038 0.092 Vibrational dental device 100 (2) 1 Yes End-1 Min 97.35 0.100 0.130 Vibrational dental device 100 (2) 1 No End-1 Min 106 0.126 0.108 In exemplary embodiments, the vibrational dental device can be configured to deliver g-forces above those found in prior art devices indicated for use with aligners or without aligners.\",\n \"FIG.\",\n \"5A and Table 2 show the measured g-force values (Gp-p) of the typodont mounted with different weights while subject to vibration by vibrational dental device 100 and by the AcceleDent Aura™ with the aligner.\",\n \"FIG.\",\n \"5B and Table 3 shows the measured g-force values (Gp-p) of the typodont mounted with different weights while subject to vibration by vibrational dental device 100 and by the AcceleDent Aura™ without the aligner.\",\n \"As described herein, results shown in FIGS.\",\n \"5A and 5B and Tables 1 and 2 were average values and standard deviations of the measured g-force values (Gp-p) on the typodont caused by the two testing devices of vibrational dental device 100 and the two testing devices of AcceleDent Aura™.\",\n \"As shown in FIGS.\",\n \"5A and 5B, vibrational dental device 100 produced greater acceleration than the AcceleDent Aura™ at various simulated biting forces (under various weights).\",\n \"When the typodont was fitted an aligner (as shown in FIG.\",\n \"5A and Table 1), depending on the simulated biting force, the AcceleDent Aura™ caused very low acceleration levels of the typodont with g-force values from less than 0.01 G to no greater than 0.02 G. In contrast, vibrational dental device 100 resulted in higher acceleration levels of the typodont with g-force values ranging from about 0.04 G to about 0.076 G. In particular, the two-pound and four-pound weights (or simulated biting force) caused the AcceleDent Aura™'s measured average g-force values to drop to very low levels of 0.0135 G and 0.002 G, respectively.\",\n \"When the typodont was without an aligner (as shown in FIG.\",\n \"5B and Table 2), depending on the simulated biting force, the AcceleDent Aura™ similarly caused very low acceleration levels with g-force values from less than 0.01 G to no greater than 0.04 G. Again, in contrast, vibrational dental device 100 resulted in multi-fold higher acceleration levels with g-force values ranging from about 0.04 G to about 0.15 G. These results suggest that vibrational dental device 100 can produce greater acceleration magnitude of the typodont under different simulated biting forces than the AcceleDent Aura™ with or without aligners.\",\n \"TABLE 2 Average g-force values (Gp-p) of the typodont mounted with different weights while subject to vibration by vibrational dental device 100 and by the AcceleDent Aura ™ with the aligner.\",\n \"4 lb 2 lb 1 lb Device Average SD Average SD Average SD AcceleDent 0.002 0.0000 0.0135 0.0035 0.011 0.0042 Aura ™ Vibrational 0.053 0.0113 0.0390 0.0085 0.076 0.0339 dental device 100 TABLE 3 Average g-force values (Gp-p) of the typodont mounted with different weights while subject to vibration by vibrational dental device 100 and by the AcceleDent Aura ™ without the aligner.\",\n \"4 lb 2 lb 1 lb Device Average SD Average SD Average SD AcceleDent 0.0020 0.0000 0.0150 0.0014 0.0345 0.0049 Aura ™ Vibrational 0.0365 0.0163 0.0635 0.0247 0.1505 0.0346 dental device 100 Example 2 Vibrational dental device 100 and AcceleDent Aura™ produce distinct vibration frequencies, and accelerations, and are used for different treatment duration, but they produce about the same number of oscillations per treatment.\",\n \"The different vibration variables of the AcceleDent Aura™ and vibrational dental device 100 may be perceived differently by cells residing in the alveolar bone and the periodontal tissue.\",\n \"In this example, acceleration profiles of the two devices are quantified and compared, and the efficacy of the mechanical vibration generated by these two devices to stimulate cells, including osteoblasts, periodontal ligament fibroblasts, and osteoclasts was quantitatively evaluated and compared.\",\n \"To measure the acceleration profiles of both vibrational dental device 100 and AcceleDent Aura™, an accelerometer Slamstick C (Mide Technology Corp, MA) was attached to the top surface of a mouthpiece and inserted into the mouth cavity of a volunteer as instructed by the manual of the manufacturer.\",\n \"All data were recorded for 20 second intervals at a recording frequency of 800 Hz.\",\n \"During recording, the mouthpiece was kept in the horizontal plane.\",\n \"Fast Fourier Transform (FFT) was applied to determine the frequency content of the recordings.\",\n \"For both vibrational dental device 100 and AcceleDent Aura™, three devices of each were tested and average peak acceleration magnitudes of the three devices in three orthogonal directions, including X-horizontal, Y-horizontal, and vertical dimensions were obtained.\",\n \"Commercially available cells, including human osteoblasts, human periodontal ligament fibroblasts, and human osteoclasts (Lonza, Inc., Walkersville, Md.)\",\n \"were cultured according to the manufacturer's instructions.\",\n \"For all experiments, the cells were plated in multi-well tissue culture plates at a cell density of 7,500 cells/cm2 and placed in an incubator prior to vibration treatment.\",\n \"The cells were taken out from the incubator immediately prior to vibration treatment.\",\n \"The human osteoblasts, human periodontal ligament fibroblasts, and human osteoclasts samples were respectively separated into three groups, a first group subject to vibration treatment by AcceleDent Aura™, a second group subject to vibration treatment by an exemplary embodiment of vibrational dental device 100, and a control group handled identically to the other two groups but not subject to vibration treatment.\",\n \"Vibration treatment was applied by placing the device between the cell culture plates and a plastic box.\",\n \"The cell culture plates, the device, and the plastic box were securely fastened together by industrial elastic bands.\",\n \"The plastic box and the industrial elastic bands isolated the vibrations generated by the devices from being transmitted to the experimental countertop.\",\n \"A tri-axial accelerometer was directly attached to the top of the cell culture plates to verify the applied vibration frequency and acceleration magnitude.\",\n \"Vibration treatment of the cells was applied daily at room temperature for a period of three days.\",\n \"Each day, the first groups of osteoblasts, fibroblasts, and osteoclasts were subject to vibration treatment by AcceleDent Aura™ at a frequency of 30 Hz for 20 minutes.\",\n \"The second groups of osteoblasts, fibroblasts, and osteoclasts were subject to vibration treatment by vibrational dental device 100 at a frequency from about 100 Hz to about 120 Hz for 5 minutes and subsequently left at room temperature for 15 minutes to match the 20 minutes room temperature exposure of the first groups.\",\n \"The control groups were left at room temperate for 20 minutes without any vibration treatment.\",\n \"For osteoblasts and periodontal ligament fibroblasts, cell proliferation or cell density (cells/cm2) over a three-day period was used as a marker for the cells' responsivity to the vibration stimuli.\",\n \"A standard spectrophotometric MTS assay was used for determining cell density according to the manufacturer's instructions (XTT Assay, ATCC™).\",\n \"The cell sample size for each group of osteoblasts and periodontal ligament fibroblasts was 5.Mean cell numbers of each group were calculated based on the measured cell densities of the cell samples of each group.\",\n \"To quantify osteoclasts' responsivity to the vibration stimuli, TRAP optical density was measured over a three-day period.\",\n \"The cell sample size for each group of osteoclast was 12.Datasets were presented as means and standard deviations.\",\n \"The three groups were statistically compared to each other via Fisher tests.\",\n \"A significance value of 0.05 was used for all datasets.\",\n \"FIG.\",\n \"6 and Table 4 show the average peak acceleration magnitudes of AcceleDent Aura™ and vibrational dental device 100 recorded with the accelerometer in three orthogonal directions.\",\n \"As shown in FIG.\",\n \"6 and Table 4, the average peak accelerations of the three sample devices of AcceleDent Aura™ were measured about 0.12 G in the medial-lateral or X-horizontal direction, about 0.15 G in the anterior-posterior or Y-horizontal direction, and about 0.15 G in the vertical direction.\",\n \"The average peak accelerations of the three sample devices of vibrational dental device 100 were measured about 0.23 G in the medial-lateral or X-horizontal direction, about 0.33 G in the anterior-posterior Y-horizontal direction, and about 0.07 G in the vertical direction.\",\n \"Combining the average acceleration magnitudes in the two horizontal directions resulted in an average peak acceleration in the horizontal dimension of about 0.18 G for the AcceleDent Aura™ devices and about 0.41 G for the vibrational dental devices 100.Combining the average acceleration magnitudes in all three directions resulted in an average Total Resultant acceleration magnitude of about 0.24 G for the AcceleDent Aura™ devices and about 0.41 G for the vibrational dental devices 100.As shown in FIG.\",\n \"6, for both AcceleDent Aura™ and vibrational dental devices 100, variability across the three sample devices was low.\",\n \"TABLE 4 Average peak acceleration magnitudes of vibrational dental device 100 and the AcceleDent Aura ™ AcceleDent Aura ™ Vibrational dental device 100 X 0.12 G 0.23 G Y 0.15 G 0.33 G Horizontal 0.18 G 0.41 G Vertical 0.15 G 0.07 G Total Resultant 0.24 G 0.41 G FIG.\",\n \"7 graphically compares average total displacement of the vibratory motion produced by AcceleDent Aura™ and by vibrational dental device 100.As shown in FIG.\",\n \"7, the average total displacement of the vibratory motion produced by AcceleDent Aura™ was about 140 μm and about 14 μm by vibrational dental device 100.Thus, as shown in FIGS.\",\n \"6 and 7, vibrational dental device 100 achieved smaller displacements in spite of greater peak acceleration magnitudes by using a vibration frequency that is about four times greater than that of AcceleDent Aura™.\",\n \"FIG.\",\n \"8 shows mean cell numbers of three groups of osteoblasts.\",\n \"FIG.\",\n \"9 shows mean cell numbers of three groups of fibroblasts.\",\n \"The cell numbers are presented in an arbitrary unit for the purpose of comparison.\",\n \"FIG.\",\n \"10 shows mean activity of three groups of osteoclasts presented in optical density (OD) measurements.\",\n \"Daggers in FIGS.\",\n \"8-10 mark statistically significant differences between control samples and samples subject to vibration treatment.\",\n \"Asterisks mark statistically significant differences samples subject to vibration treatment AcceleDent Aura™ and samples subject to vibration treatment by vibrational dental device 100.Surprisingly, as shown in FIG.\",\n \"8, the group of osteoblasts subject to vibration treatment by vibrational dental device 100 had significantly greater (p<0.05) cell proliferation than the group of osteoblasts subject to vibration treatment by AcceleDent Aura™ on day 2 and day 3.Similarly, as shown in FIG.\",\n \"9, the group of fibroblasts subject to vibration treatment by vibrational dental device 100 had significantly greater (p<0.05) cell proliferation than the group of fibroblasts subject to vibration treatment by AcceleDent Aura™ on day 2 and day 3.As shown in FIG.\",\n \"10, both AcceleDent Aura™ and vibrational dental device 100 were capable of moderately increasing the activity of osteoclasts as compared with the control group.\",\n \"This example demonstrates the surprising results that vibration treatment by vibrational dental device 100 enhanced proliferation of human osteoblasts and periodontal ligament fibroblasts to a significantly greater level than AcceleDent Aura™ The in vitro experimental results presented in this example suggest that different cell types and tissues, such as the human osteoblasts and human periodontal ligament fibroblasts, can be more responsive to the vibration variables used by vibrational dental device 100.For example, vibrational dental device 100 produces vibratory motions at a frequency from about 100 Hz to about 120 Hz, about four times of that of AcceleDent Aura™, with greater peak acceleration magnitudes That superior results could be obtained in one-fourth the time required by the AcceleDent Aura™ could result in superior clinical results in orthodontics, as shorter treatment periods generally correlate to better user compliance and adherence.\",\n \"Additionally, the difference in the peak acceleration magnitude produced by AcceleDent Aura™ and vibrational dental device 100 was significant.\",\n \"As shown in Table 1, while AcceleDent Aura™ produced peak accelerations on the order of 0.15 G in all three directions, the peak accelerations produced by vibrational dental device 100 in the horizontal direction was about six times of that in the vertical direction.\",\n \"This spatial anisotropy in acceleration magnitudes generated by vibrational dental device 100 may have directly contributed to the greater proliferation rates of the periodontal ligament fibroblast and osteoblast samples as cells may sense vibrations preferentially in the horizontal direction.\",\n \"The Total Resultant peak acceleration magnitude of vibrational dental device 100 was about 70% greater than that of AcceleDent Aura™ As shown in FIGS.\",\n \"6 and 7, the greater peak acceleration magnitude of vibrational dental device 100 was achieved via a greater vibration frequency and not a greater displacement magnitude.\",\n \"In fact, as shown in FIG.\",\n \"7, the displacement magnitude produced by vibrational dental device 100 was an order of magnitude smaller than that produced by AcceleDent Aura™.\",\n \"This may be clinically important because small displacements induced by vibrations could reduce discomfort to the patients, thereby correlating with better user compliance.\",\n \"Example 3 An exemplary embodiment of vibrational dental device 100 is used to subject periodontal cells for a period of vibrational treatment.\",\n \"The periodontal cells include human osteoblasts in alveolar bone and periodontal ligament fibroblasts.\",\n \"The periodontal cells are treated for less than about 20 minutes, for example for about 5 minutes, at a frequency higher than about 80 Hz, for example from about 100 Hz to about 120 Hz, daily over a period of time, which lasts for about a few days to a couple of weeks.\",\n \"At the end of the period of time, the number of periodontal cells, including osteoblasts in alveolar bone and periodontal ligament fibroblasts, is increased.\",\n \"Example 4 An exemplary embodiment of vibrational dental device 100 is used to subject periodontal cells for a period of vibrational treatment.\",\n \"The periodontal cells include human osteoblasts in alveolar bone and periodontal ligament fibroblasts.\",\n \"The periodontal cells are treated for less than about 20 minutes, for example for about 5 minutes, at a frequency higher than about 80 Hz, for example from about 100 Hz to about 120 Hz, daily over a period of time, which lasts for about a couple of weeks to about a month.\",\n \"At the end of the period of time, the number of periodontal cells, including osteoblasts in alveolar bone and periodontal ligament fibroblasts, is increased.\",\n \"Example 5 An exemplary embodiment of vibrational dental device 100 is used to subject periodontal cells for a period of vibrational treatment.\",\n \"The periodontal cells include human osteoblasts in alveolar bone and periodontal ligament fibroblasts.\",\n \"The periodontal cells are treated for less than about 20 minutes, for example for about 5 minutes, at a frequency higher than about 80 Hz, for example from about 100 Hz to about 120 Hz, daily over a period of time, which lasts for about a month to a couple of months.\",\n \"At the end of the period of time, the number of periodontal cells, including osteoblasts in alveolar bone and periodontal ligament fibroblasts, is increased.\",\n \"Example 6 An exemplary embodiment of vibrational dental device 100 is used to subject periodontal cells for a period of vibrational treatment.\",\n \"The periodontal cells include human osteoblasts in alveolar bone and periodontal ligament fibroblasts.\",\n \"The periodontal cells are treated for less than about 20 minutes, for example for about 5 minutes, at a frequency higher than about 80 Hz, for example from about 100 Hz to about 120 Hz, daily over a period of time, which lasts for about a couple of months to about a few months.\",\n \"At the end of the period of time, the number of periodontal cells, including osteoblasts in alveolar bone and periodontal ligament fibroblasts, is increased.\",\n \"Example 7 An exemplary embodiment of vibrational dental device 100 is provided to a user for a period of vibrational treatment.\",\n \"While wearing an orthodontic aligner, the user uses vibrational dental device 100 by clamping the mouthpiece 102 between his or her teeth for less than about, for example about 5 minutes at a frequency higher than about 80 Hz, for example from about 100 Hz to about 120 Hz daily, during the period of vibrational treatment.\",\n \"The period of vibrational treatment lasts for about 2 days to about a few days.\",\n \"At the end of the period of vibrational treatment, the number of periodontal cells, including osteoblasts in alveolar bone and periodontal ligament fibroblasts, of the teeth that are subject to the vibrational treatment by vibrational dental device 100 is increased.\",\n \"Additionally, a desired movement of all or some of the teeth subject to vibrational treatment by vibrational dental device 100 is achieved at the end of the period of vibrational treatment.\",\n \"Example 8 An exemplary embodiment of vibrational dental device 100 is provided to a user for a period of vibrational treatment.\",\n \"While wearing an orthodontic aligner, the user uses vibrational dental device 100 by clamping the mouthpiece 102 between his or her teeth for less than about 20 minutes, for example for about 5 minutes, at a frequency from higher than about 80 Hz, for example about 100 Hz to about 120 Hz, daily during the period of vibrational treatment.\",\n \"The period of vibrational treatment lasts for about a few days to a couple of weeks.\",\n \"At the end of the period of vibrational treatment, the number of periodontal cells, including osteoblasts in alveolar bone and periodontal ligament fibroblasts, of the teeth that are subject to the vibrational treatment by vibrational dental device 100 is increased.\",\n \"Additionally, a desired movement of all or some of the teeth subject to vibrational treatment by vibrational dental device 100 is achieved at the end of the period of vibrational treatment.\",\n \"Example 9 An exemplary embodiment of vibrational dental device 100 is provided to a user for a period of vibrational treatment.\",\n \"While wearing an orthodontic aligner, the user uses vibrational dental device 100 by clamping the mouthpiece 102 between his or her teeth for less than about 80 Hz, for example for about 5 minutes, at a frequency higher than about 80 Hz, for example from about 100 Hz to about 120 Hz, daily during the period of vibrational treatment.\",\n \"The period of vibrational treatment lasts for about a couple of weeks to about a month.\",\n \"At the end of the period of vibrational treatment, the number of periodontal cells, including osteoblasts in alveolar bone and periodontal ligament fibroblasts, of the teeth that are subject to the vibrational treatment by vibrational dental device 100 is increased.\",\n \"Additionally, a desired movement of all or some of the teeth subject to vibrational treatment by vibrational dental device 100 is achieved at the end of the period of vibrational treatment.\",\n \"Example 10 An exemplary embodiment of vibrational dental device 100 is provided to a user for a period of vibrational treatment.\",\n \"While wearing an orthodontic aligner, the user uses vibrational dental device 100 by clamping the mouthpiece 102 between his or her teeth for less than about 20 minutes, for example for about 5 minutes, at a frequency higher than about 80 Hz, for example from about 100 Hz daily to about 120 Hz during the period of vibrational treatment.\",\n \"The period of vibrational treatment lasts for about a month to a couple of months.\",\n \"At the end of the period of vibrational treatment, the number of periodontal cells, including osteoblasts in alveolar bone and periodontal ligament fibroblasts, of the teeth that are subject to the vibrational treatment by vibrational dental device 100 is increased.\",\n \"Additionally, a desired movement of all or some of the teeth subject to vibrational treatment by vibrational dental device 100 is achieved at the end of the period of vibrational treatment.\",\n \"Example 11 An exemplary embodiment of vibrational dental device 100 is provided to a user for a period of vibrational treatment.\",\n \"While wearing an orthodontic aligner, the user uses vibrational dental device 100 by clamping the mouthpiece 102 between his or her teeth for less than about 20 minutes, for example for about 5 minutes, at a frequency higher than about 80 Hz, for example from about 100 Hz to about 120 Hz, daily during the period of vibrational treatment.\",\n \"The period of vibrational treatment lasts for about a couple of months to a few months.\",\n \"At the end of the period of vibrational treatment, the number of periodontal cells, including osteoblasts in alveolar bone and periodontal ligament fibroblasts, of the teeth that are subject to the vibrational treatment by vibrational dental device 100 is increased.\",\n \"Additionally, a desired movement of all or some of the teeth subject to vibrational treatment by vibrational dental device 100 is achieved at the end of the period of vibrational treatment.\",\n \"The above-described examples suggest that vibrational dental device 100 described herein may be utilized in a variety of procedures and methods for increasing cell proliferation.\",\n \"An exemplary method 200 for increasing cell proliferation may use one or more features of the embodiments of vibrational dental device 100, described above in reference to FIGS.\",\n \"1-5.Exemplary embodiments of method 200 are described below with reference to FIG.\",\n \"8.As shown in FIG.\",\n \"8, method 200 may include steps 210-230.Step 210 may include providing vibrational dental device 100.As described above, while in operation, vibrational dental device 100 can be configured to vibrate at a frequency higher than about 80 Hz and an acceleration magnitude ranging between about 0.03 G and about 0.2 G. For example, vibrational dental device 100 may vibrate at a frequency between about 100 Hz and about 120 Hz.\",\n \"Step 220 may include mechanically stimulating, using vibrational dental device 100, cells for about less than 20 minutes, for example for about 5 minutes, daily over a period of time.\",\n \"The cells may include one of human osteoblasts and fibroblasts.\",\n \"As described herein, the period of time may last until a desirable result has achieved.\",\n \"In some embodiments, the period of time may last for a couple of days up to a few months.\",\n \"Step 230 may include increasing the number of the cells at the end of the period of time.\",\n \"As described herein, an increase of the number of cells may be represented by an increase of the cell density, which indicates cell proliferation.\",\n \"Step 230 may further include quantitatively evaluating the cell number and/or cell density daily.\",\n \"As described herein, additional steps may be added to method 200.For example, method 200 may include increasing or decreasing the frequency and/or acceleration magnitude of vibrational dental device 100 based on the response of the cells to vibration treatment.\",\n \"Method 200 may also include detecting characteristics of the vibration produced by vibrational dental device 100 and/or characteristics of the vibration applied to the cells by vibrational dental device 100.Also, some steps may be omitted or repeated, and/or may be performed simultaneously.\",\n \"The above-described examples may further suggest that vibrational dental device 100 may stimulate more response of human osteoblasts and periodontal ligament fibroblasts during orthodontic treatment than AcceleDent Aura™.\",\n \"Therefore, vibrational dental device 100 described herein may be utilized in a variety of procedures and methods for accelerating orthodontic tooth movement in orthodontic treatments.\",\n \"An exemplary method 300 for accelerating orthodontic tooth movement may use one or more features of the embodiments of vibrational dental device 100, described above in reference to FIGS.\",\n \"1-5.Exemplary embodiments of method 300 are described below with reference to FIG.\",\n \"9.As shown in FIG.\",\n \"9, method 300 may include steps 310 and 320.Step 310 may include providing a mouthpiece of vibrational dental device 100 between the occlusal surfaces of a user's teeth to be clamped by the user's teeth.\",\n \"As described above, while in operation, vibrational dental device 100 is capable of vibrating at a frequency higher than about 80 Hz and an acceleration magnitude ranging between about 0.03 G and about 0.2 G. For example, vibrational dental device 100 may vibrate at a frequency between about 100 Hz and 120 Hz.\",\n \"Step 320 may include mechanically stimulating, using vibrational dental device 100, cells of the user for less than about 20 minutes, for example for about 5 minutes, daily at a frequency higher than 80 Hz over a period of time.\",\n \"The cells may include one of human osteoblasts and periodontal ligament fibroblasts.\",\n \"As described herein, the period of time may last until a desirable result has been achieved, such as a desired amount of tooth movement.\",\n \"In some embodiments, the period of time may last for a few of days up to a few months.\",\n \"As described herein, additional steps may be added to method 300.For example, method 300 may include increasing or decreasing the frequency and/or acceleration magnitude of vibrational dental device 100 based on the response of vibration treatment, such as the speed or amount of tooth movement.\",\n \"Method 300 may also include detecting characteristics of the vibration applied proximate to the occlusal surfaces, such as frequency and acceleration magnitude, by sensors of vibrational dental device 100.Also, some steps may be omitted or repeated, and/or may be performed simultaneously.\",\n \"The foregoing description has been presented for purposes of illustration.\",\n \"It is not exhaustive and is not limited to precise forms or embodiments disclosed.\",\n \"Modifications and adaptations of the embodiments will be apparent from consideration of the specification and practice of the disclosed embodiments.\",\n \"For example, the described implementations include hardware and software, but systems and methods consistent with the present disclosure can be implemented as hardware alone.\",\n \"In addition, while certain components have been described as being coupled to one another, such components may be integrated with one another or distributed in any suitable fashion.\",\n \"Moreover, while illustrative embodiments have been described herein, the scope includes any and all embodiments having equivalent elements, modifications, omissions, combinations (e.g., of aspects across various embodiments), adaptations and/or alterations based on the present disclosure.\",\n \"The elements in the claims are to be interpreted broadly based on the language employed in the claims and not limited to examples described in the present specification or during the prosecution of the application, which examples are to be construed as nonexclusive.\",\n \"Further, the steps of the disclosed methods can be modified in any manner, including reordering steps and/or inserting or deleting steps.\",\n \"The features and advantages of the disclosure are apparent from the detailed specification, and thus, it is intended that the appended claims cover all systems and methods falling within the true spirit and scope of the disclosure.\",\n \"As used herein, the indefinite articles “a” and “an” mean “one or more.” Similarly, the use of a plural term does not necessarily denote a plurality unless it is unambiguous in the given context.\",\n \"Words such as “and” or “or” mean “and/or” unless specifically directed otherwise.\",\n \"Further, since numerous modifications and variations will readily occur from studying the present disclosure, it is not desired to limit the disclosure to the exact construction and operation illustrated and described, and accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the disclosure.\",\n \"Other embodiments will be apparent from consideration of the specification and practice of the embodiments disclosed herein.\",\n \"It is intended that the specification and examples be considered as example only, with a true scope and spirit of the disclosed embodiments being indicated by the following claims.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875779"}}},{"rowIdx":4494975,"cells":{"text":{"kind":"list like","value":[["TRANSFORMABLE SPEECH PROCESSOR MODULE FOR A HEARING PROSTHESIS","A method for operating an external component of a cochlear implant hearing system.","The external component includes a speech processor module operable in a stand-alone mode of operation and a body-worn mode of operation, and a protective case.","The method includes operating the speech processor module in the stand-alone mode, determining when the speech processor module is mounted in the case, and operating the speech processor module in the body-worn mode in response to determining that the speech processor module is mounted in the case."],["1-14.","(canceled) 15.An external component of a cochlear implant system, comprising: a speech processor module including processing circuitry configured to receive signals output by a microphone and including a plurality of connectors establishing a power supply interface and at least one of a clinic interface or an accessory interface; and a base member, wherein the speech processor module is operable in a first configuration whereby a cover member is mechanically mated with said base member to establish an enclosure around said speech processor module, thereby substantially preventing any potential fluid ingress that could adversely impact the speech processor module, and wherein said speech processor module is operable in at least a second configuration whereby the cover member is not mechanically mated to the base member.","16.The external component of claim 15, wherein: the at least one of the clinic interface or the accessory interface comprises electrical contacts, and the cover creates a battier between the electrical contacts and fluid in an ambient environment when the speech processor module is operated in the first configuration.","17.The external component of claim 15, wherein: the speech processor module includes the accessory interface, and wherein an accessory device is configured to be placed into signal communication with the speech processor via the accessory interface.","18.The external component of claim 15, wherein: the speech processor module includes the accessory interface, the accessory interface is part of an accessory connector, and wherein an accessory device is configured to connect to the accessory connector when the speech processor module is operated in the second configuration.","19.The external component of claim 18, further comprising: the accessory device, wherein the speech processor module is in the second configuration and the accessory device is connected to the accessory connector.","20.The external component of claim 18, wherein: the speech processor module includes the accessory interface, the accessory interface is part of an accessory connector; and the external component is configured to prevent connection of the accessory device to the accessory connector when the cover is mechanically connected to the base.","21.The external component of claim 15, wherein: the speech processor module includes the accessory interface, the accessory interface is part of an accessory connector; and the external component is configured to enable connection of the accessory device to the accessory connector only when the cover is mechanically disconnected from the base.","22.The external component of claim 15, wherein: the speech processor module includes the clinic interface; and the external component is configured to prevent input into the clinic interface when the cover is mechanically connected to the base.","23.The external component of claim 15, wherein: the speech processor module includes the clinic interface; and the external component is configured to enable data input into the clinic interface only when the cover is mechanically disconnected from the base.","24.A method of utilizing an external component of a cochlear implant hearing system, the external component comprising a speech processor module operable in a stand-alone mode of operation and an external device controlled mode of operation; the method comprising: operating the speech processor module in the stand-alone mode; removably mounting the speech processor module to an apparatus configured to have said speech processor module removably mounted thereto and including external device user controls; determining whether or not to utilize an inputted external volume control setting inputted by a user to the external device user controls of the external device to control the speech processor module; and operating the speech processor in the external device controlled mode.","25.The method of claim 24, wherein: the action of determining whether or not to utilize an inputted external volume control setting inputted by a user to the external device user controls of the external device to control the speech processor module includes determining to utilize the inputted external volume control setting inputted by a user to the external device user controls of the external device to control the speech processor module; and the action of operating the speech processor in the external device controlled mode includes operating the speech processor in the external mode after the determination to use the inputted external volume control setting.","26.The method of claim 24, wherein: the action of determining whether or not to utilize an inputted external volume control setting inputted by a user to the external device user controls of the external device to control the speech processor module includes determining not to utilize the inputted external volume control setting inputted by a user to the external device user controls of the external device to control the speech processor module; and separate from the action of operating the speech processor in the external device controlled mode, preventing operation of the speech processor in the external device controlled mode after the determination not to use the inputted external volume control setting.","27.The method of claim 26, further comprising: separate from determining not to utilize an inputted external volume control setting inputted by a user to the external device user controls of the external device to control the speech processor module, determining to utilize a second inputted external volume control setting inputted by a user to the external device user controls of the external device to control the speech processor module; and separate from the action of operating the speech processor in the external device controlled mode, operating the speech processor in the external device controlled mode after the determination to use the second inputted external volume control setting based on the second inputted external volume control setting.","28.The method of claim 24, wherein when the speech processor is operated in the stand alone mode, it is protected from water at elevated atmospheric pressures.","29.The method of claim 24, the method further comprising: placing a transcutaneous transfer coil assembly into signal communication with the speech processor, wherein the transcutaneous transfer coil assembly includes a transcutaneous transfer coil and a microphone, wherein the transcutaneous transfer coil assembly is configured to protect the microphone and transfer coil from water at elevated atmospheric pressures.","30.A method, comprising: using a first external component assembly of a hearing prosthesis to evoke a first hearing percept by transcutaneously communicating electrical signals from the first external component assembly to an implanted component of the hearing prosthesis such that the implanted component stimulates tissue to evoke the first hearing percept; and after evoking the first hearing percept, replacing the first external component assembly with a second external component assembly to evoke a second hearing percept by transcutaneously communicating electrical signals from the second external component assembly to the implanted component of the hearing prosthesis such that the implanted component stimulates tissue to evoke the second hearing percept, wherein the first external component assembly is one that is readily damaged by water and the second external component assembly is one that is protected from water.","31.The method, of claim 30, wherein: the first external component assembly uses a first transcutaneous transfer coil assembly including a first transcutaneous transfer coil and a first cable to transcutaneously communicate with the implanted component; and the second external component uses a second transcutaneous transfer coil assembly including a second transcutaneous transfer coil and a second cable to transcutaneously communicate with the implanted component.","32.The method, of claim 30, wherein: the second transcutaneous transfer coil assembly also includes a microphone.","33.The method, of claim 30, further comprising: after evoking the first and second hearing percepts, using the first external component assembly to evoke a third hearing percept by transcutaneously communicating electrical signals from the first external component assembly to the implanted component of the hearing prosthesis such that the implanted component stimulates tissue to evoke the third hearing percept.","34.The method, of claim 30, wherein: the action of evoking the first hearing percept is executed while the first external component is adjustable via the recipient via a control input device of the first external component; and the action of evoking the second hearing percept is executed while the second external component is unadjustable via the recipient.","35.The method, of claim 30, further comprising: prior to evoking the second hearing percept, adjusting a functional operating parameter of the second external component; and after adjusting the functional operating parameter and before evoking the second hearing precept, placing the second external component into a water ingress protection state that results in the functional operating parameter being non-adjustable by a recipient of the hearing prosthesis, and then evoking the second hearing percept.","36.The method, of claim 30, wherein: the first external component is in the form of a component that can be worn as a behind-the-ear (BTE) device when evoking the first hearing percept; and the second external component is in the form of a body-worn component different from a BTE device when evoking the second hearing percept.","37.The method, of claim 30, wherein: the first external component is in the form of a component that can be worn as a behind-the-ear (BTE) device when evoking the first hearing percept; and the second external component is in the form of a body-worn component that cannot be worn as a BTE device.","38.The method, of claim 30, further comprising: prior to evoking the second hearing percept, adjusting a functional operating parameter of a sound processor of the second external component; and after adjusting the functional operating parameter and before evoking the second hearing precept, placing a cover over the sound processor of the second external component such that electrical contacts of the sound processor that would otherwise be exposed to the ambient environment are covered.","39.A method, comprising: setting an operating parameter of a speech processor of an external component of a hearing prosthesis, wherein the external component is in a first state; and covering at least a portion of the speech processor with a cover, wherein the external component of the hearing prosthesis is in a second state with the cover on the speech processor, and wherein the operating parameter cannot be changed when the external component is in the second state.","40.The method of claim 39, wherein: the first state is a state in which the external component can be damaged by water, and the second state is a state in which the external component is protected from damage by water.","41.The method of claim 39, wherein: the external component has no control input apparatuses that are accessible by the recipient of the hearing prosthesis when the cover is on the speech processor.","42.The method of claim 39, further comprising: uncovering the at least a portion of the speech processor such that the operating parameter can be changed.","43.The method of claim 39, wherein: the operating parameter is a volume.","44.The method of claim 39, wherein: user controls that enable the operating parameter to be set are not provided to the recipient of the hearing prosthesis when in the second state.","45.The method of claim 39, wherein: the operating parameter is set using user controls available to the recipient of the hearing prosthesis when in the first state; and the user controls that were used to set the operating parameter not provided to the recipient of the hearing prosthesis when in the second state.","46.The method of claim 39, further comprising: placing a transcutaneous transfer coil and a microphone into signal communication with the speech processor, wherein the transcutaneous transfer coil assembly includes a housing that provides protection to the microphone from water.","47.The external component of claim 15, wherein: a device is configured to connect to the speech processor module when the module is operated in the second configuration; and the external component further comprises the device, wherein the speech processor module is in the second configuration and the device is connected to the module."],["<SOH> BACKGROUND <EOH>"],["<SOH> SUMMARY <EOH>In one aspect of the invention, a method for operating an external component of a cochlear implant hearing system is disclosed.","The external component comprises a speech processor module is operable in a stand-alone mode of operation and a body-worn mode of operation, and a protective case.","The method comprises operating the speech processor module in the stand-alone mode, determining when the speech processor module is mounted in the case, and operating the speech processor module in the body-worn mode in response to determining that the speech processor module is mounted in the case.","In another aspect of the invention, a method for operating a cochlear implant hearing system is disclosed.","The method comprises operating, in a stand-alone mode of operation, a speech processor module having processing circuitry disposed in a housing, determining, via an operational mode controller, when the speech processor module is mounted in a protective case, and operating the speech processor module in a body-worn mode of operation in response to determining that the speech processor module is mounted in the case."],["CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation application of U.S. application Ser.","No.","13/729,485 filed Dec. 28, 2012, which is a continuation application of U.S. application Ser.","No.","12/703,160 filed Mar.","18, 2012, now U.S. Pat.","No.","8,352,037, which is a divisional of U.S. application Ser.","No.","10/586,524, filed Oct. 23, 2006, which is a National Stage application of International Application No.","PCT/US04/43288, filed Dec. 27, 2004, and which claims the benefit of Australian Provisional Patent Application No.","2003907138, filed Dec. 24, 2003.The content of these applications is hereby incorporated by reference herein.","BACKGROUND Field of the Invention The present invention relates to a hearing prosthesis and, more particularly, a transformable speech processor module for a hearing prosthesis.","Related Art The use of medical devices to provide therapy to individuals for various medical conditions has become more widespread as the advantages and benefits of such devices become more widely appreciated and accepted throughout the population.","In particular, devices such as implantable pacemakers, defibrillators, functional electrical stimulation devices such as hearing prostheses, organ assist or replacement devices, and other medical devices, have been successful in performing life saving and/or lifestyle enhancement functions for a number of individuals.","Many such medical devices often include one or more sensors, processors, controllers or other functional electrical components that are permanently or temporarily implanted in a patient.","Many such implantable devices require the transcutaneous transfer of power and/or information with external components that are part of, or operate in conjunction with, the implanted components of the medical device.","Such external components are typically removably attached to the body of the patient.","One such type of medical device is a cochlear implant system, also commonly referred to as a cochlear prosthesis.","Cochlear implant systems provide the benefit of hear to individuals suffering from severe to profound hearing loss.","Hearing loss in such individuals is due to the absence or destruction of the hair cells in the cochlea which transduce acoustic signals into nerve impulses.","Cochlear implants essentially simulate the cochlear hair cells by directly delivering electrical stimulation to the auditory nerve fibers.","This causes the brain to perceive a hearing sensation resembling the natural hearing sensation normally delivered to the auditory nerve.","Conventional cochlear implant systems primarily include an external assembly directly or indirectly attached to the body of the patient (referred to herein as the recipient), and an internal assembly which is implanted in the patient.","The external assembly typically comprises one or more microphones for detecting sound, a speech processing unit that converts detected sound, particularly speech, into an electrical coded signal, a power source, and an external transcutaneous transfer coil.","The internal assembly typically comprises an internal transcutaneous transfer coil, a stimulator unit located within a recess of the temporal bone of the recipient, and an electrode array positioned in the recipient's cochlear.","Collectively, the external coil and the internal coil form an inductively-coupled transcutaneous transfer system.","The transfer of energy via this system is controlled to effect the transmission of the electrical coded signals, referred to herein as stimulation signals, and power signals from the external speech processing unit, to the implanted stimulator unit.","Similarly, the transcutaneous transfer system may be used to effect the transmission of telemetry data from the implanted stimulator unit to the exterior speech processing unit.","Conventionally, the communications link has been in the form of a radio frequency (RF) link, although other such links have been proposed and implemented.","Once a stimulation signal has been transmitted to the implanted transcutaneous transfer coil, it is provided to the implanted stimulator unit which processes the signal and outputs one or more signals to the intra-cochlear electrode assembly which applies the electrical stimulation directly to the auditory nerve of the recipient.","The speech processor unit has traditionally been worn on the body, such as by being attached to clothing, or by being supported on the ear of the recipient.","This latter configuration is commonly referred to as a BTE (behind the ear) configuration.","The speech processor unit is relatively expensive and susceptible to damage, especially in the hands of infants or small children, or when used in an unsuitable environment.","SUMMARY In one aspect of the invention, a method for operating an external component of a cochlear implant hearing system is disclosed.","The external component comprises a speech processor module is operable in a stand-alone mode of operation and a body-worn mode of operation, and a protective case.","The method comprises operating the speech processor module in the stand-alone mode, determining when the speech processor module is mounted in the case, and operating the speech processor module in the body-worn mode in response to determining that the speech processor module is mounted in the case.","In another aspect of the invention, a method for operating a cochlear implant hearing system is disclosed.","The method comprises operating, in a stand-alone mode of operation, a speech processor module having processing circuitry disposed in a housing, determining, via an operational mode controller, when the speech processor module is mounted in a protective case, and operating the speech processor module in a body-worn mode of operation in response to determining that the speech processor module is mounted in the case.","BRIEF DESCRIPTION OF THE DRAWINGS FIG.","1A is a perspective view of one embodiment of a hearing prosthesis in which embodiments of the present invention may be advantageously implemented; FIG.","1B is a perspective view of one embodiment of a dual mode speech processing unit in accordance with one embodiment of the present invention; FIG.","2 is a perspective view of an external component system of a hearing prosthesis according to one embodiment of the present invention suitable for use with the speech processing unit illustrated in FIG.","1B; FIG.","3 is an exploded perspective view of the embodiment of illustrated in FIG.","2; FIG.","4 is an interface diagram of one embodiment of the speech processor module illustrated in FIG.","1B; FIG.","5 is a functional block of one embodiment of an aspect of the present invention; FIG.","6A is a schematic diagram of the relevant signal and electrical interfaces when the speech processor module shown in FIG.","1B is implemented in a stand-alone operational mode; and FIG.","6B is a schematic of the relevant signal and electrical interfaces when the speech processor module shown in FIG.","1B is implemented in a body-worn operational mode.","DETAILED DESCRIPTION Embodiments of the present invention are directed to a speech processor module which may be implemented in more than one mode of operation of a hearing prosthesis.","Specifically, certain embodiments of the present invention are directed to a speech processor module that can be implemented as a component of in a behind-the-ear (BTE) speech processing unit, and as a component of a body-worn speech processing unit.","The present invention is also directed to an external component system for a hearing prosthesis that enables the dual-mode speech processor module to be worn on the body of a recipient rather than behind the recipient's ear.","Advantageously, certain embodiments of certain aspects of the present invention can be implemented such that the dual-mode speech processor module is protected from adverse environmental conditions, including certain recipients.","For example, in some embodiments described herein, the external component system includes a protective case which protects the speech processor module from infants, small children, mentally handicapped, etc., and/or allows the use of the speech processor module in environments traditionally considered to be unsuitable for prosthetic hearing devices.","As a result, embodiments of the present invention enable hearing prostheses to be worn by a wide range of recipients in a wide range of environments.","Embodiments of the present invention are described below in connection with one embodiment of an exemplary hearing prosthesis, a cochlear prosthesis (also referred to as a cochlear implant system, cochlear prosthetic device and the like; “cochlear implant system” herein).","Cochlear implant systems use direct electrical stimulation of auditory nerve cells to bypass absent or defective hair cells that normally transducer acoustic vibrations into neural activity.","Such devices generally use multi-contact electrodes inserted into the scala tympani of the cochlea so that the electrodes may differentially activate auditory neurons that normally encode differential pitches of sound.","Such devices are also used to treat a smaller number of patients with bilateral degeneration of the auditory nerve.","For such patients, a cochlear implant system provides stimulation of the cochlear nucleus in the brainstem.","FIG.","1A is a schematic diagram of an exemplary cochlear implant system 100 in which embodiments of the present invention may advantageously be implemented.","Cochlear implant system 100 comprises external component assembly 142 which is directly or indirectly attached to the recipient, and an internal component assembly 144 which is temporarily or permanently implanted in the recipient.","External component assembly 142 typically comprises a microphone 120 for detecting sound, a speech processing unit 116, a power source (not shown), and an external transmitter unit 106.External transmitter unit 106 comprises an external coil 108, and preferably, an alignment magnet 110 secured directly or indirectly to external coil 108.Speech processing unit 116 processes the output of microphone 120 that are positioned, in the depicted example, by the ear 122 of the recipient.","Speech processing unit 116 generates coded signals, referred to herein as a stimulation data signals, which are provided to external transmitter unit 106 via cable 118.Internal components 144 comprise an internal receiver unit 112, a stimulator unit 126, and an electrode array 134.Internal receiver unit 112 comprises an internal transcutaneous transfer coil 124, and preferably, an alignment magnet 140 fixed relative to internal coil 124.Internal receiver unit 112 and stimulator unit 126 are hermetically sealed within a housing 128.Internal coil 124 receives power and data from external coil 108.A cable 130 extends from stimulator unit 126 to cochlea 132 and terminates in electrode array 134.Signals generated by stimulator unit 126 are applied by array 134 to the basilar membrane 136, thereby stimulating the auditory nerve 138.Collectively, external coil 108 and internal coil 124 form an inductively-coupled coil system of a transcutaneous transfer apparatus 102.In one embodiment, external coil 108 transmits and receives electrical signals to/from internal coil 124 via a radio frequency (RF) link 114.In use, implantable receiver unit 112 may be positioned in a recess of the temporal bone adjacent ear 122 of the recipient.","As noted, embodiments of the present invention are directed to a speech processor module which may be implemented in more than one mode of operation in a hearing prosthesis such as cochlear implant system 100.FIG.","1B is a perspective view of one embodiment of a dual-mode speech processor module of the present invention.","In this embodiment, the dual-mode speech processor module of the present invention is configured to be used in a behind-the-ear (BTE) speech processing unit 178, similar to speech processing unit 116 illustrated in FIG.","1A.","Behind the ear (BTE) speech processing unit 178 comprises a speech processor module 180 that contains signal processing circuitry (not shown).","A detachable ear hook 182 is provided at one end of speech processor module 180 so as to allow the speech processor to be supported behind the outer ear of the recipient of the cochlear implant system.","A detachable power supply 184 comprising a rechargeable battery or other power source (not shown) is attached to speech processor module 180 to provide power to the module.","Speech processor module 180 utilizes a built-in microphone 186 that generates signals to the signal processing circuitry housed within the speech processor module.","Built-in microphone 186 is also referred to as internal microphone 186 herein.","Speech processor module 180 includes a headpiece connector 188 and an accessories connector 190 to connect to other components of the implementing cochlear implant system or other hearing prosthesis.","In operation, cables with an appropriately configured connector extends from speech processing module 180 to a headpiece and, possible, an accessory device, as described in detail below.","Speech processing unit 178 is configured to operate in a stand-alone manner; that is, as a behind-the-ear (BTE) speech processing unit.","However, speech processing unit 178 is susceptible to damage from rough handling, such as might be experienced when used by infants or small children.","It also may not be suitable for use in adverse environments, such as environments having airborne particulates or significant moisture.","To operate under such conditions, speech processor module 180 can operate in a body-worn mode of operation in an external component system.","One embodiment of an external component system 200 of a hearing prosthesis according to the present invention is depicted in FIGS.","2 and 3.External component system 200 operationally replaces external component assembly 142 of cochlear implant system 100 illustrated in FIG.","1A to convert the cochlear implant system from a prosthesis which may be readily damaged by the recipient and/or environment, to one which is more robust or rugged and, therefore, suitable for use by infants, children, mentally handicapped and other recipients, and/or worn by any recipient in one or more adverse environmental conditions.","In certain embodiments, external component system 200 provides protection for speech processor module 180.In the embodiment shown in FIG.","2, for example, a protective case 202 is included in external component system 200 to house speech processor module 180 and an on-board power supply 216.In certain embodiments, such protection includes protecting these components from ingress of fluid such as water.","In one embodiment, for example, protective case 202 is fluid resistant.","In another embodiment, protective case 202 prevents substantially all fluid ingress, even at elevated atmospheric pressure.","Similarly, in certain embodiments, protective case 202 is at least resistant to the ingress of dust or other particulates such as airborne fumes.","In other embodiments, protective case 202 is capable of providing protection against shocks and vibration, electromagnetic interference (EMI) and other environmental conditions which may adversely affect the operational performance, integrity, and/or lifespan of speech processor module 180.External component system 200 also comprises a one-piece headpiece 208 communicably coupled to speech processor module 180 via a cable 210.As will be described in greater detail below, headpiece 208 comprises the above-noted external transmitter unit 106 including external coil 108, and alignment magnet 110 mounted in a protective housing 220 that provides the same or similar protection of its components as protective case 202.Protective case 202 comprises a base member 204 and a cover member 206 which mechanically mate with each other to form a protective enclosure in which speech processor module 180 is secured.","Protective case 202 also comprises a tray 324 on which speech processor module 180 is removably mounted.","In addition, tray 324 is configured to have on-board power supply 216 mounted adjacent to speech processor module 180 to provide power to the speech processor module as described herein.","These and other components of protective case 202 are described in further detail below.","Referring again to FIG.","1B, speech processor module 180 is configured to be connected to a detachable power supply 184 when implemented in a stand-alone mode; here, as part of a behind the ear speech processing unit 178.When the recipient or their carer wishes speech processor module 180 to be protected by case 202, ear hook 182 and power supply 184 are detached from speech processor module 180, and the speech processor module is mounted on tray 324 of protective case 202.On-board power supply 216 is also mounted on tray 324.Cover member 206 is then secured to base member 204 to provide a sealed enclosure in which speech processor module 180 and on-board power supply 216 are protected.","The resulting external component system 200 is then used in place of the external component assembly 142 illustrated in FIG.","1A.","Protective case 202 is secured to the recipient using, for example, strap(s) threaded through brackets 218.As noted, in one embodiment, an on-board power supply 216 is included in protective case 202 to provide power to speech processor module 180 when the speech processor module is installed in protective case 202.Power supply 216 may be any suitable power supply now or later developed including but not limited to rechargeable batteries.","In one embodiment, on-board power supply 216 implements batteries which are conventional, commercially-available batteries, making them significantly less expensive than detachable power supply 184.Appropriate electrical connections are provided to transfer power from on-board power supply 216 to speech processor module 180.Referring to FIG.","3, speech processor module 180 has one or more connector pins 322 for connecting speech processor module 180 to detachable power supply 184 when implementing the stand-alone operational mode.","It should be appreciated that detachable power supply 184 has a connector (not shown) constructed and arranged to mate with the appropriate pin(s) 322 of speech processor module 180 to transfer power.","As shown in FIGS.","2 and 3, when speech processor module 180 is installed in protective case 202, on-board power supply 216 may not directly contact speech processor module 180.As a result, a connector similar to that implemented in detachable power supply 184 is not used in such embodiments to directly connect on-board power supply 216 to speech processor module 180.Rather, in the illustrative embodiment, a bridge connection is provided in protective case 202 to connect the appropriate pin(s) 322 of speech processor module 180 to terminals 328 of on-board power supply 216.In one embodiment, tray 324 provides the means to electrically connect on-board power supply 216 and speech processor module 180.Tray 324 also comprises apparatus to removably secure an installed power supply 216 and speech processor module 180 to prevent damage to themselves or the other components housed in protective case 202.In the embodiment shown in FIGS.","2 and 3, on-board power supply 216 is retained between a pair of vertical posts 326.Tray 324 also includes appropriately arranged contacts to electrically mate with terminals 328 on power supply 216 when the power supply is mounted on tray 324.In the embodiment shown, power supply 216 has terminals 328 disposed along a corner of the power supply.","Accordingly, tray 324 comprises contacts disposed at the junction of vertical columns 326 and the top surface of tray 324.It should be apparent to those of ordinary skill in the art that the contacts provided in tray 324 to electrically mate with terminals 328 of on-board power supply 216 may be located at any appropriate location and be configured in any way which will achieve a desired electrical connection.","As one of ordinary skill in the art would appreciate, the manner in which on-board power supply 216 is removably mounted on tray 324 can vary depending on a variety of factors including but not limited to the anticipated environment to which external component 200 and, in particular, protective case 202, will be exposed, the weight and mass of power supply 216, the weight distribution of the power supply, etc.","As noted, speech processor module 180 is removably mounted on tray 324.In the embodiment shown in FIG.","3 speech processor module 180 is shown detached from power supply 184 and ear hook 182, exposing pins 322 and raised guide surface 330.Raised guide surface 330 is received by a complementary channel in detachable power supply 184 to cause the power supply to properly mate with pins 322 when the power supply is attached to speech processor module 180.Tray 324 comprises a connector block 332 having in one embodiment, a mechanical and electrical interface similar to that of detachable power supply 184.That is, connector block 332 comprises a connector (not shown constructed and arranged to mate with pins 322 when speech processor 180 is mounted on tray 324.In addition, connector block 332 has an integrated channel 320 configured to slidingly receive raised guide surface 330 of speech processor module 180.To mount speech processor module 180 on tray 324, the speech processor module is positioned such that raised guide surface 330 is aligned with an open end of channel 320.As speech processor module 180 is slid into position, channel 320 and raised guide surface 330 cooperate to facilitate the mating of speech processor module 180 and the connector of connector block 332.In addition, raised guide surface 330 and channel 320 cooperate to securely retain speech processor module 180 to tray 324 when the speech processor module is mounted in protective case 202.It should be appreciated, however, that additional or alternative means may be employed to removably secure speech processor module 180 to tray 324.Embodiments of tray 324 may also include other components to facilitate the removable mounting of speech processor 180.For example, in the embodiment illustrated in FIG.","3, a brace 318 which is curved to abut or be adjacent with a curved surface of speech processor module 180 is provided.","In alternative embodiments, speech processor 180 is securely retained in protective case 324 using other techniques now or later developed.","When speech processor module 180 and on-board power supply 216 are mounted on tray 324, they are electrically connected to each other.","In the embodiment shown in FIGS.","2 and 3, for example, such electrical connection is provided by tray 324 so that additional components need not be included in protective case 202, and additional steps beyond mounting speech processor 180 and power supply 216 are not necessary to attain an electrical connection.","Specifically, wiring connects the power supply contacts (not shown) on tray 324 and the connector (not shown) on connector block 332 which mates with speech processor module 180.Such wiring may be integrated, for example, into platform 336 of tray 324, or may extend below platform 336.In the latter embodiment, tray 324 preferably does not rest in the bottom surface of base member 204; rather, it rests on support members to provide a space between platform 336 and base member 204 when tray 324 is secured to the base member.","As one of ordinary skill in the art would appreciate, the type of electrical connection provided can vary depending on the particular application.","For example, the pins and sockets used to establish the battery connection can be replaced with any other type of electrical connectors.","Also, one pin 322 can provide both the positive and ground connections for transferring power to speech processor module 180.As noted, base member 204 and cover member 206 are attached to each other to provide a protective enclosure for speech processor module 180 and on-board power supply 216.Cover member 206 and base member 204 are configured also to provide the recipient or carer access the enclosure to install or remove speech processor module 180 and power supply 216.In the embodiment shown in FIGS.","2 and 3, for example, cover member 206 is removable; that is, cover member 206 and base member 204 separate from each other to expose the interior of base member 204.It should be appreciated, however, that a portion or all of cover member 206 may be configured, for example, to rotate away from base member 204 to create an aperture through which speech processor module 180 and on-board power supply 216 can be passed.","Such rotation can be provided, for example, with mechanical hinges.","There are, of course, a myriad of other arrangements that may be implemented to provide the noted access.","For example, one or more rotating, sliding, removable, or other types of doors, panels, sides, etc., may be implemented in either or both, cover member 206 and base member 204.Cover member 206 and base member 204 may be formed of any material or combination of materials suitable for the intended recipient and environment.","For example, cover and base members 206, 204 may be formed of metallic material, ceramic material, polymeric material, composites or any combination thereof.","In addition, cover and base members 206, 204 may be opaque, translucent, transparent, etc., to provide a desired view of a desired portion of the interior of protective case 202 from the recipient, carer or third party.","In the exemplary embodiment shown in FIG.","3, protective case 202 contains a gasket 302 to seal protective case 202 when cover member 206 is joined with base member 204.As noted, embodiments of protective case 202 protect components mounted therein from a variety of environmental elements such as fluids, dust, etc.","Gasket 302 is appropriately configured and formed of the appropriate material to provide the desired degree of protection from at least the environmental elements of concern.","In the embodiment shown in FIGS.","2 and 3, gasket 302 is shaped to be disposed between the mating surfaces of cover member 206 and base member 204 when the cover and base are brought together to form protective case 202.Accordingly, gasket 302 takes the shape of the perimeter of protective case 202 at the location that the cover and base members meet.","In one particular embodiment, gasket 302 provides additional protection.","As shown in FIGS.","2 and 3, gasket 302 includes a contiguous sheath 334 of fluid-impermeable, resiliently flexible material extending across the interior of the gasket.","When installed in protective case 202, this embodiment of gasket 302 seals with the perimeter wall of base member 204.This causes sheath 334 to cover speech processor module 180 and power supply 216 mounted in base member 204.Thus, in addition to preventing ingress of at least selected environmental elements, gasket 302 and sheath 334 also protect components from those environmental elements which manage to penetrate protective casing 202.Sheath 334 can be manufactured from polymeric, elastomeric or other suitable materials.","In one embodiment, sheath 334 is transparent.","Protective case 202 comprises a fixation device to removably secure cover member 206 to base member 204.In the embodiment illustrated in FIGS.","2 and 3, such a fixation device comprises a combination of an appropriately located screw and threaded hole.","Specifically, sheath 334 has an orifice 304 formed therein that is adapted to allow passage of a threaded shaft of fixation screw 214 through sheath 334.Similarly, cover member 206 has an orifice 308 adapted to allow passage of the threaded shaft of screw 214.When cover member 206 and sheath 334 are assembled with based member 204, orifice 308 and orifice 304 are aligned with each other.","Screw 214 may then pass through orifice 308 in cover member 206, and orifice 304 in sheath 334 to threadingly engage a threaded hole 310 of a post 312 on tray 324.It should be appreciated by those of ordinary skill in the art that the implemented fixation device should not degrade the integrity of the protective features implemented in protective case 202.For example, in the above embodiment in which a fixation screw 214 is implemented, at the location of screw 214, an elastomeric grommet 314 is provided to help prevent ingress of fluid into the protective case at the site of screw 214.Additionally washers, o-rings and the like may also be used as appropriate.","External component system 200 also comprises a one-piece headpiece 208 communicably coupled to speech processor module 180 via a cable 210.As noted, headpiece 208 comprises the above-noted external transmitter unit 106 including external coil 108, and magnet 110 mounted in a housing 220 that provides the same or similar protection of its components as protective case 202.In accordance with one embodiment of the present invention, headpiece 208 also comprises a second microphone 212 mounted thereon which is operable when speech processor module 180 is installed in protective case 202.When speech processor module 180 is installed in protective case 202, microphone 186 cannot be used since it will be enclosed with protective case 202.As such, external component system 200 provides an alternate or replacement microphone 212, referred to as external microphone 212.Protective case 202 has an additional orifice (not shown) provided in base member 204 to permit cable 210 to be inserted into the case.","Cable 210 extends from headpiece 208 into case 202 to mate with connector 188 of speech processor module 180.The orifice may be sealed, for example, by a grommet 316 provided around the distal end of cable 210.For example, in one embodiment, grommet 316 and orifice are constructed and arranged to prevent water from entering protective case 202.As noted, protective case 202 provides protection for speech processor module 180 and on-board power supply 216.In the embodiments described above, such protection includes protecting the components from ingress of fluid, dust or other particulates such as airborne fumes.","In other embodiments, protective case 202 is capable of providing protection against electromagnetic interference (EMI).","In such embodiments, the interior surfaces of cover member 206 and base member 204 are coated with a conformal EMI coating such as that used in cellular phones, computer systems and other electronic devices that emit or are sensitive to electromagnetic radiation.","In addition, in such embodiments gasket 302 is an EMI gasket suitable for preventing EMI from escaping through the joined surfaces of cover member 206 and base member 204.In other embodiments, protective case 202 protects the components mounted therein from vibration and/or shock.","In such embodiments, tray 324 may be suspended on a shock- and vibration-absorbing material or elements such as resilient posts or extensions disposed in or integrated with base member 204.In addition, the dimensions of tray 324 may be somewhat less than the interior dimensions of protective case 202 to reduce the likelihood of shocks to tray 324 and the components mounted thereon.","FIG.","4 is a schematic interface diagram of one embodiment of speech processor module 180 illustrated in FIGS.","2 and 3.In the embodiment shown in FIG.","4, speech processor module 180 comprises four (4) interfaces, a headpiece interface 402, an accessories interface 404, a power supply interface 406, and a clinical/diagnostic interface 408.Each of the interfaces 402-408 is supported by one or more connectors as described above with references to FIGS.","2 and 3.It should be appreciated by those of ordinary skill in the art, however, that interfaces 402-408 may be implemented in one or more connectors configured differently than that described herein.","Headpiece interface 402 comprises a microphone signal line 410, an RF/telemetry signal line 411, a voltage signal line 412 and a ground signal line 414.In the embodiment shown in FIGS.","2 and 3, these signal lines are included in cable 210 connecting headpiece 208 and speech processor module 180 via connector 188.Accessories interface 404 comprises an input audio signal line 418, an auxiliary voltage input signal line 420, an output audio signal line 422 and a ground signal line 424.These signal lines are transmitted between an accessory device (not shown) and accessories connector 190 of speech processor module 180.Power supply interface 406 comprises a power supply identifier (ID) signal e 426, a voltage signal line 428, and a ground signal line 430.These signal lines are transmitted between one or more pins 322 of speech processor module 180 and either power supply 184 or power supply 216.Clinical/diagnostic interface 408 comprises an alarm signal line 432, data in and out signal lines 434, 436, and a ground signal line 438.These signal lines are transmitted between one or more pins 322 of speech processor module 180 and a diagnostic device or display (not shown).","It should be appreciated that in the embodiment of external component system 200 illustrated in FIGS.","2 and 3, the apertures in protective case 202 which provide access by cables that connect to accessory connector 190 (providing accessory interface 404), and pin(s) 322 (providing clinical interface 408) are not shown.","Such apertures, however, are the same or similar to those described above.","In an alternative embodiment, such interfaces are available only when speech processor module 180 implements the stand-alone mode of operation.","FIG.","5 is a functional block diagram of these components of the present invention which enable speech processor module 180 to transition between stand-alone and a body-worn operational modes.","In FIG.","5 an operational mode controller 500 is implemented in speech processor module 180 to determine which operational mode speech processor module 180 is to implement, and to select the appropriate internal inputs and outputs (that is, provided as part of speech processor module 180) and external inputs and outputs (that is, provided as part of external component system 200) to enable speech processor module 180 to function in the desired operational mode.","FIGS.","6A and 6B are schematic diagrams showing a portion of the interfaces utilized by one embodiment of speech processor module 180 when implemented in both modes of operation.","In FIG.","6A, speech processor module 180 has ear hook 182 and power supply 184 attached to facilitate, in this embodiment, use as a stand-alone behind-the-ear (BTE) speech processing unit 178.Detachable power supply 184 is shown schematically, and contains a rechargeable battery 606 and an identifier resistor 604.Detachable power supply 184 is connected to speech processor module 180 via power supply interface 406.External coil 208, also shown schematically, is connected to speech processor module 180 via headpiece interface 402.It should be appreciated, however, that when in the BTE operating mode, speech processor module 180 does not utilize external microphone 212, and external transmitter unit 106 (FIG.","1A) may be used with speech processor module 180 rather than exterior component system 200.In FIG.","6B, speech processor module 180 is not attached to ear hook 182 and power supply 184.Rather, it is coupled to on-board power supply 216 and an alarm system 524.As will be described in detail below, speech processor module 180 may be connected to a variety of external components implemented in protective case 202 or other components of external component system 200 depending on the implemented functionality.","The embodiment shown in FIG.","6B is just one exemplary implementation.","In addition, external coil 208, also shown schematically, is connected to speech processor module 180 via headpiece interface 402 in the arrangement shown in FIG.","6B.","Returning to FIG.","5, in accordance with one embodiment of the present invention, operation mode controller 500 comprises an operational mode selector 502 that determines which operational mode speech processor module 180 is to implement.","As noted, in the exemplary embodiment described herein, speech processor module 180 may be implemented in a stand-alone mode as illustrated in FIG.","1B, or a body-worn mode of operation as illustrated in FIGS.","2 and 3.Operational mode selector 502 makes the noted determination based on settings or conditions sensed or received by either an external operational mode sensor 504 implemented in protective case 202, or an internal operational mode sensor 506 implemented in speech processor module 180.In one embodiment, the operational mode of speech processor module 180 is determined based on the identification of the power supply that is connected to the speech processor module.","In such an embodiment, each power supply which may be utilized in connection with speech processor module 180 includes some identifying feature.","Information regarding the identifying feature is communicated to speech processor module 180 via power supply identification (ID) signal line 426.In such embodiments, an internal operational mode sensor 506 is implemented to detect the particular identifying feature.","For example, in the embodiment illustrated in FIGS.","6A and 6B, the identifying feature is the value of a resistor included in each power supply.","Referring to FIG.","6A, detachable power supply 184 comprises a resistor 604 and, in this example, a rechargeable battery 606.Resistor 604 identifies power supply 184 as a type of detachable power supply suitable for use when speech processor module 180 implements the stand-alone mode of operation.","Referring to FIG.","6B, on-board power supply 216 comprises a resistor 654 and, in this example, a rechargeable battery 656.Resistor 654 identifies power supply 216 as a type of on-board power supply suitable for use when speech processor module 180 implements the body-worn mode of operation.","In such embodiments, internal operational mode sensor 506 measures the resistance between ID signal line 426 and ground signal line 430 to determine the resistance of resistor 604 or 654.Based on this information, the type of power supply (i.e.","one suitable for use in stand-alone mode verse one suitable for use in body-worn mode), and the desired mode of operation is determined by operational mode selector 502.The operational mode 501 is then distributed to other functional components of controller 500 as described herein.","It should also be appreciated that operational mode sensors 504, 506 may utilize other information to determine the operational mode of speech processor module 180.For example, an externally-accessible switch may be provided on speech processor unit 180 (as part of internal sensor 506) or protective case 202 (as part of external sensor 504) to enable the recipient or another to manually select the operational mode.","When implemented as part of external sensor 504, such a switch is preferably configured to prevent infants and children from changing the operational mode, as well as to prevent accidental changing of the operational mode during the intended use of the body-worn external component system 200.When implemented as part of internal sensor 506, such a switch is inaccessible once speech processor module 180 is mounted in protective case 202 making such safeguards optional.","In another embodiment, external operational mode sensor 504 includes an infrared or other sensor responsive to signals transmitted by a remote control device.","Such an embodiment allows the recipient or their carer to transmit appropriate signals to select the desired operational mode of speech processor module 180.Based on the selected mode of operation 501 generated by operational mode selector 502, a microphone selector 510 of controller 500 selects which microphone to use.","When in the stand-alone mode of operation, internal microphone 186 is utilized, as shown in FIG.","6A.","When implementing the body-worn mode of operation, microphone 212 on headpiece 208 is utilized, as shown in FIG.","6B.","Microphone selector 510 forwards, connects, routes or otherwise provides the selected microphone 511 to other components of speech processor module 180.As one of ordinary skill in the art would appreciate, external microphone 212 may be located elsewhere; however, it is preferable that the external microphone be integrated into headpiece 208 as described herein.","Such an embodiment reduces the quantity of components while also protecting the external microphone.","In the embodiment shown in FIG.","5, speech processor module 180 comprises internal alarm(s) 526 to provide the recipient or another with visual and/or audible indications of predetermined conditions occurring in the speech processor module when the speech processor module implements the stand-alone mode of operations.","Exterior alarm(s) 524 are provided in protective case 202 to provide the same or similar alarms to the recipient or another when speech processor module 180 implements the body-worn mode of operation.","In accordance with one embodiment, operational mode controller 500 comprises an alarm selector 520 that selects whether alarm conditions are to be broadcast using internal alarms 526 or external alarms 524 based on the selected operational mode 501.Referring to FIG.","6B, external alarm(s) 524 is are implemented in protective case 202 and comprises a buzzer 662 that is actuated when an alarm condition 523 is detected.","External alarm(s) 524 incorporate a switch 658 that can be thrown by the recipient or another to generate a deactivate signal 521 to disable the alarm function.","Such a switch is preferably configured to prevent the unintended changing of the state of the alarm.","In one embodiment, external alarm 524 is implemented as part of connector block 332 on tray 324.In an alternative embodiment, external alarm 524 is implemented elsewhere on tray 324 or in protective case 202.It should be understood that the above embodiment of external alarm 524 is a buzzer.","Such an audible alarm may be located at the exterior surface of protective case 202, or may be located internal to protective case 202 with an adjacent aperture in the protective case to permit the sound to travel out of the case and be heard h the recipient.","In such alternative embodiments, such an aperture is constructed and arranged to provide a degree of protection analogous to that implemented in the other components and aspects of body-worn external components 200.It should also be appreciated that the type of alarm may include visual indicators in addition to or instead of the audible alarm noted above.","Alternatively, an audible sound may be injected into the audio path to be heard by only the recipient.","In one embodiment, the type of external alarm (indicator, enunciator, internal audio, etc.","), may be selected by the recipient or another, depending on the recipient and intended use of external components 200.As one of ordinary skill in the art would find apparent, any condition may be selected to be one which qualifies as an alarm condition.","For example, in one embodiment, alarm conditions include when the transcutaneous RF link fails such as by displacement of the external antenna.","In another embodiment, alarm conditions include when protective case 202 is opened.","It should also be appreciated that a hierarchical arrangement of alarm conditions may be established, each having a unique identifying alarm.","Speech processor module 180 comprises an internal display 536 comprising, for example, a liquid crystal display (LCD) and/or one or more LEDs that display performance criteria 531 of the module.","In one embodiment, performance criteria 531 comprises battery charge state, memory state, and/or other criteria.","In one embodiment, such performance criteria is not provided to the recipient when speech processor module 180 is mounted in protective case 202.In an alternative embodiment, a portion of cover member 206 and/or base member 204 are transparent to provide a view into a protective case 202 such that internal display 536 can be seen from a position external to protective case 202.In a further embodiment, illustrated in FIG.","5, protective case 202 provide an external display 534, for example, an LCD display located in cover member 206.A display selector 530 determines whether internal display 536 implemented in speech processor module 180 or external display 534 implemented in protective case 202 is to be used to provide the recipient or another with an indication of the noted performance criteria.","Such a determination is based on selected operational mode 501 generated by operational mode selector 501.Such information may be provided to external display 534 via, for example, data out signal line 436.Speech processor module 180 also comprises internal user controls 546 through which a recipient or another can program or otherwise select functional operating parameters in speech processor module 180.For example, in one embodiment, speech processor module 180 comprises internal user controls 546 which enable, for example, program selection, volume control, etc.","In one embodiment, such user controls are not provided to the recipient when speech processor module 180 is mounted in protective case 202.In a further embodiment, illustrated in FIG.","5, protective case 202 provides external user controls 544 located, for example, in cover member 206 and/or base member 204.A user controls selector 540 determines whether internal user controls 546 of speech processor module 180 or external user controls 544 in protective case 202 are to be utilized to provide the recipient or another with the ability to control speech processor module 180.Such a determination is made based on the operational mode 501 provided by operational mode selector 502.When external user controls 544 is selected (i.e.","speech processor module 180 implements the body-worn mode of operation), the transfer of information from the external interface is provided to selector 540 via, for example, data in signal line 434 (FIG.","4).","The user control inputs 541 generated by the selected user controls 544, 546 are forwarded, routed or otherwise provided to speech processor module 180 by selector 540.Speech processor module 180 includes internal on/off control 556, typically implemented as a manual switch in the housing of the speech processor module which can be manipulated by the recipient or another.","When speech processor module 180 is mounted in protective case 202, internal on/off control 556 is no longer accessible to control the power state of speech processor module 180.In one embodiment, no additional controls are provided.","In such an embodiment, protective case 202 must be opened to provide access to the above-noted on/off switch 556 on speech processor module 180.However, such an embodiment is inconvenient and time consuming to manage.","In addition, repeated access to protective case 202 will accelerate the wearing of gasket 302 or other seal implemented in protective case 202 to provide the above-noted protection.","In another embodiment, shown in FIG.","5, an external on/off control 554 is included in protective case 202 which can be activated without having to access the internal enclosure of the protective case.","In one embodiment, external on/off control 554 includes a reed switch or other magnetically-responsive component implemented in protective case 202.In the illustrated embodiment, the external on/off control 554 generates a signal which is forwarded, routed, passed, regenerated or otherwise provided to a power relay or other component speech processor module 180 to interrupt power to the module.","In an alternate embodiment, the magnetically-responsive component is electrically interposed between on-board power supply 216 and speech processor module 180.In this embodiment, speech processor module 180 is disconnected from the power supply when the magnetic field of a magnet such as alignment magnet 110 within headpiece 208 is brought to a location adjacent to the magnetically-responsive switch.","Other embodiments are also configured to cease operation when transcutaneous RF link has been broken.","For example, in one embodiment, internal on/off control 556 causes speech processor module 180 to periodically transmit an RF signal to implantable components 144, and wait for a response.","When no response is present, speech processor module 180 enters a standby mode or turns off.","If a standby mode is implemented, speech processor module 180 periodically transmits an RF signal while in the standby mode.","If a response is received, speech processor module 180 then fully activates, starts processing sound and retransmits signals to implantable component 144.In another embodiment, external on/off control module 554 can include a manually-activated switch located on the exterior of protective case 202.Such a switch is preferably configured to prevent children from changing the power state, and from accidental changing of the power state during the intended use of the body-worn external components 200.In addition to one or more of the above embodiments, speech processor module 180 can also be adapted to shut down whenever on-board power supply 216 is being charged.","In such an embodiment, protective case 202 also comprises charging circuitry (not shown) to allow power supply 216 to be recharged when case 202 is not in use.","In another embodiment, external on/off control 554 includes an infrared or other sensor responsive to signals transmitted by a remote device operated by the recipient or their carer.","In the case of adults, the present invention provides a recipient with the flexibility of using their speech processor module 180 in a moist environment.","For infants and small children, the present invention also can be used in the comfort that the speech processor is less likely to be damaged than would be the case where the speech processor unit is used in the stand-alone mode.","The case 202 is also potentially advantageous in that it can serve to assist in preventing tampering of speech processor module 180 by a child recipient or a third party."]],"string":"[\n [\n \"TRANSFORMABLE SPEECH PROCESSOR MODULE FOR A HEARING PROSTHESIS\",\n \"A method for operating an external component of a cochlear implant hearing system.\",\n \"The external component includes a speech processor module operable in a stand-alone mode of operation and a body-worn mode of operation, and a protective case.\",\n \"The method includes operating the speech processor module in the stand-alone mode, determining when the speech processor module is mounted in the case, and operating the speech processor module in the body-worn mode in response to determining that the speech processor module is mounted in the case.\"\n ],\n [\n \"1-14.\",\n \"(canceled) 15.An external component of a cochlear implant system, comprising: a speech processor module including processing circuitry configured to receive signals output by a microphone and including a plurality of connectors establishing a power supply interface and at least one of a clinic interface or an accessory interface; and a base member, wherein the speech processor module is operable in a first configuration whereby a cover member is mechanically mated with said base member to establish an enclosure around said speech processor module, thereby substantially preventing any potential fluid ingress that could adversely impact the speech processor module, and wherein said speech processor module is operable in at least a second configuration whereby the cover member is not mechanically mated to the base member.\",\n \"16.The external component of claim 15, wherein: the at least one of the clinic interface or the accessory interface comprises electrical contacts, and the cover creates a battier between the electrical contacts and fluid in an ambient environment when the speech processor module is operated in the first configuration.\",\n \"17.The external component of claim 15, wherein: the speech processor module includes the accessory interface, and wherein an accessory device is configured to be placed into signal communication with the speech processor via the accessory interface.\",\n \"18.The external component of claim 15, wherein: the speech processor module includes the accessory interface, the accessory interface is part of an accessory connector, and wherein an accessory device is configured to connect to the accessory connector when the speech processor module is operated in the second configuration.\",\n \"19.The external component of claim 18, further comprising: the accessory device, wherein the speech processor module is in the second configuration and the accessory device is connected to the accessory connector.\",\n \"20.The external component of claim 18, wherein: the speech processor module includes the accessory interface, the accessory interface is part of an accessory connector; and the external component is configured to prevent connection of the accessory device to the accessory connector when the cover is mechanically connected to the base.\",\n \"21.The external component of claim 15, wherein: the speech processor module includes the accessory interface, the accessory interface is part of an accessory connector; and the external component is configured to enable connection of the accessory device to the accessory connector only when the cover is mechanically disconnected from the base.\",\n \"22.The external component of claim 15, wherein: the speech processor module includes the clinic interface; and the external component is configured to prevent input into the clinic interface when the cover is mechanically connected to the base.\",\n \"23.The external component of claim 15, wherein: the speech processor module includes the clinic interface; and the external component is configured to enable data input into the clinic interface only when the cover is mechanically disconnected from the base.\",\n \"24.A method of utilizing an external component of a cochlear implant hearing system, the external component comprising a speech processor module operable in a stand-alone mode of operation and an external device controlled mode of operation; the method comprising: operating the speech processor module in the stand-alone mode; removably mounting the speech processor module to an apparatus configured to have said speech processor module removably mounted thereto and including external device user controls; determining whether or not to utilize an inputted external volume control setting inputted by a user to the external device user controls of the external device to control the speech processor module; and operating the speech processor in the external device controlled mode.\",\n \"25.The method of claim 24, wherein: the action of determining whether or not to utilize an inputted external volume control setting inputted by a user to the external device user controls of the external device to control the speech processor module includes determining to utilize the inputted external volume control setting inputted by a user to the external device user controls of the external device to control the speech processor module; and the action of operating the speech processor in the external device controlled mode includes operating the speech processor in the external mode after the determination to use the inputted external volume control setting.\",\n \"26.The method of claim 24, wherein: the action of determining whether or not to utilize an inputted external volume control setting inputted by a user to the external device user controls of the external device to control the speech processor module includes determining not to utilize the inputted external volume control setting inputted by a user to the external device user controls of the external device to control the speech processor module; and separate from the action of operating the speech processor in the external device controlled mode, preventing operation of the speech processor in the external device controlled mode after the determination not to use the inputted external volume control setting.\",\n \"27.The method of claim 26, further comprising: separate from determining not to utilize an inputted external volume control setting inputted by a user to the external device user controls of the external device to control the speech processor module, determining to utilize a second inputted external volume control setting inputted by a user to the external device user controls of the external device to control the speech processor module; and separate from the action of operating the speech processor in the external device controlled mode, operating the speech processor in the external device controlled mode after the determination to use the second inputted external volume control setting based on the second inputted external volume control setting.\",\n \"28.The method of claim 24, wherein when the speech processor is operated in the stand alone mode, it is protected from water at elevated atmospheric pressures.\",\n \"29.The method of claim 24, the method further comprising: placing a transcutaneous transfer coil assembly into signal communication with the speech processor, wherein the transcutaneous transfer coil assembly includes a transcutaneous transfer coil and a microphone, wherein the transcutaneous transfer coil assembly is configured to protect the microphone and transfer coil from water at elevated atmospheric pressures.\",\n \"30.A method, comprising: using a first external component assembly of a hearing prosthesis to evoke a first hearing percept by transcutaneously communicating electrical signals from the first external component assembly to an implanted component of the hearing prosthesis such that the implanted component stimulates tissue to evoke the first hearing percept; and after evoking the first hearing percept, replacing the first external component assembly with a second external component assembly to evoke a second hearing percept by transcutaneously communicating electrical signals from the second external component assembly to the implanted component of the hearing prosthesis such that the implanted component stimulates tissue to evoke the second hearing percept, wherein the first external component assembly is one that is readily damaged by water and the second external component assembly is one that is protected from water.\",\n \"31.The method, of claim 30, wherein: the first external component assembly uses a first transcutaneous transfer coil assembly including a first transcutaneous transfer coil and a first cable to transcutaneously communicate with the implanted component; and the second external component uses a second transcutaneous transfer coil assembly including a second transcutaneous transfer coil and a second cable to transcutaneously communicate with the implanted component.\",\n \"32.The method, of claim 30, wherein: the second transcutaneous transfer coil assembly also includes a microphone.\",\n \"33.The method, of claim 30, further comprising: after evoking the first and second hearing percepts, using the first external component assembly to evoke a third hearing percept by transcutaneously communicating electrical signals from the first external component assembly to the implanted component of the hearing prosthesis such that the implanted component stimulates tissue to evoke the third hearing percept.\",\n \"34.The method, of claim 30, wherein: the action of evoking the first hearing percept is executed while the first external component is adjustable via the recipient via a control input device of the first external component; and the action of evoking the second hearing percept is executed while the second external component is unadjustable via the recipient.\",\n \"35.The method, of claim 30, further comprising: prior to evoking the second hearing percept, adjusting a functional operating parameter of the second external component; and after adjusting the functional operating parameter and before evoking the second hearing precept, placing the second external component into a water ingress protection state that results in the functional operating parameter being non-adjustable by a recipient of the hearing prosthesis, and then evoking the second hearing percept.\",\n \"36.The method, of claim 30, wherein: the first external component is in the form of a component that can be worn as a behind-the-ear (BTE) device when evoking the first hearing percept; and the second external component is in the form of a body-worn component different from a BTE device when evoking the second hearing percept.\",\n \"37.The method, of claim 30, wherein: the first external component is in the form of a component that can be worn as a behind-the-ear (BTE) device when evoking the first hearing percept; and the second external component is in the form of a body-worn component that cannot be worn as a BTE device.\",\n \"38.The method, of claim 30, further comprising: prior to evoking the second hearing percept, adjusting a functional operating parameter of a sound processor of the second external component; and after adjusting the functional operating parameter and before evoking the second hearing precept, placing a cover over the sound processor of the second external component such that electrical contacts of the sound processor that would otherwise be exposed to the ambient environment are covered.\",\n \"39.A method, comprising: setting an operating parameter of a speech processor of an external component of a hearing prosthesis, wherein the external component is in a first state; and covering at least a portion of the speech processor with a cover, wherein the external component of the hearing prosthesis is in a second state with the cover on the speech processor, and wherein the operating parameter cannot be changed when the external component is in the second state.\",\n \"40.The method of claim 39, wherein: the first state is a state in which the external component can be damaged by water, and the second state is a state in which the external component is protected from damage by water.\",\n \"41.The method of claim 39, wherein: the external component has no control input apparatuses that are accessible by the recipient of the hearing prosthesis when the cover is on the speech processor.\",\n \"42.The method of claim 39, further comprising: uncovering the at least a portion of the speech processor such that the operating parameter can be changed.\",\n \"43.The method of claim 39, wherein: the operating parameter is a volume.\",\n \"44.The method of claim 39, wherein: user controls that enable the operating parameter to be set are not provided to the recipient of the hearing prosthesis when in the second state.\",\n \"45.The method of claim 39, wherein: the operating parameter is set using user controls available to the recipient of the hearing prosthesis when in the first state; and the user controls that were used to set the operating parameter not provided to the recipient of the hearing prosthesis when in the second state.\",\n \"46.The method of claim 39, further comprising: placing a transcutaneous transfer coil and a microphone into signal communication with the speech processor, wherein the transcutaneous transfer coil assembly includes a housing that provides protection to the microphone from water.\",\n \"47.The external component of claim 15, wherein: a device is configured to connect to the speech processor module when the module is operated in the second configuration; and the external component further comprises the device, wherein the speech processor module is in the second configuration and the device is connected to the module.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>\"\n ],\n [\n \"<SOH> SUMMARY <EOH>In one aspect of the invention, a method for operating an external component of a cochlear implant hearing system is disclosed.\",\n \"The external component comprises a speech processor module is operable in a stand-alone mode of operation and a body-worn mode of operation, and a protective case.\",\n \"The method comprises operating the speech processor module in the stand-alone mode, determining when the speech processor module is mounted in the case, and operating the speech processor module in the body-worn mode in response to determining that the speech processor module is mounted in the case.\",\n \"In another aspect of the invention, a method for operating a cochlear implant hearing system is disclosed.\",\n \"The method comprises operating, in a stand-alone mode of operation, a speech processor module having processing circuitry disposed in a housing, determining, via an operational mode controller, when the speech processor module is mounted in a protective case, and operating the speech processor module in a body-worn mode of operation in response to determining that the speech processor module is mounted in the case.\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation application of U.S. application Ser.\",\n \"No.\",\n \"13/729,485 filed Dec. 28, 2012, which is a continuation application of U.S. application Ser.\",\n \"No.\",\n \"12/703,160 filed Mar.\",\n \"18, 2012, now U.S. Pat.\",\n \"No.\",\n \"8,352,037, which is a divisional of U.S. application Ser.\",\n \"No.\",\n \"10/586,524, filed Oct. 23, 2006, which is a National Stage application of International Application No.\",\n \"PCT/US04/43288, filed Dec. 27, 2004, and which claims the benefit of Australian Provisional Patent Application No.\",\n \"2003907138, filed Dec. 24, 2003.The content of these applications is hereby incorporated by reference herein.\",\n \"BACKGROUND Field of the Invention The present invention relates to a hearing prosthesis and, more particularly, a transformable speech processor module for a hearing prosthesis.\",\n \"Related Art The use of medical devices to provide therapy to individuals for various medical conditions has become more widespread as the advantages and benefits of such devices become more widely appreciated and accepted throughout the population.\",\n \"In particular, devices such as implantable pacemakers, defibrillators, functional electrical stimulation devices such as hearing prostheses, organ assist or replacement devices, and other medical devices, have been successful in performing life saving and/or lifestyle enhancement functions for a number of individuals.\",\n \"Many such medical devices often include one or more sensors, processors, controllers or other functional electrical components that are permanently or temporarily implanted in a patient.\",\n \"Many such implantable devices require the transcutaneous transfer of power and/or information with external components that are part of, or operate in conjunction with, the implanted components of the medical device.\",\n \"Such external components are typically removably attached to the body of the patient.\",\n \"One such type of medical device is a cochlear implant system, also commonly referred to as a cochlear prosthesis.\",\n \"Cochlear implant systems provide the benefit of hear to individuals suffering from severe to profound hearing loss.\",\n \"Hearing loss in such individuals is due to the absence or destruction of the hair cells in the cochlea which transduce acoustic signals into nerve impulses.\",\n \"Cochlear implants essentially simulate the cochlear hair cells by directly delivering electrical stimulation to the auditory nerve fibers.\",\n \"This causes the brain to perceive a hearing sensation resembling the natural hearing sensation normally delivered to the auditory nerve.\",\n \"Conventional cochlear implant systems primarily include an external assembly directly or indirectly attached to the body of the patient (referred to herein as the recipient), and an internal assembly which is implanted in the patient.\",\n \"The external assembly typically comprises one or more microphones for detecting sound, a speech processing unit that converts detected sound, particularly speech, into an electrical coded signal, a power source, and an external transcutaneous transfer coil.\",\n \"The internal assembly typically comprises an internal transcutaneous transfer coil, a stimulator unit located within a recess of the temporal bone of the recipient, and an electrode array positioned in the recipient's cochlear.\",\n \"Collectively, the external coil and the internal coil form an inductively-coupled transcutaneous transfer system.\",\n \"The transfer of energy via this system is controlled to effect the transmission of the electrical coded signals, referred to herein as stimulation signals, and power signals from the external speech processing unit, to the implanted stimulator unit.\",\n \"Similarly, the transcutaneous transfer system may be used to effect the transmission of telemetry data from the implanted stimulator unit to the exterior speech processing unit.\",\n \"Conventionally, the communications link has been in the form of a radio frequency (RF) link, although other such links have been proposed and implemented.\",\n \"Once a stimulation signal has been transmitted to the implanted transcutaneous transfer coil, it is provided to the implanted stimulator unit which processes the signal and outputs one or more signals to the intra-cochlear electrode assembly which applies the electrical stimulation directly to the auditory nerve of the recipient.\",\n \"The speech processor unit has traditionally been worn on the body, such as by being attached to clothing, or by being supported on the ear of the recipient.\",\n \"This latter configuration is commonly referred to as a BTE (behind the ear) configuration.\",\n \"The speech processor unit is relatively expensive and susceptible to damage, especially in the hands of infants or small children, or when used in an unsuitable environment.\",\n \"SUMMARY In one aspect of the invention, a method for operating an external component of a cochlear implant hearing system is disclosed.\",\n \"The external component comprises a speech processor module is operable in a stand-alone mode of operation and a body-worn mode of operation, and a protective case.\",\n \"The method comprises operating the speech processor module in the stand-alone mode, determining when the speech processor module is mounted in the case, and operating the speech processor module in the body-worn mode in response to determining that the speech processor module is mounted in the case.\",\n \"In another aspect of the invention, a method for operating a cochlear implant hearing system is disclosed.\",\n \"The method comprises operating, in a stand-alone mode of operation, a speech processor module having processing circuitry disposed in a housing, determining, via an operational mode controller, when the speech processor module is mounted in a protective case, and operating the speech processor module in a body-worn mode of operation in response to determining that the speech processor module is mounted in the case.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS FIG.\",\n \"1A is a perspective view of one embodiment of a hearing prosthesis in which embodiments of the present invention may be advantageously implemented; FIG.\",\n \"1B is a perspective view of one embodiment of a dual mode speech processing unit in accordance with one embodiment of the present invention; FIG.\",\n \"2 is a perspective view of an external component system of a hearing prosthesis according to one embodiment of the present invention suitable for use with the speech processing unit illustrated in FIG.\",\n \"1B; FIG.\",\n \"3 is an exploded perspective view of the embodiment of illustrated in FIG.\",\n \"2; FIG.\",\n \"4 is an interface diagram of one embodiment of the speech processor module illustrated in FIG.\",\n \"1B; FIG.\",\n \"5 is a functional block of one embodiment of an aspect of the present invention; FIG.\",\n \"6A is a schematic diagram of the relevant signal and electrical interfaces when the speech processor module shown in FIG.\",\n \"1B is implemented in a stand-alone operational mode; and FIG.\",\n \"6B is a schematic of the relevant signal and electrical interfaces when the speech processor module shown in FIG.\",\n \"1B is implemented in a body-worn operational mode.\",\n \"DETAILED DESCRIPTION Embodiments of the present invention are directed to a speech processor module which may be implemented in more than one mode of operation of a hearing prosthesis.\",\n \"Specifically, certain embodiments of the present invention are directed to a speech processor module that can be implemented as a component of in a behind-the-ear (BTE) speech processing unit, and as a component of a body-worn speech processing unit.\",\n \"The present invention is also directed to an external component system for a hearing prosthesis that enables the dual-mode speech processor module to be worn on the body of a recipient rather than behind the recipient's ear.\",\n \"Advantageously, certain embodiments of certain aspects of the present invention can be implemented such that the dual-mode speech processor module is protected from adverse environmental conditions, including certain recipients.\",\n \"For example, in some embodiments described herein, the external component system includes a protective case which protects the speech processor module from infants, small children, mentally handicapped, etc., and/or allows the use of the speech processor module in environments traditionally considered to be unsuitable for prosthetic hearing devices.\",\n \"As a result, embodiments of the present invention enable hearing prostheses to be worn by a wide range of recipients in a wide range of environments.\",\n \"Embodiments of the present invention are described below in connection with one embodiment of an exemplary hearing prosthesis, a cochlear prosthesis (also referred to as a cochlear implant system, cochlear prosthetic device and the like; “cochlear implant system” herein).\",\n \"Cochlear implant systems use direct electrical stimulation of auditory nerve cells to bypass absent or defective hair cells that normally transducer acoustic vibrations into neural activity.\",\n \"Such devices generally use multi-contact electrodes inserted into the scala tympani of the cochlea so that the electrodes may differentially activate auditory neurons that normally encode differential pitches of sound.\",\n \"Such devices are also used to treat a smaller number of patients with bilateral degeneration of the auditory nerve.\",\n \"For such patients, a cochlear implant system provides stimulation of the cochlear nucleus in the brainstem.\",\n \"FIG.\",\n \"1A is a schematic diagram of an exemplary cochlear implant system 100 in which embodiments of the present invention may advantageously be implemented.\",\n \"Cochlear implant system 100 comprises external component assembly 142 which is directly or indirectly attached to the recipient, and an internal component assembly 144 which is temporarily or permanently implanted in the recipient.\",\n \"External component assembly 142 typically comprises a microphone 120 for detecting sound, a speech processing unit 116, a power source (not shown), and an external transmitter unit 106.External transmitter unit 106 comprises an external coil 108, and preferably, an alignment magnet 110 secured directly or indirectly to external coil 108.Speech processing unit 116 processes the output of microphone 120 that are positioned, in the depicted example, by the ear 122 of the recipient.\",\n \"Speech processing unit 116 generates coded signals, referred to herein as a stimulation data signals, which are provided to external transmitter unit 106 via cable 118.Internal components 144 comprise an internal receiver unit 112, a stimulator unit 126, and an electrode array 134.Internal receiver unit 112 comprises an internal transcutaneous transfer coil 124, and preferably, an alignment magnet 140 fixed relative to internal coil 124.Internal receiver unit 112 and stimulator unit 126 are hermetically sealed within a housing 128.Internal coil 124 receives power and data from external coil 108.A cable 130 extends from stimulator unit 126 to cochlea 132 and terminates in electrode array 134.Signals generated by stimulator unit 126 are applied by array 134 to the basilar membrane 136, thereby stimulating the auditory nerve 138.Collectively, external coil 108 and internal coil 124 form an inductively-coupled coil system of a transcutaneous transfer apparatus 102.In one embodiment, external coil 108 transmits and receives electrical signals to/from internal coil 124 via a radio frequency (RF) link 114.In use, implantable receiver unit 112 may be positioned in a recess of the temporal bone adjacent ear 122 of the recipient.\",\n \"As noted, embodiments of the present invention are directed to a speech processor module which may be implemented in more than one mode of operation in a hearing prosthesis such as cochlear implant system 100.FIG.\",\n \"1B is a perspective view of one embodiment of a dual-mode speech processor module of the present invention.\",\n \"In this embodiment, the dual-mode speech processor module of the present invention is configured to be used in a behind-the-ear (BTE) speech processing unit 178, similar to speech processing unit 116 illustrated in FIG.\",\n \"1A.\",\n \"Behind the ear (BTE) speech processing unit 178 comprises a speech processor module 180 that contains signal processing circuitry (not shown).\",\n \"A detachable ear hook 182 is provided at one end of speech processor module 180 so as to allow the speech processor to be supported behind the outer ear of the recipient of the cochlear implant system.\",\n \"A detachable power supply 184 comprising a rechargeable battery or other power source (not shown) is attached to speech processor module 180 to provide power to the module.\",\n \"Speech processor module 180 utilizes a built-in microphone 186 that generates signals to the signal processing circuitry housed within the speech processor module.\",\n \"Built-in microphone 186 is also referred to as internal microphone 186 herein.\",\n \"Speech processor module 180 includes a headpiece connector 188 and an accessories connector 190 to connect to other components of the implementing cochlear implant system or other hearing prosthesis.\",\n \"In operation, cables with an appropriately configured connector extends from speech processing module 180 to a headpiece and, possible, an accessory device, as described in detail below.\",\n \"Speech processing unit 178 is configured to operate in a stand-alone manner; that is, as a behind-the-ear (BTE) speech processing unit.\",\n \"However, speech processing unit 178 is susceptible to damage from rough handling, such as might be experienced when used by infants or small children.\",\n \"It also may not be suitable for use in adverse environments, such as environments having airborne particulates or significant moisture.\",\n \"To operate under such conditions, speech processor module 180 can operate in a body-worn mode of operation in an external component system.\",\n \"One embodiment of an external component system 200 of a hearing prosthesis according to the present invention is depicted in FIGS.\",\n \"2 and 3.External component system 200 operationally replaces external component assembly 142 of cochlear implant system 100 illustrated in FIG.\",\n \"1A to convert the cochlear implant system from a prosthesis which may be readily damaged by the recipient and/or environment, to one which is more robust or rugged and, therefore, suitable for use by infants, children, mentally handicapped and other recipients, and/or worn by any recipient in one or more adverse environmental conditions.\",\n \"In certain embodiments, external component system 200 provides protection for speech processor module 180.In the embodiment shown in FIG.\",\n \"2, for example, a protective case 202 is included in external component system 200 to house speech processor module 180 and an on-board power supply 216.In certain embodiments, such protection includes protecting these components from ingress of fluid such as water.\",\n \"In one embodiment, for example, protective case 202 is fluid resistant.\",\n \"In another embodiment, protective case 202 prevents substantially all fluid ingress, even at elevated atmospheric pressure.\",\n \"Similarly, in certain embodiments, protective case 202 is at least resistant to the ingress of dust or other particulates such as airborne fumes.\",\n \"In other embodiments, protective case 202 is capable of providing protection against shocks and vibration, electromagnetic interference (EMI) and other environmental conditions which may adversely affect the operational performance, integrity, and/or lifespan of speech processor module 180.External component system 200 also comprises a one-piece headpiece 208 communicably coupled to speech processor module 180 via a cable 210.As will be described in greater detail below, headpiece 208 comprises the above-noted external transmitter unit 106 including external coil 108, and alignment magnet 110 mounted in a protective housing 220 that provides the same or similar protection of its components as protective case 202.Protective case 202 comprises a base member 204 and a cover member 206 which mechanically mate with each other to form a protective enclosure in which speech processor module 180 is secured.\",\n \"Protective case 202 also comprises a tray 324 on which speech processor module 180 is removably mounted.\",\n \"In addition, tray 324 is configured to have on-board power supply 216 mounted adjacent to speech processor module 180 to provide power to the speech processor module as described herein.\",\n \"These and other components of protective case 202 are described in further detail below.\",\n \"Referring again to FIG.\",\n \"1B, speech processor module 180 is configured to be connected to a detachable power supply 184 when implemented in a stand-alone mode; here, as part of a behind the ear speech processing unit 178.When the recipient or their carer wishes speech processor module 180 to be protected by case 202, ear hook 182 and power supply 184 are detached from speech processor module 180, and the speech processor module is mounted on tray 324 of protective case 202.On-board power supply 216 is also mounted on tray 324.Cover member 206 is then secured to base member 204 to provide a sealed enclosure in which speech processor module 180 and on-board power supply 216 are protected.\",\n \"The resulting external component system 200 is then used in place of the external component assembly 142 illustrated in FIG.\",\n \"1A.\",\n \"Protective case 202 is secured to the recipient using, for example, strap(s) threaded through brackets 218.As noted, in one embodiment, an on-board power supply 216 is included in protective case 202 to provide power to speech processor module 180 when the speech processor module is installed in protective case 202.Power supply 216 may be any suitable power supply now or later developed including but not limited to rechargeable batteries.\",\n \"In one embodiment, on-board power supply 216 implements batteries which are conventional, commercially-available batteries, making them significantly less expensive than detachable power supply 184.Appropriate electrical connections are provided to transfer power from on-board power supply 216 to speech processor module 180.Referring to FIG.\",\n \"3, speech processor module 180 has one or more connector pins 322 for connecting speech processor module 180 to detachable power supply 184 when implementing the stand-alone operational mode.\",\n \"It should be appreciated that detachable power supply 184 has a connector (not shown) constructed and arranged to mate with the appropriate pin(s) 322 of speech processor module 180 to transfer power.\",\n \"As shown in FIGS.\",\n \"2 and 3, when speech processor module 180 is installed in protective case 202, on-board power supply 216 may not directly contact speech processor module 180.As a result, a connector similar to that implemented in detachable power supply 184 is not used in such embodiments to directly connect on-board power supply 216 to speech processor module 180.Rather, in the illustrative embodiment, a bridge connection is provided in protective case 202 to connect the appropriate pin(s) 322 of speech processor module 180 to terminals 328 of on-board power supply 216.In one embodiment, tray 324 provides the means to electrically connect on-board power supply 216 and speech processor module 180.Tray 324 also comprises apparatus to removably secure an installed power supply 216 and speech processor module 180 to prevent damage to themselves or the other components housed in protective case 202.In the embodiment shown in FIGS.\",\n \"2 and 3, on-board power supply 216 is retained between a pair of vertical posts 326.Tray 324 also includes appropriately arranged contacts to electrically mate with terminals 328 on power supply 216 when the power supply is mounted on tray 324.In the embodiment shown, power supply 216 has terminals 328 disposed along a corner of the power supply.\",\n \"Accordingly, tray 324 comprises contacts disposed at the junction of vertical columns 326 and the top surface of tray 324.It should be apparent to those of ordinary skill in the art that the contacts provided in tray 324 to electrically mate with terminals 328 of on-board power supply 216 may be located at any appropriate location and be configured in any way which will achieve a desired electrical connection.\",\n \"As one of ordinary skill in the art would appreciate, the manner in which on-board power supply 216 is removably mounted on tray 324 can vary depending on a variety of factors including but not limited to the anticipated environment to which external component 200 and, in particular, protective case 202, will be exposed, the weight and mass of power supply 216, the weight distribution of the power supply, etc.\",\n \"As noted, speech processor module 180 is removably mounted on tray 324.In the embodiment shown in FIG.\",\n \"3 speech processor module 180 is shown detached from power supply 184 and ear hook 182, exposing pins 322 and raised guide surface 330.Raised guide surface 330 is received by a complementary channel in detachable power supply 184 to cause the power supply to properly mate with pins 322 when the power supply is attached to speech processor module 180.Tray 324 comprises a connector block 332 having in one embodiment, a mechanical and electrical interface similar to that of detachable power supply 184.That is, connector block 332 comprises a connector (not shown constructed and arranged to mate with pins 322 when speech processor 180 is mounted on tray 324.In addition, connector block 332 has an integrated channel 320 configured to slidingly receive raised guide surface 330 of speech processor module 180.To mount speech processor module 180 on tray 324, the speech processor module is positioned such that raised guide surface 330 is aligned with an open end of channel 320.As speech processor module 180 is slid into position, channel 320 and raised guide surface 330 cooperate to facilitate the mating of speech processor module 180 and the connector of connector block 332.In addition, raised guide surface 330 and channel 320 cooperate to securely retain speech processor module 180 to tray 324 when the speech processor module is mounted in protective case 202.It should be appreciated, however, that additional or alternative means may be employed to removably secure speech processor module 180 to tray 324.Embodiments of tray 324 may also include other components to facilitate the removable mounting of speech processor 180.For example, in the embodiment illustrated in FIG.\",\n \"3, a brace 318 which is curved to abut or be adjacent with a curved surface of speech processor module 180 is provided.\",\n \"In alternative embodiments, speech processor 180 is securely retained in protective case 324 using other techniques now or later developed.\",\n \"When speech processor module 180 and on-board power supply 216 are mounted on tray 324, they are electrically connected to each other.\",\n \"In the embodiment shown in FIGS.\",\n \"2 and 3, for example, such electrical connection is provided by tray 324 so that additional components need not be included in protective case 202, and additional steps beyond mounting speech processor 180 and power supply 216 are not necessary to attain an electrical connection.\",\n \"Specifically, wiring connects the power supply contacts (not shown) on tray 324 and the connector (not shown) on connector block 332 which mates with speech processor module 180.Such wiring may be integrated, for example, into platform 336 of tray 324, or may extend below platform 336.In the latter embodiment, tray 324 preferably does not rest in the bottom surface of base member 204; rather, it rests on support members to provide a space between platform 336 and base member 204 when tray 324 is secured to the base member.\",\n \"As one of ordinary skill in the art would appreciate, the type of electrical connection provided can vary depending on the particular application.\",\n \"For example, the pins and sockets used to establish the battery connection can be replaced with any other type of electrical connectors.\",\n \"Also, one pin 322 can provide both the positive and ground connections for transferring power to speech processor module 180.As noted, base member 204 and cover member 206 are attached to each other to provide a protective enclosure for speech processor module 180 and on-board power supply 216.Cover member 206 and base member 204 are configured also to provide the recipient or carer access the enclosure to install or remove speech processor module 180 and power supply 216.In the embodiment shown in FIGS.\",\n \"2 and 3, for example, cover member 206 is removable; that is, cover member 206 and base member 204 separate from each other to expose the interior of base member 204.It should be appreciated, however, that a portion or all of cover member 206 may be configured, for example, to rotate away from base member 204 to create an aperture through which speech processor module 180 and on-board power supply 216 can be passed.\",\n \"Such rotation can be provided, for example, with mechanical hinges.\",\n \"There are, of course, a myriad of other arrangements that may be implemented to provide the noted access.\",\n \"For example, one or more rotating, sliding, removable, or other types of doors, panels, sides, etc., may be implemented in either or both, cover member 206 and base member 204.Cover member 206 and base member 204 may be formed of any material or combination of materials suitable for the intended recipient and environment.\",\n \"For example, cover and base members 206, 204 may be formed of metallic material, ceramic material, polymeric material, composites or any combination thereof.\",\n \"In addition, cover and base members 206, 204 may be opaque, translucent, transparent, etc., to provide a desired view of a desired portion of the interior of protective case 202 from the recipient, carer or third party.\",\n \"In the exemplary embodiment shown in FIG.\",\n \"3, protective case 202 contains a gasket 302 to seal protective case 202 when cover member 206 is joined with base member 204.As noted, embodiments of protective case 202 protect components mounted therein from a variety of environmental elements such as fluids, dust, etc.\",\n \"Gasket 302 is appropriately configured and formed of the appropriate material to provide the desired degree of protection from at least the environmental elements of concern.\",\n \"In the embodiment shown in FIGS.\",\n \"2 and 3, gasket 302 is shaped to be disposed between the mating surfaces of cover member 206 and base member 204 when the cover and base are brought together to form protective case 202.Accordingly, gasket 302 takes the shape of the perimeter of protective case 202 at the location that the cover and base members meet.\",\n \"In one particular embodiment, gasket 302 provides additional protection.\",\n \"As shown in FIGS.\",\n \"2 and 3, gasket 302 includes a contiguous sheath 334 of fluid-impermeable, resiliently flexible material extending across the interior of the gasket.\",\n \"When installed in protective case 202, this embodiment of gasket 302 seals with the perimeter wall of base member 204.This causes sheath 334 to cover speech processor module 180 and power supply 216 mounted in base member 204.Thus, in addition to preventing ingress of at least selected environmental elements, gasket 302 and sheath 334 also protect components from those environmental elements which manage to penetrate protective casing 202.Sheath 334 can be manufactured from polymeric, elastomeric or other suitable materials.\",\n \"In one embodiment, sheath 334 is transparent.\",\n \"Protective case 202 comprises a fixation device to removably secure cover member 206 to base member 204.In the embodiment illustrated in FIGS.\",\n \"2 and 3, such a fixation device comprises a combination of an appropriately located screw and threaded hole.\",\n \"Specifically, sheath 334 has an orifice 304 formed therein that is adapted to allow passage of a threaded shaft of fixation screw 214 through sheath 334.Similarly, cover member 206 has an orifice 308 adapted to allow passage of the threaded shaft of screw 214.When cover member 206 and sheath 334 are assembled with based member 204, orifice 308 and orifice 304 are aligned with each other.\",\n \"Screw 214 may then pass through orifice 308 in cover member 206, and orifice 304 in sheath 334 to threadingly engage a threaded hole 310 of a post 312 on tray 324.It should be appreciated by those of ordinary skill in the art that the implemented fixation device should not degrade the integrity of the protective features implemented in protective case 202.For example, in the above embodiment in which a fixation screw 214 is implemented, at the location of screw 214, an elastomeric grommet 314 is provided to help prevent ingress of fluid into the protective case at the site of screw 214.Additionally washers, o-rings and the like may also be used as appropriate.\",\n \"External component system 200 also comprises a one-piece headpiece 208 communicably coupled to speech processor module 180 via a cable 210.As noted, headpiece 208 comprises the above-noted external transmitter unit 106 including external coil 108, and magnet 110 mounted in a housing 220 that provides the same or similar protection of its components as protective case 202.In accordance with one embodiment of the present invention, headpiece 208 also comprises a second microphone 212 mounted thereon which is operable when speech processor module 180 is installed in protective case 202.When speech processor module 180 is installed in protective case 202, microphone 186 cannot be used since it will be enclosed with protective case 202.As such, external component system 200 provides an alternate or replacement microphone 212, referred to as external microphone 212.Protective case 202 has an additional orifice (not shown) provided in base member 204 to permit cable 210 to be inserted into the case.\",\n \"Cable 210 extends from headpiece 208 into case 202 to mate with connector 188 of speech processor module 180.The orifice may be sealed, for example, by a grommet 316 provided around the distal end of cable 210.For example, in one embodiment, grommet 316 and orifice are constructed and arranged to prevent water from entering protective case 202.As noted, protective case 202 provides protection for speech processor module 180 and on-board power supply 216.In the embodiments described above, such protection includes protecting the components from ingress of fluid, dust or other particulates such as airborne fumes.\",\n \"In other embodiments, protective case 202 is capable of providing protection against electromagnetic interference (EMI).\",\n \"In such embodiments, the interior surfaces of cover member 206 and base member 204 are coated with a conformal EMI coating such as that used in cellular phones, computer systems and other electronic devices that emit or are sensitive to electromagnetic radiation.\",\n \"In addition, in such embodiments gasket 302 is an EMI gasket suitable for preventing EMI from escaping through the joined surfaces of cover member 206 and base member 204.In other embodiments, protective case 202 protects the components mounted therein from vibration and/or shock.\",\n \"In such embodiments, tray 324 may be suspended on a shock- and vibration-absorbing material or elements such as resilient posts or extensions disposed in or integrated with base member 204.In addition, the dimensions of tray 324 may be somewhat less than the interior dimensions of protective case 202 to reduce the likelihood of shocks to tray 324 and the components mounted thereon.\",\n \"FIG.\",\n \"4 is a schematic interface diagram of one embodiment of speech processor module 180 illustrated in FIGS.\",\n \"2 and 3.In the embodiment shown in FIG.\",\n \"4, speech processor module 180 comprises four (4) interfaces, a headpiece interface 402, an accessories interface 404, a power supply interface 406, and a clinical/diagnostic interface 408.Each of the interfaces 402-408 is supported by one or more connectors as described above with references to FIGS.\",\n \"2 and 3.It should be appreciated by those of ordinary skill in the art, however, that interfaces 402-408 may be implemented in one or more connectors configured differently than that described herein.\",\n \"Headpiece interface 402 comprises a microphone signal line 410, an RF/telemetry signal line 411, a voltage signal line 412 and a ground signal line 414.In the embodiment shown in FIGS.\",\n \"2 and 3, these signal lines are included in cable 210 connecting headpiece 208 and speech processor module 180 via connector 188.Accessories interface 404 comprises an input audio signal line 418, an auxiliary voltage input signal line 420, an output audio signal line 422 and a ground signal line 424.These signal lines are transmitted between an accessory device (not shown) and accessories connector 190 of speech processor module 180.Power supply interface 406 comprises a power supply identifier (ID) signal e 426, a voltage signal line 428, and a ground signal line 430.These signal lines are transmitted between one or more pins 322 of speech processor module 180 and either power supply 184 or power supply 216.Clinical/diagnostic interface 408 comprises an alarm signal line 432, data in and out signal lines 434, 436, and a ground signal line 438.These signal lines are transmitted between one or more pins 322 of speech processor module 180 and a diagnostic device or display (not shown).\",\n \"It should be appreciated that in the embodiment of external component system 200 illustrated in FIGS.\",\n \"2 and 3, the apertures in protective case 202 which provide access by cables that connect to accessory connector 190 (providing accessory interface 404), and pin(s) 322 (providing clinical interface 408) are not shown.\",\n \"Such apertures, however, are the same or similar to those described above.\",\n \"In an alternative embodiment, such interfaces are available only when speech processor module 180 implements the stand-alone mode of operation.\",\n \"FIG.\",\n \"5 is a functional block diagram of these components of the present invention which enable speech processor module 180 to transition between stand-alone and a body-worn operational modes.\",\n \"In FIG.\",\n \"5 an operational mode controller 500 is implemented in speech processor module 180 to determine which operational mode speech processor module 180 is to implement, and to select the appropriate internal inputs and outputs (that is, provided as part of speech processor module 180) and external inputs and outputs (that is, provided as part of external component system 200) to enable speech processor module 180 to function in the desired operational mode.\",\n \"FIGS.\",\n \"6A and 6B are schematic diagrams showing a portion of the interfaces utilized by one embodiment of speech processor module 180 when implemented in both modes of operation.\",\n \"In FIG.\",\n \"6A, speech processor module 180 has ear hook 182 and power supply 184 attached to facilitate, in this embodiment, use as a stand-alone behind-the-ear (BTE) speech processing unit 178.Detachable power supply 184 is shown schematically, and contains a rechargeable battery 606 and an identifier resistor 604.Detachable power supply 184 is connected to speech processor module 180 via power supply interface 406.External coil 208, also shown schematically, is connected to speech processor module 180 via headpiece interface 402.It should be appreciated, however, that when in the BTE operating mode, speech processor module 180 does not utilize external microphone 212, and external transmitter unit 106 (FIG.\",\n \"1A) may be used with speech processor module 180 rather than exterior component system 200.In FIG.\",\n \"6B, speech processor module 180 is not attached to ear hook 182 and power supply 184.Rather, it is coupled to on-board power supply 216 and an alarm system 524.As will be described in detail below, speech processor module 180 may be connected to a variety of external components implemented in protective case 202 or other components of external component system 200 depending on the implemented functionality.\",\n \"The embodiment shown in FIG.\",\n \"6B is just one exemplary implementation.\",\n \"In addition, external coil 208, also shown schematically, is connected to speech processor module 180 via headpiece interface 402 in the arrangement shown in FIG.\",\n \"6B.\",\n \"Returning to FIG.\",\n \"5, in accordance with one embodiment of the present invention, operation mode controller 500 comprises an operational mode selector 502 that determines which operational mode speech processor module 180 is to implement.\",\n \"As noted, in the exemplary embodiment described herein, speech processor module 180 may be implemented in a stand-alone mode as illustrated in FIG.\",\n \"1B, or a body-worn mode of operation as illustrated in FIGS.\",\n \"2 and 3.Operational mode selector 502 makes the noted determination based on settings or conditions sensed or received by either an external operational mode sensor 504 implemented in protective case 202, or an internal operational mode sensor 506 implemented in speech processor module 180.In one embodiment, the operational mode of speech processor module 180 is determined based on the identification of the power supply that is connected to the speech processor module.\",\n \"In such an embodiment, each power supply which may be utilized in connection with speech processor module 180 includes some identifying feature.\",\n \"Information regarding the identifying feature is communicated to speech processor module 180 via power supply identification (ID) signal line 426.In such embodiments, an internal operational mode sensor 506 is implemented to detect the particular identifying feature.\",\n \"For example, in the embodiment illustrated in FIGS.\",\n \"6A and 6B, the identifying feature is the value of a resistor included in each power supply.\",\n \"Referring to FIG.\",\n \"6A, detachable power supply 184 comprises a resistor 604 and, in this example, a rechargeable battery 606.Resistor 604 identifies power supply 184 as a type of detachable power supply suitable for use when speech processor module 180 implements the stand-alone mode of operation.\",\n \"Referring to FIG.\",\n \"6B, on-board power supply 216 comprises a resistor 654 and, in this example, a rechargeable battery 656.Resistor 654 identifies power supply 216 as a type of on-board power supply suitable for use when speech processor module 180 implements the body-worn mode of operation.\",\n \"In such embodiments, internal operational mode sensor 506 measures the resistance between ID signal line 426 and ground signal line 430 to determine the resistance of resistor 604 or 654.Based on this information, the type of power supply (i.e.\",\n \"one suitable for use in stand-alone mode verse one suitable for use in body-worn mode), and the desired mode of operation is determined by operational mode selector 502.The operational mode 501 is then distributed to other functional components of controller 500 as described herein.\",\n \"It should also be appreciated that operational mode sensors 504, 506 may utilize other information to determine the operational mode of speech processor module 180.For example, an externally-accessible switch may be provided on speech processor unit 180 (as part of internal sensor 506) or protective case 202 (as part of external sensor 504) to enable the recipient or another to manually select the operational mode.\",\n \"When implemented as part of external sensor 504, such a switch is preferably configured to prevent infants and children from changing the operational mode, as well as to prevent accidental changing of the operational mode during the intended use of the body-worn external component system 200.When implemented as part of internal sensor 506, such a switch is inaccessible once speech processor module 180 is mounted in protective case 202 making such safeguards optional.\",\n \"In another embodiment, external operational mode sensor 504 includes an infrared or other sensor responsive to signals transmitted by a remote control device.\",\n \"Such an embodiment allows the recipient or their carer to transmit appropriate signals to select the desired operational mode of speech processor module 180.Based on the selected mode of operation 501 generated by operational mode selector 502, a microphone selector 510 of controller 500 selects which microphone to use.\",\n \"When in the stand-alone mode of operation, internal microphone 186 is utilized, as shown in FIG.\",\n \"6A.\",\n \"When implementing the body-worn mode of operation, microphone 212 on headpiece 208 is utilized, as shown in FIG.\",\n \"6B.\",\n \"Microphone selector 510 forwards, connects, routes or otherwise provides the selected microphone 511 to other components of speech processor module 180.As one of ordinary skill in the art would appreciate, external microphone 212 may be located elsewhere; however, it is preferable that the external microphone be integrated into headpiece 208 as described herein.\",\n \"Such an embodiment reduces the quantity of components while also protecting the external microphone.\",\n \"In the embodiment shown in FIG.\",\n \"5, speech processor module 180 comprises internal alarm(s) 526 to provide the recipient or another with visual and/or audible indications of predetermined conditions occurring in the speech processor module when the speech processor module implements the stand-alone mode of operations.\",\n \"Exterior alarm(s) 524 are provided in protective case 202 to provide the same or similar alarms to the recipient or another when speech processor module 180 implements the body-worn mode of operation.\",\n \"In accordance with one embodiment, operational mode controller 500 comprises an alarm selector 520 that selects whether alarm conditions are to be broadcast using internal alarms 526 or external alarms 524 based on the selected operational mode 501.Referring to FIG.\",\n \"6B, external alarm(s) 524 is are implemented in protective case 202 and comprises a buzzer 662 that is actuated when an alarm condition 523 is detected.\",\n \"External alarm(s) 524 incorporate a switch 658 that can be thrown by the recipient or another to generate a deactivate signal 521 to disable the alarm function.\",\n \"Such a switch is preferably configured to prevent the unintended changing of the state of the alarm.\",\n \"In one embodiment, external alarm 524 is implemented as part of connector block 332 on tray 324.In an alternative embodiment, external alarm 524 is implemented elsewhere on tray 324 or in protective case 202.It should be understood that the above embodiment of external alarm 524 is a buzzer.\",\n \"Such an audible alarm may be located at the exterior surface of protective case 202, or may be located internal to protective case 202 with an adjacent aperture in the protective case to permit the sound to travel out of the case and be heard h the recipient.\",\n \"In such alternative embodiments, such an aperture is constructed and arranged to provide a degree of protection analogous to that implemented in the other components and aspects of body-worn external components 200.It should also be appreciated that the type of alarm may include visual indicators in addition to or instead of the audible alarm noted above.\",\n \"Alternatively, an audible sound may be injected into the audio path to be heard by only the recipient.\",\n \"In one embodiment, the type of external alarm (indicator, enunciator, internal audio, etc.\",\n \"), may be selected by the recipient or another, depending on the recipient and intended use of external components 200.As one of ordinary skill in the art would find apparent, any condition may be selected to be one which qualifies as an alarm condition.\",\n \"For example, in one embodiment, alarm conditions include when the transcutaneous RF link fails such as by displacement of the external antenna.\",\n \"In another embodiment, alarm conditions include when protective case 202 is opened.\",\n \"It should also be appreciated that a hierarchical arrangement of alarm conditions may be established, each having a unique identifying alarm.\",\n \"Speech processor module 180 comprises an internal display 536 comprising, for example, a liquid crystal display (LCD) and/or one or more LEDs that display performance criteria 531 of the module.\",\n \"In one embodiment, performance criteria 531 comprises battery charge state, memory state, and/or other criteria.\",\n \"In one embodiment, such performance criteria is not provided to the recipient when speech processor module 180 is mounted in protective case 202.In an alternative embodiment, a portion of cover member 206 and/or base member 204 are transparent to provide a view into a protective case 202 such that internal display 536 can be seen from a position external to protective case 202.In a further embodiment, illustrated in FIG.\",\n \"5, protective case 202 provide an external display 534, for example, an LCD display located in cover member 206.A display selector 530 determines whether internal display 536 implemented in speech processor module 180 or external display 534 implemented in protective case 202 is to be used to provide the recipient or another with an indication of the noted performance criteria.\",\n \"Such a determination is based on selected operational mode 501 generated by operational mode selector 501.Such information may be provided to external display 534 via, for example, data out signal line 436.Speech processor module 180 also comprises internal user controls 546 through which a recipient or another can program or otherwise select functional operating parameters in speech processor module 180.For example, in one embodiment, speech processor module 180 comprises internal user controls 546 which enable, for example, program selection, volume control, etc.\",\n \"In one embodiment, such user controls are not provided to the recipient when speech processor module 180 is mounted in protective case 202.In a further embodiment, illustrated in FIG.\",\n \"5, protective case 202 provides external user controls 544 located, for example, in cover member 206 and/or base member 204.A user controls selector 540 determines whether internal user controls 546 of speech processor module 180 or external user controls 544 in protective case 202 are to be utilized to provide the recipient or another with the ability to control speech processor module 180.Such a determination is made based on the operational mode 501 provided by operational mode selector 502.When external user controls 544 is selected (i.e.\",\n \"speech processor module 180 implements the body-worn mode of operation), the transfer of information from the external interface is provided to selector 540 via, for example, data in signal line 434 (FIG.\",\n \"4).\",\n \"The user control inputs 541 generated by the selected user controls 544, 546 are forwarded, routed or otherwise provided to speech processor module 180 by selector 540.Speech processor module 180 includes internal on/off control 556, typically implemented as a manual switch in the housing of the speech processor module which can be manipulated by the recipient or another.\",\n \"When speech processor module 180 is mounted in protective case 202, internal on/off control 556 is no longer accessible to control the power state of speech processor module 180.In one embodiment, no additional controls are provided.\",\n \"In such an embodiment, protective case 202 must be opened to provide access to the above-noted on/off switch 556 on speech processor module 180.However, such an embodiment is inconvenient and time consuming to manage.\",\n \"In addition, repeated access to protective case 202 will accelerate the wearing of gasket 302 or other seal implemented in protective case 202 to provide the above-noted protection.\",\n \"In another embodiment, shown in FIG.\",\n \"5, an external on/off control 554 is included in protective case 202 which can be activated without having to access the internal enclosure of the protective case.\",\n \"In one embodiment, external on/off control 554 includes a reed switch or other magnetically-responsive component implemented in protective case 202.In the illustrated embodiment, the external on/off control 554 generates a signal which is forwarded, routed, passed, regenerated or otherwise provided to a power relay or other component speech processor module 180 to interrupt power to the module.\",\n \"In an alternate embodiment, the magnetically-responsive component is electrically interposed between on-board power supply 216 and speech processor module 180.In this embodiment, speech processor module 180 is disconnected from the power supply when the magnetic field of a magnet such as alignment magnet 110 within headpiece 208 is brought to a location adjacent to the magnetically-responsive switch.\",\n \"Other embodiments are also configured to cease operation when transcutaneous RF link has been broken.\",\n \"For example, in one embodiment, internal on/off control 556 causes speech processor module 180 to periodically transmit an RF signal to implantable components 144, and wait for a response.\",\n \"When no response is present, speech processor module 180 enters a standby mode or turns off.\",\n \"If a standby mode is implemented, speech processor module 180 periodically transmits an RF signal while in the standby mode.\",\n \"If a response is received, speech processor module 180 then fully activates, starts processing sound and retransmits signals to implantable component 144.In another embodiment, external on/off control module 554 can include a manually-activated switch located on the exterior of protective case 202.Such a switch is preferably configured to prevent children from changing the power state, and from accidental changing of the power state during the intended use of the body-worn external components 200.In addition to one or more of the above embodiments, speech processor module 180 can also be adapted to shut down whenever on-board power supply 216 is being charged.\",\n \"In such an embodiment, protective case 202 also comprises charging circuitry (not shown) to allow power supply 216 to be recharged when case 202 is not in use.\",\n \"In another embodiment, external on/off control 554 includes an infrared or other sensor responsive to signals transmitted by a remote device operated by the recipient or their carer.\",\n \"In the case of adults, the present invention provides a recipient with the flexibility of using their speech processor module 180 in a moist environment.\",\n \"For infants and small children, the present invention also can be used in the comfort that the speech processor is less likely to be damaged than would be the case where the speech processor unit is used in the stand-alone mode.\",\n \"The case 202 is also potentially advantageous in that it can serve to assist in preventing tampering of speech processor module 180 by a child recipient or a third party.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875780"}}},{"rowIdx":4494976,"cells":{"text":{"kind":"list like","value":[["Wide Swath Offset Concrete Screed","Methods and systems for making and using a wide swath offset concrete screed apparatus for screeding wet concrete slurry.","The apparatus includes a cross support bar, an attachment mechanism for attaching the cross support bar to a liftable arm of a motorized vehicle, and a roller screed attached to the cross support bar.","The roller screed is positioned offset from the motorized vehicle used to operate the screed, allowing the motorized vehicle to drive outside the forms."],["1.An offset concrete screed apparatus for screeding wet concrete slurry, comprising: a cross support bar; means for attaching the cross support bar of the offset concrete screed apparatus to a liftable arm of a motorized vehicle; a roller screed attached to the offset concrete screed apparatus, the roller screed being configured to come in contact with the wet concrete slurry in response to the liftable arm of the motorized vehicle being lowered; and a power unit attached to the offset concrete screed apparatus, the power unit being configured to controllably rotate the roller screed; wherein the roller screed is positioned offset from the motorized vehicle allowing the motorized vehicle to be driven outside forms containing the wet concrete slurry during the screeding.","2.The offset concrete screed apparatus of claim 1, further comprising: a roller support structure configured to attach the roller screed to the offset concrete screed apparatus; and means for reducing mechanical friction between the roller support structure and the roller screed.","3.The offset concrete screed apparatus of claim 1, further comprising: one or more lateral support bars attached between the roller screed and the cross support bar; wherein the one or more lateral support bars hinge downward by no more than a predetermined amount from horizontal, defined as a support bar angle, wherein the support bar angle is no less than 3 degrees and no greater than 45 degrees; and wherein the roller support structure is positioned above the roller screed.","4.The offset concrete screed apparatus of claim 3, wherein the support bar angle is no less than 5 degrees and no greater than 25 degrees.","5.The offset concrete screed apparatus of claim 1, wherein the power unit is an electric motor.","6.The offset concrete screed apparatus of claim 1, further comprising: a screed bar attached to one or more lateral support bars; wherein the roller screed is attached to the screed bar.","7.The offset concrete screed apparatus of claim 6, further comprising: a screed bar spacer configured to be affixed to an end of the screed bar adjacent a surface of a previously poured concrete swath, the previously poured concrete swath being used as one of the forms for containing the wet concrete slurry during the screeding; wherein the screed bar spacer has a predetermined thickness of at least ⅛ inch but no great than ⅜ inch to compensate for the screeding process delta.","8.The offset concrete screed apparatus of claim 6 for screeding the wet concrete slurry into a concrete pad of a predetermined thickness, further comprising: a subgrade screeder attachment configured to be removably attached to the screed bar; wherein the subgrade screeder attachment extends below the underside of the screed bar by a depth equal to the predetermined thickness.","9.A method of screeding wet concrete slurry with an offset concrete screed apparatus, the method comprising: attaching a cross support bar of the offset concrete screed apparatus to a liftable arm of a motorized vehicle; attaching a roller screed to the offset concrete screed apparatus; attaching a power unit to the roller screed; controlling the power unit to rotate the roller screed; lowering the liftable arm of the motorized vehicle until the roller screed comes in contact with the wet concrete slurry; and driving the motorized vehicle forward to screed the wet concrete slurry; wherein the roller screed is positioned offset from the motorized vehicle allowing the motorized vehicle to be driven outside forms containing the wet concrete slurry during the screeding.","10.The method of claim 9, further comprising: providing a roller support structure to attach the roller screed to the offset concrete screed apparatus; and providing mechanical structure for reducing mechanical friction between the roller support structure and the roller screed.","11.The method of claim 9, further comprising: hinging one or more lateral support bars downward by no more than a predetermined amount from horizontal, defined as a support bar angle, wherein the support bar angle is no less than 5degrees and no greater than 25 degrees; and attaching the roller screed to the offset concrete screed apparatus with the one or more lateral support bars.","12.The method of claim 9, wherein the power unit is an electric motor.","13.The method of claim 9, further comprising: attaching a screed bar to one or more lateral support bars; wherein the roller screed is attached to the screed bar.","14.The method of claim 13, further comprising: using a previously poured concrete swath as one of the forms for containing the wet concrete slurry during the screeding; affixing a screed bar spacer to an end of the screed bar adjacent a surface of the previously poured concrete swath; and wherein the screed bar spacer has a predetermined thickness to compensate for the screeding process delta, the predetermined thickness being at least ⅛ inch but no great than ⅜ inch.","15.The method of claim 13, further comprising: removably attaching a subgrade screeder attachment to the screed bar, wherein the subgrade screeder attachment extends below an underside of the screed bar by a depth equal to a predetermined thickness; and smoothing subgrade material between the forms with the subgrade screeder attachment to a level the predetermined thickness below top edges of the forms."],["<SOH> BACKGROUND <EOH>"],["<SOH> SUMMARY <EOH>Embodiments disclosed herein address drawbacks of the conventional mechanical concrete screeds.","The presently disclosed embodiments save considerable labor in the process or leveling wet concrete.","For example, a conventional screed device requires a crew of six or more workers to pour and finish the concrete surface.","Using the various embodiments disclosed herein a similarly sized pour of concrete could easily be handled by three workers—a savings of at least 50% in labor costs.","Various embodiment disclosed herein provide methods and systems for making and using a wide swath offset concrete screed apparatus for screeding wet concrete slurry.","The apparatus includes a cross support bar, an attachment mechanism for attaching the cross support bar to a liftable arm of a motorized vehicle, and lateral support bars for attaching a screed bar to the cross support bar.","The screed bar is positioned offset from the motorized vehicle used to operate the screed, allowing the motorized vehicle to drive outside the forms."],["CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of U.S. patent application Ser.","No.","15/621,804 filed on Jun.","13, 2017, the disclosure of which is entirely incorporated herein by reference; and this application claims the benefit of the filing date of the Ser.","No.","15/621,804 application.","BACKGROUND Field of the Invention The present invention relates to a wide swath offset concrete screed for leveling poured concrete within a form, and more specifically systems and methods of making and using a wide swath concrete screed that doesn't require mechanical vibration.","Description of Related Art Wet concrete generally arrives on-site in a concrete truck for pouring into the forms to define the desired level when the concrete dries.","When the concrete is poured from the chute of the concrete truck the result is generally mounds of wet concrete—often called mud or slurry—piled above the level defined by the top edges of the forms.","The slurry must be promptly leveled as it is poured, before it hardens or sets.","Typically, the leveling is performed by a screed—a specialized tool that traverses the forms.","Smaller pours such as a sidewalk can be leveled with a hand screed that one or more workers drag along the forms to level the mounds of wet concrete.","It is not feasible to use hand screeds for larger pours such as parking lots, road surfaces, the floors of buildings or other such large, flat concrete surfaces.","The weight of the concrete being pulled off is generally too great for workers to use hand screeds.","Larger concrete projects must be poured in strips that may be ten to twenty feet wide, but can even be thirty or more feet wide.","Conventional mechanized concrete screeds are used to level the strips of concrete.","One such type of conventional mechanized screed involves the use of a vibrating screed.","A small gasoline engine is mounted on the screed with a rotating offset weight designed to impart vibration to the screed as it is dragged across the wet mud.","Some conventional vibrating screed implementations require one or more workers just outside the forms to push and guide the screed along the top of the forms as the engine vibrates the screed.","The vibration is required to prevent small pebbles from momentarily catching on the front edge of the screed and dragging small holes in the surface of the slurry before the pebble finally passes under the screed.","The vibration aids in pushing the small pebbles down into the slurry, allowing the conventional vibrating screed to pass over the pebbles with minimal perturbation to the surface of the wet concrete.","A gasoline or diesel engine is required for this conventional solution, thus requiring one or more workers to attend to the engine as the device is started and stopped many times during the course of a day's pouring.","Due to the dirt and dust present at the work site it can be difficult to keep the conventional vibrating screed from breaking down during a pour, often necessitating emergency repairs to keep pouring while concrete trucks are standing by ready to unload their wet concrete.","Published U.S. Patent Application 2009/0092444A1 to Schoen (hereinafter “Schoen”) describes a conventional wide swath motorized screeds.","The Schoen screed features a screed mechanism attached to a skid loader that a worker operates to pull the mounds of wet concrete and create a level surface.","Another implementation of a conventional mechanical screed involves attaching a conventional vibrating screed to a front end loader or skid loader.","Mounting a conventional vibrating screed on a front end loader eliminates the need for concrete workers to push the screed along as it vibrates.","SUMMARY Embodiments disclosed herein address drawbacks of the conventional mechanical concrete screeds.","The presently disclosed embodiments save considerable labor in the process or leveling wet concrete.","For example, a conventional screed device requires a crew of six or more workers to pour and finish the concrete surface.","Using the various embodiments disclosed herein a similarly sized pour of concrete could easily be handled by three workers—a savings of at least 50% in labor costs.","Various embodiment disclosed herein provide methods and systems for making and using a wide swath offset concrete screed apparatus for screeding wet concrete slurry.","The apparatus includes a cross support bar, an attachment mechanism for attaching the cross support bar to a liftable arm of a motorized vehicle, and lateral support bars for attaching a screed bar to the cross support bar.","The screed bar is positioned offset from the motorized vehicle used to operate the screed, allowing the motorized vehicle to drive outside the forms.","BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are incorporated in and constitute part of the specification, illustrate various embodiments of the invention.","Together with the general description, the drawings serve to explain the principles of the invention.","In the drawings: FIG.","1 is an oblique view of a wide swath offset concrete screed according to various embodiments disclosed herein; FIG.","2 is an oblique view depicting wide swath offset concrete screed in use as wet concrete is being poured; FIG.","3 is a close up view depicting details of the hinge assembly between the lateral support bar and the cross support bar; FIG.","4 depicts the wide swath concrete screed being used to level wet concrete using a previously poured swath of concrete in lieu of a form; FIG.","5 depicts embodiments of an optional screed bar spacer and subgrade screeder attachments that may be affixed to the screed bar; FIG.","6 depicts the wide swath offset concrete screed being raised; FIG.","7 depicts a lateral support bar configured to have a slight amount of curve; and FIG.","8 is a flowchart depicting the use of the concrete screed 100 according to various embodiments of the invention; FIGS.","9-10 are oblique views depicting embodiments of an up-down offset concrete screed; FIG.","11A depicts an embodiment of a vibrating float assembly; and FIG.","11B depicts an embodiment of a rotating float assembly.","DETAILED DESCRIPTION Typically, to pour a swath of concrete a pair of longitudinal forms is assembled at the desired level of the concrete.","The longitudinal forms run along the sides of the swath, and an end form may be positioned between the longitudinal forms, defining the end of the swath.","Once the wet concrete slurry is poured within the longitudinal forms—generally, one truckload at a time—the leveling is performed by running a screed along the top of the longitudinal forms to smooth the swath of concrete between the forms.","The term “leveling” is used to describe the smoothing process using a screed.","The result of “leveling” the wet concrete slurry with a screed produces a relatively flat surface between the forms.","This flat concrete surface that results from leveling with a screed may, or may not, be level with respect to the earth's surface.","For example, the floors of buildings, parking lots and other concrete surfaces are often designed to have a slight degree of slope in order to allow water to run off.","Concrete surfaces are often poured to slope between ⅛ inch per foot to up to ⅝ inch per foot, with ¼ inch per foot being a common value.","Therefore, the term “leveling” as it is used herein implies that the surface of the concrete is smoothed to conform to a flat surface between the top edges of the forms, and may include a built in amount of slope rather than being perfectly level relative to the earth's surface.","That is, leveling wet concrete means to smooth the surface to be relatively flat across the tops of the two forms the concrete was poured into.","In situations where multiple swaths are being poured to form a wide expanse of concrete, it is often the case that the previously poured swath of concrete, now hardened, is used in place of the forms on one side of the next swath to be poured.","In such cases where a swath is being poured beside another, previously poured swatch, a spacer may be used to compensate for the level of freshly screeded concrete being slightly lower than the level of the underside of the screed, as discussed further in conjunction with FIG.","5.Motorized screeds—that is, a screed mechanism attached to a skid loader or other motorized vehicle—are often used to save time and labor in pouring swaths of concrete.","The present inventor recognized several drawbacks inherent in the designs of conventional mechanized screeds, for example, the Schoen screed of Published U.S. Patent Application 20090092444A1.One major drawback of it is that the front end loader of the conventional Schoen screed must be driven within the forms directly ahead of the wet concrete being leveled.","Nearly all concrete is poured over one or more layers of iron rebar lying on a surface of sand which acts to strengthen and reinforce the concrete.","Using the conventional Schoen motorized screed requires the skid loader to be driven over the rebar, pushing it into the layer of sand beneath the concrete and often causing deformities in the rebar.","This would render the rebar useless unless remedied before the concrete dries.","Thus, workers must be positioned between the conventional Schoen screed and the wet concrete being leveled to pull the rebar out of the sand.","Another disadvantage of the Schoen device that the present inventor recognized involves the end form for the pour.","An end form is the form at the end of the swath being poured, for example, to define the edge of a building pad or parking lot.","A skid loader cannot be driven over the end form without destroying it.","So, in order to use the Schoen device the end form must be assembled as soon as the front end loader of the conventional Schoen screed passes that point.","Alternatively, some sort of makeshift removable bridge or ramps could be constructed over the end form, allowing the front end loader of the conventional Schoen screed to be driven up over the end forms without damaging them.","These, and other drawbacks of the conventional screeds recognized by the present inventor, are overcome by various embodiments disclosed herein.","FIG.","1 is an oblique view of a wide swath offset concrete screed 100 according to various embodiments disclosed herein.","The wide swath concrete screed is mounted on a motorized vehicle 101 such as a skid loader, an extension loader, a front end loader, a tractor, a backhoe, a truck, a tractor, a tracked loader, or other such motorized vehicle.","The wheeled vehicle 101 has a liftable mechanical arm 119 of sufficient strength to hold the screed assembly with the capability of lifting it up and down.","The offset wide swath concrete screed 100 affords the advantage of being mounted to the side of motorized vehicle 101—that is, the concrete screed 100 is mounted such that the screed bar 107 is offset to the side of the motorized vehicle 101.To be considered “offset” the screed bar 107 must be positioned outside the wheels (or track, if a tracked vehicle) in the direction of an axel of the motorized vehicle 101.This offset mounting configuration allows the motorized vehicle 101 to be driven along the outside of concrete forms 197.This is a significant advantage over conventional mechanized screeds that drive within the concrete forms.","In this way the various embodiments disclosed herein do not push the rebar 199 into the sand as the concrete is being screeded.","Moreover, the various embodiments of the wide swath concrete screed disclosed herein are able to screed concrete right to the end of the longitudinal forms without damaging the end form.","Various embodiments of screeds disclosed herein are also capable of being mounted directly in front of the motorized vehicle 101 for those situations when there is insufficient room alongside the forms 197 to drive the motorized vehicle 101, e.g., when the last swath being poured is up against a fence, wall or building.","The liftable arm 119 of the motorized vehicle 101 allows a user to lift the concrete screed 100 up and down as needed during the pour.","Since the concrete screed 100 may weigh 300 pounds or more, with an outer end that extends beyond the motorized vehicle 101 by several feet more the width of the longitudinal forms, the liftable arm 119 must have sufficient strength to withstand the rotational force due to the weight of the concrete screed 100 hanging out to the side.","The offset concrete screed 100 includes a connection mechanism 143 or structure for attaching the cross support bar 103 to the motorized vehicle 101.In some embodiments the connection mechanism 143 includes two metal plates bolted together to clamp down on the cross support bar 103 and hold it securely to the liftable arm 119.In some embodiments the connection mechanism 143 includes U-bolts, or metal cables, to secure the cross support bar 103 to the liftable arm 119.In other embodiments the connection mechanism 143 includes an adapter to fasten the cross support bar 103 to a fork lift attachment, or a three-point hitch, of the liftable arm 119.In yet other embodiments the connection mechanism 143 attaches to a hydraulic cylinder to affix the cross support bar 103 to the motorized vehicle 101.Regardless of the configuration, the various embodiments of the connection mechanism 143 includes structural means for attaching the cross support bar 103 to the liftable arm 119 of the motorized vehicle 101, either in a stationary position or in a manner capable of hinging.","A screed bar 107 is configured to pull the mounds of wet concrete slurry deposited within the forms by a concrete truck.","In this way the slurry is leveled during a pour by the action of the motorized vehicle driving back and forth on the outside of forms 197.The screed bar 107 is pulled by lateral support bars 105, which in turn, are connected to cross support bar 103.The motorized vehicle 101 may be positioned to push the cross support bar 103 in the direction of screeding movement 173, as shown in FIG.","1.Alternatively, the motorized vehicle 101 may be positioned on the other side of the cross support bar 103 so as to pull the cross support bar 103 in the direction of movement 173.In either case, the screed bar 107 is dragged behind the cross support bar 103 as the wet concrete slurry is being screeded.","This dragging motion prevents the screed bar 107 from jamming down or catching on the forms as it is moved along.","The screed bar 107 is of sufficient length for both ends to rest on the longitudinal forms 197.Typically the screed bar 107 is slightly wider than the distance between the longitudinal forms 197 so that the screed bar 107 extends beyond the longitudinal forms 197 by a few inches.","In a typical implementation the screed bar 107 may be from 6 to 24 inches longer than the distance between the longitudinal forms 197.In other implementations the screed bar 107 may be any length from the same width as the outer width of the forms up to ten or more feet wider than the width of the forms.","There is no set limit as to how much wider the screed bar 107 is as compared to the width of the forms 197.However, since workers often walk or stand just outside the forms it tends to be more safe and convenient for the width of the screed bar 107 to extend beyond the forms by no more than a few inches on each side.","For example, in some embodiments the screed bar 107 is of a sufficient length so that it extends beyond the forms by 8-10 inches on either side to keep the screed from falling inside the forms 197.Depending upon the application, the swatch of concrete may be of any given width.","For some uses the width of the concrete swath is not important.","For example, a large expanse of concrete such as a parking lot may sometimes be poured in strips or swaths of any width, up to the maximum width, that is desired by the prime contractor or suitable for the situation.","However, some applications (and some builders) require that the concrete be poured in a specific width swatch, e.g., 12 feet, 15 feet, 20 feet, 25 feet, 30 feet, or other such swath widths.","To accommodate these specific swath widths, the concrete screed 100 may be equipped with various lengths of screed bar 107.In some embodiments, the length of the screed bar 107 is fixed, and bars of various lengths are swapped out to accommodate the required swath width.","Other embodiments of the screed bar 107 are configured so that the length of the screed bar 107 may be adjusted to suit the distance between the forms 197 or other parameters.","This may be achieved by providing a telescoping screed bar 107, or by providing removable sections of the screed bar 107 which may be swapped out to achieve the desired length.","The screed bar 107 is held by two or more lateral support bars 105, which in turn, are connected to a cross support bar 103.To smooth out the mounds of wet concrete the motorized vehicle 101 is typically positioned to push the cross support bar 103.However, the cross support bar 103 is configured to pull the screed bar 107 along, dragging the wet concrete to a level format.","This pulling action aids in preventing the screed bar 107 from gouging into the longitudinal forms, thus making the screed bar 107 operate more smoothly as the wet concrete is being leveled.","FIG.","2 is an oblique view depicting wide swath offset concrete screed 100 in use as wet concrete is being poured.","The figure shows the point in time when the wet concrete from one truck has already been leveled out, the screed bar 107 has been lifted up out of the way, and motorized vehicle of 101 (not shown) of the concrete screed 100 is backed up so as to allow another truckload of wet concrete to be poured.","As shown in FIG.","2 the lateral support bar 105 is attached to the cross support bar 103 by a hinge assembly 109 configured to hinge upward as the screed bar 107 comes to rest on forms 197.The hinge assembly 109 prevents the screed bar 107 from hinging downward more than a predetermined amount, in order to lift the screed bar 107 off the forms as shown in FIG.","2.The predetermined amount—defined as the support bar angle—is measured at the point where the motorized vehicle 101's liftable arm 119 has been lowered such that the screed bar 107 just touches the forms 197.That is, the support bar angle is the angle between the axis of rotation of the hinge assembly 109 and the bottom front edge of the screed bar 107 when it is lowered to the point of just touching the forms 197.It should be clear from this that the the support bar angle does not depend upon the shape of the lateral support bar 105.At this point, if the cross support bar 103 is raised it will lift the screed bar 107 up since the hinge assembly 109 won't hinge downward past the support bar angle.","On the other hand, if the cross support bar 103 is instead lowered the hinge assembly 109 will hinge upward since the screed bar 107 is resting on the forms 197.Various embodiments are configured so the lateral support bar 105 hangs downward at a support bar angle of from 1 degree to as much as 60 degrees, or any angle within these limits, with a hang angle of 15 degrees being typical.","The lower limit of the support bar angle, 1 degrees, is determined by the distance between the axis of rotation of the hinge assembly 109 and the bottom surface of the cross support bar 103, and depends on the length of the lateral support bar 105.FIG.","3 is a close up view depicting details of one embodiment of the hinge assembly 109 between the lateral support bar 105 and the cross support bar 103.Other embodiments may use like types of structures configured to provide a hinging action such as an ordinary hinge, a rocker arm assembly, a trough holding the ends of lateral support bars 105 and flexible cable controlling the maximum hinge angle or support bar angle, a ball joint, or other like types of hinging structures.","The hinge assembly 109 connects the lateral support bar 105 to the cross support bar 103.The hinge assembly 109 allows the lateral support bar 105, and in turn the screed bar 107, to hinge upward as the device is lowered onto the longitudinal forms 199.As discussed above, the hinge assemblies 109 prevent the lateral support bars 105, and in turn the cross support bar 103, from hinging downward by more than a predetermined amount, defined as the support bar angle.","In this way the motorized vehicle 101 can lift the screed bar 107 up in the air.","The conventional Schoen screed of Published U.S. Patent Application 20090092444A1 features a mounting pocket 62 that prevents arm 48 from rotating too far downward.","Such a pocket/arm assembly could be used with embodiments disclosed herein as a hinging mechanism.","However, the present inventor recognized certain drawbacks with the Schoen pocket/arm assembly.","Namely, the pocket tends to retain wet concrete and small pebbles during the course of a working day.","This, in turn, makes the pocket difficult to clean upon completion of a work day.","At the end of each day, and perhaps even during the course of the day, the bar 48 must be rotated upward out of pocket 62 in order to clean out all the accumulated concrete and pebbles.","If the pocket 62 of the Schoen device is allowed to dry overnight without being thoroughly cleaned it will sometimes freeze in place as the bits of remaining concrete dry and harden.","The Schoen device can also freeze up while it is being used if a small pebble or bit of concrete becomes lodged between the bar 48 and pocket 62.The hinge assembly 109 overcomes these drawbacks since it is a more open design which does not tend to accumulate pebbles and wet concrete.","The hinge assembly 109 is easier to clean with a hose and water since there is no pocket for pebbles and wet concrete to gather in during the course of a day.","In various embodiments of the offset concrete screed 100, the hinge assembly 109 is rotatably connected to cross support bar 103 by a pin 121.By “rotatably connected” it is meant that the hinge assembly is connected in a manner that allows it to rotate, or hinge, about an axis.","In some implementations the pin 121 passes through, or is otherwise connected to, a pin holder bar 123.In other embodiments the pin 121 is connected directly to the cross support bar 103.The pin 121 may be a bolt of sufficient diameter (e.g., ⅜ to 1 inch) for supporting the weight of the lateral support bars 105 and screed bar 107.The bolt may be kept in place with a nut, or two nuts tightened against each other, and washers to aid in preventing wear on the bolt and hinge assembly 109.In other implementations a hinge pin, a metal rod, or other like type of pin may be used as the pin 121.In some embodiments one or more springs 167 are connected to some point on the support bar assembly to provide more downward force than the weight of the screed bar 107.The additional downward force aids in preventing the screed bar from riding up over the wet concrete slurry.","Typically, the springs 167 are configured to be removable so that weaker or stronger springs—or multiple springs—can be attached, as needed.","In this way the user is able to adjust the downward force to accommodate the conditions of the pour.","Some embodiments use compression springs to push downward on the support bar assembly.","In other embodiments leaf springs are used to provide the downward force.","The hinge assembly 109 is typically configured so that it comes to rest against cross support bar 103 when the offset concrete screed 100 is raised up in the air.","The hinge assembly 109 hinges upward in response to the concrete screed 100 being lowered so that the screed bar 107 rests on forms 197.This allows the screed bar 107 to ride along the top of the forms 197 without damaging the forms.","The hinging action also allows the screed bar 107 to ride up over an overly large mound of wet concrete to avoid putting too much horizontal strain on the screed bar 107 and concrete screed 100.If the screed bar 107 rides up over an overly large mound of wet concrete the user can simply raise the offset concrete screed 100 up in the air, back up the motorized vehicle 101, and take one or more additional passes at smoothing the large mound of wet concrete.","Since embodiments of the offset concrete screed 100 allow the motorized vehicle 101 to be driven off to the side rather than over the rebar, the user can efficiently make several passes without need to have workers reposition to rebar after each pass, as is required for conventional motorized screed devices.","FIG.","4 depicts the wide swath concrete screed 100 being used to level the wet concrete slurry 193 using a previously poured swath of concrete 195 in lieu of a form on one side.","In pouring large expanses of concrete for a parking lot or building pad it is often the case that the swaths are poured side by side with the previous day's swath acting as a form on one side of the current pour.","The very first swath poured requires a form 197 to be set up on each side of the swath to be poured.","For each subsequent swath poured after the previous swath has hardened (e.g., a day or more later) only one form 197 needs to be erected.","The previously poured swath 195, now hardened, acts as a form on the other side to contain the newly poured wet concrete slurry 193.One issue with using a previously poured swath in lieu of a form is that the process or screeding wet concrete results in a screeding process delta in which the level of the concrete is slightly lower than the level of the forms (or the form and the previously poured swath being used as a form).","For example, a screeded concrete surface may end up ¼ inch or so lower than the forms on either side—that is, have a screeding process delta of ¼ inch or so.","This is because the wet concrete slurry contains small pebbles and gravel in it.","The screeding process delta results because the screed bar 107 tends to push some of the small pebbles and gravel in front of it, causing the screeded surface of the wet concrete slurry to be slightly lower than the bottom surface of screed bar 107, e.g., ¼ inch or so lower.","This can be somewhat troublesome if the concrete is being poured in long swaths alongside a previously poured swath—now hardened—from the previous day.","If the screeding process delta was not compensated for and the form 197 was erected to be level with the previously poured swath, each newly poured swath would end up being ¼ inch or so lower than the previously poured swath beside it.","If a number of swaths were poured this way the result would be that each swath would be ¼ inch or so lower due to the screeding process delta of each swath.","In order to avoid this, it is desirable to provide forms 197 for the new swath to be poured that are at a level slightly higher than the previously poured swath to its side by an amount equal to the anticipated screeding process delta.","The slightly higher level of the form 197 compensates for the lower level of finished concrete due to the screed bar 107 pushing small pebbles and gravel in front of it.","However, if the previously poured swath (which has hardened) is being used as one of the forms 197 then it is not possible to adjust the height of the previously poured swath to compensate for the screeding process delta.","To this end, various embodiments use a screed bar spacer affixed to the bottom of screed bar 107 on the side of the previously poured swath in conjunction with the form 197 being constructed slightly higher than the level of the previously poured swath.","FIG.","4 also depicts a screed bar extension 135.The cross section of the screed bar extension 135 is typically the same as the screed bar 107, with a slightly smaller cross-sectional portion that fits into the end of the screed bar 107.One or more holes 139 may be provided for bolts 141 used to secure the screed bar extension 135 to the screed bar 107.The bolts 141 pass through holes 139 and tighten into threaded holes 137.FIG.","4 also depicts the wide swath concrete screed equipped with a scrape auger 181.The scrape auger 181 acts to push excess wet slurry concrete to one side or the other so as to aid in preventing too much wet slurry concrete from building up and pouring over the top of screed bar 107.Typically, the lower edge of the scrape auger 181 is positioned slightly above the lower edge of screed bar 107, e.g., one to three inches, but may be positioned as little as ¼ inch to as much as one foot above the lower edge of screed bar 107.The scrape auger 181 may either be affixed to the cross support bar 103 or may be affixed to lateral support bars 105 by connection points 179.Typically, connection points 179 have a bearing or greased sleeve to reduce the mechanical friction as the auger 181 rotates.","The auger 181 is rotationally powered by a power unit 183.The power unit 183 may be similar to power unit 185 depicted in FIG.","11B.","Power unit 183 may be implemented in various forms, including for example, a gas or diesel engine, an electric motor, a hydraulic motor, a rotating shaft connected to the power take-off of the motorized vehicle, a rotating linkage connected to the engine of the motorized vehicle, or other like type of power unit known to those of ordinary skill in the art.","The power unit 183 may either be connected to the cross support bar 103, or in other implementations, may be connected to one or more of the lateral support bars 105.The power unit 183 may be controlled by a user to controllably rotate the auger 181 at varying speeds.","The auger 181 may be rotated in one direction to push the wet concrete slurry towards the motorized vehicle 101, and may be controlled to rotate in the opposite direction to push the wet concrete slurry away from the motorized vehicle 101.FIG.","5 depicts embodiments 500 and 550 of an optional screed bar spacer and subgrade screeder 147 attachments that may be affixed to the screed bar.","As shown in the figure, the screed bar spacer 125 is affixed to the end of the screed bar 107 resting on a previously poured concrete surface 195 to compensate for the screeding process delta.","The screed bar spacer 125 is a removable attachment with a predetermined thickness that compensates for the level of freshly screeded concrete being slightly lower than the level of the underside of the screed bar 107 due to small pebbles and gravel being pushed in front of screed bar 107 during the screeding process.","A user simply taps the screed bar spacer 125 into position within the screed bar 107, and it is held in place by friction.","To remove the screed bar spacer 125, the user merely taps it back out.","The screed bar spacer 125 is held to the bottom side of screed bar 107 on the end that rides across the swath of previously poured, hardened concrete.","Since the level of the freshly screeded concrete will be lower by a slight amount than the bottom of the screed bar 107 due to the screeding process delta, the screed bar spacer 125 allows the screed bar 107 to pass over the newly poured concrete at a level slightly higher than the desired level of the finished concrete surface to compensate for the screeding process delta.","In this way, the newly screeded concrete will end up at approximately the same level as the previously poured concrete swath adjacent to it.","The wide swath offset concrete screed 100 may be provisioned with screed bar spacers 125 of various thicknesses, depending upon the anticipated amount of screeding process delta—that is, the amount that the newly poured concrete is anticipated to be lower.","The anticipated amount of screeding process delta depends upon the characteristics of the wet concrete slurry such as the size of the pebbles and gravel in the wet concrete slurry, how wet the concrete slurry is, the temperature of the wet concrete slurry, etc.","Since a given contractor may order wet concrete slurry many times from the same concrete supplier, the contractor will generally get a feel for the amount of screeding process delta to expect from a particular concrete provider for a given grade of concrete.","A screed bar spacer 125 for use with the various embodiments may have a predetermined thickness of as little as 1/16 inch or as much as ¾ inch, or any value in between, depending upon the characteristics of the wet concrete slurry resulting in screeding process delta.","A typical thickness for a slab of concrete 8 inches thick is ¼ inch.","In various embodiments the bottom side of the screed bar spacer 125 is smooth with rounded corners in order to push the pebbles and gravel of the wet concrete slurry underneath it during the screeding process.","This aids in preventing the pebbles and gravel from scraping along the surface of the wet concrete slurry before they pass beneath the screed bar spacer 125.In addition the screed bar spacer 125 is configured to be smooth with rounded corners aids to avoid gouging or scoring the concrete surface that it rests and slides upon.","FIG.","5 depicts another screed bar spacer embodiment—the screed bar spacer 127 which is configured with a wheel that rolls along the previously poured concrete surface 195.The screed bar spacer 127 is particularly useful when the previously poured concrete 195 has not yet hardened sufficiently to avoid scoring the surface.","The screed bar spacer 127 slides into screed bar 107, and is tightened into place with a compression bolt 133.Moreover, the screed bar spacer 127 may be configured to be adjustable by providing an elongated slot either for bolt 129 or for a bolt at point 131.FIG.","5 also depicts a subgrade screeder attachment 147.To preparing a pour site the contractor generally deposits gravel, sand or pebbles, or some other subgrade material, between the longitudinal forms 197.It is important to have a uniformly flat, level subgrade surface to pour the wet concrete slurry on, in order to ensure that the resulting concrete pad is of a uniform thickness.","According to conventional methods, the subgrade material is graded and leveled by hand with shovels or rakes.","These conventional methods of preparing the subgrade are quite a labor intensive and must be performed prior to pouring the concrete.","It generally takes at least a couple—or even several—manual laborers working to smooth and level the subgrade material by hand, and it is nearly impossible to create a uniformly flat, level subgrade surface.","The embodiments disclosed herein overcome aid in cutting down the manual labor required to prepare the subgrade materials by hand, while at the same time drastically increasing the precision of the subgrade leveling process.","The subgrade screeder attachment 147 depicted in FIG.","5 attaches to the screed bar 107 using one or more bolts 149.Alternatively, the subgrade screeder attachment 147 may be affixed to the screed bar 107 using pins, clamps, cables, chains, or other like type of structures for affixing the subgrade screeder attachment 147 in place on the screed bar 107.In other embodiments the subgrade screeder attachment 147 is attached to the screed bar 107 with a hinge mechanism so that it can be hinged upward out of the way when not in use.","The depth that the subgrade screeder attachment 147 extends below the lower level of screed bar 107 is adjustable in order to equal the desired thickness of the concrete pad being poured.","In the embodiment depicted in FIG.","5 there are a series of holes that allow the subgrade screeder attachment 147 to be set at various depths, thus creating concrete pads of various thicknesses.","In other embodiments the subgrade screeder attachment 147 has an elongated hole, or slot, to allow adjustment up and down to create various thickness of a concrete pad.","Typically, the width of the subgrade screeder attachment 147 is slightly narrower than the width of the longitudinal forms 197, for example, one to six inches narrower.","The screeder attachment 147 may be provided in multiple pieces so as to easily vary the width to accommodate the width of the longitudinal forms 197.The subgrade screeder attachment 147 is typically made of metal.","Aluminum generally provides sufficient strength, and is advantageously lightweight.","However, other implementations of the subgrade screeder attachment 147 may be made of iron, steel, or other like metals.","In some embodiments the lower edge of the subgrade screeder attachment 147 may be curved slightly in the direction of screeding movement 173.The slight curve tends to cut into the loose gravel, sand or pebbles typically used as subgrade material, thus pulling the subgrade screeder attachment 147 slightly downward to create a smooth, level subgrade surface.","In various embodiments the curved portion of the lower edge of the subgrade screeder attachment 147 is angled from as little as 15 degrees to as much as 90 degrees, relative to vertical.","In other embodiments the lower edge of the subgrade screeder attachment 147 is squared off straight, rather than having a slight curve as shown in FIG.","5.FIG.","6 depicts the wide swath offset concrete screed 100 in a raised position.","In some instances the area just outside the forms and just beyond the end of the swath of concrete being poured may have an obstacle such as a fence or building, or otherwise be inaccessible.","When this occurs it may not be possible to drive the motorized vehicle 101 very far beyond the end of the swath of concrete.","In such situations it is useful to be able to lift the concrete screed 100 high enough to permit a concrete truck to back up close enough to unload the wet concrete beneath the raised screed.","Various embodiments of the concrete screed 100 can be raise high enough to permit wet concrete to be unloaded beneath it, as shown in FIG.","6.For example, depending upon the type of motorized vehicle 101 being used, the wide swath offset concrete screed 100 can be raised to a level of fifteen feet or more.","For embodiments using an extension loader as the motorized vehicle 101 as depicted in FIG.","6 the offset concrete screed 100 can be raised to over twelve feet.","This is sufficient height to allow a concrete truck to back up and deliver its load of wet concrete slurry under the offset concrete screed 100.Other embodiments may raise the concrete screed 100 even higher, for example, for clearance beneath the screed bar 107 of 15 feet or even more, depending upon how far the liftable arm 119 of the motorized vehicle 101 is able to extend or rise in the air.","As the liftable arm 119 is lowered it is desirable not to slam it into the lateral forms 197.To aid in this some embodiments include a flow restrictor 145 in the hydraulic line to controllably constrict the flow of hydraulic fluid.","The flow restrictor 145 tends to slow down the upward and downward movement of the liftable arm 119, making it easier for a user to ease the liftable arm 119 into position as it is raised and lowered during the screeding process.","FIG.","7 depicts a lateral support bar 105 configured to have a slight amount of curve at point 175.In various embodiments it is desirable for the underside of screed bar 105 to lay relatively flat on the wet concrete slurry and the longitudinal forms 197.Having the underside of screed bar 105 flat aids in keeping it from riding up over mounds of wet concrete slurry as it is pulled along, or gouging into the wet concrete.","Further, the flat underside as it is drawn over the wet concrete slurry provides a smoothing effect that helps to produce a smooth, level surface of the finished concrete.","At the same time it is desirable to keep the cross support bar 103 several inches above the forms 197 to keep it from catching on the forms 197 and causing perturbations in the smooth surface of the concrete.","To achieve this—having the underside of screed bar 105 flat while the cross support bar 103 passes several inches above the forms 197—various embodiments of the lateral support bars 105 are configured to have a slight amount of curve.","In some embodiments the lateral support bars 105 are gradually curved along their entire length.","In other embodiments, the lateral support bars 105 are curved at a particular point, for example, at point 175 as depicted in FIG.","7.In yet other embodiments, the lateral support bars 105 are angled at a particular point rather than being gradually curved (e.g., a sharp curve).","In all of these embodiments the lateral support bars 105 are said to be curved by a lateral support bar curve 177.In various implementations the lateral support bar curve 177 may vary from as little as 1 degree to as much as 30 degrees, and may be any value in between these two extremes.","A typical value for the lateral support bar curve 177 is 4 degrees.","In some embodiments the lateral support bars 105 are approximately four feet long.","However, the length may be varied depending upon the requirements of the pour and the situation in which it is to be used to be as short as one foot or as long as twelve feet.","Using shorter lateral support bars 105 will result in the cross support bar 103 being positioned closer to the forms 197.Using longer lateral support bars 105 will result in more downward rotational force on the cross support bar 103 due to the increased leverage.","Therefore, in various embodiments the lateral support bars 105 are generally kept within three to six feet, with four feet being a typical length embodiment.","FIG.","8 is a flowchart depicting the use of the concrete screed 100 according to various embodiments of the invention.","Reference is made to the previous figures in the application, including various reference numbers shown in the figures.","The method begins at block 801 and proceeds to block 803 where the user provides a cross support bar 103.The cross support bar 103 is typically connected to the liftable arm 119 of a motorized vehicle 101.The method proceeds to block 803 for attaching the lateral support bars 105 to the cross support bar 103.This is generally done using hinge assemblies 109.In some embodiments, however, the lateral support bars 105 may be fixedly connected to the cross support bar 103, with the lateral support bars 105 themselves being capable of hinging.","The lateral support bars 105 typically have a slight amount of bend in them, e.g., approximately four degrees—that is, 4°+/−10%.","In block 807 the screed bar 107 is connected to the lateral support bars 105.Typically, the screed bar 107 is fixedly attached to the lateral support bars 105.However, in some embodiments the screed bar 107 may be connected to the lateral support bars 105 in a manner that allows the screed bar 107 to have some play or movement relative to the lateral support bars 105, e.g., a hinging motion.","In block 809 it is determined whether the longitudinal forms 197 are wider apart than the length of the screed bar 107.If the screed bar 107 needs to be longer, the method proceeds along the “YES” path to bock 811 for attachment of one or more screed bar extensions 135 to the screed bar 107, and then proceeds to block 813.If the screed bar 107 is of sufficient length for the configuration of longitudinal forms 197 the method proceeds from block 809 along the “NO” path to block 813.In block 813 of FIG.","8 it is determined whether the wet concrete slurry is to be poured into forms on either side (e.g., for the first concrete swath to be poured), or a previously poured, now hardened, swath of concrete is to be used on one side of the pour in place of the longitudinal forms for that side.","If previously poured swath of concrete is to be used in place of the forms it may be the case that the screeding will result in a screeding process delta in which the level of the concrete is slightly lower than the level of the forms, as discussed previously in conjunction with FIG.","5.If a screeding process delta—that is, a level of the concrete surface slightly lower than the scree bar surface—is anticipated, the method proceeds from block 813 along the “YES” path to block 815 to attach a screed bar spacer 125 or 127.However, if no screed bar spacer is desired the method proceeds from block 813 along the “NO” path to block 817.In block 817 the user operates the motorized vehicle 101 to screed the wet concrete slurry to a desired degree of levelness.","During the screeding process it is sometimes the case that the screed bar 107 needs to be raised, for example, to back the motorized vehicle 101 up or to allow a concrete truck to deliver another load of concrete.","If, in block 819, it is determined that the screed bar 107 needs to be raised the method proceeds along the “YES” path to block 823 to raise the screed bar 107 (or lower it if it was previously raised).","The method then proceeds to block 821 to determine whether further screeding operations need to be performed.","If further screeding is to be done, the method proceeds back to block 817 along the “YES” path.","However, if the screeding is completed the method proceeds from block 821 along the “NO” path to block 825 where the method ends.","Various activities of the method disclosed herein may be included or excluded as described above, or maybe performed in a different order than the particular examples chosen to illustrate the embodiments.","For example, it may be the case that the screed bar extension may be attached to the screed bar (block 811) prior to attaching the screed bar to the lateral support bar (block 807).","Or it may be the case that the screed bar spacer may be attached to the screed bar (block 815) prior to attaching the screed bar to the lateral support bar (block 807).","The sequence of steps for performing the method of making and using a wide swath offset concrete screed according to the various embodiments disclosed herein may be altered in many other ways as well.","FIGS.","9-10 are oblique views depicting embodiments of an up-down offset concrete screed.","The present inventor recognized the difficulty of screeding concrete into certain tight spaces—for example, screeding into the corner formed by two buildings, or screeding right up against a building or a wall.","In such tight spaces it is desirable to be able to operate the screed as closely as possible up to the limiting obstruction.","The embodiments depicted in FIGS.","9-10 make it possible to screed into tight places with only a minimum of finish work to be done by hand.","The up-down offset concrete screed embodiment features two or more vertical support bars 151.The vertical support bars 151 are designed to move up and down, as needed, during the screeding operation.","For example, it may be that the surface outside the forms on which the motorized vehicle 101 is driving is unlevel or bumpy.","If the motorized vehicle 101 moves up or down as it is traveling along, the vertical support bars 151 can move down or up, as needed, so that the screed bar 107 may remain on the forms 197.In some instances, if there is too much wet concrete slurry 193 being pushed the screed bar 107 may ride up over the slurry, leaving an unlevel spot that will require further screeding on another pass.","Each vertical support bar 151 is enclosed by a support bar sleeve 153 that allows the vertical support bar 151 to move up and down.","The end of each vertical support bar 151 is larger than the passage dimensions of the support bar sleeve 153 to prevent the vertical support bar 151 from passing through it.","This allows the cross support bar 103 to lift up the vertical support bar 151 and accompanying screed bar 107.To aid in the up/down movement the support bar sleeves 153 have bearings on their inner surface, making it easier for the vertical support bars 151 to ride up and down with the lateral force of the concrete slurry pushing against them.","Alternatively, the support bar sleeves 153 may have small wheels or lubricant instead of bearings.","The vertical support bars 151 are rotatably attached to the screed bar 107 allowing the vertical support bars 151 to rotate about an axis, the axis being in the direction of screeding—that is, the axis of rotation is in the same direction as the direction of screeding (e.g., motorized vehicle movement), allowing the direction of rotation to be back and forth at a right angle to the direction of screeding.","Similarly, the support bar sleeves 153 are rotatably attached to the cross support bar 103.In this way, if the motorized vehicle 101 drives on an unlevel or bumpy spot causing the cross support bar 103 to raise up or dip relative to the screed bar 107, the vertical support bars 151 won't bind up if they raise or drop by different amounts.","In this way the screeding operation can continue smoothly even though the cross support bar 103 does not remain parallel with the screed bar 107.The vertical support bars 151 may be rotatably attached to the screed bar 107 by a tab 155 that is welded, bolted or otherwise affixed to the screed bar 107.The tab 155 has a pin or bolt configured to pass through a hole in the vertical support bar 151, thus allowing the vertical support bars 151 to rotate relative to the screed bar 107.In other embodiments (no shown) the tab 151 is affixed to the vertical support bar 151 and has a bolt or pin that passes through a hole in the screed bar 107.FIG.","10 depicts details of an embodiment for rotatably connecting the support bar sleeves 153 to the cross support bar 103.FIG.","10 is oblique cutaway view of an embodiment of the support bar sleeve 153 that rotatably attaches the support bar sleeve 153 to the cross support bar 103.In this embodiment the hinging mechanism is a bolt 157 that is welded, or otherwise attached, to the support bar sleeve 153 and passes through a hole 159 in the cross support bar 103.The bolt 157 allows the support bar sleeve 153 to rotate as needed relative to the the cross support bar 103.Other hinge mechanisms may be used in various implementations to connect the vertical support bars 151 to either the support bar 103 or to the screed bar 107, including for example, a hinge, a flexible cable, chain links affixed to each part, a shaft and bearings, a trough or slot that supports a shaft, or other like mechanisms known to those of ordinary skill in the art.","FIG.","11A depicts an embodiment of a vibrating float assembly configured to be pulled behind the screed bar 107.In typical implementations the vibrating float assembly is fairly lightweight, for example, weighing between five and twenty-five pounds.","However, either heavier or lighter implementations may be constructed, depending upon the dimensions and materials used in the vibrating float assembly itself, and the characteristics of the concrete slurry being floated.","Typically, two or more vibrating float assemblies are rotatably affixed to the screed bar 107.In some embodiments two or more points on the screed bar 107 serve as the points of rotation for the float assemblies to hinge, or rotate, downward onto the surface of the wet concrete slurry.","In other embodiments, as shown in FIG.","11B, the float assembly itself—in the form of a roller screed—rotates about an axis connected to screed bar 107.Turning again to FIG.","11A, some embodiments feature only one float affixed to the screed bar 107.The screed bar 107 generally is configured to extend beyond the outermost and innermost vibrating float assemblies by at least a few inches.","That way, the vibrating float assemblies ride solely on the wet concrete slurry and do not extend quite to the forms.","However, in some implementations, the vibrating float assemblies may be configured to be the same width as the screed bar 107 so the outermost portions of the vibrating float assemblies ride on the forms just as the screed bar 107 does.","Each vibrating float assembly has a float pan 161.The float pans 161 are constructed in various lengths, depending upon the length of the screed bar 107 to which they are attached.","The float pans 161 attached to a particular screed bar 107 do not all necessarily need to be the same length.","For example, a 17foot screed bar 107 for use on forms 197 that are 16 feet apart may have an 8 foot float pan 161 and a seven foot float pan 161 which are spaced 2 inches apart.","This would leave 5 inches of space between the outmost edges of the float pans 161 and the forms 197.The float pan 161 features a lip that is bent upwards the full length of the pan.","The bent lip may be from one to four inches wide.","In typical implementations the bent lip is approximately two inches wide and the overall width of the pan is approximately twelve inches.","The bent lip may be bent upwards from as little as 3 degrees to as much as 60 degrees.","In typical implementations, the bent lip may be bent upwards from 35 to 55 degrees, with 45 degrees being a common amount.","The flat bottom surface of the float pan 161 is generally configured to be wider than the bent lip portion, e.g., from 2 inches to 20 inches wide.","In typical implementations, the flat bottom portion is from six to twelve inches wide.","The float pan 161 may be constructed from a number of materials, including for example, aluminum, magnesium, steel, iron, wood, composite material, or the like.","Each float pan 161 has mounted upon it a vibrating mechanism—typically an off-balance vibrating electric motor.","The electric motor may either be wired to a power source back on the motorized vehicle such as the vehicle's battery, or may have a battery pack mounted in place with it on the float pan 161.The motor and battery pack are generally mounted towards the center of the float pan 161 to evenly distribute their weight across the wet concrete slurry.","Each float pan 161 is affixed to the screed bar 107 by one or more float hinge mechanisms.","The embodiment depicted in FIG.","11A has a float hinge mechanism features a U-shaped member that fits snuggly over the screed bar 107.In some embodiments the U-shaped member may bolt, screw or otherwise be attached to the screed bar 107 so as to be more firmly attached than friction would allow.","The hinge member 163 is rotatably connected to a hinge tab 165.The hinge tab 165 is affixed to the float bar 107 by welding, bolts, rivets, screws, or other ways of attaching materials together known to those of skill in the art.","The hinge member 163 is rotatably connected to a hinge tab 165 by a bolt or pin, allowing it to rotate in the direction 169.Typically, the float hinge mechanism is configured to allow the float pan to hinge downward from horizontal by a limited amount somewhat less than 30 degrees.","For example, in one embodiment the float pan can hinge downward an amount between 1 and 15 degrees—with an amount of downward hinging between 1 and 6 degrees being typical.","To measure it another way, the hinge mechanism allows the float pan to hinge downward from 1 to 4 inches, as measured by the distance the float bar 107 is raised above the level of the forms 197 before the float pan's rear edge begins to come off the surface of the wet concrete slurry.","In this way, the float pan will gently ride on top of the concrete slurry to a horizontal position as the screed bar 107 is lowered towards the forms 197.If the float pan is allowed to hinge down into too steep of an angle, it will gouge into the wet concrete slurry as the screed bar 107 is lowered.","FIG.","11B depicts an embodiment in which the float bar is in the form of a rotating float assembly, typically called a roller screed.","The roller screed 187 is manipulated back and forth to smooth the surface of the wet concrete slurry.","In various embodiments the direction of rotation at the point where the roller screed 187 meets the wet concrete slurry is in direction 171 towards the slurry yet to be smoothed, that is, towards the wet concrete slurry that has just been delivered by a concrete truck.","In some embodiments (e.g., the embodiment of FIG.","11B) the roller screed 187 may take the place of the screed bar 107 itself, shown in FIGS.","1-6.In other embodiments one or more roller screed(s) 187 may be configured in the manner of the float pans attached behind the screed bar 107 as shown in FIG.","11A.","In various roller screed embodiments the roller screed 187 is rotated by one or more power units 185.The power unit 185 may be implemented in various forms, including for example, a gas or diesel engine, an electric motor, a hydraulic motor, a rotating shaft connected to the power take-off of the motorized vehicle, a rotating linkage connected to the engine of the motorized vehicle, or other like type of power unit known to those of ordinary skill in the art.","In various embodiments the power unit 185 may be connected to the cross support bar 103.In various embodiments the power unit 185 may be connected to one or more of the lateral support bars 105.The power unit 185 may be controlled by a user to controllably rotate the roller screed 187.This allows the rotation speed of the roller screed 187 to be adjusted, and turned on and off, so as to accommodate different pouring conditions.","In some embodiments equipped with both a roller screed 187 and an auger 181 the same power unit may be used to rotate both the roller screed 187 and the auger 181.In some roller screed embodiments the lateral support bars 105 may be configured to hinge upward as shown in FIG.","11B.","In other embodiments the lateral support bars 105 may be rigidly affixed to the cross support bar 103 without a provision to hinge upward.","In yet other embodiments one or more springs may be provided to provide downward force on the roller screed 187 in addition to the weight of the roller screed 187 itself.","In various embodiments the lateral support bars 105 may be substantially perpendicular to the cross support bar 103 as shown in FIG.","11B.","In other embodiments one or more of the lateral support bars 105 may be attached to the cross support bar 103 at angles other than substantially perpendicular to the cross support bar 103.For example, the lateral support bars 105 may angled relative to the cross support bar 103 outward away from the motorized vehicle.","In various embodiments the roller screed 187 is rotatably connected at both ends to a roller support structure 189.The roller support structure 189 may be configured on the outside and above the roller screed 187 as shown in FIG.","11B, or may be configured to pass through the center of roller screed 187.The support structure 189 is at least above the lower edge of roller screed 187 so as to avoid being dipped into the wet concrete slurry.","In most implementations the support structure 189 is above the upper edge of the roller screed 187.The support structure 189 may be directly over the roller screed 187, or may be positioned above and either ahead of or behind the roller screed 187.Some embodiments are equipped with a screed connector 191.The screed connector 191 may be configured with a mechanical friction reduction component such as ball bearings, roller bearings, greased spindle and socket, or other such means of mechanical friction reduction as are known to those of ordinary skill in the art.","The screed connector 191 may include one or more of a wheel or rollers to roll along the concrete forms or adjacent previously poured concrete surface.","The screed connector 191 may be configured to accept a screed bar spacer 125 as shown in FIG.","5.The description of the various embodiments provided above is illustrative in nature inasmuch as it is not intended to limit the invention, its application, or uses.","Thus, variations that do not depart from the intents or purposes of the invention are intended to be encompassed by the various embodiments of the present invention.","Such variations are not to be regarded as a departure from the intended scope of the present invention."]],"string":"[\n [\n \"Wide Swath Offset Concrete Screed\",\n \"Methods and systems for making and using a wide swath offset concrete screed apparatus for screeding wet concrete slurry.\",\n \"The apparatus includes a cross support bar, an attachment mechanism for attaching the cross support bar to a liftable arm of a motorized vehicle, and a roller screed attached to the cross support bar.\",\n \"The roller screed is positioned offset from the motorized vehicle used to operate the screed, allowing the motorized vehicle to drive outside the forms.\"\n ],\n [\n \"1.An offset concrete screed apparatus for screeding wet concrete slurry, comprising: a cross support bar; means for attaching the cross support bar of the offset concrete screed apparatus to a liftable arm of a motorized vehicle; a roller screed attached to the offset concrete screed apparatus, the roller screed being configured to come in contact with the wet concrete slurry in response to the liftable arm of the motorized vehicle being lowered; and a power unit attached to the offset concrete screed apparatus, the power unit being configured to controllably rotate the roller screed; wherein the roller screed is positioned offset from the motorized vehicle allowing the motorized vehicle to be driven outside forms containing the wet concrete slurry during the screeding.\",\n \"2.The offset concrete screed apparatus of claim 1, further comprising: a roller support structure configured to attach the roller screed to the offset concrete screed apparatus; and means for reducing mechanical friction between the roller support structure and the roller screed.\",\n \"3.The offset concrete screed apparatus of claim 1, further comprising: one or more lateral support bars attached between the roller screed and the cross support bar; wherein the one or more lateral support bars hinge downward by no more than a predetermined amount from horizontal, defined as a support bar angle, wherein the support bar angle is no less than 3 degrees and no greater than 45 degrees; and wherein the roller support structure is positioned above the roller screed.\",\n \"4.The offset concrete screed apparatus of claim 3, wherein the support bar angle is no less than 5 degrees and no greater than 25 degrees.\",\n \"5.The offset concrete screed apparatus of claim 1, wherein the power unit is an electric motor.\",\n \"6.The offset concrete screed apparatus of claim 1, further comprising: a screed bar attached to one or more lateral support bars; wherein the roller screed is attached to the screed bar.\",\n \"7.The offset concrete screed apparatus of claim 6, further comprising: a screed bar spacer configured to be affixed to an end of the screed bar adjacent a surface of a previously poured concrete swath, the previously poured concrete swath being used as one of the forms for containing the wet concrete slurry during the screeding; wherein the screed bar spacer has a predetermined thickness of at least ⅛ inch but no great than ⅜ inch to compensate for the screeding process delta.\",\n \"8.The offset concrete screed apparatus of claim 6 for screeding the wet concrete slurry into a concrete pad of a predetermined thickness, further comprising: a subgrade screeder attachment configured to be removably attached to the screed bar; wherein the subgrade screeder attachment extends below the underside of the screed bar by a depth equal to the predetermined thickness.\",\n \"9.A method of screeding wet concrete slurry with an offset concrete screed apparatus, the method comprising: attaching a cross support bar of the offset concrete screed apparatus to a liftable arm of a motorized vehicle; attaching a roller screed to the offset concrete screed apparatus; attaching a power unit to the roller screed; controlling the power unit to rotate the roller screed; lowering the liftable arm of the motorized vehicle until the roller screed comes in contact with the wet concrete slurry; and driving the motorized vehicle forward to screed the wet concrete slurry; wherein the roller screed is positioned offset from the motorized vehicle allowing the motorized vehicle to be driven outside forms containing the wet concrete slurry during the screeding.\",\n \"10.The method of claim 9, further comprising: providing a roller support structure to attach the roller screed to the offset concrete screed apparatus; and providing mechanical structure for reducing mechanical friction between the roller support structure and the roller screed.\",\n \"11.The method of claim 9, further comprising: hinging one or more lateral support bars downward by no more than a predetermined amount from horizontal, defined as a support bar angle, wherein the support bar angle is no less than 5degrees and no greater than 25 degrees; and attaching the roller screed to the offset concrete screed apparatus with the one or more lateral support bars.\",\n \"12.The method of claim 9, wherein the power unit is an electric motor.\",\n \"13.The method of claim 9, further comprising: attaching a screed bar to one or more lateral support bars; wherein the roller screed is attached to the screed bar.\",\n \"14.The method of claim 13, further comprising: using a previously poured concrete swath as one of the forms for containing the wet concrete slurry during the screeding; affixing a screed bar spacer to an end of the screed bar adjacent a surface of the previously poured concrete swath; and wherein the screed bar spacer has a predetermined thickness to compensate for the screeding process delta, the predetermined thickness being at least ⅛ inch but no great than ⅜ inch.\",\n \"15.The method of claim 13, further comprising: removably attaching a subgrade screeder attachment to the screed bar, wherein the subgrade screeder attachment extends below an underside of the screed bar by a depth equal to a predetermined thickness; and smoothing subgrade material between the forms with the subgrade screeder attachment to a level the predetermined thickness below top edges of the forms.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>\"\n ],\n [\n \"<SOH> SUMMARY <EOH>Embodiments disclosed herein address drawbacks of the conventional mechanical concrete screeds.\",\n \"The presently disclosed embodiments save considerable labor in the process or leveling wet concrete.\",\n \"For example, a conventional screed device requires a crew of six or more workers to pour and finish the concrete surface.\",\n \"Using the various embodiments disclosed herein a similarly sized pour of concrete could easily be handled by three workers—a savings of at least 50% in labor costs.\",\n \"Various embodiment disclosed herein provide methods and systems for making and using a wide swath offset concrete screed apparatus for screeding wet concrete slurry.\",\n \"The apparatus includes a cross support bar, an attachment mechanism for attaching the cross support bar to a liftable arm of a motorized vehicle, and lateral support bars for attaching a screed bar to the cross support bar.\",\n \"The screed bar is positioned offset from the motorized vehicle used to operate the screed, allowing the motorized vehicle to drive outside the forms.\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of U.S. patent application Ser.\",\n \"No.\",\n \"15/621,804 filed on Jun.\",\n \"13, 2017, the disclosure of which is entirely incorporated herein by reference; and this application claims the benefit of the filing date of the Ser.\",\n \"No.\",\n \"15/621,804 application.\",\n \"BACKGROUND Field of the Invention The present invention relates to a wide swath offset concrete screed for leveling poured concrete within a form, and more specifically systems and methods of making and using a wide swath concrete screed that doesn't require mechanical vibration.\",\n \"Description of Related Art Wet concrete generally arrives on-site in a concrete truck for pouring into the forms to define the desired level when the concrete dries.\",\n \"When the concrete is poured from the chute of the concrete truck the result is generally mounds of wet concrete—often called mud or slurry—piled above the level defined by the top edges of the forms.\",\n \"The slurry must be promptly leveled as it is poured, before it hardens or sets.\",\n \"Typically, the leveling is performed by a screed—a specialized tool that traverses the forms.\",\n \"Smaller pours such as a sidewalk can be leveled with a hand screed that one or more workers drag along the forms to level the mounds of wet concrete.\",\n \"It is not feasible to use hand screeds for larger pours such as parking lots, road surfaces, the floors of buildings or other such large, flat concrete surfaces.\",\n \"The weight of the concrete being pulled off is generally too great for workers to use hand screeds.\",\n \"Larger concrete projects must be poured in strips that may be ten to twenty feet wide, but can even be thirty or more feet wide.\",\n \"Conventional mechanized concrete screeds are used to level the strips of concrete.\",\n \"One such type of conventional mechanized screed involves the use of a vibrating screed.\",\n \"A small gasoline engine is mounted on the screed with a rotating offset weight designed to impart vibration to the screed as it is dragged across the wet mud.\",\n \"Some conventional vibrating screed implementations require one or more workers just outside the forms to push and guide the screed along the top of the forms as the engine vibrates the screed.\",\n \"The vibration is required to prevent small pebbles from momentarily catching on the front edge of the screed and dragging small holes in the surface of the slurry before the pebble finally passes under the screed.\",\n \"The vibration aids in pushing the small pebbles down into the slurry, allowing the conventional vibrating screed to pass over the pebbles with minimal perturbation to the surface of the wet concrete.\",\n \"A gasoline or diesel engine is required for this conventional solution, thus requiring one or more workers to attend to the engine as the device is started and stopped many times during the course of a day's pouring.\",\n \"Due to the dirt and dust present at the work site it can be difficult to keep the conventional vibrating screed from breaking down during a pour, often necessitating emergency repairs to keep pouring while concrete trucks are standing by ready to unload their wet concrete.\",\n \"Published U.S. Patent Application 2009/0092444A1 to Schoen (hereinafter “Schoen”) describes a conventional wide swath motorized screeds.\",\n \"The Schoen screed features a screed mechanism attached to a skid loader that a worker operates to pull the mounds of wet concrete and create a level surface.\",\n \"Another implementation of a conventional mechanical screed involves attaching a conventional vibrating screed to a front end loader or skid loader.\",\n \"Mounting a conventional vibrating screed on a front end loader eliminates the need for concrete workers to push the screed along as it vibrates.\",\n \"SUMMARY Embodiments disclosed herein address drawbacks of the conventional mechanical concrete screeds.\",\n \"The presently disclosed embodiments save considerable labor in the process or leveling wet concrete.\",\n \"For example, a conventional screed device requires a crew of six or more workers to pour and finish the concrete surface.\",\n \"Using the various embodiments disclosed herein a similarly sized pour of concrete could easily be handled by three workers—a savings of at least 50% in labor costs.\",\n \"Various embodiment disclosed herein provide methods and systems for making and using a wide swath offset concrete screed apparatus for screeding wet concrete slurry.\",\n \"The apparatus includes a cross support bar, an attachment mechanism for attaching the cross support bar to a liftable arm of a motorized vehicle, and lateral support bars for attaching a screed bar to the cross support bar.\",\n \"The screed bar is positioned offset from the motorized vehicle used to operate the screed, allowing the motorized vehicle to drive outside the forms.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are incorporated in and constitute part of the specification, illustrate various embodiments of the invention.\",\n \"Together with the general description, the drawings serve to explain the principles of the invention.\",\n \"In the drawings: FIG.\",\n \"1 is an oblique view of a wide swath offset concrete screed according to various embodiments disclosed herein; FIG.\",\n \"2 is an oblique view depicting wide swath offset concrete screed in use as wet concrete is being poured; FIG.\",\n \"3 is a close up view depicting details of the hinge assembly between the lateral support bar and the cross support bar; FIG.\",\n \"4 depicts the wide swath concrete screed being used to level wet concrete using a previously poured swath of concrete in lieu of a form; FIG.\",\n \"5 depicts embodiments of an optional screed bar spacer and subgrade screeder attachments that may be affixed to the screed bar; FIG.\",\n \"6 depicts the wide swath offset concrete screed being raised; FIG.\",\n \"7 depicts a lateral support bar configured to have a slight amount of curve; and FIG.\",\n \"8 is a flowchart depicting the use of the concrete screed 100 according to various embodiments of the invention; FIGS.\",\n \"9-10 are oblique views depicting embodiments of an up-down offset concrete screed; FIG.\",\n \"11A depicts an embodiment of a vibrating float assembly; and FIG.\",\n \"11B depicts an embodiment of a rotating float assembly.\",\n \"DETAILED DESCRIPTION Typically, to pour a swath of concrete a pair of longitudinal forms is assembled at the desired level of the concrete.\",\n \"The longitudinal forms run along the sides of the swath, and an end form may be positioned between the longitudinal forms, defining the end of the swath.\",\n \"Once the wet concrete slurry is poured within the longitudinal forms—generally, one truckload at a time—the leveling is performed by running a screed along the top of the longitudinal forms to smooth the swath of concrete between the forms.\",\n \"The term “leveling” is used to describe the smoothing process using a screed.\",\n \"The result of “leveling” the wet concrete slurry with a screed produces a relatively flat surface between the forms.\",\n \"This flat concrete surface that results from leveling with a screed may, or may not, be level with respect to the earth's surface.\",\n \"For example, the floors of buildings, parking lots and other concrete surfaces are often designed to have a slight degree of slope in order to allow water to run off.\",\n \"Concrete surfaces are often poured to slope between ⅛ inch per foot to up to ⅝ inch per foot, with ¼ inch per foot being a common value.\",\n \"Therefore, the term “leveling” as it is used herein implies that the surface of the concrete is smoothed to conform to a flat surface between the top edges of the forms, and may include a built in amount of slope rather than being perfectly level relative to the earth's surface.\",\n \"That is, leveling wet concrete means to smooth the surface to be relatively flat across the tops of the two forms the concrete was poured into.\",\n \"In situations where multiple swaths are being poured to form a wide expanse of concrete, it is often the case that the previously poured swath of concrete, now hardened, is used in place of the forms on one side of the next swath to be poured.\",\n \"In such cases where a swath is being poured beside another, previously poured swatch, a spacer may be used to compensate for the level of freshly screeded concrete being slightly lower than the level of the underside of the screed, as discussed further in conjunction with FIG.\",\n \"5.Motorized screeds—that is, a screed mechanism attached to a skid loader or other motorized vehicle—are often used to save time and labor in pouring swaths of concrete.\",\n \"The present inventor recognized several drawbacks inherent in the designs of conventional mechanized screeds, for example, the Schoen screed of Published U.S. Patent Application 20090092444A1.One major drawback of it is that the front end loader of the conventional Schoen screed must be driven within the forms directly ahead of the wet concrete being leveled.\",\n \"Nearly all concrete is poured over one or more layers of iron rebar lying on a surface of sand which acts to strengthen and reinforce the concrete.\",\n \"Using the conventional Schoen motorized screed requires the skid loader to be driven over the rebar, pushing it into the layer of sand beneath the concrete and often causing deformities in the rebar.\",\n \"This would render the rebar useless unless remedied before the concrete dries.\",\n \"Thus, workers must be positioned between the conventional Schoen screed and the wet concrete being leveled to pull the rebar out of the sand.\",\n \"Another disadvantage of the Schoen device that the present inventor recognized involves the end form for the pour.\",\n \"An end form is the form at the end of the swath being poured, for example, to define the edge of a building pad or parking lot.\",\n \"A skid loader cannot be driven over the end form without destroying it.\",\n \"So, in order to use the Schoen device the end form must be assembled as soon as the front end loader of the conventional Schoen screed passes that point.\",\n \"Alternatively, some sort of makeshift removable bridge or ramps could be constructed over the end form, allowing the front end loader of the conventional Schoen screed to be driven up over the end forms without damaging them.\",\n \"These, and other drawbacks of the conventional screeds recognized by the present inventor, are overcome by various embodiments disclosed herein.\",\n \"FIG.\",\n \"1 is an oblique view of a wide swath offset concrete screed 100 according to various embodiments disclosed herein.\",\n \"The wide swath concrete screed is mounted on a motorized vehicle 101 such as a skid loader, an extension loader, a front end loader, a tractor, a backhoe, a truck, a tractor, a tracked loader, or other such motorized vehicle.\",\n \"The wheeled vehicle 101 has a liftable mechanical arm 119 of sufficient strength to hold the screed assembly with the capability of lifting it up and down.\",\n \"The offset wide swath concrete screed 100 affords the advantage of being mounted to the side of motorized vehicle 101—that is, the concrete screed 100 is mounted such that the screed bar 107 is offset to the side of the motorized vehicle 101.To be considered “offset” the screed bar 107 must be positioned outside the wheels (or track, if a tracked vehicle) in the direction of an axel of the motorized vehicle 101.This offset mounting configuration allows the motorized vehicle 101 to be driven along the outside of concrete forms 197.This is a significant advantage over conventional mechanized screeds that drive within the concrete forms.\",\n \"In this way the various embodiments disclosed herein do not push the rebar 199 into the sand as the concrete is being screeded.\",\n \"Moreover, the various embodiments of the wide swath concrete screed disclosed herein are able to screed concrete right to the end of the longitudinal forms without damaging the end form.\",\n \"Various embodiments of screeds disclosed herein are also capable of being mounted directly in front of the motorized vehicle 101 for those situations when there is insufficient room alongside the forms 197 to drive the motorized vehicle 101, e.g., when the last swath being poured is up against a fence, wall or building.\",\n \"The liftable arm 119 of the motorized vehicle 101 allows a user to lift the concrete screed 100 up and down as needed during the pour.\",\n \"Since the concrete screed 100 may weigh 300 pounds or more, with an outer end that extends beyond the motorized vehicle 101 by several feet more the width of the longitudinal forms, the liftable arm 119 must have sufficient strength to withstand the rotational force due to the weight of the concrete screed 100 hanging out to the side.\",\n \"The offset concrete screed 100 includes a connection mechanism 143 or structure for attaching the cross support bar 103 to the motorized vehicle 101.In some embodiments the connection mechanism 143 includes two metal plates bolted together to clamp down on the cross support bar 103 and hold it securely to the liftable arm 119.In some embodiments the connection mechanism 143 includes U-bolts, or metal cables, to secure the cross support bar 103 to the liftable arm 119.In other embodiments the connection mechanism 143 includes an adapter to fasten the cross support bar 103 to a fork lift attachment, or a three-point hitch, of the liftable arm 119.In yet other embodiments the connection mechanism 143 attaches to a hydraulic cylinder to affix the cross support bar 103 to the motorized vehicle 101.Regardless of the configuration, the various embodiments of the connection mechanism 143 includes structural means for attaching the cross support bar 103 to the liftable arm 119 of the motorized vehicle 101, either in a stationary position or in a manner capable of hinging.\",\n \"A screed bar 107 is configured to pull the mounds of wet concrete slurry deposited within the forms by a concrete truck.\",\n \"In this way the slurry is leveled during a pour by the action of the motorized vehicle driving back and forth on the outside of forms 197.The screed bar 107 is pulled by lateral support bars 105, which in turn, are connected to cross support bar 103.The motorized vehicle 101 may be positioned to push the cross support bar 103 in the direction of screeding movement 173, as shown in FIG.\",\n \"1.Alternatively, the motorized vehicle 101 may be positioned on the other side of the cross support bar 103 so as to pull the cross support bar 103 in the direction of movement 173.In either case, the screed bar 107 is dragged behind the cross support bar 103 as the wet concrete slurry is being screeded.\",\n \"This dragging motion prevents the screed bar 107 from jamming down or catching on the forms as it is moved along.\",\n \"The screed bar 107 is of sufficient length for both ends to rest on the longitudinal forms 197.Typically the screed bar 107 is slightly wider than the distance between the longitudinal forms 197 so that the screed bar 107 extends beyond the longitudinal forms 197 by a few inches.\",\n \"In a typical implementation the screed bar 107 may be from 6 to 24 inches longer than the distance between the longitudinal forms 197.In other implementations the screed bar 107 may be any length from the same width as the outer width of the forms up to ten or more feet wider than the width of the forms.\",\n \"There is no set limit as to how much wider the screed bar 107 is as compared to the width of the forms 197.However, since workers often walk or stand just outside the forms it tends to be more safe and convenient for the width of the screed bar 107 to extend beyond the forms by no more than a few inches on each side.\",\n \"For example, in some embodiments the screed bar 107 is of a sufficient length so that it extends beyond the forms by 8-10 inches on either side to keep the screed from falling inside the forms 197.Depending upon the application, the swatch of concrete may be of any given width.\",\n \"For some uses the width of the concrete swath is not important.\",\n \"For example, a large expanse of concrete such as a parking lot may sometimes be poured in strips or swaths of any width, up to the maximum width, that is desired by the prime contractor or suitable for the situation.\",\n \"However, some applications (and some builders) require that the concrete be poured in a specific width swatch, e.g., 12 feet, 15 feet, 20 feet, 25 feet, 30 feet, or other such swath widths.\",\n \"To accommodate these specific swath widths, the concrete screed 100 may be equipped with various lengths of screed bar 107.In some embodiments, the length of the screed bar 107 is fixed, and bars of various lengths are swapped out to accommodate the required swath width.\",\n \"Other embodiments of the screed bar 107 are configured so that the length of the screed bar 107 may be adjusted to suit the distance between the forms 197 or other parameters.\",\n \"This may be achieved by providing a telescoping screed bar 107, or by providing removable sections of the screed bar 107 which may be swapped out to achieve the desired length.\",\n \"The screed bar 107 is held by two or more lateral support bars 105, which in turn, are connected to a cross support bar 103.To smooth out the mounds of wet concrete the motorized vehicle 101 is typically positioned to push the cross support bar 103.However, the cross support bar 103 is configured to pull the screed bar 107 along, dragging the wet concrete to a level format.\",\n \"This pulling action aids in preventing the screed bar 107 from gouging into the longitudinal forms, thus making the screed bar 107 operate more smoothly as the wet concrete is being leveled.\",\n \"FIG.\",\n \"2 is an oblique view depicting wide swath offset concrete screed 100 in use as wet concrete is being poured.\",\n \"The figure shows the point in time when the wet concrete from one truck has already been leveled out, the screed bar 107 has been lifted up out of the way, and motorized vehicle of 101 (not shown) of the concrete screed 100 is backed up so as to allow another truckload of wet concrete to be poured.\",\n \"As shown in FIG.\",\n \"2 the lateral support bar 105 is attached to the cross support bar 103 by a hinge assembly 109 configured to hinge upward as the screed bar 107 comes to rest on forms 197.The hinge assembly 109 prevents the screed bar 107 from hinging downward more than a predetermined amount, in order to lift the screed bar 107 off the forms as shown in FIG.\",\n \"2.The predetermined amount—defined as the support bar angle—is measured at the point where the motorized vehicle 101's liftable arm 119 has been lowered such that the screed bar 107 just touches the forms 197.That is, the support bar angle is the angle between the axis of rotation of the hinge assembly 109 and the bottom front edge of the screed bar 107 when it is lowered to the point of just touching the forms 197.It should be clear from this that the the support bar angle does not depend upon the shape of the lateral support bar 105.At this point, if the cross support bar 103 is raised it will lift the screed bar 107 up since the hinge assembly 109 won't hinge downward past the support bar angle.\",\n \"On the other hand, if the cross support bar 103 is instead lowered the hinge assembly 109 will hinge upward since the screed bar 107 is resting on the forms 197.Various embodiments are configured so the lateral support bar 105 hangs downward at a support bar angle of from 1 degree to as much as 60 degrees, or any angle within these limits, with a hang angle of 15 degrees being typical.\",\n \"The lower limit of the support bar angle, 1 degrees, is determined by the distance between the axis of rotation of the hinge assembly 109 and the bottom surface of the cross support bar 103, and depends on the length of the lateral support bar 105.FIG.\",\n \"3 is a close up view depicting details of one embodiment of the hinge assembly 109 between the lateral support bar 105 and the cross support bar 103.Other embodiments may use like types of structures configured to provide a hinging action such as an ordinary hinge, a rocker arm assembly, a trough holding the ends of lateral support bars 105 and flexible cable controlling the maximum hinge angle or support bar angle, a ball joint, or other like types of hinging structures.\",\n \"The hinge assembly 109 connects the lateral support bar 105 to the cross support bar 103.The hinge assembly 109 allows the lateral support bar 105, and in turn the screed bar 107, to hinge upward as the device is lowered onto the longitudinal forms 199.As discussed above, the hinge assemblies 109 prevent the lateral support bars 105, and in turn the cross support bar 103, from hinging downward by more than a predetermined amount, defined as the support bar angle.\",\n \"In this way the motorized vehicle 101 can lift the screed bar 107 up in the air.\",\n \"The conventional Schoen screed of Published U.S. Patent Application 20090092444A1 features a mounting pocket 62 that prevents arm 48 from rotating too far downward.\",\n \"Such a pocket/arm assembly could be used with embodiments disclosed herein as a hinging mechanism.\",\n \"However, the present inventor recognized certain drawbacks with the Schoen pocket/arm assembly.\",\n \"Namely, the pocket tends to retain wet concrete and small pebbles during the course of a working day.\",\n \"This, in turn, makes the pocket difficult to clean upon completion of a work day.\",\n \"At the end of each day, and perhaps even during the course of the day, the bar 48 must be rotated upward out of pocket 62 in order to clean out all the accumulated concrete and pebbles.\",\n \"If the pocket 62 of the Schoen device is allowed to dry overnight without being thoroughly cleaned it will sometimes freeze in place as the bits of remaining concrete dry and harden.\",\n \"The Schoen device can also freeze up while it is being used if a small pebble or bit of concrete becomes lodged between the bar 48 and pocket 62.The hinge assembly 109 overcomes these drawbacks since it is a more open design which does not tend to accumulate pebbles and wet concrete.\",\n \"The hinge assembly 109 is easier to clean with a hose and water since there is no pocket for pebbles and wet concrete to gather in during the course of a day.\",\n \"In various embodiments of the offset concrete screed 100, the hinge assembly 109 is rotatably connected to cross support bar 103 by a pin 121.By “rotatably connected” it is meant that the hinge assembly is connected in a manner that allows it to rotate, or hinge, about an axis.\",\n \"In some implementations the pin 121 passes through, or is otherwise connected to, a pin holder bar 123.In other embodiments the pin 121 is connected directly to the cross support bar 103.The pin 121 may be a bolt of sufficient diameter (e.g., ⅜ to 1 inch) for supporting the weight of the lateral support bars 105 and screed bar 107.The bolt may be kept in place with a nut, or two nuts tightened against each other, and washers to aid in preventing wear on the bolt and hinge assembly 109.In other implementations a hinge pin, a metal rod, or other like type of pin may be used as the pin 121.In some embodiments one or more springs 167 are connected to some point on the support bar assembly to provide more downward force than the weight of the screed bar 107.The additional downward force aids in preventing the screed bar from riding up over the wet concrete slurry.\",\n \"Typically, the springs 167 are configured to be removable so that weaker or stronger springs—or multiple springs—can be attached, as needed.\",\n \"In this way the user is able to adjust the downward force to accommodate the conditions of the pour.\",\n \"Some embodiments use compression springs to push downward on the support bar assembly.\",\n \"In other embodiments leaf springs are used to provide the downward force.\",\n \"The hinge assembly 109 is typically configured so that it comes to rest against cross support bar 103 when the offset concrete screed 100 is raised up in the air.\",\n \"The hinge assembly 109 hinges upward in response to the concrete screed 100 being lowered so that the screed bar 107 rests on forms 197.This allows the screed bar 107 to ride along the top of the forms 197 without damaging the forms.\",\n \"The hinging action also allows the screed bar 107 to ride up over an overly large mound of wet concrete to avoid putting too much horizontal strain on the screed bar 107 and concrete screed 100.If the screed bar 107 rides up over an overly large mound of wet concrete the user can simply raise the offset concrete screed 100 up in the air, back up the motorized vehicle 101, and take one or more additional passes at smoothing the large mound of wet concrete.\",\n \"Since embodiments of the offset concrete screed 100 allow the motorized vehicle 101 to be driven off to the side rather than over the rebar, the user can efficiently make several passes without need to have workers reposition to rebar after each pass, as is required for conventional motorized screed devices.\",\n \"FIG.\",\n \"4 depicts the wide swath concrete screed 100 being used to level the wet concrete slurry 193 using a previously poured swath of concrete 195 in lieu of a form on one side.\",\n \"In pouring large expanses of concrete for a parking lot or building pad it is often the case that the swaths are poured side by side with the previous day's swath acting as a form on one side of the current pour.\",\n \"The very first swath poured requires a form 197 to be set up on each side of the swath to be poured.\",\n \"For each subsequent swath poured after the previous swath has hardened (e.g., a day or more later) only one form 197 needs to be erected.\",\n \"The previously poured swath 195, now hardened, acts as a form on the other side to contain the newly poured wet concrete slurry 193.One issue with using a previously poured swath in lieu of a form is that the process or screeding wet concrete results in a screeding process delta in which the level of the concrete is slightly lower than the level of the forms (or the form and the previously poured swath being used as a form).\",\n \"For example, a screeded concrete surface may end up ¼ inch or so lower than the forms on either side—that is, have a screeding process delta of ¼ inch or so.\",\n \"This is because the wet concrete slurry contains small pebbles and gravel in it.\",\n \"The screeding process delta results because the screed bar 107 tends to push some of the small pebbles and gravel in front of it, causing the screeded surface of the wet concrete slurry to be slightly lower than the bottom surface of screed bar 107, e.g., ¼ inch or so lower.\",\n \"This can be somewhat troublesome if the concrete is being poured in long swaths alongside a previously poured swath—now hardened—from the previous day.\",\n \"If the screeding process delta was not compensated for and the form 197 was erected to be level with the previously poured swath, each newly poured swath would end up being ¼ inch or so lower than the previously poured swath beside it.\",\n \"If a number of swaths were poured this way the result would be that each swath would be ¼ inch or so lower due to the screeding process delta of each swath.\",\n \"In order to avoid this, it is desirable to provide forms 197 for the new swath to be poured that are at a level slightly higher than the previously poured swath to its side by an amount equal to the anticipated screeding process delta.\",\n \"The slightly higher level of the form 197 compensates for the lower level of finished concrete due to the screed bar 107 pushing small pebbles and gravel in front of it.\",\n \"However, if the previously poured swath (which has hardened) is being used as one of the forms 197 then it is not possible to adjust the height of the previously poured swath to compensate for the screeding process delta.\",\n \"To this end, various embodiments use a screed bar spacer affixed to the bottom of screed bar 107 on the side of the previously poured swath in conjunction with the form 197 being constructed slightly higher than the level of the previously poured swath.\",\n \"FIG.\",\n \"4 also depicts a screed bar extension 135.The cross section of the screed bar extension 135 is typically the same as the screed bar 107, with a slightly smaller cross-sectional portion that fits into the end of the screed bar 107.One or more holes 139 may be provided for bolts 141 used to secure the screed bar extension 135 to the screed bar 107.The bolts 141 pass through holes 139 and tighten into threaded holes 137.FIG.\",\n \"4 also depicts the wide swath concrete screed equipped with a scrape auger 181.The scrape auger 181 acts to push excess wet slurry concrete to one side or the other so as to aid in preventing too much wet slurry concrete from building up and pouring over the top of screed bar 107.Typically, the lower edge of the scrape auger 181 is positioned slightly above the lower edge of screed bar 107, e.g., one to three inches, but may be positioned as little as ¼ inch to as much as one foot above the lower edge of screed bar 107.The scrape auger 181 may either be affixed to the cross support bar 103 or may be affixed to lateral support bars 105 by connection points 179.Typically, connection points 179 have a bearing or greased sleeve to reduce the mechanical friction as the auger 181 rotates.\",\n \"The auger 181 is rotationally powered by a power unit 183.The power unit 183 may be similar to power unit 185 depicted in FIG.\",\n \"11B.\",\n \"Power unit 183 may be implemented in various forms, including for example, a gas or diesel engine, an electric motor, a hydraulic motor, a rotating shaft connected to the power take-off of the motorized vehicle, a rotating linkage connected to the engine of the motorized vehicle, or other like type of power unit known to those of ordinary skill in the art.\",\n \"The power unit 183 may either be connected to the cross support bar 103, or in other implementations, may be connected to one or more of the lateral support bars 105.The power unit 183 may be controlled by a user to controllably rotate the auger 181 at varying speeds.\",\n \"The auger 181 may be rotated in one direction to push the wet concrete slurry towards the motorized vehicle 101, and may be controlled to rotate in the opposite direction to push the wet concrete slurry away from the motorized vehicle 101.FIG.\",\n \"5 depicts embodiments 500 and 550 of an optional screed bar spacer and subgrade screeder 147 attachments that may be affixed to the screed bar.\",\n \"As shown in the figure, the screed bar spacer 125 is affixed to the end of the screed bar 107 resting on a previously poured concrete surface 195 to compensate for the screeding process delta.\",\n \"The screed bar spacer 125 is a removable attachment with a predetermined thickness that compensates for the level of freshly screeded concrete being slightly lower than the level of the underside of the screed bar 107 due to small pebbles and gravel being pushed in front of screed bar 107 during the screeding process.\",\n \"A user simply taps the screed bar spacer 125 into position within the screed bar 107, and it is held in place by friction.\",\n \"To remove the screed bar spacer 125, the user merely taps it back out.\",\n \"The screed bar spacer 125 is held to the bottom side of screed bar 107 on the end that rides across the swath of previously poured, hardened concrete.\",\n \"Since the level of the freshly screeded concrete will be lower by a slight amount than the bottom of the screed bar 107 due to the screeding process delta, the screed bar spacer 125 allows the screed bar 107 to pass over the newly poured concrete at a level slightly higher than the desired level of the finished concrete surface to compensate for the screeding process delta.\",\n \"In this way, the newly screeded concrete will end up at approximately the same level as the previously poured concrete swath adjacent to it.\",\n \"The wide swath offset concrete screed 100 may be provisioned with screed bar spacers 125 of various thicknesses, depending upon the anticipated amount of screeding process delta—that is, the amount that the newly poured concrete is anticipated to be lower.\",\n \"The anticipated amount of screeding process delta depends upon the characteristics of the wet concrete slurry such as the size of the pebbles and gravel in the wet concrete slurry, how wet the concrete slurry is, the temperature of the wet concrete slurry, etc.\",\n \"Since a given contractor may order wet concrete slurry many times from the same concrete supplier, the contractor will generally get a feel for the amount of screeding process delta to expect from a particular concrete provider for a given grade of concrete.\",\n \"A screed bar spacer 125 for use with the various embodiments may have a predetermined thickness of as little as 1/16 inch or as much as ¾ inch, or any value in between, depending upon the characteristics of the wet concrete slurry resulting in screeding process delta.\",\n \"A typical thickness for a slab of concrete 8 inches thick is ¼ inch.\",\n \"In various embodiments the bottom side of the screed bar spacer 125 is smooth with rounded corners in order to push the pebbles and gravel of the wet concrete slurry underneath it during the screeding process.\",\n \"This aids in preventing the pebbles and gravel from scraping along the surface of the wet concrete slurry before they pass beneath the screed bar spacer 125.In addition the screed bar spacer 125 is configured to be smooth with rounded corners aids to avoid gouging or scoring the concrete surface that it rests and slides upon.\",\n \"FIG.\",\n \"5 depicts another screed bar spacer embodiment—the screed bar spacer 127 which is configured with a wheel that rolls along the previously poured concrete surface 195.The screed bar spacer 127 is particularly useful when the previously poured concrete 195 has not yet hardened sufficiently to avoid scoring the surface.\",\n \"The screed bar spacer 127 slides into screed bar 107, and is tightened into place with a compression bolt 133.Moreover, the screed bar spacer 127 may be configured to be adjustable by providing an elongated slot either for bolt 129 or for a bolt at point 131.FIG.\",\n \"5 also depicts a subgrade screeder attachment 147.To preparing a pour site the contractor generally deposits gravel, sand or pebbles, or some other subgrade material, between the longitudinal forms 197.It is important to have a uniformly flat, level subgrade surface to pour the wet concrete slurry on, in order to ensure that the resulting concrete pad is of a uniform thickness.\",\n \"According to conventional methods, the subgrade material is graded and leveled by hand with shovels or rakes.\",\n \"These conventional methods of preparing the subgrade are quite a labor intensive and must be performed prior to pouring the concrete.\",\n \"It generally takes at least a couple—or even several—manual laborers working to smooth and level the subgrade material by hand, and it is nearly impossible to create a uniformly flat, level subgrade surface.\",\n \"The embodiments disclosed herein overcome aid in cutting down the manual labor required to prepare the subgrade materials by hand, while at the same time drastically increasing the precision of the subgrade leveling process.\",\n \"The subgrade screeder attachment 147 depicted in FIG.\",\n \"5 attaches to the screed bar 107 using one or more bolts 149.Alternatively, the subgrade screeder attachment 147 may be affixed to the screed bar 107 using pins, clamps, cables, chains, or other like type of structures for affixing the subgrade screeder attachment 147 in place on the screed bar 107.In other embodiments the subgrade screeder attachment 147 is attached to the screed bar 107 with a hinge mechanism so that it can be hinged upward out of the way when not in use.\",\n \"The depth that the subgrade screeder attachment 147 extends below the lower level of screed bar 107 is adjustable in order to equal the desired thickness of the concrete pad being poured.\",\n \"In the embodiment depicted in FIG.\",\n \"5 there are a series of holes that allow the subgrade screeder attachment 147 to be set at various depths, thus creating concrete pads of various thicknesses.\",\n \"In other embodiments the subgrade screeder attachment 147 has an elongated hole, or slot, to allow adjustment up and down to create various thickness of a concrete pad.\",\n \"Typically, the width of the subgrade screeder attachment 147 is slightly narrower than the width of the longitudinal forms 197, for example, one to six inches narrower.\",\n \"The screeder attachment 147 may be provided in multiple pieces so as to easily vary the width to accommodate the width of the longitudinal forms 197.The subgrade screeder attachment 147 is typically made of metal.\",\n \"Aluminum generally provides sufficient strength, and is advantageously lightweight.\",\n \"However, other implementations of the subgrade screeder attachment 147 may be made of iron, steel, or other like metals.\",\n \"In some embodiments the lower edge of the subgrade screeder attachment 147 may be curved slightly in the direction of screeding movement 173.The slight curve tends to cut into the loose gravel, sand or pebbles typically used as subgrade material, thus pulling the subgrade screeder attachment 147 slightly downward to create a smooth, level subgrade surface.\",\n \"In various embodiments the curved portion of the lower edge of the subgrade screeder attachment 147 is angled from as little as 15 degrees to as much as 90 degrees, relative to vertical.\",\n \"In other embodiments the lower edge of the subgrade screeder attachment 147 is squared off straight, rather than having a slight curve as shown in FIG.\",\n \"5.FIG.\",\n \"6 depicts the wide swath offset concrete screed 100 in a raised position.\",\n \"In some instances the area just outside the forms and just beyond the end of the swath of concrete being poured may have an obstacle such as a fence or building, or otherwise be inaccessible.\",\n \"When this occurs it may not be possible to drive the motorized vehicle 101 very far beyond the end of the swath of concrete.\",\n \"In such situations it is useful to be able to lift the concrete screed 100 high enough to permit a concrete truck to back up close enough to unload the wet concrete beneath the raised screed.\",\n \"Various embodiments of the concrete screed 100 can be raise high enough to permit wet concrete to be unloaded beneath it, as shown in FIG.\",\n \"6.For example, depending upon the type of motorized vehicle 101 being used, the wide swath offset concrete screed 100 can be raised to a level of fifteen feet or more.\",\n \"For embodiments using an extension loader as the motorized vehicle 101 as depicted in FIG.\",\n \"6 the offset concrete screed 100 can be raised to over twelve feet.\",\n \"This is sufficient height to allow a concrete truck to back up and deliver its load of wet concrete slurry under the offset concrete screed 100.Other embodiments may raise the concrete screed 100 even higher, for example, for clearance beneath the screed bar 107 of 15 feet or even more, depending upon how far the liftable arm 119 of the motorized vehicle 101 is able to extend or rise in the air.\",\n \"As the liftable arm 119 is lowered it is desirable not to slam it into the lateral forms 197.To aid in this some embodiments include a flow restrictor 145 in the hydraulic line to controllably constrict the flow of hydraulic fluid.\",\n \"The flow restrictor 145 tends to slow down the upward and downward movement of the liftable arm 119, making it easier for a user to ease the liftable arm 119 into position as it is raised and lowered during the screeding process.\",\n \"FIG.\",\n \"7 depicts a lateral support bar 105 configured to have a slight amount of curve at point 175.In various embodiments it is desirable for the underside of screed bar 105 to lay relatively flat on the wet concrete slurry and the longitudinal forms 197.Having the underside of screed bar 105 flat aids in keeping it from riding up over mounds of wet concrete slurry as it is pulled along, or gouging into the wet concrete.\",\n \"Further, the flat underside as it is drawn over the wet concrete slurry provides a smoothing effect that helps to produce a smooth, level surface of the finished concrete.\",\n \"At the same time it is desirable to keep the cross support bar 103 several inches above the forms 197 to keep it from catching on the forms 197 and causing perturbations in the smooth surface of the concrete.\",\n \"To achieve this—having the underside of screed bar 105 flat while the cross support bar 103 passes several inches above the forms 197—various embodiments of the lateral support bars 105 are configured to have a slight amount of curve.\",\n \"In some embodiments the lateral support bars 105 are gradually curved along their entire length.\",\n \"In other embodiments, the lateral support bars 105 are curved at a particular point, for example, at point 175 as depicted in FIG.\",\n \"7.In yet other embodiments, the lateral support bars 105 are angled at a particular point rather than being gradually curved (e.g., a sharp curve).\",\n \"In all of these embodiments the lateral support bars 105 are said to be curved by a lateral support bar curve 177.In various implementations the lateral support bar curve 177 may vary from as little as 1 degree to as much as 30 degrees, and may be any value in between these two extremes.\",\n \"A typical value for the lateral support bar curve 177 is 4 degrees.\",\n \"In some embodiments the lateral support bars 105 are approximately four feet long.\",\n \"However, the length may be varied depending upon the requirements of the pour and the situation in which it is to be used to be as short as one foot or as long as twelve feet.\",\n \"Using shorter lateral support bars 105 will result in the cross support bar 103 being positioned closer to the forms 197.Using longer lateral support bars 105 will result in more downward rotational force on the cross support bar 103 due to the increased leverage.\",\n \"Therefore, in various embodiments the lateral support bars 105 are generally kept within three to six feet, with four feet being a typical length embodiment.\",\n \"FIG.\",\n \"8 is a flowchart depicting the use of the concrete screed 100 according to various embodiments of the invention.\",\n \"Reference is made to the previous figures in the application, including various reference numbers shown in the figures.\",\n \"The method begins at block 801 and proceeds to block 803 where the user provides a cross support bar 103.The cross support bar 103 is typically connected to the liftable arm 119 of a motorized vehicle 101.The method proceeds to block 803 for attaching the lateral support bars 105 to the cross support bar 103.This is generally done using hinge assemblies 109.In some embodiments, however, the lateral support bars 105 may be fixedly connected to the cross support bar 103, with the lateral support bars 105 themselves being capable of hinging.\",\n \"The lateral support bars 105 typically have a slight amount of bend in them, e.g., approximately four degrees—that is, 4°+/−10%.\",\n \"In block 807 the screed bar 107 is connected to the lateral support bars 105.Typically, the screed bar 107 is fixedly attached to the lateral support bars 105.However, in some embodiments the screed bar 107 may be connected to the lateral support bars 105 in a manner that allows the screed bar 107 to have some play or movement relative to the lateral support bars 105, e.g., a hinging motion.\",\n \"In block 809 it is determined whether the longitudinal forms 197 are wider apart than the length of the screed bar 107.If the screed bar 107 needs to be longer, the method proceeds along the “YES” path to bock 811 for attachment of one or more screed bar extensions 135 to the screed bar 107, and then proceeds to block 813.If the screed bar 107 is of sufficient length for the configuration of longitudinal forms 197 the method proceeds from block 809 along the “NO” path to block 813.In block 813 of FIG.\",\n \"8 it is determined whether the wet concrete slurry is to be poured into forms on either side (e.g., for the first concrete swath to be poured), or a previously poured, now hardened, swath of concrete is to be used on one side of the pour in place of the longitudinal forms for that side.\",\n \"If previously poured swath of concrete is to be used in place of the forms it may be the case that the screeding will result in a screeding process delta in which the level of the concrete is slightly lower than the level of the forms, as discussed previously in conjunction with FIG.\",\n \"5.If a screeding process delta—that is, a level of the concrete surface slightly lower than the scree bar surface—is anticipated, the method proceeds from block 813 along the “YES” path to block 815 to attach a screed bar spacer 125 or 127.However, if no screed bar spacer is desired the method proceeds from block 813 along the “NO” path to block 817.In block 817 the user operates the motorized vehicle 101 to screed the wet concrete slurry to a desired degree of levelness.\",\n \"During the screeding process it is sometimes the case that the screed bar 107 needs to be raised, for example, to back the motorized vehicle 101 up or to allow a concrete truck to deliver another load of concrete.\",\n \"If, in block 819, it is determined that the screed bar 107 needs to be raised the method proceeds along the “YES” path to block 823 to raise the screed bar 107 (or lower it if it was previously raised).\",\n \"The method then proceeds to block 821 to determine whether further screeding operations need to be performed.\",\n \"If further screeding is to be done, the method proceeds back to block 817 along the “YES” path.\",\n \"However, if the screeding is completed the method proceeds from block 821 along the “NO” path to block 825 where the method ends.\",\n \"Various activities of the method disclosed herein may be included or excluded as described above, or maybe performed in a different order than the particular examples chosen to illustrate the embodiments.\",\n \"For example, it may be the case that the screed bar extension may be attached to the screed bar (block 811) prior to attaching the screed bar to the lateral support bar (block 807).\",\n \"Or it may be the case that the screed bar spacer may be attached to the screed bar (block 815) prior to attaching the screed bar to the lateral support bar (block 807).\",\n \"The sequence of steps for performing the method of making and using a wide swath offset concrete screed according to the various embodiments disclosed herein may be altered in many other ways as well.\",\n \"FIGS.\",\n \"9-10 are oblique views depicting embodiments of an up-down offset concrete screed.\",\n \"The present inventor recognized the difficulty of screeding concrete into certain tight spaces—for example, screeding into the corner formed by two buildings, or screeding right up against a building or a wall.\",\n \"In such tight spaces it is desirable to be able to operate the screed as closely as possible up to the limiting obstruction.\",\n \"The embodiments depicted in FIGS.\",\n \"9-10 make it possible to screed into tight places with only a minimum of finish work to be done by hand.\",\n \"The up-down offset concrete screed embodiment features two or more vertical support bars 151.The vertical support bars 151 are designed to move up and down, as needed, during the screeding operation.\",\n \"For example, it may be that the surface outside the forms on which the motorized vehicle 101 is driving is unlevel or bumpy.\",\n \"If the motorized vehicle 101 moves up or down as it is traveling along, the vertical support bars 151 can move down or up, as needed, so that the screed bar 107 may remain on the forms 197.In some instances, if there is too much wet concrete slurry 193 being pushed the screed bar 107 may ride up over the slurry, leaving an unlevel spot that will require further screeding on another pass.\",\n \"Each vertical support bar 151 is enclosed by a support bar sleeve 153 that allows the vertical support bar 151 to move up and down.\",\n \"The end of each vertical support bar 151 is larger than the passage dimensions of the support bar sleeve 153 to prevent the vertical support bar 151 from passing through it.\",\n \"This allows the cross support bar 103 to lift up the vertical support bar 151 and accompanying screed bar 107.To aid in the up/down movement the support bar sleeves 153 have bearings on their inner surface, making it easier for the vertical support bars 151 to ride up and down with the lateral force of the concrete slurry pushing against them.\",\n \"Alternatively, the support bar sleeves 153 may have small wheels or lubricant instead of bearings.\",\n \"The vertical support bars 151 are rotatably attached to the screed bar 107 allowing the vertical support bars 151 to rotate about an axis, the axis being in the direction of screeding—that is, the axis of rotation is in the same direction as the direction of screeding (e.g., motorized vehicle movement), allowing the direction of rotation to be back and forth at a right angle to the direction of screeding.\",\n \"Similarly, the support bar sleeves 153 are rotatably attached to the cross support bar 103.In this way, if the motorized vehicle 101 drives on an unlevel or bumpy spot causing the cross support bar 103 to raise up or dip relative to the screed bar 107, the vertical support bars 151 won't bind up if they raise or drop by different amounts.\",\n \"In this way the screeding operation can continue smoothly even though the cross support bar 103 does not remain parallel with the screed bar 107.The vertical support bars 151 may be rotatably attached to the screed bar 107 by a tab 155 that is welded, bolted or otherwise affixed to the screed bar 107.The tab 155 has a pin or bolt configured to pass through a hole in the vertical support bar 151, thus allowing the vertical support bars 151 to rotate relative to the screed bar 107.In other embodiments (no shown) the tab 151 is affixed to the vertical support bar 151 and has a bolt or pin that passes through a hole in the screed bar 107.FIG.\",\n \"10 depicts details of an embodiment for rotatably connecting the support bar sleeves 153 to the cross support bar 103.FIG.\",\n \"10 is oblique cutaway view of an embodiment of the support bar sleeve 153 that rotatably attaches the support bar sleeve 153 to the cross support bar 103.In this embodiment the hinging mechanism is a bolt 157 that is welded, or otherwise attached, to the support bar sleeve 153 and passes through a hole 159 in the cross support bar 103.The bolt 157 allows the support bar sleeve 153 to rotate as needed relative to the the cross support bar 103.Other hinge mechanisms may be used in various implementations to connect the vertical support bars 151 to either the support bar 103 or to the screed bar 107, including for example, a hinge, a flexible cable, chain links affixed to each part, a shaft and bearings, a trough or slot that supports a shaft, or other like mechanisms known to those of ordinary skill in the art.\",\n \"FIG.\",\n \"11A depicts an embodiment of a vibrating float assembly configured to be pulled behind the screed bar 107.In typical implementations the vibrating float assembly is fairly lightweight, for example, weighing between five and twenty-five pounds.\",\n \"However, either heavier or lighter implementations may be constructed, depending upon the dimensions and materials used in the vibrating float assembly itself, and the characteristics of the concrete slurry being floated.\",\n \"Typically, two or more vibrating float assemblies are rotatably affixed to the screed bar 107.In some embodiments two or more points on the screed bar 107 serve as the points of rotation for the float assemblies to hinge, or rotate, downward onto the surface of the wet concrete slurry.\",\n \"In other embodiments, as shown in FIG.\",\n \"11B, the float assembly itself—in the form of a roller screed—rotates about an axis connected to screed bar 107.Turning again to FIG.\",\n \"11A, some embodiments feature only one float affixed to the screed bar 107.The screed bar 107 generally is configured to extend beyond the outermost and innermost vibrating float assemblies by at least a few inches.\",\n \"That way, the vibrating float assemblies ride solely on the wet concrete slurry and do not extend quite to the forms.\",\n \"However, in some implementations, the vibrating float assemblies may be configured to be the same width as the screed bar 107 so the outermost portions of the vibrating float assemblies ride on the forms just as the screed bar 107 does.\",\n \"Each vibrating float assembly has a float pan 161.The float pans 161 are constructed in various lengths, depending upon the length of the screed bar 107 to which they are attached.\",\n \"The float pans 161 attached to a particular screed bar 107 do not all necessarily need to be the same length.\",\n \"For example, a 17foot screed bar 107 for use on forms 197 that are 16 feet apart may have an 8 foot float pan 161 and a seven foot float pan 161 which are spaced 2 inches apart.\",\n \"This would leave 5 inches of space between the outmost edges of the float pans 161 and the forms 197.The float pan 161 features a lip that is bent upwards the full length of the pan.\",\n \"The bent lip may be from one to four inches wide.\",\n \"In typical implementations the bent lip is approximately two inches wide and the overall width of the pan is approximately twelve inches.\",\n \"The bent lip may be bent upwards from as little as 3 degrees to as much as 60 degrees.\",\n \"In typical implementations, the bent lip may be bent upwards from 35 to 55 degrees, with 45 degrees being a common amount.\",\n \"The flat bottom surface of the float pan 161 is generally configured to be wider than the bent lip portion, e.g., from 2 inches to 20 inches wide.\",\n \"In typical implementations, the flat bottom portion is from six to twelve inches wide.\",\n \"The float pan 161 may be constructed from a number of materials, including for example, aluminum, magnesium, steel, iron, wood, composite material, or the like.\",\n \"Each float pan 161 has mounted upon it a vibrating mechanism—typically an off-balance vibrating electric motor.\",\n \"The electric motor may either be wired to a power source back on the motorized vehicle such as the vehicle's battery, or may have a battery pack mounted in place with it on the float pan 161.The motor and battery pack are generally mounted towards the center of the float pan 161 to evenly distribute their weight across the wet concrete slurry.\",\n \"Each float pan 161 is affixed to the screed bar 107 by one or more float hinge mechanisms.\",\n \"The embodiment depicted in FIG.\",\n \"11A has a float hinge mechanism features a U-shaped member that fits snuggly over the screed bar 107.In some embodiments the U-shaped member may bolt, screw or otherwise be attached to the screed bar 107 so as to be more firmly attached than friction would allow.\",\n \"The hinge member 163 is rotatably connected to a hinge tab 165.The hinge tab 165 is affixed to the float bar 107 by welding, bolts, rivets, screws, or other ways of attaching materials together known to those of skill in the art.\",\n \"The hinge member 163 is rotatably connected to a hinge tab 165 by a bolt or pin, allowing it to rotate in the direction 169.Typically, the float hinge mechanism is configured to allow the float pan to hinge downward from horizontal by a limited amount somewhat less than 30 degrees.\",\n \"For example, in one embodiment the float pan can hinge downward an amount between 1 and 15 degrees—with an amount of downward hinging between 1 and 6 degrees being typical.\",\n \"To measure it another way, the hinge mechanism allows the float pan to hinge downward from 1 to 4 inches, as measured by the distance the float bar 107 is raised above the level of the forms 197 before the float pan's rear edge begins to come off the surface of the wet concrete slurry.\",\n \"In this way, the float pan will gently ride on top of the concrete slurry to a horizontal position as the screed bar 107 is lowered towards the forms 197.If the float pan is allowed to hinge down into too steep of an angle, it will gouge into the wet concrete slurry as the screed bar 107 is lowered.\",\n \"FIG.\",\n \"11B depicts an embodiment in which the float bar is in the form of a rotating float assembly, typically called a roller screed.\",\n \"The roller screed 187 is manipulated back and forth to smooth the surface of the wet concrete slurry.\",\n \"In various embodiments the direction of rotation at the point where the roller screed 187 meets the wet concrete slurry is in direction 171 towards the slurry yet to be smoothed, that is, towards the wet concrete slurry that has just been delivered by a concrete truck.\",\n \"In some embodiments (e.g., the embodiment of FIG.\",\n \"11B) the roller screed 187 may take the place of the screed bar 107 itself, shown in FIGS.\",\n \"1-6.In other embodiments one or more roller screed(s) 187 may be configured in the manner of the float pans attached behind the screed bar 107 as shown in FIG.\",\n \"11A.\",\n \"In various roller screed embodiments the roller screed 187 is rotated by one or more power units 185.The power unit 185 may be implemented in various forms, including for example, a gas or diesel engine, an electric motor, a hydraulic motor, a rotating shaft connected to the power take-off of the motorized vehicle, a rotating linkage connected to the engine of the motorized vehicle, or other like type of power unit known to those of ordinary skill in the art.\",\n \"In various embodiments the power unit 185 may be connected to the cross support bar 103.In various embodiments the power unit 185 may be connected to one or more of the lateral support bars 105.The power unit 185 may be controlled by a user to controllably rotate the roller screed 187.This allows the rotation speed of the roller screed 187 to be adjusted, and turned on and off, so as to accommodate different pouring conditions.\",\n \"In some embodiments equipped with both a roller screed 187 and an auger 181 the same power unit may be used to rotate both the roller screed 187 and the auger 181.In some roller screed embodiments the lateral support bars 105 may be configured to hinge upward as shown in FIG.\",\n \"11B.\",\n \"In other embodiments the lateral support bars 105 may be rigidly affixed to the cross support bar 103 without a provision to hinge upward.\",\n \"In yet other embodiments one or more springs may be provided to provide downward force on the roller screed 187 in addition to the weight of the roller screed 187 itself.\",\n \"In various embodiments the lateral support bars 105 may be substantially perpendicular to the cross support bar 103 as shown in FIG.\",\n \"11B.\",\n \"In other embodiments one or more of the lateral support bars 105 may be attached to the cross support bar 103 at angles other than substantially perpendicular to the cross support bar 103.For example, the lateral support bars 105 may angled relative to the cross support bar 103 outward away from the motorized vehicle.\",\n \"In various embodiments the roller screed 187 is rotatably connected at both ends to a roller support structure 189.The roller support structure 189 may be configured on the outside and above the roller screed 187 as shown in FIG.\",\n \"11B, or may be configured to pass through the center of roller screed 187.The support structure 189 is at least above the lower edge of roller screed 187 so as to avoid being dipped into the wet concrete slurry.\",\n \"In most implementations the support structure 189 is above the upper edge of the roller screed 187.The support structure 189 may be directly over the roller screed 187, or may be positioned above and either ahead of or behind the roller screed 187.Some embodiments are equipped with a screed connector 191.The screed connector 191 may be configured with a mechanical friction reduction component such as ball bearings, roller bearings, greased spindle and socket, or other such means of mechanical friction reduction as are known to those of ordinary skill in the art.\",\n \"The screed connector 191 may include one or more of a wheel or rollers to roll along the concrete forms or adjacent previously poured concrete surface.\",\n \"The screed connector 191 may be configured to accept a screed bar spacer 125 as shown in FIG.\",\n \"5.The description of the various embodiments provided above is illustrative in nature inasmuch as it is not intended to limit the invention, its application, or uses.\",\n \"Thus, variations that do not depart from the intents or purposes of the invention are intended to be encompassed by the various embodiments of the present invention.\",\n \"Such variations are not to be regarded as a departure from the intended scope of the present invention.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875785"}}},{"rowIdx":4494977,"cells":{"text":{"kind":"list like","value":[["Orientation Layer for Directed Self-Assembly Patterning Process","Disclosed is a method of forming a semiconductor device using a self-assembly (DSA) patterning process.","The method includes forming a patterned feature over a substrate; applying an orientation material that includes a first polymer and a second polymer over the substrate, wherein the first polymer has a first activation energy and the second polymer has a second activation energy; baking the substrate at first temperature thereby forming a first orientation layer that includes the first polymer; baking the substrate at second temperature thereby forming a second orientation layer that includes the second polymer; and performing a directed self-assembly (DSA) process over the first and the second orientation layers."],["1.A method comprising: forming a patterned feature over a substrate, applying an orientation material that includes a first polymer and a second polymer over the substrate, wherein the first polymer has a first activation energy and the second polymer has a second activation energy; baking the substrate at first temperature thereby forming a first orientation layer that includes the first polymer; baking the substrate at second temperature thereby forming a second orientation layer that includes the second polymer; and performing a directed self-assembly (DSA) process over the first and the second orientation layers.","2.The method of claim 1, wherein the performing the DSA process includes: depositing a copolymer material over the first and the second orientation layers, wherein the copolymer material is directed self-assembling; and inducing microphase separation within the copolymer material thereby defining a first constituent of the copolymer material and a second constituent of the copolymer material.","3.The method of claim 2, wherein the copolymer material includes one or more materials from a group consisting of polystyrene-block-polydimethylsiloxane block copolymer (PS-b-PDMS), polystyrene-block-polymethylmethacrylate (PS-b-PMMA), polyethyleneoxide-block-polyisoprene (PEO-b-PI), polyethyleneoxide-block-polybutadiene (PEO-b-PBD), polyethyleneoxide-block-polystyrene (PEO-b-PS), polyethyleneoxide-block-polymethylmethacrylate (PEO-b-PMMA), polyethyleneoxide-block-polyethylethylene (PEO-b-PEE), polystyrene-block-polyvinylpyridine (PS-b-PVP), polystyrene-block-polyisoprene (PS-b-PI), polystyrene-block-polybutadiene (PS-b-PBD), polystyrene-block-polyferrocenyldimethylsilane (PS-b-PFS), polybutadiene-block-polyvinylpyridine (PBD-b-PVP), and polyisoprene-block-polymethylmethacrylate (PI-b-PMMA).","4.The method of claim 1, wherein the first activation energy is lower than the second activation energy and the first temperature is lower than the second temperature.","5.The method of claim 1, wherein a thickness of the first orientation layer that includes the first polymer ranges between about 5 nanometers and about 10 nanometers.","6.The method of claim 1, wherein the first temperature ranges between about 80° C. and about 150° C., and the second temperature ranges between about 180° C. and about 250° C. 7.The method of claim 1, wherein the first polymer includes a backbone that includes a hydroxyl group with a first amount of carbon side chains and the second polymer includes a backbone that includes a hydroxyl group with a second amount of carbon side chains, the first amount being greater than the second amount.","8.A method comprising: providing a substrate having a patterned feature formed thereon; applying an orientation material that includes a first polymer and a second polymer over the substrate; forming a first orientation layer that includes the first polymer by baking the substrate and orientation material at a first temperature; forming a second orientation layer that includes the second polymer from a portion of the orientation material floating over the first orientation layer by baking the substrate at a second temperature higher than the first temperature; and performing a directed self-assembly (DSA) process over the first and the second orientation layers.","9.The method of claim 8, further comprising forming the second orientation layer directly on a sidewall of the patterned feature and directly over the first orientation layer.","10.The method of claim 8, wherein a thickness of the first orientation layer that includes the first polymer ranges between about 5 nanometers and about 10 nanometers.","11.The method of claim 8, wherein the first temperature ranges between about 80° C. and about 150° C., and the second temperature ranges between about 180° C. and about 250° C. 12.The method of claim 8, wherein the first polymer includes a backbone that includes a hydroxyl group with a first amount of carbon side chains and the second polymer includes a backbone that includes a hydroxyl group with a second amount of carbon side chains, the first amount being greater than the second amount.","13.The method of claim 8, wherein performing the DSA process includes: depositing a copolymer material over the first and the second orientation layers, wherein the copolymer material is directed self-assembling; and inducing microphase separation within the copolymer material thereby defining a first constituent of the copolymer material and a second constituent of the copolymer material.","14.The method of claim 13, wherein the copolymer material includes one or more materials from a group consisting of polystyrene-block-polydimethylsiloxane block copolymer (PS-b-PDMS), polystyrene-block-polymethylmethacrylate (PS-b-PMMA), polyethyleneoxide-block-polyisoprene (PEO-b-PI), polyethyleneoxide-block-polybutadiene (PEO-b-PBD), polyethyleneoxide-block-polystyrene (PEO-b-PS), polyethyleneoxide-block-polymethylmethacrylate (PEO-b-PMMA), polyethyleneoxide-block-polyethylethylene (PEO-b-PEE), polystyrene-block-polyvinylpyridine (PS-b-PVP), polystyrene-block-polyisoprene (PS-b-PI), polystyrene-block-polybutadiene (PS-b-PBD), polystyrene-block-polyferrocenyldimethylsilane (PS-b-PFS), polybutadiene-block-polyvinylpyridine (PBD-b-PVP), and polyisoprene-block-polymethylmethacrylate (PI-b-PMMA).","15.A method comprising: providing a substrate having a patterned feature formed thereon; applying an orientation material that includes a first polymer and a second polymer over the substrate; forming a first orientation layer that includes the first polymer over a first portion of the substrate by baking the substrate at a first temperature; forming a second orientation layer that includes the second polymer over a second portion of the substrate including by baking the substrate at a second temperature higher than the first temperature; and performing a directed self-assembly (DSA) process over the first and the second orientation layers.","16.The method of claim 15, further comprising forming the second orientation layer from a floating portion of the orientation material directly on a sidewall of the patterned feature and directly over the first orientation layer.","17.The method of claim 15, wherein the first polymer includes a hydroxyl functional group.","18.The method of claim 15, wherein the first polymer includes a carboxyl functional group or an amide functional group.","19.The method of claim 15, wherein treating the substrate includes applying a plasma-assisted dry etching process by flowing N2/H2 or O2.20.The method of claim 19, wherein applying the plasma-assisted dry etching process includes applying the plasma-assisted dry etching process at a temperature ranging from about 0° C. to about 80° C. and at pressure ranging from about 10 millitorr (mT) to about 60 mT."],["<SOH> BACKGROUND <EOH>The present application is a divisional application of U.S. application Ser.","No.","14/918,310 filed on Oct. 20, 2015, which is hereby incorporated by reference in its entirety.","The semiconductor integrated circuit (IC) industry has experienced exponential growth.","Technological advances in IC materials and design have produced generations of ICs where each generation has smaller and more complex circuits than the previous generation.","In the course of IC evolution, functional density (i.e., the number of interconnected devices per chip area) has generally increased while geometry size (i.e., the smallest component (or line) that can be created using a fabrication process) has decreased.","This scaling down process generally provides benefits by increasing production efficiency and lowering associated costs.","Such scaling down has also increased the complexity of processing and manufacturing ICs.","For example, as optical lithography approaches its technological and economical limits, a directed self-assembly (DSA) process emerges as a potential candidate for patterning dense features.","A DSA process takes advantage of the self-assembling properties of materials, such as block copolymers (BCP), to reach nanoscale dimensions while meeting the constraints of current manufacturing.","However, while existing DSA processes have been generally adequate for their intended purposes, they have not been entirely satisfactory in every aspect."],["<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>The present disclosure is best understood from the following detailed description when read with the accompanying figures.","It is emphasized that, in accordance with the standard practice in the industry, various features are not drawn to scale and are used for illustration purposes only.","In fact, the dimensions of the various features may be arbitrarily increased or reduced for clarity of discussion.","FIG.","1 shows a flow chart of a method of fabricating a semiconductor device, according to various aspects of the present disclosure.","FIGS.","2A-2E are cross sectional views of forming a semiconductor device according to the method of FIG.","1 in accordance with some embodiments.","FIG.","3 shows a schematic view of the orientation material that is used in the method of FIG.","1 in accordance with some embodiments.","FIG.","4 shows a flow chart of a method of fabricating a semiconductor device, according to various aspects of the present disclosure.","FIGS.","5A-5E are cross sectional views of forming a semiconductor device according to the method of FIG.","4 in accordance with some embodiments.","FIG.","6 shows a schematic view of the orientation material that is used in the method of FIG.","4 in accordance with some embodiments.","FIG.","7 shows a flow chart of a method of fabricating a semiconductor device, according to various aspects of the present disclosure.","FIGS.","8A-8F are cross sectional views of forming a semiconductor device according to the method of FIG.","1 in accordance with some embodiments.","FIG.","9 shows a schematic view of the orientation material that is used in the method of FIG.","7 in accordance with some embodiments.","detailed-description description=\"Detailed Description\" end=\"lead\"?"],["BACKGROUND The present application is a divisional application of U.S. application Ser.","No.","14/918,310 filed on Oct. 20, 2015, which is hereby incorporated by reference in its entirety.","The semiconductor integrated circuit (IC) industry has experienced exponential growth.","Technological advances in IC materials and design have produced generations of ICs where each generation has smaller and more complex circuits than the previous generation.","In the course of IC evolution, functional density (i.e., the number of interconnected devices per chip area) has generally increased while geometry size (i.e., the smallest component (or line) that can be created using a fabrication process) has decreased.","This scaling down process generally provides benefits by increasing production efficiency and lowering associated costs.","Such scaling down has also increased the complexity of processing and manufacturing ICs.","For example, as optical lithography approaches its technological and economical limits, a directed self-assembly (DSA) process emerges as a potential candidate for patterning dense features.","A DSA process takes advantage of the self-assembling properties of materials, such as block copolymers (BCP), to reach nanoscale dimensions while meeting the constraints of current manufacturing.","However, while existing DSA processes have been generally adequate for their intended purposes, they have not been entirely satisfactory in every aspect.","BRIEF DESCRIPTION OF THE DRAWINGS The present disclosure is best understood from the following detailed description when read with the accompanying figures.","It is emphasized that, in accordance with the standard practice in the industry, various features are not drawn to scale and are used for illustration purposes only.","In fact, the dimensions of the various features may be arbitrarily increased or reduced for clarity of discussion.","FIG.","1 shows a flow chart of a method of fabricating a semiconductor device, according to various aspects of the present disclosure.","FIGS.","2A-2E are cross sectional views of forming a semiconductor device according to the method of FIG.","1 in accordance with some embodiments.","FIG.","3 shows a schematic view of the orientation material that is used in the method of FIG.","1 in accordance with some embodiments.","FIG.","4 shows a flow chart of a method of fabricating a semiconductor device, according to various aspects of the present disclosure.","FIGS.","5A-5E are cross sectional views of forming a semiconductor device according to the method of FIG.","4 in accordance with some embodiments.","FIG.","6 shows a schematic view of the orientation material that is used in the method of FIG.","4 in accordance with some embodiments.","FIG.","7 shows a flow chart of a method of fabricating a semiconductor device, according to various aspects of the present disclosure.","FIGS.","8A-8F are cross sectional views of forming a semiconductor device according to the method of FIG.","1 in accordance with some embodiments.","FIG.","9 shows a schematic view of the orientation material that is used in the method of FIG.","7 in accordance with some embodiments.","DETAILED DESCRIPTION The following disclosure provides many different embodiments, or examples, for implementing different features of the provided subject matter.","Specific examples of components and arrangements are described below to simplify the present disclosure.","These are, of course, merely examples and are not intended to be limiting.","For example, the formation of a first feature over or on a second feature in the description that follows may include embodiments in which the first and second features are formed in direct contact, and may also include embodiments in which additional features may be formed between the first and second features, such that the first and second features may not be in direct contact.","In addition, the present disclosure may repeat reference numerals and/or letters in the various examples.","This repetition is for the purpose of simplicity and clarity and does not in itself dictate a relationship between the various embodiments and/or configurations discussed.","Further, spatially relative terms, such as “beneath,” “below,” “lower,” “above,” “upper” and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures.","The spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures.","The apparatus may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein may likewise be interpreted accordingly.","The present disclosure is generally related to semiconductor devices, and more particularly to methods for manufacturing semiconductor devices with dense and nanoscale patterns.","When fabricating dense patterns, a directed self-assembly (DSA) process may be used to enhance and augment the existing semiconductor manufacturing capabilities.","In a typical DSA process, a block copolymer (BCP) film is formed over lithographically defined surfaces and a microphase separation is induced to cause the constituent polymer molecules to self-assemble, thus creating densely packed features with uniform dimensions and shapes.","A BCP film or simply a BCP includes polymers comprised of at least two different polymer segments.","These polymer segments are configured to assemble themselves into highly ordered structures under certain conditions such as for example, when they are exposed to an elevated temperature.","In general, a neutral layer or an orientation layer is disposed on a surface of a substrate of a lithographically defined surface before forming the BCP film.","The neutral layer has no affinity for either of the polymer segments of the BCP film.","During a DSA process, the neutral layer may be able to lead/orientate a first polymer segment for directed self-assembly.","However, in order to orientate a second polymer segment for directed self-assembly, at least one additional process (e.g., forming another neutral layer using the additional process to orientate the second polymer segment) is required.","The forming the another neutral layer generally includes multiple process to be involved such as for example, removing part of the neutral layer that leads the first polymer segment, providing a pattern for the neutral layer that is to lead the second polymer segment, and removing the patterned neutral layer.","In contrast, the present disclosure provides various embodiments of a method to form an improved neutral layer without requiring the above-identified additional processes.","Referring now to FIG.","1, a flow chart of a method 100 of forming a semiconductor device is illustrated according to various aspects of the present disclosure.","Additional operations can be provided before, during, and after the method 100, and some operations described can be replaced, eliminated, or moved around for additional embodiments of the method.","The method 100 is briefly described below.","Then, some embodiments of the method 100 will be described in conjunction with FIGS.","2A, 2B, 2C, 2D, 2E, and 3.Referring to FIGS.","1 and 2A, the method 100 begins at operation 102 by providing a substrate 202 with a pattern 204.The substrate 202 may include one or more layers of material or composition.","For example, the substrate 202 may include an elementary semiconductor, such as silicon and germanium.","The substrate 202 may also include a compound semiconductor such as silicon carbide, gallium arsenic, indium arsenide, and indium phosphide.","The substrate 202 may include an alloy semiconductor such as silicon germanium, silicon germanium carbide, gallium arsenic phosphide, and gallium indium phosphide.","The substrate 202 may also include an epitaxial layer.","For example, the substrate 202 may have an epitaxial layer overlying a bulk semiconductor.","Furthermore, the substrate 202 may include a semiconductor-on-insulator (SOI) structure.","For example, the substrate 202 may include a buried oxide (BOX) layer formed by a process such as separation by implanted oxygen (SIMOX) or other suitable technique, such as wafer bonding and grinding.","In some other embodiments, the substrate 202 may further include a top layer (not shown) overlaying a top surface of the substrate 202.As such, the top layer may include silicon oxide, silicon nitride, oxynitride, silicon carbide, titanium oxide, titanium nitride, tantalum oxide, tantalum nitride, and/or any suitable materials.","In the illustrated embodiment of FIG.","2A, pattern 204 may be a resist layer (e.g., a photoresist layer).","The resist layer may be a positive resist or a negative resist, and may be a resist suitable for deep ultraviolet (DUV), extreme ultraviolet (EUV), electron beam (e-beam), and/or other lithography processes.","In some specific embodiments, pattern 204 is formed of organic materials.","While still falling within the scope of the present disclosure, the pattern 204 may be formed of one of a variety of materials that is suitable for forming a pattern.","The pattern 204 may be formed by any suitable methods such as for example, a chemical vapor deposition (CVD) process, an atomic layer deposition (ALD) process, a spin-on coating, and/or any combination thereof.","Referring still to FIG.","2A, the substrate 202 includes an exposed top surface 203, and the pattern 204 includes a sidewall 205.According to the current embodiments, the top surface 203 of the substrate 202 and the sidewall 205 of the pattern 204 each includes a different surface characteristic.","For example, the top surface 203 includes an oxidized surface which is more reactive while the sidewall 205 includes a surface that is formed of organic materials which is less reactive.","Referring to FIG.","1, the method 100 proceeds to operation 104 by providing an orientation layer that is formed of at least two polymers (e.g., a first polymer and a second polymer).","In an embodiment, as illustrated in FIG.","3, the orientation layer includes a first polymer 302 and a second polymer 304.More specifically, the first polymer 302 includes a polymer backbone 302′ and at least an atom/unit of the backbone 302′ is replaced with or modified by a group 303; and the second polymer 304 includes a polymer backbone 304′ and at least an atom/unit of the backbone 304′ is replaced with or modified by a group 305.The group 303 is a hydroxyl group with a higher amount of carbon side chains (e.g., carbon side chains >4) and the group 305 is a hydroxyl group with a lower amount of carbon side chains (e.g., carbon side chains <2).","As such, the first polymer 302 may have a lower activation energy than the second polymer 304 may have.","That is, the first polymer 302 with the lower activation energy may be activated at a first elevated temperature and the second polymer 304 with the higher activation energy may be activated at a second elevated temperature, wherein the first elevated temperature is lower than the second elevated temperature.","Referring to FIGS.","1 and 2B, the method 100 proceeds to operation 106 with forming a first orientation layer 208.In the example of the orientation material is formed of the polymers 302 and 304 with respect to FIG.","3, as illustrated in FIG.","2B, an orientation layer 208 is formed on the top surface 203 of the substrate by baking the substrate to temperature between about 80° C. and about 150° C., wherein the orientation layer 208 is formed of the first polymer 302 (lower activation energy).","In some embodiments, during the formation of the orientation layer 208, another portion (higher activation energy) of the orientation material (i.e., the portion formed of the second polymer 304) may float above the formed orientation layer 208, illustrated as 210 in FIG.","2B.","That is, the portion 210 has not been formed as an orientation layer yet in operation 106.In some embodiments, the orientation layer 208 may have a thickness ranging between about 5 nanometers to about 10 nanometers.","The method 100 continues to operation 108 with forming a second orientation layer.","Continuing with the above example in which the orientation material is formed of the polymers in FIG.","3, a second orientation layer 210′ that is formed of the second polymer 304 is formed on the sidewall 205 by baking the substrate to temperature between about 180° C. and about 250° C. as illustrated in the embodiment of FIG.","2C.","The method 100 proceeds to operation 110 with performing a directed self-assembly (DSA) process.","In some embodiments, the operation 110 may include multiple processes in the following order: depositing a directed self-assembly (DSA) block copolymer (BCP) layer 212 over the first orientation layer 208 and the second orientation layer 210 (as illustrated in FIG.","2D); applying an elevated temperature to anneal the BCP layer 212 thereby achieving segregation in the BCP layer 212 to form first and second polymer nanostructures, 214 and 216 (as illustrated in FIG.","2E).","Generally, a BCP material includes polymers comprised of at least two different polymer segments, and these polymer segments can assemble themselves into highly ordered structures under certain conditions, such as when they are exposed to an elevated temperature.","In the current embodiment, the BCP layer 212 may include one or more of polystyrene-block-polydimethylsiloxane block copolymer (PS-b-PDMS), polystyrene-block-polymethylmethacrylate (PS-b-PMMA), polyethyleneoxide-block-polyisoprene (PEO-b-PI), polyethyleneoxide-block-polybutadiene (PEO-b-PBD), polyethyleneoxide-block-polystyrene (PEO-b-PS), polyethyleneoxide-block-polymethylmethacrylate (PEO-b-PMMA), polyethyleneoxide-block-polyethylethylene (PEO-b-PEE), polystyrene-block-polyvinylpyridine (PS-b-PVP), polystyrene-block-polyisoprene (PS-b-PI), polystyrene-block-polybutadiene (PS-b-PBD), polystyrene-block-polyferrocenyldimethylsilane (PS-b-PFS), polybutadiene-block-polyviny.","Still referring to FIGS.","1 and 2E, during the DSA process (i.e., operation 110), by choosing the height of the pattern 204 (i.e., h1), the height of the first orientation layer 208 (i.e., h2), and the materials of the BCP layer 212, the first and second polymer nanostructures 214 and 216 are formed such that they have a height approximately same as the difference of the heights h1 and h2, they are parallel to each other.","In the illustrated embodiment of FIG.","2E, the first and second polymer nanostructures 214 and 216 are aligned along direction X, and each of them extends in a direction (i.e., Y axis in FIG.","2E) that is parallel to the sidewall 205.However, the BCP layer 212 may be formed into a variety of shapes that are regularly aligned such as for example, a sphere, a cylinder, a lamellae, and any suitable shape known in the art.","The formed polymer nanostructures 214 and 216 may be later used as a pattern for a further fabrication step.","In an example, one of the polymer nanostructures (e.g., 214) may be etched away and the other polymer nanostructure (e.g., 216) may be left on the substrate as a hard mask layer to transfer a pattern onto the substrate thereby reaching a finer critical dimension (CD).","Referring now to FIG.","4, a flow chart of another method 400 of forming a semiconductor device is illustrated according to various aspects of the present disclosure.","Additional operations can be provided before, during, and after the method 400, and some operations described can be replaced, eliminated, or moved around for additional embodiments of the method.","The method 400 is briefly described below.","Then, some embodiments of the method 400 will be described in conjunction with FIGS.","5A, 5B, 5C, 5D, 5E, and 6.Referring to FIGS.","4 and 5A, the method 400 begins at operation 402 by providing a substrate 502 with a pattern 504.The substrate 502 may include one or more layers of material or composition.","For example, the substrate 502 may include an elementary semiconductor, such as silicon and germanium.","The substrate 502 may also include a compound semiconductor such as silicon carbide, gallium arsenic, indium arsenide, and indium phosphide.","The substrate 502 may include an alloy semiconductor such as silicon germanium, silicon germanium carbide, gallium arsenic phosphide, and gallium indium phosphide.","The substrate 502 may also include an epitaxial layer.","For example, the substrate 502 may have an epitaxial layer overlying a bulk semiconductor.","Furthermore, the substrate 502 may include a semiconductor-on-insulator (SOI) structure.","For example, the substrate 502 may include a buried oxide (BOX) layer formed by a process such as separation by implanted oxygen (SIMOX) or other suitable technique, such as wafer bonding and grinding.","In some other embodiments, the substrate 502 may further include a top layer (not shown) overlaying a top surface of the substrate 502.As such, the top layer may include silicon oxide, silicon nitride, oxynitride, silicon carbide, titanium oxide, titanium nitride, tantalum oxide, tantalum nitride, and/or any suitable materials.","In the illustrated embodiment of FIG.","5A, pattern 504 may be a resist layer (e.g., a photoresist layer).","The resist layer may be a positive resist or a negative resist, and may be a resist suitable for deep ultraviolet (DUV), extreme ultraviolet (EUV), electron beam (e-beam), and/or other lithography processes.","In some specific embodiments, pattern 504 is formed of organic materials.","While still falling within the scope of the present disclosure, the pattern 504 may be formed of one of a variety of materials that is suitable for forming a pattern.","The pattern 504 may be formed by any suitable methods such as for example, a chemical vapor deposition (CVD) process, an atomic layer deposition (ALD) process, a spin-on coating, and/or any combination thereof.","Referring still to FIG.","5A, the substrate 502 includes an exposed top surface 503, and the pattern 504 includes a sidewall 505.According to the current embodiments, the top surface 503 of the substrate 502 and the sidewall 505 of the pattern 504 each includes a different surface characteristic.","For example, the top surface 503 includes an oxidized surface which is more reactive to a functional group (e.g., a hydroxyl group) while the sidewall 505 includes a surface that is formed of organic materials which is less reactive to the hydroxyl group but more reactive to another functional group (e.g., an aromatic group).","Referring to FIG.","4, the method 400 proceeds to operation 404 by providing an orientation material that is formed of at least two polymers (e.g., a first polymer and a second polymer).","In an embodiment, as illustrated in FIG.","6, the orientation material includes a first polymer 602 and a second polymer 604.More specifically, the first polymer 602 includes a polymer backbone 602′ and the polymer backbone 602′ is terminated with a functional group 603; and the second polymer 604 includes a polymer backbone 604′ and the polymer backbone 604′ is terminated with a functional group 605.The functional group 603 includes at least a hydroxyl group, a carboxyl group, and/or an amide group; the functional group 605 includes at least an aromatic group.","Referring to FIGS.","4 and 5B, the method 400 proceeds to operation 406 with forming a first orientation layer 508.In the example of the orientation material is formed of the polymers 602 and 604 with respect to FIG.","6, as illustrated in FIG.","5B, an orientation layer 508 is formed on the top surface 503 of the substrate, wherein the orientation layer 508 is formed of the first polymer 602.In some embodiments, during the formation of the orientation layer 508, another portion of the orientation material (i.e., the portion formed of the second polymer 604) may float above the formed orientation layer 508, which is illustrated as 510 in FIG.","5B.","That is, the portion 510 has not been formed as an orientation layer yet in operation 406.In some embodiments, the orientation layer 508 may have a thickness ranging between about 5 nanometers to about 10 nanometers.","The method 400 continues to operation 408 with forming a second orientation layer.","Continuing with the above example in which the orientation material is formed of the polymers in FIG.","6, a second orientation layer 610′ that is formed of the second polymer 604 is formed on the sidewall 605 by baking the substrate to temperature between about 180° C. and about 250° C. as illustrated in the embodiment of FIG.","5C.","The method 400 proceeds to operation 410 with performing a directed self-assembly (DSA) process.","In some embodiments, the operation 410 may include multiple processes in the following order: depositing a directed self-assembly (DSA) block copolymer (BCP) layer 512 over the first orientation layer 508 and the second orientation layer 510 (as illustrated in FIG.","5D); applying an elevated temperature to anneal the BCP layer 512 thereby achieving segregation in the BCP layer 512 to form first and second polymer nanostructures, 514 and 516 (as illustrated in FIG.","5E).","Generally, a BCP material includes polymers comprised of at least two different polymer segments, and these polymer segments can assemble themselves into highly ordered structures under certain conditions, such as when they are exposed to an elevated temperature.","In the current embodiment, the BCP layer 512 may include one or more of polystyrene-block-polydimethylsiloxane block copolymer (PS-b-PDMS), polystyrene-block-polymethylmethacrylate (PS-b-PMMA), polyethyleneoxide-block-polyisoprene (PEO-b-PI), polyethyleneoxide-block-polybutadiene (PEO-b-PBD), polyethyleneoxide-block-polystyrene (PEO-b-PS), polyethyleneoxide-block-polymethylmethacrylate (PEO-b-PMMA), polyethyleneoxide-block-polyethylethylene (PEO-b-PEE), polystyrene-block-polyvinylpyridine (PS-b-PVP), polystyrene-block-polyisoprene (PS-b-PI), polystyrene-block-polybutadiene (PS-b-PBD), polystyrene-block-polyferrocenyldimethylsilane (PS-b-PFS), polybutadiene-block-polyviny.","Still referring to FIGS.","4 and 5E, during the DSA process (i.e., operation 510), by choosing the height of the pattern 504 (i.e., h1), the height of the first orientation layer 508 (i.e., h2), and the materials of the BCP layer 512, the first and second polymer nanostructures 514 and 516 are formed such that they have a height approximately same as the difference of the heights h1 and h2, they are parallel to each other.","In the illustrated embodiment of FIG.","5E, the first and second polymer nanostructures 514 and 516 are aligned along direction X, and each of them extends in a direction (i.e., Y axis in FIG.","5E) that is parallel to the sidewall 505.However, the BCP layer 512 may be formed into a variety of shapes that are regularly aligned such as for example, a sphere, a cylinder, a lamellae, and any suitable shape known in the art.","The formed polymer nanostructures 514 and 516 may be later used as a pattern for a further fabrication step.","In an example, one of the polymer nanostructures (e.g., 514) may be etched away and the other polymer nanostructure (e.g., 516) may be left on the substrate as a hard mask layer to transfer a pattern onto the substrate thereby reaching a finer critical dimension (CD).","Referring now to FIG.","7, a flow chart of yet another method 700 of forming a semiconductor device is illustrated according to various aspects of the present disclosure.","Additional operations can be provided before, during, and after the method 700, and some operations described can be replaced, eliminated, or moved around for additional embodiments of the method.","The method 700 is briefly described below.","Then, some embodiments of the method 700 will be described in conjunction with FIGS.","8A, 8B, 8C, 8D, 8E, 8F, and 9.Referring to FIGS.","7 and 8A, the method 700 begins at operation 702 by providing a substrate 802 with a pattern 804.The substrate 802 may include one or more layers of material or composition.","For example, the substrate 802 may include an elementary semiconductor, such as silicon and germanium.","The substrate 802 may also include a compound semiconductor such as silicon carbide, gallium arsenic, indium arsenide, and indium phosphide.","The substrate 802 may include an alloy semiconductor such as silicon germanium, silicon germanium carbide, gallium arsenic phosphide, and gallium indium phosphide.","The substrate 802 may also include an epitaxial layer.","For example, the substrate 802 may have an epitaxial layer overlying a bulk semiconductor.","Furthermore, the substrate 802 may include a semiconductor-on-insulator (SOI) structure.","For example, the substrate 802 may include a buried oxide (BOX) layer formed by a process such as separation by implanted oxygen (SIMOX) or other suitable technique, such as wafer bonding and grinding.","In some other embodiments, the substrate 802 may further include a top layer (not shown) overlaying a top surface of the substrate 802.As such, the top layer may include silicon oxide, silicon nitride, oxynitride, silicon carbide, titanium oxide, titanium nitride, tantalum oxide, tantalum nitride, and/or any suitable materials.","In the illustrated embodiment of FIG.","8A, pattern 804 may be a resist layer (e.g., a photoresist layer).","The resist layer may be a positive resist or a negative resist, and may be a resist suitable for deep ultraviolet (DUV), extreme ultraviolet (EUV), electron beam (e-beam), and/or other lithography processes.","In some specific embodiments, pattern 804 is formed of organic materials.","While still falling within the scope of the present disclosure, the pattern 804 may be formed of any of a variety of materials that is suitable for forming a pattern.","The pattern 804 may be formed by any suitable methods such as for example, a chemical vapor deposition (CVD) process, an atomic layer deposition (ALD) process, a spin-on coating, and/or any combination thereof.","Referring still to FIG.","8A, the substrate 802 includes an exposed top surface 803, and the pattern 804 includes a sidewall 805.In some embodiments, the top surface 803 of the substrate 802 and the sidewall 805 of the pattern 804 each includes a different surface characteristic.","However, in some alternative embodiments, the top surface 803 of the substrate 802 and the sidewall 805 of the pattern 804 may each have a substantial similar surface characteristic.","The method continues in operation 704 with applying a treatment 807 on the substrate 802 (more specifically, on the top surface 803 of the substrate), as illustrated in FIG.","8B.","In some embodiments, the treatment 807 may include a plasma-assisted dry etching process by flowing N2/H2 and/or O2.The etching process may be performed at temperature ranging from about 0° C. to about 80° C. and at pressure ranging from about 10 millitorr (mT) to about 60 mT.","As illustrated in FIG.","8B, the etching process (i.e., 807) may be an anisotropic process (perpendicular to the top surface 803) and thus only the top surface is treated or only the top surface's surface characteristic is changed while the sidewall 805 remains intact.","As such, after the treatment 807, the top surface 803 may include a hydrophilic surface while the sidewall 805 may include a hydrophobic surface.","Referring to FIG.","7, the method 700 proceeds to operation 706 with providing an orientation material that is formed of at least two polymers (e.g., a first polymer and a second polymer).","In an embodiment, as illustrated in FIG.","9, the orientation material includes a first polymer 902 and a second polymer 904.More specifically, the first polymer 902 includes a polymer backbone 902′ and the polymer backbone 902′ is terminated with a functional group 903; and the second polymer 904 includes a polymer backbone 904′ and the polymer backbone 904′ is terminated with a functional group 905.The functional group 903 is a hydrophilic group that is selected form a group consisting of a hydroxyl group, a carboxyl group, and an amide group; the functional group 905 is a hydrophobic group that is selected form a group consisting of a ketone group and an ether group.","Referring to FIGS.","7 and 8B, the method 700 proceeds to operation 708 with forming a first orientation layer 808.In the example of the orientation material is formed of the polymers 902 and 904 with respect to FIG.","9, as illustrated in FIG.","8C, an orientation layer 808 is formed on the top surface 803 of the substrate, wherein the orientation layer 808 is formed of the first polymer 902.By applying the treatment 807 on the substrate, the first polymer 902 terminated with the functional group 903 that includes a hydrophilic group may be more reactive to attach to the top surface 803 while the portion of the orientation material formed of the second polymer 905 may float above the orientation layer 808.That is, during the formation of the orientation layer 808, another portion of the orientation material (i.e., the portion formed of the second polymer 904) may float above the formed orientation layer 808, which is illustrated as 810 in FIG.","8B.","In some embodiments, the portion 810 has not been formed as an orientation layer yet in operation 708.In some embodiments, the orientation layer 808 may have a thickness ranging between about 5 nanometers to about 10 nanometers.","The method 700 continues to operation 710 with forming a second orientation layer.","Continuing with the above example in which the orientation material is formed of the polymers in FIG.","9, a second orientation layer 810′ that is formed of the second polymer 904 is formed on the sidewall 805 by baking the substrate to temperature between about 180° C. and about 250° C. as illustrated in the embodiment of FIG.","8D.","The method 700 proceeds to operation 712 with performing a directed self-assembly (DSA) process.","In some embodiments, the operation 712 may include multiple processes in the following order: depositing a directed self-assembly (DSA) block copolymer (BCP) layer 812 over the first orientation layer 808 and the second orientation layer 810 (as illustrated in FIG.","8E); applying an elevated temperature to anneal the BCP layer 812 thereby achieving segregation in the BCP layer 812 to form first and second polymer nanostructures, 814 and 816 (as illustrated in FIG.","8F).","Generally, a BCP material includes polymers comprised of at least two different polymer segments, and these polymer segments can assemble themselves into highly ordered structures under certain conditions, such as when they are exposed to an elevated temperature.","In the current embodiment, the BCP layer 812 may include one or more of polystyrene-block-polydimethylsiloxane block copolymer (PS-b-PDMS), polystyrene-block-polymethylmethacrylate (PS-b-PMMA), polyethyleneoxide-block-polyisoprene (PEO-b-PI), polyethyleneoxide-block-polybutadiene (PEO-b-PBD), polyethyleneoxide-block-polystyrene (PEO-b-PS), polyethyleneoxide-block-polymethylmethacrylate (PEO-b-PMMA), polyethyleneoxide-block-polyethylethylene (PEO-b-PEE), polystyrene-block-polyvinylpyridine (PS-b-PVP), polystyrene-block-polyisoprene (PS-b-PI), polystyrene-block-polybutadiene (PS-b-PBD), polystyrene-block-polyferrocenyldimethylsilane (PS-b-PFS), polybutadiene-block-polyviny.","Still referring to FIGS.","7 and 8F, during the DSA process (i.e., operation 712), by choosing the height of the pattern 804 (i.e., h1), the height of the first orientation layer 808 (i.e., h2), and the materials of the BCP layer 812, the first and second polymer nanostructures 814 and 816 are formed such that they have a height approximately same as the difference of the heights h1 and h2, they are parallel to each other.","In the illustrated embodiment of FIG.","8F, the first and second polymer nanostructures 814 and 816 are aligned along direction X, and each of them extends in a direction (i.e., Y axis in FIG.","8F) that is parallel to the sidewall 805.However, the BCP layer 812 may be formed into a variety of shapes that are regularly aligned such as for example, a sphere, a cylinder, a lamellae, and any suitable shape known in the art.","The formed polymer nanostructures 814 and 816 may be later used as a pattern for a further fabrication step.","In an example, one of the polymer nanostructures (e.g., 814) may be etched away and the other polymer nanostructure (e.g., 816) may be left on the substrate as a hard mask layer to transfer a pattern onto the substrate thereby reaching a finer critical dimension (CD).","Although in the above discussion and embodiments, the first polymer (e.g., 303, 603, and 903) is to form the first orientation layer on the top surface of the substrate (e.g., 203, 503, and 803) first and then the second polymer (e.g., 305, 605, and 905) is to form the second orientation layer on the sidewall of the pattern (e.g., 205, 505, and 805), in some alternative embodiments, the first orientation layer formed of the first polymer may be formed on the sidewall of the pattern first and the second orientation layer formed of the second polymer may be later formed on the top surface of the substrate.","For example, if the sidewall 205 has a more reactive surface than the top surface 203, the first polymer 302 with the lower activation energy may form a first orientation layer on the sidewall 205 by baking at a lower temperature and then the second polymer 304 with the higher activation energy may later from another orientation layer on the top surface by baking at a higher temperature.","Although not intended to be limiting, one or more embodiments of the present disclosure provide many benefits to a semiconductor device and the formation thereof.","For example, embodiments of the present disclosure provide methods for forming densely packed DSA patterns with uniformity and precision by using only one orientation material for a DSA process.","In some embodiments, the orientation material may be formed into two orientation layers and each of the orientation layers is configured to guide a DSA process of one of the polymer segments of a BCP material.","Without requiring a complicated patterning process and/or an additional material, such two orientation layers may be formed on respective surface.","Additionally, embodiments of the present disclosure can be easily integrated into existing fabrication flow.","In addition, even though two DSA processes are illustrated above, embodiments of the present disclosure may include more than two DSA processes where one builds upon another accumulatively.","In one exemplary aspect, the present disclosure is directed to a method of forming a semiconductor device.","The method includes forming a patterned feature over a substrate; applying an orientation material that includes a first polymer and a second polymer over the substrate, wherein the first polymer has a first activation energy and the second polymer has a second activation energy; baking the substrate at first temperature thereby forming a first orientation layer that includes the first polymer; baking the substrate at second temperature thereby forming a second orientation layer that includes the second polymer; and performing a directed self-assembly (DSA) process over the first and the second orientation layers.","In another exemplary aspect, the present disclosure is directed to a method of forming a semiconductor device.","The method includes providing a substrate having a patterned feature formed thereon; applying an orientation material that includes a first polymer and a second polymer over the substrate, wherein the first polymer is terminated with a first functional group and the second polymer is terminated with a second functional group; forming a first orientation layer that includes the first polymer on the substrate and forming a second orientation layer that includes the second polymer on the patterned feature; and performing a directed self-assembly (DSA) process over the first and the second orientation layers.","In another exemplary aspect, the present disclosure is directed to a method of forming a semiconductor device.","The method includes providing a substrate having a patterned feature formed thereon; treating the substrate thereby causing a first portion of the substrate to be hydrophilic; applying an orientation material that includes a first polymer and a second polymer over the substrate, wherein the first polymer is terminated with a first functional group and the second polymer is terminated with a second functional group; forming a first orientation layer that includes the first polymer over the first portion of the substrate and forming a second orientation layer that includes the second polymer over the patterned feature; and performing a directed self-assembly (DSA) process over the first and the second orientation layers.","The foregoing outlines features of several embodiments so that those of ordinary skill in the art may better understand the aspects of the present disclosure.","Those of ordinary skill in the art should appreciate that they may readily use the present disclosure as a basis for designing or modifying other processes and structures for carrying out the same purposes and/or achieving the same advantages of the embodiments introduced herein.","Those of ordinary skill in the art should also realize that such equivalent constructions do not depart from the spirit and scope of the present disclosure, and that they may make various changes, substitutions, and alterations herein without departing from the spirit and scope of the present disclosure."]],"string":"[\n [\n \"Orientation Layer for Directed Self-Assembly Patterning Process\",\n \"Disclosed is a method of forming a semiconductor device using a self-assembly (DSA) patterning process.\",\n \"The method includes forming a patterned feature over a substrate; applying an orientation material that includes a first polymer and a second polymer over the substrate, wherein the first polymer has a first activation energy and the second polymer has a second activation energy; baking the substrate at first temperature thereby forming a first orientation layer that includes the first polymer; baking the substrate at second temperature thereby forming a second orientation layer that includes the second polymer; and performing a directed self-assembly (DSA) process over the first and the second orientation layers.\"\n ],\n [\n \"1.A method comprising: forming a patterned feature over a substrate, applying an orientation material that includes a first polymer and a second polymer over the substrate, wherein the first polymer has a first activation energy and the second polymer has a second activation energy; baking the substrate at first temperature thereby forming a first orientation layer that includes the first polymer; baking the substrate at second temperature thereby forming a second orientation layer that includes the second polymer; and performing a directed self-assembly (DSA) process over the first and the second orientation layers.\",\n \"2.The method of claim 1, wherein the performing the DSA process includes: depositing a copolymer material over the first and the second orientation layers, wherein the copolymer material is directed self-assembling; and inducing microphase separation within the copolymer material thereby defining a first constituent of the copolymer material and a second constituent of the copolymer material.\",\n \"3.The method of claim 2, wherein the copolymer material includes one or more materials from a group consisting of polystyrene-block-polydimethylsiloxane block copolymer (PS-b-PDMS), polystyrene-block-polymethylmethacrylate (PS-b-PMMA), polyethyleneoxide-block-polyisoprene (PEO-b-PI), polyethyleneoxide-block-polybutadiene (PEO-b-PBD), polyethyleneoxide-block-polystyrene (PEO-b-PS), polyethyleneoxide-block-polymethylmethacrylate (PEO-b-PMMA), polyethyleneoxide-block-polyethylethylene (PEO-b-PEE), polystyrene-block-polyvinylpyridine (PS-b-PVP), polystyrene-block-polyisoprene (PS-b-PI), polystyrene-block-polybutadiene (PS-b-PBD), polystyrene-block-polyferrocenyldimethylsilane (PS-b-PFS), polybutadiene-block-polyvinylpyridine (PBD-b-PVP), and polyisoprene-block-polymethylmethacrylate (PI-b-PMMA).\",\n \"4.The method of claim 1, wherein the first activation energy is lower than the second activation energy and the first temperature is lower than the second temperature.\",\n \"5.The method of claim 1, wherein a thickness of the first orientation layer that includes the first polymer ranges between about 5 nanometers and about 10 nanometers.\",\n \"6.The method of claim 1, wherein the first temperature ranges between about 80° C. and about 150° C., and the second temperature ranges between about 180° C. and about 250° C. 7.The method of claim 1, wherein the first polymer includes a backbone that includes a hydroxyl group with a first amount of carbon side chains and the second polymer includes a backbone that includes a hydroxyl group with a second amount of carbon side chains, the first amount being greater than the second amount.\",\n \"8.A method comprising: providing a substrate having a patterned feature formed thereon; applying an orientation material that includes a first polymer and a second polymer over the substrate; forming a first orientation layer that includes the first polymer by baking the substrate and orientation material at a first temperature; forming a second orientation layer that includes the second polymer from a portion of the orientation material floating over the first orientation layer by baking the substrate at a second temperature higher than the first temperature; and performing a directed self-assembly (DSA) process over the first and the second orientation layers.\",\n \"9.The method of claim 8, further comprising forming the second orientation layer directly on a sidewall of the patterned feature and directly over the first orientation layer.\",\n \"10.The method of claim 8, wherein a thickness of the first orientation layer that includes the first polymer ranges between about 5 nanometers and about 10 nanometers.\",\n \"11.The method of claim 8, wherein the first temperature ranges between about 80° C. and about 150° C., and the second temperature ranges between about 180° C. and about 250° C. 12.The method of claim 8, wherein the first polymer includes a backbone that includes a hydroxyl group with a first amount of carbon side chains and the second polymer includes a backbone that includes a hydroxyl group with a second amount of carbon side chains, the first amount being greater than the second amount.\",\n \"13.The method of claim 8, wherein performing the DSA process includes: depositing a copolymer material over the first and the second orientation layers, wherein the copolymer material is directed self-assembling; and inducing microphase separation within the copolymer material thereby defining a first constituent of the copolymer material and a second constituent of the copolymer material.\",\n \"14.The method of claim 13, wherein the copolymer material includes one or more materials from a group consisting of polystyrene-block-polydimethylsiloxane block copolymer (PS-b-PDMS), polystyrene-block-polymethylmethacrylate (PS-b-PMMA), polyethyleneoxide-block-polyisoprene (PEO-b-PI), polyethyleneoxide-block-polybutadiene (PEO-b-PBD), polyethyleneoxide-block-polystyrene (PEO-b-PS), polyethyleneoxide-block-polymethylmethacrylate (PEO-b-PMMA), polyethyleneoxide-block-polyethylethylene (PEO-b-PEE), polystyrene-block-polyvinylpyridine (PS-b-PVP), polystyrene-block-polyisoprene (PS-b-PI), polystyrene-block-polybutadiene (PS-b-PBD), polystyrene-block-polyferrocenyldimethylsilane (PS-b-PFS), polybutadiene-block-polyvinylpyridine (PBD-b-PVP), and polyisoprene-block-polymethylmethacrylate (PI-b-PMMA).\",\n \"15.A method comprising: providing a substrate having a patterned feature formed thereon; applying an orientation material that includes a first polymer and a second polymer over the substrate; forming a first orientation layer that includes the first polymer over a first portion of the substrate by baking the substrate at a first temperature; forming a second orientation layer that includes the second polymer over a second portion of the substrate including by baking the substrate at a second temperature higher than the first temperature; and performing a directed self-assembly (DSA) process over the first and the second orientation layers.\",\n \"16.The method of claim 15, further comprising forming the second orientation layer from a floating portion of the orientation material directly on a sidewall of the patterned feature and directly over the first orientation layer.\",\n \"17.The method of claim 15, wherein the first polymer includes a hydroxyl functional group.\",\n \"18.The method of claim 15, wherein the first polymer includes a carboxyl functional group or an amide functional group.\",\n \"19.The method of claim 15, wherein treating the substrate includes applying a plasma-assisted dry etching process by flowing N2/H2 or O2.20.The method of claim 19, wherein applying the plasma-assisted dry etching process includes applying the plasma-assisted dry etching process at a temperature ranging from about 0° C. to about 80° C. and at pressure ranging from about 10 millitorr (mT) to about 60 mT.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>The present application is a divisional application of U.S. application Ser.\",\n \"No.\",\n \"14/918,310 filed on Oct. 20, 2015, which is hereby incorporated by reference in its entirety.\",\n \"The semiconductor integrated circuit (IC) industry has experienced exponential growth.\",\n \"Technological advances in IC materials and design have produced generations of ICs where each generation has smaller and more complex circuits than the previous generation.\",\n \"In the course of IC evolution, functional density (i.e., the number of interconnected devices per chip area) has generally increased while geometry size (i.e., the smallest component (or line) that can be created using a fabrication process) has decreased.\",\n \"This scaling down process generally provides benefits by increasing production efficiency and lowering associated costs.\",\n \"Such scaling down has also increased the complexity of processing and manufacturing ICs.\",\n \"For example, as optical lithography approaches its technological and economical limits, a directed self-assembly (DSA) process emerges as a potential candidate for patterning dense features.\",\n \"A DSA process takes advantage of the self-assembling properties of materials, such as block copolymers (BCP), to reach nanoscale dimensions while meeting the constraints of current manufacturing.\",\n \"However, while existing DSA processes have been generally adequate for their intended purposes, they have not been entirely satisfactory in every aspect.\"\n ],\n [\n \"<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>The present disclosure is best understood from the following detailed description when read with the accompanying figures.\",\n \"It is emphasized that, in accordance with the standard practice in the industry, various features are not drawn to scale and are used for illustration purposes only.\",\n \"In fact, the dimensions of the various features may be arbitrarily increased or reduced for clarity of discussion.\",\n \"FIG.\",\n \"1 shows a flow chart of a method of fabricating a semiconductor device, according to various aspects of the present disclosure.\",\n \"FIGS.\",\n \"2A-2E are cross sectional views of forming a semiconductor device according to the method of FIG.\",\n \"1 in accordance with some embodiments.\",\n \"FIG.\",\n \"3 shows a schematic view of the orientation material that is used in the method of FIG.\",\n \"1 in accordance with some embodiments.\",\n \"FIG.\",\n \"4 shows a flow chart of a method of fabricating a semiconductor device, according to various aspects of the present disclosure.\",\n \"FIGS.\",\n \"5A-5E are cross sectional views of forming a semiconductor device according to the method of FIG.\",\n \"4 in accordance with some embodiments.\",\n \"FIG.\",\n \"6 shows a schematic view of the orientation material that is used in the method of FIG.\",\n \"4 in accordance with some embodiments.\",\n \"FIG.\",\n \"7 shows a flow chart of a method of fabricating a semiconductor device, according to various aspects of the present disclosure.\",\n \"FIGS.\",\n \"8A-8F are cross sectional views of forming a semiconductor device according to the method of FIG.\",\n \"1 in accordance with some embodiments.\",\n \"FIG.\",\n \"9 shows a schematic view of the orientation material that is used in the method of FIG.\",\n \"7 in accordance with some embodiments.\",\n \"detailed-description description=\\\"Detailed Description\\\" end=\\\"lead\\\"?\"\n ],\n [\n \"BACKGROUND The present application is a divisional application of U.S. application Ser.\",\n \"No.\",\n \"14/918,310 filed on Oct. 20, 2015, which is hereby incorporated by reference in its entirety.\",\n \"The semiconductor integrated circuit (IC) industry has experienced exponential growth.\",\n \"Technological advances in IC materials and design have produced generations of ICs where each generation has smaller and more complex circuits than the previous generation.\",\n \"In the course of IC evolution, functional density (i.e., the number of interconnected devices per chip area) has generally increased while geometry size (i.e., the smallest component (or line) that can be created using a fabrication process) has decreased.\",\n \"This scaling down process generally provides benefits by increasing production efficiency and lowering associated costs.\",\n \"Such scaling down has also increased the complexity of processing and manufacturing ICs.\",\n \"For example, as optical lithography approaches its technological and economical limits, a directed self-assembly (DSA) process emerges as a potential candidate for patterning dense features.\",\n \"A DSA process takes advantage of the self-assembling properties of materials, such as block copolymers (BCP), to reach nanoscale dimensions while meeting the constraints of current manufacturing.\",\n \"However, while existing DSA processes have been generally adequate for their intended purposes, they have not been entirely satisfactory in every aspect.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS The present disclosure is best understood from the following detailed description when read with the accompanying figures.\",\n \"It is emphasized that, in accordance with the standard practice in the industry, various features are not drawn to scale and are used for illustration purposes only.\",\n \"In fact, the dimensions of the various features may be arbitrarily increased or reduced for clarity of discussion.\",\n \"FIG.\",\n \"1 shows a flow chart of a method of fabricating a semiconductor device, according to various aspects of the present disclosure.\",\n \"FIGS.\",\n \"2A-2E are cross sectional views of forming a semiconductor device according to the method of FIG.\",\n \"1 in accordance with some embodiments.\",\n \"FIG.\",\n \"3 shows a schematic view of the orientation material that is used in the method of FIG.\",\n \"1 in accordance with some embodiments.\",\n \"FIG.\",\n \"4 shows a flow chart of a method of fabricating a semiconductor device, according to various aspects of the present disclosure.\",\n \"FIGS.\",\n \"5A-5E are cross sectional views of forming a semiconductor device according to the method of FIG.\",\n \"4 in accordance with some embodiments.\",\n \"FIG.\",\n \"6 shows a schematic view of the orientation material that is used in the method of FIG.\",\n \"4 in accordance with some embodiments.\",\n \"FIG.\",\n \"7 shows a flow chart of a method of fabricating a semiconductor device, according to various aspects of the present disclosure.\",\n \"FIGS.\",\n \"8A-8F are cross sectional views of forming a semiconductor device according to the method of FIG.\",\n \"1 in accordance with some embodiments.\",\n \"FIG.\",\n \"9 shows a schematic view of the orientation material that is used in the method of FIG.\",\n \"7 in accordance with some embodiments.\",\n \"DETAILED DESCRIPTION The following disclosure provides many different embodiments, or examples, for implementing different features of the provided subject matter.\",\n \"Specific examples of components and arrangements are described below to simplify the present disclosure.\",\n \"These are, of course, merely examples and are not intended to be limiting.\",\n \"For example, the formation of a first feature over or on a second feature in the description that follows may include embodiments in which the first and second features are formed in direct contact, and may also include embodiments in which additional features may be formed between the first and second features, such that the first and second features may not be in direct contact.\",\n \"In addition, the present disclosure may repeat reference numerals and/or letters in the various examples.\",\n \"This repetition is for the purpose of simplicity and clarity and does not in itself dictate a relationship between the various embodiments and/or configurations discussed.\",\n \"Further, spatially relative terms, such as “beneath,” “below,” “lower,” “above,” “upper” and the like, may be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures.\",\n \"The spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures.\",\n \"The apparatus may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein may likewise be interpreted accordingly.\",\n \"The present disclosure is generally related to semiconductor devices, and more particularly to methods for manufacturing semiconductor devices with dense and nanoscale patterns.\",\n \"When fabricating dense patterns, a directed self-assembly (DSA) process may be used to enhance and augment the existing semiconductor manufacturing capabilities.\",\n \"In a typical DSA process, a block copolymer (BCP) film is formed over lithographically defined surfaces and a microphase separation is induced to cause the constituent polymer molecules to self-assemble, thus creating densely packed features with uniform dimensions and shapes.\",\n \"A BCP film or simply a BCP includes polymers comprised of at least two different polymer segments.\",\n \"These polymer segments are configured to assemble themselves into highly ordered structures under certain conditions such as for example, when they are exposed to an elevated temperature.\",\n \"In general, a neutral layer or an orientation layer is disposed on a surface of a substrate of a lithographically defined surface before forming the BCP film.\",\n \"The neutral layer has no affinity for either of the polymer segments of the BCP film.\",\n \"During a DSA process, the neutral layer may be able to lead/orientate a first polymer segment for directed self-assembly.\",\n \"However, in order to orientate a second polymer segment for directed self-assembly, at least one additional process (e.g., forming another neutral layer using the additional process to orientate the second polymer segment) is required.\",\n \"The forming the another neutral layer generally includes multiple process to be involved such as for example, removing part of the neutral layer that leads the first polymer segment, providing a pattern for the neutral layer that is to lead the second polymer segment, and removing the patterned neutral layer.\",\n \"In contrast, the present disclosure provides various embodiments of a method to form an improved neutral layer without requiring the above-identified additional processes.\",\n \"Referring now to FIG.\",\n \"1, a flow chart of a method 100 of forming a semiconductor device is illustrated according to various aspects of the present disclosure.\",\n \"Additional operations can be provided before, during, and after the method 100, and some operations described can be replaced, eliminated, or moved around for additional embodiments of the method.\",\n \"The method 100 is briefly described below.\",\n \"Then, some embodiments of the method 100 will be described in conjunction with FIGS.\",\n \"2A, 2B, 2C, 2D, 2E, and 3.Referring to FIGS.\",\n \"1 and 2A, the method 100 begins at operation 102 by providing a substrate 202 with a pattern 204.The substrate 202 may include one or more layers of material or composition.\",\n \"For example, the substrate 202 may include an elementary semiconductor, such as silicon and germanium.\",\n \"The substrate 202 may also include a compound semiconductor such as silicon carbide, gallium arsenic, indium arsenide, and indium phosphide.\",\n \"The substrate 202 may include an alloy semiconductor such as silicon germanium, silicon germanium carbide, gallium arsenic phosphide, and gallium indium phosphide.\",\n \"The substrate 202 may also include an epitaxial layer.\",\n \"For example, the substrate 202 may have an epitaxial layer overlying a bulk semiconductor.\",\n \"Furthermore, the substrate 202 may include a semiconductor-on-insulator (SOI) structure.\",\n \"For example, the substrate 202 may include a buried oxide (BOX) layer formed by a process such as separation by implanted oxygen (SIMOX) or other suitable technique, such as wafer bonding and grinding.\",\n \"In some other embodiments, the substrate 202 may further include a top layer (not shown) overlaying a top surface of the substrate 202.As such, the top layer may include silicon oxide, silicon nitride, oxynitride, silicon carbide, titanium oxide, titanium nitride, tantalum oxide, tantalum nitride, and/or any suitable materials.\",\n \"In the illustrated embodiment of FIG.\",\n \"2A, pattern 204 may be a resist layer (e.g., a photoresist layer).\",\n \"The resist layer may be a positive resist or a negative resist, and may be a resist suitable for deep ultraviolet (DUV), extreme ultraviolet (EUV), electron beam (e-beam), and/or other lithography processes.\",\n \"In some specific embodiments, pattern 204 is formed of organic materials.\",\n \"While still falling within the scope of the present disclosure, the pattern 204 may be formed of one of a variety of materials that is suitable for forming a pattern.\",\n \"The pattern 204 may be formed by any suitable methods such as for example, a chemical vapor deposition (CVD) process, an atomic layer deposition (ALD) process, a spin-on coating, and/or any combination thereof.\",\n \"Referring still to FIG.\",\n \"2A, the substrate 202 includes an exposed top surface 203, and the pattern 204 includes a sidewall 205.According to the current embodiments, the top surface 203 of the substrate 202 and the sidewall 205 of the pattern 204 each includes a different surface characteristic.\",\n \"For example, the top surface 203 includes an oxidized surface which is more reactive while the sidewall 205 includes a surface that is formed of organic materials which is less reactive.\",\n \"Referring to FIG.\",\n \"1, the method 100 proceeds to operation 104 by providing an orientation layer that is formed of at least two polymers (e.g., a first polymer and a second polymer).\",\n \"In an embodiment, as illustrated in FIG.\",\n \"3, the orientation layer includes a first polymer 302 and a second polymer 304.More specifically, the first polymer 302 includes a polymer backbone 302′ and at least an atom/unit of the backbone 302′ is replaced with or modified by a group 303; and the second polymer 304 includes a polymer backbone 304′ and at least an atom/unit of the backbone 304′ is replaced with or modified by a group 305.The group 303 is a hydroxyl group with a higher amount of carbon side chains (e.g., carbon side chains >4) and the group 305 is a hydroxyl group with a lower amount of carbon side chains (e.g., carbon side chains <2).\",\n \"As such, the first polymer 302 may have a lower activation energy than the second polymer 304 may have.\",\n \"That is, the first polymer 302 with the lower activation energy may be activated at a first elevated temperature and the second polymer 304 with the higher activation energy may be activated at a second elevated temperature, wherein the first elevated temperature is lower than the second elevated temperature.\",\n \"Referring to FIGS.\",\n \"1 and 2B, the method 100 proceeds to operation 106 with forming a first orientation layer 208.In the example of the orientation material is formed of the polymers 302 and 304 with respect to FIG.\",\n \"3, as illustrated in FIG.\",\n \"2B, an orientation layer 208 is formed on the top surface 203 of the substrate by baking the substrate to temperature between about 80° C. and about 150° C., wherein the orientation layer 208 is formed of the first polymer 302 (lower activation energy).\",\n \"In some embodiments, during the formation of the orientation layer 208, another portion (higher activation energy) of the orientation material (i.e., the portion formed of the second polymer 304) may float above the formed orientation layer 208, illustrated as 210 in FIG.\",\n \"2B.\",\n \"That is, the portion 210 has not been formed as an orientation layer yet in operation 106.In some embodiments, the orientation layer 208 may have a thickness ranging between about 5 nanometers to about 10 nanometers.\",\n \"The method 100 continues to operation 108 with forming a second orientation layer.\",\n \"Continuing with the above example in which the orientation material is formed of the polymers in FIG.\",\n \"3, a second orientation layer 210′ that is formed of the second polymer 304 is formed on the sidewall 205 by baking the substrate to temperature between about 180° C. and about 250° C. as illustrated in the embodiment of FIG.\",\n \"2C.\",\n \"The method 100 proceeds to operation 110 with performing a directed self-assembly (DSA) process.\",\n \"In some embodiments, the operation 110 may include multiple processes in the following order: depositing a directed self-assembly (DSA) block copolymer (BCP) layer 212 over the first orientation layer 208 and the second orientation layer 210 (as illustrated in FIG.\",\n \"2D); applying an elevated temperature to anneal the BCP layer 212 thereby achieving segregation in the BCP layer 212 to form first and second polymer nanostructures, 214 and 216 (as illustrated in FIG.\",\n \"2E).\",\n \"Generally, a BCP material includes polymers comprised of at least two different polymer segments, and these polymer segments can assemble themselves into highly ordered structures under certain conditions, such as when they are exposed to an elevated temperature.\",\n \"In the current embodiment, the BCP layer 212 may include one or more of polystyrene-block-polydimethylsiloxane block copolymer (PS-b-PDMS), polystyrene-block-polymethylmethacrylate (PS-b-PMMA), polyethyleneoxide-block-polyisoprene (PEO-b-PI), polyethyleneoxide-block-polybutadiene (PEO-b-PBD), polyethyleneoxide-block-polystyrene (PEO-b-PS), polyethyleneoxide-block-polymethylmethacrylate (PEO-b-PMMA), polyethyleneoxide-block-polyethylethylene (PEO-b-PEE), polystyrene-block-polyvinylpyridine (PS-b-PVP), polystyrene-block-polyisoprene (PS-b-PI), polystyrene-block-polybutadiene (PS-b-PBD), polystyrene-block-polyferrocenyldimethylsilane (PS-b-PFS), polybutadiene-block-polyviny.\",\n \"Still referring to FIGS.\",\n \"1 and 2E, during the DSA process (i.e., operation 110), by choosing the height of the pattern 204 (i.e., h1), the height of the first orientation layer 208 (i.e., h2), and the materials of the BCP layer 212, the first and second polymer nanostructures 214 and 216 are formed such that they have a height approximately same as the difference of the heights h1 and h2, they are parallel to each other.\",\n \"In the illustrated embodiment of FIG.\",\n \"2E, the first and second polymer nanostructures 214 and 216 are aligned along direction X, and each of them extends in a direction (i.e., Y axis in FIG.\",\n \"2E) that is parallel to the sidewall 205.However, the BCP layer 212 may be formed into a variety of shapes that are regularly aligned such as for example, a sphere, a cylinder, a lamellae, and any suitable shape known in the art.\",\n \"The formed polymer nanostructures 214 and 216 may be later used as a pattern for a further fabrication step.\",\n \"In an example, one of the polymer nanostructures (e.g., 214) may be etched away and the other polymer nanostructure (e.g., 216) may be left on the substrate as a hard mask layer to transfer a pattern onto the substrate thereby reaching a finer critical dimension (CD).\",\n \"Referring now to FIG.\",\n \"4, a flow chart of another method 400 of forming a semiconductor device is illustrated according to various aspects of the present disclosure.\",\n \"Additional operations can be provided before, during, and after the method 400, and some operations described can be replaced, eliminated, or moved around for additional embodiments of the method.\",\n \"The method 400 is briefly described below.\",\n \"Then, some embodiments of the method 400 will be described in conjunction with FIGS.\",\n \"5A, 5B, 5C, 5D, 5E, and 6.Referring to FIGS.\",\n \"4 and 5A, the method 400 begins at operation 402 by providing a substrate 502 with a pattern 504.The substrate 502 may include one or more layers of material or composition.\",\n \"For example, the substrate 502 may include an elementary semiconductor, such as silicon and germanium.\",\n \"The substrate 502 may also include a compound semiconductor such as silicon carbide, gallium arsenic, indium arsenide, and indium phosphide.\",\n \"The substrate 502 may include an alloy semiconductor such as silicon germanium, silicon germanium carbide, gallium arsenic phosphide, and gallium indium phosphide.\",\n \"The substrate 502 may also include an epitaxial layer.\",\n \"For example, the substrate 502 may have an epitaxial layer overlying a bulk semiconductor.\",\n \"Furthermore, the substrate 502 may include a semiconductor-on-insulator (SOI) structure.\",\n \"For example, the substrate 502 may include a buried oxide (BOX) layer formed by a process such as separation by implanted oxygen (SIMOX) or other suitable technique, such as wafer bonding and grinding.\",\n \"In some other embodiments, the substrate 502 may further include a top layer (not shown) overlaying a top surface of the substrate 502.As such, the top layer may include silicon oxide, silicon nitride, oxynitride, silicon carbide, titanium oxide, titanium nitride, tantalum oxide, tantalum nitride, and/or any suitable materials.\",\n \"In the illustrated embodiment of FIG.\",\n \"5A, pattern 504 may be a resist layer (e.g., a photoresist layer).\",\n \"The resist layer may be a positive resist or a negative resist, and may be a resist suitable for deep ultraviolet (DUV), extreme ultraviolet (EUV), electron beam (e-beam), and/or other lithography processes.\",\n \"In some specific embodiments, pattern 504 is formed of organic materials.\",\n \"While still falling within the scope of the present disclosure, the pattern 504 may be formed of one of a variety of materials that is suitable for forming a pattern.\",\n \"The pattern 504 may be formed by any suitable methods such as for example, a chemical vapor deposition (CVD) process, an atomic layer deposition (ALD) process, a spin-on coating, and/or any combination thereof.\",\n \"Referring still to FIG.\",\n \"5A, the substrate 502 includes an exposed top surface 503, and the pattern 504 includes a sidewall 505.According to the current embodiments, the top surface 503 of the substrate 502 and the sidewall 505 of the pattern 504 each includes a different surface characteristic.\",\n \"For example, the top surface 503 includes an oxidized surface which is more reactive to a functional group (e.g., a hydroxyl group) while the sidewall 505 includes a surface that is formed of organic materials which is less reactive to the hydroxyl group but more reactive to another functional group (e.g., an aromatic group).\",\n \"Referring to FIG.\",\n \"4, the method 400 proceeds to operation 404 by providing an orientation material that is formed of at least two polymers (e.g., a first polymer and a second polymer).\",\n \"In an embodiment, as illustrated in FIG.\",\n \"6, the orientation material includes a first polymer 602 and a second polymer 604.More specifically, the first polymer 602 includes a polymer backbone 602′ and the polymer backbone 602′ is terminated with a functional group 603; and the second polymer 604 includes a polymer backbone 604′ and the polymer backbone 604′ is terminated with a functional group 605.The functional group 603 includes at least a hydroxyl group, a carboxyl group, and/or an amide group; the functional group 605 includes at least an aromatic group.\",\n \"Referring to FIGS.\",\n \"4 and 5B, the method 400 proceeds to operation 406 with forming a first orientation layer 508.In the example of the orientation material is formed of the polymers 602 and 604 with respect to FIG.\",\n \"6, as illustrated in FIG.\",\n \"5B, an orientation layer 508 is formed on the top surface 503 of the substrate, wherein the orientation layer 508 is formed of the first polymer 602.In some embodiments, during the formation of the orientation layer 508, another portion of the orientation material (i.e., the portion formed of the second polymer 604) may float above the formed orientation layer 508, which is illustrated as 510 in FIG.\",\n \"5B.\",\n \"That is, the portion 510 has not been formed as an orientation layer yet in operation 406.In some embodiments, the orientation layer 508 may have a thickness ranging between about 5 nanometers to about 10 nanometers.\",\n \"The method 400 continues to operation 408 with forming a second orientation layer.\",\n \"Continuing with the above example in which the orientation material is formed of the polymers in FIG.\",\n \"6, a second orientation layer 610′ that is formed of the second polymer 604 is formed on the sidewall 605 by baking the substrate to temperature between about 180° C. and about 250° C. as illustrated in the embodiment of FIG.\",\n \"5C.\",\n \"The method 400 proceeds to operation 410 with performing a directed self-assembly (DSA) process.\",\n \"In some embodiments, the operation 410 may include multiple processes in the following order: depositing a directed self-assembly (DSA) block copolymer (BCP) layer 512 over the first orientation layer 508 and the second orientation layer 510 (as illustrated in FIG.\",\n \"5D); applying an elevated temperature to anneal the BCP layer 512 thereby achieving segregation in the BCP layer 512 to form first and second polymer nanostructures, 514 and 516 (as illustrated in FIG.\",\n \"5E).\",\n \"Generally, a BCP material includes polymers comprised of at least two different polymer segments, and these polymer segments can assemble themselves into highly ordered structures under certain conditions, such as when they are exposed to an elevated temperature.\",\n \"In the current embodiment, the BCP layer 512 may include one or more of polystyrene-block-polydimethylsiloxane block copolymer (PS-b-PDMS), polystyrene-block-polymethylmethacrylate (PS-b-PMMA), polyethyleneoxide-block-polyisoprene (PEO-b-PI), polyethyleneoxide-block-polybutadiene (PEO-b-PBD), polyethyleneoxide-block-polystyrene (PEO-b-PS), polyethyleneoxide-block-polymethylmethacrylate (PEO-b-PMMA), polyethyleneoxide-block-polyethylethylene (PEO-b-PEE), polystyrene-block-polyvinylpyridine (PS-b-PVP), polystyrene-block-polyisoprene (PS-b-PI), polystyrene-block-polybutadiene (PS-b-PBD), polystyrene-block-polyferrocenyldimethylsilane (PS-b-PFS), polybutadiene-block-polyviny.\",\n \"Still referring to FIGS.\",\n \"4 and 5E, during the DSA process (i.e., operation 510), by choosing the height of the pattern 504 (i.e., h1), the height of the first orientation layer 508 (i.e., h2), and the materials of the BCP layer 512, the first and second polymer nanostructures 514 and 516 are formed such that they have a height approximately same as the difference of the heights h1 and h2, they are parallel to each other.\",\n \"In the illustrated embodiment of FIG.\",\n \"5E, the first and second polymer nanostructures 514 and 516 are aligned along direction X, and each of them extends in a direction (i.e., Y axis in FIG.\",\n \"5E) that is parallel to the sidewall 505.However, the BCP layer 512 may be formed into a variety of shapes that are regularly aligned such as for example, a sphere, a cylinder, a lamellae, and any suitable shape known in the art.\",\n \"The formed polymer nanostructures 514 and 516 may be later used as a pattern for a further fabrication step.\",\n \"In an example, one of the polymer nanostructures (e.g., 514) may be etched away and the other polymer nanostructure (e.g., 516) may be left on the substrate as a hard mask layer to transfer a pattern onto the substrate thereby reaching a finer critical dimension (CD).\",\n \"Referring now to FIG.\",\n \"7, a flow chart of yet another method 700 of forming a semiconductor device is illustrated according to various aspects of the present disclosure.\",\n \"Additional operations can be provided before, during, and after the method 700, and some operations described can be replaced, eliminated, or moved around for additional embodiments of the method.\",\n \"The method 700 is briefly described below.\",\n \"Then, some embodiments of the method 700 will be described in conjunction with FIGS.\",\n \"8A, 8B, 8C, 8D, 8E, 8F, and 9.Referring to FIGS.\",\n \"7 and 8A, the method 700 begins at operation 702 by providing a substrate 802 with a pattern 804.The substrate 802 may include one or more layers of material or composition.\",\n \"For example, the substrate 802 may include an elementary semiconductor, such as silicon and germanium.\",\n \"The substrate 802 may also include a compound semiconductor such as silicon carbide, gallium arsenic, indium arsenide, and indium phosphide.\",\n \"The substrate 802 may include an alloy semiconductor such as silicon germanium, silicon germanium carbide, gallium arsenic phosphide, and gallium indium phosphide.\",\n \"The substrate 802 may also include an epitaxial layer.\",\n \"For example, the substrate 802 may have an epitaxial layer overlying a bulk semiconductor.\",\n \"Furthermore, the substrate 802 may include a semiconductor-on-insulator (SOI) structure.\",\n \"For example, the substrate 802 may include a buried oxide (BOX) layer formed by a process such as separation by implanted oxygen (SIMOX) or other suitable technique, such as wafer bonding and grinding.\",\n \"In some other embodiments, the substrate 802 may further include a top layer (not shown) overlaying a top surface of the substrate 802.As such, the top layer may include silicon oxide, silicon nitride, oxynitride, silicon carbide, titanium oxide, titanium nitride, tantalum oxide, tantalum nitride, and/or any suitable materials.\",\n \"In the illustrated embodiment of FIG.\",\n \"8A, pattern 804 may be a resist layer (e.g., a photoresist layer).\",\n \"The resist layer may be a positive resist or a negative resist, and may be a resist suitable for deep ultraviolet (DUV), extreme ultraviolet (EUV), electron beam (e-beam), and/or other lithography processes.\",\n \"In some specific embodiments, pattern 804 is formed of organic materials.\",\n \"While still falling within the scope of the present disclosure, the pattern 804 may be formed of any of a variety of materials that is suitable for forming a pattern.\",\n \"The pattern 804 may be formed by any suitable methods such as for example, a chemical vapor deposition (CVD) process, an atomic layer deposition (ALD) process, a spin-on coating, and/or any combination thereof.\",\n \"Referring still to FIG.\",\n \"8A, the substrate 802 includes an exposed top surface 803, and the pattern 804 includes a sidewall 805.In some embodiments, the top surface 803 of the substrate 802 and the sidewall 805 of the pattern 804 each includes a different surface characteristic.\",\n \"However, in some alternative embodiments, the top surface 803 of the substrate 802 and the sidewall 805 of the pattern 804 may each have a substantial similar surface characteristic.\",\n \"The method continues in operation 704 with applying a treatment 807 on the substrate 802 (more specifically, on the top surface 803 of the substrate), as illustrated in FIG.\",\n \"8B.\",\n \"In some embodiments, the treatment 807 may include a plasma-assisted dry etching process by flowing N2/H2 and/or O2.The etching process may be performed at temperature ranging from about 0° C. to about 80° C. and at pressure ranging from about 10 millitorr (mT) to about 60 mT.\",\n \"As illustrated in FIG.\",\n \"8B, the etching process (i.e., 807) may be an anisotropic process (perpendicular to the top surface 803) and thus only the top surface is treated or only the top surface's surface characteristic is changed while the sidewall 805 remains intact.\",\n \"As such, after the treatment 807, the top surface 803 may include a hydrophilic surface while the sidewall 805 may include a hydrophobic surface.\",\n \"Referring to FIG.\",\n \"7, the method 700 proceeds to operation 706 with providing an orientation material that is formed of at least two polymers (e.g., a first polymer and a second polymer).\",\n \"In an embodiment, as illustrated in FIG.\",\n \"9, the orientation material includes a first polymer 902 and a second polymer 904.More specifically, the first polymer 902 includes a polymer backbone 902′ and the polymer backbone 902′ is terminated with a functional group 903; and the second polymer 904 includes a polymer backbone 904′ and the polymer backbone 904′ is terminated with a functional group 905.The functional group 903 is a hydrophilic group that is selected form a group consisting of a hydroxyl group, a carboxyl group, and an amide group; the functional group 905 is a hydrophobic group that is selected form a group consisting of a ketone group and an ether group.\",\n \"Referring to FIGS.\",\n \"7 and 8B, the method 700 proceeds to operation 708 with forming a first orientation layer 808.In the example of the orientation material is formed of the polymers 902 and 904 with respect to FIG.\",\n \"9, as illustrated in FIG.\",\n \"8C, an orientation layer 808 is formed on the top surface 803 of the substrate, wherein the orientation layer 808 is formed of the first polymer 902.By applying the treatment 807 on the substrate, the first polymer 902 terminated with the functional group 903 that includes a hydrophilic group may be more reactive to attach to the top surface 803 while the portion of the orientation material formed of the second polymer 905 may float above the orientation layer 808.That is, during the formation of the orientation layer 808, another portion of the orientation material (i.e., the portion formed of the second polymer 904) may float above the formed orientation layer 808, which is illustrated as 810 in FIG.\",\n \"8B.\",\n \"In some embodiments, the portion 810 has not been formed as an orientation layer yet in operation 708.In some embodiments, the orientation layer 808 may have a thickness ranging between about 5 nanometers to about 10 nanometers.\",\n \"The method 700 continues to operation 710 with forming a second orientation layer.\",\n \"Continuing with the above example in which the orientation material is formed of the polymers in FIG.\",\n \"9, a second orientation layer 810′ that is formed of the second polymer 904 is formed on the sidewall 805 by baking the substrate to temperature between about 180° C. and about 250° C. as illustrated in the embodiment of FIG.\",\n \"8D.\",\n \"The method 700 proceeds to operation 712 with performing a directed self-assembly (DSA) process.\",\n \"In some embodiments, the operation 712 may include multiple processes in the following order: depositing a directed self-assembly (DSA) block copolymer (BCP) layer 812 over the first orientation layer 808 and the second orientation layer 810 (as illustrated in FIG.\",\n \"8E); applying an elevated temperature to anneal the BCP layer 812 thereby achieving segregation in the BCP layer 812 to form first and second polymer nanostructures, 814 and 816 (as illustrated in FIG.\",\n \"8F).\",\n \"Generally, a BCP material includes polymers comprised of at least two different polymer segments, and these polymer segments can assemble themselves into highly ordered structures under certain conditions, such as when they are exposed to an elevated temperature.\",\n \"In the current embodiment, the BCP layer 812 may include one or more of polystyrene-block-polydimethylsiloxane block copolymer (PS-b-PDMS), polystyrene-block-polymethylmethacrylate (PS-b-PMMA), polyethyleneoxide-block-polyisoprene (PEO-b-PI), polyethyleneoxide-block-polybutadiene (PEO-b-PBD), polyethyleneoxide-block-polystyrene (PEO-b-PS), polyethyleneoxide-block-polymethylmethacrylate (PEO-b-PMMA), polyethyleneoxide-block-polyethylethylene (PEO-b-PEE), polystyrene-block-polyvinylpyridine (PS-b-PVP), polystyrene-block-polyisoprene (PS-b-PI), polystyrene-block-polybutadiene (PS-b-PBD), polystyrene-block-polyferrocenyldimethylsilane (PS-b-PFS), polybutadiene-block-polyviny.\",\n \"Still referring to FIGS.\",\n \"7 and 8F, during the DSA process (i.e., operation 712), by choosing the height of the pattern 804 (i.e., h1), the height of the first orientation layer 808 (i.e., h2), and the materials of the BCP layer 812, the first and second polymer nanostructures 814 and 816 are formed such that they have a height approximately same as the difference of the heights h1 and h2, they are parallel to each other.\",\n \"In the illustrated embodiment of FIG.\",\n \"8F, the first and second polymer nanostructures 814 and 816 are aligned along direction X, and each of them extends in a direction (i.e., Y axis in FIG.\",\n \"8F) that is parallel to the sidewall 805.However, the BCP layer 812 may be formed into a variety of shapes that are regularly aligned such as for example, a sphere, a cylinder, a lamellae, and any suitable shape known in the art.\",\n \"The formed polymer nanostructures 814 and 816 may be later used as a pattern for a further fabrication step.\",\n \"In an example, one of the polymer nanostructures (e.g., 814) may be etched away and the other polymer nanostructure (e.g., 816) may be left on the substrate as a hard mask layer to transfer a pattern onto the substrate thereby reaching a finer critical dimension (CD).\",\n \"Although in the above discussion and embodiments, the first polymer (e.g., 303, 603, and 903) is to form the first orientation layer on the top surface of the substrate (e.g., 203, 503, and 803) first and then the second polymer (e.g., 305, 605, and 905) is to form the second orientation layer on the sidewall of the pattern (e.g., 205, 505, and 805), in some alternative embodiments, the first orientation layer formed of the first polymer may be formed on the sidewall of the pattern first and the second orientation layer formed of the second polymer may be later formed on the top surface of the substrate.\",\n \"For example, if the sidewall 205 has a more reactive surface than the top surface 203, the first polymer 302 with the lower activation energy may form a first orientation layer on the sidewall 205 by baking at a lower temperature and then the second polymer 304 with the higher activation energy may later from another orientation layer on the top surface by baking at a higher temperature.\",\n \"Although not intended to be limiting, one or more embodiments of the present disclosure provide many benefits to a semiconductor device and the formation thereof.\",\n \"For example, embodiments of the present disclosure provide methods for forming densely packed DSA patterns with uniformity and precision by using only one orientation material for a DSA process.\",\n \"In some embodiments, the orientation material may be formed into two orientation layers and each of the orientation layers is configured to guide a DSA process of one of the polymer segments of a BCP material.\",\n \"Without requiring a complicated patterning process and/or an additional material, such two orientation layers may be formed on respective surface.\",\n \"Additionally, embodiments of the present disclosure can be easily integrated into existing fabrication flow.\",\n \"In addition, even though two DSA processes are illustrated above, embodiments of the present disclosure may include more than two DSA processes where one builds upon another accumulatively.\",\n \"In one exemplary aspect, the present disclosure is directed to a method of forming a semiconductor device.\",\n \"The method includes forming a patterned feature over a substrate; applying an orientation material that includes a first polymer and a second polymer over the substrate, wherein the first polymer has a first activation energy and the second polymer has a second activation energy; baking the substrate at first temperature thereby forming a first orientation layer that includes the first polymer; baking the substrate at second temperature thereby forming a second orientation layer that includes the second polymer; and performing a directed self-assembly (DSA) process over the first and the second orientation layers.\",\n \"In another exemplary aspect, the present disclosure is directed to a method of forming a semiconductor device.\",\n \"The method includes providing a substrate having a patterned feature formed thereon; applying an orientation material that includes a first polymer and a second polymer over the substrate, wherein the first polymer is terminated with a first functional group and the second polymer is terminated with a second functional group; forming a first orientation layer that includes the first polymer on the substrate and forming a second orientation layer that includes the second polymer on the patterned feature; and performing a directed self-assembly (DSA) process over the first and the second orientation layers.\",\n \"In another exemplary aspect, the present disclosure is directed to a method of forming a semiconductor device.\",\n \"The method includes providing a substrate having a patterned feature formed thereon; treating the substrate thereby causing a first portion of the substrate to be hydrophilic; applying an orientation material that includes a first polymer and a second polymer over the substrate, wherein the first polymer is terminated with a first functional group and the second polymer is terminated with a second functional group; forming a first orientation layer that includes the first polymer over the first portion of the substrate and forming a second orientation layer that includes the second polymer over the patterned feature; and performing a directed self-assembly (DSA) process over the first and the second orientation layers.\",\n \"The foregoing outlines features of several embodiments so that those of ordinary skill in the art may better understand the aspects of the present disclosure.\",\n \"Those of ordinary skill in the art should appreciate that they may readily use the present disclosure as a basis for designing or modifying other processes and structures for carrying out the same purposes and/or achieving the same advantages of the embodiments introduced herein.\",\n \"Those of ordinary skill in the art should also realize that such equivalent constructions do not depart from the spirit and scope of the present disclosure, and that they may make various changes, substitutions, and alterations herein without departing from the spirit and scope of the present disclosure.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875788"}}},{"rowIdx":4494978,"cells":{"text":{"kind":"list like","value":[["OPERATION METHOD OF ELECTRIC POWER SOURCE DEVICE, ELECTRIC POWER SOURCE DEVICE, AND HIGH-FREQUENCY TREATMENT SYSTEM","A method of operating a power source device for a high-frequency treatment instrument adapted to perform high-frequency treatment for biological tissue includes causing a high-frequency power source circuit to output power; setting a target impedance value which gradually increases from a change-over impedance value to a stop impedance value; regularly comparing a measured impedance value to the target impedance value; causing the high-frequency power source circuit to lower the power by a first ratio if the measured impedance value is greater than the target impedance value, and to raise the power by a second ratio if the measured impedance value is smaller than the target impedance value; and causing the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value."],["1.A method of operating a power source device for a high-frequency treatment instrument adapted to perform high-frequency treatment for biological tissue, the method comprising: causing, by a control circuit, a high-frequency power source circuit to output power; acquiring, by the control circuit, a value for impedance of the biological tissue during the output; setting, by the control circuit, a target impedance value, wherein the target impedance value gradually increases from a change-over impedance value to a stop impedance value within a predetermined period, the change-over impedance value being equal to or greater by a predetermined value than a minimum value of the value for impedance, the stop impedance value representing termination of the output; repeating, by the control circuit, a first processing and a second processing on a regular basis for a period after the value for impedance reaching the change-over impedance value until the value for impedance reaching the stop impedance value, wherein the value for impedance is adopted as a measured impedance value, and wherein, in the first processing, the measured impedance value is compared to the target impedance value, and in the second processing, the high-frequency power source circuit is caused to change the power being output to decrease from current power in line with a first rule if the measured impedance value is greater than the target impedance value, and the high-frequency power source circuit is caused to change the power being output to increase from current power in line with a second rule if the measured impedance value is smaller than the target impedance value; and causing, by the control circuit, the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value.","2.The method according to claim 11, wherein the first ratio is equal to the second ratio.","3.The method according to claim 11, wherein the first ratio is unequal to the second ratio.","4.The method according to claim 1, further comprising acquiring, by the control circuit, an initial impedance value which is the value for impedance within a predetermined period after starting the output, wherein the target impedance value varies a speed of increase according to the initial impedance value.","5.The method according to claim 1, wherein the target impedance value varies a speed of increase according to a set output value.","6.The method according to claim 1, wherein the target impedance value increases linearly with time.","7-8.","(canceled) 9.A power source device for a high-frequency treatment instrument adapted to perform high-frequency treatment for biological tissue, the power source device comprising: a high-frequency power source circuit which outputs power; an output detection circuit which detects the output; and a control circuit which acquires information about the output from the output detection circuit and controls the high-frequency power source circuit, wherein the control circuit is configured to cause the high-frequency power source circuit to output the power, acquire a value for impedance of the biological tissue during the output, set a target impedance value, wherein the target impedance value gradually increases from a change-over impedance value to a stop impedance value within a predetermined period, the change-over impedance value being equal to or greater by a predetermined value than a minimum value of the value for impedance, the stop impedance value representing termination of the output, repeat a first processing and a second processing on a regular basis for a period after the value for impedance reaching the change-over impedance value until the value for impedance reaching the stop impedance value, wherein the value for impedance is adopted as a measured impedance value and wherein, in the first processing, the measured impedance value is compared to the target impedance value, and in the second processing, the high-frequency power source circuit is caused to change the power being output to decrease from current power in line with a first rule if the measured impedance value is greater than the target impedance value, and the high-frequency power source circuit is caused to change the power being output to increase from current power in line with a second rule if the measured impedance value is smaller than the target impedance value, and cause the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value.","10.","(canceled) 11.The method according to claim 1, wherein decreasing the power in line with the first rule is decreasing the power from current power by a fixed first ratio, and increasing the power in line with the second rule is increasing the power from current power by a fixed second ratio.","12.The method according to claim 3, wherein the first ratio is greater than the second ratio.","13.The method according to claim 1, wherein decreasing the power in line with the first rule is decreasing the power from current power by a fixed first value, and increasing the power in line with the second rule is increasing the power from current power by a fixed second value.","14.The method according to claim 13, wherein the first value is equal to the second value.","15.The method according to claim 13, wherein the first value is unequal to the second value.","16.The method according to claim 15, wherein the first value is greater than the second value.","17.The power source device according to claim 9, wherein decreasing the power in line with the first rule is decreasing the power from current power by a fixed first ratio, and increasing the power in line with the second rule is increasing the power from current power by a fixed second ratio.","18.The power source device according to claim 17, wherein the first ratio is equal to the second ratio.","19.The power source device according to claim 17, wherein the first ratio is unequal to the second ratio.","20.The power source device according to claim 19, wherein the first ratio is greater than the second ratio.","21.The power source device according to claim 9, wherein decreasing the power in line with the first rule is decreasing the power from current power by a fixed first value, and increasing the power in line with the second rule is increasing the power from current power by a fixed second value.","22.The power source device according to claim 21, wherein the first value is equal to the second value.","23.The power source device according to claim 21, wherein the first value is greater than the second value."],["<SOH> BACKGROUND OF THE INVENTION <EOH>"],["<SOH> BRIEF SUMMARY OF THE INVENTION <EOH>According to an aspect of the present invention, a method of operating a power source device for a high-frequency treatment instrument is adapted to perform high-frequency treatment for biological tissue.","The method comprises: causing, by a control circuit, a high-frequency power source circuit to output power; acquiring, by the control circuit, a value for impedance of the biological tissue during the output; setting, by the control circuit, a target impedance value, wherein the target impedance value gradually increases from a change-over impedance value to a stop impedance value within a predetermined period, the change-over impedance value being equal to or greater by a predetermined value than a minimum value of the value for impedance, the stop impedance value representing termination of the output; performing, by the control circuit, a comparison to cause the high-frequency power source circuit to lower or raise the power being output, for a period after the value for impedance reaching the change-over impedance value until the value for impedance reaching the stop impedance value, wherein the value for impedance is adopted as a measured impedance value and the measured impedance value is regularly compared to the target impedance value, and wherein the high-frequency power source circuit is caused to lower the power by a fixed first ratio if the measured impedance value is greater than the target impedance value, and the high-frequency power source circuit is caused to raise the power by a fixed second ratio if the measured impedance value is smaller than the target impedance value; and causing, by the control circuit, the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value.","According to an aspect of the present invention, a method of operating a power source device for a high-frequency treatment instrument is adapted to perform high-frequency treatment for biological tissue.","The method comprises: causing, by a control circuit, a high-frequency power source circuit to output power; acquiring, by the control circuit, a value for impedance of the biological tissue during the output; setting, by the control circuit, a target impedance value, wherein the target impedance value gradually increases from a change-over impedance value to a stop impedance value within a predetermined period, the change-over impedance value being equal to or greater by a predetermined value than a minimum value of the value for impedance, the stop impedance value representing termination of the output; performing, by the control circuit, a comparison to cause the high-frequency power source circuit to lower or raise the power being output, for a period after the value for impedance reaching the change-over impedance value until the value for impedance reaching the stop impedance value, wherein the value for impedance is adopted as a measured impedance value and the measured impedance value is regularly compared to the target impedance value, and wherein the high-frequency power source circuit is caused to lower the power by a fixed first value if the measured impedance value is greater than the target impedance value, and the high-frequency power source circuit is caused to raise the power by a fixed second value if the measured impedance value is smaller than the target impedance value; and causing, by the control circuit, the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value.","According to an aspect of the present invention, a method of operating a power source device for a high-frequency treatment instrument is adapted to perform high-frequency treatment for biological tissue.","The method comprises: causing, by a control circuit, a high-frequency power source circuit to output power; acquiring, by the control circuit, an initial impedance value which is a value for impedance of the biological tissue within a first period after starting the output; determining, by the control circuit, a ratio of increase of output voltage relative to time, based on the initial impedance value; causing, by the control circuit, the high-frequency power source circuit to increase an output voltage according to the ratio of increase, for a second period after the first period; acquiring, by the control circuit, a value for impedance of the biological tissue during and after the second period; terminating, by the control circuit, the second period upon the value for impedance reaching a change-over impedance value representing a minimum value; determining, by the control circuit, an additional impedance value based on the initial impedance value; setting, by the control circuit, a stop impedance value which is a sum of the change-over impedance value and the additional impedance value; setting, by the control circuit, a gradually increasing target impedance value for a third period after the value for impedance reaching the change-over impedance value until the value for impedance reaching the stop impedance value; performing, by the control circuit, a comparison to cause the high-frequency power source circuit to lower or raise the power being output, for the third period, wherein the value for impedance is adopted as a measured impedance value and the measured impedance value is regularly compared to the target impedance value, and wherein the high-frequency power source circuit is caused to lower the power by a first ratio if the measured impedance value is greater than the target impedance value, and the high-frequency power source circuit is caused to raise the power by a second ratio if the measured impedance value is smaller than the target impedance value; and causing, by the control circuit, the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value.","According to an aspect of the present invention, a power source device for a high-frequency treatment instrument is adapted to perform high-frequency treatment for biological tissue.","The power source device comprises: a high-frequency power source circuit which outputs power; an output detection circuit which detects the output; and a control circuit which acquires information about the output from the output detection circuit and controls the high-frequency power source circuit.","The control circuit is configured to cause the high-frequency power source circuit to output the power, acquire a value for impedance of the biological tissue during the output, set a target impedance value, wherein the target impedance value gradually increases from a change-over impedance value to a stop impedance value within a predetermined period, the change-over impedance value being equal to or greater by a predetermined value than a minimum value of the value for impedance, the stop impedance value representing termination of the output, perform a comparison to cause the high-frequency power source circuit to lower or raise the power being output, for a period after the value for impedance reaching the change-over impedance value until the value for impedance reaching the stop impedance value, wherein the value for impedance is adopted as a measured impedance value and the measured impedance value is regularly compared to the target impedance value, and wherein the high-frequency power source circuit is caused to lower the power by a first ratio if the measured impedance value is greater than the target impedance value, and the high-frequency power source circuit is caused to raise the power by a second ratio if the measured impedance value is smaller than the target impedance value, and cause the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value.","According to an aspect of the invention, a high-frequency treatment system includes the above-mentioned electric power source device; and the high-frequency treatment instrument.","Advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.","The advantages of the invention may be realized and obtained by means of the instrumentalities and combinations particularly pointed out hereinafter."],["CROSS-REFERENCE TO RELATED APPLICATIONS This application is a Continuation Application of PCT Application No.","PCT/JP2016/064616, filed May 17, 2016 and based upon and claiming the benefit of priority from prior Japanese Patent Application No.","2015-150480, filed Jul.","30, 2015, the entire contents of all of which are incorporated herein by reference.","BACKGROUND OF THE INVENTION 1.Field of the Invention The present invention relates to an operation method of an electric power source device for operating a high-frequency treatment instrument, an electric power source device, and a high-frequency treatment system.","2.Description of the Related Art In general, there is known a high-frequency treatment system which performs a treatment by grasping a biological tissue, which is a treatment target, by a pair of grasping members, and by supplying high-frequency electric power to the biological tissue.","In this system, the biological tissue grasped by the grasping members is heated by a high-frequency current flowing through the biological tissue.","This high-frequency treatment system is used for, for example, sealing a blood vessel.","In the high-frequency treatment system, in order to improve the precision and efficiency of the treatment, it is required to appropriately adjust an output voltage and an output current.","For example, Jpn.","Pat.","Appln.","KOKAI Publication No.","H8-98845 discloses a technique relating to controlling an output by paying attention to an impedance value of a biological tissue.","Specifically, in this technique, a maximum value and a minimum value of the impedance value measured at an initial stage of a treatment are specified.","The impedance value, which is measured during the treatment, rises after taking a minimum value.","In the process of rising, the output is stopped when the impedance value reaches a predetermined value between the specified maximum value and minimum value.","It is considered preferable that this value between the maximum value and minimum value is, for example, a mean value between the maximum value and minimum value.","In addition, for example, Jpn.","Pat.","Appln.","KOKAI Publication No.","2012-196458 discloses a technique relating to setting a target value with respect to the transition of the impedance value during the treatment, and controlling the output such that this target value and the measured actual impedance value become equal.","In the high-frequency treatment system, since the adjustment of the output voltage and output current affects the precision and efficiency of the treatment, it is required that the output voltage and output current be adjusted more appropriately.","In addition, it is known that the optimal output voltage and output current vary in accordance with a treatment target.","Accordingly, it is required that the output voltage and output current be adjusted in accordance with a treatment target.","BRIEF SUMMARY OF THE INVENTION According to an aspect of the present invention, a method of operating a power source device for a high-frequency treatment instrument is adapted to perform high-frequency treatment for biological tissue.","The method comprises: causing, by a control circuit, a high-frequency power source circuit to output power; acquiring, by the control circuit, a value for impedance of the biological tissue during the output; setting, by the control circuit, a target impedance value, wherein the target impedance value gradually increases from a change-over impedance value to a stop impedance value within a predetermined period, the change-over impedance value being equal to or greater by a predetermined value than a minimum value of the value for impedance, the stop impedance value representing termination of the output; performing, by the control circuit, a comparison to cause the high-frequency power source circuit to lower or raise the power being output, for a period after the value for impedance reaching the change-over impedance value until the value for impedance reaching the stop impedance value, wherein the value for impedance is adopted as a measured impedance value and the measured impedance value is regularly compared to the target impedance value, and wherein the high-frequency power source circuit is caused to lower the power by a fixed first ratio if the measured impedance value is greater than the target impedance value, and the high-frequency power source circuit is caused to raise the power by a fixed second ratio if the measured impedance value is smaller than the target impedance value; and causing, by the control circuit, the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value.","According to an aspect of the present invention, a method of operating a power source device for a high-frequency treatment instrument is adapted to perform high-frequency treatment for biological tissue.","The method comprises: causing, by a control circuit, a high-frequency power source circuit to output power; acquiring, by the control circuit, a value for impedance of the biological tissue during the output; setting, by the control circuit, a target impedance value, wherein the target impedance value gradually increases from a change-over impedance value to a stop impedance value within a predetermined period, the change-over impedance value being equal to or greater by a predetermined value than a minimum value of the value for impedance, the stop impedance value representing termination of the output; performing, by the control circuit, a comparison to cause the high-frequency power source circuit to lower or raise the power being output, for a period after the value for impedance reaching the change-over impedance value until the value for impedance reaching the stop impedance value, wherein the value for impedance is adopted as a measured impedance value and the measured impedance value is regularly compared to the target impedance value, and wherein the high-frequency power source circuit is caused to lower the power by a fixed first value if the measured impedance value is greater than the target impedance value, and the high-frequency power source circuit is caused to raise the power by a fixed second value if the measured impedance value is smaller than the target impedance value; and causing, by the control circuit, the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value.","According to an aspect of the present invention, a method of operating a power source device for a high-frequency treatment instrument is adapted to perform high-frequency treatment for biological tissue.","The method comprises: causing, by a control circuit, a high-frequency power source circuit to output power; acquiring, by the control circuit, an initial impedance value which is a value for impedance of the biological tissue within a first period after starting the output; determining, by the control circuit, a ratio of increase of output voltage relative to time, based on the initial impedance value; causing, by the control circuit, the high-frequency power source circuit to increase an output voltage according to the ratio of increase, for a second period after the first period; acquiring, by the control circuit, a value for impedance of the biological tissue during and after the second period; terminating, by the control circuit, the second period upon the value for impedance reaching a change-over impedance value representing a minimum value; determining, by the control circuit, an additional impedance value based on the initial impedance value; setting, by the control circuit, a stop impedance value which is a sum of the change-over impedance value and the additional impedance value; setting, by the control circuit, a gradually increasing target impedance value for a third period after the value for impedance reaching the change-over impedance value until the value for impedance reaching the stop impedance value; performing, by the control circuit, a comparison to cause the high-frequency power source circuit to lower or raise the power being output, for the third period, wherein the value for impedance is adopted as a measured impedance value and the measured impedance value is regularly compared to the target impedance value, and wherein the high-frequency power source circuit is caused to lower the power by a first ratio if the measured impedance value is greater than the target impedance value, and the high-frequency power source circuit is caused to raise the power by a second ratio if the measured impedance value is smaller than the target impedance value; and causing, by the control circuit, the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value.","According to an aspect of the present invention, a power source device for a high-frequency treatment instrument is adapted to perform high-frequency treatment for biological tissue.","The power source device comprises: a high-frequency power source circuit which outputs power; an output detection circuit which detects the output; and a control circuit which acquires information about the output from the output detection circuit and controls the high-frequency power source circuit.","The control circuit is configured to cause the high-frequency power source circuit to output the power, acquire a value for impedance of the biological tissue during the output, set a target impedance value, wherein the target impedance value gradually increases from a change-over impedance value to a stop impedance value within a predetermined period, the change-over impedance value being equal to or greater by a predetermined value than a minimum value of the value for impedance, the stop impedance value representing termination of the output, perform a comparison to cause the high-frequency power source circuit to lower or raise the power being output, for a period after the value for impedance reaching the change-over impedance value until the value for impedance reaching the stop impedance value, wherein the value for impedance is adopted as a measured impedance value and the measured impedance value is regularly compared to the target impedance value, and wherein the high-frequency power source circuit is caused to lower the power by a first ratio if the measured impedance value is greater than the target impedance value, and the high-frequency power source circuit is caused to raise the power by a second ratio if the measured impedance value is smaller than the target impedance value, and cause the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value.","According to an aspect of the invention, a high-frequency treatment system includes the above-mentioned electric power source device; and the high-frequency treatment instrument.","Advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.","The advantages of the invention may be realized and obtained by means of the instrumentalities and combinations particularly pointed out hereinafter.","BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate embodiments of the invention, and together with the general description given above and the detailed description of the embodiments given below, serve to explain the principles of the invention.","FIG.","1 is a view which schematically illustrates an example of the external appearance of a high-frequency treatment system according to an embodiment.","FIG.","2 is a block diagram which schematically illustrates a configuration example of the high-frequency treatment system according to the embodiment.","FIG.","3 is a flowchart illustrating an example of the operation of the high-frequency treatment system according to the embodiment.","FIG.","4 shows an example of variations of an electric power, a voltage, a current and an impedance relative to time in the high-frequency treatment system according to the embodiment.","FIG.","5 is a flowchart illustrating an example of first control of the high-frequency treatment system according to the embodiment.","FIG.","6 shows an example of the relationship between duration of application of a voltage to a biological tissue in second control and a vessel burst pressure of a blood vessel which is sealed by the treatment.","FIG.","7 is a flowchart illustrating an example of the second control of the high-frequency treatment system according to the embodiment.","FIG.","8 shows an example of a table including a relationship between an initial resistance value and an additional resistance value, which are used in the high-frequency treatment system according to the embodiment.","FIG.","9 shows an example of a table including a relationship between an initial resistance value, duration and an additional resistance value, which are used in the high-frequency treatment system according to the embodiment.","FIG.","10 shows an example of a graph of a target resistance value versus time in the high-frequency treatment system according to the embodiment.","FIG.","11 shows an example of a graph of an output electric power and a resistance value versus time in the high-frequency treatment system according to the embodiment.","FIG.","12 is a flowchart illustrating an example of third control of the high-frequency treatment system according to the embodiment.","DETAILED DESCRIPTION OF THE INVENTION An embodiment of the present invention will be described hereinafter with reference to the accompanying drawings.","FIG.","1 is a schematic view of a high-frequency treatment system 10 according to the present embodiment.","As illustrated in this Figure, the high-frequency treatment system 10 includes a high-frequency treatment instrument 100 which functions as a high-frequency treatment instrument, an electric power source device 200 which supplies electric power to the treatment instrument, and a footswitch 290.The high-frequency treatment instrument 100 includes a treatment portion 110, a shaft 160, and an operation portion 170.For the purpose of descriptions below, the treatment portion 110 side is referred to as a distal side, and the operation portion 170 side is referred to as a proximal side.","The high-frequency treatment system 10 is configured to grasp a biological tissue, such as a blood vessel, which is a treatment target, by the treatment portion 110.The high-frequency treatment system 10 applies a high-frequency voltage to the grasped biological tissue, thereby sealing this biological tissue.","The treatment portion 110, which is provided at a distal end of the shaft 160, is provided with a first grasping member 112 and a second grasping member 114, which are a pair of grasping members.","Those parts of the first grasping member 112 and second grasping member 114, which come in contact with the biological tissue, function as electrodes, respectively.","Specifically, the first grasping member 112 and second grasping member 114 function as bipolar electrodes.","The operation portion 170 is provided an operation portion main body 172, a stationary handle 174, a movable handle 176, and an output switch 178.The stationary handle 174 is fixed to the operation portion main body 172, and the movable handle 176 is displaced relative to the operation portion main body 172.The movable handle 176 is connected to a wire or a rod, which is inserted through the shaft 160.This wire or rod is connected to the second grasping member 114.The movement of the movable handle 176 is transmitted to the second grasping member 114.The second grasping member 114 is displaced relative to the first grasping member 112 in accordance with the movement of the movable handle 176.As a result, the first grasping member 112 and second grasping member 114 open or close relative to each other.","The output switch 178 includes, for example, two buttons.","These buttons are buttons which are pressed when high-frequency electric power is made to act on the biological tissue, which is the treatment target, by the treatment portion 110.The electric power source device 200, which detects the pressing of the button, applies a high-frequency voltage between the first grasping member 112 and second grasping member 114.As a result, the biological tissue, which is grasped by the treatment portion 110, is sealed.","The high-frequency treatment instrument 100 is configured, for example, such that the output level varies depending on which of the two buttons is pressed.","The footswitch 290 is also provided with, for example, two switches.","The two respective switches of the footswitch 290 have the same functions as the respective buttons of the output switch 178.The high-frequency treatment system 10 may be provided with both the output switch 178 and the footswitch 290, or may be provided with one of them.","Hereinafter, a description will be given on the assumption that the output switch 178 is mainly operated, but the footswitch 290 may be operated.","One end of a cable 180 is connected to the proximal side of the operation portion 170.The other end of the cable 180 is connected to the electric power source device 200.The electric power source device 200 controls the operation of the high-frequency treatment instrument 100, and supplies electric power to the high-frequency treatment instrument 100.FIG.","2 is a block diagram which schematically illustrates a configuration example of the electric power source device 200.The electric power source device 200 includes a control circuit 210, a high-frequency electric power source circuit 220, an output detection circuit 230, an A/D converter 240, a storage medium 250, an input device 262, a display 264, and a speaker 266.The control circuit 210 includes an integrated circuit or the like, such as a central processing unit (CPU), an application specific integrated circuit (ASIC), or a field programmable gate array (FPGA).","The control circuit 210 may be composed of a single integrated circuit or the like, or may be composed of a combination of a plurality of integrated circuits or the like.","The operation of the control circuit 210 is executed, for example, in accordance with a program stored in the control circuit 210 or in the storage medium 250.The control circuit 210 acquires information from each component of the electric power source device 200, and controls the operation of each component.","The high-frequency electric power source circuit 220 outputs high-frequency electric power which is supplied to the high-frequency treatment instrument 100.The high-frequency electric power source circuit 220 includes a variable DC electric power source 221, a waveform generating circuit 222, and an output circuit 223.The variable DC electric power source 221 outputs DC electric power under the control of the control circuit 210.The output of the variable DC electric power source 221 is transmitted to the output circuit 223.The waveform generating circuit 222 generates an AC waveform under the control of the control circuit 210, and outputs the generated AC waveform.","The output of the waveform generating circuit 222 is transmitted to the output circuit 223.The output circuit 223 superimposes the output of the variable DC electric power source 221 and the output of the waveform generating circuit 222, and outputs AC electric power.","This AC electric power is supplied, via the output detection circuit 230, to the first grasping member 112 and second grasping member 114 of the high-frequency treatment instrument 100.The output detection circuit 230 includes a current detection circuit 231 and a voltage detection circuit 232.The current detection circuit 231 is inserted in a circuit from the high-frequency electric power source circuit 220 to the high-frequency treatment instrument 100, and outputs an analog signal which represents a current value that is output from the high-frequency electric power source circuit 220.The voltage detection circuit 232 outputs an analog signal which represents an output voltage of the high-frequency electric power source circuit 220.The output signal of the current detection circuit 231 and the output signal of the voltage detection circuit 232 are input to the A/D converter 240.The A/D converter 240 converts the input analog signals to a digital signal, and sends the digital signal to the control circuit 210.In this manner, the control circuit 210 acquires information of the output voltage and output current of the high-frequency electric power source circuit 220.In addition, based on the output voltage and output current, the control circuit 210 calculates a value relating to an impedance of a circuit including the first grasping member 112, the biological tissue that is the treatment target, and the second grasping member 114.Specifically, the control circuit 210 acquires a value relating to the impedance of the biological tissue.","The storage medium 250 stores programs which are used in the control circuit 210, and various parameters, tables, etc.","which are used in calculations executed in the control circuit 210.The input device 262 includes an input device such as a button, a slider, a dial, a keyboard, or a touch panel.","The control circuit 210 acquires an input to the input device 262 by the user.","The display 264 includes a display device such as a liquid crystal display or an LED lamp.","The display 264 presents information relating to the high-frequency treatment system 10 to the user, under the control of the control circuit 210.The speaker 266 issues, for example, an input sound, an output sound, an alarm sound, etc., under the control of the control circuit 210.The operation of the high-frequency treatment system 10 according to the present embodiment will be described.","The user operates the input device 262 of the electric power source device 200, and sets a desired output level for the high-frequency treatment instrument 100.The output level is set, for example, for each of the plural output switches 178.The treatment portion 110 and shaft 160 are inserted, for example, into a peritoneal cavity through an abdominal wall.","The user opens or closes the treatment portion 110 by operating the movable handle 176.In this manner, the first grasping member 112 and second grasping member 114 grasp the biological tissue that is the treatment target.","When the biological tissue is grasped by the treatment portion 110, the user operates the output switch 178.The control circuit 210 of the electric power source device 200, which detected the pressing of the button of the output switch 178, outputs an instruction, which relates to driving, to the high-frequency electric power source circuit 220.The high-frequency electric power source circuit 220 applies, under the control of the control circuit 210, a high-frequency voltage to the first grasping member 112 and second grasping member 114 of the treatment portion 110, and causes a high-frequency current to flow through the biological tissue that is the treatment target.","If the high-frequency current flows, the biological tissue becomes an electrical resistance.","Thus, heat is generated in the biological tissue, and the temperature of the biological tissue rises.","As a result, the protein of the biological tissue is denatured, and the biological tissue is sealed.","By the above, the treatment of the biological tissue is completed.","The output operation of the electric power source device 200 will be described in detail.","The outline of the operation of the electric power source device 200 according to the present embodiment will be described with reference to a flowchart of FIG.","3.In step S101, the control circuit 210 determines whether the output switch 178 is turned on.","If the output switch 178 is not turned on, the process returns to step S101.In other words, the control circuit 210 stands by until the output switch 178 is turned on.","When the output switch 178 is turned on, the process advances to step S102.In step S102, the control circuit 210 executes first control.","Then, in step S103, the control circuit 210 executes second control.","Subsequently, in step S104, the control circuit 210 executes third control.","The first control, second control and third control will be described later in detail.","By the above, the output control is terminated.","In this manner, in the present embodiment, three-stage controls are executed.","Referring to FIG.","4, a description is given of an example of an output of the high-frequency treatment system 10 according to the embodiment, and an impedance relating to the biological tissue, which is calculated at the time of the output.","In FIG.","4, the horizontal axis indicates time, which is set such that an output start time is 0.The left vertical axis indicates an output electric power, an output voltage, and an output current.","The right vertical axis indicates an impedance.","In FIG.","4, a solid line indicates a variation of the output voltage, a dashed line indicates a variation of the impedance, a dashed-dotted line indicates a variation of the output electric power, and a dashed double-dotted line indicates a variation of the output current.","As described above, the control of the output of the high-frequency treatment system 10 according to the present embodiment is divided into three stages (three phases).","Accordingly, the period, during which electric power is supplied to the biological tissue, includes a first period in which the first control of a short period immediately after the output start is executed, a subsequent second period in which the second control of about one second is executed, and a subsequent third period in which the third control of about two seconds is executed.","The output by the first control is referred to as a first output, the output by the second control is referred to as a second output, and the output by the third control is referred to as a third output.","In addition, since the output by the second control is executed prior to the output by the third control, the period by the second control is referred to as a former period, and the period by the third control is referred to as a latter period.","In the first control, high-frequency electric power having a predetermined electric power value is supplied to the biological tissue during a predetermined period.","This first period is, for example, about 100 milliseconds.","During the first period, the value relating to the impedance is acquired.","In accordance with the size, kind, etc.","of the biological tissue that is the treatment target, or the state of the biological tissue, the value relating to the impedance, which is acquired at that time, will vary.","Thus, in the present embodiment, based on the value relating to the impedance which is acquired in the first period in which the first control is executed, the state of the biological tissue that is the treatment target is ascertained, and control parameters, which are used in the subsequent control, are determined.","Specifically, the control parameters, which correspond to the characteristics of the biological tissue that is the treatment target, are set.","In addition, in the first control, an overshoot of the output is suppressed by a predetermined electric power, which is not so large, being supplied to the biological tissue.","In the second control, a voltage which increases linearly is applied to the biological tissue.","The temperature of the biological tissue rises in the second period in which the second control is executed.","The second control is executed until it is detected that the value relating to the measured impedance takes a minimum value.","If the value relating to the measured impedance takes the minimum value, the control transitions to the third control.","If moisture evaporates in the second control, the value relating to the impedance increases subsequently in accordance with the rise in temperature.","In the third control, the output control is executed such that the value relating to the impedance increases linearly.","In this third period, the temperature of the biological tissue is kept substantially constant.","Hereinafter, the first to third controls will be described in detail.","[First Control] The first control will be described with reference to a flowchart illustrated in FIG.","5.In step S201, the control circuit 210 causes the high-frequency electric power source circuit 220 to supply AC electric power having a predetermined electric power value to the biological tissue that is the treatment target, which is clamped between the first grasping member 112 and second grasping member 114.By the supply of the AC electric power, an AC current flows through the biological tissue.","In step S202, the control circuit 210 acquires an impedance value relating to the biological tissue that is the treatment target.","For example, the control circuit 210 acquires the current detected by the current detection circuit 231 of the output detection circuit 230, and the voltage detected by the voltage detection circuit 232 of the output detection circuit 230, and calculates the impedance value based on these values.","Here, the calculated impedance value may be various kinds of values relating to the impedance, and may be, for example, an absolute value of the impedance which is a complex number, or may be a resistance value which is a real number component of the impedance.","An admittance, which is a reciprocal of the impedance, may be used.","In step S203, the control circuit 210 determines whether a predetermined time has passed.","Here, the predetermined time is, for example, 100 milliseconds.","If the predetermined time has not passed, the process returns to step S201.Specifically, the supply of the predetermined electric power and the acquisition of the impedance value are repeated.","When the predetermined time has passed, the first control ends, and a transition occurs to the second control.","The impedance value, which is acquired in the first control, is referred to as an initial impedance value.","The initial impedance value may be an impedance value which is first acquired, or may be a mean value or a median of impedance values acquired in some periods in the first period during which the first control is executed.","[Second Control] The second control will be described in detail.","The second control is a control which is optimized in order to stably seal a blood vessel or the like.","Here, attention is paid to a change of the impedance value at a time when the biological tissue, such as a blood vessel, is heated.","If the biological tissue is heated, the temperature of an electrolyte solution in the biological tissue rises, and the impedance decreases.","Paying attention to this decrease of the impedance, the following became clear.","FIG.","6 illustrates the relationship between duration of a voltage application (heating time) by the second control and a mean value of a vessel burst pressure (VBP).","Here, the duration of the voltage application by the second control is a time from when the second control started until when the impedance value takes the minimum value, as described above.","In addition, as described above and as illustrated in FIG.","4, the second control is a control in which the output voltage is adjusted so as to increases linearly.","The VBP indicates a pressure at which a sealed part is peeled when a water pressure is applied to the blood vessel after the seal treatment through the second control and third control.","Specifically, as the VBP becomes higher, this means that stronger sealing is performed.","In general, it is required that a VBP of 360 mmHg or above be obtained in the blood vessel after at least 90% or more of the treatment.","As illustrated in FIG.","6, the VBP tends to increase, as the time until the impedance value takes the minimum value becomes longer.","In addition, even when the time until the impedance value takes the minimum value increased to one second or more, the VBP did not increase so much.","Taking into account the result shown in FIG.","6 and the fact that a shorter treatment time is desired, it is considered that the time until the impedance value takes the minimum value should preferably be about one second.","It is understood that the time may be in a range of between about 0.5 seconds and 1.5 seconds, in which the VBP is sufficiently higher than 360 mmHg.","In consideration of these results, in the present embodiment, the output voltage in the second control is adjusted such that the time until the impedance value takes the minimum value becomes about one second.","In the present embodiment, the control circuit 210 controls the output voltage V(t) which is applied to the biological tissue in the second control, as indicated by the following equation (1): V(t)=(V(Z)/GV)×t, (1) where t is a time from the start of treatment, that is, a time from the start of the first control.","The time t may be a time from the start of the second control.","V(Z) is a constant, for example, a maximum value of the output voltage.","GV is a gradient value.","Thus, (V(Z)/GV) indicates an increase value of the output voltage per unit time, that is, an inclination (increase rate).","GV is determined based on the initial impedance value acquired in the first control.","For example, based on an initial resistance value R0, GV is determined by the following equation (2): GV=a·R0+b, (2) where a and b are fixed values.","The values a and b are empirically adjusted such that the impedance value takes the minimum value in about one second, when the output voltage V(t) is applied to the biological tissue.","The above equation (2) is not limited to an equation of a linear function, and may be another equation such as a function of a higher degree.","However, the linear function is preferable to a higher-degree function, so that the influence, which the initial resistance value R0 exerts on the above equation (1), may not become excessively large.","In addition, the above equation (1) is also a linear function relating to time.","Because of the linear function, a proper temperature rise with high stability can be obtained.","Since the output voltage is the linear function relating to time, the electric power, which is input to the biological tissue, increases in a manner of a quadratic function with respect to time.","An offset may be added to the output voltage V(t).","Specifically, the above equation (1) may be modified as follows: V(t)=(V(Z)/GV)×t+c, (3) where c is a fixed value.","According to the above equations (1) and (2), for example, in a thin blood vessel, the initial resistance value R0 is relatively high.","Thus, (V(Z)/GV), which indicates a gradient, is relatively small.","Specifically, in a thin blood vessel, the output voltage increases relatively slowly, and accordingly the input electric power increases relatively slowly.","On the other hand, for example, in a thick blood vessel, the initial resistance value R0 is relatively low.","Thus, (V(Z)/GV), which indicates the gradient, is relatively large.","Specifically, in a thick blood vessel, the output voltage increases relatively quickly, and accordingly the input electric power increases relatively quickly.","The gradient (V(Z)/GV) may be calculated at each time and used, based on the relationships of the above equations (1) and (2) and the initial resistance value R0, or may be determined based on the table prestored in the storage medium 250, which represents the relationship between the initial resistance value R0 and gradient (V(Z)/GV), and based on the initial resistance value.","The operation of the electric power source device 200 in the second control will be described with reference to a flowchart of FIG.","7.In step S301, the control circuit 210 calculates the relationship between time and output voltage V(t), based on the initial impedance value.","The output voltage V(t) is determined, for example, by using the above equations (1) and (2).","In step S302, the control circuit 210 causes the high-frequency electric power source circuit 220 to output the voltage V(t) which corresponds to time.","In step S303, the control circuit 210 acquires the impedance value of the biological tissue.","In step S304, the control circuit 210 determines whether the impedance value acquired in step S303 is a change-over impedance value or not.","Here, the change-over impedance value is an impedance value which is a condition for terminating the second control.","The change-over impedance value can be, for example, a value at a time when the variation of the impedance value is measured and the impedance value becomes the minimum value.","In order to easily detect the minimum value, a value, which has increased by a predetermined value after the impedance value took the minimum value, may be set as the change-over impedance value.","Specifically, in step S304, when the impedance value decreased and took the minimum value and then the impedance value has increased by the predetermined value, it may be determined that the impedance value has become the change-over impedance value.","In step S304, when it is determined that the impedance value is not the change-over impedance value, the process returns to step S302.On the other hand, when it is determined that the impedance value is the change-over impedance value, the second control is terminated, and a transition occurs to the third control.","By the above-described controls, the output voltage and the impedance value become as illustrated in FIG.","4.Specifically, in the second period in which the second control is executed, the output voltage increases linearly.","At this time, the output electric power increases in a manner of a quadratic function.","The impedance value acquired in the second period decreases slowly with time.","In the example illustrated in FIG.","4, when the impedance value has slightly increased after taking the minimum value, the second control is terminated.","In the meantime, although the example in which the output voltage is controlled is illustrated here, the output current or output electric power may be controlled so as to increase linearly in the same manner.","The time until the impedance value takes the minimum value is set to be about one second and is relatively slow.","It is thus possible to make unifoLitt the temperature of the biological tissue, while shortening the time of the treatment.","In addition, by setting the time until the impedance value takes the minimum value to be constant at about one second, regardless of the size, etc.","of the treatment target, it is possible to suppress a variance in results of treatments.","In the meantime, when the same energy is input, the impedance value takes the minimum value in a shorter time, as the thickness of the blood vessel becomes smaller.","By setting the time until the impedance value takes the minimum value to be about one second, a high sealing strength can be obtained stably, as illustrated in FIG.","6.","[Third Control] The third control will be described in detail.","In the third control, the output is controlled such that the measured impedance value increases with a constant rate.","In the present embodiment, a stop impedance value, which is an impedance value at a time when the output is stopped, is first determined.","Next, target impedance which increases at a constant speed from the impedance value at the start time of the third control up to the stop impedance value is set.","Specifically, the target impedance value is set as a target value of the impedance value at each time.","The control of the output is executed such that the output value is determined at predetermined time intervals, based on a difference between the target impedance value and a measured impedance value acquired by using the output detection circuit 230.In this manner, the third control is executed until the measured impedance value reaches the stop impedance value along target impedance values.","<Setting of the Stop Impedance Value in the Third Control> A determination method of the stop impedance value at the time of stopping the output will be described.","Here, a description is given of the case of using a resistance value as the impedance value.","The same applies to cases using other impedance values, aside from the resistance value.","A stop resistance value Rstop, which is a resistance value at the time of stopping the output, is calculated by, for example, the following equation (4): Rstop=Rin+Radd.","(4) Rin is a resistance value relating to the biological tissue, which is acquired at the start time of the third control.","Specifically, Rin is the resistance value corresponding to the above-described change-over impedance value.","The Rin may be the minimum impedance measured in the second control.","In addition, the initial impedance value acquired in the first control may be used for Rin.","Radd is an additional resistance value which is determined based on the initial state of the biological tissue.","Some examples of the determination method of the additional resistance value Radd will be illustrated.","(First Example) The additional resistance value Radd is calculated as a function of the initial resistance value R0.The initial resistance value R0 is the resistance value detected in the first control.","The storage medium 250 stores a table, for example, as illustrated in FIG.","8, the table representing the relationship between the additional resistance value Radd and initial resistance value R0.Based on this table and the initial resistance value R0 measured in the first control, the additional resistance value Radd is determined.","In FIG.","8, a, b, c and d represent resistance values, and have a relationship of a<b<c<d.","Specifically, as the initial resistance value R0 becomes higher, the additional resistance value Radd becomes lower.","In other words, when the treatment target is a blood vessel, a thinner blood vessel has a higher initial resistance R0, and thus the additional resistance value Radd becomes lower.","In addition, the additional resistance value Radd may be calculated based on a function representing the same relationship as in FIG.","8.","(Second Example) The additional resistance value Radd is calculated as a function of the initial resistance value R0 and duration Dt of the second control.","The duration Dt is acquired when the second control is finished.","For example, when the initial resistance value R0 is a predetermined threshold value or more, and when the duration Dt is a predetermined threshold value or less, a first additional resistance value Radd1 is selected as the additional resistance value Radd.","When the initial resistance value R0 is lower than the predetermined threshold value, or when the duration Dt is longer than the predetermined threshold value, a second additional resistance value Radd2 is selected as the additional resistance value Radd.","Here, the first additional resistance value Radd1 is lower than the second additional resistance value Radd2.In addition, the storage medium 250 stores a table, for example, as illustrated in FIG.","9, the table representing the relationship between the additional resistance value Radd, duration Dt and initial resistance value R0.Based on this table, the initial resistance value R0 measured in the first control and the duration Dt of the second control, the additional resistance value Radd may be determined.","In FIG.","9, a, b, c and d represent resistance values, and have a relationship of a<b<c<d.","Specifically, as the initial resistance value R0 becomes higher, the additional resistance value Radd becomes lower; and as the duration Dt becomes longer, the additional resistance value Radd becomes higher.","In addition, the additional resistance value Radd may be calculated based on a function representing the same relationship as in FIG.","9.Based on the initial resistance value R0 and the duration Dt of the second control, the additional resistance value Radd is determined.","Thereby, a more appropriate additional resistance value Radd can be determined than in the case in which the additional resistance value Radd is determined based on only the initial resistance value R0.","(Third Example) The additional resistance value Radd may be selected in accordance with an output level which the user sets.","For example, as the output level becomes higher, the additional resistance value Radd becomes higher; and as the output level becomes lower, the additional resistance value Radd becomes lower.","It is preferable that, like the case of the first example or the second example, the output level is used in combination with the initial resistance value R0 or the duration Dt of the second control.","A more appropriate value can be set, by the additional resistance value Radd being determined by using the output level in combination with the initial resistance value R0 or the duration Dt of the second control.","In each of the above first to third examples, for instance, as the blood vessel becomes thinner, the additional resistance value Radd becomes lower; and as the blood vessel becomes thicker, the additional resistance value Radd becomes higher.","The stop resistance value Rstop is higher than the initial resistance value R0.Like the above, when a value relating to the impedance, other than the resistance value, is used, Rin corresponds to the change-over impedance value, the additional resistance value Radd corresponds to the additional impedance value, and the initial resistance value R0 corresponds to the initial impedance value.","As described above, use is made of the initial impedance value which varies in accordance with the treatment target, for instance, the thickness of the blood vessel.","Thereby, the stop impedance value corresponding to the treatment target is appropriately set.","Since the output control is executed by using the thus determined stop impedance value, a proper treatment can be performed.","<Setting of the Target Impedance Value in the Third Control> A setting method of the target impedance value will be described.","Here, a description is given of the case in which, like the above-described stop resistance value, the resistance value is used as the impedance value.","Specifically, the case in which a target resistance value is used as the target impedance value will be described.","The same applies to the cases of using other values relating to the impedance, aside from the resistance value.","(First Example) In a first example, a time in which high-frequency electric power is output by the third control is predetermined.","A target resistance value at each time can be set such that, in this predetermined time, the resistance value linearly increases up to the stop resistance value Rstop which is calculated from the change-over resistance value Rin.","(Second Example) In a second example, a time in which high-frequency electric power is output by the third control is determined in accordance with the output level that is set by the user.","A target resistance value can be set such that, in the time determined in accordance with the output level, the resistance value linearly increases up to the calculated stop resistance value Rstop.","Specifically, as illustrated in FIG.","10, an inclination at a time when the target resistance value is indicated relative to time varies in accordance with the output level.","In other words, the speed of increase of the target resistance value varies in accordance with the output level.","In FIG.","10, L1, L2 and L3 indicate output levels, and have a relationship of L1<L2<L3.","(Third Example) In a third example, a time in which high-frequency electric power is output by the third control is determined in accordance with the resistance value (initial resistance value) acquired in the first control.","In addition, the time in which high-frequency electric power is output by the third control may be determined in accordance with the resistance value acquired in the second control.","A target resistance value can be set such that, in the determined time, the resistance value linearly increases up to the calculated stop resistance value Rstop.","Specifically, an inclination at a time when the target resistance value is indicated relative to time varies in accordance with the resistance value acquired in the first control or second control.","In other words, the speed of increase of the target resistance value varies in accordance with the resistance value acquired in the first control or second control.","For example, when the resistance value acquired in the first control or second control is low, the output time in the third control becomes shorter and the inclination becomes larger.","On the other hand, when the resistance value acquired in the first control or second control is high, the output time in the third control becomes longer and the inclination becomes smaller.","<Determination Method of Output Electric Power in the Third Control> A determination method of an output will be described.","Like the above-described case, the case in which a resistance value is used as the impedance value is described.","The same applies to the cases of using other values relating to the impedance, aside from the resistance value.","A description will be given with reference to FIG.","11.An upper part of FIG.","11 schematically illustrates a target resistance value and a measured resistance value relative to time.","Here, the target resistance value is indicated by a broken line, and the measured resistance value is indicated by a solid line.","A lower part of FIG.","11 schematically illustrates output electric power relative to time.","In the present embodiment, the output electric power is set in each step time of several-ten milliseconds.","The setting of the output electric power is executed by comparing the target resistance value and the measured resistance value.","Specifically, the target resistance value and the measured resistance value are compared at predetermined time intervals.","When the measured resistance value is higher than the target resistance value, the output electric power is decreased.","On the other hand, when the measured resistance value is lower than the target resistance value, the output electric power is increased.","In addition, when the difference between the measured resistance value and the target resistance value is less than a predetermined threshold value, the output electric power is maintained.","The output electric power at the start time of the third control may be the output electric power at the end time of the second control.","The output electric power at the start time of the third control may be a predetermined value, or may be determined by a predetermined method.","If the set value of the output electric power is frequently changed, there is concern that the output oscillates.","On the other hand, if the setting of the output electric power is executed only occasionally, the precision in control would lower, or the treatment could not be completed within a target time.","Thus, it is preferable that the interval of re-setting of output electric power, that is, the step time, is appropriately adjusted.","Examples of the determination method of the output electric power will be described.","(First Example) In a first example, a change amount of the output electric power is a predetermined ratio relative to the output electric power at that time point.","For example, this predetermined ratio is set as a first ratio.","In this case, when the initial output electric power is a first electric power, and the measured resistance value is higher than the target resistance value, the next output electric power is set at a second electric power which is lowered from the first electric power by the first ratio.","When the output is a second electric power, and the measured resistance value is lower than the target resistance value, the next output electric power is set at a third electric power which is raised from the second electric power by the first ratio.","Subsequently, the output electric power is controlled in the same manner.","For example, if the first ratio is set at 10%, the output electric power is controlled as follows.","When the output electric power is 20 W at that time point and the measured resistance value is higher than the target resistance value, the next output electric power is adjusted at 18 W. When the output electric power is 18 W and the measured resistance value is lower than the target resistance value, the next output electric power is adjusted at 19.8 W. By setting the change amount of the output electric power to be the predetermined ratio relative to the output electric power at that time point, the change amount is adjusted to a proper value at each of a time when the output electric power is large and a time when the output electric power is small.","The numerical values illustrated here are merely examples, and any numerical value can be used for the proper setting.","In the meantime, when the ratio at the time of lowering the output electric power is set as a first ratio and the ratio at the time of raising the output electric power is set as a second ratio, the first ratio and the second ratio may be equal or different.","It is preferable that the first ratio is greater than the second ratio.","For example, when the measured resistance value is higher than the target resistance value, the output is lowered by 10%.","When the measured resistance value is lower than the target resistance value, the output is raised by 5%.","In addition, when the difference between the measured resistance value and the target resistance value is within a predetermined range, the output electric power may not be changed.","(Second Example) In a second example, a change amount of the output electric power is a predetermined value.","In a case in which this predetermined ratio is set as a first value, when the measured resistance value is higher than the target resistance value, the next output electric power is adjusted at a value which is lowered from the present output electric power by a first value.","When the measured resistance value is lower than the target resistance value, the next output electric power is adjusted at a value which is higher than the present output electric power by the first value.","For example, when the change amount is set to be 2 W, the output electric power is controlled as follows.","When the output electric power is 20 W at that time point and the measured resistance value is higher than the target resistance value, the next output electric power is adjusted at 18 W. When the output electric power is 18 W and the measured resistance value is lower than the target resistance value, the next output electric power is adjusted at 20 W. By setting the change amount of the output electric power at a constant value, the hardware configuration becomes simpler, and the control of the output electric power becomes easier.","The numerical values illustrated here are merely examples, and any numerical value can be used for the proper setting.","In the meantime, the change amount at the time of raising the output and the change amount at the time of lowering the output may be equal or different.","It is preferable that the change amount at the time of lowering the output is greater than the change amount at the time of raising the output.","In addition, when the difference between the measured resistance value and the target resistance value is within a predetermined range, the output electric power may not be changed.","(Third Example) In a third example, a change amount of the output electric power is determined based on the initial resistance value R0 acquired in the first control, and the length of the second period in which the second control is executed, that is, the period from when the second control started until when the impedance values takes the minimum value.","Thus, the storage medium 250 prestores, for example, a relationship between the initial resistance value R0, the length of the second period, and the change amount of the output electric power.","The control circuit 210 determines the output electric power by referring to this relationship.","(Fourth Example) In a fourth example, a change amount of the output electric power is a predetermined value which is determined in accordance with an output level that is set by the user.","The storage medium 250 prestores a relationship between the output level and the change amount of the output electric power.","The control circuit 210 determines the output electric power by referring to this relationship.","(Fifth Example) In a fifth example, the output electric power is determined by the relationship between the measured resistance value and the target resistance value.","For example, the output electric power is set as follows.","When the measured resistance value is higher than the target resistance value, the output electric power is set at a first electric power value.","When the measured resistance value is equal to the target resistance value, the output electric power is set at a second electric power value.","When the measured resistance value is lower than the target resistance value, the output electric power is set at a third electric power value.","Here, the electric power values become greater in the order of the first electric power value, second electric power value and third electric power value.","For example, the first electric power value is 5 W, second electric power value is 8 W, and third electric power value is 10 W. The numerical values illustrated here are merely examples, and any numerical value can be used for the proper setting.","The third control, which is controlled in the above manner, will be described with reference to a flowchart of FIG.","12.In step S401, the control circuit 210 calculates the additional impedance value, based on the initial impedance value.","In step S402, the control circuit 210 sets the stop impedance value, based on the sum of the change-over impedance value and the additional impedance value.","For example, any of the methods of the above-described first to third examples may be used for the setting method of the stop impedance value.","In step S403, the control circuit 210 sets the target impedance value by using the stop impedance value.","Any of the methods of the above-described first to third examples may be used for the setting method of the target impedance value.","In step S404, the control circuit 210 causes the high-frequency electric power source circuit 220 to output, as an initial electric power, the electric power having a predetermined electric power value.","The initial electric power is, for example, the electric power at the time of the end of the second control.","In step S405, the control circuit 210 acquires the impedance value by using the value detected by the output detection circuit 230.In step S406, the control circuit 210 determines whether the measured impedance value is the stop impedance value or more.","When the measured impedance value is not the stop impedance value or more, the process advances to step S407.In step S407, the control circuit 210 compares the measured impedance value (Zm) and the target impedance value (Zt).","When the difference between the measured impedance value (Zm) and the target impedance value (Zt) is within a predetermined threshold value (Zm≈t), the process advances to step S408.In step S408, the control circuit 210 maintains the set value (set electric power) of the output electric power.","Thereafter, the process advances to step S411.In step S407, when it is determined that the measured impedance value (Zm) is greater than the target impedance value (Zt) (Zm>Zt), the process advances to step S409.In step S409, the control circuit 210 sets the set electric power to a low electric power.","Then, the process advances to step S411.In step S407, when it is determined that the measured impedance value (Zm) is less than the target impedance value (Zt) (Zm<Zt), the process advances to step S410.In step S410, the control circuit 210 sets the set electric power to a high electric power.","Then, the process advances to step S411.For example, any of the methods of the above-described first to fifth examples may be used for the method of setting the electric power in each of step S408 to step S410.In step S411, the control circuit 210 causes the high-frequency electric power source circuit 220 to output the electric power of the electric power value which is set in any one of steps S408 to step S410.Thereafter, the process returns to step S405.In step S406, when it is determined that the measured impedance is the stop impedance value or more, the process advances to step S412.In step S412, the control circuit 210 causes the high-frequency electric power source circuit 220 to stop the output.","Then, the third control is finished.","By the above, the supply of the high-frequency electric power to the high-frequency treatment instrument 100 by the electric power source device 200 is terminated.","According to the above-described control, the output and the acquired impedance value are as illustrated in FIG.","4.Specifically, in the third control, the impedance value increases linearly.","The output electric power (output voltage or output current) is adjusted such that the impedance value increases linearly.","According to the above-described third control, the impedance value increases linearly, and thus the temperature of the biological tissue is kept substantially constant.","In this manner, the treatment of the biological tissue progresses at substantially constant temperatures.","Thus, for example, the stable sealing of the blood vessel can be obtained.","In addition, since the stop impedance value, which corresponds to the characteristics of the biological tissue, is determined, the condition for finishing the treatment, which corresponds to the characteristics of the biological tissue, is determined.","Specifically, the treatment is finished at a time point when sufficient treatment is conducted, regardless of differences in characteristics of biological tissues which are treatment targets.","As described above, according to the present embodiment, in the high-frequency treatment system 10, the output, which is optimized in accordance with the treatment target, can be executed.","The above description of the embodiment is given by taking, mainly, the sealing of the blood vessel as an example.","However, the above-described technique is applicable to treatments of other biological tissues.","In addition, the above-described operation may be prepared as a mode for sealing a blood vessel, and this mode may be prepared as well as other modes in the high-frequency treatment system 10.The high-frequency treatment system 10 may be configured such that the user can select a mode corresponding to a treatment, from among these modes.","The high-frequency treatment system 10 according to the present embodiment may be configured not only to output the high-frequency electric power, but also to have a function as an ultrasonic treatment instrument, which treats a biological tissue by ultrasonic vibration, for example, by the first grasping member 112 vibrating at an ultrasonic frequency.","A treatment instrument, which also uses ultrasonic energy, can function in the same manner as in the above-described embodiment with respect to the output of the high-frequency electric power.","Additional advantages and modifications will readily occur to those skilled in the art.","Therefore, the invention in its broader aspects is not limited to the specific details and representative embodiments shown and described herein.","Accordingly, various modifications may be made without departing from the spirit or scope of the general inventive concept as defined by the appended claims and their equivalents."]],"string":"[\n [\n \"OPERATION METHOD OF ELECTRIC POWER SOURCE DEVICE, ELECTRIC POWER SOURCE DEVICE, AND HIGH-FREQUENCY TREATMENT SYSTEM\",\n \"A method of operating a power source device for a high-frequency treatment instrument adapted to perform high-frequency treatment for biological tissue includes causing a high-frequency power source circuit to output power; setting a target impedance value which gradually increases from a change-over impedance value to a stop impedance value; regularly comparing a measured impedance value to the target impedance value; causing the high-frequency power source circuit to lower the power by a first ratio if the measured impedance value is greater than the target impedance value, and to raise the power by a second ratio if the measured impedance value is smaller than the target impedance value; and causing the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value.\"\n ],\n [\n \"1.A method of operating a power source device for a high-frequency treatment instrument adapted to perform high-frequency treatment for biological tissue, the method comprising: causing, by a control circuit, a high-frequency power source circuit to output power; acquiring, by the control circuit, a value for impedance of the biological tissue during the output; setting, by the control circuit, a target impedance value, wherein the target impedance value gradually increases from a change-over impedance value to a stop impedance value within a predetermined period, the change-over impedance value being equal to or greater by a predetermined value than a minimum value of the value for impedance, the stop impedance value representing termination of the output; repeating, by the control circuit, a first processing and a second processing on a regular basis for a period after the value for impedance reaching the change-over impedance value until the value for impedance reaching the stop impedance value, wherein the value for impedance is adopted as a measured impedance value, and wherein, in the first processing, the measured impedance value is compared to the target impedance value, and in the second processing, the high-frequency power source circuit is caused to change the power being output to decrease from current power in line with a first rule if the measured impedance value is greater than the target impedance value, and the high-frequency power source circuit is caused to change the power being output to increase from current power in line with a second rule if the measured impedance value is smaller than the target impedance value; and causing, by the control circuit, the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value.\",\n \"2.The method according to claim 11, wherein the first ratio is equal to the second ratio.\",\n \"3.The method according to claim 11, wherein the first ratio is unequal to the second ratio.\",\n \"4.The method according to claim 1, further comprising acquiring, by the control circuit, an initial impedance value which is the value for impedance within a predetermined period after starting the output, wherein the target impedance value varies a speed of increase according to the initial impedance value.\",\n \"5.The method according to claim 1, wherein the target impedance value varies a speed of increase according to a set output value.\",\n \"6.The method according to claim 1, wherein the target impedance value increases linearly with time.\",\n \"7-8.\",\n \"(canceled) 9.A power source device for a high-frequency treatment instrument adapted to perform high-frequency treatment for biological tissue, the power source device comprising: a high-frequency power source circuit which outputs power; an output detection circuit which detects the output; and a control circuit which acquires information about the output from the output detection circuit and controls the high-frequency power source circuit, wherein the control circuit is configured to cause the high-frequency power source circuit to output the power, acquire a value for impedance of the biological tissue during the output, set a target impedance value, wherein the target impedance value gradually increases from a change-over impedance value to a stop impedance value within a predetermined period, the change-over impedance value being equal to or greater by a predetermined value than a minimum value of the value for impedance, the stop impedance value representing termination of the output, repeat a first processing and a second processing on a regular basis for a period after the value for impedance reaching the change-over impedance value until the value for impedance reaching the stop impedance value, wherein the value for impedance is adopted as a measured impedance value and wherein, in the first processing, the measured impedance value is compared to the target impedance value, and in the second processing, the high-frequency power source circuit is caused to change the power being output to decrease from current power in line with a first rule if the measured impedance value is greater than the target impedance value, and the high-frequency power source circuit is caused to change the power being output to increase from current power in line with a second rule if the measured impedance value is smaller than the target impedance value, and cause the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value.\",\n \"10.\",\n \"(canceled) 11.The method according to claim 1, wherein decreasing the power in line with the first rule is decreasing the power from current power by a fixed first ratio, and increasing the power in line with the second rule is increasing the power from current power by a fixed second ratio.\",\n \"12.The method according to claim 3, wherein the first ratio is greater than the second ratio.\",\n \"13.The method according to claim 1, wherein decreasing the power in line with the first rule is decreasing the power from current power by a fixed first value, and increasing the power in line with the second rule is increasing the power from current power by a fixed second value.\",\n \"14.The method according to claim 13, wherein the first value is equal to the second value.\",\n \"15.The method according to claim 13, wherein the first value is unequal to the second value.\",\n \"16.The method according to claim 15, wherein the first value is greater than the second value.\",\n \"17.The power source device according to claim 9, wherein decreasing the power in line with the first rule is decreasing the power from current power by a fixed first ratio, and increasing the power in line with the second rule is increasing the power from current power by a fixed second ratio.\",\n \"18.The power source device according to claim 17, wherein the first ratio is equal to the second ratio.\",\n \"19.The power source device according to claim 17, wherein the first ratio is unequal to the second ratio.\",\n \"20.The power source device according to claim 19, wherein the first ratio is greater than the second ratio.\",\n \"21.The power source device according to claim 9, wherein decreasing the power in line with the first rule is decreasing the power from current power by a fixed first value, and increasing the power in line with the second rule is increasing the power from current power by a fixed second value.\",\n \"22.The power source device according to claim 21, wherein the first value is equal to the second value.\",\n \"23.The power source device according to claim 21, wherein the first value is greater than the second value.\"\n ],\n [\n \"<SOH> BACKGROUND OF THE INVENTION <EOH>\"\n ],\n [\n \"<SOH> BRIEF SUMMARY OF THE INVENTION <EOH>According to an aspect of the present invention, a method of operating a power source device for a high-frequency treatment instrument is adapted to perform high-frequency treatment for biological tissue.\",\n \"The method comprises: causing, by a control circuit, a high-frequency power source circuit to output power; acquiring, by the control circuit, a value for impedance of the biological tissue during the output; setting, by the control circuit, a target impedance value, wherein the target impedance value gradually increases from a change-over impedance value to a stop impedance value within a predetermined period, the change-over impedance value being equal to or greater by a predetermined value than a minimum value of the value for impedance, the stop impedance value representing termination of the output; performing, by the control circuit, a comparison to cause the high-frequency power source circuit to lower or raise the power being output, for a period after the value for impedance reaching the change-over impedance value until the value for impedance reaching the stop impedance value, wherein the value for impedance is adopted as a measured impedance value and the measured impedance value is regularly compared to the target impedance value, and wherein the high-frequency power source circuit is caused to lower the power by a fixed first ratio if the measured impedance value is greater than the target impedance value, and the high-frequency power source circuit is caused to raise the power by a fixed second ratio if the measured impedance value is smaller than the target impedance value; and causing, by the control circuit, the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value.\",\n \"According to an aspect of the present invention, a method of operating a power source device for a high-frequency treatment instrument is adapted to perform high-frequency treatment for biological tissue.\",\n \"The method comprises: causing, by a control circuit, a high-frequency power source circuit to output power; acquiring, by the control circuit, a value for impedance of the biological tissue during the output; setting, by the control circuit, a target impedance value, wherein the target impedance value gradually increases from a change-over impedance value to a stop impedance value within a predetermined period, the change-over impedance value being equal to or greater by a predetermined value than a minimum value of the value for impedance, the stop impedance value representing termination of the output; performing, by the control circuit, a comparison to cause the high-frequency power source circuit to lower or raise the power being output, for a period after the value for impedance reaching the change-over impedance value until the value for impedance reaching the stop impedance value, wherein the value for impedance is adopted as a measured impedance value and the measured impedance value is regularly compared to the target impedance value, and wherein the high-frequency power source circuit is caused to lower the power by a fixed first value if the measured impedance value is greater than the target impedance value, and the high-frequency power source circuit is caused to raise the power by a fixed second value if the measured impedance value is smaller than the target impedance value; and causing, by the control circuit, the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value.\",\n \"According to an aspect of the present invention, a method of operating a power source device for a high-frequency treatment instrument is adapted to perform high-frequency treatment for biological tissue.\",\n \"The method comprises: causing, by a control circuit, a high-frequency power source circuit to output power; acquiring, by the control circuit, an initial impedance value which is a value for impedance of the biological tissue within a first period after starting the output; determining, by the control circuit, a ratio of increase of output voltage relative to time, based on the initial impedance value; causing, by the control circuit, the high-frequency power source circuit to increase an output voltage according to the ratio of increase, for a second period after the first period; acquiring, by the control circuit, a value for impedance of the biological tissue during and after the second period; terminating, by the control circuit, the second period upon the value for impedance reaching a change-over impedance value representing a minimum value; determining, by the control circuit, an additional impedance value based on the initial impedance value; setting, by the control circuit, a stop impedance value which is a sum of the change-over impedance value and the additional impedance value; setting, by the control circuit, a gradually increasing target impedance value for a third period after the value for impedance reaching the change-over impedance value until the value for impedance reaching the stop impedance value; performing, by the control circuit, a comparison to cause the high-frequency power source circuit to lower or raise the power being output, for the third period, wherein the value for impedance is adopted as a measured impedance value and the measured impedance value is regularly compared to the target impedance value, and wherein the high-frequency power source circuit is caused to lower the power by a first ratio if the measured impedance value is greater than the target impedance value, and the high-frequency power source circuit is caused to raise the power by a second ratio if the measured impedance value is smaller than the target impedance value; and causing, by the control circuit, the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value.\",\n \"According to an aspect of the present invention, a power source device for a high-frequency treatment instrument is adapted to perform high-frequency treatment for biological tissue.\",\n \"The power source device comprises: a high-frequency power source circuit which outputs power; an output detection circuit which detects the output; and a control circuit which acquires information about the output from the output detection circuit and controls the high-frequency power source circuit.\",\n \"The control circuit is configured to cause the high-frequency power source circuit to output the power, acquire a value for impedance of the biological tissue during the output, set a target impedance value, wherein the target impedance value gradually increases from a change-over impedance value to a stop impedance value within a predetermined period, the change-over impedance value being equal to or greater by a predetermined value than a minimum value of the value for impedance, the stop impedance value representing termination of the output, perform a comparison to cause the high-frequency power source circuit to lower or raise the power being output, for a period after the value for impedance reaching the change-over impedance value until the value for impedance reaching the stop impedance value, wherein the value for impedance is adopted as a measured impedance value and the measured impedance value is regularly compared to the target impedance value, and wherein the high-frequency power source circuit is caused to lower the power by a first ratio if the measured impedance value is greater than the target impedance value, and the high-frequency power source circuit is caused to raise the power by a second ratio if the measured impedance value is smaller than the target impedance value, and cause the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value.\",\n \"According to an aspect of the invention, a high-frequency treatment system includes the above-mentioned electric power source device; and the high-frequency treatment instrument.\",\n \"Advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.\",\n \"The advantages of the invention may be realized and obtained by means of the instrumentalities and combinations particularly pointed out hereinafter.\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATIONS This application is a Continuation Application of PCT Application No.\",\n \"PCT/JP2016/064616, filed May 17, 2016 and based upon and claiming the benefit of priority from prior Japanese Patent Application No.\",\n \"2015-150480, filed Jul.\",\n \"30, 2015, the entire contents of all of which are incorporated herein by reference.\",\n \"BACKGROUND OF THE INVENTION 1.Field of the Invention The present invention relates to an operation method of an electric power source device for operating a high-frequency treatment instrument, an electric power source device, and a high-frequency treatment system.\",\n \"2.Description of the Related Art In general, there is known a high-frequency treatment system which performs a treatment by grasping a biological tissue, which is a treatment target, by a pair of grasping members, and by supplying high-frequency electric power to the biological tissue.\",\n \"In this system, the biological tissue grasped by the grasping members is heated by a high-frequency current flowing through the biological tissue.\",\n \"This high-frequency treatment system is used for, for example, sealing a blood vessel.\",\n \"In the high-frequency treatment system, in order to improve the precision and efficiency of the treatment, it is required to appropriately adjust an output voltage and an output current.\",\n \"For example, Jpn.\",\n \"Pat.\",\n \"Appln.\",\n \"KOKAI Publication No.\",\n \"H8-98845 discloses a technique relating to controlling an output by paying attention to an impedance value of a biological tissue.\",\n \"Specifically, in this technique, a maximum value and a minimum value of the impedance value measured at an initial stage of a treatment are specified.\",\n \"The impedance value, which is measured during the treatment, rises after taking a minimum value.\",\n \"In the process of rising, the output is stopped when the impedance value reaches a predetermined value between the specified maximum value and minimum value.\",\n \"It is considered preferable that this value between the maximum value and minimum value is, for example, a mean value between the maximum value and minimum value.\",\n \"In addition, for example, Jpn.\",\n \"Pat.\",\n \"Appln.\",\n \"KOKAI Publication No.\",\n \"2012-196458 discloses a technique relating to setting a target value with respect to the transition of the impedance value during the treatment, and controlling the output such that this target value and the measured actual impedance value become equal.\",\n \"In the high-frequency treatment system, since the adjustment of the output voltage and output current affects the precision and efficiency of the treatment, it is required that the output voltage and output current be adjusted more appropriately.\",\n \"In addition, it is known that the optimal output voltage and output current vary in accordance with a treatment target.\",\n \"Accordingly, it is required that the output voltage and output current be adjusted in accordance with a treatment target.\",\n \"BRIEF SUMMARY OF THE INVENTION According to an aspect of the present invention, a method of operating a power source device for a high-frequency treatment instrument is adapted to perform high-frequency treatment for biological tissue.\",\n \"The method comprises: causing, by a control circuit, a high-frequency power source circuit to output power; acquiring, by the control circuit, a value for impedance of the biological tissue during the output; setting, by the control circuit, a target impedance value, wherein the target impedance value gradually increases from a change-over impedance value to a stop impedance value within a predetermined period, the change-over impedance value being equal to or greater by a predetermined value than a minimum value of the value for impedance, the stop impedance value representing termination of the output; performing, by the control circuit, a comparison to cause the high-frequency power source circuit to lower or raise the power being output, for a period after the value for impedance reaching the change-over impedance value until the value for impedance reaching the stop impedance value, wherein the value for impedance is adopted as a measured impedance value and the measured impedance value is regularly compared to the target impedance value, and wherein the high-frequency power source circuit is caused to lower the power by a fixed first ratio if the measured impedance value is greater than the target impedance value, and the high-frequency power source circuit is caused to raise the power by a fixed second ratio if the measured impedance value is smaller than the target impedance value; and causing, by the control circuit, the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value.\",\n \"According to an aspect of the present invention, a method of operating a power source device for a high-frequency treatment instrument is adapted to perform high-frequency treatment for biological tissue.\",\n \"The method comprises: causing, by a control circuit, a high-frequency power source circuit to output power; acquiring, by the control circuit, a value for impedance of the biological tissue during the output; setting, by the control circuit, a target impedance value, wherein the target impedance value gradually increases from a change-over impedance value to a stop impedance value within a predetermined period, the change-over impedance value being equal to or greater by a predetermined value than a minimum value of the value for impedance, the stop impedance value representing termination of the output; performing, by the control circuit, a comparison to cause the high-frequency power source circuit to lower or raise the power being output, for a period after the value for impedance reaching the change-over impedance value until the value for impedance reaching the stop impedance value, wherein the value for impedance is adopted as a measured impedance value and the measured impedance value is regularly compared to the target impedance value, and wherein the high-frequency power source circuit is caused to lower the power by a fixed first value if the measured impedance value is greater than the target impedance value, and the high-frequency power source circuit is caused to raise the power by a fixed second value if the measured impedance value is smaller than the target impedance value; and causing, by the control circuit, the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value.\",\n \"According to an aspect of the present invention, a method of operating a power source device for a high-frequency treatment instrument is adapted to perform high-frequency treatment for biological tissue.\",\n \"The method comprises: causing, by a control circuit, a high-frequency power source circuit to output power; acquiring, by the control circuit, an initial impedance value which is a value for impedance of the biological tissue within a first period after starting the output; determining, by the control circuit, a ratio of increase of output voltage relative to time, based on the initial impedance value; causing, by the control circuit, the high-frequency power source circuit to increase an output voltage according to the ratio of increase, for a second period after the first period; acquiring, by the control circuit, a value for impedance of the biological tissue during and after the second period; terminating, by the control circuit, the second period upon the value for impedance reaching a change-over impedance value representing a minimum value; determining, by the control circuit, an additional impedance value based on the initial impedance value; setting, by the control circuit, a stop impedance value which is a sum of the change-over impedance value and the additional impedance value; setting, by the control circuit, a gradually increasing target impedance value for a third period after the value for impedance reaching the change-over impedance value until the value for impedance reaching the stop impedance value; performing, by the control circuit, a comparison to cause the high-frequency power source circuit to lower or raise the power being output, for the third period, wherein the value for impedance is adopted as a measured impedance value and the measured impedance value is regularly compared to the target impedance value, and wherein the high-frequency power source circuit is caused to lower the power by a first ratio if the measured impedance value is greater than the target impedance value, and the high-frequency power source circuit is caused to raise the power by a second ratio if the measured impedance value is smaller than the target impedance value; and causing, by the control circuit, the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value.\",\n \"According to an aspect of the present invention, a power source device for a high-frequency treatment instrument is adapted to perform high-frequency treatment for biological tissue.\",\n \"The power source device comprises: a high-frequency power source circuit which outputs power; an output detection circuit which detects the output; and a control circuit which acquires information about the output from the output detection circuit and controls the high-frequency power source circuit.\",\n \"The control circuit is configured to cause the high-frequency power source circuit to output the power, acquire a value for impedance of the biological tissue during the output, set a target impedance value, wherein the target impedance value gradually increases from a change-over impedance value to a stop impedance value within a predetermined period, the change-over impedance value being equal to or greater by a predetermined value than a minimum value of the value for impedance, the stop impedance value representing termination of the output, perform a comparison to cause the high-frequency power source circuit to lower or raise the power being output, for a period after the value for impedance reaching the change-over impedance value until the value for impedance reaching the stop impedance value, wherein the value for impedance is adopted as a measured impedance value and the measured impedance value is regularly compared to the target impedance value, and wherein the high-frequency power source circuit is caused to lower the power by a first ratio if the measured impedance value is greater than the target impedance value, and the high-frequency power source circuit is caused to raise the power by a second ratio if the measured impedance value is smaller than the target impedance value, and cause the high-frequency power source circuit to terminate the output upon the value for impedance reaching the stop impedance value.\",\n \"According to an aspect of the invention, a high-frequency treatment system includes the above-mentioned electric power source device; and the high-frequency treatment instrument.\",\n \"Advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.\",\n \"The advantages of the invention may be realized and obtained by means of the instrumentalities and combinations particularly pointed out hereinafter.\",\n \"BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate embodiments of the invention, and together with the general description given above and the detailed description of the embodiments given below, serve to explain the principles of the invention.\",\n \"FIG.\",\n \"1 is a view which schematically illustrates an example of the external appearance of a high-frequency treatment system according to an embodiment.\",\n \"FIG.\",\n \"2 is a block diagram which schematically illustrates a configuration example of the high-frequency treatment system according to the embodiment.\",\n \"FIG.\",\n \"3 is a flowchart illustrating an example of the operation of the high-frequency treatment system according to the embodiment.\",\n \"FIG.\",\n \"4 shows an example of variations of an electric power, a voltage, a current and an impedance relative to time in the high-frequency treatment system according to the embodiment.\",\n \"FIG.\",\n \"5 is a flowchart illustrating an example of first control of the high-frequency treatment system according to the embodiment.\",\n \"FIG.\",\n \"6 shows an example of the relationship between duration of application of a voltage to a biological tissue in second control and a vessel burst pressure of a blood vessel which is sealed by the treatment.\",\n \"FIG.\",\n \"7 is a flowchart illustrating an example of the second control of the high-frequency treatment system according to the embodiment.\",\n \"FIG.\",\n \"8 shows an example of a table including a relationship between an initial resistance value and an additional resistance value, which are used in the high-frequency treatment system according to the embodiment.\",\n \"FIG.\",\n \"9 shows an example of a table including a relationship between an initial resistance value, duration and an additional resistance value, which are used in the high-frequency treatment system according to the embodiment.\",\n \"FIG.\",\n \"10 shows an example of a graph of a target resistance value versus time in the high-frequency treatment system according to the embodiment.\",\n \"FIG.\",\n \"11 shows an example of a graph of an output electric power and a resistance value versus time in the high-frequency treatment system according to the embodiment.\",\n \"FIG.\",\n \"12 is a flowchart illustrating an example of third control of the high-frequency treatment system according to the embodiment.\",\n \"DETAILED DESCRIPTION OF THE INVENTION An embodiment of the present invention will be described hereinafter with reference to the accompanying drawings.\",\n \"FIG.\",\n \"1 is a schematic view of a high-frequency treatment system 10 according to the present embodiment.\",\n \"As illustrated in this Figure, the high-frequency treatment system 10 includes a high-frequency treatment instrument 100 which functions as a high-frequency treatment instrument, an electric power source device 200 which supplies electric power to the treatment instrument, and a footswitch 290.The high-frequency treatment instrument 100 includes a treatment portion 110, a shaft 160, and an operation portion 170.For the purpose of descriptions below, the treatment portion 110 side is referred to as a distal side, and the operation portion 170 side is referred to as a proximal side.\",\n \"The high-frequency treatment system 10 is configured to grasp a biological tissue, such as a blood vessel, which is a treatment target, by the treatment portion 110.The high-frequency treatment system 10 applies a high-frequency voltage to the grasped biological tissue, thereby sealing this biological tissue.\",\n \"The treatment portion 110, which is provided at a distal end of the shaft 160, is provided with a first grasping member 112 and a second grasping member 114, which are a pair of grasping members.\",\n \"Those parts of the first grasping member 112 and second grasping member 114, which come in contact with the biological tissue, function as electrodes, respectively.\",\n \"Specifically, the first grasping member 112 and second grasping member 114 function as bipolar electrodes.\",\n \"The operation portion 170 is provided an operation portion main body 172, a stationary handle 174, a movable handle 176, and an output switch 178.The stationary handle 174 is fixed to the operation portion main body 172, and the movable handle 176 is displaced relative to the operation portion main body 172.The movable handle 176 is connected to a wire or a rod, which is inserted through the shaft 160.This wire or rod is connected to the second grasping member 114.The movement of the movable handle 176 is transmitted to the second grasping member 114.The second grasping member 114 is displaced relative to the first grasping member 112 in accordance with the movement of the movable handle 176.As a result, the first grasping member 112 and second grasping member 114 open or close relative to each other.\",\n \"The output switch 178 includes, for example, two buttons.\",\n \"These buttons are buttons which are pressed when high-frequency electric power is made to act on the biological tissue, which is the treatment target, by the treatment portion 110.The electric power source device 200, which detects the pressing of the button, applies a high-frequency voltage between the first grasping member 112 and second grasping member 114.As a result, the biological tissue, which is grasped by the treatment portion 110, is sealed.\",\n \"The high-frequency treatment instrument 100 is configured, for example, such that the output level varies depending on which of the two buttons is pressed.\",\n \"The footswitch 290 is also provided with, for example, two switches.\",\n \"The two respective switches of the footswitch 290 have the same functions as the respective buttons of the output switch 178.The high-frequency treatment system 10 may be provided with both the output switch 178 and the footswitch 290, or may be provided with one of them.\",\n \"Hereinafter, a description will be given on the assumption that the output switch 178 is mainly operated, but the footswitch 290 may be operated.\",\n \"One end of a cable 180 is connected to the proximal side of the operation portion 170.The other end of the cable 180 is connected to the electric power source device 200.The electric power source device 200 controls the operation of the high-frequency treatment instrument 100, and supplies electric power to the high-frequency treatment instrument 100.FIG.\",\n \"2 is a block diagram which schematically illustrates a configuration example of the electric power source device 200.The electric power source device 200 includes a control circuit 210, a high-frequency electric power source circuit 220, an output detection circuit 230, an A/D converter 240, a storage medium 250, an input device 262, a display 264, and a speaker 266.The control circuit 210 includes an integrated circuit or the like, such as a central processing unit (CPU), an application specific integrated circuit (ASIC), or a field programmable gate array (FPGA).\",\n \"The control circuit 210 may be composed of a single integrated circuit or the like, or may be composed of a combination of a plurality of integrated circuits or the like.\",\n \"The operation of the control circuit 210 is executed, for example, in accordance with a program stored in the control circuit 210 or in the storage medium 250.The control circuit 210 acquires information from each component of the electric power source device 200, and controls the operation of each component.\",\n \"The high-frequency electric power source circuit 220 outputs high-frequency electric power which is supplied to the high-frequency treatment instrument 100.The high-frequency electric power source circuit 220 includes a variable DC electric power source 221, a waveform generating circuit 222, and an output circuit 223.The variable DC electric power source 221 outputs DC electric power under the control of the control circuit 210.The output of the variable DC electric power source 221 is transmitted to the output circuit 223.The waveform generating circuit 222 generates an AC waveform under the control of the control circuit 210, and outputs the generated AC waveform.\",\n \"The output of the waveform generating circuit 222 is transmitted to the output circuit 223.The output circuit 223 superimposes the output of the variable DC electric power source 221 and the output of the waveform generating circuit 222, and outputs AC electric power.\",\n \"This AC electric power is supplied, via the output detection circuit 230, to the first grasping member 112 and second grasping member 114 of the high-frequency treatment instrument 100.The output detection circuit 230 includes a current detection circuit 231 and a voltage detection circuit 232.The current detection circuit 231 is inserted in a circuit from the high-frequency electric power source circuit 220 to the high-frequency treatment instrument 100, and outputs an analog signal which represents a current value that is output from the high-frequency electric power source circuit 220.The voltage detection circuit 232 outputs an analog signal which represents an output voltage of the high-frequency electric power source circuit 220.The output signal of the current detection circuit 231 and the output signal of the voltage detection circuit 232 are input to the A/D converter 240.The A/D converter 240 converts the input analog signals to a digital signal, and sends the digital signal to the control circuit 210.In this manner, the control circuit 210 acquires information of the output voltage and output current of the high-frequency electric power source circuit 220.In addition, based on the output voltage and output current, the control circuit 210 calculates a value relating to an impedance of a circuit including the first grasping member 112, the biological tissue that is the treatment target, and the second grasping member 114.Specifically, the control circuit 210 acquires a value relating to the impedance of the biological tissue.\",\n \"The storage medium 250 stores programs which are used in the control circuit 210, and various parameters, tables, etc.\",\n \"which are used in calculations executed in the control circuit 210.The input device 262 includes an input device such as a button, a slider, a dial, a keyboard, or a touch panel.\",\n \"The control circuit 210 acquires an input to the input device 262 by the user.\",\n \"The display 264 includes a display device such as a liquid crystal display or an LED lamp.\",\n \"The display 264 presents information relating to the high-frequency treatment system 10 to the user, under the control of the control circuit 210.The speaker 266 issues, for example, an input sound, an output sound, an alarm sound, etc., under the control of the control circuit 210.The operation of the high-frequency treatment system 10 according to the present embodiment will be described.\",\n \"The user operates the input device 262 of the electric power source device 200, and sets a desired output level for the high-frequency treatment instrument 100.The output level is set, for example, for each of the plural output switches 178.The treatment portion 110 and shaft 160 are inserted, for example, into a peritoneal cavity through an abdominal wall.\",\n \"The user opens or closes the treatment portion 110 by operating the movable handle 176.In this manner, the first grasping member 112 and second grasping member 114 grasp the biological tissue that is the treatment target.\",\n \"When the biological tissue is grasped by the treatment portion 110, the user operates the output switch 178.The control circuit 210 of the electric power source device 200, which detected the pressing of the button of the output switch 178, outputs an instruction, which relates to driving, to the high-frequency electric power source circuit 220.The high-frequency electric power source circuit 220 applies, under the control of the control circuit 210, a high-frequency voltage to the first grasping member 112 and second grasping member 114 of the treatment portion 110, and causes a high-frequency current to flow through the biological tissue that is the treatment target.\",\n \"If the high-frequency current flows, the biological tissue becomes an electrical resistance.\",\n \"Thus, heat is generated in the biological tissue, and the temperature of the biological tissue rises.\",\n \"As a result, the protein of the biological tissue is denatured, and the biological tissue is sealed.\",\n \"By the above, the treatment of the biological tissue is completed.\",\n \"The output operation of the electric power source device 200 will be described in detail.\",\n \"The outline of the operation of the electric power source device 200 according to the present embodiment will be described with reference to a flowchart of FIG.\",\n \"3.In step S101, the control circuit 210 determines whether the output switch 178 is turned on.\",\n \"If the output switch 178 is not turned on, the process returns to step S101.In other words, the control circuit 210 stands by until the output switch 178 is turned on.\",\n \"When the output switch 178 is turned on, the process advances to step S102.In step S102, the control circuit 210 executes first control.\",\n \"Then, in step S103, the control circuit 210 executes second control.\",\n \"Subsequently, in step S104, the control circuit 210 executes third control.\",\n \"The first control, second control and third control will be described later in detail.\",\n \"By the above, the output control is terminated.\",\n \"In this manner, in the present embodiment, three-stage controls are executed.\",\n \"Referring to FIG.\",\n \"4, a description is given of an example of an output of the high-frequency treatment system 10 according to the embodiment, and an impedance relating to the biological tissue, which is calculated at the time of the output.\",\n \"In FIG.\",\n \"4, the horizontal axis indicates time, which is set such that an output start time is 0.The left vertical axis indicates an output electric power, an output voltage, and an output current.\",\n \"The right vertical axis indicates an impedance.\",\n \"In FIG.\",\n \"4, a solid line indicates a variation of the output voltage, a dashed line indicates a variation of the impedance, a dashed-dotted line indicates a variation of the output electric power, and a dashed double-dotted line indicates a variation of the output current.\",\n \"As described above, the control of the output of the high-frequency treatment system 10 according to the present embodiment is divided into three stages (three phases).\",\n \"Accordingly, the period, during which electric power is supplied to the biological tissue, includes a first period in which the first control of a short period immediately after the output start is executed, a subsequent second period in which the second control of about one second is executed, and a subsequent third period in which the third control of about two seconds is executed.\",\n \"The output by the first control is referred to as a first output, the output by the second control is referred to as a second output, and the output by the third control is referred to as a third output.\",\n \"In addition, since the output by the second control is executed prior to the output by the third control, the period by the second control is referred to as a former period, and the period by the third control is referred to as a latter period.\",\n \"In the first control, high-frequency electric power having a predetermined electric power value is supplied to the biological tissue during a predetermined period.\",\n \"This first period is, for example, about 100 milliseconds.\",\n \"During the first period, the value relating to the impedance is acquired.\",\n \"In accordance with the size, kind, etc.\",\n \"of the biological tissue that is the treatment target, or the state of the biological tissue, the value relating to the impedance, which is acquired at that time, will vary.\",\n \"Thus, in the present embodiment, based on the value relating to the impedance which is acquired in the first period in which the first control is executed, the state of the biological tissue that is the treatment target is ascertained, and control parameters, which are used in the subsequent control, are determined.\",\n \"Specifically, the control parameters, which correspond to the characteristics of the biological tissue that is the treatment target, are set.\",\n \"In addition, in the first control, an overshoot of the output is suppressed by a predetermined electric power, which is not so large, being supplied to the biological tissue.\",\n \"In the second control, a voltage which increases linearly is applied to the biological tissue.\",\n \"The temperature of the biological tissue rises in the second period in which the second control is executed.\",\n \"The second control is executed until it is detected that the value relating to the measured impedance takes a minimum value.\",\n \"If the value relating to the measured impedance takes the minimum value, the control transitions to the third control.\",\n \"If moisture evaporates in the second control, the value relating to the impedance increases subsequently in accordance with the rise in temperature.\",\n \"In the third control, the output control is executed such that the value relating to the impedance increases linearly.\",\n \"In this third period, the temperature of the biological tissue is kept substantially constant.\",\n \"Hereinafter, the first to third controls will be described in detail.\",\n \"[First Control] The first control will be described with reference to a flowchart illustrated in FIG.\",\n \"5.In step S201, the control circuit 210 causes the high-frequency electric power source circuit 220 to supply AC electric power having a predetermined electric power value to the biological tissue that is the treatment target, which is clamped between the first grasping member 112 and second grasping member 114.By the supply of the AC electric power, an AC current flows through the biological tissue.\",\n \"In step S202, the control circuit 210 acquires an impedance value relating to the biological tissue that is the treatment target.\",\n \"For example, the control circuit 210 acquires the current detected by the current detection circuit 231 of the output detection circuit 230, and the voltage detected by the voltage detection circuit 232 of the output detection circuit 230, and calculates the impedance value based on these values.\",\n \"Here, the calculated impedance value may be various kinds of values relating to the impedance, and may be, for example, an absolute value of the impedance which is a complex number, or may be a resistance value which is a real number component of the impedance.\",\n \"An admittance, which is a reciprocal of the impedance, may be used.\",\n \"In step S203, the control circuit 210 determines whether a predetermined time has passed.\",\n \"Here, the predetermined time is, for example, 100 milliseconds.\",\n \"If the predetermined time has not passed, the process returns to step S201.Specifically, the supply of the predetermined electric power and the acquisition of the impedance value are repeated.\",\n \"When the predetermined time has passed, the first control ends, and a transition occurs to the second control.\",\n \"The impedance value, which is acquired in the first control, is referred to as an initial impedance value.\",\n \"The initial impedance value may be an impedance value which is first acquired, or may be a mean value or a median of impedance values acquired in some periods in the first period during which the first control is executed.\",\n \"[Second Control] The second control will be described in detail.\",\n \"The second control is a control which is optimized in order to stably seal a blood vessel or the like.\",\n \"Here, attention is paid to a change of the impedance value at a time when the biological tissue, such as a blood vessel, is heated.\",\n \"If the biological tissue is heated, the temperature of an electrolyte solution in the biological tissue rises, and the impedance decreases.\",\n \"Paying attention to this decrease of the impedance, the following became clear.\",\n \"FIG.\",\n \"6 illustrates the relationship between duration of a voltage application (heating time) by the second control and a mean value of a vessel burst pressure (VBP).\",\n \"Here, the duration of the voltage application by the second control is a time from when the second control started until when the impedance value takes the minimum value, as described above.\",\n \"In addition, as described above and as illustrated in FIG.\",\n \"4, the second control is a control in which the output voltage is adjusted so as to increases linearly.\",\n \"The VBP indicates a pressure at which a sealed part is peeled when a water pressure is applied to the blood vessel after the seal treatment through the second control and third control.\",\n \"Specifically, as the VBP becomes higher, this means that stronger sealing is performed.\",\n \"In general, it is required that a VBP of 360 mmHg or above be obtained in the blood vessel after at least 90% or more of the treatment.\",\n \"As illustrated in FIG.\",\n \"6, the VBP tends to increase, as the time until the impedance value takes the minimum value becomes longer.\",\n \"In addition, even when the time until the impedance value takes the minimum value increased to one second or more, the VBP did not increase so much.\",\n \"Taking into account the result shown in FIG.\",\n \"6 and the fact that a shorter treatment time is desired, it is considered that the time until the impedance value takes the minimum value should preferably be about one second.\",\n \"It is understood that the time may be in a range of between about 0.5 seconds and 1.5 seconds, in which the VBP is sufficiently higher than 360 mmHg.\",\n \"In consideration of these results, in the present embodiment, the output voltage in the second control is adjusted such that the time until the impedance value takes the minimum value becomes about one second.\",\n \"In the present embodiment, the control circuit 210 controls the output voltage V(t) which is applied to the biological tissue in the second control, as indicated by the following equation (1): V(t)=(V(Z)/GV)×t, (1) where t is a time from the start of treatment, that is, a time from the start of the first control.\",\n \"The time t may be a time from the start of the second control.\",\n \"V(Z) is a constant, for example, a maximum value of the output voltage.\",\n \"GV is a gradient value.\",\n \"Thus, (V(Z)/GV) indicates an increase value of the output voltage per unit time, that is, an inclination (increase rate).\",\n \"GV is determined based on the initial impedance value acquired in the first control.\",\n \"For example, based on an initial resistance value R0, GV is determined by the following equation (2): GV=a·R0+b, (2) where a and b are fixed values.\",\n \"The values a and b are empirically adjusted such that the impedance value takes the minimum value in about one second, when the output voltage V(t) is applied to the biological tissue.\",\n \"The above equation (2) is not limited to an equation of a linear function, and may be another equation such as a function of a higher degree.\",\n \"However, the linear function is preferable to a higher-degree function, so that the influence, which the initial resistance value R0 exerts on the above equation (1), may not become excessively large.\",\n \"In addition, the above equation (1) is also a linear function relating to time.\",\n \"Because of the linear function, a proper temperature rise with high stability can be obtained.\",\n \"Since the output voltage is the linear function relating to time, the electric power, which is input to the biological tissue, increases in a manner of a quadratic function with respect to time.\",\n \"An offset may be added to the output voltage V(t).\",\n \"Specifically, the above equation (1) may be modified as follows: V(t)=(V(Z)/GV)×t+c, (3) where c is a fixed value.\",\n \"According to the above equations (1) and (2), for example, in a thin blood vessel, the initial resistance value R0 is relatively high.\",\n \"Thus, (V(Z)/GV), which indicates a gradient, is relatively small.\",\n \"Specifically, in a thin blood vessel, the output voltage increases relatively slowly, and accordingly the input electric power increases relatively slowly.\",\n \"On the other hand, for example, in a thick blood vessel, the initial resistance value R0 is relatively low.\",\n \"Thus, (V(Z)/GV), which indicates the gradient, is relatively large.\",\n \"Specifically, in a thick blood vessel, the output voltage increases relatively quickly, and accordingly the input electric power increases relatively quickly.\",\n \"The gradient (V(Z)/GV) may be calculated at each time and used, based on the relationships of the above equations (1) and (2) and the initial resistance value R0, or may be determined based on the table prestored in the storage medium 250, which represents the relationship between the initial resistance value R0 and gradient (V(Z)/GV), and based on the initial resistance value.\",\n \"The operation of the electric power source device 200 in the second control will be described with reference to a flowchart of FIG.\",\n \"7.In step S301, the control circuit 210 calculates the relationship between time and output voltage V(t), based on the initial impedance value.\",\n \"The output voltage V(t) is determined, for example, by using the above equations (1) and (2).\",\n \"In step S302, the control circuit 210 causes the high-frequency electric power source circuit 220 to output the voltage V(t) which corresponds to time.\",\n \"In step S303, the control circuit 210 acquires the impedance value of the biological tissue.\",\n \"In step S304, the control circuit 210 determines whether the impedance value acquired in step S303 is a change-over impedance value or not.\",\n \"Here, the change-over impedance value is an impedance value which is a condition for terminating the second control.\",\n \"The change-over impedance value can be, for example, a value at a time when the variation of the impedance value is measured and the impedance value becomes the minimum value.\",\n \"In order to easily detect the minimum value, a value, which has increased by a predetermined value after the impedance value took the minimum value, may be set as the change-over impedance value.\",\n \"Specifically, in step S304, when the impedance value decreased and took the minimum value and then the impedance value has increased by the predetermined value, it may be determined that the impedance value has become the change-over impedance value.\",\n \"In step S304, when it is determined that the impedance value is not the change-over impedance value, the process returns to step S302.On the other hand, when it is determined that the impedance value is the change-over impedance value, the second control is terminated, and a transition occurs to the third control.\",\n \"By the above-described controls, the output voltage and the impedance value become as illustrated in FIG.\",\n \"4.Specifically, in the second period in which the second control is executed, the output voltage increases linearly.\",\n \"At this time, the output electric power increases in a manner of a quadratic function.\",\n \"The impedance value acquired in the second period decreases slowly with time.\",\n \"In the example illustrated in FIG.\",\n \"4, when the impedance value has slightly increased after taking the minimum value, the second control is terminated.\",\n \"In the meantime, although the example in which the output voltage is controlled is illustrated here, the output current or output electric power may be controlled so as to increase linearly in the same manner.\",\n \"The time until the impedance value takes the minimum value is set to be about one second and is relatively slow.\",\n \"It is thus possible to make unifoLitt the temperature of the biological tissue, while shortening the time of the treatment.\",\n \"In addition, by setting the time until the impedance value takes the minimum value to be constant at about one second, regardless of the size, etc.\",\n \"of the treatment target, it is possible to suppress a variance in results of treatments.\",\n \"In the meantime, when the same energy is input, the impedance value takes the minimum value in a shorter time, as the thickness of the blood vessel becomes smaller.\",\n \"By setting the time until the impedance value takes the minimum value to be about one second, a high sealing strength can be obtained stably, as illustrated in FIG.\",\n \"6.\",\n \"[Third Control] The third control will be described in detail.\",\n \"In the third control, the output is controlled such that the measured impedance value increases with a constant rate.\",\n \"In the present embodiment, a stop impedance value, which is an impedance value at a time when the output is stopped, is first determined.\",\n \"Next, target impedance which increases at a constant speed from the impedance value at the start time of the third control up to the stop impedance value is set.\",\n \"Specifically, the target impedance value is set as a target value of the impedance value at each time.\",\n \"The control of the output is executed such that the output value is determined at predetermined time intervals, based on a difference between the target impedance value and a measured impedance value acquired by using the output detection circuit 230.In this manner, the third control is executed until the measured impedance value reaches the stop impedance value along target impedance values.\",\n \"<Setting of the Stop Impedance Value in the Third Control> A determination method of the stop impedance value at the time of stopping the output will be described.\",\n \"Here, a description is given of the case of using a resistance value as the impedance value.\",\n \"The same applies to cases using other impedance values, aside from the resistance value.\",\n \"A stop resistance value Rstop, which is a resistance value at the time of stopping the output, is calculated by, for example, the following equation (4): Rstop=Rin+Radd.\",\n \"(4) Rin is a resistance value relating to the biological tissue, which is acquired at the start time of the third control.\",\n \"Specifically, Rin is the resistance value corresponding to the above-described change-over impedance value.\",\n \"The Rin may be the minimum impedance measured in the second control.\",\n \"In addition, the initial impedance value acquired in the first control may be used for Rin.\",\n \"Radd is an additional resistance value which is determined based on the initial state of the biological tissue.\",\n \"Some examples of the determination method of the additional resistance value Radd will be illustrated.\",\n \"(First Example) The additional resistance value Radd is calculated as a function of the initial resistance value R0.The initial resistance value R0 is the resistance value detected in the first control.\",\n \"The storage medium 250 stores a table, for example, as illustrated in FIG.\",\n \"8, the table representing the relationship between the additional resistance value Radd and initial resistance value R0.Based on this table and the initial resistance value R0 measured in the first control, the additional resistance value Radd is determined.\",\n \"In FIG.\",\n \"8, a, b, c and d represent resistance values, and have a relationship of a<b<c<d.\",\n \"Specifically, as the initial resistance value R0 becomes higher, the additional resistance value Radd becomes lower.\",\n \"In other words, when the treatment target is a blood vessel, a thinner blood vessel has a higher initial resistance R0, and thus the additional resistance value Radd becomes lower.\",\n \"In addition, the additional resistance value Radd may be calculated based on a function representing the same relationship as in FIG.\",\n \"8.\",\n \"(Second Example) The additional resistance value Radd is calculated as a function of the initial resistance value R0 and duration Dt of the second control.\",\n \"The duration Dt is acquired when the second control is finished.\",\n \"For example, when the initial resistance value R0 is a predetermined threshold value or more, and when the duration Dt is a predetermined threshold value or less, a first additional resistance value Radd1 is selected as the additional resistance value Radd.\",\n \"When the initial resistance value R0 is lower than the predetermined threshold value, or when the duration Dt is longer than the predetermined threshold value, a second additional resistance value Radd2 is selected as the additional resistance value Radd.\",\n \"Here, the first additional resistance value Radd1 is lower than the second additional resistance value Radd2.In addition, the storage medium 250 stores a table, for example, as illustrated in FIG.\",\n \"9, the table representing the relationship between the additional resistance value Radd, duration Dt and initial resistance value R0.Based on this table, the initial resistance value R0 measured in the first control and the duration Dt of the second control, the additional resistance value Radd may be determined.\",\n \"In FIG.\",\n \"9, a, b, c and d represent resistance values, and have a relationship of a<b<c<d.\",\n \"Specifically, as the initial resistance value R0 becomes higher, the additional resistance value Radd becomes lower; and as the duration Dt becomes longer, the additional resistance value Radd becomes higher.\",\n \"In addition, the additional resistance value Radd may be calculated based on a function representing the same relationship as in FIG.\",\n \"9.Based on the initial resistance value R0 and the duration Dt of the second control, the additional resistance value Radd is determined.\",\n \"Thereby, a more appropriate additional resistance value Radd can be determined than in the case in which the additional resistance value Radd is determined based on only the initial resistance value R0.\",\n \"(Third Example) The additional resistance value Radd may be selected in accordance with an output level which the user sets.\",\n \"For example, as the output level becomes higher, the additional resistance value Radd becomes higher; and as the output level becomes lower, the additional resistance value Radd becomes lower.\",\n \"It is preferable that, like the case of the first example or the second example, the output level is used in combination with the initial resistance value R0 or the duration Dt of the second control.\",\n \"A more appropriate value can be set, by the additional resistance value Radd being determined by using the output level in combination with the initial resistance value R0 or the duration Dt of the second control.\",\n \"In each of the above first to third examples, for instance, as the blood vessel becomes thinner, the additional resistance value Radd becomes lower; and as the blood vessel becomes thicker, the additional resistance value Radd becomes higher.\",\n \"The stop resistance value Rstop is higher than the initial resistance value R0.Like the above, when a value relating to the impedance, other than the resistance value, is used, Rin corresponds to the change-over impedance value, the additional resistance value Radd corresponds to the additional impedance value, and the initial resistance value R0 corresponds to the initial impedance value.\",\n \"As described above, use is made of the initial impedance value which varies in accordance with the treatment target, for instance, the thickness of the blood vessel.\",\n \"Thereby, the stop impedance value corresponding to the treatment target is appropriately set.\",\n \"Since the output control is executed by using the thus determined stop impedance value, a proper treatment can be performed.\",\n \"<Setting of the Target Impedance Value in the Third Control> A setting method of the target impedance value will be described.\",\n \"Here, a description is given of the case in which, like the above-described stop resistance value, the resistance value is used as the impedance value.\",\n \"Specifically, the case in which a target resistance value is used as the target impedance value will be described.\",\n \"The same applies to the cases of using other values relating to the impedance, aside from the resistance value.\",\n \"(First Example) In a first example, a time in which high-frequency electric power is output by the third control is predetermined.\",\n \"A target resistance value at each time can be set such that, in this predetermined time, the resistance value linearly increases up to the stop resistance value Rstop which is calculated from the change-over resistance value Rin.\",\n \"(Second Example) In a second example, a time in which high-frequency electric power is output by the third control is determined in accordance with the output level that is set by the user.\",\n \"A target resistance value can be set such that, in the time determined in accordance with the output level, the resistance value linearly increases up to the calculated stop resistance value Rstop.\",\n \"Specifically, as illustrated in FIG.\",\n \"10, an inclination at a time when the target resistance value is indicated relative to time varies in accordance with the output level.\",\n \"In other words, the speed of increase of the target resistance value varies in accordance with the output level.\",\n \"In FIG.\",\n \"10, L1, L2 and L3 indicate output levels, and have a relationship of L1<L2<L3.\",\n \"(Third Example) In a third example, a time in which high-frequency electric power is output by the third control is determined in accordance with the resistance value (initial resistance value) acquired in the first control.\",\n \"In addition, the time in which high-frequency electric power is output by the third control may be determined in accordance with the resistance value acquired in the second control.\",\n \"A target resistance value can be set such that, in the determined time, the resistance value linearly increases up to the calculated stop resistance value Rstop.\",\n \"Specifically, an inclination at a time when the target resistance value is indicated relative to time varies in accordance with the resistance value acquired in the first control or second control.\",\n \"In other words, the speed of increase of the target resistance value varies in accordance with the resistance value acquired in the first control or second control.\",\n \"For example, when the resistance value acquired in the first control or second control is low, the output time in the third control becomes shorter and the inclination becomes larger.\",\n \"On the other hand, when the resistance value acquired in the first control or second control is high, the output time in the third control becomes longer and the inclination becomes smaller.\",\n \"<Determination Method of Output Electric Power in the Third Control> A determination method of an output will be described.\",\n \"Like the above-described case, the case in which a resistance value is used as the impedance value is described.\",\n \"The same applies to the cases of using other values relating to the impedance, aside from the resistance value.\",\n \"A description will be given with reference to FIG.\",\n \"11.An upper part of FIG.\",\n \"11 schematically illustrates a target resistance value and a measured resistance value relative to time.\",\n \"Here, the target resistance value is indicated by a broken line, and the measured resistance value is indicated by a solid line.\",\n \"A lower part of FIG.\",\n \"11 schematically illustrates output electric power relative to time.\",\n \"In the present embodiment, the output electric power is set in each step time of several-ten milliseconds.\",\n \"The setting of the output electric power is executed by comparing the target resistance value and the measured resistance value.\",\n \"Specifically, the target resistance value and the measured resistance value are compared at predetermined time intervals.\",\n \"When the measured resistance value is higher than the target resistance value, the output electric power is decreased.\",\n \"On the other hand, when the measured resistance value is lower than the target resistance value, the output electric power is increased.\",\n \"In addition, when the difference between the measured resistance value and the target resistance value is less than a predetermined threshold value, the output electric power is maintained.\",\n \"The output electric power at the start time of the third control may be the output electric power at the end time of the second control.\",\n \"The output electric power at the start time of the third control may be a predetermined value, or may be determined by a predetermined method.\",\n \"If the set value of the output electric power is frequently changed, there is concern that the output oscillates.\",\n \"On the other hand, if the setting of the output electric power is executed only occasionally, the precision in control would lower, or the treatment could not be completed within a target time.\",\n \"Thus, it is preferable that the interval of re-setting of output electric power, that is, the step time, is appropriately adjusted.\",\n \"Examples of the determination method of the output electric power will be described.\",\n \"(First Example) In a first example, a change amount of the output electric power is a predetermined ratio relative to the output electric power at that time point.\",\n \"For example, this predetermined ratio is set as a first ratio.\",\n \"In this case, when the initial output electric power is a first electric power, and the measured resistance value is higher than the target resistance value, the next output electric power is set at a second electric power which is lowered from the first electric power by the first ratio.\",\n \"When the output is a second electric power, and the measured resistance value is lower than the target resistance value, the next output electric power is set at a third electric power which is raised from the second electric power by the first ratio.\",\n \"Subsequently, the output electric power is controlled in the same manner.\",\n \"For example, if the first ratio is set at 10%, the output electric power is controlled as follows.\",\n \"When the output electric power is 20 W at that time point and the measured resistance value is higher than the target resistance value, the next output electric power is adjusted at 18 W. When the output electric power is 18 W and the measured resistance value is lower than the target resistance value, the next output electric power is adjusted at 19.8 W. By setting the change amount of the output electric power to be the predetermined ratio relative to the output electric power at that time point, the change amount is adjusted to a proper value at each of a time when the output electric power is large and a time when the output electric power is small.\",\n \"The numerical values illustrated here are merely examples, and any numerical value can be used for the proper setting.\",\n \"In the meantime, when the ratio at the time of lowering the output electric power is set as a first ratio and the ratio at the time of raising the output electric power is set as a second ratio, the first ratio and the second ratio may be equal or different.\",\n \"It is preferable that the first ratio is greater than the second ratio.\",\n \"For example, when the measured resistance value is higher than the target resistance value, the output is lowered by 10%.\",\n \"When the measured resistance value is lower than the target resistance value, the output is raised by 5%.\",\n \"In addition, when the difference between the measured resistance value and the target resistance value is within a predetermined range, the output electric power may not be changed.\",\n \"(Second Example) In a second example, a change amount of the output electric power is a predetermined value.\",\n \"In a case in which this predetermined ratio is set as a first value, when the measured resistance value is higher than the target resistance value, the next output electric power is adjusted at a value which is lowered from the present output electric power by a first value.\",\n \"When the measured resistance value is lower than the target resistance value, the next output electric power is adjusted at a value which is higher than the present output electric power by the first value.\",\n \"For example, when the change amount is set to be 2 W, the output electric power is controlled as follows.\",\n \"When the output electric power is 20 W at that time point and the measured resistance value is higher than the target resistance value, the next output electric power is adjusted at 18 W. When the output electric power is 18 W and the measured resistance value is lower than the target resistance value, the next output electric power is adjusted at 20 W. By setting the change amount of the output electric power at a constant value, the hardware configuration becomes simpler, and the control of the output electric power becomes easier.\",\n \"The numerical values illustrated here are merely examples, and any numerical value can be used for the proper setting.\",\n \"In the meantime, the change amount at the time of raising the output and the change amount at the time of lowering the output may be equal or different.\",\n \"It is preferable that the change amount at the time of lowering the output is greater than the change amount at the time of raising the output.\",\n \"In addition, when the difference between the measured resistance value and the target resistance value is within a predetermined range, the output electric power may not be changed.\",\n \"(Third Example) In a third example, a change amount of the output electric power is determined based on the initial resistance value R0 acquired in the first control, and the length of the second period in which the second control is executed, that is, the period from when the second control started until when the impedance values takes the minimum value.\",\n \"Thus, the storage medium 250 prestores, for example, a relationship between the initial resistance value R0, the length of the second period, and the change amount of the output electric power.\",\n \"The control circuit 210 determines the output electric power by referring to this relationship.\",\n \"(Fourth Example) In a fourth example, a change amount of the output electric power is a predetermined value which is determined in accordance with an output level that is set by the user.\",\n \"The storage medium 250 prestores a relationship between the output level and the change amount of the output electric power.\",\n \"The control circuit 210 determines the output electric power by referring to this relationship.\",\n \"(Fifth Example) In a fifth example, the output electric power is determined by the relationship between the measured resistance value and the target resistance value.\",\n \"For example, the output electric power is set as follows.\",\n \"When the measured resistance value is higher than the target resistance value, the output electric power is set at a first electric power value.\",\n \"When the measured resistance value is equal to the target resistance value, the output electric power is set at a second electric power value.\",\n \"When the measured resistance value is lower than the target resistance value, the output electric power is set at a third electric power value.\",\n \"Here, the electric power values become greater in the order of the first electric power value, second electric power value and third electric power value.\",\n \"For example, the first electric power value is 5 W, second electric power value is 8 W, and third electric power value is 10 W. The numerical values illustrated here are merely examples, and any numerical value can be used for the proper setting.\",\n \"The third control, which is controlled in the above manner, will be described with reference to a flowchart of FIG.\",\n \"12.In step S401, the control circuit 210 calculates the additional impedance value, based on the initial impedance value.\",\n \"In step S402, the control circuit 210 sets the stop impedance value, based on the sum of the change-over impedance value and the additional impedance value.\",\n \"For example, any of the methods of the above-described first to third examples may be used for the setting method of the stop impedance value.\",\n \"In step S403, the control circuit 210 sets the target impedance value by using the stop impedance value.\",\n \"Any of the methods of the above-described first to third examples may be used for the setting method of the target impedance value.\",\n \"In step S404, the control circuit 210 causes the high-frequency electric power source circuit 220 to output, as an initial electric power, the electric power having a predetermined electric power value.\",\n \"The initial electric power is, for example, the electric power at the time of the end of the second control.\",\n \"In step S405, the control circuit 210 acquires the impedance value by using the value detected by the output detection circuit 230.In step S406, the control circuit 210 determines whether the measured impedance value is the stop impedance value or more.\",\n \"When the measured impedance value is not the stop impedance value or more, the process advances to step S407.In step S407, the control circuit 210 compares the measured impedance value (Zm) and the target impedance value (Zt).\",\n \"When the difference between the measured impedance value (Zm) and the target impedance value (Zt) is within a predetermined threshold value (Zm≈t), the process advances to step S408.In step S408, the control circuit 210 maintains the set value (set electric power) of the output electric power.\",\n \"Thereafter, the process advances to step S411.In step S407, when it is determined that the measured impedance value (Zm) is greater than the target impedance value (Zt) (Zm>Zt), the process advances to step S409.In step S409, the control circuit 210 sets the set electric power to a low electric power.\",\n \"Then, the process advances to step S411.In step S407, when it is determined that the measured impedance value (Zm) is less than the target impedance value (Zt) (Zm<Zt), the process advances to step S410.In step S410, the control circuit 210 sets the set electric power to a high electric power.\",\n \"Then, the process advances to step S411.For example, any of the methods of the above-described first to fifth examples may be used for the method of setting the electric power in each of step S408 to step S410.In step S411, the control circuit 210 causes the high-frequency electric power source circuit 220 to output the electric power of the electric power value which is set in any one of steps S408 to step S410.Thereafter, the process returns to step S405.In step S406, when it is determined that the measured impedance is the stop impedance value or more, the process advances to step S412.In step S412, the control circuit 210 causes the high-frequency electric power source circuit 220 to stop the output.\",\n \"Then, the third control is finished.\",\n \"By the above, the supply of the high-frequency electric power to the high-frequency treatment instrument 100 by the electric power source device 200 is terminated.\",\n \"According to the above-described control, the output and the acquired impedance value are as illustrated in FIG.\",\n \"4.Specifically, in the third control, the impedance value increases linearly.\",\n \"The output electric power (output voltage or output current) is adjusted such that the impedance value increases linearly.\",\n \"According to the above-described third control, the impedance value increases linearly, and thus the temperature of the biological tissue is kept substantially constant.\",\n \"In this manner, the treatment of the biological tissue progresses at substantially constant temperatures.\",\n \"Thus, for example, the stable sealing of the blood vessel can be obtained.\",\n \"In addition, since the stop impedance value, which corresponds to the characteristics of the biological tissue, is determined, the condition for finishing the treatment, which corresponds to the characteristics of the biological tissue, is determined.\",\n \"Specifically, the treatment is finished at a time point when sufficient treatment is conducted, regardless of differences in characteristics of biological tissues which are treatment targets.\",\n \"As described above, according to the present embodiment, in the high-frequency treatment system 10, the output, which is optimized in accordance with the treatment target, can be executed.\",\n \"The above description of the embodiment is given by taking, mainly, the sealing of the blood vessel as an example.\",\n \"However, the above-described technique is applicable to treatments of other biological tissues.\",\n \"In addition, the above-described operation may be prepared as a mode for sealing a blood vessel, and this mode may be prepared as well as other modes in the high-frequency treatment system 10.The high-frequency treatment system 10 may be configured such that the user can select a mode corresponding to a treatment, from among these modes.\",\n \"The high-frequency treatment system 10 according to the present embodiment may be configured not only to output the high-frequency electric power, but also to have a function as an ultrasonic treatment instrument, which treats a biological tissue by ultrasonic vibration, for example, by the first grasping member 112 vibrating at an ultrasonic frequency.\",\n \"A treatment instrument, which also uses ultrasonic energy, can function in the same manner as in the above-described embodiment with respect to the output of the high-frequency electric power.\",\n \"Additional advantages and modifications will readily occur to those skilled in the art.\",\n \"Therefore, the invention in its broader aspects is not limited to the specific details and representative embodiments shown and described herein.\",\n \"Accordingly, various modifications may be made without departing from the spirit or scope of the general inventive concept as defined by the appended claims and their equivalents.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875791"}}},{"rowIdx":4494979,"cells":{"text":{"kind":"list like","value":[["Method for improving the dissolution profile of a biologically active material","A method for improving the dissolution profile of a biologically active material"],["1.A method for improving the dissolution profile of a biologically active material, comprising the steps of: dry milling a solid biologically active material and a millable grinding matrix in a mill, for a time period sufficient to produce particles of the biologically active material dispersed in an at least partially milled grinding material.","2.The method of claim 1, wherein the particles have an average particle size equal or greater than 1 μm determined on a particle number basis.","3.A method of claim 2, wherein the average particle size of the biologically active material has been reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.","4.-52.","(canceled)"],["<SOH> BACKGROUND <EOH>Poor bioavailability is a significant problem encountered in the development of therapeutic compositions, particularly those materials containing a biologically active material that is poorly soluble in water at physiological pH.","An active material's bioavailability is the degree to which the active material becomes available to the target tissue in the body after systemic administration through, for example, oral or intravenous means.","Many factors affect bioavailability, including the form of dosage and the solubility and dissolution rate of the active material.","Poorly and slowly water-soluble materials tend to be eliminated from the gastrointestinal tract before being absorbed into the circulation.","In addition, poorly soluble active agents tend to be disfavored or even unsafe for intravenous administration due to the risk of particles of agent blocking blood flow through capillaries.","It is known that the rate of dissolution of a particulate drug will increase with increasing surface area.","One way of increasing surface area is decreasing particle size.","Consequently, methods of making finely divided or sized drugs have been studied with a view to controlling the size and size range of drug particles for pharmaceutical compositions.","For example, dry milling techniques have been used to reduce particle size and hence influence drug absorption.","However, in conventional dry milling the limit of fineness is reached generally in the region of about 100 microns (100,000 nm), at which point material cakes on the milling chamber and prevents any further diminution of particle size.","Alternatively, wet grinding may be employed to reduce particle size, but flocculation restricts the lower particle size limit to approximately 10 microns (10,000 nm).","The wet milling process, however, is prone to contamination, thereby leading to a bias in the pharmaceutical art against wet milling.","Another alternative milling technique, commercial airjet milling, has provided particles ranging in average size from as low as about 1 to about 50 microns (1,000-50,000 nm).","There are several approaches currently used to formulate poorly soluble active agents.","One approach is to prepare the active agent as a soluble salt.","Where this approach cannot be employed, alternate (usually physical) approaches are employed to improve the solubility of the active agent.","Alternate approaches generally subject the active agent to physical conditions that change the agent's physical and or chemical properties to improve its solubility.","These include process technologies such as micronization, modification of crystal or polymorphic structure, development of oil based solutions, use of co-solvents, surface stabilizers or complexing agents, micro-emulsions, super critical fluid and production of solid dispersions or solutions.","More than one of these processes may be used in combination to improve formulation of a particular therapeutic material.","Many of these approaches commonly convert a drug into an amorphous state, which generally leads to a higher dissolution rate.","However, formulation approaches that result in the production of amorphous material are not common in commercial formulations due to concerns relating to stability and the potential for material to re-crystallize.","These techniques for preparing such pharmaceutical compositions tend to be complex.","By way of example, a principal technical difficulty encountered with emulsion polymerization is the removal of contaminants, such as unreacted monomers or initiators (which may have undesirable levels of toxicity), at the end of the manufacturing process.","Another method of providing reduced particle size is the formation of pharmaceutical drug microcapsules, which techniques include micronizing, polymerisation and co-dispersion.","However, these techniques suffer from a number of disadvantages including at least the inability to produce sufficiently small particles such as those obtained by milling, and the presence of co-solvents and/or contaminants such as toxic monomers which are difficult to remove, leading to expensive manufacturing processes.","Over the last decade, intense scientific investigation has been carried out to improve the solubility of active agents by converting the agents to ultra fine powders by methods such as milling and grinding.","These techniques may be used to increase the dissolution rate of a particulate solid by increasing the overall surface area and decreasing the mean particle size.","U.S. Pat.","No.","6,634,576 discloses examples of wet-milling a solid substrate, such as a pharmaceutically active compound, to produce a “synergetic co-mixture”.","International Patent Application PCT/AU2005/001977 (Nanoparticle Composition(s) and Method for Synthesis Thereof) describes, inter alia, a method comprising the step of contacting a precursor compound with a co-reactant under mechanochemical synthesis conditions wherein a solid-state chemical reaction between the precursor compound and the co-reactant produces therapeutically active nanoparticles dispersed in a carrier matrix.","Mechanochemical synthesis, as discussed in International Patent Application PCT/AU2005/001977, refers to the use of mechanical energy to activate, initiate or promote a chemical reaction, a crystal structure transformation or a phase change in a material or a mixture of materials, for example by agitating a reaction mixture in the presence of a milling media to transfer mechanical energy to the reaction mixture, and includes without limitation “mechanochemical activation”, “mechanochemical processing”, “reactive milling”, and related processes.","International Patent Application PCT/AU2007/000910 (Methods for the preparation of biologically active compounds in nanoparticulate form) describes, inter alia, a method for dry milling raloxifene with lactose and NaCl which produced nanoparticulate raloxifene without significant aggregation problems.","One limitation of this method is an upper limit to the drug content that can be successfully milled to produce nanoparticles.","For some drugs that require a high dose this limitation may restrict the options available for the production of a commercially viable dosage form.","The present invention provides methods for improving the dissolution profile of a biologically active material which ameliorate some of the problems attendant with prior technologies, or provides an alternative thereto.","One example of a therapeutic area where this technology could be applied in is the area of acute pain management.","Many pain medications such as meloxicam (marketed as Mobic® by pharmaceutical company Boehringer Ingelheim) provides pain relief for chronic pain, but must be taken on a daily basis to maintain an effective therapeutic level.","Meloxicam is a poorly water soluble drug which is only slowly absorbed by the body (Tmax is 4-5 hours), so a method such as the present invention which provides for improved dissolution, will likely provide much faster absorption resulting in a more rapid onset of the therapeutic effect.","Meloxicam also has a long half life (15-20 hours) that means it only need be taken once a day.","By using a method such as the present invention, which provides faster absorption, a drug such as meloxicam, could be transformed from a chronic pain drug to an acute pain drug.","For meloxicam this would provide a medication that could provide therapeutic relief for acute pain, with the advantage of sustained pain relief over 24 hours.","Meloxicam also has sub-optimal bioavailability at 89% for an oral capsule, compared with an IV dosage form.","A component of this sub optimal bioavailability is also likely due to the poor water solubility of this drug.","If the low solubility does contribute to this sub optimal bioavailability, the improvement of the dissolution of this drug with a method such as the present invention could provide scope to produce a dosage form with a lower active dose whilst still providing the effective therapeutic dose.","Although the background to the present invention is discussed in the context of improving the bioavailability of materials that are poorly or slowly water soluble, the applications of the methods of the present invention are not limited to such, as is evident from the following description of the invention.","Further, although the background to the present invention is largely discussed in the context of improving the bioavailability of therapeutic or pharmaceutical compounds, the applications of the methods of the present invention are clearly not limited to such.","For example, as is evident from the following description, applications of the methods of the present invention include but are not limited to: nutraceutical and nutritional compounds, complementary medicinal compounds, veterinary therapeutic applications and agricultural chemical applications, such as pesticide, fungicide or herbicide.","Furthermore, an application of the current invention would be to materials which contain a biologically active compound such as, but not limited to a therapeutic or pharmaceutical compound, a nutraceutical or nutrient, a complementary medicinal product such as active components in plant or other naturally occurring material, a veterinary therapeutic compound or an agricultural compound such as a pesticide, fungicide or herbicide.","Specific examples would be the spice turmeric that contains the active compound curcumin, or flax seed that contains the nutrient ALA an omega-3 fatty acid.","As these specific examples indicate this invention could be applied to, but not limited to, a range of natural products such as seeds, cocoa and cocoa solids, coffee, herbs, spices, other plant materials or food materials that contain a biologically active compound.","The application of this invention to these types of materials would enable greater availability of the active compound in the materials when used in the relevant application.","For example where material subject to this invention is orally ingested the active would be more bioavailable."],["<SOH> SUMMARY OF THE INVENTION <EOH>In one aspect the present invention is directed to the unexpected finding that the dissolution profile of biologically active materials can be improved by dry milling solid biologically active material to a particle size of greater than 1 μm.","In one surprising aspect of the invention, the dissolution profile of a biologically active material can be improved without substantially reducing the particle size of the material or reducing the material to nanoparticulate form.","In another surprising aspect of the invention, the material retains its crystalline structure and is not amorphous, yet the dissolution profile of the biologically active material is improved.","In another surprising aspect of the invention, the dissolution profile of a biologically active material is improved without the need for a surfactant or stabiliser.","In another surprising aspect of the invention, the dissolution profile of a biologically active material is improved without the need for a disintegrant to be present during the milling process.","Thus, in a first aspect the invention comprises a method for improving the dissolution profile of a biologically active material, comprising the steps of: dry milling a solid biologically active material and a millable grinding matrix in a mill comprising a plurality of milling bodies, for a time period sufficient to produce particles of the biologically active material dispersed in an at least partially milled grinding material.","In one preferred embodiment, the particles have an average particle size equal or greater than 1 μm determined on a particle number basis.","More preferably, the average particle size of the biologically active material may be reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.","Even more preferably, the average particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-20 μm, 1-10 μm, 1-7.5 μm, 1-5 μm and 1-2 μm.","In another preferred embodiment, the particles have a median particle size selected from the group consisting of: equal or greater than 1 μm; and equal or greater than 2 μm, wherein the median particle size is determined on a particle volume basis.","More preferably, the percentage of particles with an average particle size greater than 1 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.","Alternatively, the percentage of particles with an average particle size greater than 2 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.","In another preferred embodiment, the median particle size may be reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.","In another preferred embodiment, the median particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-20 μm, 1-10 μm, 1-7.5 μm, 1-5 μm 1-2 μm, 2-1000 μm, 2-500 μm, 2-300 μm, 2-200 μm, 2-150 μm, 2-100 μm, 2-50 μm, 2-20 μm, 2-10 μm, 2-7.5 μm and 2-5 μm.","In another preferred embodiment, the crystallinity profile of the biologically active material is selected from the group consisting of: at least 50% of the biologically active material is crystalline, at least 60% of the biologically active material is crystalline, at least 70% of the biologically active material is crystalline, at least 75% of the biologically active material is crystalline, at least 85% of the biologically active material is crystalline, at least 90% of the biologically active material is crystalline, at least 95% of the biologically active material is crystalline and at least 98% of the biologically active material is crystalline.","More preferably, the crystallinity profile of the biologically active material is substantially equal to the crystallinity profile of the biologically active material before the material was subjected to the method as described herein.","In another preferred embodiment, the amorphous content of the biologically active material is selected from the group consisting of: less than 50% of the biologically active material is amorphous, less than 40% of the biologically active material is amorphous, less than 30% of the biologically active material is amorphous, less than 25% of the biologically active material is amorphous, less than 15% of the biologically active material is amorphous, less than 10% of the biologically active material is amorphous, less than 5% of the biologically active material is amorphous and less than 2% of the biologically active material is amorphous.","Preferably, the biologically active material has no significant increase in amorphous content after subjecting the material to the method as described herein.","In another preferred embodiment, the milling time period is a range selected from the group consisting of: between 10 minutes and 2 hours, between 10 minutes and 1 hour, between 10 minutes and 45 minutes, between 10 minutes and 30 minutes, between 5 minutes and 30 minutes, between 5 minutes and 20 minutes, between 2 minutes and 10 minutes, between 2 minutes and 5 minutes, between 1 minutes and 20 minutes, between 1 minute and 10 minutes, and between 1 minute and 5 minutes.","In another preferred embodiment, the milling medium is selected from the group consisting of: ceramics, glasses, polymers, ferromagnetics and metals.","Preferably, the milling medium is steel balls having a diameter selected from the group consisting of: between 1 and 20 mm, between 2 and 15 mm and between 3 and 10 mm.","In another preferred embodiment, the milling medium is zirconium oxide balls having a diameter selected from the group consisting of: between 1 and 20 mm, between 2 and 15 mm and between 3 and 10 mm.","Preferably, the dry milling apparatus is a mill selected from the group consisting of: attritor mills (horizontal or vertical), nutating mills, tower mills, pearl mills, planetary mills, vibratory mills, eccentric vibratory mills, gravity-dependent-type ball mills, rod mills, roller mills and crusher mills.","Preferably the milling medium within the milling apparatus is mechanically agitated by 1, 2 or 3 rotating shafts.","Preferably, the method is configured to produce the biologically active material in a continuous fashion.","Preferably, the total combined amount of biologically active material and grinding matrix in the mill at any given time is equal to or greater than a mass selected from the group consisting of: 200 grams, 500 grams, 1 kg, 2 kg, 5 kg, 10 kg, 20 kg, 30 kg, 50 kg, 75 kg, 100 kg, 150 kg, 200 kg.","Preferably, the total combined amount of biologically active material and grinding matrix is less than 2000 kg.","In another preferred embodiment, the biologically active material is selected from the group consisting of: fungicides, pesticides, herbicides, seed treatments, cosmeceuticals, cosmetics, complementary medicines, natural products, vitamins, nutrients, nutraceuticals, pharmaceutical actives, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids additives, foods and food ingredients and analogs, homologs and first order derivatives thereof.","Preferably, the biologically active material is selected from the group consisting of: anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, such as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives (hypnotics and neuroleptics), astringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (anti-parkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones (including steroids), anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines.","Preferably, the biologically active material is selected from the group consisting of: indomethacin, diclofenac, naproxen, meloxicam, metaxalone, cyclosporin A, progesterone celecoxib, cilostazol, ciprofloxacin, 2,4-dichlorophenoxyacetic acid, anthraquinone, creatine monohydrate, glyphosate, halusulfuron, mancozeb, metsulfuron, salbutamol, sulphur, tribenuran and estradiol or any salt or derivative thereof.","In another preferred embodiment, the grinding matrix is a single matrix or is a mixture of two or more matrices in any proportion.","Preferably, the major components of the grinding matrix are selected from the group consisting of: mannitol, sorbitol, Isomalt, xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, glucose, fructose, mannose, galactose, anhydrous lactose, lactose monohydrate, sucrose, maltose, trehalose, maltodextrins, dextrin, Inulin, dextrates, polydextrose, starch, wheat flour, corn flour, rice flour, rice starch, tapioca flour, tapioca starch, potato flour, potato starch, other flours and starches, milk powder, skim milk powders, other milk solids and derivatives, soy flour, soy meal or other soy products, cellulose, microcrystalline cellulose, microcrystalline cellulose based co blended materials, pregelatinized (or partially) starch, HPMC, CMC, HPC, citric acid, tartaric acid, malic acid, maleic acid fumaric acid, ascorbic acid, succinic acid, sodium citrate, sodium tartrate, sodium malate, sodium ascorbate, potassium citrate, potassium tartrate, potassium malate, potassium ascorbate, sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate and calcium carbonate.","dibasic calcium phosphate, tribasic calcium phosphate, sodium sulfate, sodium chloride, sodium metabisulphite, sodium thiosulfate, ammonium chloride, Glauber's salt, ammonium carbonate, sodium bisulfate, magnesium sulfate, potash alum, potassium chloride, sodium hydrogen sulfate, sodium hydroxide, crystalline hydroxides, hydrogen carbonates, ammonium chloride, methylamine hydrochloride, ammonium bromide, silica, thermal silica, alumina, titanium dioxide, talc, chalk, mica, kaolin, bentonite, hectorite, magnesium trisilicate, clay based materials or aluminium silicates, sodium lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate, sodium cetostearyl sulfate, sodium docusate, sodium deoxycholate, N-lauroylsarcosine sodium salt, glyceryl monostearate, glycerol distearate glyceryl palmitostearate, glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzalkonium chloride, CTAB, CTAC, Cetrimide, cetylpyridinium chloride, cetylpyridinium bromide, benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188, poloxamer 407, poloxamer 338, polyoxyl 2 stearyl ether, polyoxyl 100 stearyl ether, polyoxyl 20 stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 20 cetyl ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl 35 castor oil, polyoxyl 40 castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor oil, polyoxyl 200 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyoxyl 100 hydrogenated castor oil, polyoxyl 200 hydrogenated castor oil, cetostearyl alcohol, macrogel 15 hydroxystearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, Sucrose Palmitate, Sucrose Stearate, Sucrose Distearate, Sucrose laurate, Glycocholic acid, sodium Glycholate, Cholic Acid, Sodium Cholate, Sodium Deoxycholate, Deoxycholic acid, Sodium taurocholate, taurocholic acid, Sodium taurodeoxycholate, taurodeoxycholic acid, soy lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonate condensate/Lignosulfonate blend, Calcium Dodecylbenzene Sulfonate, Sodium Dodecylbenzene Sulfonate, Diisopropyl naphthalenesulphonate, erythritol distearate, Naphthalene Sulfonate Formaldehyde Condensate, nonylphenol ethoxylate (poe-30), Tristyrylphenol Ethoxylate, Polyoxyethylene (15) tallowalkylamines, sodium alkyl naphthalene sulfonate, sodium alkyl naphthalene sulfonate condensate, sodium alkylbenzene sulfonate, sodium isopropyl naphthalene sulfonate, Sodium Methyl Naphthalene Formaldehyde Sulfonate, sodium n-butyl naphthalene sulfonate, tridecyl alcohol ethoxylate (poe-18), Triethanolamine isodecanol phosphate ester, Triethanolamine tristyrylphosphate ester, Tristyrylphenol Ethoxylate Sulfate, Bis(2-hydroxyethyl)tallowalkylamines.","Preferably, the concentration of the single (or first) material is selected from the group consisting of: 5-99% w/w, 10-95% w/w, 15-85% w/w, of 20-80% w/w, 25-75% w/w, 30-60% w/w, 40-50% w/w.","Preferably, the concentration of the second or subsequent material is selected from the group consisting of: 5-50% w/w, 5-40% w/w, 5-30% w/w, of 5-20% w/w, 10-40% w/w, 10-30% w/w, 10-20% w/w, 20-40% w/w, or 20-30% w/w or if the second or subsequent material is a surfactant or water soluble polymer the concentration is selected from 0.1-10% w/w, 0.1-5% w/w, 0.1-2.5% w/w, of 0.1-2% w/w, 0.1-1%, 0.5-5% w/w, 0.5-3% w/w, 0.5-2% w/w, 0.5-1.5%, 0.5-1% w/w, of 0.75-1.25% w/w, 0.75-1% and 1% w/w.","Preferably, the grinding matrix is selected from the group consisting of: (a) lactose monohydrate or lactose monohydrate combined with at least one material selected from the group consisting of: xylitol; lactose anhydrous; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","(b) lactose anhydrous or lactose anhydrous combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","(c) mannitol or mannitol combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; lactose anhydrous; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","(d) Sucrose or sucrose combined with at least one material selected from the group consisting of: lactose monohydrate; lactose anhydrous; mannitol; microcrystalline cellulose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","(e) Glucose or glucose combined with at least one material selected from the group consisting of: lactose monohydrate; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","(f) Sodium chloride or sodium chloride combined with at least one material selected from the group consisting of: lactose monohydrate; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","(g) xylitol or xylitol combined with at least one material selected from the group consisting of: lactose monohydrate; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","(h) Tartaric acid or tartaric acid combined with at least one material selected from the group consisting of: lactose monohydrate; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","(i) microcrystalline cellulose or microcrystalline cellulose combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; lactose anhydrous; mannitol; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","(j) Kaolin combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","(k) Talc combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","Preferably, the grinding matrix is selected from the group consisting of: a material considered to be Generally Regarded as Safe (GRAS) for pharmaceutical products; a material considered acceptable for use in an agricultural formulation; and a material considered acceptable for use in a veterinary formulation.","In another preferred embodiment, a milling aid is used or a combination of milling aids.","Preferably, the milling aid is selected from the group consisting of: colloidal silica, a surfactant, a polymer, a stearic acid and derivatives thereof.","Preferably, the surfactant is selected from the group consisting of: polyoxyethylene alkyl ethers, polyoxyethylene stearates, polyethylene glycols (PEG), poloxamers, poloxamines, sarcosine based surfactants, polysorbates, aliphatic alcohols, alkyl and aryl sulfates, alkyl and aryl polyether sulfonates and other sulfate surfactants, trimethyl ammonium based surfactants, lecithin and other phospholipids, bile salts, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, Sorbitan fatty acid esters, Sucrose fatty acid esters, alkyl glucopyranosides, alkyl maltopyranosides, glycerol fatty acid esters, Alkyl Benzene Sulphonic Acids, Alkyl Ether Carboxylic Acids, Alkyl and aryl Phosphate esters, Alkyl and aryl Sulphate esters, Alkyl and aryl Sulphonic acids, Alkyl Phenol Phosphates esters, Alkyl Phenol Sulphates esters, Alkyl and Aryl Phosphates, Alkyl Polysaccharides, Alkylamine Ethoxylates, Alkyl-Naphthalene Sulphonates formaldehyde condensates, Sulfosuccinates, lignosulfonates, Ceto-Oleyl Alcohol Ethoxylates, Condensed Naphthalene Sulphonates, Dialkyl and Alkyl Naphthalene Sulphonates, Di-alkyl Sulphosuccinates, Ethoxylated nonylphenols, Ethylene Glycol Esters, Fatty Alcohol Alkoxylates, Hydrogenated tallowalkylamines, Mono-alkyl Sulphosuccinamates, Nonyl Phenol Ethoxylates, Sodium Oleyl N-methyl Taurate, Tallowalkylamines, linear and branched dodecylbenzene sulfonic acids Preferably, the surfactant is selected from the group consisting of: sodium lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate, sodium cetostearyl sulfate, sodium docusate, sodium deoxycholate, N-lauroylsarcosine sodium salt, glyceryl monostearate, glycerol distearate glyceryl palmitostearate, glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzalkonium chloride, CTAB, CTAC, Cetrimide, cetylpyridinium chloride, cetylpyridinium bromide, benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188, poloxamer 407, poloxamer 338, polyoxyl 2 stearyl ether, polyoxyl 100 stearyl ether, polyoxyl 20 stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 20 cetyl ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl 35 castor oil, polyoxyl 40 castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor oil, polyoxyl 200 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyoxyl 100 hydrogenated castor oil, polyoxyl 200 hydrogenated castor oil, cetostearyl alcohol, macrogel 15 hydroxystearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, Sucrose Palmitate, Sucrose Stearate, Sucrose Distearate, Sucrose laurate, Glycocholic acid, sodium Glycholate, Cholic Acid, Sodium Cholate, Sodium Deoxycholate, Deoxycholic acid, Sodium taurocholate, taurocholic acid, Sodium taurodeoxycholate, taurodeoxycholic acid, soy lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonate condensate/Lignosulfonate blend, Calcium Dodecylbenzene Sulfonate, Sodium Dodecylbenzene Sulfonate, Diisopropyl naphthalenesulphonate, erythritol distearate, Naphthalene Sulfonate Formaldehyde Condensate, nonylphenol ethoxylate (poe-30), Tristyrylphenol Ethoxylate, Polyoxyethylene (15) tallowalkylamines, sodium alkyl naphthalene sulfonate, sodium alkyl naphthalene sulfonate condensate, sodium alkylbenzene sulfonate, sodium isopropyl naphthalene sulfonate, Sodium Methyl Naphthalene Formaldehyde Sulfonate, sodium n-butyl naphthalene sulfonate, tridecyl alcohol ethoxylate (poe-18), Triethanolamine isodecanol phosphate ester, Triethanolamine tristyrylphosphate ester, Tristyrylphenol Ethoxylate Sulfate, Bis(2-hydroxyethyl)tallowalkylamines.","Preferably the polymer is selected from the list of: polyvinylpyrrolidones (PVP), polyvinylalcohol, Acrylic acid based polymers and copolymers of acrylic acid.","Preferably, the milling aid has a concentration selected from the group consisting of: 0.1-10 w/w, 0.1-5% w/w, 0.1-2.5% w/w, of 0.1-2% w/w, 0.1-1%, 0.5-5% w/w, 0.5-3% w/w, 0.5-2% w/w, 0.5-1.5%, 0.5-1% w/w, of 0.75-1.25% w/w, 0.75-1% and 1% w/w.","Preferably the biologically active ingredient is milled with lactose monohydrate; mannitol; glucose; microcrystalline cellulose; tartaric acid; or lactose monohydrate and sodium dodecyl sulfate.","Preferably, Diclofenac is milled with lactose mono-hydrate.","Preferably, Meloxicam is milled with mannitol.","Preferably, Diclofenac is milled with mannitol.","Preferably, Meloxicam is milled with glucose.","Preferably, Diclofenac is milled with glucose.","Preferably, Meloxicam is milled with microcrystalline cellulose.","Preferably, diclofenac in microcrystalline cellulose.","Preferably, Meloxicam is milled with Tartaric acid.","Preferably, Meloxicam is milled with lactose monohydrate.","Preferably, Meloxicam is milled with mannitol.","Preferably, Diclofenac is milled with lactose mono-hydrate and sodium dodecyl sulfate.","Preferably, Meloxicam is milled with lactose monohydrate and sodium dodecyl sulfate.","In another preferred embodiment, a facilitating agent or combination of facilitating agents is used.","Preferably, the facilitating agent is selected from the group consisting of: surface stabilizers, binding agents, filling agents, lubricating agents, sweeteners, flavouring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents, agents that may form part of a medicament, including a solid dosage form and other excipient required for specific drug delivery.","Preferably, the facilitating agent is added during dry milling.","Preferably, the facilitating agent is added to the milled biologically active material and grinding matrix and further processed in a mechanofusion process.","Mechanofusion milling causes mechanical energy to be applied to powders or mixtures of particles in the micrometre and nanometre.","The reasons for including facilitating agents include, but are not limited to providing better dispersibility, control of agglomeration, the release or retention of the active particles from the delivery matrix.","Examples of facilitating agents include, but are not limited to stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, sodium stearyl lactylate, zinc stearate, sodium stearate or lithium stearate, other solid state fatty acids such as oleic acid, lauric acid, palmitic acid, erucic acid, behenic acid, or derivatives (such as esters and salts), amino acids such as leucine, isoleucine, lysine, valine, methionine, phenylalanine, aspartame or acesulfame K. In a preferred aspect of manufacturing this formulation the facilitating agent is added to the milled mixture of biologically active material and co-grinding matrix and further processed in another milling device such as Mechanofusion, Cyclomixing, or impact milling such as ball milling, jet milling, or milling using a high pressure homogeniser, or combinations thereof.","In a highly preferred aspect the facilitating agent is added to the milling of the mixture of biologically active material and co-grinding matrix as some time before the end of the milling process.","Preferably, the facilitating agent is added to the dry milling at a time selected from the group consisting of: with 1-5% of the total milling time remaining, with 1-10% of the total milling time remaining, with 1-20% of the total milling time remaining, with 1-30% of the total milling time remaining, with 2-5% of the total milling time remaining, with 2-10% of the total milling time remaining, with 5-20% of the total milling time remaining and with 5-20% of the total milling time remaining.","In another preferred embodiment, a disintegrant is selected from the group consisting of: crosslinked PVP, cross linked carmellose and sodium starch glycolate.","In another preferred embodiment, the dissolution profile of the measurement sample or prototype formulation thereof is improved by a factor selected from the group consisting of: wherein X is reached in 10 minutes, wherein X is reached within 10-20 minutes, wherein X is reached within 10-30 mins, wherein X is reached within 10-40 mins, wherein X is reached within 10-50 mins, wherein X is reached within 20-30 mins, wherein X is reached within 20-40 mins, wherein X is reached within 20-50 mins, wherein X is reached within 30-40 mins, wherein X is reached within 30-50 mins and wherein X is reached within 40-50 mins, wherein X is defined as the concentration equal to the dissolution concentration achieved by a control sample or prototype formulation thereof of the biologically active material or compound after 60 minutes.","In another preferred embodiment, the dissolution profile of the measurement sample or prototype formulation thereof is improved by a factor selected from the group consisting of: wherein Y is reached in 5 minutes, wherein Y is reached within 10 minutes, wherein Y is reached within 10-15 mins, wherein Y is reached within 10-20 mins, wherein Y is reached within 10-25 mins, wherein Y is reached within 15-20 mins, wherein Y is reached within 15-25 mins, wherein Y is reached within 20-25 mins, wherein Y is defined as the concentration equal to the dissolution concentration achieved by a control sample (or prototype formulation thereof) of the biologically active material or compound after 30 minutes.","In a second aspect the invention comprises a biologically active material produced by the method described herein and composition comprising the biologically active material as described herein.","Preferably, the particles have an average particle size equal or greater than 1 μm determined on a particle number average basis.","Preferably, the average particle size of the biologically active material has been reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.","Preferably, the average particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-20 μm, 1-10 μm, 1-7.5 μm, 1-5 μm and 1-2 μm.","Preferably, the particles have a median particle size selected from the group consisting of: equal or greater than 1 μm; and equal or greater than 2 μm, wherein the median particle size is determined on a particle volume basis.","Preferably, the percentage of particles with an average particle size greater than 1 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.","Preferably, the percentage of particles with an average particle size greater than 2 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.","Preferably, the median particle size has been reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.","Preferably, the median particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-20 μm, 1-10 μm, 1-7.5 μm, 1-5 μm 1-2 μm, 2-1000 μm, 2-500 μm, 2-300 μm, 2-200 μm, 2-150 μm, 2-100 μm, 2-50 μm, 2-20 μm, 2-10 μm, 2-7.5 μm and 2-5 μm.","Preferably, the crystallinity profile of the biologically active material is selected from the group consisting of: at least 50% of the biologically active material is crystalline, at least 60% of the biologically active material is crystalline, at least 70% of the biologically active material is crystalline, at least 75% of the biologically active material is crystalline, at least 85% of the biologically active material is crystalline, at least 90% of the biologically active material is crystalline, at least 95% of the biologically active material is crystalline and at least 98% of the biologically active material is crystalline.","Preferably, the crystallinity profile of the biologically active material is substantially equal to the crystallinity profile of the biologically active material before the material was subject to the method described herein.","Preferably, the amorphous content of the biologically active material is selected from the group consisting of: less than 50% of the biologically active material is amorphous, less than 40% of the biologically active material is amorphous, less than 30% of the biologically active material is amorphous, less than 25% of the biologically active material is amorphous, less than 15% of the biologically active material is amorphous, less than 10% of the biologically active material is amorphous, less than 5% of the biologically active material is amorphous and less than 2% of the biologically active material is amorphous.","Preferably, the biologically active material has had no significant increase in amorphous content following subjecting the material to the method as described herein.","Preferably, the biologically active material is selected from the group consisting of: fungicides, pesticides, herbicides, nutraceuticals, pharmaceutical actives, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids and analogs, homologs and first order derivatives thereof.","Preferably, the biologically active material is selected from the group consisting of: anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, such as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives (hypnotics and neuroleptics), astringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (anti-parkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones (including steroids), anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines.","Preferably, the biologically active material is selected from the group consisting of: indomethacin, diclofenac, naproxen, meloxicam, metaxalone, cyclosporin A, progesterone celecoxib, cilostazol, ciprofloxacin, 2,4-dichlorophenoxyacetic acid, anthraquinone, creatine monohydrate, glyphosate, halusulfuron, mancozeb, metsulfuron, salbutamol, sulphur, tribenuran and estradiol or any salt or derivative thereof.","In one preferred embodiment, the invention comprises compositions comprising the biologically active ingredient together with a grinding matrix, a mixture of grinding matrix materials, milling aids, mixtures of milling aids, facilitating agents and/or mixtures of facilitating agents as described herein, in concentrations and ratios as described herein under the methods of the invention.","In a third aspect the invention comprises a pharmaceutical composition comprising a biologically active material produced by the method described herein and compositions described herein.","Preferably, the invention comprises pharmaceutical compositions comprising the biologically active ingredient together with a grinding matrix, a mixture of grinding matrix materials, milling aids, mixtures of milling aids, facilitating agents and/or mixtures of facilitating agents as described herein, in concentrations and ratios as described herein under the methods of the invention.","Preferably, the particles have an average particle size equal or greater than 1 μm determined on a particle number basis.","Preferably, the average particle size of the biologically active material has been reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.","Preferably, the average particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-μm, 1-10 μm, 1-7.5 μm, 1-5 μm and 1-2 μm.","Preferably, the particles have a median particle size selected from the group consisting of: equal or greater than 1 μm; and equal or greater than 2 μm, wherein the median particle size is determined on a particle volume basis.","Preferably, the percentage of particles with an average particle size greater than 1 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.","Preferably, the percentage of particles with an average particle size greater than 2 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.","Preferably, the median particle size has been reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.","Preferably, the median particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-20 μm, 1-10 μm, 1-7.5 μm, 1-5 μm 1-2 μm, 2-1000 μm, 2-500 μm, 2-300 μm, 2-200 μm, 2-150 μm, 2-100 μm, 2-50 μm, 2-20 μm, 2-10 μm, 2-7.5 μm and 2-5 μm.","Preferably, the crystallinity profile of the biologically active material is selected from the group consisting of: at least 50% of the biologically active material is crystalline, at least 60% of the biologically active material is crystalline, at least 70% of the biologically active material is crystalline, at least 75% of the biologically active material is crystalline, at least 85% of the biologically active material is crystalline, at least 90% of the biologically active material is crystalline, at least 95% of the biologically active material is crystalline and at least 98% of the biologically active material is crystalline.","Preferably, the crystallinity profile of the biologically active material is substantially equal to the crystallinity profile of the biologically active material before the material was subject to the method as described herein.","Preferably, the amorphous content of the biologically active material is selected from the group consisting of: less than 50% of the biologically active material is amorphous, less than 40% of the biologically active material is amorphous, less than 30% of the biologically active material is amorphous, less than 25% of the biologically active material is amorphous, less than 15% of the biologically active material is amorphous, less than 10% of the biologically active material is amorphous, less than 5% of the biologically active material is amorphous and less than 2% of the biologically active material is amorphous.","Preferably, the biologically active material has no significant increase in amorphous content after subjecting the material to the method as described herein.","Preferably, the biologically active material is selected from the group consisting of: new chemical entities, pharmaceutical actives, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids and analogs, homologs and first order derivatives thereof.","Preferably, the biologically active material is selected from the group consisting of: anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, such as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives (hypnotics and neuroleptics), astringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (anti-parkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones (including steroids), anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines.","Preferably, the biologically active material is selected from the group consisting of: indomethacin, diclofenac, naproxen, meloxicam, metaxalone, cyclosporin A, progesterone celecoxib, cilostazol, ciprofloxacin, 2,4-dichlorophenoxyacetic acid, anthraquinone, creatine monohydrate, glyphosate, halusulfuron, mancozeb, metsulfuron, salbutamol, sulphur, tribenuran and estradiol or any salt or derivative thereof.","Preferably cosmeceuticals, cosmetics, complementary medicines, natural products, vitamins, nutrients and nutraceuticals are selected from the group consisting of: Glycolic acids, Lactic acids, Carrageenan, Almonds, Mahogany wood, Andrographis Paniculata , Aniseed, Anthemis nobilis (chamomile), Apricot kernel, leaves of bearberry, leaves of cranberry, leaves of blueberry, leaves of pear trees, beta-carotene, black elderberry, black raspberry, black walnut shell, blackberry, bladderwrack, bletilla striata , borage seed, boysenberry, brazil nut, burdock root, butcher's broom extract, calamine, calcium gluconate, calendula, carnosic acid, Cantella asiatica , charcoal, chaste tree fruit, Chicory root extract, chitosan, choline, cichorium intybus, clematis vitalba, coffea Arabica , coumarin, crithmum maritimum , curcumin, coffee, cocoa, cocoa powder, cocoa nibs, cocoa mass, cocoa liquor, cocoa products, dogwood, Echinacea, echium lycopsis , anise, atragalus, bilberry, bitter orange, black cohosh, cat's claw, chamomile, chasteberry, cranberry, dandelion, Echinacea, ephedra, European elder Epilobium angustifolium , horse chestnut, cloves, evening primrose, fennel seed, fenugreek, feverfew, flaxseed, fumaria officinalis , garlic, geranium, ginger, ginkgo, ginseng, goldenseal, grape seed, green tea, guava, hawthorn, hayflower, hazelnut, helichrysum, hoodia, horseradish, mulbe italicum , hibiscus, hierochloe odorata , hops, horse chestnut, ilex paraguariensis , indian gooseberry, irish moss, juniper berry, kudzu root, lady's thistle, lavender, lemongrass, lentius edodes , licorice, longifolene, loquat, lotus seed, luffa cylindrica , lupine, maroinberry, marjoram, meadowsweet, milk vetch root, mimosa tenuiflora , mistletoe, mulberry, noni, kelp, oatmeal, oregano, papaya, parsley, peony root, pomegranate, pongamia glabra seed, pongamia pinnata , quinoa seed, red raspberry, rose hip, rosemary, sage, saw palmetto, soy bean, szechuan peppercorn, tephrosia purpurea, terminalia catappa, terminalia sericea , thunder god vine, thyme, turmeric, valeriana officinalis , walnuts, white tea leaf, yam, witch hazel, wormwood, yarrow, valerian, yohimbe, mangosteen, sour sob, goji berry, spirulina and durian skin.","In a fourth aspect the invention comprises a method of treating a human in need of such treatment comprising the step of administering to the human an effective amount of a pharmaceutical composition as described herein.","In a fifth aspect the invention comprises a method for manufacturing a pharmaceutical composition as described herein comprising the step of combining a therapeutically effective amount of a biologically active material prepared by a method described herein together with a pharmaceutically acceptable carrier to produce a pharmaceutically acceptable dosage form.","In a sixth aspect the invention comprises a method for manufacturing a veterinary product comprising the step of combining a therapeutically effective amount of the biologically active material prepared by a method as described herein together with an acceptable excipient to produce a dosage form acceptable for veterinary use.","In a seventh aspect the invention comprises a method for manufacturing an agricultural product comprising the step of combining an effective amount of the biologically active material prepared by a method described herein together with acceptable excipients to produce a formulation such as, but not limited to a water dispersible granule, wettable granule, dry flowable granule or soluble granule that is used to prepare a solution for use in agricultural applications.","Preferably, the product is selected from the group consisting of: herbicides, pesticides, seed treatments, herbicide safeners, plant growth regulators and fungicides.","The methods of the invention can be used to increase the dissolution of the biologically active material particles in water or other solvents, resulting in better, faster or more complete preparation and mixing.","This will result in a more consistent product performance such as better weed, disease and pest control and other practical benefits such as faster machinery, tank and sprayer cleanout, less rinsate, and a reduced impact on the environment.","In a future aspect the invention comprises a method for manufacturing an agricultural product comprising the step of combining an effective amount of the biologically active material prepared by a method described herein together with acceptable excipients to produce a formulation such as, but not limited to a water dispersible granule, wettable granule, wettable powder or a powder for seed treatment that is used to prepare a dry powder or particle suspension for use in agricultural applications.","Preferably, the product is selected from the group consisting of: herbicides, pesticides, seed treatments, herbicide safeners, plant growth regulators and fungicides.","Another preferred aspect of the method of invention would be to produce powders that have active particles with a high surface area.","Such powders would provide better performance in areas such as seed treatment where dry powders are applied to seeds as fungicides, herbicide safeners, plant growth regulators and other treatments.","The higher surface area would provide more activity per mass of active used.","In another preferred aspect actives such as pesticides, fungicides and seed treatments subject to the method of invention are formulated to produce suspensions of the actives when added to water or other solvents.","As these suspensions will have particles of very small size and high surface area they will possess at least three highly desirable traits.","The first is that small particles with high surface area will adhere better to surfaces such as leafs and other foliage that the suspension is applied to.","This will result in better rain fastness and a longer period of activity.","The second aspect is that smaller particles with a higher surface area deliver superior coverage per unit mass of active applied.","For example, if 100 particles are needed on a leaf and if the particle diameter is reduced to one third of the former diameter by the methods of this invention, then the dosage can be reduced to about 11% of the former dosage, resulting in lower cost, less residue on harvested crops, and mitigation of environmental impact.","In the third aspect the smaller particles will deliver better bioavailability.","With many low solubility actives, such as fungicides and pesticides the particles that adhere to plant material slowly dissolve over days and weeks providing continued protection from disease and pests.","With this method of invention able to deliver better bioavailability in many circumstances it will be possible to reduce the amount of active that needs to be applied.","As with the second aspect such an outcome would lower costs, minimize residues and mitigate environmental impact.","In a highly preferred aspect of the invention the powder produced in the milling process would be subject to a process such as wet or dry granulation that makes the powder free flowing and low in dust content yet easily dispersible once in water or other solvent.","Preferably the biologically active material is a herbicide, pesticide, seed treatment, herbicide safener, plant growth regulator or fungicide selected from the group consisting of: 2-phenylphenol, 8-hydroxyquinoline sulfate, acibenzolar, allyl alcohol, azoxystrobin, basic benomyl, benzalkonium chloride, biphenyl, blasticidin-S, Bordeaux mixture, Boscalid, Burgundy mixture, butylamine, Cadendazim, calcium polysulfide, Captan, carbamate fungicides, carbendazim, carvone, chloropicrin, chlorothalonil, ciclopirox, clotrimazole, conazole fungicides, Copper hydroxide, copper oxychloride, copper sulfate, copper(II) carbonate, copper(II) sulfate, cresol, cryprodinil, cuprous oxide, cycloheximide, Cymoxanil, DBCP, dehydroacetic acid, dicarboximide fungicides, difenoconazole, dimethomorph, diphenylamine, disulfiram, ethoxyquin, famoxadone, fenamidone, Fludioxonil, formaldehyde, fosetyl, Fosetyl-aluminium, furfural, griseofulvin, hexachlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole, imazalil, Imidacloprid, iodomethane, Iprodione, Lime sulfur, mancozeb, mercuric chloride, mercuric oxide, mercurous chloride, Metalaxyl, metam, methyl bromide, methyl isothiocyanate, metiram, natamycin, nystatin, organotin fungicides, oxythioquinox, pencycuron, pentachlorophenol, phenylmercury acetate, potassium thiocyanate, procymidone, propiconazole, propineb, pyraclostrobin, pyrazole fungicides, pyridine fungicides, pyrimethanil, pyrimidine fungicides, pyrrole fungicides, quinoline fungicides, quinone fungicides, sodium azide, streptomycin, sulfur, Tebucanazole, thiabendazole, thiomersal, tolnaftate, Tolylfluanid, triadimersol, tributyltin oxide, Trifloxystrobin, triflumuron, Undecylenic acid, urea fungicides, vinclozolin, Ziram, 3-dihydro-3-methyl-1, 3-thiazol-2-ylidene-xylidene, 4-D esters, 4-DB esters, 4-parathion methyl, Acetamiprid, aclonifen, acrinathrin, alachlor, allethrin, alpha-cypermethrin, Aluminium phosphide, amitraz, anilophos, azaconazole, azinphos-ethyl, azinphos-methyl, benalaxyl, benfluralin, benfuracarb, benfuresate, bensulide, benzoximate, benzoylprop-ethyl, betacyfluthrin, beta-cypermethrin, bifenox, bifenthrin, binapacryl, bioallethrin, bioallethrin S, bioresmethrin, biteranol, Brodifacoum, bromophos, bromopropylate, bromoxynil, bromoxynil esters, bupirimate, buprofezin, butacarboxim, butachlor, butamifos, butoxycarboxin, butralin, butylate, calcium sulfate, cambda-cyhalothrin, carbetamide, carboxin, chlordimeform, chlorfenvinphos, chlorflurazuron, chlormephos, chlornitrofen, chlorobenzilate, chlorophoxim, chloropropylate, chlorpropham, Chlorpyrifos, chlorpyrifos-methyl, cinmethylin, clethodim, clomazone, clopyralid esters, CMPP esters, cyanophos, cycloate, cycloprothrin, cycloxydim, cyfluthrin, cyhalothrin, cypermethrin, cyphenothrin, cyproconazole, deltamethrin, demeton-S-methyl, desmedipham, dichlorprop esters, dichlorvos, diclofop-methyldiethatyl, dicofol, difenoconazole, dimethachlor, dimethomoph, diniconazole, dinitramine, dinobuton, dioxabenzafos, dioxacarb, disulfoton, ditalimfos, dodemorph, dodine, edifenphos, emamectin, empenthrin, endosulfan, EPNethiofencarb, epoxyconazole, esfenvalerate, ethalfluralin, ethofumesate, ethoprophos, ethoxyethyl, etofenprox, etridiazole, etrimphos, Famoxadone, fenamiphos, fenarimol, fenazaquin, fenitrothion, fenobucarb, fenoxapropethyl, fenoxycarb, fenpropathrin, fenpropidin, fenpropimorph, fenthiocarb, fenthion, fenvalerate, fluazifop, fluazifop-P, fluchloralin, flucythrinate, flufenoxim, flufenoxuron, flumetralin, fluorodifen, fluoroglycofen ethyl, fluoroxypyr esters, flurecol butyl, flurochloralin, flusilazole, formothion, gamma-HCH, haloxyfop, haloxyfop-methyl, hexaflumuron, hydroprene, imibenconazole, indoxacarb, ioxynil esters, isofenphos, isoprocarb, isopropalin, isoxathion, malathion, maneb, MCPA esters, mecoprop-P esters, mephospholan, Metaldehyde, methidathion, Methomyl, methoprene, methoxychlor, metolachlor, mevinphos, monalide, myclobutanil, N-2, napropamide, nitrofen, nuarimol, oxadiazon, oxycarboxin, oxyfluorfen, penconazole, pendimethalin, permethrin, phenisopham, phenmedipham, phenothrin, phenthoate, phosalone, phosfolan, phosmet, picloram esters, pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, pretilachlor, prochloraz, profenofos, profluralin, promecarb, propachlor, propanil, propaphos, propaquizafop, propargite, propetamphos, pymetrozine, pyrachlofos, pyridate, pyrifenox, quinalphos, quizalofop-P, resmethrin, Spinetoram J, Spinetoram L, Spinosad A, Spinosad B, tau-fluvalinate, tebuconazole, Tebufenozide, tefluthrin, temephos, terbufos, tetrachlorinphos, tetraconazole, tetradifon, tetramethrin, Thiamethoxam, tolclofos-methyl, tralomethrin, triadimefon, triadimenol, triazophos, triclopyr esters, tridemorph, tridiphane, triflumizole, trifluralin, xylylcarb, 3-dihydro-3-methyl-1, 3-thiazol-2-ylidene-xylidene, 4-D esters, 4-DB esters, 4-parathion methyl, Acetamiprid, acetochlor, aclonifen, acrinathrin, alachlor, allethrin, alpha-cypermethrin, Aluminium phosphide, amitraz, anilophos, azaconazole, azinphos-ethyl, azinphos-methyl, benalaxyl, benfluralin, benfuracarb, benfuresate, bensulide, benzoximate, benzoylprop-ethyl, betacyfluthrin, beta-cypermethrin, bifenox, bifenthrin, binapacryl, bioallethrin, bioallethrin S, bioresmethrin, biteranol, Brodifacoum, bromophos, bromopropylate, bromoxynil, bromoxpil esters, bupirimate, buprofezin, Butacarboxim, butachlor, butamifos, butoxycarboxin, butralin, butylate, calcium sulfate, cambda-cyhalothrin, carbetamide, carboxin, chlordimeform, chlorfenvinphos, chlorflurazuron, chlormephos, chlornitrofen, chlorobenzilate, chlorophoxim, chloropropylate, chlorpropham, Chlorpyrifos, chlorpyrifos-methyl, cinmethylin, clethodim, clomazone, clopyralid esters, CMPP esters, cyanophos, cycloate, cycloprothrin, cycloxydim, cyfluthrin, cyhalothrin, cypermethrin, cyphenothrin, cyproconazole, deltamethrin, demeton-S-methyl, desmedipham, dichlorprop esters, dichlorvos, diclofop-methyldiethatyl, dicofol, dimethachlor, dimethomoph, diniconazole, dinitramine, dinobuton, dioxabenzafos, dioxacarb, disulfoton, ditalimfos, dodemorph, dodine, edifenphos, emamectin, empenthrin, endosulfan, EPNethiofencarb, epoxyconazole, esfenvalerate, ethalfluralin, ethofumesate, ethoprophos, ethoxyethyl, ethoxyquin, etofenprox, etridiazole, etrimphos, fenamiphos, fenarimol, fenazaquin, fenitrothion, fenobucarb, fenoxapropethyl, fenoxycarb, fenpropathrin, fenpropidin, fenpropimorph, fenthiocarb, fenthion, fenvalerate, fluazifop, fluazifop-P, fluchloralin, flucythrinate, flufenoxim, flufenoxuron, flumetralin, fluorodifen, fluoroglycofen ethyl, fluoroxypyr esters, flurecol butyl, flurochloralin, flusilazole, formothion, gamma-HCH, haloxyfop, haloxyfop-methyl, hexaflumuron, hydroprene, imibenconazole, indoxacarb, ioxynil esters, isofenphos, isoprocarb, isopropalin, isoxathion, malathion, maneb, MCPA esters, mecoprop-P esters, mephospholan, Metaldehyde, methidathion, Methomyl, methoprene, methoxychlor, mevinphos, monalide, myclobutanil, myclobutanil, N-2, napropamide, nitrofen, nuarimol, oxadiazon, oxycarboxin, oxyfluorfen, penconazole, permethrin, phenisopham, phenmedipham, phenothrin, phenthoate, phosalone, phosfolan, phosmet, picloram esters, pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, pretilachlor, prochloraz, profenofos, profluralin, promecarb, propachlor, propanil, propaphos, propaquizafop, propargite, propetamphos, pymetrozine, pyridate, pyrifenox, quinalphos, quizalofop-P, resmethrin, Spinetoram J, Spinetoram L, Spinosad A, Spinosad B, tau-fluvalinate, Tebufenozide, tefluthrin, temephos, terbufos, tetrachlorinphos, tetraconazole, tetradifon, tetramethrin, Thiamethoxam, tolclofos-methyl, tralomethrin, triadimenol, triazophos, triclopyr esters, tridemorph, tridiphane, triflumizole, trifluralin, xylylcarb and any combination thereof.","In an eighth aspect the invention comprises a method for manufacturing of a pharmaceutical formulation comprising the step of combining an effective amount of the biologically active material prepared by a method described herein together with acceptable excipients to produce a formulation that can deliver a therapeutically effective amount of active to the pulmonary or nasal area.","Such a formulation could be, but is not limited to a dry powder formulation for oral inhalation to the lungs or a formulation for nasal inhalation.","Preferably the method for manufacturing such a formulation uses lactose, mannitol, sucrose, sorbitol, xylitol or other sugars or polyols as the co-grinding matrix together with surfactant such as, but not limited to lecithin, DPPC (dipalmitoyl phosphatidylcholine), PG (phosphatidylglycerol), dipalmitoyl phosphatidyl ethanolamine (DPPE), dipalmitoyl phosphatidylinositol (DPPI) or other phospholipid.","The particle size of the material produced by the invention disclosed herein results in the materials being readily aerosolized and suitable for methods of delivery to a subject in need thereof, including pulmonary and nasal delivery methods.","While the method of the present invention has particular application in the preparation of poorly water-soluble biologically active materials, the scope of the invention is not limited thereto.","For example, the method of the present invention enables production of highly water-soluble biologically active materials.","Such materials may exhibit advantages over conventional materials by way of, for example, more rapid therapeutic action or lower dose.","In contrast, wet grinding techniques utilizing water (or other comparably polar solvents) are incapable of being applied to such materials, as the particles dissolve appreciably in the solvent.","Other aspects and advantages of the invention will become apparent to those skilled in the art from a review of the ensuing description."],["This application is a continuation of U.S. application Ser.","No.","13/925,325, filed Jun.","24, 2013, which is a continuation of U.S. application Ser.","No.","13/265,927, filed Mar.","9, 2012, which is a U.S. national stage under 35 USC § 371 of International Application Number PCT/AU2010/000465, filed on 23 Apr.","2012, which claims priority to AU Application No.","2009901741, filed on 24 Apr.","2009 and U.S.","Application No.","61/172,301, filed on 24 Apr.","2009, the entire contents of which applications is hereby incorporated by reference.","FIELD OF THE INVENTION The present invention relates to methods for improving the dissolution profile of a biologically active material.","The invention also relates to biologically active materials in particulate form produced by said methods, compositions comprising such materials, medicaments produced using said biologically active materials in particulate form and/or compositions, and to methods of treatment of an animal, including man, using a therapeutically effective amount of said biologically active materials administered by way of said medicaments.","BACKGROUND Poor bioavailability is a significant problem encountered in the development of therapeutic compositions, particularly those materials containing a biologically active material that is poorly soluble in water at physiological pH.","An active material's bioavailability is the degree to which the active material becomes available to the target tissue in the body after systemic administration through, for example, oral or intravenous means.","Many factors affect bioavailability, including the form of dosage and the solubility and dissolution rate of the active material.","Poorly and slowly water-soluble materials tend to be eliminated from the gastrointestinal tract before being absorbed into the circulation.","In addition, poorly soluble active agents tend to be disfavored or even unsafe for intravenous administration due to the risk of particles of agent blocking blood flow through capillaries.","It is known that the rate of dissolution of a particulate drug will increase with increasing surface area.","One way of increasing surface area is decreasing particle size.","Consequently, methods of making finely divided or sized drugs have been studied with a view to controlling the size and size range of drug particles for pharmaceutical compositions.","For example, dry milling techniques have been used to reduce particle size and hence influence drug absorption.","However, in conventional dry milling the limit of fineness is reached generally in the region of about 100 microns (100,000 nm), at which point material cakes on the milling chamber and prevents any further diminution of particle size.","Alternatively, wet grinding may be employed to reduce particle size, but flocculation restricts the lower particle size limit to approximately 10 microns (10,000 nm).","The wet milling process, however, is prone to contamination, thereby leading to a bias in the pharmaceutical art against wet milling.","Another alternative milling technique, commercial airjet milling, has provided particles ranging in average size from as low as about 1 to about 50 microns (1,000-50,000 nm).","There are several approaches currently used to formulate poorly soluble active agents.","One approach is to prepare the active agent as a soluble salt.","Where this approach cannot be employed, alternate (usually physical) approaches are employed to improve the solubility of the active agent.","Alternate approaches generally subject the active agent to physical conditions that change the agent's physical and or chemical properties to improve its solubility.","These include process technologies such as micronization, modification of crystal or polymorphic structure, development of oil based solutions, use of co-solvents, surface stabilizers or complexing agents, micro-emulsions, super critical fluid and production of solid dispersions or solutions.","More than one of these processes may be used in combination to improve formulation of a particular therapeutic material.","Many of these approaches commonly convert a drug into an amorphous state, which generally leads to a higher dissolution rate.","However, formulation approaches that result in the production of amorphous material are not common in commercial formulations due to concerns relating to stability and the potential for material to re-crystallize.","These techniques for preparing such pharmaceutical compositions tend to be complex.","By way of example, a principal technical difficulty encountered with emulsion polymerization is the removal of contaminants, such as unreacted monomers or initiators (which may have undesirable levels of toxicity), at the end of the manufacturing process.","Another method of providing reduced particle size is the formation of pharmaceutical drug microcapsules, which techniques include micronizing, polymerisation and co-dispersion.","However, these techniques suffer from a number of disadvantages including at least the inability to produce sufficiently small particles such as those obtained by milling, and the presence of co-solvents and/or contaminants such as toxic monomers which are difficult to remove, leading to expensive manufacturing processes.","Over the last decade, intense scientific investigation has been carried out to improve the solubility of active agents by converting the agents to ultra fine powders by methods such as milling and grinding.","These techniques may be used to increase the dissolution rate of a particulate solid by increasing the overall surface area and decreasing the mean particle size.","U.S. Pat.","No.","6,634,576 discloses examples of wet-milling a solid substrate, such as a pharmaceutically active compound, to produce a “synergetic co-mixture”.","International Patent Application PCT/AU2005/001977 (Nanoparticle Composition(s) and Method for Synthesis Thereof) describes, inter alia, a method comprising the step of contacting a precursor compound with a co-reactant under mechanochemical synthesis conditions wherein a solid-state chemical reaction between the precursor compound and the co-reactant produces therapeutically active nanoparticles dispersed in a carrier matrix.","Mechanochemical synthesis, as discussed in International Patent Application PCT/AU2005/001977, refers to the use of mechanical energy to activate, initiate or promote a chemical reaction, a crystal structure transformation or a phase change in a material or a mixture of materials, for example by agitating a reaction mixture in the presence of a milling media to transfer mechanical energy to the reaction mixture, and includes without limitation “mechanochemical activation”, “mechanochemical processing”, “reactive milling”, and related processes.","International Patent Application PCT/AU2007/000910 (Methods for the preparation of biologically active compounds in nanoparticulate form) describes, inter alia, a method for dry milling raloxifene with lactose and NaCl which produced nanoparticulate raloxifene without significant aggregation problems.","One limitation of this method is an upper limit to the drug content that can be successfully milled to produce nanoparticles.","For some drugs that require a high dose this limitation may restrict the options available for the production of a commercially viable dosage form.","The present invention provides methods for improving the dissolution profile of a biologically active material which ameliorate some of the problems attendant with prior technologies, or provides an alternative thereto.","One example of a therapeutic area where this technology could be applied in is the area of acute pain management.","Many pain medications such as meloxicam (marketed as Mobic® by pharmaceutical company Boehringer Ingelheim) provides pain relief for chronic pain, but must be taken on a daily basis to maintain an effective therapeutic level.","Meloxicam is a poorly water soluble drug which is only slowly absorbed by the body (Tmax is 4-5 hours), so a method such as the present invention which provides for improved dissolution, will likely provide much faster absorption resulting in a more rapid onset of the therapeutic effect.","Meloxicam also has a long half life (15-20 hours) that means it only need be taken once a day.","By using a method such as the present invention, which provides faster absorption, a drug such as meloxicam, could be transformed from a chronic pain drug to an acute pain drug.","For meloxicam this would provide a medication that could provide therapeutic relief for acute pain, with the advantage of sustained pain relief over 24 hours.","Meloxicam also has sub-optimal bioavailability at 89% for an oral capsule, compared with an IV dosage form.","A component of this sub optimal bioavailability is also likely due to the poor water solubility of this drug.","If the low solubility does contribute to this sub optimal bioavailability, the improvement of the dissolution of this drug with a method such as the present invention could provide scope to produce a dosage form with a lower active dose whilst still providing the effective therapeutic dose.","Although the background to the present invention is discussed in the context of improving the bioavailability of materials that are poorly or slowly water soluble, the applications of the methods of the present invention are not limited to such, as is evident from the following description of the invention.","Further, although the background to the present invention is largely discussed in the context of improving the bioavailability of therapeutic or pharmaceutical compounds, the applications of the methods of the present invention are clearly not limited to such.","For example, as is evident from the following description, applications of the methods of the present invention include but are not limited to: nutraceutical and nutritional compounds, complementary medicinal compounds, veterinary therapeutic applications and agricultural chemical applications, such as pesticide, fungicide or herbicide.","Furthermore, an application of the current invention would be to materials which contain a biologically active compound such as, but not limited to a therapeutic or pharmaceutical compound, a nutraceutical or nutrient, a complementary medicinal product such as active components in plant or other naturally occurring material, a veterinary therapeutic compound or an agricultural compound such as a pesticide, fungicide or herbicide.","Specific examples would be the spice turmeric that contains the active compound curcumin, or flax seed that contains the nutrient ALA an omega-3 fatty acid.","As these specific examples indicate this invention could be applied to, but not limited to, a range of natural products such as seeds, cocoa and cocoa solids, coffee, herbs, spices, other plant materials or food materials that contain a biologically active compound.","The application of this invention to these types of materials would enable greater availability of the active compound in the materials when used in the relevant application.","For example where material subject to this invention is orally ingested the active would be more bioavailable.","SUMMARY OF THE INVENTION In one aspect the present invention is directed to the unexpected finding that the dissolution profile of biologically active materials can be improved by dry milling solid biologically active material to a particle size of greater than 1 μm.","In one surprising aspect of the invention, the dissolution profile of a biologically active material can be improved without substantially reducing the particle size of the material or reducing the material to nanoparticulate form.","In another surprising aspect of the invention, the material retains its crystalline structure and is not amorphous, yet the dissolution profile of the biologically active material is improved.","In another surprising aspect of the invention, the dissolution profile of a biologically active material is improved without the need for a surfactant or stabiliser.","In another surprising aspect of the invention, the dissolution profile of a biologically active material is improved without the need for a disintegrant to be present during the milling process.","Thus, in a first aspect the invention comprises a method for improving the dissolution profile of a biologically active material, comprising the steps of: dry milling a solid biologically active material and a millable grinding matrix in a mill comprising a plurality of milling bodies, for a time period sufficient to produce particles of the biologically active material dispersed in an at least partially milled grinding material.","In one preferred embodiment, the particles have an average particle size equal or greater than 1 μm determined on a particle number basis.","More preferably, the average particle size of the biologically active material may be reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.","Even more preferably, the average particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-20 μm, 1-10 μm, 1-7.5 μm, 1-5 μm and 1-2 μm.","In another preferred embodiment, the particles have a median particle size selected from the group consisting of: equal or greater than 1 μm; and equal or greater than 2 μm, wherein the median particle size is determined on a particle volume basis.","More preferably, the percentage of particles with an average particle size greater than 1 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.","Alternatively, the percentage of particles with an average particle size greater than 2 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.","In another preferred embodiment, the median particle size may be reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.","In another preferred embodiment, the median particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-20 μm, 1-10 μm, 1-7.5 μm, 1-5 μm 1-2 μm, 2-1000 μm, 2-500 μm, 2-300 μm, 2-200 μm, 2-150 μm, 2-100 μm, 2-50 μm, 2-20 μm, 2-10 μm, 2-7.5 μm and 2-5 μm.","In another preferred embodiment, the crystallinity profile of the biologically active material is selected from the group consisting of: at least 50% of the biologically active material is crystalline, at least 60% of the biologically active material is crystalline, at least 70% of the biologically active material is crystalline, at least 75% of the biologically active material is crystalline, at least 85% of the biologically active material is crystalline, at least 90% of the biologically active material is crystalline, at least 95% of the biologically active material is crystalline and at least 98% of the biologically active material is crystalline.","More preferably, the crystallinity profile of the biologically active material is substantially equal to the crystallinity profile of the biologically active material before the material was subjected to the method as described herein.","In another preferred embodiment, the amorphous content of the biologically active material is selected from the group consisting of: less than 50% of the biologically active material is amorphous, less than 40% of the biologically active material is amorphous, less than 30% of the biologically active material is amorphous, less than 25% of the biologically active material is amorphous, less than 15% of the biologically active material is amorphous, less than 10% of the biologically active material is amorphous, less than 5% of the biologically active material is amorphous and less than 2% of the biologically active material is amorphous.","Preferably, the biologically active material has no significant increase in amorphous content after subjecting the material to the method as described herein.","In another preferred embodiment, the milling time period is a range selected from the group consisting of: between 10 minutes and 2 hours, between 10 minutes and 1 hour, between 10 minutes and 45 minutes, between 10 minutes and 30 minutes, between 5 minutes and 30 minutes, between 5 minutes and 20 minutes, between 2 minutes and 10 minutes, between 2 minutes and 5 minutes, between 1 minutes and 20 minutes, between 1 minute and 10 minutes, and between 1 minute and 5 minutes.","In another preferred embodiment, the milling medium is selected from the group consisting of: ceramics, glasses, polymers, ferromagnetics and metals.","Preferably, the milling medium is steel balls having a diameter selected from the group consisting of: between 1 and 20 mm, between 2 and 15 mm and between 3 and 10 mm.","In another preferred embodiment, the milling medium is zirconium oxide balls having a diameter selected from the group consisting of: between 1 and 20 mm, between 2 and 15 mm and between 3 and 10 mm.","Preferably, the dry milling apparatus is a mill selected from the group consisting of: attritor mills (horizontal or vertical), nutating mills, tower mills, pearl mills, planetary mills, vibratory mills, eccentric vibratory mills, gravity-dependent-type ball mills, rod mills, roller mills and crusher mills.","Preferably the milling medium within the milling apparatus is mechanically agitated by 1, 2 or 3 rotating shafts.","Preferably, the method is configured to produce the biologically active material in a continuous fashion.","Preferably, the total combined amount of biologically active material and grinding matrix in the mill at any given time is equal to or greater than a mass selected from the group consisting of: 200 grams, 500 grams, 1 kg, 2 kg, 5 kg, 10 kg, 20 kg, 30 kg, 50 kg, 75 kg, 100 kg, 150 kg, 200 kg.","Preferably, the total combined amount of biologically active material and grinding matrix is less than 2000 kg.","In another preferred embodiment, the biologically active material is selected from the group consisting of: fungicides, pesticides, herbicides, seed treatments, cosmeceuticals, cosmetics, complementary medicines, natural products, vitamins, nutrients, nutraceuticals, pharmaceutical actives, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids additives, foods and food ingredients and analogs, homologs and first order derivatives thereof.","Preferably, the biologically active material is selected from the group consisting of: anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, such as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives (hypnotics and neuroleptics), astringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (anti-parkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones (including steroids), anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines.","Preferably, the biologically active material is selected from the group consisting of: indomethacin, diclofenac, naproxen, meloxicam, metaxalone, cyclosporin A, progesterone celecoxib, cilostazol, ciprofloxacin, 2,4-dichlorophenoxyacetic acid, anthraquinone, creatine monohydrate, glyphosate, halusulfuron, mancozeb, metsulfuron, salbutamol, sulphur, tribenuran and estradiol or any salt or derivative thereof.","In another preferred embodiment, the grinding matrix is a single matrix or is a mixture of two or more matrices in any proportion.","Preferably, the major components of the grinding matrix are selected from the group consisting of: mannitol, sorbitol, Isomalt, xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, glucose, fructose, mannose, galactose, anhydrous lactose, lactose monohydrate, sucrose, maltose, trehalose, maltodextrins, dextrin, Inulin, dextrates, polydextrose, starch, wheat flour, corn flour, rice flour, rice starch, tapioca flour, tapioca starch, potato flour, potato starch, other flours and starches, milk powder, skim milk powders, other milk solids and derivatives, soy flour, soy meal or other soy products, cellulose, microcrystalline cellulose, microcrystalline cellulose based co blended materials, pregelatinized (or partially) starch, HPMC, CMC, HPC, citric acid, tartaric acid, malic acid, maleic acid fumaric acid, ascorbic acid, succinic acid, sodium citrate, sodium tartrate, sodium malate, sodium ascorbate, potassium citrate, potassium tartrate, potassium malate, potassium ascorbate, sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate and calcium carbonate.","dibasic calcium phosphate, tribasic calcium phosphate, sodium sulfate, sodium chloride, sodium metabisulphite, sodium thiosulfate, ammonium chloride, Glauber's salt, ammonium carbonate, sodium bisulfate, magnesium sulfate, potash alum, potassium chloride, sodium hydrogen sulfate, sodium hydroxide, crystalline hydroxides, hydrogen carbonates, ammonium chloride, methylamine hydrochloride, ammonium bromide, silica, thermal silica, alumina, titanium dioxide, talc, chalk, mica, kaolin, bentonite, hectorite, magnesium trisilicate, clay based materials or aluminium silicates, sodium lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate, sodium cetostearyl sulfate, sodium docusate, sodium deoxycholate, N-lauroylsarcosine sodium salt, glyceryl monostearate, glycerol distearate glyceryl palmitostearate, glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzalkonium chloride, CTAB, CTAC, Cetrimide, cetylpyridinium chloride, cetylpyridinium bromide, benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188, poloxamer 407, poloxamer 338, polyoxyl 2 stearyl ether, polyoxyl 100 stearyl ether, polyoxyl 20 stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 20 cetyl ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl 35 castor oil, polyoxyl 40 castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor oil, polyoxyl 200 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyoxyl 100 hydrogenated castor oil, polyoxyl 200 hydrogenated castor oil, cetostearyl alcohol, macrogel 15 hydroxystearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, Sucrose Palmitate, Sucrose Stearate, Sucrose Distearate, Sucrose laurate, Glycocholic acid, sodium Glycholate, Cholic Acid, Sodium Cholate, Sodium Deoxycholate, Deoxycholic acid, Sodium taurocholate, taurocholic acid, Sodium taurodeoxycholate, taurodeoxycholic acid, soy lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonate condensate/Lignosulfonate blend, Calcium Dodecylbenzene Sulfonate, Sodium Dodecylbenzene Sulfonate, Diisopropyl naphthalenesulphonate, erythritol distearate, Naphthalene Sulfonate Formaldehyde Condensate, nonylphenol ethoxylate (poe-30), Tristyrylphenol Ethoxylate, Polyoxyethylene (15) tallowalkylamines, sodium alkyl naphthalene sulfonate, sodium alkyl naphthalene sulfonate condensate, sodium alkylbenzene sulfonate, sodium isopropyl naphthalene sulfonate, Sodium Methyl Naphthalene Formaldehyde Sulfonate, sodium n-butyl naphthalene sulfonate, tridecyl alcohol ethoxylate (poe-18), Triethanolamine isodecanol phosphate ester, Triethanolamine tristyrylphosphate ester, Tristyrylphenol Ethoxylate Sulfate, Bis(2-hydroxyethyl)tallowalkylamines.","Preferably, the concentration of the single (or first) material is selected from the group consisting of: 5-99% w/w, 10-95% w/w, 15-85% w/w, of 20-80% w/w, 25-75% w/w, 30-60% w/w, 40-50% w/w.","Preferably, the concentration of the second or subsequent material is selected from the group consisting of: 5-50% w/w, 5-40% w/w, 5-30% w/w, of 5-20% w/w, 10-40% w/w, 10-30% w/w, 10-20% w/w, 20-40% w/w, or 20-30% w/w or if the second or subsequent material is a surfactant or water soluble polymer the concentration is selected from 0.1-10% w/w, 0.1-5% w/w, 0.1-2.5% w/w, of 0.1-2% w/w, 0.1-1%, 0.5-5% w/w, 0.5-3% w/w, 0.5-2% w/w, 0.5-1.5%, 0.5-1% w/w, of 0.75-1.25% w/w, 0.75-1% and 1% w/w.","Preferably, the grinding matrix is selected from the group consisting of: (a) lactose monohydrate or lactose monohydrate combined with at least one material selected from the group consisting of: xylitol; lactose anhydrous; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","(b) lactose anhydrous or lactose anhydrous combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","(c) mannitol or mannitol combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; lactose anhydrous; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","(d) Sucrose or sucrose combined with at least one material selected from the group consisting of: lactose monohydrate; lactose anhydrous; mannitol; microcrystalline cellulose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","(e) Glucose or glucose combined with at least one material selected from the group consisting of: lactose monohydrate; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","(f) Sodium chloride or sodium chloride combined with at least one material selected from the group consisting of: lactose monohydrate; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","(g) xylitol or xylitol combined with at least one material selected from the group consisting of: lactose monohydrate; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","(h) Tartaric acid or tartaric acid combined with at least one material selected from the group consisting of: lactose monohydrate; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","(i) microcrystalline cellulose or microcrystalline cellulose combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; lactose anhydrous; mannitol; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","(j) Kaolin combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","(k) Talc combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.","Preferably, the grinding matrix is selected from the group consisting of: a material considered to be Generally Regarded as Safe (GRAS) for pharmaceutical products; a material considered acceptable for use in an agricultural formulation; and a material considered acceptable for use in a veterinary formulation.","In another preferred embodiment, a milling aid is used or a combination of milling aids.","Preferably, the milling aid is selected from the group consisting of: colloidal silica, a surfactant, a polymer, a stearic acid and derivatives thereof.","Preferably, the surfactant is selected from the group consisting of: polyoxyethylene alkyl ethers, polyoxyethylene stearates, polyethylene glycols (PEG), poloxamers, poloxamines, sarcosine based surfactants, polysorbates, aliphatic alcohols, alkyl and aryl sulfates, alkyl and aryl polyether sulfonates and other sulfate surfactants, trimethyl ammonium based surfactants, lecithin and other phospholipids, bile salts, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, Sorbitan fatty acid esters, Sucrose fatty acid esters, alkyl glucopyranosides, alkyl maltopyranosides, glycerol fatty acid esters, Alkyl Benzene Sulphonic Acids, Alkyl Ether Carboxylic Acids, Alkyl and aryl Phosphate esters, Alkyl and aryl Sulphate esters, Alkyl and aryl Sulphonic acids, Alkyl Phenol Phosphates esters, Alkyl Phenol Sulphates esters, Alkyl and Aryl Phosphates, Alkyl Polysaccharides, Alkylamine Ethoxylates, Alkyl-Naphthalene Sulphonates formaldehyde condensates, Sulfosuccinates, lignosulfonates, Ceto-Oleyl Alcohol Ethoxylates, Condensed Naphthalene Sulphonates, Dialkyl and Alkyl Naphthalene Sulphonates, Di-alkyl Sulphosuccinates, Ethoxylated nonylphenols, Ethylene Glycol Esters, Fatty Alcohol Alkoxylates, Hydrogenated tallowalkylamines, Mono-alkyl Sulphosuccinamates, Nonyl Phenol Ethoxylates, Sodium Oleyl N-methyl Taurate, Tallowalkylamines, linear and branched dodecylbenzene sulfonic acids Preferably, the surfactant is selected from the group consisting of: sodium lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate, sodium cetostearyl sulfate, sodium docusate, sodium deoxycholate, N-lauroylsarcosine sodium salt, glyceryl monostearate, glycerol distearate glyceryl palmitostearate, glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzalkonium chloride, CTAB, CTAC, Cetrimide, cetylpyridinium chloride, cetylpyridinium bromide, benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188, poloxamer 407, poloxamer 338, polyoxyl 2 stearyl ether, polyoxyl 100 stearyl ether, polyoxyl 20 stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 20 cetyl ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl 35 castor oil, polyoxyl 40 castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor oil, polyoxyl 200 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyoxyl 100 hydrogenated castor oil, polyoxyl 200 hydrogenated castor oil, cetostearyl alcohol, macrogel 15 hydroxystearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, Sucrose Palmitate, Sucrose Stearate, Sucrose Distearate, Sucrose laurate, Glycocholic acid, sodium Glycholate, Cholic Acid, Sodium Cholate, Sodium Deoxycholate, Deoxycholic acid, Sodium taurocholate, taurocholic acid, Sodium taurodeoxycholate, taurodeoxycholic acid, soy lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonate condensate/Lignosulfonate blend, Calcium Dodecylbenzene Sulfonate, Sodium Dodecylbenzene Sulfonate, Diisopropyl naphthalenesulphonate, erythritol distearate, Naphthalene Sulfonate Formaldehyde Condensate, nonylphenol ethoxylate (poe-30), Tristyrylphenol Ethoxylate, Polyoxyethylene (15) tallowalkylamines, sodium alkyl naphthalene sulfonate, sodium alkyl naphthalene sulfonate condensate, sodium alkylbenzene sulfonate, sodium isopropyl naphthalene sulfonate, Sodium Methyl Naphthalene Formaldehyde Sulfonate, sodium n-butyl naphthalene sulfonate, tridecyl alcohol ethoxylate (poe-18), Triethanolamine isodecanol phosphate ester, Triethanolamine tristyrylphosphate ester, Tristyrylphenol Ethoxylate Sulfate, Bis(2-hydroxyethyl)tallowalkylamines.","Preferably the polymer is selected from the list of: polyvinylpyrrolidones (PVP), polyvinylalcohol, Acrylic acid based polymers and copolymers of acrylic acid.","Preferably, the milling aid has a concentration selected from the group consisting of: 0.1-10 w/w, 0.1-5% w/w, 0.1-2.5% w/w, of 0.1-2% w/w, 0.1-1%, 0.5-5% w/w, 0.5-3% w/w, 0.5-2% w/w, 0.5-1.5%, 0.5-1% w/w, of 0.75-1.25% w/w, 0.75-1% and 1% w/w.","Preferably the biologically active ingredient is milled with lactose monohydrate; mannitol; glucose; microcrystalline cellulose; tartaric acid; or lactose monohydrate and sodium dodecyl sulfate.","Preferably, Diclofenac is milled with lactose mono-hydrate.","Preferably, Meloxicam is milled with mannitol.","Preferably, Diclofenac is milled with mannitol.","Preferably, Meloxicam is milled with glucose.","Preferably, Diclofenac is milled with glucose.","Preferably, Meloxicam is milled with microcrystalline cellulose.","Preferably, diclofenac in microcrystalline cellulose.","Preferably, Meloxicam is milled with Tartaric acid.","Preferably, Meloxicam is milled with lactose monohydrate.","Preferably, Meloxicam is milled with mannitol.","Preferably, Diclofenac is milled with lactose mono-hydrate and sodium dodecyl sulfate.","Preferably, Meloxicam is milled with lactose monohydrate and sodium dodecyl sulfate.","In another preferred embodiment, a facilitating agent or combination of facilitating agents is used.","Preferably, the facilitating agent is selected from the group consisting of: surface stabilizers, binding agents, filling agents, lubricating agents, sweeteners, flavouring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents, agents that may form part of a medicament, including a solid dosage form and other excipient required for specific drug delivery.","Preferably, the facilitating agent is added during dry milling.","Preferably, the facilitating agent is added to the milled biologically active material and grinding matrix and further processed in a mechanofusion process.","Mechanofusion milling causes mechanical energy to be applied to powders or mixtures of particles in the micrometre and nanometre.","The reasons for including facilitating agents include, but are not limited to providing better dispersibility, control of agglomeration, the release or retention of the active particles from the delivery matrix.","Examples of facilitating agents include, but are not limited to stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, sodium stearyl lactylate, zinc stearate, sodium stearate or lithium stearate, other solid state fatty acids such as oleic acid, lauric acid, palmitic acid, erucic acid, behenic acid, or derivatives (such as esters and salts), amino acids such as leucine, isoleucine, lysine, valine, methionine, phenylalanine, aspartame or acesulfame K. In a preferred aspect of manufacturing this formulation the facilitating agent is added to the milled mixture of biologically active material and co-grinding matrix and further processed in another milling device such as Mechanofusion, Cyclomixing, or impact milling such as ball milling, jet milling, or milling using a high pressure homogeniser, or combinations thereof.","In a highly preferred aspect the facilitating agent is added to the milling of the mixture of biologically active material and co-grinding matrix as some time before the end of the milling process.","Preferably, the facilitating agent is added to the dry milling at a time selected from the group consisting of: with 1-5% of the total milling time remaining, with 1-10% of the total milling time remaining, with 1-20% of the total milling time remaining, with 1-30% of the total milling time remaining, with 2-5% of the total milling time remaining, with 2-10% of the total milling time remaining, with 5-20% of the total milling time remaining and with 5-20% of the total milling time remaining.","In another preferred embodiment, a disintegrant is selected from the group consisting of: crosslinked PVP, cross linked carmellose and sodium starch glycolate.","In another preferred embodiment, the dissolution profile of the measurement sample or prototype formulation thereof is improved by a factor selected from the group consisting of: wherein X is reached in 10 minutes, wherein X is reached within 10-20 minutes, wherein X is reached within 10-30 mins, wherein X is reached within 10-40 mins, wherein X is reached within 10-50 mins, wherein X is reached within 20-30 mins, wherein X is reached within 20-40 mins, wherein X is reached within 20-50 mins, wherein X is reached within 30-40 mins, wherein X is reached within 30-50 mins and wherein X is reached within 40-50 mins, wherein X is defined as the concentration equal to the dissolution concentration achieved by a control sample or prototype formulation thereof of the biologically active material or compound after 60 minutes.","In another preferred embodiment, the dissolution profile of the measurement sample or prototype formulation thereof is improved by a factor selected from the group consisting of: wherein Y is reached in 5 minutes, wherein Y is reached within 10 minutes, wherein Y is reached within 10-15 mins, wherein Y is reached within 10-20 mins, wherein Y is reached within 10-25 mins, wherein Y is reached within 15-20 mins, wherein Y is reached within 15-25 mins, wherein Y is reached within 20-25 mins, wherein Y is defined as the concentration equal to the dissolution concentration achieved by a control sample (or prototype formulation thereof) of the biologically active material or compound after 30 minutes.","In a second aspect the invention comprises a biologically active material produced by the method described herein and composition comprising the biologically active material as described herein.","Preferably, the particles have an average particle size equal or greater than 1 μm determined on a particle number average basis.","Preferably, the average particle size of the biologically active material has been reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.","Preferably, the average particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-20 μm, 1-10 μm, 1-7.5 μm, 1-5 μm and 1-2 μm.","Preferably, the particles have a median particle size selected from the group consisting of: equal or greater than 1 μm; and equal or greater than 2 μm, wherein the median particle size is determined on a particle volume basis.","Preferably, the percentage of particles with an average particle size greater than 1 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.","Preferably, the percentage of particles with an average particle size greater than 2 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.","Preferably, the median particle size has been reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.","Preferably, the median particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-20 μm, 1-10 μm, 1-7.5 μm, 1-5 μm 1-2 μm, 2-1000 μm, 2-500 μm, 2-300 μm, 2-200 μm, 2-150 μm, 2-100 μm, 2-50 μm, 2-20 μm, 2-10 μm, 2-7.5 μm and 2-5 μm.","Preferably, the crystallinity profile of the biologically active material is selected from the group consisting of: at least 50% of the biologically active material is crystalline, at least 60% of the biologically active material is crystalline, at least 70% of the biologically active material is crystalline, at least 75% of the biologically active material is crystalline, at least 85% of the biologically active material is crystalline, at least 90% of the biologically active material is crystalline, at least 95% of the biologically active material is crystalline and at least 98% of the biologically active material is crystalline.","Preferably, the crystallinity profile of the biologically active material is substantially equal to the crystallinity profile of the biologically active material before the material was subject to the method described herein.","Preferably, the amorphous content of the biologically active material is selected from the group consisting of: less than 50% of the biologically active material is amorphous, less than 40% of the biologically active material is amorphous, less than 30% of the biologically active material is amorphous, less than 25% of the biologically active material is amorphous, less than 15% of the biologically active material is amorphous, less than 10% of the biologically active material is amorphous, less than 5% of the biologically active material is amorphous and less than 2% of the biologically active material is amorphous.","Preferably, the biologically active material has had no significant increase in amorphous content following subjecting the material to the method as described herein.","Preferably, the biologically active material is selected from the group consisting of: fungicides, pesticides, herbicides, nutraceuticals, pharmaceutical actives, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids and analogs, homologs and first order derivatives thereof.","Preferably, the biologically active material is selected from the group consisting of: anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, such as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives (hypnotics and neuroleptics), astringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (anti-parkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones (including steroids), anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines.","Preferably, the biologically active material is selected from the group consisting of: indomethacin, diclofenac, naproxen, meloxicam, metaxalone, cyclosporin A, progesterone celecoxib, cilostazol, ciprofloxacin, 2,4-dichlorophenoxyacetic acid, anthraquinone, creatine monohydrate, glyphosate, halusulfuron, mancozeb, metsulfuron, salbutamol, sulphur, tribenuran and estradiol or any salt or derivative thereof.","In one preferred embodiment, the invention comprises compositions comprising the biologically active ingredient together with a grinding matrix, a mixture of grinding matrix materials, milling aids, mixtures of milling aids, facilitating agents and/or mixtures of facilitating agents as described herein, in concentrations and ratios as described herein under the methods of the invention.","In a third aspect the invention comprises a pharmaceutical composition comprising a biologically active material produced by the method described herein and compositions described herein.","Preferably, the invention comprises pharmaceutical compositions comprising the biologically active ingredient together with a grinding matrix, a mixture of grinding matrix materials, milling aids, mixtures of milling aids, facilitating agents and/or mixtures of facilitating agents as described herein, in concentrations and ratios as described herein under the methods of the invention.","Preferably, the particles have an average particle size equal or greater than 1 μm determined on a particle number basis.","Preferably, the average particle size of the biologically active material has been reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.","Preferably, the average particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-μm, 1-10 μm, 1-7.5 μm, 1-5 μm and 1-2 μm.","Preferably, the particles have a median particle size selected from the group consisting of: equal or greater than 1 μm; and equal or greater than 2 μm, wherein the median particle size is determined on a particle volume basis.","Preferably, the percentage of particles with an average particle size greater than 1 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.","Preferably, the percentage of particles with an average particle size greater than 2 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.","Preferably, the median particle size has been reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.","Preferably, the median particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-20 μm, 1-10 μm, 1-7.5 μm, 1-5 μm 1-2 μm, 2-1000 μm, 2-500 μm, 2-300 μm, 2-200 μm, 2-150 μm, 2-100 μm, 2-50 μm, 2-20 μm, 2-10 μm, 2-7.5 μm and 2-5 μm.","Preferably, the crystallinity profile of the biologically active material is selected from the group consisting of: at least 50% of the biologically active material is crystalline, at least 60% of the biologically active material is crystalline, at least 70% of the biologically active material is crystalline, at least 75% of the biologically active material is crystalline, at least 85% of the biologically active material is crystalline, at least 90% of the biologically active material is crystalline, at least 95% of the biologically active material is crystalline and at least 98% of the biologically active material is crystalline.","Preferably, the crystallinity profile of the biologically active material is substantially equal to the crystallinity profile of the biologically active material before the material was subject to the method as described herein.","Preferably, the amorphous content of the biologically active material is selected from the group consisting of: less than 50% of the biologically active material is amorphous, less than 40% of the biologically active material is amorphous, less than 30% of the biologically active material is amorphous, less than 25% of the biologically active material is amorphous, less than 15% of the biologically active material is amorphous, less than 10% of the biologically active material is amorphous, less than 5% of the biologically active material is amorphous and less than 2% of the biologically active material is amorphous.","Preferably, the biologically active material has no significant increase in amorphous content after subjecting the material to the method as described herein.","Preferably, the biologically active material is selected from the group consisting of: new chemical entities, pharmaceutical actives, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids and analogs, homologs and first order derivatives thereof.","Preferably, the biologically active material is selected from the group consisting of: anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, such as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives (hypnotics and neuroleptics), astringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (anti-parkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones (including steroids), anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines.","Preferably, the biologically active material is selected from the group consisting of: indomethacin, diclofenac, naproxen, meloxicam, metaxalone, cyclosporin A, progesterone celecoxib, cilostazol, ciprofloxacin, 2,4-dichlorophenoxyacetic acid, anthraquinone, creatine monohydrate, glyphosate, halusulfuron, mancozeb, metsulfuron, salbutamol, sulphur, tribenuran and estradiol or any salt or derivative thereof.","Preferably cosmeceuticals, cosmetics, complementary medicines, natural products, vitamins, nutrients and nutraceuticals are selected from the group consisting of: Glycolic acids, Lactic acids, Carrageenan, Almonds, Mahogany wood, Andrographis Paniculata, Aniseed, Anthemis nobilis (chamomile), Apricot kernel, leaves of bearberry, leaves of cranberry, leaves of blueberry, leaves of pear trees, beta-carotene, black elderberry, black raspberry, black walnut shell, blackberry, bladderwrack, bletilla striata, borage seed, boysenberry, brazil nut, burdock root, butcher's broom extract, calamine, calcium gluconate, calendula, carnosic acid, Cantella asiatica, charcoal, chaste tree fruit, Chicory root extract, chitosan, choline, cichorium intybus, clematis vitalba, coffea Arabica, coumarin, crithmum maritimum, curcumin, coffee, cocoa, cocoa powder, cocoa nibs, cocoa mass, cocoa liquor, cocoa products, dogwood, Echinacea, echium lycopsis, anise, atragalus, bilberry, bitter orange, black cohosh, cat's claw, chamomile, chasteberry, cranberry, dandelion, Echinacea, ephedra, European elder Epilobium angustifolium, horse chestnut, cloves, evening primrose, fennel seed, fenugreek, feverfew, flaxseed, fumaria officinalis, garlic, geranium, ginger, ginkgo, ginseng, goldenseal, grape seed, green tea, guava, hawthorn, hayflower, hazelnut, helichrysum, hoodia, horseradish, mulbe italicum, hibiscus, hierochloe odorata, hops, horse chestnut, ilex paraguariensis, indian gooseberry, irish moss, juniper berry, kudzu root, lady's thistle, lavender, lemongrass, lentius edodes, licorice, longifolene, loquat, lotus seed, luffa cylindrica, lupine, maroinberry, marjoram, meadowsweet, milk vetch root, mimosa tenuiflora, mistletoe, mulberry, noni, kelp, oatmeal, oregano, papaya, parsley, peony root, pomegranate, pongamia glabra seed, pongamia pinnata, quinoa seed, red raspberry, rose hip, rosemary, sage, saw palmetto, soy bean, szechuan peppercorn, tephrosia purpurea, terminalia catappa, terminalia sericea, thunder god vine, thyme, turmeric, valeriana officinalis, walnuts, white tea leaf, yam, witch hazel, wormwood, yarrow, valerian, yohimbe, mangosteen, sour sob, goji berry, spirulina and durian skin.","In a fourth aspect the invention comprises a method of treating a human in need of such treatment comprising the step of administering to the human an effective amount of a pharmaceutical composition as described herein.","In a fifth aspect the invention comprises a method for manufacturing a pharmaceutical composition as described herein comprising the step of combining a therapeutically effective amount of a biologically active material prepared by a method described herein together with a pharmaceutically acceptable carrier to produce a pharmaceutically acceptable dosage form.","In a sixth aspect the invention comprises a method for manufacturing a veterinary product comprising the step of combining a therapeutically effective amount of the biologically active material prepared by a method as described herein together with an acceptable excipient to produce a dosage form acceptable for veterinary use.","In a seventh aspect the invention comprises a method for manufacturing an agricultural product comprising the step of combining an effective amount of the biologically active material prepared by a method described herein together with acceptable excipients to produce a formulation such as, but not limited to a water dispersible granule, wettable granule, dry flowable granule or soluble granule that is used to prepare a solution for use in agricultural applications.","Preferably, the product is selected from the group consisting of: herbicides, pesticides, seed treatments, herbicide safeners, plant growth regulators and fungicides.","The methods of the invention can be used to increase the dissolution of the biologically active material particles in water or other solvents, resulting in better, faster or more complete preparation and mixing.","This will result in a more consistent product performance such as better weed, disease and pest control and other practical benefits such as faster machinery, tank and sprayer cleanout, less rinsate, and a reduced impact on the environment.","In a future aspect the invention comprises a method for manufacturing an agricultural product comprising the step of combining an effective amount of the biologically active material prepared by a method described herein together with acceptable excipients to produce a formulation such as, but not limited to a water dispersible granule, wettable granule, wettable powder or a powder for seed treatment that is used to prepare a dry powder or particle suspension for use in agricultural applications.","Preferably, the product is selected from the group consisting of: herbicides, pesticides, seed treatments, herbicide safeners, plant growth regulators and fungicides.","Another preferred aspect of the method of invention would be to produce powders that have active particles with a high surface area.","Such powders would provide better performance in areas such as seed treatment where dry powders are applied to seeds as fungicides, herbicide safeners, plant growth regulators and other treatments.","The higher surface area would provide more activity per mass of active used.","In another preferred aspect actives such as pesticides, fungicides and seed treatments subject to the method of invention are formulated to produce suspensions of the actives when added to water or other solvents.","As these suspensions will have particles of very small size and high surface area they will possess at least three highly desirable traits.","The first is that small particles with high surface area will adhere better to surfaces such as leafs and other foliage that the suspension is applied to.","This will result in better rain fastness and a longer period of activity.","The second aspect is that smaller particles with a higher surface area deliver superior coverage per unit mass of active applied.","For example, if 100 particles are needed on a leaf and if the particle diameter is reduced to one third of the former diameter by the methods of this invention, then the dosage can be reduced to about 11% of the former dosage, resulting in lower cost, less residue on harvested crops, and mitigation of environmental impact.","In the third aspect the smaller particles will deliver better bioavailability.","With many low solubility actives, such as fungicides and pesticides the particles that adhere to plant material slowly dissolve over days and weeks providing continued protection from disease and pests.","With this method of invention able to deliver better bioavailability in many circumstances it will be possible to reduce the amount of active that needs to be applied.","As with the second aspect such an outcome would lower costs, minimize residues and mitigate environmental impact.","In a highly preferred aspect of the invention the powder produced in the milling process would be subject to a process such as wet or dry granulation that makes the powder free flowing and low in dust content yet easily dispersible once in water or other solvent.","Preferably the biologically active material is a herbicide, pesticide, seed treatment, herbicide safener, plant growth regulator or fungicide selected from the group consisting of: 2-phenylphenol, 8-hydroxyquinoline sulfate, acibenzolar, allyl alcohol, azoxystrobin, basic benomyl, benzalkonium chloride, biphenyl, blasticidin-S, Bordeaux mixture, Boscalid, Burgundy mixture, butylamine, Cadendazim, calcium polysulfide, Captan, carbamate fungicides, carbendazim, carvone, chloropicrin, chlorothalonil, ciclopirox, clotrimazole, conazole fungicides, Copper hydroxide, copper oxychloride, copper sulfate, copper(II) carbonate, copper(II) sulfate, cresol, cryprodinil, cuprous oxide, cycloheximide, Cymoxanil, DBCP, dehydroacetic acid, dicarboximide fungicides, difenoconazole, dimethomorph, diphenylamine, disulfiram, ethoxyquin, famoxadone, fenamidone, Fludioxonil, formaldehyde, fosetyl, Fosetyl-aluminium, furfural, griseofulvin, hexachlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole, imazalil, Imidacloprid, iodomethane, Iprodione, Lime sulfur, mancozeb, mercuric chloride, mercuric oxide, mercurous chloride, Metalaxyl, metam, methyl bromide, methyl isothiocyanate, metiram, natamycin, nystatin, organotin fungicides, oxythioquinox, pencycuron, pentachlorophenol, phenylmercury acetate, potassium thiocyanate, procymidone, propiconazole, propineb, pyraclostrobin, pyrazole fungicides, pyridine fungicides, pyrimethanil, pyrimidine fungicides, pyrrole fungicides, quinoline fungicides, quinone fungicides, sodium azide, streptomycin, sulfur, Tebucanazole, thiabendazole, thiomersal, tolnaftate, Tolylfluanid, triadimersol, tributyltin oxide, Trifloxystrobin, triflumuron, Undecylenic acid, urea fungicides, vinclozolin, Ziram, 3-dihydro-3-methyl-1, 3-thiazol-2-ylidene-xylidene, 4-D esters, 4-DB esters, 4-parathion methyl, Acetamiprid, aclonifen, acrinathrin, alachlor, allethrin, alpha-cypermethrin, Aluminium phosphide, amitraz, anilophos, azaconazole, azinphos-ethyl, azinphos-methyl, benalaxyl, benfluralin, benfuracarb, benfuresate, bensulide, benzoximate, benzoylprop-ethyl, betacyfluthrin, beta-cypermethrin, bifenox, bifenthrin, binapacryl, bioallethrin, bioallethrin S, bioresmethrin, biteranol, Brodifacoum, bromophos, bromopropylate, bromoxynil, bromoxynil esters, bupirimate, buprofezin, butacarboxim, butachlor, butamifos, butoxycarboxin, butralin, butylate, calcium sulfate, cambda-cyhalothrin, carbetamide, carboxin, chlordimeform, chlorfenvinphos, chlorflurazuron, chlormephos, chlornitrofen, chlorobenzilate, chlorophoxim, chloropropylate, chlorpropham, Chlorpyrifos, chlorpyrifos-methyl, cinmethylin, clethodim, clomazone, clopyralid esters, CMPP esters, cyanophos, cycloate, cycloprothrin, cycloxydim, cyfluthrin, cyhalothrin, cypermethrin, cyphenothrin, cyproconazole, deltamethrin, demeton-S-methyl, desmedipham, dichlorprop esters, dichlorvos, diclofop-methyldiethatyl, dicofol, difenoconazole, dimethachlor, dimethomoph, diniconazole, dinitramine, dinobuton, dioxabenzafos, dioxacarb, disulfoton, ditalimfos, dodemorph, dodine, edifenphos, emamectin, empenthrin, endosulfan, EPNethiofencarb, epoxyconazole, esfenvalerate, ethalfluralin, ethofumesate, ethoprophos, ethoxyethyl, etofenprox, etridiazole, etrimphos, Famoxadone, fenamiphos, fenarimol, fenazaquin, fenitrothion, fenobucarb, fenoxapropethyl, fenoxycarb, fenpropathrin, fenpropidin, fenpropimorph, fenthiocarb, fenthion, fenvalerate, fluazifop, fluazifop-P, fluchloralin, flucythrinate, flufenoxim, flufenoxuron, flumetralin, fluorodifen, fluoroglycofen ethyl, fluoroxypyr esters, flurecol butyl, flurochloralin, flusilazole, formothion, gamma-HCH, haloxyfop, haloxyfop-methyl, hexaflumuron, hydroprene, imibenconazole, indoxacarb, ioxynil esters, isofenphos, isoprocarb, isopropalin, isoxathion, malathion, maneb, MCPA esters, mecoprop-P esters, mephospholan, Metaldehyde, methidathion, Methomyl, methoprene, methoxychlor, metolachlor, mevinphos, monalide, myclobutanil, N-2, napropamide, nitrofen, nuarimol, oxadiazon, oxycarboxin, oxyfluorfen, penconazole, pendimethalin, permethrin, phenisopham, phenmedipham, phenothrin, phenthoate, phosalone, phosfolan, phosmet, picloram esters, pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, pretilachlor, prochloraz, profenofos, profluralin, promecarb, propachlor, propanil, propaphos, propaquizafop, propargite, propetamphos, pymetrozine, pyrachlofos, pyridate, pyrifenox, quinalphos, quizalofop-P, resmethrin, Spinetoram J, Spinetoram L, Spinosad A, Spinosad B, tau-fluvalinate, tebuconazole, Tebufenozide, tefluthrin, temephos, terbufos, tetrachlorinphos, tetraconazole, tetradifon, tetramethrin, Thiamethoxam, tolclofos-methyl, tralomethrin, triadimefon, triadimenol, triazophos, triclopyr esters, tridemorph, tridiphane, triflumizole, trifluralin, xylylcarb, 3-dihydro-3-methyl-1, 3-thiazol-2-ylidene-xylidene, 4-D esters, 4-DB esters, 4-parathion methyl, Acetamiprid, acetochlor, aclonifen, acrinathrin, alachlor, allethrin, alpha-cypermethrin, Aluminium phosphide, amitraz, anilophos, azaconazole, azinphos-ethyl, azinphos-methyl, benalaxyl, benfluralin, benfuracarb, benfuresate, bensulide, benzoximate, benzoylprop-ethyl, betacyfluthrin, beta-cypermethrin, bifenox, bifenthrin, binapacryl, bioallethrin, bioallethrin S, bioresmethrin, biteranol, Brodifacoum, bromophos, bromopropylate, bromoxynil, bromoxpil esters, bupirimate, buprofezin, Butacarboxim, butachlor, butamifos, butoxycarboxin, butralin, butylate, calcium sulfate, cambda-cyhalothrin, carbetamide, carboxin, chlordimeform, chlorfenvinphos, chlorflurazuron, chlormephos, chlornitrofen, chlorobenzilate, chlorophoxim, chloropropylate, chlorpropham, Chlorpyrifos, chlorpyrifos-methyl, cinmethylin, clethodim, clomazone, clopyralid esters, CMPP esters, cyanophos, cycloate, cycloprothrin, cycloxydim, cyfluthrin, cyhalothrin, cypermethrin, cyphenothrin, cyproconazole, deltamethrin, demeton-S-methyl, desmedipham, dichlorprop esters, dichlorvos, diclofop-methyldiethatyl, dicofol, dimethachlor, dimethomoph, diniconazole, dinitramine, dinobuton, dioxabenzafos, dioxacarb, disulfoton, ditalimfos, dodemorph, dodine, edifenphos, emamectin, empenthrin, endosulfan, EPNethiofencarb, epoxyconazole, esfenvalerate, ethalfluralin, ethofumesate, ethoprophos, ethoxyethyl, ethoxyquin, etofenprox, etridiazole, etrimphos, fenamiphos, fenarimol, fenazaquin, fenitrothion, fenobucarb, fenoxapropethyl, fenoxycarb, fenpropathrin, fenpropidin, fenpropimorph, fenthiocarb, fenthion, fenvalerate, fluazifop, fluazifop-P, fluchloralin, flucythrinate, flufenoxim, flufenoxuron, flumetralin, fluorodifen, fluoroglycofen ethyl, fluoroxypyr esters, flurecol butyl, flurochloralin, flusilazole, formothion, gamma-HCH, haloxyfop, haloxyfop-methyl, hexaflumuron, hydroprene, imibenconazole, indoxacarb, ioxynil esters, isofenphos, isoprocarb, isopropalin, isoxathion, malathion, maneb, MCPA esters, mecoprop-P esters, mephospholan, Metaldehyde, methidathion, Methomyl, methoprene, methoxychlor, mevinphos, monalide, myclobutanil, myclobutanil, N-2, napropamide, nitrofen, nuarimol, oxadiazon, oxycarboxin, oxyfluorfen, penconazole, permethrin, phenisopham, phenmedipham, phenothrin, phenthoate, phosalone, phosfolan, phosmet, picloram esters, pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, pretilachlor, prochloraz, profenofos, profluralin, promecarb, propachlor, propanil, propaphos, propaquizafop, propargite, propetamphos, pymetrozine, pyridate, pyrifenox, quinalphos, quizalofop-P, resmethrin, Spinetoram J, Spinetoram L, Spinosad A, Spinosad B, tau-fluvalinate, Tebufenozide, tefluthrin, temephos, terbufos, tetrachlorinphos, tetraconazole, tetradifon, tetramethrin, Thiamethoxam, tolclofos-methyl, tralomethrin, triadimenol, triazophos, triclopyr esters, tridemorph, tridiphane, triflumizole, trifluralin, xylylcarb and any combination thereof.","In an eighth aspect the invention comprises a method for manufacturing of a pharmaceutical formulation comprising the step of combining an effective amount of the biologically active material prepared by a method described herein together with acceptable excipients to produce a formulation that can deliver a therapeutically effective amount of active to the pulmonary or nasal area.","Such a formulation could be, but is not limited to a dry powder formulation for oral inhalation to the lungs or a formulation for nasal inhalation.","Preferably the method for manufacturing such a formulation uses lactose, mannitol, sucrose, sorbitol, xylitol or other sugars or polyols as the co-grinding matrix together with surfactant such as, but not limited to lecithin, DPPC (dipalmitoyl phosphatidylcholine), PG (phosphatidylglycerol), dipalmitoyl phosphatidyl ethanolamine (DPPE), dipalmitoyl phosphatidylinositol (DPPI) or other phospholipid.","The particle size of the material produced by the invention disclosed herein results in the materials being readily aerosolized and suitable for methods of delivery to a subject in need thereof, including pulmonary and nasal delivery methods.","While the method of the present invention has particular application in the preparation of poorly water-soluble biologically active materials, the scope of the invention is not limited thereto.","For example, the method of the present invention enables production of highly water-soluble biologically active materials.","Such materials may exhibit advantages over conventional materials by way of, for example, more rapid therapeutic action or lower dose.","In contrast, wet grinding techniques utilizing water (or other comparably polar solvents) are incapable of being applied to such materials, as the particles dissolve appreciably in the solvent.","Other aspects and advantages of the invention will become apparent to those skilled in the art from a review of the ensuing description.","BRIEF DESCRIPTION OF THE DRAWINGS FIG.","1 shows the particle size distribution of Meloxicam milled in Lactose for 1 minute (B) or 2 minutes (C), respectively, compared to the particle size distribution of commercially available Meloxicam (A).","FIG.","2 shows the dissolution of Meloxicam milled in Lactose for 1 minute (B) or 2 minutes (C), respectively, compared to the dissolution of commercially available Meloxicam (A).","FIG.","3 shows the particle size distribution of Diclofenac milled in Lactose for 1 minute (B) or 2 minutes (C), respectively, compared to the particle size distribution of commercially obtained Diclofenac (A).","FIG.","4 shows the dissolution of Diclofenac milled in Lactose for 1 minute (B) or 2 minutes (C), respectively, compared to the dissolution of commercially available Diclofenac (A).","FIG.","5 shows the Differential Scanning calorimetry (DSC) traces of mannitol, 10% meloxicam milled in mannitol for 2 minutes (example 3) and 20% meloxicam milled in mannitol for 2 minutes (example 11).","FIG.","6 shows the XRD spectra of Meloxicam (A), milled lactose monohydrate (B), Meloxicam milled in Lactose at 20% for 2 minutes (example 10) (C) and Meloxicam milled in Lactose with 1% SDS at 50% for 10 minutes (example 17) (D).","FIG.","7 shows the XRD spectra of Meloxicam (A), mannitol (B), a physical mixture of 20 Meloxicam in Lactose (C) and Meloxicam milled in mannitol at 20% for 2 minutes (example 11) (D).","FIG.","8 shows the XRD spectra of Diclofenac milled in Lactose with 1% SDS at 20% for 10 minutes (A), Diclofenac milled in Lactose with 1% SDS at 30% for 10 minutes (example 12) (B), Diclofenac milled in Lactose with 1% SDS at 40% for 10 minutes (example 13) (C) and Diclofenac milled in Lactose with 1% SDS at 50% for 10 minutes (example 14) (D).","FIG.","9 shows the XRD spectra of a physical mixture of 20% Diclofenac in Lactose with 1% SDS (A), 30% Diclofenac in Lactose with 1% SDS (B), 40% Diclofenac in Lactose with 1% SDS (C) and 50% Diclofenac in Lactose with 1% SDS (D).","FIG.","10 shows the XRD spectra of a Diclofenac acid (A), Lactose monohydrate (B) and milled Lactose monohydrate (C).","FIG.","11 shows the XRD spectra of a Meloxicam (A), a physical mixture of 50% Meloxicam in Lactose with 1% SDS (B) and milled Lactose monohydrate (C).","DETAILED DESCRIPTION OF THE INVENTION General Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described.","It is to be understood that the invention includes all such variations and modifications.","The invention also includes all of the steps, features, compositions and materials referred to or indicated in the specification, individually or collectively and any and all combinations or any two or more of the steps or features.","The present invention is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only.","Functionally equivalent products, compositions and methods are clearly within the scope of the invention as described herein.","The invention described herein may include one or more ranges of values (e.g.","size, concentration etc).","A range of values will be understood to include all values within the range, including the values defining the range, and values adjacent to the range that lead to the same or substantially the same outcome as the values immediately adjacent to that value which defines the boundary to the range.","The entire disclosures of all publications (including patents, patent applications, journal articles, laboratory manuals, books, or other documents) cited herein are hereby incorporated by reference.","Inclusion does not constitute an admission is made that any of the references constitute prior art or are part of the common general knowledge of those working in the field to which this invention relates.","Throughout this specification, unless the context requires otherwise, the word “comprise” or variations, such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer, or group of integers, but not the exclusion of any other integers or group of integers.","It is also noted that in this disclosure, and particularly in the claims and/or paragraphs, terms such as “comprises”, “comprised”, “comprising” and the like can have the meaning attributed to it in US patent law; e.g., they can mean “includes”, “included”, “including”, and the like.","“Therapeutically effective amount” as used herein with respect to methods of treatment and in particular drug dosage, shall mean that dosage that provides the specific pharmacological response for which the drug is administered in a significant number of subjects in need of such treatment.","It is emphasized that “therapeutically effective amount,” administered to a particular subject in a particular instance will not always be effective in treating the diseases described herein, even though such dosage is deemed a “therapeutically effective amount” by those skilled in the art.","It is to be further understood that drug dosages are, in particular instances, measured as oral dosages, or with reference to drug levels as measured in blood.","The term “inhibit” is defined to include its generally accepted meaning which includes prohibiting, preventing, restraining, and lowering, stopping, or reversing progression or severity, and such action on a resultant symptom.","As such the present invention includes both medical therapeutic and prophylactic administration, as appropriate.","The term “biologically active material” is defined to mean a biologically active compound or a substance which comprises a biologically active compound.","In this definition, a compound is generally taken to mean a distinct chemical entity where a chemical formula or formulas can be used to describe the substance.","Such compounds would generally, but not necessarily be identified in the literature by a unique classification system such as a CAS number.","Some compounds may be more complex and have a mixed chemical structure.","For such compounds they may only have a empirical formula or be qualitatively identified.","A compound would generally be a pure material, although it would be expected that up to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% of the substance could be other impurities and the like.","Examples of biologically active compounds are, but not limited to, pharmaceutical actives, fungicides, pesticides, herbicides, nutraceuticals, cosmeceuticals, cosmetics, complementary medicines, natural products, vitamins, nutrients, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids.","A substance that contains a biologically active compound is any substance which has as one of its components a biologically active compound .",".",".",".","Examples of substances containing biologically active compounds are, but not limited to, pharmaceutical formulations and products, cosmetic formulations and products, industrial formulations and products, agricultural formulations and products, foods, seeds, cocoa and cocoa solids, coffee, herbs, spices, other plant materials, minerals, animal products, shells and other skeletal material.","Any of the terms, “biological(ly) active”, “active”, “active material” shall have the same meaning as biologically active material.","The term “grinding matrix” is defined as any inert substance that a biologically active material can or is combined with and milled.","The terms “co-grinding matrix” and “matrix” are interchangeable with “grinding matrix”.","Particle Size There are a wide range of techniques that can be utilized to characterize the particle size of a material.","Those skilled in the art also understand that almost all these techniques do not physically measure the actually particle size, as one might measure something with a ruler, but measure a physical phenomena which is interpreted to indicate a particle size.","As part of the interpretation process some assumptions need to be made to enable mathematical calculations to be made.","These assumptions deliver results such as an equivalent spherical particle size, or a hydrodynamic radius.","Amongst these various methods, two types of measurements are most commonly used.","Photon correlation spectroscopy (PCS), also known as ‘dynamic light scattering’ (DLS) is commonly used to measure particles with a size less than 10 micron.","Typically this measurement yields an equivalent hydrodynamic radius often expressed as the average size of a number distribution.","The other common particle size measurement is laser diffraction which is commonly used to measure particle size from 100 nm to 2000 micron.","This technique calculates a volume distribution of equivalent spherical particles that can be expressed using descriptors such as the median particle size or the % of particles under a given size.","Those skilled in the art recognize that different characterization techniques such as photon correlation spectroscopy and laser diffraction measure different properties of a particle ensemble.","As a result multiple techniques will give multiple answers to the question, “what is the particle size.” In theory one could convert and compare the various parameters each technique measures, however, for real world particle systems this is not practical.","As a result the particle size used to describe this invention will be given as two different sets of values that each relate to these two common measurement techniques, such that measurements could be made with either technique and then evaluated against the description of this invention.","For measurements made using a photo correlation spectroscopy instrument, or an equivalent method known in the art, the term “number average particle size” is defined as the average particle diameter as determined on a number basis.","For measurements made using a laser diffraction instrument, or an equivalent method known in the art, the term “median particle size” is defined as the median particle diameter as determined on an equivalent spherical particle volume basis.","Where the term median is used, it is understood to describe the particle size that divides the population in half such that 50% of the population is greater than or less than this size.","The median particle size is often written as D50, D(0.50) or D[0.5] or similar.","As used herein D50, D(0.50) or D[0.5] or similar shall be taken to mean ‘median particle size’.","The term “Dx of the particle size distribution” refers to the xth percentile of the distribution; thus, D90 refers to the 90th percentile, D95 refers to the 95th percentile, and so forth.","Taking D90 as an example this can often be written as, D(0.90) or D[0.9] or similar.","With respect to the median particle size and Dx an upper case D or lowercase d are interchangeable and have the same meaning.","Another commonly used way of describing a particle size distribution measured by laser diffraction, or an equivalent method known in the art, is to describe what % of a distribution is under or over a nominated size.","The term “percentage less than” also written as “%<” is defined as the percentage, by volume, of a particle size distribution under a nominated size—for example the %<1000 nm.","The term “percentage greater than” also written as “%>” is defined as the percentage, by volume, of a particle size distribution over a nominated size—for example the %>1000 nm.","The particle size used to describe this invention should be taken to mean the particle size as measured at or shortly before the time of use.","For example, the particle size is measured 2 months after the material is subject to the milling method of this invention.","In a preferred form, the particle size is measured at a time selected from the group consisting of: 1 day after milling, 2 days after milling, 5 days after milling, 1 month after milling, 2 months after milling, 3 months after milling, 4 months after milling, 5 months after milling, 6 months after milling, 1 year after milling, 2 years after milling, 5 years after milling.","For many of the materials subject to the methods of this invention the particle size can be easily measured.","Where the active material has poor water solubility and the matrix it is milled in has good water solubility the powder can simply be dispersed in an aqueous solvent.","In this scenario the matrix dissolves leaving the active material dispersed in the solvent.","This suspension can then be measured by techniques such as PCS or laser diffraction.","Suitable methods to measure an accurate particle size where the active material has substantive aqueous solubility or the matrix has low solubility in a water based dispersant are outlined below.","1.In the circumstance where insoluble matrix such as microcrystalline cellulose prevents the measurement of the active material, separation techniques such as filtration or centrifugation could be used to separate the insoluble matrix from the active material particles.","Other ancillary techniques would also be required to determine if any active material was removed by the separation technique so that this could be taken into account.","2.In the case where the active material is too soluble in water other solvents could be evaluated for the measurement of particle size.","Where a solvent could be found that active material is poorly soluble in but is a good solvent for the matrix a measurement would be relatively straight forward.","If such a solvent is difficult to find another approach would be to measure the ensemble of matrix and active material in a solvent (such as iso-octane) which both are insoluble in.","Then the powder would be measured in another solvent where the active material is soluble but the matrix is not.","Thus with a measurement of the matrix particle size and a measurement of the size of the matrix and active material together an understanding of the active material particle size can be obtained.","3.In some circumstances image analysis could be used to obtain information about the particle size distribution of the active material.","Suitable image measurement techniques might include transmission electron microscopy (TEM), scanning electron microscopy (SEM), optical microscopy and confocal microscopy.","In addition to these standard techniques some additional technique would be required to be used in parallel to differentiate the active material and matrix particles.","Depending on the chemical makeup of the materials involved possible techniques could be elemental analysis, raman spectroscopy, FTIR spectroscopy or fluorescence spectroscopy.","Other Definitions Throughout this specification, unless the context requires otherwise, the phrase “dry mill” or variations, such as “dry milling”, should be understood to refer to milling in at least the substantial absence of liquids.","If liquids are present, they are present in such amounts that the contents of the mill retain the characteristics of a dry powder.","“Flowable” means a powder having physical characteristics rendering it suitable for further processing using typical equipment used for the manufacture of pharmaceutical compositions and formulations.","Other definitions for selected terms used herein may be found within the detailed description of the invention and apply throughout.","Unless otherwise defined, all other scientific and technical terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the invention belongs.","The term “millable” means that the grinding matrix is capable of being physically degraded under the dry milling conditions of the method of the invention.","In one embodiment of the invention, the milled grinding matrix is of a comparable particle size to the biologically active material.","In another embodiment of the invention the particle size of the matrix is substantially reduced but not as small as the biologically active material Other definitions for selected terms used herein may be found within the detailed description of the invention and apply throughout.","Unless otherwise defined, all other scientific and technical terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the invention belongs.","Specific In one embodiment, the present invention is directed to a method for improving the dissolution profile of a biologically active material, the method comprising the step of: dry milling a mixture of a solid biologically active material and a millable grinding matrix, in a mill comprising a plurality of milling bodies, to produce particles of a biologically active material dispersed in at least partially milled grinding matrix.","The mixture of active material and matrix may then be separated from the milling bodies and removed from the mill.","In one aspect the mixture of active material and matrix is then further processed.","In another aspect, the grinding matrix is separated from the particles of biologically active material.","In a further aspect, at least a portion of the milled grinding matrix is separated from the particulate biologically active material.","The milling bodies are essentially resistant to fracture and erosion in the dry milling process.","The quantity of the grinding matrix relative to the quantity of biologically active material in particulate form, and the extent of milling of the grinding matrix, is sufficient to improve the dissolution profile of the active material milled.","The present invention also relates to biologically active materials produced by said methods, to medicaments produced using said biologically active materials and to methods of treatment of an animal, including man, using a therapeutically effective amount of said biologically active materials administered by way of said medicaments.","Improving the Dissolution Profile The present invention leads to the improved dissolution profile.","An improved dissolution profile has significant advantages including the improvement of bioavailability of the biologically active material in vivo.","Preferably, the improved dissolution profile is observed in vitro.","Alternatively, the improved dissolution profile is observed in vivo by the observation of an improved bioavailability profile.","Standard methods for determining the dissolution profile of a material in vitro are available in the art.","A suitable method to determine an improved dissolution profile in vitro may include determining the concentration of the sample material in a solution over a period of time and comparing the results from the sample material to a control sample.","An observation that peak solution concentration for the sample material was achieved in less time than the control sample would indicate (assuming it is statistically significant), that the sample material has an improved dissolution profile.","The measurement sample is herein defined as the mixture of biologically active material with grinding matrix and/or other additives that has been subject to the processes of the invention described here.","Herein a control sample is defined as a physical mixture (not subject to the processes described in this invention) of the components in the measurement sample with the same relative proportions of active, matrix and/or additive as the measurement sample.","For the purposes of the dissolution testing a prototype formulation of the measurement sample could also be used.","In this case the control sample would be formulated in the same way.","Standard methods for determining the improved dissolution profile of a material in vivo are available in the art.","A suitable method to determine an improved dissolution profile in a human may be after delivering the dose to measure the rate of active material absorption by measuring the plasma concentration of the sample compound over a period of time and comparing the results from the sample compound to a control.","An observation that peak plasma concentration for the sample compound was achieved in less time than the control would indicate (assuming it is statistically significant) that the sample compound has improved bioavailability and an improved dissolution profile.","Preferably, the improved dissolution profile is observed at a relevant gastrointestinal pH, when it is observed in vitro.","Preferably, the improved dissolution profile is observed at a pH which is favourable at indicating improvements in dissolution when comparing the measurement sample to the control compound.","Suitable methods for quantifying the concentration of a compound in an in vitro sample or an in vivo sample are widely available in the art.","Suitable methods could include the use of spectroscopy or radioisotope labeling.","In one preferred embodiment the method of quantification of dissolution is determined in a solution with a pH selected from the group consisting of: pH 1, pH 2, pH 3, pH 4, pH 5, pH 6, pH 7, pH 7.3, pH 7.4, pH 8, pH 9, pH 10, pH 11, pH 12, pH 13, pH 14 or a pH with 0.5 of a pH unit of any of this group.","Crystallization Profile Methods for determining the crystallinity profile of the biologically active material are widely available in the art.","Suitable methods may include X-ray diffraction, differential scanning calorimetry, raman or IR spectroscopy.","Amorphicity Profile Methods for determining the amorphous content of the biologically active material are widely available in the art.","Suitable methods may include X-ray diffraction, differential scanning calorimetry, raman or IR spectroscopy.","Grinding Matrix As will be described subsequently, selection of an appropriate grinding matrix affords particular advantageous applications of the method of the present invention.","A highly advantageous application of the method of the invention is the use of a water-soluble grinding matrix in conjunction with a poorly water-soluble biologically active material.","This affords at least two advantages.","The first being when the powder containing the biologically active material is placed into water—such as the ingestion of the powder as part of an oral medication—the matrix dissolves, releasing the particulate active material such that there is maximum surface area exposed to solution, thereby allowing a rapid dissolution of the active compound.","The second key advantage is the ability, if required, to remove or partially remove the matrix prior to further processing or formulation.","Another advantageous application of the method of the invention is the use of a water-insoluble grinding matrix, particularly in the area of agricultural use, when a biologically active material such as a fungicide is commonly delivered as part of a dry powder or a suspension.","The presence of a water insoluble matrix will afford benefits such as increased rain fastness.","Without wishing to be bound by theory, it is believed that the physical degradation (including but not limited to particle size reduction) of the millable grinding matrix affords the advantage of the invention, by acting as a more effective diluent than grinding matrix of a larger particle size.","Again, as will be described subsequently, a highly advantageous aspect of the present invention is that certain grinding matrixes appropriate for use in the method of the invention are also appropriate for use in a medicament.","The present invention encompasses methods for the production of a medicament incorporating both the biologically active material and the grinding matrix or in some cases the biologically active material and a portion of the grinding matrix, medicaments so produced, and methods of treatment of an animal, including man, using a therapeutically effective amount of said biologically active materials by way of said medicaments.","Analogously, as will be described subsequently, a highly advantageous aspect of the present invention is that certain grinding matrixes appropriate for use in the method of the invention are also appropriate for use in a carrier for an agricultural chemical, such as a pesticide, fungicide, or herbicide.","The present invention encompasses methods for the production of an agricultural chemical composition incorporating both the biologically active material in particulate form and the grinding matrix, or in some cases the biologically active material, and a portion of the grinding matrix, and agricultural chemical compositions so produced.","The medicament may include only the biologically active material together with the milled grinding matrix or, more preferably, the biologically active material and milled grinding matrix may be combined with one or more pharmaceutically acceptable carriers, as well as any desired excipients or other like agents commonly used in the preparation of medicaments.","Analogously, the agricultural chemical composition may include only the biologically active material together with the milled grinding matrix or, more preferably, the biologically active materials and milled grinding matrix may be combined with one or more carriers, as well as any desired excipients or other like agents commonly used in the preparation of agricultural chemical compositions.","In one particular form of the invention, the grinding matrix is both appropriate for use in a medicament and readily separable from the biologically active material by methods not dependent on particle size.","Such grinding matrixes are described in the following detailed description of the invention.","Such grinding matrixes are highly advantageous in that they afford significant flexibility in the extent to which the grinding matrix may be incorporated with the biologically active material into a medicament.","In a highly preferred form, the grinding matrix is harder than the biologically active material, and is thus capable of improving the dissolution profile of the active material under the dry milling conditions of the invention.","Again without wishing to be bound by theory, under these circumstances it is believed that the millable grinding matrix affords the advantage of the present invention through a second route, with the smaller particles of grinding matrix produced under the dry milling conditions enabling greater interaction with the biologically active material.","The quantity of the grinding matrix relative to the quantity of biologically active material, and the extent of physical degradation of the grinding matrix, is sufficient to improve the dissolution profile of the milled biologically active material.","The grinding matrix is not generally selected to be chemically reactive with the biologically active material under the milling conditions of the invention, excepting for example, where the matrix is deliberately chosen to undergo a mechanico-chemical reaction.","Such a reaction might be the conversion of a free base or acid to a salt or vice versa.","As stated above, the method of the present invention requires the grinding matrix to be milled with the biologically active material; that is, the grinding matrix will physically degrade under the dry milling conditions of the invention to facilitate the formation and retention of particulates of the biologically active material with improved dissolution profiles.","The precise extent of degradation required will depend on certain properties of the grinding matrix and the biologically active material, the ratio of biologically active material to grinding matrix, and the particle size distribution of the particles comprising the biologically active material.","The physical properties of the grinding matrix necessary to achieve the requisite degradation are dependent on the precise milling conditions.","For example, a harder grinding matrix may degrade to a sufficient extent provided [it is subjected to] more vigorous dry milling conditions.","Physical properties of the grinding matrix relevant to the extent that the agent will degrade under dry milling conditions include hardness, friability, as measured by indicia such as hardness, fracture toughness and brittleness index.","A low hardness (typically a Mohs Hardness less than 7) of the biologically active material is desirable to ensure fracture of the particles during processing, so that composite microstructures develop during milling.","Preferably, the hardness is less than 3 as determined using the Mohs Hardness scale.","Preferably, the grinding matrix is of low abrasivity.","Low abrasivity is desirable to minimise contamination of the mixture of the biologically active material in the grinding matrix by the milling bodies and/or the milling chamber of the media mill.","An indirect indication of the abrasivity can be obtained by measuring the level of milling-based contaminants.","Preferably, the grinding matrix has a low tendency to agglomerate during dry milling.","While it is difficult to objectively quantify the tendency to agglomerate during milling, it is possible to obtain a subjective measure by observing the level of “caking” of the grinding matrix on the milling bodies and the milling chamber of the media mill as dry milling progresses.","The grinding matrix may be an inorganic or organic substance.","In one embodiment, the grinding matrix is selected from the following, either as a single substance or a combination of two or more substances: Polyols (sugar alcohols) for example (but not limited to) mannitol, sorbitol, isomalt, xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, monosaccharides for example (but not limited to) glucose, fructose, mannose, galactose, disaccharides and trisaccharides for example (but not limited to) anhydrous lactose, lactose monohydrate, sucrose, maltose, trehalose, polysaccharides for example (but not limited to) maltodextrins, dextrin, Inulin, dextrates, polydextrose, other carbohydrates for example (but not limited to) starch, wheat flour, corn flour, rice flour, rice starch, tapioca flour, tapioca starch, potato flour, potato starch, other flours and starches, soy flour, soy meal or other soy products, cellulose, microcrystalline cellulose, microcrystalline cellulose based co blended excipients, chemically modified excipients such as pregelatinized (or partially) starch, modified celluloses such as HPMC, CMC, HPC, enteric polymer coatings such as hypromellose phthalate, cellulose acetate phthalate (Aquacoat®), polyvinyl acetate phthalate (Sureteric®), hypromellose acetate succinate (AQOAT®), and polmethacrylates (Eudragit® and Acryl-EZE®), Milk products for example (but not limited to) milk powder, skim milk powders, other milk solids and derivatives, other functional Excipients, organic acids for example (but not limited to) citric acid, tartaric acid, malic acid, maleic acid fumaric acid, ascorbic acid, succinic acid, the conjugate salt of organic acids for example (but not limited to) sodium citrate, sodium tartrate, sodium malate, sodium ascorbate, potassium citrate, potassium tartrate, potassium malate, potassium ascorbate, inorganics such as sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate and calcium carbonate.","dibasic calcium phosphate, tribasic calcium phosphate, sodium sulfate, sodium chloride, sodium metabisulphite, sodium thiosulfate, ammonium chloride, Glauber's salt, ammonium carbonate, sodium bisulfate, magnesium sulfate, potash alum, potassium chloride, sodium hydrogen sulfate, sodium hydroxide, crystalline hydroxides, hydrogen carbonates, hydrogen carbonates of pharmaceutical acceptable alkali metals, such as but not limited by, sodium, potassium, lithium, calcium, and barium, ammonium salts (or salts of volatile amines), for example (but not limited to) ammonium chloride, methylamine hydrochloride, ammonium bromide, other inorganics for example (but not limited to), thermal silica, chalk, mica, silica, alumina, titanium dioxide, talc, kaolin, bentonite, hectorite, magnesium trisilicate, other clay or clay derivatives or aluminium silicates, a surfactant for example (but not limited to) sodium lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate, sodium cetostearyl sulfate, sodium docusate, sodium deoxycholate, N-lauroylsarcosine sodium salt, glyceryl monostearate, glycerol distearate glyceryl palmitostearate, glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzalkonium chloride, CTAB, CTAC, Cetrimide, cetylpyridinium chloride, cetylpyridinium bromide, benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188, poloxamer 338, poloxamer 407 polyoxyl 2 stearyl ether, polyoxyl 100 stearyl ether, polyoxyl 20 stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 20 cetyl ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl 35 castor oil, polyoxyl 40 castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor oil, polyoxyl 200 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyoxyl 100 hydrogenated castor oil, polyoxyl 200 hydrogenated castor oil, cetostearyl alcohol, macrogel 15 hydroxystearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, Sucrose Palmitate, Sucrose Stearate, Sucrose Distearate, Sucrose laurate, Glycocholic acid, sodium Glycholate, Cholic Acid, Sodium Cholate, Sodium Deoxycholate, Deoxycholic acid, Sodium taurocholate, taurocholic acid, Sodium taurodeoxycholate, taurodeoxycholic acid, soy lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonate condensate/Lignosulfonate blend, Calcium Dodecylbenzene Sulfonate, Sodium Dodecylbenzene Sulfonate, Diisopropyl naphthalenesulphonate, erythritol distearate, Naphthalene Sulfonate Formaldehyde Condensate, nonylphenol ethoxylate (poe-30), Tristyrylphenol Ethoxylate, Polyoxyethylene (15) tallowalkylamines, sodium alkyl naphthalene sulfonate, sodium alkyl naphthalene sulfonate condensate, sodium alkylbenzene sulfonate, sodium isopropyl naphthalene sulfonate, Sodium Methyl Naphthalene Formaldehyde Sulfonate, sodium n-butyl naphthalene sulfonate, tridecyl alcohol ethoxylate (poe-18), Triethanolamine isodecanol phosphate ester, Triethanolamine tristyrylphosphate ester, Tristyrylphenol Ethoxylate Sulfate, Bis(2-hydroxyethyl)tallowalkylamines.","In a preferred embodiment, the grinding matrix is a matrix that is considered GRAS (generally regarded as safe) by persons skilled in the pharmaceutical arts.","In another preferred aspect a combination of two or more suitable matrices, such as those listed above, can be used as the grinding matrix to provide improved properties such as the reduction of caking, and greater improvement of particle size reduction.","Combination matrices may also be advantageous when the matrices have different solubility's allowing the removal or partial removal of one matrix, while leaving the other or part of the other to provide encapsulation or partial encapsulation of the biologically active material.","Another highly preferred aspect of the method is the inclusion of a suitable milling aid in the matrix to improve milling performance.","Improvements to milling performance would be things such as, but not limited to, a reduction in caking or higher recovery of powder from the mill.","Examples of suitable milling aids include surfactants, polymers and inorganics such as silica (including colloidal silica), aluminium silicates and clays.","There are a wide range of surfactants that will make suitable milling aids.","The highly preferred form is where the surfactant is a solid, or can be manufactured into a solid.","Preferably, the surfactant is selected from the group consisting of: polyoxyethylene alkyl ethers, polyoxyethylene stearates, polyethylene glycols (PEG), poloxamers, poloxamines, sarcosine based surfactants, polysorbates, aliphatic alcohols, alkyl and aryl sulfates, alkyl and aryl polyether sulfonates and other sulfate surfactants, trimethyl ammonium based surfactants, lecithin and other phospholipids, bile salts, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, Sorbitan fatty acid esters, Sucrose fatty acid esters, alkyl glucopyranosides, alkyl maltopyranosides, glycerol fatty acid esters, Alkyl Benzene Sulphonic Acids, Alkyl Ether Carboxylic Acids, Alkyl and aryl Phosphate esters, Alkyl and aryl Sulphate esters, Alkyl and aryl Sulphonic acids, Alkyl Phenol Phosphates esters, Alkyl Phenol Sulphates esters, Alkyl and Aryl Phosphates, Alkyl Polysaccharides, Alkylamine Ethoxylates, Alkyl-Naphthalene Sulphonates formaldehyde condensates, Sulfosuccinates, lignosulfonates, Ceto-Oleyl Alcohol Ethoxylates, Condensed Naphthalene Sulphonates, Dialkyl and Alkyl Naphthalene Sulphonates, Di-alkyl Sulphosuccinates, Ethoxylated nonylphenols, Ethylene Glycol Esters, Fatty Alcohol Alkoxylates, Hydrogenated tallowalkylamines, Mono-alkyl Sulphosuccinamates, Nonyl Phenol Ethoxylates, Sodium Oleyl N-methyl Taurate, Tallowalkylamines, linear and branched dodecylbenzene sulfonic acids.","Preferably, the surfactant is selected from the group consisting of: sodium lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate, sodium cetostearyl sulfate, sodium docusate, sodium deoxycholate, N-lauroylsarcosine sodium salt, glyceryl monostearate, glycerol distearate glyceryl palmitostearate, glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzalkonium chloride, CTAB, CTAC, Cetrimide, cetylpyridinium chloride, cetylpyridinium bromide, benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188, poloxamer 338, poloxamer 407 polyoxyl 2 stearyl ether, polyoxyl 100 stearyl ether, polyoxyl 20 stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 20 cetyl ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl 35 castor oil, polyoxyl 40 castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor oil, polyoxyl 200 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyoxyl 100 hydrogenated castor oil, polyoxyl 200 hydrogenated castor oil, cetostearyl alcohol, macrogel 15 hydroxystearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, Sucrose Palmitate, Sucrose Stearate, Sucrose Distearate, Sucrose laurate, Glycocholic acid, sodium Glycholate, Cholic Acid, Sodium Cholate, Sodium Deoxycholate, Deoxycholic acid, Sodium taurocholate, taurocholic acid, Sodium taurodeoxycholate, taurodeoxycholic acid, soy lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonate condensate/Lignosulfonate blend, Calcium Dodecylbenzene Sulfonate, Sodium Dodecylbenzene Sulfonate, Diisopropyl naphthalenesulphonate, erythritol distearate, Naphthalene Sulfonate Formaldehyde Condensate, nonylphenol ethoxylate (poe-30), Tristyrylphenol Ethoxylate, Polyoxyethylene (15) tallowalkylamines, sodium alkyl naphthalene sulfonate, sodium alkyl naphthalene sulfonate condensate, sodium alkylbenzene sulfonate, sodium isopropyl naphthalene sulfonate, Sodium Methyl Naphthalene Formaldehyde Sulfonate, sodium n-butyl naphthalene sulfonate, tridecyl alcohol ethoxylate (poe-18), Triethanolamine isodecanol phosphate ester, Triethanolamine tristyrylphosphate ester, Tristyrylphenol Ethoxylate Sulfate, Bis(2-hydroxyethyl)tallowalkylamines.","Preferably the polymer is selected from the list of: polyvinylpyrrolidones (PVP), polyvinylalcohol, Acrylic acid based polymers and copolymers of acrylic acid Preferably, the milling aid has a concentration selected from the group consisting of: 0.1-10% w/w, 0.1-5% w/w, 0.1-2.5% w/w, of 0.1-2% w/w, 0.1-1%, 0.5-5% w/w, 0.5-3% w/w, 0.5-2% w/w, 0.5-1.5%, 0.5-1% w/w, of 0.75-1.25% w/w, 0.75-1% and 1% w/w.","Milling Bodies In the method of the present invention, the milling bodies are preferably chemically inert and rigid.","The term “chemically-inert”, as used herein, means that the milling bodies do not react chemically with the biologically active material or the grinding matrix.","As described above, the milling bodies are essentially resistant to fracture and erosion in the milling process.","The milling bodies are desirably provided in the form of bodies which may have any of a variety of smooth, regular shapes, flat or curved surfaces, and lacking sharp or raised edges.","For example, suitable milling bodies can be in the form of bodies having ellipsoidal, ovoid, spherical or right cylindrical shapes.","Preferably, the milling bodies are provided in the form of one or more of beads, balls, spheres, rods, right cylinders, drums or radius-end right cylinders (i.e., right cylinders having hemispherical bases with the same radius as the cylinder).","Depending on the nature of the biologically active material and the grinding matrix, the milling media bodies desirably have an effective mean particle diameter (i.e.","“particle size”) between about 0.1 and 30 mm, more preferably between about 1 and about 15 mm, still more preferably between about 3 and 10 mm.","The milling bodies may comprise various substances such as ceramic, glass, metal or polymeric compositions, in a particulate form.","Suitable metal milling bodies are typically spherical and generally have good hardness (i.e.","RHC 60-70), roundness, high wear resistance, and narrow size distribution and can include, for example, balls fabricated from type 52100 chrome steel, type 316 or 440C stainless steel or type 1065 high carbon steel.","Preferred ceramics, for example, can be selected from a wide array of ceramics desirably having sufficient hardness and resistance to fracture to enable them to avoid being chipped or crushed during milling and also having sufficiently high density.","Suitable densities for milling media can range from about 1 to 15 g/cm3′, preferably from about 1 to 8 g/cm3.Preferred ceramics can be selected from steatite, aluminum oxide, zirconium oxide, zirconia-silica, yttria-stabilized zirconium oxide, magnesia-stabilized zirconium oxide, silicon nitride, silicon carbide, cobalt-stabilized tungsten carbide, and the like, as well as mixtures thereof.","Preferred glass milling media are spherical (e.g.","beads), have a narrow size distribution, are durable, and include, for example, lead-free soda lime glass and borosilicate glass.","Polymeric milling media are preferably substantially spherical and can be selected from a wide array of polymeric resins having sufficient hardness and friability to enable them to avoid being chipped or crushed during milling, abrasion-resistance to minimize attrition resulting in contamination of the product, and freedom from impurities such as metals, solvents, and residual monomers.","Preferred polymeric resins, for example, can be selected from crosslinked polystyrenes, such as polystyrene crosslinked with divinylbenzene, styrene copolymers, polyacrylates such as polymethylmethacrylate, polycarbonates, polyacetals, vinyl chloride polymers and copolymers, polyurethanes, polyamides, high density polyethylenes, polypropylenes, and the like.","The use of polymeric milling media to grind materials down to a very small particle size (as opposed to mechanochemical synthesis) is disclosed, for example, in U.S. Pat.","Nos.","5,478,705 and 5,500,331.Polymeric resins typically have densities ranging from about 0.8 to 3.0 g/cm3.Higher density polymeric resins are preferred.","Alternatively, the milling media can be composite particles comprising dense core particles having a polymeric resin adhered thereon.","Core particles can be selected from substances known to be useful as milling media, for example, glass, alumina, zirconia silica, zirconium oxide, stainless steel, and the like.","Preferred core substances have densities greater than about 2.5 g/cm3.In one embodiment of the invention, the milling media are formed from a ferromagnetic substance, thereby facilitating removal of contaminants arising from wear of the milling media by the use of magnetic separation techniques.","Each type of milling body has its own advantages.","For example, metals have the highest specific gravities, which increase grinding efficiency due to increased impact energy.","Metal costs range from low to high, but metal contamination of final product can be an issue.","Glasses are advantageous from the standpoint of low cost and the availability of small bead sizes as low as 0.004 mm.","However, the specific gravity of glasses is lower than other media and significantly more milling time is required.","Finally, ceramics are advantageous from the standpoint of low wear and contamination, ease of cleaning, and high hardness.","Dry Milling In the dry milling process of the present invention, the biologically active material and grinding matrix, in the form of crystals, powders, or the like, are combined in suitable proportions with the plurality of milling bodies in a milling chamber that is mechanically agitated (i.e.","with or without stirring) for a predetermined period of time at a predetermined intensity of agitation.","Typically, a milling apparatus is used to impart motion to the milling bodies by the external application of agitation, whereby various translational, rotational or inversion motions or combinations thereof are applied to the milling chamber and its contents, or by the internal application of agitation through a rotating shaft terminating in a blade, propeller, impeller or paddle or by a combination of both actions.","During milling, motion imparted to the milling bodies can result in application of shearing forces as well as multiple impacts or collisions having significant intensity between milling bodies and particles of the biologically active material and grinding matrix.","The nature and intensity of the forces applied by the milling bodies to the biologically active material and the grinding matrix is influenced by a wide variety of processing parameters including: the type of milling apparatus; the intensity of the forces generated, the kinematic aspects of the process; the size, density, shape, and composition of the milling bodies; the weight ratio of the biologically active material and grinding matrix mixture to the milling bodies; the duration of milling; the physical properties of both the biologically active material and the grinding matrix; the atmosphere present during activation; and others.","Advantageously, the media mill is capable of repeatedly or continuously applying mechanical compressive forces and shear stress to the biologically active material and the grinding matrix.","Suitable media mills include but are not limited to the following: high-energy ball, sand, bead or pearl mills, basket mill, planetary mill, vibratory action ball mill, multi-axial shaker/mixer, stirred ball mill, horizontal small media mill, multi-ring pulverizing mill, and the like, including small milling media.","The milling apparatus also can contain one or more rotating shafts.","In a preferred form of the invention, the dry milling is performed in a ball mill.","Throughout the remainder of the specification reference will be made to dry milling being carried out by way of a ball mill.","Examples of this type of mill are attritor mills, nutating mills, tower mills, planetary mills, vibratory mills and gravity-dependent-type ball mills.","It will be appreciated that dry milling in accordance with the method of the invention may also be achieved by any suitable means other than ball milling.","For example, dry milling may also be achieved using jet mills, rod mills, roller mills or crusher mills.","Biologically Active Material The biologically active material includes active compounds, including compounds for veterinary and human use such as but not limited to, pharmaceutical actives, nutraceuticals, cosmeceuticals, cosmetics, complementary medicines, natural products, vitamins, nutrients, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids.","and agricultural compounds such as pesticides, herbicides and fungicides, germinating agents and the like.","Other biologically active materials include, but are not limited to, foods, seeds, cocoa and cocoa solids, coffee, herbs, spices, other plant materials, minerals, animal products, shells and other skeletal material.","In a preferred form of the invention, the biologically active material is an organic compound.","In a highly preferred form of the invention, the biologically active material is an organic, therapeutically active compound for veterinary or human use.","In a preferred form of the invention, the biologically active material is an inorganic compound.","In a highly preferred form of the invention, the biologically active material is sulphur, copper hydroxide, an organometallic complex or copper oxychloride.","The biologically active material is ordinarily a material for which one of skill in the art desires improved dissolution properties.","The biologically active material may be a conventional active agent or drug, although the process of the invention may be employed on formulations or agents that already have reduced particle size compared to their conventional form.","Biologically active materials suitable for use in the invention include actives, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids, and analogs, homologs and first order derivatives thereof.","The biologically active material can be selected from a variety of known classes of drugs, including, but not limited to: anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, such as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives (hypnotics and neuroleptics), astringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (anti-Parkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones (including steroids), anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines.","A description of these classes of active agents and a listing of species within each class can be found in Martindale's The Extra Pharmacopoeia, 31st Edition (The Pharmaceutical Press, London, 1996), specifically incorporated by reference.","Another source of active agents is the Physicians Desk Reference (60th Ed., pub.","2005), familiar to those of skill in the art.","The active agents are commercially available and/or can be prepared by techniques known in the art.","An exhaustive list of drugs for which the methods of the invention are suitable would be burdensomely long for this specification; however, reference to the general pharmacopoeia listed above would allow one of skill in the art to select virtually any drug to which the method of the invention may be applied.","In addition it is also expected that new chemical entities (NCE) and other actives for which the methods of the invention are suitable will be created or become commercially available in the future.","Notwithstanding the general applicability of the method of the invention, more specific examples of biologically active materials include, but are not limited to: haloperidol (dopamine antagonist), DL isoproterenol hydrochloride (β-adrenergic agonist), terfenadine (H1-antagonist), propranolol hydrochloride (β-adrenergic antagonist), desipramine hydrochloride (antidepressant), sildenafil citrate, tadalafil and vardenafil.","Minor analgesics (cyclooxygenase inhibitors), fenamic acids, Piroxicam, Cox-2 inhibitors, and Naproxen, and others, may all benefit from being prepared.","As discussed in the context of the background to the invention, biologically active materials that are poorly water soluble at gastrointestinal pH will particularly benefit from being prepared, and the method of the present invention is particularly advantageously applied to materials that are poorly water soluble at gastrointestinal pH.","Such materials include, but are not limited to: albendazole, albendazole sulfoxide, alfaxalone, acetyl digoxin, acyclovir analogs, alprostadil, aminofostin, anipamil, antithrombin III, atenolol, azidothymidine, beclobrate, beclomethasone, belomycin, benzocaine and derivatives, beta carotene, beta endorphin, beta interferon, bezafibrate, binovum, biperiden, bromazepam, bromocryptine, bucindolol, buflomedil, bupivacaine, busulfan, cadralazine, camptothesin, canthaxanthin, captopril, carbamazepine, carboprost, cefalexin, cefalotin, cefamandole, cefazedone, cefluoroxime, cefinenoxime, cefoperazone, cefotaxime, cefoxitin, cefsulodin, ceftizoxime, chlorambucil, chromoglycinic acid, ciclonicate, ciglitazone, clonidine, cortexolone, corticosterone, cortisol, cortisone, cyclophosphamide, cyclosporin A and other cyclosporins, cytarabine, desocryptin, desogestrel, dexamethasone esters such as the acetate, dezocine, diazepam, diclofenac, dideoxyadenosine, dideoxyinosine, digitoxin, digoxin, dihydroergotamine, dihydroergotoxin, diltiazem, dopamine antagonists, doxorubicin, econazole, endralazine, enkephalin, enalapril, epoprostenol, estradiol, estramustine, etofibrate, etoposide, factor ix, factor viii, felbamate, fenbendazole, fenofibrate, fexofenedine, flunarizin, flurbiprofen, 5-fluorouracil, flurazepam, fosfomycin, fosmidomycin, furosemide, gallopamil, gamma interferon, gentamicin, gepefrine, gliclazide, glipizide, griseofulvin, haptoglobulin, hepatitis B vaccine, hydralazine, hydrochlorothiazide, hydrocortisone, ibuprofen, ibuproxam, indinavir, indomethacin, iodinated aromatic x-ray contrast agents such as iodamide, ipratropium bromide, ketoconazole, ketoprofen, ketotifen, ketotifen fumarate, K-strophanthin, labetalol, lactobacillus vaccine, lidocaine, lidoflazin, lisuride, lisuride hydrogen maleate, lorazepam, lovastatin, mefenamic acid, melphalan, memantin, mesulergin, metergoline, methotrexate, methyl digoxin, methylprednisolone, metronidazole, metisoprenol, metipranolol, metkephamide, metolazone, metoprolol, metoprolol tartrate, miconazole, miconazole nitrate, minoxidil, misonidazol, molsidomin, nadolol, nafiverine, nafazatrom, naproxen, natural insulins, nesapidil, nicardipine, nicorandil, nifedipine, niludipin, nimodipine, nitrazepam, nitrendipine, nitrocamptothesin, 9-nitrocamptothesin, olanzapine, oxazepam, oxprenolol, oxytetracycline, penicillins such as penicillin G benethamine, penecillin O, phenylbutazone, picotamide, pindolol, piposulfan, piretanide, piribedil, piroxicam, pirprofen, plasminogenici activator, prednisolone, prednisone, pregnenolone, procarbacin, procaterol, progesterone, proinsulin, propafenone, propanolol, propentofyllin, propofol, propranolol, raloxifene, rifapentin, simvastatin, semi-synthetic insulins, sobrerol, somastotine and its derivatives, somatropin, stilamine, sulfinalol hydrochloride, sulfinpyrazone, suloctidil, suprofen, sulproston, synthetic insulins, talinolol, taxol, taxotere, testosterone, testosterone propionate, testosterone undecanoate, tetracane HI, tiaramide HCl, tolmetin, tranilast, triquilar, tromantadine HCl, urokinase, valium, verapamil, vidarabine, vidarabine phosphate sodium salt, vinblastine, vinburin, vincamine, vincristine, vindesine, vinpocetine, vitamin A, vitamin E succinate, and x-ray contrast agents.","Drugs can be neutral species or basic or acidic as well as salts of an acid or base.","Specifically the chemical makeup and the functional groups, including an acid or base group, are generally not the determinant factor, excepting a possible chemical reaction with a specific matrix, for the successful creation of a biologically active substance with improved dissolution.","This invention is not limited to any drug specific class, application type, chemical type or function grouping.","Rather the suitability of a biologically active material for use in this invention is primarily determined by the mechanical properties of the material.","In addition, some biologically active materials may have the benefit of absorption through the skin if presented in a particle formulation.","Such biologically active materials include, but are not limited to, Voltaren (diclofenac), rofecoxib, and ibuprofen.","Conveniently, the biologically active material is capable of withstanding temperatures that are typical in uncooled dry milling, which may exceed 80° C. Therefore, materials with a melting point about 80° C. or greater are highly suitable.","For biologically active materials with lower melting points, the media mill may be cooled, thereby allowing materials with significantly lower melting temperatures to be processed according to the method of the invention.","For instance, a simple water-cooled mill will keep temperatures below 50° C., or chilled water could be used to further lower the milling temperature.","Those skilled in the art will understand that a high energy ball mill could be designed to run at any temperature between say −30 to 200° C. For some biologically active materials it may be advantageous to control the milling temperature to temperatures significantly below the melting points of the biologically active materials.","The biologically active material is obtained in a conventional form commercially and/or prepared by techniques known in the art.","It is preferred, but not essential, that the particle size of the biologically active material be less than about 1000 μm, as determined by sieve analysis.","If the coarse particle size of the biologically active material is greater than about 1000 μm, then it is preferred that the particles of the biologically active material substrate be reduced in size to less than 1000 μm using another standard milling method.","Processed Biologically Active Material Preferably, the biologically active materials, which have been subject to the methods of the invention, comprises particles of biologically active material of an average particle size diameter equal or greater than 1 μm, determined on a particle number basis.","Preferably, the biologically active materials, which have been subject to the methods of the invention, comprises particles of biologically active material of a median particle size diameter equal or greater than 1 μm, determined on a particle volume basis.","These sizes refer to particles either fully dispersed or partially agglomerated.","Agglomerates of Biologically Active Material after Processing Agglomerates comprising particles of biologically active material, said particles having a particle size within the ranges specified above, should be understood to fall within the scope of the present invention.","Agglomerates comprising particles of biologically active material, said agglomerates having a total agglomerate size within the ranges specified above, should be understood to fall within the scope of the present invention.","Agglomerates comprising particles of biologically active material, should be understood to fall within the scope of the present invention if at the time of use, or further processing, the particle size of the agglomerate is within the ranges specified above.","Processing Time Preferably, the biologically active material and the grinding matrix are dry milled for the shortest time necessary to form the mixture of the biologically active material in the grinding matrix such that the active material has improved dissolution to minimise any possible contamination from the media mill and/or the plurality of milling bodies.","This time varies greatly, depending on the biologically active material and the grinding matrix, and may range from as short as 1 minute to several hours.","Dry milling times in excess of 2 hours may lead to degradation of the biologically active material and an increased level of undesirable contaminants.","Suitable rates of agitation and total milling times are adjusted for the type and size of milling apparatus as well as the milling media, the weight ratio of the biologically active material and grinding matrix mixture to the plurality of milling bodies, the chemical and physical properties of the biologically active material and grinding matrix, and other parameters that may be optimized empirically.","Inclusion of the Grinding Matrix with the Biologically Active Material and Separation of the Grinding Matrix from the Biologically Active Material In a preferred aspect, the grinding matrix is not separated from the biologically active material but is maintained with the biologically active material in the final product.","Preferably the grinding matrix is considered to be Generally Regarded as Safe (GRAS) for pharmaceutical products.","In an alternative aspect, the grinding matrix is separated from the biologically active material.","In one aspect, where the grinding matrix is not fully milled, the unmilled grinding matrix is separated from the biologically active material.","In a further aspect, at least a portion of the milled grinding matrix is separated from the biologically active material.","Any portion of the grinding matrix may be removed, including but not limited to 10%, 25%, 50%, 75%, or substantially all of the grinding matrix.","In some embodiments of the invention, a significant portion of the milled grinding matrix may comprise particles of a size similar to and/or smaller than the particles comprising the biologically active material.","Where the portion of the milled grinding matrix to be separated from the particles comprising the biologically active material comprises particles of a size similar to and/or smaller than the particles comprising the biologically active material, separation techniques based on size distribution are inapplicable.","In these circumstances, the method of the present invention may involve separation of at least a portion of the milled grinding matrix from the biologically active material by techniques including but not limited to electrostatic separation, magnetic separation, centrifugation (density separation), hydrodynamic separation, froth flotation.","Advantageously, the step of removing at least a portion of the milled grinding matrix from the biologically active material may be performed through means such as selective dissolution, washing, or sublimation.","An advantageous aspect of the invention would be the use of grinding matrix that has two or more components where at least one component is water soluble and at least one component has low solubility in water.","In this case washing can be used to remove the matrix component soluble in water leaving the biologically active material encapsulated in the remaining matrix components.","In a highly advantageous aspect of the invention the matrix with low solubility is a functional excipient.","A highly advantageous aspect of the present invention is that certain grinding matrixes appropriate for use in the method of the invention (in that they physically degrade to the desired extent under dry milling conditions) are also pharmaceutically acceptable and thus appropriate for use in a medicament.","Where the method of the present invention does not involve complete separation of the grinding matrix from the biologically active material, the present invention encompasses methods for the production of a medicament incorporating both the biologically active material and at least a portion of the milled grinding matrix, medicaments so produced and methods of treatment of an animal, including man, using a therapeutically effective amount of said biologically active materials by way of said medicaments.","The medicament may include only the biologically active material and the grinding matrix or, more preferably, the biologically active materials and grinding matrix may be combined with one or more pharmaceutically acceptable carriers, as well as any desired excipients or other like agents commonly used in the preparation of medicaments.","Analogously, a highly advantageous aspect of the present invention is that certain grinding matrixes appropriate for use in the method of the invention (in that they physically degrade to a desirable extent under dry milling conditions) are also appropriate for use in an agricultural chemical composition.","Where the method of the present invention does not involve complete separation of the grinding matrix from the biologically active material, the present invention encompasses methods for the production of a agricultural chemical composition incorporating both the biologically active material and at least a portion of the milled grinding matrix, agricultural chemical composition so produced and methods of use of such compositions.","The agricultural chemical composition may include only the biologically active material and the grinding matrix or, more preferably, the biologically active materials and grinding matrix may be combined with one or more acceptable carriers, as well as any desired excipients or other like agents commonly used in the preparation of agricultural chemical compositions.","In one particular form of the invention, the grinding matrix is both appropriate for use in a medicament and readily separable from the biologically active material by methods not dependent on particle size.","Such grinding matrixes are described in the following detailed description of the invention.","Such grinding matrixes are highly advantageous in that they afford significant flexibility in the extent to which the grinding matrix may be incorporated with the biologically active material into a medicament.","The mixture of biologically active material and grinding matrix may then be separated from the milling bodies and removed from the mill.","In one embodiment, the grinding matrix is separated from the mixture of biologically active material and grinding matrix.","Where the grinding matrix is not fully milled, the unmilled grinding matrix is separated from the biologically active material.","In a further aspect, at least a portion of the milled grinding matrix is separated from the biologically active material.","The milling bodies are essentially resistant to fracture and erosion in the dry milling process.","The quantity of the grinding matrix relative to the quantity of biologically active material, and the extent of milling of the grinding matrix, is sufficient to provide improved dissolution of the biologically active material.","The grinding matrix is neither chemically nor mechanically reactive with the pharmaceutical material under the dry milling conditions of the method of the invention except, for example, where the matrix is deliberately chosen to undergo a mechanico-chemical reaction.","Such a reaction might be the conversion of a free base or acid to a salt or vice versa.","Preferably, the medicament is a solid dosage form, however, other dosage forms may be prepared by those of ordinary skill in the art.","In one form, after the step of separating said mixture of biologically active material and grinding matrix from the plurality of milling bodies, and before the step of using said mixture of biologically active material and grinding matrix in the manufacture of a medicament, the method may comprise the step of: removing a portion of the grinding matrix from said mixture of biologically active material and grinding matrix to provide a mixture enriched in the biologically active material; and the step of using said mixture of biologically active material and grinding matrix in the manufacture of a medicament, more particularly comprises the step of using the mixture of biologically active material and grinding matrix enriched in the biologically active material form in the manufacture of a medicament.","The present invention includes medicaments manufactured by said methods, and methods for the treatment of an animal, including man, by the administration of a therapeutically effective amount of the biologically active materials by way of said medicaments.","In another embodiment of the invention, a facilitating agent or a combination of facilitating agents is also comprised in the mixture to be milled.","Such facilitating agents appropriate for use in the invention include diluents, surfactants, polymers, binding agents, filling agents, lubricating agents, sweeteners, flavouring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents and agents that may form part of a medicament, including a solid dosage form, or other excipients required for other specific drug delivery, such as the agents and media listed below under the heading Medicinal and Pharmaceutical Compositions, or any combination thereof.","Biologically Active Materials and Compositions The present invention encompasses pharmaceutically acceptable materials produced according to the methods of the present invention, compositions including such materials, including compositions comprising such materials together with the grinding matrix, with at least a portion of the grinding matrix or separated from the grinding matrix.","The pharmaceutically acceptable materials within the compositions of the invention are present at a concentration of between about 0.1% and about 99.0% by weight.","Preferably, the concentration of pharmaceutically acceptable materials within the compositions will be about 5% to about 80% by weight, while concentrations of 10% to about 50% by weight are highly preferred.","Desirably, the concentration will be in the range of about 10 to 15% by weight, 15 to 20% by weight, 20 to 25% by weight, 25 to 30% by weight, 30 to 35% by weight, 35 to 40% by weight, 40 to 45% by weight, 45 to 50% by weight, 50 to 55% by weight, 55 to 60% by weight, 60 to 65% by weight, 65 to 70% by weight, 70 to 75% by weight or 75 to 80% by weight for the composition prior to any later removal (if desired) of any portion of the grinding matrix.","Where part or all of the grinding matrix has been removed, the relative concentration of pharmaceutically acceptable materials in the composition may be considerably higher depending on the amount of the grinding matrix that is removed.","For example, if all of the grinding matrix is removed the concentration of particles in the preparation may approach 100% by weight (subject to the presence of facilitating agents).","Compositions produced according to the present invention are not limited to the inclusion of a single species of pharmaceutically acceptable materials.","More than one species of pharmaceutically acceptable materials may therefore be present in the composition.","Where more than one species of pharmaceutically acceptable materials is present, the composition so formed may either be prepared in a dry milling step, or the pharmaceutically acceptable materials may be prepared separately and then combined to form a single composition.","Medicaments The medicaments of the present invention may include the pharmaceutically acceptable material, optionally together with the grinding matrix or at least a portion of the grinding matrix, combined with one or more pharmaceutically acceptable carriers, as well as other agents commonly used in the preparation of pharmaceutically acceptable compositions.","As used herein “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.","Preferably, the carrier is suitable for parenteral administration, intravenous, intraperitoneal, intramuscular, sublingual, pulmonary, transdermal or oral administration.","Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.","The use of such media and agents for the manufacture of medicaments is well known in the art.","Except insofar as any conventional media or agent is incompatible with the pharmaceutically acceptable material, use thereof in the manufacture of a pharmaceutical composition according to the invention is contemplated.","Pharmaceutical acceptable carriers according to the invention may include one or more of the following examples: (1) surfactants and polymers, including, but not limited to polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyvinylalcohol, crospovidone, polyvinylpyrrolidone-polyvinylacetate copolymer, cellulose derivatives, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxymethylethyl cellulose, hydroxypropylmethyl cellulose phthalate, polyacrylates and polymethacrylates, urea, sugars, polyols, and their polymers, emulsifiers, sugar gum, starch, organic acids and their salts, vinyl pyrrolidone and vinyl acetate; and or (2) binding agents such as various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose; and or (3) filling agents such as lactose monohydrate, lactose anhydrous, microcrystalline cellulose and various starches; and or (4) lubricating agents such as agents that act on the flowability of the powder to be compressed, including colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, silica gel; and or (5) sweeteners such as any natural or artificial sweetener including sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame K; and or (6) flavouring agents; and or (7) preservatives such as potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic chemicals such as phenol, or quaternary compounds such as benzalkonium chloride; and or (8) buffers; and or (9) Diluents such as pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing; and or (10) wetting agents such as corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures thereof; and or (11) disintegrants; and or (12) effervescent agents such as effervescent couples such as an organic acid (e.g., citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts), or a carbonate (e.g.","sodium carbonate, potassium carbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate) or bicarbonate (e.g.","sodium bicarbonate or potassium bicarbonate); and or (13) other pharmaceutically acceptable excipients.","Medicaments of the invention suitable for use in animals and in particular in man typically must be sterile and stable under the conditions of manufacture and storage.","The medicaments of the invention comprising the biologically active material can be formulated as a solid, a solution, a microemulsion, a liposome, or other ordered structures suitable to high drug concentration.","Actual dosage levels of the biologically active material in the medicament of the invention may be varied in accordance with the nature of the biologically active material, as well as the potential increased efficacy due to the advantages of providing and administering the biologically active material (e.g., increased solubility, more rapid dissolution, increased surface area of the biologically active material, etc.).","Thus as used herein “therapeutically effective amount” will refer to an amount of biologically active material required to effect a therapeutic response in an animal.","Amounts effective for such a use will depend on: the desired therapeutic effect; the route of administration; the potency of the biologically active material; the desired duration of treatment; the stage and severity of the disease being treated; the weight and general state of health of the patient; and the judgment of the prescribing physician.","In another embodiment, the biologically active material, optionally together with the grinding matrix or at least a portion of the grinding matrix, of the invention may be combined into a medicament with another biologically active material, or even the same biologically active material.","In the latter embodiment, a medicament may be achieved which provides for different release characteristics—early release from the biologically active material, and later release from a larger average size biologically active material.","Modes of Administration of Medicaments Comprising Biologically Active Materials Medicaments of the invention can be administered to animals, including man, in any pharmaceutically acceptable manner, such as orally, rectally, pulmonary, intravaginally, locally (powders, ointments or drops), transdermal, parenteral administration, intravenous, intraperitoneal, intramuscular, sublingual or as a buccal or nasal spray Solid dosage forms for oral administration include capsules, tablets, pills, powders, pellets, and granules.","Further, incorporating any of the normally employed excipients, such as those previously listed, and generally 5-95% of the biologically active agent, and more preferably at a concentration of 10%-75% will form a pharmaceutically acceptable non-toxic oral composition.","Medicaments of the invention may be parenterally administered as a solution of the biologically active agent suspended in an acceptable carrier, preferably an aqueous carrier.","A variety of aqueous carriers may be used, e.g.","water, buffered water, 0.4% saline, 0.3% glycine, hyaluronic acid and the like.","These compositions may be sterilized by conventional, well known sterilization techniques, or may be sterile filtered.","The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile solution prior to administration.","For aerosol administration, medicaments of the invention are preferably supplied along with a surfactant or polymer and propellant.","The surfactant or polymer must, of course, be non-toxic, and preferably soluble in the propellant.","Representative of such agents are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride.","Mixed esters, such as mixed or natural glycerides may be employed.","The surfactant or polymer may constitute 0.1%-20% by weight of the composition, preferably 0.25-5%.","The balance of the composition is ordinarily propellant.","A carrier can also be included, as desired, as with, e.g., lecithin for intranasal delivery.","Medicaments of the invention may also be administered via liposomes, which serve to target the active agent to a particular tissue, such as lymphoid tissue, or targeted selectively to cells.","Liposomes include emulsions, foams, micelles, insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers and the like.","In these preparations the composite microstructure composition is incorporated as part of a liposome, alone or in conjunction with a molecule that binds to or with other therapeutic or immunogenic compositions.","As described above, the biologically active material can be formulated into a solid dosage form (e.g., for oral or suppository administration), together with the grinding matrix or at least a portion of it.","In this case there may be little or no need to add stabilizing agents since the grinding matrix may effectively act as a solid-state stabilizer.","However, if the biologically active material is to be utilized in a liquid suspension, the particles comprising the biologically active material may require further stabilization once the solid carrier has been substantially removed to ensure the elimination, or at least minimisation of particle agglomeration.","Therapeutic Uses Therapeutic uses of the medicaments of the invention include pain relief, anti-inflammatory, migraine, asthma, and other disorders that require the active agent to be administered with a high bioavailability.","One of the main areas when rapid bioavailability of a biologically active material is required is in the relief of pain.","The minor analgesics, such as cyclooxgenase inhibitors (aspirin related drugs) may be prepared as medicaments according to the present invention.","Medicaments of the invention may also be used for treatment of eye disorders.","That is, the biologically active material may be formulated for administration on the eye as an aqueous suspension in physiological saline, or a gel.","In addition, the biologically active material may be prepared in a powder form for administration via the nose for rapid central nervous system penetration.","Treatment of cardiovascular disease may also benefit from biologically active materials according to the invention, such as treatment of angina pectoris and, in particular, molsidomine may benefit from better bioavailability.","Other therapeutic uses of the medicaments of the present invention include treatment of hair loss, sexual dysfunction, or dermal treatment of psoriasis.","The present invention will now be described with reference to the following non-limiting Examples.","The description of the Examples is in no way limiting on the preceding paragraphs of this specification, but is provided for exemplification of the methods and compositions of the invention.","EXAMPLES It will be apparent to persons skilled in the milling and pharmaceutical arts that numerous enhancements and modifications can be made to the above described processes without departing from the basic inventive concepts.","For example, in some applications the biologically active material may be pretreated and supplied to the process in the pretreated form.","All such modifications and enhancements are considered to be within the scope of the present invention, the nature of which is to be determined from the foregoing description and the appended claims.","Furthermore, the following Examples are provided for illustrative purposes only, and are not intended to limit the scope of the processes or compositions of the invention.","The following materials were used in the examples: Meloxicam (Dayang, China), Diclofenac (Unique, India), Lactose monohydrate (Capsulac 60, Meggle, Germany), Mannitol (Sigma-Aldrich, US), Tartaric Acid (BDH, UK), Sorbitol (Sigma-Aldrich, US), Glucose (Ajax Finechem, Australia), Microcrystalline Cellulose (Sigma-Aldrich, US).","A Union Process attritor mill (model 1HD, 110 mL milling chamber), fitted with a 4 arm rotating shaft, was used to conduct the milling experiments.","Steel balls ( 5/16″, 300 g) were used as grinding media in the milling experiments.","The mill was loaded through the loading port, with dry materials and matrices added initially, followed by the grinding media.","The milling process was conducted at room temperature with the shaft rotating at 500 rpm.","Upon completion of milling, the milled powder was discharged from the mill and sieved to remove grinding media.","The particle size distribution (PSD) was determined using a Malvern Mastersizer 2000 fitted with a Malvern Hydro 2000S pump unit.","Dispersant used (0.01M HCl, RI: 1.33).","Measurement settings used: Measurement Time: 12 secs, Measurement cycles: 3.Result generated by averaging the 3 measurements.","Meloxicam specific conditions: Refractive index (RI): 1.73, absorption: 0.01.Diclofenac specific conditions: RI: 1.69, absorption: 0.01.Samples were prepared by adding 200 mg of milled powder to 5.0 mL of a 1% PVP solution in 0.01M hydrochloric acid (HCl), vortexing for 1 min, then sonicating with a horn for 1 min until samples dispersed.","From this solution enough was added into the dispersant to attain a desired obscuration level of the red laser of =2.0%.","Dissolution behaviour of milled materials as well as unmilled controls were determined using an automated Varian 7025 dissolution unit fitted with a Cary 50 Tablet UV visible spectrometer.","Dissolution settings used were according to USP 2 with stirrer speed at 100 rpm.","Meloxicam specific conditions: wavelength A=362 nm, pH 6.1 (10 mM Phosphate buffer), standard sized gelatine capsules contained 15 mg Meloxicam, for example, a capsule prepared from a 10 wt % Meloxicam milling required 150 mg milled powder.","Diclofenac specific conditions: wavelength λ=276 nm, pH 5.75 (10 mM Citrate buffer), standard sized gelatine capsules contained 20 mg Diclofenac, for example, a capsule prepared from a 10 wt % Diclofenac milling required 200 mg milled powder.","Capsules of milled materials were filled using Profill® equipment.","Un-milled control samples were prepared by hand-filling appropriately sized capsules.","Each dissolution result was obtained by averaging results from 3 capsules.","Quantitative results are given as the time to reach X and Y. X is defined as the concentration equal to the dissolution concentration achieved by a control sample (or prototype formulation thereof) of the biologically active material or compound after 60 minutes.","Y is defined as the concentration equal to the dissolution concentration achieved by a control sample (or prototype formulation thereof) of the biologically active material or compound after 30 minutes.","Powder X-Ray diffraction (XRD) patterns were measured with a Diffractometer D 5000, Kristalloflex (Siemens).","The measurement range was from 5-18 degrees 2-Theta.","The slit width was set to 2 mm and the cathode ray tube was operated at 40 kV and 35 mA.","Measurements were recorded at room temperature.","The recorded traces were subsequently processed using Bruker EVA software to obtain the diffraction pattern.","DSC traces where measured using a TA instruments DSC Q10.The data was obtained using a heating rate of 10° C./min under nitrogen flow.","AluminiumTzero open pans where used for the measurements.","Example 1.10% Meloxicam in Lactose Mono-Hydrate A mixture of Meloxicam (0.60 g) and Lactose monohydrate (5.40 g) was milled for either 1 (B) or 2 (C) minutes.","PSDs of the milled products and unmilled material (A) are shown in FIG.","1.The dissolution behaviour is shown in FIG.","2.Results are summarised in Table 1 together with results obtained for an un-milled control (A), prepared by physically mixing Meloxicam (0.40 g) and Lactose monohydrate (3.60 g) in a vial until the appearance was homogenous.","FIG.","1 shows that after 1 minute of milling the particle size is reduced by about half.","After another minute of milling the particle size has further reduced but is still mostly in the range of 1-10 micron.","In contrast to this the dissolution of the material milled for 1 minute is only slightly faster than the unmilled control sample.","The dissolution at 2 minutes is dramatically improved over both the 1 minute and unmilled material.","In Table 1 the median size and quantitative assessment of the dissolution are shown.","According to the measures X and Y (set out above) the material milled for 2 minutes has a much improved dissolution compared with both the unmilled and the milled for 1 minute sample.","As the change in size of material from 1 to 2 mins is of the same order as the change in size from unmilled to 1 minute the primary reason for the improved dissolution for the 2 minute sample cannot be particle size reduction.","TABLE 1 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 8.79 μm 30 60 1 min (B) 4.86 μm 23 45 2 min (C) 2.53 μm 8 11 Example 2.10% Diclofenac in Lactose Mono-Hydrate A mixture of Diclofenac (0.60 g) and lactose monohydrate (5.40 g) was milled for either 1 (B) or 2 (C) minutes.","PSDs of the milled products and unmilled material (A) are shown in FIG.","3.The dissolution behaviour is shown in FIG.","4.Results are summarised in Table 2 together with results obtained for an un-milled control (A), prepared by physically mixing Diclofenac (0.40 g) and Lactose monohydrate (3.60 g) in a vial until the appearance was homogenous.","The data for Diclofenac milled in lactose monohydrate is very similar to the data in Example 1.FIG.","3 shows that after 1 minute of milling the particle size is reduced by just over 50%.","After another minute of milling the particle size has reduced a little more giving two milled materials in the range 2-4 micron.","Again in contrast to this the dissolution of the material milled for 1 minute is only slightly faster than the unmilled control sample.","The dissolution at 2 minutes is dramatically improved over both the 1 minute and unmilled material.","In Table 1 the median size and quantitative assessment of the dissolution are shown.","According to the measures X and Y (set out above) the material milled for 2 minutes has a much improved dissolution compared with both the unmilled and the milled for 1 minute sample.","As the size of the material from 1 to 2 mins is quite similar this size difference cannot be the primary reason for the improved dissolution for the 2 minute sample.","TABLE 2 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 9.50 μm 30 60 1 min (B) 4.09 μm 18 29 2 min (C) 2.57 μm 8 10 Example 3.10% Meloxicam in Mannitol A mixture of Meloxicam (0.60 g) and Mannitol (5.40 g) was milled for either 1 (B) or 2 (C) minutes.","PSDs of the milled products and unmilled material (A) were measured as well as the dissolution behaviour.","Results are summarised in Table 3.The un-milled control (A) was prepared by physically mixing Meloxicam (0.40 g) and Mannitol (3.60 g) in a vial until the appearance was homogenous.","The PSD shows that the material milled for 1 and 2 minutes has a reduced size compared with the unmilled material, but the size reduction is not dramatic.","According to the dissolution measures X and Y both materials have a much improved dissolution rate compared with the unmilled sample.","This data also shows that once enough milling energy has been input to deliver the improved dissolution (1 minute milling), further size reduction (2 minutes) has little impact on the dissolution rate.","In FIG.","5 a DSC trace of material milled for 2 minutes is shown compared with the DSC trace of mannitol.","The trace only shows one melt other than mannitol at approximately 240° C. being the normal melting point of meloxicam.","This DSC trace shows no indication of any amorphous material or other forms of meloxicam being present.","This indicates the meloxicam has retained its crystallinity during the milling process.","TABLE 3 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 8.79 μm 30 60 1 min (B) 3.80 μm 10 12 2 min (C) 2.19 μm 8 9 Example 4 10% Diclofenac in Mannitol A mixture of Diclofenac (0.60 g) and Mannitol (5.40 g) was milled for either 1 (B) or 2 (C) minutes.","PSDs of the milled products and unmilled material (A) were measured as well as the dissolution behaviour.","Results are summarised in Table 4.The un-milled control (A) was prepared by physically mixing Diclofenac (0.40 g) and Mannitol (3.60 g) in a vial until the appearance was homogenous.","The PSD shows that the material milled for 1 and 2 minutes has a reduced size compared with the unmilled material, but the size is still in the range 1-10 microns.","According to the dissolution measures X and Y both materials have a much improved dissolution rate compared with the unmilled sample.","Again the data also shows that once enough milling energy has been input to deliver the improved dissolution (1 minute milling), further size reduction (2 minutes) has little impact on the dissolution rate.","TABLE 4 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 9.50 μm 30 60 1 min (B) 2.20 μm 8 11 2 min (C) 1.23 μm 8 11 Example 5 10% Meloxicam in Glucose A mixture of Meloxicam (0.60 g) and Glucose (5.40 g) was milled for either 1 (B) or 2 (C) minutes.","PSDs of the milled products and unmilled material (A) were measured as well as the dissolution behaviour.","Results are summarised in Table 5.The un-milled control (A) was prepared by physically mixing Meloxicam (0.40 g) and Glucose (3.60 g) in a vial until the appearance was homogenous.","The PSD shows that the material milled for 1 and 2 minutes has a reduced size compared with the unmilled material.","There is about a 50% reduction from unmilled to 1 minute and about another 50% reduction from 1 minute to 2 minutes.","According to the dissolution measures X and Y both milled materials have a much improved dissolution rate compared with the unmilled sample.","Again the data shows that the improved dissolution is independent of the final particle size, instead most improvement has come from the milling of the active with the grinding matrix.","TABLE 5 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 8.79 μm 30 60 1 min (B) 4.04 μm 9 10 2 min (C) 1.61 μm 7 8 Example 6.10% Diclofenac in Glucose A mixture of Diclofenac (0.60 g) and Glucose (5.40 g) was milled for either 1 (B) or 2 (C) minutes.","PSDs of the milled products and unmilled material (A) were measured as well as the dissolution behaviour.","Results are summarised in Table 6.The un-milled control (A) was prepared by physically mixing Diclofenac (0.40 g) and Glucose (3.60 g) in a vial until the appearance was homogenous.","The PSD shows that the material milled for 1 and 2 minutes has a reduced size compared with the unmilled material, There is about a 60% reduction from unmilled to 1 minute and about another 30% reduction from 1 minute to 2 minutes.","According to the dissolution measures X and Y the material milled for 1 minute has a greatly improved dissolution rate compared with the unmilled sample.","The material milled for 2 minutes has a much slower dissolution rate compared with sample B and is only slightly improved compared with the unmilled material even though the particle size is smaller.","TABLE 6 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 9.50 μm 30 60 1 min (B) 3.13 μm 15 24 2 min (C) 1.97 μm 25 55 Example 7.10% Meloxicam in Microcrystalline Cellulose A mixture of Meloxicam (0.60 g) and microcrystalline Cellulose (5.40 g) was milled for either 1 (B) or 2 (C) minutes.","No PSD was measured due to interference from insoluble excipient.","Dissolution behaviour of milled products and unmilled material (A) were measured.","Results are summarised in Table 7.The un-milled control (A) was prepared by physically mixing Meloxicam (0.40 g) and microcrystalline Cellulose (3.60 g) in a vial until the appearance was homogenous.","According to the dissolution measures X and Y both milled materials have an improved dissolution rate compared with the unmilled sample.","TABLE 7 Time to Reach Concentration Milling Time Y (min) X (min) Un-milled (A) 30 60 1 min (B) 10 14 2 min (C) 9 10 Example 8.10% Diclofenac in Microcrystalline Cellulose A mixture of Diclofenac (0.60 g) and microcrystalline Cellulose (5.40 g) was milled for either 1 (B) or 2 (C) minutes.","No PSD was measured due to interference from insoluble excipient.","Dissolution behaviour of milled products and unmilled material (A) were measured.","Results are summarised in Table 7.The un-milled control (A) was prepared by physically mixing Diclofenac (0.40 g) and microcrystalline Cellulose (3.60 g) in a vial until the appearance was homogenous.","According to the dissolution measures X and Y both milled materials have an improved dissolution rate compared with the unmilled sample.","TABLE 8 Time to Reach Concentration Milling Time Y (min) X (min) Un-milled (A) 30 60 1 min (B) 18 28 2 min (C) 24 31 Example 9.10% Meloxicam in Tartaric Acid A mixture of Meloxicam (0.60 g) and Tartaric acid (5.40 g) was milled for either 1 (B) or 2 (C) minutes.","PSDs of the milled products and unmilled material (A) were measured as well as dissolution behaviour#.","Results summarised in Table 9.The un-milled control (A) was prepared by physically mixing Meloxicam (0.40 g) and Tartaric acid (3.60 g) in a vial until the appearance was homogenous.","The PSD shows that the material milled for 1 and 2 minutes has a reduced size compared with the unmilled material, There is about a 40% reduction from unmilled to 1 minute and about another 40% reduction from 1 minute to 2 minutes.","According to the dissolution measures X and Y both milled materials have a much improved dissolution rate compared with the unmilled sample.","The dissolution data indicates that both milled materials have very fast dissolution even though the size reduction upon milling is not large.","TABLE 9 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 8.79 μm 30 60 1 min (B) 5.10 μm 9 11 2 min (C) 3.03 μm 8 9 #Dissolution test measured in 100 mM phosphate buffer at pH 5.8.Example 10.20% Meloxicam in Lactose Mono-Hydrate A mixture of Meloxicam (1.20 g) and Lactose monohydrate (4.80 g) was milled for either 1 (B) or 2 (C) minutes.","PSDs of the milled products and unmilled material (A) were measured as well as dissolution behaviour.","Results summarised in Table 10.The un-milled control (A) was prepared by physically mixing Meloxicam (0.80 g) and Lactose monohydrate (3.20 g) in a vial until the appearance was homogenous.","The PSD shows that the material milled for 1 and 2 minutes has a reduced size compared with the unmilled material.","According to the dissolution measures X and Y both milled materials have an improved dissolution rate compared with the unmilled sample.","In FIG.","6 the XRD spectra of the material milled for 2 minutes is shown.","The spectra of pure meloxicam and pure milled lactose are also shown.","These show that most meloxicam peaks are obscured by the lactose spectra.","The clearest meloxicam peak is located at 2 theta 15°.","For the material milled for 2 mins this peak is small (due to only 20% meloxicam) but evidence of the presence of crystalline meloxicam after milling.","The spectra also indicate that the lactose is still crystalline after milling as well.","TABLE 10 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 8.79 μm 30 60 1 min (B) 5.72 μm 14 26 2 min (C) 3.52 μm 17 20 Example 11.20% Meloxicam in Mannitol A mixture of Meloxicam (1.20 g) and Mannitol (4.80 g) was milled for either 1 (B) or 2 (C) minutes.","PSDs of the milled products and unmilled material (A) were measured as well as dissolution behaviour.","Results are summarised in Table 11.The un-milled control (A) was prepared by physically mixing Meloxicam (0.80 g) and Mannitol (3.20 g) in a vial until the appearance was homogenous.","The PSD shows that the material milled for 1 and 2 minutes has a reduced size compared with the unmilled material.","The level of size reduction compared with the material milled at 10% (example 3) is the same.","The dissolution rate for the material milled at 20% is slightly slower than the rate for material milled at 10% (example 3) but the rate is still a good improvement over that of the unmilled material.","Again this data would indicate than the improvement in dissolution observed is not primarily a function of particle size.","In FIG.","5 a DSC trace of material milled for 2 minutes is shown compared with the DSC trace of mannitol.","The trace only shows one melt other than mannitol at approximately 240° C. being the normal melting point of meloxicam.","This DSC trace shows no indication of any amorphous material or other forms of meloxicam being present.","This indicates the meloxicam has retained its crystallinity during the milling process.","In FIG.","7 the XRD spectra of the material milled for 2 minutes is shown.","The spectra of pure meloxicam, pure mannitol and a 20% physical mixture of meloxicam in mannitol are also shown.","These show that most meloxicam peaks are obscured by the mannitol spectra.","The clearest meloxicam peak is located at 2 theta 13°.","The spectra indicate that both the meloxicam and mannitol are still crystalline after milling.","TABLE 11 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 8.79 μm 30 60 1 min (B) 3.53 μm 14 22 2 min (C) 2.39 μm 18 21 Example 12.30% Diclofenac in 69% Lactose Mono-Hydrate and 1% Sodium Dodecyl Sulfate A mixture of Diclofenac (1.80 g), Lactose monohydrate (4.14 g) and Sodium dodecyl sulfate (SDS) (0.06 g) was milled for 10 minutes (B).","PSDs of the milled product and unmilled material (A) were measured as well as dissolution behaviour.","Results are summarised in Table 12.The un-milled control (A) was prepared by physically mixing Diclofenac (1.20 g), Lactose monohydrate (2.76 g) and SDS (0.04 g) in a vial until the appearance was homogenous.","At the higher API content 1% SDS has been used as a milling aid to help provide good flow during milling.","The same concentration of SDS was also include in the unmilled control sample for dissolution measurements so that any improvement in the dissolution due to the SDS is accounted for.","At this API concentration the milling time has also been extended to provide more milling energy.","The PSD achieved here is similar to the 2 minute sample from example 2 (10%) and the dissolution measures X and Y have also shown a similar level of improved dissolution.","This example demonstrates that the improved dissolution through the synergistic milling of API and grinding matrix is achieved at higher API levels.","In FIG.","8 the XRD spectra of the diclofenac milled at various weight percentages from 20-50% is shown.","The 20% material was produced in the same way as this example only with different amounts of diclofenac and lactose so as to achieve 20% w/w diclofenac overall.","In FIG.","9 spectra of unmilled physical mixtures of the same compositions are shown as a comparison.","In FIG.","10 spectra are also shown for pure diclofenac, pure lactose and pure milled lactose.","FIG.","10 indicates there are unobscured peaks located at 2 theta 11°, 15° and a partially obscured peak at 28°.","When these peaks are compared between FIG.","8 (milled) and FIG.","9 (physical mixture) the spectra indicates that the material produced by this example is still crystalline after milling.","TABLE 12 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 9.50 μm 30 60 10 min (B) 2.75 μm 12 13 Example 13.40% Diclofenac in 59% Lactose Mono-Hydrate and 1% Sodium Dodecyl Sulfate A mixture of Diclofenac (2.40 g), Lactose monohydrate (3.54 g) and Sodium dodecyl sulfate (SDS) (0.06 g) was milled for 10 minutes (B).","PSDs of the milled product and unmilled material (A) were measured as well as dissolution behaviour.","Results are summarised in Table 13.The un-milled control (A) was prepared by physically mixing Diclofenac (1.60 g), Lactose monohydrate (2.36 g) and SDS (0.04 g) in a vial until the appearance was homogenous.","At this API concentration the PSD achieved is slightly coarser compare to example 12 (30%).","The dissolution measures X and Y showed improved dissolution.","In FIG.","8 the XRD spectra of the diclofenac milled at various weight percentages from 20-50% is shown.","The 20% material was produced in the same way as example 12 only with different amounts of diclofenac and lactose so as to achieve 20% w/w diclofenac overall.","In FIG.","9 spectra of unmilled physical mixtures of the same compositions are shown as a comparison.","In FIG.","10 spectra are also shown for pure diclofenac, pure lactose and pure milled lactose.","FIG.","10 indicates there are unobscured peaks located at 2 theta 11°, 15° and a partially obscured peak at 28°.","When these peaks are compared between FIG.","8 (milled) and FIG.","9 (physical mixture) the spectra indicates that the material produced by this example is still crystalline after milling.","TABLE 13 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 9.50 μm 30 60 10 min (B) 4.45 μm 18 25 Example 14.50% Diclofenac in 49% Lactose Mono-Hydrate and 1% Sodium Dodecyl Sulfate A mixture of Diclofenac (3.00 g), Lactose monohydrate (2.94 g) and Sodium dodecyl sulfate (SDS) (0.06 g) was milled for 10 minutes (B).","PSDs of the milled product and unmilled material (A) were measured as well as dissolution behaviour.","Results are summarised in Table 14.The un-milled control (A) was prepared by physically mixing Diclofenac (2.00 g), Lactose monohydrate (1.96 g) and SDS (0.04 g) in a vial until the appearance was homogenous.","At this API concentration the PSD achieved is slightly coarser compare to example 12 (30%) and example 13 (40%).","The dissolution measures X and Y still clearly indicate improved dissolution.","This example demonstrates that the improved dissolution through the synergistic milling of API and grinding matrix is achieved at API levels up to at least 50%.","In FIG.","8 the XRD spectra of the diclofenac milled at various weight percentages from 20-50% is shown.","The 20% material was produced in the same way as example 12 only with different amounts of diclofenac and lactose so as to achieve 20% w/w diclofenac overall.","In FIG.","9 spectra of unmilled physical mixtures of the same compositions are shown as a comparison.","In FIG.","10 spectra are also shown for pure diclofenac, pure lactose and pure milled lactose.","FIG.","10 indicates there are unobscured peaks located at 2 theta 11°, 15° and a partially obscured peak at 28°.","When these peaks are compared between FIG.","8 (milled) and FIG.","9 (physical mixture) the spectra indicates that the material produced by this example is still crystalline after milling.","TABLE 14 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 9.50 μm 30 60 10 min (B) 5.65 μm 23 33 Example 15.30% Meloxicam in 69% Lactose Mono-Hydrate and 1% Sodium Dodecyl Sulfate A mixture of Meloxicam (1.80 g), Lactose monohydrate (4.14 g) and Sodium dodecyl sulfate (SDS) (0.06 g) was milled for 10 minutes (B).","PSDs of the milled product and unmilled material (A) were measured as well as dissolution behaviour.","Results are summarised in Table 15.The un-milled control (A) was prepared by physically mixing Meloxicam (1.20 g), Lactose monohydrate (2.76 g) and SDS (0.04 g) in a vial until the appearance was homogenous.","Like the Diclofenac examples at higher API content 1% SDS has also been used as a milling aid with the high Meloxicam content millings to help provide good flow during milling.","The same concentration of SDS was also include in the unmilled control sample for dissolution measurements so that any improvement in the dissolution due to the SDS is accounted for.","At this API concentration the milling time has also been extended to provide more milling energy.","The PSD achieved here is slightly larger than the 2 minute sample from example 1 (10%).","The dissolution measures X and Y show slightly more improvement in the dissolution compared with the 2 minute sample of example 1.TABLE 15 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 8.79 μm 30 60 10 min (B) 3.69 μm 6 7 Example 16.40% Meloxicam in 59% Lactose Mono-Hydrate and 1% Sodium Dodecyl Sulfate A mixture of Meloxicam (2.40 g), Lactose monohydrate (3.54 g) and Sodium dodecyl sulfate (SDS) (0.06 g) was milled for 10 minutes (B).","PSDs of the milled product and unmilled material (A) were measured as well as dissolution behaviour.","Results are summarised in Table 16.The un-milled control (A) was prepared by physically mixing Meloxicam (1.60 g), Lactose monohydrate (2.36 g) and SDS (0.04 g) in a vial until the appearance was homogenous.","The PSD achieved here is slightly larger than 30% sample (example 15) but the dissolution measures X and Y are virtually the same, again indicating strongly improved dissolution.","TABLE 16 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 8.79 μm 30 60 10 min (B) 4.91 μm 7 8 Example 17.50% Meloxicam in 49% Lactose Mono-Hydrate and 1% Sodium Dodecyl Sulfate A mixture of Meloxicam (3.00 g), Lactose monohydrate (2.94 g) and Sodium dodecyl sulfate (SDS) (0.06 g) was milled for 10 minutes (B).","PSDs of the milled product and unmilled material (A) were measured as well as dissolution behaviour.","Results are summarised in Table 17.The un-milled control (A) was prepared by physically mixing Meloxicam (2.00 g), Lactose monohydrate (1.96 g) and SDS (0.04 g) in a vial until the appearance was homogenous.","The PSD achieved here is slightly larger than 40% sample (example 16) and is only slightly smaller than the unmilled material.","The dissolution measures X and Y are very similar to the 30 and 40%, again indicating strongly improved dissolution.","This series of millings at high Meloxicam content (example 15, 16, 17) clearly demonstrates that improved dissolution by synergistic milling of API with a grinding matrix is possible to at least 50%.","The PSD distributions for this series also indicate that the improved dissolution observed from this process is independent of particle size.","From 30% to 50% the PSD almost doubles yet the dissolution has remained relatively constant indicating little or no influence from particle size.","In FIG.","6 the XRD spectra of the material is shown (Spectra D).","The spectra of pure meloxicam and pure milled lactose are also shown.","These show that most meloxicam peaks are obscured by the lactose spectra.","The clearest meloxicam peak is located at 2 theta 15°.","In FIG.","11 the spectra of a physical mixture of the material milled is also shown.","The spectra indicates the presence of crystalline meloxicam after milling.","The spectra also indicate that the lactose is still crystalline after milling as well.","TABLE 17 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 8.79 μm 30 60 10 min (B) 6.22 μm 10 13"]],"string":"[\n [\n \"Method for improving the dissolution profile of a biologically active material\",\n \"A method for improving the dissolution profile of a biologically active material\"\n ],\n [\n \"1.A method for improving the dissolution profile of a biologically active material, comprising the steps of: dry milling a solid biologically active material and a millable grinding matrix in a mill, for a time period sufficient to produce particles of the biologically active material dispersed in an at least partially milled grinding material.\",\n \"2.The method of claim 1, wherein the particles have an average particle size equal or greater than 1 μm determined on a particle number basis.\",\n \"3.A method of claim 2, wherein the average particle size of the biologically active material has been reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.\",\n \"4.-52.\",\n \"(canceled)\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>Poor bioavailability is a significant problem encountered in the development of therapeutic compositions, particularly those materials containing a biologically active material that is poorly soluble in water at physiological pH.\",\n \"An active material's bioavailability is the degree to which the active material becomes available to the target tissue in the body after systemic administration through, for example, oral or intravenous means.\",\n \"Many factors affect bioavailability, including the form of dosage and the solubility and dissolution rate of the active material.\",\n \"Poorly and slowly water-soluble materials tend to be eliminated from the gastrointestinal tract before being absorbed into the circulation.\",\n \"In addition, poorly soluble active agents tend to be disfavored or even unsafe for intravenous administration due to the risk of particles of agent blocking blood flow through capillaries.\",\n \"It is known that the rate of dissolution of a particulate drug will increase with increasing surface area.\",\n \"One way of increasing surface area is decreasing particle size.\",\n \"Consequently, methods of making finely divided or sized drugs have been studied with a view to controlling the size and size range of drug particles for pharmaceutical compositions.\",\n \"For example, dry milling techniques have been used to reduce particle size and hence influence drug absorption.\",\n \"However, in conventional dry milling the limit of fineness is reached generally in the region of about 100 microns (100,000 nm), at which point material cakes on the milling chamber and prevents any further diminution of particle size.\",\n \"Alternatively, wet grinding may be employed to reduce particle size, but flocculation restricts the lower particle size limit to approximately 10 microns (10,000 nm).\",\n \"The wet milling process, however, is prone to contamination, thereby leading to a bias in the pharmaceutical art against wet milling.\",\n \"Another alternative milling technique, commercial airjet milling, has provided particles ranging in average size from as low as about 1 to about 50 microns (1,000-50,000 nm).\",\n \"There are several approaches currently used to formulate poorly soluble active agents.\",\n \"One approach is to prepare the active agent as a soluble salt.\",\n \"Where this approach cannot be employed, alternate (usually physical) approaches are employed to improve the solubility of the active agent.\",\n \"Alternate approaches generally subject the active agent to physical conditions that change the agent's physical and or chemical properties to improve its solubility.\",\n \"These include process technologies such as micronization, modification of crystal or polymorphic structure, development of oil based solutions, use of co-solvents, surface stabilizers or complexing agents, micro-emulsions, super critical fluid and production of solid dispersions or solutions.\",\n \"More than one of these processes may be used in combination to improve formulation of a particular therapeutic material.\",\n \"Many of these approaches commonly convert a drug into an amorphous state, which generally leads to a higher dissolution rate.\",\n \"However, formulation approaches that result in the production of amorphous material are not common in commercial formulations due to concerns relating to stability and the potential for material to re-crystallize.\",\n \"These techniques for preparing such pharmaceutical compositions tend to be complex.\",\n \"By way of example, a principal technical difficulty encountered with emulsion polymerization is the removal of contaminants, such as unreacted monomers or initiators (which may have undesirable levels of toxicity), at the end of the manufacturing process.\",\n \"Another method of providing reduced particle size is the formation of pharmaceutical drug microcapsules, which techniques include micronizing, polymerisation and co-dispersion.\",\n \"However, these techniques suffer from a number of disadvantages including at least the inability to produce sufficiently small particles such as those obtained by milling, and the presence of co-solvents and/or contaminants such as toxic monomers which are difficult to remove, leading to expensive manufacturing processes.\",\n \"Over the last decade, intense scientific investigation has been carried out to improve the solubility of active agents by converting the agents to ultra fine powders by methods such as milling and grinding.\",\n \"These techniques may be used to increase the dissolution rate of a particulate solid by increasing the overall surface area and decreasing the mean particle size.\",\n \"U.S. Pat.\",\n \"No.\",\n \"6,634,576 discloses examples of wet-milling a solid substrate, such as a pharmaceutically active compound, to produce a “synergetic co-mixture”.\",\n \"International Patent Application PCT/AU2005/001977 (Nanoparticle Composition(s) and Method for Synthesis Thereof) describes, inter alia, a method comprising the step of contacting a precursor compound with a co-reactant under mechanochemical synthesis conditions wherein a solid-state chemical reaction between the precursor compound and the co-reactant produces therapeutically active nanoparticles dispersed in a carrier matrix.\",\n \"Mechanochemical synthesis, as discussed in International Patent Application PCT/AU2005/001977, refers to the use of mechanical energy to activate, initiate or promote a chemical reaction, a crystal structure transformation or a phase change in a material or a mixture of materials, for example by agitating a reaction mixture in the presence of a milling media to transfer mechanical energy to the reaction mixture, and includes without limitation “mechanochemical activation”, “mechanochemical processing”, “reactive milling”, and related processes.\",\n \"International Patent Application PCT/AU2007/000910 (Methods for the preparation of biologically active compounds in nanoparticulate form) describes, inter alia, a method for dry milling raloxifene with lactose and NaCl which produced nanoparticulate raloxifene without significant aggregation problems.\",\n \"One limitation of this method is an upper limit to the drug content that can be successfully milled to produce nanoparticles.\",\n \"For some drugs that require a high dose this limitation may restrict the options available for the production of a commercially viable dosage form.\",\n \"The present invention provides methods for improving the dissolution profile of a biologically active material which ameliorate some of the problems attendant with prior technologies, or provides an alternative thereto.\",\n \"One example of a therapeutic area where this technology could be applied in is the area of acute pain management.\",\n \"Many pain medications such as meloxicam (marketed as Mobic® by pharmaceutical company Boehringer Ingelheim) provides pain relief for chronic pain, but must be taken on a daily basis to maintain an effective therapeutic level.\",\n \"Meloxicam is a poorly water soluble drug which is only slowly absorbed by the body (Tmax is 4-5 hours), so a method such as the present invention which provides for improved dissolution, will likely provide much faster absorption resulting in a more rapid onset of the therapeutic effect.\",\n \"Meloxicam also has a long half life (15-20 hours) that means it only need be taken once a day.\",\n \"By using a method such as the present invention, which provides faster absorption, a drug such as meloxicam, could be transformed from a chronic pain drug to an acute pain drug.\",\n \"For meloxicam this would provide a medication that could provide therapeutic relief for acute pain, with the advantage of sustained pain relief over 24 hours.\",\n \"Meloxicam also has sub-optimal bioavailability at 89% for an oral capsule, compared with an IV dosage form.\",\n \"A component of this sub optimal bioavailability is also likely due to the poor water solubility of this drug.\",\n \"If the low solubility does contribute to this sub optimal bioavailability, the improvement of the dissolution of this drug with a method such as the present invention could provide scope to produce a dosage form with a lower active dose whilst still providing the effective therapeutic dose.\",\n \"Although the background to the present invention is discussed in the context of improving the bioavailability of materials that are poorly or slowly water soluble, the applications of the methods of the present invention are not limited to such, as is evident from the following description of the invention.\",\n \"Further, although the background to the present invention is largely discussed in the context of improving the bioavailability of therapeutic or pharmaceutical compounds, the applications of the methods of the present invention are clearly not limited to such.\",\n \"For example, as is evident from the following description, applications of the methods of the present invention include but are not limited to: nutraceutical and nutritional compounds, complementary medicinal compounds, veterinary therapeutic applications and agricultural chemical applications, such as pesticide, fungicide or herbicide.\",\n \"Furthermore, an application of the current invention would be to materials which contain a biologically active compound such as, but not limited to a therapeutic or pharmaceutical compound, a nutraceutical or nutrient, a complementary medicinal product such as active components in plant or other naturally occurring material, a veterinary therapeutic compound or an agricultural compound such as a pesticide, fungicide or herbicide.\",\n \"Specific examples would be the spice turmeric that contains the active compound curcumin, or flax seed that contains the nutrient ALA an omega-3 fatty acid.\",\n \"As these specific examples indicate this invention could be applied to, but not limited to, a range of natural products such as seeds, cocoa and cocoa solids, coffee, herbs, spices, other plant materials or food materials that contain a biologically active compound.\",\n \"The application of this invention to these types of materials would enable greater availability of the active compound in the materials when used in the relevant application.\",\n \"For example where material subject to this invention is orally ingested the active would be more bioavailable.\"\n ],\n [\n \"<SOH> SUMMARY OF THE INVENTION <EOH>In one aspect the present invention is directed to the unexpected finding that the dissolution profile of biologically active materials can be improved by dry milling solid biologically active material to a particle size of greater than 1 μm.\",\n \"In one surprising aspect of the invention, the dissolution profile of a biologically active material can be improved without substantially reducing the particle size of the material or reducing the material to nanoparticulate form.\",\n \"In another surprising aspect of the invention, the material retains its crystalline structure and is not amorphous, yet the dissolution profile of the biologically active material is improved.\",\n \"In another surprising aspect of the invention, the dissolution profile of a biologically active material is improved without the need for a surfactant or stabiliser.\",\n \"In another surprising aspect of the invention, the dissolution profile of a biologically active material is improved without the need for a disintegrant to be present during the milling process.\",\n \"Thus, in a first aspect the invention comprises a method for improving the dissolution profile of a biologically active material, comprising the steps of: dry milling a solid biologically active material and a millable grinding matrix in a mill comprising a plurality of milling bodies, for a time period sufficient to produce particles of the biologically active material dispersed in an at least partially milled grinding material.\",\n \"In one preferred embodiment, the particles have an average particle size equal or greater than 1 μm determined on a particle number basis.\",\n \"More preferably, the average particle size of the biologically active material may be reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.\",\n \"Even more preferably, the average particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-20 μm, 1-10 μm, 1-7.5 μm, 1-5 μm and 1-2 μm.\",\n \"In another preferred embodiment, the particles have a median particle size selected from the group consisting of: equal or greater than 1 μm; and equal or greater than 2 μm, wherein the median particle size is determined on a particle volume basis.\",\n \"More preferably, the percentage of particles with an average particle size greater than 1 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.\",\n \"Alternatively, the percentage of particles with an average particle size greater than 2 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.\",\n \"In another preferred embodiment, the median particle size may be reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.\",\n \"In another preferred embodiment, the median particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-20 μm, 1-10 μm, 1-7.5 μm, 1-5 μm 1-2 μm, 2-1000 μm, 2-500 μm, 2-300 μm, 2-200 μm, 2-150 μm, 2-100 μm, 2-50 μm, 2-20 μm, 2-10 μm, 2-7.5 μm and 2-5 μm.\",\n \"In another preferred embodiment, the crystallinity profile of the biologically active material is selected from the group consisting of: at least 50% of the biologically active material is crystalline, at least 60% of the biologically active material is crystalline, at least 70% of the biologically active material is crystalline, at least 75% of the biologically active material is crystalline, at least 85% of the biologically active material is crystalline, at least 90% of the biologically active material is crystalline, at least 95% of the biologically active material is crystalline and at least 98% of the biologically active material is crystalline.\",\n \"More preferably, the crystallinity profile of the biologically active material is substantially equal to the crystallinity profile of the biologically active material before the material was subjected to the method as described herein.\",\n \"In another preferred embodiment, the amorphous content of the biologically active material is selected from the group consisting of: less than 50% of the biologically active material is amorphous, less than 40% of the biologically active material is amorphous, less than 30% of the biologically active material is amorphous, less than 25% of the biologically active material is amorphous, less than 15% of the biologically active material is amorphous, less than 10% of the biologically active material is amorphous, less than 5% of the biologically active material is amorphous and less than 2% of the biologically active material is amorphous.\",\n \"Preferably, the biologically active material has no significant increase in amorphous content after subjecting the material to the method as described herein.\",\n \"In another preferred embodiment, the milling time period is a range selected from the group consisting of: between 10 minutes and 2 hours, between 10 minutes and 1 hour, between 10 minutes and 45 minutes, between 10 minutes and 30 minutes, between 5 minutes and 30 minutes, between 5 minutes and 20 minutes, between 2 minutes and 10 minutes, between 2 minutes and 5 minutes, between 1 minutes and 20 minutes, between 1 minute and 10 minutes, and between 1 minute and 5 minutes.\",\n \"In another preferred embodiment, the milling medium is selected from the group consisting of: ceramics, glasses, polymers, ferromagnetics and metals.\",\n \"Preferably, the milling medium is steel balls having a diameter selected from the group consisting of: between 1 and 20 mm, between 2 and 15 mm and between 3 and 10 mm.\",\n \"In another preferred embodiment, the milling medium is zirconium oxide balls having a diameter selected from the group consisting of: between 1 and 20 mm, between 2 and 15 mm and between 3 and 10 mm.\",\n \"Preferably, the dry milling apparatus is a mill selected from the group consisting of: attritor mills (horizontal or vertical), nutating mills, tower mills, pearl mills, planetary mills, vibratory mills, eccentric vibratory mills, gravity-dependent-type ball mills, rod mills, roller mills and crusher mills.\",\n \"Preferably the milling medium within the milling apparatus is mechanically agitated by 1, 2 or 3 rotating shafts.\",\n \"Preferably, the method is configured to produce the biologically active material in a continuous fashion.\",\n \"Preferably, the total combined amount of biologically active material and grinding matrix in the mill at any given time is equal to or greater than a mass selected from the group consisting of: 200 grams, 500 grams, 1 kg, 2 kg, 5 kg, 10 kg, 20 kg, 30 kg, 50 kg, 75 kg, 100 kg, 150 kg, 200 kg.\",\n \"Preferably, the total combined amount of biologically active material and grinding matrix is less than 2000 kg.\",\n \"In another preferred embodiment, the biologically active material is selected from the group consisting of: fungicides, pesticides, herbicides, seed treatments, cosmeceuticals, cosmetics, complementary medicines, natural products, vitamins, nutrients, nutraceuticals, pharmaceutical actives, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids additives, foods and food ingredients and analogs, homologs and first order derivatives thereof.\",\n \"Preferably, the biologically active material is selected from the group consisting of: anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, such as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives (hypnotics and neuroleptics), astringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (anti-parkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones (including steroids), anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines.\",\n \"Preferably, the biologically active material is selected from the group consisting of: indomethacin, diclofenac, naproxen, meloxicam, metaxalone, cyclosporin A, progesterone celecoxib, cilostazol, ciprofloxacin, 2,4-dichlorophenoxyacetic acid, anthraquinone, creatine monohydrate, glyphosate, halusulfuron, mancozeb, metsulfuron, salbutamol, sulphur, tribenuran and estradiol or any salt or derivative thereof.\",\n \"In another preferred embodiment, the grinding matrix is a single matrix or is a mixture of two or more matrices in any proportion.\",\n \"Preferably, the major components of the grinding matrix are selected from the group consisting of: mannitol, sorbitol, Isomalt, xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, glucose, fructose, mannose, galactose, anhydrous lactose, lactose monohydrate, sucrose, maltose, trehalose, maltodextrins, dextrin, Inulin, dextrates, polydextrose, starch, wheat flour, corn flour, rice flour, rice starch, tapioca flour, tapioca starch, potato flour, potato starch, other flours and starches, milk powder, skim milk powders, other milk solids and derivatives, soy flour, soy meal or other soy products, cellulose, microcrystalline cellulose, microcrystalline cellulose based co blended materials, pregelatinized (or partially) starch, HPMC, CMC, HPC, citric acid, tartaric acid, malic acid, maleic acid fumaric acid, ascorbic acid, succinic acid, sodium citrate, sodium tartrate, sodium malate, sodium ascorbate, potassium citrate, potassium tartrate, potassium malate, potassium ascorbate, sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate and calcium carbonate.\",\n \"dibasic calcium phosphate, tribasic calcium phosphate, sodium sulfate, sodium chloride, sodium metabisulphite, sodium thiosulfate, ammonium chloride, Glauber's salt, ammonium carbonate, sodium bisulfate, magnesium sulfate, potash alum, potassium chloride, sodium hydrogen sulfate, sodium hydroxide, crystalline hydroxides, hydrogen carbonates, ammonium chloride, methylamine hydrochloride, ammonium bromide, silica, thermal silica, alumina, titanium dioxide, talc, chalk, mica, kaolin, bentonite, hectorite, magnesium trisilicate, clay based materials or aluminium silicates, sodium lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate, sodium cetostearyl sulfate, sodium docusate, sodium deoxycholate, N-lauroylsarcosine sodium salt, glyceryl monostearate, glycerol distearate glyceryl palmitostearate, glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzalkonium chloride, CTAB, CTAC, Cetrimide, cetylpyridinium chloride, cetylpyridinium bromide, benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188, poloxamer 407, poloxamer 338, polyoxyl 2 stearyl ether, polyoxyl 100 stearyl ether, polyoxyl 20 stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 20 cetyl ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl 35 castor oil, polyoxyl 40 castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor oil, polyoxyl 200 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyoxyl 100 hydrogenated castor oil, polyoxyl 200 hydrogenated castor oil, cetostearyl alcohol, macrogel 15 hydroxystearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, Sucrose Palmitate, Sucrose Stearate, Sucrose Distearate, Sucrose laurate, Glycocholic acid, sodium Glycholate, Cholic Acid, Sodium Cholate, Sodium Deoxycholate, Deoxycholic acid, Sodium taurocholate, taurocholic acid, Sodium taurodeoxycholate, taurodeoxycholic acid, soy lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonate condensate/Lignosulfonate blend, Calcium Dodecylbenzene Sulfonate, Sodium Dodecylbenzene Sulfonate, Diisopropyl naphthalenesulphonate, erythritol distearate, Naphthalene Sulfonate Formaldehyde Condensate, nonylphenol ethoxylate (poe-30), Tristyrylphenol Ethoxylate, Polyoxyethylene (15) tallowalkylamines, sodium alkyl naphthalene sulfonate, sodium alkyl naphthalene sulfonate condensate, sodium alkylbenzene sulfonate, sodium isopropyl naphthalene sulfonate, Sodium Methyl Naphthalene Formaldehyde Sulfonate, sodium n-butyl naphthalene sulfonate, tridecyl alcohol ethoxylate (poe-18), Triethanolamine isodecanol phosphate ester, Triethanolamine tristyrylphosphate ester, Tristyrylphenol Ethoxylate Sulfate, Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"Preferably, the concentration of the single (or first) material is selected from the group consisting of: 5-99% w/w, 10-95% w/w, 15-85% w/w, of 20-80% w/w, 25-75% w/w, 30-60% w/w, 40-50% w/w.\",\n \"Preferably, the concentration of the second or subsequent material is selected from the group consisting of: 5-50% w/w, 5-40% w/w, 5-30% w/w, of 5-20% w/w, 10-40% w/w, 10-30% w/w, 10-20% w/w, 20-40% w/w, or 20-30% w/w or if the second or subsequent material is a surfactant or water soluble polymer the concentration is selected from 0.1-10% w/w, 0.1-5% w/w, 0.1-2.5% w/w, of 0.1-2% w/w, 0.1-1%, 0.5-5% w/w, 0.5-3% w/w, 0.5-2% w/w, 0.5-1.5%, 0.5-1% w/w, of 0.75-1.25% w/w, 0.75-1% and 1% w/w.\",\n \"Preferably, the grinding matrix is selected from the group consisting of: (a) lactose monohydrate or lactose monohydrate combined with at least one material selected from the group consisting of: xylitol; lactose anhydrous; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"(b) lactose anhydrous or lactose anhydrous combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"(c) mannitol or mannitol combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; lactose anhydrous; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"(d) Sucrose or sucrose combined with at least one material selected from the group consisting of: lactose monohydrate; lactose anhydrous; mannitol; microcrystalline cellulose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"(e) Glucose or glucose combined with at least one material selected from the group consisting of: lactose monohydrate; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"(f) Sodium chloride or sodium chloride combined with at least one material selected from the group consisting of: lactose monohydrate; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"(g) xylitol or xylitol combined with at least one material selected from the group consisting of: lactose monohydrate; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"(h) Tartaric acid or tartaric acid combined with at least one material selected from the group consisting of: lactose monohydrate; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"(i) microcrystalline cellulose or microcrystalline cellulose combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; lactose anhydrous; mannitol; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"(j) Kaolin combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"(k) Talc combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"Preferably, the grinding matrix is selected from the group consisting of: a material considered to be Generally Regarded as Safe (GRAS) for pharmaceutical products; a material considered acceptable for use in an agricultural formulation; and a material considered acceptable for use in a veterinary formulation.\",\n \"In another preferred embodiment, a milling aid is used or a combination of milling aids.\",\n \"Preferably, the milling aid is selected from the group consisting of: colloidal silica, a surfactant, a polymer, a stearic acid and derivatives thereof.\",\n \"Preferably, the surfactant is selected from the group consisting of: polyoxyethylene alkyl ethers, polyoxyethylene stearates, polyethylene glycols (PEG), poloxamers, poloxamines, sarcosine based surfactants, polysorbates, aliphatic alcohols, alkyl and aryl sulfates, alkyl and aryl polyether sulfonates and other sulfate surfactants, trimethyl ammonium based surfactants, lecithin and other phospholipids, bile salts, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, Sorbitan fatty acid esters, Sucrose fatty acid esters, alkyl glucopyranosides, alkyl maltopyranosides, glycerol fatty acid esters, Alkyl Benzene Sulphonic Acids, Alkyl Ether Carboxylic Acids, Alkyl and aryl Phosphate esters, Alkyl and aryl Sulphate esters, Alkyl and aryl Sulphonic acids, Alkyl Phenol Phosphates esters, Alkyl Phenol Sulphates esters, Alkyl and Aryl Phosphates, Alkyl Polysaccharides, Alkylamine Ethoxylates, Alkyl-Naphthalene Sulphonates formaldehyde condensates, Sulfosuccinates, lignosulfonates, Ceto-Oleyl Alcohol Ethoxylates, Condensed Naphthalene Sulphonates, Dialkyl and Alkyl Naphthalene Sulphonates, Di-alkyl Sulphosuccinates, Ethoxylated nonylphenols, Ethylene Glycol Esters, Fatty Alcohol Alkoxylates, Hydrogenated tallowalkylamines, Mono-alkyl Sulphosuccinamates, Nonyl Phenol Ethoxylates, Sodium Oleyl N-methyl Taurate, Tallowalkylamines, linear and branched dodecylbenzene sulfonic acids Preferably, the surfactant is selected from the group consisting of: sodium lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate, sodium cetostearyl sulfate, sodium docusate, sodium deoxycholate, N-lauroylsarcosine sodium salt, glyceryl monostearate, glycerol distearate glyceryl palmitostearate, glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzalkonium chloride, CTAB, CTAC, Cetrimide, cetylpyridinium chloride, cetylpyridinium bromide, benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188, poloxamer 407, poloxamer 338, polyoxyl 2 stearyl ether, polyoxyl 100 stearyl ether, polyoxyl 20 stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 20 cetyl ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl 35 castor oil, polyoxyl 40 castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor oil, polyoxyl 200 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyoxyl 100 hydrogenated castor oil, polyoxyl 200 hydrogenated castor oil, cetostearyl alcohol, macrogel 15 hydroxystearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, Sucrose Palmitate, Sucrose Stearate, Sucrose Distearate, Sucrose laurate, Glycocholic acid, sodium Glycholate, Cholic Acid, Sodium Cholate, Sodium Deoxycholate, Deoxycholic acid, Sodium taurocholate, taurocholic acid, Sodium taurodeoxycholate, taurodeoxycholic acid, soy lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonate condensate/Lignosulfonate blend, Calcium Dodecylbenzene Sulfonate, Sodium Dodecylbenzene Sulfonate, Diisopropyl naphthalenesulphonate, erythritol distearate, Naphthalene Sulfonate Formaldehyde Condensate, nonylphenol ethoxylate (poe-30), Tristyrylphenol Ethoxylate, Polyoxyethylene (15) tallowalkylamines, sodium alkyl naphthalene sulfonate, sodium alkyl naphthalene sulfonate condensate, sodium alkylbenzene sulfonate, sodium isopropyl naphthalene sulfonate, Sodium Methyl Naphthalene Formaldehyde Sulfonate, sodium n-butyl naphthalene sulfonate, tridecyl alcohol ethoxylate (poe-18), Triethanolamine isodecanol phosphate ester, Triethanolamine tristyrylphosphate ester, Tristyrylphenol Ethoxylate Sulfate, Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"Preferably the polymer is selected from the list of: polyvinylpyrrolidones (PVP), polyvinylalcohol, Acrylic acid based polymers and copolymers of acrylic acid.\",\n \"Preferably, the milling aid has a concentration selected from the group consisting of: 0.1-10 w/w, 0.1-5% w/w, 0.1-2.5% w/w, of 0.1-2% w/w, 0.1-1%, 0.5-5% w/w, 0.5-3% w/w, 0.5-2% w/w, 0.5-1.5%, 0.5-1% w/w, of 0.75-1.25% w/w, 0.75-1% and 1% w/w.\",\n \"Preferably the biologically active ingredient is milled with lactose monohydrate; mannitol; glucose; microcrystalline cellulose; tartaric acid; or lactose monohydrate and sodium dodecyl sulfate.\",\n \"Preferably, Diclofenac is milled with lactose mono-hydrate.\",\n \"Preferably, Meloxicam is milled with mannitol.\",\n \"Preferably, Diclofenac is milled with mannitol.\",\n \"Preferably, Meloxicam is milled with glucose.\",\n \"Preferably, Diclofenac is milled with glucose.\",\n \"Preferably, Meloxicam is milled with microcrystalline cellulose.\",\n \"Preferably, diclofenac in microcrystalline cellulose.\",\n \"Preferably, Meloxicam is milled with Tartaric acid.\",\n \"Preferably, Meloxicam is milled with lactose monohydrate.\",\n \"Preferably, Meloxicam is milled with mannitol.\",\n \"Preferably, Diclofenac is milled with lactose mono-hydrate and sodium dodecyl sulfate.\",\n \"Preferably, Meloxicam is milled with lactose monohydrate and sodium dodecyl sulfate.\",\n \"In another preferred embodiment, a facilitating agent or combination of facilitating agents is used.\",\n \"Preferably, the facilitating agent is selected from the group consisting of: surface stabilizers, binding agents, filling agents, lubricating agents, sweeteners, flavouring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents, agents that may form part of a medicament, including a solid dosage form and other excipient required for specific drug delivery.\",\n \"Preferably, the facilitating agent is added during dry milling.\",\n \"Preferably, the facilitating agent is added to the milled biologically active material and grinding matrix and further processed in a mechanofusion process.\",\n \"Mechanofusion milling causes mechanical energy to be applied to powders or mixtures of particles in the micrometre and nanometre.\",\n \"The reasons for including facilitating agents include, but are not limited to providing better dispersibility, control of agglomeration, the release or retention of the active particles from the delivery matrix.\",\n \"Examples of facilitating agents include, but are not limited to stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, sodium stearyl lactylate, zinc stearate, sodium stearate or lithium stearate, other solid state fatty acids such as oleic acid, lauric acid, palmitic acid, erucic acid, behenic acid, or derivatives (such as esters and salts), amino acids such as leucine, isoleucine, lysine, valine, methionine, phenylalanine, aspartame or acesulfame K. In a preferred aspect of manufacturing this formulation the facilitating agent is added to the milled mixture of biologically active material and co-grinding matrix and further processed in another milling device such as Mechanofusion, Cyclomixing, or impact milling such as ball milling, jet milling, or milling using a high pressure homogeniser, or combinations thereof.\",\n \"In a highly preferred aspect the facilitating agent is added to the milling of the mixture of biologically active material and co-grinding matrix as some time before the end of the milling process.\",\n \"Preferably, the facilitating agent is added to the dry milling at a time selected from the group consisting of: with 1-5% of the total milling time remaining, with 1-10% of the total milling time remaining, with 1-20% of the total milling time remaining, with 1-30% of the total milling time remaining, with 2-5% of the total milling time remaining, with 2-10% of the total milling time remaining, with 5-20% of the total milling time remaining and with 5-20% of the total milling time remaining.\",\n \"In another preferred embodiment, a disintegrant is selected from the group consisting of: crosslinked PVP, cross linked carmellose and sodium starch glycolate.\",\n \"In another preferred embodiment, the dissolution profile of the measurement sample or prototype formulation thereof is improved by a factor selected from the group consisting of: wherein X is reached in 10 minutes, wherein X is reached within 10-20 minutes, wherein X is reached within 10-30 mins, wherein X is reached within 10-40 mins, wherein X is reached within 10-50 mins, wherein X is reached within 20-30 mins, wherein X is reached within 20-40 mins, wherein X is reached within 20-50 mins, wherein X is reached within 30-40 mins, wherein X is reached within 30-50 mins and wherein X is reached within 40-50 mins, wherein X is defined as the concentration equal to the dissolution concentration achieved by a control sample or prototype formulation thereof of the biologically active material or compound after 60 minutes.\",\n \"In another preferred embodiment, the dissolution profile of the measurement sample or prototype formulation thereof is improved by a factor selected from the group consisting of: wherein Y is reached in 5 minutes, wherein Y is reached within 10 minutes, wherein Y is reached within 10-15 mins, wherein Y is reached within 10-20 mins, wherein Y is reached within 10-25 mins, wherein Y is reached within 15-20 mins, wherein Y is reached within 15-25 mins, wherein Y is reached within 20-25 mins, wherein Y is defined as the concentration equal to the dissolution concentration achieved by a control sample (or prototype formulation thereof) of the biologically active material or compound after 30 minutes.\",\n \"In a second aspect the invention comprises a biologically active material produced by the method described herein and composition comprising the biologically active material as described herein.\",\n \"Preferably, the particles have an average particle size equal or greater than 1 μm determined on a particle number average basis.\",\n \"Preferably, the average particle size of the biologically active material has been reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.\",\n \"Preferably, the average particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-20 μm, 1-10 μm, 1-7.5 μm, 1-5 μm and 1-2 μm.\",\n \"Preferably, the particles have a median particle size selected from the group consisting of: equal or greater than 1 μm; and equal or greater than 2 μm, wherein the median particle size is determined on a particle volume basis.\",\n \"Preferably, the percentage of particles with an average particle size greater than 1 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.\",\n \"Preferably, the percentage of particles with an average particle size greater than 2 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.\",\n \"Preferably, the median particle size has been reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.\",\n \"Preferably, the median particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-20 μm, 1-10 μm, 1-7.5 μm, 1-5 μm 1-2 μm, 2-1000 μm, 2-500 μm, 2-300 μm, 2-200 μm, 2-150 μm, 2-100 μm, 2-50 μm, 2-20 μm, 2-10 μm, 2-7.5 μm and 2-5 μm.\",\n \"Preferably, the crystallinity profile of the biologically active material is selected from the group consisting of: at least 50% of the biologically active material is crystalline, at least 60% of the biologically active material is crystalline, at least 70% of the biologically active material is crystalline, at least 75% of the biologically active material is crystalline, at least 85% of the biologically active material is crystalline, at least 90% of the biologically active material is crystalline, at least 95% of the biologically active material is crystalline and at least 98% of the biologically active material is crystalline.\",\n \"Preferably, the crystallinity profile of the biologically active material is substantially equal to the crystallinity profile of the biologically active material before the material was subject to the method described herein.\",\n \"Preferably, the amorphous content of the biologically active material is selected from the group consisting of: less than 50% of the biologically active material is amorphous, less than 40% of the biologically active material is amorphous, less than 30% of the biologically active material is amorphous, less than 25% of the biologically active material is amorphous, less than 15% of the biologically active material is amorphous, less than 10% of the biologically active material is amorphous, less than 5% of the biologically active material is amorphous and less than 2% of the biologically active material is amorphous.\",\n \"Preferably, the biologically active material has had no significant increase in amorphous content following subjecting the material to the method as described herein.\",\n \"Preferably, the biologically active material is selected from the group consisting of: fungicides, pesticides, herbicides, nutraceuticals, pharmaceutical actives, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids and analogs, homologs and first order derivatives thereof.\",\n \"Preferably, the biologically active material is selected from the group consisting of: anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, such as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives (hypnotics and neuroleptics), astringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (anti-parkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones (including steroids), anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines.\",\n \"Preferably, the biologically active material is selected from the group consisting of: indomethacin, diclofenac, naproxen, meloxicam, metaxalone, cyclosporin A, progesterone celecoxib, cilostazol, ciprofloxacin, 2,4-dichlorophenoxyacetic acid, anthraquinone, creatine monohydrate, glyphosate, halusulfuron, mancozeb, metsulfuron, salbutamol, sulphur, tribenuran and estradiol or any salt or derivative thereof.\",\n \"In one preferred embodiment, the invention comprises compositions comprising the biologically active ingredient together with a grinding matrix, a mixture of grinding matrix materials, milling aids, mixtures of milling aids, facilitating agents and/or mixtures of facilitating agents as described herein, in concentrations and ratios as described herein under the methods of the invention.\",\n \"In a third aspect the invention comprises a pharmaceutical composition comprising a biologically active material produced by the method described herein and compositions described herein.\",\n \"Preferably, the invention comprises pharmaceutical compositions comprising the biologically active ingredient together with a grinding matrix, a mixture of grinding matrix materials, milling aids, mixtures of milling aids, facilitating agents and/or mixtures of facilitating agents as described herein, in concentrations and ratios as described herein under the methods of the invention.\",\n \"Preferably, the particles have an average particle size equal or greater than 1 μm determined on a particle number basis.\",\n \"Preferably, the average particle size of the biologically active material has been reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.\",\n \"Preferably, the average particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-μm, 1-10 μm, 1-7.5 μm, 1-5 μm and 1-2 μm.\",\n \"Preferably, the particles have a median particle size selected from the group consisting of: equal or greater than 1 μm; and equal or greater than 2 μm, wherein the median particle size is determined on a particle volume basis.\",\n \"Preferably, the percentage of particles with an average particle size greater than 1 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.\",\n \"Preferably, the percentage of particles with an average particle size greater than 2 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.\",\n \"Preferably, the median particle size has been reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.\",\n \"Preferably, the median particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-20 μm, 1-10 μm, 1-7.5 μm, 1-5 μm 1-2 μm, 2-1000 μm, 2-500 μm, 2-300 μm, 2-200 μm, 2-150 μm, 2-100 μm, 2-50 μm, 2-20 μm, 2-10 μm, 2-7.5 μm and 2-5 μm.\",\n \"Preferably, the crystallinity profile of the biologically active material is selected from the group consisting of: at least 50% of the biologically active material is crystalline, at least 60% of the biologically active material is crystalline, at least 70% of the biologically active material is crystalline, at least 75% of the biologically active material is crystalline, at least 85% of the biologically active material is crystalline, at least 90% of the biologically active material is crystalline, at least 95% of the biologically active material is crystalline and at least 98% of the biologically active material is crystalline.\",\n \"Preferably, the crystallinity profile of the biologically active material is substantially equal to the crystallinity profile of the biologically active material before the material was subject to the method as described herein.\",\n \"Preferably, the amorphous content of the biologically active material is selected from the group consisting of: less than 50% of the biologically active material is amorphous, less than 40% of the biologically active material is amorphous, less than 30% of the biologically active material is amorphous, less than 25% of the biologically active material is amorphous, less than 15% of the biologically active material is amorphous, less than 10% of the biologically active material is amorphous, less than 5% of the biologically active material is amorphous and less than 2% of the biologically active material is amorphous.\",\n \"Preferably, the biologically active material has no significant increase in amorphous content after subjecting the material to the method as described herein.\",\n \"Preferably, the biologically active material is selected from the group consisting of: new chemical entities, pharmaceutical actives, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids and analogs, homologs and first order derivatives thereof.\",\n \"Preferably, the biologically active material is selected from the group consisting of: anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, such as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives (hypnotics and neuroleptics), astringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (anti-parkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones (including steroids), anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines.\",\n \"Preferably, the biologically active material is selected from the group consisting of: indomethacin, diclofenac, naproxen, meloxicam, metaxalone, cyclosporin A, progesterone celecoxib, cilostazol, ciprofloxacin, 2,4-dichlorophenoxyacetic acid, anthraquinone, creatine monohydrate, glyphosate, halusulfuron, mancozeb, metsulfuron, salbutamol, sulphur, tribenuran and estradiol or any salt or derivative thereof.\",\n \"Preferably cosmeceuticals, cosmetics, complementary medicines, natural products, vitamins, nutrients and nutraceuticals are selected from the group consisting of: Glycolic acids, Lactic acids, Carrageenan, Almonds, Mahogany wood, Andrographis Paniculata , Aniseed, Anthemis nobilis (chamomile), Apricot kernel, leaves of bearberry, leaves of cranberry, leaves of blueberry, leaves of pear trees, beta-carotene, black elderberry, black raspberry, black walnut shell, blackberry, bladderwrack, bletilla striata , borage seed, boysenberry, brazil nut, burdock root, butcher's broom extract, calamine, calcium gluconate, calendula, carnosic acid, Cantella asiatica , charcoal, chaste tree fruit, Chicory root extract, chitosan, choline, cichorium intybus, clematis vitalba, coffea Arabica , coumarin, crithmum maritimum , curcumin, coffee, cocoa, cocoa powder, cocoa nibs, cocoa mass, cocoa liquor, cocoa products, dogwood, Echinacea, echium lycopsis , anise, atragalus, bilberry, bitter orange, black cohosh, cat's claw, chamomile, chasteberry, cranberry, dandelion, Echinacea, ephedra, European elder Epilobium angustifolium , horse chestnut, cloves, evening primrose, fennel seed, fenugreek, feverfew, flaxseed, fumaria officinalis , garlic, geranium, ginger, ginkgo, ginseng, goldenseal, grape seed, green tea, guava, hawthorn, hayflower, hazelnut, helichrysum, hoodia, horseradish, mulbe italicum , hibiscus, hierochloe odorata , hops, horse chestnut, ilex paraguariensis , indian gooseberry, irish moss, juniper berry, kudzu root, lady's thistle, lavender, lemongrass, lentius edodes , licorice, longifolene, loquat, lotus seed, luffa cylindrica , lupine, maroinberry, marjoram, meadowsweet, milk vetch root, mimosa tenuiflora , mistletoe, mulberry, noni, kelp, oatmeal, oregano, papaya, parsley, peony root, pomegranate, pongamia glabra seed, pongamia pinnata , quinoa seed, red raspberry, rose hip, rosemary, sage, saw palmetto, soy bean, szechuan peppercorn, tephrosia purpurea, terminalia catappa, terminalia sericea , thunder god vine, thyme, turmeric, valeriana officinalis , walnuts, white tea leaf, yam, witch hazel, wormwood, yarrow, valerian, yohimbe, mangosteen, sour sob, goji berry, spirulina and durian skin.\",\n \"In a fourth aspect the invention comprises a method of treating a human in need of such treatment comprising the step of administering to the human an effective amount of a pharmaceutical composition as described herein.\",\n \"In a fifth aspect the invention comprises a method for manufacturing a pharmaceutical composition as described herein comprising the step of combining a therapeutically effective amount of a biologically active material prepared by a method described herein together with a pharmaceutically acceptable carrier to produce a pharmaceutically acceptable dosage form.\",\n \"In a sixth aspect the invention comprises a method for manufacturing a veterinary product comprising the step of combining a therapeutically effective amount of the biologically active material prepared by a method as described herein together with an acceptable excipient to produce a dosage form acceptable for veterinary use.\",\n \"In a seventh aspect the invention comprises a method for manufacturing an agricultural product comprising the step of combining an effective amount of the biologically active material prepared by a method described herein together with acceptable excipients to produce a formulation such as, but not limited to a water dispersible granule, wettable granule, dry flowable granule or soluble granule that is used to prepare a solution for use in agricultural applications.\",\n \"Preferably, the product is selected from the group consisting of: herbicides, pesticides, seed treatments, herbicide safeners, plant growth regulators and fungicides.\",\n \"The methods of the invention can be used to increase the dissolution of the biologically active material particles in water or other solvents, resulting in better, faster or more complete preparation and mixing.\",\n \"This will result in a more consistent product performance such as better weed, disease and pest control and other practical benefits such as faster machinery, tank and sprayer cleanout, less rinsate, and a reduced impact on the environment.\",\n \"In a future aspect the invention comprises a method for manufacturing an agricultural product comprising the step of combining an effective amount of the biologically active material prepared by a method described herein together with acceptable excipients to produce a formulation such as, but not limited to a water dispersible granule, wettable granule, wettable powder or a powder for seed treatment that is used to prepare a dry powder or particle suspension for use in agricultural applications.\",\n \"Preferably, the product is selected from the group consisting of: herbicides, pesticides, seed treatments, herbicide safeners, plant growth regulators and fungicides.\",\n \"Another preferred aspect of the method of invention would be to produce powders that have active particles with a high surface area.\",\n \"Such powders would provide better performance in areas such as seed treatment where dry powders are applied to seeds as fungicides, herbicide safeners, plant growth regulators and other treatments.\",\n \"The higher surface area would provide more activity per mass of active used.\",\n \"In another preferred aspect actives such as pesticides, fungicides and seed treatments subject to the method of invention are formulated to produce suspensions of the actives when added to water or other solvents.\",\n \"As these suspensions will have particles of very small size and high surface area they will possess at least three highly desirable traits.\",\n \"The first is that small particles with high surface area will adhere better to surfaces such as leafs and other foliage that the suspension is applied to.\",\n \"This will result in better rain fastness and a longer period of activity.\",\n \"The second aspect is that smaller particles with a higher surface area deliver superior coverage per unit mass of active applied.\",\n \"For example, if 100 particles are needed on a leaf and if the particle diameter is reduced to one third of the former diameter by the methods of this invention, then the dosage can be reduced to about 11% of the former dosage, resulting in lower cost, less residue on harvested crops, and mitigation of environmental impact.\",\n \"In the third aspect the smaller particles will deliver better bioavailability.\",\n \"With many low solubility actives, such as fungicides and pesticides the particles that adhere to plant material slowly dissolve over days and weeks providing continued protection from disease and pests.\",\n \"With this method of invention able to deliver better bioavailability in many circumstances it will be possible to reduce the amount of active that needs to be applied.\",\n \"As with the second aspect such an outcome would lower costs, minimize residues and mitigate environmental impact.\",\n \"In a highly preferred aspect of the invention the powder produced in the milling process would be subject to a process such as wet or dry granulation that makes the powder free flowing and low in dust content yet easily dispersible once in water or other solvent.\",\n \"Preferably the biologically active material is a herbicide, pesticide, seed treatment, herbicide safener, plant growth regulator or fungicide selected from the group consisting of: 2-phenylphenol, 8-hydroxyquinoline sulfate, acibenzolar, allyl alcohol, azoxystrobin, basic benomyl, benzalkonium chloride, biphenyl, blasticidin-S, Bordeaux mixture, Boscalid, Burgundy mixture, butylamine, Cadendazim, calcium polysulfide, Captan, carbamate fungicides, carbendazim, carvone, chloropicrin, chlorothalonil, ciclopirox, clotrimazole, conazole fungicides, Copper hydroxide, copper oxychloride, copper sulfate, copper(II) carbonate, copper(II) sulfate, cresol, cryprodinil, cuprous oxide, cycloheximide, Cymoxanil, DBCP, dehydroacetic acid, dicarboximide fungicides, difenoconazole, dimethomorph, diphenylamine, disulfiram, ethoxyquin, famoxadone, fenamidone, Fludioxonil, formaldehyde, fosetyl, Fosetyl-aluminium, furfural, griseofulvin, hexachlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole, imazalil, Imidacloprid, iodomethane, Iprodione, Lime sulfur, mancozeb, mercuric chloride, mercuric oxide, mercurous chloride, Metalaxyl, metam, methyl bromide, methyl isothiocyanate, metiram, natamycin, nystatin, organotin fungicides, oxythioquinox, pencycuron, pentachlorophenol, phenylmercury acetate, potassium thiocyanate, procymidone, propiconazole, propineb, pyraclostrobin, pyrazole fungicides, pyridine fungicides, pyrimethanil, pyrimidine fungicides, pyrrole fungicides, quinoline fungicides, quinone fungicides, sodium azide, streptomycin, sulfur, Tebucanazole, thiabendazole, thiomersal, tolnaftate, Tolylfluanid, triadimersol, tributyltin oxide, Trifloxystrobin, triflumuron, Undecylenic acid, urea fungicides, vinclozolin, Ziram, 3-dihydro-3-methyl-1, 3-thiazol-2-ylidene-xylidene, 4-D esters, 4-DB esters, 4-parathion methyl, Acetamiprid, aclonifen, acrinathrin, alachlor, allethrin, alpha-cypermethrin, Aluminium phosphide, amitraz, anilophos, azaconazole, azinphos-ethyl, azinphos-methyl, benalaxyl, benfluralin, benfuracarb, benfuresate, bensulide, benzoximate, benzoylprop-ethyl, betacyfluthrin, beta-cypermethrin, bifenox, bifenthrin, binapacryl, bioallethrin, bioallethrin S, bioresmethrin, biteranol, Brodifacoum, bromophos, bromopropylate, bromoxynil, bromoxynil esters, bupirimate, buprofezin, butacarboxim, butachlor, butamifos, butoxycarboxin, butralin, butylate, calcium sulfate, cambda-cyhalothrin, carbetamide, carboxin, chlordimeform, chlorfenvinphos, chlorflurazuron, chlormephos, chlornitrofen, chlorobenzilate, chlorophoxim, chloropropylate, chlorpropham, Chlorpyrifos, chlorpyrifos-methyl, cinmethylin, clethodim, clomazone, clopyralid esters, CMPP esters, cyanophos, cycloate, cycloprothrin, cycloxydim, cyfluthrin, cyhalothrin, cypermethrin, cyphenothrin, cyproconazole, deltamethrin, demeton-S-methyl, desmedipham, dichlorprop esters, dichlorvos, diclofop-methyldiethatyl, dicofol, difenoconazole, dimethachlor, dimethomoph, diniconazole, dinitramine, dinobuton, dioxabenzafos, dioxacarb, disulfoton, ditalimfos, dodemorph, dodine, edifenphos, emamectin, empenthrin, endosulfan, EPNethiofencarb, epoxyconazole, esfenvalerate, ethalfluralin, ethofumesate, ethoprophos, ethoxyethyl, etofenprox, etridiazole, etrimphos, Famoxadone, fenamiphos, fenarimol, fenazaquin, fenitrothion, fenobucarb, fenoxapropethyl, fenoxycarb, fenpropathrin, fenpropidin, fenpropimorph, fenthiocarb, fenthion, fenvalerate, fluazifop, fluazifop-P, fluchloralin, flucythrinate, flufenoxim, flufenoxuron, flumetralin, fluorodifen, fluoroglycofen ethyl, fluoroxypyr esters, flurecol butyl, flurochloralin, flusilazole, formothion, gamma-HCH, haloxyfop, haloxyfop-methyl, hexaflumuron, hydroprene, imibenconazole, indoxacarb, ioxynil esters, isofenphos, isoprocarb, isopropalin, isoxathion, malathion, maneb, MCPA esters, mecoprop-P esters, mephospholan, Metaldehyde, methidathion, Methomyl, methoprene, methoxychlor, metolachlor, mevinphos, monalide, myclobutanil, N-2, napropamide, nitrofen, nuarimol, oxadiazon, oxycarboxin, oxyfluorfen, penconazole, pendimethalin, permethrin, phenisopham, phenmedipham, phenothrin, phenthoate, phosalone, phosfolan, phosmet, picloram esters, pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, pretilachlor, prochloraz, profenofos, profluralin, promecarb, propachlor, propanil, propaphos, propaquizafop, propargite, propetamphos, pymetrozine, pyrachlofos, pyridate, pyrifenox, quinalphos, quizalofop-P, resmethrin, Spinetoram J, Spinetoram L, Spinosad A, Spinosad B, tau-fluvalinate, tebuconazole, Tebufenozide, tefluthrin, temephos, terbufos, tetrachlorinphos, tetraconazole, tetradifon, tetramethrin, Thiamethoxam, tolclofos-methyl, tralomethrin, triadimefon, triadimenol, triazophos, triclopyr esters, tridemorph, tridiphane, triflumizole, trifluralin, xylylcarb, 3-dihydro-3-methyl-1, 3-thiazol-2-ylidene-xylidene, 4-D esters, 4-DB esters, 4-parathion methyl, Acetamiprid, acetochlor, aclonifen, acrinathrin, alachlor, allethrin, alpha-cypermethrin, Aluminium phosphide, amitraz, anilophos, azaconazole, azinphos-ethyl, azinphos-methyl, benalaxyl, benfluralin, benfuracarb, benfuresate, bensulide, benzoximate, benzoylprop-ethyl, betacyfluthrin, beta-cypermethrin, bifenox, bifenthrin, binapacryl, bioallethrin, bioallethrin S, bioresmethrin, biteranol, Brodifacoum, bromophos, bromopropylate, bromoxynil, bromoxpil esters, bupirimate, buprofezin, Butacarboxim, butachlor, butamifos, butoxycarboxin, butralin, butylate, calcium sulfate, cambda-cyhalothrin, carbetamide, carboxin, chlordimeform, chlorfenvinphos, chlorflurazuron, chlormephos, chlornitrofen, chlorobenzilate, chlorophoxim, chloropropylate, chlorpropham, Chlorpyrifos, chlorpyrifos-methyl, cinmethylin, clethodim, clomazone, clopyralid esters, CMPP esters, cyanophos, cycloate, cycloprothrin, cycloxydim, cyfluthrin, cyhalothrin, cypermethrin, cyphenothrin, cyproconazole, deltamethrin, demeton-S-methyl, desmedipham, dichlorprop esters, dichlorvos, diclofop-methyldiethatyl, dicofol, dimethachlor, dimethomoph, diniconazole, dinitramine, dinobuton, dioxabenzafos, dioxacarb, disulfoton, ditalimfos, dodemorph, dodine, edifenphos, emamectin, empenthrin, endosulfan, EPNethiofencarb, epoxyconazole, esfenvalerate, ethalfluralin, ethofumesate, ethoprophos, ethoxyethyl, ethoxyquin, etofenprox, etridiazole, etrimphos, fenamiphos, fenarimol, fenazaquin, fenitrothion, fenobucarb, fenoxapropethyl, fenoxycarb, fenpropathrin, fenpropidin, fenpropimorph, fenthiocarb, fenthion, fenvalerate, fluazifop, fluazifop-P, fluchloralin, flucythrinate, flufenoxim, flufenoxuron, flumetralin, fluorodifen, fluoroglycofen ethyl, fluoroxypyr esters, flurecol butyl, flurochloralin, flusilazole, formothion, gamma-HCH, haloxyfop, haloxyfop-methyl, hexaflumuron, hydroprene, imibenconazole, indoxacarb, ioxynil esters, isofenphos, isoprocarb, isopropalin, isoxathion, malathion, maneb, MCPA esters, mecoprop-P esters, mephospholan, Metaldehyde, methidathion, Methomyl, methoprene, methoxychlor, mevinphos, monalide, myclobutanil, myclobutanil, N-2, napropamide, nitrofen, nuarimol, oxadiazon, oxycarboxin, oxyfluorfen, penconazole, permethrin, phenisopham, phenmedipham, phenothrin, phenthoate, phosalone, phosfolan, phosmet, picloram esters, pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, pretilachlor, prochloraz, profenofos, profluralin, promecarb, propachlor, propanil, propaphos, propaquizafop, propargite, propetamphos, pymetrozine, pyridate, pyrifenox, quinalphos, quizalofop-P, resmethrin, Spinetoram J, Spinetoram L, Spinosad A, Spinosad B, tau-fluvalinate, Tebufenozide, tefluthrin, temephos, terbufos, tetrachlorinphos, tetraconazole, tetradifon, tetramethrin, Thiamethoxam, tolclofos-methyl, tralomethrin, triadimenol, triazophos, triclopyr esters, tridemorph, tridiphane, triflumizole, trifluralin, xylylcarb and any combination thereof.\",\n \"In an eighth aspect the invention comprises a method for manufacturing of a pharmaceutical formulation comprising the step of combining an effective amount of the biologically active material prepared by a method described herein together with acceptable excipients to produce a formulation that can deliver a therapeutically effective amount of active to the pulmonary or nasal area.\",\n \"Such a formulation could be, but is not limited to a dry powder formulation for oral inhalation to the lungs or a formulation for nasal inhalation.\",\n \"Preferably the method for manufacturing such a formulation uses lactose, mannitol, sucrose, sorbitol, xylitol or other sugars or polyols as the co-grinding matrix together with surfactant such as, but not limited to lecithin, DPPC (dipalmitoyl phosphatidylcholine), PG (phosphatidylglycerol), dipalmitoyl phosphatidyl ethanolamine (DPPE), dipalmitoyl phosphatidylinositol (DPPI) or other phospholipid.\",\n \"The particle size of the material produced by the invention disclosed herein results in the materials being readily aerosolized and suitable for methods of delivery to a subject in need thereof, including pulmonary and nasal delivery methods.\",\n \"While the method of the present invention has particular application in the preparation of poorly water-soluble biologically active materials, the scope of the invention is not limited thereto.\",\n \"For example, the method of the present invention enables production of highly water-soluble biologically active materials.\",\n \"Such materials may exhibit advantages over conventional materials by way of, for example, more rapid therapeutic action or lower dose.\",\n \"In contrast, wet grinding techniques utilizing water (or other comparably polar solvents) are incapable of being applied to such materials, as the particles dissolve appreciably in the solvent.\",\n \"Other aspects and advantages of the invention will become apparent to those skilled in the art from a review of the ensuing description.\"\n ],\n [\n \"This application is a continuation of U.S. application Ser.\",\n \"No.\",\n \"13/925,325, filed Jun.\",\n \"24, 2013, which is a continuation of U.S. application Ser.\",\n \"No.\",\n \"13/265,927, filed Mar.\",\n \"9, 2012, which is a U.S. national stage under 35 USC § 371 of International Application Number PCT/AU2010/000465, filed on 23 Apr.\",\n \"2012, which claims priority to AU Application No.\",\n \"2009901741, filed on 24 Apr.\",\n \"2009 and U.S.\",\n \"Application No.\",\n \"61/172,301, filed on 24 Apr.\",\n \"2009, the entire contents of which applications is hereby incorporated by reference.\",\n \"FIELD OF THE INVENTION The present invention relates to methods for improving the dissolution profile of a biologically active material.\",\n \"The invention also relates to biologically active materials in particulate form produced by said methods, compositions comprising such materials, medicaments produced using said biologically active materials in particulate form and/or compositions, and to methods of treatment of an animal, including man, using a therapeutically effective amount of said biologically active materials administered by way of said medicaments.\",\n \"BACKGROUND Poor bioavailability is a significant problem encountered in the development of therapeutic compositions, particularly those materials containing a biologically active material that is poorly soluble in water at physiological pH.\",\n \"An active material's bioavailability is the degree to which the active material becomes available to the target tissue in the body after systemic administration through, for example, oral or intravenous means.\",\n \"Many factors affect bioavailability, including the form of dosage and the solubility and dissolution rate of the active material.\",\n \"Poorly and slowly water-soluble materials tend to be eliminated from the gastrointestinal tract before being absorbed into the circulation.\",\n \"In addition, poorly soluble active agents tend to be disfavored or even unsafe for intravenous administration due to the risk of particles of agent blocking blood flow through capillaries.\",\n \"It is known that the rate of dissolution of a particulate drug will increase with increasing surface area.\",\n \"One way of increasing surface area is decreasing particle size.\",\n \"Consequently, methods of making finely divided or sized drugs have been studied with a view to controlling the size and size range of drug particles for pharmaceutical compositions.\",\n \"For example, dry milling techniques have been used to reduce particle size and hence influence drug absorption.\",\n \"However, in conventional dry milling the limit of fineness is reached generally in the region of about 100 microns (100,000 nm), at which point material cakes on the milling chamber and prevents any further diminution of particle size.\",\n \"Alternatively, wet grinding may be employed to reduce particle size, but flocculation restricts the lower particle size limit to approximately 10 microns (10,000 nm).\",\n \"The wet milling process, however, is prone to contamination, thereby leading to a bias in the pharmaceutical art against wet milling.\",\n \"Another alternative milling technique, commercial airjet milling, has provided particles ranging in average size from as low as about 1 to about 50 microns (1,000-50,000 nm).\",\n \"There are several approaches currently used to formulate poorly soluble active agents.\",\n \"One approach is to prepare the active agent as a soluble salt.\",\n \"Where this approach cannot be employed, alternate (usually physical) approaches are employed to improve the solubility of the active agent.\",\n \"Alternate approaches generally subject the active agent to physical conditions that change the agent's physical and or chemical properties to improve its solubility.\",\n \"These include process technologies such as micronization, modification of crystal or polymorphic structure, development of oil based solutions, use of co-solvents, surface stabilizers or complexing agents, micro-emulsions, super critical fluid and production of solid dispersions or solutions.\",\n \"More than one of these processes may be used in combination to improve formulation of a particular therapeutic material.\",\n \"Many of these approaches commonly convert a drug into an amorphous state, which generally leads to a higher dissolution rate.\",\n \"However, formulation approaches that result in the production of amorphous material are not common in commercial formulations due to concerns relating to stability and the potential for material to re-crystallize.\",\n \"These techniques for preparing such pharmaceutical compositions tend to be complex.\",\n \"By way of example, a principal technical difficulty encountered with emulsion polymerization is the removal of contaminants, such as unreacted monomers or initiators (which may have undesirable levels of toxicity), at the end of the manufacturing process.\",\n \"Another method of providing reduced particle size is the formation of pharmaceutical drug microcapsules, which techniques include micronizing, polymerisation and co-dispersion.\",\n \"However, these techniques suffer from a number of disadvantages including at least the inability to produce sufficiently small particles such as those obtained by milling, and the presence of co-solvents and/or contaminants such as toxic monomers which are difficult to remove, leading to expensive manufacturing processes.\",\n \"Over the last decade, intense scientific investigation has been carried out to improve the solubility of active agents by converting the agents to ultra fine powders by methods such as milling and grinding.\",\n \"These techniques may be used to increase the dissolution rate of a particulate solid by increasing the overall surface area and decreasing the mean particle size.\",\n \"U.S. Pat.\",\n \"No.\",\n \"6,634,576 discloses examples of wet-milling a solid substrate, such as a pharmaceutically active compound, to produce a “synergetic co-mixture”.\",\n \"International Patent Application PCT/AU2005/001977 (Nanoparticle Composition(s) and Method for Synthesis Thereof) describes, inter alia, a method comprising the step of contacting a precursor compound with a co-reactant under mechanochemical synthesis conditions wherein a solid-state chemical reaction between the precursor compound and the co-reactant produces therapeutically active nanoparticles dispersed in a carrier matrix.\",\n \"Mechanochemical synthesis, as discussed in International Patent Application PCT/AU2005/001977, refers to the use of mechanical energy to activate, initiate or promote a chemical reaction, a crystal structure transformation or a phase change in a material or a mixture of materials, for example by agitating a reaction mixture in the presence of a milling media to transfer mechanical energy to the reaction mixture, and includes without limitation “mechanochemical activation”, “mechanochemical processing”, “reactive milling”, and related processes.\",\n \"International Patent Application PCT/AU2007/000910 (Methods for the preparation of biologically active compounds in nanoparticulate form) describes, inter alia, a method for dry milling raloxifene with lactose and NaCl which produced nanoparticulate raloxifene without significant aggregation problems.\",\n \"One limitation of this method is an upper limit to the drug content that can be successfully milled to produce nanoparticles.\",\n \"For some drugs that require a high dose this limitation may restrict the options available for the production of a commercially viable dosage form.\",\n \"The present invention provides methods for improving the dissolution profile of a biologically active material which ameliorate some of the problems attendant with prior technologies, or provides an alternative thereto.\",\n \"One example of a therapeutic area where this technology could be applied in is the area of acute pain management.\",\n \"Many pain medications such as meloxicam (marketed as Mobic® by pharmaceutical company Boehringer Ingelheim) provides pain relief for chronic pain, but must be taken on a daily basis to maintain an effective therapeutic level.\",\n \"Meloxicam is a poorly water soluble drug which is only slowly absorbed by the body (Tmax is 4-5 hours), so a method such as the present invention which provides for improved dissolution, will likely provide much faster absorption resulting in a more rapid onset of the therapeutic effect.\",\n \"Meloxicam also has a long half life (15-20 hours) that means it only need be taken once a day.\",\n \"By using a method such as the present invention, which provides faster absorption, a drug such as meloxicam, could be transformed from a chronic pain drug to an acute pain drug.\",\n \"For meloxicam this would provide a medication that could provide therapeutic relief for acute pain, with the advantage of sustained pain relief over 24 hours.\",\n \"Meloxicam also has sub-optimal bioavailability at 89% for an oral capsule, compared with an IV dosage form.\",\n \"A component of this sub optimal bioavailability is also likely due to the poor water solubility of this drug.\",\n \"If the low solubility does contribute to this sub optimal bioavailability, the improvement of the dissolution of this drug with a method such as the present invention could provide scope to produce a dosage form with a lower active dose whilst still providing the effective therapeutic dose.\",\n \"Although the background to the present invention is discussed in the context of improving the bioavailability of materials that are poorly or slowly water soluble, the applications of the methods of the present invention are not limited to such, as is evident from the following description of the invention.\",\n \"Further, although the background to the present invention is largely discussed in the context of improving the bioavailability of therapeutic or pharmaceutical compounds, the applications of the methods of the present invention are clearly not limited to such.\",\n \"For example, as is evident from the following description, applications of the methods of the present invention include but are not limited to: nutraceutical and nutritional compounds, complementary medicinal compounds, veterinary therapeutic applications and agricultural chemical applications, such as pesticide, fungicide or herbicide.\",\n \"Furthermore, an application of the current invention would be to materials which contain a biologically active compound such as, but not limited to a therapeutic or pharmaceutical compound, a nutraceutical or nutrient, a complementary medicinal product such as active components in plant or other naturally occurring material, a veterinary therapeutic compound or an agricultural compound such as a pesticide, fungicide or herbicide.\",\n \"Specific examples would be the spice turmeric that contains the active compound curcumin, or flax seed that contains the nutrient ALA an omega-3 fatty acid.\",\n \"As these specific examples indicate this invention could be applied to, but not limited to, a range of natural products such as seeds, cocoa and cocoa solids, coffee, herbs, spices, other plant materials or food materials that contain a biologically active compound.\",\n \"The application of this invention to these types of materials would enable greater availability of the active compound in the materials when used in the relevant application.\",\n \"For example where material subject to this invention is orally ingested the active would be more bioavailable.\",\n \"SUMMARY OF THE INVENTION In one aspect the present invention is directed to the unexpected finding that the dissolution profile of biologically active materials can be improved by dry milling solid biologically active material to a particle size of greater than 1 μm.\",\n \"In one surprising aspect of the invention, the dissolution profile of a biologically active material can be improved without substantially reducing the particle size of the material or reducing the material to nanoparticulate form.\",\n \"In another surprising aspect of the invention, the material retains its crystalline structure and is not amorphous, yet the dissolution profile of the biologically active material is improved.\",\n \"In another surprising aspect of the invention, the dissolution profile of a biologically active material is improved without the need for a surfactant or stabiliser.\",\n \"In another surprising aspect of the invention, the dissolution profile of a biologically active material is improved without the need for a disintegrant to be present during the milling process.\",\n \"Thus, in a first aspect the invention comprises a method for improving the dissolution profile of a biologically active material, comprising the steps of: dry milling a solid biologically active material and a millable grinding matrix in a mill comprising a plurality of milling bodies, for a time period sufficient to produce particles of the biologically active material dispersed in an at least partially milled grinding material.\",\n \"In one preferred embodiment, the particles have an average particle size equal or greater than 1 μm determined on a particle number basis.\",\n \"More preferably, the average particle size of the biologically active material may be reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.\",\n \"Even more preferably, the average particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-20 μm, 1-10 μm, 1-7.5 μm, 1-5 μm and 1-2 μm.\",\n \"In another preferred embodiment, the particles have a median particle size selected from the group consisting of: equal or greater than 1 μm; and equal or greater than 2 μm, wherein the median particle size is determined on a particle volume basis.\",\n \"More preferably, the percentage of particles with an average particle size greater than 1 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.\",\n \"Alternatively, the percentage of particles with an average particle size greater than 2 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.\",\n \"In another preferred embodiment, the median particle size may be reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.\",\n \"In another preferred embodiment, the median particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-20 μm, 1-10 μm, 1-7.5 μm, 1-5 μm 1-2 μm, 2-1000 μm, 2-500 μm, 2-300 μm, 2-200 μm, 2-150 μm, 2-100 μm, 2-50 μm, 2-20 μm, 2-10 μm, 2-7.5 μm and 2-5 μm.\",\n \"In another preferred embodiment, the crystallinity profile of the biologically active material is selected from the group consisting of: at least 50% of the biologically active material is crystalline, at least 60% of the biologically active material is crystalline, at least 70% of the biologically active material is crystalline, at least 75% of the biologically active material is crystalline, at least 85% of the biologically active material is crystalline, at least 90% of the biologically active material is crystalline, at least 95% of the biologically active material is crystalline and at least 98% of the biologically active material is crystalline.\",\n \"More preferably, the crystallinity profile of the biologically active material is substantially equal to the crystallinity profile of the biologically active material before the material was subjected to the method as described herein.\",\n \"In another preferred embodiment, the amorphous content of the biologically active material is selected from the group consisting of: less than 50% of the biologically active material is amorphous, less than 40% of the biologically active material is amorphous, less than 30% of the biologically active material is amorphous, less than 25% of the biologically active material is amorphous, less than 15% of the biologically active material is amorphous, less than 10% of the biologically active material is amorphous, less than 5% of the biologically active material is amorphous and less than 2% of the biologically active material is amorphous.\",\n \"Preferably, the biologically active material has no significant increase in amorphous content after subjecting the material to the method as described herein.\",\n \"In another preferred embodiment, the milling time period is a range selected from the group consisting of: between 10 minutes and 2 hours, between 10 minutes and 1 hour, between 10 minutes and 45 minutes, between 10 minutes and 30 minutes, between 5 minutes and 30 minutes, between 5 minutes and 20 minutes, between 2 minutes and 10 minutes, between 2 minutes and 5 minutes, between 1 minutes and 20 minutes, between 1 minute and 10 minutes, and between 1 minute and 5 minutes.\",\n \"In another preferred embodiment, the milling medium is selected from the group consisting of: ceramics, glasses, polymers, ferromagnetics and metals.\",\n \"Preferably, the milling medium is steel balls having a diameter selected from the group consisting of: between 1 and 20 mm, between 2 and 15 mm and between 3 and 10 mm.\",\n \"In another preferred embodiment, the milling medium is zirconium oxide balls having a diameter selected from the group consisting of: between 1 and 20 mm, between 2 and 15 mm and between 3 and 10 mm.\",\n \"Preferably, the dry milling apparatus is a mill selected from the group consisting of: attritor mills (horizontal or vertical), nutating mills, tower mills, pearl mills, planetary mills, vibratory mills, eccentric vibratory mills, gravity-dependent-type ball mills, rod mills, roller mills and crusher mills.\",\n \"Preferably the milling medium within the milling apparatus is mechanically agitated by 1, 2 or 3 rotating shafts.\",\n \"Preferably, the method is configured to produce the biologically active material in a continuous fashion.\",\n \"Preferably, the total combined amount of biologically active material and grinding matrix in the mill at any given time is equal to or greater than a mass selected from the group consisting of: 200 grams, 500 grams, 1 kg, 2 kg, 5 kg, 10 kg, 20 kg, 30 kg, 50 kg, 75 kg, 100 kg, 150 kg, 200 kg.\",\n \"Preferably, the total combined amount of biologically active material and grinding matrix is less than 2000 kg.\",\n \"In another preferred embodiment, the biologically active material is selected from the group consisting of: fungicides, pesticides, herbicides, seed treatments, cosmeceuticals, cosmetics, complementary medicines, natural products, vitamins, nutrients, nutraceuticals, pharmaceutical actives, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids additives, foods and food ingredients and analogs, homologs and first order derivatives thereof.\",\n \"Preferably, the biologically active material is selected from the group consisting of: anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, such as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives (hypnotics and neuroleptics), astringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (anti-parkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones (including steroids), anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines.\",\n \"Preferably, the biologically active material is selected from the group consisting of: indomethacin, diclofenac, naproxen, meloxicam, metaxalone, cyclosporin A, progesterone celecoxib, cilostazol, ciprofloxacin, 2,4-dichlorophenoxyacetic acid, anthraquinone, creatine monohydrate, glyphosate, halusulfuron, mancozeb, metsulfuron, salbutamol, sulphur, tribenuran and estradiol or any salt or derivative thereof.\",\n \"In another preferred embodiment, the grinding matrix is a single matrix or is a mixture of two or more matrices in any proportion.\",\n \"Preferably, the major components of the grinding matrix are selected from the group consisting of: mannitol, sorbitol, Isomalt, xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, glucose, fructose, mannose, galactose, anhydrous lactose, lactose monohydrate, sucrose, maltose, trehalose, maltodextrins, dextrin, Inulin, dextrates, polydextrose, starch, wheat flour, corn flour, rice flour, rice starch, tapioca flour, tapioca starch, potato flour, potato starch, other flours and starches, milk powder, skim milk powders, other milk solids and derivatives, soy flour, soy meal or other soy products, cellulose, microcrystalline cellulose, microcrystalline cellulose based co blended materials, pregelatinized (or partially) starch, HPMC, CMC, HPC, citric acid, tartaric acid, malic acid, maleic acid fumaric acid, ascorbic acid, succinic acid, sodium citrate, sodium tartrate, sodium malate, sodium ascorbate, potassium citrate, potassium tartrate, potassium malate, potassium ascorbate, sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate and calcium carbonate.\",\n \"dibasic calcium phosphate, tribasic calcium phosphate, sodium sulfate, sodium chloride, sodium metabisulphite, sodium thiosulfate, ammonium chloride, Glauber's salt, ammonium carbonate, sodium bisulfate, magnesium sulfate, potash alum, potassium chloride, sodium hydrogen sulfate, sodium hydroxide, crystalline hydroxides, hydrogen carbonates, ammonium chloride, methylamine hydrochloride, ammonium bromide, silica, thermal silica, alumina, titanium dioxide, talc, chalk, mica, kaolin, bentonite, hectorite, magnesium trisilicate, clay based materials or aluminium silicates, sodium lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate, sodium cetostearyl sulfate, sodium docusate, sodium deoxycholate, N-lauroylsarcosine sodium salt, glyceryl monostearate, glycerol distearate glyceryl palmitostearate, glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzalkonium chloride, CTAB, CTAC, Cetrimide, cetylpyridinium chloride, cetylpyridinium bromide, benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188, poloxamer 407, poloxamer 338, polyoxyl 2 stearyl ether, polyoxyl 100 stearyl ether, polyoxyl 20 stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 20 cetyl ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl 35 castor oil, polyoxyl 40 castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor oil, polyoxyl 200 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyoxyl 100 hydrogenated castor oil, polyoxyl 200 hydrogenated castor oil, cetostearyl alcohol, macrogel 15 hydroxystearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, Sucrose Palmitate, Sucrose Stearate, Sucrose Distearate, Sucrose laurate, Glycocholic acid, sodium Glycholate, Cholic Acid, Sodium Cholate, Sodium Deoxycholate, Deoxycholic acid, Sodium taurocholate, taurocholic acid, Sodium taurodeoxycholate, taurodeoxycholic acid, soy lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonate condensate/Lignosulfonate blend, Calcium Dodecylbenzene Sulfonate, Sodium Dodecylbenzene Sulfonate, Diisopropyl naphthalenesulphonate, erythritol distearate, Naphthalene Sulfonate Formaldehyde Condensate, nonylphenol ethoxylate (poe-30), Tristyrylphenol Ethoxylate, Polyoxyethylene (15) tallowalkylamines, sodium alkyl naphthalene sulfonate, sodium alkyl naphthalene sulfonate condensate, sodium alkylbenzene sulfonate, sodium isopropyl naphthalene sulfonate, Sodium Methyl Naphthalene Formaldehyde Sulfonate, sodium n-butyl naphthalene sulfonate, tridecyl alcohol ethoxylate (poe-18), Triethanolamine isodecanol phosphate ester, Triethanolamine tristyrylphosphate ester, Tristyrylphenol Ethoxylate Sulfate, Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"Preferably, the concentration of the single (or first) material is selected from the group consisting of: 5-99% w/w, 10-95% w/w, 15-85% w/w, of 20-80% w/w, 25-75% w/w, 30-60% w/w, 40-50% w/w.\",\n \"Preferably, the concentration of the second or subsequent material is selected from the group consisting of: 5-50% w/w, 5-40% w/w, 5-30% w/w, of 5-20% w/w, 10-40% w/w, 10-30% w/w, 10-20% w/w, 20-40% w/w, or 20-30% w/w or if the second or subsequent material is a surfactant or water soluble polymer the concentration is selected from 0.1-10% w/w, 0.1-5% w/w, 0.1-2.5% w/w, of 0.1-2% w/w, 0.1-1%, 0.5-5% w/w, 0.5-3% w/w, 0.5-2% w/w, 0.5-1.5%, 0.5-1% w/w, of 0.75-1.25% w/w, 0.75-1% and 1% w/w.\",\n \"Preferably, the grinding matrix is selected from the group consisting of: (a) lactose monohydrate or lactose monohydrate combined with at least one material selected from the group consisting of: xylitol; lactose anhydrous; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"(b) lactose anhydrous or lactose anhydrous combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"(c) mannitol or mannitol combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; lactose anhydrous; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"(d) Sucrose or sucrose combined with at least one material selected from the group consisting of: lactose monohydrate; lactose anhydrous; mannitol; microcrystalline cellulose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"(e) Glucose or glucose combined with at least one material selected from the group consisting of: lactose monohydrate; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"(f) Sodium chloride or sodium chloride combined with at least one material selected from the group consisting of: lactose monohydrate; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"(g) xylitol or xylitol combined with at least one material selected from the group consisting of: lactose monohydrate; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"(h) Tartaric acid or tartaric acid combined with at least one material selected from the group consisting of: lactose monohydrate; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"(i) microcrystalline cellulose or microcrystalline cellulose combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; lactose anhydrous; mannitol; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"(j) Kaolin combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"(k) Talc combined with at least one material selected from the group consisting of: lactose monohydrate; xylitol; lactose anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose; sodium chloride; kaolin; calcium carbonate; malic acid; tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl sulfate or other alkyl sulfate surfactants with a chain length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl naphthalene sulfonate condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl naphthalenesulphonate; erythritol distearate; linear and branched dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl naphthalene sulfonate condensate; sodium alkylbenzene sulfonate; sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"Preferably, the grinding matrix is selected from the group consisting of: a material considered to be Generally Regarded as Safe (GRAS) for pharmaceutical products; a material considered acceptable for use in an agricultural formulation; and a material considered acceptable for use in a veterinary formulation.\",\n \"In another preferred embodiment, a milling aid is used or a combination of milling aids.\",\n \"Preferably, the milling aid is selected from the group consisting of: colloidal silica, a surfactant, a polymer, a stearic acid and derivatives thereof.\",\n \"Preferably, the surfactant is selected from the group consisting of: polyoxyethylene alkyl ethers, polyoxyethylene stearates, polyethylene glycols (PEG), poloxamers, poloxamines, sarcosine based surfactants, polysorbates, aliphatic alcohols, alkyl and aryl sulfates, alkyl and aryl polyether sulfonates and other sulfate surfactants, trimethyl ammonium based surfactants, lecithin and other phospholipids, bile salts, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, Sorbitan fatty acid esters, Sucrose fatty acid esters, alkyl glucopyranosides, alkyl maltopyranosides, glycerol fatty acid esters, Alkyl Benzene Sulphonic Acids, Alkyl Ether Carboxylic Acids, Alkyl and aryl Phosphate esters, Alkyl and aryl Sulphate esters, Alkyl and aryl Sulphonic acids, Alkyl Phenol Phosphates esters, Alkyl Phenol Sulphates esters, Alkyl and Aryl Phosphates, Alkyl Polysaccharides, Alkylamine Ethoxylates, Alkyl-Naphthalene Sulphonates formaldehyde condensates, Sulfosuccinates, lignosulfonates, Ceto-Oleyl Alcohol Ethoxylates, Condensed Naphthalene Sulphonates, Dialkyl and Alkyl Naphthalene Sulphonates, Di-alkyl Sulphosuccinates, Ethoxylated nonylphenols, Ethylene Glycol Esters, Fatty Alcohol Alkoxylates, Hydrogenated tallowalkylamines, Mono-alkyl Sulphosuccinamates, Nonyl Phenol Ethoxylates, Sodium Oleyl N-methyl Taurate, Tallowalkylamines, linear and branched dodecylbenzene sulfonic acids Preferably, the surfactant is selected from the group consisting of: sodium lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate, sodium cetostearyl sulfate, sodium docusate, sodium deoxycholate, N-lauroylsarcosine sodium salt, glyceryl monostearate, glycerol distearate glyceryl palmitostearate, glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzalkonium chloride, CTAB, CTAC, Cetrimide, cetylpyridinium chloride, cetylpyridinium bromide, benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188, poloxamer 407, poloxamer 338, polyoxyl 2 stearyl ether, polyoxyl 100 stearyl ether, polyoxyl 20 stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 20 cetyl ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl 35 castor oil, polyoxyl 40 castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor oil, polyoxyl 200 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyoxyl 100 hydrogenated castor oil, polyoxyl 200 hydrogenated castor oil, cetostearyl alcohol, macrogel 15 hydroxystearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, Sucrose Palmitate, Sucrose Stearate, Sucrose Distearate, Sucrose laurate, Glycocholic acid, sodium Glycholate, Cholic Acid, Sodium Cholate, Sodium Deoxycholate, Deoxycholic acid, Sodium taurocholate, taurocholic acid, Sodium taurodeoxycholate, taurodeoxycholic acid, soy lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonate condensate/Lignosulfonate blend, Calcium Dodecylbenzene Sulfonate, Sodium Dodecylbenzene Sulfonate, Diisopropyl naphthalenesulphonate, erythritol distearate, Naphthalene Sulfonate Formaldehyde Condensate, nonylphenol ethoxylate (poe-30), Tristyrylphenol Ethoxylate, Polyoxyethylene (15) tallowalkylamines, sodium alkyl naphthalene sulfonate, sodium alkyl naphthalene sulfonate condensate, sodium alkylbenzene sulfonate, sodium isopropyl naphthalene sulfonate, Sodium Methyl Naphthalene Formaldehyde Sulfonate, sodium n-butyl naphthalene sulfonate, tridecyl alcohol ethoxylate (poe-18), Triethanolamine isodecanol phosphate ester, Triethanolamine tristyrylphosphate ester, Tristyrylphenol Ethoxylate Sulfate, Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"Preferably the polymer is selected from the list of: polyvinylpyrrolidones (PVP), polyvinylalcohol, Acrylic acid based polymers and copolymers of acrylic acid.\",\n \"Preferably, the milling aid has a concentration selected from the group consisting of: 0.1-10 w/w, 0.1-5% w/w, 0.1-2.5% w/w, of 0.1-2% w/w, 0.1-1%, 0.5-5% w/w, 0.5-3% w/w, 0.5-2% w/w, 0.5-1.5%, 0.5-1% w/w, of 0.75-1.25% w/w, 0.75-1% and 1% w/w.\",\n \"Preferably the biologically active ingredient is milled with lactose monohydrate; mannitol; glucose; microcrystalline cellulose; tartaric acid; or lactose monohydrate and sodium dodecyl sulfate.\",\n \"Preferably, Diclofenac is milled with lactose mono-hydrate.\",\n \"Preferably, Meloxicam is milled with mannitol.\",\n \"Preferably, Diclofenac is milled with mannitol.\",\n \"Preferably, Meloxicam is milled with glucose.\",\n \"Preferably, Diclofenac is milled with glucose.\",\n \"Preferably, Meloxicam is milled with microcrystalline cellulose.\",\n \"Preferably, diclofenac in microcrystalline cellulose.\",\n \"Preferably, Meloxicam is milled with Tartaric acid.\",\n \"Preferably, Meloxicam is milled with lactose monohydrate.\",\n \"Preferably, Meloxicam is milled with mannitol.\",\n \"Preferably, Diclofenac is milled with lactose mono-hydrate and sodium dodecyl sulfate.\",\n \"Preferably, Meloxicam is milled with lactose monohydrate and sodium dodecyl sulfate.\",\n \"In another preferred embodiment, a facilitating agent or combination of facilitating agents is used.\",\n \"Preferably, the facilitating agent is selected from the group consisting of: surface stabilizers, binding agents, filling agents, lubricating agents, sweeteners, flavouring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents, agents that may form part of a medicament, including a solid dosage form and other excipient required for specific drug delivery.\",\n \"Preferably, the facilitating agent is added during dry milling.\",\n \"Preferably, the facilitating agent is added to the milled biologically active material and grinding matrix and further processed in a mechanofusion process.\",\n \"Mechanofusion milling causes mechanical energy to be applied to powders or mixtures of particles in the micrometre and nanometre.\",\n \"The reasons for including facilitating agents include, but are not limited to providing better dispersibility, control of agglomeration, the release or retention of the active particles from the delivery matrix.\",\n \"Examples of facilitating agents include, but are not limited to stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, sodium stearyl lactylate, zinc stearate, sodium stearate or lithium stearate, other solid state fatty acids such as oleic acid, lauric acid, palmitic acid, erucic acid, behenic acid, or derivatives (such as esters and salts), amino acids such as leucine, isoleucine, lysine, valine, methionine, phenylalanine, aspartame or acesulfame K. In a preferred aspect of manufacturing this formulation the facilitating agent is added to the milled mixture of biologically active material and co-grinding matrix and further processed in another milling device such as Mechanofusion, Cyclomixing, or impact milling such as ball milling, jet milling, or milling using a high pressure homogeniser, or combinations thereof.\",\n \"In a highly preferred aspect the facilitating agent is added to the milling of the mixture of biologically active material and co-grinding matrix as some time before the end of the milling process.\",\n \"Preferably, the facilitating agent is added to the dry milling at a time selected from the group consisting of: with 1-5% of the total milling time remaining, with 1-10% of the total milling time remaining, with 1-20% of the total milling time remaining, with 1-30% of the total milling time remaining, with 2-5% of the total milling time remaining, with 2-10% of the total milling time remaining, with 5-20% of the total milling time remaining and with 5-20% of the total milling time remaining.\",\n \"In another preferred embodiment, a disintegrant is selected from the group consisting of: crosslinked PVP, cross linked carmellose and sodium starch glycolate.\",\n \"In another preferred embodiment, the dissolution profile of the measurement sample or prototype formulation thereof is improved by a factor selected from the group consisting of: wherein X is reached in 10 minutes, wherein X is reached within 10-20 minutes, wherein X is reached within 10-30 mins, wherein X is reached within 10-40 mins, wherein X is reached within 10-50 mins, wherein X is reached within 20-30 mins, wherein X is reached within 20-40 mins, wherein X is reached within 20-50 mins, wherein X is reached within 30-40 mins, wherein X is reached within 30-50 mins and wherein X is reached within 40-50 mins, wherein X is defined as the concentration equal to the dissolution concentration achieved by a control sample or prototype formulation thereof of the biologically active material or compound after 60 minutes.\",\n \"In another preferred embodiment, the dissolution profile of the measurement sample or prototype formulation thereof is improved by a factor selected from the group consisting of: wherein Y is reached in 5 minutes, wherein Y is reached within 10 minutes, wherein Y is reached within 10-15 mins, wherein Y is reached within 10-20 mins, wherein Y is reached within 10-25 mins, wherein Y is reached within 15-20 mins, wherein Y is reached within 15-25 mins, wherein Y is reached within 20-25 mins, wherein Y is defined as the concentration equal to the dissolution concentration achieved by a control sample (or prototype formulation thereof) of the biologically active material or compound after 30 minutes.\",\n \"In a second aspect the invention comprises a biologically active material produced by the method described herein and composition comprising the biologically active material as described herein.\",\n \"Preferably, the particles have an average particle size equal or greater than 1 μm determined on a particle number average basis.\",\n \"Preferably, the average particle size of the biologically active material has been reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.\",\n \"Preferably, the average particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-20 μm, 1-10 μm, 1-7.5 μm, 1-5 μm and 1-2 μm.\",\n \"Preferably, the particles have a median particle size selected from the group consisting of: equal or greater than 1 μm; and equal or greater than 2 μm, wherein the median particle size is determined on a particle volume basis.\",\n \"Preferably, the percentage of particles with an average particle size greater than 1 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.\",\n \"Preferably, the percentage of particles with an average particle size greater than 2 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.\",\n \"Preferably, the median particle size has been reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.\",\n \"Preferably, the median particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-20 μm, 1-10 μm, 1-7.5 μm, 1-5 μm 1-2 μm, 2-1000 μm, 2-500 μm, 2-300 μm, 2-200 μm, 2-150 μm, 2-100 μm, 2-50 μm, 2-20 μm, 2-10 μm, 2-7.5 μm and 2-5 μm.\",\n \"Preferably, the crystallinity profile of the biologically active material is selected from the group consisting of: at least 50% of the biologically active material is crystalline, at least 60% of the biologically active material is crystalline, at least 70% of the biologically active material is crystalline, at least 75% of the biologically active material is crystalline, at least 85% of the biologically active material is crystalline, at least 90% of the biologically active material is crystalline, at least 95% of the biologically active material is crystalline and at least 98% of the biologically active material is crystalline.\",\n \"Preferably, the crystallinity profile of the biologically active material is substantially equal to the crystallinity profile of the biologically active material before the material was subject to the method described herein.\",\n \"Preferably, the amorphous content of the biologically active material is selected from the group consisting of: less than 50% of the biologically active material is amorphous, less than 40% of the biologically active material is amorphous, less than 30% of the biologically active material is amorphous, less than 25% of the biologically active material is amorphous, less than 15% of the biologically active material is amorphous, less than 10% of the biologically active material is amorphous, less than 5% of the biologically active material is amorphous and less than 2% of the biologically active material is amorphous.\",\n \"Preferably, the biologically active material has had no significant increase in amorphous content following subjecting the material to the method as described herein.\",\n \"Preferably, the biologically active material is selected from the group consisting of: fungicides, pesticides, herbicides, nutraceuticals, pharmaceutical actives, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids and analogs, homologs and first order derivatives thereof.\",\n \"Preferably, the biologically active material is selected from the group consisting of: anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, such as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives (hypnotics and neuroleptics), astringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (anti-parkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones (including steroids), anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines.\",\n \"Preferably, the biologically active material is selected from the group consisting of: indomethacin, diclofenac, naproxen, meloxicam, metaxalone, cyclosporin A, progesterone celecoxib, cilostazol, ciprofloxacin, 2,4-dichlorophenoxyacetic acid, anthraquinone, creatine monohydrate, glyphosate, halusulfuron, mancozeb, metsulfuron, salbutamol, sulphur, tribenuran and estradiol or any salt or derivative thereof.\",\n \"In one preferred embodiment, the invention comprises compositions comprising the biologically active ingredient together with a grinding matrix, a mixture of grinding matrix materials, milling aids, mixtures of milling aids, facilitating agents and/or mixtures of facilitating agents as described herein, in concentrations and ratios as described herein under the methods of the invention.\",\n \"In a third aspect the invention comprises a pharmaceutical composition comprising a biologically active material produced by the method described herein and compositions described herein.\",\n \"Preferably, the invention comprises pharmaceutical compositions comprising the biologically active ingredient together with a grinding matrix, a mixture of grinding matrix materials, milling aids, mixtures of milling aids, facilitating agents and/or mixtures of facilitating agents as described herein, in concentrations and ratios as described herein under the methods of the invention.\",\n \"Preferably, the particles have an average particle size equal or greater than 1 μm determined on a particle number basis.\",\n \"Preferably, the average particle size of the biologically active material has been reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.\",\n \"Preferably, the average particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-μm, 1-10 μm, 1-7.5 μm, 1-5 μm and 1-2 μm.\",\n \"Preferably, the particles have a median particle size selected from the group consisting of: equal or greater than 1 μm; and equal or greater than 2 μm, wherein the median particle size is determined on a particle volume basis.\",\n \"Preferably, the percentage of particles with an average particle size greater than 1 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.\",\n \"Preferably, the percentage of particles with an average particle size greater than 2 μm on a particle volume basis is a percentage selected from the group consisting of: 50%, 60%, 70%, 80%, 90%, 100%.\",\n \"Preferably, the median particle size has been reduced by a factor selected from the group consisting of: less than 5%, less than 10%, less than 20%, less than 30%, less than 40%, less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95% and less than 99%.\",\n \"Preferably, the median particle size falls within the range selected from the group consisting of: 1-1000 μm, 1-500 μm, 1-300 μm, 1-200 μm, 1-150 μm, 1-100 μm, 1-50 μm, 1-20 μm, 1-10 μm, 1-7.5 μm, 1-5 μm 1-2 μm, 2-1000 μm, 2-500 μm, 2-300 μm, 2-200 μm, 2-150 μm, 2-100 μm, 2-50 μm, 2-20 μm, 2-10 μm, 2-7.5 μm and 2-5 μm.\",\n \"Preferably, the crystallinity profile of the biologically active material is selected from the group consisting of: at least 50% of the biologically active material is crystalline, at least 60% of the biologically active material is crystalline, at least 70% of the biologically active material is crystalline, at least 75% of the biologically active material is crystalline, at least 85% of the biologically active material is crystalline, at least 90% of the biologically active material is crystalline, at least 95% of the biologically active material is crystalline and at least 98% of the biologically active material is crystalline.\",\n \"Preferably, the crystallinity profile of the biologically active material is substantially equal to the crystallinity profile of the biologically active material before the material was subject to the method as described herein.\",\n \"Preferably, the amorphous content of the biologically active material is selected from the group consisting of: less than 50% of the biologically active material is amorphous, less than 40% of the biologically active material is amorphous, less than 30% of the biologically active material is amorphous, less than 25% of the biologically active material is amorphous, less than 15% of the biologically active material is amorphous, less than 10% of the biologically active material is amorphous, less than 5% of the biologically active material is amorphous and less than 2% of the biologically active material is amorphous.\",\n \"Preferably, the biologically active material has no significant increase in amorphous content after subjecting the material to the method as described herein.\",\n \"Preferably, the biologically active material is selected from the group consisting of: new chemical entities, pharmaceutical actives, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids and analogs, homologs and first order derivatives thereof.\",\n \"Preferably, the biologically active material is selected from the group consisting of: anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, such as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives (hypnotics and neuroleptics), astringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (anti-parkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones (including steroids), anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines.\",\n \"Preferably, the biologically active material is selected from the group consisting of: indomethacin, diclofenac, naproxen, meloxicam, metaxalone, cyclosporin A, progesterone celecoxib, cilostazol, ciprofloxacin, 2,4-dichlorophenoxyacetic acid, anthraquinone, creatine monohydrate, glyphosate, halusulfuron, mancozeb, metsulfuron, salbutamol, sulphur, tribenuran and estradiol or any salt or derivative thereof.\",\n \"Preferably cosmeceuticals, cosmetics, complementary medicines, natural products, vitamins, nutrients and nutraceuticals are selected from the group consisting of: Glycolic acids, Lactic acids, Carrageenan, Almonds, Mahogany wood, Andrographis Paniculata, Aniseed, Anthemis nobilis (chamomile), Apricot kernel, leaves of bearberry, leaves of cranberry, leaves of blueberry, leaves of pear trees, beta-carotene, black elderberry, black raspberry, black walnut shell, blackberry, bladderwrack, bletilla striata, borage seed, boysenberry, brazil nut, burdock root, butcher's broom extract, calamine, calcium gluconate, calendula, carnosic acid, Cantella asiatica, charcoal, chaste tree fruit, Chicory root extract, chitosan, choline, cichorium intybus, clematis vitalba, coffea Arabica, coumarin, crithmum maritimum, curcumin, coffee, cocoa, cocoa powder, cocoa nibs, cocoa mass, cocoa liquor, cocoa products, dogwood, Echinacea, echium lycopsis, anise, atragalus, bilberry, bitter orange, black cohosh, cat's claw, chamomile, chasteberry, cranberry, dandelion, Echinacea, ephedra, European elder Epilobium angustifolium, horse chestnut, cloves, evening primrose, fennel seed, fenugreek, feverfew, flaxseed, fumaria officinalis, garlic, geranium, ginger, ginkgo, ginseng, goldenseal, grape seed, green tea, guava, hawthorn, hayflower, hazelnut, helichrysum, hoodia, horseradish, mulbe italicum, hibiscus, hierochloe odorata, hops, horse chestnut, ilex paraguariensis, indian gooseberry, irish moss, juniper berry, kudzu root, lady's thistle, lavender, lemongrass, lentius edodes, licorice, longifolene, loquat, lotus seed, luffa cylindrica, lupine, maroinberry, marjoram, meadowsweet, milk vetch root, mimosa tenuiflora, mistletoe, mulberry, noni, kelp, oatmeal, oregano, papaya, parsley, peony root, pomegranate, pongamia glabra seed, pongamia pinnata, quinoa seed, red raspberry, rose hip, rosemary, sage, saw palmetto, soy bean, szechuan peppercorn, tephrosia purpurea, terminalia catappa, terminalia sericea, thunder god vine, thyme, turmeric, valeriana officinalis, walnuts, white tea leaf, yam, witch hazel, wormwood, yarrow, valerian, yohimbe, mangosteen, sour sob, goji berry, spirulina and durian skin.\",\n \"In a fourth aspect the invention comprises a method of treating a human in need of such treatment comprising the step of administering to the human an effective amount of a pharmaceutical composition as described herein.\",\n \"In a fifth aspect the invention comprises a method for manufacturing a pharmaceutical composition as described herein comprising the step of combining a therapeutically effective amount of a biologically active material prepared by a method described herein together with a pharmaceutically acceptable carrier to produce a pharmaceutically acceptable dosage form.\",\n \"In a sixth aspect the invention comprises a method for manufacturing a veterinary product comprising the step of combining a therapeutically effective amount of the biologically active material prepared by a method as described herein together with an acceptable excipient to produce a dosage form acceptable for veterinary use.\",\n \"In a seventh aspect the invention comprises a method for manufacturing an agricultural product comprising the step of combining an effective amount of the biologically active material prepared by a method described herein together with acceptable excipients to produce a formulation such as, but not limited to a water dispersible granule, wettable granule, dry flowable granule or soluble granule that is used to prepare a solution for use in agricultural applications.\",\n \"Preferably, the product is selected from the group consisting of: herbicides, pesticides, seed treatments, herbicide safeners, plant growth regulators and fungicides.\",\n \"The methods of the invention can be used to increase the dissolution of the biologically active material particles in water or other solvents, resulting in better, faster or more complete preparation and mixing.\",\n \"This will result in a more consistent product performance such as better weed, disease and pest control and other practical benefits such as faster machinery, tank and sprayer cleanout, less rinsate, and a reduced impact on the environment.\",\n \"In a future aspect the invention comprises a method for manufacturing an agricultural product comprising the step of combining an effective amount of the biologically active material prepared by a method described herein together with acceptable excipients to produce a formulation such as, but not limited to a water dispersible granule, wettable granule, wettable powder or a powder for seed treatment that is used to prepare a dry powder or particle suspension for use in agricultural applications.\",\n \"Preferably, the product is selected from the group consisting of: herbicides, pesticides, seed treatments, herbicide safeners, plant growth regulators and fungicides.\",\n \"Another preferred aspect of the method of invention would be to produce powders that have active particles with a high surface area.\",\n \"Such powders would provide better performance in areas such as seed treatment where dry powders are applied to seeds as fungicides, herbicide safeners, plant growth regulators and other treatments.\",\n \"The higher surface area would provide more activity per mass of active used.\",\n \"In another preferred aspect actives such as pesticides, fungicides and seed treatments subject to the method of invention are formulated to produce suspensions of the actives when added to water or other solvents.\",\n \"As these suspensions will have particles of very small size and high surface area they will possess at least three highly desirable traits.\",\n \"The first is that small particles with high surface area will adhere better to surfaces such as leafs and other foliage that the suspension is applied to.\",\n \"This will result in better rain fastness and a longer period of activity.\",\n \"The second aspect is that smaller particles with a higher surface area deliver superior coverage per unit mass of active applied.\",\n \"For example, if 100 particles are needed on a leaf and if the particle diameter is reduced to one third of the former diameter by the methods of this invention, then the dosage can be reduced to about 11% of the former dosage, resulting in lower cost, less residue on harvested crops, and mitigation of environmental impact.\",\n \"In the third aspect the smaller particles will deliver better bioavailability.\",\n \"With many low solubility actives, such as fungicides and pesticides the particles that adhere to plant material slowly dissolve over days and weeks providing continued protection from disease and pests.\",\n \"With this method of invention able to deliver better bioavailability in many circumstances it will be possible to reduce the amount of active that needs to be applied.\",\n \"As with the second aspect such an outcome would lower costs, minimize residues and mitigate environmental impact.\",\n \"In a highly preferred aspect of the invention the powder produced in the milling process would be subject to a process such as wet or dry granulation that makes the powder free flowing and low in dust content yet easily dispersible once in water or other solvent.\",\n \"Preferably the biologically active material is a herbicide, pesticide, seed treatment, herbicide safener, plant growth regulator or fungicide selected from the group consisting of: 2-phenylphenol, 8-hydroxyquinoline sulfate, acibenzolar, allyl alcohol, azoxystrobin, basic benomyl, benzalkonium chloride, biphenyl, blasticidin-S, Bordeaux mixture, Boscalid, Burgundy mixture, butylamine, Cadendazim, calcium polysulfide, Captan, carbamate fungicides, carbendazim, carvone, chloropicrin, chlorothalonil, ciclopirox, clotrimazole, conazole fungicides, Copper hydroxide, copper oxychloride, copper sulfate, copper(II) carbonate, copper(II) sulfate, cresol, cryprodinil, cuprous oxide, cycloheximide, Cymoxanil, DBCP, dehydroacetic acid, dicarboximide fungicides, difenoconazole, dimethomorph, diphenylamine, disulfiram, ethoxyquin, famoxadone, fenamidone, Fludioxonil, formaldehyde, fosetyl, Fosetyl-aluminium, furfural, griseofulvin, hexachlorobenzene, hexachlorobutadiene, hexachlorophene, hexaconazole, imazalil, Imidacloprid, iodomethane, Iprodione, Lime sulfur, mancozeb, mercuric chloride, mercuric oxide, mercurous chloride, Metalaxyl, metam, methyl bromide, methyl isothiocyanate, metiram, natamycin, nystatin, organotin fungicides, oxythioquinox, pencycuron, pentachlorophenol, phenylmercury acetate, potassium thiocyanate, procymidone, propiconazole, propineb, pyraclostrobin, pyrazole fungicides, pyridine fungicides, pyrimethanil, pyrimidine fungicides, pyrrole fungicides, quinoline fungicides, quinone fungicides, sodium azide, streptomycin, sulfur, Tebucanazole, thiabendazole, thiomersal, tolnaftate, Tolylfluanid, triadimersol, tributyltin oxide, Trifloxystrobin, triflumuron, Undecylenic acid, urea fungicides, vinclozolin, Ziram, 3-dihydro-3-methyl-1, 3-thiazol-2-ylidene-xylidene, 4-D esters, 4-DB esters, 4-parathion methyl, Acetamiprid, aclonifen, acrinathrin, alachlor, allethrin, alpha-cypermethrin, Aluminium phosphide, amitraz, anilophos, azaconazole, azinphos-ethyl, azinphos-methyl, benalaxyl, benfluralin, benfuracarb, benfuresate, bensulide, benzoximate, benzoylprop-ethyl, betacyfluthrin, beta-cypermethrin, bifenox, bifenthrin, binapacryl, bioallethrin, bioallethrin S, bioresmethrin, biteranol, Brodifacoum, bromophos, bromopropylate, bromoxynil, bromoxynil esters, bupirimate, buprofezin, butacarboxim, butachlor, butamifos, butoxycarboxin, butralin, butylate, calcium sulfate, cambda-cyhalothrin, carbetamide, carboxin, chlordimeform, chlorfenvinphos, chlorflurazuron, chlormephos, chlornitrofen, chlorobenzilate, chlorophoxim, chloropropylate, chlorpropham, Chlorpyrifos, chlorpyrifos-methyl, cinmethylin, clethodim, clomazone, clopyralid esters, CMPP esters, cyanophos, cycloate, cycloprothrin, cycloxydim, cyfluthrin, cyhalothrin, cypermethrin, cyphenothrin, cyproconazole, deltamethrin, demeton-S-methyl, desmedipham, dichlorprop esters, dichlorvos, diclofop-methyldiethatyl, dicofol, difenoconazole, dimethachlor, dimethomoph, diniconazole, dinitramine, dinobuton, dioxabenzafos, dioxacarb, disulfoton, ditalimfos, dodemorph, dodine, edifenphos, emamectin, empenthrin, endosulfan, EPNethiofencarb, epoxyconazole, esfenvalerate, ethalfluralin, ethofumesate, ethoprophos, ethoxyethyl, etofenprox, etridiazole, etrimphos, Famoxadone, fenamiphos, fenarimol, fenazaquin, fenitrothion, fenobucarb, fenoxapropethyl, fenoxycarb, fenpropathrin, fenpropidin, fenpropimorph, fenthiocarb, fenthion, fenvalerate, fluazifop, fluazifop-P, fluchloralin, flucythrinate, flufenoxim, flufenoxuron, flumetralin, fluorodifen, fluoroglycofen ethyl, fluoroxypyr esters, flurecol butyl, flurochloralin, flusilazole, formothion, gamma-HCH, haloxyfop, haloxyfop-methyl, hexaflumuron, hydroprene, imibenconazole, indoxacarb, ioxynil esters, isofenphos, isoprocarb, isopropalin, isoxathion, malathion, maneb, MCPA esters, mecoprop-P esters, mephospholan, Metaldehyde, methidathion, Methomyl, methoprene, methoxychlor, metolachlor, mevinphos, monalide, myclobutanil, N-2, napropamide, nitrofen, nuarimol, oxadiazon, oxycarboxin, oxyfluorfen, penconazole, pendimethalin, permethrin, phenisopham, phenmedipham, phenothrin, phenthoate, phosalone, phosfolan, phosmet, picloram esters, pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, pretilachlor, prochloraz, profenofos, profluralin, promecarb, propachlor, propanil, propaphos, propaquizafop, propargite, propetamphos, pymetrozine, pyrachlofos, pyridate, pyrifenox, quinalphos, quizalofop-P, resmethrin, Spinetoram J, Spinetoram L, Spinosad A, Spinosad B, tau-fluvalinate, tebuconazole, Tebufenozide, tefluthrin, temephos, terbufos, tetrachlorinphos, tetraconazole, tetradifon, tetramethrin, Thiamethoxam, tolclofos-methyl, tralomethrin, triadimefon, triadimenol, triazophos, triclopyr esters, tridemorph, tridiphane, triflumizole, trifluralin, xylylcarb, 3-dihydro-3-methyl-1, 3-thiazol-2-ylidene-xylidene, 4-D esters, 4-DB esters, 4-parathion methyl, Acetamiprid, acetochlor, aclonifen, acrinathrin, alachlor, allethrin, alpha-cypermethrin, Aluminium phosphide, amitraz, anilophos, azaconazole, azinphos-ethyl, azinphos-methyl, benalaxyl, benfluralin, benfuracarb, benfuresate, bensulide, benzoximate, benzoylprop-ethyl, betacyfluthrin, beta-cypermethrin, bifenox, bifenthrin, binapacryl, bioallethrin, bioallethrin S, bioresmethrin, biteranol, Brodifacoum, bromophos, bromopropylate, bromoxynil, bromoxpil esters, bupirimate, buprofezin, Butacarboxim, butachlor, butamifos, butoxycarboxin, butralin, butylate, calcium sulfate, cambda-cyhalothrin, carbetamide, carboxin, chlordimeform, chlorfenvinphos, chlorflurazuron, chlormephos, chlornitrofen, chlorobenzilate, chlorophoxim, chloropropylate, chlorpropham, Chlorpyrifos, chlorpyrifos-methyl, cinmethylin, clethodim, clomazone, clopyralid esters, CMPP esters, cyanophos, cycloate, cycloprothrin, cycloxydim, cyfluthrin, cyhalothrin, cypermethrin, cyphenothrin, cyproconazole, deltamethrin, demeton-S-methyl, desmedipham, dichlorprop esters, dichlorvos, diclofop-methyldiethatyl, dicofol, dimethachlor, dimethomoph, diniconazole, dinitramine, dinobuton, dioxabenzafos, dioxacarb, disulfoton, ditalimfos, dodemorph, dodine, edifenphos, emamectin, empenthrin, endosulfan, EPNethiofencarb, epoxyconazole, esfenvalerate, ethalfluralin, ethofumesate, ethoprophos, ethoxyethyl, ethoxyquin, etofenprox, etridiazole, etrimphos, fenamiphos, fenarimol, fenazaquin, fenitrothion, fenobucarb, fenoxapropethyl, fenoxycarb, fenpropathrin, fenpropidin, fenpropimorph, fenthiocarb, fenthion, fenvalerate, fluazifop, fluazifop-P, fluchloralin, flucythrinate, flufenoxim, flufenoxuron, flumetralin, fluorodifen, fluoroglycofen ethyl, fluoroxypyr esters, flurecol butyl, flurochloralin, flusilazole, formothion, gamma-HCH, haloxyfop, haloxyfop-methyl, hexaflumuron, hydroprene, imibenconazole, indoxacarb, ioxynil esters, isofenphos, isoprocarb, isopropalin, isoxathion, malathion, maneb, MCPA esters, mecoprop-P esters, mephospholan, Metaldehyde, methidathion, Methomyl, methoprene, methoxychlor, mevinphos, monalide, myclobutanil, myclobutanil, N-2, napropamide, nitrofen, nuarimol, oxadiazon, oxycarboxin, oxyfluorfen, penconazole, permethrin, phenisopham, phenmedipham, phenothrin, phenthoate, phosalone, phosfolan, phosmet, picloram esters, pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, pretilachlor, prochloraz, profenofos, profluralin, promecarb, propachlor, propanil, propaphos, propaquizafop, propargite, propetamphos, pymetrozine, pyridate, pyrifenox, quinalphos, quizalofop-P, resmethrin, Spinetoram J, Spinetoram L, Spinosad A, Spinosad B, tau-fluvalinate, Tebufenozide, tefluthrin, temephos, terbufos, tetrachlorinphos, tetraconazole, tetradifon, tetramethrin, Thiamethoxam, tolclofos-methyl, tralomethrin, triadimenol, triazophos, triclopyr esters, tridemorph, tridiphane, triflumizole, trifluralin, xylylcarb and any combination thereof.\",\n \"In an eighth aspect the invention comprises a method for manufacturing of a pharmaceutical formulation comprising the step of combining an effective amount of the biologically active material prepared by a method described herein together with acceptable excipients to produce a formulation that can deliver a therapeutically effective amount of active to the pulmonary or nasal area.\",\n \"Such a formulation could be, but is not limited to a dry powder formulation for oral inhalation to the lungs or a formulation for nasal inhalation.\",\n \"Preferably the method for manufacturing such a formulation uses lactose, mannitol, sucrose, sorbitol, xylitol or other sugars or polyols as the co-grinding matrix together with surfactant such as, but not limited to lecithin, DPPC (dipalmitoyl phosphatidylcholine), PG (phosphatidylglycerol), dipalmitoyl phosphatidyl ethanolamine (DPPE), dipalmitoyl phosphatidylinositol (DPPI) or other phospholipid.\",\n \"The particle size of the material produced by the invention disclosed herein results in the materials being readily aerosolized and suitable for methods of delivery to a subject in need thereof, including pulmonary and nasal delivery methods.\",\n \"While the method of the present invention has particular application in the preparation of poorly water-soluble biologically active materials, the scope of the invention is not limited thereto.\",\n \"For example, the method of the present invention enables production of highly water-soluble biologically active materials.\",\n \"Such materials may exhibit advantages over conventional materials by way of, for example, more rapid therapeutic action or lower dose.\",\n \"In contrast, wet grinding techniques utilizing water (or other comparably polar solvents) are incapable of being applied to such materials, as the particles dissolve appreciably in the solvent.\",\n \"Other aspects and advantages of the invention will become apparent to those skilled in the art from a review of the ensuing description.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS FIG.\",\n \"1 shows the particle size distribution of Meloxicam milled in Lactose for 1 minute (B) or 2 minutes (C), respectively, compared to the particle size distribution of commercially available Meloxicam (A).\",\n \"FIG.\",\n \"2 shows the dissolution of Meloxicam milled in Lactose for 1 minute (B) or 2 minutes (C), respectively, compared to the dissolution of commercially available Meloxicam (A).\",\n \"FIG.\",\n \"3 shows the particle size distribution of Diclofenac milled in Lactose for 1 minute (B) or 2 minutes (C), respectively, compared to the particle size distribution of commercially obtained Diclofenac (A).\",\n \"FIG.\",\n \"4 shows the dissolution of Diclofenac milled in Lactose for 1 minute (B) or 2 minutes (C), respectively, compared to the dissolution of commercially available Diclofenac (A).\",\n \"FIG.\",\n \"5 shows the Differential Scanning calorimetry (DSC) traces of mannitol, 10% meloxicam milled in mannitol for 2 minutes (example 3) and 20% meloxicam milled in mannitol for 2 minutes (example 11).\",\n \"FIG.\",\n \"6 shows the XRD spectra of Meloxicam (A), milled lactose monohydrate (B), Meloxicam milled in Lactose at 20% for 2 minutes (example 10) (C) and Meloxicam milled in Lactose with 1% SDS at 50% for 10 minutes (example 17) (D).\",\n \"FIG.\",\n \"7 shows the XRD spectra of Meloxicam (A), mannitol (B), a physical mixture of 20 Meloxicam in Lactose (C) and Meloxicam milled in mannitol at 20% for 2 minutes (example 11) (D).\",\n \"FIG.\",\n \"8 shows the XRD spectra of Diclofenac milled in Lactose with 1% SDS at 20% for 10 minutes (A), Diclofenac milled in Lactose with 1% SDS at 30% for 10 minutes (example 12) (B), Diclofenac milled in Lactose with 1% SDS at 40% for 10 minutes (example 13) (C) and Diclofenac milled in Lactose with 1% SDS at 50% for 10 minutes (example 14) (D).\",\n \"FIG.\",\n \"9 shows the XRD spectra of a physical mixture of 20% Diclofenac in Lactose with 1% SDS (A), 30% Diclofenac in Lactose with 1% SDS (B), 40% Diclofenac in Lactose with 1% SDS (C) and 50% Diclofenac in Lactose with 1% SDS (D).\",\n \"FIG.\",\n \"10 shows the XRD spectra of a Diclofenac acid (A), Lactose monohydrate (B) and milled Lactose monohydrate (C).\",\n \"FIG.\",\n \"11 shows the XRD spectra of a Meloxicam (A), a physical mixture of 50% Meloxicam in Lactose with 1% SDS (B) and milled Lactose monohydrate (C).\",\n \"DETAILED DESCRIPTION OF THE INVENTION General Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described.\",\n \"It is to be understood that the invention includes all such variations and modifications.\",\n \"The invention also includes all of the steps, features, compositions and materials referred to or indicated in the specification, individually or collectively and any and all combinations or any two or more of the steps or features.\",\n \"The present invention is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only.\",\n \"Functionally equivalent products, compositions and methods are clearly within the scope of the invention as described herein.\",\n \"The invention described herein may include one or more ranges of values (e.g.\",\n \"size, concentration etc).\",\n \"A range of values will be understood to include all values within the range, including the values defining the range, and values adjacent to the range that lead to the same or substantially the same outcome as the values immediately adjacent to that value which defines the boundary to the range.\",\n \"The entire disclosures of all publications (including patents, patent applications, journal articles, laboratory manuals, books, or other documents) cited herein are hereby incorporated by reference.\",\n \"Inclusion does not constitute an admission is made that any of the references constitute prior art or are part of the common general knowledge of those working in the field to which this invention relates.\",\n \"Throughout this specification, unless the context requires otherwise, the word “comprise” or variations, such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer, or group of integers, but not the exclusion of any other integers or group of integers.\",\n \"It is also noted that in this disclosure, and particularly in the claims and/or paragraphs, terms such as “comprises”, “comprised”, “comprising” and the like can have the meaning attributed to it in US patent law; e.g., they can mean “includes”, “included”, “including”, and the like.\",\n \"“Therapeutically effective amount” as used herein with respect to methods of treatment and in particular drug dosage, shall mean that dosage that provides the specific pharmacological response for which the drug is administered in a significant number of subjects in need of such treatment.\",\n \"It is emphasized that “therapeutically effective amount,” administered to a particular subject in a particular instance will not always be effective in treating the diseases described herein, even though such dosage is deemed a “therapeutically effective amount” by those skilled in the art.\",\n \"It is to be further understood that drug dosages are, in particular instances, measured as oral dosages, or with reference to drug levels as measured in blood.\",\n \"The term “inhibit” is defined to include its generally accepted meaning which includes prohibiting, preventing, restraining, and lowering, stopping, or reversing progression or severity, and such action on a resultant symptom.\",\n \"As such the present invention includes both medical therapeutic and prophylactic administration, as appropriate.\",\n \"The term “biologically active material” is defined to mean a biologically active compound or a substance which comprises a biologically active compound.\",\n \"In this definition, a compound is generally taken to mean a distinct chemical entity where a chemical formula or formulas can be used to describe the substance.\",\n \"Such compounds would generally, but not necessarily be identified in the literature by a unique classification system such as a CAS number.\",\n \"Some compounds may be more complex and have a mixed chemical structure.\",\n \"For such compounds they may only have a empirical formula or be qualitatively identified.\",\n \"A compound would generally be a pure material, although it would be expected that up to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% of the substance could be other impurities and the like.\",\n \"Examples of biologically active compounds are, but not limited to, pharmaceutical actives, fungicides, pesticides, herbicides, nutraceuticals, cosmeceuticals, cosmetics, complementary medicines, natural products, vitamins, nutrients, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids.\",\n \"A substance that contains a biologically active compound is any substance which has as one of its components a biologically active compound .\",\n \".\",\n \".\",\n \".\",\n \"Examples of substances containing biologically active compounds are, but not limited to, pharmaceutical formulations and products, cosmetic formulations and products, industrial formulations and products, agricultural formulations and products, foods, seeds, cocoa and cocoa solids, coffee, herbs, spices, other plant materials, minerals, animal products, shells and other skeletal material.\",\n \"Any of the terms, “biological(ly) active”, “active”, “active material” shall have the same meaning as biologically active material.\",\n \"The term “grinding matrix” is defined as any inert substance that a biologically active material can or is combined with and milled.\",\n \"The terms “co-grinding matrix” and “matrix” are interchangeable with “grinding matrix”.\",\n \"Particle Size There are a wide range of techniques that can be utilized to characterize the particle size of a material.\",\n \"Those skilled in the art also understand that almost all these techniques do not physically measure the actually particle size, as one might measure something with a ruler, but measure a physical phenomena which is interpreted to indicate a particle size.\",\n \"As part of the interpretation process some assumptions need to be made to enable mathematical calculations to be made.\",\n \"These assumptions deliver results such as an equivalent spherical particle size, or a hydrodynamic radius.\",\n \"Amongst these various methods, two types of measurements are most commonly used.\",\n \"Photon correlation spectroscopy (PCS), also known as ‘dynamic light scattering’ (DLS) is commonly used to measure particles with a size less than 10 micron.\",\n \"Typically this measurement yields an equivalent hydrodynamic radius often expressed as the average size of a number distribution.\",\n \"The other common particle size measurement is laser diffraction which is commonly used to measure particle size from 100 nm to 2000 micron.\",\n \"This technique calculates a volume distribution of equivalent spherical particles that can be expressed using descriptors such as the median particle size or the % of particles under a given size.\",\n \"Those skilled in the art recognize that different characterization techniques such as photon correlation spectroscopy and laser diffraction measure different properties of a particle ensemble.\",\n \"As a result multiple techniques will give multiple answers to the question, “what is the particle size.” In theory one could convert and compare the various parameters each technique measures, however, for real world particle systems this is not practical.\",\n \"As a result the particle size used to describe this invention will be given as two different sets of values that each relate to these two common measurement techniques, such that measurements could be made with either technique and then evaluated against the description of this invention.\",\n \"For measurements made using a photo correlation spectroscopy instrument, or an equivalent method known in the art, the term “number average particle size” is defined as the average particle diameter as determined on a number basis.\",\n \"For measurements made using a laser diffraction instrument, or an equivalent method known in the art, the term “median particle size” is defined as the median particle diameter as determined on an equivalent spherical particle volume basis.\",\n \"Where the term median is used, it is understood to describe the particle size that divides the population in half such that 50% of the population is greater than or less than this size.\",\n \"The median particle size is often written as D50, D(0.50) or D[0.5] or similar.\",\n \"As used herein D50, D(0.50) or D[0.5] or similar shall be taken to mean ‘median particle size’.\",\n \"The term “Dx of the particle size distribution” refers to the xth percentile of the distribution; thus, D90 refers to the 90th percentile, D95 refers to the 95th percentile, and so forth.\",\n \"Taking D90 as an example this can often be written as, D(0.90) or D[0.9] or similar.\",\n \"With respect to the median particle size and Dx an upper case D or lowercase d are interchangeable and have the same meaning.\",\n \"Another commonly used way of describing a particle size distribution measured by laser diffraction, or an equivalent method known in the art, is to describe what % of a distribution is under or over a nominated size.\",\n \"The term “percentage less than” also written as “%<” is defined as the percentage, by volume, of a particle size distribution under a nominated size—for example the %<1000 nm.\",\n \"The term “percentage greater than” also written as “%>” is defined as the percentage, by volume, of a particle size distribution over a nominated size—for example the %>1000 nm.\",\n \"The particle size used to describe this invention should be taken to mean the particle size as measured at or shortly before the time of use.\",\n \"For example, the particle size is measured 2 months after the material is subject to the milling method of this invention.\",\n \"In a preferred form, the particle size is measured at a time selected from the group consisting of: 1 day after milling, 2 days after milling, 5 days after milling, 1 month after milling, 2 months after milling, 3 months after milling, 4 months after milling, 5 months after milling, 6 months after milling, 1 year after milling, 2 years after milling, 5 years after milling.\",\n \"For many of the materials subject to the methods of this invention the particle size can be easily measured.\",\n \"Where the active material has poor water solubility and the matrix it is milled in has good water solubility the powder can simply be dispersed in an aqueous solvent.\",\n \"In this scenario the matrix dissolves leaving the active material dispersed in the solvent.\",\n \"This suspension can then be measured by techniques such as PCS or laser diffraction.\",\n \"Suitable methods to measure an accurate particle size where the active material has substantive aqueous solubility or the matrix has low solubility in a water based dispersant are outlined below.\",\n \"1.In the circumstance where insoluble matrix such as microcrystalline cellulose prevents the measurement of the active material, separation techniques such as filtration or centrifugation could be used to separate the insoluble matrix from the active material particles.\",\n \"Other ancillary techniques would also be required to determine if any active material was removed by the separation technique so that this could be taken into account.\",\n \"2.In the case where the active material is too soluble in water other solvents could be evaluated for the measurement of particle size.\",\n \"Where a solvent could be found that active material is poorly soluble in but is a good solvent for the matrix a measurement would be relatively straight forward.\",\n \"If such a solvent is difficult to find another approach would be to measure the ensemble of matrix and active material in a solvent (such as iso-octane) which both are insoluble in.\",\n \"Then the powder would be measured in another solvent where the active material is soluble but the matrix is not.\",\n \"Thus with a measurement of the matrix particle size and a measurement of the size of the matrix and active material together an understanding of the active material particle size can be obtained.\",\n \"3.In some circumstances image analysis could be used to obtain information about the particle size distribution of the active material.\",\n \"Suitable image measurement techniques might include transmission electron microscopy (TEM), scanning electron microscopy (SEM), optical microscopy and confocal microscopy.\",\n \"In addition to these standard techniques some additional technique would be required to be used in parallel to differentiate the active material and matrix particles.\",\n \"Depending on the chemical makeup of the materials involved possible techniques could be elemental analysis, raman spectroscopy, FTIR spectroscopy or fluorescence spectroscopy.\",\n \"Other Definitions Throughout this specification, unless the context requires otherwise, the phrase “dry mill” or variations, such as “dry milling”, should be understood to refer to milling in at least the substantial absence of liquids.\",\n \"If liquids are present, they are present in such amounts that the contents of the mill retain the characteristics of a dry powder.\",\n \"“Flowable” means a powder having physical characteristics rendering it suitable for further processing using typical equipment used for the manufacture of pharmaceutical compositions and formulations.\",\n \"Other definitions for selected terms used herein may be found within the detailed description of the invention and apply throughout.\",\n \"Unless otherwise defined, all other scientific and technical terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the invention belongs.\",\n \"The term “millable” means that the grinding matrix is capable of being physically degraded under the dry milling conditions of the method of the invention.\",\n \"In one embodiment of the invention, the milled grinding matrix is of a comparable particle size to the biologically active material.\",\n \"In another embodiment of the invention the particle size of the matrix is substantially reduced but not as small as the biologically active material Other definitions for selected terms used herein may be found within the detailed description of the invention and apply throughout.\",\n \"Unless otherwise defined, all other scientific and technical terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the invention belongs.\",\n \"Specific In one embodiment, the present invention is directed to a method for improving the dissolution profile of a biologically active material, the method comprising the step of: dry milling a mixture of a solid biologically active material and a millable grinding matrix, in a mill comprising a plurality of milling bodies, to produce particles of a biologically active material dispersed in at least partially milled grinding matrix.\",\n \"The mixture of active material and matrix may then be separated from the milling bodies and removed from the mill.\",\n \"In one aspect the mixture of active material and matrix is then further processed.\",\n \"In another aspect, the grinding matrix is separated from the particles of biologically active material.\",\n \"In a further aspect, at least a portion of the milled grinding matrix is separated from the particulate biologically active material.\",\n \"The milling bodies are essentially resistant to fracture and erosion in the dry milling process.\",\n \"The quantity of the grinding matrix relative to the quantity of biologically active material in particulate form, and the extent of milling of the grinding matrix, is sufficient to improve the dissolution profile of the active material milled.\",\n \"The present invention also relates to biologically active materials produced by said methods, to medicaments produced using said biologically active materials and to methods of treatment of an animal, including man, using a therapeutically effective amount of said biologically active materials administered by way of said medicaments.\",\n \"Improving the Dissolution Profile The present invention leads to the improved dissolution profile.\",\n \"An improved dissolution profile has significant advantages including the improvement of bioavailability of the biologically active material in vivo.\",\n \"Preferably, the improved dissolution profile is observed in vitro.\",\n \"Alternatively, the improved dissolution profile is observed in vivo by the observation of an improved bioavailability profile.\",\n \"Standard methods for determining the dissolution profile of a material in vitro are available in the art.\",\n \"A suitable method to determine an improved dissolution profile in vitro may include determining the concentration of the sample material in a solution over a period of time and comparing the results from the sample material to a control sample.\",\n \"An observation that peak solution concentration for the sample material was achieved in less time than the control sample would indicate (assuming it is statistically significant), that the sample material has an improved dissolution profile.\",\n \"The measurement sample is herein defined as the mixture of biologically active material with grinding matrix and/or other additives that has been subject to the processes of the invention described here.\",\n \"Herein a control sample is defined as a physical mixture (not subject to the processes described in this invention) of the components in the measurement sample with the same relative proportions of active, matrix and/or additive as the measurement sample.\",\n \"For the purposes of the dissolution testing a prototype formulation of the measurement sample could also be used.\",\n \"In this case the control sample would be formulated in the same way.\",\n \"Standard methods for determining the improved dissolution profile of a material in vivo are available in the art.\",\n \"A suitable method to determine an improved dissolution profile in a human may be after delivering the dose to measure the rate of active material absorption by measuring the plasma concentration of the sample compound over a period of time and comparing the results from the sample compound to a control.\",\n \"An observation that peak plasma concentration for the sample compound was achieved in less time than the control would indicate (assuming it is statistically significant) that the sample compound has improved bioavailability and an improved dissolution profile.\",\n \"Preferably, the improved dissolution profile is observed at a relevant gastrointestinal pH, when it is observed in vitro.\",\n \"Preferably, the improved dissolution profile is observed at a pH which is favourable at indicating improvements in dissolution when comparing the measurement sample to the control compound.\",\n \"Suitable methods for quantifying the concentration of a compound in an in vitro sample or an in vivo sample are widely available in the art.\",\n \"Suitable methods could include the use of spectroscopy or radioisotope labeling.\",\n \"In one preferred embodiment the method of quantification of dissolution is determined in a solution with a pH selected from the group consisting of: pH 1, pH 2, pH 3, pH 4, pH 5, pH 6, pH 7, pH 7.3, pH 7.4, pH 8, pH 9, pH 10, pH 11, pH 12, pH 13, pH 14 or a pH with 0.5 of a pH unit of any of this group.\",\n \"Crystallization Profile Methods for determining the crystallinity profile of the biologically active material are widely available in the art.\",\n \"Suitable methods may include X-ray diffraction, differential scanning calorimetry, raman or IR spectroscopy.\",\n \"Amorphicity Profile Methods for determining the amorphous content of the biologically active material are widely available in the art.\",\n \"Suitable methods may include X-ray diffraction, differential scanning calorimetry, raman or IR spectroscopy.\",\n \"Grinding Matrix As will be described subsequently, selection of an appropriate grinding matrix affords particular advantageous applications of the method of the present invention.\",\n \"A highly advantageous application of the method of the invention is the use of a water-soluble grinding matrix in conjunction with a poorly water-soluble biologically active material.\",\n \"This affords at least two advantages.\",\n \"The first being when the powder containing the biologically active material is placed into water—such as the ingestion of the powder as part of an oral medication—the matrix dissolves, releasing the particulate active material such that there is maximum surface area exposed to solution, thereby allowing a rapid dissolution of the active compound.\",\n \"The second key advantage is the ability, if required, to remove or partially remove the matrix prior to further processing or formulation.\",\n \"Another advantageous application of the method of the invention is the use of a water-insoluble grinding matrix, particularly in the area of agricultural use, when a biologically active material such as a fungicide is commonly delivered as part of a dry powder or a suspension.\",\n \"The presence of a water insoluble matrix will afford benefits such as increased rain fastness.\",\n \"Without wishing to be bound by theory, it is believed that the physical degradation (including but not limited to particle size reduction) of the millable grinding matrix affords the advantage of the invention, by acting as a more effective diluent than grinding matrix of a larger particle size.\",\n \"Again, as will be described subsequently, a highly advantageous aspect of the present invention is that certain grinding matrixes appropriate for use in the method of the invention are also appropriate for use in a medicament.\",\n \"The present invention encompasses methods for the production of a medicament incorporating both the biologically active material and the grinding matrix or in some cases the biologically active material and a portion of the grinding matrix, medicaments so produced, and methods of treatment of an animal, including man, using a therapeutically effective amount of said biologically active materials by way of said medicaments.\",\n \"Analogously, as will be described subsequently, a highly advantageous aspect of the present invention is that certain grinding matrixes appropriate for use in the method of the invention are also appropriate for use in a carrier for an agricultural chemical, such as a pesticide, fungicide, or herbicide.\",\n \"The present invention encompasses methods for the production of an agricultural chemical composition incorporating both the biologically active material in particulate form and the grinding matrix, or in some cases the biologically active material, and a portion of the grinding matrix, and agricultural chemical compositions so produced.\",\n \"The medicament may include only the biologically active material together with the milled grinding matrix or, more preferably, the biologically active material and milled grinding matrix may be combined with one or more pharmaceutically acceptable carriers, as well as any desired excipients or other like agents commonly used in the preparation of medicaments.\",\n \"Analogously, the agricultural chemical composition may include only the biologically active material together with the milled grinding matrix or, more preferably, the biologically active materials and milled grinding matrix may be combined with one or more carriers, as well as any desired excipients or other like agents commonly used in the preparation of agricultural chemical compositions.\",\n \"In one particular form of the invention, the grinding matrix is both appropriate for use in a medicament and readily separable from the biologically active material by methods not dependent on particle size.\",\n \"Such grinding matrixes are described in the following detailed description of the invention.\",\n \"Such grinding matrixes are highly advantageous in that they afford significant flexibility in the extent to which the grinding matrix may be incorporated with the biologically active material into a medicament.\",\n \"In a highly preferred form, the grinding matrix is harder than the biologically active material, and is thus capable of improving the dissolution profile of the active material under the dry milling conditions of the invention.\",\n \"Again without wishing to be bound by theory, under these circumstances it is believed that the millable grinding matrix affords the advantage of the present invention through a second route, with the smaller particles of grinding matrix produced under the dry milling conditions enabling greater interaction with the biologically active material.\",\n \"The quantity of the grinding matrix relative to the quantity of biologically active material, and the extent of physical degradation of the grinding matrix, is sufficient to improve the dissolution profile of the milled biologically active material.\",\n \"The grinding matrix is not generally selected to be chemically reactive with the biologically active material under the milling conditions of the invention, excepting for example, where the matrix is deliberately chosen to undergo a mechanico-chemical reaction.\",\n \"Such a reaction might be the conversion of a free base or acid to a salt or vice versa.\",\n \"As stated above, the method of the present invention requires the grinding matrix to be milled with the biologically active material; that is, the grinding matrix will physically degrade under the dry milling conditions of the invention to facilitate the formation and retention of particulates of the biologically active material with improved dissolution profiles.\",\n \"The precise extent of degradation required will depend on certain properties of the grinding matrix and the biologically active material, the ratio of biologically active material to grinding matrix, and the particle size distribution of the particles comprising the biologically active material.\",\n \"The physical properties of the grinding matrix necessary to achieve the requisite degradation are dependent on the precise milling conditions.\",\n \"For example, a harder grinding matrix may degrade to a sufficient extent provided [it is subjected to] more vigorous dry milling conditions.\",\n \"Physical properties of the grinding matrix relevant to the extent that the agent will degrade under dry milling conditions include hardness, friability, as measured by indicia such as hardness, fracture toughness and brittleness index.\",\n \"A low hardness (typically a Mohs Hardness less than 7) of the biologically active material is desirable to ensure fracture of the particles during processing, so that composite microstructures develop during milling.\",\n \"Preferably, the hardness is less than 3 as determined using the Mohs Hardness scale.\",\n \"Preferably, the grinding matrix is of low abrasivity.\",\n \"Low abrasivity is desirable to minimise contamination of the mixture of the biologically active material in the grinding matrix by the milling bodies and/or the milling chamber of the media mill.\",\n \"An indirect indication of the abrasivity can be obtained by measuring the level of milling-based contaminants.\",\n \"Preferably, the grinding matrix has a low tendency to agglomerate during dry milling.\",\n \"While it is difficult to objectively quantify the tendency to agglomerate during milling, it is possible to obtain a subjective measure by observing the level of “caking” of the grinding matrix on the milling bodies and the milling chamber of the media mill as dry milling progresses.\",\n \"The grinding matrix may be an inorganic or organic substance.\",\n \"In one embodiment, the grinding matrix is selected from the following, either as a single substance or a combination of two or more substances: Polyols (sugar alcohols) for example (but not limited to) mannitol, sorbitol, isomalt, xylitol, maltitol, lactitol, erythritol, arabitol, ribitol, monosaccharides for example (but not limited to) glucose, fructose, mannose, galactose, disaccharides and trisaccharides for example (but not limited to) anhydrous lactose, lactose monohydrate, sucrose, maltose, trehalose, polysaccharides for example (but not limited to) maltodextrins, dextrin, Inulin, dextrates, polydextrose, other carbohydrates for example (but not limited to) starch, wheat flour, corn flour, rice flour, rice starch, tapioca flour, tapioca starch, potato flour, potato starch, other flours and starches, soy flour, soy meal or other soy products, cellulose, microcrystalline cellulose, microcrystalline cellulose based co blended excipients, chemically modified excipients such as pregelatinized (or partially) starch, modified celluloses such as HPMC, CMC, HPC, enteric polymer coatings such as hypromellose phthalate, cellulose acetate phthalate (Aquacoat®), polyvinyl acetate phthalate (Sureteric®), hypromellose acetate succinate (AQOAT®), and polmethacrylates (Eudragit® and Acryl-EZE®), Milk products for example (but not limited to) milk powder, skim milk powders, other milk solids and derivatives, other functional Excipients, organic acids for example (but not limited to) citric acid, tartaric acid, malic acid, maleic acid fumaric acid, ascorbic acid, succinic acid, the conjugate salt of organic acids for example (but not limited to) sodium citrate, sodium tartrate, sodium malate, sodium ascorbate, potassium citrate, potassium tartrate, potassium malate, potassium ascorbate, inorganics such as sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate and calcium carbonate.\",\n \"dibasic calcium phosphate, tribasic calcium phosphate, sodium sulfate, sodium chloride, sodium metabisulphite, sodium thiosulfate, ammonium chloride, Glauber's salt, ammonium carbonate, sodium bisulfate, magnesium sulfate, potash alum, potassium chloride, sodium hydrogen sulfate, sodium hydroxide, crystalline hydroxides, hydrogen carbonates, hydrogen carbonates of pharmaceutical acceptable alkali metals, such as but not limited by, sodium, potassium, lithium, calcium, and barium, ammonium salts (or salts of volatile amines), for example (but not limited to) ammonium chloride, methylamine hydrochloride, ammonium bromide, other inorganics for example (but not limited to), thermal silica, chalk, mica, silica, alumina, titanium dioxide, talc, kaolin, bentonite, hectorite, magnesium trisilicate, other clay or clay derivatives or aluminium silicates, a surfactant for example (but not limited to) sodium lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate, sodium cetostearyl sulfate, sodium docusate, sodium deoxycholate, N-lauroylsarcosine sodium salt, glyceryl monostearate, glycerol distearate glyceryl palmitostearate, glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzalkonium chloride, CTAB, CTAC, Cetrimide, cetylpyridinium chloride, cetylpyridinium bromide, benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188, poloxamer 338, poloxamer 407 polyoxyl 2 stearyl ether, polyoxyl 100 stearyl ether, polyoxyl 20 stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 20 cetyl ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl 35 castor oil, polyoxyl 40 castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor oil, polyoxyl 200 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyoxyl 100 hydrogenated castor oil, polyoxyl 200 hydrogenated castor oil, cetostearyl alcohol, macrogel 15 hydroxystearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, Sucrose Palmitate, Sucrose Stearate, Sucrose Distearate, Sucrose laurate, Glycocholic acid, sodium Glycholate, Cholic Acid, Sodium Cholate, Sodium Deoxycholate, Deoxycholic acid, Sodium taurocholate, taurocholic acid, Sodium taurodeoxycholate, taurodeoxycholic acid, soy lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonate condensate/Lignosulfonate blend, Calcium Dodecylbenzene Sulfonate, Sodium Dodecylbenzene Sulfonate, Diisopropyl naphthalenesulphonate, erythritol distearate, Naphthalene Sulfonate Formaldehyde Condensate, nonylphenol ethoxylate (poe-30), Tristyrylphenol Ethoxylate, Polyoxyethylene (15) tallowalkylamines, sodium alkyl naphthalene sulfonate, sodium alkyl naphthalene sulfonate condensate, sodium alkylbenzene sulfonate, sodium isopropyl naphthalene sulfonate, Sodium Methyl Naphthalene Formaldehyde Sulfonate, sodium n-butyl naphthalene sulfonate, tridecyl alcohol ethoxylate (poe-18), Triethanolamine isodecanol phosphate ester, Triethanolamine tristyrylphosphate ester, Tristyrylphenol Ethoxylate Sulfate, Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"In a preferred embodiment, the grinding matrix is a matrix that is considered GRAS (generally regarded as safe) by persons skilled in the pharmaceutical arts.\",\n \"In another preferred aspect a combination of two or more suitable matrices, such as those listed above, can be used as the grinding matrix to provide improved properties such as the reduction of caking, and greater improvement of particle size reduction.\",\n \"Combination matrices may also be advantageous when the matrices have different solubility's allowing the removal or partial removal of one matrix, while leaving the other or part of the other to provide encapsulation or partial encapsulation of the biologically active material.\",\n \"Another highly preferred aspect of the method is the inclusion of a suitable milling aid in the matrix to improve milling performance.\",\n \"Improvements to milling performance would be things such as, but not limited to, a reduction in caking or higher recovery of powder from the mill.\",\n \"Examples of suitable milling aids include surfactants, polymers and inorganics such as silica (including colloidal silica), aluminium silicates and clays.\",\n \"There are a wide range of surfactants that will make suitable milling aids.\",\n \"The highly preferred form is where the surfactant is a solid, or can be manufactured into a solid.\",\n \"Preferably, the surfactant is selected from the group consisting of: polyoxyethylene alkyl ethers, polyoxyethylene stearates, polyethylene glycols (PEG), poloxamers, poloxamines, sarcosine based surfactants, polysorbates, aliphatic alcohols, alkyl and aryl sulfates, alkyl and aryl polyether sulfonates and other sulfate surfactants, trimethyl ammonium based surfactants, lecithin and other phospholipids, bile salts, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, Sorbitan fatty acid esters, Sucrose fatty acid esters, alkyl glucopyranosides, alkyl maltopyranosides, glycerol fatty acid esters, Alkyl Benzene Sulphonic Acids, Alkyl Ether Carboxylic Acids, Alkyl and aryl Phosphate esters, Alkyl and aryl Sulphate esters, Alkyl and aryl Sulphonic acids, Alkyl Phenol Phosphates esters, Alkyl Phenol Sulphates esters, Alkyl and Aryl Phosphates, Alkyl Polysaccharides, Alkylamine Ethoxylates, Alkyl-Naphthalene Sulphonates formaldehyde condensates, Sulfosuccinates, lignosulfonates, Ceto-Oleyl Alcohol Ethoxylates, Condensed Naphthalene Sulphonates, Dialkyl and Alkyl Naphthalene Sulphonates, Di-alkyl Sulphosuccinates, Ethoxylated nonylphenols, Ethylene Glycol Esters, Fatty Alcohol Alkoxylates, Hydrogenated tallowalkylamines, Mono-alkyl Sulphosuccinamates, Nonyl Phenol Ethoxylates, Sodium Oleyl N-methyl Taurate, Tallowalkylamines, linear and branched dodecylbenzene sulfonic acids.\",\n \"Preferably, the surfactant is selected from the group consisting of: sodium lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate, sodium cetostearyl sulfate, sodium docusate, sodium deoxycholate, N-lauroylsarcosine sodium salt, glyceryl monostearate, glycerol distearate glyceryl palmitostearate, glyceryl behenate, glyceryl caprylate, glyceryl oleate, benzalkonium chloride, CTAB, CTAC, Cetrimide, cetylpyridinium chloride, cetylpyridinium bromide, benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188, poloxamer 338, poloxamer 407 polyoxyl 2 stearyl ether, polyoxyl 100 stearyl ether, polyoxyl 20 stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 20 cetyl ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl 35 castor oil, polyoxyl 40 castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor oil, polyoxyl 200 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyoxyl 100 hydrogenated castor oil, polyoxyl 200 hydrogenated castor oil, cetostearyl alcohol, macrogel 15 hydroxystearate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, Sucrose Palmitate, Sucrose Stearate, Sucrose Distearate, Sucrose laurate, Glycocholic acid, sodium Glycholate, Cholic Acid, Sodium Cholate, Sodium Deoxycholate, Deoxycholic acid, Sodium taurocholate, taurocholic acid, Sodium taurodeoxycholate, taurodeoxycholic acid, soy lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonate condensate/Lignosulfonate blend, Calcium Dodecylbenzene Sulfonate, Sodium Dodecylbenzene Sulfonate, Diisopropyl naphthalenesulphonate, erythritol distearate, Naphthalene Sulfonate Formaldehyde Condensate, nonylphenol ethoxylate (poe-30), Tristyrylphenol Ethoxylate, Polyoxyethylene (15) tallowalkylamines, sodium alkyl naphthalene sulfonate, sodium alkyl naphthalene sulfonate condensate, sodium alkylbenzene sulfonate, sodium isopropyl naphthalene sulfonate, Sodium Methyl Naphthalene Formaldehyde Sulfonate, sodium n-butyl naphthalene sulfonate, tridecyl alcohol ethoxylate (poe-18), Triethanolamine isodecanol phosphate ester, Triethanolamine tristyrylphosphate ester, Tristyrylphenol Ethoxylate Sulfate, Bis(2-hydroxyethyl)tallowalkylamines.\",\n \"Preferably the polymer is selected from the list of: polyvinylpyrrolidones (PVP), polyvinylalcohol, Acrylic acid based polymers and copolymers of acrylic acid Preferably, the milling aid has a concentration selected from the group consisting of: 0.1-10% w/w, 0.1-5% w/w, 0.1-2.5% w/w, of 0.1-2% w/w, 0.1-1%, 0.5-5% w/w, 0.5-3% w/w, 0.5-2% w/w, 0.5-1.5%, 0.5-1% w/w, of 0.75-1.25% w/w, 0.75-1% and 1% w/w.\",\n \"Milling Bodies In the method of the present invention, the milling bodies are preferably chemically inert and rigid.\",\n \"The term “chemically-inert”, as used herein, means that the milling bodies do not react chemically with the biologically active material or the grinding matrix.\",\n \"As described above, the milling bodies are essentially resistant to fracture and erosion in the milling process.\",\n \"The milling bodies are desirably provided in the form of bodies which may have any of a variety of smooth, regular shapes, flat or curved surfaces, and lacking sharp or raised edges.\",\n \"For example, suitable milling bodies can be in the form of bodies having ellipsoidal, ovoid, spherical or right cylindrical shapes.\",\n \"Preferably, the milling bodies are provided in the form of one or more of beads, balls, spheres, rods, right cylinders, drums or radius-end right cylinders (i.e., right cylinders having hemispherical bases with the same radius as the cylinder).\",\n \"Depending on the nature of the biologically active material and the grinding matrix, the milling media bodies desirably have an effective mean particle diameter (i.e.\",\n \"“particle size”) between about 0.1 and 30 mm, more preferably between about 1 and about 15 mm, still more preferably between about 3 and 10 mm.\",\n \"The milling bodies may comprise various substances such as ceramic, glass, metal or polymeric compositions, in a particulate form.\",\n \"Suitable metal milling bodies are typically spherical and generally have good hardness (i.e.\",\n \"RHC 60-70), roundness, high wear resistance, and narrow size distribution and can include, for example, balls fabricated from type 52100 chrome steel, type 316 or 440C stainless steel or type 1065 high carbon steel.\",\n \"Preferred ceramics, for example, can be selected from a wide array of ceramics desirably having sufficient hardness and resistance to fracture to enable them to avoid being chipped or crushed during milling and also having sufficiently high density.\",\n \"Suitable densities for milling media can range from about 1 to 15 g/cm3′, preferably from about 1 to 8 g/cm3.Preferred ceramics can be selected from steatite, aluminum oxide, zirconium oxide, zirconia-silica, yttria-stabilized zirconium oxide, magnesia-stabilized zirconium oxide, silicon nitride, silicon carbide, cobalt-stabilized tungsten carbide, and the like, as well as mixtures thereof.\",\n \"Preferred glass milling media are spherical (e.g.\",\n \"beads), have a narrow size distribution, are durable, and include, for example, lead-free soda lime glass and borosilicate glass.\",\n \"Polymeric milling media are preferably substantially spherical and can be selected from a wide array of polymeric resins having sufficient hardness and friability to enable them to avoid being chipped or crushed during milling, abrasion-resistance to minimize attrition resulting in contamination of the product, and freedom from impurities such as metals, solvents, and residual monomers.\",\n \"Preferred polymeric resins, for example, can be selected from crosslinked polystyrenes, such as polystyrene crosslinked with divinylbenzene, styrene copolymers, polyacrylates such as polymethylmethacrylate, polycarbonates, polyacetals, vinyl chloride polymers and copolymers, polyurethanes, polyamides, high density polyethylenes, polypropylenes, and the like.\",\n \"The use of polymeric milling media to grind materials down to a very small particle size (as opposed to mechanochemical synthesis) is disclosed, for example, in U.S. Pat.\",\n \"Nos.\",\n \"5,478,705 and 5,500,331.Polymeric resins typically have densities ranging from about 0.8 to 3.0 g/cm3.Higher density polymeric resins are preferred.\",\n \"Alternatively, the milling media can be composite particles comprising dense core particles having a polymeric resin adhered thereon.\",\n \"Core particles can be selected from substances known to be useful as milling media, for example, glass, alumina, zirconia silica, zirconium oxide, stainless steel, and the like.\",\n \"Preferred core substances have densities greater than about 2.5 g/cm3.In one embodiment of the invention, the milling media are formed from a ferromagnetic substance, thereby facilitating removal of contaminants arising from wear of the milling media by the use of magnetic separation techniques.\",\n \"Each type of milling body has its own advantages.\",\n \"For example, metals have the highest specific gravities, which increase grinding efficiency due to increased impact energy.\",\n \"Metal costs range from low to high, but metal contamination of final product can be an issue.\",\n \"Glasses are advantageous from the standpoint of low cost and the availability of small bead sizes as low as 0.004 mm.\",\n \"However, the specific gravity of glasses is lower than other media and significantly more milling time is required.\",\n \"Finally, ceramics are advantageous from the standpoint of low wear and contamination, ease of cleaning, and high hardness.\",\n \"Dry Milling In the dry milling process of the present invention, the biologically active material and grinding matrix, in the form of crystals, powders, or the like, are combined in suitable proportions with the plurality of milling bodies in a milling chamber that is mechanically agitated (i.e.\",\n \"with or without stirring) for a predetermined period of time at a predetermined intensity of agitation.\",\n \"Typically, a milling apparatus is used to impart motion to the milling bodies by the external application of agitation, whereby various translational, rotational or inversion motions or combinations thereof are applied to the milling chamber and its contents, or by the internal application of agitation through a rotating shaft terminating in a blade, propeller, impeller or paddle or by a combination of both actions.\",\n \"During milling, motion imparted to the milling bodies can result in application of shearing forces as well as multiple impacts or collisions having significant intensity between milling bodies and particles of the biologically active material and grinding matrix.\",\n \"The nature and intensity of the forces applied by the milling bodies to the biologically active material and the grinding matrix is influenced by a wide variety of processing parameters including: the type of milling apparatus; the intensity of the forces generated, the kinematic aspects of the process; the size, density, shape, and composition of the milling bodies; the weight ratio of the biologically active material and grinding matrix mixture to the milling bodies; the duration of milling; the physical properties of both the biologically active material and the grinding matrix; the atmosphere present during activation; and others.\",\n \"Advantageously, the media mill is capable of repeatedly or continuously applying mechanical compressive forces and shear stress to the biologically active material and the grinding matrix.\",\n \"Suitable media mills include but are not limited to the following: high-energy ball, sand, bead or pearl mills, basket mill, planetary mill, vibratory action ball mill, multi-axial shaker/mixer, stirred ball mill, horizontal small media mill, multi-ring pulverizing mill, and the like, including small milling media.\",\n \"The milling apparatus also can contain one or more rotating shafts.\",\n \"In a preferred form of the invention, the dry milling is performed in a ball mill.\",\n \"Throughout the remainder of the specification reference will be made to dry milling being carried out by way of a ball mill.\",\n \"Examples of this type of mill are attritor mills, nutating mills, tower mills, planetary mills, vibratory mills and gravity-dependent-type ball mills.\",\n \"It will be appreciated that dry milling in accordance with the method of the invention may also be achieved by any suitable means other than ball milling.\",\n \"For example, dry milling may also be achieved using jet mills, rod mills, roller mills or crusher mills.\",\n \"Biologically Active Material The biologically active material includes active compounds, including compounds for veterinary and human use such as but not limited to, pharmaceutical actives, nutraceuticals, cosmeceuticals, cosmetics, complementary medicines, natural products, vitamins, nutrients, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids.\",\n \"and agricultural compounds such as pesticides, herbicides and fungicides, germinating agents and the like.\",\n \"Other biologically active materials include, but are not limited to, foods, seeds, cocoa and cocoa solids, coffee, herbs, spices, other plant materials, minerals, animal products, shells and other skeletal material.\",\n \"In a preferred form of the invention, the biologically active material is an organic compound.\",\n \"In a highly preferred form of the invention, the biologically active material is an organic, therapeutically active compound for veterinary or human use.\",\n \"In a preferred form of the invention, the biologically active material is an inorganic compound.\",\n \"In a highly preferred form of the invention, the biologically active material is sulphur, copper hydroxide, an organometallic complex or copper oxychloride.\",\n \"The biologically active material is ordinarily a material for which one of skill in the art desires improved dissolution properties.\",\n \"The biologically active material may be a conventional active agent or drug, although the process of the invention may be employed on formulations or agents that already have reduced particle size compared to their conventional form.\",\n \"Biologically active materials suitable for use in the invention include actives, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids, and analogs, homologs and first order derivatives thereof.\",\n \"The biologically active material can be selected from a variety of known classes of drugs, including, but not limited to: anti-obesity drugs, central nervous system stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, cardiovascular agents, anti-inflammatory agents, such as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives (hypnotics and neuroleptics), astringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood products and substitutes, cardiac inotropic agents, contrast media, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (anti-Parkinsonian agents), haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones (including steroids), anti-allergic agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines.\",\n \"A description of these classes of active agents and a listing of species within each class can be found in Martindale's The Extra Pharmacopoeia, 31st Edition (The Pharmaceutical Press, London, 1996), specifically incorporated by reference.\",\n \"Another source of active agents is the Physicians Desk Reference (60th Ed., pub.\",\n \"2005), familiar to those of skill in the art.\",\n \"The active agents are commercially available and/or can be prepared by techniques known in the art.\",\n \"An exhaustive list of drugs for which the methods of the invention are suitable would be burdensomely long for this specification; however, reference to the general pharmacopoeia listed above would allow one of skill in the art to select virtually any drug to which the method of the invention may be applied.\",\n \"In addition it is also expected that new chemical entities (NCE) and other actives for which the methods of the invention are suitable will be created or become commercially available in the future.\",\n \"Notwithstanding the general applicability of the method of the invention, more specific examples of biologically active materials include, but are not limited to: haloperidol (dopamine antagonist), DL isoproterenol hydrochloride (β-adrenergic agonist), terfenadine (H1-antagonist), propranolol hydrochloride (β-adrenergic antagonist), desipramine hydrochloride (antidepressant), sildenafil citrate, tadalafil and vardenafil.\",\n \"Minor analgesics (cyclooxygenase inhibitors), fenamic acids, Piroxicam, Cox-2 inhibitors, and Naproxen, and others, may all benefit from being prepared.\",\n \"As discussed in the context of the background to the invention, biologically active materials that are poorly water soluble at gastrointestinal pH will particularly benefit from being prepared, and the method of the present invention is particularly advantageously applied to materials that are poorly water soluble at gastrointestinal pH.\",\n \"Such materials include, but are not limited to: albendazole, albendazole sulfoxide, alfaxalone, acetyl digoxin, acyclovir analogs, alprostadil, aminofostin, anipamil, antithrombin III, atenolol, azidothymidine, beclobrate, beclomethasone, belomycin, benzocaine and derivatives, beta carotene, beta endorphin, beta interferon, bezafibrate, binovum, biperiden, bromazepam, bromocryptine, bucindolol, buflomedil, bupivacaine, busulfan, cadralazine, camptothesin, canthaxanthin, captopril, carbamazepine, carboprost, cefalexin, cefalotin, cefamandole, cefazedone, cefluoroxime, cefinenoxime, cefoperazone, cefotaxime, cefoxitin, cefsulodin, ceftizoxime, chlorambucil, chromoglycinic acid, ciclonicate, ciglitazone, clonidine, cortexolone, corticosterone, cortisol, cortisone, cyclophosphamide, cyclosporin A and other cyclosporins, cytarabine, desocryptin, desogestrel, dexamethasone esters such as the acetate, dezocine, diazepam, diclofenac, dideoxyadenosine, dideoxyinosine, digitoxin, digoxin, dihydroergotamine, dihydroergotoxin, diltiazem, dopamine antagonists, doxorubicin, econazole, endralazine, enkephalin, enalapril, epoprostenol, estradiol, estramustine, etofibrate, etoposide, factor ix, factor viii, felbamate, fenbendazole, fenofibrate, fexofenedine, flunarizin, flurbiprofen, 5-fluorouracil, flurazepam, fosfomycin, fosmidomycin, furosemide, gallopamil, gamma interferon, gentamicin, gepefrine, gliclazide, glipizide, griseofulvin, haptoglobulin, hepatitis B vaccine, hydralazine, hydrochlorothiazide, hydrocortisone, ibuprofen, ibuproxam, indinavir, indomethacin, iodinated aromatic x-ray contrast agents such as iodamide, ipratropium bromide, ketoconazole, ketoprofen, ketotifen, ketotifen fumarate, K-strophanthin, labetalol, lactobacillus vaccine, lidocaine, lidoflazin, lisuride, lisuride hydrogen maleate, lorazepam, lovastatin, mefenamic acid, melphalan, memantin, mesulergin, metergoline, methotrexate, methyl digoxin, methylprednisolone, metronidazole, metisoprenol, metipranolol, metkephamide, metolazone, metoprolol, metoprolol tartrate, miconazole, miconazole nitrate, minoxidil, misonidazol, molsidomin, nadolol, nafiverine, nafazatrom, naproxen, natural insulins, nesapidil, nicardipine, nicorandil, nifedipine, niludipin, nimodipine, nitrazepam, nitrendipine, nitrocamptothesin, 9-nitrocamptothesin, olanzapine, oxazepam, oxprenolol, oxytetracycline, penicillins such as penicillin G benethamine, penecillin O, phenylbutazone, picotamide, pindolol, piposulfan, piretanide, piribedil, piroxicam, pirprofen, plasminogenici activator, prednisolone, prednisone, pregnenolone, procarbacin, procaterol, progesterone, proinsulin, propafenone, propanolol, propentofyllin, propofol, propranolol, raloxifene, rifapentin, simvastatin, semi-synthetic insulins, sobrerol, somastotine and its derivatives, somatropin, stilamine, sulfinalol hydrochloride, sulfinpyrazone, suloctidil, suprofen, sulproston, synthetic insulins, talinolol, taxol, taxotere, testosterone, testosterone propionate, testosterone undecanoate, tetracane HI, tiaramide HCl, tolmetin, tranilast, triquilar, tromantadine HCl, urokinase, valium, verapamil, vidarabine, vidarabine phosphate sodium salt, vinblastine, vinburin, vincamine, vincristine, vindesine, vinpocetine, vitamin A, vitamin E succinate, and x-ray contrast agents.\",\n \"Drugs can be neutral species or basic or acidic as well as salts of an acid or base.\",\n \"Specifically the chemical makeup and the functional groups, including an acid or base group, are generally not the determinant factor, excepting a possible chemical reaction with a specific matrix, for the successful creation of a biologically active substance with improved dissolution.\",\n \"This invention is not limited to any drug specific class, application type, chemical type or function grouping.\",\n \"Rather the suitability of a biologically active material for use in this invention is primarily determined by the mechanical properties of the material.\",\n \"In addition, some biologically active materials may have the benefit of absorption through the skin if presented in a particle formulation.\",\n \"Such biologically active materials include, but are not limited to, Voltaren (diclofenac), rofecoxib, and ibuprofen.\",\n \"Conveniently, the biologically active material is capable of withstanding temperatures that are typical in uncooled dry milling, which may exceed 80° C. Therefore, materials with a melting point about 80° C. or greater are highly suitable.\",\n \"For biologically active materials with lower melting points, the media mill may be cooled, thereby allowing materials with significantly lower melting temperatures to be processed according to the method of the invention.\",\n \"For instance, a simple water-cooled mill will keep temperatures below 50° C., or chilled water could be used to further lower the milling temperature.\",\n \"Those skilled in the art will understand that a high energy ball mill could be designed to run at any temperature between say −30 to 200° C. For some biologically active materials it may be advantageous to control the milling temperature to temperatures significantly below the melting points of the biologically active materials.\",\n \"The biologically active material is obtained in a conventional form commercially and/or prepared by techniques known in the art.\",\n \"It is preferred, but not essential, that the particle size of the biologically active material be less than about 1000 μm, as determined by sieve analysis.\",\n \"If the coarse particle size of the biologically active material is greater than about 1000 μm, then it is preferred that the particles of the biologically active material substrate be reduced in size to less than 1000 μm using another standard milling method.\",\n \"Processed Biologically Active Material Preferably, the biologically active materials, which have been subject to the methods of the invention, comprises particles of biologically active material of an average particle size diameter equal or greater than 1 μm, determined on a particle number basis.\",\n \"Preferably, the biologically active materials, which have been subject to the methods of the invention, comprises particles of biologically active material of a median particle size diameter equal or greater than 1 μm, determined on a particle volume basis.\",\n \"These sizes refer to particles either fully dispersed or partially agglomerated.\",\n \"Agglomerates of Biologically Active Material after Processing Agglomerates comprising particles of biologically active material, said particles having a particle size within the ranges specified above, should be understood to fall within the scope of the present invention.\",\n \"Agglomerates comprising particles of biologically active material, said agglomerates having a total agglomerate size within the ranges specified above, should be understood to fall within the scope of the present invention.\",\n \"Agglomerates comprising particles of biologically active material, should be understood to fall within the scope of the present invention if at the time of use, or further processing, the particle size of the agglomerate is within the ranges specified above.\",\n \"Processing Time Preferably, the biologically active material and the grinding matrix are dry milled for the shortest time necessary to form the mixture of the biologically active material in the grinding matrix such that the active material has improved dissolution to minimise any possible contamination from the media mill and/or the plurality of milling bodies.\",\n \"This time varies greatly, depending on the biologically active material and the grinding matrix, and may range from as short as 1 minute to several hours.\",\n \"Dry milling times in excess of 2 hours may lead to degradation of the biologically active material and an increased level of undesirable contaminants.\",\n \"Suitable rates of agitation and total milling times are adjusted for the type and size of milling apparatus as well as the milling media, the weight ratio of the biologically active material and grinding matrix mixture to the plurality of milling bodies, the chemical and physical properties of the biologically active material and grinding matrix, and other parameters that may be optimized empirically.\",\n \"Inclusion of the Grinding Matrix with the Biologically Active Material and Separation of the Grinding Matrix from the Biologically Active Material In a preferred aspect, the grinding matrix is not separated from the biologically active material but is maintained with the biologically active material in the final product.\",\n \"Preferably the grinding matrix is considered to be Generally Regarded as Safe (GRAS) for pharmaceutical products.\",\n \"In an alternative aspect, the grinding matrix is separated from the biologically active material.\",\n \"In one aspect, where the grinding matrix is not fully milled, the unmilled grinding matrix is separated from the biologically active material.\",\n \"In a further aspect, at least a portion of the milled grinding matrix is separated from the biologically active material.\",\n \"Any portion of the grinding matrix may be removed, including but not limited to 10%, 25%, 50%, 75%, or substantially all of the grinding matrix.\",\n \"In some embodiments of the invention, a significant portion of the milled grinding matrix may comprise particles of a size similar to and/or smaller than the particles comprising the biologically active material.\",\n \"Where the portion of the milled grinding matrix to be separated from the particles comprising the biologically active material comprises particles of a size similar to and/or smaller than the particles comprising the biologically active material, separation techniques based on size distribution are inapplicable.\",\n \"In these circumstances, the method of the present invention may involve separation of at least a portion of the milled grinding matrix from the biologically active material by techniques including but not limited to electrostatic separation, magnetic separation, centrifugation (density separation), hydrodynamic separation, froth flotation.\",\n \"Advantageously, the step of removing at least a portion of the milled grinding matrix from the biologically active material may be performed through means such as selective dissolution, washing, or sublimation.\",\n \"An advantageous aspect of the invention would be the use of grinding matrix that has two or more components where at least one component is water soluble and at least one component has low solubility in water.\",\n \"In this case washing can be used to remove the matrix component soluble in water leaving the biologically active material encapsulated in the remaining matrix components.\",\n \"In a highly advantageous aspect of the invention the matrix with low solubility is a functional excipient.\",\n \"A highly advantageous aspect of the present invention is that certain grinding matrixes appropriate for use in the method of the invention (in that they physically degrade to the desired extent under dry milling conditions) are also pharmaceutically acceptable and thus appropriate for use in a medicament.\",\n \"Where the method of the present invention does not involve complete separation of the grinding matrix from the biologically active material, the present invention encompasses methods for the production of a medicament incorporating both the biologically active material and at least a portion of the milled grinding matrix, medicaments so produced and methods of treatment of an animal, including man, using a therapeutically effective amount of said biologically active materials by way of said medicaments.\",\n \"The medicament may include only the biologically active material and the grinding matrix or, more preferably, the biologically active materials and grinding matrix may be combined with one or more pharmaceutically acceptable carriers, as well as any desired excipients or other like agents commonly used in the preparation of medicaments.\",\n \"Analogously, a highly advantageous aspect of the present invention is that certain grinding matrixes appropriate for use in the method of the invention (in that they physically degrade to a desirable extent under dry milling conditions) are also appropriate for use in an agricultural chemical composition.\",\n \"Where the method of the present invention does not involve complete separation of the grinding matrix from the biologically active material, the present invention encompasses methods for the production of a agricultural chemical composition incorporating both the biologically active material and at least a portion of the milled grinding matrix, agricultural chemical composition so produced and methods of use of such compositions.\",\n \"The agricultural chemical composition may include only the biologically active material and the grinding matrix or, more preferably, the biologically active materials and grinding matrix may be combined with one or more acceptable carriers, as well as any desired excipients or other like agents commonly used in the preparation of agricultural chemical compositions.\",\n \"In one particular form of the invention, the grinding matrix is both appropriate for use in a medicament and readily separable from the biologically active material by methods not dependent on particle size.\",\n \"Such grinding matrixes are described in the following detailed description of the invention.\",\n \"Such grinding matrixes are highly advantageous in that they afford significant flexibility in the extent to which the grinding matrix may be incorporated with the biologically active material into a medicament.\",\n \"The mixture of biologically active material and grinding matrix may then be separated from the milling bodies and removed from the mill.\",\n \"In one embodiment, the grinding matrix is separated from the mixture of biologically active material and grinding matrix.\",\n \"Where the grinding matrix is not fully milled, the unmilled grinding matrix is separated from the biologically active material.\",\n \"In a further aspect, at least a portion of the milled grinding matrix is separated from the biologically active material.\",\n \"The milling bodies are essentially resistant to fracture and erosion in the dry milling process.\",\n \"The quantity of the grinding matrix relative to the quantity of biologically active material, and the extent of milling of the grinding matrix, is sufficient to provide improved dissolution of the biologically active material.\",\n \"The grinding matrix is neither chemically nor mechanically reactive with the pharmaceutical material under the dry milling conditions of the method of the invention except, for example, where the matrix is deliberately chosen to undergo a mechanico-chemical reaction.\",\n \"Such a reaction might be the conversion of a free base or acid to a salt or vice versa.\",\n \"Preferably, the medicament is a solid dosage form, however, other dosage forms may be prepared by those of ordinary skill in the art.\",\n \"In one form, after the step of separating said mixture of biologically active material and grinding matrix from the plurality of milling bodies, and before the step of using said mixture of biologically active material and grinding matrix in the manufacture of a medicament, the method may comprise the step of: removing a portion of the grinding matrix from said mixture of biologically active material and grinding matrix to provide a mixture enriched in the biologically active material; and the step of using said mixture of biologically active material and grinding matrix in the manufacture of a medicament, more particularly comprises the step of using the mixture of biologically active material and grinding matrix enriched in the biologically active material form in the manufacture of a medicament.\",\n \"The present invention includes medicaments manufactured by said methods, and methods for the treatment of an animal, including man, by the administration of a therapeutically effective amount of the biologically active materials by way of said medicaments.\",\n \"In another embodiment of the invention, a facilitating agent or a combination of facilitating agents is also comprised in the mixture to be milled.\",\n \"Such facilitating agents appropriate for use in the invention include diluents, surfactants, polymers, binding agents, filling agents, lubricating agents, sweeteners, flavouring agents, preservatives, buffers, wetting agents, disintegrants, effervescent agents and agents that may form part of a medicament, including a solid dosage form, or other excipients required for other specific drug delivery, such as the agents and media listed below under the heading Medicinal and Pharmaceutical Compositions, or any combination thereof.\",\n \"Biologically Active Materials and Compositions The present invention encompasses pharmaceutically acceptable materials produced according to the methods of the present invention, compositions including such materials, including compositions comprising such materials together with the grinding matrix, with at least a portion of the grinding matrix or separated from the grinding matrix.\",\n \"The pharmaceutically acceptable materials within the compositions of the invention are present at a concentration of between about 0.1% and about 99.0% by weight.\",\n \"Preferably, the concentration of pharmaceutically acceptable materials within the compositions will be about 5% to about 80% by weight, while concentrations of 10% to about 50% by weight are highly preferred.\",\n \"Desirably, the concentration will be in the range of about 10 to 15% by weight, 15 to 20% by weight, 20 to 25% by weight, 25 to 30% by weight, 30 to 35% by weight, 35 to 40% by weight, 40 to 45% by weight, 45 to 50% by weight, 50 to 55% by weight, 55 to 60% by weight, 60 to 65% by weight, 65 to 70% by weight, 70 to 75% by weight or 75 to 80% by weight for the composition prior to any later removal (if desired) of any portion of the grinding matrix.\",\n \"Where part or all of the grinding matrix has been removed, the relative concentration of pharmaceutically acceptable materials in the composition may be considerably higher depending on the amount of the grinding matrix that is removed.\",\n \"For example, if all of the grinding matrix is removed the concentration of particles in the preparation may approach 100% by weight (subject to the presence of facilitating agents).\",\n \"Compositions produced according to the present invention are not limited to the inclusion of a single species of pharmaceutically acceptable materials.\",\n \"More than one species of pharmaceutically acceptable materials may therefore be present in the composition.\",\n \"Where more than one species of pharmaceutically acceptable materials is present, the composition so formed may either be prepared in a dry milling step, or the pharmaceutically acceptable materials may be prepared separately and then combined to form a single composition.\",\n \"Medicaments The medicaments of the present invention may include the pharmaceutically acceptable material, optionally together with the grinding matrix or at least a portion of the grinding matrix, combined with one or more pharmaceutically acceptable carriers, as well as other agents commonly used in the preparation of pharmaceutically acceptable compositions.\",\n \"As used herein “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.\",\n \"Preferably, the carrier is suitable for parenteral administration, intravenous, intraperitoneal, intramuscular, sublingual, pulmonary, transdermal or oral administration.\",\n \"Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.\",\n \"The use of such media and agents for the manufacture of medicaments is well known in the art.\",\n \"Except insofar as any conventional media or agent is incompatible with the pharmaceutically acceptable material, use thereof in the manufacture of a pharmaceutical composition according to the invention is contemplated.\",\n \"Pharmaceutical acceptable carriers according to the invention may include one or more of the following examples: (1) surfactants and polymers, including, but not limited to polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyvinylalcohol, crospovidone, polyvinylpyrrolidone-polyvinylacetate copolymer, cellulose derivatives, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, carboxymethylethyl cellulose, hydroxypropylmethyl cellulose phthalate, polyacrylates and polymethacrylates, urea, sugars, polyols, and their polymers, emulsifiers, sugar gum, starch, organic acids and their salts, vinyl pyrrolidone and vinyl acetate; and or (2) binding agents such as various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose; and or (3) filling agents such as lactose monohydrate, lactose anhydrous, microcrystalline cellulose and various starches; and or (4) lubricating agents such as agents that act on the flowability of the powder to be compressed, including colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate, silica gel; and or (5) sweeteners such as any natural or artificial sweetener including sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acesulfame K; and or (6) flavouring agents; and or (7) preservatives such as potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic chemicals such as phenol, or quaternary compounds such as benzalkonium chloride; and or (8) buffers; and or (9) Diluents such as pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing; and or (10) wetting agents such as corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures thereof; and or (11) disintegrants; and or (12) effervescent agents such as effervescent couples such as an organic acid (e.g., citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts), or a carbonate (e.g.\",\n \"sodium carbonate, potassium carbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate) or bicarbonate (e.g.\",\n \"sodium bicarbonate or potassium bicarbonate); and or (13) other pharmaceutically acceptable excipients.\",\n \"Medicaments of the invention suitable for use in animals and in particular in man typically must be sterile and stable under the conditions of manufacture and storage.\",\n \"The medicaments of the invention comprising the biologically active material can be formulated as a solid, a solution, a microemulsion, a liposome, or other ordered structures suitable to high drug concentration.\",\n \"Actual dosage levels of the biologically active material in the medicament of the invention may be varied in accordance with the nature of the biologically active material, as well as the potential increased efficacy due to the advantages of providing and administering the biologically active material (e.g., increased solubility, more rapid dissolution, increased surface area of the biologically active material, etc.).\",\n \"Thus as used herein “therapeutically effective amount” will refer to an amount of biologically active material required to effect a therapeutic response in an animal.\",\n \"Amounts effective for such a use will depend on: the desired therapeutic effect; the route of administration; the potency of the biologically active material; the desired duration of treatment; the stage and severity of the disease being treated; the weight and general state of health of the patient; and the judgment of the prescribing physician.\",\n \"In another embodiment, the biologically active material, optionally together with the grinding matrix or at least a portion of the grinding matrix, of the invention may be combined into a medicament with another biologically active material, or even the same biologically active material.\",\n \"In the latter embodiment, a medicament may be achieved which provides for different release characteristics—early release from the biologically active material, and later release from a larger average size biologically active material.\",\n \"Modes of Administration of Medicaments Comprising Biologically Active Materials Medicaments of the invention can be administered to animals, including man, in any pharmaceutically acceptable manner, such as orally, rectally, pulmonary, intravaginally, locally (powders, ointments or drops), transdermal, parenteral administration, intravenous, intraperitoneal, intramuscular, sublingual or as a buccal or nasal spray Solid dosage forms for oral administration include capsules, tablets, pills, powders, pellets, and granules.\",\n \"Further, incorporating any of the normally employed excipients, such as those previously listed, and generally 5-95% of the biologically active agent, and more preferably at a concentration of 10%-75% will form a pharmaceutically acceptable non-toxic oral composition.\",\n \"Medicaments of the invention may be parenterally administered as a solution of the biologically active agent suspended in an acceptable carrier, preferably an aqueous carrier.\",\n \"A variety of aqueous carriers may be used, e.g.\",\n \"water, buffered water, 0.4% saline, 0.3% glycine, hyaluronic acid and the like.\",\n \"These compositions may be sterilized by conventional, well known sterilization techniques, or may be sterile filtered.\",\n \"The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile solution prior to administration.\",\n \"For aerosol administration, medicaments of the invention are preferably supplied along with a surfactant or polymer and propellant.\",\n \"The surfactant or polymer must, of course, be non-toxic, and preferably soluble in the propellant.\",\n \"Representative of such agents are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride.\",\n \"Mixed esters, such as mixed or natural glycerides may be employed.\",\n \"The surfactant or polymer may constitute 0.1%-20% by weight of the composition, preferably 0.25-5%.\",\n \"The balance of the composition is ordinarily propellant.\",\n \"A carrier can also be included, as desired, as with, e.g., lecithin for intranasal delivery.\",\n \"Medicaments of the invention may also be administered via liposomes, which serve to target the active agent to a particular tissue, such as lymphoid tissue, or targeted selectively to cells.\",\n \"Liposomes include emulsions, foams, micelles, insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers and the like.\",\n \"In these preparations the composite microstructure composition is incorporated as part of a liposome, alone or in conjunction with a molecule that binds to or with other therapeutic or immunogenic compositions.\",\n \"As described above, the biologically active material can be formulated into a solid dosage form (e.g., for oral or suppository administration), together with the grinding matrix or at least a portion of it.\",\n \"In this case there may be little or no need to add stabilizing agents since the grinding matrix may effectively act as a solid-state stabilizer.\",\n \"However, if the biologically active material is to be utilized in a liquid suspension, the particles comprising the biologically active material may require further stabilization once the solid carrier has been substantially removed to ensure the elimination, or at least minimisation of particle agglomeration.\",\n \"Therapeutic Uses Therapeutic uses of the medicaments of the invention include pain relief, anti-inflammatory, migraine, asthma, and other disorders that require the active agent to be administered with a high bioavailability.\",\n \"One of the main areas when rapid bioavailability of a biologically active material is required is in the relief of pain.\",\n \"The minor analgesics, such as cyclooxgenase inhibitors (aspirin related drugs) may be prepared as medicaments according to the present invention.\",\n \"Medicaments of the invention may also be used for treatment of eye disorders.\",\n \"That is, the biologically active material may be formulated for administration on the eye as an aqueous suspension in physiological saline, or a gel.\",\n \"In addition, the biologically active material may be prepared in a powder form for administration via the nose for rapid central nervous system penetration.\",\n \"Treatment of cardiovascular disease may also benefit from biologically active materials according to the invention, such as treatment of angina pectoris and, in particular, molsidomine may benefit from better bioavailability.\",\n \"Other therapeutic uses of the medicaments of the present invention include treatment of hair loss, sexual dysfunction, or dermal treatment of psoriasis.\",\n \"The present invention will now be described with reference to the following non-limiting Examples.\",\n \"The description of the Examples is in no way limiting on the preceding paragraphs of this specification, but is provided for exemplification of the methods and compositions of the invention.\",\n \"EXAMPLES It will be apparent to persons skilled in the milling and pharmaceutical arts that numerous enhancements and modifications can be made to the above described processes without departing from the basic inventive concepts.\",\n \"For example, in some applications the biologically active material may be pretreated and supplied to the process in the pretreated form.\",\n \"All such modifications and enhancements are considered to be within the scope of the present invention, the nature of which is to be determined from the foregoing description and the appended claims.\",\n \"Furthermore, the following Examples are provided for illustrative purposes only, and are not intended to limit the scope of the processes or compositions of the invention.\",\n \"The following materials were used in the examples: Meloxicam (Dayang, China), Diclofenac (Unique, India), Lactose monohydrate (Capsulac 60, Meggle, Germany), Mannitol (Sigma-Aldrich, US), Tartaric Acid (BDH, UK), Sorbitol (Sigma-Aldrich, US), Glucose (Ajax Finechem, Australia), Microcrystalline Cellulose (Sigma-Aldrich, US).\",\n \"A Union Process attritor mill (model 1HD, 110 mL milling chamber), fitted with a 4 arm rotating shaft, was used to conduct the milling experiments.\",\n \"Steel balls ( 5/16″, 300 g) were used as grinding media in the milling experiments.\",\n \"The mill was loaded through the loading port, with dry materials and matrices added initially, followed by the grinding media.\",\n \"The milling process was conducted at room temperature with the shaft rotating at 500 rpm.\",\n \"Upon completion of milling, the milled powder was discharged from the mill and sieved to remove grinding media.\",\n \"The particle size distribution (PSD) was determined using a Malvern Mastersizer 2000 fitted with a Malvern Hydro 2000S pump unit.\",\n \"Dispersant used (0.01M HCl, RI: 1.33).\",\n \"Measurement settings used: Measurement Time: 12 secs, Measurement cycles: 3.Result generated by averaging the 3 measurements.\",\n \"Meloxicam specific conditions: Refractive index (RI): 1.73, absorption: 0.01.Diclofenac specific conditions: RI: 1.69, absorption: 0.01.Samples were prepared by adding 200 mg of milled powder to 5.0 mL of a 1% PVP solution in 0.01M hydrochloric acid (HCl), vortexing for 1 min, then sonicating with a horn for 1 min until samples dispersed.\",\n \"From this solution enough was added into the dispersant to attain a desired obscuration level of the red laser of =2.0%.\",\n \"Dissolution behaviour of milled materials as well as unmilled controls were determined using an automated Varian 7025 dissolution unit fitted with a Cary 50 Tablet UV visible spectrometer.\",\n \"Dissolution settings used were according to USP 2 with stirrer speed at 100 rpm.\",\n \"Meloxicam specific conditions: wavelength A=362 nm, pH 6.1 (10 mM Phosphate buffer), standard sized gelatine capsules contained 15 mg Meloxicam, for example, a capsule prepared from a 10 wt % Meloxicam milling required 150 mg milled powder.\",\n \"Diclofenac specific conditions: wavelength λ=276 nm, pH 5.75 (10 mM Citrate buffer), standard sized gelatine capsules contained 20 mg Diclofenac, for example, a capsule prepared from a 10 wt % Diclofenac milling required 200 mg milled powder.\",\n \"Capsules of milled materials were filled using Profill® equipment.\",\n \"Un-milled control samples were prepared by hand-filling appropriately sized capsules.\",\n \"Each dissolution result was obtained by averaging results from 3 capsules.\",\n \"Quantitative results are given as the time to reach X and Y. X is defined as the concentration equal to the dissolution concentration achieved by a control sample (or prototype formulation thereof) of the biologically active material or compound after 60 minutes.\",\n \"Y is defined as the concentration equal to the dissolution concentration achieved by a control sample (or prototype formulation thereof) of the biologically active material or compound after 30 minutes.\",\n \"Powder X-Ray diffraction (XRD) patterns were measured with a Diffractometer D 5000, Kristalloflex (Siemens).\",\n \"The measurement range was from 5-18 degrees 2-Theta.\",\n \"The slit width was set to 2 mm and the cathode ray tube was operated at 40 kV and 35 mA.\",\n \"Measurements were recorded at room temperature.\",\n \"The recorded traces were subsequently processed using Bruker EVA software to obtain the diffraction pattern.\",\n \"DSC traces where measured using a TA instruments DSC Q10.The data was obtained using a heating rate of 10° C./min under nitrogen flow.\",\n \"AluminiumTzero open pans where used for the measurements.\",\n \"Example 1.10% Meloxicam in Lactose Mono-Hydrate A mixture of Meloxicam (0.60 g) and Lactose monohydrate (5.40 g) was milled for either 1 (B) or 2 (C) minutes.\",\n \"PSDs of the milled products and unmilled material (A) are shown in FIG.\",\n \"1.The dissolution behaviour is shown in FIG.\",\n \"2.Results are summarised in Table 1 together with results obtained for an un-milled control (A), prepared by physically mixing Meloxicam (0.40 g) and Lactose monohydrate (3.60 g) in a vial until the appearance was homogenous.\",\n \"FIG.\",\n \"1 shows that after 1 minute of milling the particle size is reduced by about half.\",\n \"After another minute of milling the particle size has further reduced but is still mostly in the range of 1-10 micron.\",\n \"In contrast to this the dissolution of the material milled for 1 minute is only slightly faster than the unmilled control sample.\",\n \"The dissolution at 2 minutes is dramatically improved over both the 1 minute and unmilled material.\",\n \"In Table 1 the median size and quantitative assessment of the dissolution are shown.\",\n \"According to the measures X and Y (set out above) the material milled for 2 minutes has a much improved dissolution compared with both the unmilled and the milled for 1 minute sample.\",\n \"As the change in size of material from 1 to 2 mins is of the same order as the change in size from unmilled to 1 minute the primary reason for the improved dissolution for the 2 minute sample cannot be particle size reduction.\",\n \"TABLE 1 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 8.79 μm 30 60 1 min (B) 4.86 μm 23 45 2 min (C) 2.53 μm 8 11 Example 2.10% Diclofenac in Lactose Mono-Hydrate A mixture of Diclofenac (0.60 g) and lactose monohydrate (5.40 g) was milled for either 1 (B) or 2 (C) minutes.\",\n \"PSDs of the milled products and unmilled material (A) are shown in FIG.\",\n \"3.The dissolution behaviour is shown in FIG.\",\n \"4.Results are summarised in Table 2 together with results obtained for an un-milled control (A), prepared by physically mixing Diclofenac (0.40 g) and Lactose monohydrate (3.60 g) in a vial until the appearance was homogenous.\",\n \"The data for Diclofenac milled in lactose monohydrate is very similar to the data in Example 1.FIG.\",\n \"3 shows that after 1 minute of milling the particle size is reduced by just over 50%.\",\n \"After another minute of milling the particle size has reduced a little more giving two milled materials in the range 2-4 micron.\",\n \"Again in contrast to this the dissolution of the material milled for 1 minute is only slightly faster than the unmilled control sample.\",\n \"The dissolution at 2 minutes is dramatically improved over both the 1 minute and unmilled material.\",\n \"In Table 1 the median size and quantitative assessment of the dissolution are shown.\",\n \"According to the measures X and Y (set out above) the material milled for 2 minutes has a much improved dissolution compared with both the unmilled and the milled for 1 minute sample.\",\n \"As the size of the material from 1 to 2 mins is quite similar this size difference cannot be the primary reason for the improved dissolution for the 2 minute sample.\",\n \"TABLE 2 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 9.50 μm 30 60 1 min (B) 4.09 μm 18 29 2 min (C) 2.57 μm 8 10 Example 3.10% Meloxicam in Mannitol A mixture of Meloxicam (0.60 g) and Mannitol (5.40 g) was milled for either 1 (B) or 2 (C) minutes.\",\n \"PSDs of the milled products and unmilled material (A) were measured as well as the dissolution behaviour.\",\n \"Results are summarised in Table 3.The un-milled control (A) was prepared by physically mixing Meloxicam (0.40 g) and Mannitol (3.60 g) in a vial until the appearance was homogenous.\",\n \"The PSD shows that the material milled for 1 and 2 minutes has a reduced size compared with the unmilled material, but the size reduction is not dramatic.\",\n \"According to the dissolution measures X and Y both materials have a much improved dissolution rate compared with the unmilled sample.\",\n \"This data also shows that once enough milling energy has been input to deliver the improved dissolution (1 minute milling), further size reduction (2 minutes) has little impact on the dissolution rate.\",\n \"In FIG.\",\n \"5 a DSC trace of material milled for 2 minutes is shown compared with the DSC trace of mannitol.\",\n \"The trace only shows one melt other than mannitol at approximately 240° C. being the normal melting point of meloxicam.\",\n \"This DSC trace shows no indication of any amorphous material or other forms of meloxicam being present.\",\n \"This indicates the meloxicam has retained its crystallinity during the milling process.\",\n \"TABLE 3 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 8.79 μm 30 60 1 min (B) 3.80 μm 10 12 2 min (C) 2.19 μm 8 9 Example 4 10% Diclofenac in Mannitol A mixture of Diclofenac (0.60 g) and Mannitol (5.40 g) was milled for either 1 (B) or 2 (C) minutes.\",\n \"PSDs of the milled products and unmilled material (A) were measured as well as the dissolution behaviour.\",\n \"Results are summarised in Table 4.The un-milled control (A) was prepared by physically mixing Diclofenac (0.40 g) and Mannitol (3.60 g) in a vial until the appearance was homogenous.\",\n \"The PSD shows that the material milled for 1 and 2 minutes has a reduced size compared with the unmilled material, but the size is still in the range 1-10 microns.\",\n \"According to the dissolution measures X and Y both materials have a much improved dissolution rate compared with the unmilled sample.\",\n \"Again the data also shows that once enough milling energy has been input to deliver the improved dissolution (1 minute milling), further size reduction (2 minutes) has little impact on the dissolution rate.\",\n \"TABLE 4 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 9.50 μm 30 60 1 min (B) 2.20 μm 8 11 2 min (C) 1.23 μm 8 11 Example 5 10% Meloxicam in Glucose A mixture of Meloxicam (0.60 g) and Glucose (5.40 g) was milled for either 1 (B) or 2 (C) minutes.\",\n \"PSDs of the milled products and unmilled material (A) were measured as well as the dissolution behaviour.\",\n \"Results are summarised in Table 5.The un-milled control (A) was prepared by physically mixing Meloxicam (0.40 g) and Glucose (3.60 g) in a vial until the appearance was homogenous.\",\n \"The PSD shows that the material milled for 1 and 2 minutes has a reduced size compared with the unmilled material.\",\n \"There is about a 50% reduction from unmilled to 1 minute and about another 50% reduction from 1 minute to 2 minutes.\",\n \"According to the dissolution measures X and Y both milled materials have a much improved dissolution rate compared with the unmilled sample.\",\n \"Again the data shows that the improved dissolution is independent of the final particle size, instead most improvement has come from the milling of the active with the grinding matrix.\",\n \"TABLE 5 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 8.79 μm 30 60 1 min (B) 4.04 μm 9 10 2 min (C) 1.61 μm 7 8 Example 6.10% Diclofenac in Glucose A mixture of Diclofenac (0.60 g) and Glucose (5.40 g) was milled for either 1 (B) or 2 (C) minutes.\",\n \"PSDs of the milled products and unmilled material (A) were measured as well as the dissolution behaviour.\",\n \"Results are summarised in Table 6.The un-milled control (A) was prepared by physically mixing Diclofenac (0.40 g) and Glucose (3.60 g) in a vial until the appearance was homogenous.\",\n \"The PSD shows that the material milled for 1 and 2 minutes has a reduced size compared with the unmilled material, There is about a 60% reduction from unmilled to 1 minute and about another 30% reduction from 1 minute to 2 minutes.\",\n \"According to the dissolution measures X and Y the material milled for 1 minute has a greatly improved dissolution rate compared with the unmilled sample.\",\n \"The material milled for 2 minutes has a much slower dissolution rate compared with sample B and is only slightly improved compared with the unmilled material even though the particle size is smaller.\",\n \"TABLE 6 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 9.50 μm 30 60 1 min (B) 3.13 μm 15 24 2 min (C) 1.97 μm 25 55 Example 7.10% Meloxicam in Microcrystalline Cellulose A mixture of Meloxicam (0.60 g) and microcrystalline Cellulose (5.40 g) was milled for either 1 (B) or 2 (C) minutes.\",\n \"No PSD was measured due to interference from insoluble excipient.\",\n \"Dissolution behaviour of milled products and unmilled material (A) were measured.\",\n \"Results are summarised in Table 7.The un-milled control (A) was prepared by physically mixing Meloxicam (0.40 g) and microcrystalline Cellulose (3.60 g) in a vial until the appearance was homogenous.\",\n \"According to the dissolution measures X and Y both milled materials have an improved dissolution rate compared with the unmilled sample.\",\n \"TABLE 7 Time to Reach Concentration Milling Time Y (min) X (min) Un-milled (A) 30 60 1 min (B) 10 14 2 min (C) 9 10 Example 8.10% Diclofenac in Microcrystalline Cellulose A mixture of Diclofenac (0.60 g) and microcrystalline Cellulose (5.40 g) was milled for either 1 (B) or 2 (C) minutes.\",\n \"No PSD was measured due to interference from insoluble excipient.\",\n \"Dissolution behaviour of milled products and unmilled material (A) were measured.\",\n \"Results are summarised in Table 7.The un-milled control (A) was prepared by physically mixing Diclofenac (0.40 g) and microcrystalline Cellulose (3.60 g) in a vial until the appearance was homogenous.\",\n \"According to the dissolution measures X and Y both milled materials have an improved dissolution rate compared with the unmilled sample.\",\n \"TABLE 8 Time to Reach Concentration Milling Time Y (min) X (min) Un-milled (A) 30 60 1 min (B) 18 28 2 min (C) 24 31 Example 9.10% Meloxicam in Tartaric Acid A mixture of Meloxicam (0.60 g) and Tartaric acid (5.40 g) was milled for either 1 (B) or 2 (C) minutes.\",\n \"PSDs of the milled products and unmilled material (A) were measured as well as dissolution behaviour#.\",\n \"Results summarised in Table 9.The un-milled control (A) was prepared by physically mixing Meloxicam (0.40 g) and Tartaric acid (3.60 g) in a vial until the appearance was homogenous.\",\n \"The PSD shows that the material milled for 1 and 2 minutes has a reduced size compared with the unmilled material, There is about a 40% reduction from unmilled to 1 minute and about another 40% reduction from 1 minute to 2 minutes.\",\n \"According to the dissolution measures X and Y both milled materials have a much improved dissolution rate compared with the unmilled sample.\",\n \"The dissolution data indicates that both milled materials have very fast dissolution even though the size reduction upon milling is not large.\",\n \"TABLE 9 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 8.79 μm 30 60 1 min (B) 5.10 μm 9 11 2 min (C) 3.03 μm 8 9 #Dissolution test measured in 100 mM phosphate buffer at pH 5.8.Example 10.20% Meloxicam in Lactose Mono-Hydrate A mixture of Meloxicam (1.20 g) and Lactose monohydrate (4.80 g) was milled for either 1 (B) or 2 (C) minutes.\",\n \"PSDs of the milled products and unmilled material (A) were measured as well as dissolution behaviour.\",\n \"Results summarised in Table 10.The un-milled control (A) was prepared by physically mixing Meloxicam (0.80 g) and Lactose monohydrate (3.20 g) in a vial until the appearance was homogenous.\",\n \"The PSD shows that the material milled for 1 and 2 minutes has a reduced size compared with the unmilled material.\",\n \"According to the dissolution measures X and Y both milled materials have an improved dissolution rate compared with the unmilled sample.\",\n \"In FIG.\",\n \"6 the XRD spectra of the material milled for 2 minutes is shown.\",\n \"The spectra of pure meloxicam and pure milled lactose are also shown.\",\n \"These show that most meloxicam peaks are obscured by the lactose spectra.\",\n \"The clearest meloxicam peak is located at 2 theta 15°.\",\n \"For the material milled for 2 mins this peak is small (due to only 20% meloxicam) but evidence of the presence of crystalline meloxicam after milling.\",\n \"The spectra also indicate that the lactose is still crystalline after milling as well.\",\n \"TABLE 10 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 8.79 μm 30 60 1 min (B) 5.72 μm 14 26 2 min (C) 3.52 μm 17 20 Example 11.20% Meloxicam in Mannitol A mixture of Meloxicam (1.20 g) and Mannitol (4.80 g) was milled for either 1 (B) or 2 (C) minutes.\",\n \"PSDs of the milled products and unmilled material (A) were measured as well as dissolution behaviour.\",\n \"Results are summarised in Table 11.The un-milled control (A) was prepared by physically mixing Meloxicam (0.80 g) and Mannitol (3.20 g) in a vial until the appearance was homogenous.\",\n \"The PSD shows that the material milled for 1 and 2 minutes has a reduced size compared with the unmilled material.\",\n \"The level of size reduction compared with the material milled at 10% (example 3) is the same.\",\n \"The dissolution rate for the material milled at 20% is slightly slower than the rate for material milled at 10% (example 3) but the rate is still a good improvement over that of the unmilled material.\",\n \"Again this data would indicate than the improvement in dissolution observed is not primarily a function of particle size.\",\n \"In FIG.\",\n \"5 a DSC trace of material milled for 2 minutes is shown compared with the DSC trace of mannitol.\",\n \"The trace only shows one melt other than mannitol at approximately 240° C. being the normal melting point of meloxicam.\",\n \"This DSC trace shows no indication of any amorphous material or other forms of meloxicam being present.\",\n \"This indicates the meloxicam has retained its crystallinity during the milling process.\",\n \"In FIG.\",\n \"7 the XRD spectra of the material milled for 2 minutes is shown.\",\n \"The spectra of pure meloxicam, pure mannitol and a 20% physical mixture of meloxicam in mannitol are also shown.\",\n \"These show that most meloxicam peaks are obscured by the mannitol spectra.\",\n \"The clearest meloxicam peak is located at 2 theta 13°.\",\n \"The spectra indicate that both the meloxicam and mannitol are still crystalline after milling.\",\n \"TABLE 11 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 8.79 μm 30 60 1 min (B) 3.53 μm 14 22 2 min (C) 2.39 μm 18 21 Example 12.30% Diclofenac in 69% Lactose Mono-Hydrate and 1% Sodium Dodecyl Sulfate A mixture of Diclofenac (1.80 g), Lactose monohydrate (4.14 g) and Sodium dodecyl sulfate (SDS) (0.06 g) was milled for 10 minutes (B).\",\n \"PSDs of the milled product and unmilled material (A) were measured as well as dissolution behaviour.\",\n \"Results are summarised in Table 12.The un-milled control (A) was prepared by physically mixing Diclofenac (1.20 g), Lactose monohydrate (2.76 g) and SDS (0.04 g) in a vial until the appearance was homogenous.\",\n \"At the higher API content 1% SDS has been used as a milling aid to help provide good flow during milling.\",\n \"The same concentration of SDS was also include in the unmilled control sample for dissolution measurements so that any improvement in the dissolution due to the SDS is accounted for.\",\n \"At this API concentration the milling time has also been extended to provide more milling energy.\",\n \"The PSD achieved here is similar to the 2 minute sample from example 2 (10%) and the dissolution measures X and Y have also shown a similar level of improved dissolution.\",\n \"This example demonstrates that the improved dissolution through the synergistic milling of API and grinding matrix is achieved at higher API levels.\",\n \"In FIG.\",\n \"8 the XRD spectra of the diclofenac milled at various weight percentages from 20-50% is shown.\",\n \"The 20% material was produced in the same way as this example only with different amounts of diclofenac and lactose so as to achieve 20% w/w diclofenac overall.\",\n \"In FIG.\",\n \"9 spectra of unmilled physical mixtures of the same compositions are shown as a comparison.\",\n \"In FIG.\",\n \"10 spectra are also shown for pure diclofenac, pure lactose and pure milled lactose.\",\n \"FIG.\",\n \"10 indicates there are unobscured peaks located at 2 theta 11°, 15° and a partially obscured peak at 28°.\",\n \"When these peaks are compared between FIG.\",\n \"8 (milled) and FIG.\",\n \"9 (physical mixture) the spectra indicates that the material produced by this example is still crystalline after milling.\",\n \"TABLE 12 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 9.50 μm 30 60 10 min (B) 2.75 μm 12 13 Example 13.40% Diclofenac in 59% Lactose Mono-Hydrate and 1% Sodium Dodecyl Sulfate A mixture of Diclofenac (2.40 g), Lactose monohydrate (3.54 g) and Sodium dodecyl sulfate (SDS) (0.06 g) was milled for 10 minutes (B).\",\n \"PSDs of the milled product and unmilled material (A) were measured as well as dissolution behaviour.\",\n \"Results are summarised in Table 13.The un-milled control (A) was prepared by physically mixing Diclofenac (1.60 g), Lactose monohydrate (2.36 g) and SDS (0.04 g) in a vial until the appearance was homogenous.\",\n \"At this API concentration the PSD achieved is slightly coarser compare to example 12 (30%).\",\n \"The dissolution measures X and Y showed improved dissolution.\",\n \"In FIG.\",\n \"8 the XRD spectra of the diclofenac milled at various weight percentages from 20-50% is shown.\",\n \"The 20% material was produced in the same way as example 12 only with different amounts of diclofenac and lactose so as to achieve 20% w/w diclofenac overall.\",\n \"In FIG.\",\n \"9 spectra of unmilled physical mixtures of the same compositions are shown as a comparison.\",\n \"In FIG.\",\n \"10 spectra are also shown for pure diclofenac, pure lactose and pure milled lactose.\",\n \"FIG.\",\n \"10 indicates there are unobscured peaks located at 2 theta 11°, 15° and a partially obscured peak at 28°.\",\n \"When these peaks are compared between FIG.\",\n \"8 (milled) and FIG.\",\n \"9 (physical mixture) the spectra indicates that the material produced by this example is still crystalline after milling.\",\n \"TABLE 13 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 9.50 μm 30 60 10 min (B) 4.45 μm 18 25 Example 14.50% Diclofenac in 49% Lactose Mono-Hydrate and 1% Sodium Dodecyl Sulfate A mixture of Diclofenac (3.00 g), Lactose monohydrate (2.94 g) and Sodium dodecyl sulfate (SDS) (0.06 g) was milled for 10 minutes (B).\",\n \"PSDs of the milled product and unmilled material (A) were measured as well as dissolution behaviour.\",\n \"Results are summarised in Table 14.The un-milled control (A) was prepared by physically mixing Diclofenac (2.00 g), Lactose monohydrate (1.96 g) and SDS (0.04 g) in a vial until the appearance was homogenous.\",\n \"At this API concentration the PSD achieved is slightly coarser compare to example 12 (30%) and example 13 (40%).\",\n \"The dissolution measures X and Y still clearly indicate improved dissolution.\",\n \"This example demonstrates that the improved dissolution through the synergistic milling of API and grinding matrix is achieved at API levels up to at least 50%.\",\n \"In FIG.\",\n \"8 the XRD spectra of the diclofenac milled at various weight percentages from 20-50% is shown.\",\n \"The 20% material was produced in the same way as example 12 only with different amounts of diclofenac and lactose so as to achieve 20% w/w diclofenac overall.\",\n \"In FIG.\",\n \"9 spectra of unmilled physical mixtures of the same compositions are shown as a comparison.\",\n \"In FIG.\",\n \"10 spectra are also shown for pure diclofenac, pure lactose and pure milled lactose.\",\n \"FIG.\",\n \"10 indicates there are unobscured peaks located at 2 theta 11°, 15° and a partially obscured peak at 28°.\",\n \"When these peaks are compared between FIG.\",\n \"8 (milled) and FIG.\",\n \"9 (physical mixture) the spectra indicates that the material produced by this example is still crystalline after milling.\",\n \"TABLE 14 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 9.50 μm 30 60 10 min (B) 5.65 μm 23 33 Example 15.30% Meloxicam in 69% Lactose Mono-Hydrate and 1% Sodium Dodecyl Sulfate A mixture of Meloxicam (1.80 g), Lactose monohydrate (4.14 g) and Sodium dodecyl sulfate (SDS) (0.06 g) was milled for 10 minutes (B).\",\n \"PSDs of the milled product and unmilled material (A) were measured as well as dissolution behaviour.\",\n \"Results are summarised in Table 15.The un-milled control (A) was prepared by physically mixing Meloxicam (1.20 g), Lactose monohydrate (2.76 g) and SDS (0.04 g) in a vial until the appearance was homogenous.\",\n \"Like the Diclofenac examples at higher API content 1% SDS has also been used as a milling aid with the high Meloxicam content millings to help provide good flow during milling.\",\n \"The same concentration of SDS was also include in the unmilled control sample for dissolution measurements so that any improvement in the dissolution due to the SDS is accounted for.\",\n \"At this API concentration the milling time has also been extended to provide more milling energy.\",\n \"The PSD achieved here is slightly larger than the 2 minute sample from example 1 (10%).\",\n \"The dissolution measures X and Y show slightly more improvement in the dissolution compared with the 2 minute sample of example 1.TABLE 15 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 8.79 μm 30 60 10 min (B) 3.69 μm 6 7 Example 16.40% Meloxicam in 59% Lactose Mono-Hydrate and 1% Sodium Dodecyl Sulfate A mixture of Meloxicam (2.40 g), Lactose monohydrate (3.54 g) and Sodium dodecyl sulfate (SDS) (0.06 g) was milled for 10 minutes (B).\",\n \"PSDs of the milled product and unmilled material (A) were measured as well as dissolution behaviour.\",\n \"Results are summarised in Table 16.The un-milled control (A) was prepared by physically mixing Meloxicam (1.60 g), Lactose monohydrate (2.36 g) and SDS (0.04 g) in a vial until the appearance was homogenous.\",\n \"The PSD achieved here is slightly larger than 30% sample (example 15) but the dissolution measures X and Y are virtually the same, again indicating strongly improved dissolution.\",\n \"TABLE 16 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 8.79 μm 30 60 10 min (B) 4.91 μm 7 8 Example 17.50% Meloxicam in 49% Lactose Mono-Hydrate and 1% Sodium Dodecyl Sulfate A mixture of Meloxicam (3.00 g), Lactose monohydrate (2.94 g) and Sodium dodecyl sulfate (SDS) (0.06 g) was milled for 10 minutes (B).\",\n \"PSDs of the milled product and unmilled material (A) were measured as well as dissolution behaviour.\",\n \"Results are summarised in Table 17.The un-milled control (A) was prepared by physically mixing Meloxicam (2.00 g), Lactose monohydrate (1.96 g) and SDS (0.04 g) in a vial until the appearance was homogenous.\",\n \"The PSD achieved here is slightly larger than 40% sample (example 16) and is only slightly smaller than the unmilled material.\",\n \"The dissolution measures X and Y are very similar to the 30 and 40%, again indicating strongly improved dissolution.\",\n \"This series of millings at high Meloxicam content (example 15, 16, 17) clearly demonstrates that improved dissolution by synergistic milling of API with a grinding matrix is possible to at least 50%.\",\n \"The PSD distributions for this series also indicate that the improved dissolution observed from this process is independent of particle size.\",\n \"From 30% to 50% the PSD almost doubles yet the dissolution has remained relatively constant indicating little or no influence from particle size.\",\n \"In FIG.\",\n \"6 the XRD spectra of the material is shown (Spectra D).\",\n \"The spectra of pure meloxicam and pure milled lactose are also shown.\",\n \"These show that most meloxicam peaks are obscured by the lactose spectra.\",\n \"The clearest meloxicam peak is located at 2 theta 15°.\",\n \"In FIG.\",\n \"11 the spectra of a physical mixture of the material milled is also shown.\",\n \"The spectra indicates the presence of crystalline meloxicam after milling.\",\n \"The spectra also indicate that the lactose is still crystalline after milling as well.\",\n \"TABLE 17 Time to Reach Size Concentration Milling Time D (0.50) Y (min) X (min) Un-milled (A) 8.79 μm 30 60 10 min (B) 6.22 μm 10 13\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875794"}}},{"rowIdx":4494980,"cells":{"text":{"kind":"list like","value":[["NON-TRANSITORY COMPUTER-READABLE STORAGE MEDIUM, ENCODING APPARATUS, AND ENCODING METHOD","A non-transitory computer-readable storage medium storing a program that causes a computer to execute a process including detecting, from a text, one of a plurality of first strings included in first information, each of the plurality of first strings being associated with control information, determining whether to execute a determination process based on the control information associated with a specified string when the specified string is detected from the text, the determination process determining whether the second string is included in second information, the second information including at least one of third string being associated with another coded string, the second string being a string that includes the specified string at the beginning of the second string, executing the determination process when the determination process is determined to be executed and transforming the second string into the another coded string associated with the third string."],["1.A non-transitory computer-readable storage medium storing a program that causes a computer to execute a process, the process comprising: detecting, from a text, one of a plurality of first strings included in first information stored in a storage device, each of the plurality of first strings being associated with control information and different coded strings respectively; determining whether to execute a determination process based on the control information associated with a specified string included in the plurality of first strings when the specified string is detected from the text, the control information indicating whether to execute the determination process, the determination process determining whether the second string is included in second information stored in the storage device, the second information including at least one of third string being associated with another coded string, the second string being a string that includes the specified string at the beginning of the second string and being longer than the specified string; executing the determination process when the determination process is determined to be executed in the determining and transforming the second string into the another coded string associated with the third string when the second string is included in the second information; transforming the specified string into the coded string associated with the specified string; and outputting the text after at least one of the second string and the specified string is transformed.","2.The non-transitory computer-readable storage medium according to claim 1, wherein each of the first strings is morphemes.","3.The non-transitory computer-readable storage medium according to claim 2, wherein the second information includes a plurality of third strings; wherein each of the plurality of third strings is stored in different storage areas in the storage device respectively, in accordance with a morpheme at the beginning of each of the plurality of third strings; and wherein the determination process is executed by referring a storage area corresponding to the specified string.","4.The non-transitory computer-readable storage medium according to claim 3, wherein each of the plurality of third strings is a combination of a plurality of fourth strings included in the plurality of first strings; wherein the storage device further stores position information indicating whether each of the different storage areas store the plurality of first strings; and wherein the determination process is executed by further referring the position information.","5.The non-transitory computer-readable storage medium according to claim 4, wherein the position information further indicates a position of the plurality of fourth strings in each of the third string.","6.An encoding apparatus comprising: a memory that stores first information and second information, the first information including a plurality of first strings associated with control information and different coded strings respectively; and a processor coupled to the memory and the processor configured to execute a process, the process including: detecting, from a text, one of a plurality of first strings included in the first information; determining whether to execute a determination process based on the control information associated with a specified string included in the plurality of first strings when the specified string is detected from the text, the control information indicating whether to execute the determination process, the determination process determining whether the second string is included in second information stored in the storage device, the second information including at least one of third string being associated with another coded string, the second string being a string that includes the specified string at the beginning of the second string and being longer than the specified string; executing the determination process when the determination process is determined to be executed in the determining and transforming the second string into the another coded string associated with the third string when the second string is included in the second information; transforming the specified string into the coded string associated with the specified string; and outputting the text after at least one of the second string and the specified string is transformed.","7.An encoding method executed by a computer, the encoding method comprising: detecting, from a text, one of a plurality of first strings included in first information stored in a storage device, each of the plurality of first strings being associated with control information and different coded strings respectively; determining whether to execute a determination process based on the control information associated with a specified string included in the plurality of first strings when the specified string is detected from the text, the control information indicating whether to execute the determination process, the determination process determining whether the second string is included in second information stored in the storage device, the second information including at least one of third string being associated with another coded string, the second string being a string that includes the specified string at the beginning of the second string and being longer than the specified string; executing the determination process when the determination process is determined to be executed in the determining and transforming the second string into the another coded string associated with the third string when the second string is included in the second information; transforming the specified string into the coded string associated with the specified string; and outputting the text after at least one of the second string and the specified string is transformed."],["<SOH> BACKGROUND <EOH>Morphological analysis is a process of dividing a text into morphemes and assigning information about parts of speech to each morpheme.","In some cases, each morpheme obtained by using the morphological analysis is used as a word.","A document information storage apparatus that encodes and stores morphemes extracted from document information has been known (see, for example, PTL 1).","The document information storage apparatus performs the morphological analysis to extract the morphemes from inputted document information as components of the document information, encodes the extracted morphemes, compresses the encoded morphemes, and stores the compressed encoded morphemes in a storage unit."],["<SOH> SUMMARY <EOH>At a suggestion, a non-transitory computer-readable storage medium storing a program that causes a computer to execute a process, the process including detecting, from a text, one of a plurality of first strings included in first information stored in a storage device, each of the plurality of first strings being associated with control information and different coded strings respectively, determining whether to execute a determination process based on the control information associated with the specified string when a specified string included in the plurality of first strings is detected from the text, the control information indicating whether to execute the determination process, the determination process determining whether the second string is included in second information stored in the storage device, the second information including at least one of third string being associated with another coded string, the second string being a string that includes the specified string at the beginning of the second string and being longer than the specified string, executing the determination process when the determination process is determined to be executed in the determining and transforming the second string into the another coded string associated with the third string when the second string is included in the second information, transforming the specified string into the coded string associated with the specified string, and outputting the text after at least one of the second string and the specified string is transformed.","The object and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the claims.","It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are not restrictive of the invention, as claimed."],["CROSS-REFERENCE TO RELATED APPLICATION(S) This application is a continuation application of International Application PCT/JP2015/071171, filed on Jul.","24, 2015, the entire contents of which are incorporated herein by reference.","FIELD The present disclosure relates to a non-transitory computer-readable storage medium, an encoding apparatus, and an encoding method.","BACKGROUND Morphological analysis is a process of dividing a text into morphemes and assigning information about parts of speech to each morpheme.","In some cases, each morpheme obtained by using the morphological analysis is used as a word.","A document information storage apparatus that encodes and stores morphemes extracted from document information has been known (see, for example, PTL 1).","The document information storage apparatus performs the morphological analysis to extract the morphemes from inputted document information as components of the document information, encodes the extracted morphemes, compresses the encoded morphemes, and stores the compressed encoded morphemes in a storage unit.","CITATION LIST Patent Literature PTL 1: Japanese Laid-open Patent Publication No.","11-85790 SUMMARY At a suggestion, a non-transitory computer-readable storage medium storing a program that causes a computer to execute a process, the process including detecting, from a text, one of a plurality of first strings included in first information stored in a storage device, each of the plurality of first strings being associated with control information and different coded strings respectively, determining whether to execute a determination process based on the control information associated with the specified string when a specified string included in the plurality of first strings is detected from the text, the control information indicating whether to execute the determination process, the determination process determining whether the second string is included in second information stored in the storage device, the second information including at least one of third string being associated with another coded string, the second string being a string that includes the specified string at the beginning of the second string and being longer than the specified string, executing the determination process when the determination process is determined to be executed in the determining and transforming the second string into the another coded string associated with the third string when the second string is included in the second information, transforming the specified string into the coded string associated with the specified string, and outputting the text after at least one of the second string and the specified string is transformed.","The object and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the claims.","It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are not restrictive of the invention, as claimed.","BRIEF DESCRIPTION OF DRAWINGS FIG.","1 illustrates a morphological analysis dictionary.","FIG.","2 illustrates a postal code dictionary.","FIG.","3 illustrates an encoding process with the morphological analysis dictionary and the postal code dictionary.","FIG.","4 illustrates a morphological analysis dictionary to which codes in the postal code dictionary are added.","FIG.","5 illustrates a functional structure of an encoding apparatus.","FIG.","6 is a flowchart of the encoding process.","FIG.","7 illustrates a specific example of the functional structure of the encoding apparatus.","FIG.","8 illustrates a morphological analysis dictionary that includes switch information.","FIG.","9 illustrates an address dictionary.","FIG.","10 is a flowchart of a process of setting the switch information.","FIG.","11 is a flowchart of a specific example of the encoding process.","FIG.","12 illustrates a functional structure of the encoding apparatus in which search for strings that are not recorded is omitted.","FIG.","13 illustrates an address dictionary in which prefectures are divided into blocks.","FIG.","14 illustrates morpheme position information.","FIG.","15 is a flowchart of the encoding process in which search for strings that are not recorded is omitted.","FIG.","16 is a flowchart of a process of narrowing the blocks.","FIG.","17 illustrates filter information stored in a working area.","FIG.","18 illustrates an error message dictionary.","FIG.","19 illustrates the structure of an information processing apparatus.","DESCRIPTION OF EMBODIMENTS In some cases where two dictionaries are used for a two-step encoding process to improve a compression ratio, the process time of the above conventional encoding process is long.","In an aspect, it is an object of the present disclosure to improve the efficiency of the two-step encoding process on a text to be encoded.","An embodiment will now be described in detail with reference to the drawings.","The document information storage apparatus in PTL 1 encodes a document in a manner in which a code that is recorded in a postal code dictionary, a synonym dictionary, or another dictionary is assigned to one or more morphemes that are extracted from the document by using morphological analysis.","FIG.","1 illustrates an example of a morphological analysis dictionary used in morphological analysis.","The morphological analysis dictionary in FIG.","1 includes morphemes, parts of speech, and codes.","The parts of speech represent the parts of speech of the morphemes.","The codes represent the codes that are associated with the respective morphemes.","FIG.","2 illustrates an example of the postal code dictionary.","The postal code dictionary in FIG.","2 includes strings and codes.","The strings each include morphemes representing an address to which a postal code is assigned.","The codes represent the postal codes that are associated with the respective strings.","FIG.","3 illustrates an example of an encoding process with the morphological analysis dictionary in FIG.","1 and the postal code dictionary in FIG.","2.In the case where a text 301 to be encoded that is “Kanagawa Ken Kawasaki Shi Nakahara Ku Kamikodanaka in Live” is inputted, the text 301 to be encoded is first divided into morphemes by morphological analysis in a first pass.","Each morpheme is converted into a code recorded in the morphological analysis dictionary, and an encoded text 302 is created.","For example, “Kanagawa” that is the front morpheme in the text 301 to be encoded is converted into a hexadecimal code of 0×0105.Subsequently, encoding in a second pass is performed such that strings included in the encoded text 302 are compared with strings recorded in the postal code dictionary, and, in the case where the two strings match with each other, the strings are converted into the codes recorded in the postal code dictionary, and an encoded text 303 is created.","According to this example, a string that is “Kanagawa Ken Kawasaki Shi Nakahara Ku Kamikodanaka” is converted into a code of 211-0053.Thus, the encoding in the second pass enables the result of encoding in the first pass to be further compressed because the morphemes representing the address are converted into the code.","During the morphological analysis in the first pass, the morphological analysis dictionary is used to rapidly extract the morphemes, each of which is a minimum unit having a part of speech or a meaning.","In the morphological analysis dictionary, a single code is assigned to a single morpheme.","During the encoding in the second pass, the postal code dictionary is used to rapidly extract the strings representing the addresses.","In the postal code dictionary, a single code is assigned to morphemes.","The number of the morphemes, to which the code is assigned, differs between the two dictionaries as above.","Accordingly, the encoding process is divided into two passes (two steps) of the first pass and the second pass.","The two-pass encoding process takes a longer time and uses more calculation resources such as storage areas than a single-pass encoding process.","FIG.","4 illustrates an example of the morphological analysis dictionary to which the codes in the postal code dictionary are added to perform the same process as the two-pass encoding process in a single pass.","In the morphological analysis dictionary in FIG.","4, a string that is “Kanagawa Ken Kawasaki Shi Nakahara Ku Kamikodanaka” is recorded as the morpheme and associated with a code of 211-0053.However, the frequency of appearance of the string representing the address in the text is lower than the frequency of appearance of the morphemes representing place names included in the address.","Accordingly, in the case where the morphemes are extracted in descending order of the statistical frequency of appearance during the morphological analysis, the string representing the address is much less likely to be extracted.","For this reason, the encoded text 303 is not created from the text 301 to be encoded but the encoded text 302 is created even when the morphological analysis dictionary in FIG.","4 is used.","Consequently, the codes in the postal code dictionary are not used, and the compression ratio is not improved.","During the encoding in the second pass, the postal code dictionary is searched for all of the morphemes of the result of the morphological analysis in an exact longest match manner to assign one of the codes in the postal code dictionary to the string representing the address.","In this case, the postal code dictionary is referred the same number of times as the number of the morphemes for an exact longest match search, and this takes an enormous amount of time.","This problem is not limited to the case where the postal code dictionary is used during the encoding in the second pass and arises also in the case where a dictionary that includes other strings other than the address is used.","FIG.","5 illustrates an example of a functional structure of an encoding apparatus according to the embodiment.","An encoding apparatus 501 in FIG.","5 includes a storage unit 511, an encoder 512, and an output unit 513.The storage unit 511 stores morpheme segment information 521 and string encoding information 522.The string encoding information 522 includes records.","A recorded string and a code that is associated with the recorded string are recorded in each of the records.","The morpheme segment information 521 includes records including respective morphemes and is used to segment the morphemes.","The morpheme segment information 521 includes records including the respective front morphemes of the recorded strings of the records included in the string encoding information 522.The encoder 512 encodes a text to be encoded based on the morpheme segment information 521 and the string encoding information 522 and creates the encoded text.","The output unit 513 outputs the encoded text.","FIG.","6 is a flowchart of an example of the encoding process that the encoding apparatus 501 in FIG.","5 performs.","The encoder 512 first analyzes the text to be encoded based on the morpheme segment information 521 (step 601).","The encoder 512 searches the string encoding information for a string to be encoded that begins with one of the morphemes and that is included in the text to be encoded in response to identification of the one of the morphemes included in the record corresponding to one of the recorded strings among the records included in the morpheme segment information 521 (step 602).","When the string to be encoded corresponds to the one of the recorded strings, the encoder 512 converts the string to be encoded into the code associated with the one of the recorded strings (step 603).","The output unit 513 outputs the encoded text that includes the code after conversion (step 604).","The encoding apparatus 501 can improve the efficiency of the two-step encoding process on the text to be encoded.","FIG.","7 illustrates a specific example of the encoding apparatus 501 in FIG.","5.The encoder 512 in FIG.","7 includes an analyzer 711, a determining unit 712, a converter 713, and a converter 714.The storage unit 511 stores a morphological analysis dictionary 721 and an address dictionary 722.The morphological analysis dictionary 721 and the address dictionary 722 correspond to the morpheme segment information 521 and the string encoding information 522 in FIG.","5, respectively.","FIG.","8 illustrates an example of the morphological analysis dictionary 721.The morphological analysis dictionary 721 in FIG.","8 includes morphemes, the parts of speech, codes, and flags.","The parts of speech represent the parts of speech of the morphemes.","The codes represent the codes that are associated with the respective morphemes.","The flags are switch information representing whether the morphological analysis dictionary 721 is switched to the address dictionary 722.A flag value of a logic “1” represents that switching is performed.","A flag value of a logic “0” represents that switching is not performed.","According to this example, the flags corresponding to the front morphemes of the strings representing the prefectures are set to a logic “1”.For example, the part of speech of “Tokyo” is a noun, the code thereof is C1,and the flag thereof is a logic “1”.","The part of speech of “Kawasaki” is a noun, the code thereof is C4, and the flag thereof is a logic “0”.","FIG.","9 illustrates an example of the address dictionary 722.The address dictionary 722 in FIG.","9 includes strings and codes.","The strings include the morphemes representing the address.","The codes represent the codes that are associated with the respective strings.","The codes may be the postal codes.","The strings recorded in the address dictionary 722 are divided into blocks corresponding to the prefectures.","A separator 901 represents the start position of a block for “Tokyo To”.","A separator 902 represents the start position of a block for “Kanagawa Ken”.","For example, the code of “Tokyo To Suginami Ku” is D1.The code of “Kanagawa Ken Kawasaki Shi Nakahara Ku” is D3.The analyzer 711 sets the switch information in the morphological analysis dictionary 721 and performs the morphological analysis on the text to be encoded based on the morphological analysis dictionary 721 to divide the text to be encoded into the morphemes.","The determining unit 712 determines whether switching to the address dictionary 722 is performed for each morpheme created by the analyzer 711.The converter 713 converts the morphemes into the codes in the morphological analysis dictionary 721.The converter 714 converts the morphemes representing the address into the code in the address dictionary 722.FIG.","10 is a flowchart of an example of a process of setting the switch information that the analyzer 711 performs.","At the beginning of the process of setting the switch information, the flags of all of the morphemes in the morphological analysis dictionary 721 are set to a logic “0”.","The analyzer 711 first performs the morphological analysis on the strings recorded in the address dictionary 722 based on the morphological analysis dictionary 721 to divide the strings into the morphemes (step 1001).","The analyzer 711 selects the front morpheme of each string from the morphemes in the morphological analysis dictionary 721, changes the flag of the selected morpheme to a logic “1” to set the switch information (step 1002).","The analyzer 711 may set a pointer representing the start position of each block in the address dictionary 722 as the switch information instead of the flag.","In this case, a pointer representing the position of the separator 901 is set as the switch information for “Tokyo”, and a pointer representing the position of the separator 902 is set as the switch information for “Kanagawa”.","FIG.","11 is a flowchart of a specific example of the encoding process that the encoding apparatus 501 in FIG.","7 performs.","The analyzer 711 first performs the morphological analysis on the text to be encoded based on the morphological analysis dictionary 721 (step 1101) to extract the morphemes from the text to be encoded in order from the front (step 1102).","Subsequently, the determining unit 712 determines whether the switch information for each morpheme extracted by the analyzer 711 in the morphological analysis dictionary 721 represents switching (step 1103).","In the case where the switch information represents switching (step 1103, YES), the determining unit 712 searches the address dictionary 722 for a string to be encoded (morpheme group) that begins with the extracted morpheme and that is included in the text to be encoded (step 1104).","At this time, the determining unit 712 searches the block indicated by the switch information for the string to be encoded and checks whether the string to be encoded is recorded in the block.","The determining unit 712 can check whether the string to be encoded is recorded in the block in a manner in which the string to be encoded and each recorded string in the block are compared by using, for example, the exact longest match search.","In the case where the string to be encoded is recorded in the address dictionary 722 (step 1104, YES), the converter 714 converts the string to be encoded into the code recorded in the address dictionary 722 (step 1105).","The determining unit 712 checks whether the last morpheme in the text to be encoded is converted into the code (step 1106).","In the case where the last morpheme is not converted into the code (step 1106, NO), the determining unit 712 repeatedly performs the processes at the step 1101 and later on the remaining text.","In the case where the switch information does not represent switching (step 1103, NO), the converter 713 converts each morpheme extracted by the analyzer 711 into the code recorded in the morphological analysis dictionary 721 (step 1108).","The encoder 512 performs the processes at the step 1106 and later.","In the case where the string to be encoded is not recorded in the address dictionary 722 (step 1104, NO), the encoder 512 performs the processes at the step 1108 and later.","In the case where the last morpheme is converted into the code (step 1106, YES), the output unit 513 outputs the encoded text that includes a row of the codes (step 1107).","For example, a text to be encoded that is “Kanagawa Ken Kawasaki Shi Nakahara Ku In Live” is divided into “Kanagawa/Ken/Kawasaki/Shi/Nakahara/Ku/In/Live”.","In the morphological analysis dictionary 721 in FIG.","8, the flag “1” for “Kanagawa” represents switching, the block for “Kanagawa” in the address dictionary 722 in FIG.","9 is searched for a string that begins with “Kanagawa”, and a recorded string that is “Kanagawa Ken Kawasaki Shi Nakahara Ku” is detected.","Then, “Kanagawa/Ken/Kawasaki/Shi/Nakahara/Ku” is converted into the corresponding code D3, and the following “In” and “Live” are converted into the codes in the morphological analysis dictionary 721.In the case where the pointers are used in the morphological analysis dictionary 721 instead of the flags, the presence of a pointer corresponding to the morphemes results in determination that the switch information represents switching, and the absence of a pointer results in determination that the switch information does not represent switching.","In this encoding process, the morphological analysis dictionary 721 is switched to the address dictionary 722 when each recorded string in the address dictionary 722 appears, and accordingly, the two-pass encoding process can be performed in a single pass.","This enables the two-step encoding process to be speeded up and reduces calculation resources such as storage areas used for the encoding process.","The recorded strings are divided into the blocks corresponding to the front morphemes and recorded in the address dictionary 722.This enables the subject of the search to be limited to the block corresponding to the front morpheme of the string to be encoded.","Consequently, the blocks to be searched are limited, and the efficiency of the search process is improved.","However, in the encoding process in FIG.","11, whenever the switch information representing switching is detected, the string to be encoded included in the text to be encoded is compared with all of the recorded strings in the corresponding block in the address dictionary 722 by using the exact longest match search.","For this reason, in the case where a large number of the recorded strings are included in the block, the search process at the step 1104 takes a long time.","For example, a text to be encoded that is “Kanagawa To Go” is divided into “Kanagawa/To/Go”.","In the morphological analysis dictionary 721 in FIG.","8, the flag “1” for “Kanagawa” represents switching, and the address dictionary 722 is searched for a string that begins with “Kanagawa”.","However, none of the recorded strings in the address dictionary 722 include “To”.","For this reason, “Kanagawa” is converted into the code in the morphological analysis dictionary 721.In the case where one of the morphemes in the text to be encoded matches one of the front morphemes of the recorded strings in the address dictionary 722, but the string to be encoded that begins with the morpheme matches none of the recorded strings in the address dictionary 722 as described above, the search time wastes.","In view of this, it is preferable that search for strings that are not recorded in the address dictionary 722 be omitted to further speed up the encoding process.","FIG.","12 illustrates a specific example of the encoding apparatus 501 in which search for strings that are not recorded in the address dictionary 722 is omitted.","The structure of the encoding apparatus 501 in FIG.","12 is the same as in the encoding apparatus 501 in FIG.","7.The storage unit 511 stores morpheme position information 1211 in addition to the morphological analysis dictionary 721 and the address dictionary 722 and includes a working area 1212.The morpheme position information 1211 represents a recorded-string position of each morpheme included in the recorded strings in the address dictionary 722.The working area 1212 is used to determine whether a string is recorded in the address dictionary 722 by using the morpheme position information 1211 and may be a stack.","FIG.","13 illustrates an example of the address dictionary 722 in which the addresses of the prefectures are divided into the blocks.","“Tokyo 1” and “Tokyo 2” represent the address block name of “Tokyo To”, and “Kanagawa 1” to “Kanagawa 5” represent the address block name of “Kanagawa Ken”.","FIG.","14 illustrates an example of the morpheme position information 1211 corresponding to the address dictionary 722 in FIG.","13.The morpheme position information 1211 in FIG.","14 includes morphemes, offsets, and filter information about the blocks of the prefectures.","The morphemes represent the morphemes included in the recorded strings in the address dictionary 722.The offsets represent the recorded-string positions of the morphemes.","For example, a combination of “Tokyo” and the offset “1” represents that the front morpheme of the recorded string is “Tokyo”, and a combination of “Tama” and the offset “3” represents that the third morpheme of the recorded string is “Tama”.","The filter information is expressed by a bit string that includes bit values the number of which is equal to the number of the blocks.","When one of the bit values for a block is a logic “1”, one of the recorded strings included in the block includes the morpheme at a position represented by the offset.","When one of the bit values for a block is a logic “0”, all of the recorded strings included in the block do not include the morpheme at a position represented by the offset.","For example, the bit value “1” for “Tokyo 1” corresponding to the combination of “Tokyo” and the offset “1” represents that the block for “Tokyo 1” includes a recorded string in which the front morpheme is “Tokyo”.","The bit value “0” for “Kanagawa 1” corresponding to the combination of “Tokyo” and the offset “1” represents that the block for “Kanagawa 1” includes no recorded string in which the front morpheme is “Tokyo”.","The bit value “1” for “Tokyo 1” corresponding to the combination of “Tama” and the offset “3” represents that the block for “Tokyo 1” includes a recorded string in which the third morpheme is “Tama”.","The bit value “1” for “Kanagawa 3” corresponding to a combination of “Tama” and the offset “5” represents that the block for “Kanagawa 3” includes a recorded string in which the fifth morpheme is “Tama”.","The use of the morpheme position information 1211 enables determination whether a string to be encoded is recorded in the address dictionary 722 without comparison between the string to be encoded and the recorded strings.","In addition, in the case where the string to be encoded is recorded in the address dictionary 722, the block that includes the string to be encoded can be narrowed from the blocks corresponding to the same front morpheme.","FIG.","15 is a flowchart of a specific example of the encoding process that the encoding apparatus 501 in FIG.","12 performs.","Processes at step 1501 to step 1503 and step 1506 to step 1509 are the same as the processes at the step 1101 to the step 1103 and the step 1105 to the step 1108 in FIG.","11.In the case where the switch information represents switching (step 1503, YES), the determining unit 712 narrows the blocks by using the morpheme position information 1211 to specify the block in the address dictionary 722 that is to be searched (step 1504).","The determining unit 712 searches the block to be searched for the string to be encoded (step 1505).","In the case where there is the block to be searched, the string to be encoded is recorded in the block to be searched (step 1505, YES), and accordingly, the encoder 512 performs the processes at the step 1506 and later.","In the case where there is no block to be searched, the string to be encoded is not recorded in the address dictionary 722 (step 1505, NO), and accordingly, the encoder 512 performs the processes at the step 1509 and later.","In this case, the address dictionary 722 is not searched for the string to be encoded.","FIG.","16 is a flowchart of an example of the process of narrowing the blocks that is performed at the step 1504 in FIG.","15.The determining unit 712 first sets a variable X, which represents an offset, to 1 (step 1601) and sets a variable W, which represents a morpheme, to the morpheme extracted at the step 1502 (step 1602).","Subsequently, the determining unit 712 searches the morpheme position information 1211 for the bit string of the filter information corresponding to X and W (step 1603) and checks whether there is the corresponding filter information (step 1604).","In the case where there is the corresponding filter information (step 1604, YES), the determining unit 712 adds the filter information to the working area 1212 (step 1607) and increments X by 1 (step 1608).","The determining unit 712 sets W to the next morpheme in the text to be encoded (step 1602) and repeatedly performs the processes at the step 1603 and later.","In the case where there is no corresponding filter information (step 1604, NO), the determining unit 712 refers the filter information stored in the working area 1212 to specify the blocks in which the bit values for all of the morphemes are “1” (step 1605).","The determining unit 712 checks the number of the specified blocks (step 1606).","In the case where the number of the specified block is 1 (step 1606, YES), the determining unit 712 decides that this block is the block to be searched (step 1607).","In the case where the number of the specified blocks is 2 or more (step 1606, NO), the determining unit 712 determines that the string to be encoded is not recorded in the address dictionary 722 and finishes the process.","FIG.","17 illustrates an example of the filter information stored in the working area 1212.For example, a text to be encoded that is “Kanagawa Ken Kawasaki Shi Tama Ku Noborito In Live” is divided into “Kanagawa/Ken/Kawasaki/Shi/Tama/Ku/Noborito/In/Live”.","In the morphological analysis dictionary 721 in FIG.","8, the flag “1” for “Kanagawa” at the front represents switching, and accordingly, the morpheme position information 1211 in FIG.","14 is searched for the filter information corresponding to a combination of “Kanagawa” and the offset “1”.","The bit string of the corresponding filter information includes the bit value “1” in the blocks for “Kanagawa 1” to “Kanagawa 5”.","Accordingly, this bit string is added to the working area 1212.Similarly, the morpheme position information 1211 is searched for the filter information corresponding to the following combinations of the morphemes and the offsets, and the filter information is added to the working area 1212.“Ken” and “2” “Kawasaki” and “3” “Shi” and “4” “Tama” and “5” “Ku” and “6” “Noborito” and “7” However, the morpheme position information 1211 includes no filter information corresponding to the next combination of the morpheme “In” and the offset “8”, and accordingly, seven pieces of the filter information in FIG.","17 are referred to specify the blocks in which the bit values for all of the morphemes are “1”.","At this time, the determining unit 712 may specify the blocks in which the bit values for all of the morphemes are “1” by an operation of logical conjunction of the bit strings in the vertical direction that include seven bit values and that correspond to the respective blocks in FIG.","17 and a bit string that includes seven bit values of “1”.","In this case, the block for “Kanagawa 3” alone is the block in which the bit values for all of the morphemes are “1”, and accordingly, this block is determined to be the block to be searched.","Subsequently, the block for “Kanagawa 3” in the address dictionary 722 in FIG.","13 is searched for the string to be encoded that is “Kanagawa/Ken/Kawasaki/Shi/Tama/Ku/Noborito”.","“Kanagawa/Ken/Kawasaki/Shi/Tama/Ku/Noborito” is converted into the corresponding code.","The following “In” and “Live ” are converted into the codes in the morphological analysis dictionary 721.A text to be encoded that is “Tokyo To Tama Shi Ichinomiya In Live” is divided into “Tokyo/To/Tama/Shi/Ichinomiya/In/Live”.","In the morphological analysis dictionary 721 in FIG.","8, the flag “1” for “Tokyo” at the front represents switching, and accordingly, the morpheme position information 1211 in FIG.","14 is searched for the filter information corresponding to the combination of “Tokyo” and the offset “1”.","The bit string of the corresponding filter information includes the bit value “1” in the blocks of “Tokyo 1” and “Tokyo 2”, and accordingly, this bit string is added to the working area 1212.Similarly, the morpheme position information 1211 is searched for the filter information corresponding to the following combinations of the morphemes and the offsets, and the filter information is added to the working area 1212.“To” and “2” “Tama” and “3” “Shi” and “4” “Ichinomiya” and “5” However, the morpheme position information 1211 includes no filter information corresponding to the next combination of the morpheme “In” and the offset “6”, and accordingly, five pieces of the filter information are referred to specify the blocks in which the bit values for all of the morphemes are “1”.","In the case where the block for “Tokyo 1” alone is the concerned block, and this block is determined to be the block to be searched.","Subsequently, the block for “Tokyo 1” in the address dictionary 722 in FIG.","13 is searched for the string to be encoded that is “Tokyo/To/Tama/Shi/Ichinomiya”.","“Tokyo/To/Tama/Shi/Ichinomiya” is converted into the corresponding code.","The following “In” and “Live” are converted into the codes in the morphological analysis dictionary 721.The text to be encoded that is “Kanagawa To Go” is divided into “Kanagawa/To/Go”.","In the morphological analysis dictionary 721 in FIG.","8, the flag “1” for “Kanagawa” at the front represents switching, the morpheme position information 1211 in FIG.","14 is searched for the filter information corresponding to the combination of “Kanagawa” and the offset “1”.","The bit string of the corresponding filter information includes the bit value “1” in the blocks for “Kanagawa 1” to “Kanagawa 5”, and accordingly, this bit string is added to the working area 1212.However, the morpheme position information 1211 includes no filter information corresponding to the next combination of the morpheme “To” and the offset “2”, and accordingly, the filter information for “Kanagawa” is referred to specify the blocks in which the bit values are “1”.","In this case, the five blocks for “Kanagawa 1” to “Kanagawa 5” are concerned, and it is determined that no strings that begin with “Kanagawa” are recorded in the address dictionary 722.Accordingly, the address dictionary 722 is not searched for “Kanagawa”, and “Kanagawa” is converted into the code in the morphological analysis dictionary 721.In the case where one of the morphemes in the text to be encoded matches one of the front morphemes of the recorded strings in the address dictionary 722, but the string to be encoded that begins with the morpheme matches none of the recorded strings as described above, the encoding apparatus 501 in FIG.","12 omits search of the address dictionary 722.This reduces an unnecessary search process and further speeds up the encoding process.","A dictionary that includes other strings other than the addresses can be used for the encoding in the second pass instead of the address dictionary 722.For example, a proper noun dictionary that includes proper noun strings, a phrase dictionary that includes phrase strings, an idiomatic phrase dictionary that includes idiomatic phrase strings, an error message dictionary that includes error message strings, or another dictionary may be used instead of the address dictionary 722.FIG.","18 illustrates an example of the error message dictionary.","The error message dictionary in FIG.","18 includes error messages and codes.","The error messages include morphemes representing the error messages.","The codes represent the codes that are associated with the respective error messages.","For example, the code of “File Deliver Start” is 0×e001, and the code of “Memory Allocate Error” is 0×e002.The error messages may be divided into blocks corresponding to the front morphemes and recorded in the error message dictionary as in the case of the address dictionary 722 in FIG.","9.The structures of the encoding apparatus 501 in FIG.","5, FIG.","7, and FIG.","12 are illustrated by way of example.","Some components may be omitted or changed in accordance with the usage and conditions of the encoding apparatus 501.The flow charts in FIG.","6, FIG.","10, FIG.","11, FIG.","15, and FIG.","16 are illustrated by way of example.","Some processes may be omitted or changed in accordance with the structure and conditions of the encoding apparatus 501.For example, in the case where the switch information is set in the morphological analysis dictionary 721 in advance, the process of setting the switch information in FIG.","10 can be omitted.","The morphological analysis dictionary in FIG.","8, the address dictionaries in FIG.","9 and FIG.","13, the morpheme position information in FIG.","14, and the error message dictionary in FIG.","18 are illustrated by way of example.","Another morphological analysis dictionary, another address dictionary, another morpheme position information, or another error message dictionary may be used in accordance with the structure and conditions of the encoding apparatus 501.For example, in the encoding apparatus 501 in FIG.","12, the address dictionary in FIG.","9 may be used instead of the address dictionary in FIG.","13.The encoding apparatus 501 in FIG.","5, FIG.","7, and FIG.","12 can be made by using, for example, an information-processing apparatus (computer) illustrated in FIG.","19.The information-processing apparatus in FIG.","19 includes a central processing unit (CPU) 1901, a memory 1902, an input device 1903, an output device 1904, an auxiliary storage device 1905, a medium drive 1906, and a network connection device 1907.These components are connected to each other with a bus 1908.The memory 1902 is, for example, a semiconductor memory such as a read only memory (ROM), a random access memory (RAM), or a flash memory.","The memory 1902 stores a program for the encoding process and data.","The memory 1902 can be used as the storage unit 511 in FIG.","5, FIG.","7, and FIG.","12.The CPU 1901 (processor) executes the program by using, for example, the memory 1902 and thereby functions as the encoder 512, the analyzer 711, the determining unit 712, the converter 713, and the converter 714 in FIG.","5, FIG.","7, and FIG.","12 to perform the encoding process.","The input device 1903 is, for example, a keyboard or a pointing device and is used to input instructions and information from a user or an operator.","The output device 1904 is, for example, a display device, a printer, or a speaker and is used to output an enquiry or a processing result to a user or an operator.","The auxiliary storage device 1905 is, for example, a magnetic disk device, an optical disk device, a magneto-optical disk device, or a tape device.","The auxiliary storage device 1905 may be a hard disk drive or a flash memory.","The information-processing apparatus stores the program and the data in the auxiliary storage device 1905 and can use the program and the data that are loaded into the memory 1902.The auxiliary storage device 1905 can be used as the storage unit 511 in FIG.","5, FIG.","7, and FIG.","12.The medium drive 1906 drives a portable recording medium 1909 and accesses recorded contents thereof.","Examples of the portable recording medium 1909 include a memory device, a flexible disk, an optical disk, and a magneto-optical disk.","The portable recording medium 1909 may be a compact disk read only memory (CD-ROM), a digital versatile disk (DVD), or a universal serial bus (USB) memory.","A user or an operator stores the program and the data into the portable recording medium 1909 and can use the program and the data that are loaded into the memory 1902.Such a readable recording medium of the computer that stores the program and the data is a physical (non-volatile) recording medium such as the memory 1902, the auxiliary storage device 1905, and the portable recording medium 1909.The network connection device 1907 is a communication interface that is connected to a communication network such as a local area network (LAN) or the Internet and that performs data conversion during communication.","The information-processing apparatus uses the network connection device 1907 to receive the program and the data from an external device and can use the program and the data that are loaded into the memory 1902.The network connection device 1907 can be used as the output unit 513 in FIG.","5, FIG.","7, and FIG.","12.The information-processing apparatus does not necessarily include all of the components in FIG.","19.Some components can be omitted in accordance with the usage and the conditions.","For example, in the case where no instructions or information is inputted from a user or an operator, the input device 1903 may be omitted.","In the case where neither enquiry nor processing result is outputted to a user or an operator, the output device 1904 may be omitted.","In the case where the information-processing apparatus does not access the portable recording medium 1909 or the communication network, the medium drive 1906 or the network connection device 1907 may be omitted.","The embodiment of the disclosure and the advantages thereof are described in detail.","A person skilled in the art can made various modifications, additions, and omissions without departing from the scope of the present disclosure that is clearly recited in claims.","All examples and conditional language recited herein are intended for pedagogical purposes to aid the reader in understanding the invention and the concepts contributed by the inventor to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions, nor does the organization of such examples in the specification relate to a showing of the superiority and inferiority of the invention.","Although the embodiment of the present invention has been described in detail, it should be understood that the various changes, substitutions, and alterations could be made hereto without departing from the spirit and scope of the invention."]],"string":"[\n [\n \"NON-TRANSITORY COMPUTER-READABLE STORAGE MEDIUM, ENCODING APPARATUS, AND ENCODING METHOD\",\n \"A non-transitory computer-readable storage medium storing a program that causes a computer to execute a process including detecting, from a text, one of a plurality of first strings included in first information, each of the plurality of first strings being associated with control information, determining whether to execute a determination process based on the control information associated with a specified string when the specified string is detected from the text, the determination process determining whether the second string is included in second information, the second information including at least one of third string being associated with another coded string, the second string being a string that includes the specified string at the beginning of the second string, executing the determination process when the determination process is determined to be executed and transforming the second string into the another coded string associated with the third string.\"\n ],\n [\n \"1.A non-transitory computer-readable storage medium storing a program that causes a computer to execute a process, the process comprising: detecting, from a text, one of a plurality of first strings included in first information stored in a storage device, each of the plurality of first strings being associated with control information and different coded strings respectively; determining whether to execute a determination process based on the control information associated with a specified string included in the plurality of first strings when the specified string is detected from the text, the control information indicating whether to execute the determination process, the determination process determining whether the second string is included in second information stored in the storage device, the second information including at least one of third string being associated with another coded string, the second string being a string that includes the specified string at the beginning of the second string and being longer than the specified string; executing the determination process when the determination process is determined to be executed in the determining and transforming the second string into the another coded string associated with the third string when the second string is included in the second information; transforming the specified string into the coded string associated with the specified string; and outputting the text after at least one of the second string and the specified string is transformed.\",\n \"2.The non-transitory computer-readable storage medium according to claim 1, wherein each of the first strings is morphemes.\",\n \"3.The non-transitory computer-readable storage medium according to claim 2, wherein the second information includes a plurality of third strings; wherein each of the plurality of third strings is stored in different storage areas in the storage device respectively, in accordance with a morpheme at the beginning of each of the plurality of third strings; and wherein the determination process is executed by referring a storage area corresponding to the specified string.\",\n \"4.The non-transitory computer-readable storage medium according to claim 3, wherein each of the plurality of third strings is a combination of a plurality of fourth strings included in the plurality of first strings; wherein the storage device further stores position information indicating whether each of the different storage areas store the plurality of first strings; and wherein the determination process is executed by further referring the position information.\",\n \"5.The non-transitory computer-readable storage medium according to claim 4, wherein the position information further indicates a position of the plurality of fourth strings in each of the third string.\",\n \"6.An encoding apparatus comprising: a memory that stores first information and second information, the first information including a plurality of first strings associated with control information and different coded strings respectively; and a processor coupled to the memory and the processor configured to execute a process, the process including: detecting, from a text, one of a plurality of first strings included in the first information; determining whether to execute a determination process based on the control information associated with a specified string included in the plurality of first strings when the specified string is detected from the text, the control information indicating whether to execute the determination process, the determination process determining whether the second string is included in second information stored in the storage device, the second information including at least one of third string being associated with another coded string, the second string being a string that includes the specified string at the beginning of the second string and being longer than the specified string; executing the determination process when the determination process is determined to be executed in the determining and transforming the second string into the another coded string associated with the third string when the second string is included in the second information; transforming the specified string into the coded string associated with the specified string; and outputting the text after at least one of the second string and the specified string is transformed.\",\n \"7.An encoding method executed by a computer, the encoding method comprising: detecting, from a text, one of a plurality of first strings included in first information stored in a storage device, each of the plurality of first strings being associated with control information and different coded strings respectively; determining whether to execute a determination process based on the control information associated with a specified string included in the plurality of first strings when the specified string is detected from the text, the control information indicating whether to execute the determination process, the determination process determining whether the second string is included in second information stored in the storage device, the second information including at least one of third string being associated with another coded string, the second string being a string that includes the specified string at the beginning of the second string and being longer than the specified string; executing the determination process when the determination process is determined to be executed in the determining and transforming the second string into the another coded string associated with the third string when the second string is included in the second information; transforming the specified string into the coded string associated with the specified string; and outputting the text after at least one of the second string and the specified string is transformed.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>Morphological analysis is a process of dividing a text into morphemes and assigning information about parts of speech to each morpheme.\",\n \"In some cases, each morpheme obtained by using the morphological analysis is used as a word.\",\n \"A document information storage apparatus that encodes and stores morphemes extracted from document information has been known (see, for example, PTL 1).\",\n \"The document information storage apparatus performs the morphological analysis to extract the morphemes from inputted document information as components of the document information, encodes the extracted morphemes, compresses the encoded morphemes, and stores the compressed encoded morphemes in a storage unit.\"\n ],\n [\n \"<SOH> SUMMARY <EOH>At a suggestion, a non-transitory computer-readable storage medium storing a program that causes a computer to execute a process, the process including detecting, from a text, one of a plurality of first strings included in first information stored in a storage device, each of the plurality of first strings being associated with control information and different coded strings respectively, determining whether to execute a determination process based on the control information associated with the specified string when a specified string included in the plurality of first strings is detected from the text, the control information indicating whether to execute the determination process, the determination process determining whether the second string is included in second information stored in the storage device, the second information including at least one of third string being associated with another coded string, the second string being a string that includes the specified string at the beginning of the second string and being longer than the specified string, executing the determination process when the determination process is determined to be executed in the determining and transforming the second string into the another coded string associated with the third string when the second string is included in the second information, transforming the specified string into the coded string associated with the specified string, and outputting the text after at least one of the second string and the specified string is transformed.\",\n \"The object and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the claims.\",\n \"It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are not restrictive of the invention, as claimed.\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATION(S) This application is a continuation application of International Application PCT/JP2015/071171, filed on Jul.\",\n \"24, 2015, the entire contents of which are incorporated herein by reference.\",\n \"FIELD The present disclosure relates to a non-transitory computer-readable storage medium, an encoding apparatus, and an encoding method.\",\n \"BACKGROUND Morphological analysis is a process of dividing a text into morphemes and assigning information about parts of speech to each morpheme.\",\n \"In some cases, each morpheme obtained by using the morphological analysis is used as a word.\",\n \"A document information storage apparatus that encodes and stores morphemes extracted from document information has been known (see, for example, PTL 1).\",\n \"The document information storage apparatus performs the morphological analysis to extract the morphemes from inputted document information as components of the document information, encodes the extracted morphemes, compresses the encoded morphemes, and stores the compressed encoded morphemes in a storage unit.\",\n \"CITATION LIST Patent Literature PTL 1: Japanese Laid-open Patent Publication No.\",\n \"11-85790 SUMMARY At a suggestion, a non-transitory computer-readable storage medium storing a program that causes a computer to execute a process, the process including detecting, from a text, one of a plurality of first strings included in first information stored in a storage device, each of the plurality of first strings being associated with control information and different coded strings respectively, determining whether to execute a determination process based on the control information associated with the specified string when a specified string included in the plurality of first strings is detected from the text, the control information indicating whether to execute the determination process, the determination process determining whether the second string is included in second information stored in the storage device, the second information including at least one of third string being associated with another coded string, the second string being a string that includes the specified string at the beginning of the second string and being longer than the specified string, executing the determination process when the determination process is determined to be executed in the determining and transforming the second string into the another coded string associated with the third string when the second string is included in the second information, transforming the specified string into the coded string associated with the specified string, and outputting the text after at least one of the second string and the specified string is transformed.\",\n \"The object and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the claims.\",\n \"It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are not restrictive of the invention, as claimed.\",\n \"BRIEF DESCRIPTION OF DRAWINGS FIG.\",\n \"1 illustrates a morphological analysis dictionary.\",\n \"FIG.\",\n \"2 illustrates a postal code dictionary.\",\n \"FIG.\",\n \"3 illustrates an encoding process with the morphological analysis dictionary and the postal code dictionary.\",\n \"FIG.\",\n \"4 illustrates a morphological analysis dictionary to which codes in the postal code dictionary are added.\",\n \"FIG.\",\n \"5 illustrates a functional structure of an encoding apparatus.\",\n \"FIG.\",\n \"6 is a flowchart of the encoding process.\",\n \"FIG.\",\n \"7 illustrates a specific example of the functional structure of the encoding apparatus.\",\n \"FIG.\",\n \"8 illustrates a morphological analysis dictionary that includes switch information.\",\n \"FIG.\",\n \"9 illustrates an address dictionary.\",\n \"FIG.\",\n \"10 is a flowchart of a process of setting the switch information.\",\n \"FIG.\",\n \"11 is a flowchart of a specific example of the encoding process.\",\n \"FIG.\",\n \"12 illustrates a functional structure of the encoding apparatus in which search for strings that are not recorded is omitted.\",\n \"FIG.\",\n \"13 illustrates an address dictionary in which prefectures are divided into blocks.\",\n \"FIG.\",\n \"14 illustrates morpheme position information.\",\n \"FIG.\",\n \"15 is a flowchart of the encoding process in which search for strings that are not recorded is omitted.\",\n \"FIG.\",\n \"16 is a flowchart of a process of narrowing the blocks.\",\n \"FIG.\",\n \"17 illustrates filter information stored in a working area.\",\n \"FIG.\",\n \"18 illustrates an error message dictionary.\",\n \"FIG.\",\n \"19 illustrates the structure of an information processing apparatus.\",\n \"DESCRIPTION OF EMBODIMENTS In some cases where two dictionaries are used for a two-step encoding process to improve a compression ratio, the process time of the above conventional encoding process is long.\",\n \"In an aspect, it is an object of the present disclosure to improve the efficiency of the two-step encoding process on a text to be encoded.\",\n \"An embodiment will now be described in detail with reference to the drawings.\",\n \"The document information storage apparatus in PTL 1 encodes a document in a manner in which a code that is recorded in a postal code dictionary, a synonym dictionary, or another dictionary is assigned to one or more morphemes that are extracted from the document by using morphological analysis.\",\n \"FIG.\",\n \"1 illustrates an example of a morphological analysis dictionary used in morphological analysis.\",\n \"The morphological analysis dictionary in FIG.\",\n \"1 includes morphemes, parts of speech, and codes.\",\n \"The parts of speech represent the parts of speech of the morphemes.\",\n \"The codes represent the codes that are associated with the respective morphemes.\",\n \"FIG.\",\n \"2 illustrates an example of the postal code dictionary.\",\n \"The postal code dictionary in FIG.\",\n \"2 includes strings and codes.\",\n \"The strings each include morphemes representing an address to which a postal code is assigned.\",\n \"The codes represent the postal codes that are associated with the respective strings.\",\n \"FIG.\",\n \"3 illustrates an example of an encoding process with the morphological analysis dictionary in FIG.\",\n \"1 and the postal code dictionary in FIG.\",\n \"2.In the case where a text 301 to be encoded that is “Kanagawa Ken Kawasaki Shi Nakahara Ku Kamikodanaka in Live” is inputted, the text 301 to be encoded is first divided into morphemes by morphological analysis in a first pass.\",\n \"Each morpheme is converted into a code recorded in the morphological analysis dictionary, and an encoded text 302 is created.\",\n \"For example, “Kanagawa” that is the front morpheme in the text 301 to be encoded is converted into a hexadecimal code of 0×0105.Subsequently, encoding in a second pass is performed such that strings included in the encoded text 302 are compared with strings recorded in the postal code dictionary, and, in the case where the two strings match with each other, the strings are converted into the codes recorded in the postal code dictionary, and an encoded text 303 is created.\",\n \"According to this example, a string that is “Kanagawa Ken Kawasaki Shi Nakahara Ku Kamikodanaka” is converted into a code of 211-0053.Thus, the encoding in the second pass enables the result of encoding in the first pass to be further compressed because the morphemes representing the address are converted into the code.\",\n \"During the morphological analysis in the first pass, the morphological analysis dictionary is used to rapidly extract the morphemes, each of which is a minimum unit having a part of speech or a meaning.\",\n \"In the morphological analysis dictionary, a single code is assigned to a single morpheme.\",\n \"During the encoding in the second pass, the postal code dictionary is used to rapidly extract the strings representing the addresses.\",\n \"In the postal code dictionary, a single code is assigned to morphemes.\",\n \"The number of the morphemes, to which the code is assigned, differs between the two dictionaries as above.\",\n \"Accordingly, the encoding process is divided into two passes (two steps) of the first pass and the second pass.\",\n \"The two-pass encoding process takes a longer time and uses more calculation resources such as storage areas than a single-pass encoding process.\",\n \"FIG.\",\n \"4 illustrates an example of the morphological analysis dictionary to which the codes in the postal code dictionary are added to perform the same process as the two-pass encoding process in a single pass.\",\n \"In the morphological analysis dictionary in FIG.\",\n \"4, a string that is “Kanagawa Ken Kawasaki Shi Nakahara Ku Kamikodanaka” is recorded as the morpheme and associated with a code of 211-0053.However, the frequency of appearance of the string representing the address in the text is lower than the frequency of appearance of the morphemes representing place names included in the address.\",\n \"Accordingly, in the case where the morphemes are extracted in descending order of the statistical frequency of appearance during the morphological analysis, the string representing the address is much less likely to be extracted.\",\n \"For this reason, the encoded text 303 is not created from the text 301 to be encoded but the encoded text 302 is created even when the morphological analysis dictionary in FIG.\",\n \"4 is used.\",\n \"Consequently, the codes in the postal code dictionary are not used, and the compression ratio is not improved.\",\n \"During the encoding in the second pass, the postal code dictionary is searched for all of the morphemes of the result of the morphological analysis in an exact longest match manner to assign one of the codes in the postal code dictionary to the string representing the address.\",\n \"In this case, the postal code dictionary is referred the same number of times as the number of the morphemes for an exact longest match search, and this takes an enormous amount of time.\",\n \"This problem is not limited to the case where the postal code dictionary is used during the encoding in the second pass and arises also in the case where a dictionary that includes other strings other than the address is used.\",\n \"FIG.\",\n \"5 illustrates an example of a functional structure of an encoding apparatus according to the embodiment.\",\n \"An encoding apparatus 501 in FIG.\",\n \"5 includes a storage unit 511, an encoder 512, and an output unit 513.The storage unit 511 stores morpheme segment information 521 and string encoding information 522.The string encoding information 522 includes records.\",\n \"A recorded string and a code that is associated with the recorded string are recorded in each of the records.\",\n \"The morpheme segment information 521 includes records including respective morphemes and is used to segment the morphemes.\",\n \"The morpheme segment information 521 includes records including the respective front morphemes of the recorded strings of the records included in the string encoding information 522.The encoder 512 encodes a text to be encoded based on the morpheme segment information 521 and the string encoding information 522 and creates the encoded text.\",\n \"The output unit 513 outputs the encoded text.\",\n \"FIG.\",\n \"6 is a flowchart of an example of the encoding process that the encoding apparatus 501 in FIG.\",\n \"5 performs.\",\n \"The encoder 512 first analyzes the text to be encoded based on the morpheme segment information 521 (step 601).\",\n \"The encoder 512 searches the string encoding information for a string to be encoded that begins with one of the morphemes and that is included in the text to be encoded in response to identification of the one of the morphemes included in the record corresponding to one of the recorded strings among the records included in the morpheme segment information 521 (step 602).\",\n \"When the string to be encoded corresponds to the one of the recorded strings, the encoder 512 converts the string to be encoded into the code associated with the one of the recorded strings (step 603).\",\n \"The output unit 513 outputs the encoded text that includes the code after conversion (step 604).\",\n \"The encoding apparatus 501 can improve the efficiency of the two-step encoding process on the text to be encoded.\",\n \"FIG.\",\n \"7 illustrates a specific example of the encoding apparatus 501 in FIG.\",\n \"5.The encoder 512 in FIG.\",\n \"7 includes an analyzer 711, a determining unit 712, a converter 713, and a converter 714.The storage unit 511 stores a morphological analysis dictionary 721 and an address dictionary 722.The morphological analysis dictionary 721 and the address dictionary 722 correspond to the morpheme segment information 521 and the string encoding information 522 in FIG.\",\n \"5, respectively.\",\n \"FIG.\",\n \"8 illustrates an example of the morphological analysis dictionary 721.The morphological analysis dictionary 721 in FIG.\",\n \"8 includes morphemes, the parts of speech, codes, and flags.\",\n \"The parts of speech represent the parts of speech of the morphemes.\",\n \"The codes represent the codes that are associated with the respective morphemes.\",\n \"The flags are switch information representing whether the morphological analysis dictionary 721 is switched to the address dictionary 722.A flag value of a logic “1” represents that switching is performed.\",\n \"A flag value of a logic “0” represents that switching is not performed.\",\n \"According to this example, the flags corresponding to the front morphemes of the strings representing the prefectures are set to a logic “1”.For example, the part of speech of “Tokyo” is a noun, the code thereof is C1,and the flag thereof is a logic “1”.\",\n \"The part of speech of “Kawasaki” is a noun, the code thereof is C4, and the flag thereof is a logic “0”.\",\n \"FIG.\",\n \"9 illustrates an example of the address dictionary 722.The address dictionary 722 in FIG.\",\n \"9 includes strings and codes.\",\n \"The strings include the morphemes representing the address.\",\n \"The codes represent the codes that are associated with the respective strings.\",\n \"The codes may be the postal codes.\",\n \"The strings recorded in the address dictionary 722 are divided into blocks corresponding to the prefectures.\",\n \"A separator 901 represents the start position of a block for “Tokyo To”.\",\n \"A separator 902 represents the start position of a block for “Kanagawa Ken”.\",\n \"For example, the code of “Tokyo To Suginami Ku” is D1.The code of “Kanagawa Ken Kawasaki Shi Nakahara Ku” is D3.The analyzer 711 sets the switch information in the morphological analysis dictionary 721 and performs the morphological analysis on the text to be encoded based on the morphological analysis dictionary 721 to divide the text to be encoded into the morphemes.\",\n \"The determining unit 712 determines whether switching to the address dictionary 722 is performed for each morpheme created by the analyzer 711.The converter 713 converts the morphemes into the codes in the morphological analysis dictionary 721.The converter 714 converts the morphemes representing the address into the code in the address dictionary 722.FIG.\",\n \"10 is a flowchart of an example of a process of setting the switch information that the analyzer 711 performs.\",\n \"At the beginning of the process of setting the switch information, the flags of all of the morphemes in the morphological analysis dictionary 721 are set to a logic “0”.\",\n \"The analyzer 711 first performs the morphological analysis on the strings recorded in the address dictionary 722 based on the morphological analysis dictionary 721 to divide the strings into the morphemes (step 1001).\",\n \"The analyzer 711 selects the front morpheme of each string from the morphemes in the morphological analysis dictionary 721, changes the flag of the selected morpheme to a logic “1” to set the switch information (step 1002).\",\n \"The analyzer 711 may set a pointer representing the start position of each block in the address dictionary 722 as the switch information instead of the flag.\",\n \"In this case, a pointer representing the position of the separator 901 is set as the switch information for “Tokyo”, and a pointer representing the position of the separator 902 is set as the switch information for “Kanagawa”.\",\n \"FIG.\",\n \"11 is a flowchart of a specific example of the encoding process that the encoding apparatus 501 in FIG.\",\n \"7 performs.\",\n \"The analyzer 711 first performs the morphological analysis on the text to be encoded based on the morphological analysis dictionary 721 (step 1101) to extract the morphemes from the text to be encoded in order from the front (step 1102).\",\n \"Subsequently, the determining unit 712 determines whether the switch information for each morpheme extracted by the analyzer 711 in the morphological analysis dictionary 721 represents switching (step 1103).\",\n \"In the case where the switch information represents switching (step 1103, YES), the determining unit 712 searches the address dictionary 722 for a string to be encoded (morpheme group) that begins with the extracted morpheme and that is included in the text to be encoded (step 1104).\",\n \"At this time, the determining unit 712 searches the block indicated by the switch information for the string to be encoded and checks whether the string to be encoded is recorded in the block.\",\n \"The determining unit 712 can check whether the string to be encoded is recorded in the block in a manner in which the string to be encoded and each recorded string in the block are compared by using, for example, the exact longest match search.\",\n \"In the case where the string to be encoded is recorded in the address dictionary 722 (step 1104, YES), the converter 714 converts the string to be encoded into the code recorded in the address dictionary 722 (step 1105).\",\n \"The determining unit 712 checks whether the last morpheme in the text to be encoded is converted into the code (step 1106).\",\n \"In the case where the last morpheme is not converted into the code (step 1106, NO), the determining unit 712 repeatedly performs the processes at the step 1101 and later on the remaining text.\",\n \"In the case where the switch information does not represent switching (step 1103, NO), the converter 713 converts each morpheme extracted by the analyzer 711 into the code recorded in the morphological analysis dictionary 721 (step 1108).\",\n \"The encoder 512 performs the processes at the step 1106 and later.\",\n \"In the case where the string to be encoded is not recorded in the address dictionary 722 (step 1104, NO), the encoder 512 performs the processes at the step 1108 and later.\",\n \"In the case where the last morpheme is converted into the code (step 1106, YES), the output unit 513 outputs the encoded text that includes a row of the codes (step 1107).\",\n \"For example, a text to be encoded that is “Kanagawa Ken Kawasaki Shi Nakahara Ku In Live” is divided into “Kanagawa/Ken/Kawasaki/Shi/Nakahara/Ku/In/Live”.\",\n \"In the morphological analysis dictionary 721 in FIG.\",\n \"8, the flag “1” for “Kanagawa” represents switching, the block for “Kanagawa” in the address dictionary 722 in FIG.\",\n \"9 is searched for a string that begins with “Kanagawa”, and a recorded string that is “Kanagawa Ken Kawasaki Shi Nakahara Ku” is detected.\",\n \"Then, “Kanagawa/Ken/Kawasaki/Shi/Nakahara/Ku” is converted into the corresponding code D3, and the following “In” and “Live” are converted into the codes in the morphological analysis dictionary 721.In the case where the pointers are used in the morphological analysis dictionary 721 instead of the flags, the presence of a pointer corresponding to the morphemes results in determination that the switch information represents switching, and the absence of a pointer results in determination that the switch information does not represent switching.\",\n \"In this encoding process, the morphological analysis dictionary 721 is switched to the address dictionary 722 when each recorded string in the address dictionary 722 appears, and accordingly, the two-pass encoding process can be performed in a single pass.\",\n \"This enables the two-step encoding process to be speeded up and reduces calculation resources such as storage areas used for the encoding process.\",\n \"The recorded strings are divided into the blocks corresponding to the front morphemes and recorded in the address dictionary 722.This enables the subject of the search to be limited to the block corresponding to the front morpheme of the string to be encoded.\",\n \"Consequently, the blocks to be searched are limited, and the efficiency of the search process is improved.\",\n \"However, in the encoding process in FIG.\",\n \"11, whenever the switch information representing switching is detected, the string to be encoded included in the text to be encoded is compared with all of the recorded strings in the corresponding block in the address dictionary 722 by using the exact longest match search.\",\n \"For this reason, in the case where a large number of the recorded strings are included in the block, the search process at the step 1104 takes a long time.\",\n \"For example, a text to be encoded that is “Kanagawa To Go” is divided into “Kanagawa/To/Go”.\",\n \"In the morphological analysis dictionary 721 in FIG.\",\n \"8, the flag “1” for “Kanagawa” represents switching, and the address dictionary 722 is searched for a string that begins with “Kanagawa”.\",\n \"However, none of the recorded strings in the address dictionary 722 include “To”.\",\n \"For this reason, “Kanagawa” is converted into the code in the morphological analysis dictionary 721.In the case where one of the morphemes in the text to be encoded matches one of the front morphemes of the recorded strings in the address dictionary 722, but the string to be encoded that begins with the morpheme matches none of the recorded strings in the address dictionary 722 as described above, the search time wastes.\",\n \"In view of this, it is preferable that search for strings that are not recorded in the address dictionary 722 be omitted to further speed up the encoding process.\",\n \"FIG.\",\n \"12 illustrates a specific example of the encoding apparatus 501 in which search for strings that are not recorded in the address dictionary 722 is omitted.\",\n \"The structure of the encoding apparatus 501 in FIG.\",\n \"12 is the same as in the encoding apparatus 501 in FIG.\",\n \"7.The storage unit 511 stores morpheme position information 1211 in addition to the morphological analysis dictionary 721 and the address dictionary 722 and includes a working area 1212.The morpheme position information 1211 represents a recorded-string position of each morpheme included in the recorded strings in the address dictionary 722.The working area 1212 is used to determine whether a string is recorded in the address dictionary 722 by using the morpheme position information 1211 and may be a stack.\",\n \"FIG.\",\n \"13 illustrates an example of the address dictionary 722 in which the addresses of the prefectures are divided into the blocks.\",\n \"“Tokyo 1” and “Tokyo 2” represent the address block name of “Tokyo To”, and “Kanagawa 1” to “Kanagawa 5” represent the address block name of “Kanagawa Ken”.\",\n \"FIG.\",\n \"14 illustrates an example of the morpheme position information 1211 corresponding to the address dictionary 722 in FIG.\",\n \"13.The morpheme position information 1211 in FIG.\",\n \"14 includes morphemes, offsets, and filter information about the blocks of the prefectures.\",\n \"The morphemes represent the morphemes included in the recorded strings in the address dictionary 722.The offsets represent the recorded-string positions of the morphemes.\",\n \"For example, a combination of “Tokyo” and the offset “1” represents that the front morpheme of the recorded string is “Tokyo”, and a combination of “Tama” and the offset “3” represents that the third morpheme of the recorded string is “Tama”.\",\n \"The filter information is expressed by a bit string that includes bit values the number of which is equal to the number of the blocks.\",\n \"When one of the bit values for a block is a logic “1”, one of the recorded strings included in the block includes the morpheme at a position represented by the offset.\",\n \"When one of the bit values for a block is a logic “0”, all of the recorded strings included in the block do not include the morpheme at a position represented by the offset.\",\n \"For example, the bit value “1” for “Tokyo 1” corresponding to the combination of “Tokyo” and the offset “1” represents that the block for “Tokyo 1” includes a recorded string in which the front morpheme is “Tokyo”.\",\n \"The bit value “0” for “Kanagawa 1” corresponding to the combination of “Tokyo” and the offset “1” represents that the block for “Kanagawa 1” includes no recorded string in which the front morpheme is “Tokyo”.\",\n \"The bit value “1” for “Tokyo 1” corresponding to the combination of “Tama” and the offset “3” represents that the block for “Tokyo 1” includes a recorded string in which the third morpheme is “Tama”.\",\n \"The bit value “1” for “Kanagawa 3” corresponding to a combination of “Tama” and the offset “5” represents that the block for “Kanagawa 3” includes a recorded string in which the fifth morpheme is “Tama”.\",\n \"The use of the morpheme position information 1211 enables determination whether a string to be encoded is recorded in the address dictionary 722 without comparison between the string to be encoded and the recorded strings.\",\n \"In addition, in the case where the string to be encoded is recorded in the address dictionary 722, the block that includes the string to be encoded can be narrowed from the blocks corresponding to the same front morpheme.\",\n \"FIG.\",\n \"15 is a flowchart of a specific example of the encoding process that the encoding apparatus 501 in FIG.\",\n \"12 performs.\",\n \"Processes at step 1501 to step 1503 and step 1506 to step 1509 are the same as the processes at the step 1101 to the step 1103 and the step 1105 to the step 1108 in FIG.\",\n \"11.In the case where the switch information represents switching (step 1503, YES), the determining unit 712 narrows the blocks by using the morpheme position information 1211 to specify the block in the address dictionary 722 that is to be searched (step 1504).\",\n \"The determining unit 712 searches the block to be searched for the string to be encoded (step 1505).\",\n \"In the case where there is the block to be searched, the string to be encoded is recorded in the block to be searched (step 1505, YES), and accordingly, the encoder 512 performs the processes at the step 1506 and later.\",\n \"In the case where there is no block to be searched, the string to be encoded is not recorded in the address dictionary 722 (step 1505, NO), and accordingly, the encoder 512 performs the processes at the step 1509 and later.\",\n \"In this case, the address dictionary 722 is not searched for the string to be encoded.\",\n \"FIG.\",\n \"16 is a flowchart of an example of the process of narrowing the blocks that is performed at the step 1504 in FIG.\",\n \"15.The determining unit 712 first sets a variable X, which represents an offset, to 1 (step 1601) and sets a variable W, which represents a morpheme, to the morpheme extracted at the step 1502 (step 1602).\",\n \"Subsequently, the determining unit 712 searches the morpheme position information 1211 for the bit string of the filter information corresponding to X and W (step 1603) and checks whether there is the corresponding filter information (step 1604).\",\n \"In the case where there is the corresponding filter information (step 1604, YES), the determining unit 712 adds the filter information to the working area 1212 (step 1607) and increments X by 1 (step 1608).\",\n \"The determining unit 712 sets W to the next morpheme in the text to be encoded (step 1602) and repeatedly performs the processes at the step 1603 and later.\",\n \"In the case where there is no corresponding filter information (step 1604, NO), the determining unit 712 refers the filter information stored in the working area 1212 to specify the blocks in which the bit values for all of the morphemes are “1” (step 1605).\",\n \"The determining unit 712 checks the number of the specified blocks (step 1606).\",\n \"In the case where the number of the specified block is 1 (step 1606, YES), the determining unit 712 decides that this block is the block to be searched (step 1607).\",\n \"In the case where the number of the specified blocks is 2 or more (step 1606, NO), the determining unit 712 determines that the string to be encoded is not recorded in the address dictionary 722 and finishes the process.\",\n \"FIG.\",\n \"17 illustrates an example of the filter information stored in the working area 1212.For example, a text to be encoded that is “Kanagawa Ken Kawasaki Shi Tama Ku Noborito In Live” is divided into “Kanagawa/Ken/Kawasaki/Shi/Tama/Ku/Noborito/In/Live”.\",\n \"In the morphological analysis dictionary 721 in FIG.\",\n \"8, the flag “1” for “Kanagawa” at the front represents switching, and accordingly, the morpheme position information 1211 in FIG.\",\n \"14 is searched for the filter information corresponding to a combination of “Kanagawa” and the offset “1”.\",\n \"The bit string of the corresponding filter information includes the bit value “1” in the blocks for “Kanagawa 1” to “Kanagawa 5”.\",\n \"Accordingly, this bit string is added to the working area 1212.Similarly, the morpheme position information 1211 is searched for the filter information corresponding to the following combinations of the morphemes and the offsets, and the filter information is added to the working area 1212.“Ken” and “2” “Kawasaki” and “3” “Shi” and “4” “Tama” and “5” “Ku” and “6” “Noborito” and “7” However, the morpheme position information 1211 includes no filter information corresponding to the next combination of the morpheme “In” and the offset “8”, and accordingly, seven pieces of the filter information in FIG.\",\n \"17 are referred to specify the blocks in which the bit values for all of the morphemes are “1”.\",\n \"At this time, the determining unit 712 may specify the blocks in which the bit values for all of the morphemes are “1” by an operation of logical conjunction of the bit strings in the vertical direction that include seven bit values and that correspond to the respective blocks in FIG.\",\n \"17 and a bit string that includes seven bit values of “1”.\",\n \"In this case, the block for “Kanagawa 3” alone is the block in which the bit values for all of the morphemes are “1”, and accordingly, this block is determined to be the block to be searched.\",\n \"Subsequently, the block for “Kanagawa 3” in the address dictionary 722 in FIG.\",\n \"13 is searched for the string to be encoded that is “Kanagawa/Ken/Kawasaki/Shi/Tama/Ku/Noborito”.\",\n \"“Kanagawa/Ken/Kawasaki/Shi/Tama/Ku/Noborito” is converted into the corresponding code.\",\n \"The following “In” and “Live ” are converted into the codes in the morphological analysis dictionary 721.A text to be encoded that is “Tokyo To Tama Shi Ichinomiya In Live” is divided into “Tokyo/To/Tama/Shi/Ichinomiya/In/Live”.\",\n \"In the morphological analysis dictionary 721 in FIG.\",\n \"8, the flag “1” for “Tokyo” at the front represents switching, and accordingly, the morpheme position information 1211 in FIG.\",\n \"14 is searched for the filter information corresponding to the combination of “Tokyo” and the offset “1”.\",\n \"The bit string of the corresponding filter information includes the bit value “1” in the blocks of “Tokyo 1” and “Tokyo 2”, and accordingly, this bit string is added to the working area 1212.Similarly, the morpheme position information 1211 is searched for the filter information corresponding to the following combinations of the morphemes and the offsets, and the filter information is added to the working area 1212.“To” and “2” “Tama” and “3” “Shi” and “4” “Ichinomiya” and “5” However, the morpheme position information 1211 includes no filter information corresponding to the next combination of the morpheme “In” and the offset “6”, and accordingly, five pieces of the filter information are referred to specify the blocks in which the bit values for all of the morphemes are “1”.\",\n \"In the case where the block for “Tokyo 1” alone is the concerned block, and this block is determined to be the block to be searched.\",\n \"Subsequently, the block for “Tokyo 1” in the address dictionary 722 in FIG.\",\n \"13 is searched for the string to be encoded that is “Tokyo/To/Tama/Shi/Ichinomiya”.\",\n \"“Tokyo/To/Tama/Shi/Ichinomiya” is converted into the corresponding code.\",\n \"The following “In” and “Live” are converted into the codes in the morphological analysis dictionary 721.The text to be encoded that is “Kanagawa To Go” is divided into “Kanagawa/To/Go”.\",\n \"In the morphological analysis dictionary 721 in FIG.\",\n \"8, the flag “1” for “Kanagawa” at the front represents switching, the morpheme position information 1211 in FIG.\",\n \"14 is searched for the filter information corresponding to the combination of “Kanagawa” and the offset “1”.\",\n \"The bit string of the corresponding filter information includes the bit value “1” in the blocks for “Kanagawa 1” to “Kanagawa 5”, and accordingly, this bit string is added to the working area 1212.However, the morpheme position information 1211 includes no filter information corresponding to the next combination of the morpheme “To” and the offset “2”, and accordingly, the filter information for “Kanagawa” is referred to specify the blocks in which the bit values are “1”.\",\n \"In this case, the five blocks for “Kanagawa 1” to “Kanagawa 5” are concerned, and it is determined that no strings that begin with “Kanagawa” are recorded in the address dictionary 722.Accordingly, the address dictionary 722 is not searched for “Kanagawa”, and “Kanagawa” is converted into the code in the morphological analysis dictionary 721.In the case where one of the morphemes in the text to be encoded matches one of the front morphemes of the recorded strings in the address dictionary 722, but the string to be encoded that begins with the morpheme matches none of the recorded strings as described above, the encoding apparatus 501 in FIG.\",\n \"12 omits search of the address dictionary 722.This reduces an unnecessary search process and further speeds up the encoding process.\",\n \"A dictionary that includes other strings other than the addresses can be used for the encoding in the second pass instead of the address dictionary 722.For example, a proper noun dictionary that includes proper noun strings, a phrase dictionary that includes phrase strings, an idiomatic phrase dictionary that includes idiomatic phrase strings, an error message dictionary that includes error message strings, or another dictionary may be used instead of the address dictionary 722.FIG.\",\n \"18 illustrates an example of the error message dictionary.\",\n \"The error message dictionary in FIG.\",\n \"18 includes error messages and codes.\",\n \"The error messages include morphemes representing the error messages.\",\n \"The codes represent the codes that are associated with the respective error messages.\",\n \"For example, the code of “File Deliver Start” is 0×e001, and the code of “Memory Allocate Error” is 0×e002.The error messages may be divided into blocks corresponding to the front morphemes and recorded in the error message dictionary as in the case of the address dictionary 722 in FIG.\",\n \"9.The structures of the encoding apparatus 501 in FIG.\",\n \"5, FIG.\",\n \"7, and FIG.\",\n \"12 are illustrated by way of example.\",\n \"Some components may be omitted or changed in accordance with the usage and conditions of the encoding apparatus 501.The flow charts in FIG.\",\n \"6, FIG.\",\n \"10, FIG.\",\n \"11, FIG.\",\n \"15, and FIG.\",\n \"16 are illustrated by way of example.\",\n \"Some processes may be omitted or changed in accordance with the structure and conditions of the encoding apparatus 501.For example, in the case where the switch information is set in the morphological analysis dictionary 721 in advance, the process of setting the switch information in FIG.\",\n \"10 can be omitted.\",\n \"The morphological analysis dictionary in FIG.\",\n \"8, the address dictionaries in FIG.\",\n \"9 and FIG.\",\n \"13, the morpheme position information in FIG.\",\n \"14, and the error message dictionary in FIG.\",\n \"18 are illustrated by way of example.\",\n \"Another morphological analysis dictionary, another address dictionary, another morpheme position information, or another error message dictionary may be used in accordance with the structure and conditions of the encoding apparatus 501.For example, in the encoding apparatus 501 in FIG.\",\n \"12, the address dictionary in FIG.\",\n \"9 may be used instead of the address dictionary in FIG.\",\n \"13.The encoding apparatus 501 in FIG.\",\n \"5, FIG.\",\n \"7, and FIG.\",\n \"12 can be made by using, for example, an information-processing apparatus (computer) illustrated in FIG.\",\n \"19.The information-processing apparatus in FIG.\",\n \"19 includes a central processing unit (CPU) 1901, a memory 1902, an input device 1903, an output device 1904, an auxiliary storage device 1905, a medium drive 1906, and a network connection device 1907.These components are connected to each other with a bus 1908.The memory 1902 is, for example, a semiconductor memory such as a read only memory (ROM), a random access memory (RAM), or a flash memory.\",\n \"The memory 1902 stores a program for the encoding process and data.\",\n \"The memory 1902 can be used as the storage unit 511 in FIG.\",\n \"5, FIG.\",\n \"7, and FIG.\",\n \"12.The CPU 1901 (processor) executes the program by using, for example, the memory 1902 and thereby functions as the encoder 512, the analyzer 711, the determining unit 712, the converter 713, and the converter 714 in FIG.\",\n \"5, FIG.\",\n \"7, and FIG.\",\n \"12 to perform the encoding process.\",\n \"The input device 1903 is, for example, a keyboard or a pointing device and is used to input instructions and information from a user or an operator.\",\n \"The output device 1904 is, for example, a display device, a printer, or a speaker and is used to output an enquiry or a processing result to a user or an operator.\",\n \"The auxiliary storage device 1905 is, for example, a magnetic disk device, an optical disk device, a magneto-optical disk device, or a tape device.\",\n \"The auxiliary storage device 1905 may be a hard disk drive or a flash memory.\",\n \"The information-processing apparatus stores the program and the data in the auxiliary storage device 1905 and can use the program and the data that are loaded into the memory 1902.The auxiliary storage device 1905 can be used as the storage unit 511 in FIG.\",\n \"5, FIG.\",\n \"7, and FIG.\",\n \"12.The medium drive 1906 drives a portable recording medium 1909 and accesses recorded contents thereof.\",\n \"Examples of the portable recording medium 1909 include a memory device, a flexible disk, an optical disk, and a magneto-optical disk.\",\n \"The portable recording medium 1909 may be a compact disk read only memory (CD-ROM), a digital versatile disk (DVD), or a universal serial bus (USB) memory.\",\n \"A user or an operator stores the program and the data into the portable recording medium 1909 and can use the program and the data that are loaded into the memory 1902.Such a readable recording medium of the computer that stores the program and the data is a physical (non-volatile) recording medium such as the memory 1902, the auxiliary storage device 1905, and the portable recording medium 1909.The network connection device 1907 is a communication interface that is connected to a communication network such as a local area network (LAN) or the Internet and that performs data conversion during communication.\",\n \"The information-processing apparatus uses the network connection device 1907 to receive the program and the data from an external device and can use the program and the data that are loaded into the memory 1902.The network connection device 1907 can be used as the output unit 513 in FIG.\",\n \"5, FIG.\",\n \"7, and FIG.\",\n \"12.The information-processing apparatus does not necessarily include all of the components in FIG.\",\n \"19.Some components can be omitted in accordance with the usage and the conditions.\",\n \"For example, in the case where no instructions or information is inputted from a user or an operator, the input device 1903 may be omitted.\",\n \"In the case where neither enquiry nor processing result is outputted to a user or an operator, the output device 1904 may be omitted.\",\n \"In the case where the information-processing apparatus does not access the portable recording medium 1909 or the communication network, the medium drive 1906 or the network connection device 1907 may be omitted.\",\n \"The embodiment of the disclosure and the advantages thereof are described in detail.\",\n \"A person skilled in the art can made various modifications, additions, and omissions without departing from the scope of the present disclosure that is clearly recited in claims.\",\n \"All examples and conditional language recited herein are intended for pedagogical purposes to aid the reader in understanding the invention and the concepts contributed by the inventor to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions, nor does the organization of such examples in the specification relate to a showing of the superiority and inferiority of the invention.\",\n \"Although the embodiment of the present invention has been described in detail, it should be understood that the various changes, substitutions, and alterations could be made hereto without departing from the spirit and scope of the invention.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875802"}}},{"rowIdx":4494981,"cells":{"text":{"kind":"list like","value":[["SYSTEM AND METHOD FOR THE DISPLAY OF RESTRICTED INFORMATION ON PRIVATE DISPLAYS","The present invention is directed to a system and method for restricting data, or portions thereof, to specific display devices when accessed by a user.","Furthermore, the system and method of the invention are directed, in part, to evaluating in real time, the access level of a device and restricting the availability of sensitive information on the device according to the access level as determined by device location and hardware configuration."],["1.A computer-implemented method for preventing inadvertent violations of confidentiality, the method comprising: by one or more processors executing program instructions: determining, for a dataset including patient medical information, an access restriction level of the dataset; receiving, from a display device, a request for the dataset; accessing data indicating that a physical size of the display device is larger than a threshold physical size; determining, based at least in part on the data indicating that the physical size of the display device is larger than a threshold physical size, an access restriction level of the display device; comparing the access restriction level of the display device and the access restriction level of the dataset; and in response to the comparison, denying the request for the dataset that includes patient medical information.","2.The computer-implemented method of claim 1, wherein the request is associated with access credentials from a user, the method further comprising: by one or more processors executing program instructions: receiving, from a second display device that is smaller than the threshold physical size, a second request for the dataset, wherein the second request is associated with the access credentials; accessing second data indicative of a physical size of the second display device; determining, based at least in part on the physical size of the second display device, a second access restriction level of the second display device; comparing the second access restriction level of the second display device and the access restriction level of the dataset; and in response to the comparison of the second access restriction level of the second display device and the access restriction level of the dataset, communicating the dataset to the second display device.","3.The computer-implemented method of claim 1, wherein the physical size is an area or a length associated with a dimension of the display device.","4.The computer-implemented method of claim 1 further comprising: by one or more processors executing program instructions: monitoring a hardware configuration of the display device; and dynamically updating the access restriction level of the display device in response to a change in the hardware configuration that causes a change in the physical size of the display device.","5.The computer-implemented method of claim 1, further comprising: by one or more processors executing program instructions: authenticating a user of the display device; and updating the access restriction level of the display device in response to authenticating the user.","6.The computer-implemented method of claim 1, wherein the physical size is an area or a length associated with a dimension of a display screen of the display device.","7.The computer-implemented method of claim 1, wherein determining the access restriction level of the display device further comprises: by one or more processors executing program instructions: determining the access restriction level of the display device based at least in part on a location of the display device.","8.The computer-implemented method of claim 1, wherein the computer-implemented method further comprises: by one or more processors executing program instructions: receiving, from the display device, a request for an audio feature associated with the dataset; determining an audio configuration of the display device; and in response to determining that the audio configuration is not configured to output audio through a private audio device, denying the request for the audio feature.","9.The computer-implemented method of claim 1, wherein the computer-implemented method further comprises: by one or more processors executing program instructions: receiving, from the display device, a request for an audio feature associated with the dataset; determining an audio configuration of the display device; and in response to determining that the audio configuration is configured to output audio through a private audio device, communicating the audio feature to the display device.","10.The computer-implemented method of claim 1, further comprising: by one or more processors executing program instructions: receiving input data from the display device when the access restriction level of the display device satisfies a threshold; and updating the dataset to include the input data.","11.A system for preventing inadvertent disclosure of private information, the system comprising: a non-transitory computer readable storage medium having program instructions embodied therewith; and one or more processors configured to execute the program instructions to cause the one or more processors to: receive, from a display device, a request for a dataset of patient medical information, wherein the dataset includes a first visual feature and a second visual feature; determine a first access restriction level of the first visual feature and a second access restriction level of the second visual feature; access data indicative of a physical size characteristic of the display device; determine, based at least in part on the physical size characteristic of the display device, an access restriction level of the display device; compare the access restriction level of the display device and the first access restriction level; compare the access restriction level of the display device and the second access restriction level; in response to the comparison of the access restriction level of the display device to the first access restriction level, communicate the first visual feature of the dataset to the display device; and in response to the comparison of the access restriction level of the display device to the second access restriction level, restrict the display device from accessing the second visual feature.","12.The system of claim 11, wherein the first visual feature and the second visual feature show different categories of medical information.","13.The system of claim 11, wherein the one or more processors are configured to execute the program instructions to further cause the one or more processors to: access data indicative of a physical size characteristic of a second display device; determine, based at least in part on the physical size characteristic of the second display device, an access restriction level of the second display device; compare the access restriction level of the second display device and the access restriction level of the dataset; and in response to the comparison, communicate the first visual feature and the second visual feature of the dataset to the second display device.","14.The system of claim 11, wherein the physical size characteristic includes at least one of: a display screen length of the display device; a display screen area of the display device; or a category of device type, wherein the device type is associated with a range of display sizes.","15.The system of claim 11, wherein determining the access restriction level of the display device further comprises: determining the access restriction level of the display device based at least in part on a location of the display device.","16.The system of claim 11, wherein the one or more processors are configured to execute the program instructions to further cause the one or more processors to: in response to the comparison of the access restriction level of the display device to the second access restriction level, cause the display device to show an indicator that the access of the second visual feature is restricted.","17.A computer program product comprising a non-transitory computer readable storage medium having program instructions embodied therewith, the program instructions executable by one or more processors to cause the one or more processors to: determine, based at least in part on patient medical information in a dataset, an access restriction level of the dataset; receive, from a display device, a request for the dataset; access data indicative of a physical size characteristic of the display device; determine, based at least in part on the physical size characteristic of the display device, an access restriction level of the display device; compare the access restriction level of the display device and the access restriction level of the dataset; and in response to the comparison, communicate the dataset to the display device.","18.The computer program product of claim 17, wherein the program instructions are executable by one or more processors to further cause the one or more processors to: receive a request for an audio feature associated with the dataset; determine an audio configuration of the display device; and in response to determining that the audio configuration is configured to output audio through a private audio device, communicate the audio feature to the display device.","19.The computer program product of claim 17, wherein the program instructions are executable by one or more processors to further cause the one or more processors to: receive a request for an audio feature associated with the dataset; determine an audio configuration of the display device; and in response to determining that the audio configuration is not configured to output audio through a private audio device, restricting access of the audio feature from the display device.","20.The computer program product of claim 17, wherein data indicative of the physical size characteristic includes at least one of: a length; an area; and a category of device type, wherein the device type is associated with a range of display sizes."],["<SOH> BACKGROUND OF THE INVENTION <EOH>In many environments where people use computers, their computer display may be visible to other users.","This can be a significant problem when the displayed information is private, restricted, or sensitive.","For example, doctors and other healthcare workers routinely display patients' private healthcare information on computer monitors in hospitals, clinics, and doctors' offices.","With the migration of medical records to digital form, including the use of Electronic Medical Records systems (EMR), this practice is only set to increase.","A doctor using a computer to view his patient's healthcare information at a nursing station may be authorized to view that information.","However, other doctors and healthcare workers at the nursing station, unassociated with the patient, may not be authorized to view that same private information, or some portions of the patent's information.","Laws such as HIPAA require that the privacy of healthcare information be protected, and significant penalties can be incurred for failing to do so.","Therefore, a problem arises of restricting data to only authorized users, when such data is only obtainable or useful in a public, or semi-private setting.","This problem extends beyond the medical field to other situations in which private, restricted, or sensitive information may be viewed on computers.","For example, financial, or other confidential information might be displayed at inopportune times and locations in an office, showroom or factory."],["<SOH> SUMMARY OF THE INVENTION <EOH>In one arrangement of a system and method described herein, a computer system is configured to selectively display, or to transmit for display, data depending on the accessibility level of the requesting device.","In one particular configuration, the present invention is directed to a computer implemented method for selectively displaying information stored in a server or database on a remote display device, the method comprising, using a remote display device to request, using a data request module, a dataset stored in the memory of a remote computer, the dataset having a specified access restriction level; transmitting, to a computer controlling access to the dataset having a specified access restriction level, at least data relating to the display characteristics of the remote display device using a device configuration module which comprises code executing in a processor.","The method also includes identifying the access restriction level of the display device using a restriction level module which comprises code executing in the processor; and comparing, with a comparison module configured as code executing in the processor, the access restriction level of the display device and the access restriction level of the requested dataset.","Furthermore, once the access level of the requesting device has been compared to the access level of the requested data, the processor is configured to transmit the requested dataset to the display device when (i.e., upon determination that) the access restriction level of the display device is above a pre-set threshold using a transmission module.","The display device is then caused to display the dataset with a display module configured as code executing in a processor.","In a further, optional arrangement, in addition to conditioning the transmission of the requested dataset upon the access restriction level being determined as being above a pre-set threshold, the transmission can be further conditioned to be based upon a determination of the device type and or ID of the device to which the dataset is to be transmitted for an assessment as to whether to complete that task, and arranged to not transmit the requested dataset in the event that the transmission is being directed to hardware fails the assessment.","As such, requested datasets can be controllably distributed in response to requests only to approved or known displays, mobile devices, and so on.","The system and method, in more particular arrangements in accordance with certain implementations of the invention, can also include the use of a location awareness module, configured as code executed on a processor, which cause the processor to evaluate the access condition level of the features of the data object and determines based on location, to display or restrict the information.","The system and method described further includes providing a user with options for displaying sensitive or private information across a combination of conventional computer displays, specialized computer displays, and mobile devices that have screens that are easily viewed by the user but not by others.","This combination allows a user to efficiently interact with a computer with a standard computer monitor, but only view restricted information using devices that have “private displays,” i.e.","displays that are easily viewed by the user but not others nearby.","These and other aspects, features, and arrangements of the invention can be appreciated from the accompanying drawing figures and discussion of certain embodiments of the invention."],["CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser.","No.","15/356,082, filed Nov. 18, 2016, which is a continuation of U.S. patent application Ser.","No.","14/509,721, filed Oct. 8, 2014, which claims the benefit of U.S.","Provisional Patent Application No.","61/888,757, filed Oct. 9, 2013 and U.S.","Provisional Patent Application No.","61/888,372, filed Oct. 8, 2013.The entire disclosure of each of the above items is hereby made part of this specification as if set forth fully herein and incorporated by reference for all purposes, for all that it contains.","Any and all applications for which a foreign or domestic priority claim is identified in the Application Data Sheet as filed with the present application are hereby incorporated by reference under 37 CFR 1.57.FIELD OF THE INVENTION The present invention is directed to a system and method for restricting data, or portions thereof, to specific display devices when accessed by a user.","Furthermore, the system and method of the invention are directed, in part, to evaluating in real time, the access level of a device and restricting the availability of sensitive information on the device according to the access level.","BACKGROUND OF THE INVENTION In many environments where people use computers, their computer display may be visible to other users.","This can be a significant problem when the displayed information is private, restricted, or sensitive.","For example, doctors and other healthcare workers routinely display patients' private healthcare information on computer monitors in hospitals, clinics, and doctors' offices.","With the migration of medical records to digital form, including the use of Electronic Medical Records systems (EMR), this practice is only set to increase.","A doctor using a computer to view his patient's healthcare information at a nursing station may be authorized to view that information.","However, other doctors and healthcare workers at the nursing station, unassociated with the patient, may not be authorized to view that same private information, or some portions of the patent's information.","Laws such as HIPAA require that the privacy of healthcare information be protected, and significant penalties can be incurred for failing to do so.","Therefore, a problem arises of restricting data to only authorized users, when such data is only obtainable or useful in a public, or semi-private setting.","This problem extends beyond the medical field to other situations in which private, restricted, or sensitive information may be viewed on computers.","For example, financial, or other confidential information might be displayed at inopportune times and locations in an office, showroom or factory.","SUMMARY OF THE INVENTION In one arrangement of a system and method described herein, a computer system is configured to selectively display, or to transmit for display, data depending on the accessibility level of the requesting device.","In one particular configuration, the present invention is directed to a computer implemented method for selectively displaying information stored in a server or database on a remote display device, the method comprising, using a remote display device to request, using a data request module, a dataset stored in the memory of a remote computer, the dataset having a specified access restriction level; transmitting, to a computer controlling access to the dataset having a specified access restriction level, at least data relating to the display characteristics of the remote display device using a device configuration module which comprises code executing in a processor.","The method also includes identifying the access restriction level of the display device using a restriction level module which comprises code executing in the processor; and comparing, with a comparison module configured as code executing in the processor, the access restriction level of the display device and the access restriction level of the requested dataset.","Furthermore, once the access level of the requesting device has been compared to the access level of the requested data, the processor is configured to transmit the requested dataset to the display device when (i.e., upon determination that) the access restriction level of the display device is above a pre-set threshold using a transmission module.","The display device is then caused to display the dataset with a display module configured as code executing in a processor.","In a further, optional arrangement, in addition to conditioning the transmission of the requested dataset upon the access restriction level being determined as being above a pre-set threshold, the transmission can be further conditioned to be based upon a determination of the device type and or ID of the device to which the dataset is to be transmitted for an assessment as to whether to complete that task, and arranged to not transmit the requested dataset in the event that the transmission is being directed to hardware fails the assessment.","As such, requested datasets can be controllably distributed in response to requests only to approved or known displays, mobile devices, and so on.","The system and method, in more particular arrangements in accordance with certain implementations of the invention, can also include the use of a location awareness module, configured as code executed on a processor, which cause the processor to evaluate the access condition level of the features of the data object and determines based on location, to display or restrict the information.","The system and method described further includes providing a user with options for displaying sensitive or private information across a combination of conventional computer displays, specialized computer displays, and mobile devices that have screens that are easily viewed by the user but not by others.","This combination allows a user to efficiently interact with a computer with a standard computer monitor, but only view restricted information using devices that have “private displays,” i.e.","displays that are easily viewed by the user but not others nearby.","These and other aspects, features, and arrangements of the invention can be appreciated from the accompanying drawing figures and discussion of certain embodiments of the invention.","BRIEF DESCRIPTIONS OF THE DRAWINGS FIGS.","1A-1C are illustrative diagrams of an information restriction system in accordance with various embodiments.","FIG.","2 is a diagram of a mobile device and a private and non-private (public) display as can be used in the information restriction system such as shown in FIGS.","1A-1C.","FIG.","3 is an example of private and non-private displays according to one embodiment of the described system.","FIG.","4 is an example of a display device configured in accordance with an embodiment of the described system.","FIG.","5 is an alternative example of a display device configured in accordance with an embodiment of the described system.","FIGS.","6A-6D provides examples of the steps taken by an information restriction system in accordance with embodiments described herein.","FIG.","7 provides a block diagram of an example system in accordance with an embodiment of the present invention.","FIG.","8 provides a flow detailing the steps of an embodiment of the method described herein.","FIG.","9 provides examples of displays with various restriction levels and examples of device privacy levels and information privacy rules according to an embodiment of the present invention.","FIG.","10 is an illustrated diagram of the elements of the system of an embodiment of the present invention.","DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION By way of overview and introduction, the system and methods describe a computer system configured to restrict access and distribute private information to approved access devices depending on a privacy level associated with that device.","As used herein, and for the purposes of discussion, information that a user deems to be particularly private, restricted or sensitive, will be termed “restricted” or “private.” For example, private or restricted information is data or information which a user prefers, or is obligated, legally or contractually, to keep confidential or not to disclose to a third party without consent.","As will be appreciated from context, the verb “restricting” refers to the actions taken in response to instructions executing in a processor to control information flow such as to a particular display.","Furthermore, the “privacy level” of a device is determined according to a combination of factors, including but not limited to, the type of private information the user seeks to display, the location of the user, and the nature of the display device that the user is attempting the access and display the information.","For ease of explanation, the following examples refer to medical records.","However, those possessing a level of ordinary skill in the art will appreciate that additional private material, such as government documents, financial records, personal communications, and commercial or journalistic materials are envisioned and contemplated by the described system and method.","Likewise, as used herein, “data” can be any information conveyable to a user through a device.","For example data can include audio data, audiovisual data, images, 3D renderings or simulations, as well as web links or system portals to remotely accessible software or datasets.","Purely for illustration purposes, and as a non-limiting example, the data could incorporate multiple types of data, such as both an audio file and a 3D image associated with it.","Furthermore, the terms “viewer” and “user” are used interchangeably to describe an individual (or group of individuals) that interfaces with a computing device of the present invention.","As another non-limited example, users or viewers can include medical professionals such as radiologists and other doctors, as well as hospital staff, or other individuals involved in acquisition, interpretation, analysis, storage, management, or other tasks related to medical images.","In other embodiments, users can include any individuals or groups of individuals that generate, transmit, view, and/or otherwise work with images of any type.","Turning to FIG.","1A, an example of the computer system configured to implement the selective display of information on remote devices is provided.","In the illustrated configuration, the patient data is obtained from a local network 110 of hospital subsystems 120-144, and computer devices 150a-b, each configured to input, output, store or process information concerning a patient.","In one arrangement, one or more medical scanners, such as MRI scanners 120, are connected to the network 110.As a non-limiting example, the MRI scanners 120 can be used to acquire MRI images from patients, and can share the acquired images with other devices on the network 110 by either directly storing MRI scanner images in a local storage, or uploading the images of a particular patient to that patient's data storage location in a patient database.","One or more CT scanners 122 can also be coupled to the network 110.The CT scanners 122 can also be used to acquire images and, like the MRI scanner 120, can then store those images and/or share those images with other devices via the network 110.Any other scanner or device capable of inputting or generating information that can be presented to the user as images, graphics, text, or sound, including ultrasound, angiography, nuclear medicine, radiography, endoscopy, pathology, dermatology, etc.","can be connected to network 110.In another arrangement, a Picture Archiving and Communications System (PACS) 136 and/or PACS workstation 138 can be connected to the network 110.The PACS 136 is typically used for the storage, retrieval, distribution and presentation of images (such as those created and/or generated by the MRI scanner 120 and CT Scanner 122).","The medical images can be stored in an independent format, an open source format, or a proprietary format.","A common format for image storage in the PACS system is the Digital Imaging and Communications in Medicine (DICOM) format.","The stored images may be transmitted digitally to a network accessible storage location via the PACS system, thus often reducing or eliminating the need for manually creating, filing, or transporting film jackets.","A Radiology Information System (RIS) 140 can also be connected to the network 110, as shown in the illustrated embodiment of FIG.","1A.","The radiology information system 140 is typically a computerized data storage system that is used by radiology departments to store, manipulate and distribute patient radiological information such as radiology reports.","As shown, an Electronic Medical Record (EMR) system 142 and EMR workstation 137 can be connected to the network 110.The EMR system 142, when provided, is configured to store and make accessible to a plurality of medical practitioners computerized medical records.","There can also be attached to the network 110 a Laboratory Information Systems 144.Laboratory Information System 144 is a system which typically is configured to store information created or generated by clinical laboratories Likewise, a Digital Pathology System 146 can be also attached to the network and used to digitally manage and store information related to medical pathology.","Further components can be available on the network 110, such as a Computer Aided Diagnosis System (CAD) 148 and 3D Processing System 149, which can be used to analyze images and create new views of the information, e.g., 3D volumetric display, Multiplanar Reconstruction (MPR) and Maximum Intensity Projection reconstruction (MIP) respectively.","In other embodiments, other computing devices that store, provide, acquire, and/or otherwise manipulate medical data can also be coupled to the network 110 and can be in communication with one or more of the devices illustrated in FIG.","1A.","For example, each of the devices described are configured to update a patient record stored in a database, such that all of the data for a given patient is accessible from a parent computing device having sufficient access privileges.","As shown in more detail in FIG.","1B, general and mobile computing devices, 150a and 150b, are connected to the network 110 and are used to access all or portions of the patient data.","In one arrangement, the patient data is obtained from a file system located in the server 170.Alternatively, the computing devices are configured to access discrete pieces of information or data pertaining to a particular patient or group of patients from storage or memory locations connected directly to each of the subsystems.","In FIGS.","1a and 1b the computing device 150a is labeled as a mobile device and computing device 150b is labeled as a parent computer.","However, alternative computing devices are possible and understood.","In one particular configuration of the network 110, the computing devices 150a and 150b can be a computer having software or hardware modules 151-157.In other embodiments, the modules can reside on another computing device, such as a web server or other server, and the user directly interacts with a second computing device that is connected to the web server via a computer network.","In one embodiment, the modules include some or all of the software utilized by the inventions described herein.","In one non-limiting example, the computing device 150a or 150b is selected from one of a variety of computing platforms such as a server, a desktop computer, a workstation, a laptop computer, a mobile computer, a Smartphone, a tablet computer, a wearable computer such as a smart watch, a wearable computer that may be interfaced to a head mounted or heads-up display, a cell phone, a personal digital assistant, a gaming system, a kiosk, an audio player, any other device that utilizes a graphical user interface, including office equipment, automobiles, airplane cockpits, household appliances, automated teller machines, self-service checkouts at stores, information and other kiosks, ticketing kiosks, vending machines, industrial equipment, and/or a television, as a non-exhaustive set of examples.","The computing devices 150a and 150b are configurable to interface with various networked devices in order to communicate, receive or update medical information that are stored centrally in a database or distributed among the various systems present in the network.","It should be noted and appreciated that the computing devices 150a and 150b are general computing devices and are configurable to display any type of data commonly displayed on general computing systems.","Depending on the embodiment, the other devices illustrated in FIG.","1a (besides the computing device 150) can include some or all of the same components discussed above with reference to the computing device 150.As shown in FIGS.","1A-1C, also connected to the network 110 are one or more databases 160, 162, 164, 166 that support functionality of the various computing devices connected to the network 110 and which provide a repository for instructions and algorithms related to the functioning of various embodiments of the present inventions described herein.","The databases are commonly used and understood data structures or tables that are accessible remotely, either through a server or other type of direct or remote computer configured appropriately to enable access and retention of data.","In one arrangement, the data stored in the databases are accessible to servers 170, desktop computers 150a, mobile computers 150b, or other computing devices directly connected to the network, or given access to the network 110 through a network link or portal.","The databases of the system illustrated includes a User Preferences Database 160 configured as a data storage location which contains tables and indexes that allow the computer to store and obtain data regarding a particular users/site preferences.","Site preferences allow a user to set privacy levels manually depending on the display device.","For example, a user can store a global access level in the user preference database that sets the privacy level for all medical test results regardless of hardware configuration.","Also attached to the network is an Authentication Database 162, configured as a data storage location accessible by a processor suitably configured by code executing therein to provide user authentication services for a user.","Such services include signing into, or accessing, the network from a computer such as a mobile device.","Furthermore, the Authentication Database 162 contains data used to configure a processor to authenticate a new user, or an already authenticated mobile user with a different display device.","The Authentication Database 162 also contains code to configure a processor to access rules governing user privileges in terms of modifying the privacy level of a device depending on the privileges associated with that user.","As an example, executives or high-ranking officials have user privileges that allow for the modification of the device privacy level so as to permit the display of private information on devices not independently possessing the required privacy level.","As further provided in FIGS.","1A-B, the system includes a Device Interaction Database 164.The Device Interaction Database 164 provides storage and indexing of data related to the input and output functionality or capabilities of a display of a given type or particular device identification (e.g., a MAC address in the case of a device with an integrated display).","Furthermore, the Device Interaction Database 164, in one arrangement, also stores and provides the system with the capabilities of parent computers in terms of input and output functions.","Additionally, the Device Interaction Database 164 stores and provides access to data relating to how different actions and inputs (such as inputs from a mobile device or remote computer) are to be handled by the system, e.g., multitouch, accelerometer, microphone, etc., are communicated to and presented as user input to parent computers.","In one arrangement, this data is presented as algorithms for evaluating and determining the access level of a device based on how the device handles inputs and outputs of the device under evaluation.","Additional rules or algorithms are stored in the database regarding different outputs from parent computers, such as images, user interfaces, sound, etc., are transmitted to and presented on mobile devices.","As shown in further detail in FIG.","1C, an Information Restriction Database 166 is also connected to the network 110 and is configured to provide and store data relating to characteristics of the data stored and accessible by the network.","For example, the Information Restriction Database 166 provides data detailing the privacy levels or restrictions present for a given portion of patient data.","For instance, the Information Restriction Database 166 provides data in the form of rules or algorithms that instructs the remote display device, and/or a computer having access to data requests by a remote display device, to restrict access to all, or a portion of the information depending on at least the hardware configurations and/or the location for a given portion of the data set.","In this regard, the rules or algorithms maintained in the database 166 can configure a processor to make a determination on the basis of the hardware configuration of the requesting device, an identification of the requesting device, or both, as to whether to provide the requested dataset or not.","For instance, the requested dataset can be restricted, and therefore not provided, in the event that the hardware fails this determination.","In one example, the Information Restriction Database 166 is configured to store rules to evaluate medical exams to determine the restriction status Likewise, other rules for data, such as patient's information, site preferences regarding restricted information and user preferences regarding restricted information are stored in the Information Restriction Database 166.Information Restriction Database 166 contains information that configures a processor to assign a privacy level for data stored or accessible on the network.","For example, data generated by each of the devices on the network, 120-144, are assigned a privacy level according to specific data handling rules stored in the Information Restriction Database 166.The Information Restriction Database 166 also includes rules accessible by a processor in order to evaluate data sets, objects, files, folders and other collections of data and determine, based on the nature of the data, the proper restriction level for the information.","For example, the system described is configured to evaluate the contents of the medical record and determine, based on the content, if the information should be restricted to a private display.","These evaluations can be made in response to a data request by a user of the system.","Alternatively, the records evaluated by the present system are preconfigured or coded with a general privacy level, or specific privacy level for individual data elements within the record.","In one arrangement, the Information Restriction Database 166 cooperates with a privacy classification module to configure a processor to assign a privacy level for data based on the type of information (audio, visual, etc.)","as well as the information content.","As an example, the privacy level classification module configures the processor to assign a given privacy level to the result of a lung biopsy according to the outcome of the test.","In one arrangement, the privacy classification module cooperates with the Information Restriction Database 166 by instructing a processor to classify or assign data at a given privacy level based on pre-set rules.","In one instance, all the data is assigned a specific level of privacy at different organizational levels.","For example, the data is assigned a privacy level according to a hospital or department preference, an individual doctor preference (user preference), or a user group (group preference).","In one further configuration the privacy module cooperates with the Information Restriction Database 166 to assign a set privacy level to all the data associated with an individual.","Alternatively, the privacy level assignment module configures the processor to assign privacy levels for data depending on the accessing or requesting device.","For example, the processor is configured, through an instruction set, to generate general or specific categories and privacy levels for restricted devices, such as Smartphones 210, Smartwatches 330, tablet computers, and Wearable computers with heads-up displays (HUD), such as the heads-up display 402, and virtual reality headsets.","The system described is also configurable to evaluate the privacy level of desktop computers with heads-up displays or other small displays, where the restricted data may only be displayed on the private displays connected to these devices.","The system described is also configurable to evaluate the privacy level of desktop computers with standard monitors, where the restricted data may be displayed on systems that are located in a pre-defined or user identified secure location, for example in an office where the display is only viewable by the user.","In one arrangement, the system is configurable to only allow the display of certain types of restricted information on certain types of private displays.","For example, positive results of an HIV test might only be allowed to be displayed on mobile devices with screens smaller than 5″.","In a further embodiment, information restriction rules contained within the Information Restriction Database 166 apply to information that a user can input.","For example, prescriptions for medication might be classified as restricted information so that doctors would only be able to enter prescriptions for medications on devices with private displays.","Without loss of generality, any of the embodiments described herein can include restrictions that comprise controls which are responsive to the device connected at the end of the network path which has the display of the requesting device.","The hardware connected on this path can be analyzed by code executing in a processor in order to determine the device type and/or ID of the device to which the dataset is to be transmitted.","Whether transmission of the dataset is to be restricted can be assessed in view of this determination.","If the device type or device ID is known to or approved by the system (e.g., based on look-ups to stored reference or authorization data), then that transmission can proceed.","On the other hand, if the device type or device ID are not known or approved by the system, the system can be configured to not transmit the requested dataset in view of the hardware connected in that network path.","The system described herein can be implemented as a series of modules comprising code and executed in a processor which responds to user events, hardware connections, or both.","In part, the system illustrated herein is also configured to access, retrieve, obtain and otherwise receive information that is used in support of various functionalities described herein, and can include input and output devices or be configured to communicate with such devices through network ports and drivers configured or connected for that purpose.","Turning to FIG.","7, the system or network 110 utilized in the various embodiments of the invention implements a series of steps to control the display of data on remote accessing devices based on the hardware configuration and/or location of the remote accessing device.","The methods described herein are implemented utilizing the elements of the network as provided in FIG.","1.However, it should be appreciated that other additional or alternative arrangements are possible.","For example, the described steps are implemented by one or more computing devices, such as the computing device 150a, but the methods are not limited to performance by the computing device 150a and should be interpreted to include performance by any one or more of the computing devices, such as additional computers or server.","The information restriction and distribution system of the present invention selectively displays information requested by a computer user based on the access level of the data and the hardware and/or location data of the computer on which the data will be reviewed.","The system enables a user to review some portions of private or restricted data on standard display devices, e.g.","computers, smartphones, computer tablets, interactive displays, while still ensuring that other portions that are more sensitive, are only accessible to a user on a “private display,” i.e., those displays that are not easily viewed by others nearby.","With reference to FIGS.","7 and 8, the information restriction and distribution system is implemented and initiated by at least one request module 710 which comprises code executing in a processor 700 to request a specific data set, such as a medical record, from a medical record database 705 according to step 810.In the illustrated arrangement, access to the Device Interaction database 164, the Information restriction database 166 and the Medical Record Database 705 are controlled by a network controller 701, which comprises a processor configured with code executing therein.","Contemporaneous with, or subsequent to, the requesting step 810, the hardware configuration and/or location of the requesting device (i.e., the display device) is transmitted to the controlling processor as in step 820, using a hardware configuration transmitting module 720 configured as code executing in the processor 700.In one arrangement the hardware and location data are obtained by a processor configured with sub-modules to query the device operating system or hardware modules to obtain the necessary information.","For instance, geolocation data, such as coordinates obtained from a GPS or equivalent receiver or transponder are used to evaluate the location of the output device.","Other examples of technologies that could be used to evaluate the location of the output device include near-field communication technologies, Bluetooth and/or other low energy proximity sensing technologies.","Likewise, data relating to the hardware configuration of the output device, such as audio capabilities, video display capabilities and input capabilities can be obtained from an application or operating system residing on the output device.","In the alternative, the location or hardware configuration is supplied manually and transmitted according to step 820.Once the display device has been evaluated for its location and capabilities, a privacy level is assigned to that output device and may be optionally stored in the device interaction database for future reference or transmitted in real-time to a server or database.","For example, a privacy level assignment step 830 includes receiving, by the controlling processor 701, the location and configuration data transmitted by the display device processor 700 and comparing that information to preset privacy levels and rules in the Device Interaction Database and Information Restriction Database.","In one arrangement this step is carried out using a privacy level assignment module 715, which operates as code executing in the controller processor 701.In one arrangement, if the privacy level of a given output device is above a minimum threshold, or pre-set limit, then the assignment module 715 configures the controller processor 701 to assign the output device a “private” level.","This privacy level can, in one configuration, take the form of an entry in a table in the Information Restriction Database or the Device Interaction Database.","In an alternative embodiment, the assignment module 715 instructs the controller processor 701 to assign different portions of output components of the output device differing privacy levels depending on the hardware configuration (e.g., device type, MAC address, or other hardware-identifying information or hardware setting information), or location of the output device.","For example, the controller processor 701 is instructed by the privacy level module 715 to classify on output device as a “private” device for visual data only, but as a public device for audio data, or an audio component of multi-media data.","In a further arrangement the privacy level assignment module 715 further instructs the controller processor 701 to query each output device connected to the network on a periodic basis and updates the privacy level depending on the function, location, size, and accessibility of the output device.","In an alternative, the privacy level assignment module 715 includes a sub-module that configures the controller processor 701 to set privacy levels specific devices.","For example, an administrator device is set to the maximum level of privacy regardless of the hardware or location data.","In still a further arrangement, privacy level assignment module 715 includes a sub-module that configures the controller processor 701 to evaluate, in real-time, the privacy level of an output device depending the proximity of other individuals, general access level of data, or other factors, as can be obtained through a variety of system inputs.","For example, where a output device is classified as a video “private”, audio “public” device, such as a nursing station computer, the privacy level assignment module 715 configures the controller processor 701 to reclassify the output device with an audio “private” level in the event that a private audio display device (e.g.","a headset, wireless or wired to the network) is connected to the output device.","It should be noted that in some cases, conventional computer monitors may be considered private displays, for example in cases where they are physically located in places were only the user of the computer can view the computer screen, such as an office.","Alternatively, devices that can be classified as having private displays include smartphones, PDAs, tablets computers, interactive displays, and wearable computers, including devices with heads-up displays (HUD), such as Google Glass, virtual reality displays, such as Oculus Rift, and smartwatches, such as Apple Watch.","In another example, a private display might be a computer display that is only clearly visible only to users wearing specialized glasses.","In another example, a private display might be a computer display that is only clearly visible to a user who is positioned at a specific spatial position relative to the display.","In the process steps of FIG.","8, once the privacy level of the output device has been determined, it is compared to the privacy level of the data requested from the medical record database as in step 840.In one arrangement, a comparison module 725, configured as code executing in the controller processor 701, instructs the processor to evaluate the privacy level of the data requested and determine if the requesting output device has a sufficient privacy level to allow the display of the requested data.","In the event that the requesting device has a sufficient privacy level compared to the requested information, the some or all of the requested data is transmitted from the medical database to the output device, as in step 850.In a particular embodiment, a data transmission module 735, configured as code executing in the controller processor 701 instructs the processor to transmit those portions of the requested data to the display device.","Furthermore, the system described is configured to segment, or access segmented private information such that portions of the private information are distributed across multiple devices depending on the privacy level of the device and the privacy level of the information.","Once the data has been received by the display device, it is displayed or output by the display device, according to step 860.In a particular embodiment, a display module 730 configured as code executing in the display device processor 700 instructions the processor to display the permitted data received from the medical record database.","In the event that a hardware configuration or location changes in the output device, such as the connection of an external headset, a real-time device evaluation module 740 configures the display device processor to communicate the updated status of the display device to the controller processor 701.This, in turn, causes the controller processor 701 to update the privacy level of the output device and cause additional, newly available data to be sent to the output device for display.","Returning to FIG.","2, once a display device has been assigned a privacy level, data accessed by that output device will be conditioned based on the privacy level of the device as a whole, or the individual components of the output device.","Requesting data from a device having an insufficient privacy level will result in a placeholder data being sent to the output device indicating that the data is not accessible from the given device.","As illustrated, the display configuration 200 includes computer display 220, and a mobile device 210.In the illustrated configuration, both the computer and the mobile device are classified as private devices.","As such, when data is requested, it can be displayed on either of the requesting devices.","Alternatively, the display configuration 201 includes a computer display 222 and the same mobile device 201.In this configuration, the computer display 222 is not classified as a private device, while the mobile device 201 is classified as a private device for displaying the data requested.","In one configuration, a placeholder note or statement indicating the user is not able to access the requested data using that particular device is supplied to the screen.","In a further arrangement, the placeholder data indicates the necessary level of privacy needed for the data to be viewed on that device.","In a further example, the mobile device 210 and the restricted computer 222 are used together to allow the user to view medical information on a same patient.","However, in this configuration restricted information is only displayed on output device 210.Similarly, restricted information in the form of audio would only be playable on device 210, which is classified as a “private display” as it related to audio information.","In one particular configuration as illustrated in FIG.","3, a large, publically viewable display 310, as well as a mobile device 320, and wearable device 330 are incorporated into the system described.","The computer display 310, because of its large size and location, is classifiable as a “non-private” display, and is prohibited from displaying private level information.","Alternatively, the mobile device 320 is classified according to the system as a “private display.” In a circumstance where the data requested by the mobile device includes an audio and visual component, the data returned by the system will include only visual data, but not audio data.","This is due to the privacy level assessment module 715 as described in FIG.","7, instructing the processor to determine that the audio configuration of the mobile device did not permit the output of audio information.","Thus, the privacy level assignment module 715 configures the controller processor 701 to classify the output device 320 as a private device for visual data, but as a public device for audio data.","In the example shown, device 320 and the computer associated with display 310 are both accessing information on the same patient.","Here, the user is authorized to view information on a particular patient.","Since device 320 has a private display, the user can access restricted visual information.","In the event that the user connected a private audio peripheral device to device 320, then restricted audio information is also accessible by the user.","Furthermore, additional or alternative information is available to the smartwatch 330 based on the audio and display configurations available to the user.","As shown in FIG.","4, the display configuration 400 provides an example of a heads-up display (HUD) 402 connected to a conventional computer, such as a desktop or laptop computer, or that can be part of a wearable computer.","View 401 is an example of the visual field observable while wearing a HUD such as example HUD 402.In the example shown the user is viewing information related to a patient that is being displayed on a computer monitor and being displayed on the HUD.","In the example, region 414 is information in the user's visual field being presented by the HUD.","In the example shown, the HUD is classified as a private display and therefore the user is able to view restricted information via the HUD (example region 414) that is not displayed on the computer display 412, which is a non-private display.","Other head mounted display systems could also be classified as private displays, including those in which the display of the system is the only thing the user can see while wearing them, such as a virtual reality display system.","Turning to a non-medical example of information restriction, FIG.","5 illustrates the use of the system in a retail environment.","Computer display 510 is evaluated by the restrictive data display system and determined to be a public display, thus only displaying information related to a specific good or service (e.g., cars) for sale.","In this configuration, the controller processor of FIG.","7 restricts portions of the data requested from the database depending on the privacy level of the display.","As shown, the public display only provides general information concerning the item for sale.","However, through the implementation of the steps and modules provided herein, a user of a private display configuration device is able to access pricing information or other data.","FIGS.","6A-6D illustrate flow charts detailing specific implementations and embodiments of the system and method for restricting information based on output device characteristics.","FIG.","6A is a flow chart illustrating steps related to systems and methods that manage the display and/or input of restricted information on devices with private vs. non-private displays.","In a step 611 the user attempts to access data located or routed by the server 170.As a response, the characteristics of the requesting device are transmitted to the server 170.As shown in step 612, information rules are retrieved from Information Restriction Database 166 and the device characteristics are evaluated against the restriction rules in the database 166.For example, the device characteristics and information restriction rules are also utilized in the authentication process such that the user only is authenticated when he is using a device with a private display.","For example, an EMR can be configured with Information Restriction Rules that prevent any access with devices that do not have private displays.","The server 170, in one configuration, authenticates the user by requesting credentials (e.g., username, password, fingerprint, etc.,) as shown in step 614.In another embodiment, steps 612 and 614 are reversed, so that user authentication occurs before information restriction rules are retrieved.","As provided in Step 616, the user utilizes computing device 180 to access information communicated by server 170, server 170 utilizes Information Restriction Rules stored in Information Restriction Database 166 to determine which information is restricted and will only communicate restricted information to devices characterized as having private displays.","In an additional step 618, the system is configured to allow the input or transmission of private information, if that information is being entered on a device having a private display.","The input or “display” of information could apply to visually displayed information, e.g., images, text, graphs, etc., as well as audio information.","FIG.","6B provides an example of a flow diagram of the implementation of the authentication step 614, for example, by a series of modules configured as code executing in a processor.","As shown in step 612, the requesting device hardware configuration is provided to the server 170, using a transmitting module 720 as provided in FIG.","7.In turn the server 170 implements an evaluation step 622 to determine if the hardware configuration meets the requirements for a private display.","In one arrangement this is implemented using the module 715.In this particular configuration, if the display device does not have a private display, then the data is not accessed and provided to the mobile device.","Alternatively, if the requesting device is equipped with a private display, then the server 170 requests authentication data as in step 624.In the event that the log-in credentials are verified, according to a verification step 625, the user is authenticated, as in step 627.In one configuration, the authentication is accomplished as a series of modules configured as code executing in the processor of the server and configured to instruct the processor to access the user database, compare the user credentials to a stored table of users and to confirm authentication of a user.","Once the user is authenticated and the device characteristics have been evaluated by the system according to steps 631-633 of FIG.","6c, the data requested is either transmitted to the display device or a placeholder statement is transmitted to the display device, according to the privacy level of the device, the user credentials and the privacy level of the information requested, as in step 635.FIG.","6D provides an alternative flow diagram of the operation of the system of restricting access to data based on the privacy level of the device.","As shown, the user is authenticated by the server as in step 641 and transmits the device configuration to the server.","The server also retrieves the user preferences, the device configuration and the interface preferences as well as retrieving Information Restriction rules from the information restriction rules database 166 as in step 642.Once the rules are retrieved, the authenticated user is permitted by a processor suitably configured by code, to access a list of datasets, such as a patient list, that the authenticated user is permitted to access, as in step 644.Once the user causes the selection of a particular data set, the processor is configured by code to transmit only data that meets the privacy level on the device as in step 648.In step 649, the processor of the user device is configured by code to display the selected information received.","FIG.","9 provides examples of various display devices (910, 912, 914, 916) having differing restriction levels.","FIG.","9 also provides examples of the relative privacy levels and information privacy rules attached to each device according to a database or look-up table.","Table 920 is an example of the Device Privacy Levels assigned to various devices based on the hardware configuration and/or location.","The higher privacy levels are assigned to devices that are more secure in terms of their ability to prevent people other than the user from viewing and/or hearing information presented by the device.","While the example shows six privacy levels, labeled 0 to 5, in practice any number of privacy levels greater than one can be utilized.","In a particular arrangement, the device privacy levels may also vary depending on the device user.","In one arrangement, the access level for a particular device can change in response to specific or authenticated user that is currently using the device.","For example, a device that is authenticated using a login/password, fingerprint scanner, or other biometric based access device has a privacy level that reflects the privacy level assigned to that user regardless of the hardware configuration.","The Device Privacy Levels may be set as a user, group and/or site preference, and may be stored, for example, in the Device Interaction Database 164 or Information Restriction Database 166.In the example of the Device Privacy Levels shown, the Privacy Level assigned to computer monitor 910 is dependent on its location, i.e., the privacy level is set to 4 if located in a private doctor's office, 2 if located in a nursing station, 0 if located in another location or if its location is unknown.","In one arrangement, devices with unknown locations are assigned a privacy level based on the hardware configuration of the device.","In the alternative, the system described assigns devices having an unknown location to a pre-set privacy level.","In one particular arrangement, smartphone 912 is assigned a Privacy Level 4 when it is located in the hospital.","The location of the smartphone 912 is determined in one instance by GPS transponders or another technology capable of locating its position.","In this particular configuration, when the smartphone is no longer located within the hospital, the device is assigned a Privacy Level of 3.Alternatively, the smartwatch 914 is assigned a privacy level of 4, regardless of its location.","Likewise, heads-up display 916 would be assigned a Privacy Level of 5, regardless of its location.","Table 930 illustrates example Information Privacy Rules that determine whether information can be presented on a device based on the Device Privacy Level of a given device.","Information Restriction Rules may be set as a user, group and/or site preference, and may be stored, for example, in Information Restriction Database 166.In one embodiment, information will be displayed on a device when the Privacy Level of the Device is greater than or equal to the Privacy Level of the Information.","For example, the results of a Fetal Ultrasound are assigned an Information Privacy Level of 3 in the example shown.","Therefore, the results of the Fetal Ultrasound would be displayed on any device with a Device Privacy Level of 3 or greater.","Information Privacy Rules, in one arrangement, assigns an Information Privacy Level to virtually any type of information.","For example, various types of information about a patient may be assigned different privacy levels.","As illustrated, a patient's gender, which is generally apparent based on the patient's name and appearance, may be assigned a low Privacy Level, such as 0.Alternatively, the patient's date of birth may be assigned a higher Privacy Level, such as 1, as illustrated in Table 930.It should be appreciated that whether or not a particular test or exam has been ordered or performed on a patient may reveal private information about the patient, and therefore that information may also be assigned a Privacy Level.","For example, the fact that a Fetal Ultrasound has been ordered or performed on a patient indicates that the patient was pregnant at that time of the test.","Thus, the ordering of certain tests (e.g., Fetal Ultrasound) is assigned a Privacy Level of 2.Therefore, an Electronic Medical Records (EMR) or other medical record systems that contain a record of tests requested or performed are also subject to Device Privacy Levels.","In the example shown, the results of the Fetal Ultrasound, which can include information such as images, audio information, measurements, a report, etc., are assigned an Information Privacy Level of 3.Information Privacy Rules may be stored, for example, in Information Restriction Database 166.Information Privacy Rules may vary based on user, group, and site preferences.","In addition, Information Privacy Rules may vary based on characteristics of the patient and/or may be determined automatically based on characteristics of the patient.","For example, Information Privacy Rules might differ for pregnant vs. non-pregnant women, minors vs. adults, and patient's with a particular diagnosis vs. those without that diagnosis.","In addition, Information Restriction Rules could be set explicitly for a particular patient.","In one configuration, the Information Restriction Rules are configured based on instructions or rules set by the patient or the patient's physician or care giver.","In the alternative, a patient who is a notorious or public figure could implement Information Privacy Rules with elevated Information Privacy Levels based on instructions by the patient or an administrator of the hospital caring for the patient.","Depending on the embodiment, the methods described with reference to the flowcharts, as well as any other methods discussed herein, can include fewer or additional blocks and/or the blocks can be performed in a different order than is illustrated.","As illustrated in FIG.","10, the server and other computers of the described system can be implemented according to the computing system 1300 illustrated in FIG.","10.As shown, the computer system 1300 includes a processor 1302, a memory 1304, a storage device 1306, a high-speed interface 1308 connecting to the memory 1304 and multiple high-speed expansion ports 1310, and a low-speed interface 1312 connecting to a low-speed expansion port 1314 and the storage device 1306.Each of the processor 1302, the memory 1304, the storage device 1306, the high-speed interface 1308, the high-speed expansion ports 1310, and the low-speed interface 1312, are interconnected using various buses, and can be mounted on a common motherboard as shown in FIG.","9, or in other manners as appropriate.","The processor 1302 can process instructions for execution within the computing device 1300, including instructions stored in the memory 1304 or on the storage device 1306 to display graphical information for a GUI on an external input/output device, such as a display 1316 coupled to the high-speed interface 1308.In other embodiments, multiple processors and/or multiple buses can be used, as appropriate, along with multiple memories and types of memory.","Also, multiple computing devices can be connected, with each device providing portions of the necessary operations (e.g., as a server bank, a group of blade servers, or a multi-processor system).","A mobile computing device 1350 may include a processor 1352, a memory 1364, and an input/output device such as a display 1354, a communication interface 1366, and a transceiver 1368, among other components.","The mobile computing device 1350 can also be provided with a storage device, such as a micro-drive or other device, to provide additional storage.","Each of the processor 1352, the memory 1364, the display 1354, the communication interface 1366, and the transceiver 1368, are interconnected using various buses, and several of the components can be mounted on a common motherboard or in other manners as appropriate.","The processor 1352 can communicate with a user through a control interface 1358 and a display interface 1356 coupled to the display 1354.The display 1354 can be, for example, a TFT (Thin-Film-Transistor Liquid Crystal Display) display or an OLED (Organic Light Emitting Diode) display, or other appropriate display technology.","The display interface 1356 can comprise appropriate circuitry for driving the display 1354 to present graphical and other information to a user.","The control interface 1358 can receive commands from a user and convert them for submission to the processor 1352.In addition, an external interface 1362 can provide communication with the processor 1352, so as to enable near area communication of the mobile computing device 1350 with other devices.","The external interface 1362 can provide, for example, for wired communication in some embodiments, or for wireless communication in other embodiments, and multiple interfaces can also be used.","The memory 1364 stores information within the mobile computing device 1350.The memory 1364 can be implemented as one or more of a computer-readable medium or media, a volatile memory unit or units, or a non-volatile memory unit or units.","An expansion memory 1374 can also be provided and connected to the mobile computing device 1350 through an expansion interface 1372, which can include, for example, a SIMM (Single In Line Memory Module) card interface.","The expansion memory 1374 can provide extra storage space for the mobile computing device 1350, or can also store applications or other information for the mobile computing device 1350.Specifically, the expansion memory 1374 can include instructions to carry out or supplement the processes described above, and can include secure information also.","Thus, for example, the expansion memory 1374 can be provided as a security module for the mobile computing device 1350, and can be programmed with instructions that permit secure use of the mobile computing device 1350.In addition, secure applications can be provided via the SIMM cards, along with additional information, such as placing identifying information on the SIMM card in a non-hackable manner.","The mobile computing device 1350 can communicate wirelessly through the communication interface 1366, which can include digital signal processing circuitry where necessary.","The communication interface 1366 can provide for communications under various modes or protocols, such as GSM voice calls (Global System for Mobile communications), SMS (Short Message Service), EMS (Enhanced Messaging Service), or MMS messaging (Multimedia Messaging Service), CDMA (code division multiple access), TDMA (time division multiple access), PDC (Personal Digital Cellular), WCDMA (Wideband Code Division Multiple Access), CDMA2000, or GPRS (General Packet Radio Service), among others.","Such communication can occur, for example, through the transceiver 1368 using a radio-frequency.","In addition, short-range communication can occur, such as using a Bluetooth, WiFi, or other such transceiver (not shown).","In addition, a GPS (Global Positioning System) receiver module 1370 can provide additional navigation- and location-related wireless data to the mobile computing device 1350, which can be used as appropriate by applications running on the mobile computing device 1350.The mobile computing device 1350 can also communicate audibly using an audio codec 1360, which can receive spoken information from a user and convert it to usable digital information.","The audio codec 1360 can likewise generate audible sound for a user, such as through a speaker, e.g., in a handset of the mobile computing device 1350.Such sound can include sound from voice telephone calls, recorded sound (e.g., voice messages, music files, etc.)","and sound generated by applications operating on the mobile computing device 1350.The mobile computing device 1350 can be implemented in a number of different forms, as shown in FIG.","10.For example, it can be implemented as a cellular telephone 1380.It can also be implemented as part of a smart-phone 1382, personal digital assistant, or other similar mobile device.","Various embodiments of the systems and techniques described here can be realized in digital electronic circuitry, integrated circuitry, specially designed ASICs (application specific integrated circuits), computer hardware, firmware, software, and/or combinations thereof.","These various embodiments can include embodiment in one or more computer programs that are executable and/or interpretable on a programmable system including at least one programmable processor, which can be special or general purpose, coupled to receive data and instructions from, and to transmit data and instructions to, a storage system, at least one input device, and at least one output device.","These computer programs (also known as programs, software, software applications or code) include machine instructions for a programmable processor, and can be implemented in a high-level procedural and/or object-oriented programming language, and/or in assembly/machine language.","As used herein, the terms machine-readable storage medium and computer-readable storage medium refer to any non-transitory computer program product, apparatus and/or device (e.g., magnetic discs, optical disks, memory, Programmable Logic Devices (PLDs)) used to provide machine instructions and/or data to a programmable processor, including a machine-readable storage medium that receives machine instructions as a machine-readable signal.","The term machine-readable signal refers to any signal used to provide machine instructions and/or data to a programmable processor.","A non-transitory machine-readable storage medium does not include a transitory machine-readable signal.","To provide for interaction with a user, the systems and techniques described here can be implemented on a computer having a display device (e.g., a CRT (cathode ray tube) or LCD (liquid crystal display) monitor) for displaying information to the user and one or more input devices, such as a keyboard, pointing device (e.g., a mouse or a trackball), touch screen, or microphone, by which the user can provide input to the computer.","Other kinds of devices can be used to provide for interaction with a user as well; for example, feedback provided to the user can be any form of sensory feedback (e.g., visual feedback, auditory feedback, or tactile feedback); and input from the user can be received in any form, including acoustic, speech, or tactile input.","The systems and techniques described here can be implemented in a computing system that includes a back end component (e.g., as a data server 1324), or that includes a middleware component (e.g., an application server 1320), or that includes a front end component (e.g., a client computer 1322 having a graphical user interface or a Web browser through which a user can interact with an embodiment of the systems and techniques described here), or any combination of such back end, middleware, or front end components.","The components of the system can be interconnected by any form or medium of digital data communication (e.g., a communication network).","Examples of communication networks include a local area network (LAN), a wide area network (WAN), and the Internet.","The computing system can include clients and servers.","A client and server are generally remote from each other and typically interact through a communication network.","The relationship of client and server arises by virtue of computer programs running on the respective computers and having a client-server relationship to each other.","While this specification contains many specific embodiment details, these should not be construed as limitations on the scope of any embodiment or of what can be claimed, but rather as descriptions of features that can be specific to particular embodiments of particular embodiments.","Certain features that are described in this specification in the context of separate embodiments can also be implemented in combination in a single embodiment.","Conversely, various features that are described in the context of a single embodiment can also be implemented in multiple embodiments separately or in any suitable subcombination.","Moreover, although features can be described above as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination can be directed to a subcombination or variation of a subcombination.","Similarly, while operations are depicted in the drawings in a particular order, this should not be understood as requiring that such operations be performed in the particular order shown or in sequential order, or that all illustrated operations be performed, to achieve desirable results.","In certain circumstances, multitasking and parallel processing can be advantageous.","Moreover, the separation of various system components in the embodiments described above should not be understood as requiring such separation in all embodiments, and it should be understood that the described program components and systems can generally be integrated together in a single software product or packaged into multiple software products.","The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.","As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.","It will be further understood that the terms “comprises” and/or “comprising”, when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.","It should be noted that use of ordinal terms such as “first,” “second,” “third,” etc., in the claims to modify a claim element does not by itself connote any priority, precedence, or order of one claim element over another or the temporal order in which acts of a method are performed, but are used merely as labels to distinguish one claim element having a certain name from another element having a same name (but for use of the ordinal term) to distinguish the claim elements.","Also, the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.","The use of “including,” “comprising,” or “having,” “containing,” “involving,” and variations thereof herein, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.","Particular embodiments of the subject matter described in this specification have been described.","Other embodiments are within the scope of the following claims.","For example, the actions recited in the claims can be performed in a different order and still achieve desirable results.","As one example, the processes depicted in the accompanying figures do not necessarily require the particular order shown, or sequential order, to achieve desirable results.","In certain embodiments, multitasking and parallel processing can be advantageous.","Unless the context clearly requires otherwise, throughout the description, the words “comprise,” “comprising,” and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in a sense of “including, but not limited to.” Words using the singular or plural number also include the plural or singular number respectively.","Additionally, the words “herein,” “hereunder,” “above,” “below,” and words of similar import refer to this application as a whole and not to any particular portions of this application.","When the word “or” is used in reference to a list of two or more items, that word covers all of the following interpretations of the word: any of the items in the list, all of the items in the list and any combination of the items in the list.","The above description of embodiments of the Restricted Display systems and methods is not intended to be exhaustive or to limit the systems and methods described to the precise form disclosed.","While specific embodiments of, and examples for, the Restricted Display device systems and methods are described herein for illustrative purposes, various equivalent modifications are possible within the scope of other Restricted Display systems and methods, as those skilled in the relevant art will recognize.","The teachings of the Restricted Display systems and methods provided herein can be applied to other processing and measurement systems and methods, not only for the systems and methods described above.","While medical and commercial applications were used as examples, the systems and methods described herein can be applied to any field where it may be desirable to restrict display of private or sensitive information, such as military, financial, legal, insurance, and law enforcement applications.","The elements and acts of the various embodiments described above can be combined to provide further embodiments.","These and other changes can be made to the Restricted Display systems and methods in light of the above detailed description.","In general, in the following claims, the terms used should not be construed to limit the Restricted Display systems and methods to the specific embodiments disclosed in the specification and the claims, but should be construed to include all systems and methods that operate under the claims.","Accordingly, the Restricted Display systems and methods are not limited by the disclosure, but instead the scope of the Restricted Display systems and methods is to be determined entirely by the claims.","It should be understood that various combinations, alternatives and modifications of the present invention could be devised by those skilled in the art in view of this disclosure.","The present invention is intended to embrace all such alternatives, modifications and variances that fall within the scope of the appended claims.","While the invention has been particularly shown and described with reference to a preferred embodiment thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention."]],"string":"[\n [\n \"SYSTEM AND METHOD FOR THE DISPLAY OF RESTRICTED INFORMATION ON PRIVATE DISPLAYS\",\n \"The present invention is directed to a system and method for restricting data, or portions thereof, to specific display devices when accessed by a user.\",\n \"Furthermore, the system and method of the invention are directed, in part, to evaluating in real time, the access level of a device and restricting the availability of sensitive information on the device according to the access level as determined by device location and hardware configuration.\"\n ],\n [\n \"1.A computer-implemented method for preventing inadvertent violations of confidentiality, the method comprising: by one or more processors executing program instructions: determining, for a dataset including patient medical information, an access restriction level of the dataset; receiving, from a display device, a request for the dataset; accessing data indicating that a physical size of the display device is larger than a threshold physical size; determining, based at least in part on the data indicating that the physical size of the display device is larger than a threshold physical size, an access restriction level of the display device; comparing the access restriction level of the display device and the access restriction level of the dataset; and in response to the comparison, denying the request for the dataset that includes patient medical information.\",\n \"2.The computer-implemented method of claim 1, wherein the request is associated with access credentials from a user, the method further comprising: by one or more processors executing program instructions: receiving, from a second display device that is smaller than the threshold physical size, a second request for the dataset, wherein the second request is associated with the access credentials; accessing second data indicative of a physical size of the second display device; determining, based at least in part on the physical size of the second display device, a second access restriction level of the second display device; comparing the second access restriction level of the second display device and the access restriction level of the dataset; and in response to the comparison of the second access restriction level of the second display device and the access restriction level of the dataset, communicating the dataset to the second display device.\",\n \"3.The computer-implemented method of claim 1, wherein the physical size is an area or a length associated with a dimension of the display device.\",\n \"4.The computer-implemented method of claim 1 further comprising: by one or more processors executing program instructions: monitoring a hardware configuration of the display device; and dynamically updating the access restriction level of the display device in response to a change in the hardware configuration that causes a change in the physical size of the display device.\",\n \"5.The computer-implemented method of claim 1, further comprising: by one or more processors executing program instructions: authenticating a user of the display device; and updating the access restriction level of the display device in response to authenticating the user.\",\n \"6.The computer-implemented method of claim 1, wherein the physical size is an area or a length associated with a dimension of a display screen of the display device.\",\n \"7.The computer-implemented method of claim 1, wherein determining the access restriction level of the display device further comprises: by one or more processors executing program instructions: determining the access restriction level of the display device based at least in part on a location of the display device.\",\n \"8.The computer-implemented method of claim 1, wherein the computer-implemented method further comprises: by one or more processors executing program instructions: receiving, from the display device, a request for an audio feature associated with the dataset; determining an audio configuration of the display device; and in response to determining that the audio configuration is not configured to output audio through a private audio device, denying the request for the audio feature.\",\n \"9.The computer-implemented method of claim 1, wherein the computer-implemented method further comprises: by one or more processors executing program instructions: receiving, from the display device, a request for an audio feature associated with the dataset; determining an audio configuration of the display device; and in response to determining that the audio configuration is configured to output audio through a private audio device, communicating the audio feature to the display device.\",\n \"10.The computer-implemented method of claim 1, further comprising: by one or more processors executing program instructions: receiving input data from the display device when the access restriction level of the display device satisfies a threshold; and updating the dataset to include the input data.\",\n \"11.A system for preventing inadvertent disclosure of private information, the system comprising: a non-transitory computer readable storage medium having program instructions embodied therewith; and one or more processors configured to execute the program instructions to cause the one or more processors to: receive, from a display device, a request for a dataset of patient medical information, wherein the dataset includes a first visual feature and a second visual feature; determine a first access restriction level of the first visual feature and a second access restriction level of the second visual feature; access data indicative of a physical size characteristic of the display device; determine, based at least in part on the physical size characteristic of the display device, an access restriction level of the display device; compare the access restriction level of the display device and the first access restriction level; compare the access restriction level of the display device and the second access restriction level; in response to the comparison of the access restriction level of the display device to the first access restriction level, communicate the first visual feature of the dataset to the display device; and in response to the comparison of the access restriction level of the display device to the second access restriction level, restrict the display device from accessing the second visual feature.\",\n \"12.The system of claim 11, wherein the first visual feature and the second visual feature show different categories of medical information.\",\n \"13.The system of claim 11, wherein the one or more processors are configured to execute the program instructions to further cause the one or more processors to: access data indicative of a physical size characteristic of a second display device; determine, based at least in part on the physical size characteristic of the second display device, an access restriction level of the second display device; compare the access restriction level of the second display device and the access restriction level of the dataset; and in response to the comparison, communicate the first visual feature and the second visual feature of the dataset to the second display device.\",\n \"14.The system of claim 11, wherein the physical size characteristic includes at least one of: a display screen length of the display device; a display screen area of the display device; or a category of device type, wherein the device type is associated with a range of display sizes.\",\n \"15.The system of claim 11, wherein determining the access restriction level of the display device further comprises: determining the access restriction level of the display device based at least in part on a location of the display device.\",\n \"16.The system of claim 11, wherein the one or more processors are configured to execute the program instructions to further cause the one or more processors to: in response to the comparison of the access restriction level of the display device to the second access restriction level, cause the display device to show an indicator that the access of the second visual feature is restricted.\",\n \"17.A computer program product comprising a non-transitory computer readable storage medium having program instructions embodied therewith, the program instructions executable by one or more processors to cause the one or more processors to: determine, based at least in part on patient medical information in a dataset, an access restriction level of the dataset; receive, from a display device, a request for the dataset; access data indicative of a physical size characteristic of the display device; determine, based at least in part on the physical size characteristic of the display device, an access restriction level of the display device; compare the access restriction level of the display device and the access restriction level of the dataset; and in response to the comparison, communicate the dataset to the display device.\",\n \"18.The computer program product of claim 17, wherein the program instructions are executable by one or more processors to further cause the one or more processors to: receive a request for an audio feature associated with the dataset; determine an audio configuration of the display device; and in response to determining that the audio configuration is configured to output audio through a private audio device, communicate the audio feature to the display device.\",\n \"19.The computer program product of claim 17, wherein the program instructions are executable by one or more processors to further cause the one or more processors to: receive a request for an audio feature associated with the dataset; determine an audio configuration of the display device; and in response to determining that the audio configuration is not configured to output audio through a private audio device, restricting access of the audio feature from the display device.\",\n \"20.The computer program product of claim 17, wherein data indicative of the physical size characteristic includes at least one of: a length; an area; and a category of device type, wherein the device type is associated with a range of display sizes.\"\n ],\n [\n \"<SOH> BACKGROUND OF THE INVENTION <EOH>In many environments where people use computers, their computer display may be visible to other users.\",\n \"This can be a significant problem when the displayed information is private, restricted, or sensitive.\",\n \"For example, doctors and other healthcare workers routinely display patients' private healthcare information on computer monitors in hospitals, clinics, and doctors' offices.\",\n \"With the migration of medical records to digital form, including the use of Electronic Medical Records systems (EMR), this practice is only set to increase.\",\n \"A doctor using a computer to view his patient's healthcare information at a nursing station may be authorized to view that information.\",\n \"However, other doctors and healthcare workers at the nursing station, unassociated with the patient, may not be authorized to view that same private information, or some portions of the patent's information.\",\n \"Laws such as HIPAA require that the privacy of healthcare information be protected, and significant penalties can be incurred for failing to do so.\",\n \"Therefore, a problem arises of restricting data to only authorized users, when such data is only obtainable or useful in a public, or semi-private setting.\",\n \"This problem extends beyond the medical field to other situations in which private, restricted, or sensitive information may be viewed on computers.\",\n \"For example, financial, or other confidential information might be displayed at inopportune times and locations in an office, showroom or factory.\"\n ],\n [\n \"<SOH> SUMMARY OF THE INVENTION <EOH>In one arrangement of a system and method described herein, a computer system is configured to selectively display, or to transmit for display, data depending on the accessibility level of the requesting device.\",\n \"In one particular configuration, the present invention is directed to a computer implemented method for selectively displaying information stored in a server or database on a remote display device, the method comprising, using a remote display device to request, using a data request module, a dataset stored in the memory of a remote computer, the dataset having a specified access restriction level; transmitting, to a computer controlling access to the dataset having a specified access restriction level, at least data relating to the display characteristics of the remote display device using a device configuration module which comprises code executing in a processor.\",\n \"The method also includes identifying the access restriction level of the display device using a restriction level module which comprises code executing in the processor; and comparing, with a comparison module configured as code executing in the processor, the access restriction level of the display device and the access restriction level of the requested dataset.\",\n \"Furthermore, once the access level of the requesting device has been compared to the access level of the requested data, the processor is configured to transmit the requested dataset to the display device when (i.e., upon determination that) the access restriction level of the display device is above a pre-set threshold using a transmission module.\",\n \"The display device is then caused to display the dataset with a display module configured as code executing in a processor.\",\n \"In a further, optional arrangement, in addition to conditioning the transmission of the requested dataset upon the access restriction level being determined as being above a pre-set threshold, the transmission can be further conditioned to be based upon a determination of the device type and or ID of the device to which the dataset is to be transmitted for an assessment as to whether to complete that task, and arranged to not transmit the requested dataset in the event that the transmission is being directed to hardware fails the assessment.\",\n \"As such, requested datasets can be controllably distributed in response to requests only to approved or known displays, mobile devices, and so on.\",\n \"The system and method, in more particular arrangements in accordance with certain implementations of the invention, can also include the use of a location awareness module, configured as code executed on a processor, which cause the processor to evaluate the access condition level of the features of the data object and determines based on location, to display or restrict the information.\",\n \"The system and method described further includes providing a user with options for displaying sensitive or private information across a combination of conventional computer displays, specialized computer displays, and mobile devices that have screens that are easily viewed by the user but not by others.\",\n \"This combination allows a user to efficiently interact with a computer with a standard computer monitor, but only view restricted information using devices that have “private displays,” i.e.\",\n \"displays that are easily viewed by the user but not others nearby.\",\n \"These and other aspects, features, and arrangements of the invention can be appreciated from the accompanying drawing figures and discussion of certain embodiments of the invention.\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser.\",\n \"No.\",\n \"15/356,082, filed Nov. 18, 2016, which is a continuation of U.S. patent application Ser.\",\n \"No.\",\n \"14/509,721, filed Oct. 8, 2014, which claims the benefit of U.S.\",\n \"Provisional Patent Application No.\",\n \"61/888,757, filed Oct. 9, 2013 and U.S.\",\n \"Provisional Patent Application No.\",\n \"61/888,372, filed Oct. 8, 2013.The entire disclosure of each of the above items is hereby made part of this specification as if set forth fully herein and incorporated by reference for all purposes, for all that it contains.\",\n \"Any and all applications for which a foreign or domestic priority claim is identified in the Application Data Sheet as filed with the present application are hereby incorporated by reference under 37 CFR 1.57.FIELD OF THE INVENTION The present invention is directed to a system and method for restricting data, or portions thereof, to specific display devices when accessed by a user.\",\n \"Furthermore, the system and method of the invention are directed, in part, to evaluating in real time, the access level of a device and restricting the availability of sensitive information on the device according to the access level.\",\n \"BACKGROUND OF THE INVENTION In many environments where people use computers, their computer display may be visible to other users.\",\n \"This can be a significant problem when the displayed information is private, restricted, or sensitive.\",\n \"For example, doctors and other healthcare workers routinely display patients' private healthcare information on computer monitors in hospitals, clinics, and doctors' offices.\",\n \"With the migration of medical records to digital form, including the use of Electronic Medical Records systems (EMR), this practice is only set to increase.\",\n \"A doctor using a computer to view his patient's healthcare information at a nursing station may be authorized to view that information.\",\n \"However, other doctors and healthcare workers at the nursing station, unassociated with the patient, may not be authorized to view that same private information, or some portions of the patent's information.\",\n \"Laws such as HIPAA require that the privacy of healthcare information be protected, and significant penalties can be incurred for failing to do so.\",\n \"Therefore, a problem arises of restricting data to only authorized users, when such data is only obtainable or useful in a public, or semi-private setting.\",\n \"This problem extends beyond the medical field to other situations in which private, restricted, or sensitive information may be viewed on computers.\",\n \"For example, financial, or other confidential information might be displayed at inopportune times and locations in an office, showroom or factory.\",\n \"SUMMARY OF THE INVENTION In one arrangement of a system and method described herein, a computer system is configured to selectively display, or to transmit for display, data depending on the accessibility level of the requesting device.\",\n \"In one particular configuration, the present invention is directed to a computer implemented method for selectively displaying information stored in a server or database on a remote display device, the method comprising, using a remote display device to request, using a data request module, a dataset stored in the memory of a remote computer, the dataset having a specified access restriction level; transmitting, to a computer controlling access to the dataset having a specified access restriction level, at least data relating to the display characteristics of the remote display device using a device configuration module which comprises code executing in a processor.\",\n \"The method also includes identifying the access restriction level of the display device using a restriction level module which comprises code executing in the processor; and comparing, with a comparison module configured as code executing in the processor, the access restriction level of the display device and the access restriction level of the requested dataset.\",\n \"Furthermore, once the access level of the requesting device has been compared to the access level of the requested data, the processor is configured to transmit the requested dataset to the display device when (i.e., upon determination that) the access restriction level of the display device is above a pre-set threshold using a transmission module.\",\n \"The display device is then caused to display the dataset with a display module configured as code executing in a processor.\",\n \"In a further, optional arrangement, in addition to conditioning the transmission of the requested dataset upon the access restriction level being determined as being above a pre-set threshold, the transmission can be further conditioned to be based upon a determination of the device type and or ID of the device to which the dataset is to be transmitted for an assessment as to whether to complete that task, and arranged to not transmit the requested dataset in the event that the transmission is being directed to hardware fails the assessment.\",\n \"As such, requested datasets can be controllably distributed in response to requests only to approved or known displays, mobile devices, and so on.\",\n \"The system and method, in more particular arrangements in accordance with certain implementations of the invention, can also include the use of a location awareness module, configured as code executed on a processor, which cause the processor to evaluate the access condition level of the features of the data object and determines based on location, to display or restrict the information.\",\n \"The system and method described further includes providing a user with options for displaying sensitive or private information across a combination of conventional computer displays, specialized computer displays, and mobile devices that have screens that are easily viewed by the user but not by others.\",\n \"This combination allows a user to efficiently interact with a computer with a standard computer monitor, but only view restricted information using devices that have “private displays,” i.e.\",\n \"displays that are easily viewed by the user but not others nearby.\",\n \"These and other aspects, features, and arrangements of the invention can be appreciated from the accompanying drawing figures and discussion of certain embodiments of the invention.\",\n \"BRIEF DESCRIPTIONS OF THE DRAWINGS FIGS.\",\n \"1A-1C are illustrative diagrams of an information restriction system in accordance with various embodiments.\",\n \"FIG.\",\n \"2 is a diagram of a mobile device and a private and non-private (public) display as can be used in the information restriction system such as shown in FIGS.\",\n \"1A-1C.\",\n \"FIG.\",\n \"3 is an example of private and non-private displays according to one embodiment of the described system.\",\n \"FIG.\",\n \"4 is an example of a display device configured in accordance with an embodiment of the described system.\",\n \"FIG.\",\n \"5 is an alternative example of a display device configured in accordance with an embodiment of the described system.\",\n \"FIGS.\",\n \"6A-6D provides examples of the steps taken by an information restriction system in accordance with embodiments described herein.\",\n \"FIG.\",\n \"7 provides a block diagram of an example system in accordance with an embodiment of the present invention.\",\n \"FIG.\",\n \"8 provides a flow detailing the steps of an embodiment of the method described herein.\",\n \"FIG.\",\n \"9 provides examples of displays with various restriction levels and examples of device privacy levels and information privacy rules according to an embodiment of the present invention.\",\n \"FIG.\",\n \"10 is an illustrated diagram of the elements of the system of an embodiment of the present invention.\",\n \"DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION By way of overview and introduction, the system and methods describe a computer system configured to restrict access and distribute private information to approved access devices depending on a privacy level associated with that device.\",\n \"As used herein, and for the purposes of discussion, information that a user deems to be particularly private, restricted or sensitive, will be termed “restricted” or “private.” For example, private or restricted information is data or information which a user prefers, or is obligated, legally or contractually, to keep confidential or not to disclose to a third party without consent.\",\n \"As will be appreciated from context, the verb “restricting” refers to the actions taken in response to instructions executing in a processor to control information flow such as to a particular display.\",\n \"Furthermore, the “privacy level” of a device is determined according to a combination of factors, including but not limited to, the type of private information the user seeks to display, the location of the user, and the nature of the display device that the user is attempting the access and display the information.\",\n \"For ease of explanation, the following examples refer to medical records.\",\n \"However, those possessing a level of ordinary skill in the art will appreciate that additional private material, such as government documents, financial records, personal communications, and commercial or journalistic materials are envisioned and contemplated by the described system and method.\",\n \"Likewise, as used herein, “data” can be any information conveyable to a user through a device.\",\n \"For example data can include audio data, audiovisual data, images, 3D renderings or simulations, as well as web links or system portals to remotely accessible software or datasets.\",\n \"Purely for illustration purposes, and as a non-limiting example, the data could incorporate multiple types of data, such as both an audio file and a 3D image associated with it.\",\n \"Furthermore, the terms “viewer” and “user” are used interchangeably to describe an individual (or group of individuals) that interfaces with a computing device of the present invention.\",\n \"As another non-limited example, users or viewers can include medical professionals such as radiologists and other doctors, as well as hospital staff, or other individuals involved in acquisition, interpretation, analysis, storage, management, or other tasks related to medical images.\",\n \"In other embodiments, users can include any individuals or groups of individuals that generate, transmit, view, and/or otherwise work with images of any type.\",\n \"Turning to FIG.\",\n \"1A, an example of the computer system configured to implement the selective display of information on remote devices is provided.\",\n \"In the illustrated configuration, the patient data is obtained from a local network 110 of hospital subsystems 120-144, and computer devices 150a-b, each configured to input, output, store or process information concerning a patient.\",\n \"In one arrangement, one or more medical scanners, such as MRI scanners 120, are connected to the network 110.As a non-limiting example, the MRI scanners 120 can be used to acquire MRI images from patients, and can share the acquired images with other devices on the network 110 by either directly storing MRI scanner images in a local storage, or uploading the images of a particular patient to that patient's data storage location in a patient database.\",\n \"One or more CT scanners 122 can also be coupled to the network 110.The CT scanners 122 can also be used to acquire images and, like the MRI scanner 120, can then store those images and/or share those images with other devices via the network 110.Any other scanner or device capable of inputting or generating information that can be presented to the user as images, graphics, text, or sound, including ultrasound, angiography, nuclear medicine, radiography, endoscopy, pathology, dermatology, etc.\",\n \"can be connected to network 110.In another arrangement, a Picture Archiving and Communications System (PACS) 136 and/or PACS workstation 138 can be connected to the network 110.The PACS 136 is typically used for the storage, retrieval, distribution and presentation of images (such as those created and/or generated by the MRI scanner 120 and CT Scanner 122).\",\n \"The medical images can be stored in an independent format, an open source format, or a proprietary format.\",\n \"A common format for image storage in the PACS system is the Digital Imaging and Communications in Medicine (DICOM) format.\",\n \"The stored images may be transmitted digitally to a network accessible storage location via the PACS system, thus often reducing or eliminating the need for manually creating, filing, or transporting film jackets.\",\n \"A Radiology Information System (RIS) 140 can also be connected to the network 110, as shown in the illustrated embodiment of FIG.\",\n \"1A.\",\n \"The radiology information system 140 is typically a computerized data storage system that is used by radiology departments to store, manipulate and distribute patient radiological information such as radiology reports.\",\n \"As shown, an Electronic Medical Record (EMR) system 142 and EMR workstation 137 can be connected to the network 110.The EMR system 142, when provided, is configured to store and make accessible to a plurality of medical practitioners computerized medical records.\",\n \"There can also be attached to the network 110 a Laboratory Information Systems 144.Laboratory Information System 144 is a system which typically is configured to store information created or generated by clinical laboratories Likewise, a Digital Pathology System 146 can be also attached to the network and used to digitally manage and store information related to medical pathology.\",\n \"Further components can be available on the network 110, such as a Computer Aided Diagnosis System (CAD) 148 and 3D Processing System 149, which can be used to analyze images and create new views of the information, e.g., 3D volumetric display, Multiplanar Reconstruction (MPR) and Maximum Intensity Projection reconstruction (MIP) respectively.\",\n \"In other embodiments, other computing devices that store, provide, acquire, and/or otherwise manipulate medical data can also be coupled to the network 110 and can be in communication with one or more of the devices illustrated in FIG.\",\n \"1A.\",\n \"For example, each of the devices described are configured to update a patient record stored in a database, such that all of the data for a given patient is accessible from a parent computing device having sufficient access privileges.\",\n \"As shown in more detail in FIG.\",\n \"1B, general and mobile computing devices, 150a and 150b, are connected to the network 110 and are used to access all or portions of the patient data.\",\n \"In one arrangement, the patient data is obtained from a file system located in the server 170.Alternatively, the computing devices are configured to access discrete pieces of information or data pertaining to a particular patient or group of patients from storage or memory locations connected directly to each of the subsystems.\",\n \"In FIGS.\",\n \"1a and 1b the computing device 150a is labeled as a mobile device and computing device 150b is labeled as a parent computer.\",\n \"However, alternative computing devices are possible and understood.\",\n \"In one particular configuration of the network 110, the computing devices 150a and 150b can be a computer having software or hardware modules 151-157.In other embodiments, the modules can reside on another computing device, such as a web server or other server, and the user directly interacts with a second computing device that is connected to the web server via a computer network.\",\n \"In one embodiment, the modules include some or all of the software utilized by the inventions described herein.\",\n \"In one non-limiting example, the computing device 150a or 150b is selected from one of a variety of computing platforms such as a server, a desktop computer, a workstation, a laptop computer, a mobile computer, a Smartphone, a tablet computer, a wearable computer such as a smart watch, a wearable computer that may be interfaced to a head mounted or heads-up display, a cell phone, a personal digital assistant, a gaming system, a kiosk, an audio player, any other device that utilizes a graphical user interface, including office equipment, automobiles, airplane cockpits, household appliances, automated teller machines, self-service checkouts at stores, information and other kiosks, ticketing kiosks, vending machines, industrial equipment, and/or a television, as a non-exhaustive set of examples.\",\n \"The computing devices 150a and 150b are configurable to interface with various networked devices in order to communicate, receive or update medical information that are stored centrally in a database or distributed among the various systems present in the network.\",\n \"It should be noted and appreciated that the computing devices 150a and 150b are general computing devices and are configurable to display any type of data commonly displayed on general computing systems.\",\n \"Depending on the embodiment, the other devices illustrated in FIG.\",\n \"1a (besides the computing device 150) can include some or all of the same components discussed above with reference to the computing device 150.As shown in FIGS.\",\n \"1A-1C, also connected to the network 110 are one or more databases 160, 162, 164, 166 that support functionality of the various computing devices connected to the network 110 and which provide a repository for instructions and algorithms related to the functioning of various embodiments of the present inventions described herein.\",\n \"The databases are commonly used and understood data structures or tables that are accessible remotely, either through a server or other type of direct or remote computer configured appropriately to enable access and retention of data.\",\n \"In one arrangement, the data stored in the databases are accessible to servers 170, desktop computers 150a, mobile computers 150b, or other computing devices directly connected to the network, or given access to the network 110 through a network link or portal.\",\n \"The databases of the system illustrated includes a User Preferences Database 160 configured as a data storage location which contains tables and indexes that allow the computer to store and obtain data regarding a particular users/site preferences.\",\n \"Site preferences allow a user to set privacy levels manually depending on the display device.\",\n \"For example, a user can store a global access level in the user preference database that sets the privacy level for all medical test results regardless of hardware configuration.\",\n \"Also attached to the network is an Authentication Database 162, configured as a data storage location accessible by a processor suitably configured by code executing therein to provide user authentication services for a user.\",\n \"Such services include signing into, or accessing, the network from a computer such as a mobile device.\",\n \"Furthermore, the Authentication Database 162 contains data used to configure a processor to authenticate a new user, or an already authenticated mobile user with a different display device.\",\n \"The Authentication Database 162 also contains code to configure a processor to access rules governing user privileges in terms of modifying the privacy level of a device depending on the privileges associated with that user.\",\n \"As an example, executives or high-ranking officials have user privileges that allow for the modification of the device privacy level so as to permit the display of private information on devices not independently possessing the required privacy level.\",\n \"As further provided in FIGS.\",\n \"1A-B, the system includes a Device Interaction Database 164.The Device Interaction Database 164 provides storage and indexing of data related to the input and output functionality or capabilities of a display of a given type or particular device identification (e.g., a MAC address in the case of a device with an integrated display).\",\n \"Furthermore, the Device Interaction Database 164, in one arrangement, also stores and provides the system with the capabilities of parent computers in terms of input and output functions.\",\n \"Additionally, the Device Interaction Database 164 stores and provides access to data relating to how different actions and inputs (such as inputs from a mobile device or remote computer) are to be handled by the system, e.g., multitouch, accelerometer, microphone, etc., are communicated to and presented as user input to parent computers.\",\n \"In one arrangement, this data is presented as algorithms for evaluating and determining the access level of a device based on how the device handles inputs and outputs of the device under evaluation.\",\n \"Additional rules or algorithms are stored in the database regarding different outputs from parent computers, such as images, user interfaces, sound, etc., are transmitted to and presented on mobile devices.\",\n \"As shown in further detail in FIG.\",\n \"1C, an Information Restriction Database 166 is also connected to the network 110 and is configured to provide and store data relating to characteristics of the data stored and accessible by the network.\",\n \"For example, the Information Restriction Database 166 provides data detailing the privacy levels or restrictions present for a given portion of patient data.\",\n \"For instance, the Information Restriction Database 166 provides data in the form of rules or algorithms that instructs the remote display device, and/or a computer having access to data requests by a remote display device, to restrict access to all, or a portion of the information depending on at least the hardware configurations and/or the location for a given portion of the data set.\",\n \"In this regard, the rules or algorithms maintained in the database 166 can configure a processor to make a determination on the basis of the hardware configuration of the requesting device, an identification of the requesting device, or both, as to whether to provide the requested dataset or not.\",\n \"For instance, the requested dataset can be restricted, and therefore not provided, in the event that the hardware fails this determination.\",\n \"In one example, the Information Restriction Database 166 is configured to store rules to evaluate medical exams to determine the restriction status Likewise, other rules for data, such as patient's information, site preferences regarding restricted information and user preferences regarding restricted information are stored in the Information Restriction Database 166.Information Restriction Database 166 contains information that configures a processor to assign a privacy level for data stored or accessible on the network.\",\n \"For example, data generated by each of the devices on the network, 120-144, are assigned a privacy level according to specific data handling rules stored in the Information Restriction Database 166.The Information Restriction Database 166 also includes rules accessible by a processor in order to evaluate data sets, objects, files, folders and other collections of data and determine, based on the nature of the data, the proper restriction level for the information.\",\n \"For example, the system described is configured to evaluate the contents of the medical record and determine, based on the content, if the information should be restricted to a private display.\",\n \"These evaluations can be made in response to a data request by a user of the system.\",\n \"Alternatively, the records evaluated by the present system are preconfigured or coded with a general privacy level, or specific privacy level for individual data elements within the record.\",\n \"In one arrangement, the Information Restriction Database 166 cooperates with a privacy classification module to configure a processor to assign a privacy level for data based on the type of information (audio, visual, etc.)\",\n \"as well as the information content.\",\n \"As an example, the privacy level classification module configures the processor to assign a given privacy level to the result of a lung biopsy according to the outcome of the test.\",\n \"In one arrangement, the privacy classification module cooperates with the Information Restriction Database 166 by instructing a processor to classify or assign data at a given privacy level based on pre-set rules.\",\n \"In one instance, all the data is assigned a specific level of privacy at different organizational levels.\",\n \"For example, the data is assigned a privacy level according to a hospital or department preference, an individual doctor preference (user preference), or a user group (group preference).\",\n \"In one further configuration the privacy module cooperates with the Information Restriction Database 166 to assign a set privacy level to all the data associated with an individual.\",\n \"Alternatively, the privacy level assignment module configures the processor to assign privacy levels for data depending on the accessing or requesting device.\",\n \"For example, the processor is configured, through an instruction set, to generate general or specific categories and privacy levels for restricted devices, such as Smartphones 210, Smartwatches 330, tablet computers, and Wearable computers with heads-up displays (HUD), such as the heads-up display 402, and virtual reality headsets.\",\n \"The system described is also configurable to evaluate the privacy level of desktop computers with heads-up displays or other small displays, where the restricted data may only be displayed on the private displays connected to these devices.\",\n \"The system described is also configurable to evaluate the privacy level of desktop computers with standard monitors, where the restricted data may be displayed on systems that are located in a pre-defined or user identified secure location, for example in an office where the display is only viewable by the user.\",\n \"In one arrangement, the system is configurable to only allow the display of certain types of restricted information on certain types of private displays.\",\n \"For example, positive results of an HIV test might only be allowed to be displayed on mobile devices with screens smaller than 5″.\",\n \"In a further embodiment, information restriction rules contained within the Information Restriction Database 166 apply to information that a user can input.\",\n \"For example, prescriptions for medication might be classified as restricted information so that doctors would only be able to enter prescriptions for medications on devices with private displays.\",\n \"Without loss of generality, any of the embodiments described herein can include restrictions that comprise controls which are responsive to the device connected at the end of the network path which has the display of the requesting device.\",\n \"The hardware connected on this path can be analyzed by code executing in a processor in order to determine the device type and/or ID of the device to which the dataset is to be transmitted.\",\n \"Whether transmission of the dataset is to be restricted can be assessed in view of this determination.\",\n \"If the device type or device ID is known to or approved by the system (e.g., based on look-ups to stored reference or authorization data), then that transmission can proceed.\",\n \"On the other hand, if the device type or device ID are not known or approved by the system, the system can be configured to not transmit the requested dataset in view of the hardware connected in that network path.\",\n \"The system described herein can be implemented as a series of modules comprising code and executed in a processor which responds to user events, hardware connections, or both.\",\n \"In part, the system illustrated herein is also configured to access, retrieve, obtain and otherwise receive information that is used in support of various functionalities described herein, and can include input and output devices or be configured to communicate with such devices through network ports and drivers configured or connected for that purpose.\",\n \"Turning to FIG.\",\n \"7, the system or network 110 utilized in the various embodiments of the invention implements a series of steps to control the display of data on remote accessing devices based on the hardware configuration and/or location of the remote accessing device.\",\n \"The methods described herein are implemented utilizing the elements of the network as provided in FIG.\",\n \"1.However, it should be appreciated that other additional or alternative arrangements are possible.\",\n \"For example, the described steps are implemented by one or more computing devices, such as the computing device 150a, but the methods are not limited to performance by the computing device 150a and should be interpreted to include performance by any one or more of the computing devices, such as additional computers or server.\",\n \"The information restriction and distribution system of the present invention selectively displays information requested by a computer user based on the access level of the data and the hardware and/or location data of the computer on which the data will be reviewed.\",\n \"The system enables a user to review some portions of private or restricted data on standard display devices, e.g.\",\n \"computers, smartphones, computer tablets, interactive displays, while still ensuring that other portions that are more sensitive, are only accessible to a user on a “private display,” i.e., those displays that are not easily viewed by others nearby.\",\n \"With reference to FIGS.\",\n \"7 and 8, the information restriction and distribution system is implemented and initiated by at least one request module 710 which comprises code executing in a processor 700 to request a specific data set, such as a medical record, from a medical record database 705 according to step 810.In the illustrated arrangement, access to the Device Interaction database 164, the Information restriction database 166 and the Medical Record Database 705 are controlled by a network controller 701, which comprises a processor configured with code executing therein.\",\n \"Contemporaneous with, or subsequent to, the requesting step 810, the hardware configuration and/or location of the requesting device (i.e., the display device) is transmitted to the controlling processor as in step 820, using a hardware configuration transmitting module 720 configured as code executing in the processor 700.In one arrangement the hardware and location data are obtained by a processor configured with sub-modules to query the device operating system or hardware modules to obtain the necessary information.\",\n \"For instance, geolocation data, such as coordinates obtained from a GPS or equivalent receiver or transponder are used to evaluate the location of the output device.\",\n \"Other examples of technologies that could be used to evaluate the location of the output device include near-field communication technologies, Bluetooth and/or other low energy proximity sensing technologies.\",\n \"Likewise, data relating to the hardware configuration of the output device, such as audio capabilities, video display capabilities and input capabilities can be obtained from an application or operating system residing on the output device.\",\n \"In the alternative, the location or hardware configuration is supplied manually and transmitted according to step 820.Once the display device has been evaluated for its location and capabilities, a privacy level is assigned to that output device and may be optionally stored in the device interaction database for future reference or transmitted in real-time to a server or database.\",\n \"For example, a privacy level assignment step 830 includes receiving, by the controlling processor 701, the location and configuration data transmitted by the display device processor 700 and comparing that information to preset privacy levels and rules in the Device Interaction Database and Information Restriction Database.\",\n \"In one arrangement this step is carried out using a privacy level assignment module 715, which operates as code executing in the controller processor 701.In one arrangement, if the privacy level of a given output device is above a minimum threshold, or pre-set limit, then the assignment module 715 configures the controller processor 701 to assign the output device a “private” level.\",\n \"This privacy level can, in one configuration, take the form of an entry in a table in the Information Restriction Database or the Device Interaction Database.\",\n \"In an alternative embodiment, the assignment module 715 instructs the controller processor 701 to assign different portions of output components of the output device differing privacy levels depending on the hardware configuration (e.g., device type, MAC address, or other hardware-identifying information or hardware setting information), or location of the output device.\",\n \"For example, the controller processor 701 is instructed by the privacy level module 715 to classify on output device as a “private” device for visual data only, but as a public device for audio data, or an audio component of multi-media data.\",\n \"In a further arrangement the privacy level assignment module 715 further instructs the controller processor 701 to query each output device connected to the network on a periodic basis and updates the privacy level depending on the function, location, size, and accessibility of the output device.\",\n \"In an alternative, the privacy level assignment module 715 includes a sub-module that configures the controller processor 701 to set privacy levels specific devices.\",\n \"For example, an administrator device is set to the maximum level of privacy regardless of the hardware or location data.\",\n \"In still a further arrangement, privacy level assignment module 715 includes a sub-module that configures the controller processor 701 to evaluate, in real-time, the privacy level of an output device depending the proximity of other individuals, general access level of data, or other factors, as can be obtained through a variety of system inputs.\",\n \"For example, where a output device is classified as a video “private”, audio “public” device, such as a nursing station computer, the privacy level assignment module 715 configures the controller processor 701 to reclassify the output device with an audio “private” level in the event that a private audio display device (e.g.\",\n \"a headset, wireless or wired to the network) is connected to the output device.\",\n \"It should be noted that in some cases, conventional computer monitors may be considered private displays, for example in cases where they are physically located in places were only the user of the computer can view the computer screen, such as an office.\",\n \"Alternatively, devices that can be classified as having private displays include smartphones, PDAs, tablets computers, interactive displays, and wearable computers, including devices with heads-up displays (HUD), such as Google Glass, virtual reality displays, such as Oculus Rift, and smartwatches, such as Apple Watch.\",\n \"In another example, a private display might be a computer display that is only clearly visible only to users wearing specialized glasses.\",\n \"In another example, a private display might be a computer display that is only clearly visible to a user who is positioned at a specific spatial position relative to the display.\",\n \"In the process steps of FIG.\",\n \"8, once the privacy level of the output device has been determined, it is compared to the privacy level of the data requested from the medical record database as in step 840.In one arrangement, a comparison module 725, configured as code executing in the controller processor 701, instructs the processor to evaluate the privacy level of the data requested and determine if the requesting output device has a sufficient privacy level to allow the display of the requested data.\",\n \"In the event that the requesting device has a sufficient privacy level compared to the requested information, the some or all of the requested data is transmitted from the medical database to the output device, as in step 850.In a particular embodiment, a data transmission module 735, configured as code executing in the controller processor 701 instructs the processor to transmit those portions of the requested data to the display device.\",\n \"Furthermore, the system described is configured to segment, or access segmented private information such that portions of the private information are distributed across multiple devices depending on the privacy level of the device and the privacy level of the information.\",\n \"Once the data has been received by the display device, it is displayed or output by the display device, according to step 860.In a particular embodiment, a display module 730 configured as code executing in the display device processor 700 instructions the processor to display the permitted data received from the medical record database.\",\n \"In the event that a hardware configuration or location changes in the output device, such as the connection of an external headset, a real-time device evaluation module 740 configures the display device processor to communicate the updated status of the display device to the controller processor 701.This, in turn, causes the controller processor 701 to update the privacy level of the output device and cause additional, newly available data to be sent to the output device for display.\",\n \"Returning to FIG.\",\n \"2, once a display device has been assigned a privacy level, data accessed by that output device will be conditioned based on the privacy level of the device as a whole, or the individual components of the output device.\",\n \"Requesting data from a device having an insufficient privacy level will result in a placeholder data being sent to the output device indicating that the data is not accessible from the given device.\",\n \"As illustrated, the display configuration 200 includes computer display 220, and a mobile device 210.In the illustrated configuration, both the computer and the mobile device are classified as private devices.\",\n \"As such, when data is requested, it can be displayed on either of the requesting devices.\",\n \"Alternatively, the display configuration 201 includes a computer display 222 and the same mobile device 201.In this configuration, the computer display 222 is not classified as a private device, while the mobile device 201 is classified as a private device for displaying the data requested.\",\n \"In one configuration, a placeholder note or statement indicating the user is not able to access the requested data using that particular device is supplied to the screen.\",\n \"In a further arrangement, the placeholder data indicates the necessary level of privacy needed for the data to be viewed on that device.\",\n \"In a further example, the mobile device 210 and the restricted computer 222 are used together to allow the user to view medical information on a same patient.\",\n \"However, in this configuration restricted information is only displayed on output device 210.Similarly, restricted information in the form of audio would only be playable on device 210, which is classified as a “private display” as it related to audio information.\",\n \"In one particular configuration as illustrated in FIG.\",\n \"3, a large, publically viewable display 310, as well as a mobile device 320, and wearable device 330 are incorporated into the system described.\",\n \"The computer display 310, because of its large size and location, is classifiable as a “non-private” display, and is prohibited from displaying private level information.\",\n \"Alternatively, the mobile device 320 is classified according to the system as a “private display.” In a circumstance where the data requested by the mobile device includes an audio and visual component, the data returned by the system will include only visual data, but not audio data.\",\n \"This is due to the privacy level assessment module 715 as described in FIG.\",\n \"7, instructing the processor to determine that the audio configuration of the mobile device did not permit the output of audio information.\",\n \"Thus, the privacy level assignment module 715 configures the controller processor 701 to classify the output device 320 as a private device for visual data, but as a public device for audio data.\",\n \"In the example shown, device 320 and the computer associated with display 310 are both accessing information on the same patient.\",\n \"Here, the user is authorized to view information on a particular patient.\",\n \"Since device 320 has a private display, the user can access restricted visual information.\",\n \"In the event that the user connected a private audio peripheral device to device 320, then restricted audio information is also accessible by the user.\",\n \"Furthermore, additional or alternative information is available to the smartwatch 330 based on the audio and display configurations available to the user.\",\n \"As shown in FIG.\",\n \"4, the display configuration 400 provides an example of a heads-up display (HUD) 402 connected to a conventional computer, such as a desktop or laptop computer, or that can be part of a wearable computer.\",\n \"View 401 is an example of the visual field observable while wearing a HUD such as example HUD 402.In the example shown the user is viewing information related to a patient that is being displayed on a computer monitor and being displayed on the HUD.\",\n \"In the example, region 414 is information in the user's visual field being presented by the HUD.\",\n \"In the example shown, the HUD is classified as a private display and therefore the user is able to view restricted information via the HUD (example region 414) that is not displayed on the computer display 412, which is a non-private display.\",\n \"Other head mounted display systems could also be classified as private displays, including those in which the display of the system is the only thing the user can see while wearing them, such as a virtual reality display system.\",\n \"Turning to a non-medical example of information restriction, FIG.\",\n \"5 illustrates the use of the system in a retail environment.\",\n \"Computer display 510 is evaluated by the restrictive data display system and determined to be a public display, thus only displaying information related to a specific good or service (e.g., cars) for sale.\",\n \"In this configuration, the controller processor of FIG.\",\n \"7 restricts portions of the data requested from the database depending on the privacy level of the display.\",\n \"As shown, the public display only provides general information concerning the item for sale.\",\n \"However, through the implementation of the steps and modules provided herein, a user of a private display configuration device is able to access pricing information or other data.\",\n \"FIGS.\",\n \"6A-6D illustrate flow charts detailing specific implementations and embodiments of the system and method for restricting information based on output device characteristics.\",\n \"FIG.\",\n \"6A is a flow chart illustrating steps related to systems and methods that manage the display and/or input of restricted information on devices with private vs. non-private displays.\",\n \"In a step 611 the user attempts to access data located or routed by the server 170.As a response, the characteristics of the requesting device are transmitted to the server 170.As shown in step 612, information rules are retrieved from Information Restriction Database 166 and the device characteristics are evaluated against the restriction rules in the database 166.For example, the device characteristics and information restriction rules are also utilized in the authentication process such that the user only is authenticated when he is using a device with a private display.\",\n \"For example, an EMR can be configured with Information Restriction Rules that prevent any access with devices that do not have private displays.\",\n \"The server 170, in one configuration, authenticates the user by requesting credentials (e.g., username, password, fingerprint, etc.,) as shown in step 614.In another embodiment, steps 612 and 614 are reversed, so that user authentication occurs before information restriction rules are retrieved.\",\n \"As provided in Step 616, the user utilizes computing device 180 to access information communicated by server 170, server 170 utilizes Information Restriction Rules stored in Information Restriction Database 166 to determine which information is restricted and will only communicate restricted information to devices characterized as having private displays.\",\n \"In an additional step 618, the system is configured to allow the input or transmission of private information, if that information is being entered on a device having a private display.\",\n \"The input or “display” of information could apply to visually displayed information, e.g., images, text, graphs, etc., as well as audio information.\",\n \"FIG.\",\n \"6B provides an example of a flow diagram of the implementation of the authentication step 614, for example, by a series of modules configured as code executing in a processor.\",\n \"As shown in step 612, the requesting device hardware configuration is provided to the server 170, using a transmitting module 720 as provided in FIG.\",\n \"7.In turn the server 170 implements an evaluation step 622 to determine if the hardware configuration meets the requirements for a private display.\",\n \"In one arrangement this is implemented using the module 715.In this particular configuration, if the display device does not have a private display, then the data is not accessed and provided to the mobile device.\",\n \"Alternatively, if the requesting device is equipped with a private display, then the server 170 requests authentication data as in step 624.In the event that the log-in credentials are verified, according to a verification step 625, the user is authenticated, as in step 627.In one configuration, the authentication is accomplished as a series of modules configured as code executing in the processor of the server and configured to instruct the processor to access the user database, compare the user credentials to a stored table of users and to confirm authentication of a user.\",\n \"Once the user is authenticated and the device characteristics have been evaluated by the system according to steps 631-633 of FIG.\",\n \"6c, the data requested is either transmitted to the display device or a placeholder statement is transmitted to the display device, according to the privacy level of the device, the user credentials and the privacy level of the information requested, as in step 635.FIG.\",\n \"6D provides an alternative flow diagram of the operation of the system of restricting access to data based on the privacy level of the device.\",\n \"As shown, the user is authenticated by the server as in step 641 and transmits the device configuration to the server.\",\n \"The server also retrieves the user preferences, the device configuration and the interface preferences as well as retrieving Information Restriction rules from the information restriction rules database 166 as in step 642.Once the rules are retrieved, the authenticated user is permitted by a processor suitably configured by code, to access a list of datasets, such as a patient list, that the authenticated user is permitted to access, as in step 644.Once the user causes the selection of a particular data set, the processor is configured by code to transmit only data that meets the privacy level on the device as in step 648.In step 649, the processor of the user device is configured by code to display the selected information received.\",\n \"FIG.\",\n \"9 provides examples of various display devices (910, 912, 914, 916) having differing restriction levels.\",\n \"FIG.\",\n \"9 also provides examples of the relative privacy levels and information privacy rules attached to each device according to a database or look-up table.\",\n \"Table 920 is an example of the Device Privacy Levels assigned to various devices based on the hardware configuration and/or location.\",\n \"The higher privacy levels are assigned to devices that are more secure in terms of their ability to prevent people other than the user from viewing and/or hearing information presented by the device.\",\n \"While the example shows six privacy levels, labeled 0 to 5, in practice any number of privacy levels greater than one can be utilized.\",\n \"In a particular arrangement, the device privacy levels may also vary depending on the device user.\",\n \"In one arrangement, the access level for a particular device can change in response to specific or authenticated user that is currently using the device.\",\n \"For example, a device that is authenticated using a login/password, fingerprint scanner, or other biometric based access device has a privacy level that reflects the privacy level assigned to that user regardless of the hardware configuration.\",\n \"The Device Privacy Levels may be set as a user, group and/or site preference, and may be stored, for example, in the Device Interaction Database 164 or Information Restriction Database 166.In the example of the Device Privacy Levels shown, the Privacy Level assigned to computer monitor 910 is dependent on its location, i.e., the privacy level is set to 4 if located in a private doctor's office, 2 if located in a nursing station, 0 if located in another location or if its location is unknown.\",\n \"In one arrangement, devices with unknown locations are assigned a privacy level based on the hardware configuration of the device.\",\n \"In the alternative, the system described assigns devices having an unknown location to a pre-set privacy level.\",\n \"In one particular arrangement, smartphone 912 is assigned a Privacy Level 4 when it is located in the hospital.\",\n \"The location of the smartphone 912 is determined in one instance by GPS transponders or another technology capable of locating its position.\",\n \"In this particular configuration, when the smartphone is no longer located within the hospital, the device is assigned a Privacy Level of 3.Alternatively, the smartwatch 914 is assigned a privacy level of 4, regardless of its location.\",\n \"Likewise, heads-up display 916 would be assigned a Privacy Level of 5, regardless of its location.\",\n \"Table 930 illustrates example Information Privacy Rules that determine whether information can be presented on a device based on the Device Privacy Level of a given device.\",\n \"Information Restriction Rules may be set as a user, group and/or site preference, and may be stored, for example, in Information Restriction Database 166.In one embodiment, information will be displayed on a device when the Privacy Level of the Device is greater than or equal to the Privacy Level of the Information.\",\n \"For example, the results of a Fetal Ultrasound are assigned an Information Privacy Level of 3 in the example shown.\",\n \"Therefore, the results of the Fetal Ultrasound would be displayed on any device with a Device Privacy Level of 3 or greater.\",\n \"Information Privacy Rules, in one arrangement, assigns an Information Privacy Level to virtually any type of information.\",\n \"For example, various types of information about a patient may be assigned different privacy levels.\",\n \"As illustrated, a patient's gender, which is generally apparent based on the patient's name and appearance, may be assigned a low Privacy Level, such as 0.Alternatively, the patient's date of birth may be assigned a higher Privacy Level, such as 1, as illustrated in Table 930.It should be appreciated that whether or not a particular test or exam has been ordered or performed on a patient may reveal private information about the patient, and therefore that information may also be assigned a Privacy Level.\",\n \"For example, the fact that a Fetal Ultrasound has been ordered or performed on a patient indicates that the patient was pregnant at that time of the test.\",\n \"Thus, the ordering of certain tests (e.g., Fetal Ultrasound) is assigned a Privacy Level of 2.Therefore, an Electronic Medical Records (EMR) or other medical record systems that contain a record of tests requested or performed are also subject to Device Privacy Levels.\",\n \"In the example shown, the results of the Fetal Ultrasound, which can include information such as images, audio information, measurements, a report, etc., are assigned an Information Privacy Level of 3.Information Privacy Rules may be stored, for example, in Information Restriction Database 166.Information Privacy Rules may vary based on user, group, and site preferences.\",\n \"In addition, Information Privacy Rules may vary based on characteristics of the patient and/or may be determined automatically based on characteristics of the patient.\",\n \"For example, Information Privacy Rules might differ for pregnant vs. non-pregnant women, minors vs. adults, and patient's with a particular diagnosis vs. those without that diagnosis.\",\n \"In addition, Information Restriction Rules could be set explicitly for a particular patient.\",\n \"In one configuration, the Information Restriction Rules are configured based on instructions or rules set by the patient or the patient's physician or care giver.\",\n \"In the alternative, a patient who is a notorious or public figure could implement Information Privacy Rules with elevated Information Privacy Levels based on instructions by the patient or an administrator of the hospital caring for the patient.\",\n \"Depending on the embodiment, the methods described with reference to the flowcharts, as well as any other methods discussed herein, can include fewer or additional blocks and/or the blocks can be performed in a different order than is illustrated.\",\n \"As illustrated in FIG.\",\n \"10, the server and other computers of the described system can be implemented according to the computing system 1300 illustrated in FIG.\",\n \"10.As shown, the computer system 1300 includes a processor 1302, a memory 1304, a storage device 1306, a high-speed interface 1308 connecting to the memory 1304 and multiple high-speed expansion ports 1310, and a low-speed interface 1312 connecting to a low-speed expansion port 1314 and the storage device 1306.Each of the processor 1302, the memory 1304, the storage device 1306, the high-speed interface 1308, the high-speed expansion ports 1310, and the low-speed interface 1312, are interconnected using various buses, and can be mounted on a common motherboard as shown in FIG.\",\n \"9, or in other manners as appropriate.\",\n \"The processor 1302 can process instructions for execution within the computing device 1300, including instructions stored in the memory 1304 or on the storage device 1306 to display graphical information for a GUI on an external input/output device, such as a display 1316 coupled to the high-speed interface 1308.In other embodiments, multiple processors and/or multiple buses can be used, as appropriate, along with multiple memories and types of memory.\",\n \"Also, multiple computing devices can be connected, with each device providing portions of the necessary operations (e.g., as a server bank, a group of blade servers, or a multi-processor system).\",\n \"A mobile computing device 1350 may include a processor 1352, a memory 1364, and an input/output device such as a display 1354, a communication interface 1366, and a transceiver 1368, among other components.\",\n \"The mobile computing device 1350 can also be provided with a storage device, such as a micro-drive or other device, to provide additional storage.\",\n \"Each of the processor 1352, the memory 1364, the display 1354, the communication interface 1366, and the transceiver 1368, are interconnected using various buses, and several of the components can be mounted on a common motherboard or in other manners as appropriate.\",\n \"The processor 1352 can communicate with a user through a control interface 1358 and a display interface 1356 coupled to the display 1354.The display 1354 can be, for example, a TFT (Thin-Film-Transistor Liquid Crystal Display) display or an OLED (Organic Light Emitting Diode) display, or other appropriate display technology.\",\n \"The display interface 1356 can comprise appropriate circuitry for driving the display 1354 to present graphical and other information to a user.\",\n \"The control interface 1358 can receive commands from a user and convert them for submission to the processor 1352.In addition, an external interface 1362 can provide communication with the processor 1352, so as to enable near area communication of the mobile computing device 1350 with other devices.\",\n \"The external interface 1362 can provide, for example, for wired communication in some embodiments, or for wireless communication in other embodiments, and multiple interfaces can also be used.\",\n \"The memory 1364 stores information within the mobile computing device 1350.The memory 1364 can be implemented as one or more of a computer-readable medium or media, a volatile memory unit or units, or a non-volatile memory unit or units.\",\n \"An expansion memory 1374 can also be provided and connected to the mobile computing device 1350 through an expansion interface 1372, which can include, for example, a SIMM (Single In Line Memory Module) card interface.\",\n \"The expansion memory 1374 can provide extra storage space for the mobile computing device 1350, or can also store applications or other information for the mobile computing device 1350.Specifically, the expansion memory 1374 can include instructions to carry out or supplement the processes described above, and can include secure information also.\",\n \"Thus, for example, the expansion memory 1374 can be provided as a security module for the mobile computing device 1350, and can be programmed with instructions that permit secure use of the mobile computing device 1350.In addition, secure applications can be provided via the SIMM cards, along with additional information, such as placing identifying information on the SIMM card in a non-hackable manner.\",\n \"The mobile computing device 1350 can communicate wirelessly through the communication interface 1366, which can include digital signal processing circuitry where necessary.\",\n \"The communication interface 1366 can provide for communications under various modes or protocols, such as GSM voice calls (Global System for Mobile communications), SMS (Short Message Service), EMS (Enhanced Messaging Service), or MMS messaging (Multimedia Messaging Service), CDMA (code division multiple access), TDMA (time division multiple access), PDC (Personal Digital Cellular), WCDMA (Wideband Code Division Multiple Access), CDMA2000, or GPRS (General Packet Radio Service), among others.\",\n \"Such communication can occur, for example, through the transceiver 1368 using a radio-frequency.\",\n \"In addition, short-range communication can occur, such as using a Bluetooth, WiFi, or other such transceiver (not shown).\",\n \"In addition, a GPS (Global Positioning System) receiver module 1370 can provide additional navigation- and location-related wireless data to the mobile computing device 1350, which can be used as appropriate by applications running on the mobile computing device 1350.The mobile computing device 1350 can also communicate audibly using an audio codec 1360, which can receive spoken information from a user and convert it to usable digital information.\",\n \"The audio codec 1360 can likewise generate audible sound for a user, such as through a speaker, e.g., in a handset of the mobile computing device 1350.Such sound can include sound from voice telephone calls, recorded sound (e.g., voice messages, music files, etc.)\",\n \"and sound generated by applications operating on the mobile computing device 1350.The mobile computing device 1350 can be implemented in a number of different forms, as shown in FIG.\",\n \"10.For example, it can be implemented as a cellular telephone 1380.It can also be implemented as part of a smart-phone 1382, personal digital assistant, or other similar mobile device.\",\n \"Various embodiments of the systems and techniques described here can be realized in digital electronic circuitry, integrated circuitry, specially designed ASICs (application specific integrated circuits), computer hardware, firmware, software, and/or combinations thereof.\",\n \"These various embodiments can include embodiment in one or more computer programs that are executable and/or interpretable on a programmable system including at least one programmable processor, which can be special or general purpose, coupled to receive data and instructions from, and to transmit data and instructions to, a storage system, at least one input device, and at least one output device.\",\n \"These computer programs (also known as programs, software, software applications or code) include machine instructions for a programmable processor, and can be implemented in a high-level procedural and/or object-oriented programming language, and/or in assembly/machine language.\",\n \"As used herein, the terms machine-readable storage medium and computer-readable storage medium refer to any non-transitory computer program product, apparatus and/or device (e.g., magnetic discs, optical disks, memory, Programmable Logic Devices (PLDs)) used to provide machine instructions and/or data to a programmable processor, including a machine-readable storage medium that receives machine instructions as a machine-readable signal.\",\n \"The term machine-readable signal refers to any signal used to provide machine instructions and/or data to a programmable processor.\",\n \"A non-transitory machine-readable storage medium does not include a transitory machine-readable signal.\",\n \"To provide for interaction with a user, the systems and techniques described here can be implemented on a computer having a display device (e.g., a CRT (cathode ray tube) or LCD (liquid crystal display) monitor) for displaying information to the user and one or more input devices, such as a keyboard, pointing device (e.g., a mouse or a trackball), touch screen, or microphone, by which the user can provide input to the computer.\",\n \"Other kinds of devices can be used to provide for interaction with a user as well; for example, feedback provided to the user can be any form of sensory feedback (e.g., visual feedback, auditory feedback, or tactile feedback); and input from the user can be received in any form, including acoustic, speech, or tactile input.\",\n \"The systems and techniques described here can be implemented in a computing system that includes a back end component (e.g., as a data server 1324), or that includes a middleware component (e.g., an application server 1320), or that includes a front end component (e.g., a client computer 1322 having a graphical user interface or a Web browser through which a user can interact with an embodiment of the systems and techniques described here), or any combination of such back end, middleware, or front end components.\",\n \"The components of the system can be interconnected by any form or medium of digital data communication (e.g., a communication network).\",\n \"Examples of communication networks include a local area network (LAN), a wide area network (WAN), and the Internet.\",\n \"The computing system can include clients and servers.\",\n \"A client and server are generally remote from each other and typically interact through a communication network.\",\n \"The relationship of client and server arises by virtue of computer programs running on the respective computers and having a client-server relationship to each other.\",\n \"While this specification contains many specific embodiment details, these should not be construed as limitations on the scope of any embodiment or of what can be claimed, but rather as descriptions of features that can be specific to particular embodiments of particular embodiments.\",\n \"Certain features that are described in this specification in the context of separate embodiments can also be implemented in combination in a single embodiment.\",\n \"Conversely, various features that are described in the context of a single embodiment can also be implemented in multiple embodiments separately or in any suitable subcombination.\",\n \"Moreover, although features can be described above as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination can be directed to a subcombination or variation of a subcombination.\",\n \"Similarly, while operations are depicted in the drawings in a particular order, this should not be understood as requiring that such operations be performed in the particular order shown or in sequential order, or that all illustrated operations be performed, to achieve desirable results.\",\n \"In certain circumstances, multitasking and parallel processing can be advantageous.\",\n \"Moreover, the separation of various system components in the embodiments described above should not be understood as requiring such separation in all embodiments, and it should be understood that the described program components and systems can generally be integrated together in a single software product or packaged into multiple software products.\",\n \"The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.\",\n \"As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.\",\n \"It will be further understood that the terms “comprises” and/or “comprising”, when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.\",\n \"It should be noted that use of ordinal terms such as “first,” “second,” “third,” etc., in the claims to modify a claim element does not by itself connote any priority, precedence, or order of one claim element over another or the temporal order in which acts of a method are performed, but are used merely as labels to distinguish one claim element having a certain name from another element having a same name (but for use of the ordinal term) to distinguish the claim elements.\",\n \"Also, the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.\",\n \"The use of “including,” “comprising,” or “having,” “containing,” “involving,” and variations thereof herein, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.\",\n \"Particular embodiments of the subject matter described in this specification have been described.\",\n \"Other embodiments are within the scope of the following claims.\",\n \"For example, the actions recited in the claims can be performed in a different order and still achieve desirable results.\",\n \"As one example, the processes depicted in the accompanying figures do not necessarily require the particular order shown, or sequential order, to achieve desirable results.\",\n \"In certain embodiments, multitasking and parallel processing can be advantageous.\",\n \"Unless the context clearly requires otherwise, throughout the description, the words “comprise,” “comprising,” and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in a sense of “including, but not limited to.” Words using the singular or plural number also include the plural or singular number respectively.\",\n \"Additionally, the words “herein,” “hereunder,” “above,” “below,” and words of similar import refer to this application as a whole and not to any particular portions of this application.\",\n \"When the word “or” is used in reference to a list of two or more items, that word covers all of the following interpretations of the word: any of the items in the list, all of the items in the list and any combination of the items in the list.\",\n \"The above description of embodiments of the Restricted Display systems and methods is not intended to be exhaustive or to limit the systems and methods described to the precise form disclosed.\",\n \"While specific embodiments of, and examples for, the Restricted Display device systems and methods are described herein for illustrative purposes, various equivalent modifications are possible within the scope of other Restricted Display systems and methods, as those skilled in the relevant art will recognize.\",\n \"The teachings of the Restricted Display systems and methods provided herein can be applied to other processing and measurement systems and methods, not only for the systems and methods described above.\",\n \"While medical and commercial applications were used as examples, the systems and methods described herein can be applied to any field where it may be desirable to restrict display of private or sensitive information, such as military, financial, legal, insurance, and law enforcement applications.\",\n \"The elements and acts of the various embodiments described above can be combined to provide further embodiments.\",\n \"These and other changes can be made to the Restricted Display systems and methods in light of the above detailed description.\",\n \"In general, in the following claims, the terms used should not be construed to limit the Restricted Display systems and methods to the specific embodiments disclosed in the specification and the claims, but should be construed to include all systems and methods that operate under the claims.\",\n \"Accordingly, the Restricted Display systems and methods are not limited by the disclosure, but instead the scope of the Restricted Display systems and methods is to be determined entirely by the claims.\",\n \"It should be understood that various combinations, alternatives and modifications of the present invention could be devised by those skilled in the art in view of this disclosure.\",\n \"The present invention is intended to embrace all such alternatives, modifications and variances that fall within the scope of the appended claims.\",\n \"While the invention has been particularly shown and described with reference to a preferred embodiment thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875805"}}},{"rowIdx":4494982,"cells":{"text":{"kind":"list like","value":[["IDENTIFYING RELATIONSHIPS OF INTEREST OF ENTITIES","A method, system and computer program product for identifying relationships of interest of entities in a data modeling environment, where the data modeling environment represents objects as entities with links representing relationships between the entities.","A query is received, where the query includes entity(ies) and link(s) with at least one of the entities or links designated as an output item.","The query is analyzed to identify each dumbbell in the query, where a dumbbell is a link with a first entity at a first end of the link and a second entity at a second end of the link.","Each identified dumbbell is examined to determine if the dumbbell includes an output item; and, if the dumbbell includes an output item, adding the dumbbell to a catalogue of relationships if a dumbbell is not already listed having the link type and entity types of the identified dumbbell."],["1.A computer-implemented method for identifying relationships of interest of entities in a data modeling environment, wherein the data modeling environment represents objects as entities with links representing relationships between the entities, comprising: receiving a query, the query comprising one or more entities and one or more links with at least one of the entities or links designated as an output item; analyzing, by a processor, the query to identify each dumbbell in the query, wherein a dumbbell is a link with a first entity at a first end of the link and a second entity at a second end of the link; examining, by the processor, each identified dumbbell to determine if the dumbbell includes an output item; and adding the dumbbell to a catalogue of relationships including a link type and entity types of the dumbbell in response to the dumbbell including an output item.","2.The method as recited in claim 1 further comprising: determining if a dumbbell having link types and entity types is already stored in the catalogue of relationships and adding the dumbbell in response to a stored dumbbell not existing.","3.The method as recited in claim 1, wherein property values are discarded from the link and the entities of a dumbbell being added to the catalogue of relationships.","4.The method as recited in claim 1 further comprising: repeating said receiving, analyzing, examining and adding for multiple queries to generate a list of relationships for each item type.","5.The method as recited in claim 4 further comprising: using the list of relationships when a user runs a keyword search and is presented with a mixed item type list of matching results, wherein the list of relationships is used to filter item types.","6.The method as recited in claim 4 further comprising: using the list of relationships for an item type to provide an advanced facet for searching.","7.The method as recited in claim 4 further comprising: providing a filtered expansion for an item type based on the list of relationships for the item type.","8.The method as recited in claim 4 further comprising: enabling automatic generation of suggested relationships of interest for an item type based on the list of relationships for the item type."],["<SOH> BACKGROUND <EOH>In a rich data environment in which entities, links, and properties (ELP) data needs to be searched, facets can assist with the filtering of matching results.","In most faceting user interfaces, facets are generated from properties and metadata of the items listed and the list of available facets can be navigated via scrolling.","In an ELP data environment, facets can also be generated from linked entities and their properties.","For example, a search for “John Smith” could return a list of matching person entities.","Facets generated by legal end types specified by a schema could include “Linked to crime” or more specifically “Linked to crime: assault”.","Given this capability, in a law enforcement deployment of a schema, the number of potential combinations of advanced facets could easily reach the 1000s and become unusable if presented to the user in their entirety.","Consequently, configuration is required to ensure the user is only presented with advanced facets that are useful.","In order to make the most of this capability, there is either a configuration overhead for the administrator or an interaction overhead for the user."],["<SOH> SUMMARY <EOH>In one embodiment of the present invention, a computer-implemented method for identifying relationships of interest of entities in a data modeling environment comprises receiving a query, where the data modeling environment represents objects as entities with links representing relationships between the entities and where the query comprises one or more entities and one or more links with at least one of the entities or links designated as an output item.","The method further comprises analyzing, by a processor, the query to identify each dumbbell in the query, wherein a dumbbell is a link with a first entity at a first end of the link and a second entity at a second end of the link.","The method additionally comprises examining, by the processor, each identified dumbbell to determine if the dumbbell includes an output item.","Furthermore, the method comprises adding the dumbbell to a catalogue of relationships including a link type and entity types of the dumbbell in response to the dumbbell including an output item.","Other forms of the embodiment of the method described above are in a system and in a computer program product.","The foregoing has outlined rather generally the features and technical advantages of one or more embodiments of the present invention in order that the detailed description of the present invention that follows may be better understood.","Additional features and advantages of the present invention will be described hereinafter which may form the subject of the claims of the present invention."],["TECHNICAL FIELD The present invention relates generally to identifying relationships of interest of entities, and more particularly to identifying relationships of interest of entities in a data analysis environment.","BACKGROUND In a rich data environment in which entities, links, and properties (ELP) data needs to be searched, facets can assist with the filtering of matching results.","In most faceting user interfaces, facets are generated from properties and metadata of the items listed and the list of available facets can be navigated via scrolling.","In an ELP data environment, facets can also be generated from linked entities and their properties.","For example, a search for “John Smith” could return a list of matching person entities.","Facets generated by legal end types specified by a schema could include “Linked to crime” or more specifically “Linked to crime: assault”.","Given this capability, in a law enforcement deployment of a schema, the number of potential combinations of advanced facets could easily reach the 1000s and become unusable if presented to the user in their entirety.","Consequently, configuration is required to ensure the user is only presented with advanced facets that are useful.","In order to make the most of this capability, there is either a configuration overhead for the administrator or an interaction overhead for the user.","SUMMARY In one embodiment of the present invention, a computer-implemented method for identifying relationships of interest of entities in a data modeling environment comprises receiving a query, where the data modeling environment represents objects as entities with links representing relationships between the entities and where the query comprises one or more entities and one or more links with at least one of the entities or links designated as an output item.","The method further comprises analyzing, by a processor, the query to identify each dumbbell in the query, wherein a dumbbell is a link with a first entity at a first end of the link and a second entity at a second end of the link.","The method additionally comprises examining, by the processor, each identified dumbbell to determine if the dumbbell includes an output item.","Furthermore, the method comprises adding the dumbbell to a catalogue of relationships including a link type and entity types of the dumbbell in response to the dumbbell including an output item.","Other forms of the embodiment of the method described above are in a system and in a computer program product.","The foregoing has outlined rather generally the features and technical advantages of one or more embodiments of the present invention in order that the detailed description of the present invention that follows may be better understood.","Additional features and advantages of the present invention will be described hereinafter which may form the subject of the claims of the present invention.","BRIEF DESCRIPTION OF THE DRAWINGS A better understanding of the present invention can be obtained when the following detailed description is considered in conjunction with the following drawings, in which: FIG.","1 is a block diagram illustrating an example embodiment of a system in which the present invention may be implemented; FIGS.","2A and 2B are schematic diagrams illustrating linked entities in accordance with aspects of the present invention; FIG.","3 is a flow diagram of a first example embodiment of a method in accordance with the present invention; FIGS.","4A and 4B are schematic diagrams of an example query with FIG.","4B showing extracted relationships of interest in accordance with an aspect of the present invention; FIGS.","5A and 5B are schematic diagrams illustrating an example user interface with advanced facets in accordance with an aspect of the present invention; FIG.","6 is block diagram of an example embodiment of a system in accordance with the present invention; FIG.","7 is a block diagram of an embodiment of a computer system or cloud server in which the present invention may be implemented; FIG.","8 is a schematic diagram of a cloud computing environment in which the present invention may be implemented; and FIG.","9 is a diagram of abstraction model layers of a cloud computing environment in which the present invention may be implemented.","It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale.","For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity.","Further, where considered appropriate, reference numbers may be repeated among the figures to indicate corresponding or analogous features.","DETAILED DESCRIPTION A method and a system are provided for identifying relationships of interest of entities.","Information may be expressed in terms of entities, links, and properties (ELP) that may be analyzed using data models.","For example, a data model may provide a platform for manipulating and storing types of entities, links, and properties as controlled by a deployment-specific schema.","An example of a data model environment is IBM i2 Analyze (IBM and i2 are trademarks of International Business Machines Corporation) that is an enterprise intelligence analysis environment that facilitates information sharing and intelligence production with the flexibility of both web-based and rich desktop clients.","It accelerates analysis of large volumes of data through an extensible, service-oriented environment, designed to integrate into existing enterprise infrastructure, and simplify database connectivity.","i2 Analyze supports operational analysis and improves situational awareness by providing faster, more informed decision making across and inside organizations.","The described method and system enables a user to create and save a query that is harvested to capture relationships between entities that may be deemed of interest.","The method and system may use the types of link to obtain advanced facets for searching on the query.","Referring to FIG.","1, a block diagram illustrates an example embodiment of a system 100 in which the described method may be implemented.","The system 100 may include a data modeling system 120 for providing data visualization and a database management system 111 with access to data sources 101, 102 from which data may be retrieved.","The data modeling system 120 and database management system 111 may be provided on one or more servers 110 for provision as a web-based system with a data modeling system client 140 which may be a rich desktop client providing a client user interface (UI) 150.The described data modeling system 120 includes a relationship processing component 130 for providing the described functionality of relationship analysis and provision of advanced facets based on relationship types.","The client UI 150 may include a query input component 151 for receiving input of a user query as described further below.","The client UI 150 may display a generated data model of retrieved data from the data sources 101, 102 including entities 161-164, links 171-173, and properties 181, 182 of the entities and links.","Data connectors may be used to acquire data from the data sources 101, 102 and may convert requested data into entities 161-164, links 171-173, and properties 181, 182 to be displayed to the user in the client UI 150.In a described data model environment, entities, links, and properties are defined as follows.","Entities and links may be referred to as items.","An “entity” represents an object.","This may be a real world physical object such as a “Person” or a “Car”, or a conceptual object, such as a “Meeting” or an “Insurance Claim”.","A “link” associates two entities with each other.","For example, a “Person” entity might be associated with a “Car” entity through an “Owns” link.","A “property” stores a value that characterizes an entity or a link.","For example, a “Person” entity might have properties that record its given name, surname, date of birth, and hair color.","The simplest relationship in an ELP data model involves two entities that are connected with a single link.","These kinds of relationships are the building blocks for data structures that contain chains and networks of entities with any number of links between them.","Because of what these relationships look like when they appear in visualizations, the structure is sometimes called a “dumbbell”.","Referring to FIGS.","2A and 2B, schematic diagrams 200, 250 show a dumbbell formed of two entities 161, 162 with a link 171.For example, the first entity 161 may be a person of name “Anna Harvey” with a date of birth of “May 5, 1974” and the second entity may be a car of manufacture “Ford”, make “Mondeo” (Ford and Mondeo are trademarks of Ford Motor Company), year “2007”.","The link 171 may indicate that the person “owns” the car.","The properties may be stored in cards as illustrated in FIG.","2B.","FIG.","2B shows that the first entity 161 and the second entity 162 each have an identifier 211, 221 that is unique within a deployment of the platform, a type 212, 222 which determines what properties the entity can have, and metadata 213, 223 such as the time when the entity was created and modified.","The entities 161, 162 may store their properties in one or more cards 214, 224 that they contain.","Usually, a card contains properties whose values were supplied by a single source at a particular time.","Different cards for a single entity may come from different sources.","The cards themselves may have an identifier and metadata.","The link 171 between two entities 161, 162 may also include an identifier 231, a type 232, metadata 233 and cards 234.In addition, the link 171 includes an indication of the entity 161 the link is from 237 and the entity 162 the link is to 238 such that the link 171 has a direction.","In addition, a link 171 may include a direction 235 and a strength 236.The types 212, 222, 232 for entities and links are defined by the schema and the type categorizes the host and determines the categories it can have.","A link type is similar to an entity type but contains more information.","The link type also specifies what types of entities can be at the ends of that link.","Referring to FIG.","3, a flow diagram 300 shows an example embodiment of the described method.","The method identifies links representing relationships of interest in a data modeling system.","The data modeling system may represent objects as entities with links representing relationships between the entities.","Entities and links are referred to as items.","A link joining two entities is referred to as a dumbbell.","The method may receive 301 a query, the query comprising one or more entities and, optionally, one or more links.","The query may be created and saved by a user of the data modeling system.","In a saved query, one or more of the items (i.e.","an entity or a link) is designated as an output item.","An output item may be interpreted as being of significant interest as the query returns items of these types to the user.","An output item determines the item type that will be returned by the response to the query.","The query may be analyzed 302 to identify each dumbbell in the query.","It may be determined 303 if there is a dumbbell in the query that has not already been considered.","If there are no dumbbells that have not already been considered, then the method may end 304.If there is a dumbbell that has not already been considered, it may be examined to determine 305 if the dumbbell includes an output item in the form of the dumbbell's link or one of the end entities.","If the dumbbell does not include an output item, the dumbbell may be discarded 306 as the identified relationship does not contain an item to be returned in the query.","If the dumbbell does include an output item, then the dumbbell is kept 307 and the property values of the items of the dumbbell are discarded.","The property values are discarded as, when relationships are surfaced in other parts of the application, the property values will not be relevant.","A kept dumbbell, including the link type and entity types, may be added 308 to a catalogue of relationships if a dumbbell is not already listed having the link type and entity types.","A catalogue may be any data structure that stores relationships, for example, person-offender-crime.","The method may then loop to determine 303 if there is another dumbbell in the query that has not yet been considered.","The method may be repeated for each saved query so as to generate a list of relationships for each item type.","A list of relationships may be generated for all saved queries input via the user interface.","Alternatively, a list of relationships may be generated for saved queries for a specified user of the user interface.","These lists may be used when a user runs a keyword search and is presented with a mixed item type list of matching results.","The mixed item type list may be ordered or filtered by item types.","For example, when viewing a list of person entities in a text search results user interface, filters may allow the user to shortlist only those persons linked to a crime by an offender link.","Referring to FIGS.","4A and 4B, in a data analysis environment, such as IBM i2 Analyze, a user may create and save queries 400 that may be re-run to find items of interest.","These queries may be harvested to capture relationships between items that may be deemed interesting.","Referring to FIG.","4A a schematic diagram shows a query 400 including a person entity 401 that is designated as an output item.","The query 400 will return person items 401 linked to a vehicle 402 by an owner link 411 and linked to a crime 403 in the form of an assault by an offender link 412, where the crime 403 is also linked to a specified location 404 of a town/city by any link type 413.In FIG.","4A, the structure of the query 400 suggests the user is interested in persons 401 linked to assault crimes 403 by an offender link type 412 and also persons 401 who own 411 a vehicle 402.Curating a list of these relationships of interest can inform a shortlist of advanced facets to be displayed from the potential list of 1000s.","The creation and maintenance of a list of relationships of interest may be carried out by crawling the saved queries available to a given user as well as those created and run by that user.","All queries may be deconstructed into a list of dumbbells (i.e., a person entity linked to a crime entity).","A dumbbell can be identified programmatically by finding each link and then identifying the entities at each end as entity creation is a precondition for creating a link.","In a saved query, at least one item must be designated as the output of the query.","In FIG.","4A, the person entity 401 is marked as the output.","Output items may be interpreted as being of significant interest as the query is going to return items of these types to the user.","Applying the described method, the query 400 in FIG.","4A may be deconstructed to the dumbbells 421, 422 illustrated in FIG.","4B.","As both of these dumbbells 421, 422 feature the designated output, in this case the person entity 401, they can both be considered relationships of interest.","The relationship between the crime 403 and location 404 is not deemed of primary interest, as the user has not expressed an interest in being returned crimes or locations.","In this case, the relationships to be included in the list for person items are: 1.Linked to vehicle by owner link; and 2.Linked to crime of type.","It may be noted the value of the crime type is not included in this embodiment.","Some embodiments may take values such as the crime type into account, so that the relationship Person-Offender-Crime (Burglary) is recorded as interesting whereas the relationship Person-Offender-Crime (Vandalism) is not.","The value of these lists is realized when a user runs a basic keyword search and is presented with a mixed item type list of matching results.","Upon filtering by “Person”, facets can be generated with reference to the list of relationships of interest for that type.","Referring to FIG.","5A a schematic diagram of options in the client UI 150 is shown for the person output.","Standard facets 540 may be offered in the UI based on properties, for example, in the form of “Gender” 550 of “Male” 551 or “Female” 552, and “Nationality” 560 in the form of “British” 561 or “French” 562.Advanced facets 510 may be offered in the UI to the user based on the relationships of interest.","For example, an advanced facet of “Vehicle” 520 may include an option of “Owner of vehicle” 521 which may return results.","As another example, an advanced facet of “Crime” 530 may include “Offender of crime: Assault” 531, “Offender of crime: Burglary” 532, and “Offender of crime: Theft” 533.These allow the user to filter the list not by properties of the person items, but by their relationships with other item types, all without user configuration or administrator overhead.","The method may provide automatic generation of suggested relationships of interest on link type, such as “Offender: Crime”, and “Offender: Burglary”.","This may provide the ability to perform a filtered expand based on a relationship of interest on link type, “Offender: Crime”, and “Offender: Burglary”.","High performance of this pattern is supported by dumbbell indexing, an indexing strategy that can be powered by search platforms.","Dumbbell indexing is supported by search platforms such as Solr (Solr is a trade mark of Apache Software Foundation) and allows an index to be constructed based on the connectivity of items.","When a filter is applied, an expensive query does not have to be executed as the index can already provide the results.","In another embodiment, this list of relationships may be used to power an enhanced filtered expand of chart items.","FIG.","5A shows an example embodiment of a display of the client UI 150 that illustrates how a user may select a person item, in this example “Gene Hendricks” 570 on a network chart.","The user may be offered options 571 including the option of “Advanced Expand” 572.“Advanced Expand” 572 may expand to options such as “Owner of vehicle” 573, “Offender of crime: Assault” 574, “Offender of crime: Burglary” 575, and “Offender of crime: Theft” 576 in accordance with the list above.","Referring to FIG.","6, a block diagram shows an example embodiment of the described relationship processing component 130.The relationship processing component 130 may include at least one processor 601, a hardware module, or a circuit for executing the functions of the described components which may be software units executing on the at least one processor.","Multiple processors running parallel processing threads may be provided enabling parallel processing of some or all of the functions of the components.","Memory 602 may be configured to provide computer instructions 603 to the at least one processor 601 to carry out the functionality of the components.","As described in relation to FIG.","1, the relationship processing component 130 may be provided as associated with or integral to a data modeling system 120 which has access to one or more data sources.","The relationship processing component 130 may include a query receiving component 610 for receiving a user query as input and saved in a client UI of the relationship processing component 130.The query may include at least one output item identified by the query receiving component 610.The relationship processing component 130 may include a query analysis component 620 for analyzing the received query.","The query analysis component 620 may include a dumbbell identifying component 621 for identifying dumbbells in the query in the form of a link with entities at either end.","The query analysis component 620 may include a dumbbell analyzing component 622 for examining a dumbbell to determine if the dumbbell includes an output item of the query.","The query analysis component 620 may further include a dumbbell adding component 623 for adding a dumbbell which includes an output item to a catalogue of relationships as maintained by a relationship catalogue component 630.The added dumbbell may include the link type and entity types.","The method may be repeated for each saved query so as to generate a list of relationships for each item type maintained by a list of relationships component 632.These lists may be used when a user runs a keyword search and is presented with a mixed item type list of matching results.","The data modeling system 120 may have a data modeling system client 140 for providing a user interface to a user.","The data modeling system client 140 may include a user interface search filtering component 640 for using the list of relationships for filtering item types when a user runs a keyword search and is presented with a mixed item type list of matching results.","The data modeling system client 140 may also include an advanced facet component 642 for using the list of relationships for an item type to provide an advanced facet for searching at the user interface.","The data modeling system client 140 may also include a filtered expansion component 644 for providing a filtered expansion for an item type based on the list of relationships for the item type.","The data modeling system client 140 may also include an automatic generation component 646 for enabling automatic generation of suggested relationships of interest for an item type based on the list of relationships for the item type.","Referring now to FIG.","7, a schematic of an example of a system 700 in the form of a computer system or server is shown.","A computer system or server 712 may be operational with numerous other general purpose or special purpose computing system environments or configurations.","Examples of well-known computing systems, environments, and/or configurations that may be suitable for use with computer system/server 712 include, but are not limited to, personal computer systems, server computer systems, thin clients, thick clients, hand-held or laptop devices, multiprocessor systems, microprocessor-based systems, set top boxes, programmable consumer electronics, network PCs, minicomputer systems, mainframe computer systems, and distributed cloud computing environments that include any of the above systems or devices, and the like.","Computer system/server 712 may be described in the general context of computer system-executable instructions, such as program modules, being executed by a computer system.","Generally, program modules may include routines, programs, objects, components, logic, data structures, and so on that perform particular tasks or implement particular abstract data types.","Computer system/server 712 may be practiced in distributed cloud computing environments where tasks are performed by remote processing devices that are linked through a communications network.","In a distributed cloud computing environment, program modules may be located in both local and remote computer system storage media including memory storage devices.","In FIG.","7, a computer system/server 712 is shown in the form of a general-purpose computing device.","The components of the computer system/server 712 may include, but are not limited to, one or more processors or processing units 716, a system memory 728, and a bus 718 that couples various system components including system memory 728 to processor 716.Bus 718 represents one or more of any of several types of bus structures, including a memory bus or memory controller, a peripheral bus, an accelerated graphics port, and a processor or local bus using any of a variety of bus architectures.","By way of example, and not limitation, such architectures include Industry Standard Architecture (ISA) bus, Micro Channel Architecture (MCA) bus, Enhanced ISA (EISA) bus, Video Electronics Standards Association (VESA) local bus, and Peripheral Component Interconnects (PCI) bus.","Computer system/server 712 typically includes a variety of computer system readable media.","Such media may be any available media that is accessible by computer system/server 712, and it includes both volatile and non-volatile media, removable and non-removable media.","System memory 728 can include computer system readable media in the form of volatile memory, such as random access memory (RAM) 730 and/or cache memory 732.Computer system/server 712 may further include other removable/non-removable, volatile/non-volatile computer system storage media.","By way of example only, storage system 734 can be provided for reading from and writing to a non-removable, non-volatile magnetic media (not shown and typically called a “hard drive”).","Although not shown, a magnetic disk drive for reading from and writing to a removable, non-volatile magnetic disk (e.g., a “floppy disk”), and an optical disk drive for reading from or writing to a removable, non-volatile optical disk such as a CD-ROM, DVD-ROM or other optical media can be provided.","In such instances, each can be connected to bus 718 by one or more data media interfaces.","As will be further depicted and described below, memory 728 may include at least one program product having a set (e.g., at least one) of program modules that are configured to carry out the functions of embodiments of the invention.","Program/utility 740, having a set (at least one) of program modules 742, may be stored in memory 728 by way of example, and not limitation, as well as an operating system, one or more application programs, other program modules, and program data.","Each of the operating system, one or more application programs, other program modules, and program data or some combination thereof, may include an implementation of a networking environment.","Program modules 742 generally carry out the functions and/or methodologies of embodiments of the invention as described herein.","Computer system/server 712 may also communicate with one or more external devices 714 such as a keyboard, a pointing device, a display 724, etc.","; one or more devices that enable a user to interact with computer system/server 712; and/or any devices (e.g., network card, modem, etc.)","that enable computer system/server 712 to communicate with one or more other computing devices.","Such communication can occur via Input/Output (I/O) interfaces 722.Still yet, computer system/server 712 can communicate with one or more networks such as a local area network (LAN), a general wide area network (WAN), and/or a public network (e.g., the Internet) via network adapter 720.As depicted, network adapter 720 communicates with the other components of computer system/server 712 via bus 718.It should be understood that although not shown, other hardware and/or software components could be used in conjunction with computer system/server 712.Examples, include, but are not limited to: microcode, device drivers, redundant processing units, external disk drive arrays, RAID systems, tape drives, and data archival storage systems, etc.","The present invention may be a system, a method, and/or a computer program product.","The computer program product may include a computer readable storage medium (or media) having computer readable program instructions thereon for causing a processor to carry out aspects of the present invention.","The computer readable storage medium can be a tangible device that can retain and store instructions for use by an instruction execution device.","The computer readable storage medium may be, for example, but is not limited to, an electronic storage device, a magnetic storage device, an optical storage device, an electromagnetic storage device, a semiconductor storage device, or any suitable combination of the foregoing.","A non-exhaustive list of more specific examples of the computer readable storage medium includes the following: a portable computer diskette, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or Flash memory), a static random access memory (SRAM), a portable compact disc read-only memory (CD-ROM), a digital versatile disk (DVD), a memory stick, a floppy disk, a mechanically encoded device such as punch-cards or raised structures in a groove having instructions recorded thereon, and any suitable combination of the foregoing.","A computer readable storage medium, as used herein, is not to be construed as being transitory signals per se, such as radio waves or other freely propagating electromagnetic waves, electromagnetic waves propagating through a waveguide or other transmission media (e.g., light pulses passing through a fiber-optic cable), or electrical signals transmitted through a wire.","Computer readable program instructions described herein can be downloaded to respective computing/processing devices from a computer readable storage medium or to an external computer or external storage device via a network, for example, the Internet, a local area network, a wide area network and/or a wireless network.","The network may comprise copper transmission cables, optical transmission fibers, wireless transmission, routers, firewalls, switches, gateway computers and/or edge servers.","A network adapter card or network interface in each computing/processing device receives computer readable program instructions from the network and forwards the computer readable program instructions for storage in a computer readable storage medium within the respective computing/processing device.","Computer readable program instructions for carrying out operations of the present invention may be assembler instructions, instruction-set-architecture (ISA) instructions, machine instructions, machine dependent instructions, microcode, firmware instructions, state-setting data, or either source code or object code written in any combination of one or more programming languages, including an object oriented programming language such as Smalltalk, C++ or the like, and conventional procedural programming languages, such as the “C” programming language or similar programming languages.","The computer readable program instructions may execute entirely on the user's computer, partly on the user's computer, as a stand-alone software package, partly on the user's computer and partly on a remote computer or entirely on the remote computer or server.","In the latter scenario, the remote computer may be connected to the user's computer through any type of network, including a local area network (LAN) or a wide area network (WAN), or the connection may be made to an external computer (for example, through the Internet using an Internet Service Provider).","In some embodiments, electronic circuitry including, for example, programmable logic circuitry, field-programmable gate arrays (FPGA), or programmable logic arrays (PLA) may execute the computer readable program instructions by utilizing state information of the computer readable program instructions to personalize the electronic circuitry, in order to perform aspects of the present invention.","Aspects of the present invention are described herein with reference to flowchart illustrations and/or block diagrams of methods, apparatus (systems), and computer program products according to embodiments of the invention.","It will be understood that each block of the flowchart illustrations and/or block diagrams, and combinations of blocks in the flowchart illustrations and/or block diagrams, can be implemented by computer readable program instructions.","These computer readable program instructions may be provided to a processor of a general purpose computer, special purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer or other programmable data processing apparatus, create means for implementing the functions/acts specified in the flowchart and/or block diagram block or blocks.","These computer readable program instructions may also be stored in a computer readable storage medium that can direct a computer, a programmable data processing apparatus, and/or other devices to function in a particular manner, such that the computer readable storage medium having instructions stored therein comprises an article of manufacture including instructions which implement aspects of the function/act specified in the flowchart and/or block diagram block or blocks.","The computer readable program instructions may also be loaded onto a computer, other programmable data processing apparatus, or other device to cause a series of operational steps to be performed on the computer, other programmable apparatus or other device to produce a computer implemented process, such that the instructions which execute on the computer, other programmable apparatus, or other device implement the functions/acts specified in the flowchart and/or block diagram block or blocks.","The flowchart and block diagrams in the Figures illustrate the architecture, functionality, and operation of possible implementations of systems, methods, and computer program products according to various embodiments of the present invention.","In this regard, each block in the flowchart or block diagrams may represent a module, segment, or portion of instructions, which comprises one or more executable instructions for implementing the specified logical function(s).","In some alternative implementations, the functions noted in the block may occur out of the order noted in the Figures.","For example, two blocks shown in succession may, in fact, be executed substantially concurrently, or the blocks may sometimes be executed in the reverse order, depending upon the functionality involved.","It will also be noted that each block of the block diagrams and/or flowchart illustration, and combinations of blocks in the block diagrams and/or flowchart illustration, can be implemented by special purpose hardware-based systems that perform the specified functions or acts or carry out combinations of special purpose hardware and computer instructions.","Cloud Computing It is to be understood that although this disclosure includes a detailed description on cloud computing, implementation of the teachings recited herein are not limited to a cloud computing environment.","Rather, embodiments of the present invention are capable of being implemented in conjunction with any other type of computing environment now known or later developed.","Cloud computing is a model of service delivery for enabling convenient, on-demand network access to a shared pool of configurable computing resources (e.g., networks, network bandwidth, servers, processing, memory, storage, applications, virtual machines, and services) that can be rapidly provisioned and released with minimal management effort or interaction with a provider of the service.","This cloud model may include at least five characteristics, at least three service models, and at least four deployment models.","Characteristics are as follows: On-demand self-service: a cloud consumer can unilaterally provision computing capabilities, such as server time and network storage, as needed automatically without requiring human interaction with the service's provider.","Broad network access: capabilities are available over a network and accessed through standard mechanisms that promote use by heterogeneous thin or thick client platforms (e.g., mobile phones, laptops, and PDAs).","Resource pooling: the provider's computing resources are pooled to serve multiple consumers using a multi-tenant model, with different physical and virtual resources dynamically assigned and reassigned according to demand.","There is a sense of location independence in that the consumer generally has no control or knowledge over the exact location of the provided resources but may be able to specify location at a higher level of abstraction (e.g., country, state, or datacenter).","Rapid elasticity: capabilities can be rapidly and elastically provisioned, in some cases automatically, to quickly scale out and rapidly released to quickly scale in.","To the consumer, the capabilities available for provisioning often appear to be unlimited and can be purchased in any quantity at any time.","Measured service: cloud systems automatically control and optimize resource use by leveraging a metering capability at some level of abstraction appropriate to the type of service (e.g., storage, processing, bandwidth, and active user accounts).","Resource usage can be monitored, controlled, and reported, providing transparency for both the provider and consumer of the utilized service.","Service Models are as follows: Software as a Service (SaaS): the capability provided to the consumer is to use the provider's applications running on a cloud infrastructure.","The applications are accessible from various client devices through a thin client interface such as a web browser (e.g., web-based e-mail).","The consumer does not manage or control the underlying cloud infrastructure including network, servers, operating systems, storage, or even individual application capabilities, with the possible exception of limited user-specific application configuration settings.","Platform as a Service (PaaS): the capability provided to the consumer is to deploy onto the cloud infrastructure consumer-created or acquired applications created using programming languages and tools supported by the provider.","The consumer does not manage or control the underlying cloud infrastructure including networks, servers, operating systems, or storage, but has control over the deployed applications and possibly application hosting environment configurations.","Infrastructure as a Service (IaaS): the capability provided to the consumer is to provision processing, storage, networks, and other fundamental computing resources where the consumer is able to deploy and run arbitrary software, which can include operating systems and applications.","The consumer does not manage or control the underlying cloud infrastructure but has control over operating systems, storage, deployed applications, and possibly limited control of select networking components (e.g., host firewalls).","Deployment Models are as follows: Private cloud: the cloud infrastructure is operated solely for an organization.","It may be managed by the organization or a third party and may exist on-premises or off-premises.","Community cloud: the cloud infrastructure is shared by several organizations and supports a specific community that has shared concerns (e.g., mission, security requirements, policy, and compliance considerations).","It may be managed by the organizations or a third party and may exist on-premises or off-premises.","Public cloud: the cloud infrastructure is made available to the general public or a large industry group and is owned by an organization selling cloud services.","Hybrid cloud: the cloud infrastructure is a composition of two or more clouds (private, community, or public) that remain unique entities but are bound together by standardized or proprietary technology that enables data and application portability (e.g., cloud bursting for load-balancing between clouds).","A cloud computing environment is service oriented with a focus on statelessness, low coupling, modularity, and semantic interoperability.","At the heart of cloud computing is an infrastructure that includes a network of interconnected nodes.","Referring now to FIG.","8, illustrative cloud computing environment 850 is depicted.","As shown, cloud computing environment 850 includes one or more cloud computing nodes 810 with which local computing devices used by cloud consumers, such as, for example, personal digital assistant (PDA) or cellular telephone 854A, desktop computer 854B, laptop computer 854C, and/or automobile computer system 854N may communicate.","Nodes 810 may communicate with one another.","They may be grouped (not shown) physically or virtually, in one or more networks, such as Private, Community, Public, or Hybrid clouds as described hereinabove, or a combination thereof.","This allows cloud computing environment 850 to offer infrastructure, platforms and/or software as services for which a cloud consumer does not need to maintain resources on a local computing device.","It is understood that the types of computing devices 854A-N shown in FIG.","8 are intended to be illustrative only and that computing nodes 810 and cloud computing environment 850 can communicate with any type of computerized device over any type of network and/or network addressable connection (e.g., using a web browser).","Referring now to FIG.","9, a set of functional abstraction layers provided by cloud computing environment 950 (FIG.","9) is shown.","It should be understood in advance that the components, layers, and functions shown in FIG.","9 are intended to be illustrative only and embodiments of the invention are not limited thereto.","As depicted, the following layers and corresponding functions are provided: Hardware and software layer 960 includes hardware and software components.","Examples of hardware components include: mainframes 961; RISC (Reduced Instruction Set Computer) architecture based servers 962; servers 963; blade servers 964; storage devices 965; and networks and networking components 966.In some embodiments, software components include network application server software 967 and database software 968.Virtualization layer 970 provides an abstraction layer from which the following examples of virtual entities may be provided: virtual servers 971; virtual storage 972; virtual networks 973, including virtual private networks; virtual applications and operating systems 974; and virtual clients 975.In one example, management layer 980 may provide the functions described below.","Resource provisioning 981 provides dynamic procurement of computing resources and other resources that are utilized to perform tasks within the cloud computing environment.","Metering and Pricing 982 provide cost tracking as resources are utilized within the cloud computing environment, and billing or invoicing for consumption of these resources.","In one example, these resources may include application software licenses.","Security provides identity verification for cloud consumers and tasks, as well as protection for data and other resources.","User portal 983 provides access to the cloud computing environment for consumers and system administrators.","Service level management 984 provides cloud computing resource allocation and management such that required service levels are met.","Service Level Agreement (SLA) planning and fulfillment 985 provides pre-arrangement for, and procurement of, cloud computing resources for which a future requirement is anticipated in accordance with an SLA.","Workloads layer 990 provides examples of functionality for which the cloud computing environment may be utilized.","Examples of workloads and functions which may be provided from this layer include: mapping and navigation 991; software development and lifecycle management 992; virtual classroom education delivery 993; data analytics processing 994; transaction processing 995; and data model relationship processing 996.The descriptions of the various embodiments of the present invention have been presented for purposes of illustration, but are not intended to be exhaustive or limited to the embodiments disclosed.","Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments.","The terminology used herein was chosen to best explain the principles of the embodiments, the practical application or technical improvement over technologies found in the marketplace, or to enable others of ordinary skill in the art to understand the embodiments disclosed herein.","Improvements and modifications can be made to the foregoing without departing from the scope of the present invention."]],"string":"[\n [\n \"IDENTIFYING RELATIONSHIPS OF INTEREST OF ENTITIES\",\n \"A method, system and computer program product for identifying relationships of interest of entities in a data modeling environment, where the data modeling environment represents objects as entities with links representing relationships between the entities.\",\n \"A query is received, where the query includes entity(ies) and link(s) with at least one of the entities or links designated as an output item.\",\n \"The query is analyzed to identify each dumbbell in the query, where a dumbbell is a link with a first entity at a first end of the link and a second entity at a second end of the link.\",\n \"Each identified dumbbell is examined to determine if the dumbbell includes an output item; and, if the dumbbell includes an output item, adding the dumbbell to a catalogue of relationships if a dumbbell is not already listed having the link type and entity types of the identified dumbbell.\"\n ],\n [\n \"1.A computer-implemented method for identifying relationships of interest of entities in a data modeling environment, wherein the data modeling environment represents objects as entities with links representing relationships between the entities, comprising: receiving a query, the query comprising one or more entities and one or more links with at least one of the entities or links designated as an output item; analyzing, by a processor, the query to identify each dumbbell in the query, wherein a dumbbell is a link with a first entity at a first end of the link and a second entity at a second end of the link; examining, by the processor, each identified dumbbell to determine if the dumbbell includes an output item; and adding the dumbbell to a catalogue of relationships including a link type and entity types of the dumbbell in response to the dumbbell including an output item.\",\n \"2.The method as recited in claim 1 further comprising: determining if a dumbbell having link types and entity types is already stored in the catalogue of relationships and adding the dumbbell in response to a stored dumbbell not existing.\",\n \"3.The method as recited in claim 1, wherein property values are discarded from the link and the entities of a dumbbell being added to the catalogue of relationships.\",\n \"4.The method as recited in claim 1 further comprising: repeating said receiving, analyzing, examining and adding for multiple queries to generate a list of relationships for each item type.\",\n \"5.The method as recited in claim 4 further comprising: using the list of relationships when a user runs a keyword search and is presented with a mixed item type list of matching results, wherein the list of relationships is used to filter item types.\",\n \"6.The method as recited in claim 4 further comprising: using the list of relationships for an item type to provide an advanced facet for searching.\",\n \"7.The method as recited in claim 4 further comprising: providing a filtered expansion for an item type based on the list of relationships for the item type.\",\n \"8.The method as recited in claim 4 further comprising: enabling automatic generation of suggested relationships of interest for an item type based on the list of relationships for the item type.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>In a rich data environment in which entities, links, and properties (ELP) data needs to be searched, facets can assist with the filtering of matching results.\",\n \"In most faceting user interfaces, facets are generated from properties and metadata of the items listed and the list of available facets can be navigated via scrolling.\",\n \"In an ELP data environment, facets can also be generated from linked entities and their properties.\",\n \"For example, a search for “John Smith” could return a list of matching person entities.\",\n \"Facets generated by legal end types specified by a schema could include “Linked to crime” or more specifically “Linked to crime: assault”.\",\n \"Given this capability, in a law enforcement deployment of a schema, the number of potential combinations of advanced facets could easily reach the 1000s and become unusable if presented to the user in their entirety.\",\n \"Consequently, configuration is required to ensure the user is only presented with advanced facets that are useful.\",\n \"In order to make the most of this capability, there is either a configuration overhead for the administrator or an interaction overhead for the user.\"\n ],\n [\n \"<SOH> SUMMARY <EOH>In one embodiment of the present invention, a computer-implemented method for identifying relationships of interest of entities in a data modeling environment comprises receiving a query, where the data modeling environment represents objects as entities with links representing relationships between the entities and where the query comprises one or more entities and one or more links with at least one of the entities or links designated as an output item.\",\n \"The method further comprises analyzing, by a processor, the query to identify each dumbbell in the query, wherein a dumbbell is a link with a first entity at a first end of the link and a second entity at a second end of the link.\",\n \"The method additionally comprises examining, by the processor, each identified dumbbell to determine if the dumbbell includes an output item.\",\n \"Furthermore, the method comprises adding the dumbbell to a catalogue of relationships including a link type and entity types of the dumbbell in response to the dumbbell including an output item.\",\n \"Other forms of the embodiment of the method described above are in a system and in a computer program product.\",\n \"The foregoing has outlined rather generally the features and technical advantages of one or more embodiments of the present invention in order that the detailed description of the present invention that follows may be better understood.\",\n \"Additional features and advantages of the present invention will be described hereinafter which may form the subject of the claims of the present invention.\"\n ],\n [\n \"TECHNICAL FIELD The present invention relates generally to identifying relationships of interest of entities, and more particularly to identifying relationships of interest of entities in a data analysis environment.\",\n \"BACKGROUND In a rich data environment in which entities, links, and properties (ELP) data needs to be searched, facets can assist with the filtering of matching results.\",\n \"In most faceting user interfaces, facets are generated from properties and metadata of the items listed and the list of available facets can be navigated via scrolling.\",\n \"In an ELP data environment, facets can also be generated from linked entities and their properties.\",\n \"For example, a search for “John Smith” could return a list of matching person entities.\",\n \"Facets generated by legal end types specified by a schema could include “Linked to crime” or more specifically “Linked to crime: assault”.\",\n \"Given this capability, in a law enforcement deployment of a schema, the number of potential combinations of advanced facets could easily reach the 1000s and become unusable if presented to the user in their entirety.\",\n \"Consequently, configuration is required to ensure the user is only presented with advanced facets that are useful.\",\n \"In order to make the most of this capability, there is either a configuration overhead for the administrator or an interaction overhead for the user.\",\n \"SUMMARY In one embodiment of the present invention, a computer-implemented method for identifying relationships of interest of entities in a data modeling environment comprises receiving a query, where the data modeling environment represents objects as entities with links representing relationships between the entities and where the query comprises one or more entities and one or more links with at least one of the entities or links designated as an output item.\",\n \"The method further comprises analyzing, by a processor, the query to identify each dumbbell in the query, wherein a dumbbell is a link with a first entity at a first end of the link and a second entity at a second end of the link.\",\n \"The method additionally comprises examining, by the processor, each identified dumbbell to determine if the dumbbell includes an output item.\",\n \"Furthermore, the method comprises adding the dumbbell to a catalogue of relationships including a link type and entity types of the dumbbell in response to the dumbbell including an output item.\",\n \"Other forms of the embodiment of the method described above are in a system and in a computer program product.\",\n \"The foregoing has outlined rather generally the features and technical advantages of one or more embodiments of the present invention in order that the detailed description of the present invention that follows may be better understood.\",\n \"Additional features and advantages of the present invention will be described hereinafter which may form the subject of the claims of the present invention.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS A better understanding of the present invention can be obtained when the following detailed description is considered in conjunction with the following drawings, in which: FIG.\",\n \"1 is a block diagram illustrating an example embodiment of a system in which the present invention may be implemented; FIGS.\",\n \"2A and 2B are schematic diagrams illustrating linked entities in accordance with aspects of the present invention; FIG.\",\n \"3 is a flow diagram of a first example embodiment of a method in accordance with the present invention; FIGS.\",\n \"4A and 4B are schematic diagrams of an example query with FIG.\",\n \"4B showing extracted relationships of interest in accordance with an aspect of the present invention; FIGS.\",\n \"5A and 5B are schematic diagrams illustrating an example user interface with advanced facets in accordance with an aspect of the present invention; FIG.\",\n \"6 is block diagram of an example embodiment of a system in accordance with the present invention; FIG.\",\n \"7 is a block diagram of an embodiment of a computer system or cloud server in which the present invention may be implemented; FIG.\",\n \"8 is a schematic diagram of a cloud computing environment in which the present invention may be implemented; and FIG.\",\n \"9 is a diagram of abstraction model layers of a cloud computing environment in which the present invention may be implemented.\",\n \"It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale.\",\n \"For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity.\",\n \"Further, where considered appropriate, reference numbers may be repeated among the figures to indicate corresponding or analogous features.\",\n \"DETAILED DESCRIPTION A method and a system are provided for identifying relationships of interest of entities.\",\n \"Information may be expressed in terms of entities, links, and properties (ELP) that may be analyzed using data models.\",\n \"For example, a data model may provide a platform for manipulating and storing types of entities, links, and properties as controlled by a deployment-specific schema.\",\n \"An example of a data model environment is IBM i2 Analyze (IBM and i2 are trademarks of International Business Machines Corporation) that is an enterprise intelligence analysis environment that facilitates information sharing and intelligence production with the flexibility of both web-based and rich desktop clients.\",\n \"It accelerates analysis of large volumes of data through an extensible, service-oriented environment, designed to integrate into existing enterprise infrastructure, and simplify database connectivity.\",\n \"i2 Analyze supports operational analysis and improves situational awareness by providing faster, more informed decision making across and inside organizations.\",\n \"The described method and system enables a user to create and save a query that is harvested to capture relationships between entities that may be deemed of interest.\",\n \"The method and system may use the types of link to obtain advanced facets for searching on the query.\",\n \"Referring to FIG.\",\n \"1, a block diagram illustrates an example embodiment of a system 100 in which the described method may be implemented.\",\n \"The system 100 may include a data modeling system 120 for providing data visualization and a database management system 111 with access to data sources 101, 102 from which data may be retrieved.\",\n \"The data modeling system 120 and database management system 111 may be provided on one or more servers 110 for provision as a web-based system with a data modeling system client 140 which may be a rich desktop client providing a client user interface (UI) 150.The described data modeling system 120 includes a relationship processing component 130 for providing the described functionality of relationship analysis and provision of advanced facets based on relationship types.\",\n \"The client UI 150 may include a query input component 151 for receiving input of a user query as described further below.\",\n \"The client UI 150 may display a generated data model of retrieved data from the data sources 101, 102 including entities 161-164, links 171-173, and properties 181, 182 of the entities and links.\",\n \"Data connectors may be used to acquire data from the data sources 101, 102 and may convert requested data into entities 161-164, links 171-173, and properties 181, 182 to be displayed to the user in the client UI 150.In a described data model environment, entities, links, and properties are defined as follows.\",\n \"Entities and links may be referred to as items.\",\n \"An “entity” represents an object.\",\n \"This may be a real world physical object such as a “Person” or a “Car”, or a conceptual object, such as a “Meeting” or an “Insurance Claim”.\",\n \"A “link” associates two entities with each other.\",\n \"For example, a “Person” entity might be associated with a “Car” entity through an “Owns” link.\",\n \"A “property” stores a value that characterizes an entity or a link.\",\n \"For example, a “Person” entity might have properties that record its given name, surname, date of birth, and hair color.\",\n \"The simplest relationship in an ELP data model involves two entities that are connected with a single link.\",\n \"These kinds of relationships are the building blocks for data structures that contain chains and networks of entities with any number of links between them.\",\n \"Because of what these relationships look like when they appear in visualizations, the structure is sometimes called a “dumbbell”.\",\n \"Referring to FIGS.\",\n \"2A and 2B, schematic diagrams 200, 250 show a dumbbell formed of two entities 161, 162 with a link 171.For example, the first entity 161 may be a person of name “Anna Harvey” with a date of birth of “May 5, 1974” and the second entity may be a car of manufacture “Ford”, make “Mondeo” (Ford and Mondeo are trademarks of Ford Motor Company), year “2007”.\",\n \"The link 171 may indicate that the person “owns” the car.\",\n \"The properties may be stored in cards as illustrated in FIG.\",\n \"2B.\",\n \"FIG.\",\n \"2B shows that the first entity 161 and the second entity 162 each have an identifier 211, 221 that is unique within a deployment of the platform, a type 212, 222 which determines what properties the entity can have, and metadata 213, 223 such as the time when the entity was created and modified.\",\n \"The entities 161, 162 may store their properties in one or more cards 214, 224 that they contain.\",\n \"Usually, a card contains properties whose values were supplied by a single source at a particular time.\",\n \"Different cards for a single entity may come from different sources.\",\n \"The cards themselves may have an identifier and metadata.\",\n \"The link 171 between two entities 161, 162 may also include an identifier 231, a type 232, metadata 233 and cards 234.In addition, the link 171 includes an indication of the entity 161 the link is from 237 and the entity 162 the link is to 238 such that the link 171 has a direction.\",\n \"In addition, a link 171 may include a direction 235 and a strength 236.The types 212, 222, 232 for entities and links are defined by the schema and the type categorizes the host and determines the categories it can have.\",\n \"A link type is similar to an entity type but contains more information.\",\n \"The link type also specifies what types of entities can be at the ends of that link.\",\n \"Referring to FIG.\",\n \"3, a flow diagram 300 shows an example embodiment of the described method.\",\n \"The method identifies links representing relationships of interest in a data modeling system.\",\n \"The data modeling system may represent objects as entities with links representing relationships between the entities.\",\n \"Entities and links are referred to as items.\",\n \"A link joining two entities is referred to as a dumbbell.\",\n \"The method may receive 301 a query, the query comprising one or more entities and, optionally, one or more links.\",\n \"The query may be created and saved by a user of the data modeling system.\",\n \"In a saved query, one or more of the items (i.e.\",\n \"an entity or a link) is designated as an output item.\",\n \"An output item may be interpreted as being of significant interest as the query returns items of these types to the user.\",\n \"An output item determines the item type that will be returned by the response to the query.\",\n \"The query may be analyzed 302 to identify each dumbbell in the query.\",\n \"It may be determined 303 if there is a dumbbell in the query that has not already been considered.\",\n \"If there are no dumbbells that have not already been considered, then the method may end 304.If there is a dumbbell that has not already been considered, it may be examined to determine 305 if the dumbbell includes an output item in the form of the dumbbell's link or one of the end entities.\",\n \"If the dumbbell does not include an output item, the dumbbell may be discarded 306 as the identified relationship does not contain an item to be returned in the query.\",\n \"If the dumbbell does include an output item, then the dumbbell is kept 307 and the property values of the items of the dumbbell are discarded.\",\n \"The property values are discarded as, when relationships are surfaced in other parts of the application, the property values will not be relevant.\",\n \"A kept dumbbell, including the link type and entity types, may be added 308 to a catalogue of relationships if a dumbbell is not already listed having the link type and entity types.\",\n \"A catalogue may be any data structure that stores relationships, for example, person-offender-crime.\",\n \"The method may then loop to determine 303 if there is another dumbbell in the query that has not yet been considered.\",\n \"The method may be repeated for each saved query so as to generate a list of relationships for each item type.\",\n \"A list of relationships may be generated for all saved queries input via the user interface.\",\n \"Alternatively, a list of relationships may be generated for saved queries for a specified user of the user interface.\",\n \"These lists may be used when a user runs a keyword search and is presented with a mixed item type list of matching results.\",\n \"The mixed item type list may be ordered or filtered by item types.\",\n \"For example, when viewing a list of person entities in a text search results user interface, filters may allow the user to shortlist only those persons linked to a crime by an offender link.\",\n \"Referring to FIGS.\",\n \"4A and 4B, in a data analysis environment, such as IBM i2 Analyze, a user may create and save queries 400 that may be re-run to find items of interest.\",\n \"These queries may be harvested to capture relationships between items that may be deemed interesting.\",\n \"Referring to FIG.\",\n \"4A a schematic diagram shows a query 400 including a person entity 401 that is designated as an output item.\",\n \"The query 400 will return person items 401 linked to a vehicle 402 by an owner link 411 and linked to a crime 403 in the form of an assault by an offender link 412, where the crime 403 is also linked to a specified location 404 of a town/city by any link type 413.In FIG.\",\n \"4A, the structure of the query 400 suggests the user is interested in persons 401 linked to assault crimes 403 by an offender link type 412 and also persons 401 who own 411 a vehicle 402.Curating a list of these relationships of interest can inform a shortlist of advanced facets to be displayed from the potential list of 1000s.\",\n \"The creation and maintenance of a list of relationships of interest may be carried out by crawling the saved queries available to a given user as well as those created and run by that user.\",\n \"All queries may be deconstructed into a list of dumbbells (i.e., a person entity linked to a crime entity).\",\n \"A dumbbell can be identified programmatically by finding each link and then identifying the entities at each end as entity creation is a precondition for creating a link.\",\n \"In a saved query, at least one item must be designated as the output of the query.\",\n \"In FIG.\",\n \"4A, the person entity 401 is marked as the output.\",\n \"Output items may be interpreted as being of significant interest as the query is going to return items of these types to the user.\",\n \"Applying the described method, the query 400 in FIG.\",\n \"4A may be deconstructed to the dumbbells 421, 422 illustrated in FIG.\",\n \"4B.\",\n \"As both of these dumbbells 421, 422 feature the designated output, in this case the person entity 401, they can both be considered relationships of interest.\",\n \"The relationship between the crime 403 and location 404 is not deemed of primary interest, as the user has not expressed an interest in being returned crimes or locations.\",\n \"In this case, the relationships to be included in the list for person items are: 1.Linked to vehicle by owner link; and 2.Linked to crime of type.\",\n \"It may be noted the value of the crime type is not included in this embodiment.\",\n \"Some embodiments may take values such as the crime type into account, so that the relationship Person-Offender-Crime (Burglary) is recorded as interesting whereas the relationship Person-Offender-Crime (Vandalism) is not.\",\n \"The value of these lists is realized when a user runs a basic keyword search and is presented with a mixed item type list of matching results.\",\n \"Upon filtering by “Person”, facets can be generated with reference to the list of relationships of interest for that type.\",\n \"Referring to FIG.\",\n \"5A a schematic diagram of options in the client UI 150 is shown for the person output.\",\n \"Standard facets 540 may be offered in the UI based on properties, for example, in the form of “Gender” 550 of “Male” 551 or “Female” 552, and “Nationality” 560 in the form of “British” 561 or “French” 562.Advanced facets 510 may be offered in the UI to the user based on the relationships of interest.\",\n \"For example, an advanced facet of “Vehicle” 520 may include an option of “Owner of vehicle” 521 which may return results.\",\n \"As another example, an advanced facet of “Crime” 530 may include “Offender of crime: Assault” 531, “Offender of crime: Burglary” 532, and “Offender of crime: Theft” 533.These allow the user to filter the list not by properties of the person items, but by their relationships with other item types, all without user configuration or administrator overhead.\",\n \"The method may provide automatic generation of suggested relationships of interest on link type, such as “Offender: Crime”, and “Offender: Burglary”.\",\n \"This may provide the ability to perform a filtered expand based on a relationship of interest on link type, “Offender: Crime”, and “Offender: Burglary”.\",\n \"High performance of this pattern is supported by dumbbell indexing, an indexing strategy that can be powered by search platforms.\",\n \"Dumbbell indexing is supported by search platforms such as Solr (Solr is a trade mark of Apache Software Foundation) and allows an index to be constructed based on the connectivity of items.\",\n \"When a filter is applied, an expensive query does not have to be executed as the index can already provide the results.\",\n \"In another embodiment, this list of relationships may be used to power an enhanced filtered expand of chart items.\",\n \"FIG.\",\n \"5A shows an example embodiment of a display of the client UI 150 that illustrates how a user may select a person item, in this example “Gene Hendricks” 570 on a network chart.\",\n \"The user may be offered options 571 including the option of “Advanced Expand” 572.“Advanced Expand” 572 may expand to options such as “Owner of vehicle” 573, “Offender of crime: Assault” 574, “Offender of crime: Burglary” 575, and “Offender of crime: Theft” 576 in accordance with the list above.\",\n \"Referring to FIG.\",\n \"6, a block diagram shows an example embodiment of the described relationship processing component 130.The relationship processing component 130 may include at least one processor 601, a hardware module, or a circuit for executing the functions of the described components which may be software units executing on the at least one processor.\",\n \"Multiple processors running parallel processing threads may be provided enabling parallel processing of some or all of the functions of the components.\",\n \"Memory 602 may be configured to provide computer instructions 603 to the at least one processor 601 to carry out the functionality of the components.\",\n \"As described in relation to FIG.\",\n \"1, the relationship processing component 130 may be provided as associated with or integral to a data modeling system 120 which has access to one or more data sources.\",\n \"The relationship processing component 130 may include a query receiving component 610 for receiving a user query as input and saved in a client UI of the relationship processing component 130.The query may include at least one output item identified by the query receiving component 610.The relationship processing component 130 may include a query analysis component 620 for analyzing the received query.\",\n \"The query analysis component 620 may include a dumbbell identifying component 621 for identifying dumbbells in the query in the form of a link with entities at either end.\",\n \"The query analysis component 620 may include a dumbbell analyzing component 622 for examining a dumbbell to determine if the dumbbell includes an output item of the query.\",\n \"The query analysis component 620 may further include a dumbbell adding component 623 for adding a dumbbell which includes an output item to a catalogue of relationships as maintained by a relationship catalogue component 630.The added dumbbell may include the link type and entity types.\",\n \"The method may be repeated for each saved query so as to generate a list of relationships for each item type maintained by a list of relationships component 632.These lists may be used when a user runs a keyword search and is presented with a mixed item type list of matching results.\",\n \"The data modeling system 120 may have a data modeling system client 140 for providing a user interface to a user.\",\n \"The data modeling system client 140 may include a user interface search filtering component 640 for using the list of relationships for filtering item types when a user runs a keyword search and is presented with a mixed item type list of matching results.\",\n \"The data modeling system client 140 may also include an advanced facet component 642 for using the list of relationships for an item type to provide an advanced facet for searching at the user interface.\",\n \"The data modeling system client 140 may also include a filtered expansion component 644 for providing a filtered expansion for an item type based on the list of relationships for the item type.\",\n \"The data modeling system client 140 may also include an automatic generation component 646 for enabling automatic generation of suggested relationships of interest for an item type based on the list of relationships for the item type.\",\n \"Referring now to FIG.\",\n \"7, a schematic of an example of a system 700 in the form of a computer system or server is shown.\",\n \"A computer system or server 712 may be operational with numerous other general purpose or special purpose computing system environments or configurations.\",\n \"Examples of well-known computing systems, environments, and/or configurations that may be suitable for use with computer system/server 712 include, but are not limited to, personal computer systems, server computer systems, thin clients, thick clients, hand-held or laptop devices, multiprocessor systems, microprocessor-based systems, set top boxes, programmable consumer electronics, network PCs, minicomputer systems, mainframe computer systems, and distributed cloud computing environments that include any of the above systems or devices, and the like.\",\n \"Computer system/server 712 may be described in the general context of computer system-executable instructions, such as program modules, being executed by a computer system.\",\n \"Generally, program modules may include routines, programs, objects, components, logic, data structures, and so on that perform particular tasks or implement particular abstract data types.\",\n \"Computer system/server 712 may be practiced in distributed cloud computing environments where tasks are performed by remote processing devices that are linked through a communications network.\",\n \"In a distributed cloud computing environment, program modules may be located in both local and remote computer system storage media including memory storage devices.\",\n \"In FIG.\",\n \"7, a computer system/server 712 is shown in the form of a general-purpose computing device.\",\n \"The components of the computer system/server 712 may include, but are not limited to, one or more processors or processing units 716, a system memory 728, and a bus 718 that couples various system components including system memory 728 to processor 716.Bus 718 represents one or more of any of several types of bus structures, including a memory bus or memory controller, a peripheral bus, an accelerated graphics port, and a processor or local bus using any of a variety of bus architectures.\",\n \"By way of example, and not limitation, such architectures include Industry Standard Architecture (ISA) bus, Micro Channel Architecture (MCA) bus, Enhanced ISA (EISA) bus, Video Electronics Standards Association (VESA) local bus, and Peripheral Component Interconnects (PCI) bus.\",\n \"Computer system/server 712 typically includes a variety of computer system readable media.\",\n \"Such media may be any available media that is accessible by computer system/server 712, and it includes both volatile and non-volatile media, removable and non-removable media.\",\n \"System memory 728 can include computer system readable media in the form of volatile memory, such as random access memory (RAM) 730 and/or cache memory 732.Computer system/server 712 may further include other removable/non-removable, volatile/non-volatile computer system storage media.\",\n \"By way of example only, storage system 734 can be provided for reading from and writing to a non-removable, non-volatile magnetic media (not shown and typically called a “hard drive”).\",\n \"Although not shown, a magnetic disk drive for reading from and writing to a removable, non-volatile magnetic disk (e.g., a “floppy disk”), and an optical disk drive for reading from or writing to a removable, non-volatile optical disk such as a CD-ROM, DVD-ROM or other optical media can be provided.\",\n \"In such instances, each can be connected to bus 718 by one or more data media interfaces.\",\n \"As will be further depicted and described below, memory 728 may include at least one program product having a set (e.g., at least one) of program modules that are configured to carry out the functions of embodiments of the invention.\",\n \"Program/utility 740, having a set (at least one) of program modules 742, may be stored in memory 728 by way of example, and not limitation, as well as an operating system, one or more application programs, other program modules, and program data.\",\n \"Each of the operating system, one or more application programs, other program modules, and program data or some combination thereof, may include an implementation of a networking environment.\",\n \"Program modules 742 generally carry out the functions and/or methodologies of embodiments of the invention as described herein.\",\n \"Computer system/server 712 may also communicate with one or more external devices 714 such as a keyboard, a pointing device, a display 724, etc.\",\n \"; one or more devices that enable a user to interact with computer system/server 712; and/or any devices (e.g., network card, modem, etc.)\",\n \"that enable computer system/server 712 to communicate with one or more other computing devices.\",\n \"Such communication can occur via Input/Output (I/O) interfaces 722.Still yet, computer system/server 712 can communicate with one or more networks such as a local area network (LAN), a general wide area network (WAN), and/or a public network (e.g., the Internet) via network adapter 720.As depicted, network adapter 720 communicates with the other components of computer system/server 712 via bus 718.It should be understood that although not shown, other hardware and/or software components could be used in conjunction with computer system/server 712.Examples, include, but are not limited to: microcode, device drivers, redundant processing units, external disk drive arrays, RAID systems, tape drives, and data archival storage systems, etc.\",\n \"The present invention may be a system, a method, and/or a computer program product.\",\n \"The computer program product may include a computer readable storage medium (or media) having computer readable program instructions thereon for causing a processor to carry out aspects of the present invention.\",\n \"The computer readable storage medium can be a tangible device that can retain and store instructions for use by an instruction execution device.\",\n \"The computer readable storage medium may be, for example, but is not limited to, an electronic storage device, a magnetic storage device, an optical storage device, an electromagnetic storage device, a semiconductor storage device, or any suitable combination of the foregoing.\",\n \"A non-exhaustive list of more specific examples of the computer readable storage medium includes the following: a portable computer diskette, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or Flash memory), a static random access memory (SRAM), a portable compact disc read-only memory (CD-ROM), a digital versatile disk (DVD), a memory stick, a floppy disk, a mechanically encoded device such as punch-cards or raised structures in a groove having instructions recorded thereon, and any suitable combination of the foregoing.\",\n \"A computer readable storage medium, as used herein, is not to be construed as being transitory signals per se, such as radio waves or other freely propagating electromagnetic waves, electromagnetic waves propagating through a waveguide or other transmission media (e.g., light pulses passing through a fiber-optic cable), or electrical signals transmitted through a wire.\",\n \"Computer readable program instructions described herein can be downloaded to respective computing/processing devices from a computer readable storage medium or to an external computer or external storage device via a network, for example, the Internet, a local area network, a wide area network and/or a wireless network.\",\n \"The network may comprise copper transmission cables, optical transmission fibers, wireless transmission, routers, firewalls, switches, gateway computers and/or edge servers.\",\n \"A network adapter card or network interface in each computing/processing device receives computer readable program instructions from the network and forwards the computer readable program instructions for storage in a computer readable storage medium within the respective computing/processing device.\",\n \"Computer readable program instructions for carrying out operations of the present invention may be assembler instructions, instruction-set-architecture (ISA) instructions, machine instructions, machine dependent instructions, microcode, firmware instructions, state-setting data, or either source code or object code written in any combination of one or more programming languages, including an object oriented programming language such as Smalltalk, C++ or the like, and conventional procedural programming languages, such as the “C” programming language or similar programming languages.\",\n \"The computer readable program instructions may execute entirely on the user's computer, partly on the user's computer, as a stand-alone software package, partly on the user's computer and partly on a remote computer or entirely on the remote computer or server.\",\n \"In the latter scenario, the remote computer may be connected to the user's computer through any type of network, including a local area network (LAN) or a wide area network (WAN), or the connection may be made to an external computer (for example, through the Internet using an Internet Service Provider).\",\n \"In some embodiments, electronic circuitry including, for example, programmable logic circuitry, field-programmable gate arrays (FPGA), or programmable logic arrays (PLA) may execute the computer readable program instructions by utilizing state information of the computer readable program instructions to personalize the electronic circuitry, in order to perform aspects of the present invention.\",\n \"Aspects of the present invention are described herein with reference to flowchart illustrations and/or block diagrams of methods, apparatus (systems), and computer program products according to embodiments of the invention.\",\n \"It will be understood that each block of the flowchart illustrations and/or block diagrams, and combinations of blocks in the flowchart illustrations and/or block diagrams, can be implemented by computer readable program instructions.\",\n \"These computer readable program instructions may be provided to a processor of a general purpose computer, special purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer or other programmable data processing apparatus, create means for implementing the functions/acts specified in the flowchart and/or block diagram block or blocks.\",\n \"These computer readable program instructions may also be stored in a computer readable storage medium that can direct a computer, a programmable data processing apparatus, and/or other devices to function in a particular manner, such that the computer readable storage medium having instructions stored therein comprises an article of manufacture including instructions which implement aspects of the function/act specified in the flowchart and/or block diagram block or blocks.\",\n \"The computer readable program instructions may also be loaded onto a computer, other programmable data processing apparatus, or other device to cause a series of operational steps to be performed on the computer, other programmable apparatus or other device to produce a computer implemented process, such that the instructions which execute on the computer, other programmable apparatus, or other device implement the functions/acts specified in the flowchart and/or block diagram block or blocks.\",\n \"The flowchart and block diagrams in the Figures illustrate the architecture, functionality, and operation of possible implementations of systems, methods, and computer program products according to various embodiments of the present invention.\",\n \"In this regard, each block in the flowchart or block diagrams may represent a module, segment, or portion of instructions, which comprises one or more executable instructions for implementing the specified logical function(s).\",\n \"In some alternative implementations, the functions noted in the block may occur out of the order noted in the Figures.\",\n \"For example, two blocks shown in succession may, in fact, be executed substantially concurrently, or the blocks may sometimes be executed in the reverse order, depending upon the functionality involved.\",\n \"It will also be noted that each block of the block diagrams and/or flowchart illustration, and combinations of blocks in the block diagrams and/or flowchart illustration, can be implemented by special purpose hardware-based systems that perform the specified functions or acts or carry out combinations of special purpose hardware and computer instructions.\",\n \"Cloud Computing It is to be understood that although this disclosure includes a detailed description on cloud computing, implementation of the teachings recited herein are not limited to a cloud computing environment.\",\n \"Rather, embodiments of the present invention are capable of being implemented in conjunction with any other type of computing environment now known or later developed.\",\n \"Cloud computing is a model of service delivery for enabling convenient, on-demand network access to a shared pool of configurable computing resources (e.g., networks, network bandwidth, servers, processing, memory, storage, applications, virtual machines, and services) that can be rapidly provisioned and released with minimal management effort or interaction with a provider of the service.\",\n \"This cloud model may include at least five characteristics, at least three service models, and at least four deployment models.\",\n \"Characteristics are as follows: On-demand self-service: a cloud consumer can unilaterally provision computing capabilities, such as server time and network storage, as needed automatically without requiring human interaction with the service's provider.\",\n \"Broad network access: capabilities are available over a network and accessed through standard mechanisms that promote use by heterogeneous thin or thick client platforms (e.g., mobile phones, laptops, and PDAs).\",\n \"Resource pooling: the provider's computing resources are pooled to serve multiple consumers using a multi-tenant model, with different physical and virtual resources dynamically assigned and reassigned according to demand.\",\n \"There is a sense of location independence in that the consumer generally has no control or knowledge over the exact location of the provided resources but may be able to specify location at a higher level of abstraction (e.g., country, state, or datacenter).\",\n \"Rapid elasticity: capabilities can be rapidly and elastically provisioned, in some cases automatically, to quickly scale out and rapidly released to quickly scale in.\",\n \"To the consumer, the capabilities available for provisioning often appear to be unlimited and can be purchased in any quantity at any time.\",\n \"Measured service: cloud systems automatically control and optimize resource use by leveraging a metering capability at some level of abstraction appropriate to the type of service (e.g., storage, processing, bandwidth, and active user accounts).\",\n \"Resource usage can be monitored, controlled, and reported, providing transparency for both the provider and consumer of the utilized service.\",\n \"Service Models are as follows: Software as a Service (SaaS): the capability provided to the consumer is to use the provider's applications running on a cloud infrastructure.\",\n \"The applications are accessible from various client devices through a thin client interface such as a web browser (e.g., web-based e-mail).\",\n \"The consumer does not manage or control the underlying cloud infrastructure including network, servers, operating systems, storage, or even individual application capabilities, with the possible exception of limited user-specific application configuration settings.\",\n \"Platform as a Service (PaaS): the capability provided to the consumer is to deploy onto the cloud infrastructure consumer-created or acquired applications created using programming languages and tools supported by the provider.\",\n \"The consumer does not manage or control the underlying cloud infrastructure including networks, servers, operating systems, or storage, but has control over the deployed applications and possibly application hosting environment configurations.\",\n \"Infrastructure as a Service (IaaS): the capability provided to the consumer is to provision processing, storage, networks, and other fundamental computing resources where the consumer is able to deploy and run arbitrary software, which can include operating systems and applications.\",\n \"The consumer does not manage or control the underlying cloud infrastructure but has control over operating systems, storage, deployed applications, and possibly limited control of select networking components (e.g., host firewalls).\",\n \"Deployment Models are as follows: Private cloud: the cloud infrastructure is operated solely for an organization.\",\n \"It may be managed by the organization or a third party and may exist on-premises or off-premises.\",\n \"Community cloud: the cloud infrastructure is shared by several organizations and supports a specific community that has shared concerns (e.g., mission, security requirements, policy, and compliance considerations).\",\n \"It may be managed by the organizations or a third party and may exist on-premises or off-premises.\",\n \"Public cloud: the cloud infrastructure is made available to the general public or a large industry group and is owned by an organization selling cloud services.\",\n \"Hybrid cloud: the cloud infrastructure is a composition of two or more clouds (private, community, or public) that remain unique entities but are bound together by standardized or proprietary technology that enables data and application portability (e.g., cloud bursting for load-balancing between clouds).\",\n \"A cloud computing environment is service oriented with a focus on statelessness, low coupling, modularity, and semantic interoperability.\",\n \"At the heart of cloud computing is an infrastructure that includes a network of interconnected nodes.\",\n \"Referring now to FIG.\",\n \"8, illustrative cloud computing environment 850 is depicted.\",\n \"As shown, cloud computing environment 850 includes one or more cloud computing nodes 810 with which local computing devices used by cloud consumers, such as, for example, personal digital assistant (PDA) or cellular telephone 854A, desktop computer 854B, laptop computer 854C, and/or automobile computer system 854N may communicate.\",\n \"Nodes 810 may communicate with one another.\",\n \"They may be grouped (not shown) physically or virtually, in one or more networks, such as Private, Community, Public, or Hybrid clouds as described hereinabove, or a combination thereof.\",\n \"This allows cloud computing environment 850 to offer infrastructure, platforms and/or software as services for which a cloud consumer does not need to maintain resources on a local computing device.\",\n \"It is understood that the types of computing devices 854A-N shown in FIG.\",\n \"8 are intended to be illustrative only and that computing nodes 810 and cloud computing environment 850 can communicate with any type of computerized device over any type of network and/or network addressable connection (e.g., using a web browser).\",\n \"Referring now to FIG.\",\n \"9, a set of functional abstraction layers provided by cloud computing environment 950 (FIG.\",\n \"9) is shown.\",\n \"It should be understood in advance that the components, layers, and functions shown in FIG.\",\n \"9 are intended to be illustrative only and embodiments of the invention are not limited thereto.\",\n \"As depicted, the following layers and corresponding functions are provided: Hardware and software layer 960 includes hardware and software components.\",\n \"Examples of hardware components include: mainframes 961; RISC (Reduced Instruction Set Computer) architecture based servers 962; servers 963; blade servers 964; storage devices 965; and networks and networking components 966.In some embodiments, software components include network application server software 967 and database software 968.Virtualization layer 970 provides an abstraction layer from which the following examples of virtual entities may be provided: virtual servers 971; virtual storage 972; virtual networks 973, including virtual private networks; virtual applications and operating systems 974; and virtual clients 975.In one example, management layer 980 may provide the functions described below.\",\n \"Resource provisioning 981 provides dynamic procurement of computing resources and other resources that are utilized to perform tasks within the cloud computing environment.\",\n \"Metering and Pricing 982 provide cost tracking as resources are utilized within the cloud computing environment, and billing or invoicing for consumption of these resources.\",\n \"In one example, these resources may include application software licenses.\",\n \"Security provides identity verification for cloud consumers and tasks, as well as protection for data and other resources.\",\n \"User portal 983 provides access to the cloud computing environment for consumers and system administrators.\",\n \"Service level management 984 provides cloud computing resource allocation and management such that required service levels are met.\",\n \"Service Level Agreement (SLA) planning and fulfillment 985 provides pre-arrangement for, and procurement of, cloud computing resources for which a future requirement is anticipated in accordance with an SLA.\",\n \"Workloads layer 990 provides examples of functionality for which the cloud computing environment may be utilized.\",\n \"Examples of workloads and functions which may be provided from this layer include: mapping and navigation 991; software development and lifecycle management 992; virtual classroom education delivery 993; data analytics processing 994; transaction processing 995; and data model relationship processing 996.The descriptions of the various embodiments of the present invention have been presented for purposes of illustration, but are not intended to be exhaustive or limited to the embodiments disclosed.\",\n \"Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments.\",\n \"The terminology used herein was chosen to best explain the principles of the embodiments, the practical application or technical improvement over technologies found in the marketplace, or to enable others of ordinary skill in the art to understand the embodiments disclosed herein.\",\n \"Improvements and modifications can be made to the foregoing without departing from the scope of the present invention.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875806"}}},{"rowIdx":4494983,"cells":{"text":{"kind":"list like","value":[["FTM PROTOCOL WITH ANGLE OF ARRIVAL AND ANGLE OF DEPARTURE","Apparatuses and methods are disclosed for performing ranging operations between a first device and a second device.","The first device may receive, from the second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information.","The first device may transmit a first FTM frame to the second device, may receive an acknowledgement (ACK) frame from the second device, and may transmit, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames."],["1.A method of performing a ranging operation between a first device and a second device, comprising: receiving, from the second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; transmitting a first FTM frame to the second device; receiving an acknowledgement (ACK) frame from the second device; and transmitting, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.","2.The method of claim 1, wherein the request is embedded within a vendor specific information element (VSIE) of the FTM request frame.","3.The method of claim 1, wherein the angle information comprises at least one of angle of departure (AoD) information of the first FTM frame or angle of arrival (AoA) information of the ACK frame.","4.The method of claim 1, wherein the timing information indicates a difference between a time of departure (TOD) of the first FTM frame and a time of arrival (TOA) of the ACK frame.","5.The method of claim 1, wherein the angle information is embedded within one member of the group consisting of a time of departure (TOD) field and a time of arrival (TOA) field of the second FTM frame.","6.The method of claim 5, wherein the timing information is embedded within the other member of the group consisting of the TOD field and the TOA field of the second FTM frame.","7.The method of claim 1, further comprising: embedding, into a beacon frame, information indicating whether the first device is capable of estimating angle of arrival (AoA) information or angle of departure (AoD) information; and broadcasting the beacon frame to at least the second device.","8.The method of claim 1, further comprising: transmitting, to the second device, a response frame indicating a level of accuracy with which the first device is to estimate the angle information.","9.The method of claim 8, wherein the response frame comprises the first FTM frame, and the indicated level of accuracy is embedded in an information element (IE) of the first FTM frame.","10.The method of claim 1, further comprising: estimating an angle of arrival (AoA) of the ACK frame using a plurality of different antenna patterns of the first device.","11.The method of claim 1, further comprising: estimating an angle of departure (AoD) of the first FTM frame using a plurality of different antenna patterns of the first device.","12.A first device, comprising: one or more processors; and a memory configured to store instructions that, when executed by the one or more processors, causes the first device to: receive, from a second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; transmit a first FTM frame to the second device; receive an acknowledgement (ACK) frame from the second device; and transmit, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.","13.The first device of claim 12, wherein the request is embedded within a vendor specific information element (VSIE) of the FTM request frame.","14.The first device of claim 12, wherein the angle information comprises at least one of angle of departure (AoD) information of the first FTM frame or angle of arrival (AoA) information of the ACK frame.","15.The first device of claim 12, wherein the timing information indicates a difference between a time of departure (TOD) of the first FTM frame and a time of arrival (TOA) of the ACK frame.","16.The first device of claim 12, wherein the angle information is embedded within one member of the group consisting of a time of departure (TOD) field and a time of arrival (TOA) field of the second FTM frame.","17.The first device of claim 16, wherein the timing information is embedded within the other member of the group consisting of the TOD field and the TOA field of the second FTM frame.","18.The first device of claim 12, wherein execution of the instructions further causes the first device to: embed, into a beacon frame, information indicating whether the first device is capable of estimating angle of arrival (AoA) information or angle of departure (AoD) information; and broadcast the beacon frame to at least the second device.","19.The first device of claim 12, wherein execution of the instructions further causes the first device to: transmit, to the second device, a response frame indicating a level of accuracy the with which first device is to estimate the angle information.","20.The first device of claim 19, wherein the response frame comprises the first FTM frame, and the indicated level of accuracy is embedded in an information element (IE) of the first FTM frame.","21.The first device of claim 12, wherein execution of the instructions further causes the first device to: estimate an angle of arrival (AoA) of the ACK frame using a plurality of different antenna patterns of the first device.","22.The first device of claim 12, wherein execution of the instructions further causes the first device to: estimate an angle of departure (AoD) of the first FTM frame using a plurality of different antenna patterns of the first device.","23.A non-transitory computer-readable storage medium comprising one or more programs containing instructions that, when executed by one or more processors of a first device, cause the first device to perform a ranging operation with a second device by performing operations comprising: receiving, from the second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; transmitting a first FTM frame to the second device; receiving an acknowledgement (ACK) frame from the second device; and transmitting, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.","24.The non-transitory computer-readable storage medium of claim 23, wherein the angle information comprises at least one of angle of departure (AoD) information of the first FTM frame or angle of arrival (AoA) information of the ACK frame.","25.The non-transitory computer-readable storage medium of claim 23, wherein the timing information indicates a difference between a time of departure (TOD) of the first FTM frame and a time of arrival (TOA) of the ACK frame.","26.The non-transitory computer-readable storage medium of claim 23, wherein the angle information is embedded within one member of the group consisting of a time of departure (TOD) field and a time of arrival (TOA) field of the second FTM frame.","27.The non-transitory computer-readable storage medium of claim 26, wherein the timing information is embedded within the other member of the group consisting of the TOD field and the TOA field of the second FTM frame.","28.The non-transitory computer-readable storage medium of claim 23, wherein execution of the instructions causes the first device to perform operations further comprising: estimating an angle of arrival (AoA) of the ACK frame using a plurality of different antenna patterns of the first device.","29.The non-transitory computer-readable storage medium of claim 23, wherein execution of the instructions causes the first device to perform operations further comprising: estimating an angle of departure (AoD) of the first FTM frame using a plurality of different antenna patterns of the first device.","30.A first device, comprising: means for receiving, from a second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; means for transmitting a first FTM frame to the second device; means for receiving an acknowledgement (ACK) frame from the second device; and means for transmitting, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames."],["<SOH> BACKGROUND OF RELATED ART <EOH>The recent proliferation of Wi-Fig access points in wireless local area networks (WLANs) has made it possible for positioning systems to use these access points for position determination, especially in areas where there are a large concentration of active Wi-Fi access points (e.g., urban cores, shopping centers, office buildings, sporting venues, and so on).","For example, a wireless device such as a cell phone or tablet computer may use the round trip time (RTT) of signals exchanged with an access point (AP) to determine the distance between the wireless device and the AP.","Once the distances between the wireless device and three APs having known locations are determined, the location of the wireless device may be determined using trilateration techniques.","It would be desirable to determine the location of a wireless device using a fewer number of other devices as reference points without sacrificing accuracy."],["<SOH> SUMMARY <EOH>This Summary is provided to introduce in a simplified form a selection of concepts that are further described below in the Detailed Description.","This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to limit the scope of the claimed subject matter.","One innovative aspect of the subject matter described in this disclosure can be implemented as a method for performing a ranging operation between a first device and a second device.","The method may include receiving, from the second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; transmitting a first FTM frame to the second device; receiving an acknowledgement (ACK) frame from the second device; and transmitting, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.","The angle information may include at least one of angle of departure (AoD) information of the first FTM frame or angle of arrival (AoA) information of the ACK frame.","The timing information may indicate a difference between a time of departure (TOD) of the first FTM frame and a time of arrival (TOA) of the ACK frame.","In some aspects, the request may be embedded within a vendor specific information element (VSIE) of the FTM request frame.","Another innovative aspect of the subject matter described in this disclosure can be implemented in a wireless network to perform ranging operations between a first device and a second device.","In some implementations, the first device may include one or more processors and a memory configured to store instructions.","The instructions, when executed by the one or more processors, may cause the first device to receive, from the second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; transmit a first FTM frame to the second device; receive an acknowledgement (ACK) frame from the second device; and transmit, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.","Another innovative aspect of the subject matter described in this disclosure can be implemented in a non-transitory computer-readable storage medium.","The non-transitory computer-readable storage medium may store instructions that, when executed by one or more processors of a first device, cause the first device to perform a number of operations.","In some implementations, the number of operations may include receiving, from a second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; transmitting a first FTM frame to the second device; receiving an acknowledgement (ACK) frame from the second device; and transmitting, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.","Another innovative aspect of the subject matter described in this disclosure can be implemented in a first device.","In some implementations, the first device may include means for receiving, from a second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; means for transmitting a first FTM frame to the second device; means for receiving an acknowledgement (ACK) frame from the second device; and means for transmitting, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames."],["CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. patent application Ser.","No.","15/013,304 entitled “FTM Protocol with Angle of Arrival and Angle of Departure” filed Feb. 2, 2016, which claims priority to U.S.","Provisional Patent Application No.","62/114,479 entitled “FTM Protocol with Angle of Arrival and Angle of Departure” filed Feb. 10, 2015, the entireties of both of which are incorporated by reference herein.","TECHNICAL FIELD The example embodiments relate generally to wireless networks, and specifically to ranging operations performed between wireless devices.","BACKGROUND OF RELATED ART The recent proliferation of Wi-Fig access points in wireless local area networks (WLANs) has made it possible for positioning systems to use these access points for position determination, especially in areas where there are a large concentration of active Wi-Fi access points (e.g., urban cores, shopping centers, office buildings, sporting venues, and so on).","For example, a wireless device such as a cell phone or tablet computer may use the round trip time (RTT) of signals exchanged with an access point (AP) to determine the distance between the wireless device and the AP.","Once the distances between the wireless device and three APs having known locations are determined, the location of the wireless device may be determined using trilateration techniques.","It would be desirable to determine the location of a wireless device using a fewer number of other devices as reference points without sacrificing accuracy.","SUMMARY This Summary is provided to introduce in a simplified form a selection of concepts that are further described below in the Detailed Description.","This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to limit the scope of the claimed subject matter.","One innovative aspect of the subject matter described in this disclosure can be implemented as a method for performing a ranging operation between a first device and a second device.","The method may include receiving, from the second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; transmitting a first FTM frame to the second device; receiving an acknowledgement (ACK) frame from the second device; and transmitting, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.","The angle information may include at least one of angle of departure (AoD) information of the first FTM frame or angle of arrival (AoA) information of the ACK frame.","The timing information may indicate a difference between a time of departure (TOD) of the first FTM frame and a time of arrival (TOA) of the ACK frame.","In some aspects, the request may be embedded within a vendor specific information element (VSIE) of the FTM request frame.","Another innovative aspect of the subject matter described in this disclosure can be implemented in a wireless network to perform ranging operations between a first device and a second device.","In some implementations, the first device may include one or more processors and a memory configured to store instructions.","The instructions, when executed by the one or more processors, may cause the first device to receive, from the second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; transmit a first FTM frame to the second device; receive an acknowledgement (ACK) frame from the second device; and transmit, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.","Another innovative aspect of the subject matter described in this disclosure can be implemented in a non-transitory computer-readable storage medium.","The non-transitory computer-readable storage medium may store instructions that, when executed by one or more processors of a first device, cause the first device to perform a number of operations.","In some implementations, the number of operations may include receiving, from a second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; transmitting a first FTM frame to the second device; receiving an acknowledgement (ACK) frame from the second device; and transmitting, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.","Another innovative aspect of the subject matter described in this disclosure can be implemented in a first device.","In some implementations, the first device may include means for receiving, from a second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; means for transmitting a first FTM frame to the second device; means for receiving an acknowledgement (ACK) frame from the second device; and means for transmitting, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.","BRIEF DESCRIPTION OF THE DRAWINGS The example embodiments are illustrated by way of example and are not intended to be limited by the figures of the accompanying drawings.","Like numbers reference like elements throughout the drawings and specification.","FIG.","1 is a block diagram of a WLAN system within which the example embodiments may be implemented.","FIG.","2 is a block diagram of a wireless device in accordance with example embodiments.","FIG.","3 shows a signal diagram of an example ranging operation.","FIG.","4 shows a signal diagram of another example ranging operation.","FIG.","5A shows a signal diagram of a ranging operation in accordance with example embodiments.","FIG.","5B shows a sequence diagram depicting the ranging operation of FIG.","5A in accordance with example embodiments.","FIG.","6 depicts an example FTM frame in accordance with example embodiments.","FIG.","7A depicts an example angle of arrival field of the FTM frame of FIG.","6, in accordance with example embodiments.","FIG.","7B depicts an example angle of departure field of the FTM frame of FIG.","6, in accordance with example embodiments.","FIG.","8 depicts another example FTM frame in accordance with example embodiments.","FIG.","9 depicts an example angle of arrival and angle of departure field of the FTM frame of FIG.","8, in accordance with example embodiments.","FIG.","10 depicts a coordinate system for use with example embodiments.","FIG.","11 shows an illustrative flowchart depicting an example ranging operation in accordance with example embodiments.","FIG.","12 shows an illustrative flowchart depicting another example ranging operation in accordance with example embodiments.","DETAILED DESCRIPTION The example embodiments are described below in the context of ranging operations performed by and between Wi-Fi enabled devices for simplicity only.","It is to be understood that the example embodiments are equally applicable for performing ranging operations using signals of other various wireless standards or protocols, and for performing ranging operations between various devices (e.g., between a STA and a wireless AP, between APs, between STAs, and so on).","Thus, although the example embodiments are described below in the context of a WLAN system, the example embodiments are equally applicable to other wireless networks (e.g., cellular networks, pico networks, femto networks, satellite networks), as well as for systems using signals of one or more wired standards or protocols (e.g., Ethernet and/or HomePlug/PLC standards).","As used herein, the terms WLAN and Wi-Fi may include communications governed by the IEEE 802.11 standards, Bluetooth, HiperLAN (a set of wireless standards, comparable to the IEEE 802.11 standards, used primarily in Europe), and other technologies having relatively short radio propagation range.","Thus, the terms “WLAN” and “Wi-Fi” may be used interchangeably herein.","In addition, although described below in terms of an infrastructure WLAN system including one or more APs and a number of STAs, the example embodiments are equally applicable to other WLAN systems including, for example, multiple WLANs, Independent Basic Service Set (IBSS) systems, peer-to-peer systems (e.g., operating according to the Wi-Fi Direct protocols), and/or Hotspots.","In addition, although described herein in terms of exchanging data frames between wireless devices, the example embodiments may be applied to the exchange of any data unit, packet, frame, and/or signal between wireless devices.","Thus, the term “frame” may include any signal, frame, packet, or data unit such as, for example, protocol data units (PDUs), media access control (MAC) protocol data units (MPDUs), and physical layer convergence procedure protocol data units (PPDUs).","The term “A-MPDU” may refer to aggregated MPDUs.","As used herein, the term “time value” may refer to a difference in time between a time of departure (TOD) of one frame from a given device and a time of arrival (TOA) of another frame at the given device.","Further, the term “angle information” may refer to information indicating a direction of one device relative to another device and/or to information from which the direction of one device relative to another device may be derived.","The terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting of the aspects.","As used herein, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.","It will be further understood that the terms “comprises,” “comprising,” “includes” or “including,” when used herein, specify the presence of stated features, integers, steps, operations, elements, or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, or groups thereof.","Moreover, it is understood that the word “or” has the same meaning as the Boolean operator “OR,” that is, it encompasses the possibilities of “either” and “both” and is not limited to “exclusive or” (“XOR”), unless expressly stated otherwise.","It is also understood that the symbol “I” between two adjacent words has the same meaning as “or” unless expressly stated otherwise.","In the following description, numerous specific details are set forth such as examples of specific components, circuits, and processes to provide a thorough understanding of this disclosure.","Also, in the following description and for purposes of explanation, specific nomenclature is set forth to provide a thorough understanding of the example embodiments.","However, it will be apparent to one skilled in the art that these specific details may not be required to practice the example embodiments.","In other instances, well-known circuits and devices are shown in block diagram form to avoid obscuring the present disclosure.","The term “coupled” as used herein means connected directly to or connected through one or more intervening components or circuits.","Any of the signals provided over various buses described herein may be time-multiplexed with other signals and provided over one or more common buses.","Additionally, the interconnection between circuit elements or software blocks may be shown as buses or as single signal lines.","Each of the buses may alternatively be a single signal line, and each of the single signal lines may alternatively be buses, and a single line or bus might represent any one or more of a myriad of physical or logical mechanisms for communication between components.","The example embodiments are not to be construed as limited to specific examples described herein but rather to include within their scopes all embodiments defined by the appended claims.","The techniques described herein may be implemented in hardware, software, firmware, or any combination thereof, unless specifically described as being implemented in a specific manner Any features described as modules or components may also be implemented together in an integrated logic device or separately as discrete but interoperable logic devices.","If implemented in software, the techniques may be realized at least in part by a non-transitory processor-readable storage medium comprising instructions that, when executed, performs one or more of the methods described above.","The non-transitory processor-readable data storage medium may form part of a computer program product, which may include packaging materials.","The non-transitory processor-readable storage medium may comprise random access memory (RAM) such as synchronous dynamic random access memory (SDRAM), read only memory (ROM), non-volatile random access memory (NVRAM), electrically erasable programmable read-only memory (EEPROM), FLASH memory, other known storage media, and the like.","The techniques additionally, or alternatively, may be realized at least in part by a processor-readable communication medium that carries or communicates code in the form of instructions or data structures and that may be accessed, read, and/or executed by a computer or other processor.","The various illustrative logical blocks, modules, circuits and instructions described in connection with the embodiments disclosed herein may be executed by one or more processors, such as one or more digital signal processors (DSPs), general purpose microprocessors, application specific integrated circuits (ASICs), application specific instruction set processors (ASIPs), field programmable gate arrays (FPGAs), or other equivalent integrated or discrete logic circuitry.","The term “processor,” as used herein may refer to any of the foregoing structure or any other structure suitable for implementation of the techniques described herein.","In addition, in some aspects, the functionality described herein may be provided within dedicated software modules or hardware modules configured as described herein.","Also, the techniques could be fully implemented in one or more circuits or logic elements.","A general purpose processor may be a microprocessor, but in the alternative, the processor may be any conventional processor, controller, microcontroller, or state machine.","A processor may also be implemented as a combination of computing devices (e.g., a combination of a DSP and a microprocessor), a plurality of microprocessors, one or more microprocessors in conjunction with a DSP core, or any other suitable configuration.","FIG.","1 is a block diagram of a wireless system 100 within which the example embodiments may be implemented.","The wireless system 100 is shown to include four wireless stations STA1-STA4, a wireless access point (AP) 110, and a wireless local area network (WLAN) 120.The WLAN 120 may be formed by a plurality of Wi-Fi access points (APs) that may operate according to the IEEE 802.11 family of standards (or according to other suitable wireless protocols).","Thus, although only one AP 110 is shown in FIG.","1 for simplicity, it is to be understood that WLAN 120 may be formed by any number of access points such as AP 110.The AP 110 is assigned a unique media access control (MAC) address that is programmed therein by, for example, the manufacturer of the access point.","Similarly, each of stations STA1-STA4 is also assigned a unique MAC address.","For some embodiments, the wireless system 100 may correspond to a multiple-input multiple-output (MIMO) wireless network, and may support single-user MIMO (SU-MIMO) and multi-user (MU-MIMO) communications.","Further, although the WLAN 120 is depicted in FIG.","1 as an infrastructure BSS, for other example embodiments, WLAN 120 may be an IBSS, an ad-hoc network, or a peer-to-peer (P2P) network (e.g., operating according to the Wi-Fi Direct protocols).","Each of stations STA1-STA4 may be any suitable Wi-Fi enabled wireless device including, for example, a cell phone, personal digital assistant (PDA), tablet device, laptop computer, or the like.","Each of stations STA1-STA4 may also be referred to as a user equipment (UE), a subscriber station, a mobile unit, a subscriber unit, a wireless unit, a remote unit, a mobile device, a wireless device, a wireless communications device, a remote device, a mobile subscriber station, an access terminal, a mobile terminal, a wireless terminal, a remote terminal, a handset, a user agent, a mobile client, a client, or some other suitable terminology.","For at least some embodiments, each of stations STA1-STA4 may include one or more transceivers, one or more processing resources (e.g., processors and/or ASICs), one or more memory resources, and a power source (e.g., a battery).","The memory resources may include a non-transitory computer-readable medium (e.g., one or more nonvolatile memory elements, such as EPROM, EEPROM, Flash memory, a hard drive, etc.)","that stores instructions for performing operations described below with respect to FIGS.","5A, 5B, 11, and 12.The AP 110 may be any suitable device that allows one or more wireless devices to connect to a network (e.g., a local area network (LAN), wide area network (WAN), metropolitan area network (MAN), and/or the Internet) via AP 110 using Wi-Fi, Bluetooth, or any other suitable wireless communication standards.","For at least one embodiment, AP 110 may include one or more transceivers, one or more processing resources (e.g., processors and/or ASICs), one or more memory resources, and a power source.","The memory resources may include a non-transitory computer-readable medium (e.g., one or more nonvolatile memory elements, such as EPROM, EEPROM, Flash memory, a hard drive, etc.)","that stores instructions for performing operations described below with respect to FIGS.","5A, 5B, 11, and 12.For the stations STA1-STA4 and/or AP 110, the one or more transceivers may include Wi-Fi transceivers, Bluetooth transceivers, cellular transceivers, and/or other suitable radio frequency (RF) transceivers (not shown for simplicity) to transmit and receive wireless communication signals.","Each transceiver may communicate with other wireless devices in distinct operating frequency bands and/or using distinct communication protocols.","For example, the Wi-Fi transceiver may communicate within a 2.4 GHz frequency band, within a 5 GHz frequency band in accordance with the IEEE 802.11 specification, and/or within a 60 GHz frequency band.","The cellular transceiver may communicate within various RF frequency bands in accordance with a 4G Long Term Evolution (LTE) protocol described by the 3rd Generation Partnership Project (3GPP) (e.g., between approximately 700 MHz and approximately 3.9 GHz) and/or in accordance with other cellular protocols (e.g., a Global System for Mobile (GSM) communications protocol).","In other embodiments, the transceivers included within each of the stations STA1-STA4 may be any technically feasible transceiver such as a ZigBee transceiver described by a specification from the ZigBee specification, a WiGig transceiver, and/or a HomePlug transceiver described a specification from the HomePlug Alliance.","For at least some embodiments, each of the stations STA1-STA4 and AP 110 may include radio frequency (RF) ranging circuitry (e.g., formed using well-known software modules, hardware components, and/or a suitable combination thereof) that may be used to estimate the distance between itself and another Wi-Fi enabled device and to determine the location of itself, relative to one or more other wireless devices, using ranging techniques described herein.","In addition, each of the stations STA1-STA4 and/or AP 110 may include a local memory (not shown in FIG.","1 for simplicity) to store a cache of Wi-Fi access point and/or station data.","For at least some embodiments, ranging operations described herein may be performed without using the AP 110, for example, by having a number of the stations operating in an ad-hoc or peer-to-peer mode, thereby allowing the stations to range one another even when outside the reception range of AP 110 or a visible WLAN (or other wireless network).","In addition, for at least some example embodiments, ranging operations described herein may be performed between two APs that are in wireless range of each other.","FIG.","2 shows a wireless device 200 that may be one embodiment of the stations STA1-STA4 and/or AP 110 of FIG.","1.The wireless device 200 may include a PHY device 210 including at least a number of transceivers 211 and a baseband processor 212, may include a MAC 220 including at least a number of contention engines 221 and frame formatting circuitry 222, may include a processor 230, may include a memory 240, and may include a number of antennas 250(1)-250(n).","The transceivers 211 may be coupled to antennas 250(1)-250(n), either directly or through an antenna selection circuit (not shown for simplicity).","The transceivers 211 may be used to transmit signals to and receive signals from AP 110, other stations, and/or other suitable wireless devices (see also FIG.","1), and may be used to scan the surrounding environment to detect and identify nearby access points and other wireless devices (e.g., within wireless range of wireless device 200).","Although not shown in FIG.","2 for simplicity, the transceivers 211 may include any number of transmit chains to process and transmit signals to other wireless devices via antennas 250(1)-250(n), and may include any number of receive chains to process signals received from antennas 250(1)-250(n).","Thus, for example embodiments, the wireless device 200 may be configured for MIMO operations.","The MIMO operations may include SU-MIMO operations and/or MU-MIMO operations.","The baseband processor 212 may be used to process signals received from processor 230 and/or memory 240 and to forward the processed signals to transceivers 211 for transmission via one or more of antennas 250(1)-250(n), and may be used to process signals received from one or more of antennas 250(1)-250(n) via transceivers 211 and to forward the processed signals to processor 230 and/or memory 240.For purposes of discussion herein, MAC 220 is shown in FIG.","2 as being coupled between PHY device 210 and processor 230.For actual embodiments, PHY device 210, MAC 220, processor 230, and/or memory 240 may be connected together using one or more buses (not shown for simplicity).","The contention engines 221 may contend for access to one or more shared wireless mediums, and may also store packets for transmission over the one or more shared wireless mediums.","For other embodiments, the contention engines 221 may be separate from MAC 220.For still other embodiments, the contention engines 221 may be implemented as one or more software modules (e.g., stored in memory 240 or stored in memory provided within MAC 220) containing instructions that, when executed by processor 230, perform the functions of contention engines 221.The frame formatting circuitry 222 may be used to create and/or format frames received from processor 230 and/or memory 240 (e.g., by adding MAC headers to PDUs provided by processor 230), and may be used to re-format frames received from PHY device 210 (e.g., by stripping MAC headers from frames received from PHY device 210).","Memory 240 includes a Wi-Fi database 241 that may store location data, configuration information, data rates, MAC addresses, and other suitable information about (or pertaining to) a number of access points, stations, and/or other wireless devices.","The Wi-Fi database 241 may also store profile information for a number of wireless devices.","The profile information for a given wireless device may include information including, for example, the wireless device's service set identification (SSID), channel information, received signal strength indicator (RSSI) values, goodput values, channel state information (CSI), and connection history with wireless device 200.Memory 240 may also include a non-transitory computer-readable medium (e.g., one or more nonvolatile memory elements, such as EPROM, EEPROM, Flash memory, a hard drive, and so on) that may store the following software (SW) modules: a ranging SW module 242 to determine RTT values and/or to estimate the distance between wireless device 200 and one or more other devices, for example, as described below for one or more operations of FIGS.","5A, 5B, 11, and 12; an angle determination SW module 243 to determine angle of arrival (AoA) information of signals received by wireless device 200 and/or to determine angle of departure (AoD) information of signals transmitted from wireless device 200, for example, as described below for one or more operations of FIGS.","5A, 5B, 11, and 12; a timestamp SW module 244 to capture timestamps of signals received by wireless device 200 (e.g., TOA information) and/or to capture timestamps of signals transmitted from wireless device 200 (e.g., TOD information), for example, as described below for one or more operations of FIGS.","5A, 5B, 11, and 12; a frame formation and exchange SW module 245 to create, send, and/or receive frames or packets and/or to embed TOA information, TOD information, AoA information, and/or AoD information into selected frames or packets, for example, as described below for one or more operations of FIGS.","5A, 5B, 11, and 12; and a positioning SW module 246 to determine the location of wireless device 200 based on the distances determined by the ranging SW module 242 and/or the angle information determined by the angle determination SW module 243, for example, as described below for one or more operations of FIGS.","5A, 5B, 11, and 12.Each software module includes instructions that, when executed by processor 230, cause the wireless device 200 to perform the corresponding functions.","The non-transitory computer-readable medium of memory 240 thus includes instructions for performing all or a portion of the operations of 5A, 5B, 11, and 12.Processor 230, which is coupled to PHY 210, MAC 220, and memory 240, may be one or more suitable processors capable of executing scripts or instructions of one or more software programs stored in wireless device 200 (e.g., within memory 240).","For example, processor 230 may execute the ranging SW module 242 to determine RTT values and/or to estimate the distance between wireless device 200 and one or more other devices.","Processor 230 may execute the angle determination SW module 243 to determine AoA information of signals received by wireless device 200 and/or to determine AoD information of signals transmitted from wireless device 200.Processor 230 may execute the timestamp SW module 244 to capture timestamps of signals received by wireless device 200 (e.g., TOA information) and/or to capture timestamps of signals transmitted from wireless device 200 (e.g., TOD information).","Processor 230 may execute the frame formation and exchange SW module 245 to create, send, and/or receive frames or packets and/or to embed TOA information, TOD information, AoA information, and/or AoD information into selected frames or packets.","Processor 230 may execute the positioning SW module 246 to determine the location of wireless device 200 based on the distances determined by the ranging SW module 242, the angle information determined by the angle determination SW module 243, and/or other suitable information indicative of the position of wireless device 200 relative to one or more other devices.","As mentioned above, the distance between a pair of devices may be determined using the RTT of signals exchanged between the devices.","For example, FIG.","3 shows a signal diagram of an example ranging operation 300 between a first device D1 and a second device D2.The distance (d) between the first device D1 and the second device D2 may be estimated as d=c*RTT/2, where c is the speed of light, and RTT is the summation of the actual signal propagation times of a request (REQ) frame and an acknowledgement (ACK) frame exchanged between device D1 and device D2.Device D1 and device D2 may each be, for example, an access point (e.g., AP 110 of FIG.","1), a station (e.g., one of stations STA1-STA4 of FIG.","1), or another suitable wireless device (e.g., wireless device 200 of FIG.","2).","More specifically, device D2 may estimate the RTT between itself and device D1 using the time of departure (TOD) of the REQ frame transmitted from device D2, the time of arrival (TOA) of the ACK frame received by device D2, and the SIFS duration of device D1.The SIFS duration, which stands for the short interframe space duration, indicates the duration of time between device D1 receiving the REQ frame and transmitting the ACK frame.","The SIFS duration, a range of values for which are provided by the IEEE 802.11 standards, provides Wi-Fi enabled devices time to switch their transceivers from a receive mode (e.g., to receive the REQ frame) to a transmit mode (e.g., to transmit the ACK frame).","Because different make-and-models (and sometimes even same make-and-models) of communication devices have different processing delays, the precise value of SIFS may vary between devices (and even between successive frame receptions/transmissions in the same device).","As a result, the value of SIFS is typically estimated, which often leads to errors in estimating the distance between two devices.","More specifically, the IEEE 802.11 standards define the SIFS duration as 10 us+/−900 ns at 2.4 GHz, 16 us+/−900 ns at 5 GHz, and 3 us+/−900 ns at 60 GHz.","These “standard” SIFS durations include tolerances that may decrease the accuracy of RTT estimates.","For example, even if the SIFS duration of device D1 may be estimated within +/−25 ns, a ranging error of +/−7.5 meters may result (which may be unacceptable for many positioning systems).","To reduce ranging errors resulting from uncertainties in the value of SIFS, recent revisions to the IEEE 802.11 standards call for each ranging device to capture timestamps of incoming and outgoing frames so that the value of RTT may be determined without using SIFS.","For example, FIG.","4 shows a signal diagram of an example ranging operation 400 between device D1 and device D2 performed using Fine Timing Measurement (FTM) frames in accordance with the IEEE 802.11REVmc standards.","Device D1 and device D2 may each be, for example, an access point (e.g., AP 110 of FIG.","1), a station (e.g., one of stations STA1-STA4 of FIG.","1), or other suitable wireless device (e.g., wireless device 200 of FIG.","2).","For the example of FIG.","4, device D2 requests the ranging operation; thus, device D2 is the initiator device (or alternatively the requestor device) and device D1 is the responder device.","Note that the term “initiator device” may also refer to an initiator STA, and the term “responder device” may also refer to a responder STA.","Device D2 may request or initiate the ranging operation by transmitting an FTM request (FTM_REQ) frame to device D1.The FTM_REQ frame may also include a request for device D1 to capture timestamps (e.g., TOA information) of frames received by device D1 and to capture timestamps (e.g., TOD information) of frames transmitted from device D1.Device D1 receives the FTM_REQ frame, and may acknowledge the requested ranging operation by transmitting an acknowledgement (ACK) frame to device D2.The ACK frame may indicate whether device D1 is capable of capturing the requested timestamps.","It is noted that the exchange of the FTM_REQ frame and the ACK frame is a handshake process that not only signals an intent to perform a ranging operation but also allows devices D1 and D2 to determine whether each other supports capturing timestamps.","At time ta1, device D1 transmits a first FTM (FTM_1) frame to device D2, and may capture the TOD of the FTM_1 frame as time ta1.Device D2 receives the FTM_1 frame at time ta2, and may capture the TOA of the FTM_1 frame as time ta2.Device D2 responds by transmitting an ACK frame to device D1 at time ta3, and may capture the TOD of the ACK frame as time ta3.Device D1 receives the ACK frame at time ta4, and may capture the TOA of the ACK frame at time ta4.At time tb1, device D1 transmits to device D2 a second FTM (FTM_2) frame that includes the timestamps captured at times ta1 and ta4 (e.g., the TOD of the FTM_1 frame and the TOA of the ACK frame).","Device D2 receives the FTM_2 frame at time tb2, and may capture its timestamp as time tb2.Device D2 transmits an ACK frame to device D1 at time tb3.Device D1 receives the ACK frame at time tb4.This process may continue for any number of subsequent FTM and ACK frame exchanges between devices D1 and D2, for example, where device D1 embeds the timestamps of a given FTM and ACK frame exchange into a subsequent FTM frame transmitted to device D2.Upon receiving the FTM_2 frame at time tb2, device D2 has timestamp values for times ta1, ta2, ta3, and ta4 that correspond to the TOD of the FTM_1 frame transmitted from device D1, the TOA of the FTM_1 frame at device D2, the TOD of the ACK frame transmitted from device D2, and the TOA of the ACK frame at device D1, respectively.","Thereafter, device D2 may determine RTT as (ta4−ta3)+(ta2−ta1).","Because the RTT estimate does not involve estimating SIFS for either device D1 or device D2, the RTT estimate does not involve errors resulting from uncertainties of SIFS durations.","Consequently, the accuracy of the resulting estimate of the distance between devices D1 and D2 is improved (e.g., as compared to the ranging operation 300 of FIG.","3).","A device may perform this ranging operation with at least three other devices having known locations, and use known trilateration techniques to estimate its location.","Note that the example ranging operation 400 may continue.","For example, device D2 may transmit an ACK frame to device D1 at time tb3 (e.g., to acknowledge reception of the FTM_2 frame).","Device D1 receives the ACK frame at time tm, and may record the TOA of the ACK frame as time tm.","Device D1 may embed another time value in an FTM_3 frame, and then transmit the FTM_3 frame to device D2 at time tc1.The time value embedded in the FTM_3 frame may indicate a difference time value equal to tb4−tb1.While RTT techniques may be used to determine a given device's location relative to another device, the given device may need to perform ranging operations with three other devices to determine its actual position.","More specifically, performing ranging operation 400 with three other devices may involve three separate exchanges of FTM frames (with the three other devices), which not only consumes valuable time but also consumes limited bandwidth of a shared wireless medium.","These are at least some of the technical problems to be solved by the example embodiments.","Two measurements that may be used in addition to RTT information to determine the relative positions of two wireless devices are the angle of arrival (AoA) of signals received by the devices and the angle of departure (AoD) of signals transmitted by the devices.","For example, if a second device has RTT information between itself and a first device, then the second device may estimate the distance between itself and the first device, as described above with respect to FIG.","4.If the second device also has AoA information and/or AoD information for frames exchanged with the first device, then the second device may determine a direction of itself relative to the first device (e.g., an angle between the first and second devices relative to a reference line or direction).","The second device may then use the determined direction and the RTT information to estimate its position relative to the first device.","Further, if the position of the first device is known by the second device, then the second device may determine its actual position using the known position of the first device, the distance between the first and second devices, and the direction of the second device relative to the first device.","Accordingly, it would be advantageous to exchange AoA information and/or AoD information during ranging operations, for example, so that a wireless device may estimate its actual position using the known position of only one other wireless device.","Thus, example apparatuses and methods are disclosed that may allow AoA information and/or AoD information to be exchanged between wireless devices during ranging operations without additional frame exchanges.","More specifically, for at least some embodiments, a first device may determine AoA information and/or AoD information of frames exchanged with a second device during a ranging operation, and then embed the determined AoA information and/or AoD information in a subsequent FTM frame transmitted to the second device.","In this manner, the second device may use the estimated distance to the first device, the direction of the first device relative to the second device, and a known location of the first device to determine the actual position of the second device.","These and other details of the example embodiments, which provide one or more technical solutions to the aforementioned technical problems, are described in more detail below.","FIG.","5A shows a signal diagram of a ranging operation 500 between a first device D1 and a second device D2 in accordance with example embodiments, and FIG.","5B shows a sequence diagram 510 depicting the example ranging operation 500 of FIG.","5A.","Device D1 and device D2 may each be, for example, an access point (e.g., AP 110 of FIG.","1), a station (e.g., one of stations STA1-STA4 of FIG.","1), or another suitable wireless device (e.g., wireless device 200 of FIG.","2).","As the initiator device, device D2 may transmit, to device D1, a request to perform a ranging operation and to indicate its capabilities (512).","The requested capabilities may include, for example, the ability to estimate AoA and AoD information and/or the ability to capture timestamps.","For some implementations, the request may be an FTM_REQ frame, as depicted in FIG.","5A.","The FTM_REQ frame may include a request for device D1 to estimate AoA and/or AoD information.","The FTM_REQ frame may also request a level of accuracy for the estimated AoA and/or AoD information.","Device D1 may receive the request to perform the ranging operation and to indicate its capabilities to device D2 (513).","As the responder device, device D1 may respond to the request by transmitting a response to device D2 (514).","For some implementations, the response may be an ACK frame, as depicted in FIG.","5A.","The ACK frame may indicate whether device D1 is capable of capturing timestamps, may indicate whether device D1 is capable of estimating AoA and AoD information, and/or may indicate a level of accuracy for the estimated AoA and AoD information.","Device D2 may receive the response from device D1, and decode the capabilities (if any) provided by device D1 (515).","After the above handshake process, devices D1 and D2 may exchange FTM frames to perform the ranging operation 500.At time ta1, device D1 transmits an FTM_1 frame to device D2, records the TOD of the FTM_1 frame as time ta1, and may determine the AoD of the FTM_1 frame (denoted in FIG.","5A as AoDa) (516).","Device D2 receives the FTM_1 frame from device D1 at time ta2, and records the TOA of the FTM_1 frame as time to (517).","Device D2 then transmits an ACK frame to device D1 at time ta3, and records the TOD of the ACK frame as time ta3 (518).","Device D1 receives the ACK frame from device D2 at time ta4, records the TOA of the ACK frame as time ta4, and may determine the AoA of the ACK frame (denoted in FIG.","5A as AoAa) (519).","Then, device D1 may embed a time value and angle information in an FTM_2 frame, and transmit the FTM_2 frame to device D2 at time tb1 (520).","The time value (tvalue) may indicate a difference in time between the TOA of the ACK frame received at device D1 and the TOD of the FTM _1 frame transmitted from device D1 (e.g., tvalue=ta4−ta1).","The angle information, which may indicate a direction of device D2 relative to device D1, may include the AoA of the ACK frame received at device D1 (e.g., AoAa) and/or the AoD of the FTM_1 frame transmitted from device D1 (e.g., AoDa).","Note that although device D1 is depicted in FIG.","5A as transmitting a difference time value (ta4−ta1), for other embodiments, device D1 may instead embed the timestamps ta1 and ta4 in the FTM_2 frame.","In some aspects, device D1 may record the TOD of the FTM_2 frame as time tb1, and may determine the AoD of the FTM_2 frame (denoted in FIG.","5A as AoDb).","Device D2 receives the FTM_2 frame at time tb2, and decodes the embedded time value and angle information (521).","At this point, device D2 has sufficient information to estimate its location relative to device D1.More specifically, device D2 may estimate that it is a distance d=c*RTT/2 from device D1 along a direction indicated by the angle information embedded within the FTM_2 frame, where RTT=(ta4−ta3)+(ta2−ta1) (522).","Because device D2 may estimate the distance to device D1 (e.g., based on the RTT value) as well as its direction relative to device D1 (e.g., based on the AoA and/or AoD information embedded in the FTM_2 frame), device D2 may estimate its location relative to device D2.If the actual location of device D1 is known, then device D2 may determine its actual location based on the known location of device D1 and its location relative to device D1.For example, if device D1 is an access point and device D2 is a station, then device D2 may retrieve the location of device D1 (e.g., from a local memory such as the Wi-Fi database 241 of FIG.","2 and/or from any suitable service that stores location information for actively deployed access points).","Thereafter, device D2 may determine its actual location using the location of device D2 relative to device D1, the determined distance between device D1 and device D2, and the known location of device D1.Referring again to FIG.","5A, device D2 may transmit an ACK frame to device D1 at time tb3 (e.g., to acknowledge reception of the FTM_2 frame).","Device D1 receives the ACK frame at time tb4, may record the TOA of the ACK frame as time tb4, and may determine the AoA of the ACK frame (denoted in FIG.","5A as AoAb).","Device D1 may embed another time value and angle information in an FTM_3 frame, and then transmit the FTM_3 frame to device D2 at time tc1.The time value embedded in the FTM_3 frame may indicate a difference time value equal to tb4−tb1, and the angle information embedded in the FTM_3 frame may include the angle information values AoAb and/or AoDb.","Thus, as described above, the example embodiments may allow a first wireless device to determine AoA and/or AoD information of a first set of signals exchanged with a second wireless device, and embed the determined AoA and/or AoD information in a second signal transmitted to the second wireless device.","The second wireless device may use the embedded AoA and/or AoD information in combination with RTT information to estimate its location relative to the first wireless device.","As mentioned above, the initiator device may request the responder device to commence the ranging operation, for example, by transmitting an FTM_REQ frame to the responder device.","The FTM_REQ frame may include a request for the responder device to determine and embed AoA and/or AoD information in one or more subsequent FTM frames.","In some aspects, a dedicated bit in the Vendor Specific Information Element (VSIE) of the FTM_REQ frame may be used (e.g., asserted) to request the responder device to determine AoA and/or AoD information and to embed the determined AoA and/or AoD information in subsequent FTM frames.","In other aspects, a reserved bit of the FTM_REQ frame's VSIE may be used (e.g., asserted) to request the responder device to determine AoA and/or AoD information and to embed the determined AoA and/or AoD information in subsequent FTM frames.","In still other aspects, different bits in the FTM_REQ frame's VSIE may be used (e.g., asserted) to separately request the responder device to embed AoA information and AoD information into subsequent FTM frames.","This may be desirable, for example, when the initiator device needs only one of the AoA information and AoD information to determine its direction relative to device D1.When the responder device receives an FTM_REQ frame that includes a request for AoA and/or AoD information (e.g., the FTM_REQ frame includes an asserted “request” bit in its VSIE), the responder device may infer that the initiator device is capable of decoding AoA and/or AoD information embedded in subsequent FTM frames.","In response thereto, the responder device may either (i) assert one or more bits of a VSIE in the first FTM frame (e.g., the FTM_1 frame) indicating its ability to determine AoA and/or AoD information and confirming that the determined AoA and/or AoD information is to be embedded in subsequent FTM frames or (ii) de-assert the one or more bits of the VSIE in the FTM_1 frame indicating its inability to determine AoA and/or AoD information and/or indicating that AoA and/or AoD information will not be embedded in subsequent FTM frames.","Alternatively, the responder device may indicate that AoA and/or AoD information will not be included in subsequent FTM frames by not including the VSIE in the FTM_1 frame (e.g., to reduce the transmit time of the first FTM frame).","For other embodiments, the responder device may include its acceptance or rejection of the request for AoA and/or AoD information in the ACK frame sent in response to reception of the FTM_REQ frame.","The initiator device may also include, in the FTM_REQ frame, an indication of a desired level of accuracy for AoA and/or AoD measurements by the responder device.","The indication of the desired level of accuracy may be embedded in one or more dedicated bits in the VSIE of the FTM_REQ frame, in one or more reserved bits in the VSIE of the FTM_REQ frame, or in any other suitable bits of the FTM_REQ frame.","In response to receiving an indication of the desired level of accuracy for AoA and/or AoD measurements, the responder device may include, in the FTM_1 frame, an indication of the level of accuracy for the AoA and/or AoD measurements to be embedded in subsequent FTM frames.","The responder device may use the same one or more bit locations of the VSIE in the FTM_1 frame for the response that the initiator device used in the VSIE in the FTM_REQ frame for the request.","For at least some implementations in which the responder device is an access point, the responder device may embed, into a beacon frame, information indicating whether the responder device is capable of estimating AoA and/or AoD information of one or more frames exchanged between the initiator device and the responder device.","In some aspects, this information may be embedded within an information element (IE) or a vendor-specific information element (VSIE) of the beacon frame.","The responder device may broadcast the beacon frame, for example, according to a target beacon transmission time (TBTT) schedule.","FIG.","6 depicts an example FTM frame 600, in accordance with example embodiments.","The FTM frame 600 may include a category field 601, a public action field 602, a dialog token field 603, a follow up dialog token field 604, a TOD field 605, a TOA field 606, a TOD error field 607, a TOA error field 608, an optional LCI report field 609, an optional location civic report field 610, an optional FTM parameters field 611, an optional AoA field 612, and/or an optional AoD field 613.For at least one embodiment, the TOD field 605 may include 6 bytes, the TOA field 606 may include 6 bytes, the AoA field 612 may include 5 bytes, and the AoD field 613 may include 5 bytes (although for other embodiments, other field lengths may be used).","The AoA field 612 may include AoA information for frames exchanged during a ranging operation, and the AoD field 613 may include AoD information for frames exchanged during the ranging operation.","For example, referring also to FIG.","5A, the responder device (e.g., device D1) may embed AoA information of the received ACK frame into the AoA field 612 of FTM frame 600, and may embed AoD information of the FTM_1 frame into the AoD field 613 of FTM frame 600.In some aspects, the responder device may embed TOA information of the received ACK frame into the TOA field 606 of FTM frame 600, and may embed TOD information of the FTM_1 frame into the TOD field 605 of FTM frame 600.Thereafter, the responder device may use the FTM frame 600 as the FTM_2 frame in the example ranging operation 500 of FIG.","5A, for example, to transmit angle information (e.g., AoDa and/or AoAa) and the time value (e.g., ta4−ta1) to the initiator device.","FIG.","7A depicts an example field 700 that may be one embodiment of the AoA field 612 of FIG.","6.The field 700 may include an Element ID field 701, a Length field 702, and an AoA field 703.For at least one embodiment, the Element ID field 701 may include one byte, the Length field 702 may include one byte, and the AoA field 703 may include 5 bytes (although for other embodiments, other field lengths may be used).","The Element ID field 701 may store an element ID value indicating that field 700 contains angle of arrival information for a selected frame (e.g., the AoA information for the ACK frame received from device D2 in the example ranging operation 500 of FIG.","5A).","The Length field 702 may store a value indicating a length (in bytes) of field 700.The AoA field 703 may store angle of arrival information for the selected frame.","More specifically, in some implementations, the AoA field 703 may store values for Theta_AoA and Phi_AoA which, as described in more detail below with respect to FIG.","10, may indicate angle of arrival information of the selected frame.","FIG.","7B depicts an example field 710 that may be one embodiment of the AoD field 613 of FIG.","6.The field 710 may include an Element ID field 711, a Length field 712, and an AoD field 713.For at least one embodiment, the Element ID field 711 may include one byte, the Length field 712 may include one byte, and the AoD field 713 may include 5 bytes (although for other embodiments, other field lengths may be used).","The Element ID field 711 may store an element ID value indicating that field 710 contains angle of departure information for a selected frame (e.g., the AoD information for the FTM_1 frame used in the example ranging operation 500 of FIG.","5A).","The Length field 712 may store a value indicating a length (in bytes) of field 710.The AoD field 713 may store angle of departure information for the selected frame.","More specifically, in some implementations, the AoD field 713 may store values for Theta_AoD and Phi_AoD which, as described in more detail below with respect to FIG.","10, may indicate angle of departure information of the selected frame.","FIG.","8 depicts another example FTM frame 800, in accordance with example embodiments.","The FTM frame 800 is similar to FTM frame 600 of FIG.","6, except that instead of including separate AoA and AoD fields 612 and 613, respectively, FTM frame 800 includes a combined AoA and AoD field 803.For at least one embodiment, the TOD field 605 may include 6 bytes, the TOA field 606 may include 6 bytes, and the combined AoA and AoD field 803 may include 8 bytes (although for other embodiments, other field lengths may be used).","The combined AoA and AoD field 803 may include both AoA and AoD information for frames exchanged during a ranging operation.","For example, referring also to FIG.","5A, the responder device (e.g., device D1) may embed AoA information of the received ACK frame and AoD information of the FTM_1 frame into the combined AoD and AoD field 803 of FTM frame 800.In some aspects, the responder device may embed TOA information of the received ACK frame into the TOA field 606 of FTM frame 800, and may embed TOD information of the FTM_1 frame into the TOD field 605 of FTM frame 800.Thereafter, the responder device D1 may use the FTM frame 800 as the FTM_2 frame in the example ranging operation 500 of FIG.","5, for example, to transmit information indicating values for AoDa, AoAa, and ta4−ta1 to device D2.For example embodiments in which the AoA field 612 and the AoD field 613 of FTM frame 600 each include 5 bytes and the combined AoA and AoD field 803 of FTM frame 800 includes 8 bytes, the FTM frame 800 of FIG.","8 may include 2 fewer bytes than the FTM frame 600 of FIG.","6, and thus may be transmitted in less time than FTM frame 600 (albeit at a cost of less resolution).","FIG.","9 depicts an example field 900 that may be one embodiment of the combined AoA and AoD 803 of FIG.","8.The field 900 may include an Element ID field 901, a Length field 902, an AoA field 903, and an AoD field 904.For at least one embodiment, the Element ID field 901 may include one byte, the Length field 902 may include one byte, the AoA field 903 may include 3 bytes, and the AoD field 904 may include 3 bytes (although for other embodiments, other field lengths may be used).","The Element ID field 901 may store an element ID value indicating that field 900 contains angle of arrival and angle of departure information for a selected frame exchange (e.g., the AoA of the ACK frame received from device D2 and the AoD of the FTM_1 frame in the example ranging operation 500 of FIG.","5A).","The Length field 902 may store a value indicating a length (in bytes) of field 900.The AoA field 903 may store angle of arrival information for the selected frame exchange, and the AoD field 904 may store angle of departure information for the selected frame exchange.","More specifically, in some implementations, the AoA field 903 may store values for Theta_AoA and Phi_AoA, and the AoD field 904 may store values for Theta_AoD and Phi_AoD which, as described in more detail below with respect to FIG.","10, may indicate angle of arrival and angle of departure information for frames exchanged during a ranging operation.","FIG.","10 is an example 3-dimensional coordinate system 1000 for representing the position of a wireless device using a radius “r” and angles “theta” and “phi.” As depicted in FIG.","10, phi may be an angle with respect to the horizontal (x-y) plane, while theta may be an angle with respect to the vertical (z) axis.","Phi may range from 0° to 360°, while theta may range from 0° to 180° .","The radius r is the distance between the origin and a point coordinate (r, θ, and φ) representing the location of a wireless device relative to the origin.","Referring also to FIG.","9, the first 12 bits of the AoA field 903 may be used to indicate a value for Theta_AoA, and the second 12 bits of the AoA field 903 may be used to indicate a value for Phi_AoA.","Similarly, the first 12 bits of the AoD field 904 may be used to indicate a value for Theta_AoD, and the second 12 bits of the AoD field 904 may be used to indicate a value for Phi_AoD.","For the example field 900 of FIG.","9, the 12-bit values for Theta_AoA and Theta_AoD may provide a resolution of approximately 0.044° (180° divided by (212−1)), while the 12-bit values for Phi_AoA and Phi_AoD may provide a resolution of approximately 0.088° (360° divided by (212−1)).","FTM frames formatted according to current FTM protocols (e.g., as defined by the IEEE 802.11REVmc standards) include a 6-byte TOD field and a 6-byte TOA field to store TOD and TOA information, respectively (e.g., to embed timestamp values ta1 and ta4 of FIG.","5A).","Because an RTT value may be calculated using a single time difference value (e.g., ta4−ta1) rather than two individual timestamp values (e.g., ta4 and ta1), one of these TOD and TOA fields may be re-purposed to store AoA and AoD information, thereby eliminating the need for an FTM frame to include a separate field that stores AoA and AoD information (and thus reducing the size of the FTM frame).","More specifically, in accordance with example embodiments, one of the TOD and TOA fields of an FTM frame may be used store a single time difference value for a ranging operation, and the other of the TOD and TOA fields of the FTM frame may be used to store AoA and AoD information for the ranging operation without compromising accuracy of RTT estimates.","Referring also to FIGS.","5A, 6, and 8, for some implementations, the TOD field 605 of FTM frame 600 or FTM frame 800 may be used to store the time value (ta4−ta1), and the TOA field 606 of FTM frame 600 or FTM frame 800 may be used to store AoA and AoD information (e.g., AoAa and AoDa).","In some aspects, the TOA field 606 may store four 12-bit values: Theta_AoA, Phi_AoA, Theta_AoD, and Phi_AoD.","The format of the TOA field 606 may be expressed as: {Theta_AoA[0:11], Phi_AoA[0:11], Theta_AoD [0:11], Phi_AoD[0:11]}.","For other implementations, the TOA field 606 of FTM frame 600 or FTM frame 800 may be used to store the time difference value (ta4−ta1), and the TOD field 605 of FTM frame 600 or FTM frame 800 may be used to store AoA and AoD information (e.g., AoAa and AoDa).","In some aspects, the TOD 605 field may store four 12-bit values: Theta_AoA, Phi_AoA, Theta_AoD, and Phi_AoD.","The format of the TOD field 605 may be expressed as: {Theta_AoA[0:11], Phi_AoA[0:11], Theta_AoD[0:11], Phi_AoD[0:11]}.","Any suitable techniques may be used to estimate AoA information of frames received by the responder device and/or to estimate AoD information for frames transmitted from the responder device.","For at least some embodiments, the responder device may use a number of different antenna patterns when estimating the AoA information of ACK frames received from the initiator device.","More specifically, when the responder device includes a number N>2 antennas, the responder device may selectively enable different combinations of the antennas and estimate the channel conditions for a corresponding number of different antenna patterns.","The channel condition estimates may be used to estimate AoA information of the ACK frame for various antenna patterns.","Because ACK frames typically include one or more predetermined bit patterns (e.g., known to the responder device), ACK frames may be well suited for estimating channel conditions.","The responder device may use the entire ACK frame for estimating channel conditions and/or estimating AoA information.","Using the entire ACK frame may allow the responder device to switch between the various antenna patterns during reception of the ACK frame.","When the responder device cannot process the entire ACK frame (e.g., the responder device may be able to process only legacy fields such as the legacy long training field (L-LTF)), then the responder device may estimate the channel conditions and AoA information using a sequence of N exchanged FTM and ACK frames (e.g., using one FTM/ACK frame exchange for each antenna pattern).","As mentioned above, the responder device may estimate AoA information using any suitable technique.","These techniques may include (but are not limited to): correlation; maximum likelihood estimation; Multiple Signal Classification (MUSIC) techniques, including variants such as Root-MUSIC, Cyclic MUSIC, or Smooth MUSIC; Estimation of Signal Parameters using Rotational Invariance Techniques (ESPRIT); Matrix Pencil; or other techniques for estimating AoA information.","Thus, as described above with respect to FIG.","10, an initiator device may use RTT information and AoA/AoD information to estimate a relative distance vector indicating its position relative to a responder device.","If the 3-dimensional (3D) location of the responder device is known, then the relative distance vector may allow the initiator device to estimate its own 3D location.","If only the 2-dimensional (2D) location of the responder device is known, then the initiator device may estimate its own 2D location by projecting the estimated relative distance vector onto the 2D plane.","FIG.","11 is an illustrative flow chart depicting an example ranging operation 1100 between a first device D1 and a second device D2 in accordance with example embodiments.","Device D1 and device D2 may each be, for example, an access point (e.g., AP 110 of FIG.","1), a station (e.g., one of stations STA1-STA4 of FIG.","1), or other suitable wireless device (e.g., wireless device 200 of FIG.","2).","For the example operation 1100 of FIG.","11, device D2 is the initiator device, and device D1 is the responder device.","First, device D2 transmits, to device D1, an FTM_REQ frame that includes a request for device D1 to estimate AoA and/or AoD information for one or more frames exchanged between device D1 and device D2 (1102).","The FTM_REQ frame may also indicate a desired level of accuracy for the requested AoA/AoD information.","Device D1 receives the FTM_REQ frame, and then transmits an ACK frame indicating whether device D1 is capable of estimating AoA and/or AoD information (and whether the estimated AoA and/or AoD information will be included in subsequent FTM frames) (1104).","The ACK frame may include the level of accuracy to be provided for the requested AoA/AoD information.","Device D1 transmits an FTM_1 frame to device D2, records the TOD of the FTM_1 frame as time t1, and estimates the AoD of the FTM_1 frame (1106).","For other embodiments, the FTM_1 frame may indicate whether device D1 is capable of estimating AoA and/or AoD information (and whether the estimated AoA and/or AoD information will be included in subsequent FTM frames).","Device D2 receives the FTM_1 frame, and records the TOA of the FTM_1 frame as time t2 (1108).","Device D2 transmits an ACK frame to device D1, and records the TOD of the ACK frame as time t3 (1110).","Device D1 receives the ACK frame at time t4, records the TOA of the ACK frame as time t4, and estimates the AoA of the ACK frame (1112).","Device D1 transmits, to device D2, an FTM_2 frame that includes a time value and angle information (1114).","The time value may indicate a difference in time between the TOD of the FTM_1 frame transmitted from device D1 and the TOA of the ACK frame received at device D1 (e.g., the time value may be equal to t4−t1).","The angle information may indicate a direction of device D2 relative to device D1.In some aspects, the angle information may include the AoD of the FTM_1 frame transmitted from device D1 and/or the AoA of the ACK frame received at device D1 (1114).","For other embodiments, the FTM_2 frame may include the actual timestamps for times t1 and t4 (e.g., rather than the time value indicating the difference in time between time t4 and time t1).","Device D2 may determine a distance between itself and device D1 based on one or more RTT values (1116).","For example, device D2 may determine the distance d between device D1 and device D2 using the expression d=c*RTT/2, where c is the speed of light, and RTT is the summation of the actual signal propagation times of the FTM_1 frame and the ACK frame.","More specifically, the value of RTT may be determined as (t4−t1)−(t3−t2).","Thereafter, device D2 may determine its location relative to device D1 based, at least in part, on the determined distance and the angle information (1118).","FIG.","12 is an illustrative flow chart depicting another example ranging operation 1200 between a first device D1 and a second device D2 in accordance with example embodiments.","The first device D1 and the second device D2 may each be, for example, an access point (e.g., AP 110 of FIG.","1), a station (e.g., one of stations STA1-STA4 of FIG.","1), or other suitable wireless device (e.g., wireless device 200 of FIG.","2).","For the example operation 1200 of FIG.","21, the second device D2 is the initiator device, and the first device D1 is the responder device.","The first device may receive, from the second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information (1202).","In some aspects, the request may be embedded within a vendor specific information element (VSIE) of the FTM request frame.","The first device may transmit a first FTM frame to the second device (1204).","In some implementations, the first FTM frame may indicate a level of accuracy the with which first device is to estimate the angle information.","In some aspects, the indicated level of accuracy is embedded in an information element (IE) of the first FTM frame.","The first device may receive an acknowledgement (ACK) frame from the second device (1206), and may transmit, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames (1208).","The angle information may include at least one of angle of departure (AoD) information of the first FTM frame or angle of arrival (AoA) information of the ACK frame.","The timing information may indicate a difference between a time of departure (TOD) of the first FTM frame and a time of arrival (TOA) of the ACK frame.","The first device may estimate an AoA of the ACK frame using a plurality of different antenna patterns (1208), and may estimate an AoD of the first FTM frame using a plurality of different antenna patterns (1210).","Those of skill in the art will appreciate that information and signals may be represented using any of a variety of different technologies and techniques.","For example, data, instructions, commands, information, signals, bits, symbols, and chips that may be referenced throughout the above description may be represented by voltages, currents, electromagnetic waves, magnetic fields or particles, optical fields or particles, or any combination thereof.","Further, those of skill in the art will appreciate that the various illustrative logical blocks, modules, circuits, and algorithm steps described in connection with the aspects disclosed herein may be implemented as electronic hardware, computer software, or combinations of both.","To clearly illustrate this interchangeability of hardware and software, various illustrative components, blocks, modules, circuits, and steps have been described above generally in terms of their functionality.","Whether such functionality is implemented as hardware or software depends upon the particular application and design constraints imposed on the overall system.","Skilled artisans may implement the described functionality in varying ways for each particular application, but such implementation decisions should not be interpreted as causing a departure from the scope of the disclosure.","The methods, sequences or algorithms described in connection with the aspects disclosed herein may be embodied directly in hardware, in a software module executed by a processor, or in a combination of the two.","A software module may reside in RAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory, registers, hard disk, a removable disk, a CD-ROM, or any other form of storage medium known in the art.","An exemplary storage medium is coupled to the processor such that the processor can read information from, and write information to, the storage medium.","In the alternative, the storage medium may be integral to the processor.","Accordingly, one aspect of the disclosure can include a non-transitory computer readable media embodying a method for time and frequency synchronization in non-geosynchronous satellite communication systems.","The term “non-transitory” does not exclude any physical storage medium or memory and particularly does not exclude dynamic memory (e.g., conventional random access memory (RAM)) but rather excludes only the interpretation that the medium can be construed as a transitory propagating signal.","While the foregoing disclosure shows illustrative aspects, it should be noted that various changes and modifications could be made herein without departing from the scope of the appended claims.","The functions, steps or actions of the method claims in accordance with aspects described herein need not be performed in any particular order unless expressly stated otherwise.","Furthermore, although elements may be described or claimed in the singular, the plural is contemplated unless limitation to the singular is explicitly stated.","Accordingly, the disclosure is not limited to the illustrated examples and any means for performing the functionality described herein are included in aspects of the disclosure."]],"string":"[\n [\n \"FTM PROTOCOL WITH ANGLE OF ARRIVAL AND ANGLE OF DEPARTURE\",\n \"Apparatuses and methods are disclosed for performing ranging operations between a first device and a second device.\",\n \"The first device may receive, from the second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information.\",\n \"The first device may transmit a first FTM frame to the second device, may receive an acknowledgement (ACK) frame from the second device, and may transmit, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.\"\n ],\n [\n \"1.A method of performing a ranging operation between a first device and a second device, comprising: receiving, from the second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; transmitting a first FTM frame to the second device; receiving an acknowledgement (ACK) frame from the second device; and transmitting, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.\",\n \"2.The method of claim 1, wherein the request is embedded within a vendor specific information element (VSIE) of the FTM request frame.\",\n \"3.The method of claim 1, wherein the angle information comprises at least one of angle of departure (AoD) information of the first FTM frame or angle of arrival (AoA) information of the ACK frame.\",\n \"4.The method of claim 1, wherein the timing information indicates a difference between a time of departure (TOD) of the first FTM frame and a time of arrival (TOA) of the ACK frame.\",\n \"5.The method of claim 1, wherein the angle information is embedded within one member of the group consisting of a time of departure (TOD) field and a time of arrival (TOA) field of the second FTM frame.\",\n \"6.The method of claim 5, wherein the timing information is embedded within the other member of the group consisting of the TOD field and the TOA field of the second FTM frame.\",\n \"7.The method of claim 1, further comprising: embedding, into a beacon frame, information indicating whether the first device is capable of estimating angle of arrival (AoA) information or angle of departure (AoD) information; and broadcasting the beacon frame to at least the second device.\",\n \"8.The method of claim 1, further comprising: transmitting, to the second device, a response frame indicating a level of accuracy with which the first device is to estimate the angle information.\",\n \"9.The method of claim 8, wherein the response frame comprises the first FTM frame, and the indicated level of accuracy is embedded in an information element (IE) of the first FTM frame.\",\n \"10.The method of claim 1, further comprising: estimating an angle of arrival (AoA) of the ACK frame using a plurality of different antenna patterns of the first device.\",\n \"11.The method of claim 1, further comprising: estimating an angle of departure (AoD) of the first FTM frame using a plurality of different antenna patterns of the first device.\",\n \"12.A first device, comprising: one or more processors; and a memory configured to store instructions that, when executed by the one or more processors, causes the first device to: receive, from a second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; transmit a first FTM frame to the second device; receive an acknowledgement (ACK) frame from the second device; and transmit, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.\",\n \"13.The first device of claim 12, wherein the request is embedded within a vendor specific information element (VSIE) of the FTM request frame.\",\n \"14.The first device of claim 12, wherein the angle information comprises at least one of angle of departure (AoD) information of the first FTM frame or angle of arrival (AoA) information of the ACK frame.\",\n \"15.The first device of claim 12, wherein the timing information indicates a difference between a time of departure (TOD) of the first FTM frame and a time of arrival (TOA) of the ACK frame.\",\n \"16.The first device of claim 12, wherein the angle information is embedded within one member of the group consisting of a time of departure (TOD) field and a time of arrival (TOA) field of the second FTM frame.\",\n \"17.The first device of claim 16, wherein the timing information is embedded within the other member of the group consisting of the TOD field and the TOA field of the second FTM frame.\",\n \"18.The first device of claim 12, wherein execution of the instructions further causes the first device to: embed, into a beacon frame, information indicating whether the first device is capable of estimating angle of arrival (AoA) information or angle of departure (AoD) information; and broadcast the beacon frame to at least the second device.\",\n \"19.The first device of claim 12, wherein execution of the instructions further causes the first device to: transmit, to the second device, a response frame indicating a level of accuracy the with which first device is to estimate the angle information.\",\n \"20.The first device of claim 19, wherein the response frame comprises the first FTM frame, and the indicated level of accuracy is embedded in an information element (IE) of the first FTM frame.\",\n \"21.The first device of claim 12, wherein execution of the instructions further causes the first device to: estimate an angle of arrival (AoA) of the ACK frame using a plurality of different antenna patterns of the first device.\",\n \"22.The first device of claim 12, wherein execution of the instructions further causes the first device to: estimate an angle of departure (AoD) of the first FTM frame using a plurality of different antenna patterns of the first device.\",\n \"23.A non-transitory computer-readable storage medium comprising one or more programs containing instructions that, when executed by one or more processors of a first device, cause the first device to perform a ranging operation with a second device by performing operations comprising: receiving, from the second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; transmitting a first FTM frame to the second device; receiving an acknowledgement (ACK) frame from the second device; and transmitting, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.\",\n \"24.The non-transitory computer-readable storage medium of claim 23, wherein the angle information comprises at least one of angle of departure (AoD) information of the first FTM frame or angle of arrival (AoA) information of the ACK frame.\",\n \"25.The non-transitory computer-readable storage medium of claim 23, wherein the timing information indicates a difference between a time of departure (TOD) of the first FTM frame and a time of arrival (TOA) of the ACK frame.\",\n \"26.The non-transitory computer-readable storage medium of claim 23, wherein the angle information is embedded within one member of the group consisting of a time of departure (TOD) field and a time of arrival (TOA) field of the second FTM frame.\",\n \"27.The non-transitory computer-readable storage medium of claim 26, wherein the timing information is embedded within the other member of the group consisting of the TOD field and the TOA field of the second FTM frame.\",\n \"28.The non-transitory computer-readable storage medium of claim 23, wherein execution of the instructions causes the first device to perform operations further comprising: estimating an angle of arrival (AoA) of the ACK frame using a plurality of different antenna patterns of the first device.\",\n \"29.The non-transitory computer-readable storage medium of claim 23, wherein execution of the instructions causes the first device to perform operations further comprising: estimating an angle of departure (AoD) of the first FTM frame using a plurality of different antenna patterns of the first device.\",\n \"30.A first device, comprising: means for receiving, from a second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; means for transmitting a first FTM frame to the second device; means for receiving an acknowledgement (ACK) frame from the second device; and means for transmitting, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.\"\n ],\n [\n \"<SOH> BACKGROUND OF RELATED ART <EOH>The recent proliferation of Wi-Fig access points in wireless local area networks (WLANs) has made it possible for positioning systems to use these access points for position determination, especially in areas where there are a large concentration of active Wi-Fi access points (e.g., urban cores, shopping centers, office buildings, sporting venues, and so on).\",\n \"For example, a wireless device such as a cell phone or tablet computer may use the round trip time (RTT) of signals exchanged with an access point (AP) to determine the distance between the wireless device and the AP.\",\n \"Once the distances between the wireless device and three APs having known locations are determined, the location of the wireless device may be determined using trilateration techniques.\",\n \"It would be desirable to determine the location of a wireless device using a fewer number of other devices as reference points without sacrificing accuracy.\"\n ],\n [\n \"<SOH> SUMMARY <EOH>This Summary is provided to introduce in a simplified form a selection of concepts that are further described below in the Detailed Description.\",\n \"This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to limit the scope of the claimed subject matter.\",\n \"One innovative aspect of the subject matter described in this disclosure can be implemented as a method for performing a ranging operation between a first device and a second device.\",\n \"The method may include receiving, from the second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; transmitting a first FTM frame to the second device; receiving an acknowledgement (ACK) frame from the second device; and transmitting, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.\",\n \"The angle information may include at least one of angle of departure (AoD) information of the first FTM frame or angle of arrival (AoA) information of the ACK frame.\",\n \"The timing information may indicate a difference between a time of departure (TOD) of the first FTM frame and a time of arrival (TOA) of the ACK frame.\",\n \"In some aspects, the request may be embedded within a vendor specific information element (VSIE) of the FTM request frame.\",\n \"Another innovative aspect of the subject matter described in this disclosure can be implemented in a wireless network to perform ranging operations between a first device and a second device.\",\n \"In some implementations, the first device may include one or more processors and a memory configured to store instructions.\",\n \"The instructions, when executed by the one or more processors, may cause the first device to receive, from the second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; transmit a first FTM frame to the second device; receive an acknowledgement (ACK) frame from the second device; and transmit, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.\",\n \"Another innovative aspect of the subject matter described in this disclosure can be implemented in a non-transitory computer-readable storage medium.\",\n \"The non-transitory computer-readable storage medium may store instructions that, when executed by one or more processors of a first device, cause the first device to perform a number of operations.\",\n \"In some implementations, the number of operations may include receiving, from a second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; transmitting a first FTM frame to the second device; receiving an acknowledgement (ACK) frame from the second device; and transmitting, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.\",\n \"Another innovative aspect of the subject matter described in this disclosure can be implemented in a first device.\",\n \"In some implementations, the first device may include means for receiving, from a second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; means for transmitting a first FTM frame to the second device; means for receiving an acknowledgement (ACK) frame from the second device; and means for transmitting, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. patent application Ser.\",\n \"No.\",\n \"15/013,304 entitled “FTM Protocol with Angle of Arrival and Angle of Departure” filed Feb. 2, 2016, which claims priority to U.S.\",\n \"Provisional Patent Application No.\",\n \"62/114,479 entitled “FTM Protocol with Angle of Arrival and Angle of Departure” filed Feb. 10, 2015, the entireties of both of which are incorporated by reference herein.\",\n \"TECHNICAL FIELD The example embodiments relate generally to wireless networks, and specifically to ranging operations performed between wireless devices.\",\n \"BACKGROUND OF RELATED ART The recent proliferation of Wi-Fig access points in wireless local area networks (WLANs) has made it possible for positioning systems to use these access points for position determination, especially in areas where there are a large concentration of active Wi-Fi access points (e.g., urban cores, shopping centers, office buildings, sporting venues, and so on).\",\n \"For example, a wireless device such as a cell phone or tablet computer may use the round trip time (RTT) of signals exchanged with an access point (AP) to determine the distance between the wireless device and the AP.\",\n \"Once the distances between the wireless device and three APs having known locations are determined, the location of the wireless device may be determined using trilateration techniques.\",\n \"It would be desirable to determine the location of a wireless device using a fewer number of other devices as reference points without sacrificing accuracy.\",\n \"SUMMARY This Summary is provided to introduce in a simplified form a selection of concepts that are further described below in the Detailed Description.\",\n \"This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to limit the scope of the claimed subject matter.\",\n \"One innovative aspect of the subject matter described in this disclosure can be implemented as a method for performing a ranging operation between a first device and a second device.\",\n \"The method may include receiving, from the second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; transmitting a first FTM frame to the second device; receiving an acknowledgement (ACK) frame from the second device; and transmitting, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.\",\n \"The angle information may include at least one of angle of departure (AoD) information of the first FTM frame or angle of arrival (AoA) information of the ACK frame.\",\n \"The timing information may indicate a difference between a time of departure (TOD) of the first FTM frame and a time of arrival (TOA) of the ACK frame.\",\n \"In some aspects, the request may be embedded within a vendor specific information element (VSIE) of the FTM request frame.\",\n \"Another innovative aspect of the subject matter described in this disclosure can be implemented in a wireless network to perform ranging operations between a first device and a second device.\",\n \"In some implementations, the first device may include one or more processors and a memory configured to store instructions.\",\n \"The instructions, when executed by the one or more processors, may cause the first device to receive, from the second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; transmit a first FTM frame to the second device; receive an acknowledgement (ACK) frame from the second device; and transmit, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.\",\n \"Another innovative aspect of the subject matter described in this disclosure can be implemented in a non-transitory computer-readable storage medium.\",\n \"The non-transitory computer-readable storage medium may store instructions that, when executed by one or more processors of a first device, cause the first device to perform a number of operations.\",\n \"In some implementations, the number of operations may include receiving, from a second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; transmitting a first FTM frame to the second device; receiving an acknowledgement (ACK) frame from the second device; and transmitting, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.\",\n \"Another innovative aspect of the subject matter described in this disclosure can be implemented in a first device.\",\n \"In some implementations, the first device may include means for receiving, from a second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information; means for transmitting a first FTM frame to the second device; means for receiving an acknowledgement (ACK) frame from the second device; and means for transmitting, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS The example embodiments are illustrated by way of example and are not intended to be limited by the figures of the accompanying drawings.\",\n \"Like numbers reference like elements throughout the drawings and specification.\",\n \"FIG.\",\n \"1 is a block diagram of a WLAN system within which the example embodiments may be implemented.\",\n \"FIG.\",\n \"2 is a block diagram of a wireless device in accordance with example embodiments.\",\n \"FIG.\",\n \"3 shows a signal diagram of an example ranging operation.\",\n \"FIG.\",\n \"4 shows a signal diagram of another example ranging operation.\",\n \"FIG.\",\n \"5A shows a signal diagram of a ranging operation in accordance with example embodiments.\",\n \"FIG.\",\n \"5B shows a sequence diagram depicting the ranging operation of FIG.\",\n \"5A in accordance with example embodiments.\",\n \"FIG.\",\n \"6 depicts an example FTM frame in accordance with example embodiments.\",\n \"FIG.\",\n \"7A depicts an example angle of arrival field of the FTM frame of FIG.\",\n \"6, in accordance with example embodiments.\",\n \"FIG.\",\n \"7B depicts an example angle of departure field of the FTM frame of FIG.\",\n \"6, in accordance with example embodiments.\",\n \"FIG.\",\n \"8 depicts another example FTM frame in accordance with example embodiments.\",\n \"FIG.\",\n \"9 depicts an example angle of arrival and angle of departure field of the FTM frame of FIG.\",\n \"8, in accordance with example embodiments.\",\n \"FIG.\",\n \"10 depicts a coordinate system for use with example embodiments.\",\n \"FIG.\",\n \"11 shows an illustrative flowchart depicting an example ranging operation in accordance with example embodiments.\",\n \"FIG.\",\n \"12 shows an illustrative flowchart depicting another example ranging operation in accordance with example embodiments.\",\n \"DETAILED DESCRIPTION The example embodiments are described below in the context of ranging operations performed by and between Wi-Fi enabled devices for simplicity only.\",\n \"It is to be understood that the example embodiments are equally applicable for performing ranging operations using signals of other various wireless standards or protocols, and for performing ranging operations between various devices (e.g., between a STA and a wireless AP, between APs, between STAs, and so on).\",\n \"Thus, although the example embodiments are described below in the context of a WLAN system, the example embodiments are equally applicable to other wireless networks (e.g., cellular networks, pico networks, femto networks, satellite networks), as well as for systems using signals of one or more wired standards or protocols (e.g., Ethernet and/or HomePlug/PLC standards).\",\n \"As used herein, the terms WLAN and Wi-Fi may include communications governed by the IEEE 802.11 standards, Bluetooth, HiperLAN (a set of wireless standards, comparable to the IEEE 802.11 standards, used primarily in Europe), and other technologies having relatively short radio propagation range.\",\n \"Thus, the terms “WLAN” and “Wi-Fi” may be used interchangeably herein.\",\n \"In addition, although described below in terms of an infrastructure WLAN system including one or more APs and a number of STAs, the example embodiments are equally applicable to other WLAN systems including, for example, multiple WLANs, Independent Basic Service Set (IBSS) systems, peer-to-peer systems (e.g., operating according to the Wi-Fi Direct protocols), and/or Hotspots.\",\n \"In addition, although described herein in terms of exchanging data frames between wireless devices, the example embodiments may be applied to the exchange of any data unit, packet, frame, and/or signal between wireless devices.\",\n \"Thus, the term “frame” may include any signal, frame, packet, or data unit such as, for example, protocol data units (PDUs), media access control (MAC) protocol data units (MPDUs), and physical layer convergence procedure protocol data units (PPDUs).\",\n \"The term “A-MPDU” may refer to aggregated MPDUs.\",\n \"As used herein, the term “time value” may refer to a difference in time between a time of departure (TOD) of one frame from a given device and a time of arrival (TOA) of another frame at the given device.\",\n \"Further, the term “angle information” may refer to information indicating a direction of one device relative to another device and/or to information from which the direction of one device relative to another device may be derived.\",\n \"The terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting of the aspects.\",\n \"As used herein, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.\",\n \"It will be further understood that the terms “comprises,” “comprising,” “includes” or “including,” when used herein, specify the presence of stated features, integers, steps, operations, elements, or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, or groups thereof.\",\n \"Moreover, it is understood that the word “or” has the same meaning as the Boolean operator “OR,” that is, it encompasses the possibilities of “either” and “both” and is not limited to “exclusive or” (“XOR”), unless expressly stated otherwise.\",\n \"It is also understood that the symbol “I” between two adjacent words has the same meaning as “or” unless expressly stated otherwise.\",\n \"In the following description, numerous specific details are set forth such as examples of specific components, circuits, and processes to provide a thorough understanding of this disclosure.\",\n \"Also, in the following description and for purposes of explanation, specific nomenclature is set forth to provide a thorough understanding of the example embodiments.\",\n \"However, it will be apparent to one skilled in the art that these specific details may not be required to practice the example embodiments.\",\n \"In other instances, well-known circuits and devices are shown in block diagram form to avoid obscuring the present disclosure.\",\n \"The term “coupled” as used herein means connected directly to or connected through one or more intervening components or circuits.\",\n \"Any of the signals provided over various buses described herein may be time-multiplexed with other signals and provided over one or more common buses.\",\n \"Additionally, the interconnection between circuit elements or software blocks may be shown as buses or as single signal lines.\",\n \"Each of the buses may alternatively be a single signal line, and each of the single signal lines may alternatively be buses, and a single line or bus might represent any one or more of a myriad of physical or logical mechanisms for communication between components.\",\n \"The example embodiments are not to be construed as limited to specific examples described herein but rather to include within their scopes all embodiments defined by the appended claims.\",\n \"The techniques described herein may be implemented in hardware, software, firmware, or any combination thereof, unless specifically described as being implemented in a specific manner Any features described as modules or components may also be implemented together in an integrated logic device or separately as discrete but interoperable logic devices.\",\n \"If implemented in software, the techniques may be realized at least in part by a non-transitory processor-readable storage medium comprising instructions that, when executed, performs one or more of the methods described above.\",\n \"The non-transitory processor-readable data storage medium may form part of a computer program product, which may include packaging materials.\",\n \"The non-transitory processor-readable storage medium may comprise random access memory (RAM) such as synchronous dynamic random access memory (SDRAM), read only memory (ROM), non-volatile random access memory (NVRAM), electrically erasable programmable read-only memory (EEPROM), FLASH memory, other known storage media, and the like.\",\n \"The techniques additionally, or alternatively, may be realized at least in part by a processor-readable communication medium that carries or communicates code in the form of instructions or data structures and that may be accessed, read, and/or executed by a computer or other processor.\",\n \"The various illustrative logical blocks, modules, circuits and instructions described in connection with the embodiments disclosed herein may be executed by one or more processors, such as one or more digital signal processors (DSPs), general purpose microprocessors, application specific integrated circuits (ASICs), application specific instruction set processors (ASIPs), field programmable gate arrays (FPGAs), or other equivalent integrated or discrete logic circuitry.\",\n \"The term “processor,” as used herein may refer to any of the foregoing structure or any other structure suitable for implementation of the techniques described herein.\",\n \"In addition, in some aspects, the functionality described herein may be provided within dedicated software modules or hardware modules configured as described herein.\",\n \"Also, the techniques could be fully implemented in one or more circuits or logic elements.\",\n \"A general purpose processor may be a microprocessor, but in the alternative, the processor may be any conventional processor, controller, microcontroller, or state machine.\",\n \"A processor may also be implemented as a combination of computing devices (e.g., a combination of a DSP and a microprocessor), a plurality of microprocessors, one or more microprocessors in conjunction with a DSP core, or any other suitable configuration.\",\n \"FIG.\",\n \"1 is a block diagram of a wireless system 100 within which the example embodiments may be implemented.\",\n \"The wireless system 100 is shown to include four wireless stations STA1-STA4, a wireless access point (AP) 110, and a wireless local area network (WLAN) 120.The WLAN 120 may be formed by a plurality of Wi-Fi access points (APs) that may operate according to the IEEE 802.11 family of standards (or according to other suitable wireless protocols).\",\n \"Thus, although only one AP 110 is shown in FIG.\",\n \"1 for simplicity, it is to be understood that WLAN 120 may be formed by any number of access points such as AP 110.The AP 110 is assigned a unique media access control (MAC) address that is programmed therein by, for example, the manufacturer of the access point.\",\n \"Similarly, each of stations STA1-STA4 is also assigned a unique MAC address.\",\n \"For some embodiments, the wireless system 100 may correspond to a multiple-input multiple-output (MIMO) wireless network, and may support single-user MIMO (SU-MIMO) and multi-user (MU-MIMO) communications.\",\n \"Further, although the WLAN 120 is depicted in FIG.\",\n \"1 as an infrastructure BSS, for other example embodiments, WLAN 120 may be an IBSS, an ad-hoc network, or a peer-to-peer (P2P) network (e.g., operating according to the Wi-Fi Direct protocols).\",\n \"Each of stations STA1-STA4 may be any suitable Wi-Fi enabled wireless device including, for example, a cell phone, personal digital assistant (PDA), tablet device, laptop computer, or the like.\",\n \"Each of stations STA1-STA4 may also be referred to as a user equipment (UE), a subscriber station, a mobile unit, a subscriber unit, a wireless unit, a remote unit, a mobile device, a wireless device, a wireless communications device, a remote device, a mobile subscriber station, an access terminal, a mobile terminal, a wireless terminal, a remote terminal, a handset, a user agent, a mobile client, a client, or some other suitable terminology.\",\n \"For at least some embodiments, each of stations STA1-STA4 may include one or more transceivers, one or more processing resources (e.g., processors and/or ASICs), one or more memory resources, and a power source (e.g., a battery).\",\n \"The memory resources may include a non-transitory computer-readable medium (e.g., one or more nonvolatile memory elements, such as EPROM, EEPROM, Flash memory, a hard drive, etc.)\",\n \"that stores instructions for performing operations described below with respect to FIGS.\",\n \"5A, 5B, 11, and 12.The AP 110 may be any suitable device that allows one or more wireless devices to connect to a network (e.g., a local area network (LAN), wide area network (WAN), metropolitan area network (MAN), and/or the Internet) via AP 110 using Wi-Fi, Bluetooth, or any other suitable wireless communication standards.\",\n \"For at least one embodiment, AP 110 may include one or more transceivers, one or more processing resources (e.g., processors and/or ASICs), one or more memory resources, and a power source.\",\n \"The memory resources may include a non-transitory computer-readable medium (e.g., one or more nonvolatile memory elements, such as EPROM, EEPROM, Flash memory, a hard drive, etc.)\",\n \"that stores instructions for performing operations described below with respect to FIGS.\",\n \"5A, 5B, 11, and 12.For the stations STA1-STA4 and/or AP 110, the one or more transceivers may include Wi-Fi transceivers, Bluetooth transceivers, cellular transceivers, and/or other suitable radio frequency (RF) transceivers (not shown for simplicity) to transmit and receive wireless communication signals.\",\n \"Each transceiver may communicate with other wireless devices in distinct operating frequency bands and/or using distinct communication protocols.\",\n \"For example, the Wi-Fi transceiver may communicate within a 2.4 GHz frequency band, within a 5 GHz frequency band in accordance with the IEEE 802.11 specification, and/or within a 60 GHz frequency band.\",\n \"The cellular transceiver may communicate within various RF frequency bands in accordance with a 4G Long Term Evolution (LTE) protocol described by the 3rd Generation Partnership Project (3GPP) (e.g., between approximately 700 MHz and approximately 3.9 GHz) and/or in accordance with other cellular protocols (e.g., a Global System for Mobile (GSM) communications protocol).\",\n \"In other embodiments, the transceivers included within each of the stations STA1-STA4 may be any technically feasible transceiver such as a ZigBee transceiver described by a specification from the ZigBee specification, a WiGig transceiver, and/or a HomePlug transceiver described a specification from the HomePlug Alliance.\",\n \"For at least some embodiments, each of the stations STA1-STA4 and AP 110 may include radio frequency (RF) ranging circuitry (e.g., formed using well-known software modules, hardware components, and/or a suitable combination thereof) that may be used to estimate the distance between itself and another Wi-Fi enabled device and to determine the location of itself, relative to one or more other wireless devices, using ranging techniques described herein.\",\n \"In addition, each of the stations STA1-STA4 and/or AP 110 may include a local memory (not shown in FIG.\",\n \"1 for simplicity) to store a cache of Wi-Fi access point and/or station data.\",\n \"For at least some embodiments, ranging operations described herein may be performed without using the AP 110, for example, by having a number of the stations operating in an ad-hoc or peer-to-peer mode, thereby allowing the stations to range one another even when outside the reception range of AP 110 or a visible WLAN (or other wireless network).\",\n \"In addition, for at least some example embodiments, ranging operations described herein may be performed between two APs that are in wireless range of each other.\",\n \"FIG.\",\n \"2 shows a wireless device 200 that may be one embodiment of the stations STA1-STA4 and/or AP 110 of FIG.\",\n \"1.The wireless device 200 may include a PHY device 210 including at least a number of transceivers 211 and a baseband processor 212, may include a MAC 220 including at least a number of contention engines 221 and frame formatting circuitry 222, may include a processor 230, may include a memory 240, and may include a number of antennas 250(1)-250(n).\",\n \"The transceivers 211 may be coupled to antennas 250(1)-250(n), either directly or through an antenna selection circuit (not shown for simplicity).\",\n \"The transceivers 211 may be used to transmit signals to and receive signals from AP 110, other stations, and/or other suitable wireless devices (see also FIG.\",\n \"1), and may be used to scan the surrounding environment to detect and identify nearby access points and other wireless devices (e.g., within wireless range of wireless device 200).\",\n \"Although not shown in FIG.\",\n \"2 for simplicity, the transceivers 211 may include any number of transmit chains to process and transmit signals to other wireless devices via antennas 250(1)-250(n), and may include any number of receive chains to process signals received from antennas 250(1)-250(n).\",\n \"Thus, for example embodiments, the wireless device 200 may be configured for MIMO operations.\",\n \"The MIMO operations may include SU-MIMO operations and/or MU-MIMO operations.\",\n \"The baseband processor 212 may be used to process signals received from processor 230 and/or memory 240 and to forward the processed signals to transceivers 211 for transmission via one or more of antennas 250(1)-250(n), and may be used to process signals received from one or more of antennas 250(1)-250(n) via transceivers 211 and to forward the processed signals to processor 230 and/or memory 240.For purposes of discussion herein, MAC 220 is shown in FIG.\",\n \"2 as being coupled between PHY device 210 and processor 230.For actual embodiments, PHY device 210, MAC 220, processor 230, and/or memory 240 may be connected together using one or more buses (not shown for simplicity).\",\n \"The contention engines 221 may contend for access to one or more shared wireless mediums, and may also store packets for transmission over the one or more shared wireless mediums.\",\n \"For other embodiments, the contention engines 221 may be separate from MAC 220.For still other embodiments, the contention engines 221 may be implemented as one or more software modules (e.g., stored in memory 240 or stored in memory provided within MAC 220) containing instructions that, when executed by processor 230, perform the functions of contention engines 221.The frame formatting circuitry 222 may be used to create and/or format frames received from processor 230 and/or memory 240 (e.g., by adding MAC headers to PDUs provided by processor 230), and may be used to re-format frames received from PHY device 210 (e.g., by stripping MAC headers from frames received from PHY device 210).\",\n \"Memory 240 includes a Wi-Fi database 241 that may store location data, configuration information, data rates, MAC addresses, and other suitable information about (or pertaining to) a number of access points, stations, and/or other wireless devices.\",\n \"The Wi-Fi database 241 may also store profile information for a number of wireless devices.\",\n \"The profile information for a given wireless device may include information including, for example, the wireless device's service set identification (SSID), channel information, received signal strength indicator (RSSI) values, goodput values, channel state information (CSI), and connection history with wireless device 200.Memory 240 may also include a non-transitory computer-readable medium (e.g., one or more nonvolatile memory elements, such as EPROM, EEPROM, Flash memory, a hard drive, and so on) that may store the following software (SW) modules: a ranging SW module 242 to determine RTT values and/or to estimate the distance between wireless device 200 and one or more other devices, for example, as described below for one or more operations of FIGS.\",\n \"5A, 5B, 11, and 12; an angle determination SW module 243 to determine angle of arrival (AoA) information of signals received by wireless device 200 and/or to determine angle of departure (AoD) information of signals transmitted from wireless device 200, for example, as described below for one or more operations of FIGS.\",\n \"5A, 5B, 11, and 12; a timestamp SW module 244 to capture timestamps of signals received by wireless device 200 (e.g., TOA information) and/or to capture timestamps of signals transmitted from wireless device 200 (e.g., TOD information), for example, as described below for one or more operations of FIGS.\",\n \"5A, 5B, 11, and 12; a frame formation and exchange SW module 245 to create, send, and/or receive frames or packets and/or to embed TOA information, TOD information, AoA information, and/or AoD information into selected frames or packets, for example, as described below for one or more operations of FIGS.\",\n \"5A, 5B, 11, and 12; and a positioning SW module 246 to determine the location of wireless device 200 based on the distances determined by the ranging SW module 242 and/or the angle information determined by the angle determination SW module 243, for example, as described below for one or more operations of FIGS.\",\n \"5A, 5B, 11, and 12.Each software module includes instructions that, when executed by processor 230, cause the wireless device 200 to perform the corresponding functions.\",\n \"The non-transitory computer-readable medium of memory 240 thus includes instructions for performing all or a portion of the operations of 5A, 5B, 11, and 12.Processor 230, which is coupled to PHY 210, MAC 220, and memory 240, may be one or more suitable processors capable of executing scripts or instructions of one or more software programs stored in wireless device 200 (e.g., within memory 240).\",\n \"For example, processor 230 may execute the ranging SW module 242 to determine RTT values and/or to estimate the distance between wireless device 200 and one or more other devices.\",\n \"Processor 230 may execute the angle determination SW module 243 to determine AoA information of signals received by wireless device 200 and/or to determine AoD information of signals transmitted from wireless device 200.Processor 230 may execute the timestamp SW module 244 to capture timestamps of signals received by wireless device 200 (e.g., TOA information) and/or to capture timestamps of signals transmitted from wireless device 200 (e.g., TOD information).\",\n \"Processor 230 may execute the frame formation and exchange SW module 245 to create, send, and/or receive frames or packets and/or to embed TOA information, TOD information, AoA information, and/or AoD information into selected frames or packets.\",\n \"Processor 230 may execute the positioning SW module 246 to determine the location of wireless device 200 based on the distances determined by the ranging SW module 242, the angle information determined by the angle determination SW module 243, and/or other suitable information indicative of the position of wireless device 200 relative to one or more other devices.\",\n \"As mentioned above, the distance between a pair of devices may be determined using the RTT of signals exchanged between the devices.\",\n \"For example, FIG.\",\n \"3 shows a signal diagram of an example ranging operation 300 between a first device D1 and a second device D2.The distance (d) between the first device D1 and the second device D2 may be estimated as d=c*RTT/2, where c is the speed of light, and RTT is the summation of the actual signal propagation times of a request (REQ) frame and an acknowledgement (ACK) frame exchanged between device D1 and device D2.Device D1 and device D2 may each be, for example, an access point (e.g., AP 110 of FIG.\",\n \"1), a station (e.g., one of stations STA1-STA4 of FIG.\",\n \"1), or another suitable wireless device (e.g., wireless device 200 of FIG.\",\n \"2).\",\n \"More specifically, device D2 may estimate the RTT between itself and device D1 using the time of departure (TOD) of the REQ frame transmitted from device D2, the time of arrival (TOA) of the ACK frame received by device D2, and the SIFS duration of device D1.The SIFS duration, which stands for the short interframe space duration, indicates the duration of time between device D1 receiving the REQ frame and transmitting the ACK frame.\",\n \"The SIFS duration, a range of values for which are provided by the IEEE 802.11 standards, provides Wi-Fi enabled devices time to switch their transceivers from a receive mode (e.g., to receive the REQ frame) to a transmit mode (e.g., to transmit the ACK frame).\",\n \"Because different make-and-models (and sometimes even same make-and-models) of communication devices have different processing delays, the precise value of SIFS may vary between devices (and even between successive frame receptions/transmissions in the same device).\",\n \"As a result, the value of SIFS is typically estimated, which often leads to errors in estimating the distance between two devices.\",\n \"More specifically, the IEEE 802.11 standards define the SIFS duration as 10 us+/−900 ns at 2.4 GHz, 16 us+/−900 ns at 5 GHz, and 3 us+/−900 ns at 60 GHz.\",\n \"These “standard” SIFS durations include tolerances that may decrease the accuracy of RTT estimates.\",\n \"For example, even if the SIFS duration of device D1 may be estimated within +/−25 ns, a ranging error of +/−7.5 meters may result (which may be unacceptable for many positioning systems).\",\n \"To reduce ranging errors resulting from uncertainties in the value of SIFS, recent revisions to the IEEE 802.11 standards call for each ranging device to capture timestamps of incoming and outgoing frames so that the value of RTT may be determined without using SIFS.\",\n \"For example, FIG.\",\n \"4 shows a signal diagram of an example ranging operation 400 between device D1 and device D2 performed using Fine Timing Measurement (FTM) frames in accordance with the IEEE 802.11REVmc standards.\",\n \"Device D1 and device D2 may each be, for example, an access point (e.g., AP 110 of FIG.\",\n \"1), a station (e.g., one of stations STA1-STA4 of FIG.\",\n \"1), or other suitable wireless device (e.g., wireless device 200 of FIG.\",\n \"2).\",\n \"For the example of FIG.\",\n \"4, device D2 requests the ranging operation; thus, device D2 is the initiator device (or alternatively the requestor device) and device D1 is the responder device.\",\n \"Note that the term “initiator device” may also refer to an initiator STA, and the term “responder device” may also refer to a responder STA.\",\n \"Device D2 may request or initiate the ranging operation by transmitting an FTM request (FTM_REQ) frame to device D1.The FTM_REQ frame may also include a request for device D1 to capture timestamps (e.g., TOA information) of frames received by device D1 and to capture timestamps (e.g., TOD information) of frames transmitted from device D1.Device D1 receives the FTM_REQ frame, and may acknowledge the requested ranging operation by transmitting an acknowledgement (ACK) frame to device D2.The ACK frame may indicate whether device D1 is capable of capturing the requested timestamps.\",\n \"It is noted that the exchange of the FTM_REQ frame and the ACK frame is a handshake process that not only signals an intent to perform a ranging operation but also allows devices D1 and D2 to determine whether each other supports capturing timestamps.\",\n \"At time ta1, device D1 transmits a first FTM (FTM_1) frame to device D2, and may capture the TOD of the FTM_1 frame as time ta1.Device D2 receives the FTM_1 frame at time ta2, and may capture the TOA of the FTM_1 frame as time ta2.Device D2 responds by transmitting an ACK frame to device D1 at time ta3, and may capture the TOD of the ACK frame as time ta3.Device D1 receives the ACK frame at time ta4, and may capture the TOA of the ACK frame at time ta4.At time tb1, device D1 transmits to device D2 a second FTM (FTM_2) frame that includes the timestamps captured at times ta1 and ta4 (e.g., the TOD of the FTM_1 frame and the TOA of the ACK frame).\",\n \"Device D2 receives the FTM_2 frame at time tb2, and may capture its timestamp as time tb2.Device D2 transmits an ACK frame to device D1 at time tb3.Device D1 receives the ACK frame at time tb4.This process may continue for any number of subsequent FTM and ACK frame exchanges between devices D1 and D2, for example, where device D1 embeds the timestamps of a given FTM and ACK frame exchange into a subsequent FTM frame transmitted to device D2.Upon receiving the FTM_2 frame at time tb2, device D2 has timestamp values for times ta1, ta2, ta3, and ta4 that correspond to the TOD of the FTM_1 frame transmitted from device D1, the TOA of the FTM_1 frame at device D2, the TOD of the ACK frame transmitted from device D2, and the TOA of the ACK frame at device D1, respectively.\",\n \"Thereafter, device D2 may determine RTT as (ta4−ta3)+(ta2−ta1).\",\n \"Because the RTT estimate does not involve estimating SIFS for either device D1 or device D2, the RTT estimate does not involve errors resulting from uncertainties of SIFS durations.\",\n \"Consequently, the accuracy of the resulting estimate of the distance between devices D1 and D2 is improved (e.g., as compared to the ranging operation 300 of FIG.\",\n \"3).\",\n \"A device may perform this ranging operation with at least three other devices having known locations, and use known trilateration techniques to estimate its location.\",\n \"Note that the example ranging operation 400 may continue.\",\n \"For example, device D2 may transmit an ACK frame to device D1 at time tb3 (e.g., to acknowledge reception of the FTM_2 frame).\",\n \"Device D1 receives the ACK frame at time tm, and may record the TOA of the ACK frame as time tm.\",\n \"Device D1 may embed another time value in an FTM_3 frame, and then transmit the FTM_3 frame to device D2 at time tc1.The time value embedded in the FTM_3 frame may indicate a difference time value equal to tb4−tb1.While RTT techniques may be used to determine a given device's location relative to another device, the given device may need to perform ranging operations with three other devices to determine its actual position.\",\n \"More specifically, performing ranging operation 400 with three other devices may involve three separate exchanges of FTM frames (with the three other devices), which not only consumes valuable time but also consumes limited bandwidth of a shared wireless medium.\",\n \"These are at least some of the technical problems to be solved by the example embodiments.\",\n \"Two measurements that may be used in addition to RTT information to determine the relative positions of two wireless devices are the angle of arrival (AoA) of signals received by the devices and the angle of departure (AoD) of signals transmitted by the devices.\",\n \"For example, if a second device has RTT information between itself and a first device, then the second device may estimate the distance between itself and the first device, as described above with respect to FIG.\",\n \"4.If the second device also has AoA information and/or AoD information for frames exchanged with the first device, then the second device may determine a direction of itself relative to the first device (e.g., an angle between the first and second devices relative to a reference line or direction).\",\n \"The second device may then use the determined direction and the RTT information to estimate its position relative to the first device.\",\n \"Further, if the position of the first device is known by the second device, then the second device may determine its actual position using the known position of the first device, the distance between the first and second devices, and the direction of the second device relative to the first device.\",\n \"Accordingly, it would be advantageous to exchange AoA information and/or AoD information during ranging operations, for example, so that a wireless device may estimate its actual position using the known position of only one other wireless device.\",\n \"Thus, example apparatuses and methods are disclosed that may allow AoA information and/or AoD information to be exchanged between wireless devices during ranging operations without additional frame exchanges.\",\n \"More specifically, for at least some embodiments, a first device may determine AoA information and/or AoD information of frames exchanged with a second device during a ranging operation, and then embed the determined AoA information and/or AoD information in a subsequent FTM frame transmitted to the second device.\",\n \"In this manner, the second device may use the estimated distance to the first device, the direction of the first device relative to the second device, and a known location of the first device to determine the actual position of the second device.\",\n \"These and other details of the example embodiments, which provide one or more technical solutions to the aforementioned technical problems, are described in more detail below.\",\n \"FIG.\",\n \"5A shows a signal diagram of a ranging operation 500 between a first device D1 and a second device D2 in accordance with example embodiments, and FIG.\",\n \"5B shows a sequence diagram 510 depicting the example ranging operation 500 of FIG.\",\n \"5A.\",\n \"Device D1 and device D2 may each be, for example, an access point (e.g., AP 110 of FIG.\",\n \"1), a station (e.g., one of stations STA1-STA4 of FIG.\",\n \"1), or another suitable wireless device (e.g., wireless device 200 of FIG.\",\n \"2).\",\n \"As the initiator device, device D2 may transmit, to device D1, a request to perform a ranging operation and to indicate its capabilities (512).\",\n \"The requested capabilities may include, for example, the ability to estimate AoA and AoD information and/or the ability to capture timestamps.\",\n \"For some implementations, the request may be an FTM_REQ frame, as depicted in FIG.\",\n \"5A.\",\n \"The FTM_REQ frame may include a request for device D1 to estimate AoA and/or AoD information.\",\n \"The FTM_REQ frame may also request a level of accuracy for the estimated AoA and/or AoD information.\",\n \"Device D1 may receive the request to perform the ranging operation and to indicate its capabilities to device D2 (513).\",\n \"As the responder device, device D1 may respond to the request by transmitting a response to device D2 (514).\",\n \"For some implementations, the response may be an ACK frame, as depicted in FIG.\",\n \"5A.\",\n \"The ACK frame may indicate whether device D1 is capable of capturing timestamps, may indicate whether device D1 is capable of estimating AoA and AoD information, and/or may indicate a level of accuracy for the estimated AoA and AoD information.\",\n \"Device D2 may receive the response from device D1, and decode the capabilities (if any) provided by device D1 (515).\",\n \"After the above handshake process, devices D1 and D2 may exchange FTM frames to perform the ranging operation 500.At time ta1, device D1 transmits an FTM_1 frame to device D2, records the TOD of the FTM_1 frame as time ta1, and may determine the AoD of the FTM_1 frame (denoted in FIG.\",\n \"5A as AoDa) (516).\",\n \"Device D2 receives the FTM_1 frame from device D1 at time ta2, and records the TOA of the FTM_1 frame as time to (517).\",\n \"Device D2 then transmits an ACK frame to device D1 at time ta3, and records the TOD of the ACK frame as time ta3 (518).\",\n \"Device D1 receives the ACK frame from device D2 at time ta4, records the TOA of the ACK frame as time ta4, and may determine the AoA of the ACK frame (denoted in FIG.\",\n \"5A as AoAa) (519).\",\n \"Then, device D1 may embed a time value and angle information in an FTM_2 frame, and transmit the FTM_2 frame to device D2 at time tb1 (520).\",\n \"The time value (tvalue) may indicate a difference in time between the TOA of the ACK frame received at device D1 and the TOD of the FTM _1 frame transmitted from device D1 (e.g., tvalue=ta4−ta1).\",\n \"The angle information, which may indicate a direction of device D2 relative to device D1, may include the AoA of the ACK frame received at device D1 (e.g., AoAa) and/or the AoD of the FTM_1 frame transmitted from device D1 (e.g., AoDa).\",\n \"Note that although device D1 is depicted in FIG.\",\n \"5A as transmitting a difference time value (ta4−ta1), for other embodiments, device D1 may instead embed the timestamps ta1 and ta4 in the FTM_2 frame.\",\n \"In some aspects, device D1 may record the TOD of the FTM_2 frame as time tb1, and may determine the AoD of the FTM_2 frame (denoted in FIG.\",\n \"5A as AoDb).\",\n \"Device D2 receives the FTM_2 frame at time tb2, and decodes the embedded time value and angle information (521).\",\n \"At this point, device D2 has sufficient information to estimate its location relative to device D1.More specifically, device D2 may estimate that it is a distance d=c*RTT/2 from device D1 along a direction indicated by the angle information embedded within the FTM_2 frame, where RTT=(ta4−ta3)+(ta2−ta1) (522).\",\n \"Because device D2 may estimate the distance to device D1 (e.g., based on the RTT value) as well as its direction relative to device D1 (e.g., based on the AoA and/or AoD information embedded in the FTM_2 frame), device D2 may estimate its location relative to device D2.If the actual location of device D1 is known, then device D2 may determine its actual location based on the known location of device D1 and its location relative to device D1.For example, if device D1 is an access point and device D2 is a station, then device D2 may retrieve the location of device D1 (e.g., from a local memory such as the Wi-Fi database 241 of FIG.\",\n \"2 and/or from any suitable service that stores location information for actively deployed access points).\",\n \"Thereafter, device D2 may determine its actual location using the location of device D2 relative to device D1, the determined distance between device D1 and device D2, and the known location of device D1.Referring again to FIG.\",\n \"5A, device D2 may transmit an ACK frame to device D1 at time tb3 (e.g., to acknowledge reception of the FTM_2 frame).\",\n \"Device D1 receives the ACK frame at time tb4, may record the TOA of the ACK frame as time tb4, and may determine the AoA of the ACK frame (denoted in FIG.\",\n \"5A as AoAb).\",\n \"Device D1 may embed another time value and angle information in an FTM_3 frame, and then transmit the FTM_3 frame to device D2 at time tc1.The time value embedded in the FTM_3 frame may indicate a difference time value equal to tb4−tb1, and the angle information embedded in the FTM_3 frame may include the angle information values AoAb and/or AoDb.\",\n \"Thus, as described above, the example embodiments may allow a first wireless device to determine AoA and/or AoD information of a first set of signals exchanged with a second wireless device, and embed the determined AoA and/or AoD information in a second signal transmitted to the second wireless device.\",\n \"The second wireless device may use the embedded AoA and/or AoD information in combination with RTT information to estimate its location relative to the first wireless device.\",\n \"As mentioned above, the initiator device may request the responder device to commence the ranging operation, for example, by transmitting an FTM_REQ frame to the responder device.\",\n \"The FTM_REQ frame may include a request for the responder device to determine and embed AoA and/or AoD information in one or more subsequent FTM frames.\",\n \"In some aspects, a dedicated bit in the Vendor Specific Information Element (VSIE) of the FTM_REQ frame may be used (e.g., asserted) to request the responder device to determine AoA and/or AoD information and to embed the determined AoA and/or AoD information in subsequent FTM frames.\",\n \"In other aspects, a reserved bit of the FTM_REQ frame's VSIE may be used (e.g., asserted) to request the responder device to determine AoA and/or AoD information and to embed the determined AoA and/or AoD information in subsequent FTM frames.\",\n \"In still other aspects, different bits in the FTM_REQ frame's VSIE may be used (e.g., asserted) to separately request the responder device to embed AoA information and AoD information into subsequent FTM frames.\",\n \"This may be desirable, for example, when the initiator device needs only one of the AoA information and AoD information to determine its direction relative to device D1.When the responder device receives an FTM_REQ frame that includes a request for AoA and/or AoD information (e.g., the FTM_REQ frame includes an asserted “request” bit in its VSIE), the responder device may infer that the initiator device is capable of decoding AoA and/or AoD information embedded in subsequent FTM frames.\",\n \"In response thereto, the responder device may either (i) assert one or more bits of a VSIE in the first FTM frame (e.g., the FTM_1 frame) indicating its ability to determine AoA and/or AoD information and confirming that the determined AoA and/or AoD information is to be embedded in subsequent FTM frames or (ii) de-assert the one or more bits of the VSIE in the FTM_1 frame indicating its inability to determine AoA and/or AoD information and/or indicating that AoA and/or AoD information will not be embedded in subsequent FTM frames.\",\n \"Alternatively, the responder device may indicate that AoA and/or AoD information will not be included in subsequent FTM frames by not including the VSIE in the FTM_1 frame (e.g., to reduce the transmit time of the first FTM frame).\",\n \"For other embodiments, the responder device may include its acceptance or rejection of the request for AoA and/or AoD information in the ACK frame sent in response to reception of the FTM_REQ frame.\",\n \"The initiator device may also include, in the FTM_REQ frame, an indication of a desired level of accuracy for AoA and/or AoD measurements by the responder device.\",\n \"The indication of the desired level of accuracy may be embedded in one or more dedicated bits in the VSIE of the FTM_REQ frame, in one or more reserved bits in the VSIE of the FTM_REQ frame, or in any other suitable bits of the FTM_REQ frame.\",\n \"In response to receiving an indication of the desired level of accuracy for AoA and/or AoD measurements, the responder device may include, in the FTM_1 frame, an indication of the level of accuracy for the AoA and/or AoD measurements to be embedded in subsequent FTM frames.\",\n \"The responder device may use the same one or more bit locations of the VSIE in the FTM_1 frame for the response that the initiator device used in the VSIE in the FTM_REQ frame for the request.\",\n \"For at least some implementations in which the responder device is an access point, the responder device may embed, into a beacon frame, information indicating whether the responder device is capable of estimating AoA and/or AoD information of one or more frames exchanged between the initiator device and the responder device.\",\n \"In some aspects, this information may be embedded within an information element (IE) or a vendor-specific information element (VSIE) of the beacon frame.\",\n \"The responder device may broadcast the beacon frame, for example, according to a target beacon transmission time (TBTT) schedule.\",\n \"FIG.\",\n \"6 depicts an example FTM frame 600, in accordance with example embodiments.\",\n \"The FTM frame 600 may include a category field 601, a public action field 602, a dialog token field 603, a follow up dialog token field 604, a TOD field 605, a TOA field 606, a TOD error field 607, a TOA error field 608, an optional LCI report field 609, an optional location civic report field 610, an optional FTM parameters field 611, an optional AoA field 612, and/or an optional AoD field 613.For at least one embodiment, the TOD field 605 may include 6 bytes, the TOA field 606 may include 6 bytes, the AoA field 612 may include 5 bytes, and the AoD field 613 may include 5 bytes (although for other embodiments, other field lengths may be used).\",\n \"The AoA field 612 may include AoA information for frames exchanged during a ranging operation, and the AoD field 613 may include AoD information for frames exchanged during the ranging operation.\",\n \"For example, referring also to FIG.\",\n \"5A, the responder device (e.g., device D1) may embed AoA information of the received ACK frame into the AoA field 612 of FTM frame 600, and may embed AoD information of the FTM_1 frame into the AoD field 613 of FTM frame 600.In some aspects, the responder device may embed TOA information of the received ACK frame into the TOA field 606 of FTM frame 600, and may embed TOD information of the FTM_1 frame into the TOD field 605 of FTM frame 600.Thereafter, the responder device may use the FTM frame 600 as the FTM_2 frame in the example ranging operation 500 of FIG.\",\n \"5A, for example, to transmit angle information (e.g., AoDa and/or AoAa) and the time value (e.g., ta4−ta1) to the initiator device.\",\n \"FIG.\",\n \"7A depicts an example field 700 that may be one embodiment of the AoA field 612 of FIG.\",\n \"6.The field 700 may include an Element ID field 701, a Length field 702, and an AoA field 703.For at least one embodiment, the Element ID field 701 may include one byte, the Length field 702 may include one byte, and the AoA field 703 may include 5 bytes (although for other embodiments, other field lengths may be used).\",\n \"The Element ID field 701 may store an element ID value indicating that field 700 contains angle of arrival information for a selected frame (e.g., the AoA information for the ACK frame received from device D2 in the example ranging operation 500 of FIG.\",\n \"5A).\",\n \"The Length field 702 may store a value indicating a length (in bytes) of field 700.The AoA field 703 may store angle of arrival information for the selected frame.\",\n \"More specifically, in some implementations, the AoA field 703 may store values for Theta_AoA and Phi_AoA which, as described in more detail below with respect to FIG.\",\n \"10, may indicate angle of arrival information of the selected frame.\",\n \"FIG.\",\n \"7B depicts an example field 710 that may be one embodiment of the AoD field 613 of FIG.\",\n \"6.The field 710 may include an Element ID field 711, a Length field 712, and an AoD field 713.For at least one embodiment, the Element ID field 711 may include one byte, the Length field 712 may include one byte, and the AoD field 713 may include 5 bytes (although for other embodiments, other field lengths may be used).\",\n \"The Element ID field 711 may store an element ID value indicating that field 710 contains angle of departure information for a selected frame (e.g., the AoD information for the FTM_1 frame used in the example ranging operation 500 of FIG.\",\n \"5A).\",\n \"The Length field 712 may store a value indicating a length (in bytes) of field 710.The AoD field 713 may store angle of departure information for the selected frame.\",\n \"More specifically, in some implementations, the AoD field 713 may store values for Theta_AoD and Phi_AoD which, as described in more detail below with respect to FIG.\",\n \"10, may indicate angle of departure information of the selected frame.\",\n \"FIG.\",\n \"8 depicts another example FTM frame 800, in accordance with example embodiments.\",\n \"The FTM frame 800 is similar to FTM frame 600 of FIG.\",\n \"6, except that instead of including separate AoA and AoD fields 612 and 613, respectively, FTM frame 800 includes a combined AoA and AoD field 803.For at least one embodiment, the TOD field 605 may include 6 bytes, the TOA field 606 may include 6 bytes, and the combined AoA and AoD field 803 may include 8 bytes (although for other embodiments, other field lengths may be used).\",\n \"The combined AoA and AoD field 803 may include both AoA and AoD information for frames exchanged during a ranging operation.\",\n \"For example, referring also to FIG.\",\n \"5A, the responder device (e.g., device D1) may embed AoA information of the received ACK frame and AoD information of the FTM_1 frame into the combined AoD and AoD field 803 of FTM frame 800.In some aspects, the responder device may embed TOA information of the received ACK frame into the TOA field 606 of FTM frame 800, and may embed TOD information of the FTM_1 frame into the TOD field 605 of FTM frame 800.Thereafter, the responder device D1 may use the FTM frame 800 as the FTM_2 frame in the example ranging operation 500 of FIG.\",\n \"5, for example, to transmit information indicating values for AoDa, AoAa, and ta4−ta1 to device D2.For example embodiments in which the AoA field 612 and the AoD field 613 of FTM frame 600 each include 5 bytes and the combined AoA and AoD field 803 of FTM frame 800 includes 8 bytes, the FTM frame 800 of FIG.\",\n \"8 may include 2 fewer bytes than the FTM frame 600 of FIG.\",\n \"6, and thus may be transmitted in less time than FTM frame 600 (albeit at a cost of less resolution).\",\n \"FIG.\",\n \"9 depicts an example field 900 that may be one embodiment of the combined AoA and AoD 803 of FIG.\",\n \"8.The field 900 may include an Element ID field 901, a Length field 902, an AoA field 903, and an AoD field 904.For at least one embodiment, the Element ID field 901 may include one byte, the Length field 902 may include one byte, the AoA field 903 may include 3 bytes, and the AoD field 904 may include 3 bytes (although for other embodiments, other field lengths may be used).\",\n \"The Element ID field 901 may store an element ID value indicating that field 900 contains angle of arrival and angle of departure information for a selected frame exchange (e.g., the AoA of the ACK frame received from device D2 and the AoD of the FTM_1 frame in the example ranging operation 500 of FIG.\",\n \"5A).\",\n \"The Length field 902 may store a value indicating a length (in bytes) of field 900.The AoA field 903 may store angle of arrival information for the selected frame exchange, and the AoD field 904 may store angle of departure information for the selected frame exchange.\",\n \"More specifically, in some implementations, the AoA field 903 may store values for Theta_AoA and Phi_AoA, and the AoD field 904 may store values for Theta_AoD and Phi_AoD which, as described in more detail below with respect to FIG.\",\n \"10, may indicate angle of arrival and angle of departure information for frames exchanged during a ranging operation.\",\n \"FIG.\",\n \"10 is an example 3-dimensional coordinate system 1000 for representing the position of a wireless device using a radius “r” and angles “theta” and “phi.” As depicted in FIG.\",\n \"10, phi may be an angle with respect to the horizontal (x-y) plane, while theta may be an angle with respect to the vertical (z) axis.\",\n \"Phi may range from 0° to 360°, while theta may range from 0° to 180° .\",\n \"The radius r is the distance between the origin and a point coordinate (r, θ, and φ) representing the location of a wireless device relative to the origin.\",\n \"Referring also to FIG.\",\n \"9, the first 12 bits of the AoA field 903 may be used to indicate a value for Theta_AoA, and the second 12 bits of the AoA field 903 may be used to indicate a value for Phi_AoA.\",\n \"Similarly, the first 12 bits of the AoD field 904 may be used to indicate a value for Theta_AoD, and the second 12 bits of the AoD field 904 may be used to indicate a value for Phi_AoD.\",\n \"For the example field 900 of FIG.\",\n \"9, the 12-bit values for Theta_AoA and Theta_AoD may provide a resolution of approximately 0.044° (180° divided by (212−1)), while the 12-bit values for Phi_AoA and Phi_AoD may provide a resolution of approximately 0.088° (360° divided by (212−1)).\",\n \"FTM frames formatted according to current FTM protocols (e.g., as defined by the IEEE 802.11REVmc standards) include a 6-byte TOD field and a 6-byte TOA field to store TOD and TOA information, respectively (e.g., to embed timestamp values ta1 and ta4 of FIG.\",\n \"5A).\",\n \"Because an RTT value may be calculated using a single time difference value (e.g., ta4−ta1) rather than two individual timestamp values (e.g., ta4 and ta1), one of these TOD and TOA fields may be re-purposed to store AoA and AoD information, thereby eliminating the need for an FTM frame to include a separate field that stores AoA and AoD information (and thus reducing the size of the FTM frame).\",\n \"More specifically, in accordance with example embodiments, one of the TOD and TOA fields of an FTM frame may be used store a single time difference value for a ranging operation, and the other of the TOD and TOA fields of the FTM frame may be used to store AoA and AoD information for the ranging operation without compromising accuracy of RTT estimates.\",\n \"Referring also to FIGS.\",\n \"5A, 6, and 8, for some implementations, the TOD field 605 of FTM frame 600 or FTM frame 800 may be used to store the time value (ta4−ta1), and the TOA field 606 of FTM frame 600 or FTM frame 800 may be used to store AoA and AoD information (e.g., AoAa and AoDa).\",\n \"In some aspects, the TOA field 606 may store four 12-bit values: Theta_AoA, Phi_AoA, Theta_AoD, and Phi_AoD.\",\n \"The format of the TOA field 606 may be expressed as: {Theta_AoA[0:11], Phi_AoA[0:11], Theta_AoD [0:11], Phi_AoD[0:11]}.\",\n \"For other implementations, the TOA field 606 of FTM frame 600 or FTM frame 800 may be used to store the time difference value (ta4−ta1), and the TOD field 605 of FTM frame 600 or FTM frame 800 may be used to store AoA and AoD information (e.g., AoAa and AoDa).\",\n \"In some aspects, the TOD 605 field may store four 12-bit values: Theta_AoA, Phi_AoA, Theta_AoD, and Phi_AoD.\",\n \"The format of the TOD field 605 may be expressed as: {Theta_AoA[0:11], Phi_AoA[0:11], Theta_AoD[0:11], Phi_AoD[0:11]}.\",\n \"Any suitable techniques may be used to estimate AoA information of frames received by the responder device and/or to estimate AoD information for frames transmitted from the responder device.\",\n \"For at least some embodiments, the responder device may use a number of different antenna patterns when estimating the AoA information of ACK frames received from the initiator device.\",\n \"More specifically, when the responder device includes a number N>2 antennas, the responder device may selectively enable different combinations of the antennas and estimate the channel conditions for a corresponding number of different antenna patterns.\",\n \"The channel condition estimates may be used to estimate AoA information of the ACK frame for various antenna patterns.\",\n \"Because ACK frames typically include one or more predetermined bit patterns (e.g., known to the responder device), ACK frames may be well suited for estimating channel conditions.\",\n \"The responder device may use the entire ACK frame for estimating channel conditions and/or estimating AoA information.\",\n \"Using the entire ACK frame may allow the responder device to switch between the various antenna patterns during reception of the ACK frame.\",\n \"When the responder device cannot process the entire ACK frame (e.g., the responder device may be able to process only legacy fields such as the legacy long training field (L-LTF)), then the responder device may estimate the channel conditions and AoA information using a sequence of N exchanged FTM and ACK frames (e.g., using one FTM/ACK frame exchange for each antenna pattern).\",\n \"As mentioned above, the responder device may estimate AoA information using any suitable technique.\",\n \"These techniques may include (but are not limited to): correlation; maximum likelihood estimation; Multiple Signal Classification (MUSIC) techniques, including variants such as Root-MUSIC, Cyclic MUSIC, or Smooth MUSIC; Estimation of Signal Parameters using Rotational Invariance Techniques (ESPRIT); Matrix Pencil; or other techniques for estimating AoA information.\",\n \"Thus, as described above with respect to FIG.\",\n \"10, an initiator device may use RTT information and AoA/AoD information to estimate a relative distance vector indicating its position relative to a responder device.\",\n \"If the 3-dimensional (3D) location of the responder device is known, then the relative distance vector may allow the initiator device to estimate its own 3D location.\",\n \"If only the 2-dimensional (2D) location of the responder device is known, then the initiator device may estimate its own 2D location by projecting the estimated relative distance vector onto the 2D plane.\",\n \"FIG.\",\n \"11 is an illustrative flow chart depicting an example ranging operation 1100 between a first device D1 and a second device D2 in accordance with example embodiments.\",\n \"Device D1 and device D2 may each be, for example, an access point (e.g., AP 110 of FIG.\",\n \"1), a station (e.g., one of stations STA1-STA4 of FIG.\",\n \"1), or other suitable wireless device (e.g., wireless device 200 of FIG.\",\n \"2).\",\n \"For the example operation 1100 of FIG.\",\n \"11, device D2 is the initiator device, and device D1 is the responder device.\",\n \"First, device D2 transmits, to device D1, an FTM_REQ frame that includes a request for device D1 to estimate AoA and/or AoD information for one or more frames exchanged between device D1 and device D2 (1102).\",\n \"The FTM_REQ frame may also indicate a desired level of accuracy for the requested AoA/AoD information.\",\n \"Device D1 receives the FTM_REQ frame, and then transmits an ACK frame indicating whether device D1 is capable of estimating AoA and/or AoD information (and whether the estimated AoA and/or AoD information will be included in subsequent FTM frames) (1104).\",\n \"The ACK frame may include the level of accuracy to be provided for the requested AoA/AoD information.\",\n \"Device D1 transmits an FTM_1 frame to device D2, records the TOD of the FTM_1 frame as time t1, and estimates the AoD of the FTM_1 frame (1106).\",\n \"For other embodiments, the FTM_1 frame may indicate whether device D1 is capable of estimating AoA and/or AoD information (and whether the estimated AoA and/or AoD information will be included in subsequent FTM frames).\",\n \"Device D2 receives the FTM_1 frame, and records the TOA of the FTM_1 frame as time t2 (1108).\",\n \"Device D2 transmits an ACK frame to device D1, and records the TOD of the ACK frame as time t3 (1110).\",\n \"Device D1 receives the ACK frame at time t4, records the TOA of the ACK frame as time t4, and estimates the AoA of the ACK frame (1112).\",\n \"Device D1 transmits, to device D2, an FTM_2 frame that includes a time value and angle information (1114).\",\n \"The time value may indicate a difference in time between the TOD of the FTM_1 frame transmitted from device D1 and the TOA of the ACK frame received at device D1 (e.g., the time value may be equal to t4−t1).\",\n \"The angle information may indicate a direction of device D2 relative to device D1.In some aspects, the angle information may include the AoD of the FTM_1 frame transmitted from device D1 and/or the AoA of the ACK frame received at device D1 (1114).\",\n \"For other embodiments, the FTM_2 frame may include the actual timestamps for times t1 and t4 (e.g., rather than the time value indicating the difference in time between time t4 and time t1).\",\n \"Device D2 may determine a distance between itself and device D1 based on one or more RTT values (1116).\",\n \"For example, device D2 may determine the distance d between device D1 and device D2 using the expression d=c*RTT/2, where c is the speed of light, and RTT is the summation of the actual signal propagation times of the FTM_1 frame and the ACK frame.\",\n \"More specifically, the value of RTT may be determined as (t4−t1)−(t3−t2).\",\n \"Thereafter, device D2 may determine its location relative to device D1 based, at least in part, on the determined distance and the angle information (1118).\",\n \"FIG.\",\n \"12 is an illustrative flow chart depicting another example ranging operation 1200 between a first device D1 and a second device D2 in accordance with example embodiments.\",\n \"The first device D1 and the second device D2 may each be, for example, an access point (e.g., AP 110 of FIG.\",\n \"1), a station (e.g., one of stations STA1-STA4 of FIG.\",\n \"1), or other suitable wireless device (e.g., wireless device 200 of FIG.\",\n \"2).\",\n \"For the example operation 1200 of FIG.\",\n \"21, the second device D2 is the initiator device, and the first device D1 is the responder device.\",\n \"The first device may receive, from the second device, a fine timing measurement (FTM) request frame including a request to estimate angle information for a number of frames exchanged with the second device and indicating a level of accuracy for the estimated angle information (1202).\",\n \"In some aspects, the request may be embedded within a vendor specific information element (VSIE) of the FTM request frame.\",\n \"The first device may transmit a first FTM frame to the second device (1204).\",\n \"In some implementations, the first FTM frame may indicate a level of accuracy the with which first device is to estimate the angle information.\",\n \"In some aspects, the indicated level of accuracy is embedded in an information element (IE) of the first FTM frame.\",\n \"The first device may receive an acknowledgement (ACK) frame from the second device (1206), and may transmit, to the second device, a second FTM frame including angle information of the first FTM frame and timing information of one or more of the exchanged frames (1208).\",\n \"The angle information may include at least one of angle of departure (AoD) information of the first FTM frame or angle of arrival (AoA) information of the ACK frame.\",\n \"The timing information may indicate a difference between a time of departure (TOD) of the first FTM frame and a time of arrival (TOA) of the ACK frame.\",\n \"The first device may estimate an AoA of the ACK frame using a plurality of different antenna patterns (1208), and may estimate an AoD of the first FTM frame using a plurality of different antenna patterns (1210).\",\n \"Those of skill in the art will appreciate that information and signals may be represented using any of a variety of different technologies and techniques.\",\n \"For example, data, instructions, commands, information, signals, bits, symbols, and chips that may be referenced throughout the above description may be represented by voltages, currents, electromagnetic waves, magnetic fields or particles, optical fields or particles, or any combination thereof.\",\n \"Further, those of skill in the art will appreciate that the various illustrative logical blocks, modules, circuits, and algorithm steps described in connection with the aspects disclosed herein may be implemented as electronic hardware, computer software, or combinations of both.\",\n \"To clearly illustrate this interchangeability of hardware and software, various illustrative components, blocks, modules, circuits, and steps have been described above generally in terms of their functionality.\",\n \"Whether such functionality is implemented as hardware or software depends upon the particular application and design constraints imposed on the overall system.\",\n \"Skilled artisans may implement the described functionality in varying ways for each particular application, but such implementation decisions should not be interpreted as causing a departure from the scope of the disclosure.\",\n \"The methods, sequences or algorithms described in connection with the aspects disclosed herein may be embodied directly in hardware, in a software module executed by a processor, or in a combination of the two.\",\n \"A software module may reside in RAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory, registers, hard disk, a removable disk, a CD-ROM, or any other form of storage medium known in the art.\",\n \"An exemplary storage medium is coupled to the processor such that the processor can read information from, and write information to, the storage medium.\",\n \"In the alternative, the storage medium may be integral to the processor.\",\n \"Accordingly, one aspect of the disclosure can include a non-transitory computer readable media embodying a method for time and frequency synchronization in non-geosynchronous satellite communication systems.\",\n \"The term “non-transitory” does not exclude any physical storage medium or memory and particularly does not exclude dynamic memory (e.g., conventional random access memory (RAM)) but rather excludes only the interpretation that the medium can be construed as a transitory propagating signal.\",\n \"While the foregoing disclosure shows illustrative aspects, it should be noted that various changes and modifications could be made herein without departing from the scope of the appended claims.\",\n \"The functions, steps or actions of the method claims in accordance with aspects described herein need not be performed in any particular order unless expressly stated otherwise.\",\n \"Furthermore, although elements may be described or claimed in the singular, the plural is contemplated unless limitation to the singular is explicitly stated.\",\n \"Accordingly, the disclosure is not limited to the illustrated examples and any means for performing the functionality described herein are included in aspects of the disclosure.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875807"}}},{"rowIdx":4494984,"cells":{"text":{"kind":"list like","value":[["SYSTEMS, APPARATUSES, AND METHODS FOR MEASURING SUBMERGED SURFACES","The present disclosure provides systems, apparatuses, and methods for measuring submerged surfaces.","Embodiments include a measurement apparatus including a main frame, a source positioned outside a pipe and connected to the main frame, and a detector positioned outside the pipe at a location diametrically opposite the source and connected to the main frame.","The source may transmit a first amount of radiation.","The detector may receive a second amount of radiation, determine a composition of the pipe based on the first and second amounts of radiation, and send at least one measurement signal.","A control canister positioned on the main frame or on a remotely operated vehicle (ROV) attached to the apparatus may receive the at least one measurement signal from the detector and convey the at least one measurement signal to software located topside."],["1.A measurement apparatus, comprising: a main frame; a source positioned outside a section of pipe located underwater and connected to the main frame, the source configured to transmit a continuous first amount of radiation; a detector positioned outside the pipe and connected to the main frame at a location diametrically opposite the source, the detector configured to receive a continuous second amount of radiation, determine a composition of the section of pipe based on the first and second amounts of radiation, and send at least one measurement signal; a control system positioned on the main frame or on a remotely operated vehicle (ROV) attached to the apparatus, the control canister including a data acquisition system (DAQ) configured to receive the at least one measurement signal from the detector and convey the at least one measurement signal to software located topside; and at least one buoyancy structure positioned on the main frame, the at least one buoyancy structure configured to hold the apparatus in place on the pipe, wherein the apparatus is configured to be at least one of autonomously, semi-autonomously, and manually controlled to be moved along the pipe and take multiple measurements of sections of the pipe.","2.The measurement apparatus of claim 1, wherein the apparatus is autonomously controlled via at least a battery and wireless connections to the ROV.","3.The measurement apparatus of claim 1, wherein the apparatus is manually controlled via at least an underwater diver and the ROV.","4.The measurement apparatus of claim 1, further comprising a stabilizing system positioned beneath the at least one buoyancy structure and within the main frame, the stabilizing system configured to act as a ballast assist in maintaining the stability of the apparatus on the pipe.","5.A measurement apparatus, comprising: a main frame; a source positioned outside a pipe and connected to the main frame, the source configured to transmit a first amount of radiation; a detector positioned outside the pipe and connected to the main frame at a location diametrically opposite the source, the detector configured to receive a second amount of radiation, determine a composition of the pipe based on the first and second amounts of radiation, and send at least one measurement signal; a control canister positioned on the main frame or on a remotely operated vehicle (ROV) attached to the apparatus, the control canister configured to receive the at least one measurement signal from the detector and convey the at least one measurement signal to software located topside; and at least one buoyancy structure positioned on the main frame, the at least one buoyancy structure configured to hold the apparatus in place on the pipe.","6.The measurement apparatus of claim 5, wherein the source and detector are each connected to the main frame using a support frame.","7.The measurement apparatus of claim 5, wherein the source and detector are each mounted within a source carriage and detector carriage, respectively.","8.The measurement apparatus of claim 7, further comprising at least one roller attached to at least one of each opposing side of the main frame and an end of each of the source carriage and detector carriage, respectively, the at least one roller configured to assist in moving the apparatus along the pipe.","9.The measurement apparatus of claim 5, further comprising at least two crawlers positioned beneath the apparatus, the at least two crawlers configured to assist in moving the apparatus along the pipe.","10.The measurement apparatus of claim 5, further comprising a distance counter attached to the apparatus, the distance counter configured to measure and control the speed and distance traveled by the apparatus.","11.The measurement apparatus of claim 5, further comprising at least one brush attached to the apparatus, the at least one brush configured to clean debris on the pipe.","12.The measurement apparatus of claim 7, further comprising a cleaning structure attached to a forward-direction facing end of at least one of the source carriage and detector carriage, the cleaning structure configured to move debris away from the pipe.","13.The measurement apparatus of claim 5, wherein the source includes a collimator to direct the first amount of radiation towards the pipe.","14.The measurement apparatus of claim 13, wherein the source includes a shutter to open or close the collimator.","15.The measurement apparatus of claim 14, wherein the source includes electric motors to activate the shutter.","16.The measurement apparatus of claim 5, wherein the control canister includes a data acquisition (DAQ) system configured to assist in receiving the at least one measurement signal from the detector and convey the at least one measurement signal to software located topside.","17.The measurement apparatus of claim 5, further comprising a stabilizing system positioned beneath the at least one buoyancy structure and within the main frame, the stabilizing system configured to act as a ballast assist in maintaining the stability of the apparatus on the pipe.","18.The measurement apparatus of claim 17, wherein the stabilizing system includes a brick of lead attached to electric motors configured to move the brick of lead transversally within the main frame of the apparatus to maintain the stability of the apparatus on the pipe.","19.The measurement apparatus of claim 5, further comprising a handle mounted on the main frame, the handle configured to provide for manual or ROV-assisted manipulation and placement of the apparatus.","20.The measurement apparatus of claim 5, further comprising at least one sensor located within the main frame, the at least one sensor configured to take a measurement of the pipe and send at least one signal based on the measurement.","21.The measurement apparatus of claim 20, wherein the at least one sensor is a pulsed eddy current (PEC) sensor.","22.The measurement apparatus of claim 5, further comprising hydraulic clamps attached to the apparatus, the hydraulic clamps configured to attach the apparatus on the pipe.","23.The measurement apparatus of claim 22, further comprising at least one hydraulic line between the ROV and the apparatus, the at least one hydraulic line configured to activate the hydraulic clamps.","24.The measurement apparatus of claim 5, further comprising at least one electrical line between the ROV and the apparatus, the at least one electrical line configured to provide power to run the measurement apparatus.","25.The measurement apparatus of claim 5, wherein the first and second amounts of radiation are gamma rays.","26.The measurement apparatus of claim 25, wherein the gamma rays are derived from 137Cs.","27.A method for measuring submerged pipelines, comprising: connecting an attachment of a measurement apparatus to a remotely operated vehicle (ROV), wherein the measurement apparatus comprises: a main frame; a source positioned outside a section of pipe and connected to the main frame, the source configured to transmit a first amount of radiation; a detector positioned outside the section of pipe and connected to the main frame at a location diametrically opposite the source, the detector configured to receive a second amount of radiation, determine a composition of the section of pipe based on the first and second amounts of radiation, and send at least one measurement signal; a control canister positioned on the main frame or on the ROV, the control canister configured to receive the at least one measurement signal from the detector and convey the at least one measurement signal to software located topside; and at least one buoyancy structure positioned on the main frame, the at least one buoyancy structure configured to hold the apparatus in place on the pipe, lowering and placing the measurement apparatus upon the section of pipe using the ROV; taking a measurement of the section of pipe using the detector to create the at least one measurement signal; sending the at least one measurement signal from the detector to the control canister; and conveying the at least one measurement signal from the control canister to the software located topside.","28.The method of claim 27, further comprising moving the measurement apparatus to another section of the pipe using the ROV after each round of measurements.","29.A system, comprising: a remotely operated vehicle (ROV); and a measurement apparatus connected to the ROV, the measurement apparatus comprising: a main frame; a source positioned outside a section of pipe and connected to the main frame, the source configured to transmit a first amount of radiation; a detector positioned outside the section of pipe and connected to the main frame at a location diametrically opposite the source, the detector configured to receive a second amount of radiation, determine a composition of the section of pipe based on the first and second amounts of radiation, and send at least one measurement signal; and a control canister positioned on the main frame or on the ROV, the control canister configured to receive the at least one measurement signal from the detector and convey the at least one measurement signal to software located topside, wherein the software is configured such that a user may access the software to view the composition and other properties of the section of pipe and to control movement of the apparatus via the ROV."],["<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG.","1 is an isometric view of a measurement apparatus positioned on a section of pipe, according to an exemplary embodiment of the present disclosure.","FIG.","2 is a side view of the measurement apparatus shown in FIG.","1 .","FIG.","3 is a top view of the measurement apparatus shown in FIG.","1 .","FIG.","4 is an isometric view of a measurement apparatus positioned on a section of pipe, according to an exemplary embodiment of the present disclosure.","FIG.","5 is a side view of the measurement apparatus shown in FIG.","4 .","FIG.","6 is a top view of the measurement apparatus shown in FIG.","4 .","FIG.","7 is an illustration of a graphic user interface for software connected to a measurement apparatus and located topside, according to an exemplary embodiment of the present disclosure.","FIG.","8 is a front view of a measurement apparatus including a rotating plate positioned on a section of pipe, according to an exemplary embodiment of the present disclosure.","detailed-description description=\"Detailed Description\" end=\"lead\"?"],["This application is a continuation of U.S. patent application Ser.","No.","15/141,269, filed Apr.","28, 2016, which claims the benefit of U.S.","Provisional Patent Application No.","62/153,944, filed Apr.","28, 2015, each of which are incorporated herein by reference.","BRIEF DESCRIPTION OF THE DRAWINGS FIG.","1 is an isometric view of a measurement apparatus positioned on a section of pipe, according to an exemplary embodiment of the present disclosure.","FIG.","2 is a side view of the measurement apparatus shown in FIG.","1.FIG.","3 is a top view of the measurement apparatus shown in FIG.","1.FIG.","4 is an isometric view of a measurement apparatus positioned on a section of pipe, according to an exemplary embodiment of the present disclosure.","FIG.","5 is a side view of the measurement apparatus shown in FIG.","4.FIG.","6 is a top view of the measurement apparatus shown in FIG.","4.FIG.","7 is an illustration of a graphic user interface for software connected to a measurement apparatus and located topside, according to an exemplary embodiment of the present disclosure.","FIG.","8 is a front view of a measurement apparatus including a rotating plate positioned on a section of pipe, according to an exemplary embodiment of the present disclosure.","DESCRIPTION OF EMBODIMENTS A submerged or submarine pipeline is a pipeline passing under water, which is typically laid on a seabed, or inside a trench below the seabed.","The pipeline may also be located partially on-land.","Submarine pipelines are used primarily to carry oil or gas but may also be used to transport other materials.","Plugging by hydrates and/or other media in pipelines is one of the major flow assurance challenges facing the oil and gas industry because it prevents the flow of media in the pipeline and causes substantial interruption and losses in operations.","As oil and gas production moves into harsh and challenging environments, including deep subsea environments, there is a growing need to prevent this plug formation.","The value of remediation methods for plug formation depends on the speed and efficiency in locating an accumulation or plug in the pipeline.","The media flowing in the pipeline, including gas, oil, wax, asphaltene, hydrates, paraffin, and sand have varied and/or minimal differences in their respective densities and composition.","Detecting these differences in densities and composition allows for the ability to locate total or partial blockage in the pipe.","A way to detect these differences in densities is by the use of radiation to measure the density of the contents of the pipeline.","Methods of using radiation, including gamma rays, to determine the density of pipelines (including to measure flow and hold-up in the pipelines) are disclosed in U.S. Pat.","No.","7,402,796, U.S. Pat.","No.","4,795,903, U.S. Pat.","No.","4,667,515, U.S. Patent Pub.","No.","2012/0087467 A1, and U.S. Patent Pub.","No.","2008/0137808 A1, all of which are incorporated herein by reference.","These methods include placing a “source” of radiation outside a pipeline for directing radiation from the source through a portion of the pipeline, and placing a “detector” at a location outside the pipeline opposite the source of radiation for detecting the radiation and measuring the density of the pipeline.","The amount of radiation which subsequently exits the pipeline depends upon the mass of the media contained within the pipeline and its ability to absorb radiation.","Thus, a reduction in the amount of radiation which reaches the detector indicates an increased bulk density of the media flowing through or contained within the pipeline as more radiation is absorbed by the media.","The primary existing tool providing for inspection of submerged pipelines in subsea environments is the “Discovery” tool provided by Tracerco™.","This tool, however, is extremely complex, and functions by making a tomography of the pipeline.","Each measurement of a “slice” of the pipeline takes about 20 minutes.","The tool is also very heavy (approximately two tons) and requires dredging around the pipeline to be operated.","Additionally, operation of the tool is very expensive and time-consuming, and requires the use of additional complex subsea operations.","Embodiments of the present disclosure relate generally to non-destructive measuring systems, apparatuses, and methods, and in particular though non-limiting embodiments, to systems, apparatuses and methods for measuring submerged pipelines.","The present disclosure provides improved apparatuses, systems, and methods for the measurement of submerged surfaces, including measurement of submerged pipelines.","The disclosed embodiment includes a measurement apparatus having a source/emitter and a detector connected to a main frame and configured to detect density and/or composition of a section of pipeline.","The measurement apparatus may be configured for attachment to an ROV.","The attachment to the ROV may be through a hydraulic and/or electrical system.","According to exemplary embodiments of the present disclosure, methods are provided for measuring submerged pipelines.","Steps may include connecting a measurement apparatus to an ROV, and using the ROV to lower and place the apparatus upon a submerged pipeline such that the apparatus securely fits on the pipeline.","A source and a detector of the apparatus may then be used to measure the density and/or composition of the section of the submerged pipeline and create an at least one measurement signal.","The at least one measurement signal may then be sent via software on the apparatus to software on the ROV and/or to software located topside.","This improved method of measurement of submerged pipelines may be performed in ranges of approximately 3,000 meters to 4,700 meters below sea level.","The measurement apparatus may be moved along the submerged pipeline as needed using the ROV.","Exemplary embodiments of the present disclosure may include traction rollers and/or crawlers and/or wheels attached to the apparatus, allowing the apparatus to move along the pipe.","The rollers and/or crawlers and/or wheels may be powered by electric or hydraulic motors.","The rollers and/or crawlers and/or wheels may be arranged such that the main frame of the apparatus is in close proximity to an outer surface of the section of pipe without scraping or contacting the surface.","The number of rollers and/or crawlers and/or wheels may vary in different embodiments of the disclosure.","The rollers and/or crawlers and/or wheels may allow for quick and efficient guidance of the measurement apparatus along the pipeline by an ROV.","Exemplary embodiments of the present disclosure may also include a stabilizing system including a brick of lead positioned within the main frame of the apparatus to act as a ballast assist in maintaining the stability of the apparatus along the pipe.","The apparatus may also include a handle allowing for ROV-assisted manipulation of the measurement apparatus along the pipe.","Embodiments of the present disclosure therefore allow for miles of pipeline to be measured in a single day.","The measurement apparatus may be securely and quickly guided along the pipeline using the connection to the ROV.","The measurement apparatus may be employed to measure vast sections of pipeline for potential problem areas.","In this way, the present disclosure allows for efficient, low cost measurement of the pipeline.","Although discussed herein in conjunction with pipelines, the measurement apparatus may be used on vessels or other surfaces.","Embodiments of the present disclosure provide for measuring the content of submerged surfaces, including submerged pipelines, in a more efficient manner that does not affect the measured material, requires less process downtime for installation, is non-intrusive, and is easily deployable.","Embodiments of the present disclosure provide for a faster, cheaper, and more reliable method for diagnosing flow abnormalities due to partial or total plugs within pipelines without substantial interruption to pipeline operations.","Referring to FIGS.","1 to 3, different views of a measurement apparatus 10 are shown.","In FIG.","1, an exemplary embodiment of a measurement apparatus 10 positioned on a section of pipe 22 is shown.","Measurement apparatus 10 may include a main frame 12, a radiation source 19 connected to the main frame 12, and a radiation detector 20 connected to the main frame 12.In an exemplary embodiment, the main frame 12 may have a rectangular shape.","In alternative embodiments, the main frame 12 may have other shapes suitable for the measurement functions of the apparatus 10.In an exemplary embodiment, the main frame 12 may be made of aluminum.","However, the main frame 12 may be made of other materials suitable for the measurement functions of the apparatus 10.In particular embodiments, the apparatus 10 may perform measurements on a section of pipe 22 with a diameter of approximately ten to eighteen inches.","However, the apparatus 10 may also perform measurements on pipes with larger or smaller diameters.","In exemplary embodiments, the apparatus 10 may weigh approximately 150 pounds in water and 380 pounds in air, which is substantially less than existing measurement apparatuses performing similar functions.","In various embodiments, source 19 and/or detector 20 may be positioned outside the pipe 22 and connected to the main frame 12.In an exemplary embodiment, both source 19 and/or detector 20 may be connected to the apparatus 10 using an elongated support frame 14 having a plurality of grooves and tracks configured for attachment to vertical bars holding the source 19 and/or detector 20 in a secured carriage.","See, e.g, FIG.","1.The vertical bars may be attached to the support frame 14 using mechanical attachments such as screws and/or bolts.","Alternatively, other mechanical configurations may be used to attach the bars to the support frame 14, including circumferential straps, magnets, ties, quick releases, snap locks, or other combinations thereof, and/or other suitable systems.","In alternative embodiments, source 19 and/or detector 20 may be connected to the main frame 12 using other suitable methods.","In some embodiments, the support frame 14 may be connected to electrical or electro-hydraulic linear actuators or hydraulic cylinders, that may in turn be connected to the source 19 and/or detector 20, and configured to adjust the source 19 and/or the detector 20 in a direction perpendicular to the pipe 22.In an exemplary embodiment, the support frame 14 may be made of aluminum.","Alternatively, the support frame 14 may be made of other materials suitable for attaching support frame 14 to the main frame 12 and securely holding the source 19 and/or detector 20 in place.","In particular embodiments, source 19 and/or detector 20 may each be attached to cleaning structures 19a, 20a configured to move debris away from the pipe 22 during measurement of the pipe 22.In exemplary embodiments, cleaning structures 19a, 20a may each have a cone shape to more efficiently move debris and other material away from the pipe 22.In alternative embodiments, cleaning structures 19a, 20a may have other shapes suitable for performing this function.","Cleaning structures 19a, 20a may be attached to the front end, back end, and/or the sides of the source 19 and/or detector 20.In embodiments of the present disclosure, source 19 and/or detector 20 may be securely held in a source carriage and/or detector carriage, respectively.","In an exemplary embodiment, the source carriage and/or detector carriage may be made of titanium, which is permeable to radiation.","Source 19 may include a radiation source contained within a radiation source holder and configured to transmit a continuous first amount of radiation through a section of the pipe 22.In exemplary embodiments, this first amount of radiation may be gamma rays.","In this embodiment, the radiation is generally a radioactive isotope as used in conventional (single source and detector) density gauges where the radiation source is commonly 662 keV gamma radiation (approximately 100-200 millicurie) from a cesium-137 isotope (137Cs).","Alternatively, this first amount of radiation may be derived from other radioactive sources, including X-rays.","In exemplary embodiments, source holder of source 19 may be at least one of the SHLD, SHF, SHLG, SHLM, and SR source holders for radiation-based measurement offered by VEGA Americas, Inc.","Source 19 may be positioned at a location outside the pipe 22.Source 19 may include a collimator to direct the first amount of radiation towards the pipe 22.In exemplary embodiments, source 19 may also include a shutter to open or close the collimator.","In this embodiment, source 19 may include electric motors to activate the shutter, i.e., turn the shutter on and off and let out radiation as needed.","Particularly, source 19 may use a solenoid to achieve this function.","In alternative embodiments, source 19 may include an electrical linear actuator and/or hydraulic cylinder and/or other suitable devices to achieve this function.","If the shutter is on, the first amount of radiation will be transmitted from the source 19 using the collimator.","If the shutter is off, the first amount of radiation will not be transmitted from the source 19.In alternative embodiments, source 19 may include other available methods to transmit and/or direct the radiation towards the pipe 22.In a particular embodiment, source 19 may weigh approximately sixty pounds.","Detector 20 may be positioned outside a section of the pipe 22 at a location diametrically opposite the source 19.See, e.g., FIG.","3.However, detector 20 may also be positioned at other locations on the pipe 22 as needed to most effectively detect and/or receive radiation from the source 19.Detector 20 may be configured to receive a second amount of radiation from the source 19 after the first amount of radiation has passed through the section of the pipe 22.Detector 20 may then be configured to determine a composition of media flowing within the section of the pipe 22 based on the first and second amounts of radiation, and then send at least one measurement signal based on this determined composition via inbuilt signal conditioning software of detector 20 to software on an ROV attached to the apparatus 10 and/or directly to software located topside.","In a particular embodiment, detector 20 may be configured to determine a density of the media flowing and/or stagnant within the section of the pipe 22.In a particular embodiment, detector 20 may weigh approximately fifteen pounds.","In exemplary embodiments, detector 20 may be at least one of the MiniTrac 31 and MiniTrac 32 detectors for radiation-based density measurement offered by VEGA Americas, Inc.","In this embodiment, detector 20 may include signal conditioning instruments and software such as the VEGAMET 624 which may power the MiniTrac 31 and process and display measured values such as the at least one measurement signal.","In various embodiments, detector 20 may make measurements of section of pipe 22 constantly at a high frequency.","However, in some embodiments, due to the random nature of the radiation emitted from source 19, these measurements may be averaged and dampened via a multi-pass software filter in the detector 20 that changes the frequency of the update to the output based on the step change of sensed value.","In an exemplary embodiment, apparatus 10 may increase its productivity from 1 to 20 ft/min, which equals up to 9.5 Km of pipeline/day.","In particular embodiments, more than one measurement of a section of pipe 22 may be taken by the apparatus 10 at one time.","In some embodiments, it may be possible to include more than one detector 20 and/or if necessary, more than one source 19, to either sense a larger area on the pipe 22 and/or improve accuracy of the readings by the apparatus 10.As shown in FIGS.","1 to 3, control canister 23 may be positioned on the main frame 12 of the apparatus 10 in a location below handle 36.Alternatively, control canister 23 may be located in an ROV attached to apparatus 10.In an exemplary embodiment, control canister 23 may include software configured to receive the at least one measurement signal from the detector 20, and convey the at least one measurement signal to software located in the ROV and/or to directly to software viewable and/or controlled by topside personnel.","Software in the control canister 23 may be a Supervisory Control And Data Acquisition (SCADA) system used for remote monitoring and control that operates with coded signals over communication channels (using typically one communication channel per remote station).","In various embodiments, software of control canister 23 may include a data acquisition (DAQ) system using coded signals over communication channels to acquire information about the status of remote equipment for display or for recording functions.","In this embodiment, DAQ system in control canister 23 may include sensors, DAQ measurement hardware, and a computer with programmable software.","In particular embodiments, control canister 23 may include a local data acquisition board configured to receive and convey the at least one measurement signal to the software on ROV and/or software located topside and viewable and/or controlled by topside personnel.","In this embodiment, control canister 23 may also include motor controllers for a propulsion drive and ballast drive, gyro, inclinometers, and/or an Ethernet to a signal conditioner (e.g., an RS232 signal conditioner).","In alternative embodiments, control canister 20 may include other suitable configurations to assist in receiving and conveying the at least one measurement signal to software in the ROV and/or directly to software viewable and controlled by topside personnel.","In an exemplary embodiment, control canister 23 may have a cylindrical shape.","In an alternative embodiment, control canister 23 may have other shapes suitable for performing its receiving and conveying functions.","In particular embodiment, control canister 23 may be made of titanium.","Alternatively, control canister 23 may be made of other suitable materials.","In an example embodiment, control canister 23 may include a DAQ system offered by National Instruments™.","In various embodiments, apparatus 10 may include at least one buoyancy structure 25 positioned on the main frame 12.At least one buoyancy structure 25 may be configured to hold the apparatus 10 in place on the pipe 22.In an exemplary embodiment, apparatus 10 may include two buoyancy structures 25 positioned on the main frame 12, with the control canister 23 positioned between the two buoyancy structures 25.See, e.g., FIG.","1.In exemplary embodiments, at least one buoyancy structure 25 may be made of foam.","In alternative embodiments, at least one buoyancy structure 25 may be a ballast tank having variable or non-variable buoyancy control.","In this embodiment, the ballast tank buoyancy structure 25 may be securable over a portion of the main frame 12.In particular embodiments, apparatus 10 may further include a stabilizing system such as for e.g.","a brick of lead positioned beneath the at least one buoyancy structure 25 and within the main frame 12.The brick of lead may be configured to act as a ballast assist in maintaining the stability of the apparatus 10 on the pipe 22.In this embodiment, the stabilizing system may include attachments to electric motors configured to move the brick of lead transversally within the apparatus 10.For example, if the apparatus 10 moves in an unwanted left or right direction once it is placed on the pipe 22, the electric motors may be used to move the brick of lead in the opposite direction to ensure proper balancing and positioning of the apparatus 10 on the pipe 22.In exemplary embodiments, stabilizing system may include attachments to inclinometers configured to measure angles of slope (or tilt), elevation, or depression of the apparatus 10 with respect to gravity, and thereby further assist in positioning the apparatus 10 on the pipe 22.In an exemplary embodiment, the inclinometers may be located within the control canister 23.In some embodiments, the apparatus 10 may also be securable to and positioned on the pipe 22 using hydraulic clamps or electrically operated via motor or electrical linear actuator.","Apparatus 10 may include at least one roller 18 attached to each opposing side of the main frame 12.At least one roller 18 may be configured to assist in moving the apparatus 10 along the pipe 22.In a particular embodiment, apparatus 10 may include two rollers 18 attached to each opposing side of the main frame 12.See, e.g., FIG.","3.In exemplary embodiments, at least one roller 18 may be made of rubber such as for e.g., urethane rubber.","In this embodiment, apparatus 10 may include hydraulic or electric motors connected to at least one roller 18 and configured to rotate at least one roller 18 and move the apparatus 10 along the pipe 22.In an alternative embodiment, at least one roller 18 may not be motorized and apparatus 10 may be mechanically moved along the pipe 22.In some embodiments, apparatus 10 may also include at least two crawlers 16 positioned beneath ends and/or sides of the apparatus 10.See, e.g., FIG.","2.At least two crawlers 16 may be configured to work in tandem with at least one roller 18 to assist in faster and more efficient movement of the apparatus 10 along the pipe 22.In various embodiments, at least two crawlers 16 may either be motorized or non-motorized.","In exemplary embodiments, apparatus 10 may include a handle 36 mounted on the main frame 12.Handle 36 may be configured to provide for manipulation and placement of the apparatus 10 via an arm of the ROV or by manual manipulation.","In some embodiments, apparatus 10 may also include secondary handles 37 on either a front end, back end, and/or sides of the main frame 12.Secondary handles 37 may act as a contingency for the ROV to move the apparatus 10 along the pipe 22 if the motorized rollers 18 and/or crawlers 16 are not functioning properly.","In some embodiments, a distance counter 27 may be attached to the apparatus 10.Distance counter 27 may be configured to measure and control the speed and distance traveled by the apparatus 10.Distance counters 27 or distance measuring wheels may be used to efficiently and quickly measure distances traveled by apparatus 10 attached to distance counter 27 and/or other tools/apparatuses attached to the distance counter 27.In exemplary embodiments, the distance counter 27 may be connected by a signal cable to the control canister 23, which may then send the measurement information to software on an ROV and/or directly to topside personnel.","In exemplary embodiments, this functionality of the distance counter 27 may be incorporated into a propulsion drive circuit, where an encoder used as feedback for closed loop speed control of the drive may also be utilized for distance traveled data.","In embodiments, apparatus 10 may be attached to an ROV by connecting an ROV attachment 38 to an arm of the ROV, thereby allowing the ROV to move the apparatus 10 along pipe 22.In exemplary embodiments, the apparatus 10 may be moved along the pipe 22 at variable speeds ranging from approximately one to twenty feet per minute, depending on the content of the pipe 22, and the nature of any blockage within the pipe 22.Attachment 38 may include electrical, hydraulic, and/or signal connections or lines within the attachment 38 that connect the ROV to the apparatus 10, and vice-versa.","Hydraulic lines of attachment 38 may be configured to control the several hydraulic connections discussed herein, including the hydraulic clamps.","Electrical lines of attachment 38 may be configured to provide power to run the measurement apparatus 10 (and disclosed parts requiring electric power, including the electric motors and propulsion).","Measurement apparatus 10 may include a battery or may alternatively be run using main power from the ROV.","In an exemplary embodiment, the signal connections may include for e.g.","fiber optic cables configured to convey the various measurement signals discussed herein from the control canister 22 to software located topside via an Ethernet connection.","In embodiments of the present disclosure, apparatus 10 may be autonomous, semi-autonomous, or manually controlled.","In the autonomous embodiment of the apparatus 10, apparatus 10 may be powered by a battery pack and/or connected wirelessly (e.g.","Bluetooth) to the ROV or a vessel or monitoring system.","In the manually controlled embodiment, apparatus 10 may be controlled by via a diver or an ROV attached to an attachment 38 of apparatus 10.In the semi-autonomous embodiment of the apparatus 10, apparatus 10 may include an acoustic modem or other equivalent device in combination with for e.g.","attachment to an ROV.","Apparatus 10 may further include brushes 17 attached to the front end, back end, and/or sides of the main frame 12.Brushes 17 may be configured to clean debris and/or other material from the pipe 22 prior to measurement of the pipe 22.In an exemplary embodiment, three brushes 17 may be attached to an end of the main frame 12 that faces a forward direction of travel by the apparatus 10 along the pipe 22.See, e.g., FIG.","1.However, the apparatus 10 may include a greater or lesser number of brushes 17 necessary to clean the pipe 22 prior to being measured by apparatus 10.In some embodiments, trenches down either side of the pipeline/flowline 22 may be dredged using a jetter skid.","In some embodiments, apparatus 10 may include a low pressure (approximately 120 psi greater than ambient pressure) centrifugal pump with nozzles immediately in front of the rollers/tracks 18 to clean the contact area.","Referring to FIGS.","4 to 6, different views of measurement apparatus 11 are shown.","As shown, measurement apparatus 11 may have substantially the same features as apparatus 10 described herein, with some modifications.","Particularly, apparatus 11 may include source 19, detector 20, cleaning structures 19a, 20a, elongated support frame 14, at least one buoyancy structure 25, brushes 17, at least one roller 18, and at least two crawlers 16 described herein, as well as attachment 38 described herein from apparatus 10 to an arm of an ROV for moving apparatus 10 along pipe 22.However, apparatus 11 may not include a control canister 23 positioned on the main frame 12 of apparatus 10.See, e.g., FIG.","5.Rather, control canister 23 may be located external to apparatus 11.For example, control canister 23 may be located at the ROV attached to apparatus 11.Embodiments of the present disclosure may also not include distance counters 27 to measure distance traveled by apparatus 11 since software in control canister 23 located in ROV attached to apparatus 11 may be used to perform this function.","Further, in this embodiment, at least one roller 18 may not be attached to the main frame 12; rather, at least one roller 18 may be attached directly to an end of the detector 20 carriage opposite cleaning structure 20a, and an end of the source 19 carriage opposite cleaning structure 19a.","For example, two rollers may be attached to an end of each of source 19 and detector 20 at each opposing side of apparatus 11.See FIG.","5.Embodiments of the present disclosure may also include cleaning structures 19a, 20a having cone shapes but with more pointy edges than cleaning structures 19a, 20a of apparatus 10 to more efficiently move debris and other material away from the pipe 22.Embodiments of the present disclosure for apparatus 11 are not limited to these particular configurations and may include more or less features, including features described herein relating to apparatus 10.Referring now to FIG.","7, an illustration of a graphic user interface (GUI) for software 30 connected to a measurement apparatus 10, 11 and located topside is shown.","Software 30 may receive the at least one measurement signal described herein from control canister 23 via an Ethernet or other suitable connection.","FIG.","4 is simply an exemplary embodiment of the GUI for this software 30.In this exemplary embodiment, the software 30 may be a SCADA (Supervisory Control And Data Acquisition) system.","Software 30 may provide a method to monitor, receive, save to a local hard drive on a computer topside, and/or display to topside personnel the at least one measurement signal, including for example, density and other composition data of a pipe 22, as well as other data related to apparatus 10, 11.GUI and/or software 30 may take other suitable forms necessary to provide relevant information regarding the apparatus 10, 11 and/or the composition of the pipe 22 to topside personnel viewing the GUI 30 and controlling the ROV and/or apparatus 10, 11.GUI 30 may include several indicators for topside personnel to easily manipulate and control the apparatus 10, 11, and to view the relevant density/composition in a section of the pipe 22.In an exemplary embodiment, GUI 30 may include an “open” or “close” shutter status indicator for the shutter contained within the source 19.In this embodiment, the shutter being “open” indicates that radiation is being continuously transmitted from the source 19 via the collimator as described herein.","The shutter being in the “close” position indicates that radiation is not being emitted from the source 19, and that it is safe for a diver to approach the apparatus 10, 11, if needed.","Due to the particular importance and function of the shutter contained within the source 19, the GUI 30 may also include an additional identifier configured to flash a particular color.","For example, the identifier may flash the color red if the shutter is in the “open” position to indicate that radiation is being transmitted from source 19.In an exemplary embodiment, the GUI 30 may include a water intrusion alarm for the source 19, detector 20, and/or control canister 23.This water intrusion alarm may also be configured to flash a particular color if water has somehow entered the source 19, detector 20, and/or control canister 23, thereby indicating a dangerous environment such that the measurement process must be immediately stopped.","In some embodiments, GUI 30 may include a motion control indicator allowing for topside personnel to control the speed and direction of the apparatus 10, 11.For example, the motion control indicator may be used to move the apparatus 10, 11 in reverse or forward directions along the pipe 22, stop the apparatus 10, 11, and/or set a fixed but variable speed of movement of the apparatus 10, 11.In an exemplary embodiment, GUI 30 may include indicators showing the pressure within apparatus 10, 11.GUI 30 may also include indicators showing the temperature within the source 19, detector 20, and/or control canister 23.If the indicator shows a dangerously high temperature, topside personnel may immediately stop the measurement process by closing the shutter.","In some embodiments, GUI 30 may also include an “open” or “close” status indicator for the hydraulic clamps described herein.","In various embodiments, the GUI 30 may include several identifiers for properties of the section of pipe 22 being measured by the apparatus 10, 11, as well as identifiers relating to movement of the apparatus 10, 11.These identifiers may include but are not limited to outputs showing relevant density, percentage of density, distance traveled, time traveled, and amplitude.","For example, GUI 30 may include a visual indicator for the density of the pipe 22 with values ranging from 0 to 1.0.See FIG.","7.In this exemplary embodiment, if the apparatus 10, 11 detects hydrates in the pipe 22, the value shown in the indicator may jump from 0 to 1.If the apparatus 10, 11 detects oil in the pipe 22, the value may jump from 0 to 0.8.If the apparatus 10, 11 detects wax in the pipe 22, the value may jump from 0 to 0.7.The relationship between these outputs may also be visually depicted using a graph.","See, e.g, FIG.","4.The configuration of this particular GUI 30 and apparatus 10, 11 may therefore provide for an immediate Go/No Go indication using a few quick measurements of the section of pipe 22.Referring to FIG.","8, an alternative embodiment of apparatus 10, 11 positioned on a section of pipe 22 is shown.","In this embodiment, source 19 and detector 20 are shown as attached to opposing ends of a rotating plate 60 attached to the main frame 12 described herein.","In some embodiments, hydraulic and/or electric motors 50 may be positioned within main frame 12 and attached to rotating plate 60 to actuate rotating plate 60.As shown, gears 32 may be located on an underside surface of rotating plate 60 adjacent to surface of pipe 22 and configured to assist hydraulic and/or electric motors 50 in rotation of plate 60 and attached source 19 and/or detector 20.In particular embodiments, source 19 and/or detector 20 may each rotate in a 180° angle (or a greater angle to assure more overlap of the area being measured) in both a counter-clockwise direction, A, and clockwise direction, B, to perform a multi-faceted 360° scan of a section of pipe 22 and measure composition of the section of pipe 22.According to exemplary embodiments, methods are provided for the measurement of submerged surfaces.","In an exemplary embodiment, a method includes attaching a measurement apparatus 10, 11 described herein to an ROV, and using the ROV to lower and place apparatus 10, 11 upon an exterior of a section of submerged pipeline 22.Measurement apparatus 10, 11 may have substantially the same features as measurement apparatuses 10, 11 described herein, including a main frame 12, source 19, detector 20, and/or control canister 23.Source 19 may then be used to transmit a continuous first amount of radiation towards the section of pipe 22.Detector 20 may then be used to receive and detect a second amount of radiation, determine a composition of the pipe 22 based on the first and second amounts of radiation, and create and send at least one measurement signal based on this composition of the pipe 22 to the control canister 23.Control canister 23 may be located on the main frame 12 of the apparatus 10, 11 or directly on the ROV attached to apparatus 10, 11.Control canister 23 may then be used to convey the at least one measurement signal to software on the ROV, which may then be outputted to software 30 located topside.","Alternatively, control canister 23 may convey the at least one measurement signal directly to software 30 located topside.","Once the section of pipe 22 is measured, additional measurements of the same section of pipe 22 may be made, and/or the apparatus 10, 11 may be moved along the pipe 22 using the ROV for measurement of another section of pipe 22.Embodiments of the present disclosure may also be used in conjunction with the inspection apparatus having multiple pulsed eddy current (PEC) sensors disclosed in U.S. patent app.","Ser.","No.","14/868,048, which is incorporated herein by reference.","The PEC sensors may be configured to take measurements of a section of the pipeline 22 on which the inspection apparatus is placed and send multiple signals which are eventually converted into a single measurement signal for conveyance to an ROV.","An average wall thickness of the section of the pipeline 22 may then be calculated from this measurement signal.","In an exemplary embodiment, a second measurement of this section of pipe 22 may be taken using an ultrasonic sensor if the average wall thickness of the section of pipe 22 is below a desired amount.","In some embodiments, this inspection apparatus may be placed adjacent to measurement apparatus 10, 11 described herein on a pipe 22 and both sets of measurements may be taken simultaneously.","In alternative embodiments, at least one PEC sensor may be incorporated into an embodiment of the apparatus 10, 11 described herein (for example, within a side of the main frame 12) so as to take simultaneous multiple measurements of the pipe 22.While the embodiments are described with reference to various implementations and exploitations, it will be understood that these embodiments are illustrative and that the scope of the disclosures is not limited to them.","Many variations, modifications, additions, and improvements are possible.","Further still, any steps described herein may be carried out in any desired order, and any desired steps may be added or deleted."]],"string":"[\n [\n \"SYSTEMS, APPARATUSES, AND METHODS FOR MEASURING SUBMERGED SURFACES\",\n \"The present disclosure provides systems, apparatuses, and methods for measuring submerged surfaces.\",\n \"Embodiments include a measurement apparatus including a main frame, a source positioned outside a pipe and connected to the main frame, and a detector positioned outside the pipe at a location diametrically opposite the source and connected to the main frame.\",\n \"The source may transmit a first amount of radiation.\",\n \"The detector may receive a second amount of radiation, determine a composition of the pipe based on the first and second amounts of radiation, and send at least one measurement signal.\",\n \"A control canister positioned on the main frame or on a remotely operated vehicle (ROV) attached to the apparatus may receive the at least one measurement signal from the detector and convey the at least one measurement signal to software located topside.\"\n ],\n [\n \"1.A measurement apparatus, comprising: a main frame; a source positioned outside a section of pipe located underwater and connected to the main frame, the source configured to transmit a continuous first amount of radiation; a detector positioned outside the pipe and connected to the main frame at a location diametrically opposite the source, the detector configured to receive a continuous second amount of radiation, determine a composition of the section of pipe based on the first and second amounts of radiation, and send at least one measurement signal; a control system positioned on the main frame or on a remotely operated vehicle (ROV) attached to the apparatus, the control canister including a data acquisition system (DAQ) configured to receive the at least one measurement signal from the detector and convey the at least one measurement signal to software located topside; and at least one buoyancy structure positioned on the main frame, the at least one buoyancy structure configured to hold the apparatus in place on the pipe, wherein the apparatus is configured to be at least one of autonomously, semi-autonomously, and manually controlled to be moved along the pipe and take multiple measurements of sections of the pipe.\",\n \"2.The measurement apparatus of claim 1, wherein the apparatus is autonomously controlled via at least a battery and wireless connections to the ROV.\",\n \"3.The measurement apparatus of claim 1, wherein the apparatus is manually controlled via at least an underwater diver and the ROV.\",\n \"4.The measurement apparatus of claim 1, further comprising a stabilizing system positioned beneath the at least one buoyancy structure and within the main frame, the stabilizing system configured to act as a ballast assist in maintaining the stability of the apparatus on the pipe.\",\n \"5.A measurement apparatus, comprising: a main frame; a source positioned outside a pipe and connected to the main frame, the source configured to transmit a first amount of radiation; a detector positioned outside the pipe and connected to the main frame at a location diametrically opposite the source, the detector configured to receive a second amount of radiation, determine a composition of the pipe based on the first and second amounts of radiation, and send at least one measurement signal; a control canister positioned on the main frame or on a remotely operated vehicle (ROV) attached to the apparatus, the control canister configured to receive the at least one measurement signal from the detector and convey the at least one measurement signal to software located topside; and at least one buoyancy structure positioned on the main frame, the at least one buoyancy structure configured to hold the apparatus in place on the pipe.\",\n \"6.The measurement apparatus of claim 5, wherein the source and detector are each connected to the main frame using a support frame.\",\n \"7.The measurement apparatus of claim 5, wherein the source and detector are each mounted within a source carriage and detector carriage, respectively.\",\n \"8.The measurement apparatus of claim 7, further comprising at least one roller attached to at least one of each opposing side of the main frame and an end of each of the source carriage and detector carriage, respectively, the at least one roller configured to assist in moving the apparatus along the pipe.\",\n \"9.The measurement apparatus of claim 5, further comprising at least two crawlers positioned beneath the apparatus, the at least two crawlers configured to assist in moving the apparatus along the pipe.\",\n \"10.The measurement apparatus of claim 5, further comprising a distance counter attached to the apparatus, the distance counter configured to measure and control the speed and distance traveled by the apparatus.\",\n \"11.The measurement apparatus of claim 5, further comprising at least one brush attached to the apparatus, the at least one brush configured to clean debris on the pipe.\",\n \"12.The measurement apparatus of claim 7, further comprising a cleaning structure attached to a forward-direction facing end of at least one of the source carriage and detector carriage, the cleaning structure configured to move debris away from the pipe.\",\n \"13.The measurement apparatus of claim 5, wherein the source includes a collimator to direct the first amount of radiation towards the pipe.\",\n \"14.The measurement apparatus of claim 13, wherein the source includes a shutter to open or close the collimator.\",\n \"15.The measurement apparatus of claim 14, wherein the source includes electric motors to activate the shutter.\",\n \"16.The measurement apparatus of claim 5, wherein the control canister includes a data acquisition (DAQ) system configured to assist in receiving the at least one measurement signal from the detector and convey the at least one measurement signal to software located topside.\",\n \"17.The measurement apparatus of claim 5, further comprising a stabilizing system positioned beneath the at least one buoyancy structure and within the main frame, the stabilizing system configured to act as a ballast assist in maintaining the stability of the apparatus on the pipe.\",\n \"18.The measurement apparatus of claim 17, wherein the stabilizing system includes a brick of lead attached to electric motors configured to move the brick of lead transversally within the main frame of the apparatus to maintain the stability of the apparatus on the pipe.\",\n \"19.The measurement apparatus of claim 5, further comprising a handle mounted on the main frame, the handle configured to provide for manual or ROV-assisted manipulation and placement of the apparatus.\",\n \"20.The measurement apparatus of claim 5, further comprising at least one sensor located within the main frame, the at least one sensor configured to take a measurement of the pipe and send at least one signal based on the measurement.\",\n \"21.The measurement apparatus of claim 20, wherein the at least one sensor is a pulsed eddy current (PEC) sensor.\",\n \"22.The measurement apparatus of claim 5, further comprising hydraulic clamps attached to the apparatus, the hydraulic clamps configured to attach the apparatus on the pipe.\",\n \"23.The measurement apparatus of claim 22, further comprising at least one hydraulic line between the ROV and the apparatus, the at least one hydraulic line configured to activate the hydraulic clamps.\",\n \"24.The measurement apparatus of claim 5, further comprising at least one electrical line between the ROV and the apparatus, the at least one electrical line configured to provide power to run the measurement apparatus.\",\n \"25.The measurement apparatus of claim 5, wherein the first and second amounts of radiation are gamma rays.\",\n \"26.The measurement apparatus of claim 25, wherein the gamma rays are derived from 137Cs.\",\n \"27.A method for measuring submerged pipelines, comprising: connecting an attachment of a measurement apparatus to a remotely operated vehicle (ROV), wherein the measurement apparatus comprises: a main frame; a source positioned outside a section of pipe and connected to the main frame, the source configured to transmit a first amount of radiation; a detector positioned outside the section of pipe and connected to the main frame at a location diametrically opposite the source, the detector configured to receive a second amount of radiation, determine a composition of the section of pipe based on the first and second amounts of radiation, and send at least one measurement signal; a control canister positioned on the main frame or on the ROV, the control canister configured to receive the at least one measurement signal from the detector and convey the at least one measurement signal to software located topside; and at least one buoyancy structure positioned on the main frame, the at least one buoyancy structure configured to hold the apparatus in place on the pipe, lowering and placing the measurement apparatus upon the section of pipe using the ROV; taking a measurement of the section of pipe using the detector to create the at least one measurement signal; sending the at least one measurement signal from the detector to the control canister; and conveying the at least one measurement signal from the control canister to the software located topside.\",\n \"28.The method of claim 27, further comprising moving the measurement apparatus to another section of the pipe using the ROV after each round of measurements.\",\n \"29.A system, comprising: a remotely operated vehicle (ROV); and a measurement apparatus connected to the ROV, the measurement apparatus comprising: a main frame; a source positioned outside a section of pipe and connected to the main frame, the source configured to transmit a first amount of radiation; a detector positioned outside the section of pipe and connected to the main frame at a location diametrically opposite the source, the detector configured to receive a second amount of radiation, determine a composition of the section of pipe based on the first and second amounts of radiation, and send at least one measurement signal; and a control canister positioned on the main frame or on the ROV, the control canister configured to receive the at least one measurement signal from the detector and convey the at least one measurement signal to software located topside, wherein the software is configured such that a user may access the software to view the composition and other properties of the section of pipe and to control movement of the apparatus via the ROV.\"\n ],\n [\n \"<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG.\",\n \"1 is an isometric view of a measurement apparatus positioned on a section of pipe, according to an exemplary embodiment of the present disclosure.\",\n \"FIG.\",\n \"2 is a side view of the measurement apparatus shown in FIG.\",\n \"1 .\",\n \"FIG.\",\n \"3 is a top view of the measurement apparatus shown in FIG.\",\n \"1 .\",\n \"FIG.\",\n \"4 is an isometric view of a measurement apparatus positioned on a section of pipe, according to an exemplary embodiment of the present disclosure.\",\n \"FIG.\",\n \"5 is a side view of the measurement apparatus shown in FIG.\",\n \"4 .\",\n \"FIG.\",\n \"6 is a top view of the measurement apparatus shown in FIG.\",\n \"4 .\",\n \"FIG.\",\n \"7 is an illustration of a graphic user interface for software connected to a measurement apparatus and located topside, according to an exemplary embodiment of the present disclosure.\",\n \"FIG.\",\n \"8 is a front view of a measurement apparatus including a rotating plate positioned on a section of pipe, according to an exemplary embodiment of the present disclosure.\",\n \"detailed-description description=\\\"Detailed Description\\\" end=\\\"lead\\\"?\"\n ],\n [\n \"This application is a continuation of U.S. patent application Ser.\",\n \"No.\",\n \"15/141,269, filed Apr.\",\n \"28, 2016, which claims the benefit of U.S.\",\n \"Provisional Patent Application No.\",\n \"62/153,944, filed Apr.\",\n \"28, 2015, each of which are incorporated herein by reference.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS FIG.\",\n \"1 is an isometric view of a measurement apparatus positioned on a section of pipe, according to an exemplary embodiment of the present disclosure.\",\n \"FIG.\",\n \"2 is a side view of the measurement apparatus shown in FIG.\",\n \"1.FIG.\",\n \"3 is a top view of the measurement apparatus shown in FIG.\",\n \"1.FIG.\",\n \"4 is an isometric view of a measurement apparatus positioned on a section of pipe, according to an exemplary embodiment of the present disclosure.\",\n \"FIG.\",\n \"5 is a side view of the measurement apparatus shown in FIG.\",\n \"4.FIG.\",\n \"6 is a top view of the measurement apparatus shown in FIG.\",\n \"4.FIG.\",\n \"7 is an illustration of a graphic user interface for software connected to a measurement apparatus and located topside, according to an exemplary embodiment of the present disclosure.\",\n \"FIG.\",\n \"8 is a front view of a measurement apparatus including a rotating plate positioned on a section of pipe, according to an exemplary embodiment of the present disclosure.\",\n \"DESCRIPTION OF EMBODIMENTS A submerged or submarine pipeline is a pipeline passing under water, which is typically laid on a seabed, or inside a trench below the seabed.\",\n \"The pipeline may also be located partially on-land.\",\n \"Submarine pipelines are used primarily to carry oil or gas but may also be used to transport other materials.\",\n \"Plugging by hydrates and/or other media in pipelines is one of the major flow assurance challenges facing the oil and gas industry because it prevents the flow of media in the pipeline and causes substantial interruption and losses in operations.\",\n \"As oil and gas production moves into harsh and challenging environments, including deep subsea environments, there is a growing need to prevent this plug formation.\",\n \"The value of remediation methods for plug formation depends on the speed and efficiency in locating an accumulation or plug in the pipeline.\",\n \"The media flowing in the pipeline, including gas, oil, wax, asphaltene, hydrates, paraffin, and sand have varied and/or minimal differences in their respective densities and composition.\",\n \"Detecting these differences in densities and composition allows for the ability to locate total or partial blockage in the pipe.\",\n \"A way to detect these differences in densities is by the use of radiation to measure the density of the contents of the pipeline.\",\n \"Methods of using radiation, including gamma rays, to determine the density of pipelines (including to measure flow and hold-up in the pipelines) are disclosed in U.S. Pat.\",\n \"No.\",\n \"7,402,796, U.S. Pat.\",\n \"No.\",\n \"4,795,903, U.S. Pat.\",\n \"No.\",\n \"4,667,515, U.S. Patent Pub.\",\n \"No.\",\n \"2012/0087467 A1, and U.S. Patent Pub.\",\n \"No.\",\n \"2008/0137808 A1, all of which are incorporated herein by reference.\",\n \"These methods include placing a “source” of radiation outside a pipeline for directing radiation from the source through a portion of the pipeline, and placing a “detector” at a location outside the pipeline opposite the source of radiation for detecting the radiation and measuring the density of the pipeline.\",\n \"The amount of radiation which subsequently exits the pipeline depends upon the mass of the media contained within the pipeline and its ability to absorb radiation.\",\n \"Thus, a reduction in the amount of radiation which reaches the detector indicates an increased bulk density of the media flowing through or contained within the pipeline as more radiation is absorbed by the media.\",\n \"The primary existing tool providing for inspection of submerged pipelines in subsea environments is the “Discovery” tool provided by Tracerco™.\",\n \"This tool, however, is extremely complex, and functions by making a tomography of the pipeline.\",\n \"Each measurement of a “slice” of the pipeline takes about 20 minutes.\",\n \"The tool is also very heavy (approximately two tons) and requires dredging around the pipeline to be operated.\",\n \"Additionally, operation of the tool is very expensive and time-consuming, and requires the use of additional complex subsea operations.\",\n \"Embodiments of the present disclosure relate generally to non-destructive measuring systems, apparatuses, and methods, and in particular though non-limiting embodiments, to systems, apparatuses and methods for measuring submerged pipelines.\",\n \"The present disclosure provides improved apparatuses, systems, and methods for the measurement of submerged surfaces, including measurement of submerged pipelines.\",\n \"The disclosed embodiment includes a measurement apparatus having a source/emitter and a detector connected to a main frame and configured to detect density and/or composition of a section of pipeline.\",\n \"The measurement apparatus may be configured for attachment to an ROV.\",\n \"The attachment to the ROV may be through a hydraulic and/or electrical system.\",\n \"According to exemplary embodiments of the present disclosure, methods are provided for measuring submerged pipelines.\",\n \"Steps may include connecting a measurement apparatus to an ROV, and using the ROV to lower and place the apparatus upon a submerged pipeline such that the apparatus securely fits on the pipeline.\",\n \"A source and a detector of the apparatus may then be used to measure the density and/or composition of the section of the submerged pipeline and create an at least one measurement signal.\",\n \"The at least one measurement signal may then be sent via software on the apparatus to software on the ROV and/or to software located topside.\",\n \"This improved method of measurement of submerged pipelines may be performed in ranges of approximately 3,000 meters to 4,700 meters below sea level.\",\n \"The measurement apparatus may be moved along the submerged pipeline as needed using the ROV.\",\n \"Exemplary embodiments of the present disclosure may include traction rollers and/or crawlers and/or wheels attached to the apparatus, allowing the apparatus to move along the pipe.\",\n \"The rollers and/or crawlers and/or wheels may be powered by electric or hydraulic motors.\",\n \"The rollers and/or crawlers and/or wheels may be arranged such that the main frame of the apparatus is in close proximity to an outer surface of the section of pipe without scraping or contacting the surface.\",\n \"The number of rollers and/or crawlers and/or wheels may vary in different embodiments of the disclosure.\",\n \"The rollers and/or crawlers and/or wheels may allow for quick and efficient guidance of the measurement apparatus along the pipeline by an ROV.\",\n \"Exemplary embodiments of the present disclosure may also include a stabilizing system including a brick of lead positioned within the main frame of the apparatus to act as a ballast assist in maintaining the stability of the apparatus along the pipe.\",\n \"The apparatus may also include a handle allowing for ROV-assisted manipulation of the measurement apparatus along the pipe.\",\n \"Embodiments of the present disclosure therefore allow for miles of pipeline to be measured in a single day.\",\n \"The measurement apparatus may be securely and quickly guided along the pipeline using the connection to the ROV.\",\n \"The measurement apparatus may be employed to measure vast sections of pipeline for potential problem areas.\",\n \"In this way, the present disclosure allows for efficient, low cost measurement of the pipeline.\",\n \"Although discussed herein in conjunction with pipelines, the measurement apparatus may be used on vessels or other surfaces.\",\n \"Embodiments of the present disclosure provide for measuring the content of submerged surfaces, including submerged pipelines, in a more efficient manner that does not affect the measured material, requires less process downtime for installation, is non-intrusive, and is easily deployable.\",\n \"Embodiments of the present disclosure provide for a faster, cheaper, and more reliable method for diagnosing flow abnormalities due to partial or total plugs within pipelines without substantial interruption to pipeline operations.\",\n \"Referring to FIGS.\",\n \"1 to 3, different views of a measurement apparatus 10 are shown.\",\n \"In FIG.\",\n \"1, an exemplary embodiment of a measurement apparatus 10 positioned on a section of pipe 22 is shown.\",\n \"Measurement apparatus 10 may include a main frame 12, a radiation source 19 connected to the main frame 12, and a radiation detector 20 connected to the main frame 12.In an exemplary embodiment, the main frame 12 may have a rectangular shape.\",\n \"In alternative embodiments, the main frame 12 may have other shapes suitable for the measurement functions of the apparatus 10.In an exemplary embodiment, the main frame 12 may be made of aluminum.\",\n \"However, the main frame 12 may be made of other materials suitable for the measurement functions of the apparatus 10.In particular embodiments, the apparatus 10 may perform measurements on a section of pipe 22 with a diameter of approximately ten to eighteen inches.\",\n \"However, the apparatus 10 may also perform measurements on pipes with larger or smaller diameters.\",\n \"In exemplary embodiments, the apparatus 10 may weigh approximately 150 pounds in water and 380 pounds in air, which is substantially less than existing measurement apparatuses performing similar functions.\",\n \"In various embodiments, source 19 and/or detector 20 may be positioned outside the pipe 22 and connected to the main frame 12.In an exemplary embodiment, both source 19 and/or detector 20 may be connected to the apparatus 10 using an elongated support frame 14 having a plurality of grooves and tracks configured for attachment to vertical bars holding the source 19 and/or detector 20 in a secured carriage.\",\n \"See, e.g, FIG.\",\n \"1.The vertical bars may be attached to the support frame 14 using mechanical attachments such as screws and/or bolts.\",\n \"Alternatively, other mechanical configurations may be used to attach the bars to the support frame 14, including circumferential straps, magnets, ties, quick releases, snap locks, or other combinations thereof, and/or other suitable systems.\",\n \"In alternative embodiments, source 19 and/or detector 20 may be connected to the main frame 12 using other suitable methods.\",\n \"In some embodiments, the support frame 14 may be connected to electrical or electro-hydraulic linear actuators or hydraulic cylinders, that may in turn be connected to the source 19 and/or detector 20, and configured to adjust the source 19 and/or the detector 20 in a direction perpendicular to the pipe 22.In an exemplary embodiment, the support frame 14 may be made of aluminum.\",\n \"Alternatively, the support frame 14 may be made of other materials suitable for attaching support frame 14 to the main frame 12 and securely holding the source 19 and/or detector 20 in place.\",\n \"In particular embodiments, source 19 and/or detector 20 may each be attached to cleaning structures 19a, 20a configured to move debris away from the pipe 22 during measurement of the pipe 22.In exemplary embodiments, cleaning structures 19a, 20a may each have a cone shape to more efficiently move debris and other material away from the pipe 22.In alternative embodiments, cleaning structures 19a, 20a may have other shapes suitable for performing this function.\",\n \"Cleaning structures 19a, 20a may be attached to the front end, back end, and/or the sides of the source 19 and/or detector 20.In embodiments of the present disclosure, source 19 and/or detector 20 may be securely held in a source carriage and/or detector carriage, respectively.\",\n \"In an exemplary embodiment, the source carriage and/or detector carriage may be made of titanium, which is permeable to radiation.\",\n \"Source 19 may include a radiation source contained within a radiation source holder and configured to transmit a continuous first amount of radiation through a section of the pipe 22.In exemplary embodiments, this first amount of radiation may be gamma rays.\",\n \"In this embodiment, the radiation is generally a radioactive isotope as used in conventional (single source and detector) density gauges where the radiation source is commonly 662 keV gamma radiation (approximately 100-200 millicurie) from a cesium-137 isotope (137Cs).\",\n \"Alternatively, this first amount of radiation may be derived from other radioactive sources, including X-rays.\",\n \"In exemplary embodiments, source holder of source 19 may be at least one of the SHLD, SHF, SHLG, SHLM, and SR source holders for radiation-based measurement offered by VEGA Americas, Inc.\",\n \"Source 19 may be positioned at a location outside the pipe 22.Source 19 may include a collimator to direct the first amount of radiation towards the pipe 22.In exemplary embodiments, source 19 may also include a shutter to open or close the collimator.\",\n \"In this embodiment, source 19 may include electric motors to activate the shutter, i.e., turn the shutter on and off and let out radiation as needed.\",\n \"Particularly, source 19 may use a solenoid to achieve this function.\",\n \"In alternative embodiments, source 19 may include an electrical linear actuator and/or hydraulic cylinder and/or other suitable devices to achieve this function.\",\n \"If the shutter is on, the first amount of radiation will be transmitted from the source 19 using the collimator.\",\n \"If the shutter is off, the first amount of radiation will not be transmitted from the source 19.In alternative embodiments, source 19 may include other available methods to transmit and/or direct the radiation towards the pipe 22.In a particular embodiment, source 19 may weigh approximately sixty pounds.\",\n \"Detector 20 may be positioned outside a section of the pipe 22 at a location diametrically opposite the source 19.See, e.g., FIG.\",\n \"3.However, detector 20 may also be positioned at other locations on the pipe 22 as needed to most effectively detect and/or receive radiation from the source 19.Detector 20 may be configured to receive a second amount of radiation from the source 19 after the first amount of radiation has passed through the section of the pipe 22.Detector 20 may then be configured to determine a composition of media flowing within the section of the pipe 22 based on the first and second amounts of radiation, and then send at least one measurement signal based on this determined composition via inbuilt signal conditioning software of detector 20 to software on an ROV attached to the apparatus 10 and/or directly to software located topside.\",\n \"In a particular embodiment, detector 20 may be configured to determine a density of the media flowing and/or stagnant within the section of the pipe 22.In a particular embodiment, detector 20 may weigh approximately fifteen pounds.\",\n \"In exemplary embodiments, detector 20 may be at least one of the MiniTrac 31 and MiniTrac 32 detectors for radiation-based density measurement offered by VEGA Americas, Inc.\",\n \"In this embodiment, detector 20 may include signal conditioning instruments and software such as the VEGAMET 624 which may power the MiniTrac 31 and process and display measured values such as the at least one measurement signal.\",\n \"In various embodiments, detector 20 may make measurements of section of pipe 22 constantly at a high frequency.\",\n \"However, in some embodiments, due to the random nature of the radiation emitted from source 19, these measurements may be averaged and dampened via a multi-pass software filter in the detector 20 that changes the frequency of the update to the output based on the step change of sensed value.\",\n \"In an exemplary embodiment, apparatus 10 may increase its productivity from 1 to 20 ft/min, which equals up to 9.5 Km of pipeline/day.\",\n \"In particular embodiments, more than one measurement of a section of pipe 22 may be taken by the apparatus 10 at one time.\",\n \"In some embodiments, it may be possible to include more than one detector 20 and/or if necessary, more than one source 19, to either sense a larger area on the pipe 22 and/or improve accuracy of the readings by the apparatus 10.As shown in FIGS.\",\n \"1 to 3, control canister 23 may be positioned on the main frame 12 of the apparatus 10 in a location below handle 36.Alternatively, control canister 23 may be located in an ROV attached to apparatus 10.In an exemplary embodiment, control canister 23 may include software configured to receive the at least one measurement signal from the detector 20, and convey the at least one measurement signal to software located in the ROV and/or to directly to software viewable and/or controlled by topside personnel.\",\n \"Software in the control canister 23 may be a Supervisory Control And Data Acquisition (SCADA) system used for remote monitoring and control that operates with coded signals over communication channels (using typically one communication channel per remote station).\",\n \"In various embodiments, software of control canister 23 may include a data acquisition (DAQ) system using coded signals over communication channels to acquire information about the status of remote equipment for display or for recording functions.\",\n \"In this embodiment, DAQ system in control canister 23 may include sensors, DAQ measurement hardware, and a computer with programmable software.\",\n \"In particular embodiments, control canister 23 may include a local data acquisition board configured to receive and convey the at least one measurement signal to the software on ROV and/or software located topside and viewable and/or controlled by topside personnel.\",\n \"In this embodiment, control canister 23 may also include motor controllers for a propulsion drive and ballast drive, gyro, inclinometers, and/or an Ethernet to a signal conditioner (e.g., an RS232 signal conditioner).\",\n \"In alternative embodiments, control canister 20 may include other suitable configurations to assist in receiving and conveying the at least one measurement signal to software in the ROV and/or directly to software viewable and controlled by topside personnel.\",\n \"In an exemplary embodiment, control canister 23 may have a cylindrical shape.\",\n \"In an alternative embodiment, control canister 23 may have other shapes suitable for performing its receiving and conveying functions.\",\n \"In particular embodiment, control canister 23 may be made of titanium.\",\n \"Alternatively, control canister 23 may be made of other suitable materials.\",\n \"In an example embodiment, control canister 23 may include a DAQ system offered by National Instruments™.\",\n \"In various embodiments, apparatus 10 may include at least one buoyancy structure 25 positioned on the main frame 12.At least one buoyancy structure 25 may be configured to hold the apparatus 10 in place on the pipe 22.In an exemplary embodiment, apparatus 10 may include two buoyancy structures 25 positioned on the main frame 12, with the control canister 23 positioned between the two buoyancy structures 25.See, e.g., FIG.\",\n \"1.In exemplary embodiments, at least one buoyancy structure 25 may be made of foam.\",\n \"In alternative embodiments, at least one buoyancy structure 25 may be a ballast tank having variable or non-variable buoyancy control.\",\n \"In this embodiment, the ballast tank buoyancy structure 25 may be securable over a portion of the main frame 12.In particular embodiments, apparatus 10 may further include a stabilizing system such as for e.g.\",\n \"a brick of lead positioned beneath the at least one buoyancy structure 25 and within the main frame 12.The brick of lead may be configured to act as a ballast assist in maintaining the stability of the apparatus 10 on the pipe 22.In this embodiment, the stabilizing system may include attachments to electric motors configured to move the brick of lead transversally within the apparatus 10.For example, if the apparatus 10 moves in an unwanted left or right direction once it is placed on the pipe 22, the electric motors may be used to move the brick of lead in the opposite direction to ensure proper balancing and positioning of the apparatus 10 on the pipe 22.In exemplary embodiments, stabilizing system may include attachments to inclinometers configured to measure angles of slope (or tilt), elevation, or depression of the apparatus 10 with respect to gravity, and thereby further assist in positioning the apparatus 10 on the pipe 22.In an exemplary embodiment, the inclinometers may be located within the control canister 23.In some embodiments, the apparatus 10 may also be securable to and positioned on the pipe 22 using hydraulic clamps or electrically operated via motor or electrical linear actuator.\",\n \"Apparatus 10 may include at least one roller 18 attached to each opposing side of the main frame 12.At least one roller 18 may be configured to assist in moving the apparatus 10 along the pipe 22.In a particular embodiment, apparatus 10 may include two rollers 18 attached to each opposing side of the main frame 12.See, e.g., FIG.\",\n \"3.In exemplary embodiments, at least one roller 18 may be made of rubber such as for e.g., urethane rubber.\",\n \"In this embodiment, apparatus 10 may include hydraulic or electric motors connected to at least one roller 18 and configured to rotate at least one roller 18 and move the apparatus 10 along the pipe 22.In an alternative embodiment, at least one roller 18 may not be motorized and apparatus 10 may be mechanically moved along the pipe 22.In some embodiments, apparatus 10 may also include at least two crawlers 16 positioned beneath ends and/or sides of the apparatus 10.See, e.g., FIG.\",\n \"2.At least two crawlers 16 may be configured to work in tandem with at least one roller 18 to assist in faster and more efficient movement of the apparatus 10 along the pipe 22.In various embodiments, at least two crawlers 16 may either be motorized or non-motorized.\",\n \"In exemplary embodiments, apparatus 10 may include a handle 36 mounted on the main frame 12.Handle 36 may be configured to provide for manipulation and placement of the apparatus 10 via an arm of the ROV or by manual manipulation.\",\n \"In some embodiments, apparatus 10 may also include secondary handles 37 on either a front end, back end, and/or sides of the main frame 12.Secondary handles 37 may act as a contingency for the ROV to move the apparatus 10 along the pipe 22 if the motorized rollers 18 and/or crawlers 16 are not functioning properly.\",\n \"In some embodiments, a distance counter 27 may be attached to the apparatus 10.Distance counter 27 may be configured to measure and control the speed and distance traveled by the apparatus 10.Distance counters 27 or distance measuring wheels may be used to efficiently and quickly measure distances traveled by apparatus 10 attached to distance counter 27 and/or other tools/apparatuses attached to the distance counter 27.In exemplary embodiments, the distance counter 27 may be connected by a signal cable to the control canister 23, which may then send the measurement information to software on an ROV and/or directly to topside personnel.\",\n \"In exemplary embodiments, this functionality of the distance counter 27 may be incorporated into a propulsion drive circuit, where an encoder used as feedback for closed loop speed control of the drive may also be utilized for distance traveled data.\",\n \"In embodiments, apparatus 10 may be attached to an ROV by connecting an ROV attachment 38 to an arm of the ROV, thereby allowing the ROV to move the apparatus 10 along pipe 22.In exemplary embodiments, the apparatus 10 may be moved along the pipe 22 at variable speeds ranging from approximately one to twenty feet per minute, depending on the content of the pipe 22, and the nature of any blockage within the pipe 22.Attachment 38 may include electrical, hydraulic, and/or signal connections or lines within the attachment 38 that connect the ROV to the apparatus 10, and vice-versa.\",\n \"Hydraulic lines of attachment 38 may be configured to control the several hydraulic connections discussed herein, including the hydraulic clamps.\",\n \"Electrical lines of attachment 38 may be configured to provide power to run the measurement apparatus 10 (and disclosed parts requiring electric power, including the electric motors and propulsion).\",\n \"Measurement apparatus 10 may include a battery or may alternatively be run using main power from the ROV.\",\n \"In an exemplary embodiment, the signal connections may include for e.g.\",\n \"fiber optic cables configured to convey the various measurement signals discussed herein from the control canister 22 to software located topside via an Ethernet connection.\",\n \"In embodiments of the present disclosure, apparatus 10 may be autonomous, semi-autonomous, or manually controlled.\",\n \"In the autonomous embodiment of the apparatus 10, apparatus 10 may be powered by a battery pack and/or connected wirelessly (e.g.\",\n \"Bluetooth) to the ROV or a vessel or monitoring system.\",\n \"In the manually controlled embodiment, apparatus 10 may be controlled by via a diver or an ROV attached to an attachment 38 of apparatus 10.In the semi-autonomous embodiment of the apparatus 10, apparatus 10 may include an acoustic modem or other equivalent device in combination with for e.g.\",\n \"attachment to an ROV.\",\n \"Apparatus 10 may further include brushes 17 attached to the front end, back end, and/or sides of the main frame 12.Brushes 17 may be configured to clean debris and/or other material from the pipe 22 prior to measurement of the pipe 22.In an exemplary embodiment, three brushes 17 may be attached to an end of the main frame 12 that faces a forward direction of travel by the apparatus 10 along the pipe 22.See, e.g., FIG.\",\n \"1.However, the apparatus 10 may include a greater or lesser number of brushes 17 necessary to clean the pipe 22 prior to being measured by apparatus 10.In some embodiments, trenches down either side of the pipeline/flowline 22 may be dredged using a jetter skid.\",\n \"In some embodiments, apparatus 10 may include a low pressure (approximately 120 psi greater than ambient pressure) centrifugal pump with nozzles immediately in front of the rollers/tracks 18 to clean the contact area.\",\n \"Referring to FIGS.\",\n \"4 to 6, different views of measurement apparatus 11 are shown.\",\n \"As shown, measurement apparatus 11 may have substantially the same features as apparatus 10 described herein, with some modifications.\",\n \"Particularly, apparatus 11 may include source 19, detector 20, cleaning structures 19a, 20a, elongated support frame 14, at least one buoyancy structure 25, brushes 17, at least one roller 18, and at least two crawlers 16 described herein, as well as attachment 38 described herein from apparatus 10 to an arm of an ROV for moving apparatus 10 along pipe 22.However, apparatus 11 may not include a control canister 23 positioned on the main frame 12 of apparatus 10.See, e.g., FIG.\",\n \"5.Rather, control canister 23 may be located external to apparatus 11.For example, control canister 23 may be located at the ROV attached to apparatus 11.Embodiments of the present disclosure may also not include distance counters 27 to measure distance traveled by apparatus 11 since software in control canister 23 located in ROV attached to apparatus 11 may be used to perform this function.\",\n \"Further, in this embodiment, at least one roller 18 may not be attached to the main frame 12; rather, at least one roller 18 may be attached directly to an end of the detector 20 carriage opposite cleaning structure 20a, and an end of the source 19 carriage opposite cleaning structure 19a.\",\n \"For example, two rollers may be attached to an end of each of source 19 and detector 20 at each opposing side of apparatus 11.See FIG.\",\n \"5.Embodiments of the present disclosure may also include cleaning structures 19a, 20a having cone shapes but with more pointy edges than cleaning structures 19a, 20a of apparatus 10 to more efficiently move debris and other material away from the pipe 22.Embodiments of the present disclosure for apparatus 11 are not limited to these particular configurations and may include more or less features, including features described herein relating to apparatus 10.Referring now to FIG.\",\n \"7, an illustration of a graphic user interface (GUI) for software 30 connected to a measurement apparatus 10, 11 and located topside is shown.\",\n \"Software 30 may receive the at least one measurement signal described herein from control canister 23 via an Ethernet or other suitable connection.\",\n \"FIG.\",\n \"4 is simply an exemplary embodiment of the GUI for this software 30.In this exemplary embodiment, the software 30 may be a SCADA (Supervisory Control And Data Acquisition) system.\",\n \"Software 30 may provide a method to monitor, receive, save to a local hard drive on a computer topside, and/or display to topside personnel the at least one measurement signal, including for example, density and other composition data of a pipe 22, as well as other data related to apparatus 10, 11.GUI and/or software 30 may take other suitable forms necessary to provide relevant information regarding the apparatus 10, 11 and/or the composition of the pipe 22 to topside personnel viewing the GUI 30 and controlling the ROV and/or apparatus 10, 11.GUI 30 may include several indicators for topside personnel to easily manipulate and control the apparatus 10, 11, and to view the relevant density/composition in a section of the pipe 22.In an exemplary embodiment, GUI 30 may include an “open” or “close” shutter status indicator for the shutter contained within the source 19.In this embodiment, the shutter being “open” indicates that radiation is being continuously transmitted from the source 19 via the collimator as described herein.\",\n \"The shutter being in the “close” position indicates that radiation is not being emitted from the source 19, and that it is safe for a diver to approach the apparatus 10, 11, if needed.\",\n \"Due to the particular importance and function of the shutter contained within the source 19, the GUI 30 may also include an additional identifier configured to flash a particular color.\",\n \"For example, the identifier may flash the color red if the shutter is in the “open” position to indicate that radiation is being transmitted from source 19.In an exemplary embodiment, the GUI 30 may include a water intrusion alarm for the source 19, detector 20, and/or control canister 23.This water intrusion alarm may also be configured to flash a particular color if water has somehow entered the source 19, detector 20, and/or control canister 23, thereby indicating a dangerous environment such that the measurement process must be immediately stopped.\",\n \"In some embodiments, GUI 30 may include a motion control indicator allowing for topside personnel to control the speed and direction of the apparatus 10, 11.For example, the motion control indicator may be used to move the apparatus 10, 11 in reverse or forward directions along the pipe 22, stop the apparatus 10, 11, and/or set a fixed but variable speed of movement of the apparatus 10, 11.In an exemplary embodiment, GUI 30 may include indicators showing the pressure within apparatus 10, 11.GUI 30 may also include indicators showing the temperature within the source 19, detector 20, and/or control canister 23.If the indicator shows a dangerously high temperature, topside personnel may immediately stop the measurement process by closing the shutter.\",\n \"In some embodiments, GUI 30 may also include an “open” or “close” status indicator for the hydraulic clamps described herein.\",\n \"In various embodiments, the GUI 30 may include several identifiers for properties of the section of pipe 22 being measured by the apparatus 10, 11, as well as identifiers relating to movement of the apparatus 10, 11.These identifiers may include but are not limited to outputs showing relevant density, percentage of density, distance traveled, time traveled, and amplitude.\",\n \"For example, GUI 30 may include a visual indicator for the density of the pipe 22 with values ranging from 0 to 1.0.See FIG.\",\n \"7.In this exemplary embodiment, if the apparatus 10, 11 detects hydrates in the pipe 22, the value shown in the indicator may jump from 0 to 1.If the apparatus 10, 11 detects oil in the pipe 22, the value may jump from 0 to 0.8.If the apparatus 10, 11 detects wax in the pipe 22, the value may jump from 0 to 0.7.The relationship between these outputs may also be visually depicted using a graph.\",\n \"See, e.g, FIG.\",\n \"4.The configuration of this particular GUI 30 and apparatus 10, 11 may therefore provide for an immediate Go/No Go indication using a few quick measurements of the section of pipe 22.Referring to FIG.\",\n \"8, an alternative embodiment of apparatus 10, 11 positioned on a section of pipe 22 is shown.\",\n \"In this embodiment, source 19 and detector 20 are shown as attached to opposing ends of a rotating plate 60 attached to the main frame 12 described herein.\",\n \"In some embodiments, hydraulic and/or electric motors 50 may be positioned within main frame 12 and attached to rotating plate 60 to actuate rotating plate 60.As shown, gears 32 may be located on an underside surface of rotating plate 60 adjacent to surface of pipe 22 and configured to assist hydraulic and/or electric motors 50 in rotation of plate 60 and attached source 19 and/or detector 20.In particular embodiments, source 19 and/or detector 20 may each rotate in a 180° angle (or a greater angle to assure more overlap of the area being measured) in both a counter-clockwise direction, A, and clockwise direction, B, to perform a multi-faceted 360° scan of a section of pipe 22 and measure composition of the section of pipe 22.According to exemplary embodiments, methods are provided for the measurement of submerged surfaces.\",\n \"In an exemplary embodiment, a method includes attaching a measurement apparatus 10, 11 described herein to an ROV, and using the ROV to lower and place apparatus 10, 11 upon an exterior of a section of submerged pipeline 22.Measurement apparatus 10, 11 may have substantially the same features as measurement apparatuses 10, 11 described herein, including a main frame 12, source 19, detector 20, and/or control canister 23.Source 19 may then be used to transmit a continuous first amount of radiation towards the section of pipe 22.Detector 20 may then be used to receive and detect a second amount of radiation, determine a composition of the pipe 22 based on the first and second amounts of radiation, and create and send at least one measurement signal based on this composition of the pipe 22 to the control canister 23.Control canister 23 may be located on the main frame 12 of the apparatus 10, 11 or directly on the ROV attached to apparatus 10, 11.Control canister 23 may then be used to convey the at least one measurement signal to software on the ROV, which may then be outputted to software 30 located topside.\",\n \"Alternatively, control canister 23 may convey the at least one measurement signal directly to software 30 located topside.\",\n \"Once the section of pipe 22 is measured, additional measurements of the same section of pipe 22 may be made, and/or the apparatus 10, 11 may be moved along the pipe 22 using the ROV for measurement of another section of pipe 22.Embodiments of the present disclosure may also be used in conjunction with the inspection apparatus having multiple pulsed eddy current (PEC) sensors disclosed in U.S. patent app.\",\n \"Ser.\",\n \"No.\",\n \"14/868,048, which is incorporated herein by reference.\",\n \"The PEC sensors may be configured to take measurements of a section of the pipeline 22 on which the inspection apparatus is placed and send multiple signals which are eventually converted into a single measurement signal for conveyance to an ROV.\",\n \"An average wall thickness of the section of the pipeline 22 may then be calculated from this measurement signal.\",\n \"In an exemplary embodiment, a second measurement of this section of pipe 22 may be taken using an ultrasonic sensor if the average wall thickness of the section of pipe 22 is below a desired amount.\",\n \"In some embodiments, this inspection apparatus may be placed adjacent to measurement apparatus 10, 11 described herein on a pipe 22 and both sets of measurements may be taken simultaneously.\",\n \"In alternative embodiments, at least one PEC sensor may be incorporated into an embodiment of the apparatus 10, 11 described herein (for example, within a side of the main frame 12) so as to take simultaneous multiple measurements of the pipe 22.While the embodiments are described with reference to various implementations and exploitations, it will be understood that these embodiments are illustrative and that the scope of the disclosures is not limited to them.\",\n \"Many variations, modifications, additions, and improvements are possible.\",\n \"Further still, any steps described herein may be carried out in any desired order, and any desired steps may be added or deleted.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875810"}}},{"rowIdx":4494985,"cells":{"text":{"kind":"list like","value":[["REAL-TIME OR JUST-IN-TIME ONLINE ASSISTANCE FOR INDIVIDUALS TO HELP THEM IN ACHIEVING PERSONALIZED HEALTH GOALS","A method and a system for providing real-time assistance to users in achieving their personalized health goals through a mobile phone with an integrated software application by uploading the photographs to a secured database of the software application of the mobile phone provided with specific text comments or requests placed in appropriately classified input queues for assigning to a qualified nutritionist or an Artificial Intelligence (AI) Program for analyzing the uploaded photographs and generating specific modifications to the food items on the photograph of a meal by applying the user-specific weight-loss/meal modification rules, displaying the analysis information and the specific modifications on the food items to the user on the mobile phone screen.","The system and method also comprises a container, a partition plate, a closable lid for storing the food items that are rejected by the nutritionist or the AI and a placemat printed with colored squares patterns."],["1.A method for providing real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the food items stored in a container or a device on a plate comprising steps of: providing a container; storing the rejected food items in the container; creating a partition of the plate into which the rejected food items are placed using the device; providing a placemat printed with colored squares patterns of standard color and size located around the periphery of plate for providing size reference for estimating size and/or quantity of food items on the plate, said placemat is placed under the plate; and providing a closable lid with a knob for closing the container to cover the rejected food items.","2.The method according to claim 1, wherein the square patterns serve as reference for determining the angle of the camera while taking the image providing further input to analyze the size of the food item.","3.The method according to claim 1, wherein the standard colors of the square patterns serve as reference for recognizing the color of the food items by comparing it with standard colors.","4.The method according to claim 1, wherein the nutritional values calculated are displayed in a tabular form and each food item is labeled by its predominant nutritional attribute for storing in the secured database.","5.The method according to claim 1, wherein generates personalized reports for individual users with stored nutritional attribute data.","6.A system for providing real-time assistance to users in achieving their personalized health goals through a mobile phone comprising of: a mobile phone integrated with a software application; one or more secured databases to store the photographs of the food items/meals, generated ranked weight-loss rules/meal modification rules, suggested modifications; a processor for performing analysis of nutritional information; wherein comprises a container a device provided with a closable lid and a knob for categorizing the food items for consuming placed on a plate; wherein creates a partition of the plate into which the rejected food items are placed using the device, and wherein comprises a placemat printed with colored squares of standard size for providing size reference for estimating size and/or quantity of food items on the plate that is placed on top of the placemat.","7.The system according to claim 6, wherein a user accesses the software application by registering with it by providing the personalized profile parameters, personalized health goals, other health goals.","8.The system according to claim 6, wherein provides a personalized coaching through a two-way rich media on various queries.","9.The system according to claim 6, wherein stores all the captured photographs, uploaded data and personalized profile parameters, personalized health goals and other health goals.","10.The system according to claim 9, wherein generates reports depicting past trends, current status and future predictions and displays the reports at the time of analyzing."],["<SOH> BACKGROUND <EOH>The burden of being overweight or obese, in terms of health problems and expenditures, is well known.","Numerous weight loss approaches exist that require substantial changes to diets and exercise routines, sustained tracking and detailed numeric analysis of ingredients, caloric values, fat content, etc.","Individuals are unable to adhere to and maintain these requirements, which typically leads to temporary weight loss, but the lost weight is regained, sometimes repeatedly.","Weight loss approaches based on diet plans require individuals to first remember to follow the plans, and second, to do a good job of actually following the plans.","Individuals often have difficulty remembering their respective list of foods to avoid or reduce.","Tools are available to analyze the content of foods, and many individuals try to adjust their eating to comply with their respective diet plans.","Users packed with busy work schedules and under social pressure to join others in the act of eating find it very difficult to sustain over time.","Pre-packaged diets packages help in this regard, but they are expensive and individuals can get tired of eating the same items over and over, which leads to non-adherence.","Further, deprivation of certain favorite food items results in frustration and can lead to abandonment.","Other approaches provide detailed information regarding the calories, fat, sodium, etc., content of foods, and rely on the diligence of the individual to check, analyze and modify their eating habits in order to stay within their dietary plans or guidelines.","Again, adherence eventually breaks down because of the amount of detailed effort involved, and only the most diligent individuals continue for the longer term.","Many systems or methods or devices have been introduced globally to adopt good dietary habits to build healthier lifestyle.","Since it has become impractical for most individuals to exercise for more than an hour or two a day, modifying their food intake is more effective than exercise.","U.S. Pat.","No.","6,478,736 discloses a health management system for a person, in which the person's resting metabolic rate (RMR) is determined at intervals using an indirect calorimeter.","RMR values are used in setting and revising goals in, for example, a weight control program.","The effects of a weight control program on RMR can hence be compensated for, which enables an improved weight control program to be developed.","In one embodiment, the person is provided with a portable electronic device, for use as a caloric intake calculator, caloric expenditure calculator, and caloric balance calculator.","This user needs to carry the system whenever he or she wishes to consume food, which is not feasible all the time.","U.S. Pat.","No.","7,959,567 relates to an apparatus for detecting at least one of human physiological and contextual information from the body of a wearer that includes a sensor device adapted to be worn on the body having one or more sensors selected from the group consisting of physiological sensors and contextual sensors and an I/O device in electronic communication with said sensor device.","The I/O device includes means for displaying information and a dial, the dial being supported for rotational movement about an external surface of the I/O device.","The dial enables the wearer to enter information into the I/O device.","The I/O device may further include at least one button that also enables the wearer to enter information into the I/O device.","The task of entering information relating to type and quantity of meals sometimes results in inaccurate estimation of caloric content if a user is not sure about the relative size of the meal.","U.S. Pat.","No.","5,454,721 discloses a system intended to teach individuals the relationship between the visual size and a few nutritional characteristics of portions of food by using either a life size image of, or the corporeal finger of the individual, as a scale against images of different sized portions of different kinds of food, while showing a few nutritional characteristics of such portions.","The system proposed is minimal when compared to the present invention's features.","This system does not evaluate the user's ability to visually estimate macro and micronutrient content of meals nor does it permit analysis of an individual's dietary pro-activities.","US20070179359 discloses a receiving a caloric request and a resting metabolic rate, computing an expended number of calories based on the user's resting metabolic rate and physical activity performed by the user, computing a consumed number of calories based on food the user consumes, determining a status for the user based on whether the user is to consume calories or expend calories, and sending an alert to the user.","This method calculates the estimated calories based on the physical activity performed by the user and resting metabolic rate.","Performing physical activity is not feasible for every user at every time with respect to their busy schedule.","However, these techniques can sometimes be difficult to employ.","As an example, during a busy day, people may forget to exercise or count caloric intake.","As another example, people who are traveling may be unable to easily locate activity centers or food sources that help them to manage their health.","Often, people lack the motivation to live healthy lives.","The advent of smart phones with built-in cameras makes it possible to provide real-time assistance in the form of suggestions or comments on meals about to be consumed.","Therefore, there is a need to provide a method and system operable by a software application integrated with a smart mobile phone to maintain a healthy lifestyle by a user attaining real-time assistance in estimating nutritional attributes in a meal, modifying the meal and encouraging them to maintain health for a longer duration."],["<SOH> SUMMARY OF THE INVENTION <EOH>The invention comprises a method for providing real-time assistance to users in achieving their personalized health goals through a mobile phone comprising steps of: installing a software application in the user's mobile phone; registering with the said software application by providing personalized profile parameters, personalized health goals, other health goals of a user; providing a secured database to store photographs of food items/meals to be consumed by a user; analyzing the profile parameters of each user and generating specific ranked weight-loss rules/meal modification rules applicable to that particular user; generating specific modifications to the food items on the photograph of a meal by applying the user-specific weight-loss/meal modification rules; displaying the analysis information and the specific modifications on the food items to the user on the mobile phone screen; tracking the status/modification stage of the image by providing a speed indicator, and displaying a timeline of previously uploaded photographs of meals consumed, modifications, and other information, along with the means to rate the quality of the modifications and the level of adherence by the user.","A feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing.","Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the food items by a nutritionist/Artificial Intelligence (AI) for providing suggested modifications.","Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the food items by a nutritionist/Artificial Intelligence (AI) and providing adherence/evaluation by the registered user.","Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user obtains assistance in neutralizing a food craving.","Yet another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the unconsumed food items stored in a container or a device or a plate.","A further feature of this invention comprises a system for providing real-time assistance to users in achieving their personalized health goals through a mobile phone comprising of: a mobile phone integrated with a software application; one or more secured databases to store the photographs of the food items/meals, generated ranked weight-loss rules/meal modification rules, suggested modifications; a processor for performing analysis of nutritional information; wherein comprises a container or a device provided with a closable lid and a knob for categorizing the food items for consuming placed on a plate, wherein creates a partition of the plate into which the rejected food items are placed using the device, and wherein comprises a placemat printed with colored squares of standard size for providing size reference for estimating size and/or quantity of food items on the plate that is placed on top of the placemat.","Another feature of this system is to generate reports depicting past trends, current status and future predictions and displays the reports at the time of analyzing."],["FIELD OF INVENTION The present invention relates to providing an individual a real-time or an online assistance in achieving personalized health and wellness goals such as weight loss, adherence to various types of diets, prevention of heart disease or cancer, proper medication-taking, etc.","Further, the present invention provides a smart-phone application with facilities for individuals to upload a picture of a meal they are about to consume and receive a real-time or just-in-time modification to the meal generated by a qualified nutritionist or an artificial intelligence (AI) program.","Specifically, the present invention eliminates the need for individuals to remember dietary plans or guidelines or analyze any detailed information about the meal, and makes it very easy for individuals to maintain health.","BACKGROUND The burden of being overweight or obese, in terms of health problems and expenditures, is well known.","Numerous weight loss approaches exist that require substantial changes to diets and exercise routines, sustained tracking and detailed numeric analysis of ingredients, caloric values, fat content, etc.","Individuals are unable to adhere to and maintain these requirements, which typically leads to temporary weight loss, but the lost weight is regained, sometimes repeatedly.","Weight loss approaches based on diet plans require individuals to first remember to follow the plans, and second, to do a good job of actually following the plans.","Individuals often have difficulty remembering their respective list of foods to avoid or reduce.","Tools are available to analyze the content of foods, and many individuals try to adjust their eating to comply with their respective diet plans.","Users packed with busy work schedules and under social pressure to join others in the act of eating find it very difficult to sustain over time.","Pre-packaged diets packages help in this regard, but they are expensive and individuals can get tired of eating the same items over and over, which leads to non-adherence.","Further, deprivation of certain favorite food items results in frustration and can lead to abandonment.","Other approaches provide detailed information regarding the calories, fat, sodium, etc., content of foods, and rely on the diligence of the individual to check, analyze and modify their eating habits in order to stay within their dietary plans or guidelines.","Again, adherence eventually breaks down because of the amount of detailed effort involved, and only the most diligent individuals continue for the longer term.","Many systems or methods or devices have been introduced globally to adopt good dietary habits to build healthier lifestyle.","Since it has become impractical for most individuals to exercise for more than an hour or two a day, modifying their food intake is more effective than exercise.","U.S. Pat.","No.","6,478,736 discloses a health management system for a person, in which the person's resting metabolic rate (RMR) is determined at intervals using an indirect calorimeter.","RMR values are used in setting and revising goals in, for example, a weight control program.","The effects of a weight control program on RMR can hence be compensated for, which enables an improved weight control program to be developed.","In one embodiment, the person is provided with a portable electronic device, for use as a caloric intake calculator, caloric expenditure calculator, and caloric balance calculator.","This user needs to carry the system whenever he or she wishes to consume food, which is not feasible all the time.","U.S. Pat.","No.","7,959,567 relates to an apparatus for detecting at least one of human physiological and contextual information from the body of a wearer that includes a sensor device adapted to be worn on the body having one or more sensors selected from the group consisting of physiological sensors and contextual sensors and an I/O device in electronic communication with said sensor device.","The I/O device includes means for displaying information and a dial, the dial being supported for rotational movement about an external surface of the I/O device.","The dial enables the wearer to enter information into the I/O device.","The I/O device may further include at least one button that also enables the wearer to enter information into the I/O device.","The task of entering information relating to type and quantity of meals sometimes results in inaccurate estimation of caloric content if a user is not sure about the relative size of the meal.","U.S. Pat.","No.","5,454,721 discloses a system intended to teach individuals the relationship between the visual size and a few nutritional characteristics of portions of food by using either a life size image of, or the corporeal finger of the individual, as a scale against images of different sized portions of different kinds of food, while showing a few nutritional characteristics of such portions.","The system proposed is minimal when compared to the present invention's features.","This system does not evaluate the user's ability to visually estimate macro and micronutrient content of meals nor does it permit analysis of an individual's dietary pro-activities.","US20070179359 discloses a receiving a caloric request and a resting metabolic rate, computing an expended number of calories based on the user's resting metabolic rate and physical activity performed by the user, computing a consumed number of calories based on food the user consumes, determining a status for the user based on whether the user is to consume calories or expend calories, and sending an alert to the user.","This method calculates the estimated calories based on the physical activity performed by the user and resting metabolic rate.","Performing physical activity is not feasible for every user at every time with respect to their busy schedule.","However, these techniques can sometimes be difficult to employ.","As an example, during a busy day, people may forget to exercise or count caloric intake.","As another example, people who are traveling may be unable to easily locate activity centers or food sources that help them to manage their health.","Often, people lack the motivation to live healthy lives.","The advent of smart phones with built-in cameras makes it possible to provide real-time assistance in the form of suggestions or comments on meals about to be consumed.","Therefore, there is a need to provide a method and system operable by a software application integrated with a smart mobile phone to maintain a healthy lifestyle by a user attaining real-time assistance in estimating nutritional attributes in a meal, modifying the meal and encouraging them to maintain health for a longer duration.","SUMMARY OF THE INVENTION The invention comprises a method for providing real-time assistance to users in achieving their personalized health goals through a mobile phone comprising steps of: installing a software application in the user's mobile phone; registering with the said software application by providing personalized profile parameters, personalized health goals, other health goals of a user; providing a secured database to store photographs of food items/meals to be consumed by a user; analyzing the profile parameters of each user and generating specific ranked weight-loss rules/meal modification rules applicable to that particular user; generating specific modifications to the food items on the photograph of a meal by applying the user-specific weight-loss/meal modification rules; displaying the analysis information and the specific modifications on the food items to the user on the mobile phone screen; tracking the status/modification stage of the image by providing a speed indicator, and displaying a timeline of previously uploaded photographs of meals consumed, modifications, and other information, along with the means to rate the quality of the modifications and the level of adherence by the user.","A feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing.","Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the food items by a nutritionist/Artificial Intelligence (AI) for providing suggested modifications.","Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the food items by a nutritionist/Artificial Intelligence (AI) and providing adherence/evaluation by the registered user.","Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user obtains assistance in neutralizing a food craving.","Yet another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the unconsumed food items stored in a container or a device or a plate.","A further feature of this invention comprises a system for providing real-time assistance to users in achieving their personalized health goals through a mobile phone comprising of: a mobile phone integrated with a software application; one or more secured databases to store the photographs of the food items/meals, generated ranked weight-loss rules/meal modification rules, suggested modifications; a processor for performing analysis of nutritional information; wherein comprises a container or a device provided with a closable lid and a knob for categorizing the food items for consuming placed on a plate, wherein creates a partition of the plate into which the rejected food items are placed using the device, and wherein comprises a placemat printed with colored squares of standard size for providing size reference for estimating size and/or quantity of food items on the plate that is placed on top of the placemat.","Another feature of this system is to generate reports depicting past trends, current status and future predictions and displays the reports at the time of analyzing.","BRIEF DESCRIPTION OF DRAWINGS: FIG.","1a: illustrates the process flow for downloading and registering with the mobile phone application according to the preferred embodiment.","FIG.","1b: illustrates the process flow for generation of user-specific ranked weight-loss rules according to the preferred embodiment.","FIG.","2: illustrates the process flow for sending a meal-time reminder to the registered user according to the preferred embodiment.","FIG.","3: illustrates the process flow for storing the uploaded photographs in a secured database and queuing of the photographs according to the preferred embodiment.","FIG.","4a: illustrates the process flow for nutritionists to access the system for providing modifications according to the preferred embodiment.","FIG.","4b: illustrates the process flow for the AI Program to provide modifications according to the preferred embodiment.","FIG.","5: illustrates the process flow for notifying the users regarding the suggested modifications and sending the appropriate data according to the preferred embodiment.","FIG.","6: illustrates the process flow for escalating exceptions for further handling by experts according to the preferred embodiment.","FIG.","7: illustrates the process flow for viewing a timeline of their past meal photographs, modifications and comments and indicating their adherence to the modifications according to the preferred embodiment.","FIG.","8: illustrates the process flow for setting up ‘Help Groups’ for assistance according to the preferred embodiment.","FIG.","9: illustrates the process flow assisting the ‘Help Groups’ dealing with food cravings at any time according to the preferred embodiment.","FIG.","10: illustrates the process flow for requesting assistance from a nutritionist, dietician or other professional at any time according to the preferred embodiment.","FIG.","11: illustrates the process flow for calculating the modification quality ratings by nutritionist and user's adherence to it according to the preferred embodiment.","FIG.","12a-b: illustrates a container into which rejected food items as part of the nutritionist's modification are placed according to the preferred embodiment.","FIG.","12c: illustrates a device for creating a partition on a plate into which rejected food items are placed according to the preferred embodiment.","FIG.","12d: illustrates a pouch-like device into which rejected food items are placed according to the preferred embodiment.","FIG.","13a: illustrates a processed image of a plate with food items that have been color-coded based on their dominant nutritional attribute value according to the preferred embodiment.","FIG.","13b: illustrates a processed image of a plate with food items that are superimposed, pie-charts or other like representations indicating the relative proportions of various nutritional attributes of each food item according to the preferred embodiment.","FIG.","14a: illustrates a placemat printed with grey and white squares of one-inch size to provide a sizing reference with the plate placed on top of the placemat according to the preferred embodiment.","FIG.","14b: illustrates a placemat printed with colored squares of one-inch size to provide color and sizing reference with the plate placed on top of the placemat according to the preferred embodiment.","FIG.","15: illustrates a plate partition as shown in FIG.","12c printed with standard sized colored squares that serve as reference in identifying and estimating the food items on the plate according to the preferred embodiment.","FIG.","16: illustrates the process flow for estimating the nutritional values of the food items for either a plate of food or the food items set aside as the modification and report generation according to the preferred embodiment.","FIG.","17: illustrates the process flow for predicting a user's craving times and responding to it according to the preferred embodiment.","FIG.","18: illustrates the process flow for monitoring the user's eating patterns and flag issues raised by the user according to the preferred embodiment.","FIG.","19: illustrates the process flow for providing coaching to a user through two-way rich media according to the preferred embodiment.","DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS A preferred embodiment of the present invention addresses the needs of individuals desiring to lose weight by modifying their food intake by analyzing the content of foods and assisting the individuals to adjust their eating to comply with their respective diet plans.","The preferred embodiment provides a smart mobile phone application provided with facilities for individuals to upload a picture of a plate of food items or meals they are about to consume and receive a real-time or just-in-time modification to the meal generated by a nutritionist or an artificial intelligence (AI) program.","The modification is generated based on the individual's personalized profile parameters, personalized weight-loss goals and the meal to be consumed as well as the history of meals previously consumed.","Since the modification is generated at the point of consumption, the individual does not need to remember any dietary plans or guidelines or analyze any detailed information about the meal in order to make practical decisions about what to eat.","The individual uploads a picture of the meal, receives a real time modification and eats the meal according to the modification.","In the mobile application, individuals register as users and enter certain required profile parameters, and use the smart-phone camera to take photographs of meals and upload them to a secured database.","Authorized nutritionists, dieticians or professionals examine the uploaded photographs and related information and compose specific modifications to the meals based on the individuals' respective profile parameters and their personalized weight-loss goals.","The user receives a customized modification to the uploaded photograph by a qualified nutritionist.","This greatly simplifies the weight-loss regimen.","Nutritionists or dieticians edit or add pre-configured clarifying text, graphics, audio or video to the uploaded photographs in order to indicate the specific modifications.","This embodiment also envisions the use of artificial intelligence techniques to algorithmically select uploaded photographs, apply user-specific weight-loss rules, generate and compose suitable modifications for the associated users.","In cases where the photographs are not readable, the nutritionist or the artificial intelligence program marks them as exceptions and sets up a queue for further handling by more skilled human experts.","Once the modifications are composed, push notifications are automatically sent to the respective users to view the modifications.","The time of elapse of tracking for each photograph is monitored, and if it is elapsed beyond certain threshold limits delay notifications, tips and other information are automatically sent.","The mobile application also displays a timeline of past photographs, modifications and comments, so the user may scroll back and forth to examine them at any time, zoom in to a specific past photograph, indicate actual adherence to the modifications and rate their quality, timeliness and effectiveness.","The preferred embodiment also enables users to get answers to weight-loss or other health-related questions at any time by initiating a help request and directing it to a nutritionist or a dietician or other health professional, or an artificial intelligence program.","Also, the users to get assistance in dealing with food cravings at any time by initiating a craving help request to assigned helper or friend groups, who may respond and attempt to distract the requesting user.","A further provision aggregates, for a particular user, the nutritional values of the food ingested on a particular day, and suggest what items may be eaten at the end of the day to ensure that the user's specific daily dietary limits are not exceeded.","This also provides information regarding nearby restaurant menus or grocery store items in the vicinity of the user's current location and suggests consuming the food items available in the restaurant menus or grocery stores.","The present invention also provides a separate container or plate separator device for placing food items that are flagged as ‘do not eat at this meal’ or rejected as part of the nutritionist's modification, for ingestion by the user, a different person or animal, or for disposal, at a later time.","In addition to this, the present invention also provides a placemat printed with grey and white or color patterned squares of standard size to provide a sizing and color reference, as assistance for estimating the nature, size and/or quantity of food items on a plate that is placed on top of the placemat.","Referring now to FIG.","1a, illustrates a process flow for downloading and registering with the mobile phone application by an individual user.","An individual can locate and download the mobile application from play store or from a website and to activate the application by installing in the mobile phone [2].","The application prompts the individual to enter the mobile phone number and receives a verification code and sends an authentication code as one-time-password to the mobile phone number for verification.","The application then allows the user to enter the one-time-password [6].","The system verifies the entered code and permits the user for further data entry [8] that includes personalized profile parameters, personalized health goal, other health goals, personalized weight-loss goals, etc.","[10].","The user's personalized profile parameters include age, gender, body shape, current weight & height, target weight, blood pressure, cholesterol, blood sugar, etc.","The personalized health goals include target amount of weight to reduce, target amount of blood pressure or blood sugar to be attained, etc.","Further, the user then accepts the terms and conditions of the system to attain the assistance of the application and completes the registration [12].","The system stores the selected user data in the mobile phone application and in the secured server [14] with respective databases as secured server user database [16] and secured mobile app user database [18].","Where, the user can be a person or a parent or a caregiver or a pet-owner seeking real-time assistance.","FIG.","1b, illustrates the process flow for generation of user-specific ranked weight-loss rules based on user-profile parameters and other user data from the secured server database.","The system reads the user data and parameters [14] from the secured server user database [16].","These user personalized profile parameters and other parameters such as recent meal history serve as inputs to the algorithms for generating the user specific ranked weight-loss rules.","The ranked weight-loss rules also include meal modification rules that are generated by various algorithms for different health goals that are assigned based on the specific user's profile data and/or health goals.","The system generates the user specific ranked rules for weight-loss [20] and stores the generated rules in a database of user specific ranked rules for weight loss [22].","FIG.","2, illustrates the process flow for sending a meal-time reminder to the registered user by prompting the user to activate the mobile application.","The application runs a typical ‘Meal-Time Monitor’ routine [24] in the background that detects the occurrence of a ‘typical meal-time’, based on past history of meals and other relevant data entered by a registered user that is stored in the secured mobile application user database [18].","When an impending meal-time is detected, the application displays a Meal-Time Reminder as a notification [26] that is displayed on the mobile phone screen.","Simultaneously, the application also activates the camera and displays the camera icon for the user to capture a photograph of the next meal [28].","The users can also use 2D or a 3D camera affixed to their eyeglass or other means to capture photographs of the food item/meals to be consumed.","Further, the users are allowed to capture photographs of the food items at a grocery store to attain personalized instructions on their suitability, based on personalized health profile and other health goals.","The registered user can also capture and upload additional or sequential photographs representing additional servings at a particular meal.","The user captures multiple photographs of the meal [30], views them, and selects the best photograph with respect to clarity and uploads it [32] by clicking on the ‘upload’ button.","Before uploading, the user is allowed to add specific graphical modifications or text comments or audio comments or requests and/or other related information to the captured photographs.","These comments also include specific queries with respect to their weight-loss or health goals.","Further, means are provided for the registered users to add annotations by clicking or touching on the mobile phone screen on certain food items in the modified image to indicate respective food item names and to provide specific requests to the nutritionist.","Additionally, means are provided for the registered user to seek advice from the nutritionist or AI on what to eat for dessert at the end of the meal, given the meal that has just been consumed and receive a response; on what to eat for dinner at the end of the day, given all the meals that have been consumed thus far and receive a response and to seek advice on food item or recipe swaps to improve the quality of their nutritional intake.","FIG.","3, illustrates the process flow for storing the uploaded photographs in a secured database and queuing of the photographs to initiate further action.","After uploading the best photographs by the registered users, the uploaded photographs are received, identified, time-stamped &associated with other user data [34], and stored in a secured database of uploaded photographs.","All the data received from multiple users is stored in a secured database of meal photographs, time stamps and other user data [36].","The system then sorts the data using pre-defined criteria and generates an input queue of photographs and associated data for further action by nutritionists, dieticians and other professionals [38].","The System also generates an input queue of photographs for input to an Artificial Intelligence (AI) Program [40] and the further process is depicted in FIG.","4b.","The input queues are classified based on the specific text comments or requests attached to the uploaded photographs for assigning to a particular nutritionist or an AI.","This classification is attained by providing specific filters that include by user, by associated nutritionist, by artificial intelligence program or the like for assigning the uploaded photographs.","Additional filters are also provided based on meal modification rules or other criteria to further classify the input queues, thereby presenting an input queue of uploaded photographs to which same rules or criteria are to be applied.","FIG.","4a illustrates the process flow for nutritionists to access the system for providing modifications on the uploaded photographs of the food items.","Nutritionists log in to the system to view the input queues of uploaded photographs, compose and save meal modifications.","In the customary manner, nutritionists, dieticians or other authorized professionals log in to the system [44] after their authentication.","Further, the system displays sorted input queues of photographs and associated information based on their respective authorizations [46].","As new photographs are continuously uploaded by users, the system continuously refreshes the sorted input queues [48].","A particular nutritionist, dietician or professional with proper authorizations, who has accessed his or her respective sorted queue, views thumbnails of the uploaded photographs and associated data and selects a particular photograph [50].","The System then displays a larger version of the selected photograph along with the applicable Ranked Weight-loss Rules for the Particular User [60].","The rules are generated using the Database of User-Specific Diet Rules [62] and the Database of User-Specific Ranked Rules for Weight Loss [22] according to the present embodiment.","In other embodiments, the user-specific ranked rules may reflect other health objectives such as waist-reduction, heart-healthy, cancer-prevention, diabetes management, etc., or rules that enforce adherence to certain diets, e.g.","DASH (Dietary Approaches to Stop Hypertension) Diet, etc.","The Nutritionist analyzes the selected photograph and categorizes the food items in the meal [52].","The nutritionist then applies the user's respective weight-loss rules to compose specific Meal Modifications and Comments by using web-based applications or mobile phone applications or tablet-based applications, and saves those [54] to the Secured Output Queue [66].","The composed meal modifications and comments by the nutritionist include text based or graphic based comments or modifications on the photographs and also estimates of the nutritional attributes and their corresponding values of the food items or meals to be consumed or rejected by a user.","The text based comments include generic eating instructions, personalized eating instructions, pre-configured textual comments and textual indicators on the modifications to indicate the increase or decrease in the quantity of the food to be consumed.","The graphic based comments include free-form line drawings, visual effects for increasing/decreasing the appearance of the food items, pre-configured clarifying graphics, pre-configured graphical indicators to indicate the increase or decrease in the quantity of the food to be consumed, magnification/de-magnification of specific food items indicating consumption levels.","Means are provided for vocal comments and video comments to be attached.","These comments are stored in the secured database as a data set associated with a specific image or from a specific registered user.","All these Photographs, modifications and associated data are also stored in the Secured Database of Food Items, Values, Modifications and Rules as an archive [56].","If the nutritionist is unable to recognize or categorize the food items in any photograph, then the nutritionist generates an exception for that particular photograph [58].","The nutritionist makes suggestions to reduce one item or to increase other items to compensate for nutritional values based on the specific user goals.","Also, the nutritionist manually composes specific modifications to photographs based on the user's past meal history or user's specific dietary restrictions, profile parameters, personalized weight-loss goals or personalized diet plans.","In one embodiment, there exists a means on the mobile phone to view a suggested eating sequence for eating food items in the photograph which is automatically projected by the registered user by clicking on the said means include an icon or the like.","This suggested eating sequence can be an unconventional sequence projected as a numbered list.","The exception marked photographs [58] are reverted back to the respective registered user, thereby enabling the user to modify or add clarifying comments to that particular food item and re-upload the photograph.","In one embodiment, the nutritionist provides appropriate observations, or asks questions to a particular user depending on their diet; determines the consumable calories by a particular user based on the target amount of calories to be reduced, and determine the quantity of food items to be reduced/increased; uses pre-configured or free graphical/alphanumeric editing tools to indicate the food items to be modified and also sends encouraging or congratulatory comments when the plate of food needs no suggestions.","In all embodiments, the nutritionist may be a dietician or a veterinarian or other professional, providing assistance to individual adults, parents on behalf of children, adults on behalf of their parents, pet-owners and so on.","FIG.","4b illustrates the process flow for the AI Program to provide modifications on the uploaded photographs of the food items.","The automated programs using artificial intelligence (AI) techniques access input queues of uploaded photographs and associated data, select a photograph, access the associated data and user-specific weight-loss rules to generate and compose modifications and comments.","The AI program selects a photograph in the input queue [72] to apply known exception rules from the database Known Exception Rules Database [76] on the selected photograph [74].","If exception rules apply, the AI Program generates an exception immediately [82] and assigning an exception mark to that particular image if unrecognizable or not clear to be properly analyzed or if the program is unable to generate modifications.","The AI program sets up an exception queue for queuing of photographs marked with exceptions and automatically send notifications to an expert panel or agent for further processing and selects the next photograph from the input queue.","The AI program analyzes the selected photograph, categorizes the food Items and applies user rules [78] to compose meal modifications [80] and saves them to a Secured Output Queue [66].","All Photographs, modifications and associated data are also stored in the Secured Database of Food Items, Values, Modifications and Rules as an archive [56].","The user-specific diet and weight-loss rules [78] are generated using the database of User-Specific Diet Rules [62] and the database of user-specific weight-loss rules based on their respective profile data [64] stored in the database of User-Specific Ranked Weight Loss Rules [22].","The AI program also displays a timeline of past photographs, modifications and comments to the registered user for examination and sends automated reminders or notifications including tips related to health, weight-loss, meal-time reminders or the like.","In one embodiment, the AI program suggests modifications to reduce one item or to increase another item to compensate nutritional values based on specific user goals and overlays color shading within the food item borders to indicate each item's respective dominant nutritional attribute thereby assisting the nutritionist to recognize the items need to be modified.","The AI program automatically edits the uploaded image by inserting text icons and graphics to convey the suggested modifications for approval by the nutritionist.","In one embodiment, the AI directs the nutritionist to estimate the nutritional attributes of the food items after identifying the respective food items, and by intimating the particular user's amount of nutritional attributes consumed on a particular day, enables the nutritionist to recommend the items to be eaten by the end of that day to maintain the user's specific daily dietary limits.","In another embodiment, the AI determines the current physical location of a user from the mobile phone to provide information relating to restaurants, menu items, grocery stores, and other places where meals or food items are available in the vicinity of the user's current location and intimates a particular user the amount of nutritional attributes consumed on a particular day and recommends the items that are available in restaurants, grocery stores, etc., in the vicinity of the user's current location to be eaten by the end of that day to maintain the user's specific daily dietary limits.","In yet another embodiment, the AI intimates the user on the amount of nutritional values to be consumed on a meal by meal, daily, weekly or other time period basis.","In one embodiment, the AI automatically generates and displays personalized/opening messages along with a calorie or other nutritional attribute value to be consumed for that day or to be consumed for lunch or to be consumed for dinner; automatically generates and displays personalized/opening messages with recommendations for the next meal as specific food items or recipe modifications or restaurant menu choices or products available in store shelves with modifications.","In another embodiment, the AI monitors and analyzes the user's eating patterns and flags serious issues that prevent achievement of user objectives, and initiates or recommends a counseling session with an adviser or different AI program to provide personalized or general advice.","FIG.","5 illustrates the process flow for notifying the users regarding the suggested modifications and sending the appropriate data to them.","The system notifies the users that a modification is ready to be viewed and enables the user to view the modification and comments.","The System continuously scans the Secured Output Queue [66], Selects the next available item, reads the user bandwidth setting from the user profile parameters [84] stored in the Secured Server User Database [16].","Each image in the output queue is consolidated with the its respective identifiers, time-stamps, modifications, comments and other associated information to save the entire data set in the secured server database.","Based on the user bandwidth setting, the system either composes the full dataset [86], including the uploaded photograph, modifications, comments, and other associated information that is to be sent to the respective mobile phone, or the system composes a subset that excludes the uploaded photograph [88].The system then identifies the user's mobile number and sends a push notification with the full data set [90], or the data subset [96].","The sub-data set consists of modifications, comments and associated information, but not the image uploaded by the registered user.","The user upon seeing the push notification opens it [92], and the mobile application automatically displays the full dataset, including the photograph, modifications and comments [94] or overlays the data subset on the photograph in the mobile application database, and then displays the photograph, modifications and comments [98].","FIG.","6 illustrates the process flow for escalating exceptions for further handling by experts.","An exception is manually generated by a nutritionist if he or she is unable to recognize or categorize items in an uploaded photograph [58].","Similarly, the AI Program generates an immediate exception if known exception rules applied to a particular uploaded photograph [82].","In both cases, the subject photographs and associated data are flagged as exceptions and transferred to an exception queue [100].","An expert nutritionist selects a particular photograph from the exception queue [102], analyzes the selected photograph and categorizes the food items [104] to compose the modification [110] by applying the weight-loss rules for the particular user [60] and save these modifications to the Secured Output Queue[66].","If the expert nutritionist is unable to analyze the Photograph, he or she appends an ‘Apology’ customer service type message [106] and saves it to the Secured Output Queue [66].","FIG.","7 illustrates the user process flow for viewing a timeline of their past meal photographs, modifications and comments and indicating their adherence to the modifications by providing rating on the quality of the modifications.","The registered user activates the mobile application [112], opens the Timeline view and scrolls through the photographs [114].","The user then selects a particular photograph and views it, the modifications and comments in more detail [116].","In one embodiment, means are provided in the Timeline view for the user to enter health information such as weight, waist circumference, blood pressure, blood sugar, etc.","manually/automatically by importing from various devices.","While viewing the photograph, modifications and comments, user may evaluate and rate the quality and effectiveness of the modifications [118], by selecting the appropriate graphical or other indicators provided in the display.","The evaluation is also attained by providing comments, star-rating on a scale representing the quality of the modifications or by dragging on the timeline by holding a slider.","The user rating is stored in the Modification Rating Database [120].","The user may also enter his or her adherence to the modifications by selecting the provided indicators [122], for example, whether he or she implemented the modifications fully or partially by uploading a second image depicting the actual post-consumption left-over's or unconsumed food items set aside.","Adherence indications are stored in the User Adherence Database [124].","FIG.","8 illustrates the process flow for setting up ‘help groups’ for assistance by selecting individuals from their known contacts as well as from other users of the mobile application.","The user may call upon any of the groups for assistance in dealing with a food craving, at any time of day.","Any individual or individuals from the called-upon group may respond via any means available and try to distract or dissuade the user from succumbing to the craving.","It is not necessary for ‘Help Friend’ Group members to be registered users of the application or services.","The user activates the app in the usual manner [112], and uses the app function to set up at least one named ‘Help Friend’ groups [130].","Multiple such groups can be set up.","The user then selects certain personal contacts in order to invite them to join that particular group [132].","The system immediately sends Pre-Configured Text Message (SMS) invitation to the invitees [134], and resends the invitation one more time if any invitee does not respond after a set period [136].","If an invitee responds in the affirmative [138], then the system registers that invitee as a member of the user's named ‘Help Friend’ group [140].","If an invitee responds in the negative [142], the system does not register that invitee as a member of the user's named ‘Help Friend’ group and notifies the user that the invitation has been declined [144].","FIG.","9 illustrates the process flow assisting the ‘Help Groups’ dealing with food cravings at any time of the day.","The user activates the app in the usual manner [112].","Assuming at least one named ‘Help Friend’ group with at least one contact has been set-up.","The user can request assistance in dealing with a food craving at any time by selecting a particular named ‘Help Friend’ group [146].","The system immediately dispatches ‘Help’ push notifications to the members of the selected named group [148].","Any member of the named group, regardless of whether or not they are registered users, responds by any available means to help the user [150], including SMS (text messaging), chats, phone call, sending information (e.g.","jokes, cartoons, videos, links, etc.)","and attempts to distract the requesting registered user from the craving.","Craving help requests are maintained open for a specified duration and are automatically closed after receiving at least one response, or at the end of the duration, whichever occurs first.","Alternatively, the AI automatically responds to the craving request to distract the registered user from the craving at typical snack-craving times or at anytime or if there is no response from any helper or group after a set duration.","This AI automatically engages different friends when having different kinds of cravings by mapping specific cravings to a given friend's profile, sends a reminder or a notification to a specially-designated friend to proactively distract a specific registered user from a craving and analyzes patterns of craving to predict the next time of day when a registered user might get a craving and proactively suggests or engages a friend to respond to the craving.","FIG.","10 illustrates the process flow for requesting assistance from a helper, nutritionist, dietician or other professional (Expert') at any time.","The user may have a diet related question, may have taken a photograph of a meal and want a modification, or may want a modification to a recipe before cooking, or may be at a restaurant and want a menu item modification, etc.","The user activates the app in the usual manner [112].","Assuming at least one ‘Expert’ with his or her contact information has been set up, the user can request help with any relevant subject matter as described above.","The user composes a help request [152] by adding textual data and attaching photographs or other documents to the request.","The user then selects at least one expert contact to send the request [154].","The system immediately sends a push notification to the selected expert [156].","The expert views the help request [158] and responds [160] by any available means to help the user, including SMS (text messaging), chats, phone call, or sending information (e.g.","jokes, cartoons, videos, links, etc.","), or suggest modifications using textual and graphical tools.","FIG.","11 illustrates the process flow for calculating the modification quality ratings by nutritionist and user's adherence to it and stored in their respective databases.","The system reads the modification quality ratings in the modification rating database [120], sorts the data by nutritionist and calculates an overall quality rating that is, for example, an average of user ratings for a particular nutritionist over a set time period [162].","It then stores the nutritionist-respective ratings in the database of modification quality ratings by nutritionist [164].","Similarly, the system reads the user adherence database [124] sorts the data by user and calculates the user adherence indicator for each user [166].","It then stores the user-respective indicators in the database of user adherence to modifications by user [168].","FIG.","12a-b illustrates a container into which rejected food items as part of the nutritionist's modification are placed.","The container [170] accommodates food items that are flagged as ‘not for eating at this meal’ representing rejected food items as part of the nutritionist modification, for disposal or ingestion at a later time.","In one embodiment, the container [172] is inbuilt into a plate [174] equipped with a separate lid [176] for accommodating food items that are flagged as ‘not for eating at this meal’ representing rejected as part of the nutritionist modification as shown in FIG.","12b.","FIG.","12c illustrates a device for creating a partition on the plate into which rejected food items are placed.","The device [178] that creates a partition on the plate [174] into which food items flagged as ‘not for eating at this meal’, representing rejected as part of the nutritionist's modification for consumption or disposal at later stage.","FIG.","12d illustrates a pouch-like device into which rejected food items are placed.","The pouch-like device into which food items flagged as ‘not for eating at this meal’ as part of the nutritionist's modification for consumption or disposal at a later stage.","FIG.","13a illustrates a processed image of a plate with food items that have been color-coded based on their dominant nutritional attribute value depicting white for food items that are mostly carbohydrate, like rice, red for protein-dominant items or green for vegetable/fiber-dominant items.","FIG.","13b illustrates a processed image of a plate with food items on which are superimposed, pie-charts or other like representations indicating the relative proportions of various nutritional attributes of each food item such as, for example, a pie chart on a rice-based item showing a majority of carbohydrate ‘C’, followed by fiber ‘F’, protein ‘P’ and sodium ‘S’.","FIG.","14a a placemat printed with grey and white squares of one-inch or standard size to provide a sizing reference as an aid for estimating the size and/or quantity of the food items on a plate that is placed on top of the placemat.","FIG.","14b illustrates a placemat printed with colored squares of one-inch or standard size to provide color and sizing reference as an aid for identifying the food items and estimating their size and/or quantity on a plate that is placed on top of the placemat.","FIG.","15 shows a plate partition device shown in FIG.","12c printed with standard sized colored squares that serve as reference in identifying and estimating food items on the plate.","FIG.","16 illustrates the process flow for estimating the nutritional values of the food items for either a plate of food or the food items set aside or rejected as the modification, and report generation.","The photograph of a plate of food or modification is analyzed [251] for individual food items, identified and labeled [252], and their respective number or quantities are estimated [253].The total nutritional attribute values such as carbohydrate, protein, fiber, etc.","of each food item in the photograph are calculated [255], by taking the product of the quantity or number of a specific food item and its respective nutritional attribute values from a database [254] of such values for a large number of food items.","The calculated values are displayed [259] in tabular form and each item is labeled by its predominant nutritional attribute [260].","These calculations are stored in a database [258], and personalized reports are generated [261] for individual users.","These reports also depict past trends, current status and future predictions and display them at the time of analyzing.","FIG.","17 illustrates the process flow for predicting a user's craving times and generating proactive distractions to it.","Snacking adds unnecessary calories, carbs, sodium, fats etc., to the daily intake and can thwart weight-loss.","A user may get a craving at some time of day for a snack; these cravings typically last several minutes and by distracting the person, attention is diverted and the craving passes.","The ‘Buzz’ function is a means to request ‘distractions’ from friends or others.","When a user has a craving and uses the ‘Buzz’ function [271], the use is time-stamped [272], and the buzz requests are stored in a database [273].","These requests are analyzed and typical craving times of day are computed [274], for that particular user and stored in a database [275].","At a typical craving time [276], the system checks if the user has already used the Buzz function [277].","If the user has not used the Buzz function, the system automatically sends a proactive Buzz request to the user's friends [279].","If the user has already used the Buzz function, no action is taken and any automated buzz is suspended [278].","After a predetermined delay, the system automatically sends a buzz response to the user [281], drawing from a database of automatic buzz responses [280].","All buzzes and responses are recorded [282] and stored in a database [283].","FIG.","18 illustrates the process flow for monitoring the user's eating patterns and flag issues raised by the user and providing personalized advice.","At any preset time, e.g.","end of day [293], the AI, nutritionists or other staff analyze the user-uploaded images [294], from the database of user-uploaded images [295], applying issue-analysis criteria [292].","The criteria may include ‘eating the same food items 3 days in a row’, ‘eating more than 5 servings of carbohydrates’, etc.","The findings from the analysis are stored in a database [296].","A nutritionist or other staff professional views the findings for a particular user and manually composes personalized tips [297] that are stored in a database of personalized tips [300].","At some convenient time of day, the system automatically sends the personalized tips to the respective user [301].","Alternatively, an artificial intelligence (AI) program [298] may compose such personalized tips.","An artificial intelligence program [299] also flags issues that may be detrimental to achievement of user objectives (such as eating too many calories, which would not help achieve a weight-loss objective) and store such issues in a database [302].","This database may be used by a counselor to provide advice to the user on flagged issues [303].","The artificial intelligence program [304] would use the database [302] to compose and send personalized messages to advise the user about their respective flagged issues.","FIG.","19 illustrates the process flow for providing coaching to a user through two-way rich media.","The registered user's questions are received [311] by the system and stored in a database [312].","An authorized or user-assigned nutritionist [313] selects a question and views associated user information [314], which may be in the forms of text, images, graphics, voice, etc.","stored in a database [315].","Based on analysis of the questions and associated information, the nutritionist or other professional manually composes a multi-media response [317], selecting and attaching appropriate content from the database [316] and storing the response in a database [319].","Alternatively, an artificial intelligence program [318] may compose and store the response.","The system sends the response to the user [320].","The user may view the response and enter further clarifying questions or comments [321].","Such two-way interactions continue until the user concludes the interaction.","Various modifications and adaptations on the described preferred embodiments can be configured without departing from the scope and spirit of the invention.","Therefore, it is to be understood that within the scope of the appended claims, the invention may be practiced other than as specifically described herein."]],"string":"[\n [\n \"REAL-TIME OR JUST-IN-TIME ONLINE ASSISTANCE FOR INDIVIDUALS TO HELP THEM IN ACHIEVING PERSONALIZED HEALTH GOALS\",\n \"A method and a system for providing real-time assistance to users in achieving their personalized health goals through a mobile phone with an integrated software application by uploading the photographs to a secured database of the software application of the mobile phone provided with specific text comments or requests placed in appropriately classified input queues for assigning to a qualified nutritionist or an Artificial Intelligence (AI) Program for analyzing the uploaded photographs and generating specific modifications to the food items on the photograph of a meal by applying the user-specific weight-loss/meal modification rules, displaying the analysis information and the specific modifications on the food items to the user on the mobile phone screen.\",\n \"The system and method also comprises a container, a partition plate, a closable lid for storing the food items that are rejected by the nutritionist or the AI and a placemat printed with colored squares patterns.\"\n ],\n [\n \"1.A method for providing real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the food items stored in a container or a device on a plate comprising steps of: providing a container; storing the rejected food items in the container; creating a partition of the plate into which the rejected food items are placed using the device; providing a placemat printed with colored squares patterns of standard color and size located around the periphery of plate for providing size reference for estimating size and/or quantity of food items on the plate, said placemat is placed under the plate; and providing a closable lid with a knob for closing the container to cover the rejected food items.\",\n \"2.The method according to claim 1, wherein the square patterns serve as reference for determining the angle of the camera while taking the image providing further input to analyze the size of the food item.\",\n \"3.The method according to claim 1, wherein the standard colors of the square patterns serve as reference for recognizing the color of the food items by comparing it with standard colors.\",\n \"4.The method according to claim 1, wherein the nutritional values calculated are displayed in a tabular form and each food item is labeled by its predominant nutritional attribute for storing in the secured database.\",\n \"5.The method according to claim 1, wherein generates personalized reports for individual users with stored nutritional attribute data.\",\n \"6.A system for providing real-time assistance to users in achieving their personalized health goals through a mobile phone comprising of: a mobile phone integrated with a software application; one or more secured databases to store the photographs of the food items/meals, generated ranked weight-loss rules/meal modification rules, suggested modifications; a processor for performing analysis of nutritional information; wherein comprises a container a device provided with a closable lid and a knob for categorizing the food items for consuming placed on a plate; wherein creates a partition of the plate into which the rejected food items are placed using the device, and wherein comprises a placemat printed with colored squares of standard size for providing size reference for estimating size and/or quantity of food items on the plate that is placed on top of the placemat.\",\n \"7.The system according to claim 6, wherein a user accesses the software application by registering with it by providing the personalized profile parameters, personalized health goals, other health goals.\",\n \"8.The system according to claim 6, wherein provides a personalized coaching through a two-way rich media on various queries.\",\n \"9.The system according to claim 6, wherein stores all the captured photographs, uploaded data and personalized profile parameters, personalized health goals and other health goals.\",\n \"10.The system according to claim 9, wherein generates reports depicting past trends, current status and future predictions and displays the reports at the time of analyzing.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>The burden of being overweight or obese, in terms of health problems and expenditures, is well known.\",\n \"Numerous weight loss approaches exist that require substantial changes to diets and exercise routines, sustained tracking and detailed numeric analysis of ingredients, caloric values, fat content, etc.\",\n \"Individuals are unable to adhere to and maintain these requirements, which typically leads to temporary weight loss, but the lost weight is regained, sometimes repeatedly.\",\n \"Weight loss approaches based on diet plans require individuals to first remember to follow the plans, and second, to do a good job of actually following the plans.\",\n \"Individuals often have difficulty remembering their respective list of foods to avoid or reduce.\",\n \"Tools are available to analyze the content of foods, and many individuals try to adjust their eating to comply with their respective diet plans.\",\n \"Users packed with busy work schedules and under social pressure to join others in the act of eating find it very difficult to sustain over time.\",\n \"Pre-packaged diets packages help in this regard, but they are expensive and individuals can get tired of eating the same items over and over, which leads to non-adherence.\",\n \"Further, deprivation of certain favorite food items results in frustration and can lead to abandonment.\",\n \"Other approaches provide detailed information regarding the calories, fat, sodium, etc., content of foods, and rely on the diligence of the individual to check, analyze and modify their eating habits in order to stay within their dietary plans or guidelines.\",\n \"Again, adherence eventually breaks down because of the amount of detailed effort involved, and only the most diligent individuals continue for the longer term.\",\n \"Many systems or methods or devices have been introduced globally to adopt good dietary habits to build healthier lifestyle.\",\n \"Since it has become impractical for most individuals to exercise for more than an hour or two a day, modifying their food intake is more effective than exercise.\",\n \"U.S. Pat.\",\n \"No.\",\n \"6,478,736 discloses a health management system for a person, in which the person's resting metabolic rate (RMR) is determined at intervals using an indirect calorimeter.\",\n \"RMR values are used in setting and revising goals in, for example, a weight control program.\",\n \"The effects of a weight control program on RMR can hence be compensated for, which enables an improved weight control program to be developed.\",\n \"In one embodiment, the person is provided with a portable electronic device, for use as a caloric intake calculator, caloric expenditure calculator, and caloric balance calculator.\",\n \"This user needs to carry the system whenever he or she wishes to consume food, which is not feasible all the time.\",\n \"U.S. Pat.\",\n \"No.\",\n \"7,959,567 relates to an apparatus for detecting at least one of human physiological and contextual information from the body of a wearer that includes a sensor device adapted to be worn on the body having one or more sensors selected from the group consisting of physiological sensors and contextual sensors and an I/O device in electronic communication with said sensor device.\",\n \"The I/O device includes means for displaying information and a dial, the dial being supported for rotational movement about an external surface of the I/O device.\",\n \"The dial enables the wearer to enter information into the I/O device.\",\n \"The I/O device may further include at least one button that also enables the wearer to enter information into the I/O device.\",\n \"The task of entering information relating to type and quantity of meals sometimes results in inaccurate estimation of caloric content if a user is not sure about the relative size of the meal.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,454,721 discloses a system intended to teach individuals the relationship between the visual size and a few nutritional characteristics of portions of food by using either a life size image of, or the corporeal finger of the individual, as a scale against images of different sized portions of different kinds of food, while showing a few nutritional characteristics of such portions.\",\n \"The system proposed is minimal when compared to the present invention's features.\",\n \"This system does not evaluate the user's ability to visually estimate macro and micronutrient content of meals nor does it permit analysis of an individual's dietary pro-activities.\",\n \"US20070179359 discloses a receiving a caloric request and a resting metabolic rate, computing an expended number of calories based on the user's resting metabolic rate and physical activity performed by the user, computing a consumed number of calories based on food the user consumes, determining a status for the user based on whether the user is to consume calories or expend calories, and sending an alert to the user.\",\n \"This method calculates the estimated calories based on the physical activity performed by the user and resting metabolic rate.\",\n \"Performing physical activity is not feasible for every user at every time with respect to their busy schedule.\",\n \"However, these techniques can sometimes be difficult to employ.\",\n \"As an example, during a busy day, people may forget to exercise or count caloric intake.\",\n \"As another example, people who are traveling may be unable to easily locate activity centers or food sources that help them to manage their health.\",\n \"Often, people lack the motivation to live healthy lives.\",\n \"The advent of smart phones with built-in cameras makes it possible to provide real-time assistance in the form of suggestions or comments on meals about to be consumed.\",\n \"Therefore, there is a need to provide a method and system operable by a software application integrated with a smart mobile phone to maintain a healthy lifestyle by a user attaining real-time assistance in estimating nutritional attributes in a meal, modifying the meal and encouraging them to maintain health for a longer duration.\"\n ],\n [\n \"<SOH> SUMMARY OF THE INVENTION <EOH>The invention comprises a method for providing real-time assistance to users in achieving their personalized health goals through a mobile phone comprising steps of: installing a software application in the user's mobile phone; registering with the said software application by providing personalized profile parameters, personalized health goals, other health goals of a user; providing a secured database to store photographs of food items/meals to be consumed by a user; analyzing the profile parameters of each user and generating specific ranked weight-loss rules/meal modification rules applicable to that particular user; generating specific modifications to the food items on the photograph of a meal by applying the user-specific weight-loss/meal modification rules; displaying the analysis information and the specific modifications on the food items to the user on the mobile phone screen; tracking the status/modification stage of the image by providing a speed indicator, and displaying a timeline of previously uploaded photographs of meals consumed, modifications, and other information, along with the means to rate the quality of the modifications and the level of adherence by the user.\",\n \"A feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing.\",\n \"Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the food items by a nutritionist/Artificial Intelligence (AI) for providing suggested modifications.\",\n \"Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the food items by a nutritionist/Artificial Intelligence (AI) and providing adherence/evaluation by the registered user.\",\n \"Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user obtains assistance in neutralizing a food craving.\",\n \"Yet another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the unconsumed food items stored in a container or a device or a plate.\",\n \"A further feature of this invention comprises a system for providing real-time assistance to users in achieving their personalized health goals through a mobile phone comprising of: a mobile phone integrated with a software application; one or more secured databases to store the photographs of the food items/meals, generated ranked weight-loss rules/meal modification rules, suggested modifications; a processor for performing analysis of nutritional information; wherein comprises a container or a device provided with a closable lid and a knob for categorizing the food items for consuming placed on a plate, wherein creates a partition of the plate into which the rejected food items are placed using the device, and wherein comprises a placemat printed with colored squares of standard size for providing size reference for estimating size and/or quantity of food items on the plate that is placed on top of the placemat.\",\n \"Another feature of this system is to generate reports depicting past trends, current status and future predictions and displays the reports at the time of analyzing.\"\n ],\n [\n \"FIELD OF INVENTION The present invention relates to providing an individual a real-time or an online assistance in achieving personalized health and wellness goals such as weight loss, adherence to various types of diets, prevention of heart disease or cancer, proper medication-taking, etc.\",\n \"Further, the present invention provides a smart-phone application with facilities for individuals to upload a picture of a meal they are about to consume and receive a real-time or just-in-time modification to the meal generated by a qualified nutritionist or an artificial intelligence (AI) program.\",\n \"Specifically, the present invention eliminates the need for individuals to remember dietary plans or guidelines or analyze any detailed information about the meal, and makes it very easy for individuals to maintain health.\",\n \"BACKGROUND The burden of being overweight or obese, in terms of health problems and expenditures, is well known.\",\n \"Numerous weight loss approaches exist that require substantial changes to diets and exercise routines, sustained tracking and detailed numeric analysis of ingredients, caloric values, fat content, etc.\",\n \"Individuals are unable to adhere to and maintain these requirements, which typically leads to temporary weight loss, but the lost weight is regained, sometimes repeatedly.\",\n \"Weight loss approaches based on diet plans require individuals to first remember to follow the plans, and second, to do a good job of actually following the plans.\",\n \"Individuals often have difficulty remembering their respective list of foods to avoid or reduce.\",\n \"Tools are available to analyze the content of foods, and many individuals try to adjust their eating to comply with their respective diet plans.\",\n \"Users packed with busy work schedules and under social pressure to join others in the act of eating find it very difficult to sustain over time.\",\n \"Pre-packaged diets packages help in this regard, but they are expensive and individuals can get tired of eating the same items over and over, which leads to non-adherence.\",\n \"Further, deprivation of certain favorite food items results in frustration and can lead to abandonment.\",\n \"Other approaches provide detailed information regarding the calories, fat, sodium, etc., content of foods, and rely on the diligence of the individual to check, analyze and modify their eating habits in order to stay within their dietary plans or guidelines.\",\n \"Again, adherence eventually breaks down because of the amount of detailed effort involved, and only the most diligent individuals continue for the longer term.\",\n \"Many systems or methods or devices have been introduced globally to adopt good dietary habits to build healthier lifestyle.\",\n \"Since it has become impractical for most individuals to exercise for more than an hour or two a day, modifying their food intake is more effective than exercise.\",\n \"U.S. Pat.\",\n \"No.\",\n \"6,478,736 discloses a health management system for a person, in which the person's resting metabolic rate (RMR) is determined at intervals using an indirect calorimeter.\",\n \"RMR values are used in setting and revising goals in, for example, a weight control program.\",\n \"The effects of a weight control program on RMR can hence be compensated for, which enables an improved weight control program to be developed.\",\n \"In one embodiment, the person is provided with a portable electronic device, for use as a caloric intake calculator, caloric expenditure calculator, and caloric balance calculator.\",\n \"This user needs to carry the system whenever he or she wishes to consume food, which is not feasible all the time.\",\n \"U.S. Pat.\",\n \"No.\",\n \"7,959,567 relates to an apparatus for detecting at least one of human physiological and contextual information from the body of a wearer that includes a sensor device adapted to be worn on the body having one or more sensors selected from the group consisting of physiological sensors and contextual sensors and an I/O device in electronic communication with said sensor device.\",\n \"The I/O device includes means for displaying information and a dial, the dial being supported for rotational movement about an external surface of the I/O device.\",\n \"The dial enables the wearer to enter information into the I/O device.\",\n \"The I/O device may further include at least one button that also enables the wearer to enter information into the I/O device.\",\n \"The task of entering information relating to type and quantity of meals sometimes results in inaccurate estimation of caloric content if a user is not sure about the relative size of the meal.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,454,721 discloses a system intended to teach individuals the relationship between the visual size and a few nutritional characteristics of portions of food by using either a life size image of, or the corporeal finger of the individual, as a scale against images of different sized portions of different kinds of food, while showing a few nutritional characteristics of such portions.\",\n \"The system proposed is minimal when compared to the present invention's features.\",\n \"This system does not evaluate the user's ability to visually estimate macro and micronutrient content of meals nor does it permit analysis of an individual's dietary pro-activities.\",\n \"US20070179359 discloses a receiving a caloric request and a resting metabolic rate, computing an expended number of calories based on the user's resting metabolic rate and physical activity performed by the user, computing a consumed number of calories based on food the user consumes, determining a status for the user based on whether the user is to consume calories or expend calories, and sending an alert to the user.\",\n \"This method calculates the estimated calories based on the physical activity performed by the user and resting metabolic rate.\",\n \"Performing physical activity is not feasible for every user at every time with respect to their busy schedule.\",\n \"However, these techniques can sometimes be difficult to employ.\",\n \"As an example, during a busy day, people may forget to exercise or count caloric intake.\",\n \"As another example, people who are traveling may be unable to easily locate activity centers or food sources that help them to manage their health.\",\n \"Often, people lack the motivation to live healthy lives.\",\n \"The advent of smart phones with built-in cameras makes it possible to provide real-time assistance in the form of suggestions or comments on meals about to be consumed.\",\n \"Therefore, there is a need to provide a method and system operable by a software application integrated with a smart mobile phone to maintain a healthy lifestyle by a user attaining real-time assistance in estimating nutritional attributes in a meal, modifying the meal and encouraging them to maintain health for a longer duration.\",\n \"SUMMARY OF THE INVENTION The invention comprises a method for providing real-time assistance to users in achieving their personalized health goals through a mobile phone comprising steps of: installing a software application in the user's mobile phone; registering with the said software application by providing personalized profile parameters, personalized health goals, other health goals of a user; providing a secured database to store photographs of food items/meals to be consumed by a user; analyzing the profile parameters of each user and generating specific ranked weight-loss rules/meal modification rules applicable to that particular user; generating specific modifications to the food items on the photograph of a meal by applying the user-specific weight-loss/meal modification rules; displaying the analysis information and the specific modifications on the food items to the user on the mobile phone screen; tracking the status/modification stage of the image by providing a speed indicator, and displaying a timeline of previously uploaded photographs of meals consumed, modifications, and other information, along with the means to rate the quality of the modifications and the level of adherence by the user.\",\n \"A feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing.\",\n \"Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the food items by a nutritionist/Artificial Intelligence (AI) for providing suggested modifications.\",\n \"Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the food items by a nutritionist/Artificial Intelligence (AI) and providing adherence/evaluation by the registered user.\",\n \"Another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user obtains assistance in neutralizing a food craving.\",\n \"Yet another feature of this invention is to provide real-time assistance to users in achieving their personalized health goals through a mobile phone, wherein the registered user submits specific information for analyzing the uploaded photographs of the unconsumed food items stored in a container or a device or a plate.\",\n \"A further feature of this invention comprises a system for providing real-time assistance to users in achieving their personalized health goals through a mobile phone comprising of: a mobile phone integrated with a software application; one or more secured databases to store the photographs of the food items/meals, generated ranked weight-loss rules/meal modification rules, suggested modifications; a processor for performing analysis of nutritional information; wherein comprises a container or a device provided with a closable lid and a knob for categorizing the food items for consuming placed on a plate, wherein creates a partition of the plate into which the rejected food items are placed using the device, and wherein comprises a placemat printed with colored squares of standard size for providing size reference for estimating size and/or quantity of food items on the plate that is placed on top of the placemat.\",\n \"Another feature of this system is to generate reports depicting past trends, current status and future predictions and displays the reports at the time of analyzing.\",\n \"BRIEF DESCRIPTION OF DRAWINGS: FIG.\",\n \"1a: illustrates the process flow for downloading and registering with the mobile phone application according to the preferred embodiment.\",\n \"FIG.\",\n \"1b: illustrates the process flow for generation of user-specific ranked weight-loss rules according to the preferred embodiment.\",\n \"FIG.\",\n \"2: illustrates the process flow for sending a meal-time reminder to the registered user according to the preferred embodiment.\",\n \"FIG.\",\n \"3: illustrates the process flow for storing the uploaded photographs in a secured database and queuing of the photographs according to the preferred embodiment.\",\n \"FIG.\",\n \"4a: illustrates the process flow for nutritionists to access the system for providing modifications according to the preferred embodiment.\",\n \"FIG.\",\n \"4b: illustrates the process flow for the AI Program to provide modifications according to the preferred embodiment.\",\n \"FIG.\",\n \"5: illustrates the process flow for notifying the users regarding the suggested modifications and sending the appropriate data according to the preferred embodiment.\",\n \"FIG.\",\n \"6: illustrates the process flow for escalating exceptions for further handling by experts according to the preferred embodiment.\",\n \"FIG.\",\n \"7: illustrates the process flow for viewing a timeline of their past meal photographs, modifications and comments and indicating their adherence to the modifications according to the preferred embodiment.\",\n \"FIG.\",\n \"8: illustrates the process flow for setting up ‘Help Groups’ for assistance according to the preferred embodiment.\",\n \"FIG.\",\n \"9: illustrates the process flow assisting the ‘Help Groups’ dealing with food cravings at any time according to the preferred embodiment.\",\n \"FIG.\",\n \"10: illustrates the process flow for requesting assistance from a nutritionist, dietician or other professional at any time according to the preferred embodiment.\",\n \"FIG.\",\n \"11: illustrates the process flow for calculating the modification quality ratings by nutritionist and user's adherence to it according to the preferred embodiment.\",\n \"FIG.\",\n \"12a-b: illustrates a container into which rejected food items as part of the nutritionist's modification are placed according to the preferred embodiment.\",\n \"FIG.\",\n \"12c: illustrates a device for creating a partition on a plate into which rejected food items are placed according to the preferred embodiment.\",\n \"FIG.\",\n \"12d: illustrates a pouch-like device into which rejected food items are placed according to the preferred embodiment.\",\n \"FIG.\",\n \"13a: illustrates a processed image of a plate with food items that have been color-coded based on their dominant nutritional attribute value according to the preferred embodiment.\",\n \"FIG.\",\n \"13b: illustrates a processed image of a plate with food items that are superimposed, pie-charts or other like representations indicating the relative proportions of various nutritional attributes of each food item according to the preferred embodiment.\",\n \"FIG.\",\n \"14a: illustrates a placemat printed with grey and white squares of one-inch size to provide a sizing reference with the plate placed on top of the placemat according to the preferred embodiment.\",\n \"FIG.\",\n \"14b: illustrates a placemat printed with colored squares of one-inch size to provide color and sizing reference with the plate placed on top of the placemat according to the preferred embodiment.\",\n \"FIG.\",\n \"15: illustrates a plate partition as shown in FIG.\",\n \"12c printed with standard sized colored squares that serve as reference in identifying and estimating the food items on the plate according to the preferred embodiment.\",\n \"FIG.\",\n \"16: illustrates the process flow for estimating the nutritional values of the food items for either a plate of food or the food items set aside as the modification and report generation according to the preferred embodiment.\",\n \"FIG.\",\n \"17: illustrates the process flow for predicting a user's craving times and responding to it according to the preferred embodiment.\",\n \"FIG.\",\n \"18: illustrates the process flow for monitoring the user's eating patterns and flag issues raised by the user according to the preferred embodiment.\",\n \"FIG.\",\n \"19: illustrates the process flow for providing coaching to a user through two-way rich media according to the preferred embodiment.\",\n \"DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS A preferred embodiment of the present invention addresses the needs of individuals desiring to lose weight by modifying their food intake by analyzing the content of foods and assisting the individuals to adjust their eating to comply with their respective diet plans.\",\n \"The preferred embodiment provides a smart mobile phone application provided with facilities for individuals to upload a picture of a plate of food items or meals they are about to consume and receive a real-time or just-in-time modification to the meal generated by a nutritionist or an artificial intelligence (AI) program.\",\n \"The modification is generated based on the individual's personalized profile parameters, personalized weight-loss goals and the meal to be consumed as well as the history of meals previously consumed.\",\n \"Since the modification is generated at the point of consumption, the individual does not need to remember any dietary plans or guidelines or analyze any detailed information about the meal in order to make practical decisions about what to eat.\",\n \"The individual uploads a picture of the meal, receives a real time modification and eats the meal according to the modification.\",\n \"In the mobile application, individuals register as users and enter certain required profile parameters, and use the smart-phone camera to take photographs of meals and upload them to a secured database.\",\n \"Authorized nutritionists, dieticians or professionals examine the uploaded photographs and related information and compose specific modifications to the meals based on the individuals' respective profile parameters and their personalized weight-loss goals.\",\n \"The user receives a customized modification to the uploaded photograph by a qualified nutritionist.\",\n \"This greatly simplifies the weight-loss regimen.\",\n \"Nutritionists or dieticians edit or add pre-configured clarifying text, graphics, audio or video to the uploaded photographs in order to indicate the specific modifications.\",\n \"This embodiment also envisions the use of artificial intelligence techniques to algorithmically select uploaded photographs, apply user-specific weight-loss rules, generate and compose suitable modifications for the associated users.\",\n \"In cases where the photographs are not readable, the nutritionist or the artificial intelligence program marks them as exceptions and sets up a queue for further handling by more skilled human experts.\",\n \"Once the modifications are composed, push notifications are automatically sent to the respective users to view the modifications.\",\n \"The time of elapse of tracking for each photograph is monitored, and if it is elapsed beyond certain threshold limits delay notifications, tips and other information are automatically sent.\",\n \"The mobile application also displays a timeline of past photographs, modifications and comments, so the user may scroll back and forth to examine them at any time, zoom in to a specific past photograph, indicate actual adherence to the modifications and rate their quality, timeliness and effectiveness.\",\n \"The preferred embodiment also enables users to get answers to weight-loss or other health-related questions at any time by initiating a help request and directing it to a nutritionist or a dietician or other health professional, or an artificial intelligence program.\",\n \"Also, the users to get assistance in dealing with food cravings at any time by initiating a craving help request to assigned helper or friend groups, who may respond and attempt to distract the requesting user.\",\n \"A further provision aggregates, for a particular user, the nutritional values of the food ingested on a particular day, and suggest what items may be eaten at the end of the day to ensure that the user's specific daily dietary limits are not exceeded.\",\n \"This also provides information regarding nearby restaurant menus or grocery store items in the vicinity of the user's current location and suggests consuming the food items available in the restaurant menus or grocery stores.\",\n \"The present invention also provides a separate container or plate separator device for placing food items that are flagged as ‘do not eat at this meal’ or rejected as part of the nutritionist's modification, for ingestion by the user, a different person or animal, or for disposal, at a later time.\",\n \"In addition to this, the present invention also provides a placemat printed with grey and white or color patterned squares of standard size to provide a sizing and color reference, as assistance for estimating the nature, size and/or quantity of food items on a plate that is placed on top of the placemat.\",\n \"Referring now to FIG.\",\n \"1a, illustrates a process flow for downloading and registering with the mobile phone application by an individual user.\",\n \"An individual can locate and download the mobile application from play store or from a website and to activate the application by installing in the mobile phone [2].\",\n \"The application prompts the individual to enter the mobile phone number and receives a verification code and sends an authentication code as one-time-password to the mobile phone number for verification.\",\n \"The application then allows the user to enter the one-time-password [6].\",\n \"The system verifies the entered code and permits the user for further data entry [8] that includes personalized profile parameters, personalized health goal, other health goals, personalized weight-loss goals, etc.\",\n \"[10].\",\n \"The user's personalized profile parameters include age, gender, body shape, current weight & height, target weight, blood pressure, cholesterol, blood sugar, etc.\",\n \"The personalized health goals include target amount of weight to reduce, target amount of blood pressure or blood sugar to be attained, etc.\",\n \"Further, the user then accepts the terms and conditions of the system to attain the assistance of the application and completes the registration [12].\",\n \"The system stores the selected user data in the mobile phone application and in the secured server [14] with respective databases as secured server user database [16] and secured mobile app user database [18].\",\n \"Where, the user can be a person or a parent or a caregiver or a pet-owner seeking real-time assistance.\",\n \"FIG.\",\n \"1b, illustrates the process flow for generation of user-specific ranked weight-loss rules based on user-profile parameters and other user data from the secured server database.\",\n \"The system reads the user data and parameters [14] from the secured server user database [16].\",\n \"These user personalized profile parameters and other parameters such as recent meal history serve as inputs to the algorithms for generating the user specific ranked weight-loss rules.\",\n \"The ranked weight-loss rules also include meal modification rules that are generated by various algorithms for different health goals that are assigned based on the specific user's profile data and/or health goals.\",\n \"The system generates the user specific ranked rules for weight-loss [20] and stores the generated rules in a database of user specific ranked rules for weight loss [22].\",\n \"FIG.\",\n \"2, illustrates the process flow for sending a meal-time reminder to the registered user by prompting the user to activate the mobile application.\",\n \"The application runs a typical ‘Meal-Time Monitor’ routine [24] in the background that detects the occurrence of a ‘typical meal-time’, based on past history of meals and other relevant data entered by a registered user that is stored in the secured mobile application user database [18].\",\n \"When an impending meal-time is detected, the application displays a Meal-Time Reminder as a notification [26] that is displayed on the mobile phone screen.\",\n \"Simultaneously, the application also activates the camera and displays the camera icon for the user to capture a photograph of the next meal [28].\",\n \"The users can also use 2D or a 3D camera affixed to their eyeglass or other means to capture photographs of the food item/meals to be consumed.\",\n \"Further, the users are allowed to capture photographs of the food items at a grocery store to attain personalized instructions on their suitability, based on personalized health profile and other health goals.\",\n \"The registered user can also capture and upload additional or sequential photographs representing additional servings at a particular meal.\",\n \"The user captures multiple photographs of the meal [30], views them, and selects the best photograph with respect to clarity and uploads it [32] by clicking on the ‘upload’ button.\",\n \"Before uploading, the user is allowed to add specific graphical modifications or text comments or audio comments or requests and/or other related information to the captured photographs.\",\n \"These comments also include specific queries with respect to their weight-loss or health goals.\",\n \"Further, means are provided for the registered users to add annotations by clicking or touching on the mobile phone screen on certain food items in the modified image to indicate respective food item names and to provide specific requests to the nutritionist.\",\n \"Additionally, means are provided for the registered user to seek advice from the nutritionist or AI on what to eat for dessert at the end of the meal, given the meal that has just been consumed and receive a response; on what to eat for dinner at the end of the day, given all the meals that have been consumed thus far and receive a response and to seek advice on food item or recipe swaps to improve the quality of their nutritional intake.\",\n \"FIG.\",\n \"3, illustrates the process flow for storing the uploaded photographs in a secured database and queuing of the photographs to initiate further action.\",\n \"After uploading the best photographs by the registered users, the uploaded photographs are received, identified, time-stamped &associated with other user data [34], and stored in a secured database of uploaded photographs.\",\n \"All the data received from multiple users is stored in a secured database of meal photographs, time stamps and other user data [36].\",\n \"The system then sorts the data using pre-defined criteria and generates an input queue of photographs and associated data for further action by nutritionists, dieticians and other professionals [38].\",\n \"The System also generates an input queue of photographs for input to an Artificial Intelligence (AI) Program [40] and the further process is depicted in FIG.\",\n \"4b.\",\n \"The input queues are classified based on the specific text comments or requests attached to the uploaded photographs for assigning to a particular nutritionist or an AI.\",\n \"This classification is attained by providing specific filters that include by user, by associated nutritionist, by artificial intelligence program or the like for assigning the uploaded photographs.\",\n \"Additional filters are also provided based on meal modification rules or other criteria to further classify the input queues, thereby presenting an input queue of uploaded photographs to which same rules or criteria are to be applied.\",\n \"FIG.\",\n \"4a illustrates the process flow for nutritionists to access the system for providing modifications on the uploaded photographs of the food items.\",\n \"Nutritionists log in to the system to view the input queues of uploaded photographs, compose and save meal modifications.\",\n \"In the customary manner, nutritionists, dieticians or other authorized professionals log in to the system [44] after their authentication.\",\n \"Further, the system displays sorted input queues of photographs and associated information based on their respective authorizations [46].\",\n \"As new photographs are continuously uploaded by users, the system continuously refreshes the sorted input queues [48].\",\n \"A particular nutritionist, dietician or professional with proper authorizations, who has accessed his or her respective sorted queue, views thumbnails of the uploaded photographs and associated data and selects a particular photograph [50].\",\n \"The System then displays a larger version of the selected photograph along with the applicable Ranked Weight-loss Rules for the Particular User [60].\",\n \"The rules are generated using the Database of User-Specific Diet Rules [62] and the Database of User-Specific Ranked Rules for Weight Loss [22] according to the present embodiment.\",\n \"In other embodiments, the user-specific ranked rules may reflect other health objectives such as waist-reduction, heart-healthy, cancer-prevention, diabetes management, etc., or rules that enforce adherence to certain diets, e.g.\",\n \"DASH (Dietary Approaches to Stop Hypertension) Diet, etc.\",\n \"The Nutritionist analyzes the selected photograph and categorizes the food items in the meal [52].\",\n \"The nutritionist then applies the user's respective weight-loss rules to compose specific Meal Modifications and Comments by using web-based applications or mobile phone applications or tablet-based applications, and saves those [54] to the Secured Output Queue [66].\",\n \"The composed meal modifications and comments by the nutritionist include text based or graphic based comments or modifications on the photographs and also estimates of the nutritional attributes and their corresponding values of the food items or meals to be consumed or rejected by a user.\",\n \"The text based comments include generic eating instructions, personalized eating instructions, pre-configured textual comments and textual indicators on the modifications to indicate the increase or decrease in the quantity of the food to be consumed.\",\n \"The graphic based comments include free-form line drawings, visual effects for increasing/decreasing the appearance of the food items, pre-configured clarifying graphics, pre-configured graphical indicators to indicate the increase or decrease in the quantity of the food to be consumed, magnification/de-magnification of specific food items indicating consumption levels.\",\n \"Means are provided for vocal comments and video comments to be attached.\",\n \"These comments are stored in the secured database as a data set associated with a specific image or from a specific registered user.\",\n \"All these Photographs, modifications and associated data are also stored in the Secured Database of Food Items, Values, Modifications and Rules as an archive [56].\",\n \"If the nutritionist is unable to recognize or categorize the food items in any photograph, then the nutritionist generates an exception for that particular photograph [58].\",\n \"The nutritionist makes suggestions to reduce one item or to increase other items to compensate for nutritional values based on the specific user goals.\",\n \"Also, the nutritionist manually composes specific modifications to photographs based on the user's past meal history or user's specific dietary restrictions, profile parameters, personalized weight-loss goals or personalized diet plans.\",\n \"In one embodiment, there exists a means on the mobile phone to view a suggested eating sequence for eating food items in the photograph which is automatically projected by the registered user by clicking on the said means include an icon or the like.\",\n \"This suggested eating sequence can be an unconventional sequence projected as a numbered list.\",\n \"The exception marked photographs [58] are reverted back to the respective registered user, thereby enabling the user to modify or add clarifying comments to that particular food item and re-upload the photograph.\",\n \"In one embodiment, the nutritionist provides appropriate observations, or asks questions to a particular user depending on their diet; determines the consumable calories by a particular user based on the target amount of calories to be reduced, and determine the quantity of food items to be reduced/increased; uses pre-configured or free graphical/alphanumeric editing tools to indicate the food items to be modified and also sends encouraging or congratulatory comments when the plate of food needs no suggestions.\",\n \"In all embodiments, the nutritionist may be a dietician or a veterinarian or other professional, providing assistance to individual adults, parents on behalf of children, adults on behalf of their parents, pet-owners and so on.\",\n \"FIG.\",\n \"4b illustrates the process flow for the AI Program to provide modifications on the uploaded photographs of the food items.\",\n \"The automated programs using artificial intelligence (AI) techniques access input queues of uploaded photographs and associated data, select a photograph, access the associated data and user-specific weight-loss rules to generate and compose modifications and comments.\",\n \"The AI program selects a photograph in the input queue [72] to apply known exception rules from the database Known Exception Rules Database [76] on the selected photograph [74].\",\n \"If exception rules apply, the AI Program generates an exception immediately [82] and assigning an exception mark to that particular image if unrecognizable or not clear to be properly analyzed or if the program is unable to generate modifications.\",\n \"The AI program sets up an exception queue for queuing of photographs marked with exceptions and automatically send notifications to an expert panel or agent for further processing and selects the next photograph from the input queue.\",\n \"The AI program analyzes the selected photograph, categorizes the food Items and applies user rules [78] to compose meal modifications [80] and saves them to a Secured Output Queue [66].\",\n \"All Photographs, modifications and associated data are also stored in the Secured Database of Food Items, Values, Modifications and Rules as an archive [56].\",\n \"The user-specific diet and weight-loss rules [78] are generated using the database of User-Specific Diet Rules [62] and the database of user-specific weight-loss rules based on their respective profile data [64] stored in the database of User-Specific Ranked Weight Loss Rules [22].\",\n \"The AI program also displays a timeline of past photographs, modifications and comments to the registered user for examination and sends automated reminders or notifications including tips related to health, weight-loss, meal-time reminders or the like.\",\n \"In one embodiment, the AI program suggests modifications to reduce one item or to increase another item to compensate nutritional values based on specific user goals and overlays color shading within the food item borders to indicate each item's respective dominant nutritional attribute thereby assisting the nutritionist to recognize the items need to be modified.\",\n \"The AI program automatically edits the uploaded image by inserting text icons and graphics to convey the suggested modifications for approval by the nutritionist.\",\n \"In one embodiment, the AI directs the nutritionist to estimate the nutritional attributes of the food items after identifying the respective food items, and by intimating the particular user's amount of nutritional attributes consumed on a particular day, enables the nutritionist to recommend the items to be eaten by the end of that day to maintain the user's specific daily dietary limits.\",\n \"In another embodiment, the AI determines the current physical location of a user from the mobile phone to provide information relating to restaurants, menu items, grocery stores, and other places where meals or food items are available in the vicinity of the user's current location and intimates a particular user the amount of nutritional attributes consumed on a particular day and recommends the items that are available in restaurants, grocery stores, etc., in the vicinity of the user's current location to be eaten by the end of that day to maintain the user's specific daily dietary limits.\",\n \"In yet another embodiment, the AI intimates the user on the amount of nutritional values to be consumed on a meal by meal, daily, weekly or other time period basis.\",\n \"In one embodiment, the AI automatically generates and displays personalized/opening messages along with a calorie or other nutritional attribute value to be consumed for that day or to be consumed for lunch or to be consumed for dinner; automatically generates and displays personalized/opening messages with recommendations for the next meal as specific food items or recipe modifications or restaurant menu choices or products available in store shelves with modifications.\",\n \"In another embodiment, the AI monitors and analyzes the user's eating patterns and flags serious issues that prevent achievement of user objectives, and initiates or recommends a counseling session with an adviser or different AI program to provide personalized or general advice.\",\n \"FIG.\",\n \"5 illustrates the process flow for notifying the users regarding the suggested modifications and sending the appropriate data to them.\",\n \"The system notifies the users that a modification is ready to be viewed and enables the user to view the modification and comments.\",\n \"The System continuously scans the Secured Output Queue [66], Selects the next available item, reads the user bandwidth setting from the user profile parameters [84] stored in the Secured Server User Database [16].\",\n \"Each image in the output queue is consolidated with the its respective identifiers, time-stamps, modifications, comments and other associated information to save the entire data set in the secured server database.\",\n \"Based on the user bandwidth setting, the system either composes the full dataset [86], including the uploaded photograph, modifications, comments, and other associated information that is to be sent to the respective mobile phone, or the system composes a subset that excludes the uploaded photograph [88].The system then identifies the user's mobile number and sends a push notification with the full data set [90], or the data subset [96].\",\n \"The sub-data set consists of modifications, comments and associated information, but not the image uploaded by the registered user.\",\n \"The user upon seeing the push notification opens it [92], and the mobile application automatically displays the full dataset, including the photograph, modifications and comments [94] or overlays the data subset on the photograph in the mobile application database, and then displays the photograph, modifications and comments [98].\",\n \"FIG.\",\n \"6 illustrates the process flow for escalating exceptions for further handling by experts.\",\n \"An exception is manually generated by a nutritionist if he or she is unable to recognize or categorize items in an uploaded photograph [58].\",\n \"Similarly, the AI Program generates an immediate exception if known exception rules applied to a particular uploaded photograph [82].\",\n \"In both cases, the subject photographs and associated data are flagged as exceptions and transferred to an exception queue [100].\",\n \"An expert nutritionist selects a particular photograph from the exception queue [102], analyzes the selected photograph and categorizes the food items [104] to compose the modification [110] by applying the weight-loss rules for the particular user [60] and save these modifications to the Secured Output Queue[66].\",\n \"If the expert nutritionist is unable to analyze the Photograph, he or she appends an ‘Apology’ customer service type message [106] and saves it to the Secured Output Queue [66].\",\n \"FIG.\",\n \"7 illustrates the user process flow for viewing a timeline of their past meal photographs, modifications and comments and indicating their adherence to the modifications by providing rating on the quality of the modifications.\",\n \"The registered user activates the mobile application [112], opens the Timeline view and scrolls through the photographs [114].\",\n \"The user then selects a particular photograph and views it, the modifications and comments in more detail [116].\",\n \"In one embodiment, means are provided in the Timeline view for the user to enter health information such as weight, waist circumference, blood pressure, blood sugar, etc.\",\n \"manually/automatically by importing from various devices.\",\n \"While viewing the photograph, modifications and comments, user may evaluate and rate the quality and effectiveness of the modifications [118], by selecting the appropriate graphical or other indicators provided in the display.\",\n \"The evaluation is also attained by providing comments, star-rating on a scale representing the quality of the modifications or by dragging on the timeline by holding a slider.\",\n \"The user rating is stored in the Modification Rating Database [120].\",\n \"The user may also enter his or her adherence to the modifications by selecting the provided indicators [122], for example, whether he or she implemented the modifications fully or partially by uploading a second image depicting the actual post-consumption left-over's or unconsumed food items set aside.\",\n \"Adherence indications are stored in the User Adherence Database [124].\",\n \"FIG.\",\n \"8 illustrates the process flow for setting up ‘help groups’ for assistance by selecting individuals from their known contacts as well as from other users of the mobile application.\",\n \"The user may call upon any of the groups for assistance in dealing with a food craving, at any time of day.\",\n \"Any individual or individuals from the called-upon group may respond via any means available and try to distract or dissuade the user from succumbing to the craving.\",\n \"It is not necessary for ‘Help Friend’ Group members to be registered users of the application or services.\",\n \"The user activates the app in the usual manner [112], and uses the app function to set up at least one named ‘Help Friend’ groups [130].\",\n \"Multiple such groups can be set up.\",\n \"The user then selects certain personal contacts in order to invite them to join that particular group [132].\",\n \"The system immediately sends Pre-Configured Text Message (SMS) invitation to the invitees [134], and resends the invitation one more time if any invitee does not respond after a set period [136].\",\n \"If an invitee responds in the affirmative [138], then the system registers that invitee as a member of the user's named ‘Help Friend’ group [140].\",\n \"If an invitee responds in the negative [142], the system does not register that invitee as a member of the user's named ‘Help Friend’ group and notifies the user that the invitation has been declined [144].\",\n \"FIG.\",\n \"9 illustrates the process flow assisting the ‘Help Groups’ dealing with food cravings at any time of the day.\",\n \"The user activates the app in the usual manner [112].\",\n \"Assuming at least one named ‘Help Friend’ group with at least one contact has been set-up.\",\n \"The user can request assistance in dealing with a food craving at any time by selecting a particular named ‘Help Friend’ group [146].\",\n \"The system immediately dispatches ‘Help’ push notifications to the members of the selected named group [148].\",\n \"Any member of the named group, regardless of whether or not they are registered users, responds by any available means to help the user [150], including SMS (text messaging), chats, phone call, sending information (e.g.\",\n \"jokes, cartoons, videos, links, etc.)\",\n \"and attempts to distract the requesting registered user from the craving.\",\n \"Craving help requests are maintained open for a specified duration and are automatically closed after receiving at least one response, or at the end of the duration, whichever occurs first.\",\n \"Alternatively, the AI automatically responds to the craving request to distract the registered user from the craving at typical snack-craving times or at anytime or if there is no response from any helper or group after a set duration.\",\n \"This AI automatically engages different friends when having different kinds of cravings by mapping specific cravings to a given friend's profile, sends a reminder or a notification to a specially-designated friend to proactively distract a specific registered user from a craving and analyzes patterns of craving to predict the next time of day when a registered user might get a craving and proactively suggests or engages a friend to respond to the craving.\",\n \"FIG.\",\n \"10 illustrates the process flow for requesting assistance from a helper, nutritionist, dietician or other professional (Expert') at any time.\",\n \"The user may have a diet related question, may have taken a photograph of a meal and want a modification, or may want a modification to a recipe before cooking, or may be at a restaurant and want a menu item modification, etc.\",\n \"The user activates the app in the usual manner [112].\",\n \"Assuming at least one ‘Expert’ with his or her contact information has been set up, the user can request help with any relevant subject matter as described above.\",\n \"The user composes a help request [152] by adding textual data and attaching photographs or other documents to the request.\",\n \"The user then selects at least one expert contact to send the request [154].\",\n \"The system immediately sends a push notification to the selected expert [156].\",\n \"The expert views the help request [158] and responds [160] by any available means to help the user, including SMS (text messaging), chats, phone call, or sending information (e.g.\",\n \"jokes, cartoons, videos, links, etc.\",\n \"), or suggest modifications using textual and graphical tools.\",\n \"FIG.\",\n \"11 illustrates the process flow for calculating the modification quality ratings by nutritionist and user's adherence to it and stored in their respective databases.\",\n \"The system reads the modification quality ratings in the modification rating database [120], sorts the data by nutritionist and calculates an overall quality rating that is, for example, an average of user ratings for a particular nutritionist over a set time period [162].\",\n \"It then stores the nutritionist-respective ratings in the database of modification quality ratings by nutritionist [164].\",\n \"Similarly, the system reads the user adherence database [124] sorts the data by user and calculates the user adherence indicator for each user [166].\",\n \"It then stores the user-respective indicators in the database of user adherence to modifications by user [168].\",\n \"FIG.\",\n \"12a-b illustrates a container into which rejected food items as part of the nutritionist's modification are placed.\",\n \"The container [170] accommodates food items that are flagged as ‘not for eating at this meal’ representing rejected food items as part of the nutritionist modification, for disposal or ingestion at a later time.\",\n \"In one embodiment, the container [172] is inbuilt into a plate [174] equipped with a separate lid [176] for accommodating food items that are flagged as ‘not for eating at this meal’ representing rejected as part of the nutritionist modification as shown in FIG.\",\n \"12b.\",\n \"FIG.\",\n \"12c illustrates a device for creating a partition on the plate into which rejected food items are placed.\",\n \"The device [178] that creates a partition on the plate [174] into which food items flagged as ‘not for eating at this meal’, representing rejected as part of the nutritionist's modification for consumption or disposal at later stage.\",\n \"FIG.\",\n \"12d illustrates a pouch-like device into which rejected food items are placed.\",\n \"The pouch-like device into which food items flagged as ‘not for eating at this meal’ as part of the nutritionist's modification for consumption or disposal at a later stage.\",\n \"FIG.\",\n \"13a illustrates a processed image of a plate with food items that have been color-coded based on their dominant nutritional attribute value depicting white for food items that are mostly carbohydrate, like rice, red for protein-dominant items or green for vegetable/fiber-dominant items.\",\n \"FIG.\",\n \"13b illustrates a processed image of a plate with food items on which are superimposed, pie-charts or other like representations indicating the relative proportions of various nutritional attributes of each food item such as, for example, a pie chart on a rice-based item showing a majority of carbohydrate ‘C’, followed by fiber ‘F’, protein ‘P’ and sodium ‘S’.\",\n \"FIG.\",\n \"14a a placemat printed with grey and white squares of one-inch or standard size to provide a sizing reference as an aid for estimating the size and/or quantity of the food items on a plate that is placed on top of the placemat.\",\n \"FIG.\",\n \"14b illustrates a placemat printed with colored squares of one-inch or standard size to provide color and sizing reference as an aid for identifying the food items and estimating their size and/or quantity on a plate that is placed on top of the placemat.\",\n \"FIG.\",\n \"15 shows a plate partition device shown in FIG.\",\n \"12c printed with standard sized colored squares that serve as reference in identifying and estimating food items on the plate.\",\n \"FIG.\",\n \"16 illustrates the process flow for estimating the nutritional values of the food items for either a plate of food or the food items set aside or rejected as the modification, and report generation.\",\n \"The photograph of a plate of food or modification is analyzed [251] for individual food items, identified and labeled [252], and their respective number or quantities are estimated [253].The total nutritional attribute values such as carbohydrate, protein, fiber, etc.\",\n \"of each food item in the photograph are calculated [255], by taking the product of the quantity or number of a specific food item and its respective nutritional attribute values from a database [254] of such values for a large number of food items.\",\n \"The calculated values are displayed [259] in tabular form and each item is labeled by its predominant nutritional attribute [260].\",\n \"These calculations are stored in a database [258], and personalized reports are generated [261] for individual users.\",\n \"These reports also depict past trends, current status and future predictions and display them at the time of analyzing.\",\n \"FIG.\",\n \"17 illustrates the process flow for predicting a user's craving times and generating proactive distractions to it.\",\n \"Snacking adds unnecessary calories, carbs, sodium, fats etc., to the daily intake and can thwart weight-loss.\",\n \"A user may get a craving at some time of day for a snack; these cravings typically last several minutes and by distracting the person, attention is diverted and the craving passes.\",\n \"The ‘Buzz’ function is a means to request ‘distractions’ from friends or others.\",\n \"When a user has a craving and uses the ‘Buzz’ function [271], the use is time-stamped [272], and the buzz requests are stored in a database [273].\",\n \"These requests are analyzed and typical craving times of day are computed [274], for that particular user and stored in a database [275].\",\n \"At a typical craving time [276], the system checks if the user has already used the Buzz function [277].\",\n \"If the user has not used the Buzz function, the system automatically sends a proactive Buzz request to the user's friends [279].\",\n \"If the user has already used the Buzz function, no action is taken and any automated buzz is suspended [278].\",\n \"After a predetermined delay, the system automatically sends a buzz response to the user [281], drawing from a database of automatic buzz responses [280].\",\n \"All buzzes and responses are recorded [282] and stored in a database [283].\",\n \"FIG.\",\n \"18 illustrates the process flow for monitoring the user's eating patterns and flag issues raised by the user and providing personalized advice.\",\n \"At any preset time, e.g.\",\n \"end of day [293], the AI, nutritionists or other staff analyze the user-uploaded images [294], from the database of user-uploaded images [295], applying issue-analysis criteria [292].\",\n \"The criteria may include ‘eating the same food items 3 days in a row’, ‘eating more than 5 servings of carbohydrates’, etc.\",\n \"The findings from the analysis are stored in a database [296].\",\n \"A nutritionist or other staff professional views the findings for a particular user and manually composes personalized tips [297] that are stored in a database of personalized tips [300].\",\n \"At some convenient time of day, the system automatically sends the personalized tips to the respective user [301].\",\n \"Alternatively, an artificial intelligence (AI) program [298] may compose such personalized tips.\",\n \"An artificial intelligence program [299] also flags issues that may be detrimental to achievement of user objectives (such as eating too many calories, which would not help achieve a weight-loss objective) and store such issues in a database [302].\",\n \"This database may be used by a counselor to provide advice to the user on flagged issues [303].\",\n \"The artificial intelligence program [304] would use the database [302] to compose and send personalized messages to advise the user about their respective flagged issues.\",\n \"FIG.\",\n \"19 illustrates the process flow for providing coaching to a user through two-way rich media.\",\n \"The registered user's questions are received [311] by the system and stored in a database [312].\",\n \"An authorized or user-assigned nutritionist [313] selects a question and views associated user information [314], which may be in the forms of text, images, graphics, voice, etc.\",\n \"stored in a database [315].\",\n \"Based on analysis of the questions and associated information, the nutritionist or other professional manually composes a multi-media response [317], selecting and attaching appropriate content from the database [316] and storing the response in a database [319].\",\n \"Alternatively, an artificial intelligence program [318] may compose and store the response.\",\n \"The system sends the response to the user [320].\",\n \"The user may view the response and enter further clarifying questions or comments [321].\",\n \"Such two-way interactions continue until the user concludes the interaction.\",\n \"Various modifications and adaptations on the described preferred embodiments can be configured without departing from the scope and spirit of the invention.\",\n \"Therefore, it is to be understood that within the scope of the appended claims, the invention may be practiced other than as specifically described herein.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875812"}}},{"rowIdx":4494986,"cells":{"text":{"kind":"list like","value":[["Slim Booster Bars for Electronic Devices","A wireless device includes at least one slim radiating system having a slim radiating structure and a radio-frequency system.","The slim radiating structure includes one or more booster bars.","The booster bar has slim width and height factors that facilitate its integration within the wireless device and the excitation of a resonant mode in the ground plane layer, and has a location factor that enables it to achieve the most favorable radio-frequency performance for the available space to allocate the booster bar.","The at least one slim radiating system may be configured to transmit and receive electromagnetic wave signals in one or more frequency regions of the electromagnetic spectrum."],["1.A wireless handheld or portable electronic device comprising: a slim radiating system configured to transmit and receive electromagnetic wave signals in a first frequency region, the slim radiating system comprising: a slim radiating structure comprising a ground plane layer and a first booster bar comprising a single standard layer of dielectric material including electrically connected top and bottom conductive surfaces, the first booster bar having a slim width factor greater than 3 and a slim height factor greater than 3 and being separated from the ground plane layer by a gap and having a location factor in a range of 0.3 to 1.8, wherein the first booster bar fits in an imaginary sphere having a radius smaller than ⅓ of a free-space wavelength corresponding to a lowest frequency of the first frequency region divided by two times n (pi); a first external conductive path; a radio-frequency system comprising a first matching circuit configured to provide impedance matching within the first frequency region at the first external conductive path; and a first internal conductive path coupling the first booster bar to the radio-frequency system.","2.The wireless handheld or portable electronic device of claim 1, wherein: the slim radiating system is configured to transmit and receive electromagnetic wave signals in a second frequency region, wherein a lowest frequency of the second frequency region is at a frequency higher than a highest frequency of the first frequency region; the slim radiating system comprises a second internal conductive path and a second external conductive path; the slim radiating structure comprises a second booster bar; the second booster bar comprises a single standard layer of dielectric material including a top and a bottom conductive surfaces electrically connected, has a slim width factor greater than 3 and a slim height factor greater than 3, and is separated from the ground plane layer by a gap and has a location factor in a range of 0.3 to 1.8; the second booster bar fits in an imaginary sphere having a radius smaller than ⅓ of a free-space wavelength corresponding to a lowest frequency of the first frequency region, divided by two times n (pi); the second internal conductive path couples the second booster bar to the radio-frequency system; and the radio-frequency system comprises a second matching circuit configured to provide impedance matching within the second frequency region at the second external conductive path.","3.The wireless handheld or portable electronic device of claim 2, wherein: the slim radiating system is configured to transmit and receive electromagnetic wave signals in a third frequency region, wherein a highest frequency of the third frequency region is at a frequency lower than a lowest frequency of the first frequency region; the slim radiating system comprises a third internal conductive path and a third external conductive path; the slim radiating structure comprises a booster element including third and fourth booster bars, the third booster bar being adjacent to the fourth booster bar, and wherein the third and fourth booster bars are electrically connected; each of the third and fourth booster bars comprises a single standard layer of dielectric material including a top and a bottom conductive surfaces electrically connected; the booster element has a slim width factor greater than 6 and a slim height factor greater than 6, and is separated from the ground plane layer by a gap and has a location factor in a range of 0.3 to 1.8; the booster element fits in an imaginary sphere having a radius smaller than ⅓ of a free-space wavelength corresponding to a lowest frequency of the first frequency region divided by two times n (pi); the third internal conductive path couples the booster element to the radio-frequency system; and the radio-frequency system comprises a third matching circuit configured to provide impedance matching within the third frequency region at the third external conductive path.","4.The wireless handheld or portable electronic device of claim 1, wherein: the slim radiating system is configured to transmit and receive electromagnetic wave signals in a second frequency region, wherein a lowest frequency of the second frequency region is at a frequency higher than a highest frequency of the first frequency region; and the first matching circuit is further configured to provide impedance matching within the second frequency region at the first external conductive path.","5.The wireless handheld or portable electronic device of claim 4, wherein the first matching circuit comprises a single branch.","6.The wireless handheld or portable electronic device of claim 4, wherein the first matching circuit comprises no more than seven lumped components.","7.The wireless handheld or portable electronic device of claim 4, wherein the first frequency region comprises an 824-960 MHz frequency range.","8.The wireless handheld or portable electronic device of claim 7, wherein the second frequency region comprises a 1710-2170 MHz frequency range.","9.The wireless handheld or portable electronic device of claim 1, wherein the first booster bar features a first resonance frequency greater than 2,700 MHz, when measured in a monopole configuration in a platform comprising a substantially square conductive surface made of copper, the platform comprising sides of 60 centimeters and a thickness of 0.5 millimeters.","10.A wireless handheld or portable electronic device comprising: a slim radiating system configured to transmit and receive electromagnetic wave signals in a first frequency region, the slim radiating system comprising: a slim radiating structure comprising a ground plane layer and a booster element including first and second booster bars that are adjacent and electrically connected to each other, each of the first and second booster bars comprising a single standard layer of dielectric material including electrically connected top and bottom conductive surfaces, and having a slim width factor greater than 3.5 and a slim height factor greater than 4, each of the first and second booster bars being separated from the ground plane layer by a gap and having a location factor in a range of 0.3 to 1.8, wherein the booster element fits in an imaginary sphere having a radius smaller than ⅓ of a free-space wavelength corresponding to a lowest frequency of the first frequency region, divided by two times n (pi); a first external conductive path; a radio-frequency system comprising a first matching circuit configured to provide impedance matching within the first frequency region at the first external conductive path; and a first internal conductive path coupling the first booster element to the radio-frequency system.","11.The wireless handheld or portable electronic device of claim 10, wherein: the slim radiating system is configured to transmit and receive electromagnetic wave signals in a second frequency region, wherein a lowest frequency of the second frequency region is at a frequency higher than a highest frequency of the first frequency region; the slim radiating system comprises a second internal conductive path and a second external conductive path; the slim radiating structure comprises a third booster bar comprising a single standard layer of dielectric material including electrically connected top and bottom conductive surfaces, and having a slim width factor greater than 3.5 and a slim height factor greater than 4, the third booster bar being separated from the ground plane layer by a gap and having a location factor in a range of 0.3 to 1.8; the second internal conductive path couples the third booster bar to the radio-frequency system; and the radio-frequency system comprises a second matching circuit configured to provide impedance matching within the second frequency region at the second external conductive path.","12.The wireless handheld or portable electronic device of claim 10, wherein a minimum distance between the top conductive surface and the bottom conductive surface of each of the first and second booster bars is no greater than 3 millimeters.","13.The wireless handheld or portable electronic device of claim 10, wherein the first frequency region comprises a 698-960 MHz frequency range.","14.A wireless electronic device comprising: a slim radiating system configured to transmit and receive electromagnetic wave signals in a first frequency region and in a second frequency region, wherein a lowest frequency of the second frequency region is at a frequency higher than a highest frequency of the first frequency region, the slim radiating system comprising: a slim radiating structure comprising a ground plane layer and a booster bar comprising a single standard layer of dielectric material including electrically connected top and bottom conductive surfaces, a longest dimension of the booster bar being at least 3 times greater than a shortest dimension of the booster bar, the booster bar being separated from the ground plane layer by a gap and having a location factor in a range of 0.3 to 1.8, wherein the booster bar fits in an imaginary sphere having a radius smaller than ⅓ of a free-space wavelength corresponding to a lowest frequency of the first frequency region divided by two times n (pi); an external conductive path; a radio-frequency system comprising a matching circuit configured to provide impedance matching within the first and second frequency regions at the external conductive path; and an internal conductive path coupling the booster bar to the radio-frequency system.","15.The wireless electronic device of claim 14, wherein the longest dimension of the booster bar is at least 4 times greater than the shortest dimension of the booster bar.","16.The wireless electronic device of claim 14, wherein the matching circuit comprises seven or fewer components.","17.The wireless electronic device of claim 16, wherein: the matching circuit comprises a ladder topology with five stages in the sequence: series-parallel-series-parallel-series; and each stage comprises one component.","18.The wireless handheld or portable electronic device of claim 16, wherein: the matching circuit comprises a ladder topology with five stages in the sequence: series-parallel-series-parallel-series; and one of the five stages comprises a parallel LC circuit, and another one of the five stages comprises a series LC circuit.","19.The wireless handheld or portable electronic device of claim 14, wherein the booster bar has a first resonance frequency greater than 2,700 MHz, when measured in a monopole configuration in a platform comprising a substantially square conductive surface made of copper, the platform comprising sides of 60 centimeters and a thickness of 0.5 millimeters."],["<SOH> BACKGROUND <EOH>Wireless electronic devices typically handle one or more cellular communication standards, and/or wireless connectivity standards, and/or broadcast standards, each standard being allocated in one or more frequency bands, and the frequency bands being contained within one or more regions of the electromagnetic spectrum.","For that purpose, a typical wireless electronic device must include a radiating system capable of operating in one or more frequency regions with an acceptable radio-electric performance (in terms of for instance reflection coefficient, standing wave ratio, impedance bandwidth, gain, efficiency, or radiation pattern).","The integration of the radiating system within the wireless electronic device must be effective to ensure that the overall device attains good radio-electric performance (such as for example in terms of radiated power, received power, sensitivity) without being disrupted by electronic components and/or human loading.","Additionally, a space within the wireless electronic device is usually limited and the radiating system has to be included in the available space.","The radiating system is expected to be small enough to occupy as little space as possible within the device, which then allows for smaller devices, or for the addition of more specific components and functionalities into the device.","At the same time, it is sometimes convenient for the radiating system to be flat since this allows for slim devices.","Thus, many of the demands for wireless devices also translate to specific demands for the radiating systems thereof.","This is even more critical in the case in which the wireless device is a multifunctional wireless device.","Commonly-owned patent applications WO2008/009391 and US2008/0018543 describe a multifunctional wireless device.","The entire disclosure of aforesaid application numbers WO2008/009391 and US2008/0018543 are hereby incorporated by reference.","For a good wireless connection, high efficiency is further required.","Other more common design demands for radiating systems are the reflection coefficient (or standing-wave ratio, SWR) and the impedance which is supposed to be about 50 ohms.","Other demands for radiating systems for wireless handheld or portable devices are competitive cost and a low SAR.","Furthermore, a radiating system has to be integrated into a device or, in other words, a wireless device has to be constructed such that an appropriate radiating system may be integrated therein which puts additional constraints by consideration of the mechanical fit, the electrical fit, and the assembly fit.","Of further importance, usually, is the robustness of the radiating system, which means that the radiating system does not change its properties upon smaller shocks to the device and the human loading.","Besides radio-frequency performance, small size and reduced interaction with human body and nearby electronic components, one of the current limitations of the prior-art is that generally the antenna system is customized for every particular wireless handheld device model.","The mechanical architecture of each device model is different and the volume available for the antenna severely depends on the form factor of the wireless device model together with the arrangement of the multiple components embedded into the device (e.g., displays, keyboards, battery, connectors, cameras, flashes, speakers, chipsets, memory devices, etc.).","As a result, the antenna within the device is mostly designed ad hoc for every model, resulting in a higher cost and a delayed time to market.","In turn, as typically the design and integration of an antenna element for a radiating structure is customized for each wireless device, different form factors or platforms, or a different distribution of the functional blocks of the device will force to redesign the antenna element and its integration inside the device almost from scratch.","A radiating system for a wireless handheld or portable device typically includes a radiating structure comprising an antenna element which operates in combination with a ground plane layer providing a determined radio-frequency performance in one or more frequency regions of the electromagnetic spectrum.","Typically, the antenna element has a dimension close to an integer multiple of a quarter of the wavelength at a frequency of operation of the radiating structure, so that the antenna element is at resonance or substantially close to resonance at the frequency of operation, and a radiation mode is excited on the antenna element.","Antenna elements operating in multiple frequency bands allocated at different regions of the electromagnetic spectrum usually present complex mechanical designs and considerable dimensions, mainly due to the fact that antenna performance is highly related to the electrical dimensions of the antenna element.","A further problem associated to the integration of the radiating structure, and in particular to the integration of the antenna element in a wireless device is that the volume dedicated for such integration has continuously shrunk with the appearance of new smaller and/or thinner form factors for wireless devices, and with the increasing convergence of different functionalities in a same wireless device.","Therefore, from the conventional wisdom perspective, the trend in seeking for slimmer wireless device is incompatible with maximizing the performance of a traditional antenna device, which again, it is known to have a high correlation between antenna size (relative to the operating wavelengths) and performance.","Some techniques to miniaturize and/or optimize the multiband behavior of an antenna element have been described in the prior art.","However the radiating structures described therein still rely on exciting a radiation mode on the antenna element for each one of the frequency bands of operation.","This fact leads to complex mechanical designs and large antennas that usually are very sensitive to external effects (such as for instance the presence of plastic or dielectric covers that surround the wireless device), to components of the wireless device (such as for instance, but not limited to, a speaker, a microphone, a connector, a display, a shield can, a vibrating module, a battery, or an electronic module or subsystem) placed either in the vicinity of, or even underneath, the radiating element, and/or to the human loading.","A multiband antenna system is sensitive to any of the above mentioned aspects because they may alter the electromagnetic coupling between the different geometrical portions of the radiating element, which usually translates into detuning effects, degradation of the radio-frequency performance of the antenna system and/or the radio-frequency performance of the wireless device, and/or greater interaction with the user (such as an increased level of SAR).","In this sense, a radiating system such as the one described in the present invention not requiring a complex and/or large antenna formed by multiple arms, slots, apertures and/or openings and a complex mechanical design is preferable in order to minimize such undesired external effects and simplify the integration within the wireless device.","Some other attempts have focused on antenna elements not requiring a complex geometry while still providing some degree of miniaturization by using an antenna element that is not resonant in the one or more frequency ranges of operation of the wireless device.","For example, WO2007/128340 discloses a wireless portable device comprising a non-resonant antenna element for receiving broadcast signals (such as, for instance, DVB-H, DMB, T-DMB or FM).","The wireless portable device further comprises a ground plane layer that is used in combination with said antenna element.","Although the antenna element has a first resonant frequency above the frequency range of operation of the wireless device, the antenna element is still the main responsible for the radiation process and for the radio-frequency performance of the wireless device.","This is clear from the fact that no radiation mode can be excited on the ground plane layer because the ground plane layer is electrically short at the frequencies of operation (i.e., its dimensions are much smaller than the wavelength).","For this kind of non-resonant antenna elements, a matching circuitry is added for matching the antenna to a level of SWR in a limited frequency range, which in this particular case can be around SWR<6.Such level of SWR together with the limited bandwidth results in antenna elements which are only acceptable for reception of electromagnetic wave signals but not desirable for transmission of electromagnetic wave signals.","With such limitations, while the performance of the wireless portable device may be sufficient for reception of electromagnetic wave signals (such as those of a broadcast service), the antenna element could not provide an acceptable performance (for example, in terms of reflection coefficient or gain) for a communication service requiring also the transmission of electromagnetic wave signals.","Commonly-owned patent applications WO2008/119699 and US2010/0109955 describe a wireless handheld or portable device comprising a radiating system capable of operating in two frequency regions.","The radiating system comprises an antenna element having a resonant frequency outside said two frequency regions, and a ground plane layer.","In this wireless device, while the ground plane layer contributes to enhance the electromagnetic performance of the radiating system in the two frequency regions of operation, it is still necessary to excite a radiation mode on the antenna element.","In fact, the radiating system relies on the relationship between a resonant frequency of the antenna element and a resonant frequency of the ground plane layer in order for the radiating system to operate properly in said two frequency regions.","Nevertheless, the solution still relies on an antenna element whose size is related to a resonant frequency that is outside of the two frequency regions.","The entire disclosures of the aforesaid application numbers WO2008/119699 and US2010/0109955 are hereby incorporated by reference.","A different radiating system is disclosed in U.S. Pat.","No.","6,674,411, in which a planar inverted-L antenna (i.e., a patch antenna) has a radiating element composed by a rectangular plate placed above and substantially parallel to a ground plane.","The antenna is connected to a matching network that provides a match in one frequency band in a first frequency region, and in one frequency band in a second frequency region.","Thus the antenna system is limited to single-band operation in both frequency regions.","When operation in more bands is sought, the antenna system requires of a switched (active) matching network that provides non-simultaneous impedance matching in each frequency band.","So in spite of having an antenna that occupies a large volume (20×10×8 mm3), not more than dual-band operation may be provided simultaneously.","For at least the above reasons, wireless device manufacturers regard the volume dedicated to the integration of the radiating structure, and in particular the antenna element, as being a toll to pay in order to provide wireless communication capabilities to the handheld or portable device.","In order to reduce as much as possible the volume occupied into the wireless handheld or portable device, recent trends in handset antenna design are oriented to maximize the contribution of the ground plane to the radiation process by using very small non-resonant elements.","However, non-resonant elements usually are forced to include a complex radio-frequency system.","Thus, the challenge of these techniques mainly relies on said complexity (combination of inductors, capacitors, and transmission lines), which is required to satisfy impedance bandwidth and efficiency specifications.","Commonly owned patent applications, WO2010/015365, and WO2010/015364 are intended for solving some of the aforementioned drawbacks.","Namely, they describe a wireless handheld or portable device comprising a radiating system including a radiating structure and a radio-frequency system.","The radiating structure is formed by a ground plane layer presenting suitable dimensions as for supporting at least one efficient radiation mode and at least one radiation booster capable of coupling electromagnetic energy to said ground plane layer.","The radiation booster is not resonant in any of the frequency regions of operation and, consequently, a radio-frequency system is used to properly match the radiating structure to the desired frequency bands of operation.","More particularly, in WO2010/015364 each radiation booster is intended for providing operation in a particular frequency region.","Thus, the radio-frequency system is designed in such a way that the first internal port associated to the first radiation booster is highly isolated from the second internal port associated to a second radiation booster.","Said radio-frequency system usually comprises a matching network including resonators for each one of the frequency regions of operation and a set of filters for each one of the frequency regions of operation.","Thus, said radio-frequency system requires multiple stages and the performance of the radiating systems in terms of efficiency may be affected by the additional losses of the components.","As each radiation booster is generally intended for providing operation in a particular frequency region, the bandwidth capabilities may be limited for some applications requiring very wide bandwidth specially at the low frequency region, as for example for wireless devices operating at LTE700, GSM850 and GSM900.Commonly owned patent applications WO2014/012796 and US2014/0015730 disclose a concentrated wireless device comprising a radiating system including a radiating structure and a radio-frequency system, such device operating two or more frequency regions of the electromagnetic spectrum.","A feature of said radiating system is that the operation in at least two frequency regions is achieved by one radiation booster, or by at least two radiation boosters, or by at least one radiation booster and at least one antenna element, wherein the radio-frequency system modifies the impedance of the radiating structure, providing impedance matching to the radiating system in the at least two frequency regions of operation of the radiating system.","The entire disclosure of aforesaid application numbers WO2014/012796 and US2014/0015730 are hereby incorporated by reference.","Commonly owned patent applications WO2014/012842 and US2014/0015728 disclose very compact, small size and light weight radiation boosters operating in single or in multiple frequency bands.","Such radiation boosters are configured to be used in radiating systems that may be embedded into a wireless handheld device.","Said patent applications further disclose radiation booster structures and their manufacturing methods that enable reducing the cost of both the booster and the entire wireless device embedding said booster inside the device.","The entire disclosure of aforesaid application numbers WO2014/012842 and US2014/0015728 are hereby incorporated by reference.","Another technique, as disclosed in U.S. Pat.","No.","7,274,340, is based on the use of two coupling elements.","According to the invention, quad-band operation (GSM 1800/1900 and GSM850/900 bands) is provided with two coupling elements: a low-band (LB) coupling element (for the GSM850/900 bands), and a high-band (HB) coupling element (for the GSM1800/1900 bands), where the impedance matching is provided through the addition of two matching circuits, one for the LB coupling element and another one for the HB coupling element.","In spite of using non-resonant elements, the size of the element for the low band is significantly large, being 1/9.3 times the free-space wavelength of the lowest frequency for the low frequency band.","Due to such size, the low band element would be a resonant element at the high band.","Additionally, the operation of this solution is closely linked to the alignment of the maximum E-field intensity of the ground plane and the coupling element.","The size of the low band element undesirably contributes to increase the printed circuit board (PCB) space required by the antenna module.","According to the invention, the bandwidth at the low frequency region is 133 MHz (from 821 MHz to 954 MHz) that is insufficient for some applications requiring very wide bandwidth, especially at the low frequency region, as for example for wireless devices operating at LTE700, GSM850 and GSM900.Therefore, a wireless device not requiring an antenna element and including a slim radiating system would be advantageous to make simpler the integration of the slim radiating structure into the wireless electronic device minimizing the amount of the electronic device that is allocated towards the slim radiating system, and to provide a suitable radio-frequency performance to operate in a wide range of communication bands.","The volume freed up by the absence of a large and complex antenna element would enable smaller and/or thinner devices, as slim electronic devices, or even to adopt radically new form factors which are not feasible today due to the presence of an antenna element featuring a considerable volume.","Furthermore, by eliminating precisely the element that requires customization, a standard solution is sought which should only require minor adjustments to be implemented in different wireless electronic devices."],["<SOH> SUMMARY <EOH>It is an object of the present invention to provide an electronic device (such as for instance but not limited to a mobile phone, a smartphone, a phablet, a PDA, an MP3 player, a headset, a USB dongle, a laptop computer, a tablet, a gaming device, a GPS system, a digital camera, a wearable device as a smart watch, a PCMCIA, Cardbus 32 card, a sensor, or generally a multifunction wireless device which combines the functionality of multiple devices) containing a slim radiating system that covers a wide range of radio-frequencies and handles multiple communication bands while exhibiting a suitable radio-frequency performance.","It is another object of the invention to provide a slim radiating system suitable for being included within electronic devices, and more preferably within slim electronic devices.","It is another object of the invention to provide a standard slim radiating system which only requires minor adjustments to be included within different electronic devices.","Another object of the invention refers to the location (on the device) of radiation boosters and, more particularly, booster bars for obtaining the most favorable frequency bandwidth values.","An electronic device according to the invention may have a candy-bar shape, which means that its configuration is given by a single body.","It may also have a two-body configuration such as a clamshell, flip-type, swivel-type or slider structure.","In some other cases, the device may have a configuration comprising three or more bodies.","It may further or additionally have a twist configuration in which a body portion (e.g.","with a screen) can be twisted (i.e., rotated around two or more axes of rotation which are preferably not parallel).","The electronic device may comprise a memory module, a processing circuitry module, a user interface module, a battery, and a wireless communication module.","The wireless communication module may include a slim radiating system, a radio-frequency transceiver circuit, a power amplifier circuit and a base-band module.","The slim radiating system may be coupled to the power amplifier via a conductive path and to the radio transceiver circuit via a conductive path.","The wireless communication module may include a multiplexing stage coupled to the slim radiating system via a conductive path.","A slim radiating system in accordance with the invention may include a slim radiating structure, a radio-frequency system, at least one internal conductive path and at least one external conductive path.","The slim radiating structure may include a ground element and at least one radiation booster, which in some embodiments may be a booster bar, separated from the ground element by a gap.","A slim radiating structure may comprise a ground element and one, two, three, four or even more radiation boosters.","In some preferred embodiments, said radiation boosters may be booster bars featuring an elongated shape.","In preferred embodiments, each booster bar or radiation booster is separated from the ground element by a gap.","An aspect of the present invention relates to the use of the ground element (or ground plane layer) of the slim radiating system as a main source of radiation.","A radiation booster includes a dielectric material and in some embodiments, a single standard layer of dielectric material spacing two or more conductive elements.","A single standard layer of dielectric material refers to dielectric material with a standard thickness, which is available off-the-shelf.","For example, 0.025″ (0.635 mm), 0.047″ (1.2 mm), 0.093″ (2.36 mm) or 0.125″ (3.175 mm) are common/standard thicknesses for dielectric materials which are available in the market.","Examples of dielectric materials may include fiber-glass FR4, Cuclad, Alumina, Kapton, Ceramic and for instance commercial laminates and substrates from Rogers® Corporation (R03000® and R04000® laminates, Duroid substrates and alike) or other suitable non-conductive materials.","The radiation booster may be formed by printing or depositing conductive material in a first and a second surface of the dielectric material (e.g.","top and bottom) and adding several vias to electrically connect the conductive material in the first surface with the conductive material in the second surface.","The conductive material in the first and second surfaces may have a substantially polygonal shape.","Some possible polygonal shapes are for instance, but not limited to, squares, rectangles, and trapezoids.","When the conductive material in said first and second surfaces has an elongated shape, for instance a rectangular shape, the radiation booster takes the form of a booster bar; a booster bar may also include vias that electrically connect the conductive material in the first surface with the conductive material in the second surface.","The elongated shape of a booster bar is characterized by two slim form factors: a slim width factor and a slim height factor.","The slim width factor is a ratio between a length of the booster bar and a width of the booster bar.","The slim height factor is a ratio between the length of the booster bar and a height of the booster bar.","The slim width factor characterizes the ratio between the length and the width of the booster bar, whereas the slim height factor characterizes the ratio between the length and the height of the booster bar.","In a preferred embodiment, the value for the slim width factor and the slim height factor is greater than 2, for instance in one or more of those embodiments the value for the slim width factor is greater than 3, and preferably larger than 3.5, and the slim height factor is greater than 4.In another preferred embodiment, the value for the slim width factor is greater than 6 and/or the slim height factor is greater than 6.In another preferred embodiment, the value for the slim width factor is greater than 6 and/or the slim height factor is larger than 9.In some less preferred embodiments, the values for both the slim width factor and the slim height factor are between 1 and 2.The slim width factor and the slim height factor of a booster bar may take any of the values listed above yet being smaller than 25, and preferably smaller than 10.A radiation booster may comprise one, two or more booster bars electrically connected, forming a booster element that fits in an imaginary sphere having a diameter smaller than ⅓ of a radiansphere corresponding to the lowest frequency of operation of the slim radiating system.","Such a booster element may also be characterized by a slim width factor, a slim height factor, and a location factor.","Any booster element according to the present invention may be limited by a slim width factor and a slim height factor, each of these factors being between 1 and 10, and preferably between 2 and 10.An advantageous aspect of the invention refers to a booster bar built on a single standard layer of dielectric material that is manufactured at a competitive cost.","Another advantageous aspect of the invention refers to a booster bar having a slim width factor and/or slim height factor that enables the booster bar to occupy only a small portion within the electronic wireless device and making it suitable for its integration within slim electronic devices or flexible electronic devices.","Another advantageous aspect of the present invention refers to the location and slim form factors of a booster bar to guarantee the most advantageous frequency bandwidth for the available space.","A radiation booster, like for instance a booster bar, is separated from the ground plane layer by a gap.","In the context of this document, the gap refers to a minimum distance between a point at an edge of the ground plane layer and a point at an edge of the bottom conductive surface of the radiation booster.","The location of the radiation booster is characterized by a location factor that is a ratio between the width of the radiation booster and the gap.","In a preferred example, the location factor is between 0.5 and 2.In another preferred example, the location factor is between 0.3 and 1.8.Each radiation booster of the slim radiating system advantageously couples the electromagnetic energy from the radio-frequency system to the ground element in transmission, and from the ground element to the radio-frequency system in reception.","The radiation boosters excite a radiation mode in the ground element enabling the radiation from the ground element.","The form factor of the radiation booster, together with its location in relation to the ground element, is configured to achieve a proper excitation of the radiation mode of the ground element.","The location factor is selected to achieve the most favorable frequency bandwidth for a radiation booster with a certain form factor, particularly a booster bar.","Apart from the form factor of the radiation booster, the gap is also relevant for properly exciting a radiation mode in the ground plane layer and to achieve the most advantageous frequency bandwidth.","The bandwidth of the slim radiating system may be degraded if the location factor is not properly selected.","The location factor and the slim form factors of a booster bar are selected to ensure the most favorable frequency bandwidth while minimizing/reducing the amount of space allocated towards the integration of the booster bar within the electronic device.","The slim radiating structure is mounted within the electronic device and is coupled to the radio-frequency system via a conductive path.","The radiation booster is coupled to the ground element via a conductive path and is located at certain distance from the ground element.","Said conductive path comprises a conductive element which may be linear or include a surface; the conductive element may comprise, for instance but not limited to, a metallic strip and/or a conductive trace.","In some embodiments, a slim radiating structure comprises one ground element or conductive material acting as a ground plane for the slim radiating structure.","In some other embodiments, a slim radiating structure may comprise two, three or more ground elements or conductive materials acting as a ground plane for the radiating structure.","In such embodiments, the plurality of ground elements may be electrically interconnected one to each other.","The at least one radiation booster for a slim radiating structure according to the present invention may have a maximum size at least smaller than 1/15 of the free-space wavelength corresponding to the lowest frequency of the first frequency region of operation.","In some cases, said maximum size may be also smaller than 1/20, and/or 1/25, and/or 1/30, and/or 1/50, and/or 1/100 of the free-space wavelength corresponding to the lowest frequency of the first frequency region of operation.","In some cases, the at least one radiation booster fits in an imaginary sphere having a diameter smaller than ⅓, or preferably smaller than ¼, or preferably smaller than ⅙, or even more preferably smaller than 1/10 of a radiansphere at said free-space wavelength.","The radiansphere is defined as an imaginary sphere having a radius equal to the operating wavelength divided by two times π (pi).","Furthermore, in some examples, the at least one radiation booster also has a maximum size smaller than 1/15, and/or 1/20, and/or 1/25, and/or 1/30, and/or 1/50 of the free-space wavelength corresponding to the lowest frequency of the second frequency region of operation.","In some cases, the at least one radiation booster fits in an imaginary sphere having a diameter smaller than ⅓, or preferably smaller than ¼, or preferably smaller than ⅙, or even more preferably smaller than 1/10 of a radiansphere at said free-space wavelength.","Additionally, in some of these examples the at least one radiation booster has a maximum size larger than 1/1400, 1/700, 1/350, 1/250, 1 / 180 , 1/140, or 1/120 times the free-space wavelength corresponding to the lowest frequency of said first frequency region.","The maximum size of a radiation booster is preferably defined by the largest dimension of a booster box that completely encloses said radiation booster, and in which the radiation booster is inscribed.","More specifically, a booster box for a radiation booster is defined as being the minimum-sized parallelepiped of square or rectangular faces that completely encloses the radiation booster and wherein each one of the faces of said minimum-sized parallelepiped is tangent to at least a point of said radiation booster.","Moreover, each possible pair of faces of said minimum-size parallelepiped sharing an edge forms an inner angle of 90°.","In those cases in which the radiating structure comprises more than one radiation booster, a different booster box is defined for each of them.","In some preferred examples, the area defined by the two largest dimensions of a booster box is advantageously small compared to the square of the wavelength corresponding to the lowest frequency of the first frequency region; in particular, a ratio between said area and the square of the wavelength corresponding to the lowest frequency of the first frequency region may be advantageously smaller than at least one of the following percentages: 0.15%, 0.12%, 0.10%, 0.08%, 0.06%, 0.04%, or even 0.02%.","In some of these examples, a ratio between the area defined by the two largest dimensions of a booster box and the square of the wavelength corresponding to the lowest frequency of the second frequency region may also be advantageously smaller than at least one of the following percentages: 0.50%, 0.45%, 0.40%, 0.35%, 0.30%, 0.25%, 0.20%, 0.15%, 0.10%, or even 0.05%.","Moreover, in some embodiments according to the present invention, the at least one radiation booster will entirely fit inside a limiting volume equal or smaller than L3/25000, and in some cases equal or smaller than L3/50000, L3/100000, L3/150000, L3/200000, L3/300000, L3/400000, or even smaller than L3/500000, being L the wavelength corresponding to the lowest frequency of the first frequency region of operation.","A slim radiating system according to the invention is configured to handle multiple communication bands, and to provide coverage and an acceptable level of reflection coefficient in a wide range of communication bands in one or more frequency regions of operation exhibiting a suitable radio-frequency performance.","The slim radiating system is designed to transmit and receive radio-frequency signals in multiple communication bands of interest, including frequency bands that may be added, for instance, through the deployment of future cellular telephone bands and/or data service bands.","In the context of this document, a frequency band preferably refers to a range of frequencies used by a particular cellular communication standard, a wireless connectivity standard or a broadcast standard, while a frequency region preferably refers to a continuum of frequencies of the electromagnetic spectrum.","For example, the GSM 1800 standard is allocated in a frequency band from 1710 MHz to 1880 MHz while the GSM 1900 standard is allocated in a frequency band from 1850 MHz to 1990 MHz.","A device operating the GSM 1800 and the GSM1900 standards must have a radiating system capable of operating in a frequency region from 1710 MHz to 1990 MHz.","As another example, a wireless device operating the GSM 850 standard (allocated in a frequency band from 824 MHz to 894 MHz) and the GSM 1800 standard must have a radiating system capable of operating in two separate frequency regions.","Some frequency bands that the slim radiating system may be configured to transmit and receive signals in are, for example, GSM 850 (824-894 MHz), GSM 900 (880-960 MHz), GSM 1800 (1710-1880 MHz), GSM 1900 (1850-1990 MHz), WCDMA 2100 (1920-2170 MHz), CDMA 1700 (1710-2155 MHz), LTE 700 (698-798 MHz), LTE 800 (791-862 MHz), LTE 2600 (2500-2690 MHz), LTE 3500 (3.4-3.6 GHz), LTE 3700 (3.6-3.8 GHz), WiFi or WLAN (2.4-2.5 GHz and/or 4.9-5.9 GHz), etc.","A wireless handheld or portable device according to the present invention may operate one, two, three, four or more cellular communication standards, wireless connectivity standards, and/or broadcasts standards, each standard being allocated in one, two or more frequency bands, and said frequency bands being contained within one, two or more frequency regions of the electromagnetic spectrum.","The slim radiating system is designed to provide an acceptable level of reflection coefficient in the frequency regions of operation.","A slim radiating system according to the present invention is configured to operate in at least one frequency region.","In some embodiments, the slim radiating system is configured to operate in a first frequency region comprising at least a first frequency band, and a second frequency region comprising at least a second frequency band.","Such radiating system is configured to satisfy the radio-frequency bandwidths and frequency coverage goals.","A slim radiating system according to the present invention may advantageously feature an impedance bandwidth in the first frequency region larger than 5%, 10%, 15%, or even larger than 20%.","In addition, such radiating system may also feature an impedance bandwidth in the second frequency region larger than 5%, 10%, 15%, 20%, 25%, 30%, 35%, or even larger than 40%.","The impedance bandwidth is defined as the difference between the highest and lowest frequencies of a frequency region, divided by the central frequency of the same frequency region.","Due to the small size of the radiation boosters, the radiation boosters and booster bars may be electrically short at some or all frequencies of operation.","A slim radiating structure according to the present invention may feature a first resonant frequency, measured at an internal path, at a frequency higher (i.e.","above) than the highest frequency of the first frequency region of operation when said radio-frequency system is disconnected.","Moreover, when the radio-frequency system is disconnected, the input impedance of the slim radiating structure measured at the internal path may have an important reactance, in particular a capacitive reactance, within the frequencies of said first frequency region.","In this case, a ratio between the first resonant frequency of the slim radiating structure and the highest frequency of the first frequency region is advantageously greater than 1.2.In some cases, said ratio may be even greater than one or more of the following values: 1.5, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, or 3.0.In some examples, a ratio between said first resonant frequency and the lowest frequency of the first frequency region of operation is advantageously greater than 1.3, or even greater than one or more of the following values: 1.4, 1.5, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, or 3.0.In some embodiments, the first resonant frequency of the slim radiating structure, measured at an internal path when the radio-frequency system is disconnected, is above the highest frequency of the second frequency region, wherein a ratio between said first resonant frequency and said highest frequency of the second frequency region may be larger than one or more of the following values: 1.0, 1.1, 1.2, 1.4, 1.6, 1.8, or 2.0.In some other embodiments, said first resonant frequency is within the second frequency region.","In some other examples, said first resonant frequency is above the highest frequency of the first frequency region and below the lowest frequency of the second frequency region.","In the context of this document, a resonant frequency associated to a radiation booster of the slim radiating structure preferably refers to a frequency at which the input impedance of the slim radiating structure, the impedance being measured at the internal path coupling the radiation booster to the radio-frequency system when the radio-frequency system is not connected, has an imaginary part equal or substantially equal to zero.","The radio-frequency system may comprise one or more matching circuits that modify the impedance of the slim radiating structure providing impedance matching to the slim radiating system, at an external path, in one or more frequency regions of operation of the slim radiating system.","A radio-frequency system according to the invention may include at least one matching network with a plurality of stages, for instance, two, three, four, five, six or more stages.","A stage comprises one or more circuit components (for example but not limited to, inductors, capacitors, resistors, jumpers, short-circuits, delay lines, or other reactive or resistive components).","In some cases, a stage has a substantially inductive behavior in the frequency region or regions of operation of the slim radiating system, while another stage has a substantially capacitive behavior in said frequency region/s, and yet a third one may have a substantially resistive behavior in said frequency region/s.","In an example, a stage may substantially behave as a resonant circuit (such as, for instance, a parallel LC resonant circuit or a series LC resonant circuit) in at least one frequency region of operation of the slim radiating system.","The use of stages having a resonant circuit behavior allows one part of a given matching network be effectively connected to another part of said matching network for a given range of frequencies, or in a given frequency region, and be effectively disabled for another range of frequencies, or in another frequency region.","In some examples, the at least one matching network alternates stages connected in series (i.e.","cascaded) with stages connected in parallel (i.e.","shunted), forming a ladder structure.","In some cases, a matching network comprising two stages forms an L-shaped structure (i.e.","series-parallel or parallel-series).","In some cases, a matching network comprising three stages forms either a pi-shaped structure (i.e.","parallel-series-parallel) or a T-shaped structure (i.e.","series-parallel-series).","In some embodiments, a radio-frequency system according to the present invention comprises a matching circuit in a ladder topology.","Such matching circuit preferably comprises one reactive component per stage.","In some other embodiments, a radio-frequency system according to the present invention comprises a matching circuit at least including a series LC resonant circuit and a parallel LC resonant circuit.","In a preferred embodiment, an electronic device comprises a slim radiating system configured to transmit and receive electromagnetic wave signals in at least one frequency region of the electromagnetic spectrum, and comprising a slim radiating structure, a radio-frequency system, at least one internal conductive path and at least one external conductive path.","The slim radiating structure comprises at least one ground element and at least one booster bar.","The at least one internal conductive path comprises a conductive element that couples the at least one booster bar to the radio-frequency system.","The radio-frequency system comprises at least one matching circuit modifying the impedance of the slim radiating structure providing impedance matching to the slim radiating system in the at least one frequency region at the at least one external conductive path.","The at least one booster bar has an elongated shape, and is characterized by a slim width factor greater than 3 and a slim height factor greater than 3, is separated from the at least one ground element by a gap and is characterized by a location factor between 0.5 and 2.Another preferred embodiment relates to an electronic device including a slim radiating system that comprises a slim radiating structure, a radio-frequency system, an internal conductive path and at least one external conductive path; the slim radiating system is configured to transmit and receive electromagnetic wave signals in a first frequency region and a second frequency region.","The slim radiating structure comprises at least one ground element, and one booster bar separated from the ground element by a gap and is characterized by a location factor between 0.3 and 1.8.The internal conductive path comprises a conductive element that couples the booster bar to the radio-frequency system.","The radio-frequency system comprises a matching circuit that modifies the impedance of the slim radiating structure providing impedance matching to the slim radiating system in the first and second frequency regions at the at least one external conductive path.","The first and second frequency regions are preferably separated so that the lowest frequency of the second frequency region is above the highest frequency of the first frequency region.","Some preferred matching circuits for such preferred embodiment are described in FIGS.","15A-15F .","Further, an advantageous aspect of the invention refers to a radio-frequency system comprising a matching circuit that provides impedance matching to the slim radiating system in first and second frequency regions preferably not requiring a filtering circuit or component that separates frequencies of the first frequency region from frequencies of the second frequency region (e.g.","a diplexer, a bank of filters, etc.)","for providing impedance matching in the first frequency region and second frequency region independently (i.e.","in two separate branches or paths).","Thus preferred matching circuits may provide impedance matching in said first and second frequency regions with one branch.","According to the present invention, some preferred matching circuits preferably comprise seven or less components, for instance: two, three, four, five, six or seven.","Such matching circuits preferably do not comprise active circuits or components.","In some embodiments in which the slim radiating system is configured to transmit and receive signals in a first frequency region and a second frequency region, a ratio between the lowest frequency of the second frequency region and the lowest frequency of the first frequency region may be greater than 1.5.In some of these embodiments, said ratio may be also greater than 1.8, 2.0, 2.2, or 2.4.In addition, in some embodiments in which the slim radiating system is configured to operate signals from first and second frequency regions, a ratio between the lowest frequency of the second frequency and the highest frequency of the first frequency region may be greater than 1.2, 1.5, 1.8, 2.0, 2.2, or 2.4.Accordingly, an advantageous aspect of such radio-frequency system is its efficiency in that impedance matching in the first and second frequency regions may be provided with one matching circuit using a reduced number of components, which consequently introduces lower losses in the radio-frequency system and makes it more robust against the tolerances of the components.","Moreover, by not including filtering circuits such as diplexers, the radio-frequency system avoids the insertion losses characterizing such type of circuits and the necessity of having two separate matching circuits, which consequently makes the radio-frequency system have less components and the slim radiating system smaller in terms of area occupied in the device.","In a third preferred embodiment, an electronic device includes a slim radiating system comprising a slim radiating structure, a radio-frequency system, first and second internal conductive paths and at least one external conductive path; the slim radiating system is configured to transmit and receive electromagnetic wave signals in a first frequency region and a second frequency region.","The slim radiating structure comprises at least one ground plane layer, first and second radiation boosters, each of the first and second radiation boosters being separated from the ground plane layer by a gap.","The first internal conductive path comprises a conductive element that couples the first radiation booster to the radio-frequency system, and the second internal conductive path comprises a conductive element that couples the second radiation booster to the radio-frequency system.","The radio-frequency system comprises a matching circuit coupled to the first and second internal conductive paths and to the external conductive path, the matching circuit modifies the impedance of the slim radiating structure providing impedance matching to the slim radiating system in the first and second frequency regions.","In some cases, the slim radiating system may comprise a first external conductive path and a second external conductive path, and the radio-frequency system may include a diplexer circuitry that advantageously filters signals from first and second frequency regions, said signals being matched in impedance in the first and second frequency regions by the matching circuit within the radio-frequency system.","A first port of the diplexer is connected to the matching circuit, and the two remaining ports of the diplexer are connected to the first and second external conductive paths.","The first and second external paths comprise, respectively, signals for frequencies from the first frequency region, and signals for frequencies from the second frequency region.","A further aspect of the present invention relates to a test platform for electromagnetically characterizing radiation boosters.","Said platform comprises a substantially square conductive surface on top of which, and substantially close to the central point, the element to be characterized is mounted perpendicular to said surface in a monopole configuration, said conductive surface acting as the ground plane.","The substantially square conductive surface comprises sides with a dimension larger than a reference operating wavelength.","In the context of the present invention, said reference operating wavelength is the free-space wavelength equivalent to a frequency of 900 MHz.","A substantially square conductive surface according to the present invention is made of copper with sides measuring 60 centimeters, and a thickness of 0.5 millimeters.","In the test configuration as set forth above, a booster bar according to the present invention may be characterized by a ratio between the first resonance frequency and the reference frequency (900 MHz) being larger than a minimum ratio of 3.0.In some cases, said ratio may be even larger than a minimum ratio such as: 3.4, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.6 or 7.0.A booster bar according to the present invention may also be characterized by a radiation efficiency measured in said platform, at a frequency equal to 900 MHz, being less than 50%, preferably being less than 40%, 30%, 20%, or 10%, and in some cases being less than 7.5%, 5%, or 2.5%.","All those are quite remarkably low efficiency values considering the additional 1:3 frequency mismatch and beyond obtained in some of the embodiments as described above.","Such a frequency shift would introduce further mismatch losses that would result in an overall antenna efficiency below 5%, and quite typically below 2%, which would be ordinarily considered unacceptable for a mobile phone or wireless application.","Still, quite surprisingly, when combining at least one booster bar with the radio-frequency system of a slim radiating system according to the present invention, said slim radiating system recovers the efficiency required for the performance of a typical wireless device."],["CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser.","No.","14/807,449 filed Jul.","23, 2015, which claims priority under 35 U.S.C.","§119(e) from U.S.","Provisional Patent Application Ser.","No.","62/028,494, filed Jul.","24, 2014, U.S.","Provisional Patent Application Ser.","No.","62/064,716, filed Oct. 16, 2014, U.S.","Provisional Patent Application Ser.","No.","62/072,671, filed Oct. 30, 2014, and U.S.","Provisional Patent Application Ser.","No.","62/152,991, filed Apr.","27, 2015, the entire contents of which are hereby incorporated by reference.","In addition, this application claims foreign priority under 35 U.S.C.","§119(a)-(d) to Application No.","EP 14178369.6 filed on Jul.","24, 2014, Application No.","EP 14189253.9 filed on Oct. 16, 2014, Application No.","EP 14191145.3 filed on Oct. 30, 3014, and Application No.","EP 15165167.6 filed on Apr.","27, 2015, the entire contents of which are hereby incorporated by reference.","STATEMENT OF RESEARCH FUNDING This patent application is part of a project that has received funding from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement No.","674491.FIELD OF THE INVENTION The present invention relates generally to the field of electronic devices which require the transmission and/or reception of electromagnetic wave signals, and more particularly, to slim radiating structures in wireless electronic devices.","BACKGROUND Wireless electronic devices typically handle one or more cellular communication standards, and/or wireless connectivity standards, and/or broadcast standards, each standard being allocated in one or more frequency bands, and the frequency bands being contained within one or more regions of the electromagnetic spectrum.","For that purpose, a typical wireless electronic device must include a radiating system capable of operating in one or more frequency regions with an acceptable radio-electric performance (in terms of for instance reflection coefficient, standing wave ratio, impedance bandwidth, gain, efficiency, or radiation pattern).","The integration of the radiating system within the wireless electronic device must be effective to ensure that the overall device attains good radio-electric performance (such as for example in terms of radiated power, received power, sensitivity) without being disrupted by electronic components and/or human loading.","Additionally, a space within the wireless electronic device is usually limited and the radiating system has to be included in the available space.","The radiating system is expected to be small enough to occupy as little space as possible within the device, which then allows for smaller devices, or for the addition of more specific components and functionalities into the device.","At the same time, it is sometimes convenient for the radiating system to be flat since this allows for slim devices.","Thus, many of the demands for wireless devices also translate to specific demands for the radiating systems thereof.","This is even more critical in the case in which the wireless device is a multifunctional wireless device.","Commonly-owned patent applications WO2008/009391 and US2008/0018543 describe a multifunctional wireless device.","The entire disclosure of aforesaid application numbers WO2008/009391 and US2008/0018543 are hereby incorporated by reference.","For a good wireless connection, high efficiency is further required.","Other more common design demands for radiating systems are the reflection coefficient (or standing-wave ratio, SWR) and the impedance which is supposed to be about 50 ohms.","Other demands for radiating systems for wireless handheld or portable devices are competitive cost and a low SAR.","Furthermore, a radiating system has to be integrated into a device or, in other words, a wireless device has to be constructed such that an appropriate radiating system may be integrated therein which puts additional constraints by consideration of the mechanical fit, the electrical fit, and the assembly fit.","Of further importance, usually, is the robustness of the radiating system, which means that the radiating system does not change its properties upon smaller shocks to the device and the human loading.","Besides radio-frequency performance, small size and reduced interaction with human body and nearby electronic components, one of the current limitations of the prior-art is that generally the antenna system is customized for every particular wireless handheld device model.","The mechanical architecture of each device model is different and the volume available for the antenna severely depends on the form factor of the wireless device model together with the arrangement of the multiple components embedded into the device (e.g., displays, keyboards, battery, connectors, cameras, flashes, speakers, chipsets, memory devices, etc.).","As a result, the antenna within the device is mostly designed ad hoc for every model, resulting in a higher cost and a delayed time to market.","In turn, as typically the design and integration of an antenna element for a radiating structure is customized for each wireless device, different form factors or platforms, or a different distribution of the functional blocks of the device will force to redesign the antenna element and its integration inside the device almost from scratch.","A radiating system for a wireless handheld or portable device typically includes a radiating structure comprising an antenna element which operates in combination with a ground plane layer providing a determined radio-frequency performance in one or more frequency regions of the electromagnetic spectrum.","Typically, the antenna element has a dimension close to an integer multiple of a quarter of the wavelength at a frequency of operation of the radiating structure, so that the antenna element is at resonance or substantially close to resonance at the frequency of operation, and a radiation mode is excited on the antenna element.","Antenna elements operating in multiple frequency bands allocated at different regions of the electromagnetic spectrum usually present complex mechanical designs and considerable dimensions, mainly due to the fact that antenna performance is highly related to the electrical dimensions of the antenna element.","A further problem associated to the integration of the radiating structure, and in particular to the integration of the antenna element in a wireless device is that the volume dedicated for such integration has continuously shrunk with the appearance of new smaller and/or thinner form factors for wireless devices, and with the increasing convergence of different functionalities in a same wireless device.","Therefore, from the conventional wisdom perspective, the trend in seeking for slimmer wireless device is incompatible with maximizing the performance of a traditional antenna device, which again, it is known to have a high correlation between antenna size (relative to the operating wavelengths) and performance.","Some techniques to miniaturize and/or optimize the multiband behavior of an antenna element have been described in the prior art.","However the radiating structures described therein still rely on exciting a radiation mode on the antenna element for each one of the frequency bands of operation.","This fact leads to complex mechanical designs and large antennas that usually are very sensitive to external effects (such as for instance the presence of plastic or dielectric covers that surround the wireless device), to components of the wireless device (such as for instance, but not limited to, a speaker, a microphone, a connector, a display, a shield can, a vibrating module, a battery, or an electronic module or subsystem) placed either in the vicinity of, or even underneath, the radiating element, and/or to the human loading.","A multiband antenna system is sensitive to any of the above mentioned aspects because they may alter the electromagnetic coupling between the different geometrical portions of the radiating element, which usually translates into detuning effects, degradation of the radio-frequency performance of the antenna system and/or the radio-frequency performance of the wireless device, and/or greater interaction with the user (such as an increased level of SAR).","In this sense, a radiating system such as the one described in the present invention not requiring a complex and/or large antenna formed by multiple arms, slots, apertures and/or openings and a complex mechanical design is preferable in order to minimize such undesired external effects and simplify the integration within the wireless device.","Some other attempts have focused on antenna elements not requiring a complex geometry while still providing some degree of miniaturization by using an antenna element that is not resonant in the one or more frequency ranges of operation of the wireless device.","For example, WO2007/128340 discloses a wireless portable device comprising a non-resonant antenna element for receiving broadcast signals (such as, for instance, DVB-H, DMB, T-DMB or FM).","The wireless portable device further comprises a ground plane layer that is used in combination with said antenna element.","Although the antenna element has a first resonant frequency above the frequency range of operation of the wireless device, the antenna element is still the main responsible for the radiation process and for the radio-frequency performance of the wireless device.","This is clear from the fact that no radiation mode can be excited on the ground plane layer because the ground plane layer is electrically short at the frequencies of operation (i.e., its dimensions are much smaller than the wavelength).","For this kind of non-resonant antenna elements, a matching circuitry is added for matching the antenna to a level of SWR in a limited frequency range, which in this particular case can be around SWR<6.Such level of SWR together with the limited bandwidth results in antenna elements which are only acceptable for reception of electromagnetic wave signals but not desirable for transmission of electromagnetic wave signals.","With such limitations, while the performance of the wireless portable device may be sufficient for reception of electromagnetic wave signals (such as those of a broadcast service), the antenna element could not provide an acceptable performance (for example, in terms of reflection coefficient or gain) for a communication service requiring also the transmission of electromagnetic wave signals.","Commonly-owned patent applications WO2008/119699 and US2010/0109955 describe a wireless handheld or portable device comprising a radiating system capable of operating in two frequency regions.","The radiating system comprises an antenna element having a resonant frequency outside said two frequency regions, and a ground plane layer.","In this wireless device, while the ground plane layer contributes to enhance the electromagnetic performance of the radiating system in the two frequency regions of operation, it is still necessary to excite a radiation mode on the antenna element.","In fact, the radiating system relies on the relationship between a resonant frequency of the antenna element and a resonant frequency of the ground plane layer in order for the radiating system to operate properly in said two frequency regions.","Nevertheless, the solution still relies on an antenna element whose size is related to a resonant frequency that is outside of the two frequency regions.","The entire disclosures of the aforesaid application numbers WO2008/119699 and US2010/0109955 are hereby incorporated by reference.","A different radiating system is disclosed in U.S. Pat.","No.","6,674,411, in which a planar inverted-L antenna (i.e., a patch antenna) has a radiating element composed by a rectangular plate placed above and substantially parallel to a ground plane.","The antenna is connected to a matching network that provides a match in one frequency band in a first frequency region, and in one frequency band in a second frequency region.","Thus the antenna system is limited to single-band operation in both frequency regions.","When operation in more bands is sought, the antenna system requires of a switched (active) matching network that provides non-simultaneous impedance matching in each frequency band.","So in spite of having an antenna that occupies a large volume (20×10×8 mm3), not more than dual-band operation may be provided simultaneously.","For at least the above reasons, wireless device manufacturers regard the volume dedicated to the integration of the radiating structure, and in particular the antenna element, as being a toll to pay in order to provide wireless communication capabilities to the handheld or portable device.","In order to reduce as much as possible the volume occupied into the wireless handheld or portable device, recent trends in handset antenna design are oriented to maximize the contribution of the ground plane to the radiation process by using very small non-resonant elements.","However, non-resonant elements usually are forced to include a complex radio-frequency system.","Thus, the challenge of these techniques mainly relies on said complexity (combination of inductors, capacitors, and transmission lines), which is required to satisfy impedance bandwidth and efficiency specifications.","Commonly owned patent applications, WO2010/015365, and WO2010/015364 are intended for solving some of the aforementioned drawbacks.","Namely, they describe a wireless handheld or portable device comprising a radiating system including a radiating structure and a radio-frequency system.","The radiating structure is formed by a ground plane layer presenting suitable dimensions as for supporting at least one efficient radiation mode and at least one radiation booster capable of coupling electromagnetic energy to said ground plane layer.","The radiation booster is not resonant in any of the frequency regions of operation and, consequently, a radio-frequency system is used to properly match the radiating structure to the desired frequency bands of operation.","More particularly, in WO2010/015364 each radiation booster is intended for providing operation in a particular frequency region.","Thus, the radio-frequency system is designed in such a way that the first internal port associated to the first radiation booster is highly isolated from the second internal port associated to a second radiation booster.","Said radio-frequency system usually comprises a matching network including resonators for each one of the frequency regions of operation and a set of filters for each one of the frequency regions of operation.","Thus, said radio-frequency system requires multiple stages and the performance of the radiating systems in terms of efficiency may be affected by the additional losses of the components.","As each radiation booster is generally intended for providing operation in a particular frequency region, the bandwidth capabilities may be limited for some applications requiring very wide bandwidth specially at the low frequency region, as for example for wireless devices operating at LTE700, GSM850 and GSM900.Commonly owned patent applications WO2014/012796 and US2014/0015730 disclose a concentrated wireless device comprising a radiating system including a radiating structure and a radio-frequency system, such device operating two or more frequency regions of the electromagnetic spectrum.","A feature of said radiating system is that the operation in at least two frequency regions is achieved by one radiation booster, or by at least two radiation boosters, or by at least one radiation booster and at least one antenna element, wherein the radio-frequency system modifies the impedance of the radiating structure, providing impedance matching to the radiating system in the at least two frequency regions of operation of the radiating system.","The entire disclosure of aforesaid application numbers WO2014/012796 and US2014/0015730 are hereby incorporated by reference.","Commonly owned patent applications WO2014/012842 and US2014/0015728 disclose very compact, small size and light weight radiation boosters operating in single or in multiple frequency bands.","Such radiation boosters are configured to be used in radiating systems that may be embedded into a wireless handheld device.","Said patent applications further disclose radiation booster structures and their manufacturing methods that enable reducing the cost of both the booster and the entire wireless device embedding said booster inside the device.","The entire disclosure of aforesaid application numbers WO2014/012842 and US2014/0015728 are hereby incorporated by reference.","Another technique, as disclosed in U.S. Pat.","No.","7,274,340, is based on the use of two coupling elements.","According to the invention, quad-band operation (GSM 1800/1900 and GSM850/900 bands) is provided with two coupling elements: a low-band (LB) coupling element (for the GSM850/900 bands), and a high-band (HB) coupling element (for the GSM1800/1900 bands), where the impedance matching is provided through the addition of two matching circuits, one for the LB coupling element and another one for the HB coupling element.","In spite of using non-resonant elements, the size of the element for the low band is significantly large, being 1/9.3 times the free-space wavelength of the lowest frequency for the low frequency band.","Due to such size, the low band element would be a resonant element at the high band.","Additionally, the operation of this solution is closely linked to the alignment of the maximum E-field intensity of the ground plane and the coupling element.","The size of the low band element undesirably contributes to increase the printed circuit board (PCB) space required by the antenna module.","According to the invention, the bandwidth at the low frequency region is 133 MHz (from 821 MHz to 954 MHz) that is insufficient for some applications requiring very wide bandwidth, especially at the low frequency region, as for example for wireless devices operating at LTE700, GSM850 and GSM900.Therefore, a wireless device not requiring an antenna element and including a slim radiating system would be advantageous to make simpler the integration of the slim radiating structure into the wireless electronic device minimizing the amount of the electronic device that is allocated towards the slim radiating system, and to provide a suitable radio-frequency performance to operate in a wide range of communication bands.","The volume freed up by the absence of a large and complex antenna element would enable smaller and/or thinner devices, as slim electronic devices, or even to adopt radically new form factors which are not feasible today due to the presence of an antenna element featuring a considerable volume.","Furthermore, by eliminating precisely the element that requires customization, a standard solution is sought which should only require minor adjustments to be implemented in different wireless electronic devices.","SUMMARY It is an object of the present invention to provide an electronic device (such as for instance but not limited to a mobile phone, a smartphone, a phablet, a PDA, an MP3 player, a headset, a USB dongle, a laptop computer, a tablet, a gaming device, a GPS system, a digital camera, a wearable device as a smart watch, a PCMCIA, Cardbus 32 card, a sensor, or generally a multifunction wireless device which combines the functionality of multiple devices) containing a slim radiating system that covers a wide range of radio-frequencies and handles multiple communication bands while exhibiting a suitable radio-frequency performance.","It is another object of the invention to provide a slim radiating system suitable for being included within electronic devices, and more preferably within slim electronic devices.","It is another object of the invention to provide a standard slim radiating system which only requires minor adjustments to be included within different electronic devices.","Another object of the invention refers to the location (on the device) of radiation boosters and, more particularly, booster bars for obtaining the most favorable frequency bandwidth values.","An electronic device according to the invention may have a candy-bar shape, which means that its configuration is given by a single body.","It may also have a two-body configuration such as a clamshell, flip-type, swivel-type or slider structure.","In some other cases, the device may have a configuration comprising three or more bodies.","It may further or additionally have a twist configuration in which a body portion (e.g.","with a screen) can be twisted (i.e., rotated around two or more axes of rotation which are preferably not parallel).","The electronic device may comprise a memory module, a processing circuitry module, a user interface module, a battery, and a wireless communication module.","The wireless communication module may include a slim radiating system, a radio-frequency transceiver circuit, a power amplifier circuit and a base-band module.","The slim radiating system may be coupled to the power amplifier via a conductive path and to the radio transceiver circuit via a conductive path.","The wireless communication module may include a multiplexing stage coupled to the slim radiating system via a conductive path.","A slim radiating system in accordance with the invention may include a slim radiating structure, a radio-frequency system, at least one internal conductive path and at least one external conductive path.","The slim radiating structure may include a ground element and at least one radiation booster, which in some embodiments may be a booster bar, separated from the ground element by a gap.","A slim radiating structure may comprise a ground element and one, two, three, four or even more radiation boosters.","In some preferred embodiments, said radiation boosters may be booster bars featuring an elongated shape.","In preferred embodiments, each booster bar or radiation booster is separated from the ground element by a gap.","An aspect of the present invention relates to the use of the ground element (or ground plane layer) of the slim radiating system as a main source of radiation.","A radiation booster includes a dielectric material and in some embodiments, a single standard layer of dielectric material spacing two or more conductive elements.","A single standard layer of dielectric material refers to dielectric material with a standard thickness, which is available off-the-shelf.","For example, 0.025″ (0.635 mm), 0.047″ (1.2 mm), 0.093″ (2.36 mm) or 0.125″ (3.175 mm) are common/standard thicknesses for dielectric materials which are available in the market.","Examples of dielectric materials may include fiber-glass FR4, Cuclad, Alumina, Kapton, Ceramic and for instance commercial laminates and substrates from Rogers® Corporation (R03000® and R04000® laminates, Duroid substrates and alike) or other suitable non-conductive materials.","The radiation booster may be formed by printing or depositing conductive material in a first and a second surface of the dielectric material (e.g.","top and bottom) and adding several vias to electrically connect the conductive material in the first surface with the conductive material in the second surface.","The conductive material in the first and second surfaces may have a substantially polygonal shape.","Some possible polygonal shapes are for instance, but not limited to, squares, rectangles, and trapezoids.","When the conductive material in said first and second surfaces has an elongated shape, for instance a rectangular shape, the radiation booster takes the form of a booster bar; a booster bar may also include vias that electrically connect the conductive material in the first surface with the conductive material in the second surface.","The elongated shape of a booster bar is characterized by two slim form factors: a slim width factor and a slim height factor.","The slim width factor is a ratio between a length of the booster bar and a width of the booster bar.","The slim height factor is a ratio between the length of the booster bar and a height of the booster bar.","The slim width factor characterizes the ratio between the length and the width of the booster bar, whereas the slim height factor characterizes the ratio between the length and the height of the booster bar.","In a preferred embodiment, the value for the slim width factor and the slim height factor is greater than 2, for instance in one or more of those embodiments the value for the slim width factor is greater than 3, and preferably larger than 3.5, and the slim height factor is greater than 4.In another preferred embodiment, the value for the slim width factor is greater than 6 and/or the slim height factor is greater than 6.In another preferred embodiment, the value for the slim width factor is greater than 6 and/or the slim height factor is larger than 9.In some less preferred embodiments, the values for both the slim width factor and the slim height factor are between 1 and 2.The slim width factor and the slim height factor of a booster bar may take any of the values listed above yet being smaller than 25, and preferably smaller than 10.A radiation booster may comprise one, two or more booster bars electrically connected, forming a booster element that fits in an imaginary sphere having a diameter smaller than ⅓ of a radiansphere corresponding to the lowest frequency of operation of the slim radiating system.","Such a booster element may also be characterized by a slim width factor, a slim height factor, and a location factor.","Any booster element according to the present invention may be limited by a slim width factor and a slim height factor, each of these factors being between 1 and 10, and preferably between 2 and 10.An advantageous aspect of the invention refers to a booster bar built on a single standard layer of dielectric material that is manufactured at a competitive cost.","Another advantageous aspect of the invention refers to a booster bar having a slim width factor and/or slim height factor that enables the booster bar to occupy only a small portion within the electronic wireless device and making it suitable for its integration within slim electronic devices or flexible electronic devices.","Another advantageous aspect of the present invention refers to the location and slim form factors of a booster bar to guarantee the most advantageous frequency bandwidth for the available space.","A radiation booster, like for instance a booster bar, is separated from the ground plane layer by a gap.","In the context of this document, the gap refers to a minimum distance between a point at an edge of the ground plane layer and a point at an edge of the bottom conductive surface of the radiation booster.","The location of the radiation booster is characterized by a location factor that is a ratio between the width of the radiation booster and the gap.","In a preferred example, the location factor is between 0.5 and 2.In another preferred example, the location factor is between 0.3 and 1.8.Each radiation booster of the slim radiating system advantageously couples the electromagnetic energy from the radio-frequency system to the ground element in transmission, and from the ground element to the radio-frequency system in reception.","The radiation boosters excite a radiation mode in the ground element enabling the radiation from the ground element.","The form factor of the radiation booster, together with its location in relation to the ground element, is configured to achieve a proper excitation of the radiation mode of the ground element.","The location factor is selected to achieve the most favorable frequency bandwidth for a radiation booster with a certain form factor, particularly a booster bar.","Apart from the form factor of the radiation booster, the gap is also relevant for properly exciting a radiation mode in the ground plane layer and to achieve the most advantageous frequency bandwidth.","The bandwidth of the slim radiating system may be degraded if the location factor is not properly selected.","The location factor and the slim form factors of a booster bar are selected to ensure the most favorable frequency bandwidth while minimizing/reducing the amount of space allocated towards the integration of the booster bar within the electronic device.","The slim radiating structure is mounted within the electronic device and is coupled to the radio-frequency system via a conductive path.","The radiation booster is coupled to the ground element via a conductive path and is located at certain distance from the ground element.","Said conductive path comprises a conductive element which may be linear or include a surface; the conductive element may comprise, for instance but not limited to, a metallic strip and/or a conductive trace.","In some embodiments, a slim radiating structure comprises one ground element or conductive material acting as a ground plane for the slim radiating structure.","In some other embodiments, a slim radiating structure may comprise two, three or more ground elements or conductive materials acting as a ground plane for the radiating structure.","In such embodiments, the plurality of ground elements may be electrically interconnected one to each other.","The at least one radiation booster for a slim radiating structure according to the present invention may have a maximum size at least smaller than 1/15 of the free-space wavelength corresponding to the lowest frequency of the first frequency region of operation.","In some cases, said maximum size may be also smaller than 1/20, and/or 1/25, and/or 1/30, and/or 1/50, and/or 1/100 of the free-space wavelength corresponding to the lowest frequency of the first frequency region of operation.","In some cases, the at least one radiation booster fits in an imaginary sphere having a diameter smaller than ⅓, or preferably smaller than ¼, or preferably smaller than ⅙, or even more preferably smaller than 1/10 of a radiansphere at said free-space wavelength.","The radiansphere is defined as an imaginary sphere having a radius equal to the operating wavelength divided by two times π (pi).","Furthermore, in some examples, the at least one radiation booster also has a maximum size smaller than 1/15, and/or 1/20, and/or 1/25, and/or 1/30, and/or 1/50 of the free-space wavelength corresponding to the lowest frequency of the second frequency region of operation.","In some cases, the at least one radiation booster fits in an imaginary sphere having a diameter smaller than ⅓, or preferably smaller than ¼, or preferably smaller than ⅙, or even more preferably smaller than 1/10 of a radiansphere at said free-space wavelength.","Additionally, in some of these examples the at least one radiation booster has a maximum size larger than 1/1400, 1/700, 1/350, 1/250, 1/180, 1/140, or 1/120 times the free-space wavelength corresponding to the lowest frequency of said first frequency region.","The maximum size of a radiation booster is preferably defined by the largest dimension of a booster box that completely encloses said radiation booster, and in which the radiation booster is inscribed.","More specifically, a booster box for a radiation booster is defined as being the minimum-sized parallelepiped of square or rectangular faces that completely encloses the radiation booster and wherein each one of the faces of said minimum-sized parallelepiped is tangent to at least a point of said radiation booster.","Moreover, each possible pair of faces of said minimum-size parallelepiped sharing an edge forms an inner angle of 90°.","In those cases in which the radiating structure comprises more than one radiation booster, a different booster box is defined for each of them.","In some preferred examples, the area defined by the two largest dimensions of a booster box is advantageously small compared to the square of the wavelength corresponding to the lowest frequency of the first frequency region; in particular, a ratio between said area and the square of the wavelength corresponding to the lowest frequency of the first frequency region may be advantageously smaller than at least one of the following percentages: 0.15%, 0.12%, 0.10%, 0.08%, 0.06%, 0.04%, or even 0.02%.","In some of these examples, a ratio between the area defined by the two largest dimensions of a booster box and the square of the wavelength corresponding to the lowest frequency of the second frequency region may also be advantageously smaller than at least one of the following percentages: 0.50%, 0.45%, 0.40%, 0.35%, 0.30%, 0.25%, 0.20%, 0.15%, 0.10%, or even 0.05%.","Moreover, in some embodiments according to the present invention, the at least one radiation booster will entirely fit inside a limiting volume equal or smaller than L3/25000, and in some cases equal or smaller than L3/50000, L3/100000, L3/150000, L3/200000, L3/300000, L3/400000, or even smaller than L3/500000, being L the wavelength corresponding to the lowest frequency of the first frequency region of operation.","A slim radiating system according to the invention is configured to handle multiple communication bands, and to provide coverage and an acceptable level of reflection coefficient in a wide range of communication bands in one or more frequency regions of operation exhibiting a suitable radio-frequency performance.","The slim radiating system is designed to transmit and receive radio-frequency signals in multiple communication bands of interest, including frequency bands that may be added, for instance, through the deployment of future cellular telephone bands and/or data service bands.","In the context of this document, a frequency band preferably refers to a range of frequencies used by a particular cellular communication standard, a wireless connectivity standard or a broadcast standard, while a frequency region preferably refers to a continuum of frequencies of the electromagnetic spectrum.","For example, the GSM 1800 standard is allocated in a frequency band from 1710 MHz to 1880 MHz while the GSM 1900 standard is allocated in a frequency band from 1850 MHz to 1990 MHz.","A device operating the GSM 1800 and the GSM1900 standards must have a radiating system capable of operating in a frequency region from 1710 MHz to 1990 MHz.","As another example, a wireless device operating the GSM 850 standard (allocated in a frequency band from 824 MHz to 894 MHz) and the GSM 1800 standard must have a radiating system capable of operating in two separate frequency regions.","Some frequency bands that the slim radiating system may be configured to transmit and receive signals in are, for example, GSM 850 (824-894 MHz), GSM 900 (880-960 MHz), GSM 1800 (1710-1880 MHz), GSM 1900 (1850-1990 MHz), WCDMA 2100 (1920-2170 MHz), CDMA 1700 (1710-2155 MHz), LTE 700 (698-798 MHz), LTE 800 (791-862 MHz), LTE 2600 (2500-2690 MHz), LTE 3500 (3.4-3.6 GHz), LTE 3700 (3.6-3.8 GHz), WiFi or WLAN (2.4-2.5 GHz and/or 4.9-5.9 GHz), etc.","A wireless handheld or portable device according to the present invention may operate one, two, three, four or more cellular communication standards, wireless connectivity standards, and/or broadcasts standards, each standard being allocated in one, two or more frequency bands, and said frequency bands being contained within one, two or more frequency regions of the electromagnetic spectrum.","The slim radiating system is designed to provide an acceptable level of reflection coefficient in the frequency regions of operation.","A slim radiating system according to the present invention is configured to operate in at least one frequency region.","In some embodiments, the slim radiating system is configured to operate in a first frequency region comprising at least a first frequency band, and a second frequency region comprising at least a second frequency band.","Such radiating system is configured to satisfy the radio-frequency bandwidths and frequency coverage goals.","A slim radiating system according to the present invention may advantageously feature an impedance bandwidth in the first frequency region larger than 5%, 10%, 15%, or even larger than 20%.","In addition, such radiating system may also feature an impedance bandwidth in the second frequency region larger than 5%, 10%, 15%, 20%, 25%, 30%, 35%, or even larger than 40%.","The impedance bandwidth is defined as the difference between the highest and lowest frequencies of a frequency region, divided by the central frequency of the same frequency region.","Due to the small size of the radiation boosters, the radiation boosters and booster bars may be electrically short at some or all frequencies of operation.","A slim radiating structure according to the present invention may feature a first resonant frequency, measured at an internal path, at a frequency higher (i.e.","above) than the highest frequency of the first frequency region of operation when said radio-frequency system is disconnected.","Moreover, when the radio-frequency system is disconnected, the input impedance of the slim radiating structure measured at the internal path may have an important reactance, in particular a capacitive reactance, within the frequencies of said first frequency region.","In this case, a ratio between the first resonant frequency of the slim radiating structure and the highest frequency of the first frequency region is advantageously greater than 1.2.In some cases, said ratio may be even greater than one or more of the following values: 1.5, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, or 3.0.In some examples, a ratio between said first resonant frequency and the lowest frequency of the first frequency region of operation is advantageously greater than 1.3, or even greater than one or more of the following values: 1.4, 1.5, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, or 3.0.In some embodiments, the first resonant frequency of the slim radiating structure, measured at an internal path when the radio-frequency system is disconnected, is above the highest frequency of the second frequency region, wherein a ratio between said first resonant frequency and said highest frequency of the second frequency region may be larger than one or more of the following values: 1.0, 1.1, 1.2, 1.4, 1.6, 1.8, or 2.0.In some other embodiments, said first resonant frequency is within the second frequency region.","In some other examples, said first resonant frequency is above the highest frequency of the first frequency region and below the lowest frequency of the second frequency region.","In the context of this document, a resonant frequency associated to a radiation booster of the slim radiating structure preferably refers to a frequency at which the input impedance of the slim radiating structure, the impedance being measured at the internal path coupling the radiation booster to the radio-frequency system when the radio-frequency system is not connected, has an imaginary part equal or substantially equal to zero.","The radio-frequency system may comprise one or more matching circuits that modify the impedance of the slim radiating structure providing impedance matching to the slim radiating system, at an external path, in one or more frequency regions of operation of the slim radiating system.","A radio-frequency system according to the invention may include at least one matching network with a plurality of stages, for instance, two, three, four, five, six or more stages.","A stage comprises one or more circuit components (for example but not limited to, inductors, capacitors, resistors, jumpers, short-circuits, delay lines, or other reactive or resistive components).","In some cases, a stage has a substantially inductive behavior in the frequency region or regions of operation of the slim radiating system, while another stage has a substantially capacitive behavior in said frequency region/s, and yet a third one may have a substantially resistive behavior in said frequency region/s.","In an example, a stage may substantially behave as a resonant circuit (such as, for instance, a parallel LC resonant circuit or a series LC resonant circuit) in at least one frequency region of operation of the slim radiating system.","The use of stages having a resonant circuit behavior allows one part of a given matching network be effectively connected to another part of said matching network for a given range of frequencies, or in a given frequency region, and be effectively disabled for another range of frequencies, or in another frequency region.","In some examples, the at least one matching network alternates stages connected in series (i.e.","cascaded) with stages connected in parallel (i.e.","shunted), forming a ladder structure.","In some cases, a matching network comprising two stages forms an L-shaped structure (i.e.","series-parallel or parallel-series).","In some cases, a matching network comprising three stages forms either a pi-shaped structure (i.e.","parallel-series-parallel) or a T-shaped structure (i.e.","series-parallel-series).","In some embodiments, a radio-frequency system according to the present invention comprises a matching circuit in a ladder topology.","Such matching circuit preferably comprises one reactive component per stage.","In some other embodiments, a radio-frequency system according to the present invention comprises a matching circuit at least including a series LC resonant circuit and a parallel LC resonant circuit.","In a preferred embodiment, an electronic device comprises a slim radiating system configured to transmit and receive electromagnetic wave signals in at least one frequency region of the electromagnetic spectrum, and comprising a slim radiating structure, a radio-frequency system, at least one internal conductive path and at least one external conductive path.","The slim radiating structure comprises at least one ground element and at least one booster bar.","The at least one internal conductive path comprises a conductive element that couples the at least one booster bar to the radio-frequency system.","The radio-frequency system comprises at least one matching circuit modifying the impedance of the slim radiating structure providing impedance matching to the slim radiating system in the at least one frequency region at the at least one external conductive path.","The at least one booster bar has an elongated shape, and is characterized by a slim width factor greater than 3 and a slim height factor greater than 3, is separated from the at least one ground element by a gap and is characterized by a location factor between 0.5 and 2.Another preferred embodiment relates to an electronic device including a slim radiating system that comprises a slim radiating structure, a radio-frequency system, an internal conductive path and at least one external conductive path; the slim radiating system is configured to transmit and receive electromagnetic wave signals in a first frequency region and a second frequency region.","The slim radiating structure comprises at least one ground element, and one booster bar separated from the ground element by a gap and is characterized by a location factor between 0.3 and 1.8.The internal conductive path comprises a conductive element that couples the booster bar to the radio-frequency system.","The radio-frequency system comprises a matching circuit that modifies the impedance of the slim radiating structure providing impedance matching to the slim radiating system in the first and second frequency regions at the at least one external conductive path.","The first and second frequency regions are preferably separated so that the lowest frequency of the second frequency region is above the highest frequency of the first frequency region.","Some preferred matching circuits for such preferred embodiment are described in FIGS.","15A-15F.","Further, an advantageous aspect of the invention refers to a radio-frequency system comprising a matching circuit that provides impedance matching to the slim radiating system in first and second frequency regions preferably not requiring a filtering circuit or component that separates frequencies of the first frequency region from frequencies of the second frequency region (e.g.","a diplexer, a bank of filters, etc.)","for providing impedance matching in the first frequency region and second frequency region independently (i.e.","in two separate branches or paths).","Thus preferred matching circuits may provide impedance matching in said first and second frequency regions with one branch.","According to the present invention, some preferred matching circuits preferably comprise seven or less components, for instance: two, three, four, five, six or seven.","Such matching circuits preferably do not comprise active circuits or components.","In some embodiments in which the slim radiating system is configured to transmit and receive signals in a first frequency region and a second frequency region, a ratio between the lowest frequency of the second frequency region and the lowest frequency of the first frequency region may be greater than 1.5.In some of these embodiments, said ratio may be also greater than 1.8, 2.0, 2.2, or 2.4.In addition, in some embodiments in which the slim radiating system is configured to operate signals from first and second frequency regions, a ratio between the lowest frequency of the second frequency and the highest frequency of the first frequency region may be greater than 1.2, 1.5, 1.8, 2.0, 2.2, or 2.4.Accordingly, an advantageous aspect of such radio-frequency system is its efficiency in that impedance matching in the first and second frequency regions may be provided with one matching circuit using a reduced number of components, which consequently introduces lower losses in the radio-frequency system and makes it more robust against the tolerances of the components.","Moreover, by not including filtering circuits such as diplexers, the radio-frequency system avoids the insertion losses characterizing such type of circuits and the necessity of having two separate matching circuits, which consequently makes the radio-frequency system have less components and the slim radiating system smaller in terms of area occupied in the device.","In a third preferred embodiment, an electronic device includes a slim radiating system comprising a slim radiating structure, a radio-frequency system, first and second internal conductive paths and at least one external conductive path; the slim radiating system is configured to transmit and receive electromagnetic wave signals in a first frequency region and a second frequency region.","The slim radiating structure comprises at least one ground plane layer, first and second radiation boosters, each of the first and second radiation boosters being separated from the ground plane layer by a gap.","The first internal conductive path comprises a conductive element that couples the first radiation booster to the radio-frequency system, and the second internal conductive path comprises a conductive element that couples the second radiation booster to the radio-frequency system.","The radio-frequency system comprises a matching circuit coupled to the first and second internal conductive paths and to the external conductive path, the matching circuit modifies the impedance of the slim radiating structure providing impedance matching to the slim radiating system in the first and second frequency regions.","In some cases, the slim radiating system may comprise a first external conductive path and a second external conductive path, and the radio-frequency system may include a diplexer circuitry that advantageously filters signals from first and second frequency regions, said signals being matched in impedance in the first and second frequency regions by the matching circuit within the radio-frequency system.","A first port of the diplexer is connected to the matching circuit, and the two remaining ports of the diplexer are connected to the first and second external conductive paths.","The first and second external paths comprise, respectively, signals for frequencies from the first frequency region, and signals for frequencies from the second frequency region.","A further aspect of the present invention relates to a test platform for electromagnetically characterizing radiation boosters.","Said platform comprises a substantially square conductive surface on top of which, and substantially close to the central point, the element to be characterized is mounted perpendicular to said surface in a monopole configuration, said conductive surface acting as the ground plane.","The substantially square conductive surface comprises sides with a dimension larger than a reference operating wavelength.","In the context of the present invention, said reference operating wavelength is the free-space wavelength equivalent to a frequency of 900 MHz.","A substantially square conductive surface according to the present invention is made of copper with sides measuring 60 centimeters, and a thickness of 0.5 millimeters.","In the test configuration as set forth above, a booster bar according to the present invention may be characterized by a ratio between the first resonance frequency and the reference frequency (900 MHz) being larger than a minimum ratio of 3.0.In some cases, said ratio may be even larger than a minimum ratio such as: 3.4, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.6 or 7.0.A booster bar according to the present invention may also be characterized by a radiation efficiency measured in said platform, at a frequency equal to 900 MHz, being less than 50%, preferably being less than 40%, 30%, 20%, or 10%, and in some cases being less than 7.5%, 5%, or 2.5%.","All those are quite remarkably low efficiency values considering the additional 1:3 frequency mismatch and beyond obtained in some of the embodiments as described above.","Such a frequency shift would introduce further mismatch losses that would result in an overall antenna efficiency below 5%, and quite typically below 2%, which would be ordinarily considered unacceptable for a mobile phone or wireless application.","Still, quite surprisingly, when combining at least one booster bar with the radio-frequency system of a slim radiating system according to the present invention, said slim radiating system recovers the efficiency required for the performance of a typical wireless device.","BRIEF DESCRIPTION OF THE DRAWINGS Embodiments of the invention are shown in the enclosed figures.","FIGS.","1A-1B—Show examples of wireless handheld devices including slim radiating systems according to preferred embodiments of the invention.","FIGS.","2A-2D—Block diagram representations of five examples of slim radiating systems in according with some preferred embodiments of the present invention.","FIG.","3—Shows a perspective view of an example of a slim radiating structure including a booster bar in accordance with the present invention.","FIGS.","4A-4B—Graphs showing bandwidth performances of several slim radiating systems as a function of the booster bar's width and gap dimensions.","FIG.","5—Graph showing bandwidth performances of a slim radiating system as a function of the booster bar's width and gap dimensions for three different depth values.","FIG.","6—Graph showing an example of an acceptable radio-electric frequency behavior for a slim radiating system in accordance with the present invention.","FIG.","7—Shows a perspective view of an example of slim radiating structure including four booster bars in accordance with a preferred embodiment.","FIG.","8—Plan view of an exemplary radio-frequency system coupled to a slim radiating structure in accordance with the present invention.","FIG.","9—Graph showing the radio-electric frequency behavior of a slim radiating system including the slim radiating structure of FIG.","7 and the radio-frequency system of FIG.","8.FIG.","10—Perspective view of an exemplary slim radiating structure including three booster bars in accordance with a preferred embodiment.","FIG.","11—Plan view of an example of a radio-frequency system coupled to a slim radiating structure in accordance with the present invention.","FIG.","12—Graph showing the radio-electric frequency behavior of a slim radiating system including the slim radiating structure of FIG.","10 and the radio-frequency system of FIG.","11.FIG.","13—Shows another exemplary slim radiating structure according to the invention.","FIGS.","14A-14B—Show schematic representations of radio-frequency systems in accordance with a preferred embodiment.","FIGS.","15A-15F—Show six preferred matching circuits for some embodiments of the present invention.","FIGS.","16A-16F—Show the impedance transformation of an exemplary slim radiating system as the different stages of a matching circuit in the radio-frequency system are added.","FIG.","17—Shows the reflection coefficient of exemplary slim radiating system of FIG.","16F.","FIG.","18A-18B—Show the impedance and the reflection coefficient of an exemplary slim radiating system comprising a radio-frequency system according to the invention.","FIG.","19—Shows an exemplary radiation booster according to the invention.","FIG.","20—Shows a slim radiating structure and an internal path in the form of a conductive trace in accordance with a preferred embodiment.","FIG.","21A-21B—Show a test platform for the electromagnetic characterization of radiation boosters.","FIG.","22—Shows the radiation efficiency and antenna efficiency of a radiation booster according to the present invention measured with the test platform depicted in FIGS.","21A and 21B.","DETAILED DESCRIPTION Further characteristics and advantages of the invention will become apparent in view of the detailed description of some preferred embodiments which follows.","Said detailed description of some preferred embodiments of the invention is given for purposes of illustration only and in no way is meant as a definition of the limits of the invention, made with reference to the accompanying figures.","Illustrative wireless electronic devices including a slim radiating system in accordance with the present invention are shown in FIGS.","1A and 1B.","In the particular arrangement of FIG.","1A, the wireless electronic device 100 is a smartphone although it might represent other wireless electronic devices such as for instance a phablet or a tablet.","The slim radiating system includes a first booster bar 101, a second booster bar 102, a booster element 110, and a ground element 105 (which may be included in a layer of a multilayer printed circuit board).","The booster element 110 comprises two contiguous booster bars: the third booster bar 103 and the fourth booster bar 104.The first booster bar 101 is coupled to a radio-frequency system 109 via a conductive path 106, the second booster bar 102 is coupled to the radio-frequency system 109 via a conductive path 107, and the booster element 110 is coupled to the radio-frequency system 109 via a conductive path 108.In FIG.","1B there is shown a wireless handheld device 150 in an exploded perspective view, the device comprises a slim radiating structure and a radio-frequency system 153.The slim radiating structure comprises a radiation booster 151 taking the form of a booster bar with an elongated shape, and a ground plane layer 152.The booster bar 151 is coupled to the radio-frequency system via the internal conductive path 154 which, in this particular example, may be a conductive trace.","In the examples of FIGS.","1A and 1B, the booster bars are arranged on a part of the device free of ground plane, so there is no ground plane in the orthogonal projection of the booster bars onto the plane comprising the ground plane layers 105 and 152, respectively.","In other embodiments, the orthogonal projection of a booster bar or other radiation booster onto the plane comprising the ground plane layer may be overlapped partially or completely by the ground plane layer.","FIG.","2A shows a block diagram representation of a slim radiating system for an electronic device.","The slim radiating system 201a comprises slim radiating structure 202a, radio-frequency system 203a, internal conductive path 204a, and external conductive path 205a.","The slim radiating structure is coupled to the radio-frequency system via the internal path 204a, and to other RF circuitry for handling RF wave signals via the external path 205a.","A slim radiating system in accordance with this block diagram is configured to operate in at least one frequency region, or in at least two frequency regions, or in at least three frequency regions.","FIG.","2B shows another block diagram of a slim radiating system for an electronic device according to the present invention.","The slim radiating system 201b comprises slim radiating structure 202b, radio-frequency system 203b, two internal conductive paths 204b and 205b, and two external conductive paths 206b and 207b.","The slim radiating structure is coupled to the radio-frequency system via the internal paths 204b and 205b, and to other RF circuitry for handling RF wave signals via the external paths 206b and 207b.","A slim radiating system in accordance with this block diagram is configured to operate in at least two frequency regions, or in at least three frequency regions.","FIG.","2C shows another block diagram of a slim radiating system for an electronic device according to the present invention.","The slim radiating system 201c comprises slim radiating structure 202c, radio-frequency system 203c, three internal conductive paths 204c, 205c and 206c, and three external conductive paths 207c, 208c, and 209c.","The slim radiating structure is coupled to the radio-frequency system via the internal conductive paths 204c, 205c and 206c, and to other RF circuitry for handling RF wave signals via the external conductive paths 207c, 208c and 209c.","A slim radiating system in accordance with this block diagram is configured to operate in at least three frequency regions.","FIG.","2D shows another block diagram of a slim radiating system for an electronic device according to the present invention.","The slim radiating system 201d is similar to 201a from FIG.","2A.","It comprises slim radiating structure 202a, radio-frequency system 203d, internal conductive path 204a, and two external conductive paths 205d and 206d.","The slim radiating structure is coupled to the radio-frequency system via the internal paths 204a, and to other RF circuitry for handling RF wave signals via the external paths 205d and 206d.","The radio-frequency system 203d may comprise a matching circuit configured to provide impedance matching in at least two frequency regions, and a diplexer may be connected to said matching circuit and coupled to the external paths.","A slim radiating system in accordance with this block diagram is configured to operate in at least two frequency regions.","The radio-frequency system 203d is convenient for the interconnection with an RF (radio-frequency) front-end module or RF circuitry that includes separate inputs for signals from the first frequency region and the second frequency region.","If such RF front-end module (not illustrated) had one input/output for all the signals, the radio-frequency system 203a from FIG.","2A would be more suitable.","FIG.","3 illustrates a preferred example of a slim radiating structure 301 according to the present invention.","The slim radiating structure comprises a booster bar 303 and a ground plane layer 302, the booster bar comprises a single standard layer of dielectric material 306 with a top 304 and a bottom 305 conductive surfaces.","The booster bar has a length 310, a width 311 and a height 312.The length of the booster bar is taken along the dimension that is substantially parallel to the ground plane layer in the top or bottom conductive surface, the width is taken along the dimension that is substantially perpendicular to the ground plane layer in the top or bottom conductive surface, and the height is taken as the minimum distance between the top conductive surface and the bottom conductive surface.","In some embodiments the booster bar comprises pads on a first and a second surface so that the mounting of the booster can be reversed and top and bottom sides can be interchanged.","The size and shape of the booster bar is characterized by a slim width factor and a slim height form factor.","The slim width factor is a ratio between the length and the width of the booster bar, and the slim height factor is a ratio between the length and height of the booster bar, being the slim width factor and the slim height factor preferably larger than 3.In this example, where the booster is configured to operate in one or more frequency bands within the 600 MHz-6 GHz range (e.g.","GSM 850 (824-894 MHz), GSM 900 (880-960 MHz), GSM 1800 (1710-1880 MHz), GSM 1900 (1850-1990 MHz), WCDMA 2100 (1920-2170 MHz), CDMA 1700 (1710-2155 MHz), LTE 700 (698-798 MHz), LTE 800 (791-862 MHz), LTE 2600 (2500-2690 MHz), LTE 3500 (3.4-3.6 GHz), LTE 3700 (3.6-3.8 GHz), WiFi (2.4-2.5 GHz and/or 4.9-5.9 GHz)), the length is 10 millimeters, the width is 3.2 millimeters and the height is 3.2 millimeters, being the slim width factor 3.125 and the slim height factor 3.125, all those dimensions in these and other embodiments, within a typical tolerance of, for instance +/−1%-3% and in some occasions up to a 10% variation.","The booster bar is separated from the ground plane by a gap 313; the gap is taken as the minimum distance between the bottom conductive layer and the ground plane layer.","The gap distance plus the booster bar's width 311 is characterized as the depth of the radiation booster.","The location of the booster bar in relation to the ground plane layer is characterized by a location factor.","The location factor is a ratio between the width of the booster bar and the gap, being the location factor preferably in the range of between 0.5 and 2.In this example, the width is 3.2 mm and the gap is 3.3 mm, being the location factor 0.96 and the depth 6.5 mm, all those dimensions within a typical tolerance of, for instance +/−10% variation.","FIG.","4A and FIG.","4B illustrate two examples of the relevance of the location and width of the booster bar in the radio-frequency performance of the slim radiating system; the radio-frequency performance of the slim radiating system is affected by the location of the booster bar with respect to the ground plane layer and the width of the booster bar.","FIG.","4A and FIG.","4B plot the potential bandwidths achieved by six slim radiating systems as a function of the booster bar's width and gap dimensions.","Curve 401 represents the potential bandwidth of a slim radiating system comprising a booster bar characterized by a height of 2.4 mm and a length of 11.5 mm.","Curve 402 represents the potential bandwidth of a slim radiating system that includes a booster bar having a height of 3.2 mm and a length of 9 mm.","Curve 403 represents the potential bandwidth of a slim radiating system comprising a booster bar characterized by a height of 2.4 mm and a length of 10.5 mm.","Curve 404 represents the potential bandwidth of a slim radiating system comprising a booster bar characterized by a height of 3.2 mm and a length of 7 mm.","Curve 405 represents the potential bandwidth of a slim radiating system comprising a booster bar characterized by a height of 2.4 mm and a length of 9 mm.","Curve 406 represents the potential bandwidth of a slim radiating system comprising a booster bar characterized by a height of 2.4 mm and a length of 7 mm.","As shown in FIG.","4A and FIG.","4B, the potential bandwidth of the slim radiating system depends on the width dimension of the booster bar and the location of the booster bar in relation to the ground plane layer; for each of the curves, there is a region where the most favorable bandwidth values are achieved.","In this invention, such region is referred as the effective bandwidth region which corresponds to a range of location factor values that provide the region of most advantageous bandwidth values for the slim radiating system.","The preferred values for the location factor are in the range of between 0.5 and 2.Such result is against conventional wisdom as the wider the width of the antenna element, the greater the bandwidth as, for example, in a monopole antenna.","FIG.","5 illustrates another example of the effect of the booster bar's location and width on the radio-frequency performance of a slim radiating system; the radio-frequency performance of the slim radiating system is affected by the location of the booster bar with respect to the ground plane layer and the width of the booster bar.","FIG.","5 plots the potential bandwidth achieved by the slim radiating system as a function of the booster bar's width and gap dimensions; the three curves 501, 502 and 503 represent the potential bandwidth of a slim radiating system comprising a booster bar having a height of 3.2 mm and a length of 7 mm.","Curve 501 refers to the booster bar having a depth of 7.5 mm, curve 502 corresponds to a depth of 7 mm and curve 503 is for a depth of 6.5 mm.","As previously shown in FIGS.","4A and 4B, the potential bandwidth of the slim radiating system depends on the gap that separates the booster bar from the ground plane layer and the width of the booster bar; for each of the curves, there is an effective bandwidth region where the most advantageous bandwidth values are achieved.","One way to characterize the radio-frequency performance of the slim radiating system entails the use of a reflection coefficient plot; a reflection coefficient of less than −4.4 dB is generally acceptable.","FIG.","6 illustrates an example of an acceptable radio-frequency performance for a slim radiating system according to the present invention.","The slim radiating system comprises a booster bar which is characterized by a width form factor of 3.125, a height form factor of 3.125 and a location factor of 0.96.Curve 601 shows the reflection coefficient of the slim radiating system versus frequency, and line 602 shows an acceptable reference level for the reflection coefficient.","In this example, the reflection coefficient is less than −4.4 dB for all the frequencies of the operating frequency region which covers a frequency range of about 824 MHz to about 960 MHz.","Such frequency range enables the slim radiating system to be used to cover at least two communication frequency bands such as a band from 824 MHz to 894 MHz and a band from 880 MHz to 960 MHz.","These two bands are examples of bands that can be covered by a slim radiating system; other bands may also be handled by the slim radiating system.","In another embodiment, a suitable radio-frequency performance for the slim radiating system corresponds to a reflection coefficient of −6 dB or less for all the frequencies of the operating frequency range.","FIG.","7 illustrates a preferred example of a slim radiating structure according to the present invention suitable for a slim radiating system configured to operate in three frequency regions.","The slim radiating structure 701 comprises a first booster bar 702, a second booster bar 703, a booster element 704 comprising two adjacent booster bars 705 and 706, and a ground plane layer 707.As shown in FIG.","3, each booster bar comprises a single standard layer of dielectric material with top and bottom conductive surfaces; in this example the dielectric material has a height of 3.2 mm.","In this example, the first and second booster bars 702, 703 have a slim width factor of 3.125, a slim height factor of 3.125, and a location factor of 0.96; the booster element 704 has a slim width factor of 6.25, a slim height factor of 6.25 and a location factor of 0.96.In general, any suitable shape may be used for the ground plane layer.","FIG.","7 illustrates an example of a slim radiating structure according to the present invention suitable for a slim radiating system configured to operate in three frequency regions.","The ground plane layer 707 includes clearance regions that may be used to mount other components of the electronic wireless device, or to adjust the ground plane layer to the shape of the electronic wireless device housing or for SAR purposes.","The ground plane rectangle 708 (represented with dashed lines for illustrative purposes only) is characterized as the minimum sized rectangle that encompasses the ground plane layer 707.That is, the ground plane rectangle is a rectangle whose sides are tangent to at least one point the ground plane layer.","In accordance with the present invention, a first long side of the ground plane layer refers to a long side of the ground plane rectangle 709 or 710; a second long side of the ground plane layer refers to a second long side of the ground plane rectangle 710 or 709; a first short side of the ground plane layer refers to a first short side of the ground plane rectangle 711 or 712; and a second short side of the ground plane layer relates to a second short side of the ground plane rectangle 712 or 711.FIG.","8 shows an example of a radio-frequency system 805 coupled to a slim radiating structure 801 via internal conductive paths 802, 803 and 804.An example of a suitable slim radiating structure 801 to be coupled to the radio-frequency system 805 is the slim radiating structure shown in FIG.","7.The radio-frequency system 805 comprises a first matching circuit 806, a second matching circuit 807, and a third matching circuit 808.The first matching circuit 806 is configured to ensure that the slim radiating system is impedance-matched at a first frequency region to other circuitry coupled via external conductive path 809.The second matching circuit 807 is configured to provide impedance matching at a second frequency region for other circuitry coupled to external conductive path 810.The third matching circuit 808 is configured to guarantee that the slim radiating system is matched in impedance at a third frequency region at the external conductive path 811.The first, second and third matching networks are therefore configured to ensure an acceptable reference level for the reflection coefficient over an entirety of the first, second and third operating frequency ranges.","Each of the first, second and third matching circuits comprises a network of passive components such as inductors and capacitors, which are arranged with a suitable architecture like, for instance, an inductor plus an LC network.","Other suitable matching circuits may be used to ensure that the slim radiating system is matched in impedance at the operating frequency ranges; other suitable matching circuits may comprise a network of passive and/or active components, which may be arranged with other suitable architectures.","FIG.","9 illustrates the radio-frequency performance of the slim radiating system resulting from the interconnection of the slim radiating structure 701 to the radio-frequency system 805.Curve 901 shows the reflection coefficient of the slim radiating system versus frequency at a terminal in the external path 809, curve 902 shows the reflection coefficient of the slim radiating system versus frequency at a terminal in the external path 810, curve 903 shows the reflection coefficient of the slim radiating system versus frequency at a terminal in the external path 811, and line 904 shows an acceptable reference level for the reflection coefficient.","In this example, the reflection coefficient 901 is less than −4.4 dB for all the frequencies of a first operating frequency region 905, the reflection coefficient 902 is less than −4.4 dB for all the frequencies of a second operating frequency region 906, and the reflection coefficient 903 is less than −4.4 dB for all the frequencies of a third operating frequency region 907.The first operating frequency region 905 of the slim radiating system covers a first frequency range of about 698 MHz to about 798 MHz, the second operating frequency region 906 of the slim radiating system covers a frequency range of about 824 MHz to about 960 MHz, and the third operating frequency region 907 of the slim radiating system covers a third frequency range of about 1710 MHz to about 2690 MHz.","The first frequency range enables the slim radiating system to be used to cover at least three communication bands such as a band from 699 MHz to 746 MHz, a band from 746 MHz to 787 MHz, and a band from 758 MHz to 798 MHz.","The second frequency range enables the slim radiating system to cover at least two communication frequency bands such as a band from 824 MHz to 894 MHz and a band from 880 MHz to 960 MHz.","The third frequency range enables the slim radiating system to cover at least five communication frequency bands such as a band from 1710 MHz to 1880 MHz, a band from 1850 MHz to 1990 MHz, a band from 1920 MHz to 2170 MHz, a band from 2300 MHz to 2400 MHz, and a band from 2496 MHz to 2690 MHz.","Other desirable communication frequency bands may also be handled by the slim radiating system.","FIG.","10 illustrates another example of a slim radiating structure in accordance to the present invention; the slim radiating structure is suitable for a slim radiating system that is configured to operate in at least two frequency regions.","The slim radiating structure 1001 comprises a first booster element 1002 including a first booster bar 1003 and a second booster bar 1004 adjacent to the first booster bar; the slim radiating structure 1001 further comprises a third booster bar 1005, and a ground plane layer 1006.As shown in FIG.","3, each booster bar may be formed by a single standard layer of dielectric material with top and bottom conductive surfaces.","In this example, the dielectric material has a height of 2.4 mm; the first booster element 1002 has a slim width factor of 8, a slim height factor of 10, and a location factor of 0.375; the third booster bar 1005 has a slim width factor of 4, a slim height factor of 5 and a location factor of 0.375.FIG.","11 shows an example of a radio-frequency system 1101 coupled to a slim radiating structure 1102 via internal conductive paths 1103 and 1104.An example of a suitable slim radiating structure 1102 to be coupled to the radio-frequency system 1101 is illustrated in FIG.","10.The radio-frequency system 1101 comprises a matching circuit being configured to ensure that the slim radiating system is impedance-matched to other circuitry coupled via external conductive path 1105 at a first frequency region and a second frequency region.","The matching network is therefore configured to ensure an acceptable reference level for the reflection coefficient over an entirety of the first and second operating frequency ranges.","The matching circuit comprises a network of passive components such as inductors, capacitors and transmission lines, which are arranged with a suitable architecture as shown in FIG.","11.Other suitable matching circuits may be used to ensure that the slim radiating system is impedance matched at the operating frequency ranges; other suitable matching circuits may comprise a network of passive and/or active components, which may be arranged with other suitable architectures.","FIG.","12 illustrates the radio-frequency performance of the slim radiating system resulting from the interconnection of the slim radiating structure 1001 to the radio-frequency system 1101.Curve 1201 shows the reflection coefficient of the slim radiating system versus frequency at a terminal in the external path 1105, and line 1202 shows an acceptable reference level for the reflection coefficient.","In this example, the reflection coefficient 1201 is less than −4.4 dB for all the frequencies of the first and second frequency regions.","The first operating frequency region of the slim radiating system covers a first frequency range of about 698 MHz to about 960 MHz, and the second operating frequency region of the slim radiating system coves a frequency range of about 1710 MHz to about 3800 MHz.","The first frequency range enables the slim radiating system to be used for covering at least five communication bands such as a band from 699 MHz to 746 MHz, a band from 746 MHz to 787 MHz, a band from 758 MHz to 798 MHz, a band from 824 MHz to 894 MHz, and a band from 880 MHz to 960 MHz.","The second frequency range enables the slim radiating system to cover at least seven communication frequency bands such as a band from 1710 MHz to 1880 MHz, a band from 1850 MHz to 1990 MHz, a band from 1920 MHz to 2170 MHz, a band from 2300 MHz to 2400 MHz, a band from 2496 MHz to 2690 MHz, a band from 3400 MHz to 3600 MHz, and a band from 3600 MHz to 3800 MHz.","Other desirable communication frequency bands may also be handled by the slim radiating system.","Another example of a slim radiating structure is shown in FIG.","13.The slim radiating structure 1300 comprises ground plane layer 1302 on a printed circuit board 1307, and radiation booster 1301 characterized by a slim width factor between 1 and 2, and a slim height factor between 1 and 2.The radiation booster 1301 is separated from the ground plane layer by a gap and is characterized by a location factor between 0.5 and 2, preferably between 0.5 and 1.The ground plane layer may be inscribed in ground plane rectangle 1306 (in dashed lines for illustrative purposes only), and the radiation booster may be inscribed in booster box 1305 (in dashed lines for illustrative purposes only).","A wireless electronic device comprising a slim radiating system that includes slim radiating structure 1300 may advantageously provide penta-band operation: two frequency bands in the first frequency region, like for example the frequency bands corresponding to the GSM 850 and GSM 900 cellular communication standards (i.e.","the first frequency region comprising the 824 MHz to 960 MHz frequency range), and three frequency bands in the second frequency region, like for example the frequency bands corresponding to the GSM 1800, GSM 1900 and WCDMA 2100 cellular communication standards (i.e.","the second frequency region comprising the 1710 MHz to 2170 MHz frequency range).","In another example, a device according to the present invention could provide triple-band or quad-band operation with at least two frequency bands in the first frequency region, and at least another two frequency bands in the second frequency region, wherein first and second frequency regions do not overlap in frequency.","Such device could operate, for instance but not limited to, the GSM 850 and GSM 900 cellular communication standards, and the GSM 1800 and GSM 1900 cellular communication standards.","FIG.","14A illustrates a radio-frequency system 1400 that comprises a first port 1401, a second port 1402, and a matching circuit 1403.Such radio-frequency system is particularly convenient to be used in the slim radiating system of FIG.","2A.","Port 1401 may be connected to an internal conductive path (for instance 204a), and port 1402 may be connected to an external conductive path (for instance 205a).","The matching circuit 1403 may be configured to provide impedance matching in at least one frequency region, or in at least two frequency regions, or in at least three frequency regions.","FIG.","14B illustrates another radio-frequency system 1410 comprising a first port 1411, a second port 1412, a third port 1413, a matching circuit 1414, a diplexer 1415, and a conductive path 1416 connecting the matching circuit to the diplexer.","In reception, the diplexer 1415 is configured to split the signal from conductive path 1416 in a first signal extracted at port 1412, preferably comprising the frequencies corresponding to the first frequency region, and in a second signal extracted at port 1413, preferably comprising the frequencies corresponding to the second frequency region; in transmission, diplexer 1415 combines signals from ports 1412 and 1413 and are extracted in conductive path 1416.The matching circuit 1414 provides impedance matching to the slim radiating system in the first and second frequency regions.","Ports 1412 and 1413 may be respectively connected to first and second external paths as shown in FIG.","2D.","FIGS.","15A to 15F show preferred matching circuits configured to provide impedance matching in at least two frequency regions.","FIG.","15A shows matching circuit 1500 comprising first and second ports 1501 and 1502, and a circuit including five stages forming a ladder topology (series-parallel-series-parallel-series).","The first stage, which is connected to port 1501, is an inductor in series 1503, the second stage is a shunted inductor 1504, the third stage is a capacitor in series 1505, the fourth stage is an inductor in parallel 1506, and the fifth stage is a capacitor in series 1507, said fifth stage being connected to the second port 1502.In FIG.","15B there is shown matching circuit 1510 comprising six stages that form an alternative ladder topology (series-parallel-series-parallel-series-parallel).","The first stage (in series) is connected to the first port 1501 of the matching circuit, and the sixth stage comprising an inductor in parallel 1511 is connected to the second port 1502 of the matching circuit.","FIG.","15C depicts another preferred matching circuit 1520 comprising two stages: the first stage comprises a capacitor in parallel 1521, and the second stage comprises an inductor in series 1522.A preferred range of capacitor values for shunted capacitor 1521 of matching circuit 1520 is 0.01pF to 30pF.","FIG.","15D shows another preferred matching circuit 1530 comprising a series inductor 1531 connected to port 1501 and to a series LC resonator formed by inductive component 1532a and capacitive component 1532b.","The LC resonator is connected to an LC resonator in parallel, comprising inductor 1533a and capacitor 1533b, and to a series capacitor 1534.The series capacitor is connected to second port 1502 of the matching circuit 1530.This matching circuit comprises a single branch formed by four stages (series-series-parallel-series).","FIG.","15E shows a fifth preferred matching circuit 1540 comprising: inductor 1541 in series connected to port 1501, inductor 1542 in parallel, capacitor 1543 in series, inductor 1544a and capacitor 1544b in parallel forming a parallel LC circuit, and capacitor 1545 in series connected to port 1502.FIG.","15F illustrates another preferred matching circuit 1550 that is similar to matching circuit 1540 with the difference that capacitor 1545 is connected to inductor in series 1551 forming a series LC circuit, and said inductor being connected to port 1502 instead of capacitor 1545 as in FIG.","15E.","Inductors 1503, 1531 and 1541 corresponding to the first stage of matching circuits 1500, 1510, 1530, 1540 and 1550 may preferably have a value in the range of 0.1 nH to 80 nH.","Matching circuits 1500, 1510, 1520, 1530, 1540, and 1550 are suitable for being used as matching circuit 203a and 203d shown in FIGS.","2A and 2D.","FIG.","16A shows the impedance 1600 of a slim radiating system comprising a radiation booster, measured at its internal conductive path, when it is disconnected from a radio-frequency system as disclosed in the present invention.","Points 1601 and 1602 from said impedance correspond to the lowest and highest frequencies of a first frequency region (in this example, said frequencies are 824 MHz and 960 MHz); and points 1603 and 1604 correspond to the lowest and highest frequencies of a second frequency region (for this particular example, said frequencies are 1710 MHz and 2170 MHz).","The impedance 1600 has a substantially large negative reactance, namely the impedance in the first frequency region is capacitive, for the entire range of frequencies limited by points 1601 and 1602, and is also capacitive for the frequencies of the second frequency region.","The first resonant frequency of said slim radiating structure is at a frequency above the highest frequency of the second frequency region (as indicated by point 1604).","FIGS.","16B to 16F show the evolution of the impedance of slim radiating system of FIG.","16A after the slim radiating system is connected to a radio-frequency system comprising a matching circuit like 1500 as the stages are added successively to the matching circuit.","FIG.","16B shows the impedance 1610 when the matching circuit only comprises the first stage (an inductor in series).","In FIG.","16C, the impedance 1620 of the slim radiating system is shown after adding the inductor in parallel (corresponding to the second stage) to the matching circuit.","The impedance 1630 from FIG.","16D is obtained after the series capacitor from the third stage is added.","The impedance 1640 from FIG.","16E is obtained after the shunted inductor from the fourth stage is added.","And with the addition of the fifth stage corresponding to another capacitor in series, the impedance 1650 of the slim radiating system is obtained.","In addition to the impedance 1650 as shown in FIG.","16F, the reflection coefficient 1700, when the slim radiating structure is connected to a radio-frequency system comprising the five-stage ladder matching network is also shown in FIG.","17.In this particular example, the operating frequency range for the radiating system covers a first frequency region at least comprising the range of frequencies delimited by points 1701 and 1702 (824 MHz and 960 MHz respectively), and a second frequency region at least comprising the range of frequencies delimited by points 1703 and 1704 (1710 MHz and 2170 MHz respectively), wherein said points establish a minimum level of reflection coefficient for a good radio-frequency performance for this particular example, although in other embodiments said minimum level could be, for example, −4.4dB.","A ratio between the lowest frequency of the second frequency region and the lowest frequency of the first frequency region is, for this particular case, greater than 1.5 and even greater than 2.0.In addition, a ratio between the first resonant frequency of the slim radiating structure measured at an internal path, when disconnected from the radio-frequency system, and the lowest frequency of the first frequency region is greater than 1.3, also greater than 2.0, and even greater than 2.4.FIGS.","18A and 18B show the impedance and reflection coefficient of another exemplary embodiment.","Such embodiment corresponds to a slim radiating system comprising a slim radiating structure featuring an impedance similar to that of FIG.","16A, and a radio-frequency system according to the present invention.","The radio-frequency system comprises a six-stage matching circuit in a ladder topology, like for example matching circuit 1510 from FIG.","15B.","The impedance 1800, when the slim radiating structure is connected to such radio-frequency system, is shown in FIG.","18A.","In said figure, points 1801 and 1802 refer to the lower and higher frequencies of a first frequency region (824 MHz and 960 MHz respectively), and points 1803 and 1804 refer to the lower and higher frequencies of a second frequency region (1710 MHz and 2170 MHz respectively).","The reflection coefficient 1810 of FIG.","18B corresponds to the slim radiating system of FIG.","18A.","The operating frequency range for a slim radiating system according to this particular embodiment at least covers a first frequency region including the first range delimited by points 1811 and 1812 (824 MHz and 960 MHz), and a second frequency region including the second range delimited by points 1813 and 1814 (1710 MHz and 2170 MHz).","FIG.","19 shows a radiation booster 1900 comprising conducting surfaces 1901 and 1902, a dielectric material 1904 (shown transparent for illustrative purposes only), and a plurality of vias 1903 electrically interconnecting the two conducting surfaces 1901 and 1902 (in other examples, said conducting surfaces may be interconnected by just one via).","Said radiation booster is a booster bar featuring a slim width factor of 3.125, and a slim height factor of 3.125.The booster bar 1900 may be used, for example, in slim radiating structure 1300 instead of radiation booster 1301.A booster bar such as 1900 is configured to be used in slim radiating systems according to the present invention, and in particular in each and every embodiment of the present invention.","As such, a slim radiating system comprising a slim radiating structure, a radio-frequency system and at least one external conductive path, wherein the slim radiating structure comprises a radiation booster like, for example, 1900 and a ground plane layer, may be configured to transmit and receive electromagnetic wave signals in at least one frequency region, or in at least two frequency regions.","The radio-frequency system comprises a matching circuit configured to provide impedance matching to the slim radiating system in said at least one or at least two frequency regions at the at least one external path.","FIG.","20 shows a slim radiating structure comprising a radiation booster (e.g.","booster bar) 2001, a ground plane layer 2002.There is also shown a conductive element 2003 that may advantageously function as an internal conductive path.","The conductive element 2003 is connected to radiation booster 2001, advantageously tuning the input impedance of the radiation booster prior its connection to a radio-frequency system (not shown).","The conductive element may improve the efficiency of the slim radiating system comprising said slim radiating structure, or make the slim radiating system operable in more frequency bands in at least one frequency regions or in at least two frequency regions.","In this example, the booster bar features a height of 2.4 mm, a slim width factor of 4, a slim height factor of 5, and a location factor of 0.33.Although the conductive element 2003 is L-shaped, in other examples the conductive element may take other forms as well such as a straight I.","The electrical length of conductive element 2003 may be shorter than 10% of the free-space wavelength corresponding to the lowest frequency of the first frequency region, and preferably it may be shorter than 5% of said free-space wavelength.","FIG.","21A schematically shows, in a 3D perspective, a test platform for the characterization of radiation boosters.","The platform comprises substantially square conductive surface 2101 and connector 2102 (for instance an SMA connector) electrically connected to the device or element 2100 to be characterized.","The conductive surface 2101 has sides with a length larger than the reference operating wavelength corresponding to the reference frequency.","For instance, at 900 MHz, said sides are at least 60 centimeters long.","The conductive surface may be a sheet or plate made of copper, for example.","The connector 2102 is placed substantially in the center of conductive surface 2101.In FIG.","21B the same test platform of FIG.","21A is schematically represented in a 2D perspective wherein the conductive surface 2101 is partially drawn.","In this example, the element that is to be characterized 2100 in FIG.","21A corresponds to booster bar 1900 from FIG.","19, which is arranged so that its largest dimension is perpendicular to conductive surface 2101, and one of the first or second conductive surfaces (1901 or 1902 of FIG.","19) is in direct electrical contact with connector 2102 (for clearer interpretation of the orientation of radiation booster 1900, via holes 1903 connecting the first and second conductive surfaces of the radiation booster are also drawn in FIG.","21B).","The radiation booster 1900 lies on a dielectric material (not shown) attached to the conductive surface 2101 so as to minimize the distance between radiation booster 1900 and surface 2101.Said dielectric material may be a dielectric tape or coating, for example.","FIG.","22 shows a graph of the radiation efficiency and antenna efficiency measured in a test platform like the one shown in FIG.","21A and FIG.","21B, when the element 2100 to be characterized is radiation booster 1900.In this particular example, the radiation efficiency measured 2201 (represented with a solid line) at 900 MHz is less than 5%, and the antenna efficiency measured 2202 (represented with a dashed line) at 900 MHz is less than 1%.","The foregoing is merely illustrative of the principles of this invention and various modifications can be made by those skilled in the art without departing from the scope and spirit of the invention.","So even though that in the illustrative examples described above in connection with the figures some particular designs of booster bars with specific values for the slim width factor, the slim height factor, and the location factor have been used, many other designs of boosters bars in accordance with the invention having for example different slim width factor, slim height factor, and/or location factor could have been equally used in the slim radiating structures."]],"string":"[\n [\n \"Slim Booster Bars for Electronic Devices\",\n \"A wireless device includes at least one slim radiating system having a slim radiating structure and a radio-frequency system.\",\n \"The slim radiating structure includes one or more booster bars.\",\n \"The booster bar has slim width and height factors that facilitate its integration within the wireless device and the excitation of a resonant mode in the ground plane layer, and has a location factor that enables it to achieve the most favorable radio-frequency performance for the available space to allocate the booster bar.\",\n \"The at least one slim radiating system may be configured to transmit and receive electromagnetic wave signals in one or more frequency regions of the electromagnetic spectrum.\"\n ],\n [\n \"1.A wireless handheld or portable electronic device comprising: a slim radiating system configured to transmit and receive electromagnetic wave signals in a first frequency region, the slim radiating system comprising: a slim radiating structure comprising a ground plane layer and a first booster bar comprising a single standard layer of dielectric material including electrically connected top and bottom conductive surfaces, the first booster bar having a slim width factor greater than 3 and a slim height factor greater than 3 and being separated from the ground plane layer by a gap and having a location factor in a range of 0.3 to 1.8, wherein the first booster bar fits in an imaginary sphere having a radius smaller than ⅓ of a free-space wavelength corresponding to a lowest frequency of the first frequency region divided by two times n (pi); a first external conductive path; a radio-frequency system comprising a first matching circuit configured to provide impedance matching within the first frequency region at the first external conductive path; and a first internal conductive path coupling the first booster bar to the radio-frequency system.\",\n \"2.The wireless handheld or portable electronic device of claim 1, wherein: the slim radiating system is configured to transmit and receive electromagnetic wave signals in a second frequency region, wherein a lowest frequency of the second frequency region is at a frequency higher than a highest frequency of the first frequency region; the slim radiating system comprises a second internal conductive path and a second external conductive path; the slim radiating structure comprises a second booster bar; the second booster bar comprises a single standard layer of dielectric material including a top and a bottom conductive surfaces electrically connected, has a slim width factor greater than 3 and a slim height factor greater than 3, and is separated from the ground plane layer by a gap and has a location factor in a range of 0.3 to 1.8; the second booster bar fits in an imaginary sphere having a radius smaller than ⅓ of a free-space wavelength corresponding to a lowest frequency of the first frequency region, divided by two times n (pi); the second internal conductive path couples the second booster bar to the radio-frequency system; and the radio-frequency system comprises a second matching circuit configured to provide impedance matching within the second frequency region at the second external conductive path.\",\n \"3.The wireless handheld or portable electronic device of claim 2, wherein: the slim radiating system is configured to transmit and receive electromagnetic wave signals in a third frequency region, wherein a highest frequency of the third frequency region is at a frequency lower than a lowest frequency of the first frequency region; the slim radiating system comprises a third internal conductive path and a third external conductive path; the slim radiating structure comprises a booster element including third and fourth booster bars, the third booster bar being adjacent to the fourth booster bar, and wherein the third and fourth booster bars are electrically connected; each of the third and fourth booster bars comprises a single standard layer of dielectric material including a top and a bottom conductive surfaces electrically connected; the booster element has a slim width factor greater than 6 and a slim height factor greater than 6, and is separated from the ground plane layer by a gap and has a location factor in a range of 0.3 to 1.8; the booster element fits in an imaginary sphere having a radius smaller than ⅓ of a free-space wavelength corresponding to a lowest frequency of the first frequency region divided by two times n (pi); the third internal conductive path couples the booster element to the radio-frequency system; and the radio-frequency system comprises a third matching circuit configured to provide impedance matching within the third frequency region at the third external conductive path.\",\n \"4.The wireless handheld or portable electronic device of claim 1, wherein: the slim radiating system is configured to transmit and receive electromagnetic wave signals in a second frequency region, wherein a lowest frequency of the second frequency region is at a frequency higher than a highest frequency of the first frequency region; and the first matching circuit is further configured to provide impedance matching within the second frequency region at the first external conductive path.\",\n \"5.The wireless handheld or portable electronic device of claim 4, wherein the first matching circuit comprises a single branch.\",\n \"6.The wireless handheld or portable electronic device of claim 4, wherein the first matching circuit comprises no more than seven lumped components.\",\n \"7.The wireless handheld or portable electronic device of claim 4, wherein the first frequency region comprises an 824-960 MHz frequency range.\",\n \"8.The wireless handheld or portable electronic device of claim 7, wherein the second frequency region comprises a 1710-2170 MHz frequency range.\",\n \"9.The wireless handheld or portable electronic device of claim 1, wherein the first booster bar features a first resonance frequency greater than 2,700 MHz, when measured in a monopole configuration in a platform comprising a substantially square conductive surface made of copper, the platform comprising sides of 60 centimeters and a thickness of 0.5 millimeters.\",\n \"10.A wireless handheld or portable electronic device comprising: a slim radiating system configured to transmit and receive electromagnetic wave signals in a first frequency region, the slim radiating system comprising: a slim radiating structure comprising a ground plane layer and a booster element including first and second booster bars that are adjacent and electrically connected to each other, each of the first and second booster bars comprising a single standard layer of dielectric material including electrically connected top and bottom conductive surfaces, and having a slim width factor greater than 3.5 and a slim height factor greater than 4, each of the first and second booster bars being separated from the ground plane layer by a gap and having a location factor in a range of 0.3 to 1.8, wherein the booster element fits in an imaginary sphere having a radius smaller than ⅓ of a free-space wavelength corresponding to a lowest frequency of the first frequency region, divided by two times n (pi); a first external conductive path; a radio-frequency system comprising a first matching circuit configured to provide impedance matching within the first frequency region at the first external conductive path; and a first internal conductive path coupling the first booster element to the radio-frequency system.\",\n \"11.The wireless handheld or portable electronic device of claim 10, wherein: the slim radiating system is configured to transmit and receive electromagnetic wave signals in a second frequency region, wherein a lowest frequency of the second frequency region is at a frequency higher than a highest frequency of the first frequency region; the slim radiating system comprises a second internal conductive path and a second external conductive path; the slim radiating structure comprises a third booster bar comprising a single standard layer of dielectric material including electrically connected top and bottom conductive surfaces, and having a slim width factor greater than 3.5 and a slim height factor greater than 4, the third booster bar being separated from the ground plane layer by a gap and having a location factor in a range of 0.3 to 1.8; the second internal conductive path couples the third booster bar to the radio-frequency system; and the radio-frequency system comprises a second matching circuit configured to provide impedance matching within the second frequency region at the second external conductive path.\",\n \"12.The wireless handheld or portable electronic device of claim 10, wherein a minimum distance between the top conductive surface and the bottom conductive surface of each of the first and second booster bars is no greater than 3 millimeters.\",\n \"13.The wireless handheld or portable electronic device of claim 10, wherein the first frequency region comprises a 698-960 MHz frequency range.\",\n \"14.A wireless electronic device comprising: a slim radiating system configured to transmit and receive electromagnetic wave signals in a first frequency region and in a second frequency region, wherein a lowest frequency of the second frequency region is at a frequency higher than a highest frequency of the first frequency region, the slim radiating system comprising: a slim radiating structure comprising a ground plane layer and a booster bar comprising a single standard layer of dielectric material including electrically connected top and bottom conductive surfaces, a longest dimension of the booster bar being at least 3 times greater than a shortest dimension of the booster bar, the booster bar being separated from the ground plane layer by a gap and having a location factor in a range of 0.3 to 1.8, wherein the booster bar fits in an imaginary sphere having a radius smaller than ⅓ of a free-space wavelength corresponding to a lowest frequency of the first frequency region divided by two times n (pi); an external conductive path; a radio-frequency system comprising a matching circuit configured to provide impedance matching within the first and second frequency regions at the external conductive path; and an internal conductive path coupling the booster bar to the radio-frequency system.\",\n \"15.The wireless electronic device of claim 14, wherein the longest dimension of the booster bar is at least 4 times greater than the shortest dimension of the booster bar.\",\n \"16.The wireless electronic device of claim 14, wherein the matching circuit comprises seven or fewer components.\",\n \"17.The wireless electronic device of claim 16, wherein: the matching circuit comprises a ladder topology with five stages in the sequence: series-parallel-series-parallel-series; and each stage comprises one component.\",\n \"18.The wireless handheld or portable electronic device of claim 16, wherein: the matching circuit comprises a ladder topology with five stages in the sequence: series-parallel-series-parallel-series; and one of the five stages comprises a parallel LC circuit, and another one of the five stages comprises a series LC circuit.\",\n \"19.The wireless handheld or portable electronic device of claim 14, wherein the booster bar has a first resonance frequency greater than 2,700 MHz, when measured in a monopole configuration in a platform comprising a substantially square conductive surface made of copper, the platform comprising sides of 60 centimeters and a thickness of 0.5 millimeters.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>Wireless electronic devices typically handle one or more cellular communication standards, and/or wireless connectivity standards, and/or broadcast standards, each standard being allocated in one or more frequency bands, and the frequency bands being contained within one or more regions of the electromagnetic spectrum.\",\n \"For that purpose, a typical wireless electronic device must include a radiating system capable of operating in one or more frequency regions with an acceptable radio-electric performance (in terms of for instance reflection coefficient, standing wave ratio, impedance bandwidth, gain, efficiency, or radiation pattern).\",\n \"The integration of the radiating system within the wireless electronic device must be effective to ensure that the overall device attains good radio-electric performance (such as for example in terms of radiated power, received power, sensitivity) without being disrupted by electronic components and/or human loading.\",\n \"Additionally, a space within the wireless electronic device is usually limited and the radiating system has to be included in the available space.\",\n \"The radiating system is expected to be small enough to occupy as little space as possible within the device, which then allows for smaller devices, or for the addition of more specific components and functionalities into the device.\",\n \"At the same time, it is sometimes convenient for the radiating system to be flat since this allows for slim devices.\",\n \"Thus, many of the demands for wireless devices also translate to specific demands for the radiating systems thereof.\",\n \"This is even more critical in the case in which the wireless device is a multifunctional wireless device.\",\n \"Commonly-owned patent applications WO2008/009391 and US2008/0018543 describe a multifunctional wireless device.\",\n \"The entire disclosure of aforesaid application numbers WO2008/009391 and US2008/0018543 are hereby incorporated by reference.\",\n \"For a good wireless connection, high efficiency is further required.\",\n \"Other more common design demands for radiating systems are the reflection coefficient (or standing-wave ratio, SWR) and the impedance which is supposed to be about 50 ohms.\",\n \"Other demands for radiating systems for wireless handheld or portable devices are competitive cost and a low SAR.\",\n \"Furthermore, a radiating system has to be integrated into a device or, in other words, a wireless device has to be constructed such that an appropriate radiating system may be integrated therein which puts additional constraints by consideration of the mechanical fit, the electrical fit, and the assembly fit.\",\n \"Of further importance, usually, is the robustness of the radiating system, which means that the radiating system does not change its properties upon smaller shocks to the device and the human loading.\",\n \"Besides radio-frequency performance, small size and reduced interaction with human body and nearby electronic components, one of the current limitations of the prior-art is that generally the antenna system is customized for every particular wireless handheld device model.\",\n \"The mechanical architecture of each device model is different and the volume available for the antenna severely depends on the form factor of the wireless device model together with the arrangement of the multiple components embedded into the device (e.g., displays, keyboards, battery, connectors, cameras, flashes, speakers, chipsets, memory devices, etc.).\",\n \"As a result, the antenna within the device is mostly designed ad hoc for every model, resulting in a higher cost and a delayed time to market.\",\n \"In turn, as typically the design and integration of an antenna element for a radiating structure is customized for each wireless device, different form factors or platforms, or a different distribution of the functional blocks of the device will force to redesign the antenna element and its integration inside the device almost from scratch.\",\n \"A radiating system for a wireless handheld or portable device typically includes a radiating structure comprising an antenna element which operates in combination with a ground plane layer providing a determined radio-frequency performance in one or more frequency regions of the electromagnetic spectrum.\",\n \"Typically, the antenna element has a dimension close to an integer multiple of a quarter of the wavelength at a frequency of operation of the radiating structure, so that the antenna element is at resonance or substantially close to resonance at the frequency of operation, and a radiation mode is excited on the antenna element.\",\n \"Antenna elements operating in multiple frequency bands allocated at different regions of the electromagnetic spectrum usually present complex mechanical designs and considerable dimensions, mainly due to the fact that antenna performance is highly related to the electrical dimensions of the antenna element.\",\n \"A further problem associated to the integration of the radiating structure, and in particular to the integration of the antenna element in a wireless device is that the volume dedicated for such integration has continuously shrunk with the appearance of new smaller and/or thinner form factors for wireless devices, and with the increasing convergence of different functionalities in a same wireless device.\",\n \"Therefore, from the conventional wisdom perspective, the trend in seeking for slimmer wireless device is incompatible with maximizing the performance of a traditional antenna device, which again, it is known to have a high correlation between antenna size (relative to the operating wavelengths) and performance.\",\n \"Some techniques to miniaturize and/or optimize the multiband behavior of an antenna element have been described in the prior art.\",\n \"However the radiating structures described therein still rely on exciting a radiation mode on the antenna element for each one of the frequency bands of operation.\",\n \"This fact leads to complex mechanical designs and large antennas that usually are very sensitive to external effects (such as for instance the presence of plastic or dielectric covers that surround the wireless device), to components of the wireless device (such as for instance, but not limited to, a speaker, a microphone, a connector, a display, a shield can, a vibrating module, a battery, or an electronic module or subsystem) placed either in the vicinity of, or even underneath, the radiating element, and/or to the human loading.\",\n \"A multiband antenna system is sensitive to any of the above mentioned aspects because they may alter the electromagnetic coupling between the different geometrical portions of the radiating element, which usually translates into detuning effects, degradation of the radio-frequency performance of the antenna system and/or the radio-frequency performance of the wireless device, and/or greater interaction with the user (such as an increased level of SAR).\",\n \"In this sense, a radiating system such as the one described in the present invention not requiring a complex and/or large antenna formed by multiple arms, slots, apertures and/or openings and a complex mechanical design is preferable in order to minimize such undesired external effects and simplify the integration within the wireless device.\",\n \"Some other attempts have focused on antenna elements not requiring a complex geometry while still providing some degree of miniaturization by using an antenna element that is not resonant in the one or more frequency ranges of operation of the wireless device.\",\n \"For example, WO2007/128340 discloses a wireless portable device comprising a non-resonant antenna element for receiving broadcast signals (such as, for instance, DVB-H, DMB, T-DMB or FM).\",\n \"The wireless portable device further comprises a ground plane layer that is used in combination with said antenna element.\",\n \"Although the antenna element has a first resonant frequency above the frequency range of operation of the wireless device, the antenna element is still the main responsible for the radiation process and for the radio-frequency performance of the wireless device.\",\n \"This is clear from the fact that no radiation mode can be excited on the ground plane layer because the ground plane layer is electrically short at the frequencies of operation (i.e., its dimensions are much smaller than the wavelength).\",\n \"For this kind of non-resonant antenna elements, a matching circuitry is added for matching the antenna to a level of SWR in a limited frequency range, which in this particular case can be around SWR<6.Such level of SWR together with the limited bandwidth results in antenna elements which are only acceptable for reception of electromagnetic wave signals but not desirable for transmission of electromagnetic wave signals.\",\n \"With such limitations, while the performance of the wireless portable device may be sufficient for reception of electromagnetic wave signals (such as those of a broadcast service), the antenna element could not provide an acceptable performance (for example, in terms of reflection coefficient or gain) for a communication service requiring also the transmission of electromagnetic wave signals.\",\n \"Commonly-owned patent applications WO2008/119699 and US2010/0109955 describe a wireless handheld or portable device comprising a radiating system capable of operating in two frequency regions.\",\n \"The radiating system comprises an antenna element having a resonant frequency outside said two frequency regions, and a ground plane layer.\",\n \"In this wireless device, while the ground plane layer contributes to enhance the electromagnetic performance of the radiating system in the two frequency regions of operation, it is still necessary to excite a radiation mode on the antenna element.\",\n \"In fact, the radiating system relies on the relationship between a resonant frequency of the antenna element and a resonant frequency of the ground plane layer in order for the radiating system to operate properly in said two frequency regions.\",\n \"Nevertheless, the solution still relies on an antenna element whose size is related to a resonant frequency that is outside of the two frequency regions.\",\n \"The entire disclosures of the aforesaid application numbers WO2008/119699 and US2010/0109955 are hereby incorporated by reference.\",\n \"A different radiating system is disclosed in U.S. Pat.\",\n \"No.\",\n \"6,674,411, in which a planar inverted-L antenna (i.e., a patch antenna) has a radiating element composed by a rectangular plate placed above and substantially parallel to a ground plane.\",\n \"The antenna is connected to a matching network that provides a match in one frequency band in a first frequency region, and in one frequency band in a second frequency region.\",\n \"Thus the antenna system is limited to single-band operation in both frequency regions.\",\n \"When operation in more bands is sought, the antenna system requires of a switched (active) matching network that provides non-simultaneous impedance matching in each frequency band.\",\n \"So in spite of having an antenna that occupies a large volume (20×10×8 mm3), not more than dual-band operation may be provided simultaneously.\",\n \"For at least the above reasons, wireless device manufacturers regard the volume dedicated to the integration of the radiating structure, and in particular the antenna element, as being a toll to pay in order to provide wireless communication capabilities to the handheld or portable device.\",\n \"In order to reduce as much as possible the volume occupied into the wireless handheld or portable device, recent trends in handset antenna design are oriented to maximize the contribution of the ground plane to the radiation process by using very small non-resonant elements.\",\n \"However, non-resonant elements usually are forced to include a complex radio-frequency system.\",\n \"Thus, the challenge of these techniques mainly relies on said complexity (combination of inductors, capacitors, and transmission lines), which is required to satisfy impedance bandwidth and efficiency specifications.\",\n \"Commonly owned patent applications, WO2010/015365, and WO2010/015364 are intended for solving some of the aforementioned drawbacks.\",\n \"Namely, they describe a wireless handheld or portable device comprising a radiating system including a radiating structure and a radio-frequency system.\",\n \"The radiating structure is formed by a ground plane layer presenting suitable dimensions as for supporting at least one efficient radiation mode and at least one radiation booster capable of coupling electromagnetic energy to said ground plane layer.\",\n \"The radiation booster is not resonant in any of the frequency regions of operation and, consequently, a radio-frequency system is used to properly match the radiating structure to the desired frequency bands of operation.\",\n \"More particularly, in WO2010/015364 each radiation booster is intended for providing operation in a particular frequency region.\",\n \"Thus, the radio-frequency system is designed in such a way that the first internal port associated to the first radiation booster is highly isolated from the second internal port associated to a second radiation booster.\",\n \"Said radio-frequency system usually comprises a matching network including resonators for each one of the frequency regions of operation and a set of filters for each one of the frequency regions of operation.\",\n \"Thus, said radio-frequency system requires multiple stages and the performance of the radiating systems in terms of efficiency may be affected by the additional losses of the components.\",\n \"As each radiation booster is generally intended for providing operation in a particular frequency region, the bandwidth capabilities may be limited for some applications requiring very wide bandwidth specially at the low frequency region, as for example for wireless devices operating at LTE700, GSM850 and GSM900.Commonly owned patent applications WO2014/012796 and US2014/0015730 disclose a concentrated wireless device comprising a radiating system including a radiating structure and a radio-frequency system, such device operating two or more frequency regions of the electromagnetic spectrum.\",\n \"A feature of said radiating system is that the operation in at least two frequency regions is achieved by one radiation booster, or by at least two radiation boosters, or by at least one radiation booster and at least one antenna element, wherein the radio-frequency system modifies the impedance of the radiating structure, providing impedance matching to the radiating system in the at least two frequency regions of operation of the radiating system.\",\n \"The entire disclosure of aforesaid application numbers WO2014/012796 and US2014/0015730 are hereby incorporated by reference.\",\n \"Commonly owned patent applications WO2014/012842 and US2014/0015728 disclose very compact, small size and light weight radiation boosters operating in single or in multiple frequency bands.\",\n \"Such radiation boosters are configured to be used in radiating systems that may be embedded into a wireless handheld device.\",\n \"Said patent applications further disclose radiation booster structures and their manufacturing methods that enable reducing the cost of both the booster and the entire wireless device embedding said booster inside the device.\",\n \"The entire disclosure of aforesaid application numbers WO2014/012842 and US2014/0015728 are hereby incorporated by reference.\",\n \"Another technique, as disclosed in U.S. Pat.\",\n \"No.\",\n \"7,274,340, is based on the use of two coupling elements.\",\n \"According to the invention, quad-band operation (GSM 1800/1900 and GSM850/900 bands) is provided with two coupling elements: a low-band (LB) coupling element (for the GSM850/900 bands), and a high-band (HB) coupling element (for the GSM1800/1900 bands), where the impedance matching is provided through the addition of two matching circuits, one for the LB coupling element and another one for the HB coupling element.\",\n \"In spite of using non-resonant elements, the size of the element for the low band is significantly large, being 1/9.3 times the free-space wavelength of the lowest frequency for the low frequency band.\",\n \"Due to such size, the low band element would be a resonant element at the high band.\",\n \"Additionally, the operation of this solution is closely linked to the alignment of the maximum E-field intensity of the ground plane and the coupling element.\",\n \"The size of the low band element undesirably contributes to increase the printed circuit board (PCB) space required by the antenna module.\",\n \"According to the invention, the bandwidth at the low frequency region is 133 MHz (from 821 MHz to 954 MHz) that is insufficient for some applications requiring very wide bandwidth, especially at the low frequency region, as for example for wireless devices operating at LTE700, GSM850 and GSM900.Therefore, a wireless device not requiring an antenna element and including a slim radiating system would be advantageous to make simpler the integration of the slim radiating structure into the wireless electronic device minimizing the amount of the electronic device that is allocated towards the slim radiating system, and to provide a suitable radio-frequency performance to operate in a wide range of communication bands.\",\n \"The volume freed up by the absence of a large and complex antenna element would enable smaller and/or thinner devices, as slim electronic devices, or even to adopt radically new form factors which are not feasible today due to the presence of an antenna element featuring a considerable volume.\",\n \"Furthermore, by eliminating precisely the element that requires customization, a standard solution is sought which should only require minor adjustments to be implemented in different wireless electronic devices.\"\n ],\n [\n \"<SOH> SUMMARY <EOH>It is an object of the present invention to provide an electronic device (such as for instance but not limited to a mobile phone, a smartphone, a phablet, a PDA, an MP3 player, a headset, a USB dongle, a laptop computer, a tablet, a gaming device, a GPS system, a digital camera, a wearable device as a smart watch, a PCMCIA, Cardbus 32 card, a sensor, or generally a multifunction wireless device which combines the functionality of multiple devices) containing a slim radiating system that covers a wide range of radio-frequencies and handles multiple communication bands while exhibiting a suitable radio-frequency performance.\",\n \"It is another object of the invention to provide a slim radiating system suitable for being included within electronic devices, and more preferably within slim electronic devices.\",\n \"It is another object of the invention to provide a standard slim radiating system which only requires minor adjustments to be included within different electronic devices.\",\n \"Another object of the invention refers to the location (on the device) of radiation boosters and, more particularly, booster bars for obtaining the most favorable frequency bandwidth values.\",\n \"An electronic device according to the invention may have a candy-bar shape, which means that its configuration is given by a single body.\",\n \"It may also have a two-body configuration such as a clamshell, flip-type, swivel-type or slider structure.\",\n \"In some other cases, the device may have a configuration comprising three or more bodies.\",\n \"It may further or additionally have a twist configuration in which a body portion (e.g.\",\n \"with a screen) can be twisted (i.e., rotated around two or more axes of rotation which are preferably not parallel).\",\n \"The electronic device may comprise a memory module, a processing circuitry module, a user interface module, a battery, and a wireless communication module.\",\n \"The wireless communication module may include a slim radiating system, a radio-frequency transceiver circuit, a power amplifier circuit and a base-band module.\",\n \"The slim radiating system may be coupled to the power amplifier via a conductive path and to the radio transceiver circuit via a conductive path.\",\n \"The wireless communication module may include a multiplexing stage coupled to the slim radiating system via a conductive path.\",\n \"A slim radiating system in accordance with the invention may include a slim radiating structure, a radio-frequency system, at least one internal conductive path and at least one external conductive path.\",\n \"The slim radiating structure may include a ground element and at least one radiation booster, which in some embodiments may be a booster bar, separated from the ground element by a gap.\",\n \"A slim radiating structure may comprise a ground element and one, two, three, four or even more radiation boosters.\",\n \"In some preferred embodiments, said radiation boosters may be booster bars featuring an elongated shape.\",\n \"In preferred embodiments, each booster bar or radiation booster is separated from the ground element by a gap.\",\n \"An aspect of the present invention relates to the use of the ground element (or ground plane layer) of the slim radiating system as a main source of radiation.\",\n \"A radiation booster includes a dielectric material and in some embodiments, a single standard layer of dielectric material spacing two or more conductive elements.\",\n \"A single standard layer of dielectric material refers to dielectric material with a standard thickness, which is available off-the-shelf.\",\n \"For example, 0.025″ (0.635 mm), 0.047″ (1.2 mm), 0.093″ (2.36 mm) or 0.125″ (3.175 mm) are common/standard thicknesses for dielectric materials which are available in the market.\",\n \"Examples of dielectric materials may include fiber-glass FR4, Cuclad, Alumina, Kapton, Ceramic and for instance commercial laminates and substrates from Rogers® Corporation (R03000® and R04000® laminates, Duroid substrates and alike) or other suitable non-conductive materials.\",\n \"The radiation booster may be formed by printing or depositing conductive material in a first and a second surface of the dielectric material (e.g.\",\n \"top and bottom) and adding several vias to electrically connect the conductive material in the first surface with the conductive material in the second surface.\",\n \"The conductive material in the first and second surfaces may have a substantially polygonal shape.\",\n \"Some possible polygonal shapes are for instance, but not limited to, squares, rectangles, and trapezoids.\",\n \"When the conductive material in said first and second surfaces has an elongated shape, for instance a rectangular shape, the radiation booster takes the form of a booster bar; a booster bar may also include vias that electrically connect the conductive material in the first surface with the conductive material in the second surface.\",\n \"The elongated shape of a booster bar is characterized by two slim form factors: a slim width factor and a slim height factor.\",\n \"The slim width factor is a ratio between a length of the booster bar and a width of the booster bar.\",\n \"The slim height factor is a ratio between the length of the booster bar and a height of the booster bar.\",\n \"The slim width factor characterizes the ratio between the length and the width of the booster bar, whereas the slim height factor characterizes the ratio between the length and the height of the booster bar.\",\n \"In a preferred embodiment, the value for the slim width factor and the slim height factor is greater than 2, for instance in one or more of those embodiments the value for the slim width factor is greater than 3, and preferably larger than 3.5, and the slim height factor is greater than 4.In another preferred embodiment, the value for the slim width factor is greater than 6 and/or the slim height factor is greater than 6.In another preferred embodiment, the value for the slim width factor is greater than 6 and/or the slim height factor is larger than 9.In some less preferred embodiments, the values for both the slim width factor and the slim height factor are between 1 and 2.The slim width factor and the slim height factor of a booster bar may take any of the values listed above yet being smaller than 25, and preferably smaller than 10.A radiation booster may comprise one, two or more booster bars electrically connected, forming a booster element that fits in an imaginary sphere having a diameter smaller than ⅓ of a radiansphere corresponding to the lowest frequency of operation of the slim radiating system.\",\n \"Such a booster element may also be characterized by a slim width factor, a slim height factor, and a location factor.\",\n \"Any booster element according to the present invention may be limited by a slim width factor and a slim height factor, each of these factors being between 1 and 10, and preferably between 2 and 10.An advantageous aspect of the invention refers to a booster bar built on a single standard layer of dielectric material that is manufactured at a competitive cost.\",\n \"Another advantageous aspect of the invention refers to a booster bar having a slim width factor and/or slim height factor that enables the booster bar to occupy only a small portion within the electronic wireless device and making it suitable for its integration within slim electronic devices or flexible electronic devices.\",\n \"Another advantageous aspect of the present invention refers to the location and slim form factors of a booster bar to guarantee the most advantageous frequency bandwidth for the available space.\",\n \"A radiation booster, like for instance a booster bar, is separated from the ground plane layer by a gap.\",\n \"In the context of this document, the gap refers to a minimum distance between a point at an edge of the ground plane layer and a point at an edge of the bottom conductive surface of the radiation booster.\",\n \"The location of the radiation booster is characterized by a location factor that is a ratio between the width of the radiation booster and the gap.\",\n \"In a preferred example, the location factor is between 0.5 and 2.In another preferred example, the location factor is between 0.3 and 1.8.Each radiation booster of the slim radiating system advantageously couples the electromagnetic energy from the radio-frequency system to the ground element in transmission, and from the ground element to the radio-frequency system in reception.\",\n \"The radiation boosters excite a radiation mode in the ground element enabling the radiation from the ground element.\",\n \"The form factor of the radiation booster, together with its location in relation to the ground element, is configured to achieve a proper excitation of the radiation mode of the ground element.\",\n \"The location factor is selected to achieve the most favorable frequency bandwidth for a radiation booster with a certain form factor, particularly a booster bar.\",\n \"Apart from the form factor of the radiation booster, the gap is also relevant for properly exciting a radiation mode in the ground plane layer and to achieve the most advantageous frequency bandwidth.\",\n \"The bandwidth of the slim radiating system may be degraded if the location factor is not properly selected.\",\n \"The location factor and the slim form factors of a booster bar are selected to ensure the most favorable frequency bandwidth while minimizing/reducing the amount of space allocated towards the integration of the booster bar within the electronic device.\",\n \"The slim radiating structure is mounted within the electronic device and is coupled to the radio-frequency system via a conductive path.\",\n \"The radiation booster is coupled to the ground element via a conductive path and is located at certain distance from the ground element.\",\n \"Said conductive path comprises a conductive element which may be linear or include a surface; the conductive element may comprise, for instance but not limited to, a metallic strip and/or a conductive trace.\",\n \"In some embodiments, a slim radiating structure comprises one ground element or conductive material acting as a ground plane for the slim radiating structure.\",\n \"In some other embodiments, a slim radiating structure may comprise two, three or more ground elements or conductive materials acting as a ground plane for the radiating structure.\",\n \"In such embodiments, the plurality of ground elements may be electrically interconnected one to each other.\",\n \"The at least one radiation booster for a slim radiating structure according to the present invention may have a maximum size at least smaller than 1/15 of the free-space wavelength corresponding to the lowest frequency of the first frequency region of operation.\",\n \"In some cases, said maximum size may be also smaller than 1/20, and/or 1/25, and/or 1/30, and/or 1/50, and/or 1/100 of the free-space wavelength corresponding to the lowest frequency of the first frequency region of operation.\",\n \"In some cases, the at least one radiation booster fits in an imaginary sphere having a diameter smaller than ⅓, or preferably smaller than ¼, or preferably smaller than ⅙, or even more preferably smaller than 1/10 of a radiansphere at said free-space wavelength.\",\n \"The radiansphere is defined as an imaginary sphere having a radius equal to the operating wavelength divided by two times π (pi).\",\n \"Furthermore, in some examples, the at least one radiation booster also has a maximum size smaller than 1/15, and/or 1/20, and/or 1/25, and/or 1/30, and/or 1/50 of the free-space wavelength corresponding to the lowest frequency of the second frequency region of operation.\",\n \"In some cases, the at least one radiation booster fits in an imaginary sphere having a diameter smaller than ⅓, or preferably smaller than ¼, or preferably smaller than ⅙, or even more preferably smaller than 1/10 of a radiansphere at said free-space wavelength.\",\n \"Additionally, in some of these examples the at least one radiation booster has a maximum size larger than 1/1400, 1/700, 1/350, 1/250, 1 / 180 , 1/140, or 1/120 times the free-space wavelength corresponding to the lowest frequency of said first frequency region.\",\n \"The maximum size of a radiation booster is preferably defined by the largest dimension of a booster box that completely encloses said radiation booster, and in which the radiation booster is inscribed.\",\n \"More specifically, a booster box for a radiation booster is defined as being the minimum-sized parallelepiped of square or rectangular faces that completely encloses the radiation booster and wherein each one of the faces of said minimum-sized parallelepiped is tangent to at least a point of said radiation booster.\",\n \"Moreover, each possible pair of faces of said minimum-size parallelepiped sharing an edge forms an inner angle of 90°.\",\n \"In those cases in which the radiating structure comprises more than one radiation booster, a different booster box is defined for each of them.\",\n \"In some preferred examples, the area defined by the two largest dimensions of a booster box is advantageously small compared to the square of the wavelength corresponding to the lowest frequency of the first frequency region; in particular, a ratio between said area and the square of the wavelength corresponding to the lowest frequency of the first frequency region may be advantageously smaller than at least one of the following percentages: 0.15%, 0.12%, 0.10%, 0.08%, 0.06%, 0.04%, or even 0.02%.\",\n \"In some of these examples, a ratio between the area defined by the two largest dimensions of a booster box and the square of the wavelength corresponding to the lowest frequency of the second frequency region may also be advantageously smaller than at least one of the following percentages: 0.50%, 0.45%, 0.40%, 0.35%, 0.30%, 0.25%, 0.20%, 0.15%, 0.10%, or even 0.05%.\",\n \"Moreover, in some embodiments according to the present invention, the at least one radiation booster will entirely fit inside a limiting volume equal or smaller than L3/25000, and in some cases equal or smaller than L3/50000, L3/100000, L3/150000, L3/200000, L3/300000, L3/400000, or even smaller than L3/500000, being L the wavelength corresponding to the lowest frequency of the first frequency region of operation.\",\n \"A slim radiating system according to the invention is configured to handle multiple communication bands, and to provide coverage and an acceptable level of reflection coefficient in a wide range of communication bands in one or more frequency regions of operation exhibiting a suitable radio-frequency performance.\",\n \"The slim radiating system is designed to transmit and receive radio-frequency signals in multiple communication bands of interest, including frequency bands that may be added, for instance, through the deployment of future cellular telephone bands and/or data service bands.\",\n \"In the context of this document, a frequency band preferably refers to a range of frequencies used by a particular cellular communication standard, a wireless connectivity standard or a broadcast standard, while a frequency region preferably refers to a continuum of frequencies of the electromagnetic spectrum.\",\n \"For example, the GSM 1800 standard is allocated in a frequency band from 1710 MHz to 1880 MHz while the GSM 1900 standard is allocated in a frequency band from 1850 MHz to 1990 MHz.\",\n \"A device operating the GSM 1800 and the GSM1900 standards must have a radiating system capable of operating in a frequency region from 1710 MHz to 1990 MHz.\",\n \"As another example, a wireless device operating the GSM 850 standard (allocated in a frequency band from 824 MHz to 894 MHz) and the GSM 1800 standard must have a radiating system capable of operating in two separate frequency regions.\",\n \"Some frequency bands that the slim radiating system may be configured to transmit and receive signals in are, for example, GSM 850 (824-894 MHz), GSM 900 (880-960 MHz), GSM 1800 (1710-1880 MHz), GSM 1900 (1850-1990 MHz), WCDMA 2100 (1920-2170 MHz), CDMA 1700 (1710-2155 MHz), LTE 700 (698-798 MHz), LTE 800 (791-862 MHz), LTE 2600 (2500-2690 MHz), LTE 3500 (3.4-3.6 GHz), LTE 3700 (3.6-3.8 GHz), WiFi or WLAN (2.4-2.5 GHz and/or 4.9-5.9 GHz), etc.\",\n \"A wireless handheld or portable device according to the present invention may operate one, two, three, four or more cellular communication standards, wireless connectivity standards, and/or broadcasts standards, each standard being allocated in one, two or more frequency bands, and said frequency bands being contained within one, two or more frequency regions of the electromagnetic spectrum.\",\n \"The slim radiating system is designed to provide an acceptable level of reflection coefficient in the frequency regions of operation.\",\n \"A slim radiating system according to the present invention is configured to operate in at least one frequency region.\",\n \"In some embodiments, the slim radiating system is configured to operate in a first frequency region comprising at least a first frequency band, and a second frequency region comprising at least a second frequency band.\",\n \"Such radiating system is configured to satisfy the radio-frequency bandwidths and frequency coverage goals.\",\n \"A slim radiating system according to the present invention may advantageously feature an impedance bandwidth in the first frequency region larger than 5%, 10%, 15%, or even larger than 20%.\",\n \"In addition, such radiating system may also feature an impedance bandwidth in the second frequency region larger than 5%, 10%, 15%, 20%, 25%, 30%, 35%, or even larger than 40%.\",\n \"The impedance bandwidth is defined as the difference between the highest and lowest frequencies of a frequency region, divided by the central frequency of the same frequency region.\",\n \"Due to the small size of the radiation boosters, the radiation boosters and booster bars may be electrically short at some or all frequencies of operation.\",\n \"A slim radiating structure according to the present invention may feature a first resonant frequency, measured at an internal path, at a frequency higher (i.e.\",\n \"above) than the highest frequency of the first frequency region of operation when said radio-frequency system is disconnected.\",\n \"Moreover, when the radio-frequency system is disconnected, the input impedance of the slim radiating structure measured at the internal path may have an important reactance, in particular a capacitive reactance, within the frequencies of said first frequency region.\",\n \"In this case, a ratio between the first resonant frequency of the slim radiating structure and the highest frequency of the first frequency region is advantageously greater than 1.2.In some cases, said ratio may be even greater than one or more of the following values: 1.5, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, or 3.0.In some examples, a ratio between said first resonant frequency and the lowest frequency of the first frequency region of operation is advantageously greater than 1.3, or even greater than one or more of the following values: 1.4, 1.5, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, or 3.0.In some embodiments, the first resonant frequency of the slim radiating structure, measured at an internal path when the radio-frequency system is disconnected, is above the highest frequency of the second frequency region, wherein a ratio between said first resonant frequency and said highest frequency of the second frequency region may be larger than one or more of the following values: 1.0, 1.1, 1.2, 1.4, 1.6, 1.8, or 2.0.In some other embodiments, said first resonant frequency is within the second frequency region.\",\n \"In some other examples, said first resonant frequency is above the highest frequency of the first frequency region and below the lowest frequency of the second frequency region.\",\n \"In the context of this document, a resonant frequency associated to a radiation booster of the slim radiating structure preferably refers to a frequency at which the input impedance of the slim radiating structure, the impedance being measured at the internal path coupling the radiation booster to the radio-frequency system when the radio-frequency system is not connected, has an imaginary part equal or substantially equal to zero.\",\n \"The radio-frequency system may comprise one or more matching circuits that modify the impedance of the slim radiating structure providing impedance matching to the slim radiating system, at an external path, in one or more frequency regions of operation of the slim radiating system.\",\n \"A radio-frequency system according to the invention may include at least one matching network with a plurality of stages, for instance, two, three, four, five, six or more stages.\",\n \"A stage comprises one or more circuit components (for example but not limited to, inductors, capacitors, resistors, jumpers, short-circuits, delay lines, or other reactive or resistive components).\",\n \"In some cases, a stage has a substantially inductive behavior in the frequency region or regions of operation of the slim radiating system, while another stage has a substantially capacitive behavior in said frequency region/s, and yet a third one may have a substantially resistive behavior in said frequency region/s.\",\n \"In an example, a stage may substantially behave as a resonant circuit (such as, for instance, a parallel LC resonant circuit or a series LC resonant circuit) in at least one frequency region of operation of the slim radiating system.\",\n \"The use of stages having a resonant circuit behavior allows one part of a given matching network be effectively connected to another part of said matching network for a given range of frequencies, or in a given frequency region, and be effectively disabled for another range of frequencies, or in another frequency region.\",\n \"In some examples, the at least one matching network alternates stages connected in series (i.e.\",\n \"cascaded) with stages connected in parallel (i.e.\",\n \"shunted), forming a ladder structure.\",\n \"In some cases, a matching network comprising two stages forms an L-shaped structure (i.e.\",\n \"series-parallel or parallel-series).\",\n \"In some cases, a matching network comprising three stages forms either a pi-shaped structure (i.e.\",\n \"parallel-series-parallel) or a T-shaped structure (i.e.\",\n \"series-parallel-series).\",\n \"In some embodiments, a radio-frequency system according to the present invention comprises a matching circuit in a ladder topology.\",\n \"Such matching circuit preferably comprises one reactive component per stage.\",\n \"In some other embodiments, a radio-frequency system according to the present invention comprises a matching circuit at least including a series LC resonant circuit and a parallel LC resonant circuit.\",\n \"In a preferred embodiment, an electronic device comprises a slim radiating system configured to transmit and receive electromagnetic wave signals in at least one frequency region of the electromagnetic spectrum, and comprising a slim radiating structure, a radio-frequency system, at least one internal conductive path and at least one external conductive path.\",\n \"The slim radiating structure comprises at least one ground element and at least one booster bar.\",\n \"The at least one internal conductive path comprises a conductive element that couples the at least one booster bar to the radio-frequency system.\",\n \"The radio-frequency system comprises at least one matching circuit modifying the impedance of the slim radiating structure providing impedance matching to the slim radiating system in the at least one frequency region at the at least one external conductive path.\",\n \"The at least one booster bar has an elongated shape, and is characterized by a slim width factor greater than 3 and a slim height factor greater than 3, is separated from the at least one ground element by a gap and is characterized by a location factor between 0.5 and 2.Another preferred embodiment relates to an electronic device including a slim radiating system that comprises a slim radiating structure, a radio-frequency system, an internal conductive path and at least one external conductive path; the slim radiating system is configured to transmit and receive electromagnetic wave signals in a first frequency region and a second frequency region.\",\n \"The slim radiating structure comprises at least one ground element, and one booster bar separated from the ground element by a gap and is characterized by a location factor between 0.3 and 1.8.The internal conductive path comprises a conductive element that couples the booster bar to the radio-frequency system.\",\n \"The radio-frequency system comprises a matching circuit that modifies the impedance of the slim radiating structure providing impedance matching to the slim radiating system in the first and second frequency regions at the at least one external conductive path.\",\n \"The first and second frequency regions are preferably separated so that the lowest frequency of the second frequency region is above the highest frequency of the first frequency region.\",\n \"Some preferred matching circuits for such preferred embodiment are described in FIGS.\",\n \"15A-15F .\",\n \"Further, an advantageous aspect of the invention refers to a radio-frequency system comprising a matching circuit that provides impedance matching to the slim radiating system in first and second frequency regions preferably not requiring a filtering circuit or component that separates frequencies of the first frequency region from frequencies of the second frequency region (e.g.\",\n \"a diplexer, a bank of filters, etc.)\",\n \"for providing impedance matching in the first frequency region and second frequency region independently (i.e.\",\n \"in two separate branches or paths).\",\n \"Thus preferred matching circuits may provide impedance matching in said first and second frequency regions with one branch.\",\n \"According to the present invention, some preferred matching circuits preferably comprise seven or less components, for instance: two, three, four, five, six or seven.\",\n \"Such matching circuits preferably do not comprise active circuits or components.\",\n \"In some embodiments in which the slim radiating system is configured to transmit and receive signals in a first frequency region and a second frequency region, a ratio between the lowest frequency of the second frequency region and the lowest frequency of the first frequency region may be greater than 1.5.In some of these embodiments, said ratio may be also greater than 1.8, 2.0, 2.2, or 2.4.In addition, in some embodiments in which the slim radiating system is configured to operate signals from first and second frequency regions, a ratio between the lowest frequency of the second frequency and the highest frequency of the first frequency region may be greater than 1.2, 1.5, 1.8, 2.0, 2.2, or 2.4.Accordingly, an advantageous aspect of such radio-frequency system is its efficiency in that impedance matching in the first and second frequency regions may be provided with one matching circuit using a reduced number of components, which consequently introduces lower losses in the radio-frequency system and makes it more robust against the tolerances of the components.\",\n \"Moreover, by not including filtering circuits such as diplexers, the radio-frequency system avoids the insertion losses characterizing such type of circuits and the necessity of having two separate matching circuits, which consequently makes the radio-frequency system have less components and the slim radiating system smaller in terms of area occupied in the device.\",\n \"In a third preferred embodiment, an electronic device includes a slim radiating system comprising a slim radiating structure, a radio-frequency system, first and second internal conductive paths and at least one external conductive path; the slim radiating system is configured to transmit and receive electromagnetic wave signals in a first frequency region and a second frequency region.\",\n \"The slim radiating structure comprises at least one ground plane layer, first and second radiation boosters, each of the first and second radiation boosters being separated from the ground plane layer by a gap.\",\n \"The first internal conductive path comprises a conductive element that couples the first radiation booster to the radio-frequency system, and the second internal conductive path comprises a conductive element that couples the second radiation booster to the radio-frequency system.\",\n \"The radio-frequency system comprises a matching circuit coupled to the first and second internal conductive paths and to the external conductive path, the matching circuit modifies the impedance of the slim radiating structure providing impedance matching to the slim radiating system in the first and second frequency regions.\",\n \"In some cases, the slim radiating system may comprise a first external conductive path and a second external conductive path, and the radio-frequency system may include a diplexer circuitry that advantageously filters signals from first and second frequency regions, said signals being matched in impedance in the first and second frequency regions by the matching circuit within the radio-frequency system.\",\n \"A first port of the diplexer is connected to the matching circuit, and the two remaining ports of the diplexer are connected to the first and second external conductive paths.\",\n \"The first and second external paths comprise, respectively, signals for frequencies from the first frequency region, and signals for frequencies from the second frequency region.\",\n \"A further aspect of the present invention relates to a test platform for electromagnetically characterizing radiation boosters.\",\n \"Said platform comprises a substantially square conductive surface on top of which, and substantially close to the central point, the element to be characterized is mounted perpendicular to said surface in a monopole configuration, said conductive surface acting as the ground plane.\",\n \"The substantially square conductive surface comprises sides with a dimension larger than a reference operating wavelength.\",\n \"In the context of the present invention, said reference operating wavelength is the free-space wavelength equivalent to a frequency of 900 MHz.\",\n \"A substantially square conductive surface according to the present invention is made of copper with sides measuring 60 centimeters, and a thickness of 0.5 millimeters.\",\n \"In the test configuration as set forth above, a booster bar according to the present invention may be characterized by a ratio between the first resonance frequency and the reference frequency (900 MHz) being larger than a minimum ratio of 3.0.In some cases, said ratio may be even larger than a minimum ratio such as: 3.4, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.6 or 7.0.A booster bar according to the present invention may also be characterized by a radiation efficiency measured in said platform, at a frequency equal to 900 MHz, being less than 50%, preferably being less than 40%, 30%, 20%, or 10%, and in some cases being less than 7.5%, 5%, or 2.5%.\",\n \"All those are quite remarkably low efficiency values considering the additional 1:3 frequency mismatch and beyond obtained in some of the embodiments as described above.\",\n \"Such a frequency shift would introduce further mismatch losses that would result in an overall antenna efficiency below 5%, and quite typically below 2%, which would be ordinarily considered unacceptable for a mobile phone or wireless application.\",\n \"Still, quite surprisingly, when combining at least one booster bar with the radio-frequency system of a slim radiating system according to the present invention, said slim radiating system recovers the efficiency required for the performance of a typical wireless device.\"\n ],\n [\n \"CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser.\",\n \"No.\",\n \"14/807,449 filed Jul.\",\n \"23, 2015, which claims priority under 35 U.S.C.\",\n \"§119(e) from U.S.\",\n \"Provisional Patent Application Ser.\",\n \"No.\",\n \"62/028,494, filed Jul.\",\n \"24, 2014, U.S.\",\n \"Provisional Patent Application Ser.\",\n \"No.\",\n \"62/064,716, filed Oct. 16, 2014, U.S.\",\n \"Provisional Patent Application Ser.\",\n \"No.\",\n \"62/072,671, filed Oct. 30, 2014, and U.S.\",\n \"Provisional Patent Application Ser.\",\n \"No.\",\n \"62/152,991, filed Apr.\",\n \"27, 2015, the entire contents of which are hereby incorporated by reference.\",\n \"In addition, this application claims foreign priority under 35 U.S.C.\",\n \"§119(a)-(d) to Application No.\",\n \"EP 14178369.6 filed on Jul.\",\n \"24, 2014, Application No.\",\n \"EP 14189253.9 filed on Oct. 16, 2014, Application No.\",\n \"EP 14191145.3 filed on Oct. 30, 3014, and Application No.\",\n \"EP 15165167.6 filed on Apr.\",\n \"27, 2015, the entire contents of which are hereby incorporated by reference.\",\n \"STATEMENT OF RESEARCH FUNDING This patent application is part of a project that has received funding from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement No.\",\n \"674491.FIELD OF THE INVENTION The present invention relates generally to the field of electronic devices which require the transmission and/or reception of electromagnetic wave signals, and more particularly, to slim radiating structures in wireless electronic devices.\",\n \"BACKGROUND Wireless electronic devices typically handle one or more cellular communication standards, and/or wireless connectivity standards, and/or broadcast standards, each standard being allocated in one or more frequency bands, and the frequency bands being contained within one or more regions of the electromagnetic spectrum.\",\n \"For that purpose, a typical wireless electronic device must include a radiating system capable of operating in one or more frequency regions with an acceptable radio-electric performance (in terms of for instance reflection coefficient, standing wave ratio, impedance bandwidth, gain, efficiency, or radiation pattern).\",\n \"The integration of the radiating system within the wireless electronic device must be effective to ensure that the overall device attains good radio-electric performance (such as for example in terms of radiated power, received power, sensitivity) without being disrupted by electronic components and/or human loading.\",\n \"Additionally, a space within the wireless electronic device is usually limited and the radiating system has to be included in the available space.\",\n \"The radiating system is expected to be small enough to occupy as little space as possible within the device, which then allows for smaller devices, or for the addition of more specific components and functionalities into the device.\",\n \"At the same time, it is sometimes convenient for the radiating system to be flat since this allows for slim devices.\",\n \"Thus, many of the demands for wireless devices also translate to specific demands for the radiating systems thereof.\",\n \"This is even more critical in the case in which the wireless device is a multifunctional wireless device.\",\n \"Commonly-owned patent applications WO2008/009391 and US2008/0018543 describe a multifunctional wireless device.\",\n \"The entire disclosure of aforesaid application numbers WO2008/009391 and US2008/0018543 are hereby incorporated by reference.\",\n \"For a good wireless connection, high efficiency is further required.\",\n \"Other more common design demands for radiating systems are the reflection coefficient (or standing-wave ratio, SWR) and the impedance which is supposed to be about 50 ohms.\",\n \"Other demands for radiating systems for wireless handheld or portable devices are competitive cost and a low SAR.\",\n \"Furthermore, a radiating system has to be integrated into a device or, in other words, a wireless device has to be constructed such that an appropriate radiating system may be integrated therein which puts additional constraints by consideration of the mechanical fit, the electrical fit, and the assembly fit.\",\n \"Of further importance, usually, is the robustness of the radiating system, which means that the radiating system does not change its properties upon smaller shocks to the device and the human loading.\",\n \"Besides radio-frequency performance, small size and reduced interaction with human body and nearby electronic components, one of the current limitations of the prior-art is that generally the antenna system is customized for every particular wireless handheld device model.\",\n \"The mechanical architecture of each device model is different and the volume available for the antenna severely depends on the form factor of the wireless device model together with the arrangement of the multiple components embedded into the device (e.g., displays, keyboards, battery, connectors, cameras, flashes, speakers, chipsets, memory devices, etc.).\",\n \"As a result, the antenna within the device is mostly designed ad hoc for every model, resulting in a higher cost and a delayed time to market.\",\n \"In turn, as typically the design and integration of an antenna element for a radiating structure is customized for each wireless device, different form factors or platforms, or a different distribution of the functional blocks of the device will force to redesign the antenna element and its integration inside the device almost from scratch.\",\n \"A radiating system for a wireless handheld or portable device typically includes a radiating structure comprising an antenna element which operates in combination with a ground plane layer providing a determined radio-frequency performance in one or more frequency regions of the electromagnetic spectrum.\",\n \"Typically, the antenna element has a dimension close to an integer multiple of a quarter of the wavelength at a frequency of operation of the radiating structure, so that the antenna element is at resonance or substantially close to resonance at the frequency of operation, and a radiation mode is excited on the antenna element.\",\n \"Antenna elements operating in multiple frequency bands allocated at different regions of the electromagnetic spectrum usually present complex mechanical designs and considerable dimensions, mainly due to the fact that antenna performance is highly related to the electrical dimensions of the antenna element.\",\n \"A further problem associated to the integration of the radiating structure, and in particular to the integration of the antenna element in a wireless device is that the volume dedicated for such integration has continuously shrunk with the appearance of new smaller and/or thinner form factors for wireless devices, and with the increasing convergence of different functionalities in a same wireless device.\",\n \"Therefore, from the conventional wisdom perspective, the trend in seeking for slimmer wireless device is incompatible with maximizing the performance of a traditional antenna device, which again, it is known to have a high correlation between antenna size (relative to the operating wavelengths) and performance.\",\n \"Some techniques to miniaturize and/or optimize the multiband behavior of an antenna element have been described in the prior art.\",\n \"However the radiating structures described therein still rely on exciting a radiation mode on the antenna element for each one of the frequency bands of operation.\",\n \"This fact leads to complex mechanical designs and large antennas that usually are very sensitive to external effects (such as for instance the presence of plastic or dielectric covers that surround the wireless device), to components of the wireless device (such as for instance, but not limited to, a speaker, a microphone, a connector, a display, a shield can, a vibrating module, a battery, or an electronic module or subsystem) placed either in the vicinity of, or even underneath, the radiating element, and/or to the human loading.\",\n \"A multiband antenna system is sensitive to any of the above mentioned aspects because they may alter the electromagnetic coupling between the different geometrical portions of the radiating element, which usually translates into detuning effects, degradation of the radio-frequency performance of the antenna system and/or the radio-frequency performance of the wireless device, and/or greater interaction with the user (such as an increased level of SAR).\",\n \"In this sense, a radiating system such as the one described in the present invention not requiring a complex and/or large antenna formed by multiple arms, slots, apertures and/or openings and a complex mechanical design is preferable in order to minimize such undesired external effects and simplify the integration within the wireless device.\",\n \"Some other attempts have focused on antenna elements not requiring a complex geometry while still providing some degree of miniaturization by using an antenna element that is not resonant in the one or more frequency ranges of operation of the wireless device.\",\n \"For example, WO2007/128340 discloses a wireless portable device comprising a non-resonant antenna element for receiving broadcast signals (such as, for instance, DVB-H, DMB, T-DMB or FM).\",\n \"The wireless portable device further comprises a ground plane layer that is used in combination with said antenna element.\",\n \"Although the antenna element has a first resonant frequency above the frequency range of operation of the wireless device, the antenna element is still the main responsible for the radiation process and for the radio-frequency performance of the wireless device.\",\n \"This is clear from the fact that no radiation mode can be excited on the ground plane layer because the ground plane layer is electrically short at the frequencies of operation (i.e., its dimensions are much smaller than the wavelength).\",\n \"For this kind of non-resonant antenna elements, a matching circuitry is added for matching the antenna to a level of SWR in a limited frequency range, which in this particular case can be around SWR<6.Such level of SWR together with the limited bandwidth results in antenna elements which are only acceptable for reception of electromagnetic wave signals but not desirable for transmission of electromagnetic wave signals.\",\n \"With such limitations, while the performance of the wireless portable device may be sufficient for reception of electromagnetic wave signals (such as those of a broadcast service), the antenna element could not provide an acceptable performance (for example, in terms of reflection coefficient or gain) for a communication service requiring also the transmission of electromagnetic wave signals.\",\n \"Commonly-owned patent applications WO2008/119699 and US2010/0109955 describe a wireless handheld or portable device comprising a radiating system capable of operating in two frequency regions.\",\n \"The radiating system comprises an antenna element having a resonant frequency outside said two frequency regions, and a ground plane layer.\",\n \"In this wireless device, while the ground plane layer contributes to enhance the electromagnetic performance of the radiating system in the two frequency regions of operation, it is still necessary to excite a radiation mode on the antenna element.\",\n \"In fact, the radiating system relies on the relationship between a resonant frequency of the antenna element and a resonant frequency of the ground plane layer in order for the radiating system to operate properly in said two frequency regions.\",\n \"Nevertheless, the solution still relies on an antenna element whose size is related to a resonant frequency that is outside of the two frequency regions.\",\n \"The entire disclosures of the aforesaid application numbers WO2008/119699 and US2010/0109955 are hereby incorporated by reference.\",\n \"A different radiating system is disclosed in U.S. Pat.\",\n \"No.\",\n \"6,674,411, in which a planar inverted-L antenna (i.e., a patch antenna) has a radiating element composed by a rectangular plate placed above and substantially parallel to a ground plane.\",\n \"The antenna is connected to a matching network that provides a match in one frequency band in a first frequency region, and in one frequency band in a second frequency region.\",\n \"Thus the antenna system is limited to single-band operation in both frequency regions.\",\n \"When operation in more bands is sought, the antenna system requires of a switched (active) matching network that provides non-simultaneous impedance matching in each frequency band.\",\n \"So in spite of having an antenna that occupies a large volume (20×10×8 mm3), not more than dual-band operation may be provided simultaneously.\",\n \"For at least the above reasons, wireless device manufacturers regard the volume dedicated to the integration of the radiating structure, and in particular the antenna element, as being a toll to pay in order to provide wireless communication capabilities to the handheld or portable device.\",\n \"In order to reduce as much as possible the volume occupied into the wireless handheld or portable device, recent trends in handset antenna design are oriented to maximize the contribution of the ground plane to the radiation process by using very small non-resonant elements.\",\n \"However, non-resonant elements usually are forced to include a complex radio-frequency system.\",\n \"Thus, the challenge of these techniques mainly relies on said complexity (combination of inductors, capacitors, and transmission lines), which is required to satisfy impedance bandwidth and efficiency specifications.\",\n \"Commonly owned patent applications, WO2010/015365, and WO2010/015364 are intended for solving some of the aforementioned drawbacks.\",\n \"Namely, they describe a wireless handheld or portable device comprising a radiating system including a radiating structure and a radio-frequency system.\",\n \"The radiating structure is formed by a ground plane layer presenting suitable dimensions as for supporting at least one efficient radiation mode and at least one radiation booster capable of coupling electromagnetic energy to said ground plane layer.\",\n \"The radiation booster is not resonant in any of the frequency regions of operation and, consequently, a radio-frequency system is used to properly match the radiating structure to the desired frequency bands of operation.\",\n \"More particularly, in WO2010/015364 each radiation booster is intended for providing operation in a particular frequency region.\",\n \"Thus, the radio-frequency system is designed in such a way that the first internal port associated to the first radiation booster is highly isolated from the second internal port associated to a second radiation booster.\",\n \"Said radio-frequency system usually comprises a matching network including resonators for each one of the frequency regions of operation and a set of filters for each one of the frequency regions of operation.\",\n \"Thus, said radio-frequency system requires multiple stages and the performance of the radiating systems in terms of efficiency may be affected by the additional losses of the components.\",\n \"As each radiation booster is generally intended for providing operation in a particular frequency region, the bandwidth capabilities may be limited for some applications requiring very wide bandwidth specially at the low frequency region, as for example for wireless devices operating at LTE700, GSM850 and GSM900.Commonly owned patent applications WO2014/012796 and US2014/0015730 disclose a concentrated wireless device comprising a radiating system including a radiating structure and a radio-frequency system, such device operating two or more frequency regions of the electromagnetic spectrum.\",\n \"A feature of said radiating system is that the operation in at least two frequency regions is achieved by one radiation booster, or by at least two radiation boosters, or by at least one radiation booster and at least one antenna element, wherein the radio-frequency system modifies the impedance of the radiating structure, providing impedance matching to the radiating system in the at least two frequency regions of operation of the radiating system.\",\n \"The entire disclosure of aforesaid application numbers WO2014/012796 and US2014/0015730 are hereby incorporated by reference.\",\n \"Commonly owned patent applications WO2014/012842 and US2014/0015728 disclose very compact, small size and light weight radiation boosters operating in single or in multiple frequency bands.\",\n \"Such radiation boosters are configured to be used in radiating systems that may be embedded into a wireless handheld device.\",\n \"Said patent applications further disclose radiation booster structures and their manufacturing methods that enable reducing the cost of both the booster and the entire wireless device embedding said booster inside the device.\",\n \"The entire disclosure of aforesaid application numbers WO2014/012842 and US2014/0015728 are hereby incorporated by reference.\",\n \"Another technique, as disclosed in U.S. Pat.\",\n \"No.\",\n \"7,274,340, is based on the use of two coupling elements.\",\n \"According to the invention, quad-band operation (GSM 1800/1900 and GSM850/900 bands) is provided with two coupling elements: a low-band (LB) coupling element (for the GSM850/900 bands), and a high-band (HB) coupling element (for the GSM1800/1900 bands), where the impedance matching is provided through the addition of two matching circuits, one for the LB coupling element and another one for the HB coupling element.\",\n \"In spite of using non-resonant elements, the size of the element for the low band is significantly large, being 1/9.3 times the free-space wavelength of the lowest frequency for the low frequency band.\",\n \"Due to such size, the low band element would be a resonant element at the high band.\",\n \"Additionally, the operation of this solution is closely linked to the alignment of the maximum E-field intensity of the ground plane and the coupling element.\",\n \"The size of the low band element undesirably contributes to increase the printed circuit board (PCB) space required by the antenna module.\",\n \"According to the invention, the bandwidth at the low frequency region is 133 MHz (from 821 MHz to 954 MHz) that is insufficient for some applications requiring very wide bandwidth, especially at the low frequency region, as for example for wireless devices operating at LTE700, GSM850 and GSM900.Therefore, a wireless device not requiring an antenna element and including a slim radiating system would be advantageous to make simpler the integration of the slim radiating structure into the wireless electronic device minimizing the amount of the electronic device that is allocated towards the slim radiating system, and to provide a suitable radio-frequency performance to operate in a wide range of communication bands.\",\n \"The volume freed up by the absence of a large and complex antenna element would enable smaller and/or thinner devices, as slim electronic devices, or even to adopt radically new form factors which are not feasible today due to the presence of an antenna element featuring a considerable volume.\",\n \"Furthermore, by eliminating precisely the element that requires customization, a standard solution is sought which should only require minor adjustments to be implemented in different wireless electronic devices.\",\n \"SUMMARY It is an object of the present invention to provide an electronic device (such as for instance but not limited to a mobile phone, a smartphone, a phablet, a PDA, an MP3 player, a headset, a USB dongle, a laptop computer, a tablet, a gaming device, a GPS system, a digital camera, a wearable device as a smart watch, a PCMCIA, Cardbus 32 card, a sensor, or generally a multifunction wireless device which combines the functionality of multiple devices) containing a slim radiating system that covers a wide range of radio-frequencies and handles multiple communication bands while exhibiting a suitable radio-frequency performance.\",\n \"It is another object of the invention to provide a slim radiating system suitable for being included within electronic devices, and more preferably within slim electronic devices.\",\n \"It is another object of the invention to provide a standard slim radiating system which only requires minor adjustments to be included within different electronic devices.\",\n \"Another object of the invention refers to the location (on the device) of radiation boosters and, more particularly, booster bars for obtaining the most favorable frequency bandwidth values.\",\n \"An electronic device according to the invention may have a candy-bar shape, which means that its configuration is given by a single body.\",\n \"It may also have a two-body configuration such as a clamshell, flip-type, swivel-type or slider structure.\",\n \"In some other cases, the device may have a configuration comprising three or more bodies.\",\n \"It may further or additionally have a twist configuration in which a body portion (e.g.\",\n \"with a screen) can be twisted (i.e., rotated around two or more axes of rotation which are preferably not parallel).\",\n \"The electronic device may comprise a memory module, a processing circuitry module, a user interface module, a battery, and a wireless communication module.\",\n \"The wireless communication module may include a slim radiating system, a radio-frequency transceiver circuit, a power amplifier circuit and a base-band module.\",\n \"The slim radiating system may be coupled to the power amplifier via a conductive path and to the radio transceiver circuit via a conductive path.\",\n \"The wireless communication module may include a multiplexing stage coupled to the slim radiating system via a conductive path.\",\n \"A slim radiating system in accordance with the invention may include a slim radiating structure, a radio-frequency system, at least one internal conductive path and at least one external conductive path.\",\n \"The slim radiating structure may include a ground element and at least one radiation booster, which in some embodiments may be a booster bar, separated from the ground element by a gap.\",\n \"A slim radiating structure may comprise a ground element and one, two, three, four or even more radiation boosters.\",\n \"In some preferred embodiments, said radiation boosters may be booster bars featuring an elongated shape.\",\n \"In preferred embodiments, each booster bar or radiation booster is separated from the ground element by a gap.\",\n \"An aspect of the present invention relates to the use of the ground element (or ground plane layer) of the slim radiating system as a main source of radiation.\",\n \"A radiation booster includes a dielectric material and in some embodiments, a single standard layer of dielectric material spacing two or more conductive elements.\",\n \"A single standard layer of dielectric material refers to dielectric material with a standard thickness, which is available off-the-shelf.\",\n \"For example, 0.025″ (0.635 mm), 0.047″ (1.2 mm), 0.093″ (2.36 mm) or 0.125″ (3.175 mm) are common/standard thicknesses for dielectric materials which are available in the market.\",\n \"Examples of dielectric materials may include fiber-glass FR4, Cuclad, Alumina, Kapton, Ceramic and for instance commercial laminates and substrates from Rogers® Corporation (R03000® and R04000® laminates, Duroid substrates and alike) or other suitable non-conductive materials.\",\n \"The radiation booster may be formed by printing or depositing conductive material in a first and a second surface of the dielectric material (e.g.\",\n \"top and bottom) and adding several vias to electrically connect the conductive material in the first surface with the conductive material in the second surface.\",\n \"The conductive material in the first and second surfaces may have a substantially polygonal shape.\",\n \"Some possible polygonal shapes are for instance, but not limited to, squares, rectangles, and trapezoids.\",\n \"When the conductive material in said first and second surfaces has an elongated shape, for instance a rectangular shape, the radiation booster takes the form of a booster bar; a booster bar may also include vias that electrically connect the conductive material in the first surface with the conductive material in the second surface.\",\n \"The elongated shape of a booster bar is characterized by two slim form factors: a slim width factor and a slim height factor.\",\n \"The slim width factor is a ratio between a length of the booster bar and a width of the booster bar.\",\n \"The slim height factor is a ratio between the length of the booster bar and a height of the booster bar.\",\n \"The slim width factor characterizes the ratio between the length and the width of the booster bar, whereas the slim height factor characterizes the ratio between the length and the height of the booster bar.\",\n \"In a preferred embodiment, the value for the slim width factor and the slim height factor is greater than 2, for instance in one or more of those embodiments the value for the slim width factor is greater than 3, and preferably larger than 3.5, and the slim height factor is greater than 4.In another preferred embodiment, the value for the slim width factor is greater than 6 and/or the slim height factor is greater than 6.In another preferred embodiment, the value for the slim width factor is greater than 6 and/or the slim height factor is larger than 9.In some less preferred embodiments, the values for both the slim width factor and the slim height factor are between 1 and 2.The slim width factor and the slim height factor of a booster bar may take any of the values listed above yet being smaller than 25, and preferably smaller than 10.A radiation booster may comprise one, two or more booster bars electrically connected, forming a booster element that fits in an imaginary sphere having a diameter smaller than ⅓ of a radiansphere corresponding to the lowest frequency of operation of the slim radiating system.\",\n \"Such a booster element may also be characterized by a slim width factor, a slim height factor, and a location factor.\",\n \"Any booster element according to the present invention may be limited by a slim width factor and a slim height factor, each of these factors being between 1 and 10, and preferably between 2 and 10.An advantageous aspect of the invention refers to a booster bar built on a single standard layer of dielectric material that is manufactured at a competitive cost.\",\n \"Another advantageous aspect of the invention refers to a booster bar having a slim width factor and/or slim height factor that enables the booster bar to occupy only a small portion within the electronic wireless device and making it suitable for its integration within slim electronic devices or flexible electronic devices.\",\n \"Another advantageous aspect of the present invention refers to the location and slim form factors of a booster bar to guarantee the most advantageous frequency bandwidth for the available space.\",\n \"A radiation booster, like for instance a booster bar, is separated from the ground plane layer by a gap.\",\n \"In the context of this document, the gap refers to a minimum distance between a point at an edge of the ground plane layer and a point at an edge of the bottom conductive surface of the radiation booster.\",\n \"The location of the radiation booster is characterized by a location factor that is a ratio between the width of the radiation booster and the gap.\",\n \"In a preferred example, the location factor is between 0.5 and 2.In another preferred example, the location factor is between 0.3 and 1.8.Each radiation booster of the slim radiating system advantageously couples the electromagnetic energy from the radio-frequency system to the ground element in transmission, and from the ground element to the radio-frequency system in reception.\",\n \"The radiation boosters excite a radiation mode in the ground element enabling the radiation from the ground element.\",\n \"The form factor of the radiation booster, together with its location in relation to the ground element, is configured to achieve a proper excitation of the radiation mode of the ground element.\",\n \"The location factor is selected to achieve the most favorable frequency bandwidth for a radiation booster with a certain form factor, particularly a booster bar.\",\n \"Apart from the form factor of the radiation booster, the gap is also relevant for properly exciting a radiation mode in the ground plane layer and to achieve the most advantageous frequency bandwidth.\",\n \"The bandwidth of the slim radiating system may be degraded if the location factor is not properly selected.\",\n \"The location factor and the slim form factors of a booster bar are selected to ensure the most favorable frequency bandwidth while minimizing/reducing the amount of space allocated towards the integration of the booster bar within the electronic device.\",\n \"The slim radiating structure is mounted within the electronic device and is coupled to the radio-frequency system via a conductive path.\",\n \"The radiation booster is coupled to the ground element via a conductive path and is located at certain distance from the ground element.\",\n \"Said conductive path comprises a conductive element which may be linear or include a surface; the conductive element may comprise, for instance but not limited to, a metallic strip and/or a conductive trace.\",\n \"In some embodiments, a slim radiating structure comprises one ground element or conductive material acting as a ground plane for the slim radiating structure.\",\n \"In some other embodiments, a slim radiating structure may comprise two, three or more ground elements or conductive materials acting as a ground plane for the radiating structure.\",\n \"In such embodiments, the plurality of ground elements may be electrically interconnected one to each other.\",\n \"The at least one radiation booster for a slim radiating structure according to the present invention may have a maximum size at least smaller than 1/15 of the free-space wavelength corresponding to the lowest frequency of the first frequency region of operation.\",\n \"In some cases, said maximum size may be also smaller than 1/20, and/or 1/25, and/or 1/30, and/or 1/50, and/or 1/100 of the free-space wavelength corresponding to the lowest frequency of the first frequency region of operation.\",\n \"In some cases, the at least one radiation booster fits in an imaginary sphere having a diameter smaller than ⅓, or preferably smaller than ¼, or preferably smaller than ⅙, or even more preferably smaller than 1/10 of a radiansphere at said free-space wavelength.\",\n \"The radiansphere is defined as an imaginary sphere having a radius equal to the operating wavelength divided by two times π (pi).\",\n \"Furthermore, in some examples, the at least one radiation booster also has a maximum size smaller than 1/15, and/or 1/20, and/or 1/25, and/or 1/30, and/or 1/50 of the free-space wavelength corresponding to the lowest frequency of the second frequency region of operation.\",\n \"In some cases, the at least one radiation booster fits in an imaginary sphere having a diameter smaller than ⅓, or preferably smaller than ¼, or preferably smaller than ⅙, or even more preferably smaller than 1/10 of a radiansphere at said free-space wavelength.\",\n \"Additionally, in some of these examples the at least one radiation booster has a maximum size larger than 1/1400, 1/700, 1/350, 1/250, 1/180, 1/140, or 1/120 times the free-space wavelength corresponding to the lowest frequency of said first frequency region.\",\n \"The maximum size of a radiation booster is preferably defined by the largest dimension of a booster box that completely encloses said radiation booster, and in which the radiation booster is inscribed.\",\n \"More specifically, a booster box for a radiation booster is defined as being the minimum-sized parallelepiped of square or rectangular faces that completely encloses the radiation booster and wherein each one of the faces of said minimum-sized parallelepiped is tangent to at least a point of said radiation booster.\",\n \"Moreover, each possible pair of faces of said minimum-size parallelepiped sharing an edge forms an inner angle of 90°.\",\n \"In those cases in which the radiating structure comprises more than one radiation booster, a different booster box is defined for each of them.\",\n \"In some preferred examples, the area defined by the two largest dimensions of a booster box is advantageously small compared to the square of the wavelength corresponding to the lowest frequency of the first frequency region; in particular, a ratio between said area and the square of the wavelength corresponding to the lowest frequency of the first frequency region may be advantageously smaller than at least one of the following percentages: 0.15%, 0.12%, 0.10%, 0.08%, 0.06%, 0.04%, or even 0.02%.\",\n \"In some of these examples, a ratio between the area defined by the two largest dimensions of a booster box and the square of the wavelength corresponding to the lowest frequency of the second frequency region may also be advantageously smaller than at least one of the following percentages: 0.50%, 0.45%, 0.40%, 0.35%, 0.30%, 0.25%, 0.20%, 0.15%, 0.10%, or even 0.05%.\",\n \"Moreover, in some embodiments according to the present invention, the at least one radiation booster will entirely fit inside a limiting volume equal or smaller than L3/25000, and in some cases equal or smaller than L3/50000, L3/100000, L3/150000, L3/200000, L3/300000, L3/400000, or even smaller than L3/500000, being L the wavelength corresponding to the lowest frequency of the first frequency region of operation.\",\n \"A slim radiating system according to the invention is configured to handle multiple communication bands, and to provide coverage and an acceptable level of reflection coefficient in a wide range of communication bands in one or more frequency regions of operation exhibiting a suitable radio-frequency performance.\",\n \"The slim radiating system is designed to transmit and receive radio-frequency signals in multiple communication bands of interest, including frequency bands that may be added, for instance, through the deployment of future cellular telephone bands and/or data service bands.\",\n \"In the context of this document, a frequency band preferably refers to a range of frequencies used by a particular cellular communication standard, a wireless connectivity standard or a broadcast standard, while a frequency region preferably refers to a continuum of frequencies of the electromagnetic spectrum.\",\n \"For example, the GSM 1800 standard is allocated in a frequency band from 1710 MHz to 1880 MHz while the GSM 1900 standard is allocated in a frequency band from 1850 MHz to 1990 MHz.\",\n \"A device operating the GSM 1800 and the GSM1900 standards must have a radiating system capable of operating in a frequency region from 1710 MHz to 1990 MHz.\",\n \"As another example, a wireless device operating the GSM 850 standard (allocated in a frequency band from 824 MHz to 894 MHz) and the GSM 1800 standard must have a radiating system capable of operating in two separate frequency regions.\",\n \"Some frequency bands that the slim radiating system may be configured to transmit and receive signals in are, for example, GSM 850 (824-894 MHz), GSM 900 (880-960 MHz), GSM 1800 (1710-1880 MHz), GSM 1900 (1850-1990 MHz), WCDMA 2100 (1920-2170 MHz), CDMA 1700 (1710-2155 MHz), LTE 700 (698-798 MHz), LTE 800 (791-862 MHz), LTE 2600 (2500-2690 MHz), LTE 3500 (3.4-3.6 GHz), LTE 3700 (3.6-3.8 GHz), WiFi or WLAN (2.4-2.5 GHz and/or 4.9-5.9 GHz), etc.\",\n \"A wireless handheld or portable device according to the present invention may operate one, two, three, four or more cellular communication standards, wireless connectivity standards, and/or broadcasts standards, each standard being allocated in one, two or more frequency bands, and said frequency bands being contained within one, two or more frequency regions of the electromagnetic spectrum.\",\n \"The slim radiating system is designed to provide an acceptable level of reflection coefficient in the frequency regions of operation.\",\n \"A slim radiating system according to the present invention is configured to operate in at least one frequency region.\",\n \"In some embodiments, the slim radiating system is configured to operate in a first frequency region comprising at least a first frequency band, and a second frequency region comprising at least a second frequency band.\",\n \"Such radiating system is configured to satisfy the radio-frequency bandwidths and frequency coverage goals.\",\n \"A slim radiating system according to the present invention may advantageously feature an impedance bandwidth in the first frequency region larger than 5%, 10%, 15%, or even larger than 20%.\",\n \"In addition, such radiating system may also feature an impedance bandwidth in the second frequency region larger than 5%, 10%, 15%, 20%, 25%, 30%, 35%, or even larger than 40%.\",\n \"The impedance bandwidth is defined as the difference between the highest and lowest frequencies of a frequency region, divided by the central frequency of the same frequency region.\",\n \"Due to the small size of the radiation boosters, the radiation boosters and booster bars may be electrically short at some or all frequencies of operation.\",\n \"A slim radiating structure according to the present invention may feature a first resonant frequency, measured at an internal path, at a frequency higher (i.e.\",\n \"above) than the highest frequency of the first frequency region of operation when said radio-frequency system is disconnected.\",\n \"Moreover, when the radio-frequency system is disconnected, the input impedance of the slim radiating structure measured at the internal path may have an important reactance, in particular a capacitive reactance, within the frequencies of said first frequency region.\",\n \"In this case, a ratio between the first resonant frequency of the slim radiating structure and the highest frequency of the first frequency region is advantageously greater than 1.2.In some cases, said ratio may be even greater than one or more of the following values: 1.5, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, or 3.0.In some examples, a ratio between said first resonant frequency and the lowest frequency of the first frequency region of operation is advantageously greater than 1.3, or even greater than one or more of the following values: 1.4, 1.5, 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, or 3.0.In some embodiments, the first resonant frequency of the slim radiating structure, measured at an internal path when the radio-frequency system is disconnected, is above the highest frequency of the second frequency region, wherein a ratio between said first resonant frequency and said highest frequency of the second frequency region may be larger than one or more of the following values: 1.0, 1.1, 1.2, 1.4, 1.6, 1.8, or 2.0.In some other embodiments, said first resonant frequency is within the second frequency region.\",\n \"In some other examples, said first resonant frequency is above the highest frequency of the first frequency region and below the lowest frequency of the second frequency region.\",\n \"In the context of this document, a resonant frequency associated to a radiation booster of the slim radiating structure preferably refers to a frequency at which the input impedance of the slim radiating structure, the impedance being measured at the internal path coupling the radiation booster to the radio-frequency system when the radio-frequency system is not connected, has an imaginary part equal or substantially equal to zero.\",\n \"The radio-frequency system may comprise one or more matching circuits that modify the impedance of the slim radiating structure providing impedance matching to the slim radiating system, at an external path, in one or more frequency regions of operation of the slim radiating system.\",\n \"A radio-frequency system according to the invention may include at least one matching network with a plurality of stages, for instance, two, three, four, five, six or more stages.\",\n \"A stage comprises one or more circuit components (for example but not limited to, inductors, capacitors, resistors, jumpers, short-circuits, delay lines, or other reactive or resistive components).\",\n \"In some cases, a stage has a substantially inductive behavior in the frequency region or regions of operation of the slim radiating system, while another stage has a substantially capacitive behavior in said frequency region/s, and yet a third one may have a substantially resistive behavior in said frequency region/s.\",\n \"In an example, a stage may substantially behave as a resonant circuit (such as, for instance, a parallel LC resonant circuit or a series LC resonant circuit) in at least one frequency region of operation of the slim radiating system.\",\n \"The use of stages having a resonant circuit behavior allows one part of a given matching network be effectively connected to another part of said matching network for a given range of frequencies, or in a given frequency region, and be effectively disabled for another range of frequencies, or in another frequency region.\",\n \"In some examples, the at least one matching network alternates stages connected in series (i.e.\",\n \"cascaded) with stages connected in parallel (i.e.\",\n \"shunted), forming a ladder structure.\",\n \"In some cases, a matching network comprising two stages forms an L-shaped structure (i.e.\",\n \"series-parallel or parallel-series).\",\n \"In some cases, a matching network comprising three stages forms either a pi-shaped structure (i.e.\",\n \"parallel-series-parallel) or a T-shaped structure (i.e.\",\n \"series-parallel-series).\",\n \"In some embodiments, a radio-frequency system according to the present invention comprises a matching circuit in a ladder topology.\",\n \"Such matching circuit preferably comprises one reactive component per stage.\",\n \"In some other embodiments, a radio-frequency system according to the present invention comprises a matching circuit at least including a series LC resonant circuit and a parallel LC resonant circuit.\",\n \"In a preferred embodiment, an electronic device comprises a slim radiating system configured to transmit and receive electromagnetic wave signals in at least one frequency region of the electromagnetic spectrum, and comprising a slim radiating structure, a radio-frequency system, at least one internal conductive path and at least one external conductive path.\",\n \"The slim radiating structure comprises at least one ground element and at least one booster bar.\",\n \"The at least one internal conductive path comprises a conductive element that couples the at least one booster bar to the radio-frequency system.\",\n \"The radio-frequency system comprises at least one matching circuit modifying the impedance of the slim radiating structure providing impedance matching to the slim radiating system in the at least one frequency region at the at least one external conductive path.\",\n \"The at least one booster bar has an elongated shape, and is characterized by a slim width factor greater than 3 and a slim height factor greater than 3, is separated from the at least one ground element by a gap and is characterized by a location factor between 0.5 and 2.Another preferred embodiment relates to an electronic device including a slim radiating system that comprises a slim radiating structure, a radio-frequency system, an internal conductive path and at least one external conductive path; the slim radiating system is configured to transmit and receive electromagnetic wave signals in a first frequency region and a second frequency region.\",\n \"The slim radiating structure comprises at least one ground element, and one booster bar separated from the ground element by a gap and is characterized by a location factor between 0.3 and 1.8.The internal conductive path comprises a conductive element that couples the booster bar to the radio-frequency system.\",\n \"The radio-frequency system comprises a matching circuit that modifies the impedance of the slim radiating structure providing impedance matching to the slim radiating system in the first and second frequency regions at the at least one external conductive path.\",\n \"The first and second frequency regions are preferably separated so that the lowest frequency of the second frequency region is above the highest frequency of the first frequency region.\",\n \"Some preferred matching circuits for such preferred embodiment are described in FIGS.\",\n \"15A-15F.\",\n \"Further, an advantageous aspect of the invention refers to a radio-frequency system comprising a matching circuit that provides impedance matching to the slim radiating system in first and second frequency regions preferably not requiring a filtering circuit or component that separates frequencies of the first frequency region from frequencies of the second frequency region (e.g.\",\n \"a diplexer, a bank of filters, etc.)\",\n \"for providing impedance matching in the first frequency region and second frequency region independently (i.e.\",\n \"in two separate branches or paths).\",\n \"Thus preferred matching circuits may provide impedance matching in said first and second frequency regions with one branch.\",\n \"According to the present invention, some preferred matching circuits preferably comprise seven or less components, for instance: two, three, four, five, six or seven.\",\n \"Such matching circuits preferably do not comprise active circuits or components.\",\n \"In some embodiments in which the slim radiating system is configured to transmit and receive signals in a first frequency region and a second frequency region, a ratio between the lowest frequency of the second frequency region and the lowest frequency of the first frequency region may be greater than 1.5.In some of these embodiments, said ratio may be also greater than 1.8, 2.0, 2.2, or 2.4.In addition, in some embodiments in which the slim radiating system is configured to operate signals from first and second frequency regions, a ratio between the lowest frequency of the second frequency and the highest frequency of the first frequency region may be greater than 1.2, 1.5, 1.8, 2.0, 2.2, or 2.4.Accordingly, an advantageous aspect of such radio-frequency system is its efficiency in that impedance matching in the first and second frequency regions may be provided with one matching circuit using a reduced number of components, which consequently introduces lower losses in the radio-frequency system and makes it more robust against the tolerances of the components.\",\n \"Moreover, by not including filtering circuits such as diplexers, the radio-frequency system avoids the insertion losses characterizing such type of circuits and the necessity of having two separate matching circuits, which consequently makes the radio-frequency system have less components and the slim radiating system smaller in terms of area occupied in the device.\",\n \"In a third preferred embodiment, an electronic device includes a slim radiating system comprising a slim radiating structure, a radio-frequency system, first and second internal conductive paths and at least one external conductive path; the slim radiating system is configured to transmit and receive electromagnetic wave signals in a first frequency region and a second frequency region.\",\n \"The slim radiating structure comprises at least one ground plane layer, first and second radiation boosters, each of the first and second radiation boosters being separated from the ground plane layer by a gap.\",\n \"The first internal conductive path comprises a conductive element that couples the first radiation booster to the radio-frequency system, and the second internal conductive path comprises a conductive element that couples the second radiation booster to the radio-frequency system.\",\n \"The radio-frequency system comprises a matching circuit coupled to the first and second internal conductive paths and to the external conductive path, the matching circuit modifies the impedance of the slim radiating structure providing impedance matching to the slim radiating system in the first and second frequency regions.\",\n \"In some cases, the slim radiating system may comprise a first external conductive path and a second external conductive path, and the radio-frequency system may include a diplexer circuitry that advantageously filters signals from first and second frequency regions, said signals being matched in impedance in the first and second frequency regions by the matching circuit within the radio-frequency system.\",\n \"A first port of the diplexer is connected to the matching circuit, and the two remaining ports of the diplexer are connected to the first and second external conductive paths.\",\n \"The first and second external paths comprise, respectively, signals for frequencies from the first frequency region, and signals for frequencies from the second frequency region.\",\n \"A further aspect of the present invention relates to a test platform for electromagnetically characterizing radiation boosters.\",\n \"Said platform comprises a substantially square conductive surface on top of which, and substantially close to the central point, the element to be characterized is mounted perpendicular to said surface in a monopole configuration, said conductive surface acting as the ground plane.\",\n \"The substantially square conductive surface comprises sides with a dimension larger than a reference operating wavelength.\",\n \"In the context of the present invention, said reference operating wavelength is the free-space wavelength equivalent to a frequency of 900 MHz.\",\n \"A substantially square conductive surface according to the present invention is made of copper with sides measuring 60 centimeters, and a thickness of 0.5 millimeters.\",\n \"In the test configuration as set forth above, a booster bar according to the present invention may be characterized by a ratio between the first resonance frequency and the reference frequency (900 MHz) being larger than a minimum ratio of 3.0.In some cases, said ratio may be even larger than a minimum ratio such as: 3.4, 3.8, 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.6 or 7.0.A booster bar according to the present invention may also be characterized by a radiation efficiency measured in said platform, at a frequency equal to 900 MHz, being less than 50%, preferably being less than 40%, 30%, 20%, or 10%, and in some cases being less than 7.5%, 5%, or 2.5%.\",\n \"All those are quite remarkably low efficiency values considering the additional 1:3 frequency mismatch and beyond obtained in some of the embodiments as described above.\",\n \"Such a frequency shift would introduce further mismatch losses that would result in an overall antenna efficiency below 5%, and quite typically below 2%, which would be ordinarily considered unacceptable for a mobile phone or wireless application.\",\n \"Still, quite surprisingly, when combining at least one booster bar with the radio-frequency system of a slim radiating system according to the present invention, said slim radiating system recovers the efficiency required for the performance of a typical wireless device.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS Embodiments of the invention are shown in the enclosed figures.\",\n \"FIGS.\",\n \"1A-1B—Show examples of wireless handheld devices including slim radiating systems according to preferred embodiments of the invention.\",\n \"FIGS.\",\n \"2A-2D—Block diagram representations of five examples of slim radiating systems in according with some preferred embodiments of the present invention.\",\n \"FIG.\",\n \"3—Shows a perspective view of an example of a slim radiating structure including a booster bar in accordance with the present invention.\",\n \"FIGS.\",\n \"4A-4B—Graphs showing bandwidth performances of several slim radiating systems as a function of the booster bar's width and gap dimensions.\",\n \"FIG.\",\n \"5—Graph showing bandwidth performances of a slim radiating system as a function of the booster bar's width and gap dimensions for three different depth values.\",\n \"FIG.\",\n \"6—Graph showing an example of an acceptable radio-electric frequency behavior for a slim radiating system in accordance with the present invention.\",\n \"FIG.\",\n \"7—Shows a perspective view of an example of slim radiating structure including four booster bars in accordance with a preferred embodiment.\",\n \"FIG.\",\n \"8—Plan view of an exemplary radio-frequency system coupled to a slim radiating structure in accordance with the present invention.\",\n \"FIG.\",\n \"9—Graph showing the radio-electric frequency behavior of a slim radiating system including the slim radiating structure of FIG.\",\n \"7 and the radio-frequency system of FIG.\",\n \"8.FIG.\",\n \"10—Perspective view of an exemplary slim radiating structure including three booster bars in accordance with a preferred embodiment.\",\n \"FIG.\",\n \"11—Plan view of an example of a radio-frequency system coupled to a slim radiating structure in accordance with the present invention.\",\n \"FIG.\",\n \"12—Graph showing the radio-electric frequency behavior of a slim radiating system including the slim radiating structure of FIG.\",\n \"10 and the radio-frequency system of FIG.\",\n \"11.FIG.\",\n \"13—Shows another exemplary slim radiating structure according to the invention.\",\n \"FIGS.\",\n \"14A-14B—Show schematic representations of radio-frequency systems in accordance with a preferred embodiment.\",\n \"FIGS.\",\n \"15A-15F—Show six preferred matching circuits for some embodiments of the present invention.\",\n \"FIGS.\",\n \"16A-16F—Show the impedance transformation of an exemplary slim radiating system as the different stages of a matching circuit in the radio-frequency system are added.\",\n \"FIG.\",\n \"17—Shows the reflection coefficient of exemplary slim radiating system of FIG.\",\n \"16F.\",\n \"FIG.\",\n \"18A-18B—Show the impedance and the reflection coefficient of an exemplary slim radiating system comprising a radio-frequency system according to the invention.\",\n \"FIG.\",\n \"19—Shows an exemplary radiation booster according to the invention.\",\n \"FIG.\",\n \"20—Shows a slim radiating structure and an internal path in the form of a conductive trace in accordance with a preferred embodiment.\",\n \"FIG.\",\n \"21A-21B—Show a test platform for the electromagnetic characterization of radiation boosters.\",\n \"FIG.\",\n \"22—Shows the radiation efficiency and antenna efficiency of a radiation booster according to the present invention measured with the test platform depicted in FIGS.\",\n \"21A and 21B.\",\n \"DETAILED DESCRIPTION Further characteristics and advantages of the invention will become apparent in view of the detailed description of some preferred embodiments which follows.\",\n \"Said detailed description of some preferred embodiments of the invention is given for purposes of illustration only and in no way is meant as a definition of the limits of the invention, made with reference to the accompanying figures.\",\n \"Illustrative wireless electronic devices including a slim radiating system in accordance with the present invention are shown in FIGS.\",\n \"1A and 1B.\",\n \"In the particular arrangement of FIG.\",\n \"1A, the wireless electronic device 100 is a smartphone although it might represent other wireless electronic devices such as for instance a phablet or a tablet.\",\n \"The slim radiating system includes a first booster bar 101, a second booster bar 102, a booster element 110, and a ground element 105 (which may be included in a layer of a multilayer printed circuit board).\",\n \"The booster element 110 comprises two contiguous booster bars: the third booster bar 103 and the fourth booster bar 104.The first booster bar 101 is coupled to a radio-frequency system 109 via a conductive path 106, the second booster bar 102 is coupled to the radio-frequency system 109 via a conductive path 107, and the booster element 110 is coupled to the radio-frequency system 109 via a conductive path 108.In FIG.\",\n \"1B there is shown a wireless handheld device 150 in an exploded perspective view, the device comprises a slim radiating structure and a radio-frequency system 153.The slim radiating structure comprises a radiation booster 151 taking the form of a booster bar with an elongated shape, and a ground plane layer 152.The booster bar 151 is coupled to the radio-frequency system via the internal conductive path 154 which, in this particular example, may be a conductive trace.\",\n \"In the examples of FIGS.\",\n \"1A and 1B, the booster bars are arranged on a part of the device free of ground plane, so there is no ground plane in the orthogonal projection of the booster bars onto the plane comprising the ground plane layers 105 and 152, respectively.\",\n \"In other embodiments, the orthogonal projection of a booster bar or other radiation booster onto the plane comprising the ground plane layer may be overlapped partially or completely by the ground plane layer.\",\n \"FIG.\",\n \"2A shows a block diagram representation of a slim radiating system for an electronic device.\",\n \"The slim radiating system 201a comprises slim radiating structure 202a, radio-frequency system 203a, internal conductive path 204a, and external conductive path 205a.\",\n \"The slim radiating structure is coupled to the radio-frequency system via the internal path 204a, and to other RF circuitry for handling RF wave signals via the external path 205a.\",\n \"A slim radiating system in accordance with this block diagram is configured to operate in at least one frequency region, or in at least two frequency regions, or in at least three frequency regions.\",\n \"FIG.\",\n \"2B shows another block diagram of a slim radiating system for an electronic device according to the present invention.\",\n \"The slim radiating system 201b comprises slim radiating structure 202b, radio-frequency system 203b, two internal conductive paths 204b and 205b, and two external conductive paths 206b and 207b.\",\n \"The slim radiating structure is coupled to the radio-frequency system via the internal paths 204b and 205b, and to other RF circuitry for handling RF wave signals via the external paths 206b and 207b.\",\n \"A slim radiating system in accordance with this block diagram is configured to operate in at least two frequency regions, or in at least three frequency regions.\",\n \"FIG.\",\n \"2C shows another block diagram of a slim radiating system for an electronic device according to the present invention.\",\n \"The slim radiating system 201c comprises slim radiating structure 202c, radio-frequency system 203c, three internal conductive paths 204c, 205c and 206c, and three external conductive paths 207c, 208c, and 209c.\",\n \"The slim radiating structure is coupled to the radio-frequency system via the internal conductive paths 204c, 205c and 206c, and to other RF circuitry for handling RF wave signals via the external conductive paths 207c, 208c and 209c.\",\n \"A slim radiating system in accordance with this block diagram is configured to operate in at least three frequency regions.\",\n \"FIG.\",\n \"2D shows another block diagram of a slim radiating system for an electronic device according to the present invention.\",\n \"The slim radiating system 201d is similar to 201a from FIG.\",\n \"2A.\",\n \"It comprises slim radiating structure 202a, radio-frequency system 203d, internal conductive path 204a, and two external conductive paths 205d and 206d.\",\n \"The slim radiating structure is coupled to the radio-frequency system via the internal paths 204a, and to other RF circuitry for handling RF wave signals via the external paths 205d and 206d.\",\n \"The radio-frequency system 203d may comprise a matching circuit configured to provide impedance matching in at least two frequency regions, and a diplexer may be connected to said matching circuit and coupled to the external paths.\",\n \"A slim radiating system in accordance with this block diagram is configured to operate in at least two frequency regions.\",\n \"The radio-frequency system 203d is convenient for the interconnection with an RF (radio-frequency) front-end module or RF circuitry that includes separate inputs for signals from the first frequency region and the second frequency region.\",\n \"If such RF front-end module (not illustrated) had one input/output for all the signals, the radio-frequency system 203a from FIG.\",\n \"2A would be more suitable.\",\n \"FIG.\",\n \"3 illustrates a preferred example of a slim radiating structure 301 according to the present invention.\",\n \"The slim radiating structure comprises a booster bar 303 and a ground plane layer 302, the booster bar comprises a single standard layer of dielectric material 306 with a top 304 and a bottom 305 conductive surfaces.\",\n \"The booster bar has a length 310, a width 311 and a height 312.The length of the booster bar is taken along the dimension that is substantially parallel to the ground plane layer in the top or bottom conductive surface, the width is taken along the dimension that is substantially perpendicular to the ground plane layer in the top or bottom conductive surface, and the height is taken as the minimum distance between the top conductive surface and the bottom conductive surface.\",\n \"In some embodiments the booster bar comprises pads on a first and a second surface so that the mounting of the booster can be reversed and top and bottom sides can be interchanged.\",\n \"The size and shape of the booster bar is characterized by a slim width factor and a slim height form factor.\",\n \"The slim width factor is a ratio between the length and the width of the booster bar, and the slim height factor is a ratio between the length and height of the booster bar, being the slim width factor and the slim height factor preferably larger than 3.In this example, where the booster is configured to operate in one or more frequency bands within the 600 MHz-6 GHz range (e.g.\",\n \"GSM 850 (824-894 MHz), GSM 900 (880-960 MHz), GSM 1800 (1710-1880 MHz), GSM 1900 (1850-1990 MHz), WCDMA 2100 (1920-2170 MHz), CDMA 1700 (1710-2155 MHz), LTE 700 (698-798 MHz), LTE 800 (791-862 MHz), LTE 2600 (2500-2690 MHz), LTE 3500 (3.4-3.6 GHz), LTE 3700 (3.6-3.8 GHz), WiFi (2.4-2.5 GHz and/or 4.9-5.9 GHz)), the length is 10 millimeters, the width is 3.2 millimeters and the height is 3.2 millimeters, being the slim width factor 3.125 and the slim height factor 3.125, all those dimensions in these and other embodiments, within a typical tolerance of, for instance +/−1%-3% and in some occasions up to a 10% variation.\",\n \"The booster bar is separated from the ground plane by a gap 313; the gap is taken as the minimum distance between the bottom conductive layer and the ground plane layer.\",\n \"The gap distance plus the booster bar's width 311 is characterized as the depth of the radiation booster.\",\n \"The location of the booster bar in relation to the ground plane layer is characterized by a location factor.\",\n \"The location factor is a ratio between the width of the booster bar and the gap, being the location factor preferably in the range of between 0.5 and 2.In this example, the width is 3.2 mm and the gap is 3.3 mm, being the location factor 0.96 and the depth 6.5 mm, all those dimensions within a typical tolerance of, for instance +/−10% variation.\",\n \"FIG.\",\n \"4A and FIG.\",\n \"4B illustrate two examples of the relevance of the location and width of the booster bar in the radio-frequency performance of the slim radiating system; the radio-frequency performance of the slim radiating system is affected by the location of the booster bar with respect to the ground plane layer and the width of the booster bar.\",\n \"FIG.\",\n \"4A and FIG.\",\n \"4B plot the potential bandwidths achieved by six slim radiating systems as a function of the booster bar's width and gap dimensions.\",\n \"Curve 401 represents the potential bandwidth of a slim radiating system comprising a booster bar characterized by a height of 2.4 mm and a length of 11.5 mm.\",\n \"Curve 402 represents the potential bandwidth of a slim radiating system that includes a booster bar having a height of 3.2 mm and a length of 9 mm.\",\n \"Curve 403 represents the potential bandwidth of a slim radiating system comprising a booster bar characterized by a height of 2.4 mm and a length of 10.5 mm.\",\n \"Curve 404 represents the potential bandwidth of a slim radiating system comprising a booster bar characterized by a height of 3.2 mm and a length of 7 mm.\",\n \"Curve 405 represents the potential bandwidth of a slim radiating system comprising a booster bar characterized by a height of 2.4 mm and a length of 9 mm.\",\n \"Curve 406 represents the potential bandwidth of a slim radiating system comprising a booster bar characterized by a height of 2.4 mm and a length of 7 mm.\",\n \"As shown in FIG.\",\n \"4A and FIG.\",\n \"4B, the potential bandwidth of the slim radiating system depends on the width dimension of the booster bar and the location of the booster bar in relation to the ground plane layer; for each of the curves, there is a region where the most favorable bandwidth values are achieved.\",\n \"In this invention, such region is referred as the effective bandwidth region which corresponds to a range of location factor values that provide the region of most advantageous bandwidth values for the slim radiating system.\",\n \"The preferred values for the location factor are in the range of between 0.5 and 2.Such result is against conventional wisdom as the wider the width of the antenna element, the greater the bandwidth as, for example, in a monopole antenna.\",\n \"FIG.\",\n \"5 illustrates another example of the effect of the booster bar's location and width on the radio-frequency performance of a slim radiating system; the radio-frequency performance of the slim radiating system is affected by the location of the booster bar with respect to the ground plane layer and the width of the booster bar.\",\n \"FIG.\",\n \"5 plots the potential bandwidth achieved by the slim radiating system as a function of the booster bar's width and gap dimensions; the three curves 501, 502 and 503 represent the potential bandwidth of a slim radiating system comprising a booster bar having a height of 3.2 mm and a length of 7 mm.\",\n \"Curve 501 refers to the booster bar having a depth of 7.5 mm, curve 502 corresponds to a depth of 7 mm and curve 503 is for a depth of 6.5 mm.\",\n \"As previously shown in FIGS.\",\n \"4A and 4B, the potential bandwidth of the slim radiating system depends on the gap that separates the booster bar from the ground plane layer and the width of the booster bar; for each of the curves, there is an effective bandwidth region where the most advantageous bandwidth values are achieved.\",\n \"One way to characterize the radio-frequency performance of the slim radiating system entails the use of a reflection coefficient plot; a reflection coefficient of less than −4.4 dB is generally acceptable.\",\n \"FIG.\",\n \"6 illustrates an example of an acceptable radio-frequency performance for a slim radiating system according to the present invention.\",\n \"The slim radiating system comprises a booster bar which is characterized by a width form factor of 3.125, a height form factor of 3.125 and a location factor of 0.96.Curve 601 shows the reflection coefficient of the slim radiating system versus frequency, and line 602 shows an acceptable reference level for the reflection coefficient.\",\n \"In this example, the reflection coefficient is less than −4.4 dB for all the frequencies of the operating frequency region which covers a frequency range of about 824 MHz to about 960 MHz.\",\n \"Such frequency range enables the slim radiating system to be used to cover at least two communication frequency bands such as a band from 824 MHz to 894 MHz and a band from 880 MHz to 960 MHz.\",\n \"These two bands are examples of bands that can be covered by a slim radiating system; other bands may also be handled by the slim radiating system.\",\n \"In another embodiment, a suitable radio-frequency performance for the slim radiating system corresponds to a reflection coefficient of −6 dB or less for all the frequencies of the operating frequency range.\",\n \"FIG.\",\n \"7 illustrates a preferred example of a slim radiating structure according to the present invention suitable for a slim radiating system configured to operate in three frequency regions.\",\n \"The slim radiating structure 701 comprises a first booster bar 702, a second booster bar 703, a booster element 704 comprising two adjacent booster bars 705 and 706, and a ground plane layer 707.As shown in FIG.\",\n \"3, each booster bar comprises a single standard layer of dielectric material with top and bottom conductive surfaces; in this example the dielectric material has a height of 3.2 mm.\",\n \"In this example, the first and second booster bars 702, 703 have a slim width factor of 3.125, a slim height factor of 3.125, and a location factor of 0.96; the booster element 704 has a slim width factor of 6.25, a slim height factor of 6.25 and a location factor of 0.96.In general, any suitable shape may be used for the ground plane layer.\",\n \"FIG.\",\n \"7 illustrates an example of a slim radiating structure according to the present invention suitable for a slim radiating system configured to operate in three frequency regions.\",\n \"The ground plane layer 707 includes clearance regions that may be used to mount other components of the electronic wireless device, or to adjust the ground plane layer to the shape of the electronic wireless device housing or for SAR purposes.\",\n \"The ground plane rectangle 708 (represented with dashed lines for illustrative purposes only) is characterized as the minimum sized rectangle that encompasses the ground plane layer 707.That is, the ground plane rectangle is a rectangle whose sides are tangent to at least one point the ground plane layer.\",\n \"In accordance with the present invention, a first long side of the ground plane layer refers to a long side of the ground plane rectangle 709 or 710; a second long side of the ground plane layer refers to a second long side of the ground plane rectangle 710 or 709; a first short side of the ground plane layer refers to a first short side of the ground plane rectangle 711 or 712; and a second short side of the ground plane layer relates to a second short side of the ground plane rectangle 712 or 711.FIG.\",\n \"8 shows an example of a radio-frequency system 805 coupled to a slim radiating structure 801 via internal conductive paths 802, 803 and 804.An example of a suitable slim radiating structure 801 to be coupled to the radio-frequency system 805 is the slim radiating structure shown in FIG.\",\n \"7.The radio-frequency system 805 comprises a first matching circuit 806, a second matching circuit 807, and a third matching circuit 808.The first matching circuit 806 is configured to ensure that the slim radiating system is impedance-matched at a first frequency region to other circuitry coupled via external conductive path 809.The second matching circuit 807 is configured to provide impedance matching at a second frequency region for other circuitry coupled to external conductive path 810.The third matching circuit 808 is configured to guarantee that the slim radiating system is matched in impedance at a third frequency region at the external conductive path 811.The first, second and third matching networks are therefore configured to ensure an acceptable reference level for the reflection coefficient over an entirety of the first, second and third operating frequency ranges.\",\n \"Each of the first, second and third matching circuits comprises a network of passive components such as inductors and capacitors, which are arranged with a suitable architecture like, for instance, an inductor plus an LC network.\",\n \"Other suitable matching circuits may be used to ensure that the slim radiating system is matched in impedance at the operating frequency ranges; other suitable matching circuits may comprise a network of passive and/or active components, which may be arranged with other suitable architectures.\",\n \"FIG.\",\n \"9 illustrates the radio-frequency performance of the slim radiating system resulting from the interconnection of the slim radiating structure 701 to the radio-frequency system 805.Curve 901 shows the reflection coefficient of the slim radiating system versus frequency at a terminal in the external path 809, curve 902 shows the reflection coefficient of the slim radiating system versus frequency at a terminal in the external path 810, curve 903 shows the reflection coefficient of the slim radiating system versus frequency at a terminal in the external path 811, and line 904 shows an acceptable reference level for the reflection coefficient.\",\n \"In this example, the reflection coefficient 901 is less than −4.4 dB for all the frequencies of a first operating frequency region 905, the reflection coefficient 902 is less than −4.4 dB for all the frequencies of a second operating frequency region 906, and the reflection coefficient 903 is less than −4.4 dB for all the frequencies of a third operating frequency region 907.The first operating frequency region 905 of the slim radiating system covers a first frequency range of about 698 MHz to about 798 MHz, the second operating frequency region 906 of the slim radiating system covers a frequency range of about 824 MHz to about 960 MHz, and the third operating frequency region 907 of the slim radiating system covers a third frequency range of about 1710 MHz to about 2690 MHz.\",\n \"The first frequency range enables the slim radiating system to be used to cover at least three communication bands such as a band from 699 MHz to 746 MHz, a band from 746 MHz to 787 MHz, and a band from 758 MHz to 798 MHz.\",\n \"The second frequency range enables the slim radiating system to cover at least two communication frequency bands such as a band from 824 MHz to 894 MHz and a band from 880 MHz to 960 MHz.\",\n \"The third frequency range enables the slim radiating system to cover at least five communication frequency bands such as a band from 1710 MHz to 1880 MHz, a band from 1850 MHz to 1990 MHz, a band from 1920 MHz to 2170 MHz, a band from 2300 MHz to 2400 MHz, and a band from 2496 MHz to 2690 MHz.\",\n \"Other desirable communication frequency bands may also be handled by the slim radiating system.\",\n \"FIG.\",\n \"10 illustrates another example of a slim radiating structure in accordance to the present invention; the slim radiating structure is suitable for a slim radiating system that is configured to operate in at least two frequency regions.\",\n \"The slim radiating structure 1001 comprises a first booster element 1002 including a first booster bar 1003 and a second booster bar 1004 adjacent to the first booster bar; the slim radiating structure 1001 further comprises a third booster bar 1005, and a ground plane layer 1006.As shown in FIG.\",\n \"3, each booster bar may be formed by a single standard layer of dielectric material with top and bottom conductive surfaces.\",\n \"In this example, the dielectric material has a height of 2.4 mm; the first booster element 1002 has a slim width factor of 8, a slim height factor of 10, and a location factor of 0.375; the third booster bar 1005 has a slim width factor of 4, a slim height factor of 5 and a location factor of 0.375.FIG.\",\n \"11 shows an example of a radio-frequency system 1101 coupled to a slim radiating structure 1102 via internal conductive paths 1103 and 1104.An example of a suitable slim radiating structure 1102 to be coupled to the radio-frequency system 1101 is illustrated in FIG.\",\n \"10.The radio-frequency system 1101 comprises a matching circuit being configured to ensure that the slim radiating system is impedance-matched to other circuitry coupled via external conductive path 1105 at a first frequency region and a second frequency region.\",\n \"The matching network is therefore configured to ensure an acceptable reference level for the reflection coefficient over an entirety of the first and second operating frequency ranges.\",\n \"The matching circuit comprises a network of passive components such as inductors, capacitors and transmission lines, which are arranged with a suitable architecture as shown in FIG.\",\n \"11.Other suitable matching circuits may be used to ensure that the slim radiating system is impedance matched at the operating frequency ranges; other suitable matching circuits may comprise a network of passive and/or active components, which may be arranged with other suitable architectures.\",\n \"FIG.\",\n \"12 illustrates the radio-frequency performance of the slim radiating system resulting from the interconnection of the slim radiating structure 1001 to the radio-frequency system 1101.Curve 1201 shows the reflection coefficient of the slim radiating system versus frequency at a terminal in the external path 1105, and line 1202 shows an acceptable reference level for the reflection coefficient.\",\n \"In this example, the reflection coefficient 1201 is less than −4.4 dB for all the frequencies of the first and second frequency regions.\",\n \"The first operating frequency region of the slim radiating system covers a first frequency range of about 698 MHz to about 960 MHz, and the second operating frequency region of the slim radiating system coves a frequency range of about 1710 MHz to about 3800 MHz.\",\n \"The first frequency range enables the slim radiating system to be used for covering at least five communication bands such as a band from 699 MHz to 746 MHz, a band from 746 MHz to 787 MHz, a band from 758 MHz to 798 MHz, a band from 824 MHz to 894 MHz, and a band from 880 MHz to 960 MHz.\",\n \"The second frequency range enables the slim radiating system to cover at least seven communication frequency bands such as a band from 1710 MHz to 1880 MHz, a band from 1850 MHz to 1990 MHz, a band from 1920 MHz to 2170 MHz, a band from 2300 MHz to 2400 MHz, a band from 2496 MHz to 2690 MHz, a band from 3400 MHz to 3600 MHz, and a band from 3600 MHz to 3800 MHz.\",\n \"Other desirable communication frequency bands may also be handled by the slim radiating system.\",\n \"Another example of a slim radiating structure is shown in FIG.\",\n \"13.The slim radiating structure 1300 comprises ground plane layer 1302 on a printed circuit board 1307, and radiation booster 1301 characterized by a slim width factor between 1 and 2, and a slim height factor between 1 and 2.The radiation booster 1301 is separated from the ground plane layer by a gap and is characterized by a location factor between 0.5 and 2, preferably between 0.5 and 1.The ground plane layer may be inscribed in ground plane rectangle 1306 (in dashed lines for illustrative purposes only), and the radiation booster may be inscribed in booster box 1305 (in dashed lines for illustrative purposes only).\",\n \"A wireless electronic device comprising a slim radiating system that includes slim radiating structure 1300 may advantageously provide penta-band operation: two frequency bands in the first frequency region, like for example the frequency bands corresponding to the GSM 850 and GSM 900 cellular communication standards (i.e.\",\n \"the first frequency region comprising the 824 MHz to 960 MHz frequency range), and three frequency bands in the second frequency region, like for example the frequency bands corresponding to the GSM 1800, GSM 1900 and WCDMA 2100 cellular communication standards (i.e.\",\n \"the second frequency region comprising the 1710 MHz to 2170 MHz frequency range).\",\n \"In another example, a device according to the present invention could provide triple-band or quad-band operation with at least two frequency bands in the first frequency region, and at least another two frequency bands in the second frequency region, wherein first and second frequency regions do not overlap in frequency.\",\n \"Such device could operate, for instance but not limited to, the GSM 850 and GSM 900 cellular communication standards, and the GSM 1800 and GSM 1900 cellular communication standards.\",\n \"FIG.\",\n \"14A illustrates a radio-frequency system 1400 that comprises a first port 1401, a second port 1402, and a matching circuit 1403.Such radio-frequency system is particularly convenient to be used in the slim radiating system of FIG.\",\n \"2A.\",\n \"Port 1401 may be connected to an internal conductive path (for instance 204a), and port 1402 may be connected to an external conductive path (for instance 205a).\",\n \"The matching circuit 1403 may be configured to provide impedance matching in at least one frequency region, or in at least two frequency regions, or in at least three frequency regions.\",\n \"FIG.\",\n \"14B illustrates another radio-frequency system 1410 comprising a first port 1411, a second port 1412, a third port 1413, a matching circuit 1414, a diplexer 1415, and a conductive path 1416 connecting the matching circuit to the diplexer.\",\n \"In reception, the diplexer 1415 is configured to split the signal from conductive path 1416 in a first signal extracted at port 1412, preferably comprising the frequencies corresponding to the first frequency region, and in a second signal extracted at port 1413, preferably comprising the frequencies corresponding to the second frequency region; in transmission, diplexer 1415 combines signals from ports 1412 and 1413 and are extracted in conductive path 1416.The matching circuit 1414 provides impedance matching to the slim radiating system in the first and second frequency regions.\",\n \"Ports 1412 and 1413 may be respectively connected to first and second external paths as shown in FIG.\",\n \"2D.\",\n \"FIGS.\",\n \"15A to 15F show preferred matching circuits configured to provide impedance matching in at least two frequency regions.\",\n \"FIG.\",\n \"15A shows matching circuit 1500 comprising first and second ports 1501 and 1502, and a circuit including five stages forming a ladder topology (series-parallel-series-parallel-series).\",\n \"The first stage, which is connected to port 1501, is an inductor in series 1503, the second stage is a shunted inductor 1504, the third stage is a capacitor in series 1505, the fourth stage is an inductor in parallel 1506, and the fifth stage is a capacitor in series 1507, said fifth stage being connected to the second port 1502.In FIG.\",\n \"15B there is shown matching circuit 1510 comprising six stages that form an alternative ladder topology (series-parallel-series-parallel-series-parallel).\",\n \"The first stage (in series) is connected to the first port 1501 of the matching circuit, and the sixth stage comprising an inductor in parallel 1511 is connected to the second port 1502 of the matching circuit.\",\n \"FIG.\",\n \"15C depicts another preferred matching circuit 1520 comprising two stages: the first stage comprises a capacitor in parallel 1521, and the second stage comprises an inductor in series 1522.A preferred range of capacitor values for shunted capacitor 1521 of matching circuit 1520 is 0.01pF to 30pF.\",\n \"FIG.\",\n \"15D shows another preferred matching circuit 1530 comprising a series inductor 1531 connected to port 1501 and to a series LC resonator formed by inductive component 1532a and capacitive component 1532b.\",\n \"The LC resonator is connected to an LC resonator in parallel, comprising inductor 1533a and capacitor 1533b, and to a series capacitor 1534.The series capacitor is connected to second port 1502 of the matching circuit 1530.This matching circuit comprises a single branch formed by four stages (series-series-parallel-series).\",\n \"FIG.\",\n \"15E shows a fifth preferred matching circuit 1540 comprising: inductor 1541 in series connected to port 1501, inductor 1542 in parallel, capacitor 1543 in series, inductor 1544a and capacitor 1544b in parallel forming a parallel LC circuit, and capacitor 1545 in series connected to port 1502.FIG.\",\n \"15F illustrates another preferred matching circuit 1550 that is similar to matching circuit 1540 with the difference that capacitor 1545 is connected to inductor in series 1551 forming a series LC circuit, and said inductor being connected to port 1502 instead of capacitor 1545 as in FIG.\",\n \"15E.\",\n \"Inductors 1503, 1531 and 1541 corresponding to the first stage of matching circuits 1500, 1510, 1530, 1540 and 1550 may preferably have a value in the range of 0.1 nH to 80 nH.\",\n \"Matching circuits 1500, 1510, 1520, 1530, 1540, and 1550 are suitable for being used as matching circuit 203a and 203d shown in FIGS.\",\n \"2A and 2D.\",\n \"FIG.\",\n \"16A shows the impedance 1600 of a slim radiating system comprising a radiation booster, measured at its internal conductive path, when it is disconnected from a radio-frequency system as disclosed in the present invention.\",\n \"Points 1601 and 1602 from said impedance correspond to the lowest and highest frequencies of a first frequency region (in this example, said frequencies are 824 MHz and 960 MHz); and points 1603 and 1604 correspond to the lowest and highest frequencies of a second frequency region (for this particular example, said frequencies are 1710 MHz and 2170 MHz).\",\n \"The impedance 1600 has a substantially large negative reactance, namely the impedance in the first frequency region is capacitive, for the entire range of frequencies limited by points 1601 and 1602, and is also capacitive for the frequencies of the second frequency region.\",\n \"The first resonant frequency of said slim radiating structure is at a frequency above the highest frequency of the second frequency region (as indicated by point 1604).\",\n \"FIGS.\",\n \"16B to 16F show the evolution of the impedance of slim radiating system of FIG.\",\n \"16A after the slim radiating system is connected to a radio-frequency system comprising a matching circuit like 1500 as the stages are added successively to the matching circuit.\",\n \"FIG.\",\n \"16B shows the impedance 1610 when the matching circuit only comprises the first stage (an inductor in series).\",\n \"In FIG.\",\n \"16C, the impedance 1620 of the slim radiating system is shown after adding the inductor in parallel (corresponding to the second stage) to the matching circuit.\",\n \"The impedance 1630 from FIG.\",\n \"16D is obtained after the series capacitor from the third stage is added.\",\n \"The impedance 1640 from FIG.\",\n \"16E is obtained after the shunted inductor from the fourth stage is added.\",\n \"And with the addition of the fifth stage corresponding to another capacitor in series, the impedance 1650 of the slim radiating system is obtained.\",\n \"In addition to the impedance 1650 as shown in FIG.\",\n \"16F, the reflection coefficient 1700, when the slim radiating structure is connected to a radio-frequency system comprising the five-stage ladder matching network is also shown in FIG.\",\n \"17.In this particular example, the operating frequency range for the radiating system covers a first frequency region at least comprising the range of frequencies delimited by points 1701 and 1702 (824 MHz and 960 MHz respectively), and a second frequency region at least comprising the range of frequencies delimited by points 1703 and 1704 (1710 MHz and 2170 MHz respectively), wherein said points establish a minimum level of reflection coefficient for a good radio-frequency performance for this particular example, although in other embodiments said minimum level could be, for example, −4.4dB.\",\n \"A ratio between the lowest frequency of the second frequency region and the lowest frequency of the first frequency region is, for this particular case, greater than 1.5 and even greater than 2.0.In addition, a ratio between the first resonant frequency of the slim radiating structure measured at an internal path, when disconnected from the radio-frequency system, and the lowest frequency of the first frequency region is greater than 1.3, also greater than 2.0, and even greater than 2.4.FIGS.\",\n \"18A and 18B show the impedance and reflection coefficient of another exemplary embodiment.\",\n \"Such embodiment corresponds to a slim radiating system comprising a slim radiating structure featuring an impedance similar to that of FIG.\",\n \"16A, and a radio-frequency system according to the present invention.\",\n \"The radio-frequency system comprises a six-stage matching circuit in a ladder topology, like for example matching circuit 1510 from FIG.\",\n \"15B.\",\n \"The impedance 1800, when the slim radiating structure is connected to such radio-frequency system, is shown in FIG.\",\n \"18A.\",\n \"In said figure, points 1801 and 1802 refer to the lower and higher frequencies of a first frequency region (824 MHz and 960 MHz respectively), and points 1803 and 1804 refer to the lower and higher frequencies of a second frequency region (1710 MHz and 2170 MHz respectively).\",\n \"The reflection coefficient 1810 of FIG.\",\n \"18B corresponds to the slim radiating system of FIG.\",\n \"18A.\",\n \"The operating frequency range for a slim radiating system according to this particular embodiment at least covers a first frequency region including the first range delimited by points 1811 and 1812 (824 MHz and 960 MHz), and a second frequency region including the second range delimited by points 1813 and 1814 (1710 MHz and 2170 MHz).\",\n \"FIG.\",\n \"19 shows a radiation booster 1900 comprising conducting surfaces 1901 and 1902, a dielectric material 1904 (shown transparent for illustrative purposes only), and a plurality of vias 1903 electrically interconnecting the two conducting surfaces 1901 and 1902 (in other examples, said conducting surfaces may be interconnected by just one via).\",\n \"Said radiation booster is a booster bar featuring a slim width factor of 3.125, and a slim height factor of 3.125.The booster bar 1900 may be used, for example, in slim radiating structure 1300 instead of radiation booster 1301.A booster bar such as 1900 is configured to be used in slim radiating systems according to the present invention, and in particular in each and every embodiment of the present invention.\",\n \"As such, a slim radiating system comprising a slim radiating structure, a radio-frequency system and at least one external conductive path, wherein the slim radiating structure comprises a radiation booster like, for example, 1900 and a ground plane layer, may be configured to transmit and receive electromagnetic wave signals in at least one frequency region, or in at least two frequency regions.\",\n \"The radio-frequency system comprises a matching circuit configured to provide impedance matching to the slim radiating system in said at least one or at least two frequency regions at the at least one external path.\",\n \"FIG.\",\n \"20 shows a slim radiating structure comprising a radiation booster (e.g.\",\n \"booster bar) 2001, a ground plane layer 2002.There is also shown a conductive element 2003 that may advantageously function as an internal conductive path.\",\n \"The conductive element 2003 is connected to radiation booster 2001, advantageously tuning the input impedance of the radiation booster prior its connection to a radio-frequency system (not shown).\",\n \"The conductive element may improve the efficiency of the slim radiating system comprising said slim radiating structure, or make the slim radiating system operable in more frequency bands in at least one frequency regions or in at least two frequency regions.\",\n \"In this example, the booster bar features a height of 2.4 mm, a slim width factor of 4, a slim height factor of 5, and a location factor of 0.33.Although the conductive element 2003 is L-shaped, in other examples the conductive element may take other forms as well such as a straight I.\",\n \"The electrical length of conductive element 2003 may be shorter than 10% of the free-space wavelength corresponding to the lowest frequency of the first frequency region, and preferably it may be shorter than 5% of said free-space wavelength.\",\n \"FIG.\",\n \"21A schematically shows, in a 3D perspective, a test platform for the characterization of radiation boosters.\",\n \"The platform comprises substantially square conductive surface 2101 and connector 2102 (for instance an SMA connector) electrically connected to the device or element 2100 to be characterized.\",\n \"The conductive surface 2101 has sides with a length larger than the reference operating wavelength corresponding to the reference frequency.\",\n \"For instance, at 900 MHz, said sides are at least 60 centimeters long.\",\n \"The conductive surface may be a sheet or plate made of copper, for example.\",\n \"The connector 2102 is placed substantially in the center of conductive surface 2101.In FIG.\",\n \"21B the same test platform of FIG.\",\n \"21A is schematically represented in a 2D perspective wherein the conductive surface 2101 is partially drawn.\",\n \"In this example, the element that is to be characterized 2100 in FIG.\",\n \"21A corresponds to booster bar 1900 from FIG.\",\n \"19, which is arranged so that its largest dimension is perpendicular to conductive surface 2101, and one of the first or second conductive surfaces (1901 or 1902 of FIG.\",\n \"19) is in direct electrical contact with connector 2102 (for clearer interpretation of the orientation of radiation booster 1900, via holes 1903 connecting the first and second conductive surfaces of the radiation booster are also drawn in FIG.\",\n \"21B).\",\n \"The radiation booster 1900 lies on a dielectric material (not shown) attached to the conductive surface 2101 so as to minimize the distance between radiation booster 1900 and surface 2101.Said dielectric material may be a dielectric tape or coating, for example.\",\n \"FIG.\",\n \"22 shows a graph of the radiation efficiency and antenna efficiency measured in a test platform like the one shown in FIG.\",\n \"21A and FIG.\",\n \"21B, when the element 2100 to be characterized is radiation booster 1900.In this particular example, the radiation efficiency measured 2201 (represented with a solid line) at 900 MHz is less than 5%, and the antenna efficiency measured 2202 (represented with a dashed line) at 900 MHz is less than 1%.\",\n \"The foregoing is merely illustrative of the principles of this invention and various modifications can be made by those skilled in the art without departing from the scope and spirit of the invention.\",\n \"So even though that in the illustrative examples described above in connection with the figures some particular designs of booster bars with specific values for the slim width factor, the slim height factor, and the location factor have been used, many other designs of boosters bars in accordance with the invention having for example different slim width factor, slim height factor, and/or location factor could have been equally used in the slim radiating structures.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875817"}}},{"rowIdx":4494987,"cells":{"text":{"kind":"list like","value":[["ROTARY KNIFE FIXTURE FOR CUTTING SPIRAL, TEXTURED POTATO PIECES","A rotary knife fixture for cutting vegetable products such as raw potatoes into spiral shapes.","The knife fixture includes a ring-shaped blade holder driven rotatably within a hydraulic product flow path.","The blade holder includes at least one cutting blade, wherein the blade is twisted from a generally longitudinally aligned center axis outwardly in opposite circumferential directions with a sharpened leading edge set at a desired pitch angle.","By controlling the pitch angle of the blade in relation to the blade rotational speed and velocity at which the potato travels along the hydraulic flow path, the resultant spiral cut shape is selected.","By using multiple cutting blades at known axially spaced positions and selecting the angular position of each cutting blade in succession, the number of spiral shapes cut from each potato is selected.","The blades can have a nontextured straight-cut edge, or a textured crinkle-cut edge, or a combination."],["1.A knife fixture for cutting food products, the fixture comprising: a blade holder; and at least one cutting blade with a cutting edge, each of the at least one cutting blade extending inward from the blade holder and being twisted such that the cutting edge has a pitch angle that varies along the cutting blade.","2.The knife fixture of claim 1, wherein the blade holder forms an opening surrounding a central axis and each of the at least one cutting blade extends from the blade holder and across the opening.","3.The knife fixture of claim 2, wherein the blade holder includes a plurality of angled recesses, the at least one cutting blade being secured within the plurality of angled recesses.","4.The knife fixture of claim 3, wherein each of the at least one cutting blade is secured within the plurality of angled recesses at each end of the cutting blade.","5.The knife fixture of claim 2, wherein the blade holder is rotatable about the central axis.","6.The knife fixture of claim 2, wherein the at least one cutting blade is a plurality of cutting blades.","7.The knife fixture of claim 6, wherein the plurality of cutting blades are unconnected at the central axis.","8.The knife fixture of claim 7, wherein the plurality of cutting blades include a pair of individual blades aligned with each other along a longitudinal axis.","9.A helically twisted piece of food product produced by the knife fixture of claim 1.10.The helically twisted piece of food product of claim 9, wherein the food product is a potato.","11.A cutting system for cutting potatoes into multiple helically twisted pieces, comprising: a blade holder having a flow path therethrough; at least one cutting blade oriented across the flow path, each of the at least one cutting blade having a sharpened edge, wherein an angle of the sharpened edge increases along a length of the cutting blade towards the blade holder.","12.The system of claim 11, further comprising a drive motor configured to rotatably drive the blade holder.","13.The system of claim 11, wherein the at least one cutting blade is a plurality of cutting blades.","14.The system of claim 13, wherein the plurality of cutting blades are unconnected at an axial centerline of the flow path.","15.The system of claim 14, wherein the plurality of cutting blades include a pair of individual blades aligned with each other along a longitudinal axis.","16.The system of claim 13, further comprising a centering alignment device configured to center potatoes in the flow path for cutting engagement with the plurality of cutting blades.","17.A knife fixture for cutting food products, the knife fixture comprising: a blade holder forming an opening; and a blade carried by the blade holder, the blade having a cutting edge and a longitudinal axis oriented across the opening, the blade being twisted about the longitudinal axis.","18.The knife fixture of claim 17, further comprising another blade having a cutting edge and a longitudinal axis oriented across the opening, the another blade being twisted about its longitudinal axis.","19.The knife fixture of claim 18, wherein the longitudinal axis of the blade and the longitudinal axis of the another blade are aligned, and the blade and the another blade are unconnected at an axial centerline of the opening.","20.The knife fixture of claim 18, further comprising a third blade having a cutting edge and a longitudinal axis oriented across the opening, the third blade being twisted about its longitudinal axis, wherein the longitudinal axes of the blade, the another blade, and the third blade are not aligned."],["<SOH> BACKGROUND <EOH>Production cutting systems and related knife fixtures are useful for cutting vegetable products such as raw potatoes into spiral or helical shaped pieces, preparatory to further production processing steps such as blanching and parfrying.","In this regard, one typical production system comprises a hydraulic cutting system wherein a so-called water knife fixture is mounted along the length of an elongated tubular conduit.","A pumping device is provided to entrain the vegetable product such as raw potatoes within a propelling water flume for cutting engagement with knife blades of the water knife fixture.","The vegetable product is pumped one at a time in single file succession into and through the water conduit with a velocity and sufficient kinetic energy to carry the vegetable product through a relatively complex knife fixture which includes at least one rotary cutting blade for severing the product into a plurality of smaller pieces of generally spiral or helical shape.","The cut pieces are then carried further through a discharge conduit for appropriate subsequent processing, including cooking or blanching, parfrying, freezing and packaging steps, for subsequent finish processing and serving to customers as loops, twirls, curly fries, etc.","Examples of such hydraulic cutting systems and related rotary knife fixtures are found in U.S. Pat.","Nos.","5,168,784; 5,179,881; 5,277,546; 5,343,791; 5,394,780; 5,394,793; 5,473,967; 5,992,287; and Re.","38,149, all of which are incorporated by reference herein.","Persons skilled in the art will recognize and appreciate that mechanical production feed systems may be employed in lieu of hydraulic feed systems, as described in U.S. Pat.","Nos.","5,097,735; 5,167,177; 5,167,178; and 5,293,803, which are also incorporated by reference herein.","The present invention is directed to an improved rotary knife fixture and related cutting blades for cutting raw vegetable products, such as potatoes, into spiral shaped pieces that may or may not have textured cut surfaces, such as crinkles, waves, or other designs."],["<SOH> SUMMARY <EOH>In accordance with the invention, a rotary knife fixture is provided for cutting vegetable products such as raw potatoes into spiral shapes.","The knife fixture comprises a circular or ring-shaped blade holder adapted to be rotatably driven at a selected rotational speed within a hydraulic product flow path.","The blade holder carries at least one cutting blade rotated therewith, wherein the blade is twisted from a generally longitudinally aligned center axis outwardly in opposite radial directions with a sharpened leading edge set at a desired pitch angle.","By controlling the pitch of the blade in relation to the rotational speed of the blade and the velocity at which the potato travels along the hydraulic flow path, the resultant spiral cut shape is selected.","By using multiple cutting blades at known axially spaced positions and selecting the angular position of each cutting blade in succession, the number of spiral shapes cut from each potato is also selected.","In one preferred form, the ring-shaped blade holder of the rotary knife fixture is rotatably driven within a vegetable product flow path, such as along a hydraulic flow conduit having raw vegetables such as potatoes carried in single file there through.","The blade holder supports at least one cutting blade which is twisted from a generally longitudinally aligned center axis outwardly in opposite radial directions, and defining a pair of sharpened cutting edges presented in opposite circumferential directions.","Each half of the cutting blade is set at a selected pitch angle which varies according to specific radial position, per the formula: in-line-formulae description=\"In-line Formulae\" end=\"lead\"?","Pitch Angle=ArcTan (2×Pi×Radius/Pitch Length) (1) in-line-formulae description=\"In-line Formulae\" end=\"tail\"?","For a blade diameter equal to 4 inches (radius=2 inches), and a pitch length equal to 3 inches, each cutting blade is anchored at its outer edge on the associated ring-shaped blade holder at an angle of about 76.6°.","However, note that the specific pitch angle will vary according to radial position along the blade and the pitch length.","In use, the single cutting blade is rotatably driven, in a preferred form, at a rotational speed of about 6,000 revolutions per minute (rpm), to cut each potato traveling along the hydraulic flow conduit at a velocity of about 25 feet per second (fps) into a pair of generally spiral shaped pieces.","With a pitch length of about 3 inches potato travel per cutting blade revolution, this results in substantially optimum cutting of each potato.","In one embodiment, a cutting blade is rotatably driven at a rotational speed anywhere from about 4,000 rpm to 8,000 rpm.","In one embodiment, a cutting blade is rotatably driven at a rotational speed anywhere from about 4,000 rpm, about 5,000 rpm, about 6,000 rpm, about 7,000 rpm, or about 8,000 rpm, or at revolutions greater than 8,000 rpm.","When more than one cutting blade is used, each of the cutting blades may be physically supported in a stack of ring-shaped blade holders having a known axial dimension such as about 0.5 inch per blade holder, with the multiple blade holders being fixed for rotation together.","With this configuration, the angle Θ (theta) separating each of the supported cutting blades in succession is given by the formula: in-line-formulae description=\"In-line Formulae\" end=\"lead\"?","Θ= T/P (axial dimension of each blade holder/pitch length)×360°+360°/ N (number of cut pieces).","(2) in-line-formulae description=\"In-line Formulae\" end=\"tail\"?","Following this formula, when two cutting blades are used, each carried by a 0.5 inch thick ring-shaped blade holder (thickness=T), with a pitch length (pitch=P) of 3 inches, a total of four spiral pieces are cut from each product, and the second cutting blade is rotationally set to lag the first cutting blade by 150°.","Similarly, where three cutting blades are used, each product is cut into a total of six spiral pieces, and the second blade is oriented to lag the first blade by 120°, and the third blade is oriented to lag the second by an additional 120°, or a total lag from the first blade of about 240°.","And, where four cutting blades are used, each product is cut into a total of eight spiral pieces, and the four blades are oriented respectively to lag the immediately preceding blade by about 105°.","Accordingly, the present invention encompasses a configuration of multiple blades to produce 2, 4, 6, 8, or more spiral pieces per product.","In addition to even numbers of spiral pieces cut per product, the present invention encompasses a configuration of blades that produce 3, 5, 7, 9 or more spiral pieces per product.","An example of such a spiral piece is shown in D640,036, which is incorporated herein by reference.","A further aspect of the present invention is a cutting blade designed to have a textured or “crinkled” surface edge so that when it cuts the product, the exposed cut surface is similarly textured or crinkled.","Accordingly, in one embodiment crinkle-cut spiral pieces of product can be produced using the inventive blades and cutting system.","In any embodiment, or permutation, of cutting blades and number of cutting blades in the inventive cutting system, any number of spiral pieces can be obtained per product.","That is 2, 3, 4, 5, 6, 7, 8, 9, or 10, or more than 10 spiral pieces may be cut from each product.","In another embodiment any number or all of the cutting blades may be textured or crinkled to produce textured or crinkled cut surfaces on a spiral piece.","Thus, in one embodiment every spiral piece cut from one product may contain at least one crinkle-textured cut surface if every cutting blade in the cutting system has a crinkled surface edge.","However in another embodiment not every cutting blade in the cutting system has a wavy, textured, or crinkled edge.","Thus, in that instance, a single product may be cut to yield smooth surface spiral pieces as well as crinkle-cut spiral pieces.","By “product” is meant any vegetable or fruit or wood.","A vegetable that may be cut into 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 spiral pieces that may have smooth or textured/crinkled surfaces, includes, but is not limited to, any tuberous vegetable, beets, turnips, radish, leeks, or any root vegetable.","In one embodiment, a tuber is a potato, sweet potato, carrot, cassava, swede, or yam.","A fruit that may be cut into 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 spiral pieces that may have smooth or textured/crinkled surfaces, includes, but is not limited to, apples, squash, bell peppers, pumpkin, zucchini, cucumber, mangos, and plantains.","A vegetable or fruit when it is processed and cut according to the methods disclosed herein does not necessarily have to be whole.","That is, chunks or cut pieces of a vegetable may be pumped into the cutting system and those chunks or pieces subsequently cut with cutting blades to produce spiral pieces or spiral fragments.","The present invention in particular encompasses a new french fry that is spiral-cut and which may have smooth or crinkled surfaces.","See, for instance, the spiral potato pieces shown in FIG.","9 .","The types of spiral-cut potato wedges are a new line of edible products, and can be made in different sizes or textured or smooth surfaces according to the present invention.","Thus one embodiment of the present invention is a package containing multiple spiral-cut potato pieces or wedges wherein substantially all the spiral cut pieces or wedges are about the same or similar size to each other.","In another embodiment of the present invention is a package containing multiple spiral-cut potato pieces or wedges wherein many of the spiral cut pieces or wedges are about the same or similar size to each other.","A “package” may be a bag of the sort used to hold chips, or an open holder such as to hold fast-food french fries, or any such containment structure or vessel.","In any of these embodiments, one or more or all of the spiral cut potato pieces or wedges in a package may have a crinkle-cut surface.","In another embodiment, the spiral cut potato pieces or wedges in the package may be raw or may be cooked, such as fried, roasted, or oven-baked.","Accordingly, one embodiment of the present invention is a collection of spiral-cut potato pieces that are raw, a collection of spiral-cut potato pieces that are fried, or a collection of spiral-cut potato pieces that are oven-baked, or a collection of spiral-cut potato pieces that are roasted, wherein the pieces have smooth surfaces or have a crinkle-cut surface.","By “smooth” surface is meant a spiral cut product that has been cut with a cutting blade that has a flat, untextured, surface and edge.","By “crinkle-cut” is meant a spiral cut product that has been cut with a cutting blade that has a crinkled or wavy surface and edge, such as those shown in FIG.","10 .","In a further embodiment, the spiral-cut potato wedges may be further processed or seasoned, such as to produce battered or beer battered spiral-cut fried or oven-baked potato wedges.","Pieces of wood may also be cut into 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 spiral pieces that may have smooth or textured/crinkled surfaces.","Softwoods could be cut according to the present invention, for instance.","Examples of softwood include but are not limited to pine, redwood, fir, cedar, and larch.","Other materials may be cut according to the present invention too, such as polystyrene, foam, solid paper pulp materials, and plastics.","Other features and advantages of the invention will become more apparent from the following detailed description, taken in conjunction with the accompanying drawings which illustrate, by way of example, the principles of the invention."],["CROSS-REFENENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser.","No.","14/712,857, filed on May 14, 2015 and entitled “Rotary Knife Fixture for Cutting Spiral, Textured Potato Pieces,” which is a continuation of U.S. patent application Ser.","No.","13/647,319, filed on Oct. 8, 2012 and entitled “Rotary Knife Fixture for Cutting Spiral, Textured Potato Pieces,” now U.S. Pat.","No.","9,089,987, which claims the benefit of U.S.","Provisional Patent Application Ser.","No.","61/661,278, filed on Jun.","18, 2012 and entitled “Rotary Knife Fixture for Cutting Spiral, Textured Potato Pieces,” and claims the benefit of U.S.","Provisional Patent Application Ser.","No.","61/546,035 filed on Oct. 11, 2011 and entitled “Rotary Knife Fixture for Cutting Spiral Potato Pieces,” the contents of all of which are incorporated herein by reference in their entireties.","FIELD OF THE DISCLOSURE This invention relates generally to devices and methods for cutting food products, such as vegetable products, and particularly such as raw potatoes and the like, into spiral or helical shaped pieces, whose cut surfaces may be patterned by the design of knife blades, such as to create textured “crinkle-cut” spiral or helical pieces.","BACKGROUND Production cutting systems and related knife fixtures are useful for cutting vegetable products such as raw potatoes into spiral or helical shaped pieces, preparatory to further production processing steps such as blanching and parfrying.","In this regard, one typical production system comprises a hydraulic cutting system wherein a so-called water knife fixture is mounted along the length of an elongated tubular conduit.","A pumping device is provided to entrain the vegetable product such as raw potatoes within a propelling water flume for cutting engagement with knife blades of the water knife fixture.","The vegetable product is pumped one at a time in single file succession into and through the water conduit with a velocity and sufficient kinetic energy to carry the vegetable product through a relatively complex knife fixture which includes at least one rotary cutting blade for severing the product into a plurality of smaller pieces of generally spiral or helical shape.","The cut pieces are then carried further through a discharge conduit for appropriate subsequent processing, including cooking or blanching, parfrying, freezing and packaging steps, for subsequent finish processing and serving to customers as loops, twirls, curly fries, etc.","Examples of such hydraulic cutting systems and related rotary knife fixtures are found in U.S. Pat.","Nos.","5,168,784; 5,179,881; 5,277,546; 5,343,791; 5,394,780; 5,394,793; 5,473,967; 5,992,287; and Re.","38,149, all of which are incorporated by reference herein.","Persons skilled in the art will recognize and appreciate that mechanical production feed systems may be employed in lieu of hydraulic feed systems, as described in U.S. Pat.","Nos.","5,097,735; 5,167,177; 5,167,178; and 5,293,803, which are also incorporated by reference herein.","The present invention is directed to an improved rotary knife fixture and related cutting blades for cutting raw vegetable products, such as potatoes, into spiral shaped pieces that may or may not have textured cut surfaces, such as crinkles, waves, or other designs.","SUMMARY In accordance with the invention, a rotary knife fixture is provided for cutting vegetable products such as raw potatoes into spiral shapes.","The knife fixture comprises a circular or ring-shaped blade holder adapted to be rotatably driven at a selected rotational speed within a hydraulic product flow path.","The blade holder carries at least one cutting blade rotated therewith, wherein the blade is twisted from a generally longitudinally aligned center axis outwardly in opposite radial directions with a sharpened leading edge set at a desired pitch angle.","By controlling the pitch of the blade in relation to the rotational speed of the blade and the velocity at which the potato travels along the hydraulic flow path, the resultant spiral cut shape is selected.","By using multiple cutting blades at known axially spaced positions and selecting the angular position of each cutting blade in succession, the number of spiral shapes cut from each potato is also selected.","In one preferred form, the ring-shaped blade holder of the rotary knife fixture is rotatably driven within a vegetable product flow path, such as along a hydraulic flow conduit having raw vegetables such as potatoes carried in single file there through.","The blade holder supports at least one cutting blade which is twisted from a generally longitudinally aligned center axis outwardly in opposite radial directions, and defining a pair of sharpened cutting edges presented in opposite circumferential directions.","Each half of the cutting blade is set at a selected pitch angle which varies according to specific radial position, per the formula: Pitch Angle=ArcTan (2×Pi×Radius/Pitch Length) (1) For a blade diameter equal to 4 inches (radius=2 inches), and a pitch length equal to 3 inches, each cutting blade is anchored at its outer edge on the associated ring-shaped blade holder at an angle of about 76.6°.","However, note that the specific pitch angle will vary according to radial position along the blade and the pitch length.","In use, the single cutting blade is rotatably driven, in a preferred form, at a rotational speed of about 6,000 revolutions per minute (rpm), to cut each potato traveling along the hydraulic flow conduit at a velocity of about 25 feet per second (fps) into a pair of generally spiral shaped pieces.","With a pitch length of about 3 inches potato travel per cutting blade revolution, this results in substantially optimum cutting of each potato.","In one embodiment, a cutting blade is rotatably driven at a rotational speed anywhere from about 4,000 rpm to 8,000 rpm.","In one embodiment, a cutting blade is rotatably driven at a rotational speed anywhere from about 4,000 rpm, about 5,000 rpm, about 6,000 rpm, about 7,000 rpm, or about 8,000 rpm, or at revolutions greater than 8,000 rpm.","When more than one cutting blade is used, each of the cutting blades may be physically supported in a stack of ring-shaped blade holders having a known axial dimension such as about 0.5 inch per blade holder, with the multiple blade holders being fixed for rotation together.","With this configuration, the angle Θ (theta) separating each of the supported cutting blades in succession is given by the formula: Θ=T/P (axial dimension of each blade holder/pitch length)×360°+360°/N (number of cut pieces).","(2) Following this formula, when two cutting blades are used, each carried by a 0.5 inch thick ring-shaped blade holder (thickness=T), with a pitch length (pitch=P) of 3 inches, a total of four spiral pieces are cut from each product, and the second cutting blade is rotationally set to lag the first cutting blade by 150°.","Similarly, where three cutting blades are used, each product is cut into a total of six spiral pieces, and the second blade is oriented to lag the first blade by 120°, and the third blade is oriented to lag the second by an additional 120°, or a total lag from the first blade of about 240°.","And, where four cutting blades are used, each product is cut into a total of eight spiral pieces, and the four blades are oriented respectively to lag the immediately preceding blade by about 105°.","Accordingly, the present invention encompasses a configuration of multiple blades to produce 2, 4, 6, 8, or more spiral pieces per product.","In addition to even numbers of spiral pieces cut per product, the present invention encompasses a configuration of blades that produce 3, 5, 7, 9 or more spiral pieces per product.","An example of such a spiral piece is shown in D640,036, which is incorporated herein by reference.","A further aspect of the present invention is a cutting blade designed to have a textured or “crinkled” surface edge so that when it cuts the product, the exposed cut surface is similarly textured or crinkled.","Accordingly, in one embodiment crinkle-cut spiral pieces of product can be produced using the inventive blades and cutting system.","In any embodiment, or permutation, of cutting blades and number of cutting blades in the inventive cutting system, any number of spiral pieces can be obtained per product.","That is 2, 3, 4, 5, 6, 7, 8, 9, or 10, or more than 10 spiral pieces may be cut from each product.","In another embodiment any number or all of the cutting blades may be textured or crinkled to produce textured or crinkled cut surfaces on a spiral piece.","Thus, in one embodiment every spiral piece cut from one product may contain at least one crinkle-textured cut surface if every cutting blade in the cutting system has a crinkled surface edge.","However in another embodiment not every cutting blade in the cutting system has a wavy, textured, or crinkled edge.","Thus, in that instance, a single product may be cut to yield smooth surface spiral pieces as well as crinkle-cut spiral pieces.","By “product” is meant any vegetable or fruit or wood.","A vegetable that may be cut into 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 spiral pieces that may have smooth or textured/crinkled surfaces, includes, but is not limited to, any tuberous vegetable, beets, turnips, radish, leeks, or any root vegetable.","In one embodiment, a tuber is a potato, sweet potato, carrot, cassava, swede, or yam.","A fruit that may be cut into 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 spiral pieces that may have smooth or textured/crinkled surfaces, includes, but is not limited to, apples, squash, bell peppers, pumpkin, zucchini, cucumber, mangos, and plantains.","A vegetable or fruit when it is processed and cut according to the methods disclosed herein does not necessarily have to be whole.","That is, chunks or cut pieces of a vegetable may be pumped into the cutting system and those chunks or pieces subsequently cut with cutting blades to produce spiral pieces or spiral fragments.","The present invention in particular encompasses a new french fry that is spiral-cut and which may have smooth or crinkled surfaces.","See, for instance, the spiral potato pieces shown in FIG.","9.The types of spiral-cut potato wedges are a new line of edible products, and can be made in different sizes or textured or smooth surfaces according to the present invention.","Thus one embodiment of the present invention is a package containing multiple spiral-cut potato pieces or wedges wherein substantially all the spiral cut pieces or wedges are about the same or similar size to each other.","In another embodiment of the present invention is a package containing multiple spiral-cut potato pieces or wedges wherein many of the spiral cut pieces or wedges are about the same or similar size to each other.","A “package” may be a bag of the sort used to hold chips, or an open holder such as to hold fast-food french fries, or any such containment structure or vessel.","In any of these embodiments, one or more or all of the spiral cut potato pieces or wedges in a package may have a crinkle-cut surface.","In another embodiment, the spiral cut potato pieces or wedges in the package may be raw or may be cooked, such as fried, roasted, or oven-baked.","Accordingly, one embodiment of the present invention is a collection of spiral-cut potato pieces that are raw, a collection of spiral-cut potato pieces that are fried, or a collection of spiral-cut potato pieces that are oven-baked, or a collection of spiral-cut potato pieces that are roasted, wherein the pieces have smooth surfaces or have a crinkle-cut surface.","By “smooth” surface is meant a spiral cut product that has been cut with a cutting blade that has a flat, untextured, surface and edge.","By “crinkle-cut” is meant a spiral cut product that has been cut with a cutting blade that has a crinkled or wavy surface and edge, such as those shown in FIG.","10.In a further embodiment, the spiral-cut potato wedges may be further processed or seasoned, such as to produce battered or beer battered spiral-cut fried or oven-baked potato wedges.","Pieces of wood may also be cut into 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 spiral pieces that may have smooth or textured/crinkled surfaces.","Softwoods could be cut according to the present invention, for instance.","Examples of softwood include but are not limited to pine, redwood, fir, cedar, and larch.","Other materials may be cut according to the present invention too, such as polystyrene, foam, solid paper pulp materials, and plastics.","Other features and advantages of the invention will become more apparent from the following detailed description, taken in conjunction with the accompanying drawings which illustrate, by way of example, the principles of the invention.","BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings illustrate the invention.","In such drawings: FIG.","1 is a schematic diagram depicting a hydraulic cutting system of a type utilizing a rotatably driven knife fixture constructed in accordance with the present invention; FIG.","2 is an enlarged perspective view illustrating a drive motor and cog belt for rotatably driving the knife fixture of FIG.","1; FIG.","3 is an exploded perspective view showing rotatable mounting of the knife fixture within a rotary bearing unit; FIG.","4 is a front side perspective view of one cutting blade carried by a ring-shaped blade holder in accordance with one preferred form of the invention; FIG.","5 is a front side perspective view of a pair of cutting blades carried respectively by a corresponding pair of blade holders in accordance with one alternative preferred form of the invention; FIG.","6 is a front side perspective view of a knife fixture including three cutting blades respectively supported by three blade holders in accordance with a further alternative preferred form of the invention; FIG.","7 is a front side perspective view of four cutting blades carried respectively by four blade holders in accordance with another alternative preferred form of the invention; FIG.","8 is a drawing similar to FIG.","7 but showing four corrugated or crinkle cut knife blades; FIG.","9 is a drawing showing a spiral piece or wedge cut with the crinkle cut knife blades shown in FIG.","8; FIG.","10 is a drawing of an exemplary cutting blade designed to have textured or wavy or crinkled surfaces and edges so as to produce spiral pieces or wedges that have similarly textured, wavy, or crinkled cut surfaces; FIG.","11 is an enlarged front side perspective view taken about the circle 11 in FIG.","7, further illustrating the inclined mounting surface in the blade holder; FIG.","12 is a front side perspective view of an embodiment of a pair of cutting blades carried by a ring-shaped blade holder; and FIG.","13 is a front side perspective view of an embodiment of three cutting blades carried by a ring-shaped blade holder.","DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS This invention relates generally to devices and methods for cutting food products, such as vegetable products, and particularly such as raw potatoes and the like, into spiral or helical shaped pieces, whose cut surfaces may be patterned by the design of knife blades, such as to create “crinkle-cut” spiral or helical pieces.","More particularly, this invention relates to a rotatably driven knife fixture having a selected number of knife blades adapted to cut a raw potato or the like into generally spiral shaped pieces.","As shown in the exemplary drawings, a hydraulic cutting system comprises a conventional so-called water knife fixture referred to generally in FIG.","1 by the reference numeral 10 for cutting vegetable products such as whole potatoes 12 into spiral shaped pieces 14 for subsequent processing.","The present invention comprises a rotary driven knife fixture 10 (FIGS.","2-7) for installation into the cutting system and for rotatable driving by means of a drive motor 11 or the like.","The knife fixture 10 includes at least one rotatably driven cutting blade 16 (FIGS.","2-4) for cutting the product into a pair of generally spiral shaped pieces 14 of the same or similar size and shape.","In alternative embodiments, the single cutting blade 16 can be combined with a second cutting blade 17 (FIG.","5) to cut the product into four spiral shaped pieces, with a third cutting blade 18 (FIG.","6) to cut the product into six spiral shaped pieces, or with a fourth cutting blade 19 (FIG.","7) to cut the product into eight spiral shaped pieces.","Indeed, any number of cutting blades can be used for subdividing the product into twice the number of spiral shaped pieces of substantially similar size and shape.","FIG.","1 shows the cutting system in the form of a hydraulic cutting system comprising a tank 78 or the like for receiving a supply of vegetable products, such as the illustrative raw whole potatoes 12 in a peeled or unpeeled state.","Alternatively, these potatoes 12 can comprise halves or pieces of whole potatoes, peeled or unpeeled.","In one preferred form, these potatoes 12 comprise relatively small potatoes or potato pieces having a longitudinal length on the order of about 3 inches.","It is noted, however, that actual potato size is unimportant, as long as the potato has a diametric size to fit through the knife fixture.","As viewed in FIG.","1, the potatoes 12 are delivered via an inlet conduit 30 to a pump 32 which propels the potatoes in single file relation within a propelling water stream or flume through a tubular delivery conduit 34 into cutting engagement with the blades (not shown in FIG.","1) of the water knife fixture 10.In a typical hydraulic cutting system, the potatoes are propelled through the delivery conduit 34 at a relatively high velocity of about 25 feet per second (fps), or about 1,500 feet per minute (fpm), to provide sufficient kinetic energy whereby each potato is propelled through the knife fixture 10 to produce (as will be described in more detail herein, per the blade pitch angle) the desired elongated spiral cut pieces 14.In this regard, the delivery conduit 34 may include a centering alignment device (not shown) for substantially centering each potato 12 on a longitudinal centerline of the flow passage extending through the associated knife fixture 10, in a manner known to persons skilled in the art.","The cut strips 14 travel through a short discharge conduit 36 to a conveyor 38 or the like which transports the cut strips 14 for further processing, such as blanching, drying, batter coating, parfrying, freezing, etc.","Persons skilled in the art will recognize and appreciate that alternative form cutting systems may be used, to include, by way of example, mechanical cutting systems wherein the vegetable products such as potatoes are mechanically delivered via a chute or hopper or the like to the knife fixture 10.In either case, the knife fixture 10 is mounted along a production path and is rotatably driven for engaging and cutting the incoming products into the desired spiral shaped pieces.","FIGS.","2-3 show installation of the illustrative knife fixture 10 into a rotary bearing unit 20 in a position in-line with a production path for the vegetable products such as the potatoes 12 (FIG.","1).","In this regard, the illustrative knife fixture 10 comprises a generally ring-shaped blade holder 22 of generally annular or circular shape, and having a cross sectional area sufficient for providing a relatively stiff or sturdy structure capable of withstanding the rigors of a production environment over an extended period of time.","This blade holder 22 is secured as by means of clamp screws 23 or the like onto downstream or lower annular ring 21 or the like adapted in turn for affixation to the lower or downstream end of a rotatable bearing assembly 25 as by means of screws 25′ or the like.","As shown in FIG.","3, the bearing assembly 25 is rotatably carried within a bushing 26 mounted as by means of screws 26′ or the like onto an upstream or upper side of the enlarged plate 27, which has an opening 13 formed therein for in-line installation along the production flow path.","A flange plate 28 overlies the bearing assembly 25 for sandwiching the assembly 25 against an internal shoulder 29 within the bushing 26.A driven ring BO is mounted in turn as by means of screws 30′ onto the bearing assembly 25 for rotation therewith.","The driven ring 30 of the rotary bearing unit 20 includes a circumferential array of detents 41 for registry with teeth 42 of a cog-type drive belt 43 (FIG.","2).","This drive belt 43 is in turn reeved about a drive gear 44 on an output shaft 45 of the drive motor 11 (FIG.","2).","Accordingly, the drive motor 11 positively drives the driven ring 30 and associated bearing assembly 25 secured thereto at a known speed, preferably on the order of about 6,000 rpm in the case of the illustrative hydraulic cutting system, for correspondingly rotatably driving the knife fixture 10 at the same rotational speed.","Importantly, the cog-type drive belt 43 beneficially insures constant-speed rotatable driving of the knife fixture 10 notwithstanding periodic impact engagement of the water-propelled potatoes therewith.","In one preferred configuration as viewed in FIGS.","2-4, a single cutting blade 16 is used to cut each incoming vegetable product such as a potato 12 into two separate, generally spiral shaped pieces 14 (FIG.","1) of similar size and shape.","The cutting blade 16 is shown with a sharpened cutting edge 16′ along one side thereof.","Since the cutting blade 16 is twisted generally at a radial center, or a longitudinal centerline or axis of the hydraulic flow path, two cutting edges 16′ are defined to extend radially outwardly in opposite directions, and in opposite-facing circumferential directions.","In other words, a first portion 16A of the cutting blade 16 that is adjacent to the blade holder 22 has a cutting edge 16′ with a different pitch angle than that of a second portion 16B of the cutting blade 16 that is located further from the blade holder 22 than the first portion 16A.","A pair of clamp screws 31 or the like are secured through the respective opposite ends of the cutting blade 16 to seat the cutting blade within a shallow recess formed at an appropriate pitch angle.","More specifically, the specific pitch angle of the cutting blade 16 at each specific point along its radial length is given by the formula: Pitch Angle=ArcTan (2×Pi×Radius/Pitch Length) (1) For a total blade radius of 2 inches, and a pitch length of about 3 inches, the clamp screws 31 secure the outermost radial ends of each cutting blade 16 or 17 at a pitch angle of about 76.6° to the axial blade centerline.","It will be understood, however, that the specific pitch angle is directly proportional to the radial point along the blade, whereby the pitch angle increases from the radial center, and it is this pitch angle that determines the spiral shape of the cut product.","If more spiral shaped pieces 14 are desired from each potato 12, more cutting blades are used recognizing that each of the cutting blades cuts the incoming product in two, and thereby produces twice the number of spiral shaped pieces in comparison with the number of cutting blades used.","Importantly, the cutting blades are arranged in succession at controlled angles to obtain similar or virtually identical cut spiral shaped pieces.","More particularly, in one preferred form as viewed in FIG.","5, two cutting blades 16 and 17 are supported by separate blade holders 22 and 22′ in a stack on the associated annular ring 21, as by means of elongated screws 23.That is, aligned screw ports are formed in the second blade holder 22′ at the appropriate positions for receiving the elongated screws 23 used to fasten the drive rings 22, 22′ and the underlying annular ring 21 together for concurrent rotation.","The two cutting blades 16 and 17 are generally identical to each to each other, to include a twisted shape generally at a longitudinal center axis thereof and extending radially outwardly in opposite directions for seated engagement as by means of clamp screws 31 or the like at the selected pitch angle.","Using formula (1) above for the specific pitch angle of each blade 16 or 17 along its radial length, and wherein the total blade radius is 2 inches and the pitch length is 3 inches, the clamp screws 31 secure the outermost radial ends of each cutting blade 16 or 17 at a pitch angle of about 76.6°.","In this respect, FIG.","11 more specifically illustrates the inclined mounting surface in the blade holder 22 at the point where the clamp screws 31 secure the cutting blade 16 to the blade holder 22.In addition, when the two cutting blades 16 and 17 are rotated at about 6,000 revolutions per minute (rpm), to advance each product to be cut along the hydraulic flow path at a velocity of about 25 feet per second (fps), the two cutting blades 16 and 17 both cut the incoming product into two pieces, for a total of four spiral shaped pieces 14 of similar or identical shape.","With a pitch length of about 3 inches potato travel for each cutting blade revolution, and with each of the blade holders 22, 22′ having an axial dimension of about 0.5 inch, the angle Θ (theta) separating each of the supported cutting blades is given by the formula: Θ=T/P (axial dimension of each blade holder/pitch length)×360°+360°/N (number of cut pieces).","(2) In the case of the two cutting blades 16, 17 adapted to cut each incoming product into four generally identical spiral shaped pieces, the angle 1=150°.","FIGS.","6 and 7 illustrate two exemplary alternative preferred forms of the invention, wherein three cutting blades 16, 17 and 18 are separately supported by a stack of three ring-shaped blade holders 22, 22′, and 22″ for cutting each incoming product into a total of six spiral shaped pieces (FIG.","6), and also wherein four cutting blades 16, 17, 18 and 19 are separately supported by a stack of four ring-shaped blade holders 22, 22′, 22″, and 22′″ (FIG.","7) for cutting each incoming product into a total of eight spiral shaped pieces.","In the examples of FIGS.","6 and 7, formula (2) is followed to determine the angular setting of each cutting blade in succession in order to form the multiple spiral shaped pieces of identical or similar shapes.","In FIG.","6, the cutting blades are set at successive angles of about 120° to cut products per U.S. Patent D640,036 which is incorporated by reference herein, whereas in FIG.","7, the cutting blades are set at successive angles of about 105°.","In each case, clamp screws 31 are used to seat each of cutting blades at the selected pitch angle within the recess formed in the associated blade holder.","Similarly, screws 23 or the like are fitted and secured through aligned ports formed in the stacked blade holders for securing them together for rotation with the bearing assembly 25.Persons skilled in the art will understand and appreciate, of course, that virtually any number of cutting blades can be used, with the formula (2) determining the angular spacings of the multiple cutting blades in succession.","For example, when five cutting blades are used, a total of ten spiral shaped pieces are formed; following formula (2), the successive cutting blade angular spacings would be about 96°.","Similarly, when six cutting blades are used, a total of twelve spiral shaped pieces are formed; following formula (2), the successive cutting blade angular spacings would be about 90°.","Persons skilled in the art will also appreciate that when three or more cutting blades are used, the formula (2) determines that angular spacings of the blades as a group, but that each of the blades need only be set at one of the angular positions; that is, the blades do not need to be set at a regular lag interval, so long as one of the blades in the group is set at each one of the angular positions.","Alternately, it will be understood that other forms of the blade holders and the related interconnection means can be employed, such as the formation of steps including interengaging tabs and slots in the respective blade holders to insure the desired angular position of the cutting blades and concurrent rotation thereof.","In an alternative preferred form, the present invention encompasses a new french fry that is spiral-cut and which may have corrugated or crinkled surfaces.","See, for instance, the spiral potato pieces 14′ shown in FIG.","9.The types of spiral-cut potato wedges are a new line of edible products, and can be made in different sizes or textured surfaces according to the present invention.","Thus one embodiment of the present invention is a package containing multiple spiral-cut potato pieces or wedges 14′ wherein substantially all the spiral cut pieces or wedges are about the same or similar size to each other.","In another embodiment of the present invention is a package containing multiple spiral-cut potato pieces or wedges 14′ wherein many of the spiral cut pieces or wedges are about the same or similar size to each other.","A “package” may be a bag of the sort used to hold chips, or an open holder such as to hold fast-food french fries, or any such containment structure or vessel.","In any of these embodiments, one or more or all of the spiral cut potato pieces or wedges in a package may have a crinkle-cut surface.","In another embodiment, the spiral cut potato pieces or wedges in the package may be raw or may be cooked, such as fried, roasted, or oven-baked.","Accordingly, one embodiment of the present invention is a collection of spiral-cut potato pieces that are raw, a collection of spiral-cut potato pieces that are fried, or a collection of spiral-cut potato pieces that are oven-baked, or a collection of spiral-cut potato pieces that are roasted, wherein the pieces have smooth surfaces or have a crinkle-cut surface.","By “smooth” surface is meant a spiral cut product that has been cut with a cutting blade 16, 17, 18 or 19 that has a flat, untextured, surface and edge, as viewed in FIGS.","4-7.By “crinkle-cut” is meant a spiral cut product that has been cut using a modified knife fixture 11′ with a cutting blade 16″, 17″, 18″, or 19″ that has a crinkled or wavy surface and edge 16″, 17″, 18″, or 19′, such as those shown in FIG.","8.In a further embodiment, the spiral-cut potato wedges may be further processed or seasoned, such as to produce battered or beer battered spiral-cut fried or oven-baked potato wedges.","It will be understood, of course, that the modified knife fixture 11′ shown in FIG.","8 can be equipped with one or more of the cutting knives of a corrugated and crinkle-cut configuration, as per any one of the knife blade embodiments depicted in FIGS.","4-7.Indeed, more than four such knife blades can be used, if more than 8 spiral-cut wedges are desired.","It will also be recognized and understood that different size corrugations or crinkle-cut configurations can be used for the various knife blades, such as illustrated in FIG.","10 with respect to the corrugated knife blade 16″, and the associated cutting edge 16″'.","A variety of modifications and improvements in and to the rotary knife fixture 10 of the present invention will be apparent to those persons skilled in the art.","As one example, persons skilled in the art will understand that each of the twisted cutting blades as shown and described herein can be replaced by a pair of individual blades aligned diametrically with each other and having a pitch angle as defined by formula (1), but otherwise unconnected at the axial centerline of the flow path.","For instance, in FIG.","12, the blade 16 of FIG.","4 has been replaced by a pair of individual blades 116 aligned diametrically but otherwise unconnected at the axial centerline of the flow path.","As a further alternative, the blades do not need to be aligned diametrically, but an odd number of unconnected blades, such as three blades 216 shown in FIG.","13, can be used in the event that an odd number of product cuts is desired.","Accordingly, no limitation on the invention is intended by way of the foregoing description and accompanying drawings, except as set forth in the appended claims."]],"string":"[\n [\n \"ROTARY KNIFE FIXTURE FOR CUTTING SPIRAL, TEXTURED POTATO PIECES\",\n \"A rotary knife fixture for cutting vegetable products such as raw potatoes into spiral shapes.\",\n \"The knife fixture includes a ring-shaped blade holder driven rotatably within a hydraulic product flow path.\",\n \"The blade holder includes at least one cutting blade, wherein the blade is twisted from a generally longitudinally aligned center axis outwardly in opposite circumferential directions with a sharpened leading edge set at a desired pitch angle.\",\n \"By controlling the pitch angle of the blade in relation to the blade rotational speed and velocity at which the potato travels along the hydraulic flow path, the resultant spiral cut shape is selected.\",\n \"By using multiple cutting blades at known axially spaced positions and selecting the angular position of each cutting blade in succession, the number of spiral shapes cut from each potato is selected.\",\n \"The blades can have a nontextured straight-cut edge, or a textured crinkle-cut edge, or a combination.\"\n ],\n [\n \"1.A knife fixture for cutting food products, the fixture comprising: a blade holder; and at least one cutting blade with a cutting edge, each of the at least one cutting blade extending inward from the blade holder and being twisted such that the cutting edge has a pitch angle that varies along the cutting blade.\",\n \"2.The knife fixture of claim 1, wherein the blade holder forms an opening surrounding a central axis and each of the at least one cutting blade extends from the blade holder and across the opening.\",\n \"3.The knife fixture of claim 2, wherein the blade holder includes a plurality of angled recesses, the at least one cutting blade being secured within the plurality of angled recesses.\",\n \"4.The knife fixture of claim 3, wherein each of the at least one cutting blade is secured within the plurality of angled recesses at each end of the cutting blade.\",\n \"5.The knife fixture of claim 2, wherein the blade holder is rotatable about the central axis.\",\n \"6.The knife fixture of claim 2, wherein the at least one cutting blade is a plurality of cutting blades.\",\n \"7.The knife fixture of claim 6, wherein the plurality of cutting blades are unconnected at the central axis.\",\n \"8.The knife fixture of claim 7, wherein the plurality of cutting blades include a pair of individual blades aligned with each other along a longitudinal axis.\",\n \"9.A helically twisted piece of food product produced by the knife fixture of claim 1.10.The helically twisted piece of food product of claim 9, wherein the food product is a potato.\",\n \"11.A cutting system for cutting potatoes into multiple helically twisted pieces, comprising: a blade holder having a flow path therethrough; at least one cutting blade oriented across the flow path, each of the at least one cutting blade having a sharpened edge, wherein an angle of the sharpened edge increases along a length of the cutting blade towards the blade holder.\",\n \"12.The system of claim 11, further comprising a drive motor configured to rotatably drive the blade holder.\",\n \"13.The system of claim 11, wherein the at least one cutting blade is a plurality of cutting blades.\",\n \"14.The system of claim 13, wherein the plurality of cutting blades are unconnected at an axial centerline of the flow path.\",\n \"15.The system of claim 14, wherein the plurality of cutting blades include a pair of individual blades aligned with each other along a longitudinal axis.\",\n \"16.The system of claim 13, further comprising a centering alignment device configured to center potatoes in the flow path for cutting engagement with the plurality of cutting blades.\",\n \"17.A knife fixture for cutting food products, the knife fixture comprising: a blade holder forming an opening; and a blade carried by the blade holder, the blade having a cutting edge and a longitudinal axis oriented across the opening, the blade being twisted about the longitudinal axis.\",\n \"18.The knife fixture of claim 17, further comprising another blade having a cutting edge and a longitudinal axis oriented across the opening, the another blade being twisted about its longitudinal axis.\",\n \"19.The knife fixture of claim 18, wherein the longitudinal axis of the blade and the longitudinal axis of the another blade are aligned, and the blade and the another blade are unconnected at an axial centerline of the opening.\",\n \"20.The knife fixture of claim 18, further comprising a third blade having a cutting edge and a longitudinal axis oriented across the opening, the third blade being twisted about its longitudinal axis, wherein the longitudinal axes of the blade, the another blade, and the third blade are not aligned.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>Production cutting systems and related knife fixtures are useful for cutting vegetable products such as raw potatoes into spiral or helical shaped pieces, preparatory to further production processing steps such as blanching and parfrying.\",\n \"In this regard, one typical production system comprises a hydraulic cutting system wherein a so-called water knife fixture is mounted along the length of an elongated tubular conduit.\",\n \"A pumping device is provided to entrain the vegetable product such as raw potatoes within a propelling water flume for cutting engagement with knife blades of the water knife fixture.\",\n \"The vegetable product is pumped one at a time in single file succession into and through the water conduit with a velocity and sufficient kinetic energy to carry the vegetable product through a relatively complex knife fixture which includes at least one rotary cutting blade for severing the product into a plurality of smaller pieces of generally spiral or helical shape.\",\n \"The cut pieces are then carried further through a discharge conduit for appropriate subsequent processing, including cooking or blanching, parfrying, freezing and packaging steps, for subsequent finish processing and serving to customers as loops, twirls, curly fries, etc.\",\n \"Examples of such hydraulic cutting systems and related rotary knife fixtures are found in U.S. Pat.\",\n \"Nos.\",\n \"5,168,784; 5,179,881; 5,277,546; 5,343,791; 5,394,780; 5,394,793; 5,473,967; 5,992,287; and Re.\",\n \"38,149, all of which are incorporated by reference herein.\",\n \"Persons skilled in the art will recognize and appreciate that mechanical production feed systems may be employed in lieu of hydraulic feed systems, as described in U.S. Pat.\",\n \"Nos.\",\n \"5,097,735; 5,167,177; 5,167,178; and 5,293,803, which are also incorporated by reference herein.\",\n \"The present invention is directed to an improved rotary knife fixture and related cutting blades for cutting raw vegetable products, such as potatoes, into spiral shaped pieces that may or may not have textured cut surfaces, such as crinkles, waves, or other designs.\"\n ],\n [\n \"<SOH> SUMMARY <EOH>In accordance with the invention, a rotary knife fixture is provided for cutting vegetable products such as raw potatoes into spiral shapes.\",\n \"The knife fixture comprises a circular or ring-shaped blade holder adapted to be rotatably driven at a selected rotational speed within a hydraulic product flow path.\",\n \"The blade holder carries at least one cutting blade rotated therewith, wherein the blade is twisted from a generally longitudinally aligned center axis outwardly in opposite radial directions with a sharpened leading edge set at a desired pitch angle.\",\n \"By controlling the pitch of the blade in relation to the rotational speed of the blade and the velocity at which the potato travels along the hydraulic flow path, the resultant spiral cut shape is selected.\",\n \"By using multiple cutting blades at known axially spaced positions and selecting the angular position of each cutting blade in succession, the number of spiral shapes cut from each potato is also selected.\",\n \"In one preferred form, the ring-shaped blade holder of the rotary knife fixture is rotatably driven within a vegetable product flow path, such as along a hydraulic flow conduit having raw vegetables such as potatoes carried in single file there through.\",\n \"The blade holder supports at least one cutting blade which is twisted from a generally longitudinally aligned center axis outwardly in opposite radial directions, and defining a pair of sharpened cutting edges presented in opposite circumferential directions.\",\n \"Each half of the cutting blade is set at a selected pitch angle which varies according to specific radial position, per the formula: in-line-formulae description=\\\"In-line Formulae\\\" end=\\\"lead\\\"?\",\n \"Pitch Angle=ArcTan (2×Pi×Radius/Pitch Length) (1) in-line-formulae description=\\\"In-line Formulae\\\" end=\\\"tail\\\"?\",\n \"For a blade diameter equal to 4 inches (radius=2 inches), and a pitch length equal to 3 inches, each cutting blade is anchored at its outer edge on the associated ring-shaped blade holder at an angle of about 76.6°.\",\n \"However, note that the specific pitch angle will vary according to radial position along the blade and the pitch length.\",\n \"In use, the single cutting blade is rotatably driven, in a preferred form, at a rotational speed of about 6,000 revolutions per minute (rpm), to cut each potato traveling along the hydraulic flow conduit at a velocity of about 25 feet per second (fps) into a pair of generally spiral shaped pieces.\",\n \"With a pitch length of about 3 inches potato travel per cutting blade revolution, this results in substantially optimum cutting of each potato.\",\n \"In one embodiment, a cutting blade is rotatably driven at a rotational speed anywhere from about 4,000 rpm to 8,000 rpm.\",\n \"In one embodiment, a cutting blade is rotatably driven at a rotational speed anywhere from about 4,000 rpm, about 5,000 rpm, about 6,000 rpm, about 7,000 rpm, or about 8,000 rpm, or at revolutions greater than 8,000 rpm.\",\n \"When more than one cutting blade is used, each of the cutting blades may be physically supported in a stack of ring-shaped blade holders having a known axial dimension such as about 0.5 inch per blade holder, with the multiple blade holders being fixed for rotation together.\",\n \"With this configuration, the angle Θ (theta) separating each of the supported cutting blades in succession is given by the formula: in-line-formulae description=\\\"In-line Formulae\\\" end=\\\"lead\\\"?\",\n \"Θ= T/P (axial dimension of each blade holder/pitch length)×360°+360°/ N (number of cut pieces).\",\n \"(2) in-line-formulae description=\\\"In-line Formulae\\\" end=\\\"tail\\\"?\",\n \"Following this formula, when two cutting blades are used, each carried by a 0.5 inch thick ring-shaped blade holder (thickness=T), with a pitch length (pitch=P) of 3 inches, a total of four spiral pieces are cut from each product, and the second cutting blade is rotationally set to lag the first cutting blade by 150°.\",\n \"Similarly, where three cutting blades are used, each product is cut into a total of six spiral pieces, and the second blade is oriented to lag the first blade by 120°, and the third blade is oriented to lag the second by an additional 120°, or a total lag from the first blade of about 240°.\",\n \"And, where four cutting blades are used, each product is cut into a total of eight spiral pieces, and the four blades are oriented respectively to lag the immediately preceding blade by about 105°.\",\n \"Accordingly, the present invention encompasses a configuration of multiple blades to produce 2, 4, 6, 8, or more spiral pieces per product.\",\n \"In addition to even numbers of spiral pieces cut per product, the present invention encompasses a configuration of blades that produce 3, 5, 7, 9 or more spiral pieces per product.\",\n \"An example of such a spiral piece is shown in D640,036, which is incorporated herein by reference.\",\n \"A further aspect of the present invention is a cutting blade designed to have a textured or “crinkled” surface edge so that when it cuts the product, the exposed cut surface is similarly textured or crinkled.\",\n \"Accordingly, in one embodiment crinkle-cut spiral pieces of product can be produced using the inventive blades and cutting system.\",\n \"In any embodiment, or permutation, of cutting blades and number of cutting blades in the inventive cutting system, any number of spiral pieces can be obtained per product.\",\n \"That is 2, 3, 4, 5, 6, 7, 8, 9, or 10, or more than 10 spiral pieces may be cut from each product.\",\n \"In another embodiment any number or all of the cutting blades may be textured or crinkled to produce textured or crinkled cut surfaces on a spiral piece.\",\n \"Thus, in one embodiment every spiral piece cut from one product may contain at least one crinkle-textured cut surface if every cutting blade in the cutting system has a crinkled surface edge.\",\n \"However in another embodiment not every cutting blade in the cutting system has a wavy, textured, or crinkled edge.\",\n \"Thus, in that instance, a single product may be cut to yield smooth surface spiral pieces as well as crinkle-cut spiral pieces.\",\n \"By “product” is meant any vegetable or fruit or wood.\",\n \"A vegetable that may be cut into 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 spiral pieces that may have smooth or textured/crinkled surfaces, includes, but is not limited to, any tuberous vegetable, beets, turnips, radish, leeks, or any root vegetable.\",\n \"In one embodiment, a tuber is a potato, sweet potato, carrot, cassava, swede, or yam.\",\n \"A fruit that may be cut into 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 spiral pieces that may have smooth or textured/crinkled surfaces, includes, but is not limited to, apples, squash, bell peppers, pumpkin, zucchini, cucumber, mangos, and plantains.\",\n \"A vegetable or fruit when it is processed and cut according to the methods disclosed herein does not necessarily have to be whole.\",\n \"That is, chunks or cut pieces of a vegetable may be pumped into the cutting system and those chunks or pieces subsequently cut with cutting blades to produce spiral pieces or spiral fragments.\",\n \"The present invention in particular encompasses a new french fry that is spiral-cut and which may have smooth or crinkled surfaces.\",\n \"See, for instance, the spiral potato pieces shown in FIG.\",\n \"9 .\",\n \"The types of spiral-cut potato wedges are a new line of edible products, and can be made in different sizes or textured or smooth surfaces according to the present invention.\",\n \"Thus one embodiment of the present invention is a package containing multiple spiral-cut potato pieces or wedges wherein substantially all the spiral cut pieces or wedges are about the same or similar size to each other.\",\n \"In another embodiment of the present invention is a package containing multiple spiral-cut potato pieces or wedges wherein many of the spiral cut pieces or wedges are about the same or similar size to each other.\",\n \"A “package” may be a bag of the sort used to hold chips, or an open holder such as to hold fast-food french fries, or any such containment structure or vessel.\",\n \"In any of these embodiments, one or more or all of the spiral cut potato pieces or wedges in a package may have a crinkle-cut surface.\",\n \"In another embodiment, the spiral cut potato pieces or wedges in the package may be raw or may be cooked, such as fried, roasted, or oven-baked.\",\n \"Accordingly, one embodiment of the present invention is a collection of spiral-cut potato pieces that are raw, a collection of spiral-cut potato pieces that are fried, or a collection of spiral-cut potato pieces that are oven-baked, or a collection of spiral-cut potato pieces that are roasted, wherein the pieces have smooth surfaces or have a crinkle-cut surface.\",\n \"By “smooth” surface is meant a spiral cut product that has been cut with a cutting blade that has a flat, untextured, surface and edge.\",\n \"By “crinkle-cut” is meant a spiral cut product that has been cut with a cutting blade that has a crinkled or wavy surface and edge, such as those shown in FIG.\",\n \"10 .\",\n \"In a further embodiment, the spiral-cut potato wedges may be further processed or seasoned, such as to produce battered or beer battered spiral-cut fried or oven-baked potato wedges.\",\n \"Pieces of wood may also be cut into 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 spiral pieces that may have smooth or textured/crinkled surfaces.\",\n \"Softwoods could be cut according to the present invention, for instance.\",\n \"Examples of softwood include but are not limited to pine, redwood, fir, cedar, and larch.\",\n \"Other materials may be cut according to the present invention too, such as polystyrene, foam, solid paper pulp materials, and plastics.\",\n \"Other features and advantages of the invention will become more apparent from the following detailed description, taken in conjunction with the accompanying drawings which illustrate, by way of example, the principles of the invention.\"\n ],\n [\n \"CROSS-REFENENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser.\",\n \"No.\",\n \"14/712,857, filed on May 14, 2015 and entitled “Rotary Knife Fixture for Cutting Spiral, Textured Potato Pieces,” which is a continuation of U.S. patent application Ser.\",\n \"No.\",\n \"13/647,319, filed on Oct. 8, 2012 and entitled “Rotary Knife Fixture for Cutting Spiral, Textured Potato Pieces,” now U.S. Pat.\",\n \"No.\",\n \"9,089,987, which claims the benefit of U.S.\",\n \"Provisional Patent Application Ser.\",\n \"No.\",\n \"61/661,278, filed on Jun.\",\n \"18, 2012 and entitled “Rotary Knife Fixture for Cutting Spiral, Textured Potato Pieces,” and claims the benefit of U.S.\",\n \"Provisional Patent Application Ser.\",\n \"No.\",\n \"61/546,035 filed on Oct. 11, 2011 and entitled “Rotary Knife Fixture for Cutting Spiral Potato Pieces,” the contents of all of which are incorporated herein by reference in their entireties.\",\n \"FIELD OF THE DISCLOSURE This invention relates generally to devices and methods for cutting food products, such as vegetable products, and particularly such as raw potatoes and the like, into spiral or helical shaped pieces, whose cut surfaces may be patterned by the design of knife blades, such as to create textured “crinkle-cut” spiral or helical pieces.\",\n \"BACKGROUND Production cutting systems and related knife fixtures are useful for cutting vegetable products such as raw potatoes into spiral or helical shaped pieces, preparatory to further production processing steps such as blanching and parfrying.\",\n \"In this regard, one typical production system comprises a hydraulic cutting system wherein a so-called water knife fixture is mounted along the length of an elongated tubular conduit.\",\n \"A pumping device is provided to entrain the vegetable product such as raw potatoes within a propelling water flume for cutting engagement with knife blades of the water knife fixture.\",\n \"The vegetable product is pumped one at a time in single file succession into and through the water conduit with a velocity and sufficient kinetic energy to carry the vegetable product through a relatively complex knife fixture which includes at least one rotary cutting blade for severing the product into a plurality of smaller pieces of generally spiral or helical shape.\",\n \"The cut pieces are then carried further through a discharge conduit for appropriate subsequent processing, including cooking or blanching, parfrying, freezing and packaging steps, for subsequent finish processing and serving to customers as loops, twirls, curly fries, etc.\",\n \"Examples of such hydraulic cutting systems and related rotary knife fixtures are found in U.S. Pat.\",\n \"Nos.\",\n \"5,168,784; 5,179,881; 5,277,546; 5,343,791; 5,394,780; 5,394,793; 5,473,967; 5,992,287; and Re.\",\n \"38,149, all of which are incorporated by reference herein.\",\n \"Persons skilled in the art will recognize and appreciate that mechanical production feed systems may be employed in lieu of hydraulic feed systems, as described in U.S. Pat.\",\n \"Nos.\",\n \"5,097,735; 5,167,177; 5,167,178; and 5,293,803, which are also incorporated by reference herein.\",\n \"The present invention is directed to an improved rotary knife fixture and related cutting blades for cutting raw vegetable products, such as potatoes, into spiral shaped pieces that may or may not have textured cut surfaces, such as crinkles, waves, or other designs.\",\n \"SUMMARY In accordance with the invention, a rotary knife fixture is provided for cutting vegetable products such as raw potatoes into spiral shapes.\",\n \"The knife fixture comprises a circular or ring-shaped blade holder adapted to be rotatably driven at a selected rotational speed within a hydraulic product flow path.\",\n \"The blade holder carries at least one cutting blade rotated therewith, wherein the blade is twisted from a generally longitudinally aligned center axis outwardly in opposite radial directions with a sharpened leading edge set at a desired pitch angle.\",\n \"By controlling the pitch of the blade in relation to the rotational speed of the blade and the velocity at which the potato travels along the hydraulic flow path, the resultant spiral cut shape is selected.\",\n \"By using multiple cutting blades at known axially spaced positions and selecting the angular position of each cutting blade in succession, the number of spiral shapes cut from each potato is also selected.\",\n \"In one preferred form, the ring-shaped blade holder of the rotary knife fixture is rotatably driven within a vegetable product flow path, such as along a hydraulic flow conduit having raw vegetables such as potatoes carried in single file there through.\",\n \"The blade holder supports at least one cutting blade which is twisted from a generally longitudinally aligned center axis outwardly in opposite radial directions, and defining a pair of sharpened cutting edges presented in opposite circumferential directions.\",\n \"Each half of the cutting blade is set at a selected pitch angle which varies according to specific radial position, per the formula: Pitch Angle=ArcTan (2×Pi×Radius/Pitch Length) (1) For a blade diameter equal to 4 inches (radius=2 inches), and a pitch length equal to 3 inches, each cutting blade is anchored at its outer edge on the associated ring-shaped blade holder at an angle of about 76.6°.\",\n \"However, note that the specific pitch angle will vary according to radial position along the blade and the pitch length.\",\n \"In use, the single cutting blade is rotatably driven, in a preferred form, at a rotational speed of about 6,000 revolutions per minute (rpm), to cut each potato traveling along the hydraulic flow conduit at a velocity of about 25 feet per second (fps) into a pair of generally spiral shaped pieces.\",\n \"With a pitch length of about 3 inches potato travel per cutting blade revolution, this results in substantially optimum cutting of each potato.\",\n \"In one embodiment, a cutting blade is rotatably driven at a rotational speed anywhere from about 4,000 rpm to 8,000 rpm.\",\n \"In one embodiment, a cutting blade is rotatably driven at a rotational speed anywhere from about 4,000 rpm, about 5,000 rpm, about 6,000 rpm, about 7,000 rpm, or about 8,000 rpm, or at revolutions greater than 8,000 rpm.\",\n \"When more than one cutting blade is used, each of the cutting blades may be physically supported in a stack of ring-shaped blade holders having a known axial dimension such as about 0.5 inch per blade holder, with the multiple blade holders being fixed for rotation together.\",\n \"With this configuration, the angle Θ (theta) separating each of the supported cutting blades in succession is given by the formula: Θ=T/P (axial dimension of each blade holder/pitch length)×360°+360°/N (number of cut pieces).\",\n \"(2) Following this formula, when two cutting blades are used, each carried by a 0.5 inch thick ring-shaped blade holder (thickness=T), with a pitch length (pitch=P) of 3 inches, a total of four spiral pieces are cut from each product, and the second cutting blade is rotationally set to lag the first cutting blade by 150°.\",\n \"Similarly, where three cutting blades are used, each product is cut into a total of six spiral pieces, and the second blade is oriented to lag the first blade by 120°, and the third blade is oriented to lag the second by an additional 120°, or a total lag from the first blade of about 240°.\",\n \"And, where four cutting blades are used, each product is cut into a total of eight spiral pieces, and the four blades are oriented respectively to lag the immediately preceding blade by about 105°.\",\n \"Accordingly, the present invention encompasses a configuration of multiple blades to produce 2, 4, 6, 8, or more spiral pieces per product.\",\n \"In addition to even numbers of spiral pieces cut per product, the present invention encompasses a configuration of blades that produce 3, 5, 7, 9 or more spiral pieces per product.\",\n \"An example of such a spiral piece is shown in D640,036, which is incorporated herein by reference.\",\n \"A further aspect of the present invention is a cutting blade designed to have a textured or “crinkled” surface edge so that when it cuts the product, the exposed cut surface is similarly textured or crinkled.\",\n \"Accordingly, in one embodiment crinkle-cut spiral pieces of product can be produced using the inventive blades and cutting system.\",\n \"In any embodiment, or permutation, of cutting blades and number of cutting blades in the inventive cutting system, any number of spiral pieces can be obtained per product.\",\n \"That is 2, 3, 4, 5, 6, 7, 8, 9, or 10, or more than 10 spiral pieces may be cut from each product.\",\n \"In another embodiment any number or all of the cutting blades may be textured or crinkled to produce textured or crinkled cut surfaces on a spiral piece.\",\n \"Thus, in one embodiment every spiral piece cut from one product may contain at least one crinkle-textured cut surface if every cutting blade in the cutting system has a crinkled surface edge.\",\n \"However in another embodiment not every cutting blade in the cutting system has a wavy, textured, or crinkled edge.\",\n \"Thus, in that instance, a single product may be cut to yield smooth surface spiral pieces as well as crinkle-cut spiral pieces.\",\n \"By “product” is meant any vegetable or fruit or wood.\",\n \"A vegetable that may be cut into 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 spiral pieces that may have smooth or textured/crinkled surfaces, includes, but is not limited to, any tuberous vegetable, beets, turnips, radish, leeks, or any root vegetable.\",\n \"In one embodiment, a tuber is a potato, sweet potato, carrot, cassava, swede, or yam.\",\n \"A fruit that may be cut into 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 spiral pieces that may have smooth or textured/crinkled surfaces, includes, but is not limited to, apples, squash, bell peppers, pumpkin, zucchini, cucumber, mangos, and plantains.\",\n \"A vegetable or fruit when it is processed and cut according to the methods disclosed herein does not necessarily have to be whole.\",\n \"That is, chunks or cut pieces of a vegetable may be pumped into the cutting system and those chunks or pieces subsequently cut with cutting blades to produce spiral pieces or spiral fragments.\",\n \"The present invention in particular encompasses a new french fry that is spiral-cut and which may have smooth or crinkled surfaces.\",\n \"See, for instance, the spiral potato pieces shown in FIG.\",\n \"9.The types of spiral-cut potato wedges are a new line of edible products, and can be made in different sizes or textured or smooth surfaces according to the present invention.\",\n \"Thus one embodiment of the present invention is a package containing multiple spiral-cut potato pieces or wedges wherein substantially all the spiral cut pieces or wedges are about the same or similar size to each other.\",\n \"In another embodiment of the present invention is a package containing multiple spiral-cut potato pieces or wedges wherein many of the spiral cut pieces or wedges are about the same or similar size to each other.\",\n \"A “package” may be a bag of the sort used to hold chips, or an open holder such as to hold fast-food french fries, or any such containment structure or vessel.\",\n \"In any of these embodiments, one or more or all of the spiral cut potato pieces or wedges in a package may have a crinkle-cut surface.\",\n \"In another embodiment, the spiral cut potato pieces or wedges in the package may be raw or may be cooked, such as fried, roasted, or oven-baked.\",\n \"Accordingly, one embodiment of the present invention is a collection of spiral-cut potato pieces that are raw, a collection of spiral-cut potato pieces that are fried, or a collection of spiral-cut potato pieces that are oven-baked, or a collection of spiral-cut potato pieces that are roasted, wherein the pieces have smooth surfaces or have a crinkle-cut surface.\",\n \"By “smooth” surface is meant a spiral cut product that has been cut with a cutting blade that has a flat, untextured, surface and edge.\",\n \"By “crinkle-cut” is meant a spiral cut product that has been cut with a cutting blade that has a crinkled or wavy surface and edge, such as those shown in FIG.\",\n \"10.In a further embodiment, the spiral-cut potato wedges may be further processed or seasoned, such as to produce battered or beer battered spiral-cut fried or oven-baked potato wedges.\",\n \"Pieces of wood may also be cut into 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 spiral pieces that may have smooth or textured/crinkled surfaces.\",\n \"Softwoods could be cut according to the present invention, for instance.\",\n \"Examples of softwood include but are not limited to pine, redwood, fir, cedar, and larch.\",\n \"Other materials may be cut according to the present invention too, such as polystyrene, foam, solid paper pulp materials, and plastics.\",\n \"Other features and advantages of the invention will become more apparent from the following detailed description, taken in conjunction with the accompanying drawings which illustrate, by way of example, the principles of the invention.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings illustrate the invention.\",\n \"In such drawings: FIG.\",\n \"1 is a schematic diagram depicting a hydraulic cutting system of a type utilizing a rotatably driven knife fixture constructed in accordance with the present invention; FIG.\",\n \"2 is an enlarged perspective view illustrating a drive motor and cog belt for rotatably driving the knife fixture of FIG.\",\n \"1; FIG.\",\n \"3 is an exploded perspective view showing rotatable mounting of the knife fixture within a rotary bearing unit; FIG.\",\n \"4 is a front side perspective view of one cutting blade carried by a ring-shaped blade holder in accordance with one preferred form of the invention; FIG.\",\n \"5 is a front side perspective view of a pair of cutting blades carried respectively by a corresponding pair of blade holders in accordance with one alternative preferred form of the invention; FIG.\",\n \"6 is a front side perspective view of a knife fixture including three cutting blades respectively supported by three blade holders in accordance with a further alternative preferred form of the invention; FIG.\",\n \"7 is a front side perspective view of four cutting blades carried respectively by four blade holders in accordance with another alternative preferred form of the invention; FIG.\",\n \"8 is a drawing similar to FIG.\",\n \"7 but showing four corrugated or crinkle cut knife blades; FIG.\",\n \"9 is a drawing showing a spiral piece or wedge cut with the crinkle cut knife blades shown in FIG.\",\n \"8; FIG.\",\n \"10 is a drawing of an exemplary cutting blade designed to have textured or wavy or crinkled surfaces and edges so as to produce spiral pieces or wedges that have similarly textured, wavy, or crinkled cut surfaces; FIG.\",\n \"11 is an enlarged front side perspective view taken about the circle 11 in FIG.\",\n \"7, further illustrating the inclined mounting surface in the blade holder; FIG.\",\n \"12 is a front side perspective view of an embodiment of a pair of cutting blades carried by a ring-shaped blade holder; and FIG.\",\n \"13 is a front side perspective view of an embodiment of three cutting blades carried by a ring-shaped blade holder.\",\n \"DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS This invention relates generally to devices and methods for cutting food products, such as vegetable products, and particularly such as raw potatoes and the like, into spiral or helical shaped pieces, whose cut surfaces may be patterned by the design of knife blades, such as to create “crinkle-cut” spiral or helical pieces.\",\n \"More particularly, this invention relates to a rotatably driven knife fixture having a selected number of knife blades adapted to cut a raw potato or the like into generally spiral shaped pieces.\",\n \"As shown in the exemplary drawings, a hydraulic cutting system comprises a conventional so-called water knife fixture referred to generally in FIG.\",\n \"1 by the reference numeral 10 for cutting vegetable products such as whole potatoes 12 into spiral shaped pieces 14 for subsequent processing.\",\n \"The present invention comprises a rotary driven knife fixture 10 (FIGS.\",\n \"2-7) for installation into the cutting system and for rotatable driving by means of a drive motor 11 or the like.\",\n \"The knife fixture 10 includes at least one rotatably driven cutting blade 16 (FIGS.\",\n \"2-4) for cutting the product into a pair of generally spiral shaped pieces 14 of the same or similar size and shape.\",\n \"In alternative embodiments, the single cutting blade 16 can be combined with a second cutting blade 17 (FIG.\",\n \"5) to cut the product into four spiral shaped pieces, with a third cutting blade 18 (FIG.\",\n \"6) to cut the product into six spiral shaped pieces, or with a fourth cutting blade 19 (FIG.\",\n \"7) to cut the product into eight spiral shaped pieces.\",\n \"Indeed, any number of cutting blades can be used for subdividing the product into twice the number of spiral shaped pieces of substantially similar size and shape.\",\n \"FIG.\",\n \"1 shows the cutting system in the form of a hydraulic cutting system comprising a tank 78 or the like for receiving a supply of vegetable products, such as the illustrative raw whole potatoes 12 in a peeled or unpeeled state.\",\n \"Alternatively, these potatoes 12 can comprise halves or pieces of whole potatoes, peeled or unpeeled.\",\n \"In one preferred form, these potatoes 12 comprise relatively small potatoes or potato pieces having a longitudinal length on the order of about 3 inches.\",\n \"It is noted, however, that actual potato size is unimportant, as long as the potato has a diametric size to fit through the knife fixture.\",\n \"As viewed in FIG.\",\n \"1, the potatoes 12 are delivered via an inlet conduit 30 to a pump 32 which propels the potatoes in single file relation within a propelling water stream or flume through a tubular delivery conduit 34 into cutting engagement with the blades (not shown in FIG.\",\n \"1) of the water knife fixture 10.In a typical hydraulic cutting system, the potatoes are propelled through the delivery conduit 34 at a relatively high velocity of about 25 feet per second (fps), or about 1,500 feet per minute (fpm), to provide sufficient kinetic energy whereby each potato is propelled through the knife fixture 10 to produce (as will be described in more detail herein, per the blade pitch angle) the desired elongated spiral cut pieces 14.In this regard, the delivery conduit 34 may include a centering alignment device (not shown) for substantially centering each potato 12 on a longitudinal centerline of the flow passage extending through the associated knife fixture 10, in a manner known to persons skilled in the art.\",\n \"The cut strips 14 travel through a short discharge conduit 36 to a conveyor 38 or the like which transports the cut strips 14 for further processing, such as blanching, drying, batter coating, parfrying, freezing, etc.\",\n \"Persons skilled in the art will recognize and appreciate that alternative form cutting systems may be used, to include, by way of example, mechanical cutting systems wherein the vegetable products such as potatoes are mechanically delivered via a chute or hopper or the like to the knife fixture 10.In either case, the knife fixture 10 is mounted along a production path and is rotatably driven for engaging and cutting the incoming products into the desired spiral shaped pieces.\",\n \"FIGS.\",\n \"2-3 show installation of the illustrative knife fixture 10 into a rotary bearing unit 20 in a position in-line with a production path for the vegetable products such as the potatoes 12 (FIG.\",\n \"1).\",\n \"In this regard, the illustrative knife fixture 10 comprises a generally ring-shaped blade holder 22 of generally annular or circular shape, and having a cross sectional area sufficient for providing a relatively stiff or sturdy structure capable of withstanding the rigors of a production environment over an extended period of time.\",\n \"This blade holder 22 is secured as by means of clamp screws 23 or the like onto downstream or lower annular ring 21 or the like adapted in turn for affixation to the lower or downstream end of a rotatable bearing assembly 25 as by means of screws 25′ or the like.\",\n \"As shown in FIG.\",\n \"3, the bearing assembly 25 is rotatably carried within a bushing 26 mounted as by means of screws 26′ or the like onto an upstream or upper side of the enlarged plate 27, which has an opening 13 formed therein for in-line installation along the production flow path.\",\n \"A flange plate 28 overlies the bearing assembly 25 for sandwiching the assembly 25 against an internal shoulder 29 within the bushing 26.A driven ring BO is mounted in turn as by means of screws 30′ onto the bearing assembly 25 for rotation therewith.\",\n \"The driven ring 30 of the rotary bearing unit 20 includes a circumferential array of detents 41 for registry with teeth 42 of a cog-type drive belt 43 (FIG.\",\n \"2).\",\n \"This drive belt 43 is in turn reeved about a drive gear 44 on an output shaft 45 of the drive motor 11 (FIG.\",\n \"2).\",\n \"Accordingly, the drive motor 11 positively drives the driven ring 30 and associated bearing assembly 25 secured thereto at a known speed, preferably on the order of about 6,000 rpm in the case of the illustrative hydraulic cutting system, for correspondingly rotatably driving the knife fixture 10 at the same rotational speed.\",\n \"Importantly, the cog-type drive belt 43 beneficially insures constant-speed rotatable driving of the knife fixture 10 notwithstanding periodic impact engagement of the water-propelled potatoes therewith.\",\n \"In one preferred configuration as viewed in FIGS.\",\n \"2-4, a single cutting blade 16 is used to cut each incoming vegetable product such as a potato 12 into two separate, generally spiral shaped pieces 14 (FIG.\",\n \"1) of similar size and shape.\",\n \"The cutting blade 16 is shown with a sharpened cutting edge 16′ along one side thereof.\",\n \"Since the cutting blade 16 is twisted generally at a radial center, or a longitudinal centerline or axis of the hydraulic flow path, two cutting edges 16′ are defined to extend radially outwardly in opposite directions, and in opposite-facing circumferential directions.\",\n \"In other words, a first portion 16A of the cutting blade 16 that is adjacent to the blade holder 22 has a cutting edge 16′ with a different pitch angle than that of a second portion 16B of the cutting blade 16 that is located further from the blade holder 22 than the first portion 16A.\",\n \"A pair of clamp screws 31 or the like are secured through the respective opposite ends of the cutting blade 16 to seat the cutting blade within a shallow recess formed at an appropriate pitch angle.\",\n \"More specifically, the specific pitch angle of the cutting blade 16 at each specific point along its radial length is given by the formula: Pitch Angle=ArcTan (2×Pi×Radius/Pitch Length) (1) For a total blade radius of 2 inches, and a pitch length of about 3 inches, the clamp screws 31 secure the outermost radial ends of each cutting blade 16 or 17 at a pitch angle of about 76.6° to the axial blade centerline.\",\n \"It will be understood, however, that the specific pitch angle is directly proportional to the radial point along the blade, whereby the pitch angle increases from the radial center, and it is this pitch angle that determines the spiral shape of the cut product.\",\n \"If more spiral shaped pieces 14 are desired from each potato 12, more cutting blades are used recognizing that each of the cutting blades cuts the incoming product in two, and thereby produces twice the number of spiral shaped pieces in comparison with the number of cutting blades used.\",\n \"Importantly, the cutting blades are arranged in succession at controlled angles to obtain similar or virtually identical cut spiral shaped pieces.\",\n \"More particularly, in one preferred form as viewed in FIG.\",\n \"5, two cutting blades 16 and 17 are supported by separate blade holders 22 and 22′ in a stack on the associated annular ring 21, as by means of elongated screws 23.That is, aligned screw ports are formed in the second blade holder 22′ at the appropriate positions for receiving the elongated screws 23 used to fasten the drive rings 22, 22′ and the underlying annular ring 21 together for concurrent rotation.\",\n \"The two cutting blades 16 and 17 are generally identical to each to each other, to include a twisted shape generally at a longitudinal center axis thereof and extending radially outwardly in opposite directions for seated engagement as by means of clamp screws 31 or the like at the selected pitch angle.\",\n \"Using formula (1) above for the specific pitch angle of each blade 16 or 17 along its radial length, and wherein the total blade radius is 2 inches and the pitch length is 3 inches, the clamp screws 31 secure the outermost radial ends of each cutting blade 16 or 17 at a pitch angle of about 76.6°.\",\n \"In this respect, FIG.\",\n \"11 more specifically illustrates the inclined mounting surface in the blade holder 22 at the point where the clamp screws 31 secure the cutting blade 16 to the blade holder 22.In addition, when the two cutting blades 16 and 17 are rotated at about 6,000 revolutions per minute (rpm), to advance each product to be cut along the hydraulic flow path at a velocity of about 25 feet per second (fps), the two cutting blades 16 and 17 both cut the incoming product into two pieces, for a total of four spiral shaped pieces 14 of similar or identical shape.\",\n \"With a pitch length of about 3 inches potato travel for each cutting blade revolution, and with each of the blade holders 22, 22′ having an axial dimension of about 0.5 inch, the angle Θ (theta) separating each of the supported cutting blades is given by the formula: Θ=T/P (axial dimension of each blade holder/pitch length)×360°+360°/N (number of cut pieces).\",\n \"(2) In the case of the two cutting blades 16, 17 adapted to cut each incoming product into four generally identical spiral shaped pieces, the angle 1=150°.\",\n \"FIGS.\",\n \"6 and 7 illustrate two exemplary alternative preferred forms of the invention, wherein three cutting blades 16, 17 and 18 are separately supported by a stack of three ring-shaped blade holders 22, 22′, and 22″ for cutting each incoming product into a total of six spiral shaped pieces (FIG.\",\n \"6), and also wherein four cutting blades 16, 17, 18 and 19 are separately supported by a stack of four ring-shaped blade holders 22, 22′, 22″, and 22′″ (FIG.\",\n \"7) for cutting each incoming product into a total of eight spiral shaped pieces.\",\n \"In the examples of FIGS.\",\n \"6 and 7, formula (2) is followed to determine the angular setting of each cutting blade in succession in order to form the multiple spiral shaped pieces of identical or similar shapes.\",\n \"In FIG.\",\n \"6, the cutting blades are set at successive angles of about 120° to cut products per U.S. Patent D640,036 which is incorporated by reference herein, whereas in FIG.\",\n \"7, the cutting blades are set at successive angles of about 105°.\",\n \"In each case, clamp screws 31 are used to seat each of cutting blades at the selected pitch angle within the recess formed in the associated blade holder.\",\n \"Similarly, screws 23 or the like are fitted and secured through aligned ports formed in the stacked blade holders for securing them together for rotation with the bearing assembly 25.Persons skilled in the art will understand and appreciate, of course, that virtually any number of cutting blades can be used, with the formula (2) determining the angular spacings of the multiple cutting blades in succession.\",\n \"For example, when five cutting blades are used, a total of ten spiral shaped pieces are formed; following formula (2), the successive cutting blade angular spacings would be about 96°.\",\n \"Similarly, when six cutting blades are used, a total of twelve spiral shaped pieces are formed; following formula (2), the successive cutting blade angular spacings would be about 90°.\",\n \"Persons skilled in the art will also appreciate that when three or more cutting blades are used, the formula (2) determines that angular spacings of the blades as a group, but that each of the blades need only be set at one of the angular positions; that is, the blades do not need to be set at a regular lag interval, so long as one of the blades in the group is set at each one of the angular positions.\",\n \"Alternately, it will be understood that other forms of the blade holders and the related interconnection means can be employed, such as the formation of steps including interengaging tabs and slots in the respective blade holders to insure the desired angular position of the cutting blades and concurrent rotation thereof.\",\n \"In an alternative preferred form, the present invention encompasses a new french fry that is spiral-cut and which may have corrugated or crinkled surfaces.\",\n \"See, for instance, the spiral potato pieces 14′ shown in FIG.\",\n \"9.The types of spiral-cut potato wedges are a new line of edible products, and can be made in different sizes or textured surfaces according to the present invention.\",\n \"Thus one embodiment of the present invention is a package containing multiple spiral-cut potato pieces or wedges 14′ wherein substantially all the spiral cut pieces or wedges are about the same or similar size to each other.\",\n \"In another embodiment of the present invention is a package containing multiple spiral-cut potato pieces or wedges 14′ wherein many of the spiral cut pieces or wedges are about the same or similar size to each other.\",\n \"A “package” may be a bag of the sort used to hold chips, or an open holder such as to hold fast-food french fries, or any such containment structure or vessel.\",\n \"In any of these embodiments, one or more or all of the spiral cut potato pieces or wedges in a package may have a crinkle-cut surface.\",\n \"In another embodiment, the spiral cut potato pieces or wedges in the package may be raw or may be cooked, such as fried, roasted, or oven-baked.\",\n \"Accordingly, one embodiment of the present invention is a collection of spiral-cut potato pieces that are raw, a collection of spiral-cut potato pieces that are fried, or a collection of spiral-cut potato pieces that are oven-baked, or a collection of spiral-cut potato pieces that are roasted, wherein the pieces have smooth surfaces or have a crinkle-cut surface.\",\n \"By “smooth” surface is meant a spiral cut product that has been cut with a cutting blade 16, 17, 18 or 19 that has a flat, untextured, surface and edge, as viewed in FIGS.\",\n \"4-7.By “crinkle-cut” is meant a spiral cut product that has been cut using a modified knife fixture 11′ with a cutting blade 16″, 17″, 18″, or 19″ that has a crinkled or wavy surface and edge 16″, 17″, 18″, or 19′, such as those shown in FIG.\",\n \"8.In a further embodiment, the spiral-cut potato wedges may be further processed or seasoned, such as to produce battered or beer battered spiral-cut fried or oven-baked potato wedges.\",\n \"It will be understood, of course, that the modified knife fixture 11′ shown in FIG.\",\n \"8 can be equipped with one or more of the cutting knives of a corrugated and crinkle-cut configuration, as per any one of the knife blade embodiments depicted in FIGS.\",\n \"4-7.Indeed, more than four such knife blades can be used, if more than 8 spiral-cut wedges are desired.\",\n \"It will also be recognized and understood that different size corrugations or crinkle-cut configurations can be used for the various knife blades, such as illustrated in FIG.\",\n \"10 with respect to the corrugated knife blade 16″, and the associated cutting edge 16″'.\",\n \"A variety of modifications and improvements in and to the rotary knife fixture 10 of the present invention will be apparent to those persons skilled in the art.\",\n \"As one example, persons skilled in the art will understand that each of the twisted cutting blades as shown and described herein can be replaced by a pair of individual blades aligned diametrically with each other and having a pitch angle as defined by formula (1), but otherwise unconnected at the axial centerline of the flow path.\",\n \"For instance, in FIG.\",\n \"12, the blade 16 of FIG.\",\n \"4 has been replaced by a pair of individual blades 116 aligned diametrically but otherwise unconnected at the axial centerline of the flow path.\",\n \"As a further alternative, the blades do not need to be aligned diametrically, but an odd number of unconnected blades, such as three blades 216 shown in FIG.\",\n \"13, can be used in the event that an odd number of product cuts is desired.\",\n \"Accordingly, no limitation on the invention is intended by way of the foregoing description and accompanying drawings, except as set forth in the appended claims.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875819"}}},{"rowIdx":4494988,"cells":{"text":{"kind":"list like","value":[["Dynamic Configuration of Touch Sensor Electrode Clusters","An apparatus of one embodiment includes a sensor having a plurality of electrodes and a controller having a processor and a memory.","The memory includes logic operable to configure the plurality of electrodes of the sensor to form a first cluster pattern including a first cluster and a second cluster.","The first cluster and the second cluster each include two or more electrodes of the plurality of electrodes.","The logic is further operable to determine a value associated with a capacitance of a first cluster and configure, in response to determining the value, the plurality of electrodes to form a second cluster pattern.","The second cluster pattern includes a third cluster and a fourth cluster.","The third cluster and the fourth cluster each include two or more electrodes of the plurality of electrodes and the third cluster is interleaved with the fourth cluster such that an electrode of the third cluster is positioned between two electrodes of the fourth cluster."],["1-28.","(canceled) 29.An apparatus comprising: a sensor comprising a plurality of electrodes; and a controller comprising: a processor; and a memory comprising logic operable, when executed by the processor, to: configure the plurality of electrodes of the sensor to form a first cluster pattern comprising a first cluster and a second cluster, the first cluster and the second cluster each comprising two or more electrodes of the plurality of electrodes; determine a value associated with a capacitance of the first cluster; and configure, in response to determining the value, the plurality of electrodes to form a second cluster pattern comprising a third cluster and a fourth cluster, the third cluster and the fourth cluster each comprising two or more electrodes of the plurality of electrodes, the third cluster being interleaved with the fourth cluster such that an electrode of the third cluster is positioned between two electrodes of the fourth cluster.","30.The apparatus of claim 29, the second cluster pattern further comprising a fifth cluster, the fifth cluster comprising two or more electrodes of the plurality of electrodes, the fifth cluster being interleaved with the fourth cluster such that an electrode of the fifth cluster is positioned between two electrodes of the fourth cluster.","31.The apparatus of claim 29, further comprising a plurality of switches, wherein: configuring the plurality of electrodes to form the first cluster pattern comprises configuring one or more switches of the plurality of switches to galvanically connect each electrode of the first cluster pattern; and configuring the plurality of electrodes to form the second cluster pattern comprises configuring one or more switches of the plurality of switches to galvanically connect each electrode of the second cluster pattern.","32.The apparatus of claim 29, wherein: the third cluster comprises three or more electrodes of the plurality of electrodes; and two electrodes of the three or more electrodes of the third cluster are adjacent to one another.","33.The apparatus of claim 29, wherein determining the value comprises measuring a voltage associated with the first cluster after application of a voltage to the first cluster.","34.The apparatus of claim 29, wherein: the plurality of electrodes comprises a first electrode, a second electrode adjacent to first electrode, a third electrode adjacent to the second electrode, a fourth electrode adjacent to the third electrode, and a fifth electrode adjacent to the fourth electrode; the first cluster of the first cluster pattern comprises the first electrode, the second electrode, and the third electrode; the second cluster of the first cluster pattern comprises the fourth electrode and the fifth electrode; the third cluster of the second cluster pattern comprises the first electrode, the second electrode, and the fourth electrode; and the fourth cluster of the second cluster pattern comprises the third electrode and the fifth electrode.","35.The apparatus of claim 29, wherein the determination of the value utilizes self-capacitance measurements.","36.A method comprising: configuring a plurality of electrodes of a sensor to form a first cluster pattern comprising a first cluster and a second cluster, the first cluster and the second cluster each comprising two or more electrodes of the plurality of electrodes; determining a value associated with a capacitance of the first cluster; and configuring, in response to determining the value, the plurality of electrodes to form a second cluster pattern comprising a third cluster and a fourth cluster, the third cluster and the fourth cluster each comprising two or more electrodes of the plurality of electrodes, the third cluster being interleaved with the fourth cluster such that an electrode of the third cluster is positioned between two electrodes of the fourth cluster.","37.The method of claim 36, the second cluster pattern further comprising a fifth cluster, the fifth cluster comprising two or more electrodes of the plurality of electrodes, the fifth cluster being interleaved with the fourth cluster such that an electrode of the fifth cluster is positioned between two electrodes of the fourth cluster.","38.The method of claim 36, wherein: configuring the plurality of electrodes to form the first cluster pattern comprises configuring one or more switches of the plurality of switches to galvanically connect each electrode of the first cluster pattern; and configuring the plurality of electrodes to form the second cluster pattern comprises configuring one or more switches of the plurality of switches to galvanically connect each electrode of the second cluster pattern.","39.The method of claim 36, wherein: the third cluster comprises three or more electrodes of the plurality of electrodes; and two electrodes of the three or more electrodes of the third cluster are adjacent to one another.","40.The method of claim 36, wherein determining the value comprises measuring a voltage associated with the first cluster after application of a voltage to the first cluster.","41.The method of claim 36, wherein: the plurality of electrodes comprises a first electrode, a second electrode adjacent to first electrode, a third electrode adjacent to the second electrode, a fourth electrode adjacent to the third electrode, and a fifth electrode adjacent to the fourth electrode; the first cluster of the first cluster pattern comprises the first electrode, the second electrode, and the third electrode; the second cluster of the first cluster pattern comprises the fourth electrode and the fifth electrode; the third cluster of the second cluster pattern comprises the first electrode, the second electrode, and the fourth electrode; and the fourth cluster of the second cluster pattern comprises the third electrode and the fifth electrode.","42.The method of claim 36, wherein the determination of the value utilizes self-capacitance measurements.","43.A non-transitory computer-readable storage medium comprising logic, the logic configured to, when executed by the one or more processors, cause the one or more processors to perform operations comprising: configuring a plurality of electrodes of a sensor to form a first cluster pattern comprising a first cluster and a second cluster, the first cluster and the second cluster each comprising two or more electrodes of the plurality of electrodes; determining a value associated with a capacitance of the first cluster; and configuring, in response to determining the value, the plurality of electrodes to form a second cluster pattern comprising a third cluster and a fourth cluster, the third cluster and the fourth cluster each comprising two or more electrodes of the plurality of electrodes, the third cluster being interleaved with the fourth cluster such that an electrode of the third cluster is positioned between two electrodes of the fourth cluster.","44.The medium of claim 43, the second cluster pattern further comprising a fifth cluster, the fifth cluster comprising two or more electrodes of the plurality of electrodes, the fifth cluster being interleaved with the fourth cluster such that an electrode of the fifth cluster is positioned between two electrodes of the fourth cluster.","45.The medium of claim 43, wherein: configuring the plurality of electrodes to form the first cluster pattern comprises configuring one or more switches of the plurality of switches to galvanically connect each electrode of the first cluster pattern; and configuring the plurality of electrodes to form the second cluster pattern comprises configuring one or more switches of the plurality of switches to galvanically connect each electrode of the second cluster pattern.","46.The medium of claim 43, wherein: the third cluster comprises three or more electrodes of the plurality of electrodes; and two electrodes of the three or more electrodes of the third cluster are adjacent to one another.","47.The medium of claim 43, wherein determining the value comprises measuring a voltage associated with the first cluster after application of a voltage to the first cluster.","48.The medium of claim 43, wherein: the plurality of electrodes comprises a first electrode, a second electrode adjacent to first electrode, a third electrode adjacent to the second electrode, a fourth electrode adjacent to the third electrode, and a fifth electrode adjacent to the fourth electrode; the first cluster of the first cluster pattern comprises the first electrode, the second electrode, and the third electrode; the second cluster of the first cluster pattern comprises the fourth electrode and the fifth electrode; the third cluster of the second cluster pattern comprises the first electrode, the second electrode, and the fourth electrode; and the fourth cluster of die second cluster pattern comprises the third electrode and the fifth electrode."],["<SOH> BACKGROUND <EOH>A touch sensor may detect the presence and location of a touch or the proximity of an object (such as a user's finger or a stylus) within a touch-sensitive area of the touch sensor overlaid on a display screen, for example.","In a touch-sensitive-display application, the touch sensor may enable a user to interact directly with what is displayed on the screen, rather than indirectly with a mouse or touch pad.","A touch sensor may be attached to or provided as part of a desktop computer, laptop computer, tablet computer, personal digital assistant (PDA), Smartphone, satellite navigation device, portable media player, portable game console, kiosk computer, point-of-sale device, or other suitable device.","A control panel on a household or other appliance may include a touch sensor.","There are a number of different types of touch sensors, such as (for example) resistive touch screens, surface acoustic wave touch screens, and capacitive touch screens.","Herein, reference to a touch sensor may encompass a touch screen, and vice versa, in particular embodiments.","When an object touches or corner within proximity of the surface of the capacitive touch screen, a change in capacitance may occur within the touch screen at the location of the touch or proximity.","A controller may process the change in capacitance to determine its position on the touch screen."],["<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG.","1 illustrates an example touch sensor with an example controller that may be used in certain embodiments of the present disclosure.","FIG.","2 illustrates an example device and example electrode tracks that may be used in certain embodiments of the present disclosure.","FIG.","3A illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.","FIG.","3B illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.","FIG.","3C illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.","FIG.","4A illustrates example touch points on an example touch sensor.","FIG.","4B illustrates a graph of example measurements that may be taken by certain embodiments of a touch sensor.","FIG.","5A illustrates example touch points on an example touch sensor.","FIG.","5B illustrates a graph of example measurements that may be taken by certain embodiments of a touch sensor.","FIG.","6A illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.","FIG.","6B illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.","FIG.","7A illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.","FIG.","7B illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.","FIG.","7C illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.","FIG.","8A illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.","FIG.","8B illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.","FIG.","9A illustrates an example switch network that may be used to configure clusters in certain embodiments of a touch sensor.","FIG.","9B illustrates an example switch network that may be used to configure clusters in certain embodiments of a touch sensor.","FIG.","10 illustrates an example method for use with certain embodiments of a touch sensor.","detailed-description description=\"Detailed Description\" end=\"lead\"?"],["RELATED APPLICATION This application is a Continuation-In-Part of U.S. application Ser.","No.","13/955,352 titled “Dynamic Clustering Of Touch Sensor Electrodes,” Attorney's Docket 080900.2162, filed Jul.","31, 2013, by Samuel Brunet et al., the content of which is hereby incorporated by reference.","TECHNICAL FIELD This disclosure relates generally to touch sensor technology; and more particularly to dynamic configuration of touch sensor electrode clusters.","BACKGROUND A touch sensor may detect the presence and location of a touch or the proximity of an object (such as a user's finger or a stylus) within a touch-sensitive area of the touch sensor overlaid on a display screen, for example.","In a touch-sensitive-display application, the touch sensor may enable a user to interact directly with what is displayed on the screen, rather than indirectly with a mouse or touch pad.","A touch sensor may be attached to or provided as part of a desktop computer, laptop computer, tablet computer, personal digital assistant (PDA), Smartphone, satellite navigation device, portable media player, portable game console, kiosk computer, point-of-sale device, or other suitable device.","A control panel on a household or other appliance may include a touch sensor.","There are a number of different types of touch sensors, such as (for example) resistive touch screens, surface acoustic wave touch screens, and capacitive touch screens.","Herein, reference to a touch sensor may encompass a touch screen, and vice versa, in particular embodiments.","When an object touches or corner within proximity of the surface of the capacitive touch screen, a change in capacitance may occur within the touch screen at the location of the touch or proximity.","A controller may process the change in capacitance to determine its position on the touch screen.","BRIEF DESCRIPTION OF THE DRAWINGS FIG.","1 illustrates an example touch sensor with an example controller that may be used in certain embodiments of the present disclosure.","FIG.","2 illustrates an example device and example electrode tracks that may be used in certain embodiments of the present disclosure.","FIG.","3A illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.","FIG.","3B illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.","FIG.","3C illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.","FIG.","4A illustrates example touch points on an example touch sensor.","FIG.","4B illustrates a graph of example measurements that may be taken by certain embodiments of a touch sensor.","FIG.","5A illustrates example touch points on an example touch sensor.","FIG.","5B illustrates a graph of example measurements that may be taken by certain embodiments of a touch sensor.","FIG.","6A illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.","FIG.","6B illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.","FIG.","7A illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.","FIG.","7B illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.","FIG.","7C illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.","FIG.","8A illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.","FIG.","8B illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.","FIG.","9A illustrates an example switch network that may be used to configure clusters in certain embodiments of a touch sensor.","FIG.","9B illustrates an example switch network that may be used to configure clusters in certain embodiments of a touch sensor.","FIG.","10 illustrates an example method for use with certain embodiments of a touch sensor.","The drawings included in the Figures are not drawn to scale.","DESCRIPTION OF EXAMPLE EMBODIMENTS FIG.","1 illustrates an example touch sensor 10 with an example controller 12, according to certain embodiments of the present disclosure.","Touch sensor 10 and controller 12 may detect the presence and location of a touch or the proximity of an object within a touch sensitive area of touch sensor 10.Herein, reference to a touch sensor may encompass both the touch sensor and its controller, where appropriate.","Similarly, reference to a controller may encompass both the controller and its touch sensor, where appropriate.","Touch sensor 10 may include one or more touch-sensitive areas.","Touch sensor 10 may include an array of drive and sense electrodes (or an array of electrodes of a single type) disposed on one or more substrates, which may be made of a dielectric material.","Herein, reference to a touch sensor may encompass both the electrodes of the touch sensor and the substrate(s) that they are disposed on.","Alternatively, reference to a touch sensor may encompass the electrodes of the touch sensor, but not the substrate(s) that they are disposed on.","An electrode (whether a ground electrode, a guard electrode, a drive electrode, or a sense electrode) may be an area of conductive material forming a shape, such as for example a disc, square, rectangle, thin line, other suitable shape, or suitable combination of these.","One or more cuts in one or more layers of conductive material may (at least in part) create the shape of an electrode, and the area of the shape may (at least in part) be bounded by those cuts.","In particular embodiments, the conductive material of an electrode may occupy approximately 100% of the area of its shape.","As an example and not by way of limitation, an electrode may be made of indium tin oxide (ITO) and the ITO of the electrode may occupy approximately 100% of the area of its shape (sometimes referred to as 100% fill), where appropriate.","In particular embodiments, the conductive material of an electrode may occupy substantially less than 100% of the area of its shape.","As an example and not by way of limitation, an electrode may be made of fine lines of metal or other conductive material (FLM), such as for example copper, silver, or a copper- or silver-based material, and the fine lines of conductive material may occupy approximately 5% of the area of its shape in a hatched, mesh, or other suitable pattern.","Herein, reference to FLM encompasses such material, where appropriate.","Where appropriate, the shapes of the electrodes (or other elements) of a touch sensor may constitute in whole or in part one or more macro-features of the touch sensor.","One or more characteristics of the implementation of those shapes (such as, for example, the conductive material, fills, or patterns within the shapes) may constitute in whole or in part one or more micro-features of the touch sensor.","One or more macro-features of a touch sensor may determine one or more characteristics of its functionality, and one or more micro-features of the touch sensor may determine one or more optical features of the touch sensor, such as transmittance, refraction, or reflection.","A mechanical stack may contain the substrate (or multiple substrates) and the conductive material forming the drive or sense electrodes of touch sensor 10.As an example and not by way of limitation, the mechanical stack may include a first layer of optically clear adhesive (OCA) beneath a cover panel.","The cover panel may be clear and made of a resident material suitable for repeated touching, such as for example glass, polycarbonate, or poly(methyl methacrylate) (PMMA).","This disclosure contemplates any suitable cover panel made of any suitable material.","The first layer of OCA may be disposed between the cover panel and the substrate with the conductive material forming the drive or sense electrodes.","The mechanical stack may also include a second layer of OCA and a dielectric layer (which may be made of PET or another suitable material, similar to the substrate with the conductive material forming the drive or sense electrodes).","As an alternative, where appropriate, a thin coating of a dielectric material may be applied instead of the second layer of OCA and the dielectric layer.","The second layer of OCA may be disposed between the substrate with the conductive material making up the drive or sense electrodes and the dielectric layer, and the dielectric layer may be disposed between the second layer of OCA and an air gap to a display of a device including touch sensor 10 and controller 12.As an example only and not by way of limitation, the cover panel may have a thickness of approximately 1 mm; the first layer of OCA may have a thickness of approximately 0.05 mm; the substrate with the conductive material forming the drive or sense electrodes may have a thickness of approximately 0.05 mm; the second layer of OCA may have a thickness of approximately 0.05 mm; and the dielectric layer may have a thickness of approximately 0.05 mm.","Although this disclosure describes a particular mechanical stack with a particular number of particular layers made of particular materials and having particular thicknesses, this disclosure contemplates any suitable mechanical stack with any suitable number of any suitable layers made of any suitable materials and having any suitable thicknesses.","As an example and not by way of limitation, in particular embodiments, a layer of adhesive or dielectric may replace the dielectric layer, second layer of OCA, and air gap described above, with there being no air gap to the display.","One or more portions of the substrate of touch sensor 10 may be made of polyethylene terephthalate (PET) or another suitable material.","This disclosure contemplates any suitable substrate with any suitable portions made of any suitable material.","In particular embodiments, the drive or sense electrodes in touch sensor 10 may be made of ITO in whole or in part.","In particular embodiments, the drive or sense electrodes in touch sensor 10 may be made of fine lines or metal or other conductive material.","As an example and not by way of limitation, one or more portions of the conductive material may be copper or copper-based and have a thickness of approximately 5 μm or less and a width of approximately 10 μm or less.","As another example, one or more portions of the conductive material may be silver or silver-based and similarly have a thickness of approximately 5 μm or less and a width of approximately 10 μm or less.","This disclosure electrodes made of any suitable material.","As used herein, a capacitive node refers to a portion of touch sensor 10 that is configured to provide a distinct capacitive measurement.","In various embodiments, capacitive nodes may have different sizes, shapes, and/or configurations.","Furthermore, in some embodiments, the size, shape, and other aspects of a capacitive node may be determined by the configuration of controller 12 and may be changed dynamically during the operation of device 2.For example, in some embodiments, multiple tracks 14 may be galvanically connected and sensed together, resulting in a capacitive node spanning multiple electrodes.","Furthermore, in some embodiments, such as the embodiment of FIG.","8B, the electrodes of adjacent capacitive nodes may overlap and/or interleave.","Touch sensor 10 may implement a capacitive form of touch sensing.","In a mutual-capacitance implementation, touch sensor 10 may include an array of drive and sense electrodes forming an array of capacitive nodes.","A drive electrode and a sense electrode may form a capacitive node.","The drive and sense electrodes forming the capacitive node may come near each other, but not make electrical contact with each other.","Instead, the drive and sense electrodes may be capacitively coupled to each other across a space between them.","A pulsed or alternating voltage applied to the drive electrode (by controller 12) may induce a charge on the sense electrode, and the amount of charge induced may be susceptible to external influence (such as a touch or the proximity of an object).","When an object touches or comes within proximity of the capacitive node, a change in capacitance may occur at the capacitive node and controller 12 may measure the change in capacitance.","A touch may refer to an external object touching a capacitive node directly or touching a cover or substrate adjacent to the capacitive node.","By measuring changes in capacitance throughout the array, controller 12 may determine the position of the touch or proximity within the touch-sensitive area(s) of touch sensor 10.In a self-capacitance implementation, touch sensor 10 may include an array of electrodes of a single type that may each form a capacitive node.","In such embodiments, a capacitive node may correspond to a single electrode, or a set of multiple connected electrodes, rather than an intersection of tracks 14.When an object touches or comes within proximity of the capacitive node, a change in self-capacitance may occur at the capacitive node and controller 12 may measure the change in capacitance, for example, as a change in the amount of charge needed to raise the voltage at the capacitive node by a pre-determined amount.","As with a mutual-capacitance implementation, by measuring changes in capacitance throughout the array, controller 12 may determine the position of the touch or proximity within the touch-sensitive area(s) of touch sensor 10.This disclosure contemplates any suitable form of capacitive touch sensing.","In particular embodiments, one or more drive electrodes may together form a drive line running horizontally or vertically or in any suitable orientation.","Similarly, one or more sense electrodes may together form a sense line running horizontally or vertically or in any suitable orientation.","In particular embodiments, drive lines may run substantially perpendicular to sense lines.","Herein, reference to a drive line may encompass one or more drive electrodes making up the drive line, and vice versa, where appropriate.","Similarly, reference to a sense line may encompass one or more sense electrodes making up the sense line, and vice versa.","Touch sensor 10 may have drive and sense electrodes disposed in a pattern on one side of a single substrate.","In such a configuration, a pair of drive and sense electrodes capacitively coupled to each other across a space between them may form a capacitive node.","For a self-capacitance implementation, electrodes of only a single type may be disposed in a pattern on a single substrate.","In addition or as an alternative to having drive and sense electrodes disposed in a pattern on one side of a single substrate, touch sensor 10 may have drive electrodes disposed in a pattern on one side of a substrate and sense electrodes disposed in a pattern on another side of the substrate.","Moreover, touch sensor 10 may have drive electrodes disposed in a pattern on one side of one substrate and sense electrodes disposed in a pattern on one side of another substrate.","In such configurations, an intersection of a drive electrode and a sense electrode may form a capacitive node.","Such an intersection may be a location where the drive electrode and the sense electrode“cross” or come nearest each other in their respective planes.","The drive and sense electrodes do not make electrical contact with each other—instead they are capacitively coupled to each other across a dielectric at the intersection.","In some embodiments, this dielectric may be air.","Moreover, this disclosure contemplates electrodes disposed on any suitable number of substrates.","As described above, a change in capacitance at a capacitive node of touch sensor 10 may indicate a touch or proximity input at the position of the capacities node.","Controller 12 may detect and process the change in capacitance to determine the presence and location of the touch or proximity input.","Controller 12 may then communicate information about the touch or proximity input to one or more other components (such one or more central processing units (CPUs)) of a device that includes touch sensor 10 and controller 12, which may respond to the touch or proximity input by initiating a function of the device (or an application running on the deviee).","Although this disclosure describes a particular controller having particular functionality with respect to a particular device and a particular touch sensor, this disclosure contemplates any suitable controller having any suitable functionality with respect to any suitable device and any suitable touch sensor.","Controller 12 may be one or more integrated circuits (ICs), such as for example general-purpose microprocessors, microcontrollers, programmable logic devices or arrays, application-specific ICs (ASICs).","In particular embodiments, controller 12 comprises analog circuitry, digital logic, and digital non-volatile memory.","In particular embodiments, controller 12 is disposed on a flexible printed circuit (FPC) bonded to the substrate of touch sensor 10, as described below.","The FPC may be active or passive, where appropriate.","In particular embodiments, multiple controllers 12 are disposed on the FPC.","Controller 12 may include a processor unit, a drive unit, a sense unit, and a storage unit.","The drive unit may supply drive signals to the drive electrodes of touch sensor 10.The sense unit may sense charge at the capacitive nodes of touch sensor 10 and provide measurement signals to the processor unit representing capacitances at the capacitive nodes.","The processor unit may control the supply of drive signals to the drive electrodes by the drive unit and process measurement signals from the sense unit to detect and process the presence and location of a touch or proximity input within the touch-sensitive area(s) of touch sensor 10.The processor unit may also track changes in the position of a touch or proximity input within the touch-sensitive area(s) of touch sensor 10.The storage unit may store programming for execution by the processor unit, including programming for controlling the drive unit to supply drive signals to the drive electrodes, programming for processing measurement signals from the sense unit, and other suitable programming, where appropriate.","Although this disclosure describes a particular controller having a particular implementation with particular components, this disclosure contemplates any suitable controller having any suitable implementation with any suitable components.","Tracks 14 of conductive material disposed on the substrate of touch sensor 10 may couple the drive or sense electrodes of touch sensor 10 to connection pads 16, also disposed on the substrate of touch sensor 10.As described below, connection pads 16 facilitate coupling of tracks 14 to controller 12.Tracks 14 may extend into or around (e.g.","at the edges of) the touch-sensitive area(s) of touch sensor 10.Particular tracks 14 may provide drive connections for coupling controller 12 to drive electrodes of touch sensor 10, through which the drive unit of controller 12 may supply drive signals to the drive electrodes.","Other tracks 14 may provide sense connections for coupling controller 12 to sense electrodes of touch sensor 10, through which the sense unit of controller 12 may sense charge at the capacitive nodes of touch sensor 10.Tracks 14 may be made of fine lines of metal or other conductive material.","As an example and not by way of limitation, the conductive material of tracks 14 may be copper or copper-based and have a width of approximately 100 μm or less.","As another example, the conductive material of tracks 14 may be silver or silver-based and have a width of approximately 100 μm or less.","In particular embodiments, tracks 14 may be made of ITO in whole or in part in addition or as an alternative to fine lines of metal or other conductive material.","Although this disclosure describes particular tracks made of particular materials with particular widths, this disclosure contemplates any suitable tracks made of any suitable materials with any suitable widths.","In addition to tracks 14, touch sensor 10 may include one or more ground lines terminating at a ground connector (which may be a connection pad 16) at an edge of the substrate of touch sensor 10 (similar to tracks 14).","Connection pads 16 may be located along one or more edges of the substrate, outside the touch-sensitive area(s) of touch sensor 10.As described above, controller 12 may be on an FPC.","Connection pads 16 may be made of the same material as tracks 14 and may be bonded to the FPC using an anisotropic conductive film (ACF).","Connection 18 may include conductive lines on the FPC coupling controller 12 to connection pads 16, in turn coupling controller 12 to tracks 14 and to the drive or sense electrodes of touch sensor 10.In another embodiment, connection pads 16 may be connected to an electro-mechanical connector (such as a zero insertion force wire-to-board connector); in this embodiment, connection 18 may not need to include an FPC.","This disclosure contemplates any suitable connection 18 between controller 12 and touch sensor 10.Certain embodiments of touch sensor 10 and controller 12 may measure capacitance or a change in capacitance using any suitable method.","For example, voltage may be applied to one or more tracks 14 by opening or closing one or more switches associated with one or more tracks 14.Such switches may connect one or more tracks 14 to other portions of touch sensor 10 or controller 12 such as, for example, a voltage source (e.g.","a voltage supply rail), a current source, or any other suitable component.","Such methods may cause charge to be transferred to or from one or more portions of one or more tracks 14.In self-capacitance embodiments, the charged one or more tracks 14 may be sensed to measure a value associated with the capacitance of the one or more tracks 14.The presence of an object such as a finger or a stylus may change the amount of charge induced on the sensed track 14, and this change may be measured by controller 12 to determine the position of the object.","The position may be a distance between the object and touch sensor 10 (e.g., a hover detection) and/or a projection of a portion of the object onto touch sensor 10 (e.g., a point on touch sensor 10 where the object is touching or hovering).","Thus, in an embodiment where the surface of touch sensor 10 lies in the X-Y plane and the Z axis is orthogonal to the X-Y plane, the position may correspond to the X coordinates of the object, Y coordinates, Z coordinates, X-Y coordinates, X-Z coordinates, Y-Z coordinates, X-Y-Z coordinates, any reference position correlating with X, Y, or Z coordinates, or any other suitable position information.","In certain embodiments, the same measured values may be used to determine both of the distance between the object and touch sensor 10 and the projection of a portion of the object onto touch sensor 10.Controller 12 may also factor in additional measurements and/or calculations to determine this position.","For example, multiple tracks 14 may be sensed synchronously or in close succession, and the position of the object may be determined based on a calculation factoring in each of these measurements.","Furthermore, certain embodiments may utilize weighted averages, linear approximation, or any suitable combination thereof to facilitate the determination of the object's position.","Certain embodiments may perform measurements using any suitable number of steps that facilitate capacitance measurements.","For example, some embodiments may perform any suitable combination of pre-charging one or more tracks 14, charging one or more tracks 14, transferring charge between two or more tracks 14, discharging one or more tracks 14, and/or any other suitable step.","In some embodiments, a transfer of charge may be measured directly or indirectly.","For example, certain embodiments may utilize voltage measurements, current measurements, timing measurements, any other suitable measurement, or any combination thereof to measure capacitance or a change in capacitance at one or more capacitive nodes.","Furthermore, certain embodiments may utilize additional circuitry (such as, for example, one or more integrators, amplifiers, capacitors, switches, audio-to-digital converters, and/or any other suitable circuitry) to perform and/or enhance such measurements.","Certain embodiments may measure a value at a particular point in time, measure a change in a value over time, and/or perform any other suitable processing to facilitate the determination of an object's position relative to touch sensor 10.FIG.","2 illustrates an example device 20 and example electrode tracks 14 that may be used in certain embodiments of the present disclosure.","In the illustrated embodiment, device 20 includes touch screen 10, which includes tracks 14.In some embodiments, multiple tracks 14 may be connected to form clusters 30 (not shown), which may strengthen the electric field created by tracks 14 to provide improved sensing.","Furthermore, to provide improved precision, resolution, and/or linearity when detecting the position of a nearby object, clusters 30 may be interleaved temporally (as shown for example in the embodiments of FIGS.","6A-6B and 7A-7C) and/or spatially (as shown for example in the embodiment of FIG.","8B).","Device 20 may be any touch-sensing device or component.","In various embodiments, device 20 may be a smartphone, tablet computer, laptop computer, or any suitable device utilizing a touch sensor 10.Device 20 may include a display 21 that may be overlaid by or otherwise positioned proximate to touch sensor 10.Display 21 and touch sensor 10 may be substantially planar, curved, or have any other suitable configuration.","Tracks 14 may include any structure, configuration, and/or function described above with respect to FIG.","1.While the illustrated embodiment depicts certain tracks 14 running across display 21 perpendicular to certain other tracks 14, other embodiments may use any suitable configuration of tracks 14.For example, certain embodiments of tracks 14 may utilize different shapes, patterns, and/or configurations.","Furthermore, certain embodiments may use different types, shapes, or configurations of tracks 14 within the same touch sensor 10.For example, in some embodiments, tracks 14 may be electrode “lines” that may be parallel, perpendicular or have any suitable orientation relative to other tracks 14.In alternative embodiments, which may include certain self-capacitance embodiments, tracks 14 may be non-linear electrodes, rather than intersecting “lines” such that each column and/or row of touch sensor 10 may include multiple tracks 14, each of which is separately connected or connectable to controller 12.In such embodiments, the sensing portion of track 14 may have any suitable shape (e.g., square, round, triangular, hexagonal, or any other suitable shape).","Furthermore, such electrodes may be of a single type or multiple types, and each may form a capacitive node.","As used herein, track 14 may refer to such electrodes, the track of conductive material connecting the electrode to controller 12, or both, as appropriate.","In self capacitance embodiments, when an object touches or approaches a capacitive node, a change in self-capacitance may occur at the capacitive node and controller 12 may measure the change in capacitance.","As a particular example, a change in capacitance may be measured as a change in the amount of charge needed to raise the voltage at the capacitive node by a pre-determined amount.","By measuring changes in capacitance throughout the array of electrodes, controller 12 may determine the position of the touch or proximity within the touch-sensitive area(s) of touch sensor 10.Furthermore, multiple tracks 14 may be galvanically connected to form a cluster that can be sensed as a single capacitive node, which may increase the sensitivity of touch sensor 10 and/or reduce noise interference experienced by touch sensor 10.This disclosure contemplates any suitable form of capacitive touch sensing, where appropriate.","For example, other embodiments may utilize mutual capacitance sensing.","FIG.","3A illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor 10.Touch sensor 10 includes clusters 30a and 30b and panel 32.In the illustrated embodiment, touch sensor 10 may detect the presence and/or position of object 34, which is located a distance 36a from touch sensor 10.Panel 32 may be any material proximate to tracks 14 and configured to be positioned between tracks 14 and object 34.Panel 32 may be glass, plastic, or any suitable material through which electric fields generated by tracks 14 may interact with object 34.In certain embodiments, panel 32 may be transparent, though this is not required.","Panel 32 may be formed as a separate layer from tracks 14, and in such embodiments, panel 32 may be affixed to a portion of touch sensor 10 via an adhesive.","In some embodiments, panel 32, tracks 14, and/or one or more substrates may be integrally formed.","Clusters 30a and 30b include tracks 14a-14c and tracks 14f-14j, respectively.","A used herein, a “cluster” may refer to a single track 14 or multiple tracks 14 connected such that they can be charged and/or sensed as a single unit.","In some embodiments, tracks 14 may be “connected” by galvanically connecting the tracks 14, though any suitable method of connecting tracks 14 may be used (e.g., multiple tracks 14 may be sensed together by capacitively coupling the tracks 14 via a sufficiently large capacitance).","Furthermore, the one or more tracks 14 forming a cluster 30 may include any type, structure, and/or configuration discussed above with respect to tracks 14 of FIGS.","1 and 2.For example, certain embodiments may include a cluster 30 of parallel tracks, perpendicular tracks, or both.","As another example, certain embodiments may include one or more non-linear self-capacitance electrodes of one or more tracks 14.Thus, clusters 30 may be a set of one or more linear electrode tracks 14, a set of non-linear electrodes, or any suitable configuration of electrodes.","As a particular example, the electrodes of cluster 30 may form a triangle, square, hexagon, or other geometric shape from a perspective orthogonal to the surface of touch sensor 10.In some embodiments, a cluster 30 may include all tracks 14 of touch sensor 10.The tracks 14 of a cluster may be adjacent, though this is not required.","Furthermore, multiple clusters 30 may be sensed simultaneously or in close succession, which may allow controller to determine the position of object 34 taking into account multiple values.","Clusters 30 may include adjacent tracks and/or non-adjacent tracks 14.In the illustrated embodiment, clusters 30a and 30b each include five galvanically connected electrode tracks 14.In other embodiments, clusters 30 may have more or fewer tracks 14.Such tracks 14 may be galvanically connected by, for example, using various switches of controller 12.Galvanically connecting tracks 14 to form clusters 30 in this manner may increase the sensitivity of touch sensor 10, which may enable detection of the presence and/or position of object 34 at greater distances from touch sensor 10.Such embodiments may also reduce noise interference experienced during the sensing sequence since a stronger signal may be generated relative to the noise effects impacting the measured capacitance values.","Galvanically connecting tracks 14 to form clusters 30 may result in improved noise protective compared to touch sensors that sum measurements of the individual tracks 14, because such touch sensors may also effectively sum the noise interference experienced by the tracks 14.Object 34 may be any external object whose presence and/or position may be detected by tough sensor 10.Object 34 may be a finger, hand, stylus, or any suitable object.","In the illustrated embodiment, object 34 is a finger located distance 36a from touch sensor 10.As used herein, a distance from tough sensor 10 may refer to the distance between object 34 and panel 32, tracks 14, or any suitable portion of touch sensor 10.Ranges 38a-38c may be any suitable ranges corresponding to positions of object 34 that may trigger a change in the configuration of clusters 30, as explained further below.","For example, range 38a may be 8-20 mm and may be associated with a cluster size of five tracks 14, range 38b may be 4-10 mm and may be associated with a cluster size of three tracks 14, and range 38c may be 0-5 mm and may be associated with a cluster size of two tracks 14.Other embodiments may use any suitable values for range 38.Furthermore, various embodiments may use any number of range 38, which may be associated with any suitable cluster size.","For example, a particular embodiment may have separate ranges associated with clusters of size 1-10.Furthermore, certain embodiments may not explicitly calculate an estimated distance of object 34 from touch sensor 10.For example, certain embodiments may change cluster configurations based directly on one or more measured capacitance values (rather than using those values to determine distance 36 and then using distance 36 to determine the cluster configuration).","Thus, in some embodiments, changes in the configuration of clusters 30 may not directly correspond to the distance of object 34 from touch sensor 10.As a particular example, different objects 34 at the same distance from touch sensor 10 may result in different capacitance values measured by a single cluster 30.As another example, some embodiments may factor in the relative measurements from multiple clusters 30 in determining the appropriate cluster configuration, so different objects 34 (for example, a fingertip vs. a hand) at the same distance from touch sensor 10 and causing the same capacitive measurement at a single cluster 30 may nevertheless trigger different cluster configurations.","In operation, tracks 14a -14c are connected to form cluster 30a, and tracks 14f-14j are connected to form cluster 30b.","This connection may be a galvanic connection.","Voltage is applied to cluster 30a and 30b, and a capacitance value associated with each cluster 30 is determined using any suitable sensing method described above with respect to FIGS.","1 and 2.Clusters 30a and 30b may be sensed synchronously or sequentially.","Based on the measured values, controller 12 may determine a distance between object 34 and touch sensor 10.Based on the measured distance, controller 12 may maintain the same cluster configuration or switch to a different cluster configuration.","For example, controller 12 may determine whether the measured distance falls in one or more ranges 38.In the illustrated embodiment, distance 36a falls within range 38a.","As object 34 moves to distance 36b from touch sensor 10, controller 12 may determine that object 34 has moved within range 38b and transition to the cluster configuration shown in FIG.","3B.","Any suitable cluster configuration and/or range may be used.","FIG.","3B illustrates an example cluster configuration that may be used in certain embodiments of touch sensor 10.Touch sensor 10 includes clusters 30a, 30b, and 30c and panel 32.In the illustrated embodiment, touch sensor 10 may detect the presence and/or position of object 34, which is located a distance 36b from touch sensor 10.Clusters 30a, 30b, and 30c include tracks 14a-14c, tracks 14d-14f, and tracks 14g-14i, respectively.","Track 14j may be part of an additional cluster 30 that is not shown.","In the illustrated embodiment, clusters 30a-30c each include three galvanically connected electrode tracks 14.Such tracks 14 may be galvanically connected by, for example, using various switches of controller 12.Connecting tracks 14 to form clusters 30 in this manner may increase the sensitivity of touch sensor 10, which may enable detection of the presence and/or position of object 34 at greater distances from touch sensor 10.Clusters of three tracks 14 may be more sensitive than clusters of two tracks 14 (see, e.g., FIG.","3C) but less sensitive than clusters of live tracks 14 (see, e.g., FIG.","3A).","Certain embodiments may reduce noise interference experienced during the sensing sequence since a stronger signal may be generated relative to the noise effects impacting the measured capacitance values.","Connecting tracks 14 to form clusters 30 may result in improved noise protection compared to touch sensor than sum measurements of the individual tracks 14, because such touch sensors may also effectively sum the noise interference experienced by the tracks 14.In the illustrated embodiment, object 34 is located distance 36b from touch sensor 10, which falls within range 38b.","Controller 12 may configure clusters 30 as shown in FIG.","3B in response to determining that the measured distance 36b falls within range 38b.","If the measured distance 36 fell below a threshold value to move within range 38c, controller may configure clusters 30 as shown in FIG.","3C.","If the measured distance 36 is increased above a threshold value to move within range 38a, controller may configure clusters 30 as shown in FIG.","3A.","Any suitable cluster configuration and/or range may be used.","FIG.","3C illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.","Touch sensor 10 includes clusters 30a-30c and panel 32.In the illustrated embodiment, touch sensor 10 may detect the presence and/or position of object 34, which is located a distance 36c from touch sensor 10.Clusters 30a-30e include tracks 14a-14b, tracks 14c-14d, tracks 14e-14f, tracks 14g-14h, and tracks 14i-14j, respectively.","In the illustrated embodiment, clusters 30a-30 e each include two connected electrode tracks 14.Such tracks 14 may be galvanically connected by, for example, using various switches of controller 12.Galvanically connecting tracks 14 to form clusters 30 in this manner may increase the sensitivity of touch sensor 10, which may enable detection of the presence and/or position of object 34 at greater distances from touch sensor 10.Clusters of two tracks 14 may be more sensitive than clusters of a single track 14 (which may correspond to traditional sensing methods) but less sensitive than clusters using a greater number of tracks 14 (see, e.g., FIGS.","3A and 3B).","Certain embodiments may reduce noise interference experienced during the sensing sequence since a stronger signal may be generated relative to the noise effects impacting the measured capacitance values.","Connecting tracks 14 to form clusters 30 may result in improved noise protection compared to touch sensors that sum measurements of the individual tracks 14, because such touch sensors may also effectively sum the noise interference experienced by the tracks 14.In the illustrated embodiment, object 34 is located distance 36c from touch sensor 10, which falls within range 38c.","Controller 12 may configure clusters 30 as shown in FIG.","3C in response to determining that the measured distance 36c falls within range 38c.","If the measured distance 36 is increased to move within range 38b, controller may configure clusters 30 as shown in FIG.","3B.","If the measured distance 36 increased to move within range 38a, controller may configure clusters 30 as shown in FIG.","3A.","Other embodiments may utilize any suitable ranges and any suitable configuration of clusters 30.FIG.","4A illustrates example touch points 40 on an example touch sensor 10.Touch sensor 10 includes panel 32 and clusters 30a and 30b.","Clusters 30a and 30b include tracks 14a and 14b and tracks 14c and 14d, respectively.","Panel 32, clusters 30, and tracks 14 may have any suitable structure, configuration, and/or function described above with respect to FIGS.","1, 2, and 3A-3C.","Touch points 40a-40c represent a position of object 34 (not shown) moving from left to right across touch sensor 10.Touch points 40 may be positions where a portion of object 34 physically touches touch sensor 10, or they may be orthogonal projections of a portion of object 34 onto touch sensor 10.In the illustrated embodiments, touch points 40a-40c each fall directly above a portion of cluster 30a.","Because tracks 14a and 14b of cluster 30a may be galvanically connected and sensed together during the sensing sequence, the similar capacitance values measured at touch points 40a-40c (see FIG.","4B) may reduce the linearity of the measured position of object 34 as it moves across touch sensor 10.This issue is described further with respect to FIGS.","4B, 5A, and 5B.","This potential for reduced precision may be mitigated by cluster configurations discussed below with respect to FIGS.","7A-7C.","FIG.","4B illustrates a graph of example measurements 44 and 46 that may be taken by certain embodiments of touch sensor 10.Measurements 42a, which include measurements 44a-44c, correspond to measurements associated with cluster 30a or FIG.","4A.","Measurements 42b, which include measurements 46a-46c, correspond to measurements associated with cluster 30b of FIG.","4A.","Measurements 42a represent values measured by cluster 30a of FIG.","4A, and measurements 42b represent values measured by cluster 30b of FIG.","4A.","Measurements 44a-44c correspond to the values measured by cluster 30a at touch points 40a-40c, respectively, and measurements 46a-46c correspond to the values measured by cluster 30b at touch points 40a-40c, respectively.","As discussed above, controller 12 may evaluate multiple measurements to determine the position of object 34.For example, the measured position of object 34 may be based on capacitive values measured by multiple clusters 30.Thus, as a particular example, the position of object 34 when object 34 is located at touch point 40a may be determined using measurements 44a and 46a (as well as values measured by other clusters 30).","Furthermore, the position of object 34 may also be determined by taking into account previously measured values.","Thus, as a particular example, the position of object 34 when object 34 is located at touch point 40c may be determined using measurements 44c and 46c as well as values measured during previous sensing sequences, such as 44b and 46b.","Because tracks 14a and 14b of cluster 30a may be galvanically connected and sensed together during the sensing sequence, values measured when object 34 is located at touch points 40a-40c may not be sufficiently distinct to precisely distinguish between these touch points 40.Such measurement difficulties may be particular pronounced when clusters 30 include larger numbers of tracks 14.FIG.","5A illustrates example touch points 50 on an example touch sensor 10.Touch sensor 10 includes panel 32 and clusters 30aand 30b.","Clusters 30a and 30b include tracks 14a and 14b and tracks 14c and 14d, respectively.","Panel 32, clusters 30, and tracks 14 may have any suitable structure, configuration, and/or function described above with respect to FIGS.","1, 2, and 3A-3C.","Touch points 50a-50c represent a position of object 34 (not shown) moving from left to right across touch sensor 10.Touch points 50 may be positions where a portion of object 34 physically touches touch sensor 10, or they may be orthogonal projections of a portion of object 34 onto touch sensor 10.In the illustrated embodiments, touch points 50a-50c move from left to right, moving from cluster 30a to cluster 30b.","Because clusters 30a and 30b are not galvanically connected during their respective sensing sequences, capacitive values measured when object 34 is at touch points 50a-50c may provide improved touch resolution.","For example, such embodiments may provide increased linearity when determining the position of object 34 as it moves across touch sensor 10 in a straight line.","Certain embodiments may take advantage of improved touch-sensing precision at the borders of clusters 30 by utilizing cluster configurations discussed below with respect to FIGS.","6-9.FIG.","5B illustrates a graph of example measurements 44 that may be taken by certain embodiments of touch sensor 10.Measurements 52a, which include measurements 54a-54c, correspond to measurements associated with cluster 30a of FIG.","5A.","Measurements 52b, which include measurements 56a-56c, correspond to measurements associated with cluster 30b of FIG.","5A.","Measurements 52a represent values measured by cluster 30a of FIG.","5A, and measurements 52b represent values measured by cluster 30b of FIG.","5A.","Measurements 54a-54c correspond to the values measured by cluster 30a at touch points 50a-50c, respectively, and measurements 56a-56c correspond to the values measured by cluster 30b at touch points 50a-50c, respectively.","As discussed above, controller 12 may evaluate multiple measurements to determine the position of object 34.For example, the measured position of object 34 may be based on capacitive values measured by multiple clusters 30.Thus, as a particular example, the position of object 34 when object 34 is located at touch point 50a may be determined using measurements 54a and 56a (as well as values measured by other clusters 30).","Furthermore, the position of object 34 may also be determined by taking into account previously measured values.","Thus, as a particular example, the position of object 34 when object 34 is located at touch point 50c may be determined using measurements 54c and 56c as well as values measured during previous sensing sequences, such as 54b and 56b.","Because clusters 30a and 30b may be sensed separately, values measured when object 34 is located at touch points 50a-50c may be sufficiently distinct to precisely distinguish between these touch points 50.Certain embodiments may take advantage of this improved touch-sensing precision at the borders of clusters 30 by utilizing cluster configurations discussed below with respect to FIGS.","6-9.FIGS.","6A and 6B illustrate example cluster configurations that may be used in certain embodiments of touch sensor 10.In the illustrated embodiments, touch sensor 10 includes panel 32 and tracks 14a-j.","In FIG.","6A, tracks 14 are configured to form clusters 30a and 30b, which include tracks 14a-d and tracks 14e-h, respectively.","In FIG.","6B, tracks 14 are configured to form clusters 30c and 30d, which include tracks 14c-f and tracks 14g-i, respectively.","For purposes of simplified illustration, FIGS.","6A and 6B depict only two clusters 30.However, touch sensor 10 may be configured to include additional clusters 30 using tracks 14 that are not used in the illustrated clusters 30.For example, in FIG.","6A, tracks 14i and 14j may operate as part of additional clusters 30 (not shown) or may operate independently (e.g., tracks 14i and 14j may be sensed individually without being clustered with other tracks 14).","Panel 32, clusters 30, and tracks 14 may have any suitable structure, configuration, and/or function described above with respect to FIGS.","1, 2, and 3A-3C.","FIGS.","6A and 6B illustrate two cluster configurations that may be used in succession during a “rolling cluster” sequence.","As used herein, a rolling cluster sequence refers to a sequential shifting of the configuration of clusters 30.As explained above with respect to FIGS.","4A-4B and 5A-5B, the position of object 34 may be more precisely determined when located at or near the intersection of clusters 30.Utilizing rolling clusters may increase the likelihood that object 34 is positioned at or near the intersection of two or more clusters 30, which may improve the precision, resolution, and/or linearity of touch-sensor 10.Such improvements may be particular useful when utilizing cluster configurations with larger numbers of tracks 14 per cluster 30.Determination of the position of object 34 may be based on measurements from a single cluster pattern (e.g., the clusters 30 shown in FIG.","6B), or the position may be based on a multiple cluster patterns (e.g., the clusters 30 shown in both FIGS.","6A and 6B).","A rolling cluster sequence may involve two or more sequential cluster patterns.","For example, FIGS.","6A-6B illustrate a rolling cluster sequence that may use two cluster patterns, and FIGS.","7A-7C illustrate a rolling cluster sequence that may use three cluster patterns.","Other embodiments may use any suitable configuration of clusters 30 in any suitable rolling cluster sequence.","For example, some embodiments may used larger cluster sizes and/or different cluster shapes.","As another example, some embodiments may use different numbers of cluster patterns in a single rolling cluster sequence (e.g., four, five, six, or more difference cluster patterns used sequentially), and some embodiments may cycle through cluster patterns in different orders.","As used herein, a “cluster pattern” refers to a particular configuration of cluster 30 at a particular point in time or during a particular span of time.","In certain embodiments, controller 12 may sequentially alter the configuration of clusters 30.For example, tracks 14a-14d may be galvanically connected and sensed as cluster 30a, and tracks 14e-14h may be galvanically connected and sensed as cluster 30b, as shown in FIG.","6A.","After measuring capacitance values associated with this configuration tracks 14c-14f may be galvanically connected and sensed as cluster 30c, and tracks 14g-14j may be galvanically connected and sensed as cluster 30d, as shown in FIG.","6B.","Controller 12 may determine the position of object 34 using the various capacitance values associated with these rolling clusters.","For example, controller 12 may compare values measured by different clusters 30.As another example, controller 12 may calculate one or representative values that may indicate the position of object 34 relative to touch sensor 10.As a particular example, controller 12 may calculate a representative value for each track 14 based on the capacitance values measured from clusters 30.For example, a representative value for a particular track 14 may be calculated based on the capacitance value measured from each cluster 30 to which it belonged, and the relative representative values of tracks 14 (e.g.","the shape of a plot of the representative values) may indicate the position of object 34.One ore more additional calculations may also be used, such as, for example, weighted averages, linear approximation, and balanced position techniques.","Rolling clusters may improve the precision, resolution, and/or linearity of touch sensors 10 utilizing clusters 30 that include multiple tracks 14.Such embodiments may enable touch sensor 10 to provide improved sensitivity resulting from clustering tracks 14, as described above, while also avoiding potential reductions in precision, resolution, and/or linearity (as described with respect to FIGS.","4A and 4B) that might otherwise be created by such clustering.","FIGS.","7A-7C illustrate example cluster configurations that may be used in certain embodiments of touch sensor 10.Touch sensor 10 includes panel 32 and clusters 30a and 30b.","In FIG.","7A, clusters 30a and 30b include tracks 14a-14c and tracks 14d-14f, respectively.","In FIG.","7B, clusters 30c and 30d include tracks 14b-14d and tracks 14e-14g, respectively.","In FIG.","7C, clusters 30e and 30f include tracks 14c-14e and tracks 14f-14h, respectively.","For purposes of simplified illustration, FIGS.","7A-7C depict only clusters 30a and 30b.","However, touch sensor 10 may include additional clusters 30 using tracks 14 that are not used in the illustrated clusters 30.For example, in FIG.","7A, tracks 14g-I may operate as part of an additional cluster 30 (not shown) or may operate independently (e.g., tracks 14g-I may be sensed individually without being clustered with other tracks 14).","Panel 32, clusters 30, and tracks 14 may have any suitable structure, configuration, and/or function described above with respect to FIGS.","1, 2, 3A-3C, 6A-6B, and 7A-7C.","FIGS.","7A-7C illustrate three cluster configurations that may be used in succession during a rolling cluster sequence.","These configurations may be used in embodiments utilizing rolling clusters that shift clusters 30 successively by a single track 14.As explained above with respect to FIGS.","4A-4B, 5A-5B, and 6A-6B, the position of object 34 may be more precisely determined when located at or near the intersection of clusters 30.Utilizing rolling clusters may increase the likelihood that object 34 is positioned at or near the intersection of two or more clusters 30, which may improve the precision, resolution, and/or linearity of touch-sensor 10.Such improvements may be particular useful when utilizing cluster configurations with larger numbers of tracks 14 per cluster 30.Furthermore, utilizing rolling clusters that shift by a single track 14 may further improve the precision, resolution, and/or linearity of much sensing measurements.","In certain embodiments, controller 12 may sequentially alter the configuration of clusters 30.For example, tracks 14a-14c may be galvanically connected and sensed as cluster 30a, and tracks 14d-14f may be galvanically connected and sensed as cluster 30b, as shown in FIG.","7A.","After measuring capacitance values associated with this configuration, tracks 14b-14d may be galvanically connected and sensed as cluster 30c, and tracks 14e-14g may be galvanically connected and sensed as cluster 30d, as shown in FIG.","7B.","After measuring capacitance values associated with this configuration, tracks 14c-14e may be galvanically connected and sensed as cluster 30e, and tracks 14f-14h may be galvanically connected and sensed as cluster 30f, as shown in FIG.","7C.","Controller 12 may determine the position of object 34 using the various capacitance values associated with these rolling clusters.","For example, controller 12 may compare values measured by different clusters 30.As another example, controller 12 may calculate one or representative values that may indicate the position of object 34 relative to touch sensor 10.As a particular example, controller 12 may calculate a representative value for each track 14 based on the capacitance values measured from clusters 30.For example, a representative value for a particular track 14 may be calculated based on the capacitance value measured from each cluster 30 to which it belonged, and the relative representative values of tracks 14 (e.g.","the shape of a plot of the representative values) may indicate the position of object 34.One or more additional calculations may also be used, such as, for example, weighted averages, linear approximation, and balanced position techniques.","Rolling clusters may improve the precision, resolution, and/or linearity of touch sensors 10 utilizing clusters 30 that include multiple tracks 14.Such embodiments may enable touch sensor 10 to provide improved sensitivity resulting from clustering tracks 14, as described above, while also avoiding potential reductions in precision, resolution, and/or linearity (as described with respect to FIGS.","4A and 4B) that might otherwise be created by such clustering.","FIGS.","8A and 8B an example cluster configurations that may be used in certain embodiments of touch sensor 10.Touch sensor 10 includes panel 32 and clusters 30a-c.","In FIG.","8A, cluster 30a includes tracks 14a-14d, cluster 30b and tracks 14e-14h, and cluster 30c includes tracks 14i-14k.","Cluster 30c may also include additional tracks 14 (not shown).","For purposes of simplified illustration, FIG.","8A depicts only clusters 30a-30c.","However, touch sensor 10 may include additional clusters 30 using tracks 14 that are not used in the illustrated clusters 30.Panel 32, clusters 30, and tracks 14 may have any suitable structure, configuration, and/or junction described above with respect to FIGS.","1, 2, and 3A-3C.","FIG.","8B illustrates an example interleaved cluster configuration that may be used in certain embodiments.","In FIG.","8B, cluster 30d includes tracks 14b, 14c, and 14e; cluster 30e includes tracks 14d, 14f-14g, and 14i; and cluster 30f includes tracks 14h, and 14j-14k.","Clusters 30d and 30f may include additional tracks 14 (not shown).","For purposes of simplified illustration, FIG.","8B depicts only clusters 30d-30f.","However, touch sensor 10 may include additional clusters 30 using tracks 14 that are not used in the illustrated clusters 30.Panel 32, clusters 30, and tracks 14 may have any suitable structure, configuration, and/or function described above with respect to FIGS.","1, 2, 3A-3C, 6A-6B, and 7A-7C.","As used herein, “interleaved clusters” refers in clusters 30 having one or more tracks 14 interspersed within the outer boundary of another cluster 30 from a perspective orthogonal to the surface of touch sensor 10.Interleaved clusters may have any suitable number and/or arrangement of tracks 14 that are interleaved with the tracks 14 of another cluster 30.FIG.","8B illustrates a particular pattern of interleaved clusters 30, and other embodiments may use any suitable interleaving patterns.","Interleaving the edges of clusters 30 as shown in FIG.","8B may provide improved linearity when measuring an object moving across the surface of touch sensor 10 while touching or hovering near device 2.Such embodiments may mitigate potential redactions in precision, resolution, and/or linearity (as described with respect to FIGS.","4A and 4B) that might otherwise be created by clustering of tracks 14.In some embodiments, interleaved cluster configurations, such as the configuration illustrated in FIG.","8B, may be triggered by one or more previous measurements.","For example, one or more measurements from clusters 30 of FIG.","8A may trigger the interleaved cluster configuration of FIG.","8B.","Such embodiments may allow touch sensor 10 to achieve improved precision, resolution, and/or linearity when certain conditions are detected.","For example, interleaved configurations may be triggered when controller 12 detects sufficiently nonlinear readings of the position of object 34, which may indicate that measurements of the position of object 34 have sub-optimal linearity in detecting the movement of object 34.Furthermore, in some embodiments, interleaved cluster configurations may be used in conjunction with rolling clusters.","For example, a rolling cluster may be used with the configuration shown in FIG.","8B such that clusters 30d-f effectively “shift” along touch sensor 10, analogous to the “shifting” of clusters 30 illustrated in FIGS.","6A-B and 7A-7C.","In other embodiments, interleaved cluster configurations may be used in conjunction with the alteration of cluster sizes illustrated shown in FIGS.","3A-C. For example, when object 34 is detected at shorter distances from touch sensor 10 (e.g., distance 36b of FIG.","3B), smaller cluster sizes and non-interleaved clusters may be used, and when object 34 is detected at longer distances from touch sensor 10 (e.g., distance 36a of FIG.","3B) larger cluster sizes and interleaved clusters may be used.","Such embodiments may allow touch sensor 10 to target the use of linearity-improving configurations more precisely to situations in which the linearity of its sensing may be reduced.","FIGS.","9A and 9B illustrate an example switch network 90 that may be used to configure clusters 30 in certain embodiments of touch sensor 10 and controller 12.In the illustrated embodiment, touch sensor 10 includes panel 32 and tracks 14a-14k, which form clusters 30a-30c; and controller 12 includes switch network 90 and measurement channels 96.Panel 32, clusters 30, and tracks 14 may have any suitable structure, configuration, and/or function described above with respect to FIGS.","1, 2, 3A-3C, 6A-6B, 7A-7C, and 8A-8B.","Switch network 90 may include any number, arrangement, and/or configuration of switches that are operable to connect one or more tracks 14 to one or more measurement channels 96.Switch network 90 may be configured by controller 12 during the operation of touch sensor 10.For example, controller 12 may control switch network 90 to form the cluster patterns shown in FIGS.","3A-C, 6A-6B, 7A-7C, and 8A-8B.","Certain embodiments may use any suitable switch network 90, and the configuration shown in FIGS.","9A-B is used merely as an example.","For example, cluster patterns shown in FIGS.","6A-6B and 7A-7C may be configured using switch network 90 shown in FIGS.","9A-B, while the cluster pattern shown in FIG.","8B may rely on a more complex switch network 90 to facilitate the configuration of interleaved clusters 30.In the illustrated embodiments, switch network 90 includes switches 92 and 94.Switches 92 and 94 may be any suitable circuitry operable to connect or disconnect one or more tracks 14 from a portion of controller 12.For example, switches 92 and 94 may be any appropriate form of mechanical and/or electrical switching device operable to conduct current in the on position and/or form an open circuit in the off position.","As a particular example, switches 92 and 94 may be any appropriate form of transistor device, including field effect transistors (FETS).","In some embodiments, switches 92 and 94 may be implemented using metal oxide-semiconductor FETS (MOSFETS), such as NMOS or PMOS transistors.","The gates of switches 92 and 94 may be controlled via one or more control signals transmitted from controller 12.Switches 92 and 94 may be part of touch sensor 10 and/or controller 12, and touch sensor 10 and/or controller 12 may have any suitable number, type, and/or configuration of switches 92 and 94.Measurement channels 96 represent portions of controller 12 operable to receive and/or transmit signals to one or more tracks 14 to facilitate the taking of one or more capacitive measurements.","Measurement channels 96 may include any components and may perform any measurement functionality described above with respect to controller 12 in FIG.","1.In some embodiments, different measurement channels 96 may be physically distinct.","In other embodiments, measurement channels 96 may be logically distinct while sharing one or more common physical components.","For example, each measurement channel 96 may include distinct measurement circuitry, or one or more portions of measurement channels 96 may operate as a multiplexer, connecting one or multiple inputs to common measurement circuitry.","Switches 92 may operate to galvanically connect the tracks 14 of a particular cluster 30, while switches 94 may operate to connect a particular cluster 30 to a particular measurement channel 96.For example, as shown in FIG.","9A, switches 92a-92b are closed, and switch 92c is open, thereby galvanically connecting tracks 14a-c to form cluster 30.Furthermore, switch 94a is closed, and switches 94b-94c are open, thereby connecting cluster 30a to measurement channel 96a.","Similarly, switches 92d-92e and switch 94d are closed to form cluster 30b and connect it to measurement channel 96d, and switches 92g-92h and switch 94g are closed to form cluster 30f and connect it to measurement channel 96g.","Analogous configurations may be used to form additional clusters 30 and to connect them to their respective measurement channels 96.Furthermore, switches 94j-94k are open, thereby disconnecting tracks 14j-14k from any measurement channel 96.Such embodiments may be used to prevent tracks 14 that are not included in a cluster 30 from being measured, though this is not required.","For example, other embodiments may connect tracks 14 that are not included in a cluster 30 to a measurement channel 96.As shown in FIG.","9B, altering the state of switch network 90 may form different clusters 30 and/or connect clusters 30 to different measurement channels.","FIG.","9B illustrates a configuration of switch network 90 that may be used to form clusters 30d-30f.","Such configurations may facilitate the “shifting” of clusters described above with respect to FIGS.","6A-6B and FIGS.","7A-7C, which may be used during rolling cluster sensing sequences.","In the illustrated embodiment, switches 92a and 92d are opened and switches 92b-92c are closed to form cluster 30d.","Furthermore, switch 94b is closed to connect cluster 30d to measurement channel 96b.","Similarly, switches 92e-92f and switch 94e are closed to form cluster 30e and connect it to measurement channel 96e, and switches 92h-92i and switch 94h are closed to form cluster 30f and connect it to measurement channel 96h.","Switch network 90 may therefore facilitate alterations of the configurations of clusters 30 to improve the sensitivity of touch sensor 10 and/or provide improved precision, resolution, and/or linearity when touch sensor 10 is detecting the movement of object 34.FIG.","10 illustrates an example method for use with certain embodiments of touch sensor 10.Various embodiments may perform some, all, or none of the steps described below.","Furthermore, certain embodiments may perform these steps in different orders or in parallel, and certain embodiments may also perform additional steps.","Moreover, any suitable component of touch sensor 10 and/or controller 12 may perform one or more steps of the sensing sequence.","At step 100, controller 12 connects tracks 14 to form a first cluster pattern.","Tracks 14 may be connected galvanically, capacitively, or using any suitable method.","The first cluster pattern may have clusters 30 of any suitable size, shape, and/or configuration.","For example, the first cluster pattern may have the configurations shown in FIGS.","6-9 or any suitable configuration.","Furthermore, the first cluster pattern may include different types of clusters 30 and may include tracks 14 that are not part of a cluster 30.In some embodiments, the first cluster pattern may include interleaved clusters 30 with any suitable interleaving pattern.","At step 102, voltage is applied to the clusters 30 of the first cluster pattern.","Voltage may be applied to a cluster 30 by connecting it to a voltage source (e.g.","a voltage supply rail), a current source, or any other suitable component.","Voltage may be applied for a fixed amount of time or a variable amount of time.","In some embodiments, a predetermined amount of charge may be applied to each cluster 30.The application of voltage to cluster 30 may be performed at least in part by controller 12.Voltage may also be applied to additional clusters 30, and multiple clusters 30 may be charged simultaneously.","At step 104, controller 12 measures a plurality of first values.","Each first value is associated with the capacitance of a respective cluster 30 of the first cluster pattern, and the first values may be measured simultaneously or sequentially.","The first values may be measured using any suitable method described above with respect to FIG.","1.Each first value may be a capacitance or it may be a measurement that is proportional to, related to, or indicative of the capacitance (or change in capacitance) experienced by a cluster 30.For example, the first value may be a voltage measurement, current measurement, timing measurement, any other suitable measurement, or any combination thereof that is measured under conditions that make the measured value indicative of the capacitance (or change in capacitance) experienced by cluster 30.Furthermore, certain embodiments may utilize additional circuitry (such as, for example, one or more integrators, amplifiers, capacitors, switches, audio-to-digital converters, and/or any other suitable circuitry) to perform and/or enhance such measurements.","Certain embodiments may measure a value at a particular point in time, measure a change in a value over time, and/or perform any other suitable processing to facilitate the determination of a position of object 34 relative to touch censor 10.In certain embodiments, the determination of the first value may be performed at least in part by controller 12.The first values may be used to determine the cluster configuration, trigger one or more functions, estimate a position of object 34 relative to touch sensor 10, estimate a shape and/or size of object 34 (e.g., by analyzing the distribution of first values measured by multiple clusters 30), and/or perform any suitable function.","At step 106, controller 12 connects tracks 14 to form a second cluster pattern.","In some embodiments, the second cluster pattern may have one or more interleaved clusters 30, though this is not required.","Tracks 14 may be connected galvanically, capacitively, or using any suitable method.","The second cluster pattern may have clusters 30 of any suitable size, shape, and/or configuration.","For example, the second cluster pattern may have the configuration shown in FIG.","8B or any suitable configuration, or the second cluster pattern may have different sizes of clusters 30 and/or different interleaving patterns.","Furthermore, the second cluster pattern may include different types of clusters 30 and may include tracks 14 that are not part of a cluster 30.For example, some clusters 30 may be interleaved while other clusters 30 are not, or different clusters 30 in the second cluster pattern may have different interleaving patterns from one another.","Interleaved clusters 30 may provide improved precision, resolution, and/or linearity tor touch sensing measurements, including hover measurements.","The formation of the second cluster pattern may occur in response to the first values.","For example, one or more of the first values may trigger controller 12 to form interleaved clusters 30.Such embodiments may allow touch sensor 10 to achieve improved precision, resolution, and/or linearity when certain conditions are detected.","For example, interleaved configurations may be triggered when controller 12 detects sufficiently nonlinear readings of the position of object 34, which may indicate that measurements of the position of object 34 have sub-optimal linearity in detecting the movement of object 34.In some embodiments, interleaved cluster configurations may be used in conjunction with the alteration of cluster sizes illustrated shown in FIGS.","3A-C. For example, when object 34 is detected at shorter distances from touch sensor 10 (e.g., distance 36b of FIG.","3B), smaller cluster sizes and non-interleaved clusters 30 may be used, and when object 34 is detected at longer distances from touch sensor 10 (e.g., distance 36a of FIG.","3B) larger cluster sizes and interleaved clusters 30 may be used.","Such embodiments may allow controller 12 to target the use of linearity-improving configurations more precisely to situations in which the linearity of its sensing may be reduced.","In some embodiments, the second cluster pattern may include clusters 30 that are “shifted” configurations of the clusters 30 of the first cluster pattern.","For example, the first and second cluster patterns may be cluster patterns used in a rolling cluster embodiment, as described above with respect to FIGS.","6A-6B and 7A-7C.","In such embodiments, each cluster 30 of the second cluster pattern may include one or more tracks 14 that were included in a primary cluster 30 of the first cluster pattern and one or more tracks 14 that were included in a secondary cluster 30 of the first cluster pattern.","As used herein, “primary” and “secondary” does not indicate a greater or lesser level of importance.","In some embodiments, each cluster 30 of the second cluster pattern may include more tracks 14 from the primary cluster 30 than from the secondary cluster 30.For example, for clusters 30 of size N, each cluster 30 of the second cluster pattern may include N-1 tracks 14 from the primary cluster and a single track 14 from the secondary cluster 30.Thus, the secondary cluster pattern may shift the first cluster pattern by one track 14.Other embodiments may utilize different amounts of shifting.","For example, as shown in FIGS.","6A-6B, clusters 30 may be shifted approximately to the halfway point of clusters 30.Such embodiments may provide a balance between (1) the benefits in precision, resolution, and/or linearity provided by using rolling clusters and (2) the costs of providing additional measurements, such as time, processing resources, or other costs.","At step 108, voltage is applied to the clusters 30 of the second cluster pattern.","The application of voltage to the second cluster pattern may utilize analogous processes to those described above for step 102.At step 110, controller 12 measures a plurality of second values.","Each second value is associated with the capacitance of a respective cluster 30 of the second cluster pattern, and the second values may be measured simultaneously or sequentially.","The second values may be measured using any suitable method described above with respect to FIG.","1.Each second value may be a capacitance or it may be a measurement that is proportional to, related to, or indicative of the capacitance (or change in capacitance) experienced by a cluster 30.For example, the second value may be a voltage measurement, current measurement, timing measurement, any other suitable measurement, or any combination thereof that is measured under conditions that make the measured value indicative of the capacitance (or change in capacitance) experienced by cluster 30.Furthermore, certain embodiments may utilize additional circuitry (such as, for example, one or more integrators, amplifiers, capacitors, switches, audio-to-digital converters, and/or any other suitable circuitry) to perform and/or enhance such measurements.","Certain embodiments may measure a value at a particular point in time, measure a change in a value over time, and/or perform any other suitable processing to facilitate the determination of a position of object 34 relative to touch sensor 10.In certain embodiments, the determination of the second value may be performed at least in part by controller 12.The second values may be used to determine the cluster configuration, trigger one or more functions, estimate a distance between object 34 and touch sensor 10, estimate a shape and/or size of object 34 (e.g., by analyzing the distribution of second values measured by multiple clusters 30), and/or perform any suitable function.","At step 112, controller 12 determines a position of object 34 relative to touch sensor 10 based at least on the second values.","For example, controller 12 may calculate a representative value for each track 14 based at least on the second values associated with clusters 30 that include that track 14.The representative values may approximate the capacitance or change in capacitance that would be experienced by each 14 in a non-clustered configuration.","The representative values may therefore indicated the relative proximity of object 34 to each track 14.In some embodiments, the determination of the position of object 34 may also be based on one or more previously measured values, such as the first values.","Furthermore, some embodiments may utilize one or more additional calculations, such as, for example, weighted averages, linear approximation, or any suitable technique.","The measured position may be an estimation of where a portion of object 34 physically touches touch sensor 10.The measured position may also be an estimation of an orthogonal projection of a portion of object 34 onto touch sensor 10 (e.g., a hover position).","In some embodiments, the determination of the distance between object 34 and touch sensor 10 may be performed at least in part by controller 12.Determining the position of object 34 as described herein may enable touch sensor 10 to provide improved sensitivity resulting from clustering tracks 14, as described above, while also mitigating potential reductions in precision, resolution, and/or linearity (as described with respect to FIGS.","4A and 4B) that might otherwise be created by utilizing larger cluster sizes.","Such embodiments may also improve the precision, resolution, and/or linearity of hover measurements.","Herein, “or” inclusive and not exclusive, unless expressly indicated otherwise or indicated otherwise by context.","Therefore, herein, “A or B” means “A, B, or both,” unless expressly indicated otherwise or indicated otherwise by context.","Moreover, “and” is both joint and several, unless expressly indicated otherwise or indicated otherwise by context.","Therefore, herein, “A and B” means “A and B, jointly or severally,” unless expressly indicated otherwise or indicated otherwise by context.","This disclosure encompasses all changes, substitutions, variations, alterations, and modifications to the example embodiments herein that a person having ordinary skill in the art would comprehend.","For example, while the embodiment of FIG.","2 illustrates a particular configuration of tracks 14, any suitable configuration may be used.","As another example, while FIGS.","3A-3C, 4A, 5A, 6A-6B, 7A-7C, 8A-8B, and 9A-9B illustrate particular configurations of clusters 30, any suitable number, type, and configuration may be used.","Furthermore, some embodiments may combine two or more of the techniques described herein, such as, for example, dynamically changing cluster sizes (as shown, for example, in FIGS.","3A-3C), rolling clusters (as shown for example, in FIGS.","6A-6B and 7A-7C), and interleaved clusters (as shown for example, in FIG.","8B).","As another example, while FIGS.","3A-3C, 4A, 5A, 6A-6B, 7A-7C, 8A-8B, and 9A-9B depict a single layer of tracks 14, other embodiments may include multiple layers of tracks 14.As yet another example, while this disclosure describes certain touch-sensing operations that may be performed using the components of touch sensor 10 and controller 12, any suitable touch-sensing operations may be performed.","Furthermore, certain embodiments may alternate between or combine one or more touch-sensing methods described herein.","Moreover, although this disclosure describes and illustrates respective embodiments herein as including particular components, elements, functions, operations, or steps, any of these embodiments may include any combination or permutation of any of the components, elements, functions, operations, or steps described or illustrated anywhere herein that a person having ordinary skill in the art would comprehend.","Furthermore, reference in the appended claims to an apparatus or system or a component of an apparatus or system being adapted to, arranged to, capable of, configured to, enabled to, operable to, or operative to perform a particular function encompasses that apparatus, system, component, whether or not it or that particular function is activated, turned on, or unlocked, as long as that apparatus, system, or component is so adapted, arranged, capable, configured, enabled, operable, or operative."]],"string":"[\n [\n \"Dynamic Configuration of Touch Sensor Electrode Clusters\",\n \"An apparatus of one embodiment includes a sensor having a plurality of electrodes and a controller having a processor and a memory.\",\n \"The memory includes logic operable to configure the plurality of electrodes of the sensor to form a first cluster pattern including a first cluster and a second cluster.\",\n \"The first cluster and the second cluster each include two or more electrodes of the plurality of electrodes.\",\n \"The logic is further operable to determine a value associated with a capacitance of a first cluster and configure, in response to determining the value, the plurality of electrodes to form a second cluster pattern.\",\n \"The second cluster pattern includes a third cluster and a fourth cluster.\",\n \"The third cluster and the fourth cluster each include two or more electrodes of the plurality of electrodes and the third cluster is interleaved with the fourth cluster such that an electrode of the third cluster is positioned between two electrodes of the fourth cluster.\"\n ],\n [\n \"1-28.\",\n \"(canceled) 29.An apparatus comprising: a sensor comprising a plurality of electrodes; and a controller comprising: a processor; and a memory comprising logic operable, when executed by the processor, to: configure the plurality of electrodes of the sensor to form a first cluster pattern comprising a first cluster and a second cluster, the first cluster and the second cluster each comprising two or more electrodes of the plurality of electrodes; determine a value associated with a capacitance of the first cluster; and configure, in response to determining the value, the plurality of electrodes to form a second cluster pattern comprising a third cluster and a fourth cluster, the third cluster and the fourth cluster each comprising two or more electrodes of the plurality of electrodes, the third cluster being interleaved with the fourth cluster such that an electrode of the third cluster is positioned between two electrodes of the fourth cluster.\",\n \"30.The apparatus of claim 29, the second cluster pattern further comprising a fifth cluster, the fifth cluster comprising two or more electrodes of the plurality of electrodes, the fifth cluster being interleaved with the fourth cluster such that an electrode of the fifth cluster is positioned between two electrodes of the fourth cluster.\",\n \"31.The apparatus of claim 29, further comprising a plurality of switches, wherein: configuring the plurality of electrodes to form the first cluster pattern comprises configuring one or more switches of the plurality of switches to galvanically connect each electrode of the first cluster pattern; and configuring the plurality of electrodes to form the second cluster pattern comprises configuring one or more switches of the plurality of switches to galvanically connect each electrode of the second cluster pattern.\",\n \"32.The apparatus of claim 29, wherein: the third cluster comprises three or more electrodes of the plurality of electrodes; and two electrodes of the three or more electrodes of the third cluster are adjacent to one another.\",\n \"33.The apparatus of claim 29, wherein determining the value comprises measuring a voltage associated with the first cluster after application of a voltage to the first cluster.\",\n \"34.The apparatus of claim 29, wherein: the plurality of electrodes comprises a first electrode, a second electrode adjacent to first electrode, a third electrode adjacent to the second electrode, a fourth electrode adjacent to the third electrode, and a fifth electrode adjacent to the fourth electrode; the first cluster of the first cluster pattern comprises the first electrode, the second electrode, and the third electrode; the second cluster of the first cluster pattern comprises the fourth electrode and the fifth electrode; the third cluster of the second cluster pattern comprises the first electrode, the second electrode, and the fourth electrode; and the fourth cluster of the second cluster pattern comprises the third electrode and the fifth electrode.\",\n \"35.The apparatus of claim 29, wherein the determination of the value utilizes self-capacitance measurements.\",\n \"36.A method comprising: configuring a plurality of electrodes of a sensor to form a first cluster pattern comprising a first cluster and a second cluster, the first cluster and the second cluster each comprising two or more electrodes of the plurality of electrodes; determining a value associated with a capacitance of the first cluster; and configuring, in response to determining the value, the plurality of electrodes to form a second cluster pattern comprising a third cluster and a fourth cluster, the third cluster and the fourth cluster each comprising two or more electrodes of the plurality of electrodes, the third cluster being interleaved with the fourth cluster such that an electrode of the third cluster is positioned between two electrodes of the fourth cluster.\",\n \"37.The method of claim 36, the second cluster pattern further comprising a fifth cluster, the fifth cluster comprising two or more electrodes of the plurality of electrodes, the fifth cluster being interleaved with the fourth cluster such that an electrode of the fifth cluster is positioned between two electrodes of the fourth cluster.\",\n \"38.The method of claim 36, wherein: configuring the plurality of electrodes to form the first cluster pattern comprises configuring one or more switches of the plurality of switches to galvanically connect each electrode of the first cluster pattern; and configuring the plurality of electrodes to form the second cluster pattern comprises configuring one or more switches of the plurality of switches to galvanically connect each electrode of the second cluster pattern.\",\n \"39.The method of claim 36, wherein: the third cluster comprises three or more electrodes of the plurality of electrodes; and two electrodes of the three or more electrodes of the third cluster are adjacent to one another.\",\n \"40.The method of claim 36, wherein determining the value comprises measuring a voltage associated with the first cluster after application of a voltage to the first cluster.\",\n \"41.The method of claim 36, wherein: the plurality of electrodes comprises a first electrode, a second electrode adjacent to first electrode, a third electrode adjacent to the second electrode, a fourth electrode adjacent to the third electrode, and a fifth electrode adjacent to the fourth electrode; the first cluster of the first cluster pattern comprises the first electrode, the second electrode, and the third electrode; the second cluster of the first cluster pattern comprises the fourth electrode and the fifth electrode; the third cluster of the second cluster pattern comprises the first electrode, the second electrode, and the fourth electrode; and the fourth cluster of the second cluster pattern comprises the third electrode and the fifth electrode.\",\n \"42.The method of claim 36, wherein the determination of the value utilizes self-capacitance measurements.\",\n \"43.A non-transitory computer-readable storage medium comprising logic, the logic configured to, when executed by the one or more processors, cause the one or more processors to perform operations comprising: configuring a plurality of electrodes of a sensor to form a first cluster pattern comprising a first cluster and a second cluster, the first cluster and the second cluster each comprising two or more electrodes of the plurality of electrodes; determining a value associated with a capacitance of the first cluster; and configuring, in response to determining the value, the plurality of electrodes to form a second cluster pattern comprising a third cluster and a fourth cluster, the third cluster and the fourth cluster each comprising two or more electrodes of the plurality of electrodes, the third cluster being interleaved with the fourth cluster such that an electrode of the third cluster is positioned between two electrodes of the fourth cluster.\",\n \"44.The medium of claim 43, the second cluster pattern further comprising a fifth cluster, the fifth cluster comprising two or more electrodes of the plurality of electrodes, the fifth cluster being interleaved with the fourth cluster such that an electrode of the fifth cluster is positioned between two electrodes of the fourth cluster.\",\n \"45.The medium of claim 43, wherein: configuring the plurality of electrodes to form the first cluster pattern comprises configuring one or more switches of the plurality of switches to galvanically connect each electrode of the first cluster pattern; and configuring the plurality of electrodes to form the second cluster pattern comprises configuring one or more switches of the plurality of switches to galvanically connect each electrode of the second cluster pattern.\",\n \"46.The medium of claim 43, wherein: the third cluster comprises three or more electrodes of the plurality of electrodes; and two electrodes of the three or more electrodes of the third cluster are adjacent to one another.\",\n \"47.The medium of claim 43, wherein determining the value comprises measuring a voltage associated with the first cluster after application of a voltage to the first cluster.\",\n \"48.The medium of claim 43, wherein: the plurality of electrodes comprises a first electrode, a second electrode adjacent to first electrode, a third electrode adjacent to the second electrode, a fourth electrode adjacent to the third electrode, and a fifth electrode adjacent to the fourth electrode; the first cluster of the first cluster pattern comprises the first electrode, the second electrode, and the third electrode; the second cluster of the first cluster pattern comprises the fourth electrode and the fifth electrode; the third cluster of the second cluster pattern comprises the first electrode, the second electrode, and the fourth electrode; and the fourth cluster of die second cluster pattern comprises the third electrode and the fifth electrode.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>A touch sensor may detect the presence and location of a touch or the proximity of an object (such as a user's finger or a stylus) within a touch-sensitive area of the touch sensor overlaid on a display screen, for example.\",\n \"In a touch-sensitive-display application, the touch sensor may enable a user to interact directly with what is displayed on the screen, rather than indirectly with a mouse or touch pad.\",\n \"A touch sensor may be attached to or provided as part of a desktop computer, laptop computer, tablet computer, personal digital assistant (PDA), Smartphone, satellite navigation device, portable media player, portable game console, kiosk computer, point-of-sale device, or other suitable device.\",\n \"A control panel on a household or other appliance may include a touch sensor.\",\n \"There are a number of different types of touch sensors, such as (for example) resistive touch screens, surface acoustic wave touch screens, and capacitive touch screens.\",\n \"Herein, reference to a touch sensor may encompass a touch screen, and vice versa, in particular embodiments.\",\n \"When an object touches or corner within proximity of the surface of the capacitive touch screen, a change in capacitance may occur within the touch screen at the location of the touch or proximity.\",\n \"A controller may process the change in capacitance to determine its position on the touch screen.\"\n ],\n [\n \"<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG.\",\n \"1 illustrates an example touch sensor with an example controller that may be used in certain embodiments of the present disclosure.\",\n \"FIG.\",\n \"2 illustrates an example device and example electrode tracks that may be used in certain embodiments of the present disclosure.\",\n \"FIG.\",\n \"3A illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"3B illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"3C illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"4A illustrates example touch points on an example touch sensor.\",\n \"FIG.\",\n \"4B illustrates a graph of example measurements that may be taken by certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"5A illustrates example touch points on an example touch sensor.\",\n \"FIG.\",\n \"5B illustrates a graph of example measurements that may be taken by certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"6A illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"6B illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"7A illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"7B illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"7C illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"8A illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"8B illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"9A illustrates an example switch network that may be used to configure clusters in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"9B illustrates an example switch network that may be used to configure clusters in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"10 illustrates an example method for use with certain embodiments of a touch sensor.\",\n \"detailed-description description=\\\"Detailed Description\\\" end=\\\"lead\\\"?\"\n ],\n [\n \"RELATED APPLICATION This application is a Continuation-In-Part of U.S. application Ser.\",\n \"No.\",\n \"13/955,352 titled “Dynamic Clustering Of Touch Sensor Electrodes,” Attorney's Docket 080900.2162, filed Jul.\",\n \"31, 2013, by Samuel Brunet et al., the content of which is hereby incorporated by reference.\",\n \"TECHNICAL FIELD This disclosure relates generally to touch sensor technology; and more particularly to dynamic configuration of touch sensor electrode clusters.\",\n \"BACKGROUND A touch sensor may detect the presence and location of a touch or the proximity of an object (such as a user's finger or a stylus) within a touch-sensitive area of the touch sensor overlaid on a display screen, for example.\",\n \"In a touch-sensitive-display application, the touch sensor may enable a user to interact directly with what is displayed on the screen, rather than indirectly with a mouse or touch pad.\",\n \"A touch sensor may be attached to or provided as part of a desktop computer, laptop computer, tablet computer, personal digital assistant (PDA), Smartphone, satellite navigation device, portable media player, portable game console, kiosk computer, point-of-sale device, or other suitable device.\",\n \"A control panel on a household or other appliance may include a touch sensor.\",\n \"There are a number of different types of touch sensors, such as (for example) resistive touch screens, surface acoustic wave touch screens, and capacitive touch screens.\",\n \"Herein, reference to a touch sensor may encompass a touch screen, and vice versa, in particular embodiments.\",\n \"When an object touches or corner within proximity of the surface of the capacitive touch screen, a change in capacitance may occur within the touch screen at the location of the touch or proximity.\",\n \"A controller may process the change in capacitance to determine its position on the touch screen.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS FIG.\",\n \"1 illustrates an example touch sensor with an example controller that may be used in certain embodiments of the present disclosure.\",\n \"FIG.\",\n \"2 illustrates an example device and example electrode tracks that may be used in certain embodiments of the present disclosure.\",\n \"FIG.\",\n \"3A illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"3B illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"3C illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"4A illustrates example touch points on an example touch sensor.\",\n \"FIG.\",\n \"4B illustrates a graph of example measurements that may be taken by certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"5A illustrates example touch points on an example touch sensor.\",\n \"FIG.\",\n \"5B illustrates a graph of example measurements that may be taken by certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"6A illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"6B illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"7A illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"7B illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"7C illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"8A illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"8B illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"9A illustrates an example switch network that may be used to configure clusters in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"9B illustrates an example switch network that may be used to configure clusters in certain embodiments of a touch sensor.\",\n \"FIG.\",\n \"10 illustrates an example method for use with certain embodiments of a touch sensor.\",\n \"The drawings included in the Figures are not drawn to scale.\",\n \"DESCRIPTION OF EXAMPLE EMBODIMENTS FIG.\",\n \"1 illustrates an example touch sensor 10 with an example controller 12, according to certain embodiments of the present disclosure.\",\n \"Touch sensor 10 and controller 12 may detect the presence and location of a touch or the proximity of an object within a touch sensitive area of touch sensor 10.Herein, reference to a touch sensor may encompass both the touch sensor and its controller, where appropriate.\",\n \"Similarly, reference to a controller may encompass both the controller and its touch sensor, where appropriate.\",\n \"Touch sensor 10 may include one or more touch-sensitive areas.\",\n \"Touch sensor 10 may include an array of drive and sense electrodes (or an array of electrodes of a single type) disposed on one or more substrates, which may be made of a dielectric material.\",\n \"Herein, reference to a touch sensor may encompass both the electrodes of the touch sensor and the substrate(s) that they are disposed on.\",\n \"Alternatively, reference to a touch sensor may encompass the electrodes of the touch sensor, but not the substrate(s) that they are disposed on.\",\n \"An electrode (whether a ground electrode, a guard electrode, a drive electrode, or a sense electrode) may be an area of conductive material forming a shape, such as for example a disc, square, rectangle, thin line, other suitable shape, or suitable combination of these.\",\n \"One or more cuts in one or more layers of conductive material may (at least in part) create the shape of an electrode, and the area of the shape may (at least in part) be bounded by those cuts.\",\n \"In particular embodiments, the conductive material of an electrode may occupy approximately 100% of the area of its shape.\",\n \"As an example and not by way of limitation, an electrode may be made of indium tin oxide (ITO) and the ITO of the electrode may occupy approximately 100% of the area of its shape (sometimes referred to as 100% fill), where appropriate.\",\n \"In particular embodiments, the conductive material of an electrode may occupy substantially less than 100% of the area of its shape.\",\n \"As an example and not by way of limitation, an electrode may be made of fine lines of metal or other conductive material (FLM), such as for example copper, silver, or a copper- or silver-based material, and the fine lines of conductive material may occupy approximately 5% of the area of its shape in a hatched, mesh, or other suitable pattern.\",\n \"Herein, reference to FLM encompasses such material, where appropriate.\",\n \"Where appropriate, the shapes of the electrodes (or other elements) of a touch sensor may constitute in whole or in part one or more macro-features of the touch sensor.\",\n \"One or more characteristics of the implementation of those shapes (such as, for example, the conductive material, fills, or patterns within the shapes) may constitute in whole or in part one or more micro-features of the touch sensor.\",\n \"One or more macro-features of a touch sensor may determine one or more characteristics of its functionality, and one or more micro-features of the touch sensor may determine one or more optical features of the touch sensor, such as transmittance, refraction, or reflection.\",\n \"A mechanical stack may contain the substrate (or multiple substrates) and the conductive material forming the drive or sense electrodes of touch sensor 10.As an example and not by way of limitation, the mechanical stack may include a first layer of optically clear adhesive (OCA) beneath a cover panel.\",\n \"The cover panel may be clear and made of a resident material suitable for repeated touching, such as for example glass, polycarbonate, or poly(methyl methacrylate) (PMMA).\",\n \"This disclosure contemplates any suitable cover panel made of any suitable material.\",\n \"The first layer of OCA may be disposed between the cover panel and the substrate with the conductive material forming the drive or sense electrodes.\",\n \"The mechanical stack may also include a second layer of OCA and a dielectric layer (which may be made of PET or another suitable material, similar to the substrate with the conductive material forming the drive or sense electrodes).\",\n \"As an alternative, where appropriate, a thin coating of a dielectric material may be applied instead of the second layer of OCA and the dielectric layer.\",\n \"The second layer of OCA may be disposed between the substrate with the conductive material making up the drive or sense electrodes and the dielectric layer, and the dielectric layer may be disposed between the second layer of OCA and an air gap to a display of a device including touch sensor 10 and controller 12.As an example only and not by way of limitation, the cover panel may have a thickness of approximately 1 mm; the first layer of OCA may have a thickness of approximately 0.05 mm; the substrate with the conductive material forming the drive or sense electrodes may have a thickness of approximately 0.05 mm; the second layer of OCA may have a thickness of approximately 0.05 mm; and the dielectric layer may have a thickness of approximately 0.05 mm.\",\n \"Although this disclosure describes a particular mechanical stack with a particular number of particular layers made of particular materials and having particular thicknesses, this disclosure contemplates any suitable mechanical stack with any suitable number of any suitable layers made of any suitable materials and having any suitable thicknesses.\",\n \"As an example and not by way of limitation, in particular embodiments, a layer of adhesive or dielectric may replace the dielectric layer, second layer of OCA, and air gap described above, with there being no air gap to the display.\",\n \"One or more portions of the substrate of touch sensor 10 may be made of polyethylene terephthalate (PET) or another suitable material.\",\n \"This disclosure contemplates any suitable substrate with any suitable portions made of any suitable material.\",\n \"In particular embodiments, the drive or sense electrodes in touch sensor 10 may be made of ITO in whole or in part.\",\n \"In particular embodiments, the drive or sense electrodes in touch sensor 10 may be made of fine lines or metal or other conductive material.\",\n \"As an example and not by way of limitation, one or more portions of the conductive material may be copper or copper-based and have a thickness of approximately 5 μm or less and a width of approximately 10 μm or less.\",\n \"As another example, one or more portions of the conductive material may be silver or silver-based and similarly have a thickness of approximately 5 μm or less and a width of approximately 10 μm or less.\",\n \"This disclosure electrodes made of any suitable material.\",\n \"As used herein, a capacitive node refers to a portion of touch sensor 10 that is configured to provide a distinct capacitive measurement.\",\n \"In various embodiments, capacitive nodes may have different sizes, shapes, and/or configurations.\",\n \"Furthermore, in some embodiments, the size, shape, and other aspects of a capacitive node may be determined by the configuration of controller 12 and may be changed dynamically during the operation of device 2.For example, in some embodiments, multiple tracks 14 may be galvanically connected and sensed together, resulting in a capacitive node spanning multiple electrodes.\",\n \"Furthermore, in some embodiments, such as the embodiment of FIG.\",\n \"8B, the electrodes of adjacent capacitive nodes may overlap and/or interleave.\",\n \"Touch sensor 10 may implement a capacitive form of touch sensing.\",\n \"In a mutual-capacitance implementation, touch sensor 10 may include an array of drive and sense electrodes forming an array of capacitive nodes.\",\n \"A drive electrode and a sense electrode may form a capacitive node.\",\n \"The drive and sense electrodes forming the capacitive node may come near each other, but not make electrical contact with each other.\",\n \"Instead, the drive and sense electrodes may be capacitively coupled to each other across a space between them.\",\n \"A pulsed or alternating voltage applied to the drive electrode (by controller 12) may induce a charge on the sense electrode, and the amount of charge induced may be susceptible to external influence (such as a touch or the proximity of an object).\",\n \"When an object touches or comes within proximity of the capacitive node, a change in capacitance may occur at the capacitive node and controller 12 may measure the change in capacitance.\",\n \"A touch may refer to an external object touching a capacitive node directly or touching a cover or substrate adjacent to the capacitive node.\",\n \"By measuring changes in capacitance throughout the array, controller 12 may determine the position of the touch or proximity within the touch-sensitive area(s) of touch sensor 10.In a self-capacitance implementation, touch sensor 10 may include an array of electrodes of a single type that may each form a capacitive node.\",\n \"In such embodiments, a capacitive node may correspond to a single electrode, or a set of multiple connected electrodes, rather than an intersection of tracks 14.When an object touches or comes within proximity of the capacitive node, a change in self-capacitance may occur at the capacitive node and controller 12 may measure the change in capacitance, for example, as a change in the amount of charge needed to raise the voltage at the capacitive node by a pre-determined amount.\",\n \"As with a mutual-capacitance implementation, by measuring changes in capacitance throughout the array, controller 12 may determine the position of the touch or proximity within the touch-sensitive area(s) of touch sensor 10.This disclosure contemplates any suitable form of capacitive touch sensing.\",\n \"In particular embodiments, one or more drive electrodes may together form a drive line running horizontally or vertically or in any suitable orientation.\",\n \"Similarly, one or more sense electrodes may together form a sense line running horizontally or vertically or in any suitable orientation.\",\n \"In particular embodiments, drive lines may run substantially perpendicular to sense lines.\",\n \"Herein, reference to a drive line may encompass one or more drive electrodes making up the drive line, and vice versa, where appropriate.\",\n \"Similarly, reference to a sense line may encompass one or more sense electrodes making up the sense line, and vice versa.\",\n \"Touch sensor 10 may have drive and sense electrodes disposed in a pattern on one side of a single substrate.\",\n \"In such a configuration, a pair of drive and sense electrodes capacitively coupled to each other across a space between them may form a capacitive node.\",\n \"For a self-capacitance implementation, electrodes of only a single type may be disposed in a pattern on a single substrate.\",\n \"In addition or as an alternative to having drive and sense electrodes disposed in a pattern on one side of a single substrate, touch sensor 10 may have drive electrodes disposed in a pattern on one side of a substrate and sense electrodes disposed in a pattern on another side of the substrate.\",\n \"Moreover, touch sensor 10 may have drive electrodes disposed in a pattern on one side of one substrate and sense electrodes disposed in a pattern on one side of another substrate.\",\n \"In such configurations, an intersection of a drive electrode and a sense electrode may form a capacitive node.\",\n \"Such an intersection may be a location where the drive electrode and the sense electrode“cross” or come nearest each other in their respective planes.\",\n \"The drive and sense electrodes do not make electrical contact with each other—instead they are capacitively coupled to each other across a dielectric at the intersection.\",\n \"In some embodiments, this dielectric may be air.\",\n \"Moreover, this disclosure contemplates electrodes disposed on any suitable number of substrates.\",\n \"As described above, a change in capacitance at a capacitive node of touch sensor 10 may indicate a touch or proximity input at the position of the capacities node.\",\n \"Controller 12 may detect and process the change in capacitance to determine the presence and location of the touch or proximity input.\",\n \"Controller 12 may then communicate information about the touch or proximity input to one or more other components (such one or more central processing units (CPUs)) of a device that includes touch sensor 10 and controller 12, which may respond to the touch or proximity input by initiating a function of the device (or an application running on the deviee).\",\n \"Although this disclosure describes a particular controller having particular functionality with respect to a particular device and a particular touch sensor, this disclosure contemplates any suitable controller having any suitable functionality with respect to any suitable device and any suitable touch sensor.\",\n \"Controller 12 may be one or more integrated circuits (ICs), such as for example general-purpose microprocessors, microcontrollers, programmable logic devices or arrays, application-specific ICs (ASICs).\",\n \"In particular embodiments, controller 12 comprises analog circuitry, digital logic, and digital non-volatile memory.\",\n \"In particular embodiments, controller 12 is disposed on a flexible printed circuit (FPC) bonded to the substrate of touch sensor 10, as described below.\",\n \"The FPC may be active or passive, where appropriate.\",\n \"In particular embodiments, multiple controllers 12 are disposed on the FPC.\",\n \"Controller 12 may include a processor unit, a drive unit, a sense unit, and a storage unit.\",\n \"The drive unit may supply drive signals to the drive electrodes of touch sensor 10.The sense unit may sense charge at the capacitive nodes of touch sensor 10 and provide measurement signals to the processor unit representing capacitances at the capacitive nodes.\",\n \"The processor unit may control the supply of drive signals to the drive electrodes by the drive unit and process measurement signals from the sense unit to detect and process the presence and location of a touch or proximity input within the touch-sensitive area(s) of touch sensor 10.The processor unit may also track changes in the position of a touch or proximity input within the touch-sensitive area(s) of touch sensor 10.The storage unit may store programming for execution by the processor unit, including programming for controlling the drive unit to supply drive signals to the drive electrodes, programming for processing measurement signals from the sense unit, and other suitable programming, where appropriate.\",\n \"Although this disclosure describes a particular controller having a particular implementation with particular components, this disclosure contemplates any suitable controller having any suitable implementation with any suitable components.\",\n \"Tracks 14 of conductive material disposed on the substrate of touch sensor 10 may couple the drive or sense electrodes of touch sensor 10 to connection pads 16, also disposed on the substrate of touch sensor 10.As described below, connection pads 16 facilitate coupling of tracks 14 to controller 12.Tracks 14 may extend into or around (e.g.\",\n \"at the edges of) the touch-sensitive area(s) of touch sensor 10.Particular tracks 14 may provide drive connections for coupling controller 12 to drive electrodes of touch sensor 10, through which the drive unit of controller 12 may supply drive signals to the drive electrodes.\",\n \"Other tracks 14 may provide sense connections for coupling controller 12 to sense electrodes of touch sensor 10, through which the sense unit of controller 12 may sense charge at the capacitive nodes of touch sensor 10.Tracks 14 may be made of fine lines of metal or other conductive material.\",\n \"As an example and not by way of limitation, the conductive material of tracks 14 may be copper or copper-based and have a width of approximately 100 μm or less.\",\n \"As another example, the conductive material of tracks 14 may be silver or silver-based and have a width of approximately 100 μm or less.\",\n \"In particular embodiments, tracks 14 may be made of ITO in whole or in part in addition or as an alternative to fine lines of metal or other conductive material.\",\n \"Although this disclosure describes particular tracks made of particular materials with particular widths, this disclosure contemplates any suitable tracks made of any suitable materials with any suitable widths.\",\n \"In addition to tracks 14, touch sensor 10 may include one or more ground lines terminating at a ground connector (which may be a connection pad 16) at an edge of the substrate of touch sensor 10 (similar to tracks 14).\",\n \"Connection pads 16 may be located along one or more edges of the substrate, outside the touch-sensitive area(s) of touch sensor 10.As described above, controller 12 may be on an FPC.\",\n \"Connection pads 16 may be made of the same material as tracks 14 and may be bonded to the FPC using an anisotropic conductive film (ACF).\",\n \"Connection 18 may include conductive lines on the FPC coupling controller 12 to connection pads 16, in turn coupling controller 12 to tracks 14 and to the drive or sense electrodes of touch sensor 10.In another embodiment, connection pads 16 may be connected to an electro-mechanical connector (such as a zero insertion force wire-to-board connector); in this embodiment, connection 18 may not need to include an FPC.\",\n \"This disclosure contemplates any suitable connection 18 between controller 12 and touch sensor 10.Certain embodiments of touch sensor 10 and controller 12 may measure capacitance or a change in capacitance using any suitable method.\",\n \"For example, voltage may be applied to one or more tracks 14 by opening or closing one or more switches associated with one or more tracks 14.Such switches may connect one or more tracks 14 to other portions of touch sensor 10 or controller 12 such as, for example, a voltage source (e.g.\",\n \"a voltage supply rail), a current source, or any other suitable component.\",\n \"Such methods may cause charge to be transferred to or from one or more portions of one or more tracks 14.In self-capacitance embodiments, the charged one or more tracks 14 may be sensed to measure a value associated with the capacitance of the one or more tracks 14.The presence of an object such as a finger or a stylus may change the amount of charge induced on the sensed track 14, and this change may be measured by controller 12 to determine the position of the object.\",\n \"The position may be a distance between the object and touch sensor 10 (e.g., a hover detection) and/or a projection of a portion of the object onto touch sensor 10 (e.g., a point on touch sensor 10 where the object is touching or hovering).\",\n \"Thus, in an embodiment where the surface of touch sensor 10 lies in the X-Y plane and the Z axis is orthogonal to the X-Y plane, the position may correspond to the X coordinates of the object, Y coordinates, Z coordinates, X-Y coordinates, X-Z coordinates, Y-Z coordinates, X-Y-Z coordinates, any reference position correlating with X, Y, or Z coordinates, or any other suitable position information.\",\n \"In certain embodiments, the same measured values may be used to determine both of the distance between the object and touch sensor 10 and the projection of a portion of the object onto touch sensor 10.Controller 12 may also factor in additional measurements and/or calculations to determine this position.\",\n \"For example, multiple tracks 14 may be sensed synchronously or in close succession, and the position of the object may be determined based on a calculation factoring in each of these measurements.\",\n \"Furthermore, certain embodiments may utilize weighted averages, linear approximation, or any suitable combination thereof to facilitate the determination of the object's position.\",\n \"Certain embodiments may perform measurements using any suitable number of steps that facilitate capacitance measurements.\",\n \"For example, some embodiments may perform any suitable combination of pre-charging one or more tracks 14, charging one or more tracks 14, transferring charge between two or more tracks 14, discharging one or more tracks 14, and/or any other suitable step.\",\n \"In some embodiments, a transfer of charge may be measured directly or indirectly.\",\n \"For example, certain embodiments may utilize voltage measurements, current measurements, timing measurements, any other suitable measurement, or any combination thereof to measure capacitance or a change in capacitance at one or more capacitive nodes.\",\n \"Furthermore, certain embodiments may utilize additional circuitry (such as, for example, one or more integrators, amplifiers, capacitors, switches, audio-to-digital converters, and/or any other suitable circuitry) to perform and/or enhance such measurements.\",\n \"Certain embodiments may measure a value at a particular point in time, measure a change in a value over time, and/or perform any other suitable processing to facilitate the determination of an object's position relative to touch sensor 10.FIG.\",\n \"2 illustrates an example device 20 and example electrode tracks 14 that may be used in certain embodiments of the present disclosure.\",\n \"In the illustrated embodiment, device 20 includes touch screen 10, which includes tracks 14.In some embodiments, multiple tracks 14 may be connected to form clusters 30 (not shown), which may strengthen the electric field created by tracks 14 to provide improved sensing.\",\n \"Furthermore, to provide improved precision, resolution, and/or linearity when detecting the position of a nearby object, clusters 30 may be interleaved temporally (as shown for example in the embodiments of FIGS.\",\n \"6A-6B and 7A-7C) and/or spatially (as shown for example in the embodiment of FIG.\",\n \"8B).\",\n \"Device 20 may be any touch-sensing device or component.\",\n \"In various embodiments, device 20 may be a smartphone, tablet computer, laptop computer, or any suitable device utilizing a touch sensor 10.Device 20 may include a display 21 that may be overlaid by or otherwise positioned proximate to touch sensor 10.Display 21 and touch sensor 10 may be substantially planar, curved, or have any other suitable configuration.\",\n \"Tracks 14 may include any structure, configuration, and/or function described above with respect to FIG.\",\n \"1.While the illustrated embodiment depicts certain tracks 14 running across display 21 perpendicular to certain other tracks 14, other embodiments may use any suitable configuration of tracks 14.For example, certain embodiments of tracks 14 may utilize different shapes, patterns, and/or configurations.\",\n \"Furthermore, certain embodiments may use different types, shapes, or configurations of tracks 14 within the same touch sensor 10.For example, in some embodiments, tracks 14 may be electrode “lines” that may be parallel, perpendicular or have any suitable orientation relative to other tracks 14.In alternative embodiments, which may include certain self-capacitance embodiments, tracks 14 may be non-linear electrodes, rather than intersecting “lines” such that each column and/or row of touch sensor 10 may include multiple tracks 14, each of which is separately connected or connectable to controller 12.In such embodiments, the sensing portion of track 14 may have any suitable shape (e.g., square, round, triangular, hexagonal, or any other suitable shape).\",\n \"Furthermore, such electrodes may be of a single type or multiple types, and each may form a capacitive node.\",\n \"As used herein, track 14 may refer to such electrodes, the track of conductive material connecting the electrode to controller 12, or both, as appropriate.\",\n \"In self capacitance embodiments, when an object touches or approaches a capacitive node, a change in self-capacitance may occur at the capacitive node and controller 12 may measure the change in capacitance.\",\n \"As a particular example, a change in capacitance may be measured as a change in the amount of charge needed to raise the voltage at the capacitive node by a pre-determined amount.\",\n \"By measuring changes in capacitance throughout the array of electrodes, controller 12 may determine the position of the touch or proximity within the touch-sensitive area(s) of touch sensor 10.Furthermore, multiple tracks 14 may be galvanically connected to form a cluster that can be sensed as a single capacitive node, which may increase the sensitivity of touch sensor 10 and/or reduce noise interference experienced by touch sensor 10.This disclosure contemplates any suitable form of capacitive touch sensing, where appropriate.\",\n \"For example, other embodiments may utilize mutual capacitance sensing.\",\n \"FIG.\",\n \"3A illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor 10.Touch sensor 10 includes clusters 30a and 30b and panel 32.In the illustrated embodiment, touch sensor 10 may detect the presence and/or position of object 34, which is located a distance 36a from touch sensor 10.Panel 32 may be any material proximate to tracks 14 and configured to be positioned between tracks 14 and object 34.Panel 32 may be glass, plastic, or any suitable material through which electric fields generated by tracks 14 may interact with object 34.In certain embodiments, panel 32 may be transparent, though this is not required.\",\n \"Panel 32 may be formed as a separate layer from tracks 14, and in such embodiments, panel 32 may be affixed to a portion of touch sensor 10 via an adhesive.\",\n \"In some embodiments, panel 32, tracks 14, and/or one or more substrates may be integrally formed.\",\n \"Clusters 30a and 30b include tracks 14a-14c and tracks 14f-14j, respectively.\",\n \"A used herein, a “cluster” may refer to a single track 14 or multiple tracks 14 connected such that they can be charged and/or sensed as a single unit.\",\n \"In some embodiments, tracks 14 may be “connected” by galvanically connecting the tracks 14, though any suitable method of connecting tracks 14 may be used (e.g., multiple tracks 14 may be sensed together by capacitively coupling the tracks 14 via a sufficiently large capacitance).\",\n \"Furthermore, the one or more tracks 14 forming a cluster 30 may include any type, structure, and/or configuration discussed above with respect to tracks 14 of FIGS.\",\n \"1 and 2.For example, certain embodiments may include a cluster 30 of parallel tracks, perpendicular tracks, or both.\",\n \"As another example, certain embodiments may include one or more non-linear self-capacitance electrodes of one or more tracks 14.Thus, clusters 30 may be a set of one or more linear electrode tracks 14, a set of non-linear electrodes, or any suitable configuration of electrodes.\",\n \"As a particular example, the electrodes of cluster 30 may form a triangle, square, hexagon, or other geometric shape from a perspective orthogonal to the surface of touch sensor 10.In some embodiments, a cluster 30 may include all tracks 14 of touch sensor 10.The tracks 14 of a cluster may be adjacent, though this is not required.\",\n \"Furthermore, multiple clusters 30 may be sensed simultaneously or in close succession, which may allow controller to determine the position of object 34 taking into account multiple values.\",\n \"Clusters 30 may include adjacent tracks and/or non-adjacent tracks 14.In the illustrated embodiment, clusters 30a and 30b each include five galvanically connected electrode tracks 14.In other embodiments, clusters 30 may have more or fewer tracks 14.Such tracks 14 may be galvanically connected by, for example, using various switches of controller 12.Galvanically connecting tracks 14 to form clusters 30 in this manner may increase the sensitivity of touch sensor 10, which may enable detection of the presence and/or position of object 34 at greater distances from touch sensor 10.Such embodiments may also reduce noise interference experienced during the sensing sequence since a stronger signal may be generated relative to the noise effects impacting the measured capacitance values.\",\n \"Galvanically connecting tracks 14 to form clusters 30 may result in improved noise protective compared to touch sensors that sum measurements of the individual tracks 14, because such touch sensors may also effectively sum the noise interference experienced by the tracks 14.Object 34 may be any external object whose presence and/or position may be detected by tough sensor 10.Object 34 may be a finger, hand, stylus, or any suitable object.\",\n \"In the illustrated embodiment, object 34 is a finger located distance 36a from touch sensor 10.As used herein, a distance from tough sensor 10 may refer to the distance between object 34 and panel 32, tracks 14, or any suitable portion of touch sensor 10.Ranges 38a-38c may be any suitable ranges corresponding to positions of object 34 that may trigger a change in the configuration of clusters 30, as explained further below.\",\n \"For example, range 38a may be 8-20 mm and may be associated with a cluster size of five tracks 14, range 38b may be 4-10 mm and may be associated with a cluster size of three tracks 14, and range 38c may be 0-5 mm and may be associated with a cluster size of two tracks 14.Other embodiments may use any suitable values for range 38.Furthermore, various embodiments may use any number of range 38, which may be associated with any suitable cluster size.\",\n \"For example, a particular embodiment may have separate ranges associated with clusters of size 1-10.Furthermore, certain embodiments may not explicitly calculate an estimated distance of object 34 from touch sensor 10.For example, certain embodiments may change cluster configurations based directly on one or more measured capacitance values (rather than using those values to determine distance 36 and then using distance 36 to determine the cluster configuration).\",\n \"Thus, in some embodiments, changes in the configuration of clusters 30 may not directly correspond to the distance of object 34 from touch sensor 10.As a particular example, different objects 34 at the same distance from touch sensor 10 may result in different capacitance values measured by a single cluster 30.As another example, some embodiments may factor in the relative measurements from multiple clusters 30 in determining the appropriate cluster configuration, so different objects 34 (for example, a fingertip vs. a hand) at the same distance from touch sensor 10 and causing the same capacitive measurement at a single cluster 30 may nevertheless trigger different cluster configurations.\",\n \"In operation, tracks 14a -14c are connected to form cluster 30a, and tracks 14f-14j are connected to form cluster 30b.\",\n \"This connection may be a galvanic connection.\",\n \"Voltage is applied to cluster 30a and 30b, and a capacitance value associated with each cluster 30 is determined using any suitable sensing method described above with respect to FIGS.\",\n \"1 and 2.Clusters 30a and 30b may be sensed synchronously or sequentially.\",\n \"Based on the measured values, controller 12 may determine a distance between object 34 and touch sensor 10.Based on the measured distance, controller 12 may maintain the same cluster configuration or switch to a different cluster configuration.\",\n \"For example, controller 12 may determine whether the measured distance falls in one or more ranges 38.In the illustrated embodiment, distance 36a falls within range 38a.\",\n \"As object 34 moves to distance 36b from touch sensor 10, controller 12 may determine that object 34 has moved within range 38b and transition to the cluster configuration shown in FIG.\",\n \"3B.\",\n \"Any suitable cluster configuration and/or range may be used.\",\n \"FIG.\",\n \"3B illustrates an example cluster configuration that may be used in certain embodiments of touch sensor 10.Touch sensor 10 includes clusters 30a, 30b, and 30c and panel 32.In the illustrated embodiment, touch sensor 10 may detect the presence and/or position of object 34, which is located a distance 36b from touch sensor 10.Clusters 30a, 30b, and 30c include tracks 14a-14c, tracks 14d-14f, and tracks 14g-14i, respectively.\",\n \"Track 14j may be part of an additional cluster 30 that is not shown.\",\n \"In the illustrated embodiment, clusters 30a-30c each include three galvanically connected electrode tracks 14.Such tracks 14 may be galvanically connected by, for example, using various switches of controller 12.Connecting tracks 14 to form clusters 30 in this manner may increase the sensitivity of touch sensor 10, which may enable detection of the presence and/or position of object 34 at greater distances from touch sensor 10.Clusters of three tracks 14 may be more sensitive than clusters of two tracks 14 (see, e.g., FIG.\",\n \"3C) but less sensitive than clusters of live tracks 14 (see, e.g., FIG.\",\n \"3A).\",\n \"Certain embodiments may reduce noise interference experienced during the sensing sequence since a stronger signal may be generated relative to the noise effects impacting the measured capacitance values.\",\n \"Connecting tracks 14 to form clusters 30 may result in improved noise protection compared to touch sensor than sum measurements of the individual tracks 14, because such touch sensors may also effectively sum the noise interference experienced by the tracks 14.In the illustrated embodiment, object 34 is located distance 36b from touch sensor 10, which falls within range 38b.\",\n \"Controller 12 may configure clusters 30 as shown in FIG.\",\n \"3B in response to determining that the measured distance 36b falls within range 38b.\",\n \"If the measured distance 36 fell below a threshold value to move within range 38c, controller may configure clusters 30 as shown in FIG.\",\n \"3C.\",\n \"If the measured distance 36 is increased above a threshold value to move within range 38a, controller may configure clusters 30 as shown in FIG.\",\n \"3A.\",\n \"Any suitable cluster configuration and/or range may be used.\",\n \"FIG.\",\n \"3C illustrates an example cluster configuration that may be used in certain embodiments of a touch sensor.\",\n \"Touch sensor 10 includes clusters 30a-30c and panel 32.In the illustrated embodiment, touch sensor 10 may detect the presence and/or position of object 34, which is located a distance 36c from touch sensor 10.Clusters 30a-30e include tracks 14a-14b, tracks 14c-14d, tracks 14e-14f, tracks 14g-14h, and tracks 14i-14j, respectively.\",\n \"In the illustrated embodiment, clusters 30a-30 e each include two connected electrode tracks 14.Such tracks 14 may be galvanically connected by, for example, using various switches of controller 12.Galvanically connecting tracks 14 to form clusters 30 in this manner may increase the sensitivity of touch sensor 10, which may enable detection of the presence and/or position of object 34 at greater distances from touch sensor 10.Clusters of two tracks 14 may be more sensitive than clusters of a single track 14 (which may correspond to traditional sensing methods) but less sensitive than clusters using a greater number of tracks 14 (see, e.g., FIGS.\",\n \"3A and 3B).\",\n \"Certain embodiments may reduce noise interference experienced during the sensing sequence since a stronger signal may be generated relative to the noise effects impacting the measured capacitance values.\",\n \"Connecting tracks 14 to form clusters 30 may result in improved noise protection compared to touch sensors that sum measurements of the individual tracks 14, because such touch sensors may also effectively sum the noise interference experienced by the tracks 14.In the illustrated embodiment, object 34 is located distance 36c from touch sensor 10, which falls within range 38c.\",\n \"Controller 12 may configure clusters 30 as shown in FIG.\",\n \"3C in response to determining that the measured distance 36c falls within range 38c.\",\n \"If the measured distance 36 is increased to move within range 38b, controller may configure clusters 30 as shown in FIG.\",\n \"3B.\",\n \"If the measured distance 36 increased to move within range 38a, controller may configure clusters 30 as shown in FIG.\",\n \"3A.\",\n \"Other embodiments may utilize any suitable ranges and any suitable configuration of clusters 30.FIG.\",\n \"4A illustrates example touch points 40 on an example touch sensor 10.Touch sensor 10 includes panel 32 and clusters 30a and 30b.\",\n \"Clusters 30a and 30b include tracks 14a and 14b and tracks 14c and 14d, respectively.\",\n \"Panel 32, clusters 30, and tracks 14 may have any suitable structure, configuration, and/or function described above with respect to FIGS.\",\n \"1, 2, and 3A-3C.\",\n \"Touch points 40a-40c represent a position of object 34 (not shown) moving from left to right across touch sensor 10.Touch points 40 may be positions where a portion of object 34 physically touches touch sensor 10, or they may be orthogonal projections of a portion of object 34 onto touch sensor 10.In the illustrated embodiments, touch points 40a-40c each fall directly above a portion of cluster 30a.\",\n \"Because tracks 14a and 14b of cluster 30a may be galvanically connected and sensed together during the sensing sequence, the similar capacitance values measured at touch points 40a-40c (see FIG.\",\n \"4B) may reduce the linearity of the measured position of object 34 as it moves across touch sensor 10.This issue is described further with respect to FIGS.\",\n \"4B, 5A, and 5B.\",\n \"This potential for reduced precision may be mitigated by cluster configurations discussed below with respect to FIGS.\",\n \"7A-7C.\",\n \"FIG.\",\n \"4B illustrates a graph of example measurements 44 and 46 that may be taken by certain embodiments of touch sensor 10.Measurements 42a, which include measurements 44a-44c, correspond to measurements associated with cluster 30a or FIG.\",\n \"4A.\",\n \"Measurements 42b, which include measurements 46a-46c, correspond to measurements associated with cluster 30b of FIG.\",\n \"4A.\",\n \"Measurements 42a represent values measured by cluster 30a of FIG.\",\n \"4A, and measurements 42b represent values measured by cluster 30b of FIG.\",\n \"4A.\",\n \"Measurements 44a-44c correspond to the values measured by cluster 30a at touch points 40a-40c, respectively, and measurements 46a-46c correspond to the values measured by cluster 30b at touch points 40a-40c, respectively.\",\n \"As discussed above, controller 12 may evaluate multiple measurements to determine the position of object 34.For example, the measured position of object 34 may be based on capacitive values measured by multiple clusters 30.Thus, as a particular example, the position of object 34 when object 34 is located at touch point 40a may be determined using measurements 44a and 46a (as well as values measured by other clusters 30).\",\n \"Furthermore, the position of object 34 may also be determined by taking into account previously measured values.\",\n \"Thus, as a particular example, the position of object 34 when object 34 is located at touch point 40c may be determined using measurements 44c and 46c as well as values measured during previous sensing sequences, such as 44b and 46b.\",\n \"Because tracks 14a and 14b of cluster 30a may be galvanically connected and sensed together during the sensing sequence, values measured when object 34 is located at touch points 40a-40c may not be sufficiently distinct to precisely distinguish between these touch points 40.Such measurement difficulties may be particular pronounced when clusters 30 include larger numbers of tracks 14.FIG.\",\n \"5A illustrates example touch points 50 on an example touch sensor 10.Touch sensor 10 includes panel 32 and clusters 30aand 30b.\",\n \"Clusters 30a and 30b include tracks 14a and 14b and tracks 14c and 14d, respectively.\",\n \"Panel 32, clusters 30, and tracks 14 may have any suitable structure, configuration, and/or function described above with respect to FIGS.\",\n \"1, 2, and 3A-3C.\",\n \"Touch points 50a-50c represent a position of object 34 (not shown) moving from left to right across touch sensor 10.Touch points 50 may be positions where a portion of object 34 physically touches touch sensor 10, or they may be orthogonal projections of a portion of object 34 onto touch sensor 10.In the illustrated embodiments, touch points 50a-50c move from left to right, moving from cluster 30a to cluster 30b.\",\n \"Because clusters 30a and 30b are not galvanically connected during their respective sensing sequences, capacitive values measured when object 34 is at touch points 50a-50c may provide improved touch resolution.\",\n \"For example, such embodiments may provide increased linearity when determining the position of object 34 as it moves across touch sensor 10 in a straight line.\",\n \"Certain embodiments may take advantage of improved touch-sensing precision at the borders of clusters 30 by utilizing cluster configurations discussed below with respect to FIGS.\",\n \"6-9.FIG.\",\n \"5B illustrates a graph of example measurements 44 that may be taken by certain embodiments of touch sensor 10.Measurements 52a, which include measurements 54a-54c, correspond to measurements associated with cluster 30a of FIG.\",\n \"5A.\",\n \"Measurements 52b, which include measurements 56a-56c, correspond to measurements associated with cluster 30b of FIG.\",\n \"5A.\",\n \"Measurements 52a represent values measured by cluster 30a of FIG.\",\n \"5A, and measurements 52b represent values measured by cluster 30b of FIG.\",\n \"5A.\",\n \"Measurements 54a-54c correspond to the values measured by cluster 30a at touch points 50a-50c, respectively, and measurements 56a-56c correspond to the values measured by cluster 30b at touch points 50a-50c, respectively.\",\n \"As discussed above, controller 12 may evaluate multiple measurements to determine the position of object 34.For example, the measured position of object 34 may be based on capacitive values measured by multiple clusters 30.Thus, as a particular example, the position of object 34 when object 34 is located at touch point 50a may be determined using measurements 54a and 56a (as well as values measured by other clusters 30).\",\n \"Furthermore, the position of object 34 may also be determined by taking into account previously measured values.\",\n \"Thus, as a particular example, the position of object 34 when object 34 is located at touch point 50c may be determined using measurements 54c and 56c as well as values measured during previous sensing sequences, such as 54b and 56b.\",\n \"Because clusters 30a and 30b may be sensed separately, values measured when object 34 is located at touch points 50a-50c may be sufficiently distinct to precisely distinguish between these touch points 50.Certain embodiments may take advantage of this improved touch-sensing precision at the borders of clusters 30 by utilizing cluster configurations discussed below with respect to FIGS.\",\n \"6-9.FIGS.\",\n \"6A and 6B illustrate example cluster configurations that may be used in certain embodiments of touch sensor 10.In the illustrated embodiments, touch sensor 10 includes panel 32 and tracks 14a-j.\",\n \"In FIG.\",\n \"6A, tracks 14 are configured to form clusters 30a and 30b, which include tracks 14a-d and tracks 14e-h, respectively.\",\n \"In FIG.\",\n \"6B, tracks 14 are configured to form clusters 30c and 30d, which include tracks 14c-f and tracks 14g-i, respectively.\",\n \"For purposes of simplified illustration, FIGS.\",\n \"6A and 6B depict only two clusters 30.However, touch sensor 10 may be configured to include additional clusters 30 using tracks 14 that are not used in the illustrated clusters 30.For example, in FIG.\",\n \"6A, tracks 14i and 14j may operate as part of additional clusters 30 (not shown) or may operate independently (e.g., tracks 14i and 14j may be sensed individually without being clustered with other tracks 14).\",\n \"Panel 32, clusters 30, and tracks 14 may have any suitable structure, configuration, and/or function described above with respect to FIGS.\",\n \"1, 2, and 3A-3C.\",\n \"FIGS.\",\n \"6A and 6B illustrate two cluster configurations that may be used in succession during a “rolling cluster” sequence.\",\n \"As used herein, a rolling cluster sequence refers to a sequential shifting of the configuration of clusters 30.As explained above with respect to FIGS.\",\n \"4A-4B and 5A-5B, the position of object 34 may be more precisely determined when located at or near the intersection of clusters 30.Utilizing rolling clusters may increase the likelihood that object 34 is positioned at or near the intersection of two or more clusters 30, which may improve the precision, resolution, and/or linearity of touch-sensor 10.Such improvements may be particular useful when utilizing cluster configurations with larger numbers of tracks 14 per cluster 30.Determination of the position of object 34 may be based on measurements from a single cluster pattern (e.g., the clusters 30 shown in FIG.\",\n \"6B), or the position may be based on a multiple cluster patterns (e.g., the clusters 30 shown in both FIGS.\",\n \"6A and 6B).\",\n \"A rolling cluster sequence may involve two or more sequential cluster patterns.\",\n \"For example, FIGS.\",\n \"6A-6B illustrate a rolling cluster sequence that may use two cluster patterns, and FIGS.\",\n \"7A-7C illustrate a rolling cluster sequence that may use three cluster patterns.\",\n \"Other embodiments may use any suitable configuration of clusters 30 in any suitable rolling cluster sequence.\",\n \"For example, some embodiments may used larger cluster sizes and/or different cluster shapes.\",\n \"As another example, some embodiments may use different numbers of cluster patterns in a single rolling cluster sequence (e.g., four, five, six, or more difference cluster patterns used sequentially), and some embodiments may cycle through cluster patterns in different orders.\",\n \"As used herein, a “cluster pattern” refers to a particular configuration of cluster 30 at a particular point in time or during a particular span of time.\",\n \"In certain embodiments, controller 12 may sequentially alter the configuration of clusters 30.For example, tracks 14a-14d may be galvanically connected and sensed as cluster 30a, and tracks 14e-14h may be galvanically connected and sensed as cluster 30b, as shown in FIG.\",\n \"6A.\",\n \"After measuring capacitance values associated with this configuration tracks 14c-14f may be galvanically connected and sensed as cluster 30c, and tracks 14g-14j may be galvanically connected and sensed as cluster 30d, as shown in FIG.\",\n \"6B.\",\n \"Controller 12 may determine the position of object 34 using the various capacitance values associated with these rolling clusters.\",\n \"For example, controller 12 may compare values measured by different clusters 30.As another example, controller 12 may calculate one or representative values that may indicate the position of object 34 relative to touch sensor 10.As a particular example, controller 12 may calculate a representative value for each track 14 based on the capacitance values measured from clusters 30.For example, a representative value for a particular track 14 may be calculated based on the capacitance value measured from each cluster 30 to which it belonged, and the relative representative values of tracks 14 (e.g.\",\n \"the shape of a plot of the representative values) may indicate the position of object 34.One ore more additional calculations may also be used, such as, for example, weighted averages, linear approximation, and balanced position techniques.\",\n \"Rolling clusters may improve the precision, resolution, and/or linearity of touch sensors 10 utilizing clusters 30 that include multiple tracks 14.Such embodiments may enable touch sensor 10 to provide improved sensitivity resulting from clustering tracks 14, as described above, while also avoiding potential reductions in precision, resolution, and/or linearity (as described with respect to FIGS.\",\n \"4A and 4B) that might otherwise be created by such clustering.\",\n \"FIGS.\",\n \"7A-7C illustrate example cluster configurations that may be used in certain embodiments of touch sensor 10.Touch sensor 10 includes panel 32 and clusters 30a and 30b.\",\n \"In FIG.\",\n \"7A, clusters 30a and 30b include tracks 14a-14c and tracks 14d-14f, respectively.\",\n \"In FIG.\",\n \"7B, clusters 30c and 30d include tracks 14b-14d and tracks 14e-14g, respectively.\",\n \"In FIG.\",\n \"7C, clusters 30e and 30f include tracks 14c-14e and tracks 14f-14h, respectively.\",\n \"For purposes of simplified illustration, FIGS.\",\n \"7A-7C depict only clusters 30a and 30b.\",\n \"However, touch sensor 10 may include additional clusters 30 using tracks 14 that are not used in the illustrated clusters 30.For example, in FIG.\",\n \"7A, tracks 14g-I may operate as part of an additional cluster 30 (not shown) or may operate independently (e.g., tracks 14g-I may be sensed individually without being clustered with other tracks 14).\",\n \"Panel 32, clusters 30, and tracks 14 may have any suitable structure, configuration, and/or function described above with respect to FIGS.\",\n \"1, 2, 3A-3C, 6A-6B, and 7A-7C.\",\n \"FIGS.\",\n \"7A-7C illustrate three cluster configurations that may be used in succession during a rolling cluster sequence.\",\n \"These configurations may be used in embodiments utilizing rolling clusters that shift clusters 30 successively by a single track 14.As explained above with respect to FIGS.\",\n \"4A-4B, 5A-5B, and 6A-6B, the position of object 34 may be more precisely determined when located at or near the intersection of clusters 30.Utilizing rolling clusters may increase the likelihood that object 34 is positioned at or near the intersection of two or more clusters 30, which may improve the precision, resolution, and/or linearity of touch-sensor 10.Such improvements may be particular useful when utilizing cluster configurations with larger numbers of tracks 14 per cluster 30.Furthermore, utilizing rolling clusters that shift by a single track 14 may further improve the precision, resolution, and/or linearity of much sensing measurements.\",\n \"In certain embodiments, controller 12 may sequentially alter the configuration of clusters 30.For example, tracks 14a-14c may be galvanically connected and sensed as cluster 30a, and tracks 14d-14f may be galvanically connected and sensed as cluster 30b, as shown in FIG.\",\n \"7A.\",\n \"After measuring capacitance values associated with this configuration, tracks 14b-14d may be galvanically connected and sensed as cluster 30c, and tracks 14e-14g may be galvanically connected and sensed as cluster 30d, as shown in FIG.\",\n \"7B.\",\n \"After measuring capacitance values associated with this configuration, tracks 14c-14e may be galvanically connected and sensed as cluster 30e, and tracks 14f-14h may be galvanically connected and sensed as cluster 30f, as shown in FIG.\",\n \"7C.\",\n \"Controller 12 may determine the position of object 34 using the various capacitance values associated with these rolling clusters.\",\n \"For example, controller 12 may compare values measured by different clusters 30.As another example, controller 12 may calculate one or representative values that may indicate the position of object 34 relative to touch sensor 10.As a particular example, controller 12 may calculate a representative value for each track 14 based on the capacitance values measured from clusters 30.For example, a representative value for a particular track 14 may be calculated based on the capacitance value measured from each cluster 30 to which it belonged, and the relative representative values of tracks 14 (e.g.\",\n \"the shape of a plot of the representative values) may indicate the position of object 34.One or more additional calculations may also be used, such as, for example, weighted averages, linear approximation, and balanced position techniques.\",\n \"Rolling clusters may improve the precision, resolution, and/or linearity of touch sensors 10 utilizing clusters 30 that include multiple tracks 14.Such embodiments may enable touch sensor 10 to provide improved sensitivity resulting from clustering tracks 14, as described above, while also avoiding potential reductions in precision, resolution, and/or linearity (as described with respect to FIGS.\",\n \"4A and 4B) that might otherwise be created by such clustering.\",\n \"FIGS.\",\n \"8A and 8B an example cluster configurations that may be used in certain embodiments of touch sensor 10.Touch sensor 10 includes panel 32 and clusters 30a-c.\",\n \"In FIG.\",\n \"8A, cluster 30a includes tracks 14a-14d, cluster 30b and tracks 14e-14h, and cluster 30c includes tracks 14i-14k.\",\n \"Cluster 30c may also include additional tracks 14 (not shown).\",\n \"For purposes of simplified illustration, FIG.\",\n \"8A depicts only clusters 30a-30c.\",\n \"However, touch sensor 10 may include additional clusters 30 using tracks 14 that are not used in the illustrated clusters 30.Panel 32, clusters 30, and tracks 14 may have any suitable structure, configuration, and/or junction described above with respect to FIGS.\",\n \"1, 2, and 3A-3C.\",\n \"FIG.\",\n \"8B illustrates an example interleaved cluster configuration that may be used in certain embodiments.\",\n \"In FIG.\",\n \"8B, cluster 30d includes tracks 14b, 14c, and 14e; cluster 30e includes tracks 14d, 14f-14g, and 14i; and cluster 30f includes tracks 14h, and 14j-14k.\",\n \"Clusters 30d and 30f may include additional tracks 14 (not shown).\",\n \"For purposes of simplified illustration, FIG.\",\n \"8B depicts only clusters 30d-30f.\",\n \"However, touch sensor 10 may include additional clusters 30 using tracks 14 that are not used in the illustrated clusters 30.Panel 32, clusters 30, and tracks 14 may have any suitable structure, configuration, and/or function described above with respect to FIGS.\",\n \"1, 2, 3A-3C, 6A-6B, and 7A-7C.\",\n \"As used herein, “interleaved clusters” refers in clusters 30 having one or more tracks 14 interspersed within the outer boundary of another cluster 30 from a perspective orthogonal to the surface of touch sensor 10.Interleaved clusters may have any suitable number and/or arrangement of tracks 14 that are interleaved with the tracks 14 of another cluster 30.FIG.\",\n \"8B illustrates a particular pattern of interleaved clusters 30, and other embodiments may use any suitable interleaving patterns.\",\n \"Interleaving the edges of clusters 30 as shown in FIG.\",\n \"8B may provide improved linearity when measuring an object moving across the surface of touch sensor 10 while touching or hovering near device 2.Such embodiments may mitigate potential redactions in precision, resolution, and/or linearity (as described with respect to FIGS.\",\n \"4A and 4B) that might otherwise be created by clustering of tracks 14.In some embodiments, interleaved cluster configurations, such as the configuration illustrated in FIG.\",\n \"8B, may be triggered by one or more previous measurements.\",\n \"For example, one or more measurements from clusters 30 of FIG.\",\n \"8A may trigger the interleaved cluster configuration of FIG.\",\n \"8B.\",\n \"Such embodiments may allow touch sensor 10 to achieve improved precision, resolution, and/or linearity when certain conditions are detected.\",\n \"For example, interleaved configurations may be triggered when controller 12 detects sufficiently nonlinear readings of the position of object 34, which may indicate that measurements of the position of object 34 have sub-optimal linearity in detecting the movement of object 34.Furthermore, in some embodiments, interleaved cluster configurations may be used in conjunction with rolling clusters.\",\n \"For example, a rolling cluster may be used with the configuration shown in FIG.\",\n \"8B such that clusters 30d-f effectively “shift” along touch sensor 10, analogous to the “shifting” of clusters 30 illustrated in FIGS.\",\n \"6A-B and 7A-7C.\",\n \"In other embodiments, interleaved cluster configurations may be used in conjunction with the alteration of cluster sizes illustrated shown in FIGS.\",\n \"3A-C. For example, when object 34 is detected at shorter distances from touch sensor 10 (e.g., distance 36b of FIG.\",\n \"3B), smaller cluster sizes and non-interleaved clusters may be used, and when object 34 is detected at longer distances from touch sensor 10 (e.g., distance 36a of FIG.\",\n \"3B) larger cluster sizes and interleaved clusters may be used.\",\n \"Such embodiments may allow touch sensor 10 to target the use of linearity-improving configurations more precisely to situations in which the linearity of its sensing may be reduced.\",\n \"FIGS.\",\n \"9A and 9B illustrate an example switch network 90 that may be used to configure clusters 30 in certain embodiments of touch sensor 10 and controller 12.In the illustrated embodiment, touch sensor 10 includes panel 32 and tracks 14a-14k, which form clusters 30a-30c; and controller 12 includes switch network 90 and measurement channels 96.Panel 32, clusters 30, and tracks 14 may have any suitable structure, configuration, and/or function described above with respect to FIGS.\",\n \"1, 2, 3A-3C, 6A-6B, 7A-7C, and 8A-8B.\",\n \"Switch network 90 may include any number, arrangement, and/or configuration of switches that are operable to connect one or more tracks 14 to one or more measurement channels 96.Switch network 90 may be configured by controller 12 during the operation of touch sensor 10.For example, controller 12 may control switch network 90 to form the cluster patterns shown in FIGS.\",\n \"3A-C, 6A-6B, 7A-7C, and 8A-8B.\",\n \"Certain embodiments may use any suitable switch network 90, and the configuration shown in FIGS.\",\n \"9A-B is used merely as an example.\",\n \"For example, cluster patterns shown in FIGS.\",\n \"6A-6B and 7A-7C may be configured using switch network 90 shown in FIGS.\",\n \"9A-B, while the cluster pattern shown in FIG.\",\n \"8B may rely on a more complex switch network 90 to facilitate the configuration of interleaved clusters 30.In the illustrated embodiments, switch network 90 includes switches 92 and 94.Switches 92 and 94 may be any suitable circuitry operable to connect or disconnect one or more tracks 14 from a portion of controller 12.For example, switches 92 and 94 may be any appropriate form of mechanical and/or electrical switching device operable to conduct current in the on position and/or form an open circuit in the off position.\",\n \"As a particular example, switches 92 and 94 may be any appropriate form of transistor device, including field effect transistors (FETS).\",\n \"In some embodiments, switches 92 and 94 may be implemented using metal oxide-semiconductor FETS (MOSFETS), such as NMOS or PMOS transistors.\",\n \"The gates of switches 92 and 94 may be controlled via one or more control signals transmitted from controller 12.Switches 92 and 94 may be part of touch sensor 10 and/or controller 12, and touch sensor 10 and/or controller 12 may have any suitable number, type, and/or configuration of switches 92 and 94.Measurement channels 96 represent portions of controller 12 operable to receive and/or transmit signals to one or more tracks 14 to facilitate the taking of one or more capacitive measurements.\",\n \"Measurement channels 96 may include any components and may perform any measurement functionality described above with respect to controller 12 in FIG.\",\n \"1.In some embodiments, different measurement channels 96 may be physically distinct.\",\n \"In other embodiments, measurement channels 96 may be logically distinct while sharing one or more common physical components.\",\n \"For example, each measurement channel 96 may include distinct measurement circuitry, or one or more portions of measurement channels 96 may operate as a multiplexer, connecting one or multiple inputs to common measurement circuitry.\",\n \"Switches 92 may operate to galvanically connect the tracks 14 of a particular cluster 30, while switches 94 may operate to connect a particular cluster 30 to a particular measurement channel 96.For example, as shown in FIG.\",\n \"9A, switches 92a-92b are closed, and switch 92c is open, thereby galvanically connecting tracks 14a-c to form cluster 30.Furthermore, switch 94a is closed, and switches 94b-94c are open, thereby connecting cluster 30a to measurement channel 96a.\",\n \"Similarly, switches 92d-92e and switch 94d are closed to form cluster 30b and connect it to measurement channel 96d, and switches 92g-92h and switch 94g are closed to form cluster 30f and connect it to measurement channel 96g.\",\n \"Analogous configurations may be used to form additional clusters 30 and to connect them to their respective measurement channels 96.Furthermore, switches 94j-94k are open, thereby disconnecting tracks 14j-14k from any measurement channel 96.Such embodiments may be used to prevent tracks 14 that are not included in a cluster 30 from being measured, though this is not required.\",\n \"For example, other embodiments may connect tracks 14 that are not included in a cluster 30 to a measurement channel 96.As shown in FIG.\",\n \"9B, altering the state of switch network 90 may form different clusters 30 and/or connect clusters 30 to different measurement channels.\",\n \"FIG.\",\n \"9B illustrates a configuration of switch network 90 that may be used to form clusters 30d-30f.\",\n \"Such configurations may facilitate the “shifting” of clusters described above with respect to FIGS.\",\n \"6A-6B and FIGS.\",\n \"7A-7C, which may be used during rolling cluster sensing sequences.\",\n \"In the illustrated embodiment, switches 92a and 92d are opened and switches 92b-92c are closed to form cluster 30d.\",\n \"Furthermore, switch 94b is closed to connect cluster 30d to measurement channel 96b.\",\n \"Similarly, switches 92e-92f and switch 94e are closed to form cluster 30e and connect it to measurement channel 96e, and switches 92h-92i and switch 94h are closed to form cluster 30f and connect it to measurement channel 96h.\",\n \"Switch network 90 may therefore facilitate alterations of the configurations of clusters 30 to improve the sensitivity of touch sensor 10 and/or provide improved precision, resolution, and/or linearity when touch sensor 10 is detecting the movement of object 34.FIG.\",\n \"10 illustrates an example method for use with certain embodiments of touch sensor 10.Various embodiments may perform some, all, or none of the steps described below.\",\n \"Furthermore, certain embodiments may perform these steps in different orders or in parallel, and certain embodiments may also perform additional steps.\",\n \"Moreover, any suitable component of touch sensor 10 and/or controller 12 may perform one or more steps of the sensing sequence.\",\n \"At step 100, controller 12 connects tracks 14 to form a first cluster pattern.\",\n \"Tracks 14 may be connected galvanically, capacitively, or using any suitable method.\",\n \"The first cluster pattern may have clusters 30 of any suitable size, shape, and/or configuration.\",\n \"For example, the first cluster pattern may have the configurations shown in FIGS.\",\n \"6-9 or any suitable configuration.\",\n \"Furthermore, the first cluster pattern may include different types of clusters 30 and may include tracks 14 that are not part of a cluster 30.In some embodiments, the first cluster pattern may include interleaved clusters 30 with any suitable interleaving pattern.\",\n \"At step 102, voltage is applied to the clusters 30 of the first cluster pattern.\",\n \"Voltage may be applied to a cluster 30 by connecting it to a voltage source (e.g.\",\n \"a voltage supply rail), a current source, or any other suitable component.\",\n \"Voltage may be applied for a fixed amount of time or a variable amount of time.\",\n \"In some embodiments, a predetermined amount of charge may be applied to each cluster 30.The application of voltage to cluster 30 may be performed at least in part by controller 12.Voltage may also be applied to additional clusters 30, and multiple clusters 30 may be charged simultaneously.\",\n \"At step 104, controller 12 measures a plurality of first values.\",\n \"Each first value is associated with the capacitance of a respective cluster 30 of the first cluster pattern, and the first values may be measured simultaneously or sequentially.\",\n \"The first values may be measured using any suitable method described above with respect to FIG.\",\n \"1.Each first value may be a capacitance or it may be a measurement that is proportional to, related to, or indicative of the capacitance (or change in capacitance) experienced by a cluster 30.For example, the first value may be a voltage measurement, current measurement, timing measurement, any other suitable measurement, or any combination thereof that is measured under conditions that make the measured value indicative of the capacitance (or change in capacitance) experienced by cluster 30.Furthermore, certain embodiments may utilize additional circuitry (such as, for example, one or more integrators, amplifiers, capacitors, switches, audio-to-digital converters, and/or any other suitable circuitry) to perform and/or enhance such measurements.\",\n \"Certain embodiments may measure a value at a particular point in time, measure a change in a value over time, and/or perform any other suitable processing to facilitate the determination of a position of object 34 relative to touch censor 10.In certain embodiments, the determination of the first value may be performed at least in part by controller 12.The first values may be used to determine the cluster configuration, trigger one or more functions, estimate a position of object 34 relative to touch sensor 10, estimate a shape and/or size of object 34 (e.g., by analyzing the distribution of first values measured by multiple clusters 30), and/or perform any suitable function.\",\n \"At step 106, controller 12 connects tracks 14 to form a second cluster pattern.\",\n \"In some embodiments, the second cluster pattern may have one or more interleaved clusters 30, though this is not required.\",\n \"Tracks 14 may be connected galvanically, capacitively, or using any suitable method.\",\n \"The second cluster pattern may have clusters 30 of any suitable size, shape, and/or configuration.\",\n \"For example, the second cluster pattern may have the configuration shown in FIG.\",\n \"8B or any suitable configuration, or the second cluster pattern may have different sizes of clusters 30 and/or different interleaving patterns.\",\n \"Furthermore, the second cluster pattern may include different types of clusters 30 and may include tracks 14 that are not part of a cluster 30.For example, some clusters 30 may be interleaved while other clusters 30 are not, or different clusters 30 in the second cluster pattern may have different interleaving patterns from one another.\",\n \"Interleaved clusters 30 may provide improved precision, resolution, and/or linearity tor touch sensing measurements, including hover measurements.\",\n \"The formation of the second cluster pattern may occur in response to the first values.\",\n \"For example, one or more of the first values may trigger controller 12 to form interleaved clusters 30.Such embodiments may allow touch sensor 10 to achieve improved precision, resolution, and/or linearity when certain conditions are detected.\",\n \"For example, interleaved configurations may be triggered when controller 12 detects sufficiently nonlinear readings of the position of object 34, which may indicate that measurements of the position of object 34 have sub-optimal linearity in detecting the movement of object 34.In some embodiments, interleaved cluster configurations may be used in conjunction with the alteration of cluster sizes illustrated shown in FIGS.\",\n \"3A-C. For example, when object 34 is detected at shorter distances from touch sensor 10 (e.g., distance 36b of FIG.\",\n \"3B), smaller cluster sizes and non-interleaved clusters 30 may be used, and when object 34 is detected at longer distances from touch sensor 10 (e.g., distance 36a of FIG.\",\n \"3B) larger cluster sizes and interleaved clusters 30 may be used.\",\n \"Such embodiments may allow controller 12 to target the use of linearity-improving configurations more precisely to situations in which the linearity of its sensing may be reduced.\",\n \"In some embodiments, the second cluster pattern may include clusters 30 that are “shifted” configurations of the clusters 30 of the first cluster pattern.\",\n \"For example, the first and second cluster patterns may be cluster patterns used in a rolling cluster embodiment, as described above with respect to FIGS.\",\n \"6A-6B and 7A-7C.\",\n \"In such embodiments, each cluster 30 of the second cluster pattern may include one or more tracks 14 that were included in a primary cluster 30 of the first cluster pattern and one or more tracks 14 that were included in a secondary cluster 30 of the first cluster pattern.\",\n \"As used herein, “primary” and “secondary” does not indicate a greater or lesser level of importance.\",\n \"In some embodiments, each cluster 30 of the second cluster pattern may include more tracks 14 from the primary cluster 30 than from the secondary cluster 30.For example, for clusters 30 of size N, each cluster 30 of the second cluster pattern may include N-1 tracks 14 from the primary cluster and a single track 14 from the secondary cluster 30.Thus, the secondary cluster pattern may shift the first cluster pattern by one track 14.Other embodiments may utilize different amounts of shifting.\",\n \"For example, as shown in FIGS.\",\n \"6A-6B, clusters 30 may be shifted approximately to the halfway point of clusters 30.Such embodiments may provide a balance between (1) the benefits in precision, resolution, and/or linearity provided by using rolling clusters and (2) the costs of providing additional measurements, such as time, processing resources, or other costs.\",\n \"At step 108, voltage is applied to the clusters 30 of the second cluster pattern.\",\n \"The application of voltage to the second cluster pattern may utilize analogous processes to those described above for step 102.At step 110, controller 12 measures a plurality of second values.\",\n \"Each second value is associated with the capacitance of a respective cluster 30 of the second cluster pattern, and the second values may be measured simultaneously or sequentially.\",\n \"The second values may be measured using any suitable method described above with respect to FIG.\",\n \"1.Each second value may be a capacitance or it may be a measurement that is proportional to, related to, or indicative of the capacitance (or change in capacitance) experienced by a cluster 30.For example, the second value may be a voltage measurement, current measurement, timing measurement, any other suitable measurement, or any combination thereof that is measured under conditions that make the measured value indicative of the capacitance (or change in capacitance) experienced by cluster 30.Furthermore, certain embodiments may utilize additional circuitry (such as, for example, one or more integrators, amplifiers, capacitors, switches, audio-to-digital converters, and/or any other suitable circuitry) to perform and/or enhance such measurements.\",\n \"Certain embodiments may measure a value at a particular point in time, measure a change in a value over time, and/or perform any other suitable processing to facilitate the determination of a position of object 34 relative to touch sensor 10.In certain embodiments, the determination of the second value may be performed at least in part by controller 12.The second values may be used to determine the cluster configuration, trigger one or more functions, estimate a distance between object 34 and touch sensor 10, estimate a shape and/or size of object 34 (e.g., by analyzing the distribution of second values measured by multiple clusters 30), and/or perform any suitable function.\",\n \"At step 112, controller 12 determines a position of object 34 relative to touch sensor 10 based at least on the second values.\",\n \"For example, controller 12 may calculate a representative value for each track 14 based at least on the second values associated with clusters 30 that include that track 14.The representative values may approximate the capacitance or change in capacitance that would be experienced by each 14 in a non-clustered configuration.\",\n \"The representative values may therefore indicated the relative proximity of object 34 to each track 14.In some embodiments, the determination of the position of object 34 may also be based on one or more previously measured values, such as the first values.\",\n \"Furthermore, some embodiments may utilize one or more additional calculations, such as, for example, weighted averages, linear approximation, or any suitable technique.\",\n \"The measured position may be an estimation of where a portion of object 34 physically touches touch sensor 10.The measured position may also be an estimation of an orthogonal projection of a portion of object 34 onto touch sensor 10 (e.g., a hover position).\",\n \"In some embodiments, the determination of the distance between object 34 and touch sensor 10 may be performed at least in part by controller 12.Determining the position of object 34 as described herein may enable touch sensor 10 to provide improved sensitivity resulting from clustering tracks 14, as described above, while also mitigating potential reductions in precision, resolution, and/or linearity (as described with respect to FIGS.\",\n \"4A and 4B) that might otherwise be created by utilizing larger cluster sizes.\",\n \"Such embodiments may also improve the precision, resolution, and/or linearity of hover measurements.\",\n \"Herein, “or” inclusive and not exclusive, unless expressly indicated otherwise or indicated otherwise by context.\",\n \"Therefore, herein, “A or B” means “A, B, or both,” unless expressly indicated otherwise or indicated otherwise by context.\",\n \"Moreover, “and” is both joint and several, unless expressly indicated otherwise or indicated otherwise by context.\",\n \"Therefore, herein, “A and B” means “A and B, jointly or severally,” unless expressly indicated otherwise or indicated otherwise by context.\",\n \"This disclosure encompasses all changes, substitutions, variations, alterations, and modifications to the example embodiments herein that a person having ordinary skill in the art would comprehend.\",\n \"For example, while the embodiment of FIG.\",\n \"2 illustrates a particular configuration of tracks 14, any suitable configuration may be used.\",\n \"As another example, while FIGS.\",\n \"3A-3C, 4A, 5A, 6A-6B, 7A-7C, 8A-8B, and 9A-9B illustrate particular configurations of clusters 30, any suitable number, type, and configuration may be used.\",\n \"Furthermore, some embodiments may combine two or more of the techniques described herein, such as, for example, dynamically changing cluster sizes (as shown, for example, in FIGS.\",\n \"3A-3C), rolling clusters (as shown for example, in FIGS.\",\n \"6A-6B and 7A-7C), and interleaved clusters (as shown for example, in FIG.\",\n \"8B).\",\n \"As another example, while FIGS.\",\n \"3A-3C, 4A, 5A, 6A-6B, 7A-7C, 8A-8B, and 9A-9B depict a single layer of tracks 14, other embodiments may include multiple layers of tracks 14.As yet another example, while this disclosure describes certain touch-sensing operations that may be performed using the components of touch sensor 10 and controller 12, any suitable touch-sensing operations may be performed.\",\n \"Furthermore, certain embodiments may alternate between or combine one or more touch-sensing methods described herein.\",\n \"Moreover, although this disclosure describes and illustrates respective embodiments herein as including particular components, elements, functions, operations, or steps, any of these embodiments may include any combination or permutation of any of the components, elements, functions, operations, or steps described or illustrated anywhere herein that a person having ordinary skill in the art would comprehend.\",\n \"Furthermore, reference in the appended claims to an apparatus or system or a component of an apparatus or system being adapted to, arranged to, capable of, configured to, enabled to, operable to, or operative to perform a particular function encompasses that apparatus, system, component, whether or not it or that particular function is activated, turned on, or unlocked, as long as that apparatus, system, or component is so adapted, arranged, capable, configured, enabled, operable, or operative.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875827"}}},{"rowIdx":4494989,"cells":{"text":{"kind":"list like","value":[["WEARABLE RECORDING SYSTEM WITH MEMORY DESIGNATION","A surveillance apparatus continuously records imaged data from a camera into a circular buffer in a local memory.","When a record signal is received, the system records the video stream that was recorded before the record signal was received, and the video stream that is recorded after the record signal was received.","The recorded segment is then write-protected, so that the surveillance apparatus does not overwrite the recorded segment.","The recorded segment could then be sent to a remote memory via a wireless connection to free up local memory for future recording sessions."],["1.A recording system comprising: a pair of eyeglasses having a sensor that captures sensor data; a first memory communicatively coupled with the sensor; and a recording facility configured to: record the sensor data in the first memory; in response to a trigger signal, designate for saving a portion of the sensor data that was captured prior to occurrence of the trigger signal; and automatically overwrite portions of the sensor data that were recorded in the first memory that were not designated for saving.","2.The recording system of claim 1, further comprising copying the designated portion to a second memory.","3.The recording system of claim 2, wherein the second memory comprises a different part of the first memory, 4.The recording system of claim 2, wherein designated portion is stored in the second memory using compression.","5.The recording system of claim 2, further comprising copying to the second memory another portion the sensor data that was captured after occurrence of the trigger signal.","6.The recording system of claim 2, further comprising copying to the second memory another portion the sensor data that was captured during occurrence of the trigger signal.","7.The recording system of claim 1, further including with the designated portion, another portion of the sensor data that was captured after occurrence of the trigger signal.","8.The recording system of claim 1, further comprising a sending facility configured to transmit the designated portion to a remote memory.","9.The recording system of claim 1, wherein the sensor data comprises at least one of the following: image data and video data.","10.The recording system of claim 1, wherein the first memory comprises a circular buffer.","11.The recording system of claim 1, wherein the designated portion is stored using time compression.","12.The recording system of claim 1, wherein the designated portion is stored using frame compression.","13.The recording system of claim 1, further comprising a camera that includes the sensor interface, the first memory, and the recording facility.","14.The recording system of claim 13, wherein the camera comprises a security camera.","15.The recording system of claim 1, further comprising a cell phone including the sensor interface, the first memory, and the recording facility.","16.The recording system of claim 1, further comprising a personal area network coupled with the protecting facility and including at least two of the following: the sensor interface, the first memory, and the recording facility.","17.The recording system of claim 1, wherein the first memory is configured to record the designated portion of the sensor data in a file.","18.The recording system of claim 1, wherein the first memory is configured to record the designated portion of the sensor data in a single file.","19.The recording system of claim 1, wherein the trigger signal represents detection of at least one of the following: a motion, a sound, an image, content in a data stream, a pattern in the sensor data, a person, a human face, a computer screen, an event, a verbal command, operation of switch, and operation of a button.","20.The recording system of claim 1, further comprising the recording facility is configured to write-protect the designated portion as a write-protected portion in the first memory.","21.The recording system of claim 20, further comprising the recording facility is configured to free the write-protected portion following transmission of the designated portion.","22.The recording system of claim 1, wherein the recording facility is configured to index in the first memory the designated portion.","23.The recording system of claim 1, wherein the recording facility is configured to index the designated portion while the recording facility is still recording the sensor data into the first memory.","24.The recording system of claim 1, wherein the recording facility records the sensor data continuously, from before the trigger signal, through a pre-designated time period, and after the pre-designated time period."],["<SOH> II.","BACKGROUND <EOH>Conventional camcorders use a variety of storage formats including digital video cassettes, mini-DV cassettes, or DVD-R discs that offer a limited amount of memory to store data.","One of the major shortcomings of the existing camcorder technology is that the memory runs out too soon.","Once a portion of the memory has been recorded, there is less memory available for further recording.","Then when the memory is full, users have to return to their home/work computer or media station to transfer the recorded data from the camera to free up the memory.","This creates inconvenience and inflexibility for recording on the go.","WO 2006/044476 to Vanman describes an electronic camera mounted to a police vehicle with a circular buffer that is constantly recording.","When the camera reaches the end of the memory it records from the beginning of memory, erasing the earliest recorded data.","Such technology is often employed with surveillance cameras for long and continuous recording with little or no supervision.","However, Vanman does not distinguish or differentiate any data that is of importance.","To save data in the buffer, the user of the Vanman device needs to transfer important portions of the buffer wirelessly to a central office or physically to a DVD disc, or else risk having the interesting data be recorded over during loop recording.","Such transfers are processor intensive and may not be possible when the central office is out of range or an empty DVD disc is unavailable.","Vanman and all other extrinsic materials identified herein are incorporated by reference in their entirety.","Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.","EP 1064783 to Mann describes a camera mountable to a pair of eyeglasses that continuously saves recorded images to a circular buffer in a computer on the user's waist.","When a user wants to save a piece of recorded video, the user must stop recording and offload the data at another location before the user can record again.","Mann also discusses streaming the images directly to a wireless memory that may have a larger capacity; however, this means that the camera does not work in the absence of a wireless connection.","U.S. Pat.","No.","5,523,799 to Hattori et al.","also describes storing data in a memory having an archival portion.","However, Hattori fails to address sending data to a remote memory.","Thus, there is still a need for a recording camera that provides better recording and editing functions."],["<SOH> III.","SUMMARY OF THE INVENTION <EOH>The present invention provides apparatus, systems, and methods in which a surveillance apparatus processes images by (1) continuously recording a stream of imaged data, (2) write protecting segments of the recorded stream, and (3) sending write protected segments from a local memory to a remote memory using a wireless transmitter.","The surveillance apparatus generally has a camera functionally coupled to a local memory with a circular buffer.","As used herein, the term “a local memory functionally coupled to the camera” means that the memory that is distanced less than 20 cm from the camera, and is coupled to the camera using entirely physical connectors (e.g., wires, pins, conductive paths, etc.).","This contrasts with a “remote memory functionally coupled to the camera”, which would be a memory that is distanced from the camera by at least 20 cm, or is coupled to the camera using a wireless connection.","The circular buffer is preferably organized into a series of memory segments that loops back on itself and is organized into both available segments and write-protected segments.","This allows a recording facility to record the data stream available in portions of the circular buffer while skipping over write-protected matter.","Preferably, the local memory is large enough to store at least 5 or 10 minutes of imaged data.","Preferably, the recording facility continuously records the data stream into the circular buffer any time the surveillance apparatus is powered on.","As used herein, the term “continuous” with respect to recording a video data stream means that data is recorded at least every half second over a given ten second period.","When a signal to record is sent to the surveillance apparatus, a protecting facility designates a segment of the circular buffer to be write-protected to prevent that segment from being overwritten during the next recording loop.","Part of the write-protected portion could be a pre-recorded subset that is recorded before the signal is received, while part of the write-protected portion could be a post-recorded subset that is recorded after the signal is received.","The pre-recorded subset could be as long as 5 seconds, 10 seconds, 30 seconds, or more.","Preferably, various aspects of both the pre-recorded subset and the post-recorded subset can be configured with a user interface.","While the write-protected portions could be electronically indexed using a memory heap or a clustered index, the write-protected portions are preferably stored as separate files in the memory.","Such files could be stored in physically dis-contiguous parts of the circular buffer.","Additionally, the indexing is preferably performed while the recording facility is still recording data into the memory.","The signal to record is preferably automatically triggered by a sensor that detects an image in the camera or a sound by the camera's microphone.","For example, the signal to record could be triggered by a human face, an open book, a computer screen, a whistle, a verbal command, a recognized object, or a pattern of knocks.","Alternatively, a user interface could allow a human user to manually send the signal to record and could even allow the human user to designate a length of time of the pre-recorded subset or the post-recorded subset.","A user could send two signals, one to start recording and another to stop recording, but preferably the user merely sends a signal to start recording for a specified period of time.","In an exemplary embodiment, when the specified period of time has almost expired, say, for example, 5 seconds, 10 seconds, or longer, the user could extend the length of specified time by sending another trigger to the surveillance apparatus.","For example, the surveillance apparatus could send a warning 10 seconds before it is scheduled to stop recording by vibrating against the user; in response the user could say “don't stop” or merely cough to extend the length of the write-protected portion of memory.","While the surveillance apparatus could be a mounted on a hand-held video camera, the surveillance apparatus is preferably a small device that can be mounted inconspicuously on a person.","For example, contemplated surveillance apparatus mounts are a pair of wearable sunglasses or eyeglasses, a lapel pin, a collar button, a hat or visor, a hair pin, or a front of a purse.","Since the surveillance apparatus is typically too small to house a large amount of memory, the surveillance apparatus also preferably has a wireless transmitter that is also functionally connected to the local memory.","A sending facility uses the wireless transmitter to transmit write-protected portions of the circular buffer to a remote memory that is not physically connected to the local memory in some way.","For example, the wireless transmitter could send write-protected portions of the circular buffer to a mobile phone, or the surveillance apparatus could be plugged into a mobile phone which is then used as a wireless transmitter to forward a write-protected portion to another remote memory.","In a preferred embodiment, after a write-protected portion of the circular buffer is transferred to a remote memory, the protecting facility could remove the corresponding portion from protection so that the recording facility could use that portion to record data.","Various objects, features, aspects and advantages of the present invention will become more apparent from the following detailed description of preferred embodiments of the invention, along with the accompanying drawings in which like numerals represent like components."],["This application is a continuation of U.S. patent application Ser.","No.","15/279155 filed on Sep. 28, 2016 (pending), which is a continuation of U.S. patent application serial no.","13/790553 filed on Mar.","8, 2016 (now issued as U.S. Pat.","No.","9,485,471), which is a continuation of U.S. patent application Ser.","No.","12/560584, filed Sep. 16, 2009 (now issued as U.S. Pat.","No.","8,692,882), which is a continuation of U.S. patent application Ser.","No.","12/268286, filed Nov. 10, 2008 (now issued as U.S. Pat.","No.","7,593,034) which is a continuation-in-part of U.S. patent application Ser.","No.","11/770920, filed Jun.","29, 2007 (now issued U.S. Pat.","No.","8,310,540), which claims the benefit of U.S. provisional patent 60/824097, filed Aug. 31, 2006.This application and Ser.","No.","12/268286 are also continuations-in-part of U.S. patent application Ser.","No.","11/846217, filed Aug. 28, 2007, which claims the benefit of U.S. provisional patent 60/824095, filed Aug. 31, 2006.These and all other referenced extrinsic materials are incorporated herein by reference in their entirety.","Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.","I.","FIELD OF THE INVENTION The field of the invention is video camera recording technology.","II.","BACKGROUND Conventional camcorders use a variety of storage formats including digital video cassettes, mini-DV cassettes, or DVD-R discs that offer a limited amount of memory to store data.","One of the major shortcomings of the existing camcorder technology is that the memory runs out too soon.","Once a portion of the memory has been recorded, there is less memory available for further recording.","Then when the memory is full, users have to return to their home/work computer or media station to transfer the recorded data from the camera to free up the memory.","This creates inconvenience and inflexibility for recording on the go.","WO 2006/044476 to Vanman describes an electronic camera mounted to a police vehicle with a circular buffer that is constantly recording.","When the camera reaches the end of the memory it records from the beginning of memory, erasing the earliest recorded data.","Such technology is often employed with surveillance cameras for long and continuous recording with little or no supervision.","However, Vanman does not distinguish or differentiate any data that is of importance.","To save data in the buffer, the user of the Vanman device needs to transfer important portions of the buffer wirelessly to a central office or physically to a DVD disc, or else risk having the interesting data be recorded over during loop recording.","Such transfers are processor intensive and may not be possible when the central office is out of range or an empty DVD disc is unavailable.","Vanman and all other extrinsic materials identified herein are incorporated by reference in their entirety.","Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.","EP 1064783 to Mann describes a camera mountable to a pair of eyeglasses that continuously saves recorded images to a circular buffer in a computer on the user's waist.","When a user wants to save a piece of recorded video, the user must stop recording and offload the data at another location before the user can record again.","Mann also discusses streaming the images directly to a wireless memory that may have a larger capacity; however, this means that the camera does not work in the absence of a wireless connection.","U.S. Pat.","No.","5,523,799 to Hattori et al.","also describes storing data in a memory having an archival portion.","However, Hattori fails to address sending data to a remote memory.","Thus, there is still a need for a recording camera that provides better recording and editing functions.","III.","SUMMARY OF THE INVENTION The present invention provides apparatus, systems, and methods in which a surveillance apparatus processes images by (1) continuously recording a stream of imaged data, (2) write protecting segments of the recorded stream, and (3) sending write protected segments from a local memory to a remote memory using a wireless transmitter.","The surveillance apparatus generally has a camera functionally coupled to a local memory with a circular buffer.","As used herein, the term “a local memory functionally coupled to the camera” means that the memory that is distanced less than 20 cm from the camera, and is coupled to the camera using entirely physical connectors (e.g., wires, pins, conductive paths, etc.).","This contrasts with a “remote memory functionally coupled to the camera”, which would be a memory that is distanced from the camera by at least 20 cm, or is coupled to the camera using a wireless connection.","The circular buffer is preferably organized into a series of memory segments that loops back on itself and is organized into both available segments and write-protected segments.","This allows a recording facility to record the data stream available in portions of the circular buffer while skipping over write-protected matter.","Preferably, the local memory is large enough to store at least 5 or 10 minutes of imaged data.","Preferably, the recording facility continuously records the data stream into the circular buffer any time the surveillance apparatus is powered on.","As used herein, the term “continuous” with respect to recording a video data stream means that data is recorded at least every half second over a given ten second period.","When a signal to record is sent to the surveillance apparatus, a protecting facility designates a segment of the circular buffer to be write-protected to prevent that segment from being overwritten during the next recording loop.","Part of the write-protected portion could be a pre-recorded subset that is recorded before the signal is received, while part of the write-protected portion could be a post-recorded subset that is recorded after the signal is received.","The pre-recorded subset could be as long as 5 seconds, 10 seconds, 30 seconds, or more.","Preferably, various aspects of both the pre-recorded subset and the post-recorded subset can be configured with a user interface.","While the write-protected portions could be electronically indexed using a memory heap or a clustered index, the write-protected portions are preferably stored as separate files in the memory.","Such files could be stored in physically dis-contiguous parts of the circular buffer.","Additionally, the indexing is preferably performed while the recording facility is still recording data into the memory.","The signal to record is preferably automatically triggered by a sensor that detects an image in the camera or a sound by the camera's microphone.","For example, the signal to record could be triggered by a human face, an open book, a computer screen, a whistle, a verbal command, a recognized object, or a pattern of knocks.","Alternatively, a user interface could allow a human user to manually send the signal to record and could even allow the human user to designate a length of time of the pre-recorded subset or the post-recorded subset.","A user could send two signals, one to start recording and another to stop recording, but preferably the user merely sends a signal to start recording for a specified period of time.","In an exemplary embodiment, when the specified period of time has almost expired, say, for example, 5 seconds, 10 seconds, or longer, the user could extend the length of specified time by sending another trigger to the surveillance apparatus.","For example, the surveillance apparatus could send a warning 10 seconds before it is scheduled to stop recording by vibrating against the user; in response the user could say “don't stop” or merely cough to extend the length of the write-protected portion of memory.","While the surveillance apparatus could be a mounted on a hand-held video camera, the surveillance apparatus is preferably a small device that can be mounted inconspicuously on a person.","For example, contemplated surveillance apparatus mounts are a pair of wearable sunglasses or eyeglasses, a lapel pin, a collar button, a hat or visor, a hair pin, or a front of a purse.","Since the surveillance apparatus is typically too small to house a large amount of memory, the surveillance apparatus also preferably has a wireless transmitter that is also functionally connected to the local memory.","A sending facility uses the wireless transmitter to transmit write-protected portions of the circular buffer to a remote memory that is not physically connected to the local memory in some way.","For example, the wireless transmitter could send write-protected portions of the circular buffer to a mobile phone, or the surveillance apparatus could be plugged into a mobile phone which is then used as a wireless transmitter to forward a write-protected portion to another remote memory.","In a preferred embodiment, after a write-protected portion of the circular buffer is transferred to a remote memory, the protecting facility could remove the corresponding portion from protection so that the recording facility could use that portion to record data.","Various objects, features, aspects and advantages of the present invention will become more apparent from the following detailed description of preferred embodiments of the invention, along with the accompanying drawings in which like numerals represent like components.","IV.","BRIEF DESCRIPTION OF THE DRAWING FIG.","1 is a camera mounted on a pair of glasses connected to a circular buffer in a local memory that is controlled by a ring.","FIG.","2A and 2B show user interface buttons for the ring of FIG.","1.FIG.","3 shows a diagram representation of the circular buffer of FIG.","1.FIG.","4A-4H show representations of the circular buffer of FIG.","1 while the surveillance apparatus is in use.","V. DETAILED DESCRIPTION In FIG.","1, an example surveillance apparatus 100 generally comprising eyeglasses 110 having a camera 120 mounted at the nose bridge, and an optional viewfinder 130 applied onto one of the lenses.","A data and power cord 140 couples the camera 120 to a belt-worn recorder 160, which cooperates with a ring-shaped signaling device 150 and a remote memory 170.Those skilled in the art will appreciate that the term “surveillance” is used herein in its broadest possible sense, to include not only professional or commercial types of surveillance, but also any other type of observation, including for example an ordinary person watching a baseball game or birthday party.","The eyeglasses 110 are used here euphemistically to represent any type of camera mount.","In a preferred embodiment, the camera mount is disguised to be a common object worn by a person or lying around a house, but could also be shaped and sized to look like a camera.","Contemplated mounts include lapel pins, hair clips, shirt buttons, purses, staplers, desk clocks, tripods, head gear, hand grips, or security camera mounts.","As used herein the term “camera” means any device or collection of devices that includes an image capturing component that captures image data, and a converting component that converts the image data into digital data, possibly at least one data stream.","An image capturing component could include one or more charge-couple devices (CCD) complimentary metal-oxide-semiconductors (CMOS), CMOS focal plane arrays (CFP), radiometers, or other manners of image obtaining devices.","Camera 120 should be interpreted euphemistically to include all such variants.","Likewise, a suitable converting component could include one or more analog-to-digital converters, software codecs, or integrated circuits.","Camera 120 contains an imager lens 122 used to focus images for camera 120.Conventional lenses allow one or more of the following adjustments: aperture (to control the amount of light), zoom (to control the field-of-view), or shutter speed (to capture continuous motion.).","In preferred embodiments, these adjustments are automatically controlled by the camcorder electronics, generally to maintain constant exposure onto the imager without the manual adjustment from a user.","It is contemplated that the preferred embodiments offer direct user control of all major optical functions.","As with most modern digital recorders and camcorders, an analog-to-digital (ADC) converter is used to digitize the analog imager waveform output into a discrete digital-video signal.","Thus, the recorder can be used to record analog or digital formats.","Viewfinder image lens 130 is calibrated to have the same field of view as camera 120.Preferably, viewfinder image lens 130 is embedded in between the two glass lenses of eyeglasses 110.Preferably viewfinder image lens 130 is a zoom lens with preferred standard zoom ration of 3× in or out of the focal length of the camera.","A more sophisticated viewfinder image lens 130 is contemplated to have a greater zoom range and also has nighttime vision or is able to render images under different light conditions.","Within the lenses, viewfinder image lens 130 is outlined by tinted area or graticle and the outline graticle is embedded with glowing fiber optic filament.","Eye-glasses are made preferably from opaque, translucent, or possibly photo gray-type tint of glasses.","Alternatively, glasses change color slightly when energized.","Where the camera is a hand-held camera and is not embedded in a pair of eyeglasses, viewfinder image lens 130 can be permanently fixed to camera 120, or it can be interchangeable with lenses of different focal lengths and other properties depending on the need and circumstances of use.","Recorder 160 is any recording device that records video and/or audio/video data, including conventional recorders.","Recorder 160 preferably includes a processor 162 with software or hardware that accomplishes the functions described herein, or one or more physical memories that are collectively referred to herein as memory 166.Typically, the recorder or the camera converts analog images into a digital format to be stored in the memory, or also preferably records both audio and video input analog signals from the camera to the memory.","Those skilled in the art will also appreciate that the concepts described herein with respect to video and/or audio/video data can be applied to recordation of purely audio, or in fact any other type of data stream; this specification should be interpreted as expressly including such application.","A wearer could clip recorder 160 as a belt clip or another compact device.","Contemplated recorders include MP3 players, purses, or buttons.","It is also contemplated that recorder 160 could also comprise a cell or mobile phone having a suitable recorder application installed that is configured to communicate with the other components of apparatus 100.Although not expressly shown, recorder 160 also includes an appropriate power supply or connection, supporting electronics, or a display or other interface.","The power source can vary considerably.","For example, in embodiments where the recorded is relatively large, a suitable power source can include a rechargeable battery.","On the other hand, when the recorder is relatively small, an appropriate power source can include an external power source (e.g., transformer for wall outlet or cigarette lighter adapter).","Whether embodied in control buttons or in some other manner, it is also contemplated that recorder can include some sort of security control requiring a password and some sort of automatic turnoff feature that activates after a certain amount of inactivity.","Authentication or authorization of user access provides for ensuring a proper user of apparatus 100 retains desired control.","For example, once a user is authenticated, the user can control indexing, editing, transmitting, or adjusting content data in memory.","Recorder 160 would typically record images in digital format, but analog or combination formats are also contemplated.","Preferably, the recorder's electronics are preferably all on a unitary printed circuit board with different functions, or facilities, encoded on a programmable chip or disk.","For example, a recording facility 163 could record the data stream from camera 120 to local memory 166, a protecting facility 164 could protect segments (not shown) of recorded data on memory 166, or a sending facility 165 could transmit protected segments (not shown) of recorded data to remote memory 170.While the different facilities are preferably part of a single hardware or software program, the facilities could be split into different components as necessary.","Other facilities could be installed, for example a facility that allows editing of the received image data or protected data.","It is contemplated that such facilities could be purchased through or installed on a cell phone, possibly through an on-line application store.","The contemplated memory could vary depending on the particular configuration of the recorder.","Particularly suitable memories include commercially available micro hard drives with a 1-inch disc (which can preferably have a capacity of more than 1 GB), flash memory cards with a capacity of up to 128 MB and more, or other transient and/or permanent memory units.","Likewise, suitable memory can also include SDRAM, MRAM, racetrack memory, SIMM, DIMM, etc.","with a capacity of at least 32 MB, more preferably at least 64 MB, or most preferably above 128 MB.","In preferred embodiments, memory 166 is a SDRAM capable of storing at least 1000 frames of data.","Once received by memory 166, frames are preferably compressed by employing conventional compression rates and methods to achieve at least a 50:1 ratio.","In preferred embodiments, image data received by recorder 160 is stored in a circular buffer 167 on memory 166.Preferably, all of the free space in memory 166 is used to create circular buffer 167, however, multiple circular buffers could be created in the memory where there exist multiple cameras connected to a single recorder.","Once the recorder is turned on, image data is continuously stored in circular buffer 167 for access.","If no record or protect button is pushed, the recorder will loop back and store the image data for a said length of time.","Recording, book-marking and protecting are used synonymously herein.","Recording, book-marking and protecting means that a portion of the imaged data is write-protected upon an activation of a signal by a user and can not then be overwritten unless the write-protection is later removed.","Consequently, protected data cannot be overwritten by newly stored imaged data in the circular buffer.","The circular buffer is preferably large enough to store at least 3 minutes of data, more preferably 5 minutes and most preferred 10 minutes of data.","However, it is contemplated that depending on the size and capacity of the device, any length longer or shorter is possible.","It is preferred when the recorder is turned on the entire circular buffer is treated and stored as a single file.","Thus, if no recording is protected or bookmarked, then the entire file will be erased and the recording will start at the beginning of the circular buffer.","Signaling device 150 is shown in the figure as a ring that communicates wirelessly (e.g., BlueTooth, Skinplex, wireless USB, 802.11, 802.15, UWB, Z-Wave, IrDa, Zigbee, etc.)","with the recorder, possibly as part of a personal area network (PAN).","The ring can have any suitable interface, shown in FIGS.","2A and 2B, including for example buttons on its outer periphery, or a sensor along its inner edge.","In FIG.","2A, ring 150 has user interface 200, with a start signal button 210, a stop signal button 220, a transmit button 230, a zoom in button 240, or a zoom out button 250.Alternatively, the buttons could have decorative symbols in lieu of words of function as shown in FIG.","2B, or could even have arbitrary symbols surrounding the entirety of signaling device 150.These buttons allow a user to manipulate and control image data and to generate protected data.","In an alternative embodiment, turning the ring in one direction might produce a start signal, and continuing to turn the ring in that direction might extend backwards the time period that is protected.","Where a default time period for storing pre-start signal data is used, extending the time can be considered overriding the default.","Similarly, turning the ring in the opposite direction might produce a stop signal, and where a default time period for storing post-start signal data is used, extending the time can be considered overriding that default.","Electronics for such a ring or other control device are readily available, and for example are similar to those used in key fobs.","Indeed, signaling device 150 should be interpreted euphemistically to include key fob type device.","It is contemplated that the signaling device could be integrated into other items as an accessory and that is wearable on an individual, for example a lapel pin or a pen within a pocked protector.","It is also contemplated that the switch could be portable or can be hidden or attached to other devices such as a vehicle, furniture, etc.","The signal could also be generated in non-tactile ways, for example by an audio command or whistle, or by an automatic sensor.","Preferably, the user could configure the audio signal to match only his/her voice.","At any moment, the user can signal recorder 160 to place a “bookmark” in the recording.","This signal can be sent by pressing a button that will then transmit a signal through wires 140 that attach to the glasses then to the recorder.","The wires 140 could be fiber optic wires that are small and thin to avoid detection.","In an exemplary embodiment, the user could control the entire system using signaling device 150, for example by turning the camera on and off, recording a portion of image data, stop the recording, zooming in and out of image data; or transmitting protected data into the remote memory 170.While remote memory 170 is shown in the figure as a mobile or cell phone, remote memory 170 should be interpreted euphemistically to include any memory that is not connected to surveillance apparatus 100, for example, a DVD writer, a wireless network attached storage (NAS) device, a wireless storage area network (SAN) device, a home computer, or even a second surveillance apparatus.","Preferably, sending facility 165 sends protected segments of circular buffer 167 wirelessly to remote memory 170 whenever remote memory 170 is within range of wireless transceiver 169, possibly as part of a PAN using one or more wireless communication technologies (e.g., BlueTooth, Skinplex, wireless USB, 802.11, 802.15, UWB, Z-Wave, IrDa, Zigbee, etc.).","However, sending facility 165 could also respond to manual commands, for example through a button on signaling device 150, recorder 160, or the mobile phone itself.","In an alternative embodiment, the mobile phone does not act as a remote memory depository, and instead forwards the protected segment to a remote memory via a mobile internet or wi-fi connection.","Preferably, once protected data is transferred to a remote memory, the protected memory areas then will go back to become free memory areas that are available for further loop recording.","Write-protected data could be sent to the remote memory by an image sensor that outputs data directly in “block” format typically converted with a raster-to-block converter.","Further compression could be used before transmitting the data if wireless bandwidth is an issue.","Either DCT or wavelet transformed data on native sensor formats could be used.","The data is preferably transmitted via the Internet, but could also be transmitted using radio waves, a pager, a two-way pager, a physical cable, email, text message, picture message, or any other suitable communication mechanism.","FIG.","3 shows a diagram representation of circular buffer 167 in memory 166, with unprotected segment 320 and write-protected segment 330.Write-protected segment 330 is characterized as a predefined portion of the recording data.","The recording facility 163 continuously records the data stream 310 into circular buffer 167.The recording facility 163 records over unprotected segment 320 of circular buffer 167, while skipping over protected segments 330 of circular buffer 167.It is contemplated that the portion of the circular buffer that is marked as write-protected data cannot be overwritten once the recorder loops back to the beginning of the media.","FIGS.","4A-4H show an alternative diagram representation of a circular buffer 300 as it is being used.","In FIG.","4A the recording facility (not shown) records data stream “A” into circular buffer 400.The “ ” character is used to designate blank memory, or unprotected memory that can be overwritten.","The ellipsis “.",".",".","” is used to show that the memory can be very large relative to the number of positions shown in the figure.","It is contemplated, for example, that memory 400 can be up to several hundred megabytes, 1 GB, 2 GB, 4 GB, 8 GB, or even more.","Such memory is preferably of a flash type, non-volatile RAM, preferably in the form of a standard flash memory card.","In a preferred embodiment, circular buffer 400 comprises a logical representation of a physical memory area.","Buffer 400 can be configured to store data in the physical memory by taking into account wear-leveling across the physical memory.","In FIG.","4B the protecting facility (not shown) has protected a recent period of data stream “A” as a function of a start signal, shown by the character “I”.","The start signal can be triggered in any suitable manner, including for example manual operation of a trigger or a switch by a user.","For example, the ring of FIG.","1 could be used as a switch, or any other wearable accessory could have a switch integrated into it.","In other examples, start signals can be triggered by detection of a particular circumstance by a motion, sound or other sensor.","In an exemplary system, software can operate upon content in the data stream, such as by monitoring an entrance to a building using a data stream received from one or more cameras, and could then send a start signal when the image shows a person loitering in a certain area of the screen.","The “[” character is used to designate the start of protected memory.","Concomitantly, the portion of the data stream prior to the protected portion has once again been marked “_” to show that it is unprotected.","In protecting recent data, the system can protect a default historical time period before the start signal is sent and protect a default period after the start signal is sent (such as 30 seconds, 2 minutes, etc).","All suitable defaults are contemplated.","Alternatively, the historical time period being protected could be altered in some manner, such as by software or by a user operating a history button.","For example, if a user hits a start button, the system might default to protecting the last 30 seconds and the next 60 seconds; or it might protect the last 15 seconds and the next 2 minutes.","Preferably, before the protecting facility stops protecting data, the system sends a signal to the user that the system is about to stop write-protecting data.","For example, the system could send an audio chirp signal, or in the case of a pair of eyeglasses, a portion of the glasses could slightly vibrate to signal that the system will stop recording in 10 seconds.","If the user wishes to protect an additional 60 second time period, the user could hit a “more time” button.","In this manner a user could protect a 5 or 10 minute period, or an even much longer portion of a data stream prior to a start signal.","Indeed, if memory 400 is interpreted as a multi gigabyte flash memory, it is entirely possible that one could back up sufficiently to protect an hour or more of such a data stream.","In FIG.","4C the protecting facility has received a “stop” signal some time after receiving the start signal, thereby lengthening the protected portion of the “A” data stream.","The stop signal is shown as character “]” and could be automatically generated from software or hardware as a function of a default time after the start signal, or could be manually sent by the user of the system.","All suitable defaults are contemplated, including for example a 30 second or 1 minute time period.","Stop signals could also be generated in a variable fashion, again as a function of software or hardware, through action of a user, or in any other suitable manner.","Thus, a user can well operate a start button or other switch, a more time switch, and a stop switch, which could have the same or different interfaces.","It is also contemplated that the system could recognize a user's verbal commands for these functions.","Just as the system can utilize a default pre-start signal period of time for which a portion of the data stream is stored unless overridden in some manner, contemplated systems can utilize a default post-start signal period of time for which a portion of the data stream is stored unless overridden in some manner.","Using defaults for both pre-start and post-start signal periods allows a system to operate with an extremely high level of user convenience.","For example, in one contemplated class of systems using such defaults, a user could operate a single button, ring or other interface to initiate a start signal, and the system could respond by automatically storing a default 60 second portion of a data stream prior to the signal, as well as a default 30 time period of the data stream after the signal.","And all of that could be accomplished with a single operation of the button.","An interface could also be provided to allow the user to alter the length of time for the pre-recorded portion and the length of time for the post-recorded portion.","As should be apparent from the description above, all reasonable the default time periods are contemplated.","In FIG.","4D, the system has finished protecting the desired portion of the “A” data stream, and the recording facility continues to store a “B” data stream into circular buffer 400.Of course, the “B” data stream can be contiguous with the “A” data stream, so that differentiation of “A” and “B” streams is merely an artifact of how the data is being stored.","For example, if a system included an eyeglasses camera being used at baseball game, the wearer might watch the game for an hour or more without anything of interest happening.","During all that time the system would record image frames from the camera, looping in memory if the memory had remaining capacity for less than an hour of images.","When finally the wearer sees an interesting play that he wants to protect, he operates a start button, or perhaps a more time button to protect the previous minute of play.","Once the interesting action has completed, he operates a stop button, which thereby causes the system to complete protecting the entire “A” period of interest.","But the wearer continues watching the game, and the subsequent images, continuous with the “A” images, would be considered “B” images.","In some embodiments, the wearer can select to have more of previously recorded data to be protected.","For example, once the wearer operates the start button, the wearer could also indicates that additional previously recorded data should be protected (e.g., past 10 seconds, 30 seconds, one minute, five minutes, etc.)","while new image data is being stored and protected.","In FIG.","4E the system has again received a start signal, and has again protected a fixed or variable historical time period.","In FIG.","4F the system has received a stop signal, and has protected the entire desired portion of the “B” data stream.","In FIG.","4G the system has continued to record data, which is now depicted as data stream “C” because it follows data stream “B”.","This figure is particularly significant in that recordation of the “C” data stream skips over the protected portion of the “A” data stream.","In FIG.","4H the system received another start signal, and has protected a desired portion of the “C” data stream that straddles the protected “A” stream.","As shown, the C data stream is saved as a physically dis-contiguous file.","In a preferred embodiment, segments of recorded data are “write-protected” by being indexed in an electronic index.","This scheme allows the system to protect previously recorded areas of memory without interrupting any concurrent recording, and further allows the system to easily locate such protected segments for play-back or offloading to a remote memory.","Additionally, this allows the system to keep track of multiple fragments dis-contiguous fragments of a single write-protected segment.","The electronic index is preferably a hash table or a clustered index, but other methods of addressing memory are also suitable.","Protected data can be copied to a memory separate from the circular buffer, for example in a separate file within a local memory.","Multiple segments of protected data could thus be stored as a series of protected files in a directory structure.","In an exemplary embodiment, as soon as the data is designated in the index as being protected, the recorder searches for a remote memory in range, and immediately copies the protected data from the circular buffer to the remote memory.","Once confirmation of copying is received, the index can be updated to identify the previously protected portion of the circular buffer as being non-protected.","As previously discussed, a sending facility uses a wireless transmitter to transmit write-protected data to a remote memory.","One should note that there are many additional aspects of the inventive subject matter surrounding transmitting the data to the remote memory.","In some embodiments a surveillance apparatus participates in a PAN with other components including the remote memory.","In such embodiments the apparatus can discover other components of the system, including the remote memory or signaling devices, by sending message over one or more suitable protocols (e.g., BlueTooth, Skinplex, wireless USB, 802.11, 802.15, 802.16, UWB, Z-Wave, IrDA, Zigbee, etc.).","Component discovery can be via a push where the apparatus sends a discovery message over a protocol to remote components or via a pull where the remote components send a discovery message to the apparatus.","The components of the system can respond with a discovery response message.","Preferred discovery or discovery response messages comprise characteristics of the various responding components including buffer size, read/write rates, authentication, authorized command sets, or other parameters.","For example, the surveillance apparatus could send a discovery message out to discover any suitable remote memories in the PAN where the message is encapsulated in a BlueTooth protocol packet.","A cell phone could respond by allocating a memory area to operate as a remote memory and by sending a discovery response message back to the apparatus describing the amount of memory available.","Such an approach provides for creating surveillance apparatus products that are able to operate across multiple cell phone platforms by allowing a cell phone user to download or install an application, or possibly a driver for their specific cell phone model, capable of being discovered and operating with the apparatus.","Another aspect of transmitting data to the remote memory includes authenticating the various components with respect to access or to control remote memory.","In some embodiments, the surveillance apparatus, or even the signaling facility, can be authenticated with the remote memory via a suitable token exchange (e.g., passwords, public-private key, handshakes, etc.).","For example, a remote memory could be bound to a specific apparatus via a secret key, possibly having a UUID or GUID.","Furthermore, the components of the system can be authorized to access various levels of functionality based on their authentication.","Some apparatus could have read only access, while other could have write access, or while still others have editing capabilities.","Yet another aspect of transmitting data to the remote memory includes the remote memory providing access to multiple surveillance apparatus.","For example, a single remote memory, possibly a cell phone, could be in close proximity (e.g., physically local within 100 meters or logically local within the same network) to two or more apparatus.","The remote memory can provide image storage as necessary to each apparatus, assuming appropriate authentication or permissions.","In addition, it is contemplated that a single apparatus could have more than one camera where each camera has its data transmitted to the remote memory collectively via the apparatus or even individually, possibly where each camera has access to different remote memories, or different areas (e.g., files) in the same remote memory.","One should also note that a surveillance apparatus can employ multiple wireless protocols to interact with the various components.","For example, the apparatus's signaling device could connect to a recorded via Zigbee or Skiplex protocols while the apparatus could connect to the remote memory via IEEE 802.16.One purpose of the invention is to allow secret recording by a user.","The user can integrate the recorder as part of his/her wardrobe or even as clothing accessories, such as a pin or a hat.","Preferably, recorder will record video and audio as seen from the wearer's point of view without requiring the wearer to exert any special effort to operate the recorder.","The recorder operates for extended periods of time while remaining unobtrusive both to the wearer/operator and to the subject(s) being recorded.","In order for the device to be practical, physical size and weight are of primary importance.","The recorder portion must be small and lightweight enough to be unobtrusive.","Preferably, the size of the recorder is two inches by three inches by one-half inch and six ounces in weight including battery.","The camera or imaging component must be small and lightweight enough to be mounted on a pair of eyeglasses without conspicuous bulk or uncomfortable weight on the order of one-quarter inch by one-quarter inch by one inch or smaller and weighing one ounce or less.","Further, the imaging component must be capable of sufficient resolution that the image quality of the resulting recording is comparable with existing consumer camcorder products.","Preferred resolutions are at least 640×480 pixels.","However, more preferred resolutions include high definition quality resolutions (e.g., 720p, 1080i, 1080p, 2160p, etc.).","Since the recorder will be worn on the body and the wearer can move actively about when the device is in operation, it is important that the entire device be mechanically rugged and that all components, particularly the storage media, be impervious to the shocks resulting from such body movement.","The device is also likely to be exposed to environmental stresses such as dust and moisture so the components and packaging must accommodate this exposure.","Solid state media such as compact flash memory is particularly suitable as the recorder's storage media since it meets these requirements.","Alternatively, the recorder device can be mounted on vehicles, planes or any other objects for ease of use.","It is contemplated that the present invention can be used in military or field intelligence operations.","The advantages of the disclosed techniques are clear.","A user of the inventive subject matter can capture image data while also participating with others in an event without being trapped behind a recording device.","Furthermore, the user's hands can remain substantially free while recording.","Thus, specific embodiments and applications of recording images to a circular buffer in a local memory and transmitting it wirelessly to a remote memory have been disclosed.","It should be apparent, however, to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein.","The inventive subject matter, therefore, is not to be restricted except in the spirit of the appended claims.","Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context.","In particular, the terms “comprises” and “comprising” should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps can be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced.","Where the specification claims refers to at least one of something selected from the group consisting of A, B, C .",".",".","and N, the text should be interpreted as requiring only one element from the group, not A plus N, or B plus N, etc."]],"string":"[\n [\n \"WEARABLE RECORDING SYSTEM WITH MEMORY DESIGNATION\",\n \"A surveillance apparatus continuously records imaged data from a camera into a circular buffer in a local memory.\",\n \"When a record signal is received, the system records the video stream that was recorded before the record signal was received, and the video stream that is recorded after the record signal was received.\",\n \"The recorded segment is then write-protected, so that the surveillance apparatus does not overwrite the recorded segment.\",\n \"The recorded segment could then be sent to a remote memory via a wireless connection to free up local memory for future recording sessions.\"\n ],\n [\n \"1.A recording system comprising: a pair of eyeglasses having a sensor that captures sensor data; a first memory communicatively coupled with the sensor; and a recording facility configured to: record the sensor data in the first memory; in response to a trigger signal, designate for saving a portion of the sensor data that was captured prior to occurrence of the trigger signal; and automatically overwrite portions of the sensor data that were recorded in the first memory that were not designated for saving.\",\n \"2.The recording system of claim 1, further comprising copying the designated portion to a second memory.\",\n \"3.The recording system of claim 2, wherein the second memory comprises a different part of the first memory, 4.The recording system of claim 2, wherein designated portion is stored in the second memory using compression.\",\n \"5.The recording system of claim 2, further comprising copying to the second memory another portion the sensor data that was captured after occurrence of the trigger signal.\",\n \"6.The recording system of claim 2, further comprising copying to the second memory another portion the sensor data that was captured during occurrence of the trigger signal.\",\n \"7.The recording system of claim 1, further including with the designated portion, another portion of the sensor data that was captured after occurrence of the trigger signal.\",\n \"8.The recording system of claim 1, further comprising a sending facility configured to transmit the designated portion to a remote memory.\",\n \"9.The recording system of claim 1, wherein the sensor data comprises at least one of the following: image data and video data.\",\n \"10.The recording system of claim 1, wherein the first memory comprises a circular buffer.\",\n \"11.The recording system of claim 1, wherein the designated portion is stored using time compression.\",\n \"12.The recording system of claim 1, wherein the designated portion is stored using frame compression.\",\n \"13.The recording system of claim 1, further comprising a camera that includes the sensor interface, the first memory, and the recording facility.\",\n \"14.The recording system of claim 13, wherein the camera comprises a security camera.\",\n \"15.The recording system of claim 1, further comprising a cell phone including the sensor interface, the first memory, and the recording facility.\",\n \"16.The recording system of claim 1, further comprising a personal area network coupled with the protecting facility and including at least two of the following: the sensor interface, the first memory, and the recording facility.\",\n \"17.The recording system of claim 1, wherein the first memory is configured to record the designated portion of the sensor data in a file.\",\n \"18.The recording system of claim 1, wherein the first memory is configured to record the designated portion of the sensor data in a single file.\",\n \"19.The recording system of claim 1, wherein the trigger signal represents detection of at least one of the following: a motion, a sound, an image, content in a data stream, a pattern in the sensor data, a person, a human face, a computer screen, an event, a verbal command, operation of switch, and operation of a button.\",\n \"20.The recording system of claim 1, further comprising the recording facility is configured to write-protect the designated portion as a write-protected portion in the first memory.\",\n \"21.The recording system of claim 20, further comprising the recording facility is configured to free the write-protected portion following transmission of the designated portion.\",\n \"22.The recording system of claim 1, wherein the recording facility is configured to index in the first memory the designated portion.\",\n \"23.The recording system of claim 1, wherein the recording facility is configured to index the designated portion while the recording facility is still recording the sensor data into the first memory.\",\n \"24.The recording system of claim 1, wherein the recording facility records the sensor data continuously, from before the trigger signal, through a pre-designated time period, and after the pre-designated time period.\"\n ],\n [\n \"<SOH> II.\",\n \"BACKGROUND <EOH>Conventional camcorders use a variety of storage formats including digital video cassettes, mini-DV cassettes, or DVD-R discs that offer a limited amount of memory to store data.\",\n \"One of the major shortcomings of the existing camcorder technology is that the memory runs out too soon.\",\n \"Once a portion of the memory has been recorded, there is less memory available for further recording.\",\n \"Then when the memory is full, users have to return to their home/work computer or media station to transfer the recorded data from the camera to free up the memory.\",\n \"This creates inconvenience and inflexibility for recording on the go.\",\n \"WO 2006/044476 to Vanman describes an electronic camera mounted to a police vehicle with a circular buffer that is constantly recording.\",\n \"When the camera reaches the end of the memory it records from the beginning of memory, erasing the earliest recorded data.\",\n \"Such technology is often employed with surveillance cameras for long and continuous recording with little or no supervision.\",\n \"However, Vanman does not distinguish or differentiate any data that is of importance.\",\n \"To save data in the buffer, the user of the Vanman device needs to transfer important portions of the buffer wirelessly to a central office or physically to a DVD disc, or else risk having the interesting data be recorded over during loop recording.\",\n \"Such transfers are processor intensive and may not be possible when the central office is out of range or an empty DVD disc is unavailable.\",\n \"Vanman and all other extrinsic materials identified herein are incorporated by reference in their entirety.\",\n \"Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.\",\n \"EP 1064783 to Mann describes a camera mountable to a pair of eyeglasses that continuously saves recorded images to a circular buffer in a computer on the user's waist.\",\n \"When a user wants to save a piece of recorded video, the user must stop recording and offload the data at another location before the user can record again.\",\n \"Mann also discusses streaming the images directly to a wireless memory that may have a larger capacity; however, this means that the camera does not work in the absence of a wireless connection.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,523,799 to Hattori et al.\",\n \"also describes storing data in a memory having an archival portion.\",\n \"However, Hattori fails to address sending data to a remote memory.\",\n \"Thus, there is still a need for a recording camera that provides better recording and editing functions.\"\n ],\n [\n \"<SOH> III.\",\n \"SUMMARY OF THE INVENTION <EOH>The present invention provides apparatus, systems, and methods in which a surveillance apparatus processes images by (1) continuously recording a stream of imaged data, (2) write protecting segments of the recorded stream, and (3) sending write protected segments from a local memory to a remote memory using a wireless transmitter.\",\n \"The surveillance apparatus generally has a camera functionally coupled to a local memory with a circular buffer.\",\n \"As used herein, the term “a local memory functionally coupled to the camera” means that the memory that is distanced less than 20 cm from the camera, and is coupled to the camera using entirely physical connectors (e.g., wires, pins, conductive paths, etc.).\",\n \"This contrasts with a “remote memory functionally coupled to the camera”, which would be a memory that is distanced from the camera by at least 20 cm, or is coupled to the camera using a wireless connection.\",\n \"The circular buffer is preferably organized into a series of memory segments that loops back on itself and is organized into both available segments and write-protected segments.\",\n \"This allows a recording facility to record the data stream available in portions of the circular buffer while skipping over write-protected matter.\",\n \"Preferably, the local memory is large enough to store at least 5 or 10 minutes of imaged data.\",\n \"Preferably, the recording facility continuously records the data stream into the circular buffer any time the surveillance apparatus is powered on.\",\n \"As used herein, the term “continuous” with respect to recording a video data stream means that data is recorded at least every half second over a given ten second period.\",\n \"When a signal to record is sent to the surveillance apparatus, a protecting facility designates a segment of the circular buffer to be write-protected to prevent that segment from being overwritten during the next recording loop.\",\n \"Part of the write-protected portion could be a pre-recorded subset that is recorded before the signal is received, while part of the write-protected portion could be a post-recorded subset that is recorded after the signal is received.\",\n \"The pre-recorded subset could be as long as 5 seconds, 10 seconds, 30 seconds, or more.\",\n \"Preferably, various aspects of both the pre-recorded subset and the post-recorded subset can be configured with a user interface.\",\n \"While the write-protected portions could be electronically indexed using a memory heap or a clustered index, the write-protected portions are preferably stored as separate files in the memory.\",\n \"Such files could be stored in physically dis-contiguous parts of the circular buffer.\",\n \"Additionally, the indexing is preferably performed while the recording facility is still recording data into the memory.\",\n \"The signal to record is preferably automatically triggered by a sensor that detects an image in the camera or a sound by the camera's microphone.\",\n \"For example, the signal to record could be triggered by a human face, an open book, a computer screen, a whistle, a verbal command, a recognized object, or a pattern of knocks.\",\n \"Alternatively, a user interface could allow a human user to manually send the signal to record and could even allow the human user to designate a length of time of the pre-recorded subset or the post-recorded subset.\",\n \"A user could send two signals, one to start recording and another to stop recording, but preferably the user merely sends a signal to start recording for a specified period of time.\",\n \"In an exemplary embodiment, when the specified period of time has almost expired, say, for example, 5 seconds, 10 seconds, or longer, the user could extend the length of specified time by sending another trigger to the surveillance apparatus.\",\n \"For example, the surveillance apparatus could send a warning 10 seconds before it is scheduled to stop recording by vibrating against the user; in response the user could say “don't stop” or merely cough to extend the length of the write-protected portion of memory.\",\n \"While the surveillance apparatus could be a mounted on a hand-held video camera, the surveillance apparatus is preferably a small device that can be mounted inconspicuously on a person.\",\n \"For example, contemplated surveillance apparatus mounts are a pair of wearable sunglasses or eyeglasses, a lapel pin, a collar button, a hat or visor, a hair pin, or a front of a purse.\",\n \"Since the surveillance apparatus is typically too small to house a large amount of memory, the surveillance apparatus also preferably has a wireless transmitter that is also functionally connected to the local memory.\",\n \"A sending facility uses the wireless transmitter to transmit write-protected portions of the circular buffer to a remote memory that is not physically connected to the local memory in some way.\",\n \"For example, the wireless transmitter could send write-protected portions of the circular buffer to a mobile phone, or the surveillance apparatus could be plugged into a mobile phone which is then used as a wireless transmitter to forward a write-protected portion to another remote memory.\",\n \"In a preferred embodiment, after a write-protected portion of the circular buffer is transferred to a remote memory, the protecting facility could remove the corresponding portion from protection so that the recording facility could use that portion to record data.\",\n \"Various objects, features, aspects and advantages of the present invention will become more apparent from the following detailed description of preferred embodiments of the invention, along with the accompanying drawings in which like numerals represent like components.\"\n ],\n [\n \"This application is a continuation of U.S. patent application Ser.\",\n \"No.\",\n \"15/279155 filed on Sep. 28, 2016 (pending), which is a continuation of U.S. patent application serial no.\",\n \"13/790553 filed on Mar.\",\n \"8, 2016 (now issued as U.S. Pat.\",\n \"No.\",\n \"9,485,471), which is a continuation of U.S. patent application Ser.\",\n \"No.\",\n \"12/560584, filed Sep. 16, 2009 (now issued as U.S. Pat.\",\n \"No.\",\n \"8,692,882), which is a continuation of U.S. patent application Ser.\",\n \"No.\",\n \"12/268286, filed Nov. 10, 2008 (now issued as U.S. Pat.\",\n \"No.\",\n \"7,593,034) which is a continuation-in-part of U.S. patent application Ser.\",\n \"No.\",\n \"11/770920, filed Jun.\",\n \"29, 2007 (now issued U.S. Pat.\",\n \"No.\",\n \"8,310,540), which claims the benefit of U.S. provisional patent 60/824097, filed Aug. 31, 2006.This application and Ser.\",\n \"No.\",\n \"12/268286 are also continuations-in-part of U.S. patent application Ser.\",\n \"No.\",\n \"11/846217, filed Aug. 28, 2007, which claims the benefit of U.S. provisional patent 60/824095, filed Aug. 31, 2006.These and all other referenced extrinsic materials are incorporated herein by reference in their entirety.\",\n \"Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.\",\n \"I.\",\n \"FIELD OF THE INVENTION The field of the invention is video camera recording technology.\",\n \"II.\",\n \"BACKGROUND Conventional camcorders use a variety of storage formats including digital video cassettes, mini-DV cassettes, or DVD-R discs that offer a limited amount of memory to store data.\",\n \"One of the major shortcomings of the existing camcorder technology is that the memory runs out too soon.\",\n \"Once a portion of the memory has been recorded, there is less memory available for further recording.\",\n \"Then when the memory is full, users have to return to their home/work computer or media station to transfer the recorded data from the camera to free up the memory.\",\n \"This creates inconvenience and inflexibility for recording on the go.\",\n \"WO 2006/044476 to Vanman describes an electronic camera mounted to a police vehicle with a circular buffer that is constantly recording.\",\n \"When the camera reaches the end of the memory it records from the beginning of memory, erasing the earliest recorded data.\",\n \"Such technology is often employed with surveillance cameras for long and continuous recording with little or no supervision.\",\n \"However, Vanman does not distinguish or differentiate any data that is of importance.\",\n \"To save data in the buffer, the user of the Vanman device needs to transfer important portions of the buffer wirelessly to a central office or physically to a DVD disc, or else risk having the interesting data be recorded over during loop recording.\",\n \"Such transfers are processor intensive and may not be possible when the central office is out of range or an empty DVD disc is unavailable.\",\n \"Vanman and all other extrinsic materials identified herein are incorporated by reference in their entirety.\",\n \"Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.\",\n \"EP 1064783 to Mann describes a camera mountable to a pair of eyeglasses that continuously saves recorded images to a circular buffer in a computer on the user's waist.\",\n \"When a user wants to save a piece of recorded video, the user must stop recording and offload the data at another location before the user can record again.\",\n \"Mann also discusses streaming the images directly to a wireless memory that may have a larger capacity; however, this means that the camera does not work in the absence of a wireless connection.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,523,799 to Hattori et al.\",\n \"also describes storing data in a memory having an archival portion.\",\n \"However, Hattori fails to address sending data to a remote memory.\",\n \"Thus, there is still a need for a recording camera that provides better recording and editing functions.\",\n \"III.\",\n \"SUMMARY OF THE INVENTION The present invention provides apparatus, systems, and methods in which a surveillance apparatus processes images by (1) continuously recording a stream of imaged data, (2) write protecting segments of the recorded stream, and (3) sending write protected segments from a local memory to a remote memory using a wireless transmitter.\",\n \"The surveillance apparatus generally has a camera functionally coupled to a local memory with a circular buffer.\",\n \"As used herein, the term “a local memory functionally coupled to the camera” means that the memory that is distanced less than 20 cm from the camera, and is coupled to the camera using entirely physical connectors (e.g., wires, pins, conductive paths, etc.).\",\n \"This contrasts with a “remote memory functionally coupled to the camera”, which would be a memory that is distanced from the camera by at least 20 cm, or is coupled to the camera using a wireless connection.\",\n \"The circular buffer is preferably organized into a series of memory segments that loops back on itself and is organized into both available segments and write-protected segments.\",\n \"This allows a recording facility to record the data stream available in portions of the circular buffer while skipping over write-protected matter.\",\n \"Preferably, the local memory is large enough to store at least 5 or 10 minutes of imaged data.\",\n \"Preferably, the recording facility continuously records the data stream into the circular buffer any time the surveillance apparatus is powered on.\",\n \"As used herein, the term “continuous” with respect to recording a video data stream means that data is recorded at least every half second over a given ten second period.\",\n \"When a signal to record is sent to the surveillance apparatus, a protecting facility designates a segment of the circular buffer to be write-protected to prevent that segment from being overwritten during the next recording loop.\",\n \"Part of the write-protected portion could be a pre-recorded subset that is recorded before the signal is received, while part of the write-protected portion could be a post-recorded subset that is recorded after the signal is received.\",\n \"The pre-recorded subset could be as long as 5 seconds, 10 seconds, 30 seconds, or more.\",\n \"Preferably, various aspects of both the pre-recorded subset and the post-recorded subset can be configured with a user interface.\",\n \"While the write-protected portions could be electronically indexed using a memory heap or a clustered index, the write-protected portions are preferably stored as separate files in the memory.\",\n \"Such files could be stored in physically dis-contiguous parts of the circular buffer.\",\n \"Additionally, the indexing is preferably performed while the recording facility is still recording data into the memory.\",\n \"The signal to record is preferably automatically triggered by a sensor that detects an image in the camera or a sound by the camera's microphone.\",\n \"For example, the signal to record could be triggered by a human face, an open book, a computer screen, a whistle, a verbal command, a recognized object, or a pattern of knocks.\",\n \"Alternatively, a user interface could allow a human user to manually send the signal to record and could even allow the human user to designate a length of time of the pre-recorded subset or the post-recorded subset.\",\n \"A user could send two signals, one to start recording and another to stop recording, but preferably the user merely sends a signal to start recording for a specified period of time.\",\n \"In an exemplary embodiment, when the specified period of time has almost expired, say, for example, 5 seconds, 10 seconds, or longer, the user could extend the length of specified time by sending another trigger to the surveillance apparatus.\",\n \"For example, the surveillance apparatus could send a warning 10 seconds before it is scheduled to stop recording by vibrating against the user; in response the user could say “don't stop” or merely cough to extend the length of the write-protected portion of memory.\",\n \"While the surveillance apparatus could be a mounted on a hand-held video camera, the surveillance apparatus is preferably a small device that can be mounted inconspicuously on a person.\",\n \"For example, contemplated surveillance apparatus mounts are a pair of wearable sunglasses or eyeglasses, a lapel pin, a collar button, a hat or visor, a hair pin, or a front of a purse.\",\n \"Since the surveillance apparatus is typically too small to house a large amount of memory, the surveillance apparatus also preferably has a wireless transmitter that is also functionally connected to the local memory.\",\n \"A sending facility uses the wireless transmitter to transmit write-protected portions of the circular buffer to a remote memory that is not physically connected to the local memory in some way.\",\n \"For example, the wireless transmitter could send write-protected portions of the circular buffer to a mobile phone, or the surveillance apparatus could be plugged into a mobile phone which is then used as a wireless transmitter to forward a write-protected portion to another remote memory.\",\n \"In a preferred embodiment, after a write-protected portion of the circular buffer is transferred to a remote memory, the protecting facility could remove the corresponding portion from protection so that the recording facility could use that portion to record data.\",\n \"Various objects, features, aspects and advantages of the present invention will become more apparent from the following detailed description of preferred embodiments of the invention, along with the accompanying drawings in which like numerals represent like components.\",\n \"IV.\",\n \"BRIEF DESCRIPTION OF THE DRAWING FIG.\",\n \"1 is a camera mounted on a pair of glasses connected to a circular buffer in a local memory that is controlled by a ring.\",\n \"FIG.\",\n \"2A and 2B show user interface buttons for the ring of FIG.\",\n \"1.FIG.\",\n \"3 shows a diagram representation of the circular buffer of FIG.\",\n \"1.FIG.\",\n \"4A-4H show representations of the circular buffer of FIG.\",\n \"1 while the surveillance apparatus is in use.\",\n \"V. DETAILED DESCRIPTION In FIG.\",\n \"1, an example surveillance apparatus 100 generally comprising eyeglasses 110 having a camera 120 mounted at the nose bridge, and an optional viewfinder 130 applied onto one of the lenses.\",\n \"A data and power cord 140 couples the camera 120 to a belt-worn recorder 160, which cooperates with a ring-shaped signaling device 150 and a remote memory 170.Those skilled in the art will appreciate that the term “surveillance” is used herein in its broadest possible sense, to include not only professional or commercial types of surveillance, but also any other type of observation, including for example an ordinary person watching a baseball game or birthday party.\",\n \"The eyeglasses 110 are used here euphemistically to represent any type of camera mount.\",\n \"In a preferred embodiment, the camera mount is disguised to be a common object worn by a person or lying around a house, but could also be shaped and sized to look like a camera.\",\n \"Contemplated mounts include lapel pins, hair clips, shirt buttons, purses, staplers, desk clocks, tripods, head gear, hand grips, or security camera mounts.\",\n \"As used herein the term “camera” means any device or collection of devices that includes an image capturing component that captures image data, and a converting component that converts the image data into digital data, possibly at least one data stream.\",\n \"An image capturing component could include one or more charge-couple devices (CCD) complimentary metal-oxide-semiconductors (CMOS), CMOS focal plane arrays (CFP), radiometers, or other manners of image obtaining devices.\",\n \"Camera 120 should be interpreted euphemistically to include all such variants.\",\n \"Likewise, a suitable converting component could include one or more analog-to-digital converters, software codecs, or integrated circuits.\",\n \"Camera 120 contains an imager lens 122 used to focus images for camera 120.Conventional lenses allow one or more of the following adjustments: aperture (to control the amount of light), zoom (to control the field-of-view), or shutter speed (to capture continuous motion.).\",\n \"In preferred embodiments, these adjustments are automatically controlled by the camcorder electronics, generally to maintain constant exposure onto the imager without the manual adjustment from a user.\",\n \"It is contemplated that the preferred embodiments offer direct user control of all major optical functions.\",\n \"As with most modern digital recorders and camcorders, an analog-to-digital (ADC) converter is used to digitize the analog imager waveform output into a discrete digital-video signal.\",\n \"Thus, the recorder can be used to record analog or digital formats.\",\n \"Viewfinder image lens 130 is calibrated to have the same field of view as camera 120.Preferably, viewfinder image lens 130 is embedded in between the two glass lenses of eyeglasses 110.Preferably viewfinder image lens 130 is a zoom lens with preferred standard zoom ration of 3× in or out of the focal length of the camera.\",\n \"A more sophisticated viewfinder image lens 130 is contemplated to have a greater zoom range and also has nighttime vision or is able to render images under different light conditions.\",\n \"Within the lenses, viewfinder image lens 130 is outlined by tinted area or graticle and the outline graticle is embedded with glowing fiber optic filament.\",\n \"Eye-glasses are made preferably from opaque, translucent, or possibly photo gray-type tint of glasses.\",\n \"Alternatively, glasses change color slightly when energized.\",\n \"Where the camera is a hand-held camera and is not embedded in a pair of eyeglasses, viewfinder image lens 130 can be permanently fixed to camera 120, or it can be interchangeable with lenses of different focal lengths and other properties depending on the need and circumstances of use.\",\n \"Recorder 160 is any recording device that records video and/or audio/video data, including conventional recorders.\",\n \"Recorder 160 preferably includes a processor 162 with software or hardware that accomplishes the functions described herein, or one or more physical memories that are collectively referred to herein as memory 166.Typically, the recorder or the camera converts analog images into a digital format to be stored in the memory, or also preferably records both audio and video input analog signals from the camera to the memory.\",\n \"Those skilled in the art will also appreciate that the concepts described herein with respect to video and/or audio/video data can be applied to recordation of purely audio, or in fact any other type of data stream; this specification should be interpreted as expressly including such application.\",\n \"A wearer could clip recorder 160 as a belt clip or another compact device.\",\n \"Contemplated recorders include MP3 players, purses, or buttons.\",\n \"It is also contemplated that recorder 160 could also comprise a cell or mobile phone having a suitable recorder application installed that is configured to communicate with the other components of apparatus 100.Although not expressly shown, recorder 160 also includes an appropriate power supply or connection, supporting electronics, or a display or other interface.\",\n \"The power source can vary considerably.\",\n \"For example, in embodiments where the recorded is relatively large, a suitable power source can include a rechargeable battery.\",\n \"On the other hand, when the recorder is relatively small, an appropriate power source can include an external power source (e.g., transformer for wall outlet or cigarette lighter adapter).\",\n \"Whether embodied in control buttons or in some other manner, it is also contemplated that recorder can include some sort of security control requiring a password and some sort of automatic turnoff feature that activates after a certain amount of inactivity.\",\n \"Authentication or authorization of user access provides for ensuring a proper user of apparatus 100 retains desired control.\",\n \"For example, once a user is authenticated, the user can control indexing, editing, transmitting, or adjusting content data in memory.\",\n \"Recorder 160 would typically record images in digital format, but analog or combination formats are also contemplated.\",\n \"Preferably, the recorder's electronics are preferably all on a unitary printed circuit board with different functions, or facilities, encoded on a programmable chip or disk.\",\n \"For example, a recording facility 163 could record the data stream from camera 120 to local memory 166, a protecting facility 164 could protect segments (not shown) of recorded data on memory 166, or a sending facility 165 could transmit protected segments (not shown) of recorded data to remote memory 170.While the different facilities are preferably part of a single hardware or software program, the facilities could be split into different components as necessary.\",\n \"Other facilities could be installed, for example a facility that allows editing of the received image data or protected data.\",\n \"It is contemplated that such facilities could be purchased through or installed on a cell phone, possibly through an on-line application store.\",\n \"The contemplated memory could vary depending on the particular configuration of the recorder.\",\n \"Particularly suitable memories include commercially available micro hard drives with a 1-inch disc (which can preferably have a capacity of more than 1 GB), flash memory cards with a capacity of up to 128 MB and more, or other transient and/or permanent memory units.\",\n \"Likewise, suitable memory can also include SDRAM, MRAM, racetrack memory, SIMM, DIMM, etc.\",\n \"with a capacity of at least 32 MB, more preferably at least 64 MB, or most preferably above 128 MB.\",\n \"In preferred embodiments, memory 166 is a SDRAM capable of storing at least 1000 frames of data.\",\n \"Once received by memory 166, frames are preferably compressed by employing conventional compression rates and methods to achieve at least a 50:1 ratio.\",\n \"In preferred embodiments, image data received by recorder 160 is stored in a circular buffer 167 on memory 166.Preferably, all of the free space in memory 166 is used to create circular buffer 167, however, multiple circular buffers could be created in the memory where there exist multiple cameras connected to a single recorder.\",\n \"Once the recorder is turned on, image data is continuously stored in circular buffer 167 for access.\",\n \"If no record or protect button is pushed, the recorder will loop back and store the image data for a said length of time.\",\n \"Recording, book-marking and protecting are used synonymously herein.\",\n \"Recording, book-marking and protecting means that a portion of the imaged data is write-protected upon an activation of a signal by a user and can not then be overwritten unless the write-protection is later removed.\",\n \"Consequently, protected data cannot be overwritten by newly stored imaged data in the circular buffer.\",\n \"The circular buffer is preferably large enough to store at least 3 minutes of data, more preferably 5 minutes and most preferred 10 minutes of data.\",\n \"However, it is contemplated that depending on the size and capacity of the device, any length longer or shorter is possible.\",\n \"It is preferred when the recorder is turned on the entire circular buffer is treated and stored as a single file.\",\n \"Thus, if no recording is protected or bookmarked, then the entire file will be erased and the recording will start at the beginning of the circular buffer.\",\n \"Signaling device 150 is shown in the figure as a ring that communicates wirelessly (e.g., BlueTooth, Skinplex, wireless USB, 802.11, 802.15, UWB, Z-Wave, IrDa, Zigbee, etc.)\",\n \"with the recorder, possibly as part of a personal area network (PAN).\",\n \"The ring can have any suitable interface, shown in FIGS.\",\n \"2A and 2B, including for example buttons on its outer periphery, or a sensor along its inner edge.\",\n \"In FIG.\",\n \"2A, ring 150 has user interface 200, with a start signal button 210, a stop signal button 220, a transmit button 230, a zoom in button 240, or a zoom out button 250.Alternatively, the buttons could have decorative symbols in lieu of words of function as shown in FIG.\",\n \"2B, or could even have arbitrary symbols surrounding the entirety of signaling device 150.These buttons allow a user to manipulate and control image data and to generate protected data.\",\n \"In an alternative embodiment, turning the ring in one direction might produce a start signal, and continuing to turn the ring in that direction might extend backwards the time period that is protected.\",\n \"Where a default time period for storing pre-start signal data is used, extending the time can be considered overriding the default.\",\n \"Similarly, turning the ring in the opposite direction might produce a stop signal, and where a default time period for storing post-start signal data is used, extending the time can be considered overriding that default.\",\n \"Electronics for such a ring or other control device are readily available, and for example are similar to those used in key fobs.\",\n \"Indeed, signaling device 150 should be interpreted euphemistically to include key fob type device.\",\n \"It is contemplated that the signaling device could be integrated into other items as an accessory and that is wearable on an individual, for example a lapel pin or a pen within a pocked protector.\",\n \"It is also contemplated that the switch could be portable or can be hidden or attached to other devices such as a vehicle, furniture, etc.\",\n \"The signal could also be generated in non-tactile ways, for example by an audio command or whistle, or by an automatic sensor.\",\n \"Preferably, the user could configure the audio signal to match only his/her voice.\",\n \"At any moment, the user can signal recorder 160 to place a “bookmark” in the recording.\",\n \"This signal can be sent by pressing a button that will then transmit a signal through wires 140 that attach to the glasses then to the recorder.\",\n \"The wires 140 could be fiber optic wires that are small and thin to avoid detection.\",\n \"In an exemplary embodiment, the user could control the entire system using signaling device 150, for example by turning the camera on and off, recording a portion of image data, stop the recording, zooming in and out of image data; or transmitting protected data into the remote memory 170.While remote memory 170 is shown in the figure as a mobile or cell phone, remote memory 170 should be interpreted euphemistically to include any memory that is not connected to surveillance apparatus 100, for example, a DVD writer, a wireless network attached storage (NAS) device, a wireless storage area network (SAN) device, a home computer, or even a second surveillance apparatus.\",\n \"Preferably, sending facility 165 sends protected segments of circular buffer 167 wirelessly to remote memory 170 whenever remote memory 170 is within range of wireless transceiver 169, possibly as part of a PAN using one or more wireless communication technologies (e.g., BlueTooth, Skinplex, wireless USB, 802.11, 802.15, UWB, Z-Wave, IrDa, Zigbee, etc.).\",\n \"However, sending facility 165 could also respond to manual commands, for example through a button on signaling device 150, recorder 160, or the mobile phone itself.\",\n \"In an alternative embodiment, the mobile phone does not act as a remote memory depository, and instead forwards the protected segment to a remote memory via a mobile internet or wi-fi connection.\",\n \"Preferably, once protected data is transferred to a remote memory, the protected memory areas then will go back to become free memory areas that are available for further loop recording.\",\n \"Write-protected data could be sent to the remote memory by an image sensor that outputs data directly in “block” format typically converted with a raster-to-block converter.\",\n \"Further compression could be used before transmitting the data if wireless bandwidth is an issue.\",\n \"Either DCT or wavelet transformed data on native sensor formats could be used.\",\n \"The data is preferably transmitted via the Internet, but could also be transmitted using radio waves, a pager, a two-way pager, a physical cable, email, text message, picture message, or any other suitable communication mechanism.\",\n \"FIG.\",\n \"3 shows a diagram representation of circular buffer 167 in memory 166, with unprotected segment 320 and write-protected segment 330.Write-protected segment 330 is characterized as a predefined portion of the recording data.\",\n \"The recording facility 163 continuously records the data stream 310 into circular buffer 167.The recording facility 163 records over unprotected segment 320 of circular buffer 167, while skipping over protected segments 330 of circular buffer 167.It is contemplated that the portion of the circular buffer that is marked as write-protected data cannot be overwritten once the recorder loops back to the beginning of the media.\",\n \"FIGS.\",\n \"4A-4H show an alternative diagram representation of a circular buffer 300 as it is being used.\",\n \"In FIG.\",\n \"4A the recording facility (not shown) records data stream “A” into circular buffer 400.The “ ” character is used to designate blank memory, or unprotected memory that can be overwritten.\",\n \"The ellipsis “.\",\n \".\",\n \".\",\n \"” is used to show that the memory can be very large relative to the number of positions shown in the figure.\",\n \"It is contemplated, for example, that memory 400 can be up to several hundred megabytes, 1 GB, 2 GB, 4 GB, 8 GB, or even more.\",\n \"Such memory is preferably of a flash type, non-volatile RAM, preferably in the form of a standard flash memory card.\",\n \"In a preferred embodiment, circular buffer 400 comprises a logical representation of a physical memory area.\",\n \"Buffer 400 can be configured to store data in the physical memory by taking into account wear-leveling across the physical memory.\",\n \"In FIG.\",\n \"4B the protecting facility (not shown) has protected a recent period of data stream “A” as a function of a start signal, shown by the character “I”.\",\n \"The start signal can be triggered in any suitable manner, including for example manual operation of a trigger or a switch by a user.\",\n \"For example, the ring of FIG.\",\n \"1 could be used as a switch, or any other wearable accessory could have a switch integrated into it.\",\n \"In other examples, start signals can be triggered by detection of a particular circumstance by a motion, sound or other sensor.\",\n \"In an exemplary system, software can operate upon content in the data stream, such as by monitoring an entrance to a building using a data stream received from one or more cameras, and could then send a start signal when the image shows a person loitering in a certain area of the screen.\",\n \"The “[” character is used to designate the start of protected memory.\",\n \"Concomitantly, the portion of the data stream prior to the protected portion has once again been marked “_” to show that it is unprotected.\",\n \"In protecting recent data, the system can protect a default historical time period before the start signal is sent and protect a default period after the start signal is sent (such as 30 seconds, 2 minutes, etc).\",\n \"All suitable defaults are contemplated.\",\n \"Alternatively, the historical time period being protected could be altered in some manner, such as by software or by a user operating a history button.\",\n \"For example, if a user hits a start button, the system might default to protecting the last 30 seconds and the next 60 seconds; or it might protect the last 15 seconds and the next 2 minutes.\",\n \"Preferably, before the protecting facility stops protecting data, the system sends a signal to the user that the system is about to stop write-protecting data.\",\n \"For example, the system could send an audio chirp signal, or in the case of a pair of eyeglasses, a portion of the glasses could slightly vibrate to signal that the system will stop recording in 10 seconds.\",\n \"If the user wishes to protect an additional 60 second time period, the user could hit a “more time” button.\",\n \"In this manner a user could protect a 5 or 10 minute period, or an even much longer portion of a data stream prior to a start signal.\",\n \"Indeed, if memory 400 is interpreted as a multi gigabyte flash memory, it is entirely possible that one could back up sufficiently to protect an hour or more of such a data stream.\",\n \"In FIG.\",\n \"4C the protecting facility has received a “stop” signal some time after receiving the start signal, thereby lengthening the protected portion of the “A” data stream.\",\n \"The stop signal is shown as character “]” and could be automatically generated from software or hardware as a function of a default time after the start signal, or could be manually sent by the user of the system.\",\n \"All suitable defaults are contemplated, including for example a 30 second or 1 minute time period.\",\n \"Stop signals could also be generated in a variable fashion, again as a function of software or hardware, through action of a user, or in any other suitable manner.\",\n \"Thus, a user can well operate a start button or other switch, a more time switch, and a stop switch, which could have the same or different interfaces.\",\n \"It is also contemplated that the system could recognize a user's verbal commands for these functions.\",\n \"Just as the system can utilize a default pre-start signal period of time for which a portion of the data stream is stored unless overridden in some manner, contemplated systems can utilize a default post-start signal period of time for which a portion of the data stream is stored unless overridden in some manner.\",\n \"Using defaults for both pre-start and post-start signal periods allows a system to operate with an extremely high level of user convenience.\",\n \"For example, in one contemplated class of systems using such defaults, a user could operate a single button, ring or other interface to initiate a start signal, and the system could respond by automatically storing a default 60 second portion of a data stream prior to the signal, as well as a default 30 time period of the data stream after the signal.\",\n \"And all of that could be accomplished with a single operation of the button.\",\n \"An interface could also be provided to allow the user to alter the length of time for the pre-recorded portion and the length of time for the post-recorded portion.\",\n \"As should be apparent from the description above, all reasonable the default time periods are contemplated.\",\n \"In FIG.\",\n \"4D, the system has finished protecting the desired portion of the “A” data stream, and the recording facility continues to store a “B” data stream into circular buffer 400.Of course, the “B” data stream can be contiguous with the “A” data stream, so that differentiation of “A” and “B” streams is merely an artifact of how the data is being stored.\",\n \"For example, if a system included an eyeglasses camera being used at baseball game, the wearer might watch the game for an hour or more without anything of interest happening.\",\n \"During all that time the system would record image frames from the camera, looping in memory if the memory had remaining capacity for less than an hour of images.\",\n \"When finally the wearer sees an interesting play that he wants to protect, he operates a start button, or perhaps a more time button to protect the previous minute of play.\",\n \"Once the interesting action has completed, he operates a stop button, which thereby causes the system to complete protecting the entire “A” period of interest.\",\n \"But the wearer continues watching the game, and the subsequent images, continuous with the “A” images, would be considered “B” images.\",\n \"In some embodiments, the wearer can select to have more of previously recorded data to be protected.\",\n \"For example, once the wearer operates the start button, the wearer could also indicates that additional previously recorded data should be protected (e.g., past 10 seconds, 30 seconds, one minute, five minutes, etc.)\",\n \"while new image data is being stored and protected.\",\n \"In FIG.\",\n \"4E the system has again received a start signal, and has again protected a fixed or variable historical time period.\",\n \"In FIG.\",\n \"4F the system has received a stop signal, and has protected the entire desired portion of the “B” data stream.\",\n \"In FIG.\",\n \"4G the system has continued to record data, which is now depicted as data stream “C” because it follows data stream “B”.\",\n \"This figure is particularly significant in that recordation of the “C” data stream skips over the protected portion of the “A” data stream.\",\n \"In FIG.\",\n \"4H the system received another start signal, and has protected a desired portion of the “C” data stream that straddles the protected “A” stream.\",\n \"As shown, the C data stream is saved as a physically dis-contiguous file.\",\n \"In a preferred embodiment, segments of recorded data are “write-protected” by being indexed in an electronic index.\",\n \"This scheme allows the system to protect previously recorded areas of memory without interrupting any concurrent recording, and further allows the system to easily locate such protected segments for play-back or offloading to a remote memory.\",\n \"Additionally, this allows the system to keep track of multiple fragments dis-contiguous fragments of a single write-protected segment.\",\n \"The electronic index is preferably a hash table or a clustered index, but other methods of addressing memory are also suitable.\",\n \"Protected data can be copied to a memory separate from the circular buffer, for example in a separate file within a local memory.\",\n \"Multiple segments of protected data could thus be stored as a series of protected files in a directory structure.\",\n \"In an exemplary embodiment, as soon as the data is designated in the index as being protected, the recorder searches for a remote memory in range, and immediately copies the protected data from the circular buffer to the remote memory.\",\n \"Once confirmation of copying is received, the index can be updated to identify the previously protected portion of the circular buffer as being non-protected.\",\n \"As previously discussed, a sending facility uses a wireless transmitter to transmit write-protected data to a remote memory.\",\n \"One should note that there are many additional aspects of the inventive subject matter surrounding transmitting the data to the remote memory.\",\n \"In some embodiments a surveillance apparatus participates in a PAN with other components including the remote memory.\",\n \"In such embodiments the apparatus can discover other components of the system, including the remote memory or signaling devices, by sending message over one or more suitable protocols (e.g., BlueTooth, Skinplex, wireless USB, 802.11, 802.15, 802.16, UWB, Z-Wave, IrDA, Zigbee, etc.).\",\n \"Component discovery can be via a push where the apparatus sends a discovery message over a protocol to remote components or via a pull where the remote components send a discovery message to the apparatus.\",\n \"The components of the system can respond with a discovery response message.\",\n \"Preferred discovery or discovery response messages comprise characteristics of the various responding components including buffer size, read/write rates, authentication, authorized command sets, or other parameters.\",\n \"For example, the surveillance apparatus could send a discovery message out to discover any suitable remote memories in the PAN where the message is encapsulated in a BlueTooth protocol packet.\",\n \"A cell phone could respond by allocating a memory area to operate as a remote memory and by sending a discovery response message back to the apparatus describing the amount of memory available.\",\n \"Such an approach provides for creating surveillance apparatus products that are able to operate across multiple cell phone platforms by allowing a cell phone user to download or install an application, or possibly a driver for their specific cell phone model, capable of being discovered and operating with the apparatus.\",\n \"Another aspect of transmitting data to the remote memory includes authenticating the various components with respect to access or to control remote memory.\",\n \"In some embodiments, the surveillance apparatus, or even the signaling facility, can be authenticated with the remote memory via a suitable token exchange (e.g., passwords, public-private key, handshakes, etc.).\",\n \"For example, a remote memory could be bound to a specific apparatus via a secret key, possibly having a UUID or GUID.\",\n \"Furthermore, the components of the system can be authorized to access various levels of functionality based on their authentication.\",\n \"Some apparatus could have read only access, while other could have write access, or while still others have editing capabilities.\",\n \"Yet another aspect of transmitting data to the remote memory includes the remote memory providing access to multiple surveillance apparatus.\",\n \"For example, a single remote memory, possibly a cell phone, could be in close proximity (e.g., physically local within 100 meters or logically local within the same network) to two or more apparatus.\",\n \"The remote memory can provide image storage as necessary to each apparatus, assuming appropriate authentication or permissions.\",\n \"In addition, it is contemplated that a single apparatus could have more than one camera where each camera has its data transmitted to the remote memory collectively via the apparatus or even individually, possibly where each camera has access to different remote memories, or different areas (e.g., files) in the same remote memory.\",\n \"One should also note that a surveillance apparatus can employ multiple wireless protocols to interact with the various components.\",\n \"For example, the apparatus's signaling device could connect to a recorded via Zigbee or Skiplex protocols while the apparatus could connect to the remote memory via IEEE 802.16.One purpose of the invention is to allow secret recording by a user.\",\n \"The user can integrate the recorder as part of his/her wardrobe or even as clothing accessories, such as a pin or a hat.\",\n \"Preferably, recorder will record video and audio as seen from the wearer's point of view without requiring the wearer to exert any special effort to operate the recorder.\",\n \"The recorder operates for extended periods of time while remaining unobtrusive both to the wearer/operator and to the subject(s) being recorded.\",\n \"In order for the device to be practical, physical size and weight are of primary importance.\",\n \"The recorder portion must be small and lightweight enough to be unobtrusive.\",\n \"Preferably, the size of the recorder is two inches by three inches by one-half inch and six ounces in weight including battery.\",\n \"The camera or imaging component must be small and lightweight enough to be mounted on a pair of eyeglasses without conspicuous bulk or uncomfortable weight on the order of one-quarter inch by one-quarter inch by one inch or smaller and weighing one ounce or less.\",\n \"Further, the imaging component must be capable of sufficient resolution that the image quality of the resulting recording is comparable with existing consumer camcorder products.\",\n \"Preferred resolutions are at least 640×480 pixels.\",\n \"However, more preferred resolutions include high definition quality resolutions (e.g., 720p, 1080i, 1080p, 2160p, etc.).\",\n \"Since the recorder will be worn on the body and the wearer can move actively about when the device is in operation, it is important that the entire device be mechanically rugged and that all components, particularly the storage media, be impervious to the shocks resulting from such body movement.\",\n \"The device is also likely to be exposed to environmental stresses such as dust and moisture so the components and packaging must accommodate this exposure.\",\n \"Solid state media such as compact flash memory is particularly suitable as the recorder's storage media since it meets these requirements.\",\n \"Alternatively, the recorder device can be mounted on vehicles, planes or any other objects for ease of use.\",\n \"It is contemplated that the present invention can be used in military or field intelligence operations.\",\n \"The advantages of the disclosed techniques are clear.\",\n \"A user of the inventive subject matter can capture image data while also participating with others in an event without being trapped behind a recording device.\",\n \"Furthermore, the user's hands can remain substantially free while recording.\",\n \"Thus, specific embodiments and applications of recording images to a circular buffer in a local memory and transmitting it wirelessly to a remote memory have been disclosed.\",\n \"It should be apparent, however, to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein.\",\n \"The inventive subject matter, therefore, is not to be restricted except in the spirit of the appended claims.\",\n \"Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context.\",\n \"In particular, the terms “comprises” and “comprising” should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps can be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced.\",\n \"Where the specification claims refers to at least one of something selected from the group consisting of A, B, C .\",\n \".\",\n \".\",\n \"and N, the text should be interpreted as requiring only one element from the group, not A plus N, or B plus N, etc.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875828"}}},{"rowIdx":4494990,"cells":{"text":{"kind":"list like","value":[["Interlaced Multiband Antenna Arrays","Antenna arrays which can work simultaneously in various frequency bands thanks to the physical disposition of the elements which constitute them, and also the multiband behavior of some elements situated strategically in the array.","The configuration of the array is described based on the juxtaposition or interleaving of various conventional mono-band arrays working in the different bands of interest.","In those positions in which elements of different multiband arrays come together, a multiband antenna is employed which covers the different working frequency bands.","The advantages with respect to the classic configuration of using one array for each frequency band are: saving in cost of the global radiating system and its installation (one array replaces several), and its size and visual and environmental impact are reduced in the case of base stations and repeater stations for communication systems."],["1.An antenna array comprising: a ground plane layer; a first set of antenna elements arranged on the ground plane layer and being configured to provide operation of the antenna array in at least three frequency bands respectively corresponding to three cellular frequency bands; a second set of antenna elements arranged on the ground layer and being configured to provide operation of the antenna array in two of the three frequency bands; the first set of antenna elements and the second set of antenna elements are substantially arranged along a longitudinal direction of the antenna array; the first set of antenna elements and the second set of antenna elements are arranged on alternating positions along the longitudinal direction; and wherein a ratio of a spacing between antenna elements of the first set to a wavelength of a first frequency band of the three frequency bands is substantially half of a ratio of a spacing between antenna elements of the second set to a wavelength of a second frequency band of the three frequency bands.","2.The antenna array of claim 1, wherein a ratio between a frequency of the third frequency band and a frequency of the second frequency band is less than 1.5.3.The antenna array of claim 1, wherein a frequency for the first frequency band is situated around 900 MHz, a frequency for the second frequency band is situated around 1800 MHz, and a frequency for the third frequency band is situated around 2100 MHz.","4.The antenna array of claim 1, wherein the three frequency bands are not separated by the same scale factor.","5.A communication system comprising: a network of base stations comprising a plurality of base stations, at least some of the plurality of base stations comprising the antenna array of claim 1.6.An antenna array comprising: a ground plane layer; a first plurality of antenna elements arranged on the ground plane and being configured to provide operation of the antenna array in at least first and second frequency bands respectively corresponding to two cellular frequency bands, the first and second frequency bands being non-overlapping frequency bands; and a second plurality of antenna elements arranged on the ground plane layer and being configured to provide operation of the antenna array in the second frequency band, wherein the first plurality of antenna elements and the second plurality of antenna elements are substantially arranged along a longitudinal direction of the antenna array; and a ratio of a spacing between antenna elements providing operation at the first frequency band to an operating wavelength of the first frequency band is substantially the same as a ratio of a spacing between antenna elements providing operation at the second frequency band to an operating wavelength of the second frequency band.","7.The antenna array of claim 6, wherein the antenna elements of the first plurality and the antenna elements of the second plurality are arranged in alternating positions along the longitudinal direction of the antenna array.","8.The antenna array of claim 7, wherein a ratio between an operating frequency of the second frequency band and an operating frequency of the first frequency band is greater than two.","9.The antenna array of claim 6, wherein each antenna element of the first plurality of antenna elements comprises a plurality of electromagnetically coupled portions configured to interact with each other.","10.The antenna array of claim 9, further comprising a first distribution network configured to excite the first plurality of antenna elements, and a second distribution configured to excite the antenna elements providing operation at the second frequency band.","11.A communication system comprising: a network of base stations comprising a plurality of base stations, at least some of the plurality of base stations comprising the antenna array of claim 6.12.An antenna array comprising: a ground plane layer; a plurality of antenna elements arranged on the ground plane layer along a longitudinal direction of the antenna array; a first distribution network configured to excite the plurality of antenna elements for a first polarization; and a second distribution network configured to excite the plurality of antenna elements for a second polarization, the first and second polarizations being orthogonal polarizations, wherein: the plurality of antenna elements are configured to provide operation of the antenna array in three frequency bands respectively associated with three cellular frequency bands; the highest frequency of a first frequency band of the three frequency bands is less than the lowest frequency of a second frequency band of the three frequency bands and the lowest frequency of a third frequency band of the three frequency bands is greater than the highest frequency of the second frequency band; a ratio between a frequency of the third frequency band and a frequency of the first frequency band being smaller than 1.5; a spacing between the antenna elements of the plurality of antenna elements is less than a wavelength of the lowest operating frequency of the first frequency band; and a spacing between the antenna elements of the plurality of antenna elements is greater than a half wavelength of the highest frequency of the third frequency band.","13.The antenna array of claim 12, wherein a first spacing between a first pair of adjacent antenna elements of the plurality of antenna elements is different from a second spacing between a second pair of adjacent antenna elements of the plurality of antenna elements.","14.The antenna array of claim 12, wherein any operating frequencies of the third frequency band does not correspond to an integer factor of an operating frequency of the first frequency band.","15.The antenna array of claim 12, wherein the three frequency bands are not separated by the same scale factor.","16.The antenna array of claim 12, wherein the antenna elements of the plurality of antenna elements comprises patch antennas.","17.A communication system comprising: a network of base stations comprising a plurality of base stations, at least some of the plurality of base stations comprising the antenna array according to claim 12."],["<SOH> BACKGROUND <EOH>The present invention consists of antenna arrays which can be operated simultaneously in various frequency bands thanks to the physical disposition of the elements that constitute it, as well as the multiband behavior of some elements situated strategically in the array.","The array configuration is described on a basis of the juxtaposition or interleaving of various conventional single-band arrays operating in the different bands of interest.","In those positions where elements of different multiband arrays come together, use is made of a multiband antenna which covers the different working frequency bands.","The use of a multiband interleaved antenna array (hereinafter simply Multiband Interleaved Array, MIA) implies a great advantage over the classical solution of employing an array for each frequency band: there is a cost saving in the overall radiating system and in its installation (one array replaces several), its size is reduced as well as its visual and environmental impact in the case of base and repeater stations for communication systems.","The present invention finds its application in the field of telecommunications and more specifically in radio-communication systems.","Antennas started to be developed at the end of the nineteenth century based on the fundamental laws of electromagnetism postulated by James Clerk Maxwell in 1864.The invention of the first antenna has to be attributed to Heinrich Hertz in 1886 who demonstrated the transmission through air of electromagnetic waves.","In the mid-1940's the fundamental restrictions regarding the reduction in size of antennas were shown with respect to wavelength and at the beginning of the sixties appeared the first frequency-independent antennas (E. C. Jordan, G. A. Deschamps, J. D. Dyson, P. E. Mayes, “Developments in Broadband Antennas,” IEEE Spectrum, vol.","1, pp.","58-71, April 1964; V. H. Rumsey, Frequency-Independent Antennas.","New York Academic, 1966; R. L. Carrel, “Analysis and design of the log-periodic dipole array,” Tech.","Rep. 52, Univ.","of Illinois Antenna Lab., Contract AF33 (616)-6079, October 1961; P. E. Mayes, “Frequency Independent Antennas and Broad-Band Derivatives Thereof”, Proc.","IEEE, vol.","80, no.","1, January 1992).","At that time proposals were made for helical, spiral, log-periodic arrays, cones and structures defined exclusively by angle pieces for the implementation of broadband antennas.","Antenna array theory goes back to the works of Shelkunoff (S. A. Schellkunhoff, “A Mathematical Theory of Linear Arrays,” Bell System Technical Journal, 22,80), among other classic treatises on antenna theory.","Said theory establishes the basic design rules for shaping the radiation properties of the array (principally its radiation pattern), though its application is restricted mainly to the case of mono-band arrays.","The cause of said restriction lies in the frequency behavior of the array being highly dependent on the ratio between the distance between elements (antennas) of the array and the working wavelength.","Said spacing between elements is usually constant and preferably less than one wavelength in order to prevent the appearance of diffraction lobes.","This implies that once the spacing between elements is fixed, the operating frequency (and the corresponding wavelength) is also fixed, it being particularly difficult that the same array work simultaneously at another higher frequency, given that in that case the magnitude of the wavelength is less than the spacing between elements.","The log-periodic arrays suppose one of the first examples of antenna arrays capable of covering a broad range of frequencies (V. H. Rumsey, Frequency-Independent Antennas.","New York Academic, 1966; R. L. Carrel, “Analysis and design of the log-periodic dipole array,” Tech.","Rep. 52, Univ.","Illinois Antenna Lab., Contract AF33 (616)-6079, October 1961; P. E. Mayes, “Frequency Independent Antennas and Broad-Band Derivatives Thereof”, Proc.","IEEE, vol.","80, no.","1, January 1992).","Said arrays are based on distributing the elements that constitute it in such a manner that the spacing between adjacent elements and their length vary according to a geometric progression.","Although said antennas are capable of maintaining a same radiation and impedance pattern over a broad range of frequencies, their application in practice is restricted to some concrete cases due to their limitations regarding gain and size.","Thus for example, said antennas are not employed in cellular telephony base stations because they do not have sufficient gain (their gain is around 10 dBi when the usual requirement is for about 17 dBi for such application), they usually have linear polarization whilst in said environment antennas are required with polarization diversity, their pattern in the horizontal plane does not have the width necessary and their mechanical structure is too bulky.","The technology of individual multiband antennas is markedly more developed.","A multiband antenna is understood to be an antenna formed by a set of elements coupled to each other electromagnetically which interact with each other in order to establish the radio-electric behavior of the antenna, behavior which with respect to radiation and impedance patterns is similar in multiple frequency bands (hence the name multiband antenna).","Numerous examples of multiband antennas are described in the literature.","In 1995 antennas of the fractal or multifractal type were introduced (the coining of the terms fractal and multifractal is attributable to B.","B. Mandelbrot in his book The Fractal Geometry of Nature, W. H. Freeman and Co. 1983), antennas which by their geometry have a multifrequency behavior and, in determined cases, a reduced size (C. Puente, R. Pous, J. Romeu, X. Garcia “Antenas Fractales o Mulitfractales,” (Spanish patent P9501019).","Subsequently multi-triangular antennas were introduced (Spanish patent P9800954) which could work simultaneously in the GSM 900 and GSM 1800 bands and, more recently, multilevel antennas (Patent PCT/ES99/00296), which offer a clear example of how it is possible to shape the geometry of the antenna in order to achieve a multiband behavior."],["<SOH> SUMMARY <EOH>The present invention describes how multiband antennas can be combined in order to obtain an array that works simultaneously in several frequency bands.","A Multiband Interleaved Array (MIA) consists of an array of antennas which has the particularity of being capable of working simultaneously in various frequency bands.","This is achieved by means of using multiband antennas in strategic positions of the array.","The disposition of the elements that constitute the MIA is obtained from the juxtaposition of conventional mono-band arrays, employing as many mono-band arrays as frequency bands that it is wished to incorporate in the Multiband Interleaved Array.","In those positions in which one or various elements originating in the conventional mono-band arrays coincide, a single multiband antenna (element) shall be employed which covers simultaneously the different bands.","In the remaining non-concurrent positions, it can be chosen to employ also the same multiband antenna or else recur to a conventional mono-band antenna which works at the pertinent frequency.","The excitation at one or various frequencies of each element of the array depends therefore on the position of the element in the array and is controlled by means of the signal distribution network."],["CROSS REFERENCE TO RELATED APPLICATIONS This patent application is a continuation of U.S. patent application Ser.","No.","14/529,715, filed on Oct. 31, 2014, which is a continuation of U.S. patent application No.","13/530,249, filed on Jun.","22, 2012, which is now U.S. Pat.","No.","8,896,493, issued on Nov. 25, 2014, which is a continuation of U.S. patent application Ser.","No.","13/044,831, filed on Mar.","10, 2011, which is now U.S. Pat.","No.","8,228,256, issued on Jul.","24, 2012, which is a continuation of U.S. patent application Ser.","No.","12/476,308, filed on Jun.","2, 2009, which is now U.S. Pat.","No.","7,932,870, issued on Apr.","26, 2011, which is a continuation of U.S. patent application Ser.","No.","11/803,782, filed on May 16, 2007, which is now U.S. Pat.","No.","7,557,768, issued on Jul.","7, 2009, which is a continuation of U.S. patent application Ser.","No.","10/988,261, filed on Nov. 12, 2004, which is now U.S. Pat.","No.","7,250,918, issued on Jul.","31, 2007, which is a continuation of U.S. patent application Ser.","No.","10/135,019, filed on Apr.","23, 2002, which is now U.S. Pat.","No.","6,937,191, issued on Aug. 30, 2005, which is a continuation of International Application No.","PCT/ES99/00343, filed on Oct. 26, 1999, the entire contents of which are hereby incorporated by reference.","BACKGROUND The present invention consists of antenna arrays which can be operated simultaneously in various frequency bands thanks to the physical disposition of the elements that constitute it, as well as the multiband behavior of some elements situated strategically in the array.","The array configuration is described on a basis of the juxtaposition or interleaving of various conventional single-band arrays operating in the different bands of interest.","In those positions where elements of different multiband arrays come together, use is made of a multiband antenna which covers the different working frequency bands.","The use of a multiband interleaved antenna array (hereinafter simply Multiband Interleaved Array, MIA) implies a great advantage over the classical solution of employing an array for each frequency band: there is a cost saving in the overall radiating system and in its installation (one array replaces several), its size is reduced as well as its visual and environmental impact in the case of base and repeater stations for communication systems.","The present invention finds its application in the field of telecommunications and more specifically in radio-communication systems.","Antennas started to be developed at the end of the nineteenth century based on the fundamental laws of electromagnetism postulated by James Clerk Maxwell in 1864.The invention of the first antenna has to be attributed to Heinrich Hertz in 1886 who demonstrated the transmission through air of electromagnetic waves.","In the mid-1940's the fundamental restrictions regarding the reduction in size of antennas were shown with respect to wavelength and at the beginning of the sixties appeared the first frequency-independent antennas (E. C. Jordan, G. A. Deschamps, J. D. Dyson, P. E. Mayes, “Developments in Broadband Antennas,” IEEE Spectrum, vol.","1, pp.","58-71, April 1964; V. H. Rumsey, Frequency-Independent Antennas.","New York Academic, 1966; R. L. Carrel, “Analysis and design of the log-periodic dipole array,” Tech.","Rep. 52, Univ.","of Illinois Antenna Lab., Contract AF33 (616)-6079, October 1961; P. E. Mayes, “Frequency Independent Antennas and Broad-Band Derivatives Thereof”, Proc.","IEEE, vol.","80, no.","1, January 1992).","At that time proposals were made for helical, spiral, log-periodic arrays, cones and structures defined exclusively by angle pieces for the implementation of broadband antennas.","Antenna array theory goes back to the works of Shelkunoff (S. A. Schellkunhoff, “A Mathematical Theory of Linear Arrays,” Bell System Technical Journal, 22,80), among other classic treatises on antenna theory.","Said theory establishes the basic design rules for shaping the radiation properties of the array (principally its radiation pattern), though its application is restricted mainly to the case of mono-band arrays.","The cause of said restriction lies in the frequency behavior of the array being highly dependent on the ratio between the distance between elements (antennas) of the array and the working wavelength.","Said spacing between elements is usually constant and preferably less than one wavelength in order to prevent the appearance of diffraction lobes.","This implies that once the spacing between elements is fixed, the operating frequency (and the corresponding wavelength) is also fixed, it being particularly difficult that the same array work simultaneously at another higher frequency, given that in that case the magnitude of the wavelength is less than the spacing between elements.","The log-periodic arrays suppose one of the first examples of antenna arrays capable of covering a broad range of frequencies (V. H. Rumsey, Frequency-Independent Antennas.","New York Academic, 1966; R. L. Carrel, “Analysis and design of the log-periodic dipole array,” Tech.","Rep. 52, Univ.","Illinois Antenna Lab., Contract AF33 (616)-6079, October 1961; P. E. Mayes, “Frequency Independent Antennas and Broad-Band Derivatives Thereof”, Proc.","IEEE, vol.","80, no.","1, January 1992).","Said arrays are based on distributing the elements that constitute it in such a manner that the spacing between adjacent elements and their length vary according to a geometric progression.","Although said antennas are capable of maintaining a same radiation and impedance pattern over a broad range of frequencies, their application in practice is restricted to some concrete cases due to their limitations regarding gain and size.","Thus for example, said antennas are not employed in cellular telephony base stations because they do not have sufficient gain (their gain is around 10 dBi when the usual requirement is for about 17 dBi for such application), they usually have linear polarization whilst in said environment antennas are required with polarization diversity, their pattern in the horizontal plane does not have the width necessary and their mechanical structure is too bulky.","The technology of individual multiband antennas is markedly more developed.","A multiband antenna is understood to be an antenna formed by a set of elements coupled to each other electromagnetically which interact with each other in order to establish the radio-electric behavior of the antenna, behavior which with respect to radiation and impedance patterns is similar in multiple frequency bands (hence the name multiband antenna).","Numerous examples of multiband antennas are described in the literature.","In 1995 antennas of the fractal or multifractal type were introduced (the coining of the terms fractal and multifractal is attributable to B.","B. Mandelbrot in his book The Fractal Geometry of Nature, W. H. Freeman and Co. 1983), antennas which by their geometry have a multifrequency behavior and, in determined cases, a reduced size (C. Puente, R. Pous, J. Romeu, X. Garcia “Antenas Fractales o Mulitfractales,” (Spanish patent P9501019).","Subsequently multi-triangular antennas were introduced (Spanish patent P9800954) which could work simultaneously in the GSM 900 and GSM 1800 bands and, more recently, multilevel antennas (Patent PCT/ES99/00296), which offer a clear example of how it is possible to shape the geometry of the antenna in order to achieve a multiband behavior.","SUMMARY The present invention describes how multiband antennas can be combined in order to obtain an array that works simultaneously in several frequency bands.","A Multiband Interleaved Array (MIA) consists of an array of antennas which has the particularity of being capable of working simultaneously in various frequency bands.","This is achieved by means of using multiband antennas in strategic positions of the array.","The disposition of the elements that constitute the MIA is obtained from the juxtaposition of conventional mono-band arrays, employing as many mono-band arrays as frequency bands that it is wished to incorporate in the Multiband Interleaved Array.","In those positions in which one or various elements originating in the conventional mono-band arrays coincide, a single multiband antenna (element) shall be employed which covers simultaneously the different bands.","In the remaining non-concurrent positions, it can be chosen to employ also the same multiband antenna or else recur to a conventional mono-band antenna which works at the pertinent frequency.","The excitation at one or various frequencies of each element of the array depends therefore on the position of the element in the array and is controlled by means of the signal distribution network.","BRIEF DESCRIPTION OF THE DRAWINGS The characteristics expounded in the foregoing, are presented in graphical form making use of the figures in the drawings attached, in which is shown by way of a purely illustrative and not restrictive example, a preferred form of embodiment.","In said drawings: FIG.","1 shows the position of the elements of two classic mono-band arrays which work at frequencies f and f/2 respectively, and the disposition of elements in a multiband interleaved array, which has a dual frequency behavior (at frequencies f and f/2), working in the same manner as classic arrays but with a smaller total number of elements.","FIG.","2 shows another particular example of multiband interleaved array but with three frequencies in this case, and the respective three classic mono-band arrays which constitute it.","It is a matter of extending the case of FIGS.","1 to 3 frequencies f, f/2 and f/4.FIG.","3 shows another particular example of multiband interleaved array, in which the different working frequencies are not separated by the same scale factor.","It is a matter of extending the case of FIGS.","1 and 2 to 3 frequencies f, f/2 and f/3.FIG.","4 shows a further particular example of multiband interleaved array, in which the different working frequencies are not separated by the same scale factor.","It is a matter of extending the case of FIGS.","3 to 3 frequencies f, f/3 and f/4.FIG.","5 shows a multiband interleaved array configuration which requires a repositioning of the elements to obtain frequencies that do not correspond to an integer factor of the highest frequency.","In this particular example the frequencies f, f/2 and f/2.33 have been chosen.","FIG.","6 shows the extension of the design of an MIA to the two-dimensional or three-dimensional case, specifically, an extension of the example of FIG.","1 to two dimensions.","FIG.","7 shows one of the preferred of operating modes (AEM1).","It is a matter of an MIA in which the multiband elements are multi-triangular elements.","The array works simultaneously at dual frequencies, for example in the GSM 900 and GSM 1800 bands.","FIG.","8 shows another of the preferred operating modes (AEM2).","It is a matter of an MIA in which the multiband elements are multilevel elements.","The array works simultaneously at dual frequencies, for example in the GSM 900 and GSM 1800 bands.","FIG.","9 shows another of the preferred operating modes (AEM3).","It is a matter of an MIA in which the multiband elements are multilevel elements.","The configuration is similar to that of FIG.","8 (AEM2 mode), the difference being that the new disposition permits the total width of the antenna to be reduced.","FIG.","10 shows another example of multiband antenna which can be employed in MIAs.","It is a matter of a stacked patch antenna, which in this specific example works at two dual frequencies (for example, GSM 900 and GSM 1800).","FIG.","11 shows the disposition of said patches in the MIA type array (AEM4 configuration).","Observe that, in contrast to the previous cases, in this case multiband antennas are employed only in those positions where it is strictly necessary; in the remainder mono-band elements are employed the radiation pattern of which is sufficiently like that of the multiband element in the pertinent band.","FIG.","12 shows another configuration (AEM5), in which the elements have been rotated through 45° in order to facilitate the procurement of double polarization at +45° or −45°.","DETAILED DESCRIPTION In making the detailed description that follows of the preferred embodiment of the present invention, reference shall constantly be made to the figures of the drawings, throughout which use has been made of the same numerical references for the same or similar parts.","A multiband interleaved array (MIA) is constituted by the juxtaposition of various conventional mono-band arrays.","The conventional antenna arrays usually have a mono-band behavior (that is, they work within a relatively small frequency range, typically of the order of 10% about a center frequency) and this is not only because the elements (antennas) that constitute it have a mono-band behavior, but also because the physical spacing between elements conditions the working wavelength.","Typically, the conventional mono-band arrays are designed with a spacing between elements of around a half-wavelength, spacing which may be increased in some configurations in order to enhance directivity, though it is usually kept below one wavelength to avoid the appearance of diffraction lobes.","This purely geometric restriction (the magnitude of the wavelength conditions the geometry of the elements of the array and their relative spacing) signifies a major drawback in those environments and communication systems in which various frequency bands have to be employed simultaneously.","A clear example is the GSM cellular mobile telephony system.","Initially located in the 900 MHz band, the GSM system has turned into one of the most widespread on a world scale.","The success of the system and the spectacular growth in demand for this type of service has led to the cellular mobile telephony operators expanding its service into a new band, the 1800 MHz band, in order to provide coverage for a greater customer base.","Making use of classic mono-band antenna technology, the operators have to duplicate their antenna network in order to provide coverage simultaneously to GSM 900 and GSM 1800.Using a single MIA specially designed for the system (like that described in the particular cases of FIGS.","7 through 12), the operators reduce the cost of their network of base stations, the time to expand into the new band and the visual and environmental impact of their installations (through the simplification of the overall radiating structure).","It is important to point out that the scenario which has just been outlined above deals only with one particular example of a type of MIA and its application; as may well be gauged by anyone familiar with the subject, in no way are the MIAs which are described in the present invention restricted to said specific configuration and can easily be adapted to other frequencies and applications.","The multiband interleaved arrays base their operation on the physical disposition of the antennas which constitute them and on the particular type of element that is employed in some strategic positions of the array.","The positions of the elements in an MIA are determined from the positions of the elements in as many mono-band arrays as there are frequencies or frequency bands required.","The design of the array is, in that sense, equal to that of the mono-band arrays insomuch as it is possible to choose the current weighting for each element, in order to shape the radiation pattern according to the needs of each application.","The configuration of the MIA is obtained from the juxtaposition of the positions of the different mono-band arrays.","Naturally, such juxtaposition proves difficult to implement in practice in those positions in which various antennas of the different arrays coincide; the solution proposed in this invention rests in the use of a multiband antenna (for example of the fractal, multi-triangular, multi-level, etc.","type) which covers all the frequencies associated with its position.","A basic and particular example of how to arrange the elements in an MIA is described in FIG.","1.In the columns of the FIG.","1 (1a) and (1b) two conventional mono-band arrays are shown in which the positions of the elements (indicated by the black circles and the circumferences respectively) are chosen in such a manner that the spacing between elements is typically less than the working wavelength.","Thus, taking as reference the working frequency f of the array (1a), the array (1b) would work at a frequency f/2 as the elements have a spacing double that of the previous case.","In FIG.","1 (column 1c) the disposition is shown of the elements in the MIA which is capable of working simultaneously on the frequencies f and f/2 conserving basically the same facilities as the two arrays (1a) and (1b).","In the positions in which elements of the two conventional arrays (indicated in FIG.","1 (1c) by means of black circles located at the center of a circumference) coincide, a multiband antenna is employed capable of working in the same manner (same impedance and pattern) on the frequencies (1a) and (1b).","The remaining not common elements (indicated either by a black circle, or by a circumference) can be implemented either by means of the same multiband element employed in the common positions (and selecting the working frequency by means of the signal distribution network of the array), or by employing conventional mono-band elements.","In this example the array (1c) has a dual behavior frequency-wise (at frequencies f and f/2), working in the same manner as the arrays (1a) and (1b) but with a smaller total number of elements (12 instead of 16).","Multiple examples of multiband antennas are already described in the state of the art.","Antennas with fractal geometry, multi-triangular antennas, multi-level antennas even stacked patch antennas are some examples of antennas capable of working in like manner in multiple frequency bands.","These, and other multiband elements can be employed in the positions of the MIAs in which elements of various mono-band arrays come together.","In the following figures other MIA configurations are shown, based on the same inventive concept, though having the disposition of the elements adapted to other frequencies.","In FIG.","2 the configuration described is that of a tri-band MIA working at frequencies f, f/2 and f/4.The disposition of elements in the three classic mono-band arrays at the frequencies f, f/2 and f/4 is illustrated in the columns of FIGS.","2 (2a), (2b) and (2c) by means of black circles, circumferences and squares respectively.","The position of the elements of the MIA is determined from the configuration of the three mono-band arrays designed for each one of the three frequencies.","The three arrays come together in the MIA that is shown in column 2d of FIG.","2.In those positions where elements of the three arrays would come together (indicated in the drawing by the juxtaposition of the different geometric figures identifying each array) use is made of a multiband element.","The three-frequency array of column (2d) behaves in the same manner as the three arrays (2a), (2b) and (2c) at their respective working frequencies, but employing only 13 elements instead of the 21 required in the total of the three mono-band arrays.","FIGS.","3, 4 and 5 describe, by way of example and not restrictively, the design of other MIAs based on the same principle though at other frequencies.","In the first two cases the frequencies employed are integer multiples of a fundamental frequency; in the case of FIG.","5 the ratio between frequencies is not restricted to any particular rule, though it supposes an example of array in which the frequencies the GSM 900, GSM 1800 and UMTS services can be combined.","Specifically, FIG.","3 illustrates another particular example of multiband interleaved array, in which the different working frequencies are not separated by the same scale factor.","It concerns the extension of the case of FIGS.","1 and 2 to 3 frequencies f, f/2 and f/3.The disposition of elements of the three classic mono-band arrays at the frequencies f, f/2 and f/3 is shown in the columns of FIGS.","3 (3a), (3b) and (3c) by means of black circles, circumferences and squares respectively.","The column (3d) of FIG.","3 shows the disposition of elements in the tri-band interleaved array.","In those positions in which elements of the three arrays come together (indicated in the drawing by the juxtaposition of the different geometric figures identifying each array), use is made of a multiband element; the same strategy is followed in those positions in which elements of two arrays coincide: use should be made of a multiband element capable of covering the frequencies pertinent to its position, preferentially the same element as that used in the remaining positions, selecting those frequencies which are necessary by means of the feeder network.","Notice that as the three-frequency array of column (3d) of FIG.","3 behaves in the same manner as the three arrays (3a), (3b) and (3c) at their respective working frequencies, but employing only 12 elements instead of the 21 required in the total of the three mono-band arrays.","FIG.","4 illustrates a new particular example of multiband interleaved array, in which the different working frequencies are not separated by the same scale factor.","It concerns the extension of the case of FIGS.","3 to 3 frequencies f, f/3 and f/4.The disposition of elements of the three classic mono-band arrays at the frequencies f, f/3 and f/4 are shown in the columns of FIGS.","4 (4a), (4b) and (4c) by means of black circles, circumferences and squares respectively.","The column (4d) of FIG.","4 shows the disposition of elements in the tri-band interleaved array.","In those positions where elements of the three arrays would come together (indicated in the drawing by the juxtaposition of the different geometric figures identifying each array), use is made of a multiband element.","The three-frequency array of column (4d) of FIG.","4 behaves in the same manner as the three arrays (4a), (4b) and (4c) at their respective working frequencies, but employing only 15 elements instead of the 24 required in the total of the three mono-band arrays.","It is convenient to re-emphasis that in the particular cases of FIGS.","3 and 4 the arrays can work at 3 frequencies simultaneously.","The disposition of elements is such that the three frequencies do not always coincide in all the elements; nonetheless, by employing a tri-band antenna in those positions and selecting the working frequencies for example by means of a conventional frequency-selective network, it is possible to implement the MIA.","In some configurations of multiband interleaved array, especially in those in which the different frequencies do not correspond to an integral factor of the highest frequency 1, it is required that the elements be repositioned, as in FIG.","5.In this particular example the frequencies f, f/2 and f/2,33 have been chosen.","The disposition of elements of the three classic mono-band arrays at the frequencies f, f/2 and f/2.33 is represented in the columns of FIGS.","5 (5a), (5b) and (5c) by means of black circles, circumferences and squares respectively.","The column (5d) of FIG.","5 shows what would be the disposition of elements in the tri-band interleaved array according to the same plan as in the previous examples.","Notice how in this case the ratio of frequencies involves the collation of elements at intermediate positions which make its practical implementation difficult.","The solution to be adopted in this case consists in displacing the position of the element of the array that works at the lowest frequency (indicated by arrows) until it coincides with another element (that nearest) of the highest frequency array; then the two or more coincident elements in the new position are replaced with a multiband element.","An example of the final configuration once the elements have been repositioned, is shown in column (5e) of FIG.","5.It is important that the element displaced be preferentially that of the lowest frequency array, in this way the relative displacement in terms of the working wavelength is the least possible and the appearance of secondary or diffraction lobes is reduced to the minimum.","FIG.","6 illustrates how the configuration MIAs is not limited to the linear (one-dimensional) case, but it also includes arrays in 2 and 3 dimensions (2D and 3D).","The procedure for distributing the elements of the array in the 2D and 3D cases is the same, replacing also the different coincident elements with a single multiband antenna.","More examples of particular configurations of MIAs are described below.","In the five examples described, various designs are presented for GSM 900 and GSM 1800 systems (890 MHz-960 MHz and 1710 MHz-1880 MHz bands).","It is a question of antennas for cellular telephony base stations, which present basically the same radiofrequency behavior in both bands; by employing such versions of MIA antenna the operators reduce the number of antennas installed to one half, minimizing the cost and environmental impact of their base stations.","AEM1 Mode The AEM1 configuration, represented in FIG.","7, is based on the use of GSM 900 and GSM 1800 multi-triangular elements.","The array is obtained by interleaving two conventional mono-band arrays with spacing between elements less than one wavelength in the pertinent band (typically a spacing is chosen less than 0.9 in order to minimize the appearance of the diffraction lobe in the end-fire direction).","The original arrays can have 8 or 10 elements, depending on the gain required by the operator.","The juxtaposition of both arrays in a single MIA is achieved in this case by employing dual multi-triangular elements.","Such elements incorporate two excitation points (one for each band), which allows the working band to be selected according to their position in the array.","In FIG.","7 the position of the elements is shown, as well as their working frequencies.","The elements shown in white indicate operation in the GSM 900 band; the elements shown in black indicate operation in the GSM 1800 band and the elements marked in black in the lower triangle and in white in their two upper triangles indicate simultaneous operation in both bands.","Precisely the simultaneous operation in both bands via a single multiband element (the multi-triangular element) in such positions of the array (those positions at which those of the original mono-band arrays coincide), is one of the main characteristic features of the MIA invention.","The manner of feeding the elements of the AEM1 array is not characteristic of the invention of the MIAs and recourse may be had to any conventionally known system.","In particular and given that the multi-triangular elements are excited at two different points, it is possible to make use of an independent distribution network for each band.","Another alternative consists in employing a broadband or dual band distribution network, by coupling a combiner/diplexer which interconnects the network and the two excitation points of the multi-triangular antenna.","Finally, the antenna may therefore come with two input/output connectors (one for each band), or combined in a single connector by means of a combiner/diplexer network.","AEM2 Mode This particular configuration of AEM2, shown in FIG.","8, is based on a multilevel antenna which acts as a multiband element.","In addition to working simultaneously in the GSM 900 and GSM 1800 bands, the antenna has also double linear polarization at +45° and −45° with respect to the longitudinal axis of the array.","The fact that the antenna has double polarization signifies an additional advantage for the cellular telephony operator, since in this manner he can implement a diversity system which minimizes the effect of fading by multipath propagation.","The multilevel element which is described in FIG.","8 is more suitable than the multi-triangular element described previously since the element itself has a linear polarization at +45° in GSM 900 and at −45° in GSM 1800.The array is obtained by interleaving two conventional mono-band arrays with spacing between elements less than one wavelength in the pertinent band (typically a spacing less than 0.9 is chosen in order to minimize the appearance of the diffraction lobe in the end-fire direction).","The original arrays can have 8 or 10 elements depending on the gain required by the operator.","The juxtaposition of both arrays in a single MIA is achieved in this case by employing in-band dual multilevel elements.","Such elements incorporate two points of excitation (one for each band), which permits the working band to be selected according to their position in the array.","In FIG.","8 the position of the elements is shown, as well as their working frequencies.","The elements shown in white indicate operation in the GSM 900 band; the elements shown in black indicate operation in the GSM 1800 band and the elements marked in black in their lower triangle and in white in the upper triangles indicate simultaneous operation in both bands.","Precisely the simultaneous operation in both bands via a single multiband element (the multilevel element) in such positions of the array (those positions in which those of the original mono-band arrays coincide), is one of the main characteristic features of the MIA invention.","It is possible to achieve double polarization on a basis of exciting the multilevel element at various points on its surface, nonetheless in order to augment the isolation between connectors of different polarization, it is chosen in the example described to implement a double column to separate the +45° polarization (left-hand column) from that of −45° (right-hand column).","To increase the isolation between bands, it is even possible to interchange the polarization inclination in the columns of the array in one of the bands (for example in DCS).","The manner of feeding the elements of the array AEM2 is not characteristic of the invention of the MIAs and recourse can be had to any conventionally known system.","In particular and given that the multi-triangular elements are excited at two different points, it is possible to make use of an independent distribution network for each band and polarization.","Another alternative consists in employing a broadband or dual band distribution network, by coupling a combiner/diplexer which interconnects the network and the two excitation points of the multilevel antenna.","The antenna may then come with four input/output connectors (one for each band and polarization), or else combined in only two connectors (one for each independent polarization) by means of combiner/diplexer network in each polarization.","AEM3 Mode The AEM3 configuration, as shown in FIG.","9, is very similar to the AEM2 (the position of the multilevel elements and the type of element itself is the same as in the previous case), with the difference that the right-hand column is reversed with respect to that on the left.","In this manner an antenna with dual band and polarization is obtained, the total width of the antenna being reduced with respect to the previous case (in this particular example the width is reduced by about 10%).","In order to increase the isolation between the columns of double polarization it is convenient that oblique fins be inserted between contiguous elements.","In that case, lateral fins are also incorporated in all the elements which work in GSM 1800, fins which contribute to narrowing the radiation beam in the horizontal plane (plane at right angles to the longitudinal axis of the array).","Nor is the signal distribution system especially characteristic of the MIA configuration and the same system can be used as in the previous case.","AEM4 Mode Another example of multiband interleaved array is that termed herein AEM4 and which is shown in schematic form in FIG.","11.In this case, the multiband element is a stacked square patch antenna (FIG.","10), though it is obvious for anyone familiar with the subject that patches of other shapes could be employed.","Square- or circular-shaped types are preferred in the event that is wished to work with double polarization.","In the example of FIG.","10 the particular case is described of square patches.","The lower patch is of appropriate size for its resonant frequency (associated typically with the patch fundamental mode) to coincide with the lower band (GSM 900 in this specific case); moreover, this patch acts in turn as ground plane of the upper patch.","The latter is of a size such that its resonance is centered in the upper band (GSM 1800).","The elements of the array are mounted on a metallic or metal-coated surface which acts as ground plane for all the elements of the array.","The feeder system is preferentially of the coaxial type, a cable being employed for the lower patch and band and another for the upper patch and band.","The excitation points are collated on the bisectors of the patches (for example, the approximate excitation points are marked by means of circles on the plan view of the antenna) if vertical or horizontal polarization is desired, or on the diagonals if, on the other hand, linear polarization inclined at 45° is desired.","In the event it is desired that the array work with double polarization, each of the patches is excited additionally on the bisector or diagonal opposite (orthogonal) to the first.","The feeding of the elements of the array AEM4 is not characteristic of the invention of the MIAs and recourse can be had to any conventionally known system.","In particular and given that the stacked patch antenna is excited at two different points, it is possible to make use of an independent distribution network for each band and polarization.","Another alternative consists in employing a broadband or dual band distribution network, by coupling a combiner/diplexer which interconnects the network and the two excitation points of the multilevel antenna.","The antenna may then come with four input/output connectors (one for each band and polarization), or else combined in only two connectors (one for each independent polarization) by means of a combiner/diplexer network in each polarization.","AEM5 Mode The AEM5 configuration, as shown in FIG.","12, adopts the same approach as the AEM4, though all the elements are rotated through 45° in the plane of the antenna.","In this manner the radiation pattern is modified in the horizontal plane, in addition to rotating the polarization through 45°.","It is of interest to point out that both in the AEM4 configuration and in the AEM5, the multiband element constituted by the stacked patches is really only strictly necessary in those strategic positions in which elements originating in the conventional mono-band arrays coincide.","In the remaining positions, it shall be possible to employ indistinctly multiband or mono-band elements that work at the frequency determined for its location, as long as its radiation pattern is sufficiently like that of the stacked patch antenna in order to avoid the appearance of diffraction lobes.","It is not deemed necessary to extend further the content of this description in order that an expert in the subject can comprehend its scope and the benefits arising from the invention, as well as develop and implement in practice the object thereof.","Notwithstanding, it must be understood that the invention has been described according to a preferred embodiment thereof, for which reason it may be susceptible to modifications without this implying any alteration to its basis, it being possible that such modifications affect, in particular, the form, the size and/or the materials of manufacture."]],"string":"[\n [\n \"Interlaced Multiband Antenna Arrays\",\n \"Antenna arrays which can work simultaneously in various frequency bands thanks to the physical disposition of the elements which constitute them, and also the multiband behavior of some elements situated strategically in the array.\",\n \"The configuration of the array is described based on the juxtaposition or interleaving of various conventional mono-band arrays working in the different bands of interest.\",\n \"In those positions in which elements of different multiband arrays come together, a multiband antenna is employed which covers the different working frequency bands.\",\n \"The advantages with respect to the classic configuration of using one array for each frequency band are: saving in cost of the global radiating system and its installation (one array replaces several), and its size and visual and environmental impact are reduced in the case of base stations and repeater stations for communication systems.\"\n ],\n [\n \"1.An antenna array comprising: a ground plane layer; a first set of antenna elements arranged on the ground plane layer and being configured to provide operation of the antenna array in at least three frequency bands respectively corresponding to three cellular frequency bands; a second set of antenna elements arranged on the ground layer and being configured to provide operation of the antenna array in two of the three frequency bands; the first set of antenna elements and the second set of antenna elements are substantially arranged along a longitudinal direction of the antenna array; the first set of antenna elements and the second set of antenna elements are arranged on alternating positions along the longitudinal direction; and wherein a ratio of a spacing between antenna elements of the first set to a wavelength of a first frequency band of the three frequency bands is substantially half of a ratio of a spacing between antenna elements of the second set to a wavelength of a second frequency band of the three frequency bands.\",\n \"2.The antenna array of claim 1, wherein a ratio between a frequency of the third frequency band and a frequency of the second frequency band is less than 1.5.3.The antenna array of claim 1, wherein a frequency for the first frequency band is situated around 900 MHz, a frequency for the second frequency band is situated around 1800 MHz, and a frequency for the third frequency band is situated around 2100 MHz.\",\n \"4.The antenna array of claim 1, wherein the three frequency bands are not separated by the same scale factor.\",\n \"5.A communication system comprising: a network of base stations comprising a plurality of base stations, at least some of the plurality of base stations comprising the antenna array of claim 1.6.An antenna array comprising: a ground plane layer; a first plurality of antenna elements arranged on the ground plane and being configured to provide operation of the antenna array in at least first and second frequency bands respectively corresponding to two cellular frequency bands, the first and second frequency bands being non-overlapping frequency bands; and a second plurality of antenna elements arranged on the ground plane layer and being configured to provide operation of the antenna array in the second frequency band, wherein the first plurality of antenna elements and the second plurality of antenna elements are substantially arranged along a longitudinal direction of the antenna array; and a ratio of a spacing between antenna elements providing operation at the first frequency band to an operating wavelength of the first frequency band is substantially the same as a ratio of a spacing between antenna elements providing operation at the second frequency band to an operating wavelength of the second frequency band.\",\n \"7.The antenna array of claim 6, wherein the antenna elements of the first plurality and the antenna elements of the second plurality are arranged in alternating positions along the longitudinal direction of the antenna array.\",\n \"8.The antenna array of claim 7, wherein a ratio between an operating frequency of the second frequency band and an operating frequency of the first frequency band is greater than two.\",\n \"9.The antenna array of claim 6, wherein each antenna element of the first plurality of antenna elements comprises a plurality of electromagnetically coupled portions configured to interact with each other.\",\n \"10.The antenna array of claim 9, further comprising a first distribution network configured to excite the first plurality of antenna elements, and a second distribution configured to excite the antenna elements providing operation at the second frequency band.\",\n \"11.A communication system comprising: a network of base stations comprising a plurality of base stations, at least some of the plurality of base stations comprising the antenna array of claim 6.12.An antenna array comprising: a ground plane layer; a plurality of antenna elements arranged on the ground plane layer along a longitudinal direction of the antenna array; a first distribution network configured to excite the plurality of antenna elements for a first polarization; and a second distribution network configured to excite the plurality of antenna elements for a second polarization, the first and second polarizations being orthogonal polarizations, wherein: the plurality of antenna elements are configured to provide operation of the antenna array in three frequency bands respectively associated with three cellular frequency bands; the highest frequency of a first frequency band of the three frequency bands is less than the lowest frequency of a second frequency band of the three frequency bands and the lowest frequency of a third frequency band of the three frequency bands is greater than the highest frequency of the second frequency band; a ratio between a frequency of the third frequency band and a frequency of the first frequency band being smaller than 1.5; a spacing between the antenna elements of the plurality of antenna elements is less than a wavelength of the lowest operating frequency of the first frequency band; and a spacing between the antenna elements of the plurality of antenna elements is greater than a half wavelength of the highest frequency of the third frequency band.\",\n \"13.The antenna array of claim 12, wherein a first spacing between a first pair of adjacent antenna elements of the plurality of antenna elements is different from a second spacing between a second pair of adjacent antenna elements of the plurality of antenna elements.\",\n \"14.The antenna array of claim 12, wherein any operating frequencies of the third frequency band does not correspond to an integer factor of an operating frequency of the first frequency band.\",\n \"15.The antenna array of claim 12, wherein the three frequency bands are not separated by the same scale factor.\",\n \"16.The antenna array of claim 12, wherein the antenna elements of the plurality of antenna elements comprises patch antennas.\",\n \"17.A communication system comprising: a network of base stations comprising a plurality of base stations, at least some of the plurality of base stations comprising the antenna array according to claim 12.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>The present invention consists of antenna arrays which can be operated simultaneously in various frequency bands thanks to the physical disposition of the elements that constitute it, as well as the multiband behavior of some elements situated strategically in the array.\",\n \"The array configuration is described on a basis of the juxtaposition or interleaving of various conventional single-band arrays operating in the different bands of interest.\",\n \"In those positions where elements of different multiband arrays come together, use is made of a multiband antenna which covers the different working frequency bands.\",\n \"The use of a multiband interleaved antenna array (hereinafter simply Multiband Interleaved Array, MIA) implies a great advantage over the classical solution of employing an array for each frequency band: there is a cost saving in the overall radiating system and in its installation (one array replaces several), its size is reduced as well as its visual and environmental impact in the case of base and repeater stations for communication systems.\",\n \"The present invention finds its application in the field of telecommunications and more specifically in radio-communication systems.\",\n \"Antennas started to be developed at the end of the nineteenth century based on the fundamental laws of electromagnetism postulated by James Clerk Maxwell in 1864.The invention of the first antenna has to be attributed to Heinrich Hertz in 1886 who demonstrated the transmission through air of electromagnetic waves.\",\n \"In the mid-1940's the fundamental restrictions regarding the reduction in size of antennas were shown with respect to wavelength and at the beginning of the sixties appeared the first frequency-independent antennas (E. C. Jordan, G. A. Deschamps, J. D. Dyson, P. E. Mayes, “Developments in Broadband Antennas,” IEEE Spectrum, vol.\",\n \"1, pp.\",\n \"58-71, April 1964; V. H. Rumsey, Frequency-Independent Antennas.\",\n \"New York Academic, 1966; R. L. Carrel, “Analysis and design of the log-periodic dipole array,” Tech.\",\n \"Rep. 52, Univ.\",\n \"of Illinois Antenna Lab., Contract AF33 (616)-6079, October 1961; P. E. Mayes, “Frequency Independent Antennas and Broad-Band Derivatives Thereof”, Proc.\",\n \"IEEE, vol.\",\n \"80, no.\",\n \"1, January 1992).\",\n \"At that time proposals were made for helical, spiral, log-periodic arrays, cones and structures defined exclusively by angle pieces for the implementation of broadband antennas.\",\n \"Antenna array theory goes back to the works of Shelkunoff (S. A. Schellkunhoff, “A Mathematical Theory of Linear Arrays,” Bell System Technical Journal, 22,80), among other classic treatises on antenna theory.\",\n \"Said theory establishes the basic design rules for shaping the radiation properties of the array (principally its radiation pattern), though its application is restricted mainly to the case of mono-band arrays.\",\n \"The cause of said restriction lies in the frequency behavior of the array being highly dependent on the ratio between the distance between elements (antennas) of the array and the working wavelength.\",\n \"Said spacing between elements is usually constant and preferably less than one wavelength in order to prevent the appearance of diffraction lobes.\",\n \"This implies that once the spacing between elements is fixed, the operating frequency (and the corresponding wavelength) is also fixed, it being particularly difficult that the same array work simultaneously at another higher frequency, given that in that case the magnitude of the wavelength is less than the spacing between elements.\",\n \"The log-periodic arrays suppose one of the first examples of antenna arrays capable of covering a broad range of frequencies (V. H. Rumsey, Frequency-Independent Antennas.\",\n \"New York Academic, 1966; R. L. Carrel, “Analysis and design of the log-periodic dipole array,” Tech.\",\n \"Rep. 52, Univ.\",\n \"Illinois Antenna Lab., Contract AF33 (616)-6079, October 1961; P. E. Mayes, “Frequency Independent Antennas and Broad-Band Derivatives Thereof”, Proc.\",\n \"IEEE, vol.\",\n \"80, no.\",\n \"1, January 1992).\",\n \"Said arrays are based on distributing the elements that constitute it in such a manner that the spacing between adjacent elements and their length vary according to a geometric progression.\",\n \"Although said antennas are capable of maintaining a same radiation and impedance pattern over a broad range of frequencies, their application in practice is restricted to some concrete cases due to their limitations regarding gain and size.\",\n \"Thus for example, said antennas are not employed in cellular telephony base stations because they do not have sufficient gain (their gain is around 10 dBi when the usual requirement is for about 17 dBi for such application), they usually have linear polarization whilst in said environment antennas are required with polarization diversity, their pattern in the horizontal plane does not have the width necessary and their mechanical structure is too bulky.\",\n \"The technology of individual multiband antennas is markedly more developed.\",\n \"A multiband antenna is understood to be an antenna formed by a set of elements coupled to each other electromagnetically which interact with each other in order to establish the radio-electric behavior of the antenna, behavior which with respect to radiation and impedance patterns is similar in multiple frequency bands (hence the name multiband antenna).\",\n \"Numerous examples of multiband antennas are described in the literature.\",\n \"In 1995 antennas of the fractal or multifractal type were introduced (the coining of the terms fractal and multifractal is attributable to B.\",\n \"B. Mandelbrot in his book The Fractal Geometry of Nature, W. H. Freeman and Co. 1983), antennas which by their geometry have a multifrequency behavior and, in determined cases, a reduced size (C. Puente, R. Pous, J. Romeu, X. Garcia “Antenas Fractales o Mulitfractales,” (Spanish patent P9501019).\",\n \"Subsequently multi-triangular antennas were introduced (Spanish patent P9800954) which could work simultaneously in the GSM 900 and GSM 1800 bands and, more recently, multilevel antennas (Patent PCT/ES99/00296), which offer a clear example of how it is possible to shape the geometry of the antenna in order to achieve a multiband behavior.\"\n ],\n [\n \"<SOH> SUMMARY <EOH>The present invention describes how multiband antennas can be combined in order to obtain an array that works simultaneously in several frequency bands.\",\n \"A Multiband Interleaved Array (MIA) consists of an array of antennas which has the particularity of being capable of working simultaneously in various frequency bands.\",\n \"This is achieved by means of using multiband antennas in strategic positions of the array.\",\n \"The disposition of the elements that constitute the MIA is obtained from the juxtaposition of conventional mono-band arrays, employing as many mono-band arrays as frequency bands that it is wished to incorporate in the Multiband Interleaved Array.\",\n \"In those positions in which one or various elements originating in the conventional mono-band arrays coincide, a single multiband antenna (element) shall be employed which covers simultaneously the different bands.\",\n \"In the remaining non-concurrent positions, it can be chosen to employ also the same multiband antenna or else recur to a conventional mono-band antenna which works at the pertinent frequency.\",\n \"The excitation at one or various frequencies of each element of the array depends therefore on the position of the element in the array and is controlled by means of the signal distribution network.\"\n ],\n [\n \"CROSS REFERENCE TO RELATED APPLICATIONS This patent application is a continuation of U.S. patent application Ser.\",\n \"No.\",\n \"14/529,715, filed on Oct. 31, 2014, which is a continuation of U.S. patent application No.\",\n \"13/530,249, filed on Jun.\",\n \"22, 2012, which is now U.S. Pat.\",\n \"No.\",\n \"8,896,493, issued on Nov. 25, 2014, which is a continuation of U.S. patent application Ser.\",\n \"No.\",\n \"13/044,831, filed on Mar.\",\n \"10, 2011, which is now U.S. Pat.\",\n \"No.\",\n \"8,228,256, issued on Jul.\",\n \"24, 2012, which is a continuation of U.S. patent application Ser.\",\n \"No.\",\n \"12/476,308, filed on Jun.\",\n \"2, 2009, which is now U.S. Pat.\",\n \"No.\",\n \"7,932,870, issued on Apr.\",\n \"26, 2011, which is a continuation of U.S. patent application Ser.\",\n \"No.\",\n \"11/803,782, filed on May 16, 2007, which is now U.S. Pat.\",\n \"No.\",\n \"7,557,768, issued on Jul.\",\n \"7, 2009, which is a continuation of U.S. patent application Ser.\",\n \"No.\",\n \"10/988,261, filed on Nov. 12, 2004, which is now U.S. Pat.\",\n \"No.\",\n \"7,250,918, issued on Jul.\",\n \"31, 2007, which is a continuation of U.S. patent application Ser.\",\n \"No.\",\n \"10/135,019, filed on Apr.\",\n \"23, 2002, which is now U.S. Pat.\",\n \"No.\",\n \"6,937,191, issued on Aug. 30, 2005, which is a continuation of International Application No.\",\n \"PCT/ES99/00343, filed on Oct. 26, 1999, the entire contents of which are hereby incorporated by reference.\",\n \"BACKGROUND The present invention consists of antenna arrays which can be operated simultaneously in various frequency bands thanks to the physical disposition of the elements that constitute it, as well as the multiband behavior of some elements situated strategically in the array.\",\n \"The array configuration is described on a basis of the juxtaposition or interleaving of various conventional single-band arrays operating in the different bands of interest.\",\n \"In those positions where elements of different multiband arrays come together, use is made of a multiband antenna which covers the different working frequency bands.\",\n \"The use of a multiband interleaved antenna array (hereinafter simply Multiband Interleaved Array, MIA) implies a great advantage over the classical solution of employing an array for each frequency band: there is a cost saving in the overall radiating system and in its installation (one array replaces several), its size is reduced as well as its visual and environmental impact in the case of base and repeater stations for communication systems.\",\n \"The present invention finds its application in the field of telecommunications and more specifically in radio-communication systems.\",\n \"Antennas started to be developed at the end of the nineteenth century based on the fundamental laws of electromagnetism postulated by James Clerk Maxwell in 1864.The invention of the first antenna has to be attributed to Heinrich Hertz in 1886 who demonstrated the transmission through air of electromagnetic waves.\",\n \"In the mid-1940's the fundamental restrictions regarding the reduction in size of antennas were shown with respect to wavelength and at the beginning of the sixties appeared the first frequency-independent antennas (E. C. Jordan, G. A. Deschamps, J. D. Dyson, P. E. Mayes, “Developments in Broadband Antennas,” IEEE Spectrum, vol.\",\n \"1, pp.\",\n \"58-71, April 1964; V. H. Rumsey, Frequency-Independent Antennas.\",\n \"New York Academic, 1966; R. L. Carrel, “Analysis and design of the log-periodic dipole array,” Tech.\",\n \"Rep. 52, Univ.\",\n \"of Illinois Antenna Lab., Contract AF33 (616)-6079, October 1961; P. E. Mayes, “Frequency Independent Antennas and Broad-Band Derivatives Thereof”, Proc.\",\n \"IEEE, vol.\",\n \"80, no.\",\n \"1, January 1992).\",\n \"At that time proposals were made for helical, spiral, log-periodic arrays, cones and structures defined exclusively by angle pieces for the implementation of broadband antennas.\",\n \"Antenna array theory goes back to the works of Shelkunoff (S. A. Schellkunhoff, “A Mathematical Theory of Linear Arrays,” Bell System Technical Journal, 22,80), among other classic treatises on antenna theory.\",\n \"Said theory establishes the basic design rules for shaping the radiation properties of the array (principally its radiation pattern), though its application is restricted mainly to the case of mono-band arrays.\",\n \"The cause of said restriction lies in the frequency behavior of the array being highly dependent on the ratio between the distance between elements (antennas) of the array and the working wavelength.\",\n \"Said spacing between elements is usually constant and preferably less than one wavelength in order to prevent the appearance of diffraction lobes.\",\n \"This implies that once the spacing between elements is fixed, the operating frequency (and the corresponding wavelength) is also fixed, it being particularly difficult that the same array work simultaneously at another higher frequency, given that in that case the magnitude of the wavelength is less than the spacing between elements.\",\n \"The log-periodic arrays suppose one of the first examples of antenna arrays capable of covering a broad range of frequencies (V. H. Rumsey, Frequency-Independent Antennas.\",\n \"New York Academic, 1966; R. L. Carrel, “Analysis and design of the log-periodic dipole array,” Tech.\",\n \"Rep. 52, Univ.\",\n \"Illinois Antenna Lab., Contract AF33 (616)-6079, October 1961; P. E. Mayes, “Frequency Independent Antennas and Broad-Band Derivatives Thereof”, Proc.\",\n \"IEEE, vol.\",\n \"80, no.\",\n \"1, January 1992).\",\n \"Said arrays are based on distributing the elements that constitute it in such a manner that the spacing between adjacent elements and their length vary according to a geometric progression.\",\n \"Although said antennas are capable of maintaining a same radiation and impedance pattern over a broad range of frequencies, their application in practice is restricted to some concrete cases due to their limitations regarding gain and size.\",\n \"Thus for example, said antennas are not employed in cellular telephony base stations because they do not have sufficient gain (their gain is around 10 dBi when the usual requirement is for about 17 dBi for such application), they usually have linear polarization whilst in said environment antennas are required with polarization diversity, their pattern in the horizontal plane does not have the width necessary and their mechanical structure is too bulky.\",\n \"The technology of individual multiband antennas is markedly more developed.\",\n \"A multiband antenna is understood to be an antenna formed by a set of elements coupled to each other electromagnetically which interact with each other in order to establish the radio-electric behavior of the antenna, behavior which with respect to radiation and impedance patterns is similar in multiple frequency bands (hence the name multiband antenna).\",\n \"Numerous examples of multiband antennas are described in the literature.\",\n \"In 1995 antennas of the fractal or multifractal type were introduced (the coining of the terms fractal and multifractal is attributable to B.\",\n \"B. Mandelbrot in his book The Fractal Geometry of Nature, W. H. Freeman and Co. 1983), antennas which by their geometry have a multifrequency behavior and, in determined cases, a reduced size (C. Puente, R. Pous, J. Romeu, X. Garcia “Antenas Fractales o Mulitfractales,” (Spanish patent P9501019).\",\n \"Subsequently multi-triangular antennas were introduced (Spanish patent P9800954) which could work simultaneously in the GSM 900 and GSM 1800 bands and, more recently, multilevel antennas (Patent PCT/ES99/00296), which offer a clear example of how it is possible to shape the geometry of the antenna in order to achieve a multiband behavior.\",\n \"SUMMARY The present invention describes how multiband antennas can be combined in order to obtain an array that works simultaneously in several frequency bands.\",\n \"A Multiband Interleaved Array (MIA) consists of an array of antennas which has the particularity of being capable of working simultaneously in various frequency bands.\",\n \"This is achieved by means of using multiband antennas in strategic positions of the array.\",\n \"The disposition of the elements that constitute the MIA is obtained from the juxtaposition of conventional mono-band arrays, employing as many mono-band arrays as frequency bands that it is wished to incorporate in the Multiband Interleaved Array.\",\n \"In those positions in which one or various elements originating in the conventional mono-band arrays coincide, a single multiband antenna (element) shall be employed which covers simultaneously the different bands.\",\n \"In the remaining non-concurrent positions, it can be chosen to employ also the same multiband antenna or else recur to a conventional mono-band antenna which works at the pertinent frequency.\",\n \"The excitation at one or various frequencies of each element of the array depends therefore on the position of the element in the array and is controlled by means of the signal distribution network.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS The characteristics expounded in the foregoing, are presented in graphical form making use of the figures in the drawings attached, in which is shown by way of a purely illustrative and not restrictive example, a preferred form of embodiment.\",\n \"In said drawings: FIG.\",\n \"1 shows the position of the elements of two classic mono-band arrays which work at frequencies f and f/2 respectively, and the disposition of elements in a multiband interleaved array, which has a dual frequency behavior (at frequencies f and f/2), working in the same manner as classic arrays but with a smaller total number of elements.\",\n \"FIG.\",\n \"2 shows another particular example of multiband interleaved array but with three frequencies in this case, and the respective three classic mono-band arrays which constitute it.\",\n \"It is a matter of extending the case of FIGS.\",\n \"1 to 3 frequencies f, f/2 and f/4.FIG.\",\n \"3 shows another particular example of multiband interleaved array, in which the different working frequencies are not separated by the same scale factor.\",\n \"It is a matter of extending the case of FIGS.\",\n \"1 and 2 to 3 frequencies f, f/2 and f/3.FIG.\",\n \"4 shows a further particular example of multiband interleaved array, in which the different working frequencies are not separated by the same scale factor.\",\n \"It is a matter of extending the case of FIGS.\",\n \"3 to 3 frequencies f, f/3 and f/4.FIG.\",\n \"5 shows a multiband interleaved array configuration which requires a repositioning of the elements to obtain frequencies that do not correspond to an integer factor of the highest frequency.\",\n \"In this particular example the frequencies f, f/2 and f/2.33 have been chosen.\",\n \"FIG.\",\n \"6 shows the extension of the design of an MIA to the two-dimensional or three-dimensional case, specifically, an extension of the example of FIG.\",\n \"1 to two dimensions.\",\n \"FIG.\",\n \"7 shows one of the preferred of operating modes (AEM1).\",\n \"It is a matter of an MIA in which the multiband elements are multi-triangular elements.\",\n \"The array works simultaneously at dual frequencies, for example in the GSM 900 and GSM 1800 bands.\",\n \"FIG.\",\n \"8 shows another of the preferred operating modes (AEM2).\",\n \"It is a matter of an MIA in which the multiband elements are multilevel elements.\",\n \"The array works simultaneously at dual frequencies, for example in the GSM 900 and GSM 1800 bands.\",\n \"FIG.\",\n \"9 shows another of the preferred operating modes (AEM3).\",\n \"It is a matter of an MIA in which the multiband elements are multilevel elements.\",\n \"The configuration is similar to that of FIG.\",\n \"8 (AEM2 mode), the difference being that the new disposition permits the total width of the antenna to be reduced.\",\n \"FIG.\",\n \"10 shows another example of multiband antenna which can be employed in MIAs.\",\n \"It is a matter of a stacked patch antenna, which in this specific example works at two dual frequencies (for example, GSM 900 and GSM 1800).\",\n \"FIG.\",\n \"11 shows the disposition of said patches in the MIA type array (AEM4 configuration).\",\n \"Observe that, in contrast to the previous cases, in this case multiband antennas are employed only in those positions where it is strictly necessary; in the remainder mono-band elements are employed the radiation pattern of which is sufficiently like that of the multiband element in the pertinent band.\",\n \"FIG.\",\n \"12 shows another configuration (AEM5), in which the elements have been rotated through 45° in order to facilitate the procurement of double polarization at +45° or −45°.\",\n \"DETAILED DESCRIPTION In making the detailed description that follows of the preferred embodiment of the present invention, reference shall constantly be made to the figures of the drawings, throughout which use has been made of the same numerical references for the same or similar parts.\",\n \"A multiband interleaved array (MIA) is constituted by the juxtaposition of various conventional mono-band arrays.\",\n \"The conventional antenna arrays usually have a mono-band behavior (that is, they work within a relatively small frequency range, typically of the order of 10% about a center frequency) and this is not only because the elements (antennas) that constitute it have a mono-band behavior, but also because the physical spacing between elements conditions the working wavelength.\",\n \"Typically, the conventional mono-band arrays are designed with a spacing between elements of around a half-wavelength, spacing which may be increased in some configurations in order to enhance directivity, though it is usually kept below one wavelength to avoid the appearance of diffraction lobes.\",\n \"This purely geometric restriction (the magnitude of the wavelength conditions the geometry of the elements of the array and their relative spacing) signifies a major drawback in those environments and communication systems in which various frequency bands have to be employed simultaneously.\",\n \"A clear example is the GSM cellular mobile telephony system.\",\n \"Initially located in the 900 MHz band, the GSM system has turned into one of the most widespread on a world scale.\",\n \"The success of the system and the spectacular growth in demand for this type of service has led to the cellular mobile telephony operators expanding its service into a new band, the 1800 MHz band, in order to provide coverage for a greater customer base.\",\n \"Making use of classic mono-band antenna technology, the operators have to duplicate their antenna network in order to provide coverage simultaneously to GSM 900 and GSM 1800.Using a single MIA specially designed for the system (like that described in the particular cases of FIGS.\",\n \"7 through 12), the operators reduce the cost of their network of base stations, the time to expand into the new band and the visual and environmental impact of their installations (through the simplification of the overall radiating structure).\",\n \"It is important to point out that the scenario which has just been outlined above deals only with one particular example of a type of MIA and its application; as may well be gauged by anyone familiar with the subject, in no way are the MIAs which are described in the present invention restricted to said specific configuration and can easily be adapted to other frequencies and applications.\",\n \"The multiband interleaved arrays base their operation on the physical disposition of the antennas which constitute them and on the particular type of element that is employed in some strategic positions of the array.\",\n \"The positions of the elements in an MIA are determined from the positions of the elements in as many mono-band arrays as there are frequencies or frequency bands required.\",\n \"The design of the array is, in that sense, equal to that of the mono-band arrays insomuch as it is possible to choose the current weighting for each element, in order to shape the radiation pattern according to the needs of each application.\",\n \"The configuration of the MIA is obtained from the juxtaposition of the positions of the different mono-band arrays.\",\n \"Naturally, such juxtaposition proves difficult to implement in practice in those positions in which various antennas of the different arrays coincide; the solution proposed in this invention rests in the use of a multiband antenna (for example of the fractal, multi-triangular, multi-level, etc.\",\n \"type) which covers all the frequencies associated with its position.\",\n \"A basic and particular example of how to arrange the elements in an MIA is described in FIG.\",\n \"1.In the columns of the FIG.\",\n \"1 (1a) and (1b) two conventional mono-band arrays are shown in which the positions of the elements (indicated by the black circles and the circumferences respectively) are chosen in such a manner that the spacing between elements is typically less than the working wavelength.\",\n \"Thus, taking as reference the working frequency f of the array (1a), the array (1b) would work at a frequency f/2 as the elements have a spacing double that of the previous case.\",\n \"In FIG.\",\n \"1 (column 1c) the disposition is shown of the elements in the MIA which is capable of working simultaneously on the frequencies f and f/2 conserving basically the same facilities as the two arrays (1a) and (1b).\",\n \"In the positions in which elements of the two conventional arrays (indicated in FIG.\",\n \"1 (1c) by means of black circles located at the center of a circumference) coincide, a multiband antenna is employed capable of working in the same manner (same impedance and pattern) on the frequencies (1a) and (1b).\",\n \"The remaining not common elements (indicated either by a black circle, or by a circumference) can be implemented either by means of the same multiband element employed in the common positions (and selecting the working frequency by means of the signal distribution network of the array), or by employing conventional mono-band elements.\",\n \"In this example the array (1c) has a dual behavior frequency-wise (at frequencies f and f/2), working in the same manner as the arrays (1a) and (1b) but with a smaller total number of elements (12 instead of 16).\",\n \"Multiple examples of multiband antennas are already described in the state of the art.\",\n \"Antennas with fractal geometry, multi-triangular antennas, multi-level antennas even stacked patch antennas are some examples of antennas capable of working in like manner in multiple frequency bands.\",\n \"These, and other multiband elements can be employed in the positions of the MIAs in which elements of various mono-band arrays come together.\",\n \"In the following figures other MIA configurations are shown, based on the same inventive concept, though having the disposition of the elements adapted to other frequencies.\",\n \"In FIG.\",\n \"2 the configuration described is that of a tri-band MIA working at frequencies f, f/2 and f/4.The disposition of elements in the three classic mono-band arrays at the frequencies f, f/2 and f/4 is illustrated in the columns of FIGS.\",\n \"2 (2a), (2b) and (2c) by means of black circles, circumferences and squares respectively.\",\n \"The position of the elements of the MIA is determined from the configuration of the three mono-band arrays designed for each one of the three frequencies.\",\n \"The three arrays come together in the MIA that is shown in column 2d of FIG.\",\n \"2.In those positions where elements of the three arrays would come together (indicated in the drawing by the juxtaposition of the different geometric figures identifying each array) use is made of a multiband element.\",\n \"The three-frequency array of column (2d) behaves in the same manner as the three arrays (2a), (2b) and (2c) at their respective working frequencies, but employing only 13 elements instead of the 21 required in the total of the three mono-band arrays.\",\n \"FIGS.\",\n \"3, 4 and 5 describe, by way of example and not restrictively, the design of other MIAs based on the same principle though at other frequencies.\",\n \"In the first two cases the frequencies employed are integer multiples of a fundamental frequency; in the case of FIG.\",\n \"5 the ratio between frequencies is not restricted to any particular rule, though it supposes an example of array in which the frequencies the GSM 900, GSM 1800 and UMTS services can be combined.\",\n \"Specifically, FIG.\",\n \"3 illustrates another particular example of multiband interleaved array, in which the different working frequencies are not separated by the same scale factor.\",\n \"It concerns the extension of the case of FIGS.\",\n \"1 and 2 to 3 frequencies f, f/2 and f/3.The disposition of elements of the three classic mono-band arrays at the frequencies f, f/2 and f/3 is shown in the columns of FIGS.\",\n \"3 (3a), (3b) and (3c) by means of black circles, circumferences and squares respectively.\",\n \"The column (3d) of FIG.\",\n \"3 shows the disposition of elements in the tri-band interleaved array.\",\n \"In those positions in which elements of the three arrays come together (indicated in the drawing by the juxtaposition of the different geometric figures identifying each array), use is made of a multiband element; the same strategy is followed in those positions in which elements of two arrays coincide: use should be made of a multiband element capable of covering the frequencies pertinent to its position, preferentially the same element as that used in the remaining positions, selecting those frequencies which are necessary by means of the feeder network.\",\n \"Notice that as the three-frequency array of column (3d) of FIG.\",\n \"3 behaves in the same manner as the three arrays (3a), (3b) and (3c) at their respective working frequencies, but employing only 12 elements instead of the 21 required in the total of the three mono-band arrays.\",\n \"FIG.\",\n \"4 illustrates a new particular example of multiband interleaved array, in which the different working frequencies are not separated by the same scale factor.\",\n \"It concerns the extension of the case of FIGS.\",\n \"3 to 3 frequencies f, f/3 and f/4.The disposition of elements of the three classic mono-band arrays at the frequencies f, f/3 and f/4 are shown in the columns of FIGS.\",\n \"4 (4a), (4b) and (4c) by means of black circles, circumferences and squares respectively.\",\n \"The column (4d) of FIG.\",\n \"4 shows the disposition of elements in the tri-band interleaved array.\",\n \"In those positions where elements of the three arrays would come together (indicated in the drawing by the juxtaposition of the different geometric figures identifying each array), use is made of a multiband element.\",\n \"The three-frequency array of column (4d) of FIG.\",\n \"4 behaves in the same manner as the three arrays (4a), (4b) and (4c) at their respective working frequencies, but employing only 15 elements instead of the 24 required in the total of the three mono-band arrays.\",\n \"It is convenient to re-emphasis that in the particular cases of FIGS.\",\n \"3 and 4 the arrays can work at 3 frequencies simultaneously.\",\n \"The disposition of elements is such that the three frequencies do not always coincide in all the elements; nonetheless, by employing a tri-band antenna in those positions and selecting the working frequencies for example by means of a conventional frequency-selective network, it is possible to implement the MIA.\",\n \"In some configurations of multiband interleaved array, especially in those in which the different frequencies do not correspond to an integral factor of the highest frequency 1, it is required that the elements be repositioned, as in FIG.\",\n \"5.In this particular example the frequencies f, f/2 and f/2,33 have been chosen.\",\n \"The disposition of elements of the three classic mono-band arrays at the frequencies f, f/2 and f/2.33 is represented in the columns of FIGS.\",\n \"5 (5a), (5b) and (5c) by means of black circles, circumferences and squares respectively.\",\n \"The column (5d) of FIG.\",\n \"5 shows what would be the disposition of elements in the tri-band interleaved array according to the same plan as in the previous examples.\",\n \"Notice how in this case the ratio of frequencies involves the collation of elements at intermediate positions which make its practical implementation difficult.\",\n \"The solution to be adopted in this case consists in displacing the position of the element of the array that works at the lowest frequency (indicated by arrows) until it coincides with another element (that nearest) of the highest frequency array; then the two or more coincident elements in the new position are replaced with a multiband element.\",\n \"An example of the final configuration once the elements have been repositioned, is shown in column (5e) of FIG.\",\n \"5.It is important that the element displaced be preferentially that of the lowest frequency array, in this way the relative displacement in terms of the working wavelength is the least possible and the appearance of secondary or diffraction lobes is reduced to the minimum.\",\n \"FIG.\",\n \"6 illustrates how the configuration MIAs is not limited to the linear (one-dimensional) case, but it also includes arrays in 2 and 3 dimensions (2D and 3D).\",\n \"The procedure for distributing the elements of the array in the 2D and 3D cases is the same, replacing also the different coincident elements with a single multiband antenna.\",\n \"More examples of particular configurations of MIAs are described below.\",\n \"In the five examples described, various designs are presented for GSM 900 and GSM 1800 systems (890 MHz-960 MHz and 1710 MHz-1880 MHz bands).\",\n \"It is a question of antennas for cellular telephony base stations, which present basically the same radiofrequency behavior in both bands; by employing such versions of MIA antenna the operators reduce the number of antennas installed to one half, minimizing the cost and environmental impact of their base stations.\",\n \"AEM1 Mode The AEM1 configuration, represented in FIG.\",\n \"7, is based on the use of GSM 900 and GSM 1800 multi-triangular elements.\",\n \"The array is obtained by interleaving two conventional mono-band arrays with spacing between elements less than one wavelength in the pertinent band (typically a spacing is chosen less than 0.9 in order to minimize the appearance of the diffraction lobe in the end-fire direction).\",\n \"The original arrays can have 8 or 10 elements, depending on the gain required by the operator.\",\n \"The juxtaposition of both arrays in a single MIA is achieved in this case by employing dual multi-triangular elements.\",\n \"Such elements incorporate two excitation points (one for each band), which allows the working band to be selected according to their position in the array.\",\n \"In FIG.\",\n \"7 the position of the elements is shown, as well as their working frequencies.\",\n \"The elements shown in white indicate operation in the GSM 900 band; the elements shown in black indicate operation in the GSM 1800 band and the elements marked in black in the lower triangle and in white in their two upper triangles indicate simultaneous operation in both bands.\",\n \"Precisely the simultaneous operation in both bands via a single multiband element (the multi-triangular element) in such positions of the array (those positions at which those of the original mono-band arrays coincide), is one of the main characteristic features of the MIA invention.\",\n \"The manner of feeding the elements of the AEM1 array is not characteristic of the invention of the MIAs and recourse may be had to any conventionally known system.\",\n \"In particular and given that the multi-triangular elements are excited at two different points, it is possible to make use of an independent distribution network for each band.\",\n \"Another alternative consists in employing a broadband or dual band distribution network, by coupling a combiner/diplexer which interconnects the network and the two excitation points of the multi-triangular antenna.\",\n \"Finally, the antenna may therefore come with two input/output connectors (one for each band), or combined in a single connector by means of a combiner/diplexer network.\",\n \"AEM2 Mode This particular configuration of AEM2, shown in FIG.\",\n \"8, is based on a multilevel antenna which acts as a multiband element.\",\n \"In addition to working simultaneously in the GSM 900 and GSM 1800 bands, the antenna has also double linear polarization at +45° and −45° with respect to the longitudinal axis of the array.\",\n \"The fact that the antenna has double polarization signifies an additional advantage for the cellular telephony operator, since in this manner he can implement a diversity system which minimizes the effect of fading by multipath propagation.\",\n \"The multilevel element which is described in FIG.\",\n \"8 is more suitable than the multi-triangular element described previously since the element itself has a linear polarization at +45° in GSM 900 and at −45° in GSM 1800.The array is obtained by interleaving two conventional mono-band arrays with spacing between elements less than one wavelength in the pertinent band (typically a spacing less than 0.9 is chosen in order to minimize the appearance of the diffraction lobe in the end-fire direction).\",\n \"The original arrays can have 8 or 10 elements depending on the gain required by the operator.\",\n \"The juxtaposition of both arrays in a single MIA is achieved in this case by employing in-band dual multilevel elements.\",\n \"Such elements incorporate two points of excitation (one for each band), which permits the working band to be selected according to their position in the array.\",\n \"In FIG.\",\n \"8 the position of the elements is shown, as well as their working frequencies.\",\n \"The elements shown in white indicate operation in the GSM 900 band; the elements shown in black indicate operation in the GSM 1800 band and the elements marked in black in their lower triangle and in white in the upper triangles indicate simultaneous operation in both bands.\",\n \"Precisely the simultaneous operation in both bands via a single multiband element (the multilevel element) in such positions of the array (those positions in which those of the original mono-band arrays coincide), is one of the main characteristic features of the MIA invention.\",\n \"It is possible to achieve double polarization on a basis of exciting the multilevel element at various points on its surface, nonetheless in order to augment the isolation between connectors of different polarization, it is chosen in the example described to implement a double column to separate the +45° polarization (left-hand column) from that of −45° (right-hand column).\",\n \"To increase the isolation between bands, it is even possible to interchange the polarization inclination in the columns of the array in one of the bands (for example in DCS).\",\n \"The manner of feeding the elements of the array AEM2 is not characteristic of the invention of the MIAs and recourse can be had to any conventionally known system.\",\n \"In particular and given that the multi-triangular elements are excited at two different points, it is possible to make use of an independent distribution network for each band and polarization.\",\n \"Another alternative consists in employing a broadband or dual band distribution network, by coupling a combiner/diplexer which interconnects the network and the two excitation points of the multilevel antenna.\",\n \"The antenna may then come with four input/output connectors (one for each band and polarization), or else combined in only two connectors (one for each independent polarization) by means of combiner/diplexer network in each polarization.\",\n \"AEM3 Mode The AEM3 configuration, as shown in FIG.\",\n \"9, is very similar to the AEM2 (the position of the multilevel elements and the type of element itself is the same as in the previous case), with the difference that the right-hand column is reversed with respect to that on the left.\",\n \"In this manner an antenna with dual band and polarization is obtained, the total width of the antenna being reduced with respect to the previous case (in this particular example the width is reduced by about 10%).\",\n \"In order to increase the isolation between the columns of double polarization it is convenient that oblique fins be inserted between contiguous elements.\",\n \"In that case, lateral fins are also incorporated in all the elements which work in GSM 1800, fins which contribute to narrowing the radiation beam in the horizontal plane (plane at right angles to the longitudinal axis of the array).\",\n \"Nor is the signal distribution system especially characteristic of the MIA configuration and the same system can be used as in the previous case.\",\n \"AEM4 Mode Another example of multiband interleaved array is that termed herein AEM4 and which is shown in schematic form in FIG.\",\n \"11.In this case, the multiband element is a stacked square patch antenna (FIG.\",\n \"10), though it is obvious for anyone familiar with the subject that patches of other shapes could be employed.\",\n \"Square- or circular-shaped types are preferred in the event that is wished to work with double polarization.\",\n \"In the example of FIG.\",\n \"10 the particular case is described of square patches.\",\n \"The lower patch is of appropriate size for its resonant frequency (associated typically with the patch fundamental mode) to coincide with the lower band (GSM 900 in this specific case); moreover, this patch acts in turn as ground plane of the upper patch.\",\n \"The latter is of a size such that its resonance is centered in the upper band (GSM 1800).\",\n \"The elements of the array are mounted on a metallic or metal-coated surface which acts as ground plane for all the elements of the array.\",\n \"The feeder system is preferentially of the coaxial type, a cable being employed for the lower patch and band and another for the upper patch and band.\",\n \"The excitation points are collated on the bisectors of the patches (for example, the approximate excitation points are marked by means of circles on the plan view of the antenna) if vertical or horizontal polarization is desired, or on the diagonals if, on the other hand, linear polarization inclined at 45° is desired.\",\n \"In the event it is desired that the array work with double polarization, each of the patches is excited additionally on the bisector or diagonal opposite (orthogonal) to the first.\",\n \"The feeding of the elements of the array AEM4 is not characteristic of the invention of the MIAs and recourse can be had to any conventionally known system.\",\n \"In particular and given that the stacked patch antenna is excited at two different points, it is possible to make use of an independent distribution network for each band and polarization.\",\n \"Another alternative consists in employing a broadband or dual band distribution network, by coupling a combiner/diplexer which interconnects the network and the two excitation points of the multilevel antenna.\",\n \"The antenna may then come with four input/output connectors (one for each band and polarization), or else combined in only two connectors (one for each independent polarization) by means of a combiner/diplexer network in each polarization.\",\n \"AEM5 Mode The AEM5 configuration, as shown in FIG.\",\n \"12, adopts the same approach as the AEM4, though all the elements are rotated through 45° in the plane of the antenna.\",\n \"In this manner the radiation pattern is modified in the horizontal plane, in addition to rotating the polarization through 45°.\",\n \"It is of interest to point out that both in the AEM4 configuration and in the AEM5, the multiband element constituted by the stacked patches is really only strictly necessary in those strategic positions in which elements originating in the conventional mono-band arrays coincide.\",\n \"In the remaining positions, it shall be possible to employ indistinctly multiband or mono-band elements that work at the frequency determined for its location, as long as its radiation pattern is sufficiently like that of the stacked patch antenna in order to avoid the appearance of diffraction lobes.\",\n \"It is not deemed necessary to extend further the content of this description in order that an expert in the subject can comprehend its scope and the benefits arising from the invention, as well as develop and implement in practice the object thereof.\",\n \"Notwithstanding, it must be understood that the invention has been described according to a preferred embodiment thereof, for which reason it may be susceptible to modifications without this implying any alteration to its basis, it being possible that such modifications affect, in particular, the form, the size and/or the materials of manufacture.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875831"}}},{"rowIdx":4494991,"cells":{"text":{"kind":"list like","value":[["Treatment of Glaucoma Using Laquinimod","The subject invention provides a method of treating a subject afflicted with glaucoma, suffering from retinal ganglion cell (RGC) loss or damage, or elevated intraocular pressure (IOP), or of reducing RGC loss or damage, or reducing IOP in a subject, comprising administering to the subject an amount of laquinimod effective to treat the subject, to reduce RGC loss or damage, or to reduce IOP in the subject.","Provide also is a pharmaceutical composition, a package and a therapeutic package for treating a subject afflicted with glaucoma."],["1.A method of treating a subject afflicted with glaucoma comprising administering to the subject an amount of laquinimod effective to treat the subject.","2.The method of claim 1, wherein the administration of laquinimod is effective to reduce or inhibit a symptom of the glaucoma in the subject.","3.The method of claim 2, wherein the symptom is retinal ganglion cell damage, retinal ganglion cell loss, or elevated intraocular pressure.","4.The method of any one of claims 1-3, wherein laquinimod is laquinimod sodium.","5.The method of any one of claims 1-4, wherein the route of administration of laquinimod is intraocular, periocular, ocular, oral, systemic or topical.","6.The method of any one of claims 1-5, wherein laquinimod is administered in the form of an aerosol, an inhalable powder, an injectable, a liquid, a gel, a solid, a capsule or a tablet.","7.The method of claim 6, wherein the concentration of laquinimod in the liquid or gel is 5-100 mg/ml solution, 20-100 mg/ml solution, 10-15 mg/ml solution, or 20-50 mg/ml solution.","8.The method of any one of claims 1-7, wherein laquinimod is administered periodically.","9.The method of claim 8, wherein laquinimod is administered daily.","10.The method of claim 8, wherein laquinimod is administered more often than once daily or less often than once daily.","11.The method of any one of claims 1-10, wherein the amount laquinimod administered is at least 0.2 mg/day and/or less than 0.6 mg/day.","12.The method of any one of claims 1-10, wherein the amount laquinimod administered is 0.03-600 mg/day, 0.1-40.0 mg/day, 0.1-2.5 mg/day, 0.25-2.0 mg/day, 0.5-1.2 mg/day, 0.25 mg/day, 0.3 mg/day, 0.5 mg/day, 0.6 mg/day, 1.0 mg/day, 1.2 mg/day, 1.5 mg/day or 2.0 mg/day.","13.The method of any one of claims 1-12, wherein the amount of laquinimod administered is 0.05-4.0 mg per administration, 0.05-2.0 mg per administration, 0.2-4.0 mg per administration, 0.2-2.0 mg per administration, about 0.1 mg per administration, or about 0.5 mg per administration.","14.The method of any one of claims 1-13, further comprising administration of a second agent for the treatment of glaucoma.","15.The method of claim 14, wherein the second agent is a β-adrenergic antagonist, adrenergic agonist, parasympathomimetic, prostaglandin-like analog, or carbonic anhydrase inhibitor.","16.The method of any one of claims 8-15, wherein the periodic administration of laquinimod continues for at least 3 days, more than 30 days, more than 42 days, 8 weeks or more, at least 12 weeks, at least 24 weeks, more than 24 weeks, or 6 months or more.","17.The method of any one of claims 1-16, wherein the subject is a human patient.","18.A method of treating a subject suffering from retinal ganglion cell loss or retinal ganglion cell damage, or of reducing retinal ganglion cell loss or damage in a subject, comprising administering to the subject an amount of laquinimod effective to reduce retinal ganglion cell loss or retinal ganglion cell damage in the subject.","19.A method of treating a subject suffering from elevated intraocular pressure, or of reducing intraocular pressure in a subject, comprising administering to the subject an amount of laquinimod effective to reduce intraocular pressure in the subject.","20.A package comprising: a) a pharmaceutical composition comprising an amount of laquinimod; and b) instruction for use of the pharmaceutical composition to treat a subject afflicted with glaucoma.","21.The package of claim 20, wherein the package comprises a second pharmaceutical composition comprising an amount of a second agent for the treatment of glaucoma.","22.The package of claim 21, wherein the second agent is a β-adrenergic antagonist, adrenergic agonist, parasympathomimetic, prostaglandin-like analog, or carbonic anhydrase inhibitor.","23.The package of any one of claims 20-22, wherein the pharmaceutical composition is the form of an aerosol, an inhalable powder, an injectable, a liquid, a gel, a solid, a capsule or a tablet.","24.The package of claim 23, wherein the concentration of laquinimod in the liquid or gel is 5-100 mg/ml solution, 20-100 mg/ml solution, 10-15 mg/ml solution or 20-50 mg/ml solution.","25.The package of claim 23, wherein the tablets are coated with a coating which inhibits oxygen from contacting the core.","26.The package of claim 25, wherein the coating comprises a cellulosic polymer, a detackifier, a gloss enhancer, or pigment.","27.The package of any one of claims 20-26, wherein the pharmaceutical composition further comprises mannitol, an alkalinizing agent, an oxidation reducing agent, a lubricant, a filler, and/or a desiccant.","28.The package of claim 27, wherein the alkalinizing agent is meglumine.","29.The package of any one of claims 20-27, wherein the pharmaceutical composition is stable and free of an alkalinizing agent or an oxidation reducing agent, preferably the pharmaceutical composition is free of an alkalinizing agent and free of an oxidation reducing agent.","30.The package of any one of claims 20-29, wherein the pharmaceutical composition is stable and free of disintegrant.","31.The package of claim 27, wherein the lubricant is present in the pharmaceutical composition as solid particles.","32.The package of claim 27 or 31, wherein the lubricant is sodium stearyl fumarate or magnesium stearate.","33.The package of claim 27, wherein the filler is present in the pharmaceutical composition as solid particles.","34.The package of claim 27 or 33, wherein the filler is lactose, lactose monohydrate, starch, isomalt, mannitol, sodium starch glycolate, sorbitol, lactose spray dried, lactose anhydrouse, or a combination thereof.","35.The package of claim 27, wherein the desiccant is silica gel.","36.The package of any one of claims 20-35, wherein the pharmaceutical composition is stable and has a moisture content of no more than 4%.","37.The package of any one of claims 20-36, wherein laquinimod is present in the pharmaceutical composition as solid particles.","38.The package of any one of claims 20-37, wherein the package is a sealed packaging having a moisture permeability of not more than 15 mg/day per liter or a blister pack having a maximum moisture permeability of not more than 0.005 mg/day.","39.The package of claim 38, wherein the sealed package is a bottle or comprises an HDPE bottle, preferably the bottle is closed with a heat induction liner.","40.The package of claim 38 or 39, wherein the sealed package comprises an oxygen absorbing agent, which oxygen absorbing agent is preferably iron.","41.The package of any one of claims 20-40, wherein the amount of laquinimod in the pharmaceutical composition is at least 0.2 mg, less than 0.6 mg, 0.1-40.0 mg, 0.03-600 mg, 0.1-2.5 mg, 0.25-2.0 mg, 0.5-1.2 mg, 0.25 mg, 0.3 mg, 0.5 mg, 0.6 mg, 1.0 mg, 1.2 mg, 1.5 mg, or 2.0 mg. 42.The package of any one of claims 20-41, wherein the pharmaceutical composition comprises unit doses of laquinimod of 0.05-4.0 mg, 0.05-2.0 mg, 0.2-4.0 mg, 0.2-2.0 mg, about 0.1 mg, or about 0.5 mg. 43.The package of any one of claims 20-42, wherein the pharmaceutical composition is formulated for intraocular, periocular, ocular, oral, systemic or topical administration.","44.The package of any one of claims 20-43, for use in treating a subject afflicted with glaucoma.","45.A therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted with glaucoma, which comprises: a) one or more unit doses, each such unit dose comprising an amount of laquinimod thereof, wherein the amount of said laquinimod in said unit dose is effective, upon administration to said subject, to treat the subject, and b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said subject.","46.The therapeutic package of claim 45, wherein the package comprises a second pharmaceutical composition comprising an amount of a second agent for the treatment of glaucoma.","47.The therapeutic package of claim 46, wherein the second agent is a β-adrenergic antagonist, adrenergic agonist, parasympathomimetic, prostaglandin-like analog, or carbonic anhydrase inhibitor.","48.A pharmaceutical composition comprising an amount of laquinimod for use in treating a subject afflicted glaucoma.","49.The pharmaceutical composition of claim 48, comprising an amount of a second agent for the treatment of glaucoma.","50.The pharmaceutical composition of claim 49, wherein the second agent is a β-adrenergic antagonist, adrenergic agonist, parasympathomimetic, prostaglandin-like analog, or carbonic anhydrase inhibitor.","51.The pharmaceutical composition of any one of claims 48-50, in the form of an aerosol, an inhalable powder, an injectable, a liquid, a gel, a solid, a capsule or a tablet.","52.The pharmaceutical composition of claim 51, wherein the concentration of laquinimod in the liquid or gel is 5-100 mg/ml solution, 20-100 mg/ml solution, 10-15 mg/ml solution or 20-50 mg/ml solution.","53.The pharmaceutical composition of claim 51, comprising a unit dose of 10 μL of an aqueous pharmaceutical solution which contains in solution at least 0.2 mg laquinimod.","54.The pharmaceutical composition of any one of claims 48-53, wherein laquinimod is laquinimod sodium.","55.The pharmaceutical composition of claim 51, wherein the tablets are coated with a coating which inhibits oxygen from contacting the core.","56.The pharmaceutical composition of claim 55, wherein the coating comprises a cellulosic polymer, a detackifier, a gloss enhancer, or pigment.","57.The pharmaceutical composition of any one of claims 48-56, further comprising mannitol, an alkalinizing agent, an oxidation reducing agent, a lubricant and/or a filler.","58.The pharmaceutical composition of claim 57, wherein the alkalinizing agent is meglumine.","59.The pharmaceutical composition of any one of claims 48-57, which is free of an alkalinizing agent or an oxidation reducing agent, preferably the pharmaceutical composition is free of an alkalinizing agent and free of an oxidation reducing agent.","60.The pharmaceutical composition of any one of claims 48-59, which is stable and free of disintegrant.","61.The pharmaceutical composition of claim 57, wherein the lubricant is present in the pharmaceutical composition as solid particles.","62.The pharmaceutical composition of claim 57 or 61, wherein the lubricant is sodium stearyl fumarate or magnesium stearate.","63.The pharmaceutical composition of claim 57, wherein the filler is present in the pharmaceutical composition as solid particles.","64.The pharmaceutical composition of claim 57 or 63, wherein the filler is lactose, lactose monohydrate, starch, isomalt, mannitol, sodium starch glycolate, sorbitol, lactose spray dried, lactose anhydrouse, or a combination thereof.","65.The pharmaceutical composition of any one of claims 48-64, wherein the amount of laquinimod is at least 0.2 mg, less than 0.6 mg, 0.1-40.0 mg, 0.03-600 mg, 0.1-2.5 mg, 0.25-2.0 mg, 0.5-1.2 mg, 0.25 mg, 0.3 mg, 0.5 mg, 0.6 mg, 1.0 mg, 1.2 mg, 1.5 mg, or 2.0 mg. 66.The pharmaceutical composition of any one of claims 48-65, comprising unit doses of laquinimod of 0.05-4.0 mg, 0.05-2.0 mg, 0.2-4.0 mg, 0.2-2.0 mg, about 0.1 mg, or about 0.5 mg. 67.The pharmaceutical composition of any one of claims 48-66, formulated for intraocular, periocular, ocular, oral, systemic or topical administration.","68.The pharmaceutical composition of any one of claims 48-67, for use in treating a subject afflicted with glaucoma.","69.A pharmaceutical composition in unit dosage form, useful in treating a subject afflicted with glaucoma, which comprises an amount of laquinimod; which amount of said laquinimod in said composition is effective, upon administration to said subject of one or more of said unit dosage forms of said composition, to treat the subject.","70.A package comprising: a) a pharmaceutical composition of any one of claims 48-69; and b) instruction for use of the pharmaceutical composition to treat a subject afflicted with glaucoma.","71.Laquinimod for the manufacture of a medicament for use in treating a subject afflicted glaucoma."],["<SOH> BACKGROUND <EOH>Glaucoma is a group of ocular diseases characterized by progressive damage to the eye at least partly due to elevated intraocular pressure (IOP) (Merck Manual of Diagnosis and Therapy (1999)).","Additionally, glaucoma is characterized by retinal ganglion cell (RGC) death, axon loss and an excavated appearance of the optic nerve head (Alward 1998).","Glaucoma can be diagnosed before vision loss occurs by visual field testing and by ophthalmoscopic examination of the optic nerve to detect “cupping.” The mean IOP in normal adults is 15 to 16 mm Hg; the normal range is 10 to 21 mm Hg.","One form of management of glaucoma is based on lowering the IOP using topically applied medications (Coleman 1999).","Currently there are five major classes of medications that are used to lower the IOP: β-adrenergic antagonists, adrenergic agonists, parasympathomimetics, prostaglandin-like analogues and carbonic anhydrase inhibitors (Medeiros et al.","2002).","Although most medications are applied topically to the eye, they can cause severe systemic side effects and adversely affect the quality of the patient's life.","If additional lowering of IOP is indicated or if medication fails to sufficiently lower the IOP, laser trabeculoplasty is usually the next step.","If IOP is still not adequately controlled, incisional glaucoma surgery is indicated (Id).","The lowering of IOP, despite significantly reducing the extent of neuronal loss, does not ensure cessation of the disease process, because the loss of RGCs may continue.","Recent studies of the association between IOP regulation and visual field loss after medical or surgical intervention showed that ongoing neuronal loss reflected in visual field tests can be diminished if the IOP is low.","However, neuronal loss may continue to occur after reduction of IOP (Bakalash et al.","2002).","Glaucomatous optic neuropathy appears to result from specific pathophysiological changes and subsequent death of RGCs and their axons.","The process of RGC death is thought to be biphasic: a primary injury responsible for initiation of damage followed by a slower, secondary degeneration attributable to the hostile environment surrounding the degenerating cells (Kipnis et al.","2000).","The molecular mechanism triggering RGC death has not been identified.","Deprivation of neurotrophic factors, ischemia, chronic elevation of glutamate and disorganized nitric oxide metabolism are suspected to be possible mechanisms (Farkas et al.","2001).","In addition, it is possible that the mechanisms leading to RGC death share common features with other types of neuronal injury, such as signaling by reactive oxygen species, depolarization of mitochondria, or induction of transcriptionally regulated cell death (Weinreb et al.","1999).","Laquinimod Laquinimod (LAQ) is a novel synthetic compound with high oral bioavailability which has been suggested as an oral formulation for the treatment of Multiple Sclerosis (MS) (Polman, 2005; Sandberg-Wollheim, 2005).","Laquinimod and its sodium salt form are described, for example, in U.S. Pat.","No.","6,077,851.The mechanism of action of laquinimod is not fully understood.","Animal studies show it causes a Th1 (T helper 1 cell, which produces pro-inflammatory cytokines) to Th2 (T helper 2 cell, which produces anti-inflammatory cytokines) shift with an anti-inflammatory profile (Yang, 2004; Brück, 2011).","Another study demonstrated (mainly via the NFkB pathway) that laquinimod induced suppression of genes related to antigen presentation and corresponding inflammatory pathways (Gurevich, 2010).","Other suggested potential mechanisms of action include inhibition of leukocyte migration into the CNS, increase of axonal integrity, modulation of cytokine production, and increase in levels of brain-derived neurotrophic factor (BDNF) (Runström, 2006; Brück, 2011).","The effects of laquinimod on glaucoma have not previously been studied."],["<SOH> SUMMARY OF THE INVENTION <EOH>The subject invention provides a method of treating a subject afflicted with glaucoma comprising administering to the subject an amount of laquinimod effective to treat the subject.","The subject invention also provides a method of treating a subject suffering from retinal ganglion cell loss or retinal ganglion cell damage, or of reducing retinal ganglion cell loss or damage in a subject, comprising administering to the subject an amount of laquinimod effective to reduce retinal ganglion cell loss or retinal ganglion cell damage in the subject.","The subject invention also provides a method of treating a subject suffering from elevated intraocular pressure, or of reducing intraocular pressure in a subject, comprising administering to the subject an amount of laquinimod effective to reduce intraocular pressure in the subject.","The subject invention also provides a package comprising a) a pharmaceutical composition comprising an amount of laquinimod; and b) instruction for use of the pharmaceutical composition to treat a subject afflicted with glaucoma.","The subject invention also provides a therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted with glaucoma, which comprises a) one or more unit doses, each such unit dose comprising an amount of laquinimod thereof, wherein the amount of said laquinimod in said unit dose is effective, upon administration to said subject, to treat the subject, and b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said subject.","The subject invention also provides a pharmaceutical composition and a package as described herein for use in treating a subject afflicted with glaucoma.","The subject invention also provides a pharmaceutical composition in unit dosage form, useful in treating a subject afflicted with glaucoma, which comprises an amount of laquinimod; which amount of said laquinimod in said composition is effective, upon administration to said subject of one or more of said unit dosage forms of said composition, to treat the subject.","The subject invention also provides a package comprising a) a pharmaceutical composition as described herein; and b) instruction for use of the pharmaceutical composition to treat a subject afflicted with glaucoma.","The subject invention also provides laquinimod for the manufacture of a medicament for use in treating a subject afflicted glaucoma."],["This application claims benefit of U.S.","Provisional Application No.","61/904,962, filed Nov. 15, 2013, the entire content of which is hereby incorporated by reference herein.","Throughout this application, various publications are referred to by first author and year of publication.","Full citations for these publications are presented in a References section immediately before the claims.","Disclosures of the documents and publications referred to herein are hereby incorporated in their entireties by reference into this application.","BACKGROUND Glaucoma is a group of ocular diseases characterized by progressive damage to the eye at least partly due to elevated intraocular pressure (IOP) (Merck Manual of Diagnosis and Therapy (1999)).","Additionally, glaucoma is characterized by retinal ganglion cell (RGC) death, axon loss and an excavated appearance of the optic nerve head (Alward 1998).","Glaucoma can be diagnosed before vision loss occurs by visual field testing and by ophthalmoscopic examination of the optic nerve to detect “cupping.” The mean IOP in normal adults is 15 to 16 mm Hg; the normal range is 10 to 21 mm Hg.","One form of management of glaucoma is based on lowering the IOP using topically applied medications (Coleman 1999).","Currently there are five major classes of medications that are used to lower the IOP: β-adrenergic antagonists, adrenergic agonists, parasympathomimetics, prostaglandin-like analogues and carbonic anhydrase inhibitors (Medeiros et al.","2002).","Although most medications are applied topically to the eye, they can cause severe systemic side effects and adversely affect the quality of the patient's life.","If additional lowering of IOP is indicated or if medication fails to sufficiently lower the IOP, laser trabeculoplasty is usually the next step.","If IOP is still not adequately controlled, incisional glaucoma surgery is indicated (Id).","The lowering of IOP, despite significantly reducing the extent of neuronal loss, does not ensure cessation of the disease process, because the loss of RGCs may continue.","Recent studies of the association between IOP regulation and visual field loss after medical or surgical intervention showed that ongoing neuronal loss reflected in visual field tests can be diminished if the IOP is low.","However, neuronal loss may continue to occur after reduction of IOP (Bakalash et al.","2002).","Glaucomatous optic neuropathy appears to result from specific pathophysiological changes and subsequent death of RGCs and their axons.","The process of RGC death is thought to be biphasic: a primary injury responsible for initiation of damage followed by a slower, secondary degeneration attributable to the hostile environment surrounding the degenerating cells (Kipnis et al.","2000).","The molecular mechanism triggering RGC death has not been identified.","Deprivation of neurotrophic factors, ischemia, chronic elevation of glutamate and disorganized nitric oxide metabolism are suspected to be possible mechanisms (Farkas et al.","2001).","In addition, it is possible that the mechanisms leading to RGC death share common features with other types of neuronal injury, such as signaling by reactive oxygen species, depolarization of mitochondria, or induction of transcriptionally regulated cell death (Weinreb et al.","1999).","Laquinimod Laquinimod (LAQ) is a novel synthetic compound with high oral bioavailability which has been suggested as an oral formulation for the treatment of Multiple Sclerosis (MS) (Polman, 2005; Sandberg-Wollheim, 2005).","Laquinimod and its sodium salt form are described, for example, in U.S. Pat.","No.","6,077,851.The mechanism of action of laquinimod is not fully understood.","Animal studies show it causes a Th1 (T helper 1 cell, which produces pro-inflammatory cytokines) to Th2 (T helper 2 cell, which produces anti-inflammatory cytokines) shift with an anti-inflammatory profile (Yang, 2004; Brück, 2011).","Another study demonstrated (mainly via the NFkB pathway) that laquinimod induced suppression of genes related to antigen presentation and corresponding inflammatory pathways (Gurevich, 2010).","Other suggested potential mechanisms of action include inhibition of leukocyte migration into the CNS, increase of axonal integrity, modulation of cytokine production, and increase in levels of brain-derived neurotrophic factor (BDNF) (Runström, 2006; Brück, 2011).","The effects of laquinimod on glaucoma have not previously been studied.","SUMMARY OF THE INVENTION The subject invention provides a method of treating a subject afflicted with glaucoma comprising administering to the subject an amount of laquinimod effective to treat the subject.","The subject invention also provides a method of treating a subject suffering from retinal ganglion cell loss or retinal ganglion cell damage, or of reducing retinal ganglion cell loss or damage in a subject, comprising administering to the subject an amount of laquinimod effective to reduce retinal ganglion cell loss or retinal ganglion cell damage in the subject.","The subject invention also provides a method of treating a subject suffering from elevated intraocular pressure, or of reducing intraocular pressure in a subject, comprising administering to the subject an amount of laquinimod effective to reduce intraocular pressure in the subject.","The subject invention also provides a package comprising a) a pharmaceutical composition comprising an amount of laquinimod; and b) instruction for use of the pharmaceutical composition to treat a subject afflicted with glaucoma.","The subject invention also provides a therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted with glaucoma, which comprises a) one or more unit doses, each such unit dose comprising an amount of laquinimod thereof, wherein the amount of said laquinimod in said unit dose is effective, upon administration to said subject, to treat the subject, and b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said subject.","The subject invention also provides a pharmaceutical composition and a package as described herein for use in treating a subject afflicted with glaucoma.","The subject invention also provides a pharmaceutical composition in unit dosage form, useful in treating a subject afflicted with glaucoma, which comprises an amount of laquinimod; which amount of said laquinimod in said composition is effective, upon administration to said subject of one or more of said unit dosage forms of said composition, to treat the subject.","The subject invention also provides a package comprising a) a pharmaceutical composition as described herein; and b) instruction for use of the pharmaceutical composition to treat a subject afflicted with glaucoma.","The subject invention also provides laquinimod for the manufacture of a medicament for use in treating a subject afflicted glaucoma.","BRIEF DESCRIPTION OF THE FIGURES FIG.","1: Example 1: Mean ΔIOP (OHT minus Non-OHT) (mmHg).","FIG.","2: Example 1: % Fluoro-gold Labeled RGC Loss.","FIG.","3: Example 1: Mean Fluoro-gold Labeled RGC count per mm2.FIG.","4: Optic Nerve Injury Grade (1-5).","FIG.","5A: Example 1: Representative images of the retinas with FG-labeled RGC—Animal Number 48, Group 1, Left Eye.","FIG.","5B: Example 1: Representative images of the retinas with FG-labeled RGC—Animal Number 48, Group 1, Right Eye.","FIG.","5C: Example 1: Representative images of the retinas with FG-labeled RGC—Animal Number 59, Group 2, Left Eye.","FIG.","5D: Example 1: Representative images of the retinas with FG-labeled RGC—Animal Number 59, Group 2, Right Eye.","FIG.","5E: Example 1: Representative images of the retinas with FG-labeled RGC—Animal Number 22, Group 3, Left Eye.","FIG.","5F: Example 1: Representative images of the retinas with FG-labeled RGC—Animal Number 22, Group 3, Right Eye.","FIG.","5G: Example 1: Representative images of the retinas with FG-labeled RGC—Animal Number 31, Group 4, Left Eye.","FIG.","5H: Example 1: Representative images of the retinas with FG-labeled RGC—Animal Number 31, Group 4, Right Eye.","FIG.","5I: Example 1: Representative images of the retinas with FG-labeled RGC—Animal Number 35, Group 5, Left Eye.","FIG.","5J: Example 1: Representative images of the retinas with FG-labeled RGC—Animal Number 35, Group 5, Right Eye.","DETAILED DESCRIPTION OF THE INVENTION The subject invention provides a method of treating a subject afflicted with glaucoma comprising administering to the subject an amount of laquinimod effective to treat the subject.","In one embodiment, the administration of laquinimod is effective to reduce or inhibit a symptom of the glaucoma in the subject.","In another embodiment, the symptom is retinal ganglion cell damage, retinal ganglion cell loss, or elevated intraocular pressure.","In another embodiment, laquinimod is laquinimod sodium.","In one embodiment, the route of administration of laquinimod is intraocular, periocular, systemic or topical.","In another embodiment, laquinimod is administered via oral administration.","In another embodiment, laquinimod is administered via ocular administration.","In another embodiment, laquinimod is administered in the form of an aerosol, an inhalable powder, an injectable, a liquid, a gel, a solid, a capsule or a tablet.","In an embodiment, the concentration of laquinimod in the liquid or gel is 5-100 mg/ml solution, 20-100 mg/ml solution, 10-15 mg/ml solution, or 20-50 mg/ml solution.","In another embodiment, laquinimod is administered periodically.","In another embodiment, laquinimod is administered daily.","In another embodiment, laquinimod is administered more often than once daily.","In yet another embodiment, laquinimod is administered less often than once daily.","In one embodiment, the amount laquinimod administered is at least 0.2 mg/day and/or less than 0.6 mg/day.","In another embodiment, the amount laquinimod administered is 0.03-600 mg/day, 0.1-40.0 mg/day, 0.1-2.5 mg/day, 0.25-2.0 mg/day or 0.5-1.2 mg/day.","In another embodiment, the amount laquinimod administered is 0.25 mg/day, 0.3 mg/day, 0.5 mg/day, 0.6 mg/day, 1.0 mg/day, 1.2 mg/day, 1.5 mg/day or 2.0 mg/day.","In yet another embodiment, the amount of laquinimod administered is 0.05-4.0 mg per administration, 0.05-2.0 mg per administration, 0.2-4.0 mg per administration, 0.2-2.0 mg per administration, about 0.1 mg per administration, or about 0.5 mg per administration.","In one embodiment of the present invention, the method further comprises administration of a second agent for the treatment of glaucoma.","In another embodiment, the second agent is a β-adrenergic antagonist, adrenergic agonist, parasympathomimetic, prostaglandin-like analog, or carbonic anhydrase inhibitor.","In one embodiment, the periodic administration of laquinimod continues for at least 3 days, more than 30 days, more than 42 days, 8 weeks or more, at least 12 weeks, at least 24 weeks, more than 24 weeks, or 6 months or more.","In another embodiment, the subject is a human patient.","The subject invention also provides a method of treating a subject suffering from retinal ganglion cell loss or retinal ganglion cell damage, or of reducing retinal ganglion cell loss or damage in a subject, comprising administering to the subject an amount of laquinimod effective to reduce retinal ganglion cell loss or retinal ganglion cell damage in the subject.","The subject invention also provides a method of treating a subject suffering from elevated intraocular pressure, or of reducing intraocular pressure in a subject, comprising administering to the subject an amount of laquinimod effective to reduce intraocular pressure in the subject.","The subject invention also provides a package comprising a) a pharmaceutical composition comprising an amount of laquinimod; and b) instruction for use of the pharmaceutical composition to treat a subject afflicted with glaucoma.","In one embodiment of the present invention, the package comprises a second pharmaceutical composition comprising an amount of a second agent for the treatment of glaucoma.","In another embodiment, the second agent is a β-adrenergic antagonist, adrenergic agonist, parasympathomimetic, prostaglandin-like analog, or carbonic anhydrase inhibitor.","In one embodiment, the pharmaceutical composition is the form of an aerosol, an inhalable powder, an injectable, a liquid, a gel, a solid, a capsule or a tablet.","In another embodiment, the pharmaceutical composition is in a liquid or a gel form.","In one embodiment, the concentration of laquinimod in the liquid or gel is 5-100 mg/ml solution, 20-100 mg/ml solution, 10-15 mg/ml solution or 20-50 mg/ml solution.","In another embodiment, the pharmaceutical composition is in capsule form or in tablet form.","In another embodiment, the tablets are coated with a coating which inhibits oxygen from contacting the core.","In another embodiment, the coating comprises a cellulosic polymer, a detackifier, a gloss enhancer, or pigment.","In one embodiment, the pharmaceutical composition further comprises mannitol.","In another embodiment, the pharmaceutical composition further comprises an alkalinizing agent.","In another embodiment, the alkalinizing agent is meglumine.","In another embodiment, the pharmaceutical composition further comprises an oxidation reducing agent.","In one embodiment, the pharmaceutical composition is stable and free of an alkalinizing agent or an oxidation reducing agent.","In another embodiment, the pharmaceutical composition is free of an alkalinizing agent and free of an oxidation reducing agent.","In one embodiment, the pharmaceutical composition is stable and free of disintegrant.","In another embodiment, the pharmaceutical composition further comprises a lubricant.","In another embodiment, the lubricant is present in the pharmaceutical composition as solid particles.","In another embodiment, the lubricant is sodium stearyl fumarate or magnesium stearate.","In one embodiment, the pharmaceutical composition further comprises a filler.","In another embodiment, the filler is present in the pharmaceutical composition as solid particles.","In another embodiment, the filler is lactose, lactose monohydrate, starch, isomalt, mannitol, sodium starch glycolate, sorbitol, lactose spray dried, lactose anhydrouse, or a combination thereof.","In another embodiment, the filler is mannitol or lactose monohydrate.","In one embodiment, the package further comprises a desiccant.","In another embodiment, the desiccant is silica gel.","In one embodiment, the pharmaceutical composition is stable and has a moisture content of no more than 4%.","In another embodiment, laquinimod is present in the pharmaceutical composition as solid particles.","In another embodiment, the package is a sealed packaging having a moisture permeability of not more than 15 mg/day per liter.","In another embodiment, the sealed package is a blister pack in which the maximum moisture permeability is no more than 0.005 mg/day.","In another embodiment, the sealed package is a bottle.","In another embodiment, the bottle is closed with a heat induction liner.","In another embodiment, the sealed package comprises an HDPE bottle.","In another embodiment, the sealed package comprises an oxygen absorbing agent.","In another embodiment, the oxygen absorbing agent is iron.","In one embodiment, the amount of laquinimod in the pharmaceutical composition is at least 0.2 mg or less than 0.6 mg.","In another embodiment, the amount of laquinimod in the pharmaceutical composition is 0.1-40.0 mg, 0.03-600 mg, 0.1-2.5 mg, 0.25-2.0 mg, 0.5-1.2 mg, 0.25 mg, 0.3 mg, 0.5 mg, 0.6 mg, 1.0 mg, 1.2 mg, 1.5 mg, or 2.0 mg.","In another embodiment, the pharmaceutical composition comprises unit doses of laquinimod of 0.05-4.0 mg, 0.05-2.0 mg, 0.2-4.0 mg, 0.2-2.0 mg, about 0.1 mg, or about 0.5 mg.","In one embodiment, the pharmaceutical composition is formulated for intraocular, periocular, systemic or topical administration.","In another embodiment, the pharmaceutical composition is formulated for oral or ocular administration.","The subject invention also provides packages as described herein for use in treating a subject afflicted with glaucoma.","The subject invention also provides a therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted with glaucoma, which comprises a) one or more unit doses, each such unit dose comprising an amount of laquinimod thereof, wherein the amount of said laquinimod in said unit dose is effective, upon administration to said subject, to treat the subject, and b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said subject.","In one embodiment, the therapeutic package comprises a second pharmaceutical composition comprising an amount of a second agent for the treatment of glaucoma.","In another embodiment, the second agent is a β-adrenergic antagonist, adrenergic agonist, parasympathomimetic, prostaglandin-like analog, or carbonic anhydrase inhibitor.","The subject invention also provides a pharmaceutical composition comprising an amount of laquinimod for use in treating a subject afflicted glaucoma.","In one embodiment, the pharmaceutical composition comprises an amount of a second agent for the treatment of glaucoma.","In another embodiment, the second agent is a β-adrenergic antagonist, adrenergic agonist, parasympathomimetic, prostaglandin-like analog, or carbonic anhydrase inhibitor.","In an embodiment, the pharmaceutical composition is in the form of an aerosol, an inhalable powder, an injectable, a liquid, a gel, a solid, a capsule or a tablet.","In another embodiment, the pharmaceutical composition is in a liquid or a gel form.","In an embodiment, the concentration of laquinimod in the liquid or gel is 5-100 mg/ml solution, 20-100 mg/ml solution, 10-15 mg/ml solution or 20-50 mg/ml solution.","In another embodiment, the pharmaceutical composition comprises a unit dose of 10 μL of an aqueous pharmaceutical solution which contains in solution at least 0.2 mg laquinimod.","In another embodiment, laquinimod is laquinimod sodium.","In one embodiment, the pharmaceutical composition is in capsule form or in tablet form.","In another embodiment, the tablets are coated with a coating which inhibits oxygen from contacting the core.","In another embodiment, the coating comprises a cellulosic polymer, a detackifier, a gloss enhancer, or pigment.","In another embodiment, the pharmaceutical composition further comprises mannitol.","In one embodiment, the pharmaceutical composition further comprises an alkalinizing agent.","In another embodiment, the alkalinizing agent is meglumine.","In another embodiment, the pharmaceutical composition further comprises an oxidation reducing agent.","In one embodiment, the pharmaceutical composition is free of an alkalinizing agent or an oxidation reducing agent.","In another embodiment, the pharmaceutical composition is free of an alkalinizing agent and free of an oxidation reducing agent.","In one embodiment, the pharmaceutical composition is stable and free of disintegrant.","In another embodiment, the pharmaceutical composition further comprises a lubricant.","In another embodiment, the lubricant is present in the pharmaceutical composition as solid particles.","In another embodiment, the lubricant is sodium stearyl fumarate or magnesium stearate.","In one embodiment, the pharmaceutical composition further comprises a filler.","In another embodiment, the filler is present in the pharmaceutical composition as solid particles.","In another embodiment, the filler is lactose, lactose monohydrate, starch, isomalt, mannitol, sodium starch glycolate, sorbitol, lactose spray dried, lactose anhydrouse, or a combination thereof.","In another embodiment, the filler is mannitol or lactose monohydrate.","In one embodiment, the amount of laquinimod in the pharmaceutical composition is at least 0.2 mg or less than 0.6 mg.","In another embodiment, the amount of laquinimod in is 0.1-40.0 mg, 0.03-600 mg, 0.1-2.5 mg, 0.25-2.0 mg, 0.5-1.2 mg, 0.25 mg, 0.3 mg, 0.5 mg, 0.6 mg, 1.0 mg, 1.2 mg, 1.5 mg, or 2.0 mg.","In another embodiment, the pharmaceutical composition comprises unit doses of laquinimod of 0.05-4.0 mg, 0.05-2.0 mg, 0.2-4.0 mg, 0.2-2.0 mg, about 0.1 mg, or about 0.5 mg.","In one embodiment, the pharmaceutical composition is formulated for intraocular, periocular, systemic or topical administration.","In another embodiment, the pharmaceutical composition is formulated for oral or ocular administration.","The subject invention also provides a pharmaceutical composition as described herein for use in treating a subject afflicted with glaucoma.","The subject invention also provides a pharmaceutical composition in unit dosage form, useful in treating a subject afflicted with glaucoma, which comprises an amount of laquinimod; which amount of said laquinimod in said composition is effective, upon administration to said subject of one or more of said unit dosage forms of said composition, to treat the subject.","The subject invention also provides a package comprising a) a pharmaceutical composition as described herein; and b) instruction for use of the pharmaceutical composition to treat a subject afflicted with glaucoma.","The subject invention also provides laquinimod for the manufacture of a medicament for use in treating a subject afflicted glaucoma.","For the foregoing embodiments, each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments.","For instance, the elements recited in the method embodiments can be used in the pharmaceutical composition, package, and use embodiments described herein and vice versa.","Terms As used herein, and unless stated otherwise, each of the following terms shall have the definition set forth below.","As used herein, “laquinimod” means laquinimod acid or a pharmaceutically acceptable salt thereof.","A “salt thereof” is a salt of the instant compounds which have been modified by making acid or base salts of the compounds.","The term “pharmaceutically acceptable salt” in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention.","For example, one means of preparing such a salt is by treating a compound of the present invention with an inorganic base.","As used herein, an “amount” or “dose” of laquinimod as measured in milligrams refers to the milligrams of laquinimod acid present in a preparation, regardless of the form of the preparation.","A “dose of 0.6 mg laquinimod” means the amount of laquinimod acid in a preparation is 0.6 mg, regardless of the form of the preparation.","Thus, when in the form of a salt, e.g.","a laquinimod sodium salt, the weight of the salt form necessary to provide a dose of 0.6 mg laquinimod would be greater than 0.6 mg (e.g., 0.64 mg) due to the presence of the additional salt ion.","As used herein, a “unit dose”, “unit doses” and “unit dosage form(s)” mean a single drug administration entity/entities.","As used herein, “about” in the context of a numerical value or range means±10% of the numerical value or range recited or claimed.","As used herein, a composition that is “free” of a chemical entity means that the composition contains, if at all, an amount of the chemical entity which cannot be avoided although the chemical entity is not part of the formulation and was not affirmatively added during any part of the manufacturing process.","For example, a composition which is “free” of an alkalizing agent means that the alkalizing agent, if present at all, is a minority component of the composition by weight.","Preferably, when a composition is “free” of a component, the composition comprises less than 0.1 wt %, 0.05 wt %, 0.02 wt %, or 0.01 wt % of the component.","As used herein, “alkalizing agent” is used interchangeably with the term “alkaline-reacting component” or “alkaline agent” and refers to any pharmaceutically acceptable excipient which neutralizes protons in, and raises the pH of, the pharmaceutical composition in which it is used.","As used herein, “oxidation reducing agent” refers to a group of chemicals which includes an “antioxidant”, a “reduction agent” and a “chelating agent”.","As used herein, “antioxidant” refers to a compound selected from the group consisting of tocopherol, methionine, glutathione, tocotrienol, dimethyl glycine, betaine, butylated hydroxyanisole, butylated hydroxytoluene, turmerin, vitamin E, ascorbyl palmitate, tocopherol, deteroxime mesylate, methyl paraben, ethyl paraben, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, sodium or potassium metabisulfite, sodium or potassium sulfite, alpha tocopherol or derivatives thereof, sodium ascorbate, disodium edentate, BHA (butylated hydroxyanisole), a pharmaceutically acceptable salt or ester of the mentioned compounds, and mixtures thereof.","The term “antioxidant” as used herein also refers to Flavonoids such as those selected from the group of quercetin, morin, naringenin and hesperetin, taxifolin, afzelin, quercitrin, myricitrin, genistein, apigenin and biochanin A, flavone, flavopiridol, isoflavonoids such as the soy isoflavonoid, genistein, catechins such as the tea catechin epigallocatechin gallate, flavonol, epicatechin, hesperetin, chrysin, diosmin, hesperidin, luteolin, and rutin.","As used herein, “reduction agent” refers to a compound selected from the group consisting of thiol-containing compound, thioglycerol, mercaptoethanol, thioglycol, thiodiglycol, cysteine, thioglucose, dithiothreitol (DTT), dithio-bis-maleimidoethane (DTME), 2,6-di-tert-butyl-4-methylphenol (BHT), sodium dithionite, sodium bisulphite, formamidine sodium metabisulphite, and ammonium bisulphite.” As used herein, “chelating agent” refers to a compound selected from the group consisting of penicillamine, trientine, N,N′-diethyldithiocarbamate (DDC), 2,3,2′-tetraamine (2,3,2′-tet), neocuproine, N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), 1,10-phenanthroline (PHE), tetraethylenepentamine, triethylenetetraamine and tris(2-carboxyethyl) phosphine (TCEP), ferrioxamine, CP94, EDTA, deferoxainine B (DFO) as the methanesulfonate salt (also known as desferrioxanilne B mesylate (DFOM)), desferal from Novartis (previously Ciba-Giegy), and apoferritin.","As used herein, a pharmaceutical composition is “stable” when the composition preserves the physical stability/integrity and/or chemical stability/integrity of the active pharmaceutical ingredient during storage.","Furthermore, “stable pharmaceutical composition” is characterized by its level of degradation products not exceeding 5% at 40° C./75% RH after 6 months or 3% at 55° C./75% RH after two weeks, compared to their level in time zero.","As used herein, “effective” when referring to an amount of laquinimod refers to the quantity of laquinimod that is sufficient to yield a desired therapeutic response.","Efficacy can be measured by e.g., a reduced intraocular pressure (IOP).","Administering to the subject” or “administering to the (human) patient” means the giving of, dispensing of, or application of medicines, drugs, or remedies to a subject/patient to relieve, cure, or reduce the symptoms associated with a condition, e.g., a pathological condition.","The administration can be periodic administration.","As used herein, “periodic administration” means repeated/recurrent administration separated by a period of time.","The period of time between administrations is preferably consistent from time to time.","Periodic administration can include administration, e.g., once daily, twice daily, three times daily, four times daily, weekly, twice weekly, three times weekly, four times weekly and so on, etc.","The route of administration can be, e.g., topical.","Routes of administration can also be classified by whether the effect is local (e.g., in topical administration) or systemic (e.g., in enteral or parenteral administration).","“Local administration” as used herein shall mean administration of a compound or composition directly to where its action is desired, and specifically excludes systemic administration.","“Topical administration” of a compound or composition as used herein shall mean application of the compound or composition to body surfaces such as the skin or mucous membranes such as eyes.","“Ocular administration” as used herein shall mean application of a compound or composition to the eye of a subject or to the skin around the eye (periocular skin) of a subject, i.e., local administration.","Examples of ocular administration include topical administration directly to the eye, topical application to the eye lid or injection into a portion of the eye or eye socket.","In addition, an “ocular pharmaceutical composition” as used herein means a pharmaceutical composition formulated for ocular administration.","“Treating” as used herein encompasses, e.g., inducing inhibition, regression, or stasis of a disease or disorder, e.g., glaucoma, or alleviating, lessening, suppressing, inhibiting, reducing the severity of, eliminating or substantially eliminating, or ameliorating a symptom of the disease or disorder.","“Inhibition” of disease progression or disease complication in a subject means preventing or reducing the disease progression and/or disease complication in the subject.","A “symptom” associated with glaucoma includes any clinical or laboratory manifestation associated with glaucoma and is not limited to what the subject can feel or observe.","As used herein, a subject “afflicted” with glaucoma means the subject has been diagnosed with glaucoma.","As used herein, a subject at “baseline” is as subject prior to administration of laquinimod in a therapy as described herein.","A “pharmaceutically acceptable carrier” refers to a carrier or excipient that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.","It can be a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the subject.","It is understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided by the invention.","For example, “0.1-2.5 mg/day” includes 0.1 mg/day, 0.2 mg/day, 0.3 mg/day, etc.","up to 2.5 mg/day.","This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter.","EXPERIMENTAL DETAILS Example 1: Assessment of the Neuroprotective Efficacy of Laquinimod for the Retinal Ganglion Cell (RGC) Survival in a Rat Glaucoma Model The purpose of this study was to assess the efficacy of laquinimod in protecting against chronic ocular hypertension (OHT) and RGC degeneration in a rat model of glaucoma, created by injecting hypertonic saline into the episcleral veins in one eye of the Brown Norway rat.","In this model, RGC degeneration occurs in response to increased IOP and OHT similar to that in human patients with glaucoma.","SUMMARY The study included 5 groups (n=8 each): Group 1 (1% Laquinimod for topical administration), Group 2 (Vehicle for topical administration), Group 3 (4% Laquinimod for topical administration), Group 4 (0.25% Laquinimod for topical administration) and Group 5 (0.1% Laquinimod for oral administration).","Prior to any experimental procedure, clinical observations were performed daily, body weights were obtained, intraocular pressure (IOP) was measured and detailed ocular examinations were performed on both eyes.","Animals that were found to be clinically normal with no baseline ocular abnormalities were selected for use in the study.","The rat model of chronic ocular hypertension (OHT)/glaucoma was created in the left eye of each animal via two hypertonic saline injections (HSI) each one week apart.","The un-injected right eye served as the control.","Throughout the study, the vehicle control and the test articles were prepared weekly.","Rats were dosed once daily for oral administration (Group 5) and twice daily for topical administration groups (Groups 1-4), starting on the day of the first HSI until euthanasia.","Detailed ocular examinations were performed one week after the 2nd HSI and on the day of euthanasia.","Approximately one week prior to euthanasia, RGCs were retrogradely-labeled by bilateral injections of Fluoro-Gold (FG) into the superior colliculus in the brain.","Post-dose IOP was measured weekly for 5 weeks starting one week after the 2nd HSI until euthanasia.","For each IOP measurement time-point following the 2nd HSI, the IOP elevation was calculated as the difference between the IOP in the left eye with OHT and that in the non-OHT right eye (ΔIOP).","The ΔIOP for the 5 weekly post-HSI IOP measurements were averaged and constituted the Mean ΔIOP for each animal.","Rats which did not have individual IOP measurements of 50 mmHg in the OHT eyes were selected from a larger pool and groups (n=8 each) were matched for the Mean ΔIOP.","Other animals were removed from the study.","Animals were euthanized 5 weeks after the 2nd HSI.","The retinas were flat-mounted, slide IDs were masked and 8 regions per retina were imaged using a confocal microscope.","RGC at these regions were counted using the Image J software.","After the optic nerves were extracted, they were plastic-embedded, sectioned and stained with Toluidine Blue at Schepens Eye Research Institute, Boston, Mass.","The injury in the optic nerves was evaluated and graded by microscopic examination in a masked fashion.","There were no abnormal clinical signs or ocular abnormalities noted in any of the 40 animals in the beginning of the study.","There were no treatment-related findings in the clinical observations or ocular examinations during the study in any of the animals.","A One-Way ANOVA indicated that the group body weights were not statistically different on the day of dosing among groups (P=0.957).","Groups also did not differ in the amount of weight gained between the day of dosing and the day of euthanasia (One-Way ANOVA; P=0.559).","For five weeks post-dose, the mean ΔIOP values (OHT−Non-OHT) (Mean±SD) were 9.1±2.2 mmHg, 9.1±2.6 mmHg, 9.3±2.7 mmHg, 9.2±1.5 mmHg, and 9.1±2.9 mmHg for Groups 1, 2, 3, 4 and 5, respectively.","A One-Way ANOVA analysis indicated that the groups were well-matched for Mean ΔIOP (P>0.9).","Compared to the non-OHT retinas, % Fluoro-gold labeled-RGC Loss (Mean±SD) in the OHT retinas was 17.6±33.8, 34.8±42.7, 26.8±36.4, 21.6±21.7, and 22.9±33.1 for Groups 1, 2, 3, 4 and 5, respectively.","FG-Labeled RGC counts per mm2 were compared between the Non-OHT and the OHT retinas for each group using two-tailed paired-t tests.","Group 2 (vehicle topical; P=0.047) and Group 4 (0.25% Laquinimod topical; P=0.033) had fewer RGCs in the OHT eye compared to the Non-OHT eyes.","The number of RGCs in Group 3 (4% Laquinimod topical; P=0.071) and Group 5 (0.1% Laquinimod oral; P=0.075) were statistically different between the OHT and Non-OHT eyes.","However, in Group 1 (1% Laquinimod topical), there was no statistically significant difference in the RGC counts between the OHT and Non-OHT eyes (P=0.189).","This suggests that the daily topical application of 1% Laquinimod may be neuroprotective for the RGC.","For the optic nerves in the Non-OHT (control) eyes, the Mean Injury Grades (Mean±SD) were 1.1±0.1, 1.2±0.2, 1.2±0.2, 1.2±0.3 and 1.2±0.2 for Groups 1, 2, 3, 4 and 5, respectively.","For the optic nerves in the OHT eyes, the Mean Injury Grades (Mean±SD) for the OHT optic nerves were 2.5±1.3, 3.0±1.6, 3.0±1.5, 2.8±1.3 and 2.7±1.5 for Groups 1, 2, 3, 4, and 5 respectively.","As a secondary analysis, Mean ON Injury Grades were compared between the Non-OHT and the OHT optic nerves for each group using two-tailed paired-t tests.","The Mean ON injury grades were significantly greater in the OHT eyes compared to the Non-OHT control eyes in all groups (P<0.05).","Materials Test Article: laquinimod sodium stored at room temperature protected from light.","Control Article: 0% laquinimod sodium stored under refrigeration.","Animals Number and Species: The study quote and outline-specified data were collected on 40 Brown Norway rats (Rattus norvegicus).","Rats have been used historically as OHT models and there are no other approved alternative (non-animal methods).","The study started with 90 animals to ensure that sufficient data were available at the end of the study.","Sex: male Weight/Age Range: approximately 271.2-366.4 grams/at least 12 weeks old (adult) weighed to nearest 0.1 g. Procedure Ocular and oral exposure corresponds to the route of human exposure.","For the four topical administration groups, the test and control articles were applied topically to the surface of one eye of the test system.","The test article was administered orally for the fifth group of animals.","Preparation of Test and Control Articles All test and control articles were prepared as described below.","The final volume for the formulations described below is 200 mL but the formulations were proportionally changed to the required volume for each preparation.","Three different concentrations (0.25%, 1%, and 4%) of the test article for topical application and the test article for oral gavage (0.1%) were prepared weekly.","The control article for topical application was also prepared weekly.","The identification of the test and control articles for the topical administration was masked after preparation of the topical formulations.","TABLE 1 LAQ 4.0% Topical Formulation (40 mg/mL of LAQ) Material g/200 mL solution Laquinimod Sodium 8.52 (equivalent to 8 g Laquinimod acid) Sodium Phosphate Dibasic 7 Hydrate 2.497 Sodium Phosphate Monobasic Monohydrate 0.0942 Hydroxy Ethyl Cellulose (HEC) HX 0.3 Water for Injection Amount required to bring solution to 200 mL Table 1 Process: 1.The entire process is performed under yellow light or at dark conditions.","2.Weigh 175 g (175 mL) of water for injection in a glass container containing a stirrer.","3.Weigh and add the Sodium Phosphate Monobasic Monohydrate and Sodium Phosphate Dibasic 7 Hydrate and stir for approximately 5 minutes.","Verify complete dissolution by visual inspection of a clear transparent solution.","4.Measure the pH (Approximately 7.7-8.3).","5.Weigh and add Laquinimod Sodium to the solution.","Rinse the weighing boat from the Laquinimod Sodium remaining with ˜5 mL of water and to the solution.","Stir for approximately 5 minutes and verify complete dissolution by visual inspection of a clear transparent solution.","6.Weigh and add the Hydroxy Ethyl Cellulose HX.","7.Stir for approximately 2 hours.","8.Remove the stirrer and add the solution to a 200 mL volumetric flask.","9.Add water for injection up to 200 mL.","10.Shake manually for approximately two minutes.","11.Transfer into an appropriate container.","Wrap with aluminum foil and keep the solution refrigerated.","TABLE 2 LAQ 1.0% Topical Formulation (10 mg/mL of LAQ) Material g/200 mL solution Laquinimod Sodium 2.12 (equivalent to 2 g Laquinimod acid) Sodium Phosphate Dibasic 7 Hydrate 2.497 Sodium Phosphate Monobasic Monohydrate 0.0942 Hydroxy Ethyl Cellulose (HEC) HX 0.3 Sodium chloride 0.75 Water for Injection Amount required to bring solution to 200 mL Table 2 Process: 1.The entire process is performed under yellow light or at dark conditions.","2.Weigh 175 g (175 mL) of water for injection in a glass container containing a stirrer.","3.Weigh and add the Sodium Phosphate Monobasic Monohydrate and Sodium Phosphate Dibasic 7 Hydrate and stir for approximately 5 minutes.","Verify complete dissolution by visual inspection of a clear transparent solution.","4.Measure the pH (Approximately 7.7 to 8.3).","5.Weigh and add Laquinimod Sodium to the solution.","Rinse the weighing boat from the Laquinimod Sodium remaining with ˜5 mL of water and to the solution.","Stir for approximately 5 minutes and verify complete dissolution by visual inspection of a clear transparent solution.","6.Weigh and add the Sodium Chloride to the solution.","Stir for approximately 2 minutes.","Verify complete dissolution by visual inspection of a clear transparent solution.","7.Weigh and add the Hydroxy Ethyl Cellulose HX.","8.Stir for approximately 2 hours.","9.Remove the stirrer and add the solution to a 200 mL volumetric flask.","10.Add water for injection up to 200 mL.","11.Shake manually for approximately two minutes.","12.Transfer into an appropriate container.","Wrap with aluminum foil and keep the solution refrigerated.","TABLE 3 LAQ 0.25% Topical Formulation (2.5 mg/mL of LAQ) Material g/200 mL solution Laquinimod Sodium 0.54 (equivalent to 0.5 g Laquinimod acid) Sodium Phosphate Dibasic 7 Hydrate 2.497 Sodium Phosphate Monobasic Monohydrate 0.0942 Hydroxy Ethyl Cellulose (HEC) HX 0.3 Sodium chloride 0.94 Water for Injection Amount required to bring solution to 200 mL Table 3 Process: 1.The entire process is performed under yellow light or at dark conditions.","2.Weigh 175 g (175 mL) of water for injection in a glass container containing a stirrer.","3.Weigh and add the Sodium Phosphate Monobasic Monohydrate and Sodium Phosphate Dibasic 7 Hydrate and stir for approximately 5 minutes.","Verify complete dissolution by visual inspection of a clear transparent solution.","4.Measure the pH (Approximately 7.7-8.3).","5.Weigh and add Laquinimod Sodium to the solution.","Rinse the weighing boat from the Laquinimod Sodium remaining with ˜5 mL of water and to the solution.","Stir for approximately 5 minutes and verify complete dissolution by visual inspection of a clear transparent solution.","6.Weigh and add the Sodium Chloride to the solution.","Stir for approximately 2 minutes.","Verify complete dissolution by visual inspection of a clear transparent solution.","7.Weigh and add the Hydroxy Ethyl Cellulose HX.","8.Stir for approximately 2 hours.","9.Remove the stirrer and add the solution to a 200 mL volumetric flask.","10.Add water for injection up to 200 mL.","11.Shake manually for approximately two minutes.","12.Transfer into an appropriate container.","Wrap with aluminum foil and keep the solution refrigerated.","TABLE 4 LAQ 0% Topical Formulation (Control Article) Material g/200 mL solution Sodium Phosphate Dibasic 7 Hydrate 2.497 Sodium Phosphate Monobasic Monohydrate 0.0942 Hydroxy Ethyl Cellulose (HEC) HX 0.3 Sodium chloride 1 Water for Injection Amount required to bring solution to 200 mL Table 4 Process: 1.The entire process is performed under yellow light or at dark conditions.","2.Weigh 175 g (175 mL) of water for injection in a glass container containing a stirrer.","3.Weigh and add the Sodium Phosphate Monobasic Monohydrate and Sodium Phosphate Dibasic 7 Hydrate and stir for approximately 5 minutes.","Verify complete dissolution by visual inspection of a clear transparent solution.","4.Measure the pH (Approximately 7.7 to 8.3).","5.Weigh and add the Sodium Chloride to the solution.","Stir for approximately 2 minutes.","Verify complete dissolution by visual inspection of a clear transparent solution.","6.Weigh and add the Hydroxy Ethyl Cellulose HX.","7.Stir for approximately 2 hours.","8.Remove the stirrer and add the solution to a 200 mL volumetric flask.","9.Add water for injection up to 200 mL.","10.Shake manually for approximately two minutes.","11.Transfer into an appropriate container.","TABLE 5 LAQ 0.1% Oral Formulation (1.0 mg/mL of LAQ) Material g/200 mL solution Laquinimod Sodium 0.2 (Equivalent to 0.2 g laquinimod acid) Autoclaved Tap Water Amount required to bring solution to 200 mL Table 5 Process: 1.The entire process is performed under yellow light or at dark conditions.","2.Weigh 150 g (150 mL) of autoclaved tap water in a glass container containing a stirrer.","3.Weigh and add Laquinimod Sodium to the solution.","Rinse the remaining Laquinimod Sodium in the weighing boat with ˜5 mL of water and add to the solution.","Stir for approximately 5 minutes and verify complete dissolution by visual inspection of a clear transparent solution.","4.Add autoclaved tap water up to 200 mL.","5.Stir for 5 minutes.","6.Transfer into an appropriate amber Pre-Dose Administration and Selection of Animals: Clinical observations were performed daily according to Table 6 below: TABLE 6 Clinical Signs and Observations Observed Sign Involved System(s) Respiratory Dyspnea (abdominal breathing, CNS, pulmonary, cardiac gasping), apnea, cyanosis, tachypnea, nostril discharges Motor Activities Decrease/increase somnolence, CNS, somatomotor, sensory, loss of righting, anaesthesia, neuromuscular, autonomic catalepsy, ataxia, unusual locomotion, prostration, tremors, fasciculation Convulsion Clonic, tonic, tonic-clonic, CNS, neuromuscular, autonomic, asphyxial, opisthotonos respiratory Reflexes Corneal, righting, myotact, light, CNS, sensory, autonomic, startle reflex neuromuscular Ocular Signs Lacrimation, miosis, mydriasis, Autonomic, irritation exophthalmos, ptosis, opacity, iritis, conjunctivitis, chromodacryorrhea, relaxation of nictitating membrane Cardiovascular Signs Bradycardia, tachycardia, CNS, autonomic, cardiac, arrhythmia, vasodilation, pulmonary vasoconstriction Salivation Excessive Autonomic Piloerection Rough hair Autonomic Analgesia Decrease reaction CNS, sensory Muscle Tone Hypotonia, hypertonia Autonomic Gastrointestinal Soft stool, diarrhea, emesis, CNS, autonomic, sensory, GI diuresis, erythruria motility, kidney Skin Edema, erythema Tissue damage, irritation Animals were weighed weekly prior to initiation of dosing.","The first day the rats are weighed was designated as Study Day 1, and the beginning of Study Week 1.Ophthalmic Examinations: Animals selected for the study were examined prior to the initial administration of the test or the control articles to ensure that both eyes were free of abnormality, damage, and disease.","Both eyes were examined, scored and recorded prior to the initial dose administration using a hand held slit-lamp and a direct ophthalmoscope or the surgical microscope according to the Classification System for Grading Ocular Lesions as described in Table 7, and the Ocular Posterior Segment Scoring Scale of Table 8.Posterior segment examination was performed after topical application of Tropicamide in the conscious state, or after the rats are anesthetized with isoflorane inhalation.","Only rats showing no signs of eye irritation, ocular defects, or preexisting corneal injury were used in the study.","TABLE 7 Combined Draize and McDonald-Shadduck Scoring System CONJUNCTIVA A. REDNESS/CONGESTION 0 Vessels normal.","May appear blanched to reddish pink without perilimbal injection (except at 12:00 and 6:00 o'clock positions) with vessels of the palpebral and bulbar conjunctivae easily observed.","1 Vessels definitely injected above normal.","A flushed, reddish color predominately confined to the palpebral conjunctivae with some perilimbal injection but primarily confined to the lower and upper parts of the eye from, the 4:00 and 7:00 and 11:00 to 1:00 o'clock positions.","2*† More diffuse, deeper crimson red, individual vessels not easily discernible.","Bright red color of the palpebral conjunctiva with accompanying perilimbar injection covering at least 75% of the circumference of the perilimbal region.","3*† Diffuse beefy red.","Dark beefy red color with congestion of both the bulbar and palpebral conjunctiva along with pronounced perilimbal injection and the presence of petechia on the conjunctiva.","The B. CHEMOSIS: 0 Normal.","No swelling of the conjunctival tissue.","1 Any swelling above normal (includes nictitating membrane).","Swelling above normal without eversion of the lids (can be easily ascertained by noting that the upper and lower eyelids are positioned as in the normal eye); swelling generally starts in the lower cul-de-sac near the inner canthus which needs slit-lamp examination.","2*† Obvious swelling with partial eversion of lids.","Swelling with misalignment of the normal approximation of the lower and upper eyelids; primarily confined to the upper eyelid so that in the initial stages the misapproximation of the eyelids begins by partial eversion of the upper eyelid.","In this stage, swelling is confined generally to the upper eyelid, although it exists in the lower cul-de-sac.","Swelling with lids about half closed.","3*† Swelling definite with partial eversion of the upper and lower eyelids essentially equivalent.","This can be easily ascertained by looking at the animal straight head on and noticing the positioning of the eyelids; if the eye margins do not meet, eversion has occurred.","4*† Swelling with lids about half closed to completely closed.","Eversion of the upper eyelid is pronounced with less pronounced eversion of the lower eyelid.","It is difficult to retract the lids and observe the perilimbal region.","C. DISCHARGE: 0 Normal or no discharge.","1 Any amount different from normal (does not include small amounts observed in inner canthus of normal animals).","Discharge above normal and present on the inner portion of the eye but not on the lids or hairs of the eyelids.","One can ignore the small amount that is in the inner and outer canthus if it has not been removed prior to starting the study.","2 Discharge with moistening of lids and hairs just adjacent to lids.","Discharge is abundant, easily observed, and has collected on the lids around the hairs of the eyelids.","3 Discharge with moistening of the lids and hairs, and considerable area around the eye.","CORNEA D. OPACITY-degree of density (areas most dense taken for reading): 0 No ulceration or opacity.","Normal cornea.","Appears with the slit lamp as having a bright gray line on the endothelial surface and a bright gray line on the endothelial surface with a marble-like gray appearance of the stroma.","1* Scattered or diffuse areas of opacity (other than slight dulling of normal luster), details of iris clearly visible.","Some loss of transparency.","Only the anterior one-half of the stroma is involved as observed with an optical section of the slit lamp.","The underlying structures are clearly visible with diffuse illumination, although some cloudiness can be readily apparent with diffuse illumination.","2*† Easily discernible translucent areas, details of iris slightly obscured.","Moderate loss of transparency.","In addition to involving the anterior stroma, the cloudiness extends all the way to the endothelium.","The stroma has lost its marble-like appearance and is homogeneously white.","With diffuse illumination, underlying structures are clearly visible.","3*† Opalescent/nacreous areas, no details of iris visible, size of pupil barely discernible.","Involvement of the entire thickness of the stroma.","With optical section, the endothelial surface is still visible.","However, with diffuse illumination the underlying structures are just barely visible (to the extent that the observer is still able to grade flare, iritis, observe for pupillary response, and note lenticular changes.","4*† Opaque cornea, iris not discernible through opacity.","Involvement of the entire thickness of the stroma.","With the optical section, cannot clearly visualize the endothelium.","With diffuse illumination, the underlying structures cannot be seen.","Cloudiness removes the capability of judging and grading aqueous flare, iritis, lenticular changes, and pupillary response.","E. AREAS OF CORNEA INVOLVED: 0 Normal cornea with no area of cloudiness.","1 One-quarter (or less), but not zero.","2 Greater than one-quarter, but less than one-half.","3* Greater than one-half, but less than three-quarters.","4* Greater than three-quarters, up to whole area.","F. FLUORESCEIN STAINING: 0 Absence of fluorescein staining.","1 Slight fluorescein staining confined to a small focus.","With diffuse illumination the underlying structures are easily visible.","The outline of the papillary margin is as if there were no fluorescein staining.","2 Moderate fluorescein staining confined to a small focus.","With diffuse illumination the underlying structures are clearly visible, although there is some loss of detail.","3 Marked fluorescein staining.","Staining may involve a larger portion of the cornea.","With diffuse illumination the underlying structures are barely visible but are not completely obliterated.","4 Extreme fluorescein staining.","With diffuse illumination the underlying structures cannot be observed.","G. CORNEA PANNUS: 0 No pannus 1 Vascularization is present but vessels have not invaded the entire corneal circumference.","Where localized vessel invasion has occurred, they have not penetrated beyond 2 mm.","2 Vessels have invaded 2 mm or more around the entire corneal circumference.","IRIS 0 Normal iris without any hyperemia of the iris vessels.","Occasionally around the 12:00 to 1:00 position near the pupillary border and the 6:00 and 7:00 position near the pupillary border there is a small area around 1-3 mm in diameter in which both the secondary and tertiary vessels are slightly hyperemic.","1*† Folds above normal, congestion, swelling, circumcorneal injection (any or all of these or combination of any thereof), iris still reacting to light (sluggish reaction is positive).","Minimal injection of secondary vessels but not tertiary.","Generally, it is uniform, but may be of greater intensity at the 1:00 or 6:00 position, the tertiary vessels must be substantially hyperemic.","2*† No reaction to light, hemorrhage, gross destruction (any or all of these).","Minimal injection of tertiary vessels and minimal to moderate injection of the secondary vessels.","3*† Moderate injection of the secondary and tertiary vessels with slight swelling of the iris stroma (this gives the iris surface a slightly rupose appearance which is usually most prominent near the 3:00 and 9:00 positions).","4*† Marked injection of the secondary and tertiary vessels with marked swelling of the iris stroma.","The iris appears rugose; may be accompanied by hemorrhage (hyperemia) in the anterior chamber.","AQUEOUS FLARE 0 Absence of visible light beam in the anterior chamber (no Tyndall effect).","1 Tyndall effect is barely discernible.","The intensity of the light beam in the anterior chamber is less than the density of the slit beam as it passes through the lens.","2 The Tyndall effect in the anterior chamber is easily discernible and is of equal intensity as the density of the slit beam as it passes through the lens.","3 The Tyndall effect in the anterior chamber is easily discernible; its intensity is greater than the intensity of the slit beam as it passes through the lens.","PUPILLARY LIGHT REFLEX: 0 Normal pupillary light reflex 1 Sluggish pupillary light reflex 2 No pupillary light reflex LENS 0 Normal 1 The presence of lenticular opacities should be described and the location noted as defined below: Anterior capsule Anterior subcapsule Anterior cortical Nuclear Posterior cortical Posterior subcapsule Posterior capsule *= Positive Reaction (ISO) †= Positive Reaction (OECD) TABLE 8 Ocular Posterior Segment Scoring Scale VITREOUS BODY 0 Normal, the vitreous body is clear or transparent.","1 Abnormal, the vitreous body is not clear or not transparent and homogenous gel that fills the space between the posterior axial lens capsule, posterior chamber, and ocular fundus.","OPTIC DISC/OPTIC NERVE 0 Normal, the optic disc and optic nerve are with light red color, cupping size normal (cup-to-disc ratio <0.2), and normal sharpness of edge, without swelling, hemorrhages, notching in the optic disc and any other unusual anomalies.","1 Abnormal, the optic disc and optic nerve are not with light red color or cupping size normal (cup-to-disc ratio >0.2), and no normal sharpness of edge or with swelling, hemorrhages, notching in the optic disc and any other unusual anomalies.","RETINAL BLOOD VASCULATURE 0 Normal, the retinal arteries and veins fill in blood and normalize sharpness without hemorrhage and exudation.","1 Abnormal, the retinal arteries and veins don't fill in blood and don't have normalize sharpness or with hemorrhage and exudation.","RETINAL HEMORHAGE, EXUDATION, AND DETACHMENT 0 Normal retina with no area of hemorrhage or/and exudation or/and detachment 1 Retinal hemorrhage or/and exudation or/and detachment ≤1 quadrant area 2 1 quadrant area < retinal hemorrhage or/and exudation or/and detachment ≤ 2 quadrant areas 3 2 quadrant areas < hemorrhage or/and exudation or/and detachment ≤ 3 quadrant areas 4 3 quadrant areas < retinal hemorrhage or/and exudation or/and detachment exudation ≤ 4 quadrant areas CHOROIDAL HEMORRHAGE, EXUDATION, AND DETACHMENT 0 Normal choroid with no area of choroidal and hemorrhage or/and exudation or/and detachment 1 Choroidal hemorrhage or/and exudation or/and detachment ≤1 quadrant area 2 quadrant area < Choroidal hemorrhage or/and exudation or/and detachment ≤ 2 quadrant areas 3 2 quadrant areas < Choroidal hemorrhage or/and exudation or/and detachment ≤ 3 quadrant areas 4 quadrant areas < Choroidal hemorrhage or/and exudation or/and detachment ≤ 4 quadrant area Intraocular Pressure (IOP) Measurements: Baseline IOP measurements were taken before the initial dose administration.","After application of topical anesthesia (0.5% Proparacaine HCl Ophthalmic Solution), IOP was measured on conscious rats on both eyes using a Tono-Pen Vet tonometer (Reichert, Inc.; Depew, N.Y.).","Ten (10) IOP readings are recorded from each eye and averaged.","IOP measurements were taken around the same time (e.g., between 10 a.m. and 2 p.m.) across measurement time-points to minimize the circadian variability of IOP.","Dose Administration: Rats were separated in 5 groups.","Animals in each group receive one of the five following articles during the study: 1.Control vehicletopical 2.0.25% Laquinimod topical 3.1% Laquinimod topical 4.4% Laquinimod topical 5.0.1% Laquinimod oral Topical Dosing: Rats were dosed topically only on the surface of the left eye in which OHT was induced.","No article was administered on the un-operated right eye which served as the control.","The topical dose was administered on the surface of the left eye using a calibrated micro-pipette and a sterile tip.","The volume for each topical dose was 10 μL.","Rats were dosed twice daily, starting on the day of the first HSI until euthanasia.","The first daily dose was administered approximately between 8 a.m. and 9 a.m.","The second daily dose was administered approximately between 4 p.m. and 5 p.m. On the day of euthanasia, rats were dosed only once in the morning approximately between 8 a.m. and 9 a.m.","Oral Dosing: Rats were dosed orally daily approximately between 8 a.m. and 10 a.m., starting on the day of the first HSI until euthanasia.","The last day of dosing was the day of euthanasia.","The volume for each oral dose was 1 mL.","Post-Dose Procedures: Chronic ocular hypertension (OHT) was created through two hypertonic saline injections (HSI) which were performed one week apart in the left eye.","For each HSI, after the rats were anesthetized with a suitable anesthetic, a suture thread was passed through the left eyelid to fix it open.","A local anesthetic (e.g., 0.5% Proparacaine HCl Ophthalmic Solution) was applied on the surgery eye topically.","The conjunctiva was incised with Vannas scissors to expose an episcleral vein.","An occluder ring with a groove was fitted around the left eye to provide unobstructed passage for the selected episcleral vein while obstructing the other episcleral veins.","Using a pulled-glass needle, 50-250 μL of 1.8M hypertonic saline solution was injected into the exposed episcleral vein to scar the aqueous humor outflow pathway in an attempt to elevate IOP.","The ring was removed shortly after the injection.","The un-operated right eye served as the control.","Ophthalmic ointment was applied to both eyes to prevent corneal damage.","For each HSI procedure, buprenorphine was administered subcutaneously for approximately 24 hours to manage post-operative pains as appropriate.","Clinical observations was performed at least once daily as described in Table 6.Moribund and Dead Animals: Animals were observed once daily for moribundity/mortality as part of the clinical observations.","There were no moribound animals.","Measurements and Criterion: IOP measurements were taken once weekly starting one week after the second HSI until euthanasia (a total of 5 measurements).","After application of topical anesthesia (0.5% Proparacaine HCl Ophthalmic Solution), IOP was measured on conscious rats on both eyes using a Tono-Pen Vet tonometer (Reichert, Inc.; Depew, N.Y.).","For each time-point, ten (10) IOP readings were recorded from each eye and averaged.","IOP measurements were taken around the same time (e.g., between 10 a.m. and 2 p.m.) across measurement time-points to minimize the circadian variability of IOP.","The IOP measurements were evaluated as follows: For each time-point following the HSI, the IOP elevation was calculated as the difference between the level in the left eye with OHT and that in the normal right eye (ΔIOP).","The ΔIOP of the 5-weekly post-HSI IOP measurements were averaged and constitute the Mean ΔIOP for each animal.","For each group, ten (10) animals with a sustained IOP elevation in the OHT eye were selected from a larger pool and groups are matched for the Mean ΔIOP.","Other animals were removed from the study and euthanized.","Data was analyzed and reported for rats which did not have individual IOP measurements of 50 mmHg in the OHT eyes.","Ophthalmic Examinations: Both eyes were examined and scored at one week after the second HSI and on the day of euthanasia, for a total of two times.","Ophthalmic examinations were performed according to the Classification System for Grading Ocular Lesions as described in Table 7, and the Ocular Posterior Segment Scoring Scale of Table 8 using a hand-held slit-lamp and a direct ophthalmoscope or the surgical microscope.","Posterior segment examination was performed after the topical application of Tropicamide in the conscious state, or after the rats are anesthetized with isoflorane inhalation.","Fluoro-Gold (FG) Back-Labeling of Retinal Ganglion Cells (RGC): Approximately one week prior to euthanasia, RGC was labeled with the retrograde tracer FG.","First, animals were sedated with appropriate anesthesia.","Using a stereotaxic device, RGC was back-labeled with an injection of 2.5 μL of 4% FG into the superior colliculus in each hemisphere.","Rats received subcutaneous injections of buprenorphine for approximately 48 hours to manage post-surgery pain as appropriate.","Animals were euthanized by CO2 inhalation 5-weeks after the 2′d HSI.","Extraction and Processing of the Eyes and the Optic Nerves (ON): The eyes were immediately enucleated with the optic nerve attached.","An approximately 2.0 mm piece of the ON proximal to the globe is separated and labeled with tissue mark to indicate the orientation of the nerve.","The ON piece is placed in Modified Karnovsky's Fixative in 0.1M Na cacodylate buffer and kept at 4±2° C. overnight.","The next day ON piece was washed at least three times for at least 10 minutes each in 0.1M Na cacodylate buffer and stored in 0.1M Na cacodylate buffer at 4±2° C. After specimens were transferred to a contracted processing facility, within a week, the optic nerves were processed for plastic embedding: After post-fixation in 2% osmium tetroxide in 0.1M Na cacodylate buffer for at least 1.5 hours, ONs were dehydrated in graded ethanols, transitioned in propylene oxide and infiltrated with propylene oxide and epon mixtures.","One to five (1-5) μm-thick cross-sections were taken via a microtome at the ON end approximately 2.0 mm away from the globe.","ON sections were stained with 1% toluidine blue and cover-slipped.","The processed specimens were returned.","The identification of the ONs were masked prior to injury analysis.","The ON cross-sections were analyzed for injury by light microscopy as follows: The damaging effect of the sustained IOP elevation was assessed by qualitative microscopic analysis of the ON cross-sections using a well-established grading system described in Table 9.This method allowed damage analysis of the entire retinal ganglion cell output (the ON) in one section by light microscopy and was more sensitive than counting total axons especially if there is mild nerve damage.","Sustained IOP elevation resulted in degenerating, swollen axons and collapsed myelin sheaths in the optic nerve.","The extent of injury was then graded by light microscopy based on a pattern of damage observed in rats with elevated IOP.","TABLE 9 Grading Scale for Optic Nerve Injury Grade 1 (Normal) Normal optic nerve with healthy axons.","Grade 2 (FOCAL INJURY) Degenerating axons with myelin debris are stained densely and appear focally.","Some axonal swellings are present.","Grade 3 (INJURY SPREADING AWAY Several degenerating axons with myelin debris and axonal FROM FOCAL) swellings spread away from the focal area.","Normal axons still predominate.","Grade 4 (WIDE-SPREAD INJURY; Several degenerating axons with myelin debris and axonal EQUIVALENT NUMBER of swellings are present throughout the nerve.","There are DEGENERATING and NORMAL AXONS) approximately equal numbers of normal and abnormal axons.","Grade 5 (WIDE-SPREAD INJURY; Degenerating axons with myelin debris and swollen axons DEGENERATING AXONS LARGELY largely dominate the optic nerve, with gliosis in severe DOMINATE) cases.","The eyes were fixed in 4% paraformaldehyde (PFA) fixative at 4±2° C. for at least 24 hours.","Retinas were dissected and flat whole-mounted for confocal visualization and imaging.","The actual identification of the retinal flat-mounts was masked prior to confocal imaging.","Eight regions per retina were imaged using a confocal microscope and the RGC in each region were counted as follows: Retinal images were evaluated by confocal fluorescence microscopic examination.","A three-dimensional view of the x-axis, y-axis, and z-axis were designed and processed using a specific system of image analysis software (Leica Confocal Software) to obtain an image of the viable RGCs labeled with FG.","Two areas which were approximately 1.5 mm and 2.75 mm away from the center of the ON head were selected in each retinal quadrant (8 regions per retina) and serial images of the retinal ganglion cell layer were taken by the Confocal Microscope.","A two-dimensional maximum projection image of the serial images was used to count the viable RGCs using an image analysis software.","The number of viable RGCs per image was expressed in mm2.Evaluation Criteria The results of the study were considered in terms of the in-life observations and any microscopic observations.","IOP Criterion: For each time-point following the HSI, the IOP elevation was calculated as the difference between the level in the left eye with OHT and that in the normal right eye (ΔIOP).","The ΔIOP of the 5-weekly post-HSI IOP measurements were averaged and constitute the Mean ΔIOP for each animal.","For each group, ten (10) animals with a sustained IOP elevation in the OHT eye were selected from a larger pool and groups were matched for the Mean ΔIOP.","Other animals were removed from the study and euthanized.","Data was analyzed and reported for rats which do not have individual IOP measurements of ≥50 mmHg in the OHT eyes.","Imaging of the Retinas by Confocal Microscopy: Retinal images were evaluated by confocal fluorescence microscopic examination.","A three-dimensional view of the x-axis, y-axis, and z-axis were designed and processed using a specific system of image analysis software (Leica Confocal Software) to obtain an image of the viable RGCs labeled with FG.","Two areas which were approximately 1.5 mm and 2.75 mm away from the center of the ON head were selected in each retinal quadrant (8 regions per retina) and serial images of the retinal ganglion cell layer are taken by the Confocal Microscope.","A two-dimensional maximum projection image of the serial images was used to count the viable RGCs using an image analysis software.","The number of viable RGCs per image was expressed in mm2.Percent RGC loss in the OHT retinas was calculated in comparison to the RGC counts in the Non-OHT retina of the same animal using the following formula: (100−(100×OHT/Non-OHT Mean RGC Counts per Retina)).","The RGC counts in each Non-OHT retina were considered 100% for that animal.","The damaging effect of the sustained IOP elevation was assessed by qualitative microscopic analysis of the ON cross-sections using a well-established grading system described in Table 9.This method allowed damage analysis of the entire retinal ganglion cell output (the ON) in one section by light microscopy and was more sensitive than counting total axons especially if there is mild nerve damage.","Sustained IOP elevation resulted in degenerating, swollen axons and collapsed myelin sheaths in the optic nerve.","The extent of injury was then graded by light microscopy based on a pattern of damage observed in rats with elevated IOP.","Data Analysis: Initially One-Way ANOVA was used to address statistically significant differences among groups.","If there was a statistical significance, data of the test groups was further compared with the data of the control group using Dunnett's multiple comparison tests.","Two-Way ANOVA, paired-t-tests, % neuroprotection calculations were also performed.","Any differences between control and test animals was considered statistically significant only if the probability of the differences being due to chance is equal to or less than 5% (p≤0.05; two-tailed).","Statistical analysis is performed using Minitab, Minitab Inc, State College, Pa. Any significant difference is further assessed for biological relevance by comparison to the literature and historical data.","Results TABLE 10 % RGC Loss (100 − (100 × OHT/Non-OHT Mean RGC Counts per Retina)) Route/ Laquinimod Mean % RGC Group Percentage Loss SD % RGC Loss 1 Topical/1% 17.6 33.8 2 Topical/ 34.8 42.7 Vehicle 3 Topical/4% 26.8 36.4 4 Topical/0.25% 21.6 21.7 5 Oral/0.1% 22.9 33.1 RGC = Retinal Ganglion Cell OHT = Ocular Hypertension SD = Standard Deviation 1.Per protocol, data were analyzed and reported for forty (40) rats which did not have individual IOP measurements of 50 mmHg in the OHT eyes.","2.Body Weights: The range of the baseline body weights of the 40 rats from Groups 1-5 was 258.6-351.3 grams at the start of the study.","On the day of dosing and the first HSI, body weight range of all rats was 271.2-366.4 grams.","A One-Way ANOVA indicated that the group body weights were not statistically different on the day of dosing (P=0.957).","Rats weighed 271.4-349.3 grams on the day of euthanasia.","Groups did not differ in the amount of weight gained between the day of dosing and the day of euthanasia (One-Way ANOVA; P=0.559).","3.Clinical Observations: There were no abnormal clinical observations in the beginning of the study at the time of animal assignment.","Following the HSI surgeries, swelling of the surgery eye, swelling of the conjunctiva and scleral/corneal discoloration in the surgery eye were observed in all groups.","Following the Fluoro-Gold brain injection surgeries, hair loss and skin wounds were noted in all groups due to the hair on the skull being shaved prior to surgery and the skin on the skull being incised and sutured after surgery.","These observations were expected and related with the glaucoma model creation (HSI) and the Fluoro-gold brain injection surgeries.","Abnormal clinical observations which were not related with the HSI and FG injection surgeries were hair loss in an animal from Group 2 and in an animal from Group 5, and skin wound in 2 animals from Group 5.Since Group 2 was the vehicle control group, these abnormalities were incidental and not test-article related.","4.IOP Measurements (mmHg): None of the animals included in the study had individual IOP measurements of ≥50 mmHg in the OHT eyes.","The Mean ΔIOP (OHT−Non-OHT) (Mean±SD) was 9.1±2.2 mmHg, 9.1±2.6 mmHg, 9.3±2.7 mmHg, 9.2±1.5 mmHg, and 9.1±2.9 mmHg for Groups 1, 2, 3, 4 and 5, respectively.","A One-Way ANOVA analysis indicated that the groups were well-matched for Mean ΔIOP (P>0.9) (FIG.","1).","Representative images of the retinas with FG-labeled RGC are shown in FIGS.","5A-5J.","% FG-Labeled RGC loss in the OHT retinas compared with the corresponding non-OHT retinas is shown in Table 10.Compared to the non-OHT retinas, % RGC Loss (Mean±SD) in the OHT retinas was 17.6±33.8, 34.8±42.7, 26.8±36.4, 21.6±21.7, and 22.9±33.1 for Groups 1, 2, 3, 4 and 5, respectively (FIG.","2).","5.FG-labeled RGC counts: A Two-Way ANOVA on the RGC counts in the OHT and Non-OHT (control) eyes versus groups did not show a significant eye versus group interaction (P=0.919), indicating that groups did not differ for the RGC counts in the OHT and Non-OHT eyes (FIG.","3).","As a secondary analysis, FG-Labeled RGC counts per mm2 were compared between the Non-OHT and the OHT retinas for each group using a paired-t test (two-tailed).","Group 2 (vehicle topical; P=0.047) and Group 4 (0.25% Laquinimod topical; P=0.033) had fewer RGCs in the OHT eye compared to the Non-OHT eyes.","The number of RGCs in Group 3 (4% Laquinimod topical; P=0.071) and Group 5 (0.1% Laquinimod oral; P=0.075) were statistically marginally different between the OHT and Non-OHT eyes.","However, in Group (1% Laquinimod topical), there was no statistically significant difference in the RGC counts between the OHT and Non-OHT eyes (P=0.189).","This suggests that the daily topical application of 1% Laquinimod may be neuroprotective for the RGC.","6.Optic Nerve (ON) Injury Grades: Mean ON Injury Grades (Mean±SD) for the Non-OHT eyes were 1.1±0.1, 1.2±0.2, 1.2±0.2, 1.2±0.3 and 1.2±0.2 for Groups 1, 2, 3, 4 and 5, respectively.","Mean Injury Grades (Mean±SD) for the OHT optic nerves were 2.5±1.3, 3.0±1.6, 3.0±1.5, 2.8±1.3 and 2.7±1.5 for Groups 1, 2, 3, 4, and 5, respectively.","A Two-Way ANOVA on the Mean ON injury grades in the OHT and Non-OHT (control) eyes versus groups did not show a significant eye versus group interaction (P=0.98), indicating that groups did not differ for the injury in the OHT and Non-OHT optic nerves (FIG.","4).","As a secondary analysis, Mean ON Injury Grades were compared between the Non-OHT and the OHT optic nerves for each group using two-tailed paired-t tests.","The Mean ON injury grades were significantly greater in the OHT eyes compared to the Non-OHT control eyes in all groups (P<0.05).","7.Ophthalmic Examinations (OEs): At baseline ocular examinations prior to initial dose, there were no ocular abnormalities observed in either eye in any of the animals included in the study.","During the post-dose OEs, there were no ocular problems observed in any of the animals in the Non-OHT eyes.","However, there were some ocular abnormalities observed in the OHT eyes due to the glaucoma-model creation procedures (hypertonic saline injection surgeries into the episcleral veins) in all groups.","These abnormalities included minor congestion and chemosis (swelling) in the conjunctiva, minor corneal opacities, lack of sufficient dilation of the pupil after application of the pupil-dilating agent Tropicamide, slight opacities in the lens and presence of free-floating iris pigments in front of the lens in the OHT eyes.","The post-HSI ocular findings in the OHT eyes were observed in all groups with a similar occurrence and were not test articlerelated.","CONCLUSION The study involved daily dosing of five groups for approximately six weeks: Group 1 (1% Laquinimod topical), Group 2 (Vehicle topical), Group 3 (4% Laquinimod topical), Group 4 (0.25% Laquinimod topical) and Group 5 (0.1% Laquinimod oral).","The analyses for the RGC counts in Group 1 animals suggested a trend towards neuroprotection following daily topical application of 1% Laquinimod.","Example 2: Assessment of Efficacy of Laquinimod for Treating Patients Afflicted with Glaucoma Periodic (e.g., daily or twice daily) administration of laquinimod (oral or topical) is effective in treating glaucoma human patients.","Periodic (e.g., daily or twice daily) administration of laquinimod (oral or topical) is effective to reduce a glaucoma-associated symptom in the subject.","A laquinimod composition as described herein is administered systematically or locally to the eye of a subject suffering from glaucoma.","The administration of the composition is effective to treat the subject suffering from glaucoma.","The administration of the composition is also effective to reduce a glaucoma-associated symptom of glaucoma in the subject.","The administration of the composition is also effective to reduce intraocular pressure in the subject.","The administration of the composition is effective to reduce RGC damage and/or RGC loss, and improve RGC viability in the subject.","REFERENCES 1.“Glaucoma”, Merck Manual of Diagnosis and Therapy (1999), Merck Research Laboratories, (Whitehouse Station, N.J.), 733-738.2.Alward, “Medical Management of Glaucoma”, N Eng J Med, 1998; 339:1298-1307).","3.Bakalash et al., “Resistance of Retinal Ganglion Cells to an Increase in Intraocular Pressure is Immune-dependent”, Invest Ophthalmol Vis Sci 2002; 43:2648-2653.4.Brod et al.","(2000) Annals of Neurology, 47:127-131.5.Brück et al., (2011) “Insight into the mechanism of laquinimod action”, J. Neurol Sci.","306:173-179.6.Cepurna et al.","(2000) “Patterns of Intraocular Pressure Elevation After Aqueous Humor Outflow Obstruction in Rats.” Invest Ophthalmol Vis Sci.","41(6) (May 2000):1380-5.7.Coleman “Glaucoma”, Lancet, 1999; 354:1803-1810.8.Draize, J. H. (1965) “Appraisal of the Safety of Chemicals in Foods, Drugs, and Cosmetics.” Association of Food and Drug Officials of the United States, Austin, Tex., 1965.36-45.9.Farkas et al., “Apoptosis, Neuroprotection and Retinal Ganglion Cell Death: An Overview”, Int Ophthalmol Clin 2001; 41:111-130.10.Freireich et al.","(1966) “Quantitative comparison to toxicity of anticancer agents in mouse, rat, hamster, dog, monkey and man.” Cancer Chemother Rep, 50:219-244.11.Guidance for Industry.","In vivo drug metabolism/drug interaction studies—study design, data analysis, and recommendations for dosing and labeling, U.S. Dept.","Health and Human Svcs., FDA, Ctr.","for Drug Eval.","and Res., Ctr.","For Biologics Eval.","and Res., Clin./Pharm., November 1999 <http://www.fda.gov/cber/gdlns/metabol.pdf>.","12.Gurevich et al.","(2010) “Laquinimod suppress antigen presentation in relapsing-remitting multiple sclerosis: invitro high-throughput gene expression study.” J Neuroimmunol.","2010 Apr.","15; 221(1-2):87-94.Epub 2010 Mar.","27.13.Hla et al.","(2001) “Lysophospholipids—receptor revelations.” Science, 294(5548):1875-8.14.Horga and Montalban Jun.","4, 2008; Expert Rev Neurother., 2008; 8(5):699-714.15.ISO/IEC 17025, 2005.General Requirements for the Competence of Testing and Calibration Laboratories.","16.Kipnis et al., “T Cell Immunity To Copolymer 1 Confers Neuroprotection On The Damaged Optic Nerve: Possible Therapy For Optic Neuropathies”, Proc Natl Acad Sci 2000; 97:7446-7451.17.Kleinschmidt-DeMasters et al.","(2005) New England Journal of Medicine, 353:369-379.18.Langer-Gould et al.","(2005) New England Journal of Medicine, 353:369-379.19.McDonald, and Shadduck (1983).","Eye Irritation in Dermatotoxicology (2nd Ed.).","Edited by Marzulli F. N. Hemishpere Publishing Corp., New York, N.Y. 20.Medeiros et al., “Medical Backgrounders: Glaucoma”, Drugs of Today 2002; 38:563-570.21.National MS Society Website, retrieved Jul.","10, 2012<http://www.nationalmssociety.org/ms-clinical-care-network/researchers/clinical-study-measures/index.aspx> 22.OECD 405, Organization for Economic Co-Operation and Development (OECD), Guidelines for the Testing of Chemicals, “Acute Eye Irritation/Corrosion”, adopted 24 Apr.","2002.23.Ollivier F. J., et al.","(2007) “Ophthalmic Examination and Diagnostics Part 1: The Eye Examination and Diagnostic Procedure” in Veterinary Ophthalmology, 4th Ed.","by Gelatt, K. N. 2007, 438-483.Blackwell Publishing, Gainesville, Fla. 24.PCT International Application Publication No.","WO 2007/0047863, published Apr.","26, 2007.25.PCT International Application Publication No.","WO 2007/0146248, published Dec. 21, 2007.26.Polman et al.","(2005) “Treatment with laquinimod reduces development of active MRI lesions in relapsing MS.” Neurology.","64:987-991.27.Polman et al.","(2011) “Diagnostic Criteria for Multiple Sclerosis: 2010 Revisions to the McDonald Criteria.” Ann Neural, 69:292-302.28.Polman et al., (2005) “Diagnostic criteria for multiple sclerosis: 2005 revisions to the McDonald Criteria.” Annals of Neurology, 58(6):840-846.29.Rudick et al.","(1999) “Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS: Multiple Sclerosis Collaborative Research Group”.","Neurology.","53:1698-1704.30.Runström et al.","(2002) “Laquinimod (ABR-215062) a candidate drug for treatment of Multiple Sclerosis inhibits the development of experimental autoimmune encephalomyelitis in IFN-β knock-out mice,” (Abstract), Medicon Valley Academy, Malmoe, Sweden.","31.Sandberg-Wollheim et al.","(2005) “48-week open safety study with high-dose oral laquinimod in patients.” Mult Scler.","11:S154 (Abstract).","32.U.S.","Pat.","No.","6,077,851, issued Jun.","20, 2000 (Bjork et al).","33.U.S.","Pat.","No.","7,589,208, issued Sep. 15, 2009 (Jansson et al).","34.Vollmer et al.","(2008) “Glatiramer acetate after induction therapy with mitoxantrone in relapsing multiple sclerosis.” Multiple Sclerosis, 00:1-8.35.Weinreb et al., “Is Neuroprotection a Viable Therapy for Glaucoma?” Arch Ophthalmol 1999; 117:1540-1544.36.Yang et al.","(2004) “Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-β in Lewis rats.” J. Neuroimmunol.","156:3-9."]],"string":"[\n [\n \"Treatment of Glaucoma Using Laquinimod\",\n \"The subject invention provides a method of treating a subject afflicted with glaucoma, suffering from retinal ganglion cell (RGC) loss or damage, or elevated intraocular pressure (IOP), or of reducing RGC loss or damage, or reducing IOP in a subject, comprising administering to the subject an amount of laquinimod effective to treat the subject, to reduce RGC loss or damage, or to reduce IOP in the subject.\",\n \"Provide also is a pharmaceutical composition, a package and a therapeutic package for treating a subject afflicted with glaucoma.\"\n ],\n [\n \"1.A method of treating a subject afflicted with glaucoma comprising administering to the subject an amount of laquinimod effective to treat the subject.\",\n \"2.The method of claim 1, wherein the administration of laquinimod is effective to reduce or inhibit a symptom of the glaucoma in the subject.\",\n \"3.The method of claim 2, wherein the symptom is retinal ganglion cell damage, retinal ganglion cell loss, or elevated intraocular pressure.\",\n \"4.The method of any one of claims 1-3, wherein laquinimod is laquinimod sodium.\",\n \"5.The method of any one of claims 1-4, wherein the route of administration of laquinimod is intraocular, periocular, ocular, oral, systemic or topical.\",\n \"6.The method of any one of claims 1-5, wherein laquinimod is administered in the form of an aerosol, an inhalable powder, an injectable, a liquid, a gel, a solid, a capsule or a tablet.\",\n \"7.The method of claim 6, wherein the concentration of laquinimod in the liquid or gel is 5-100 mg/ml solution, 20-100 mg/ml solution, 10-15 mg/ml solution, or 20-50 mg/ml solution.\",\n \"8.The method of any one of claims 1-7, wherein laquinimod is administered periodically.\",\n \"9.The method of claim 8, wherein laquinimod is administered daily.\",\n \"10.The method of claim 8, wherein laquinimod is administered more often than once daily or less often than once daily.\",\n \"11.The method of any one of claims 1-10, wherein the amount laquinimod administered is at least 0.2 mg/day and/or less than 0.6 mg/day.\",\n \"12.The method of any one of claims 1-10, wherein the amount laquinimod administered is 0.03-600 mg/day, 0.1-40.0 mg/day, 0.1-2.5 mg/day, 0.25-2.0 mg/day, 0.5-1.2 mg/day, 0.25 mg/day, 0.3 mg/day, 0.5 mg/day, 0.6 mg/day, 1.0 mg/day, 1.2 mg/day, 1.5 mg/day or 2.0 mg/day.\",\n \"13.The method of any one of claims 1-12, wherein the amount of laquinimod administered is 0.05-4.0 mg per administration, 0.05-2.0 mg per administration, 0.2-4.0 mg per administration, 0.2-2.0 mg per administration, about 0.1 mg per administration, or about 0.5 mg per administration.\",\n \"14.The method of any one of claims 1-13, further comprising administration of a second agent for the treatment of glaucoma.\",\n \"15.The method of claim 14, wherein the second agent is a β-adrenergic antagonist, adrenergic agonist, parasympathomimetic, prostaglandin-like analog, or carbonic anhydrase inhibitor.\",\n \"16.The method of any one of claims 8-15, wherein the periodic administration of laquinimod continues for at least 3 days, more than 30 days, more than 42 days, 8 weeks or more, at least 12 weeks, at least 24 weeks, more than 24 weeks, or 6 months or more.\",\n \"17.The method of any one of claims 1-16, wherein the subject is a human patient.\",\n \"18.A method of treating a subject suffering from retinal ganglion cell loss or retinal ganglion cell damage, or of reducing retinal ganglion cell loss or damage in a subject, comprising administering to the subject an amount of laquinimod effective to reduce retinal ganglion cell loss or retinal ganglion cell damage in the subject.\",\n \"19.A method of treating a subject suffering from elevated intraocular pressure, or of reducing intraocular pressure in a subject, comprising administering to the subject an amount of laquinimod effective to reduce intraocular pressure in the subject.\",\n \"20.A package comprising: a) a pharmaceutical composition comprising an amount of laquinimod; and b) instruction for use of the pharmaceutical composition to treat a subject afflicted with glaucoma.\",\n \"21.The package of claim 20, wherein the package comprises a second pharmaceutical composition comprising an amount of a second agent for the treatment of glaucoma.\",\n \"22.The package of claim 21, wherein the second agent is a β-adrenergic antagonist, adrenergic agonist, parasympathomimetic, prostaglandin-like analog, or carbonic anhydrase inhibitor.\",\n \"23.The package of any one of claims 20-22, wherein the pharmaceutical composition is the form of an aerosol, an inhalable powder, an injectable, a liquid, a gel, a solid, a capsule or a tablet.\",\n \"24.The package of claim 23, wherein the concentration of laquinimod in the liquid or gel is 5-100 mg/ml solution, 20-100 mg/ml solution, 10-15 mg/ml solution or 20-50 mg/ml solution.\",\n \"25.The package of claim 23, wherein the tablets are coated with a coating which inhibits oxygen from contacting the core.\",\n \"26.The package of claim 25, wherein the coating comprises a cellulosic polymer, a detackifier, a gloss enhancer, or pigment.\",\n \"27.The package of any one of claims 20-26, wherein the pharmaceutical composition further comprises mannitol, an alkalinizing agent, an oxidation reducing agent, a lubricant, a filler, and/or a desiccant.\",\n \"28.The package of claim 27, wherein the alkalinizing agent is meglumine.\",\n \"29.The package of any one of claims 20-27, wherein the pharmaceutical composition is stable and free of an alkalinizing agent or an oxidation reducing agent, preferably the pharmaceutical composition is free of an alkalinizing agent and free of an oxidation reducing agent.\",\n \"30.The package of any one of claims 20-29, wherein the pharmaceutical composition is stable and free of disintegrant.\",\n \"31.The package of claim 27, wherein the lubricant is present in the pharmaceutical composition as solid particles.\",\n \"32.The package of claim 27 or 31, wherein the lubricant is sodium stearyl fumarate or magnesium stearate.\",\n \"33.The package of claim 27, wherein the filler is present in the pharmaceutical composition as solid particles.\",\n \"34.The package of claim 27 or 33, wherein the filler is lactose, lactose monohydrate, starch, isomalt, mannitol, sodium starch glycolate, sorbitol, lactose spray dried, lactose anhydrouse, or a combination thereof.\",\n \"35.The package of claim 27, wherein the desiccant is silica gel.\",\n \"36.The package of any one of claims 20-35, wherein the pharmaceutical composition is stable and has a moisture content of no more than 4%.\",\n \"37.The package of any one of claims 20-36, wherein laquinimod is present in the pharmaceutical composition as solid particles.\",\n \"38.The package of any one of claims 20-37, wherein the package is a sealed packaging having a moisture permeability of not more than 15 mg/day per liter or a blister pack having a maximum moisture permeability of not more than 0.005 mg/day.\",\n \"39.The package of claim 38, wherein the sealed package is a bottle or comprises an HDPE bottle, preferably the bottle is closed with a heat induction liner.\",\n \"40.The package of claim 38 or 39, wherein the sealed package comprises an oxygen absorbing agent, which oxygen absorbing agent is preferably iron.\",\n \"41.The package of any one of claims 20-40, wherein the amount of laquinimod in the pharmaceutical composition is at least 0.2 mg, less than 0.6 mg, 0.1-40.0 mg, 0.03-600 mg, 0.1-2.5 mg, 0.25-2.0 mg, 0.5-1.2 mg, 0.25 mg, 0.3 mg, 0.5 mg, 0.6 mg, 1.0 mg, 1.2 mg, 1.5 mg, or 2.0 mg. 42.The package of any one of claims 20-41, wherein the pharmaceutical composition comprises unit doses of laquinimod of 0.05-4.0 mg, 0.05-2.0 mg, 0.2-4.0 mg, 0.2-2.0 mg, about 0.1 mg, or about 0.5 mg. 43.The package of any one of claims 20-42, wherein the pharmaceutical composition is formulated for intraocular, periocular, ocular, oral, systemic or topical administration.\",\n \"44.The package of any one of claims 20-43, for use in treating a subject afflicted with glaucoma.\",\n \"45.A therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted with glaucoma, which comprises: a) one or more unit doses, each such unit dose comprising an amount of laquinimod thereof, wherein the amount of said laquinimod in said unit dose is effective, upon administration to said subject, to treat the subject, and b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said subject.\",\n \"46.The therapeutic package of claim 45, wherein the package comprises a second pharmaceutical composition comprising an amount of a second agent for the treatment of glaucoma.\",\n \"47.The therapeutic package of claim 46, wherein the second agent is a β-adrenergic antagonist, adrenergic agonist, parasympathomimetic, prostaglandin-like analog, or carbonic anhydrase inhibitor.\",\n \"48.A pharmaceutical composition comprising an amount of laquinimod for use in treating a subject afflicted glaucoma.\",\n \"49.The pharmaceutical composition of claim 48, comprising an amount of a second agent for the treatment of glaucoma.\",\n \"50.The pharmaceutical composition of claim 49, wherein the second agent is a β-adrenergic antagonist, adrenergic agonist, parasympathomimetic, prostaglandin-like analog, or carbonic anhydrase inhibitor.\",\n \"51.The pharmaceutical composition of any one of claims 48-50, in the form of an aerosol, an inhalable powder, an injectable, a liquid, a gel, a solid, a capsule or a tablet.\",\n \"52.The pharmaceutical composition of claim 51, wherein the concentration of laquinimod in the liquid or gel is 5-100 mg/ml solution, 20-100 mg/ml solution, 10-15 mg/ml solution or 20-50 mg/ml solution.\",\n \"53.The pharmaceutical composition of claim 51, comprising a unit dose of 10 μL of an aqueous pharmaceutical solution which contains in solution at least 0.2 mg laquinimod.\",\n \"54.The pharmaceutical composition of any one of claims 48-53, wherein laquinimod is laquinimod sodium.\",\n \"55.The pharmaceutical composition of claim 51, wherein the tablets are coated with a coating which inhibits oxygen from contacting the core.\",\n \"56.The pharmaceutical composition of claim 55, wherein the coating comprises a cellulosic polymer, a detackifier, a gloss enhancer, or pigment.\",\n \"57.The pharmaceutical composition of any one of claims 48-56, further comprising mannitol, an alkalinizing agent, an oxidation reducing agent, a lubricant and/or a filler.\",\n \"58.The pharmaceutical composition of claim 57, wherein the alkalinizing agent is meglumine.\",\n \"59.The pharmaceutical composition of any one of claims 48-57, which is free of an alkalinizing agent or an oxidation reducing agent, preferably the pharmaceutical composition is free of an alkalinizing agent and free of an oxidation reducing agent.\",\n \"60.The pharmaceutical composition of any one of claims 48-59, which is stable and free of disintegrant.\",\n \"61.The pharmaceutical composition of claim 57, wherein the lubricant is present in the pharmaceutical composition as solid particles.\",\n \"62.The pharmaceutical composition of claim 57 or 61, wherein the lubricant is sodium stearyl fumarate or magnesium stearate.\",\n \"63.The pharmaceutical composition of claim 57, wherein the filler is present in the pharmaceutical composition as solid particles.\",\n \"64.The pharmaceutical composition of claim 57 or 63, wherein the filler is lactose, lactose monohydrate, starch, isomalt, mannitol, sodium starch glycolate, sorbitol, lactose spray dried, lactose anhydrouse, or a combination thereof.\",\n \"65.The pharmaceutical composition of any one of claims 48-64, wherein the amount of laquinimod is at least 0.2 mg, less than 0.6 mg, 0.1-40.0 mg, 0.03-600 mg, 0.1-2.5 mg, 0.25-2.0 mg, 0.5-1.2 mg, 0.25 mg, 0.3 mg, 0.5 mg, 0.6 mg, 1.0 mg, 1.2 mg, 1.5 mg, or 2.0 mg. 66.The pharmaceutical composition of any one of claims 48-65, comprising unit doses of laquinimod of 0.05-4.0 mg, 0.05-2.0 mg, 0.2-4.0 mg, 0.2-2.0 mg, about 0.1 mg, or about 0.5 mg. 67.The pharmaceutical composition of any one of claims 48-66, formulated for intraocular, periocular, ocular, oral, systemic or topical administration.\",\n \"68.The pharmaceutical composition of any one of claims 48-67, for use in treating a subject afflicted with glaucoma.\",\n \"69.A pharmaceutical composition in unit dosage form, useful in treating a subject afflicted with glaucoma, which comprises an amount of laquinimod; which amount of said laquinimod in said composition is effective, upon administration to said subject of one or more of said unit dosage forms of said composition, to treat the subject.\",\n \"70.A package comprising: a) a pharmaceutical composition of any one of claims 48-69; and b) instruction for use of the pharmaceutical composition to treat a subject afflicted with glaucoma.\",\n \"71.Laquinimod for the manufacture of a medicament for use in treating a subject afflicted glaucoma.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>Glaucoma is a group of ocular diseases characterized by progressive damage to the eye at least partly due to elevated intraocular pressure (IOP) (Merck Manual of Diagnosis and Therapy (1999)).\",\n \"Additionally, glaucoma is characterized by retinal ganglion cell (RGC) death, axon loss and an excavated appearance of the optic nerve head (Alward 1998).\",\n \"Glaucoma can be diagnosed before vision loss occurs by visual field testing and by ophthalmoscopic examination of the optic nerve to detect “cupping.” The mean IOP in normal adults is 15 to 16 mm Hg; the normal range is 10 to 21 mm Hg.\",\n \"One form of management of glaucoma is based on lowering the IOP using topically applied medications (Coleman 1999).\",\n \"Currently there are five major classes of medications that are used to lower the IOP: β-adrenergic antagonists, adrenergic agonists, parasympathomimetics, prostaglandin-like analogues and carbonic anhydrase inhibitors (Medeiros et al.\",\n \"2002).\",\n \"Although most medications are applied topically to the eye, they can cause severe systemic side effects and adversely affect the quality of the patient's life.\",\n \"If additional lowering of IOP is indicated or if medication fails to sufficiently lower the IOP, laser trabeculoplasty is usually the next step.\",\n \"If IOP is still not adequately controlled, incisional glaucoma surgery is indicated (Id).\",\n \"The lowering of IOP, despite significantly reducing the extent of neuronal loss, does not ensure cessation of the disease process, because the loss of RGCs may continue.\",\n \"Recent studies of the association between IOP regulation and visual field loss after medical or surgical intervention showed that ongoing neuronal loss reflected in visual field tests can be diminished if the IOP is low.\",\n \"However, neuronal loss may continue to occur after reduction of IOP (Bakalash et al.\",\n \"2002).\",\n \"Glaucomatous optic neuropathy appears to result from specific pathophysiological changes and subsequent death of RGCs and their axons.\",\n \"The process of RGC death is thought to be biphasic: a primary injury responsible for initiation of damage followed by a slower, secondary degeneration attributable to the hostile environment surrounding the degenerating cells (Kipnis et al.\",\n \"2000).\",\n \"The molecular mechanism triggering RGC death has not been identified.\",\n \"Deprivation of neurotrophic factors, ischemia, chronic elevation of glutamate and disorganized nitric oxide metabolism are suspected to be possible mechanisms (Farkas et al.\",\n \"2001).\",\n \"In addition, it is possible that the mechanisms leading to RGC death share common features with other types of neuronal injury, such as signaling by reactive oxygen species, depolarization of mitochondria, or induction of transcriptionally regulated cell death (Weinreb et al.\",\n \"1999).\",\n \"Laquinimod Laquinimod (LAQ) is a novel synthetic compound with high oral bioavailability which has been suggested as an oral formulation for the treatment of Multiple Sclerosis (MS) (Polman, 2005; Sandberg-Wollheim, 2005).\",\n \"Laquinimod and its sodium salt form are described, for example, in U.S. Pat.\",\n \"No.\",\n \"6,077,851.The mechanism of action of laquinimod is not fully understood.\",\n \"Animal studies show it causes a Th1 (T helper 1 cell, which produces pro-inflammatory cytokines) to Th2 (T helper 2 cell, which produces anti-inflammatory cytokines) shift with an anti-inflammatory profile (Yang, 2004; Brück, 2011).\",\n \"Another study demonstrated (mainly via the NFkB pathway) that laquinimod induced suppression of genes related to antigen presentation and corresponding inflammatory pathways (Gurevich, 2010).\",\n \"Other suggested potential mechanisms of action include inhibition of leukocyte migration into the CNS, increase of axonal integrity, modulation of cytokine production, and increase in levels of brain-derived neurotrophic factor (BDNF) (Runström, 2006; Brück, 2011).\",\n \"The effects of laquinimod on glaucoma have not previously been studied.\"\n ],\n [\n \"<SOH> SUMMARY OF THE INVENTION <EOH>The subject invention provides a method of treating a subject afflicted with glaucoma comprising administering to the subject an amount of laquinimod effective to treat the subject.\",\n \"The subject invention also provides a method of treating a subject suffering from retinal ganglion cell loss or retinal ganglion cell damage, or of reducing retinal ganglion cell loss or damage in a subject, comprising administering to the subject an amount of laquinimod effective to reduce retinal ganglion cell loss or retinal ganglion cell damage in the subject.\",\n \"The subject invention also provides a method of treating a subject suffering from elevated intraocular pressure, or of reducing intraocular pressure in a subject, comprising administering to the subject an amount of laquinimod effective to reduce intraocular pressure in the subject.\",\n \"The subject invention also provides a package comprising a) a pharmaceutical composition comprising an amount of laquinimod; and b) instruction for use of the pharmaceutical composition to treat a subject afflicted with glaucoma.\",\n \"The subject invention also provides a therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted with glaucoma, which comprises a) one or more unit doses, each such unit dose comprising an amount of laquinimod thereof, wherein the amount of said laquinimod in said unit dose is effective, upon administration to said subject, to treat the subject, and b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said subject.\",\n \"The subject invention also provides a pharmaceutical composition and a package as described herein for use in treating a subject afflicted with glaucoma.\",\n \"The subject invention also provides a pharmaceutical composition in unit dosage form, useful in treating a subject afflicted with glaucoma, which comprises an amount of laquinimod; which amount of said laquinimod in said composition is effective, upon administration to said subject of one or more of said unit dosage forms of said composition, to treat the subject.\",\n \"The subject invention also provides a package comprising a) a pharmaceutical composition as described herein; and b) instruction for use of the pharmaceutical composition to treat a subject afflicted with glaucoma.\",\n \"The subject invention also provides laquinimod for the manufacture of a medicament for use in treating a subject afflicted glaucoma.\"\n ],\n [\n \"This application claims benefit of U.S.\",\n \"Provisional Application No.\",\n \"61/904,962, filed Nov. 15, 2013, the entire content of which is hereby incorporated by reference herein.\",\n \"Throughout this application, various publications are referred to by first author and year of publication.\",\n \"Full citations for these publications are presented in a References section immediately before the claims.\",\n \"Disclosures of the documents and publications referred to herein are hereby incorporated in their entireties by reference into this application.\",\n \"BACKGROUND Glaucoma is a group of ocular diseases characterized by progressive damage to the eye at least partly due to elevated intraocular pressure (IOP) (Merck Manual of Diagnosis and Therapy (1999)).\",\n \"Additionally, glaucoma is characterized by retinal ganglion cell (RGC) death, axon loss and an excavated appearance of the optic nerve head (Alward 1998).\",\n \"Glaucoma can be diagnosed before vision loss occurs by visual field testing and by ophthalmoscopic examination of the optic nerve to detect “cupping.” The mean IOP in normal adults is 15 to 16 mm Hg; the normal range is 10 to 21 mm Hg.\",\n \"One form of management of glaucoma is based on lowering the IOP using topically applied medications (Coleman 1999).\",\n \"Currently there are five major classes of medications that are used to lower the IOP: β-adrenergic antagonists, adrenergic agonists, parasympathomimetics, prostaglandin-like analogues and carbonic anhydrase inhibitors (Medeiros et al.\",\n \"2002).\",\n \"Although most medications are applied topically to the eye, they can cause severe systemic side effects and adversely affect the quality of the patient's life.\",\n \"If additional lowering of IOP is indicated or if medication fails to sufficiently lower the IOP, laser trabeculoplasty is usually the next step.\",\n \"If IOP is still not adequately controlled, incisional glaucoma surgery is indicated (Id).\",\n \"The lowering of IOP, despite significantly reducing the extent of neuronal loss, does not ensure cessation of the disease process, because the loss of RGCs may continue.\",\n \"Recent studies of the association between IOP regulation and visual field loss after medical or surgical intervention showed that ongoing neuronal loss reflected in visual field tests can be diminished if the IOP is low.\",\n \"However, neuronal loss may continue to occur after reduction of IOP (Bakalash et al.\",\n \"2002).\",\n \"Glaucomatous optic neuropathy appears to result from specific pathophysiological changes and subsequent death of RGCs and their axons.\",\n \"The process of RGC death is thought to be biphasic: a primary injury responsible for initiation of damage followed by a slower, secondary degeneration attributable to the hostile environment surrounding the degenerating cells (Kipnis et al.\",\n \"2000).\",\n \"The molecular mechanism triggering RGC death has not been identified.\",\n \"Deprivation of neurotrophic factors, ischemia, chronic elevation of glutamate and disorganized nitric oxide metabolism are suspected to be possible mechanisms (Farkas et al.\",\n \"2001).\",\n \"In addition, it is possible that the mechanisms leading to RGC death share common features with other types of neuronal injury, such as signaling by reactive oxygen species, depolarization of mitochondria, or induction of transcriptionally regulated cell death (Weinreb et al.\",\n \"1999).\",\n \"Laquinimod Laquinimod (LAQ) is a novel synthetic compound with high oral bioavailability which has been suggested as an oral formulation for the treatment of Multiple Sclerosis (MS) (Polman, 2005; Sandberg-Wollheim, 2005).\",\n \"Laquinimod and its sodium salt form are described, for example, in U.S. Pat.\",\n \"No.\",\n \"6,077,851.The mechanism of action of laquinimod is not fully understood.\",\n \"Animal studies show it causes a Th1 (T helper 1 cell, which produces pro-inflammatory cytokines) to Th2 (T helper 2 cell, which produces anti-inflammatory cytokines) shift with an anti-inflammatory profile (Yang, 2004; Brück, 2011).\",\n \"Another study demonstrated (mainly via the NFkB pathway) that laquinimod induced suppression of genes related to antigen presentation and corresponding inflammatory pathways (Gurevich, 2010).\",\n \"Other suggested potential mechanisms of action include inhibition of leukocyte migration into the CNS, increase of axonal integrity, modulation of cytokine production, and increase in levels of brain-derived neurotrophic factor (BDNF) (Runström, 2006; Brück, 2011).\",\n \"The effects of laquinimod on glaucoma have not previously been studied.\",\n \"SUMMARY OF THE INVENTION The subject invention provides a method of treating a subject afflicted with glaucoma comprising administering to the subject an amount of laquinimod effective to treat the subject.\",\n \"The subject invention also provides a method of treating a subject suffering from retinal ganglion cell loss or retinal ganglion cell damage, or of reducing retinal ganglion cell loss or damage in a subject, comprising administering to the subject an amount of laquinimod effective to reduce retinal ganglion cell loss or retinal ganglion cell damage in the subject.\",\n \"The subject invention also provides a method of treating a subject suffering from elevated intraocular pressure, or of reducing intraocular pressure in a subject, comprising administering to the subject an amount of laquinimod effective to reduce intraocular pressure in the subject.\",\n \"The subject invention also provides a package comprising a) a pharmaceutical composition comprising an amount of laquinimod; and b) instruction for use of the pharmaceutical composition to treat a subject afflicted with glaucoma.\",\n \"The subject invention also provides a therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted with glaucoma, which comprises a) one or more unit doses, each such unit dose comprising an amount of laquinimod thereof, wherein the amount of said laquinimod in said unit dose is effective, upon administration to said subject, to treat the subject, and b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said subject.\",\n \"The subject invention also provides a pharmaceutical composition and a package as described herein for use in treating a subject afflicted with glaucoma.\",\n \"The subject invention also provides a pharmaceutical composition in unit dosage form, useful in treating a subject afflicted with glaucoma, which comprises an amount of laquinimod; which amount of said laquinimod in said composition is effective, upon administration to said subject of one or more of said unit dosage forms of said composition, to treat the subject.\",\n \"The subject invention also provides a package comprising a) a pharmaceutical composition as described herein; and b) instruction for use of the pharmaceutical composition to treat a subject afflicted with glaucoma.\",\n \"The subject invention also provides laquinimod for the manufacture of a medicament for use in treating a subject afflicted glaucoma.\",\n \"BRIEF DESCRIPTION OF THE FIGURES FIG.\",\n \"1: Example 1: Mean ΔIOP (OHT minus Non-OHT) (mmHg).\",\n \"FIG.\",\n \"2: Example 1: % Fluoro-gold Labeled RGC Loss.\",\n \"FIG.\",\n \"3: Example 1: Mean Fluoro-gold Labeled RGC count per mm2.FIG.\",\n \"4: Optic Nerve Injury Grade (1-5).\",\n \"FIG.\",\n \"5A: Example 1: Representative images of the retinas with FG-labeled RGC—Animal Number 48, Group 1, Left Eye.\",\n \"FIG.\",\n \"5B: Example 1: Representative images of the retinas with FG-labeled RGC—Animal Number 48, Group 1, Right Eye.\",\n \"FIG.\",\n \"5C: Example 1: Representative images of the retinas with FG-labeled RGC—Animal Number 59, Group 2, Left Eye.\",\n \"FIG.\",\n \"5D: Example 1: Representative images of the retinas with FG-labeled RGC—Animal Number 59, Group 2, Right Eye.\",\n \"FIG.\",\n \"5E: Example 1: Representative images of the retinas with FG-labeled RGC—Animal Number 22, Group 3, Left Eye.\",\n \"FIG.\",\n \"5F: Example 1: Representative images of the retinas with FG-labeled RGC—Animal Number 22, Group 3, Right Eye.\",\n \"FIG.\",\n \"5G: Example 1: Representative images of the retinas with FG-labeled RGC—Animal Number 31, Group 4, Left Eye.\",\n \"FIG.\",\n \"5H: Example 1: Representative images of the retinas with FG-labeled RGC—Animal Number 31, Group 4, Right Eye.\",\n \"FIG.\",\n \"5I: Example 1: Representative images of the retinas with FG-labeled RGC—Animal Number 35, Group 5, Left Eye.\",\n \"FIG.\",\n \"5J: Example 1: Representative images of the retinas with FG-labeled RGC—Animal Number 35, Group 5, Right Eye.\",\n \"DETAILED DESCRIPTION OF THE INVENTION The subject invention provides a method of treating a subject afflicted with glaucoma comprising administering to the subject an amount of laquinimod effective to treat the subject.\",\n \"In one embodiment, the administration of laquinimod is effective to reduce or inhibit a symptom of the glaucoma in the subject.\",\n \"In another embodiment, the symptom is retinal ganglion cell damage, retinal ganglion cell loss, or elevated intraocular pressure.\",\n \"In another embodiment, laquinimod is laquinimod sodium.\",\n \"In one embodiment, the route of administration of laquinimod is intraocular, periocular, systemic or topical.\",\n \"In another embodiment, laquinimod is administered via oral administration.\",\n \"In another embodiment, laquinimod is administered via ocular administration.\",\n \"In another embodiment, laquinimod is administered in the form of an aerosol, an inhalable powder, an injectable, a liquid, a gel, a solid, a capsule or a tablet.\",\n \"In an embodiment, the concentration of laquinimod in the liquid or gel is 5-100 mg/ml solution, 20-100 mg/ml solution, 10-15 mg/ml solution, or 20-50 mg/ml solution.\",\n \"In another embodiment, laquinimod is administered periodically.\",\n \"In another embodiment, laquinimod is administered daily.\",\n \"In another embodiment, laquinimod is administered more often than once daily.\",\n \"In yet another embodiment, laquinimod is administered less often than once daily.\",\n \"In one embodiment, the amount laquinimod administered is at least 0.2 mg/day and/or less than 0.6 mg/day.\",\n \"In another embodiment, the amount laquinimod administered is 0.03-600 mg/day, 0.1-40.0 mg/day, 0.1-2.5 mg/day, 0.25-2.0 mg/day or 0.5-1.2 mg/day.\",\n \"In another embodiment, the amount laquinimod administered is 0.25 mg/day, 0.3 mg/day, 0.5 mg/day, 0.6 mg/day, 1.0 mg/day, 1.2 mg/day, 1.5 mg/day or 2.0 mg/day.\",\n \"In yet another embodiment, the amount of laquinimod administered is 0.05-4.0 mg per administration, 0.05-2.0 mg per administration, 0.2-4.0 mg per administration, 0.2-2.0 mg per administration, about 0.1 mg per administration, or about 0.5 mg per administration.\",\n \"In one embodiment of the present invention, the method further comprises administration of a second agent for the treatment of glaucoma.\",\n \"In another embodiment, the second agent is a β-adrenergic antagonist, adrenergic agonist, parasympathomimetic, prostaglandin-like analog, or carbonic anhydrase inhibitor.\",\n \"In one embodiment, the periodic administration of laquinimod continues for at least 3 days, more than 30 days, more than 42 days, 8 weeks or more, at least 12 weeks, at least 24 weeks, more than 24 weeks, or 6 months or more.\",\n \"In another embodiment, the subject is a human patient.\",\n \"The subject invention also provides a method of treating a subject suffering from retinal ganglion cell loss or retinal ganglion cell damage, or of reducing retinal ganglion cell loss or damage in a subject, comprising administering to the subject an amount of laquinimod effective to reduce retinal ganglion cell loss or retinal ganglion cell damage in the subject.\",\n \"The subject invention also provides a method of treating a subject suffering from elevated intraocular pressure, or of reducing intraocular pressure in a subject, comprising administering to the subject an amount of laquinimod effective to reduce intraocular pressure in the subject.\",\n \"The subject invention also provides a package comprising a) a pharmaceutical composition comprising an amount of laquinimod; and b) instruction for use of the pharmaceutical composition to treat a subject afflicted with glaucoma.\",\n \"In one embodiment of the present invention, the package comprises a second pharmaceutical composition comprising an amount of a second agent for the treatment of glaucoma.\",\n \"In another embodiment, the second agent is a β-adrenergic antagonist, adrenergic agonist, parasympathomimetic, prostaglandin-like analog, or carbonic anhydrase inhibitor.\",\n \"In one embodiment, the pharmaceutical composition is the form of an aerosol, an inhalable powder, an injectable, a liquid, a gel, a solid, a capsule or a tablet.\",\n \"In another embodiment, the pharmaceutical composition is in a liquid or a gel form.\",\n \"In one embodiment, the concentration of laquinimod in the liquid or gel is 5-100 mg/ml solution, 20-100 mg/ml solution, 10-15 mg/ml solution or 20-50 mg/ml solution.\",\n \"In another embodiment, the pharmaceutical composition is in capsule form or in tablet form.\",\n \"In another embodiment, the tablets are coated with a coating which inhibits oxygen from contacting the core.\",\n \"In another embodiment, the coating comprises a cellulosic polymer, a detackifier, a gloss enhancer, or pigment.\",\n \"In one embodiment, the pharmaceutical composition further comprises mannitol.\",\n \"In another embodiment, the pharmaceutical composition further comprises an alkalinizing agent.\",\n \"In another embodiment, the alkalinizing agent is meglumine.\",\n \"In another embodiment, the pharmaceutical composition further comprises an oxidation reducing agent.\",\n \"In one embodiment, the pharmaceutical composition is stable and free of an alkalinizing agent or an oxidation reducing agent.\",\n \"In another embodiment, the pharmaceutical composition is free of an alkalinizing agent and free of an oxidation reducing agent.\",\n \"In one embodiment, the pharmaceutical composition is stable and free of disintegrant.\",\n \"In another embodiment, the pharmaceutical composition further comprises a lubricant.\",\n \"In another embodiment, the lubricant is present in the pharmaceutical composition as solid particles.\",\n \"In another embodiment, the lubricant is sodium stearyl fumarate or magnesium stearate.\",\n \"In one embodiment, the pharmaceutical composition further comprises a filler.\",\n \"In another embodiment, the filler is present in the pharmaceutical composition as solid particles.\",\n \"In another embodiment, the filler is lactose, lactose monohydrate, starch, isomalt, mannitol, sodium starch glycolate, sorbitol, lactose spray dried, lactose anhydrouse, or a combination thereof.\",\n \"In another embodiment, the filler is mannitol or lactose monohydrate.\",\n \"In one embodiment, the package further comprises a desiccant.\",\n \"In another embodiment, the desiccant is silica gel.\",\n \"In one embodiment, the pharmaceutical composition is stable and has a moisture content of no more than 4%.\",\n \"In another embodiment, laquinimod is present in the pharmaceutical composition as solid particles.\",\n \"In another embodiment, the package is a sealed packaging having a moisture permeability of not more than 15 mg/day per liter.\",\n \"In another embodiment, the sealed package is a blister pack in which the maximum moisture permeability is no more than 0.005 mg/day.\",\n \"In another embodiment, the sealed package is a bottle.\",\n \"In another embodiment, the bottle is closed with a heat induction liner.\",\n \"In another embodiment, the sealed package comprises an HDPE bottle.\",\n \"In another embodiment, the sealed package comprises an oxygen absorbing agent.\",\n \"In another embodiment, the oxygen absorbing agent is iron.\",\n \"In one embodiment, the amount of laquinimod in the pharmaceutical composition is at least 0.2 mg or less than 0.6 mg.\",\n \"In another embodiment, the amount of laquinimod in the pharmaceutical composition is 0.1-40.0 mg, 0.03-600 mg, 0.1-2.5 mg, 0.25-2.0 mg, 0.5-1.2 mg, 0.25 mg, 0.3 mg, 0.5 mg, 0.6 mg, 1.0 mg, 1.2 mg, 1.5 mg, or 2.0 mg.\",\n \"In another embodiment, the pharmaceutical composition comprises unit doses of laquinimod of 0.05-4.0 mg, 0.05-2.0 mg, 0.2-4.0 mg, 0.2-2.0 mg, about 0.1 mg, or about 0.5 mg.\",\n \"In one embodiment, the pharmaceutical composition is formulated for intraocular, periocular, systemic or topical administration.\",\n \"In another embodiment, the pharmaceutical composition is formulated for oral or ocular administration.\",\n \"The subject invention also provides packages as described herein for use in treating a subject afflicted with glaucoma.\",\n \"The subject invention also provides a therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted with glaucoma, which comprises a) one or more unit doses, each such unit dose comprising an amount of laquinimod thereof, wherein the amount of said laquinimod in said unit dose is effective, upon administration to said subject, to treat the subject, and b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said subject.\",\n \"In one embodiment, the therapeutic package comprises a second pharmaceutical composition comprising an amount of a second agent for the treatment of glaucoma.\",\n \"In another embodiment, the second agent is a β-adrenergic antagonist, adrenergic agonist, parasympathomimetic, prostaglandin-like analog, or carbonic anhydrase inhibitor.\",\n \"The subject invention also provides a pharmaceutical composition comprising an amount of laquinimod for use in treating a subject afflicted glaucoma.\",\n \"In one embodiment, the pharmaceutical composition comprises an amount of a second agent for the treatment of glaucoma.\",\n \"In another embodiment, the second agent is a β-adrenergic antagonist, adrenergic agonist, parasympathomimetic, prostaglandin-like analog, or carbonic anhydrase inhibitor.\",\n \"In an embodiment, the pharmaceutical composition is in the form of an aerosol, an inhalable powder, an injectable, a liquid, a gel, a solid, a capsule or a tablet.\",\n \"In another embodiment, the pharmaceutical composition is in a liquid or a gel form.\",\n \"In an embodiment, the concentration of laquinimod in the liquid or gel is 5-100 mg/ml solution, 20-100 mg/ml solution, 10-15 mg/ml solution or 20-50 mg/ml solution.\",\n \"In another embodiment, the pharmaceutical composition comprises a unit dose of 10 μL of an aqueous pharmaceutical solution which contains in solution at least 0.2 mg laquinimod.\",\n \"In another embodiment, laquinimod is laquinimod sodium.\",\n \"In one embodiment, the pharmaceutical composition is in capsule form or in tablet form.\",\n \"In another embodiment, the tablets are coated with a coating which inhibits oxygen from contacting the core.\",\n \"In another embodiment, the coating comprises a cellulosic polymer, a detackifier, a gloss enhancer, or pigment.\",\n \"In another embodiment, the pharmaceutical composition further comprises mannitol.\",\n \"In one embodiment, the pharmaceutical composition further comprises an alkalinizing agent.\",\n \"In another embodiment, the alkalinizing agent is meglumine.\",\n \"In another embodiment, the pharmaceutical composition further comprises an oxidation reducing agent.\",\n \"In one embodiment, the pharmaceutical composition is free of an alkalinizing agent or an oxidation reducing agent.\",\n \"In another embodiment, the pharmaceutical composition is free of an alkalinizing agent and free of an oxidation reducing agent.\",\n \"In one embodiment, the pharmaceutical composition is stable and free of disintegrant.\",\n \"In another embodiment, the pharmaceutical composition further comprises a lubricant.\",\n \"In another embodiment, the lubricant is present in the pharmaceutical composition as solid particles.\",\n \"In another embodiment, the lubricant is sodium stearyl fumarate or magnesium stearate.\",\n \"In one embodiment, the pharmaceutical composition further comprises a filler.\",\n \"In another embodiment, the filler is present in the pharmaceutical composition as solid particles.\",\n \"In another embodiment, the filler is lactose, lactose monohydrate, starch, isomalt, mannitol, sodium starch glycolate, sorbitol, lactose spray dried, lactose anhydrouse, or a combination thereof.\",\n \"In another embodiment, the filler is mannitol or lactose monohydrate.\",\n \"In one embodiment, the amount of laquinimod in the pharmaceutical composition is at least 0.2 mg or less than 0.6 mg.\",\n \"In another embodiment, the amount of laquinimod in is 0.1-40.0 mg, 0.03-600 mg, 0.1-2.5 mg, 0.25-2.0 mg, 0.5-1.2 mg, 0.25 mg, 0.3 mg, 0.5 mg, 0.6 mg, 1.0 mg, 1.2 mg, 1.5 mg, or 2.0 mg.\",\n \"In another embodiment, the pharmaceutical composition comprises unit doses of laquinimod of 0.05-4.0 mg, 0.05-2.0 mg, 0.2-4.0 mg, 0.2-2.0 mg, about 0.1 mg, or about 0.5 mg.\",\n \"In one embodiment, the pharmaceutical composition is formulated for intraocular, periocular, systemic or topical administration.\",\n \"In another embodiment, the pharmaceutical composition is formulated for oral or ocular administration.\",\n \"The subject invention also provides a pharmaceutical composition as described herein for use in treating a subject afflicted with glaucoma.\",\n \"The subject invention also provides a pharmaceutical composition in unit dosage form, useful in treating a subject afflicted with glaucoma, which comprises an amount of laquinimod; which amount of said laquinimod in said composition is effective, upon administration to said subject of one or more of said unit dosage forms of said composition, to treat the subject.\",\n \"The subject invention also provides a package comprising a) a pharmaceutical composition as described herein; and b) instruction for use of the pharmaceutical composition to treat a subject afflicted with glaucoma.\",\n \"The subject invention also provides laquinimod for the manufacture of a medicament for use in treating a subject afflicted glaucoma.\",\n \"For the foregoing embodiments, each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments.\",\n \"For instance, the elements recited in the method embodiments can be used in the pharmaceutical composition, package, and use embodiments described herein and vice versa.\",\n \"Terms As used herein, and unless stated otherwise, each of the following terms shall have the definition set forth below.\",\n \"As used herein, “laquinimod” means laquinimod acid or a pharmaceutically acceptable salt thereof.\",\n \"A “salt thereof” is a salt of the instant compounds which have been modified by making acid or base salts of the compounds.\",\n \"The term “pharmaceutically acceptable salt” in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention.\",\n \"For example, one means of preparing such a salt is by treating a compound of the present invention with an inorganic base.\",\n \"As used herein, an “amount” or “dose” of laquinimod as measured in milligrams refers to the milligrams of laquinimod acid present in a preparation, regardless of the form of the preparation.\",\n \"A “dose of 0.6 mg laquinimod” means the amount of laquinimod acid in a preparation is 0.6 mg, regardless of the form of the preparation.\",\n \"Thus, when in the form of a salt, e.g.\",\n \"a laquinimod sodium salt, the weight of the salt form necessary to provide a dose of 0.6 mg laquinimod would be greater than 0.6 mg (e.g., 0.64 mg) due to the presence of the additional salt ion.\",\n \"As used herein, a “unit dose”, “unit doses” and “unit dosage form(s)” mean a single drug administration entity/entities.\",\n \"As used herein, “about” in the context of a numerical value or range means±10% of the numerical value or range recited or claimed.\",\n \"As used herein, a composition that is “free” of a chemical entity means that the composition contains, if at all, an amount of the chemical entity which cannot be avoided although the chemical entity is not part of the formulation and was not affirmatively added during any part of the manufacturing process.\",\n \"For example, a composition which is “free” of an alkalizing agent means that the alkalizing agent, if present at all, is a minority component of the composition by weight.\",\n \"Preferably, when a composition is “free” of a component, the composition comprises less than 0.1 wt %, 0.05 wt %, 0.02 wt %, or 0.01 wt % of the component.\",\n \"As used herein, “alkalizing agent” is used interchangeably with the term “alkaline-reacting component” or “alkaline agent” and refers to any pharmaceutically acceptable excipient which neutralizes protons in, and raises the pH of, the pharmaceutical composition in which it is used.\",\n \"As used herein, “oxidation reducing agent” refers to a group of chemicals which includes an “antioxidant”, a “reduction agent” and a “chelating agent”.\",\n \"As used herein, “antioxidant” refers to a compound selected from the group consisting of tocopherol, methionine, glutathione, tocotrienol, dimethyl glycine, betaine, butylated hydroxyanisole, butylated hydroxytoluene, turmerin, vitamin E, ascorbyl palmitate, tocopherol, deteroxime mesylate, methyl paraben, ethyl paraben, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, sodium or potassium metabisulfite, sodium or potassium sulfite, alpha tocopherol or derivatives thereof, sodium ascorbate, disodium edentate, BHA (butylated hydroxyanisole), a pharmaceutically acceptable salt or ester of the mentioned compounds, and mixtures thereof.\",\n \"The term “antioxidant” as used herein also refers to Flavonoids such as those selected from the group of quercetin, morin, naringenin and hesperetin, taxifolin, afzelin, quercitrin, myricitrin, genistein, apigenin and biochanin A, flavone, flavopiridol, isoflavonoids such as the soy isoflavonoid, genistein, catechins such as the tea catechin epigallocatechin gallate, flavonol, epicatechin, hesperetin, chrysin, diosmin, hesperidin, luteolin, and rutin.\",\n \"As used herein, “reduction agent” refers to a compound selected from the group consisting of thiol-containing compound, thioglycerol, mercaptoethanol, thioglycol, thiodiglycol, cysteine, thioglucose, dithiothreitol (DTT), dithio-bis-maleimidoethane (DTME), 2,6-di-tert-butyl-4-methylphenol (BHT), sodium dithionite, sodium bisulphite, formamidine sodium metabisulphite, and ammonium bisulphite.” As used herein, “chelating agent” refers to a compound selected from the group consisting of penicillamine, trientine, N,N′-diethyldithiocarbamate (DDC), 2,3,2′-tetraamine (2,3,2′-tet), neocuproine, N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), 1,10-phenanthroline (PHE), tetraethylenepentamine, triethylenetetraamine and tris(2-carboxyethyl) phosphine (TCEP), ferrioxamine, CP94, EDTA, deferoxainine B (DFO) as the methanesulfonate salt (also known as desferrioxanilne B mesylate (DFOM)), desferal from Novartis (previously Ciba-Giegy), and apoferritin.\",\n \"As used herein, a pharmaceutical composition is “stable” when the composition preserves the physical stability/integrity and/or chemical stability/integrity of the active pharmaceutical ingredient during storage.\",\n \"Furthermore, “stable pharmaceutical composition” is characterized by its level of degradation products not exceeding 5% at 40° C./75% RH after 6 months or 3% at 55° C./75% RH after two weeks, compared to their level in time zero.\",\n \"As used herein, “effective” when referring to an amount of laquinimod refers to the quantity of laquinimod that is sufficient to yield a desired therapeutic response.\",\n \"Efficacy can be measured by e.g., a reduced intraocular pressure (IOP).\",\n \"Administering to the subject” or “administering to the (human) patient” means the giving of, dispensing of, or application of medicines, drugs, or remedies to a subject/patient to relieve, cure, or reduce the symptoms associated with a condition, e.g., a pathological condition.\",\n \"The administration can be periodic administration.\",\n \"As used herein, “periodic administration” means repeated/recurrent administration separated by a period of time.\",\n \"The period of time between administrations is preferably consistent from time to time.\",\n \"Periodic administration can include administration, e.g., once daily, twice daily, three times daily, four times daily, weekly, twice weekly, three times weekly, four times weekly and so on, etc.\",\n \"The route of administration can be, e.g., topical.\",\n \"Routes of administration can also be classified by whether the effect is local (e.g., in topical administration) or systemic (e.g., in enteral or parenteral administration).\",\n \"“Local administration” as used herein shall mean administration of a compound or composition directly to where its action is desired, and specifically excludes systemic administration.\",\n \"“Topical administration” of a compound or composition as used herein shall mean application of the compound or composition to body surfaces such as the skin or mucous membranes such as eyes.\",\n \"“Ocular administration” as used herein shall mean application of a compound or composition to the eye of a subject or to the skin around the eye (periocular skin) of a subject, i.e., local administration.\",\n \"Examples of ocular administration include topical administration directly to the eye, topical application to the eye lid or injection into a portion of the eye or eye socket.\",\n \"In addition, an “ocular pharmaceutical composition” as used herein means a pharmaceutical composition formulated for ocular administration.\",\n \"“Treating” as used herein encompasses, e.g., inducing inhibition, regression, or stasis of a disease or disorder, e.g., glaucoma, or alleviating, lessening, suppressing, inhibiting, reducing the severity of, eliminating or substantially eliminating, or ameliorating a symptom of the disease or disorder.\",\n \"“Inhibition” of disease progression or disease complication in a subject means preventing or reducing the disease progression and/or disease complication in the subject.\",\n \"A “symptom” associated with glaucoma includes any clinical or laboratory manifestation associated with glaucoma and is not limited to what the subject can feel or observe.\",\n \"As used herein, a subject “afflicted” with glaucoma means the subject has been diagnosed with glaucoma.\",\n \"As used herein, a subject at “baseline” is as subject prior to administration of laquinimod in a therapy as described herein.\",\n \"A “pharmaceutically acceptable carrier” refers to a carrier or excipient that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.\",\n \"It can be a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the subject.\",\n \"It is understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided by the invention.\",\n \"For example, “0.1-2.5 mg/day” includes 0.1 mg/day, 0.2 mg/day, 0.3 mg/day, etc.\",\n \"up to 2.5 mg/day.\",\n \"This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter.\",\n \"EXPERIMENTAL DETAILS Example 1: Assessment of the Neuroprotective Efficacy of Laquinimod for the Retinal Ganglion Cell (RGC) Survival in a Rat Glaucoma Model The purpose of this study was to assess the efficacy of laquinimod in protecting against chronic ocular hypertension (OHT) and RGC degeneration in a rat model of glaucoma, created by injecting hypertonic saline into the episcleral veins in one eye of the Brown Norway rat.\",\n \"In this model, RGC degeneration occurs in response to increased IOP and OHT similar to that in human patients with glaucoma.\",\n \"SUMMARY The study included 5 groups (n=8 each): Group 1 (1% Laquinimod for topical administration), Group 2 (Vehicle for topical administration), Group 3 (4% Laquinimod for topical administration), Group 4 (0.25% Laquinimod for topical administration) and Group 5 (0.1% Laquinimod for oral administration).\",\n \"Prior to any experimental procedure, clinical observations were performed daily, body weights were obtained, intraocular pressure (IOP) was measured and detailed ocular examinations were performed on both eyes.\",\n \"Animals that were found to be clinically normal with no baseline ocular abnormalities were selected for use in the study.\",\n \"The rat model of chronic ocular hypertension (OHT)/glaucoma was created in the left eye of each animal via two hypertonic saline injections (HSI) each one week apart.\",\n \"The un-injected right eye served as the control.\",\n \"Throughout the study, the vehicle control and the test articles were prepared weekly.\",\n \"Rats were dosed once daily for oral administration (Group 5) and twice daily for topical administration groups (Groups 1-4), starting on the day of the first HSI until euthanasia.\",\n \"Detailed ocular examinations were performed one week after the 2nd HSI and on the day of euthanasia.\",\n \"Approximately one week prior to euthanasia, RGCs were retrogradely-labeled by bilateral injections of Fluoro-Gold (FG) into the superior colliculus in the brain.\",\n \"Post-dose IOP was measured weekly for 5 weeks starting one week after the 2nd HSI until euthanasia.\",\n \"For each IOP measurement time-point following the 2nd HSI, the IOP elevation was calculated as the difference between the IOP in the left eye with OHT and that in the non-OHT right eye (ΔIOP).\",\n \"The ΔIOP for the 5 weekly post-HSI IOP measurements were averaged and constituted the Mean ΔIOP for each animal.\",\n \"Rats which did not have individual IOP measurements of 50 mmHg in the OHT eyes were selected from a larger pool and groups (n=8 each) were matched for the Mean ΔIOP.\",\n \"Other animals were removed from the study.\",\n \"Animals were euthanized 5 weeks after the 2nd HSI.\",\n \"The retinas were flat-mounted, slide IDs were masked and 8 regions per retina were imaged using a confocal microscope.\",\n \"RGC at these regions were counted using the Image J software.\",\n \"After the optic nerves were extracted, they were plastic-embedded, sectioned and stained with Toluidine Blue at Schepens Eye Research Institute, Boston, Mass.\",\n \"The injury in the optic nerves was evaluated and graded by microscopic examination in a masked fashion.\",\n \"There were no abnormal clinical signs or ocular abnormalities noted in any of the 40 animals in the beginning of the study.\",\n \"There were no treatment-related findings in the clinical observations or ocular examinations during the study in any of the animals.\",\n \"A One-Way ANOVA indicated that the group body weights were not statistically different on the day of dosing among groups (P=0.957).\",\n \"Groups also did not differ in the amount of weight gained between the day of dosing and the day of euthanasia (One-Way ANOVA; P=0.559).\",\n \"For five weeks post-dose, the mean ΔIOP values (OHT−Non-OHT) (Mean±SD) were 9.1±2.2 mmHg, 9.1±2.6 mmHg, 9.3±2.7 mmHg, 9.2±1.5 mmHg, and 9.1±2.9 mmHg for Groups 1, 2, 3, 4 and 5, respectively.\",\n \"A One-Way ANOVA analysis indicated that the groups were well-matched for Mean ΔIOP (P>0.9).\",\n \"Compared to the non-OHT retinas, % Fluoro-gold labeled-RGC Loss (Mean±SD) in the OHT retinas was 17.6±33.8, 34.8±42.7, 26.8±36.4, 21.6±21.7, and 22.9±33.1 for Groups 1, 2, 3, 4 and 5, respectively.\",\n \"FG-Labeled RGC counts per mm2 were compared between the Non-OHT and the OHT retinas for each group using two-tailed paired-t tests.\",\n \"Group 2 (vehicle topical; P=0.047) and Group 4 (0.25% Laquinimod topical; P=0.033) had fewer RGCs in the OHT eye compared to the Non-OHT eyes.\",\n \"The number of RGCs in Group 3 (4% Laquinimod topical; P=0.071) and Group 5 (0.1% Laquinimod oral; P=0.075) were statistically different between the OHT and Non-OHT eyes.\",\n \"However, in Group 1 (1% Laquinimod topical), there was no statistically significant difference in the RGC counts between the OHT and Non-OHT eyes (P=0.189).\",\n \"This suggests that the daily topical application of 1% Laquinimod may be neuroprotective for the RGC.\",\n \"For the optic nerves in the Non-OHT (control) eyes, the Mean Injury Grades (Mean±SD) were 1.1±0.1, 1.2±0.2, 1.2±0.2, 1.2±0.3 and 1.2±0.2 for Groups 1, 2, 3, 4 and 5, respectively.\",\n \"For the optic nerves in the OHT eyes, the Mean Injury Grades (Mean±SD) for the OHT optic nerves were 2.5±1.3, 3.0±1.6, 3.0±1.5, 2.8±1.3 and 2.7±1.5 for Groups 1, 2, 3, 4, and 5 respectively.\",\n \"As a secondary analysis, Mean ON Injury Grades were compared between the Non-OHT and the OHT optic nerves for each group using two-tailed paired-t tests.\",\n \"The Mean ON injury grades were significantly greater in the OHT eyes compared to the Non-OHT control eyes in all groups (P<0.05).\",\n \"Materials Test Article: laquinimod sodium stored at room temperature protected from light.\",\n \"Control Article: 0% laquinimod sodium stored under refrigeration.\",\n \"Animals Number and Species: The study quote and outline-specified data were collected on 40 Brown Norway rats (Rattus norvegicus).\",\n \"Rats have been used historically as OHT models and there are no other approved alternative (non-animal methods).\",\n \"The study started with 90 animals to ensure that sufficient data were available at the end of the study.\",\n \"Sex: male Weight/Age Range: approximately 271.2-366.4 grams/at least 12 weeks old (adult) weighed to nearest 0.1 g. Procedure Ocular and oral exposure corresponds to the route of human exposure.\",\n \"For the four topical administration groups, the test and control articles were applied topically to the surface of one eye of the test system.\",\n \"The test article was administered orally for the fifth group of animals.\",\n \"Preparation of Test and Control Articles All test and control articles were prepared as described below.\",\n \"The final volume for the formulations described below is 200 mL but the formulations were proportionally changed to the required volume for each preparation.\",\n \"Three different concentrations (0.25%, 1%, and 4%) of the test article for topical application and the test article for oral gavage (0.1%) were prepared weekly.\",\n \"The control article for topical application was also prepared weekly.\",\n \"The identification of the test and control articles for the topical administration was masked after preparation of the topical formulations.\",\n \"TABLE 1 LAQ 4.0% Topical Formulation (40 mg/mL of LAQ) Material g/200 mL solution Laquinimod Sodium 8.52 (equivalent to 8 g Laquinimod acid) Sodium Phosphate Dibasic 7 Hydrate 2.497 Sodium Phosphate Monobasic Monohydrate 0.0942 Hydroxy Ethyl Cellulose (HEC) HX 0.3 Water for Injection Amount required to bring solution to 200 mL Table 1 Process: 1.The entire process is performed under yellow light or at dark conditions.\",\n \"2.Weigh 175 g (175 mL) of water for injection in a glass container containing a stirrer.\",\n \"3.Weigh and add the Sodium Phosphate Monobasic Monohydrate and Sodium Phosphate Dibasic 7 Hydrate and stir for approximately 5 minutes.\",\n \"Verify complete dissolution by visual inspection of a clear transparent solution.\",\n \"4.Measure the pH (Approximately 7.7-8.3).\",\n \"5.Weigh and add Laquinimod Sodium to the solution.\",\n \"Rinse the weighing boat from the Laquinimod Sodium remaining with ˜5 mL of water and to the solution.\",\n \"Stir for approximately 5 minutes and verify complete dissolution by visual inspection of a clear transparent solution.\",\n \"6.Weigh and add the Hydroxy Ethyl Cellulose HX.\",\n \"7.Stir for approximately 2 hours.\",\n \"8.Remove the stirrer and add the solution to a 200 mL volumetric flask.\",\n \"9.Add water for injection up to 200 mL.\",\n \"10.Shake manually for approximately two minutes.\",\n \"11.Transfer into an appropriate container.\",\n \"Wrap with aluminum foil and keep the solution refrigerated.\",\n \"TABLE 2 LAQ 1.0% Topical Formulation (10 mg/mL of LAQ) Material g/200 mL solution Laquinimod Sodium 2.12 (equivalent to 2 g Laquinimod acid) Sodium Phosphate Dibasic 7 Hydrate 2.497 Sodium Phosphate Monobasic Monohydrate 0.0942 Hydroxy Ethyl Cellulose (HEC) HX 0.3 Sodium chloride 0.75 Water for Injection Amount required to bring solution to 200 mL Table 2 Process: 1.The entire process is performed under yellow light or at dark conditions.\",\n \"2.Weigh 175 g (175 mL) of water for injection in a glass container containing a stirrer.\",\n \"3.Weigh and add the Sodium Phosphate Monobasic Monohydrate and Sodium Phosphate Dibasic 7 Hydrate and stir for approximately 5 minutes.\",\n \"Verify complete dissolution by visual inspection of a clear transparent solution.\",\n \"4.Measure the pH (Approximately 7.7 to 8.3).\",\n \"5.Weigh and add Laquinimod Sodium to the solution.\",\n \"Rinse the weighing boat from the Laquinimod Sodium remaining with ˜5 mL of water and to the solution.\",\n \"Stir for approximately 5 minutes and verify complete dissolution by visual inspection of a clear transparent solution.\",\n \"6.Weigh and add the Sodium Chloride to the solution.\",\n \"Stir for approximately 2 minutes.\",\n \"Verify complete dissolution by visual inspection of a clear transparent solution.\",\n \"7.Weigh and add the Hydroxy Ethyl Cellulose HX.\",\n \"8.Stir for approximately 2 hours.\",\n \"9.Remove the stirrer and add the solution to a 200 mL volumetric flask.\",\n \"10.Add water for injection up to 200 mL.\",\n \"11.Shake manually for approximately two minutes.\",\n \"12.Transfer into an appropriate container.\",\n \"Wrap with aluminum foil and keep the solution refrigerated.\",\n \"TABLE 3 LAQ 0.25% Topical Formulation (2.5 mg/mL of LAQ) Material g/200 mL solution Laquinimod Sodium 0.54 (equivalent to 0.5 g Laquinimod acid) Sodium Phosphate Dibasic 7 Hydrate 2.497 Sodium Phosphate Monobasic Monohydrate 0.0942 Hydroxy Ethyl Cellulose (HEC) HX 0.3 Sodium chloride 0.94 Water for Injection Amount required to bring solution to 200 mL Table 3 Process: 1.The entire process is performed under yellow light or at dark conditions.\",\n \"2.Weigh 175 g (175 mL) of water for injection in a glass container containing a stirrer.\",\n \"3.Weigh and add the Sodium Phosphate Monobasic Monohydrate and Sodium Phosphate Dibasic 7 Hydrate and stir for approximately 5 minutes.\",\n \"Verify complete dissolution by visual inspection of a clear transparent solution.\",\n \"4.Measure the pH (Approximately 7.7-8.3).\",\n \"5.Weigh and add Laquinimod Sodium to the solution.\",\n \"Rinse the weighing boat from the Laquinimod Sodium remaining with ˜5 mL of water and to the solution.\",\n \"Stir for approximately 5 minutes and verify complete dissolution by visual inspection of a clear transparent solution.\",\n \"6.Weigh and add the Sodium Chloride to the solution.\",\n \"Stir for approximately 2 minutes.\",\n \"Verify complete dissolution by visual inspection of a clear transparent solution.\",\n \"7.Weigh and add the Hydroxy Ethyl Cellulose HX.\",\n \"8.Stir for approximately 2 hours.\",\n \"9.Remove the stirrer and add the solution to a 200 mL volumetric flask.\",\n \"10.Add water for injection up to 200 mL.\",\n \"11.Shake manually for approximately two minutes.\",\n \"12.Transfer into an appropriate container.\",\n \"Wrap with aluminum foil and keep the solution refrigerated.\",\n \"TABLE 4 LAQ 0% Topical Formulation (Control Article) Material g/200 mL solution Sodium Phosphate Dibasic 7 Hydrate 2.497 Sodium Phosphate Monobasic Monohydrate 0.0942 Hydroxy Ethyl Cellulose (HEC) HX 0.3 Sodium chloride 1 Water for Injection Amount required to bring solution to 200 mL Table 4 Process: 1.The entire process is performed under yellow light or at dark conditions.\",\n \"2.Weigh 175 g (175 mL) of water for injection in a glass container containing a stirrer.\",\n \"3.Weigh and add the Sodium Phosphate Monobasic Monohydrate and Sodium Phosphate Dibasic 7 Hydrate and stir for approximately 5 minutes.\",\n \"Verify complete dissolution by visual inspection of a clear transparent solution.\",\n \"4.Measure the pH (Approximately 7.7 to 8.3).\",\n \"5.Weigh and add the Sodium Chloride to the solution.\",\n \"Stir for approximately 2 minutes.\",\n \"Verify complete dissolution by visual inspection of a clear transparent solution.\",\n \"6.Weigh and add the Hydroxy Ethyl Cellulose HX.\",\n \"7.Stir for approximately 2 hours.\",\n \"8.Remove the stirrer and add the solution to a 200 mL volumetric flask.\",\n \"9.Add water for injection up to 200 mL.\",\n \"10.Shake manually for approximately two minutes.\",\n \"11.Transfer into an appropriate container.\",\n \"TABLE 5 LAQ 0.1% Oral Formulation (1.0 mg/mL of LAQ) Material g/200 mL solution Laquinimod Sodium 0.2 (Equivalent to 0.2 g laquinimod acid) Autoclaved Tap Water Amount required to bring solution to 200 mL Table 5 Process: 1.The entire process is performed under yellow light or at dark conditions.\",\n \"2.Weigh 150 g (150 mL) of autoclaved tap water in a glass container containing a stirrer.\",\n \"3.Weigh and add Laquinimod Sodium to the solution.\",\n \"Rinse the remaining Laquinimod Sodium in the weighing boat with ˜5 mL of water and add to the solution.\",\n \"Stir for approximately 5 minutes and verify complete dissolution by visual inspection of a clear transparent solution.\",\n \"4.Add autoclaved tap water up to 200 mL.\",\n \"5.Stir for 5 minutes.\",\n \"6.Transfer into an appropriate amber Pre-Dose Administration and Selection of Animals: Clinical observations were performed daily according to Table 6 below: TABLE 6 Clinical Signs and Observations Observed Sign Involved System(s) Respiratory Dyspnea (abdominal breathing, CNS, pulmonary, cardiac gasping), apnea, cyanosis, tachypnea, nostril discharges Motor Activities Decrease/increase somnolence, CNS, somatomotor, sensory, loss of righting, anaesthesia, neuromuscular, autonomic catalepsy, ataxia, unusual locomotion, prostration, tremors, fasciculation Convulsion Clonic, tonic, tonic-clonic, CNS, neuromuscular, autonomic, asphyxial, opisthotonos respiratory Reflexes Corneal, righting, myotact, light, CNS, sensory, autonomic, startle reflex neuromuscular Ocular Signs Lacrimation, miosis, mydriasis, Autonomic, irritation exophthalmos, ptosis, opacity, iritis, conjunctivitis, chromodacryorrhea, relaxation of nictitating membrane Cardiovascular Signs Bradycardia, tachycardia, CNS, autonomic, cardiac, arrhythmia, vasodilation, pulmonary vasoconstriction Salivation Excessive Autonomic Piloerection Rough hair Autonomic Analgesia Decrease reaction CNS, sensory Muscle Tone Hypotonia, hypertonia Autonomic Gastrointestinal Soft stool, diarrhea, emesis, CNS, autonomic, sensory, GI diuresis, erythruria motility, kidney Skin Edema, erythema Tissue damage, irritation Animals were weighed weekly prior to initiation of dosing.\",\n \"The first day the rats are weighed was designated as Study Day 1, and the beginning of Study Week 1.Ophthalmic Examinations: Animals selected for the study were examined prior to the initial administration of the test or the control articles to ensure that both eyes were free of abnormality, damage, and disease.\",\n \"Both eyes were examined, scored and recorded prior to the initial dose administration using a hand held slit-lamp and a direct ophthalmoscope or the surgical microscope according to the Classification System for Grading Ocular Lesions as described in Table 7, and the Ocular Posterior Segment Scoring Scale of Table 8.Posterior segment examination was performed after topical application of Tropicamide in the conscious state, or after the rats are anesthetized with isoflorane inhalation.\",\n \"Only rats showing no signs of eye irritation, ocular defects, or preexisting corneal injury were used in the study.\",\n \"TABLE 7 Combined Draize and McDonald-Shadduck Scoring System CONJUNCTIVA A. REDNESS/CONGESTION 0 Vessels normal.\",\n \"May appear blanched to reddish pink without perilimbal injection (except at 12:00 and 6:00 o'clock positions) with vessels of the palpebral and bulbar conjunctivae easily observed.\",\n \"1 Vessels definitely injected above normal.\",\n \"A flushed, reddish color predominately confined to the palpebral conjunctivae with some perilimbal injection but primarily confined to the lower and upper parts of the eye from, the 4:00 and 7:00 and 11:00 to 1:00 o'clock positions.\",\n \"2*† More diffuse, deeper crimson red, individual vessels not easily discernible.\",\n \"Bright red color of the palpebral conjunctiva with accompanying perilimbar injection covering at least 75% of the circumference of the perilimbal region.\",\n \"3*† Diffuse beefy red.\",\n \"Dark beefy red color with congestion of both the bulbar and palpebral conjunctiva along with pronounced perilimbal injection and the presence of petechia on the conjunctiva.\",\n \"The B. CHEMOSIS: 0 Normal.\",\n \"No swelling of the conjunctival tissue.\",\n \"1 Any swelling above normal (includes nictitating membrane).\",\n \"Swelling above normal without eversion of the lids (can be easily ascertained by noting that the upper and lower eyelids are positioned as in the normal eye); swelling generally starts in the lower cul-de-sac near the inner canthus which needs slit-lamp examination.\",\n \"2*† Obvious swelling with partial eversion of lids.\",\n \"Swelling with misalignment of the normal approximation of the lower and upper eyelids; primarily confined to the upper eyelid so that in the initial stages the misapproximation of the eyelids begins by partial eversion of the upper eyelid.\",\n \"In this stage, swelling is confined generally to the upper eyelid, although it exists in the lower cul-de-sac.\",\n \"Swelling with lids about half closed.\",\n \"3*† Swelling definite with partial eversion of the upper and lower eyelids essentially equivalent.\",\n \"This can be easily ascertained by looking at the animal straight head on and noticing the positioning of the eyelids; if the eye margins do not meet, eversion has occurred.\",\n \"4*† Swelling with lids about half closed to completely closed.\",\n \"Eversion of the upper eyelid is pronounced with less pronounced eversion of the lower eyelid.\",\n \"It is difficult to retract the lids and observe the perilimbal region.\",\n \"C. DISCHARGE: 0 Normal or no discharge.\",\n \"1 Any amount different from normal (does not include small amounts observed in inner canthus of normal animals).\",\n \"Discharge above normal and present on the inner portion of the eye but not on the lids or hairs of the eyelids.\",\n \"One can ignore the small amount that is in the inner and outer canthus if it has not been removed prior to starting the study.\",\n \"2 Discharge with moistening of lids and hairs just adjacent to lids.\",\n \"Discharge is abundant, easily observed, and has collected on the lids around the hairs of the eyelids.\",\n \"3 Discharge with moistening of the lids and hairs, and considerable area around the eye.\",\n \"CORNEA D. OPACITY-degree of density (areas most dense taken for reading): 0 No ulceration or opacity.\",\n \"Normal cornea.\",\n \"Appears with the slit lamp as having a bright gray line on the endothelial surface and a bright gray line on the endothelial surface with a marble-like gray appearance of the stroma.\",\n \"1* Scattered or diffuse areas of opacity (other than slight dulling of normal luster), details of iris clearly visible.\",\n \"Some loss of transparency.\",\n \"Only the anterior one-half of the stroma is involved as observed with an optical section of the slit lamp.\",\n \"The underlying structures are clearly visible with diffuse illumination, although some cloudiness can be readily apparent with diffuse illumination.\",\n \"2*† Easily discernible translucent areas, details of iris slightly obscured.\",\n \"Moderate loss of transparency.\",\n \"In addition to involving the anterior stroma, the cloudiness extends all the way to the endothelium.\",\n \"The stroma has lost its marble-like appearance and is homogeneously white.\",\n \"With diffuse illumination, underlying structures are clearly visible.\",\n \"3*† Opalescent/nacreous areas, no details of iris visible, size of pupil barely discernible.\",\n \"Involvement of the entire thickness of the stroma.\",\n \"With optical section, the endothelial surface is still visible.\",\n \"However, with diffuse illumination the underlying structures are just barely visible (to the extent that the observer is still able to grade flare, iritis, observe for pupillary response, and note lenticular changes.\",\n \"4*† Opaque cornea, iris not discernible through opacity.\",\n \"Involvement of the entire thickness of the stroma.\",\n \"With the optical section, cannot clearly visualize the endothelium.\",\n \"With diffuse illumination, the underlying structures cannot be seen.\",\n \"Cloudiness removes the capability of judging and grading aqueous flare, iritis, lenticular changes, and pupillary response.\",\n \"E. AREAS OF CORNEA INVOLVED: 0 Normal cornea with no area of cloudiness.\",\n \"1 One-quarter (or less), but not zero.\",\n \"2 Greater than one-quarter, but less than one-half.\",\n \"3* Greater than one-half, but less than three-quarters.\",\n \"4* Greater than three-quarters, up to whole area.\",\n \"F. FLUORESCEIN STAINING: 0 Absence of fluorescein staining.\",\n \"1 Slight fluorescein staining confined to a small focus.\",\n \"With diffuse illumination the underlying structures are easily visible.\",\n \"The outline of the papillary margin is as if there were no fluorescein staining.\",\n \"2 Moderate fluorescein staining confined to a small focus.\",\n \"With diffuse illumination the underlying structures are clearly visible, although there is some loss of detail.\",\n \"3 Marked fluorescein staining.\",\n \"Staining may involve a larger portion of the cornea.\",\n \"With diffuse illumination the underlying structures are barely visible but are not completely obliterated.\",\n \"4 Extreme fluorescein staining.\",\n \"With diffuse illumination the underlying structures cannot be observed.\",\n \"G. CORNEA PANNUS: 0 No pannus 1 Vascularization is present but vessels have not invaded the entire corneal circumference.\",\n \"Where localized vessel invasion has occurred, they have not penetrated beyond 2 mm.\",\n \"2 Vessels have invaded 2 mm or more around the entire corneal circumference.\",\n \"IRIS 0 Normal iris without any hyperemia of the iris vessels.\",\n \"Occasionally around the 12:00 to 1:00 position near the pupillary border and the 6:00 and 7:00 position near the pupillary border there is a small area around 1-3 mm in diameter in which both the secondary and tertiary vessels are slightly hyperemic.\",\n \"1*† Folds above normal, congestion, swelling, circumcorneal injection (any or all of these or combination of any thereof), iris still reacting to light (sluggish reaction is positive).\",\n \"Minimal injection of secondary vessels but not tertiary.\",\n \"Generally, it is uniform, but may be of greater intensity at the 1:00 or 6:00 position, the tertiary vessels must be substantially hyperemic.\",\n \"2*† No reaction to light, hemorrhage, gross destruction (any or all of these).\",\n \"Minimal injection of tertiary vessels and minimal to moderate injection of the secondary vessels.\",\n \"3*† Moderate injection of the secondary and tertiary vessels with slight swelling of the iris stroma (this gives the iris surface a slightly rupose appearance which is usually most prominent near the 3:00 and 9:00 positions).\",\n \"4*† Marked injection of the secondary and tertiary vessels with marked swelling of the iris stroma.\",\n \"The iris appears rugose; may be accompanied by hemorrhage (hyperemia) in the anterior chamber.\",\n \"AQUEOUS FLARE 0 Absence of visible light beam in the anterior chamber (no Tyndall effect).\",\n \"1 Tyndall effect is barely discernible.\",\n \"The intensity of the light beam in the anterior chamber is less than the density of the slit beam as it passes through the lens.\",\n \"2 The Tyndall effect in the anterior chamber is easily discernible and is of equal intensity as the density of the slit beam as it passes through the lens.\",\n \"3 The Tyndall effect in the anterior chamber is easily discernible; its intensity is greater than the intensity of the slit beam as it passes through the lens.\",\n \"PUPILLARY LIGHT REFLEX: 0 Normal pupillary light reflex 1 Sluggish pupillary light reflex 2 No pupillary light reflex LENS 0 Normal 1 The presence of lenticular opacities should be described and the location noted as defined below: Anterior capsule Anterior subcapsule Anterior cortical Nuclear Posterior cortical Posterior subcapsule Posterior capsule *= Positive Reaction (ISO) †= Positive Reaction (OECD) TABLE 8 Ocular Posterior Segment Scoring Scale VITREOUS BODY 0 Normal, the vitreous body is clear or transparent.\",\n \"1 Abnormal, the vitreous body is not clear or not transparent and homogenous gel that fills the space between the posterior axial lens capsule, posterior chamber, and ocular fundus.\",\n \"OPTIC DISC/OPTIC NERVE 0 Normal, the optic disc and optic nerve are with light red color, cupping size normal (cup-to-disc ratio <0.2), and normal sharpness of edge, without swelling, hemorrhages, notching in the optic disc and any other unusual anomalies.\",\n \"1 Abnormal, the optic disc and optic nerve are not with light red color or cupping size normal (cup-to-disc ratio >0.2), and no normal sharpness of edge or with swelling, hemorrhages, notching in the optic disc and any other unusual anomalies.\",\n \"RETINAL BLOOD VASCULATURE 0 Normal, the retinal arteries and veins fill in blood and normalize sharpness without hemorrhage and exudation.\",\n \"1 Abnormal, the retinal arteries and veins don't fill in blood and don't have normalize sharpness or with hemorrhage and exudation.\",\n \"RETINAL HEMORHAGE, EXUDATION, AND DETACHMENT 0 Normal retina with no area of hemorrhage or/and exudation or/and detachment 1 Retinal hemorrhage or/and exudation or/and detachment ≤1 quadrant area 2 1 quadrant area < retinal hemorrhage or/and exudation or/and detachment ≤ 2 quadrant areas 3 2 quadrant areas < hemorrhage or/and exudation or/and detachment ≤ 3 quadrant areas 4 3 quadrant areas < retinal hemorrhage or/and exudation or/and detachment exudation ≤ 4 quadrant areas CHOROIDAL HEMORRHAGE, EXUDATION, AND DETACHMENT 0 Normal choroid with no area of choroidal and hemorrhage or/and exudation or/and detachment 1 Choroidal hemorrhage or/and exudation or/and detachment ≤1 quadrant area 2 quadrant area < Choroidal hemorrhage or/and exudation or/and detachment ≤ 2 quadrant areas 3 2 quadrant areas < Choroidal hemorrhage or/and exudation or/and detachment ≤ 3 quadrant areas 4 quadrant areas < Choroidal hemorrhage or/and exudation or/and detachment ≤ 4 quadrant area Intraocular Pressure (IOP) Measurements: Baseline IOP measurements were taken before the initial dose administration.\",\n \"After application of topical anesthesia (0.5% Proparacaine HCl Ophthalmic Solution), IOP was measured on conscious rats on both eyes using a Tono-Pen Vet tonometer (Reichert, Inc.; Depew, N.Y.).\",\n \"Ten (10) IOP readings are recorded from each eye and averaged.\",\n \"IOP measurements were taken around the same time (e.g., between 10 a.m. and 2 p.m.) across measurement time-points to minimize the circadian variability of IOP.\",\n \"Dose Administration: Rats were separated in 5 groups.\",\n \"Animals in each group receive one of the five following articles during the study: 1.Control vehicletopical 2.0.25% Laquinimod topical 3.1% Laquinimod topical 4.4% Laquinimod topical 5.0.1% Laquinimod oral Topical Dosing: Rats were dosed topically only on the surface of the left eye in which OHT was induced.\",\n \"No article was administered on the un-operated right eye which served as the control.\",\n \"The topical dose was administered on the surface of the left eye using a calibrated micro-pipette and a sterile tip.\",\n \"The volume for each topical dose was 10 μL.\",\n \"Rats were dosed twice daily, starting on the day of the first HSI until euthanasia.\",\n \"The first daily dose was administered approximately between 8 a.m. and 9 a.m.\",\n \"The second daily dose was administered approximately between 4 p.m. and 5 p.m. On the day of euthanasia, rats were dosed only once in the morning approximately between 8 a.m. and 9 a.m.\",\n \"Oral Dosing: Rats were dosed orally daily approximately between 8 a.m. and 10 a.m., starting on the day of the first HSI until euthanasia.\",\n \"The last day of dosing was the day of euthanasia.\",\n \"The volume for each oral dose was 1 mL.\",\n \"Post-Dose Procedures: Chronic ocular hypertension (OHT) was created through two hypertonic saline injections (HSI) which were performed one week apart in the left eye.\",\n \"For each HSI, after the rats were anesthetized with a suitable anesthetic, a suture thread was passed through the left eyelid to fix it open.\",\n \"A local anesthetic (e.g., 0.5% Proparacaine HCl Ophthalmic Solution) was applied on the surgery eye topically.\",\n \"The conjunctiva was incised with Vannas scissors to expose an episcleral vein.\",\n \"An occluder ring with a groove was fitted around the left eye to provide unobstructed passage for the selected episcleral vein while obstructing the other episcleral veins.\",\n \"Using a pulled-glass needle, 50-250 μL of 1.8M hypertonic saline solution was injected into the exposed episcleral vein to scar the aqueous humor outflow pathway in an attempt to elevate IOP.\",\n \"The ring was removed shortly after the injection.\",\n \"The un-operated right eye served as the control.\",\n \"Ophthalmic ointment was applied to both eyes to prevent corneal damage.\",\n \"For each HSI procedure, buprenorphine was administered subcutaneously for approximately 24 hours to manage post-operative pains as appropriate.\",\n \"Clinical observations was performed at least once daily as described in Table 6.Moribund and Dead Animals: Animals were observed once daily for moribundity/mortality as part of the clinical observations.\",\n \"There were no moribound animals.\",\n \"Measurements and Criterion: IOP measurements were taken once weekly starting one week after the second HSI until euthanasia (a total of 5 measurements).\",\n \"After application of topical anesthesia (0.5% Proparacaine HCl Ophthalmic Solution), IOP was measured on conscious rats on both eyes using a Tono-Pen Vet tonometer (Reichert, Inc.; Depew, N.Y.).\",\n \"For each time-point, ten (10) IOP readings were recorded from each eye and averaged.\",\n \"IOP measurements were taken around the same time (e.g., between 10 a.m. and 2 p.m.) across measurement time-points to minimize the circadian variability of IOP.\",\n \"The IOP measurements were evaluated as follows: For each time-point following the HSI, the IOP elevation was calculated as the difference between the level in the left eye with OHT and that in the normal right eye (ΔIOP).\",\n \"The ΔIOP of the 5-weekly post-HSI IOP measurements were averaged and constitute the Mean ΔIOP for each animal.\",\n \"For each group, ten (10) animals with a sustained IOP elevation in the OHT eye were selected from a larger pool and groups are matched for the Mean ΔIOP.\",\n \"Other animals were removed from the study and euthanized.\",\n \"Data was analyzed and reported for rats which did not have individual IOP measurements of 50 mmHg in the OHT eyes.\",\n \"Ophthalmic Examinations: Both eyes were examined and scored at one week after the second HSI and on the day of euthanasia, for a total of two times.\",\n \"Ophthalmic examinations were performed according to the Classification System for Grading Ocular Lesions as described in Table 7, and the Ocular Posterior Segment Scoring Scale of Table 8 using a hand-held slit-lamp and a direct ophthalmoscope or the surgical microscope.\",\n \"Posterior segment examination was performed after the topical application of Tropicamide in the conscious state, or after the rats are anesthetized with isoflorane inhalation.\",\n \"Fluoro-Gold (FG) Back-Labeling of Retinal Ganglion Cells (RGC): Approximately one week prior to euthanasia, RGC was labeled with the retrograde tracer FG.\",\n \"First, animals were sedated with appropriate anesthesia.\",\n \"Using a stereotaxic device, RGC was back-labeled with an injection of 2.5 μL of 4% FG into the superior colliculus in each hemisphere.\",\n \"Rats received subcutaneous injections of buprenorphine for approximately 48 hours to manage post-surgery pain as appropriate.\",\n \"Animals were euthanized by CO2 inhalation 5-weeks after the 2′d HSI.\",\n \"Extraction and Processing of the Eyes and the Optic Nerves (ON): The eyes were immediately enucleated with the optic nerve attached.\",\n \"An approximately 2.0 mm piece of the ON proximal to the globe is separated and labeled with tissue mark to indicate the orientation of the nerve.\",\n \"The ON piece is placed in Modified Karnovsky's Fixative in 0.1M Na cacodylate buffer and kept at 4±2° C. overnight.\",\n \"The next day ON piece was washed at least three times for at least 10 minutes each in 0.1M Na cacodylate buffer and stored in 0.1M Na cacodylate buffer at 4±2° C. After specimens were transferred to a contracted processing facility, within a week, the optic nerves were processed for plastic embedding: After post-fixation in 2% osmium tetroxide in 0.1M Na cacodylate buffer for at least 1.5 hours, ONs were dehydrated in graded ethanols, transitioned in propylene oxide and infiltrated with propylene oxide and epon mixtures.\",\n \"One to five (1-5) μm-thick cross-sections were taken via a microtome at the ON end approximately 2.0 mm away from the globe.\",\n \"ON sections were stained with 1% toluidine blue and cover-slipped.\",\n \"The processed specimens were returned.\",\n \"The identification of the ONs were masked prior to injury analysis.\",\n \"The ON cross-sections were analyzed for injury by light microscopy as follows: The damaging effect of the sustained IOP elevation was assessed by qualitative microscopic analysis of the ON cross-sections using a well-established grading system described in Table 9.This method allowed damage analysis of the entire retinal ganglion cell output (the ON) in one section by light microscopy and was more sensitive than counting total axons especially if there is mild nerve damage.\",\n \"Sustained IOP elevation resulted in degenerating, swollen axons and collapsed myelin sheaths in the optic nerve.\",\n \"The extent of injury was then graded by light microscopy based on a pattern of damage observed in rats with elevated IOP.\",\n \"TABLE 9 Grading Scale for Optic Nerve Injury Grade 1 (Normal) Normal optic nerve with healthy axons.\",\n \"Grade 2 (FOCAL INJURY) Degenerating axons with myelin debris are stained densely and appear focally.\",\n \"Some axonal swellings are present.\",\n \"Grade 3 (INJURY SPREADING AWAY Several degenerating axons with myelin debris and axonal FROM FOCAL) swellings spread away from the focal area.\",\n \"Normal axons still predominate.\",\n \"Grade 4 (WIDE-SPREAD INJURY; Several degenerating axons with myelin debris and axonal EQUIVALENT NUMBER of swellings are present throughout the nerve.\",\n \"There are DEGENERATING and NORMAL AXONS) approximately equal numbers of normal and abnormal axons.\",\n \"Grade 5 (WIDE-SPREAD INJURY; Degenerating axons with myelin debris and swollen axons DEGENERATING AXONS LARGELY largely dominate the optic nerve, with gliosis in severe DOMINATE) cases.\",\n \"The eyes were fixed in 4% paraformaldehyde (PFA) fixative at 4±2° C. for at least 24 hours.\",\n \"Retinas were dissected and flat whole-mounted for confocal visualization and imaging.\",\n \"The actual identification of the retinal flat-mounts was masked prior to confocal imaging.\",\n \"Eight regions per retina were imaged using a confocal microscope and the RGC in each region were counted as follows: Retinal images were evaluated by confocal fluorescence microscopic examination.\",\n \"A three-dimensional view of the x-axis, y-axis, and z-axis were designed and processed using a specific system of image analysis software (Leica Confocal Software) to obtain an image of the viable RGCs labeled with FG.\",\n \"Two areas which were approximately 1.5 mm and 2.75 mm away from the center of the ON head were selected in each retinal quadrant (8 regions per retina) and serial images of the retinal ganglion cell layer were taken by the Confocal Microscope.\",\n \"A two-dimensional maximum projection image of the serial images was used to count the viable RGCs using an image analysis software.\",\n \"The number of viable RGCs per image was expressed in mm2.Evaluation Criteria The results of the study were considered in terms of the in-life observations and any microscopic observations.\",\n \"IOP Criterion: For each time-point following the HSI, the IOP elevation was calculated as the difference between the level in the left eye with OHT and that in the normal right eye (ΔIOP).\",\n \"The ΔIOP of the 5-weekly post-HSI IOP measurements were averaged and constitute the Mean ΔIOP for each animal.\",\n \"For each group, ten (10) animals with a sustained IOP elevation in the OHT eye were selected from a larger pool and groups were matched for the Mean ΔIOP.\",\n \"Other animals were removed from the study and euthanized.\",\n \"Data was analyzed and reported for rats which do not have individual IOP measurements of ≥50 mmHg in the OHT eyes.\",\n \"Imaging of the Retinas by Confocal Microscopy: Retinal images were evaluated by confocal fluorescence microscopic examination.\",\n \"A three-dimensional view of the x-axis, y-axis, and z-axis were designed and processed using a specific system of image analysis software (Leica Confocal Software) to obtain an image of the viable RGCs labeled with FG.\",\n \"Two areas which were approximately 1.5 mm and 2.75 mm away from the center of the ON head were selected in each retinal quadrant (8 regions per retina) and serial images of the retinal ganglion cell layer are taken by the Confocal Microscope.\",\n \"A two-dimensional maximum projection image of the serial images was used to count the viable RGCs using an image analysis software.\",\n \"The number of viable RGCs per image was expressed in mm2.Percent RGC loss in the OHT retinas was calculated in comparison to the RGC counts in the Non-OHT retina of the same animal using the following formula: (100−(100×OHT/Non-OHT Mean RGC Counts per Retina)).\",\n \"The RGC counts in each Non-OHT retina were considered 100% for that animal.\",\n \"The damaging effect of the sustained IOP elevation was assessed by qualitative microscopic analysis of the ON cross-sections using a well-established grading system described in Table 9.This method allowed damage analysis of the entire retinal ganglion cell output (the ON) in one section by light microscopy and was more sensitive than counting total axons especially if there is mild nerve damage.\",\n \"Sustained IOP elevation resulted in degenerating, swollen axons and collapsed myelin sheaths in the optic nerve.\",\n \"The extent of injury was then graded by light microscopy based on a pattern of damage observed in rats with elevated IOP.\",\n \"Data Analysis: Initially One-Way ANOVA was used to address statistically significant differences among groups.\",\n \"If there was a statistical significance, data of the test groups was further compared with the data of the control group using Dunnett's multiple comparison tests.\",\n \"Two-Way ANOVA, paired-t-tests, % neuroprotection calculations were also performed.\",\n \"Any differences between control and test animals was considered statistically significant only if the probability of the differences being due to chance is equal to or less than 5% (p≤0.05; two-tailed).\",\n \"Statistical analysis is performed using Minitab, Minitab Inc, State College, Pa. Any significant difference is further assessed for biological relevance by comparison to the literature and historical data.\",\n \"Results TABLE 10 % RGC Loss (100 − (100 × OHT/Non-OHT Mean RGC Counts per Retina)) Route/ Laquinimod Mean % RGC Group Percentage Loss SD % RGC Loss 1 Topical/1% 17.6 33.8 2 Topical/ 34.8 42.7 Vehicle 3 Topical/4% 26.8 36.4 4 Topical/0.25% 21.6 21.7 5 Oral/0.1% 22.9 33.1 RGC = Retinal Ganglion Cell OHT = Ocular Hypertension SD = Standard Deviation 1.Per protocol, data were analyzed and reported for forty (40) rats which did not have individual IOP measurements of 50 mmHg in the OHT eyes.\",\n \"2.Body Weights: The range of the baseline body weights of the 40 rats from Groups 1-5 was 258.6-351.3 grams at the start of the study.\",\n \"On the day of dosing and the first HSI, body weight range of all rats was 271.2-366.4 grams.\",\n \"A One-Way ANOVA indicated that the group body weights were not statistically different on the day of dosing (P=0.957).\",\n \"Rats weighed 271.4-349.3 grams on the day of euthanasia.\",\n \"Groups did not differ in the amount of weight gained between the day of dosing and the day of euthanasia (One-Way ANOVA; P=0.559).\",\n \"3.Clinical Observations: There were no abnormal clinical observations in the beginning of the study at the time of animal assignment.\",\n \"Following the HSI surgeries, swelling of the surgery eye, swelling of the conjunctiva and scleral/corneal discoloration in the surgery eye were observed in all groups.\",\n \"Following the Fluoro-Gold brain injection surgeries, hair loss and skin wounds were noted in all groups due to the hair on the skull being shaved prior to surgery and the skin on the skull being incised and sutured after surgery.\",\n \"These observations were expected and related with the glaucoma model creation (HSI) and the Fluoro-gold brain injection surgeries.\",\n \"Abnormal clinical observations which were not related with the HSI and FG injection surgeries were hair loss in an animal from Group 2 and in an animal from Group 5, and skin wound in 2 animals from Group 5.Since Group 2 was the vehicle control group, these abnormalities were incidental and not test-article related.\",\n \"4.IOP Measurements (mmHg): None of the animals included in the study had individual IOP measurements of ≥50 mmHg in the OHT eyes.\",\n \"The Mean ΔIOP (OHT−Non-OHT) (Mean±SD) was 9.1±2.2 mmHg, 9.1±2.6 mmHg, 9.3±2.7 mmHg, 9.2±1.5 mmHg, and 9.1±2.9 mmHg for Groups 1, 2, 3, 4 and 5, respectively.\",\n \"A One-Way ANOVA analysis indicated that the groups were well-matched for Mean ΔIOP (P>0.9) (FIG.\",\n \"1).\",\n \"Representative images of the retinas with FG-labeled RGC are shown in FIGS.\",\n \"5A-5J.\",\n \"% FG-Labeled RGC loss in the OHT retinas compared with the corresponding non-OHT retinas is shown in Table 10.Compared to the non-OHT retinas, % RGC Loss (Mean±SD) in the OHT retinas was 17.6±33.8, 34.8±42.7, 26.8±36.4, 21.6±21.7, and 22.9±33.1 for Groups 1, 2, 3, 4 and 5, respectively (FIG.\",\n \"2).\",\n \"5.FG-labeled RGC counts: A Two-Way ANOVA on the RGC counts in the OHT and Non-OHT (control) eyes versus groups did not show a significant eye versus group interaction (P=0.919), indicating that groups did not differ for the RGC counts in the OHT and Non-OHT eyes (FIG.\",\n \"3).\",\n \"As a secondary analysis, FG-Labeled RGC counts per mm2 were compared between the Non-OHT and the OHT retinas for each group using a paired-t test (two-tailed).\",\n \"Group 2 (vehicle topical; P=0.047) and Group 4 (0.25% Laquinimod topical; P=0.033) had fewer RGCs in the OHT eye compared to the Non-OHT eyes.\",\n \"The number of RGCs in Group 3 (4% Laquinimod topical; P=0.071) and Group 5 (0.1% Laquinimod oral; P=0.075) were statistically marginally different between the OHT and Non-OHT eyes.\",\n \"However, in Group (1% Laquinimod topical), there was no statistically significant difference in the RGC counts between the OHT and Non-OHT eyes (P=0.189).\",\n \"This suggests that the daily topical application of 1% Laquinimod may be neuroprotective for the RGC.\",\n \"6.Optic Nerve (ON) Injury Grades: Mean ON Injury Grades (Mean±SD) for the Non-OHT eyes were 1.1±0.1, 1.2±0.2, 1.2±0.2, 1.2±0.3 and 1.2±0.2 for Groups 1, 2, 3, 4 and 5, respectively.\",\n \"Mean Injury Grades (Mean±SD) for the OHT optic nerves were 2.5±1.3, 3.0±1.6, 3.0±1.5, 2.8±1.3 and 2.7±1.5 for Groups 1, 2, 3, 4, and 5, respectively.\",\n \"A Two-Way ANOVA on the Mean ON injury grades in the OHT and Non-OHT (control) eyes versus groups did not show a significant eye versus group interaction (P=0.98), indicating that groups did not differ for the injury in the OHT and Non-OHT optic nerves (FIG.\",\n \"4).\",\n \"As a secondary analysis, Mean ON Injury Grades were compared between the Non-OHT and the OHT optic nerves for each group using two-tailed paired-t tests.\",\n \"The Mean ON injury grades were significantly greater in the OHT eyes compared to the Non-OHT control eyes in all groups (P<0.05).\",\n \"7.Ophthalmic Examinations (OEs): At baseline ocular examinations prior to initial dose, there were no ocular abnormalities observed in either eye in any of the animals included in the study.\",\n \"During the post-dose OEs, there were no ocular problems observed in any of the animals in the Non-OHT eyes.\",\n \"However, there were some ocular abnormalities observed in the OHT eyes due to the glaucoma-model creation procedures (hypertonic saline injection surgeries into the episcleral veins) in all groups.\",\n \"These abnormalities included minor congestion and chemosis (swelling) in the conjunctiva, minor corneal opacities, lack of sufficient dilation of the pupil after application of the pupil-dilating agent Tropicamide, slight opacities in the lens and presence of free-floating iris pigments in front of the lens in the OHT eyes.\",\n \"The post-HSI ocular findings in the OHT eyes were observed in all groups with a similar occurrence and were not test articlerelated.\",\n \"CONCLUSION The study involved daily dosing of five groups for approximately six weeks: Group 1 (1% Laquinimod topical), Group 2 (Vehicle topical), Group 3 (4% Laquinimod topical), Group 4 (0.25% Laquinimod topical) and Group 5 (0.1% Laquinimod oral).\",\n \"The analyses for the RGC counts in Group 1 animals suggested a trend towards neuroprotection following daily topical application of 1% Laquinimod.\",\n \"Example 2: Assessment of Efficacy of Laquinimod for Treating Patients Afflicted with Glaucoma Periodic (e.g., daily or twice daily) administration of laquinimod (oral or topical) is effective in treating glaucoma human patients.\",\n \"Periodic (e.g., daily or twice daily) administration of laquinimod (oral or topical) is effective to reduce a glaucoma-associated symptom in the subject.\",\n \"A laquinimod composition as described herein is administered systematically or locally to the eye of a subject suffering from glaucoma.\",\n \"The administration of the composition is effective to treat the subject suffering from glaucoma.\",\n \"The administration of the composition is also effective to reduce a glaucoma-associated symptom of glaucoma in the subject.\",\n \"The administration of the composition is also effective to reduce intraocular pressure in the subject.\",\n \"The administration of the composition is effective to reduce RGC damage and/or RGC loss, and improve RGC viability in the subject.\",\n \"REFERENCES 1.“Glaucoma”, Merck Manual of Diagnosis and Therapy (1999), Merck Research Laboratories, (Whitehouse Station, N.J.), 733-738.2.Alward, “Medical Management of Glaucoma”, N Eng J Med, 1998; 339:1298-1307).\",\n \"3.Bakalash et al., “Resistance of Retinal Ganglion Cells to an Increase in Intraocular Pressure is Immune-dependent”, Invest Ophthalmol Vis Sci 2002; 43:2648-2653.4.Brod et al.\",\n \"(2000) Annals of Neurology, 47:127-131.5.Brück et al., (2011) “Insight into the mechanism of laquinimod action”, J. Neurol Sci.\",\n \"306:173-179.6.Cepurna et al.\",\n \"(2000) “Patterns of Intraocular Pressure Elevation After Aqueous Humor Outflow Obstruction in Rats.” Invest Ophthalmol Vis Sci.\",\n \"41(6) (May 2000):1380-5.7.Coleman “Glaucoma”, Lancet, 1999; 354:1803-1810.8.Draize, J. H. (1965) “Appraisal of the Safety of Chemicals in Foods, Drugs, and Cosmetics.” Association of Food and Drug Officials of the United States, Austin, Tex., 1965.36-45.9.Farkas et al., “Apoptosis, Neuroprotection and Retinal Ganglion Cell Death: An Overview”, Int Ophthalmol Clin 2001; 41:111-130.10.Freireich et al.\",\n \"(1966) “Quantitative comparison to toxicity of anticancer agents in mouse, rat, hamster, dog, monkey and man.” Cancer Chemother Rep, 50:219-244.11.Guidance for Industry.\",\n \"In vivo drug metabolism/drug interaction studies—study design, data analysis, and recommendations for dosing and labeling, U.S. Dept.\",\n \"Health and Human Svcs., FDA, Ctr.\",\n \"for Drug Eval.\",\n \"and Res., Ctr.\",\n \"For Biologics Eval.\",\n \"and Res., Clin./Pharm., November 1999 <http://www.fda.gov/cber/gdlns/metabol.pdf>.\",\n \"12.Gurevich et al.\",\n \"(2010) “Laquinimod suppress antigen presentation in relapsing-remitting multiple sclerosis: invitro high-throughput gene expression study.” J Neuroimmunol.\",\n \"2010 Apr.\",\n \"15; 221(1-2):87-94.Epub 2010 Mar.\",\n \"27.13.Hla et al.\",\n \"(2001) “Lysophospholipids—receptor revelations.” Science, 294(5548):1875-8.14.Horga and Montalban Jun.\",\n \"4, 2008; Expert Rev Neurother., 2008; 8(5):699-714.15.ISO/IEC 17025, 2005.General Requirements for the Competence of Testing and Calibration Laboratories.\",\n \"16.Kipnis et al., “T Cell Immunity To Copolymer 1 Confers Neuroprotection On The Damaged Optic Nerve: Possible Therapy For Optic Neuropathies”, Proc Natl Acad Sci 2000; 97:7446-7451.17.Kleinschmidt-DeMasters et al.\",\n \"(2005) New England Journal of Medicine, 353:369-379.18.Langer-Gould et al.\",\n \"(2005) New England Journal of Medicine, 353:369-379.19.McDonald, and Shadduck (1983).\",\n \"Eye Irritation in Dermatotoxicology (2nd Ed.).\",\n \"Edited by Marzulli F. N. Hemishpere Publishing Corp., New York, N.Y. 20.Medeiros et al., “Medical Backgrounders: Glaucoma”, Drugs of Today 2002; 38:563-570.21.National MS Society Website, retrieved Jul.\",\n \"10, 2012<http://www.nationalmssociety.org/ms-clinical-care-network/researchers/clinical-study-measures/index.aspx> 22.OECD 405, Organization for Economic Co-Operation and Development (OECD), Guidelines for the Testing of Chemicals, “Acute Eye Irritation/Corrosion”, adopted 24 Apr.\",\n \"2002.23.Ollivier F. J., et al.\",\n \"(2007) “Ophthalmic Examination and Diagnostics Part 1: The Eye Examination and Diagnostic Procedure” in Veterinary Ophthalmology, 4th Ed.\",\n \"by Gelatt, K. N. 2007, 438-483.Blackwell Publishing, Gainesville, Fla. 24.PCT International Application Publication No.\",\n \"WO 2007/0047863, published Apr.\",\n \"26, 2007.25.PCT International Application Publication No.\",\n \"WO 2007/0146248, published Dec. 21, 2007.26.Polman et al.\",\n \"(2005) “Treatment with laquinimod reduces development of active MRI lesions in relapsing MS.” Neurology.\",\n \"64:987-991.27.Polman et al.\",\n \"(2011) “Diagnostic Criteria for Multiple Sclerosis: 2010 Revisions to the McDonald Criteria.” Ann Neural, 69:292-302.28.Polman et al., (2005) “Diagnostic criteria for multiple sclerosis: 2005 revisions to the McDonald Criteria.” Annals of Neurology, 58(6):840-846.29.Rudick et al.\",\n \"(1999) “Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS: Multiple Sclerosis Collaborative Research Group”.\",\n \"Neurology.\",\n \"53:1698-1704.30.Runström et al.\",\n \"(2002) “Laquinimod (ABR-215062) a candidate drug for treatment of Multiple Sclerosis inhibits the development of experimental autoimmune encephalomyelitis in IFN-β knock-out mice,” (Abstract), Medicon Valley Academy, Malmoe, Sweden.\",\n \"31.Sandberg-Wollheim et al.\",\n \"(2005) “48-week open safety study with high-dose oral laquinimod in patients.” Mult Scler.\",\n \"11:S154 (Abstract).\",\n \"32.U.S.\",\n \"Pat.\",\n \"No.\",\n \"6,077,851, issued Jun.\",\n \"20, 2000 (Bjork et al).\",\n \"33.U.S.\",\n \"Pat.\",\n \"No.\",\n \"7,589,208, issued Sep. 15, 2009 (Jansson et al).\",\n \"34.Vollmer et al.\",\n \"(2008) “Glatiramer acetate after induction therapy with mitoxantrone in relapsing multiple sclerosis.” Multiple Sclerosis, 00:1-8.35.Weinreb et al., “Is Neuroprotection a Viable Therapy for Glaucoma?” Arch Ophthalmol 1999; 117:1540-1544.36.Yang et al.\",\n \"(2004) “Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-β in Lewis rats.” J. Neuroimmunol.\",\n \"156:3-9.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875833"}}},{"rowIdx":4494992,"cells":{"text":{"kind":"list like","value":[["STOCKING LEVEL INDICATION APPARATUS AND METHOD","In some embodiments, systems, apparatuses, and methods are described herein including a shelf assembly that utilizes the accumulated weight of products stocked thereon to compress a compression member disposed within the assembly.","An electronic imaging device can be mounted proximate to the assembly and can be oriented to capture an image of the compression member to determine whether a particular shelf needs to be restocked and avoid having to manipulate or remove products from a shelf to determine a current stock level."],["1.A stock level indication assembly for a retail product storage structure, the stock level indication assembly comprising: upper and lower shelf members; a compression member disposed between the upper and lower shelf members, the compression member configured to visibly compress in response to one or more products being stocked on the upper shelf member to provide a visual indication of the number of products stocked on the upper shelf member; an electronic device proximate the upper and lower shelf members oriented and configured to detect a compression level of the compression member.","2.The stock level indication assembly of claim 1, further comprising a control circuit operably coupled to the electronic device and configured to receive a signal including the compression level of the compression member therefrom, the control circuit configured to estimate a number of the products on the shelf based at least on the signal.","3.The stock level indication assembly of claim 2, wherein the control circuit is configured to estimate the number of the products on the shelf by estimating a compression distance indicated in the signal, estimating a weight of total products on the shelf based on the estimated compression distance, accessing product location information, and estimating a number of the products on the shelf based on the product location information and the estimated weight.","4.The stock level indication assembly of claim 2, wherein the control circuit is further configured to send a low stock signal in response to a determination that the number of the products estimated to be on the shelf is at or below a predetermined number.","5.The stock level indication assembly of claim 2, wherein the compression level of the compression member includes a laterally angled compression of the compression member, and wherein the control circuit is further configured to determine a lateral distribution of products on the upper shelf member based on the laterally angled compression of the compression member.","6.The stock level indication assembly of claim 1, wherein the electronic device is mounted to a mobile assembly.","7.The stock level indication assembly of claim 1, wherein the upper and lower shelf members include front edges and the compression member is disposed between upper and lower shelf members so that a front edge thereof is recessed with respect to the front edges of the upper and lower shelf members such that bulging of the compression member after stocking does not extend past the front edges of the upper and lower shelf members.","8.The stock level indication assembly of claim 1, wherein the compression member is adhered to the upper and lower shelf members along upper and lower surfaces thereof.","9.The stock level indication assembly of claim 1, wherein the compression member has a different color or surface pattern than the upper and lower shelf members.","10.The stock level indication assembly of claim 1, wherein the upper and lower shelf members have a generally rectangular footprint with front edges and the compression member has a generally triangular footprint, the compression member being disposed between the upper and lower shelf members with an edge thereof running adjacent to the front edges of the upper and lower members.","11.The stock level indication assembly of claim 10, wherein the upper and lower shelf members are pivotably connected along rear edges thereof.","12.A method for providing a visual indication of stock level on a retail product storage structure, the method comprising: providing a shelf assembly including upper and lower shelf members and a compression member disposed therebetween, the compression member configured to visibly compress in response to one or more products being stocked on the upper shelf member to provide a visual indication of the number of products stocked on the upper shelf member; receiving the one or more products on the shelf assembly; compressing the compression member in response to the one or more products being received on the upper shelf member of the shelf assembly; detecting a compression level of the compression member via an electronic device disposed proximate the shelf assembly.","13.The method of claim 12, further comprising: receiving, at a control circuit, a signal including the compression level of the compression member transmitted from the electronic device; and estimating a number of the products on the shelf assembly based at least on the signal.","14.The method of claim 12, wherein estimating the number of products on the shelf assembly comprises: estimating a compression distance indicated in the signal; estimating a weight of the products based on the estimated compression distance; accessing product location information; and estimating a number of the products on the shelf assembly with the control circuit based on the product location information and the estimated weight.","15.The method of claim 14, further comprising sending a low stock signal with the control circuit in response to determining that the number of the products estimated to be on the shelf assembly is at or below a predetermined number.","16.A method for installing a stock level indication assembly for a retail product storage structure, the method comprising: mounting a lower shelf member to a shelf assembly; disposing a compression member on the lower shelf member; disposing an upper shelf member on the compression member; stocking one or more products on the upper shelf member such that the weight of the products compresses the compression member; and providing an electronic device proximate the shelf assembly in an orientation to detect a compression level of the compression member, the compression level of the compression member being indicative of a number of products stocked on the upper shelf member.","17.The method of claim 16, wherein disposing the compression member on the lower shelf member comprises disposing the compression member on the lower shelf member such that a front edge of the compression member is recessed from a front edge of the lower shelf member; and disposing the upper shelf member on the compression member comprises disposing the upper shelf member on the compression member such that the front edge of the compression member is recessed from a front edge of the upper shelf member.","18.The method of claim 16, further comprising adhering the compression member to the upper and lower shelf members.","19.The method of claim 16, further comprising pivotably coupling the upper and lower shelf members along at least a portion of rear edges thereof.","20.The method of claim 16, further comprising installing a scale on the shelf assembly."],["<SOH> BACKGROUND <EOH>Retail stores often utilize modular shelving units to display products for sale.","It can be important to maintain an accurate count of inventory during operation of the store.","Pursuant to this, associates often have to count products on the shelves.","It can be difficult for associates to accurately determine a count of products on the shelves and, as such, one method to ensure an accurate count to remove all of the products from the shelves.","Unfortunately, the associates must then restock the products on the shelves."],["<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>Disclosed herein are embodiments of systems, apparatuses and methods pertaining to a shelving assembly that provides an indication of a stocking level of products on the shelving assembly.","This description includes drawings, wherein: FIG.","1 is a schematic perspective view of a shelving unit having a stocking level assembly mounted thereto and an electronic imaging device oriented at the stocking level assembly in accordance with some embodiments.","FIG.","2 is a side elevation view of the stocking level assembly of FIG.","1 in an uncompressed configuration in accordance with several embodiments.","FIG.","3 is a side elevation view of the stocking level assembly of FIG.","1 in a compressed configuration in accordance with some embodiments.","FIG.","4 is an exploded perspective view of a stocking level assembly having a triangular compression member in accordance with several embodiments.","FIG.","5 is a flowchart in accordance with some embodiments.","FIG.","6 is a flowchart in accordance with several embodiments.","detailed-description description=\"Detailed Description\" end=\"lead\"?","Elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale.","For example, the dimensions and/or relative positioning of some of the elements in the figures may be exaggerated relative to other elements to help to improve understanding of various embodiments of the present invention.","Also, common but well-understood elements that are useful or necessary in a commercially feasible embodiment are often not depicted in order to facilitate a less obstructed view of these various embodiments of the present invention.","Certain actions and/or steps may be described or depicted in a particular order of occurrence while those skilled in the art will understand that such specificity with respect to sequence is not actually required.","The terms and expressions used herein have the ordinary technical meaning as is accorded to such terms and expressions by persons skilled in the technical field as set forth above except where different specific meanings have otherwise been set forth herein."],["CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser.","No.","15/585,246, filed May 3, 2017, which claims the benefit of U.S.","Provisional Application No.","62/332,270, filed May 5, 2016, which are hereby incorporated by reference herein in their entireties.","TECHNICAL FIELD This invention relates generally to retail shelving and, more particularly, to stocking level indicating shelving assemblies.","BACKGROUND Retail stores often utilize modular shelving units to display products for sale.","It can be important to maintain an accurate count of inventory during operation of the store.","Pursuant to this, associates often have to count products on the shelves.","It can be difficult for associates to accurately determine a count of products on the shelves and, as such, one method to ensure an accurate count to remove all of the products from the shelves.","Unfortunately, the associates must then restock the products on the shelves.","BRIEF DESCRIPTION OF THE DRAWINGS Disclosed herein are embodiments of systems, apparatuses and methods pertaining to a shelving assembly that provides an indication of a stocking level of products on the shelving assembly.","This description includes drawings, wherein: FIG.","1 is a schematic perspective view of a shelving unit having a stocking level assembly mounted thereto and an electronic imaging device oriented at the stocking level assembly in accordance with some embodiments.","FIG.","2 is a side elevation view of the stocking level assembly of FIG.","1 in an uncompressed configuration in accordance with several embodiments.","FIG.","3 is a side elevation view of the stocking level assembly of FIG.","1 in a compressed configuration in accordance with some embodiments.","FIG.","4 is an exploded perspective view of a stocking level assembly having a triangular compression member in accordance with several embodiments.","FIG.","5 is a flowchart in accordance with some embodiments.","FIG.","6 is a flowchart in accordance with several embodiments.","Elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale.","For example, the dimensions and/or relative positioning of some of the elements in the figures may be exaggerated relative to other elements to help to improve understanding of various embodiments of the present invention.","Also, common but well-understood elements that are useful or necessary in a commercially feasible embodiment are often not depicted in order to facilitate a less obstructed view of these various embodiments of the present invention.","Certain actions and/or steps may be described or depicted in a particular order of occurrence while those skilled in the art will understand that such specificity with respect to sequence is not actually required.","The terms and expressions used herein have the ordinary technical meaning as is accorded to such terms and expressions by persons skilled in the technical field as set forth above except where different specific meanings have otherwise been set forth herein.","DETAILED DESCRIPTION Generally speaking, pursuant to various embodiments, systems, apparatuses and methods are provided herein useful to provide a visual indication of a level or number of products stocked on a shelf of a shelving unit.","The visual indication is provided by virtue of an accumulated weight of products causing a visual compression of a compression member according to the weight.","More specifically, a shelf assembly is described herein that utilizes the accumulated weight of products stocked thereon to compress a compression member disposed within the assembly.","An electronic imaging device can be mounted proximate to the assembly and can be oriented to capture an image of the compression member to determine whether a particular shelf needs to be restocked.","Accordingly, the assembly and electronic imaging device described herein advantageously avoids having to manipulate or remove products from a shelf to determine a current stock level and helps a retail location avoid being out of product on the shelf By some approaches, a control circuit can be configured to receive the image from the electronic imaging device and analyze the image to determine a current stock level.","For example, the control circuit can be configured to associate a compression level of the compression member to a weight of the products on the assembly.","Utilizing the approximate weight and the type of product stocked on the shelf, an approximate number of products on the shelf can be extrapolated.","An example shelving unit 10 is shown in FIG.","1.Based on a particular use, multiple shelving units 10 can be aligned in a row to produce an aisle in a retail location.","The shelving unit 10 includes a base portion 12 and a back wall 14 extending upwardly therefrom.","The base portion 12 can include a base deck 16 and a kick plate 18, as commonly configured.","A plurality of shelf notches 20 are vertically disposed adjacent to lateral edges 22 of the back wall 14 to provide anchor points for shelves 24 mounted to the shelving unit 10.After the shelving unit 10 is assembled, associates can then stock products 26 on the shelves 24.If desired, as shown in FIGS.","1-3, one or more of the shelves 24 can include a stocking level indication assembly 50.The assembly 50 can be a shelf 24 configured to mount to the back wall 14 of the shelving unit 10 or can be an insert for a shelf 24 or disposed thereon.","As shown, the assembly 50 includes rigid lower and upper shelf portions or members 52, 54 with a compression portion or member 56 disposed therebetween.","The compression member 56 can be secured in the assembly, and to the shelf members 52, 54 thereof, by any suitable method, including adhesive, hardware, interlocking components, or the like.","For example, the compression member 56 can be adhered to the upper and lower surfaces of the lower and upper shelf members 52, 54, respectively.","The compression member 56 can have a first, base height corresponding to no products 26 being disposed on the assembly.","Then, as products 26 are stocked on the assembly 50, the compression member 56 can be configured to compress at a known rate such that for a given weight on the assembly, the compression member 56 will have compressed a known amount between the lower and upper shelf members 52, 54.For example, the compression member can be made of any suitably compressible material, such as rubber, a polymer, or the like.","By some approaches, outer edges 58 of the compression member 56 can be recessed from adjacent outer edges 60 of the shelf members 52, 54.So configured, when the assembly is fully stocked and the compression member 56 is compressed, bulging of the compression member 56 as a result of the compression will not extend past the outer edges 60 of the shelf members 52, 54.By other approaches, one or more of the outer edges 58 of the compression member 56 can align with the corresponding outer edges 60 of the shelf members 52, 54.As shown, in some forms, the lower and upper shelf members 52, 54 can each have a generally rectangular footprint where the outer edges 60 thereof include a front edge 62, a rear edge 64, and side edges 66 extending therebetween.","Of course, other shapes and configurations can be utilized for particular applications or if desired.","If desired, the compression member 56 can have a footprint with a similar shape as that of the lower and upper shelf members 52, 54.For example, as shown, the compression member 56 can have a generally rectangular footprint where the outer edges 58 thereof include a front edge 68, a rear edge 70, and side edges 72 running therebetween.","As discussed above, by one approach, the compression member 56 can have substantially the same footprint as the shelf members 52, 54 with the edges 62, 64, 66 of the shelf members 52, 54 generally aligned with the edges 68, 70, 72 of the compression member 56.By another approach, the compression member 56 can have a relatively smaller footprint so that the edges 68, 70, 72 thereof are recessed with respect to the edges 58, 60, 62 of the shelf members 52, 54.By yet another approach, the compression member 56 need not span the entire surface area between the shelf members 52, 54.For example, the compression member 56 can be sized to 90%, 75%, or 50% of the surface area of the shelf members 52, 54.Pursuant to this, the compression member 56 can also have a differently shaped footprint than that of the shelf members 52, 54.In one form, as shown in FIG.","4, one of the outer edges 58 of the compression member 56 can be disposed along and adjacent to the front edge 62 of the shelf members 52, 54 with one or more of the other edges 58 spaced from other outer edges 60 of the shelf members 52, 54.So configured, the compression member 56 is visible along a majority or, if desired, substantially all, of the front edge 62 of the shelf members 52, 54.As shown, the compression member 56 of this form can be generally triangular.","Of course, other shapes and configurations can be utilized, including curvilinear shapes.","So disposed, the triangular compression member 56 extends rearwardly between the shelf members 52, 54 to a point adjacent to the rear edges 66 thereof.","If desired, and to provide additional stability to the assembly 50, the shelf members 52, 54 can be pivotably coupled along the rear edges 64 thereof with a hinge 73 or the like, such as along the entire length thereof or along portions thereof.","So configured, the upper shelf member 54 can pivot with respect to the lower shelf member 52 along the rear edges 64 thereof and, therefore, can pivot to compress the compression member 56 disposed therebetween.","Moreover, with the triangular compression member 56 described above, the shelf members 52, 54 of this form are stably assembled along the front and rear edges 62, 64 thereof If desired, the compression member 56 can be visually distinct with respect to the shelf members 52, 54.For example, the compression member 56 can have a different color, such as a bright color, including yellow, orange, red, or the like, a different pattern, such as striped, cross-checked, or the like, or combinations thereof.","As shown in FIG.","1, an electronic imaging device 74, such as a camera or the like, can be mounted adjacent to the assembly 50 to capture an image thereof including the compression member 56.By one approach, the imaging device 74 can be mounted proximate to the assembly 50.The imaging device 74 can be mounted to a fixed location, such as the shelving unit 10 itself, including to one of the shelves 24, a wall of the retail location, or other structure.","With a fixed configuration, the imaging device 74 can be pivotably or slidably movable to capture images along a range so that the imaging device 74 can capture images of more than one assembly 50.In another form, the imaging device 74 can be mounted to a mobile structure or assembly, such as a cart, robot, or the like.","For example, the imaging device 74 can be configured to operate as a shopper moves a cart around the store or as a robot is programmed to move up and down aisles in the store.","Thereafter, the imaging device 74 can send the image to a computing device 76 having a control circuit therein over a wired connection or over any suitable network, utilizing radio communication, Bluetooth, WiFi, near field communication, or the like utilizing suitable receivers, transmitters, and/or transceivers.","The computing device 76 can include a memory and may generally be any processor-based device such as one or more of a computer system, a server, a networked computer, a cloud-based server, etc.","The control circuit 76 may comprise a central processing unit, a processor, a microprocessor, and the like.","The control circuit 76 may be configured to execute computer-readable instructions stored on the memory.","The memory may comprise volatile and/or non-volatile computer-readable storage memory and have stored upon it a set of computer readable instructions which, when executed by the control circuit 76, cause the system to perform operations as described herein.","The control circuit 76 receives the image and is configured to estimate a weight indicated by the assembly 50.For example, the control circuit 76 can analyze the assembly 50 in the image to determine or estimate a compression distance of the compression member 56.The control circuit 76 can achieve this by determining a distance between the shelf members 52, 54, such as between the outer or inner front edge corners 78, 80 thereof.","By one approach, the control circuit 76 can be calibrated to a particular product 26.For example, the control circuit 76 can receive an image from the imaging device 74 of the assembly 50 having no products 26 stocked thereon to establish a baseline measurement for a projection for the compression member 56.Next, the control circuit 76 can receive an image from the imaging device 74 of the assembly 50 in a fully stocked configuration to establish a top measurement for the projection for the compression member 56.The control circuit 76 can be provided with the products 26 intended for the assembly 50, such as through a remote database or server device 84 described below, to establish an intended number of products 26 and an intended weight for the fully stocked configuration.","Identification of the baseline and fully stocked images can be provided from the remote server device 84 which can be configured to coordinate tasks, such as stocking and product location.","So configured, the control circuit 76 can thereafter compare a subsequently received image, and the compression distance shown thereon, to the projection to determine an approximate weight and/or number of products 26 stocked on the assembly 50.By another approach, the assembly 50 can include a scale 82 mounted thereto and visible to the imaging device 74.The scale 82 can be any object of known dimensions so that the scale 82 can be compared to the compression distance.","For example, the scale 82 can be a label for the products 26 on the shelf 24 or a dedicated object.","If desired, the scale 82 can be mounted to one of the shelf members 52, 54, such as overhanging the gap therebetween.","Next, the control circuit 76 can be configured to estimate a total weight of products 26 on the assembly 50 based on the compression distance of the compression member 56, such as by referencing a table or the like.","The control circuit 76 can further be configured to access product location information, stored locally or on a remote database or server device 84.The product location information can identify the products 26 intended to be stocked on the assembly 50 and identify weight data of the identified products 26.From the weight of the products 26 that are intended to be stocked on the assembly 50 and the estimated weight, the control circuit 76 can estimate a number of products 26 on the assembly 50.If desired, the control circuit 76 can further compare the estimated number of products 26 on the assembly 50 to a predetermined stock number, such as a number that would indicate a low stock level.","In response to determining that the estimated number is at or below the predetermined stock number, the control circuit 76 can be configured to send out a low stock signal.","The low stock signal can be sent or routed to any suitable recipients, such as to create tasks therefor, including devices for stocking associates, devices for ordering additional stock, and the like.","Additionally, the estimated weight and/or estimated number of products can be used by the control circuit 76 to generate warning signals.","For example, if the estimates indicate that there is too much weight on the assembly 50, the control circuit 76 can be configured to send out a warning signal to suitable recipients to remove products 26 from the assembly 50.Moreover, if the estimates indicate an anomaly, such as a weight or number that do not reflect the products 26 intended to be stocked on the assembly 50, the control circuit 76 can be configured to send a warning signal to suitable recipients to check the shelving unit 10.In some embodiments, a stock level indication assembly is described herein that includes upper and lower shelf members, a compression member disposed between the upper and lower shelf members, and an electronic imaging device proximate the upper and lower shelf members oriented and configured to capture an image of the compression member.","The compression member of these embodiments can be configured to visibly compress in response to one or more products being stocked on the upper shelf member to provide a visual indication of the number of products stocked on the upper shelf member.","By several approaches, the stock level indication assembly can further include a control circuit operably coupled to the electronic imaging device.","The control circuit can be configured to receive the image from the imaging device and estimate a number of the products on the shelf based at least on the image.","By further approaches, the control circuit can be configured to estimate the number of the products on the shelf by estimating a compression distance indicated in the image, estimating a weight of total products on the shelf based on the estimated compression distance, accessing product location information, and estimating a number of the products on the shelf based on the product location information and the estimated weight.","By further approaches, the control circuit can be configured to send a low stock signal in response to determining that the number of the products estimated to be on the shelf is at or below a predetermined number.","By further approaches, the control circuit can be configured to determine a lateral distribution of products on the upper shelf member based on a laterally angled compression of the compression member.","By some approaches, the upper and lower shelf members can have a generally rectangular footprint with front edges and the compression member can have a generally triangular footprint, where the compression member is disposed between the upper and lower shelf members with an edge thereof running adjacent to the front edges of the upper and lower members.","In several embodiments, a method for providing 100 a visual indication of stock level is described herein that includes receiving 102 one or more products on a shelf assembly.","The shelf assembly can include upper and lower shelf members and a compression member disposed therebetween, where the compression member configured to visibly compress in response to one or more products being stocked on the upper shelf member to provide a visual indication of the number of products stocked on the upper shelf member.","The method can further include compressing 104 the compression member as a result of the products being received on the upper shelf member and capturing 106 an image of the shelf assembly with an electronic imaging device disposed proximate the shelf assembly.","By some approaches, the method can further include receiving 108 the image at a control circuit from the electronic imaging device and estimating 110 a number of the products on the shelf assembly based at least on the image.","By further approaches, estimating 110 the number of products on the shelf assembly can include estimating a compression distance indicated in the image, estimating a weight of the products based on the estimated compression distance, accessing product location information, and estimating a number of the products on the shelf assembly with the control circuit based on the product location information and the estimated weight.","By yet further approaches, the method can include sending 112 a low stock signal with the control circuit in response to determining that the number of the products estimated to be on the shelf assembly is at or below a predetermined number.","In some embodiments, a method for installing 200 a stock level indication assembly is described herein that includes mounting 202 a lower shelf member to a shelf assembly, disposing 204 a compression member on the lower shelf member, disposing 206 an upper shelf member on the compression member, stocking 208 one or more products on the upper shelf member such that the weight of the products compresses the compression member, and mounting 210 an electronic imaging device proximate the shelf assembly in an orientation to capture an image of the shelf assembly, the image configured to provide an indication of the number of products stocked on the upper shelf member.","By several approaches, disposing 204 the compression member on the lower shelf member can include disposing the compression member on the lower shelf member such that a front edge of the compression member is recessed from a front edge of the lower shelf member and disposing the upper shelf member on the compression member can include disposing the upper shelf member on the compression member such that the front edge of the compression member is recessed from a front edge of the upper shelf member.","By some approaches, the method can further include pivotably 212 coupling the upper and lower shelf members along at least a portion of rear edges thereof Those skilled in the art will recognize that a wide variety of other modifications, alterations, and combinations can also be made with respect to the above described embodiments without departing from the scope of the invention, and that such modifications, alterations, and combinations are to be viewed as being within the ambit of the inventive concept."]],"string":"[\n [\n \"STOCKING LEVEL INDICATION APPARATUS AND METHOD\",\n \"In some embodiments, systems, apparatuses, and methods are described herein including a shelf assembly that utilizes the accumulated weight of products stocked thereon to compress a compression member disposed within the assembly.\",\n \"An electronic imaging device can be mounted proximate to the assembly and can be oriented to capture an image of the compression member to determine whether a particular shelf needs to be restocked and avoid having to manipulate or remove products from a shelf to determine a current stock level.\"\n ],\n [\n \"1.A stock level indication assembly for a retail product storage structure, the stock level indication assembly comprising: upper and lower shelf members; a compression member disposed between the upper and lower shelf members, the compression member configured to visibly compress in response to one or more products being stocked on the upper shelf member to provide a visual indication of the number of products stocked on the upper shelf member; an electronic device proximate the upper and lower shelf members oriented and configured to detect a compression level of the compression member.\",\n \"2.The stock level indication assembly of claim 1, further comprising a control circuit operably coupled to the electronic device and configured to receive a signal including the compression level of the compression member therefrom, the control circuit configured to estimate a number of the products on the shelf based at least on the signal.\",\n \"3.The stock level indication assembly of claim 2, wherein the control circuit is configured to estimate the number of the products on the shelf by estimating a compression distance indicated in the signal, estimating a weight of total products on the shelf based on the estimated compression distance, accessing product location information, and estimating a number of the products on the shelf based on the product location information and the estimated weight.\",\n \"4.The stock level indication assembly of claim 2, wherein the control circuit is further configured to send a low stock signal in response to a determination that the number of the products estimated to be on the shelf is at or below a predetermined number.\",\n \"5.The stock level indication assembly of claim 2, wherein the compression level of the compression member includes a laterally angled compression of the compression member, and wherein the control circuit is further configured to determine a lateral distribution of products on the upper shelf member based on the laterally angled compression of the compression member.\",\n \"6.The stock level indication assembly of claim 1, wherein the electronic device is mounted to a mobile assembly.\",\n \"7.The stock level indication assembly of claim 1, wherein the upper and lower shelf members include front edges and the compression member is disposed between upper and lower shelf members so that a front edge thereof is recessed with respect to the front edges of the upper and lower shelf members such that bulging of the compression member after stocking does not extend past the front edges of the upper and lower shelf members.\",\n \"8.The stock level indication assembly of claim 1, wherein the compression member is adhered to the upper and lower shelf members along upper and lower surfaces thereof.\",\n \"9.The stock level indication assembly of claim 1, wherein the compression member has a different color or surface pattern than the upper and lower shelf members.\",\n \"10.The stock level indication assembly of claim 1, wherein the upper and lower shelf members have a generally rectangular footprint with front edges and the compression member has a generally triangular footprint, the compression member being disposed between the upper and lower shelf members with an edge thereof running adjacent to the front edges of the upper and lower members.\",\n \"11.The stock level indication assembly of claim 10, wherein the upper and lower shelf members are pivotably connected along rear edges thereof.\",\n \"12.A method for providing a visual indication of stock level on a retail product storage structure, the method comprising: providing a shelf assembly including upper and lower shelf members and a compression member disposed therebetween, the compression member configured to visibly compress in response to one or more products being stocked on the upper shelf member to provide a visual indication of the number of products stocked on the upper shelf member; receiving the one or more products on the shelf assembly; compressing the compression member in response to the one or more products being received on the upper shelf member of the shelf assembly; detecting a compression level of the compression member via an electronic device disposed proximate the shelf assembly.\",\n \"13.The method of claim 12, further comprising: receiving, at a control circuit, a signal including the compression level of the compression member transmitted from the electronic device; and estimating a number of the products on the shelf assembly based at least on the signal.\",\n \"14.The method of claim 12, wherein estimating the number of products on the shelf assembly comprises: estimating a compression distance indicated in the signal; estimating a weight of the products based on the estimated compression distance; accessing product location information; and estimating a number of the products on the shelf assembly with the control circuit based on the product location information and the estimated weight.\",\n \"15.The method of claim 14, further comprising sending a low stock signal with the control circuit in response to determining that the number of the products estimated to be on the shelf assembly is at or below a predetermined number.\",\n \"16.A method for installing a stock level indication assembly for a retail product storage structure, the method comprising: mounting a lower shelf member to a shelf assembly; disposing a compression member on the lower shelf member; disposing an upper shelf member on the compression member; stocking one or more products on the upper shelf member such that the weight of the products compresses the compression member; and providing an electronic device proximate the shelf assembly in an orientation to detect a compression level of the compression member, the compression level of the compression member being indicative of a number of products stocked on the upper shelf member.\",\n \"17.The method of claim 16, wherein disposing the compression member on the lower shelf member comprises disposing the compression member on the lower shelf member such that a front edge of the compression member is recessed from a front edge of the lower shelf member; and disposing the upper shelf member on the compression member comprises disposing the upper shelf member on the compression member such that the front edge of the compression member is recessed from a front edge of the upper shelf member.\",\n \"18.The method of claim 16, further comprising adhering the compression member to the upper and lower shelf members.\",\n \"19.The method of claim 16, further comprising pivotably coupling the upper and lower shelf members along at least a portion of rear edges thereof.\",\n \"20.The method of claim 16, further comprising installing a scale on the shelf assembly.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>Retail stores often utilize modular shelving units to display products for sale.\",\n \"It can be important to maintain an accurate count of inventory during operation of the store.\",\n \"Pursuant to this, associates often have to count products on the shelves.\",\n \"It can be difficult for associates to accurately determine a count of products on the shelves and, as such, one method to ensure an accurate count to remove all of the products from the shelves.\",\n \"Unfortunately, the associates must then restock the products on the shelves.\"\n ],\n [\n \"<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>Disclosed herein are embodiments of systems, apparatuses and methods pertaining to a shelving assembly that provides an indication of a stocking level of products on the shelving assembly.\",\n \"This description includes drawings, wherein: FIG.\",\n \"1 is a schematic perspective view of a shelving unit having a stocking level assembly mounted thereto and an electronic imaging device oriented at the stocking level assembly in accordance with some embodiments.\",\n \"FIG.\",\n \"2 is a side elevation view of the stocking level assembly of FIG.\",\n \"1 in an uncompressed configuration in accordance with several embodiments.\",\n \"FIG.\",\n \"3 is a side elevation view of the stocking level assembly of FIG.\",\n \"1 in a compressed configuration in accordance with some embodiments.\",\n \"FIG.\",\n \"4 is an exploded perspective view of a stocking level assembly having a triangular compression member in accordance with several embodiments.\",\n \"FIG.\",\n \"5 is a flowchart in accordance with some embodiments.\",\n \"FIG.\",\n \"6 is a flowchart in accordance with several embodiments.\",\n \"detailed-description description=\\\"Detailed Description\\\" end=\\\"lead\\\"?\",\n \"Elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale.\",\n \"For example, the dimensions and/or relative positioning of some of the elements in the figures may be exaggerated relative to other elements to help to improve understanding of various embodiments of the present invention.\",\n \"Also, common but well-understood elements that are useful or necessary in a commercially feasible embodiment are often not depicted in order to facilitate a less obstructed view of these various embodiments of the present invention.\",\n \"Certain actions and/or steps may be described or depicted in a particular order of occurrence while those skilled in the art will understand that such specificity with respect to sequence is not actually required.\",\n \"The terms and expressions used herein have the ordinary technical meaning as is accorded to such terms and expressions by persons skilled in the technical field as set forth above except where different specific meanings have otherwise been set forth herein.\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser.\",\n \"No.\",\n \"15/585,246, filed May 3, 2017, which claims the benefit of U.S.\",\n \"Provisional Application No.\",\n \"62/332,270, filed May 5, 2016, which are hereby incorporated by reference herein in their entireties.\",\n \"TECHNICAL FIELD This invention relates generally to retail shelving and, more particularly, to stocking level indicating shelving assemblies.\",\n \"BACKGROUND Retail stores often utilize modular shelving units to display products for sale.\",\n \"It can be important to maintain an accurate count of inventory during operation of the store.\",\n \"Pursuant to this, associates often have to count products on the shelves.\",\n \"It can be difficult for associates to accurately determine a count of products on the shelves and, as such, one method to ensure an accurate count to remove all of the products from the shelves.\",\n \"Unfortunately, the associates must then restock the products on the shelves.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS Disclosed herein are embodiments of systems, apparatuses and methods pertaining to a shelving assembly that provides an indication of a stocking level of products on the shelving assembly.\",\n \"This description includes drawings, wherein: FIG.\",\n \"1 is a schematic perspective view of a shelving unit having a stocking level assembly mounted thereto and an electronic imaging device oriented at the stocking level assembly in accordance with some embodiments.\",\n \"FIG.\",\n \"2 is a side elevation view of the stocking level assembly of FIG.\",\n \"1 in an uncompressed configuration in accordance with several embodiments.\",\n \"FIG.\",\n \"3 is a side elevation view of the stocking level assembly of FIG.\",\n \"1 in a compressed configuration in accordance with some embodiments.\",\n \"FIG.\",\n \"4 is an exploded perspective view of a stocking level assembly having a triangular compression member in accordance with several embodiments.\",\n \"FIG.\",\n \"5 is a flowchart in accordance with some embodiments.\",\n \"FIG.\",\n \"6 is a flowchart in accordance with several embodiments.\",\n \"Elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale.\",\n \"For example, the dimensions and/or relative positioning of some of the elements in the figures may be exaggerated relative to other elements to help to improve understanding of various embodiments of the present invention.\",\n \"Also, common but well-understood elements that are useful or necessary in a commercially feasible embodiment are often not depicted in order to facilitate a less obstructed view of these various embodiments of the present invention.\",\n \"Certain actions and/or steps may be described or depicted in a particular order of occurrence while those skilled in the art will understand that such specificity with respect to sequence is not actually required.\",\n \"The terms and expressions used herein have the ordinary technical meaning as is accorded to such terms and expressions by persons skilled in the technical field as set forth above except where different specific meanings have otherwise been set forth herein.\",\n \"DETAILED DESCRIPTION Generally speaking, pursuant to various embodiments, systems, apparatuses and methods are provided herein useful to provide a visual indication of a level or number of products stocked on a shelf of a shelving unit.\",\n \"The visual indication is provided by virtue of an accumulated weight of products causing a visual compression of a compression member according to the weight.\",\n \"More specifically, a shelf assembly is described herein that utilizes the accumulated weight of products stocked thereon to compress a compression member disposed within the assembly.\",\n \"An electronic imaging device can be mounted proximate to the assembly and can be oriented to capture an image of the compression member to determine whether a particular shelf needs to be restocked.\",\n \"Accordingly, the assembly and electronic imaging device described herein advantageously avoids having to manipulate or remove products from a shelf to determine a current stock level and helps a retail location avoid being out of product on the shelf By some approaches, a control circuit can be configured to receive the image from the electronic imaging device and analyze the image to determine a current stock level.\",\n \"For example, the control circuit can be configured to associate a compression level of the compression member to a weight of the products on the assembly.\",\n \"Utilizing the approximate weight and the type of product stocked on the shelf, an approximate number of products on the shelf can be extrapolated.\",\n \"An example shelving unit 10 is shown in FIG.\",\n \"1.Based on a particular use, multiple shelving units 10 can be aligned in a row to produce an aisle in a retail location.\",\n \"The shelving unit 10 includes a base portion 12 and a back wall 14 extending upwardly therefrom.\",\n \"The base portion 12 can include a base deck 16 and a kick plate 18, as commonly configured.\",\n \"A plurality of shelf notches 20 are vertically disposed adjacent to lateral edges 22 of the back wall 14 to provide anchor points for shelves 24 mounted to the shelving unit 10.After the shelving unit 10 is assembled, associates can then stock products 26 on the shelves 24.If desired, as shown in FIGS.\",\n \"1-3, one or more of the shelves 24 can include a stocking level indication assembly 50.The assembly 50 can be a shelf 24 configured to mount to the back wall 14 of the shelving unit 10 or can be an insert for a shelf 24 or disposed thereon.\",\n \"As shown, the assembly 50 includes rigid lower and upper shelf portions or members 52, 54 with a compression portion or member 56 disposed therebetween.\",\n \"The compression member 56 can be secured in the assembly, and to the shelf members 52, 54 thereof, by any suitable method, including adhesive, hardware, interlocking components, or the like.\",\n \"For example, the compression member 56 can be adhered to the upper and lower surfaces of the lower and upper shelf members 52, 54, respectively.\",\n \"The compression member 56 can have a first, base height corresponding to no products 26 being disposed on the assembly.\",\n \"Then, as products 26 are stocked on the assembly 50, the compression member 56 can be configured to compress at a known rate such that for a given weight on the assembly, the compression member 56 will have compressed a known amount between the lower and upper shelf members 52, 54.For example, the compression member can be made of any suitably compressible material, such as rubber, a polymer, or the like.\",\n \"By some approaches, outer edges 58 of the compression member 56 can be recessed from adjacent outer edges 60 of the shelf members 52, 54.So configured, when the assembly is fully stocked and the compression member 56 is compressed, bulging of the compression member 56 as a result of the compression will not extend past the outer edges 60 of the shelf members 52, 54.By other approaches, one or more of the outer edges 58 of the compression member 56 can align with the corresponding outer edges 60 of the shelf members 52, 54.As shown, in some forms, the lower and upper shelf members 52, 54 can each have a generally rectangular footprint where the outer edges 60 thereof include a front edge 62, a rear edge 64, and side edges 66 extending therebetween.\",\n \"Of course, other shapes and configurations can be utilized for particular applications or if desired.\",\n \"If desired, the compression member 56 can have a footprint with a similar shape as that of the lower and upper shelf members 52, 54.For example, as shown, the compression member 56 can have a generally rectangular footprint where the outer edges 58 thereof include a front edge 68, a rear edge 70, and side edges 72 running therebetween.\",\n \"As discussed above, by one approach, the compression member 56 can have substantially the same footprint as the shelf members 52, 54 with the edges 62, 64, 66 of the shelf members 52, 54 generally aligned with the edges 68, 70, 72 of the compression member 56.By another approach, the compression member 56 can have a relatively smaller footprint so that the edges 68, 70, 72 thereof are recessed with respect to the edges 58, 60, 62 of the shelf members 52, 54.By yet another approach, the compression member 56 need not span the entire surface area between the shelf members 52, 54.For example, the compression member 56 can be sized to 90%, 75%, or 50% of the surface area of the shelf members 52, 54.Pursuant to this, the compression member 56 can also have a differently shaped footprint than that of the shelf members 52, 54.In one form, as shown in FIG.\",\n \"4, one of the outer edges 58 of the compression member 56 can be disposed along and adjacent to the front edge 62 of the shelf members 52, 54 with one or more of the other edges 58 spaced from other outer edges 60 of the shelf members 52, 54.So configured, the compression member 56 is visible along a majority or, if desired, substantially all, of the front edge 62 of the shelf members 52, 54.As shown, the compression member 56 of this form can be generally triangular.\",\n \"Of course, other shapes and configurations can be utilized, including curvilinear shapes.\",\n \"So disposed, the triangular compression member 56 extends rearwardly between the shelf members 52, 54 to a point adjacent to the rear edges 66 thereof.\",\n \"If desired, and to provide additional stability to the assembly 50, the shelf members 52, 54 can be pivotably coupled along the rear edges 64 thereof with a hinge 73 or the like, such as along the entire length thereof or along portions thereof.\",\n \"So configured, the upper shelf member 54 can pivot with respect to the lower shelf member 52 along the rear edges 64 thereof and, therefore, can pivot to compress the compression member 56 disposed therebetween.\",\n \"Moreover, with the triangular compression member 56 described above, the shelf members 52, 54 of this form are stably assembled along the front and rear edges 62, 64 thereof If desired, the compression member 56 can be visually distinct with respect to the shelf members 52, 54.For example, the compression member 56 can have a different color, such as a bright color, including yellow, orange, red, or the like, a different pattern, such as striped, cross-checked, or the like, or combinations thereof.\",\n \"As shown in FIG.\",\n \"1, an electronic imaging device 74, such as a camera or the like, can be mounted adjacent to the assembly 50 to capture an image thereof including the compression member 56.By one approach, the imaging device 74 can be mounted proximate to the assembly 50.The imaging device 74 can be mounted to a fixed location, such as the shelving unit 10 itself, including to one of the shelves 24, a wall of the retail location, or other structure.\",\n \"With a fixed configuration, the imaging device 74 can be pivotably or slidably movable to capture images along a range so that the imaging device 74 can capture images of more than one assembly 50.In another form, the imaging device 74 can be mounted to a mobile structure or assembly, such as a cart, robot, or the like.\",\n \"For example, the imaging device 74 can be configured to operate as a shopper moves a cart around the store or as a robot is programmed to move up and down aisles in the store.\",\n \"Thereafter, the imaging device 74 can send the image to a computing device 76 having a control circuit therein over a wired connection or over any suitable network, utilizing radio communication, Bluetooth, WiFi, near field communication, or the like utilizing suitable receivers, transmitters, and/or transceivers.\",\n \"The computing device 76 can include a memory and may generally be any processor-based device such as one or more of a computer system, a server, a networked computer, a cloud-based server, etc.\",\n \"The control circuit 76 may comprise a central processing unit, a processor, a microprocessor, and the like.\",\n \"The control circuit 76 may be configured to execute computer-readable instructions stored on the memory.\",\n \"The memory may comprise volatile and/or non-volatile computer-readable storage memory and have stored upon it a set of computer readable instructions which, when executed by the control circuit 76, cause the system to perform operations as described herein.\",\n \"The control circuit 76 receives the image and is configured to estimate a weight indicated by the assembly 50.For example, the control circuit 76 can analyze the assembly 50 in the image to determine or estimate a compression distance of the compression member 56.The control circuit 76 can achieve this by determining a distance between the shelf members 52, 54, such as between the outer or inner front edge corners 78, 80 thereof.\",\n \"By one approach, the control circuit 76 can be calibrated to a particular product 26.For example, the control circuit 76 can receive an image from the imaging device 74 of the assembly 50 having no products 26 stocked thereon to establish a baseline measurement for a projection for the compression member 56.Next, the control circuit 76 can receive an image from the imaging device 74 of the assembly 50 in a fully stocked configuration to establish a top measurement for the projection for the compression member 56.The control circuit 76 can be provided with the products 26 intended for the assembly 50, such as through a remote database or server device 84 described below, to establish an intended number of products 26 and an intended weight for the fully stocked configuration.\",\n \"Identification of the baseline and fully stocked images can be provided from the remote server device 84 which can be configured to coordinate tasks, such as stocking and product location.\",\n \"So configured, the control circuit 76 can thereafter compare a subsequently received image, and the compression distance shown thereon, to the projection to determine an approximate weight and/or number of products 26 stocked on the assembly 50.By another approach, the assembly 50 can include a scale 82 mounted thereto and visible to the imaging device 74.The scale 82 can be any object of known dimensions so that the scale 82 can be compared to the compression distance.\",\n \"For example, the scale 82 can be a label for the products 26 on the shelf 24 or a dedicated object.\",\n \"If desired, the scale 82 can be mounted to one of the shelf members 52, 54, such as overhanging the gap therebetween.\",\n \"Next, the control circuit 76 can be configured to estimate a total weight of products 26 on the assembly 50 based on the compression distance of the compression member 56, such as by referencing a table or the like.\",\n \"The control circuit 76 can further be configured to access product location information, stored locally or on a remote database or server device 84.The product location information can identify the products 26 intended to be stocked on the assembly 50 and identify weight data of the identified products 26.From the weight of the products 26 that are intended to be stocked on the assembly 50 and the estimated weight, the control circuit 76 can estimate a number of products 26 on the assembly 50.If desired, the control circuit 76 can further compare the estimated number of products 26 on the assembly 50 to a predetermined stock number, such as a number that would indicate a low stock level.\",\n \"In response to determining that the estimated number is at or below the predetermined stock number, the control circuit 76 can be configured to send out a low stock signal.\",\n \"The low stock signal can be sent or routed to any suitable recipients, such as to create tasks therefor, including devices for stocking associates, devices for ordering additional stock, and the like.\",\n \"Additionally, the estimated weight and/or estimated number of products can be used by the control circuit 76 to generate warning signals.\",\n \"For example, if the estimates indicate that there is too much weight on the assembly 50, the control circuit 76 can be configured to send out a warning signal to suitable recipients to remove products 26 from the assembly 50.Moreover, if the estimates indicate an anomaly, such as a weight or number that do not reflect the products 26 intended to be stocked on the assembly 50, the control circuit 76 can be configured to send a warning signal to suitable recipients to check the shelving unit 10.In some embodiments, a stock level indication assembly is described herein that includes upper and lower shelf members, a compression member disposed between the upper and lower shelf members, and an electronic imaging device proximate the upper and lower shelf members oriented and configured to capture an image of the compression member.\",\n \"The compression member of these embodiments can be configured to visibly compress in response to one or more products being stocked on the upper shelf member to provide a visual indication of the number of products stocked on the upper shelf member.\",\n \"By several approaches, the stock level indication assembly can further include a control circuit operably coupled to the electronic imaging device.\",\n \"The control circuit can be configured to receive the image from the imaging device and estimate a number of the products on the shelf based at least on the image.\",\n \"By further approaches, the control circuit can be configured to estimate the number of the products on the shelf by estimating a compression distance indicated in the image, estimating a weight of total products on the shelf based on the estimated compression distance, accessing product location information, and estimating a number of the products on the shelf based on the product location information and the estimated weight.\",\n \"By further approaches, the control circuit can be configured to send a low stock signal in response to determining that the number of the products estimated to be on the shelf is at or below a predetermined number.\",\n \"By further approaches, the control circuit can be configured to determine a lateral distribution of products on the upper shelf member based on a laterally angled compression of the compression member.\",\n \"By some approaches, the upper and lower shelf members can have a generally rectangular footprint with front edges and the compression member can have a generally triangular footprint, where the compression member is disposed between the upper and lower shelf members with an edge thereof running adjacent to the front edges of the upper and lower members.\",\n \"In several embodiments, a method for providing 100 a visual indication of stock level is described herein that includes receiving 102 one or more products on a shelf assembly.\",\n \"The shelf assembly can include upper and lower shelf members and a compression member disposed therebetween, where the compression member configured to visibly compress in response to one or more products being stocked on the upper shelf member to provide a visual indication of the number of products stocked on the upper shelf member.\",\n \"The method can further include compressing 104 the compression member as a result of the products being received on the upper shelf member and capturing 106 an image of the shelf assembly with an electronic imaging device disposed proximate the shelf assembly.\",\n \"By some approaches, the method can further include receiving 108 the image at a control circuit from the electronic imaging device and estimating 110 a number of the products on the shelf assembly based at least on the image.\",\n \"By further approaches, estimating 110 the number of products on the shelf assembly can include estimating a compression distance indicated in the image, estimating a weight of the products based on the estimated compression distance, accessing product location information, and estimating a number of the products on the shelf assembly with the control circuit based on the product location information and the estimated weight.\",\n \"By yet further approaches, the method can include sending 112 a low stock signal with the control circuit in response to determining that the number of the products estimated to be on the shelf assembly is at or below a predetermined number.\",\n \"In some embodiments, a method for installing 200 a stock level indication assembly is described herein that includes mounting 202 a lower shelf member to a shelf assembly, disposing 204 a compression member on the lower shelf member, disposing 206 an upper shelf member on the compression member, stocking 208 one or more products on the upper shelf member such that the weight of the products compresses the compression member, and mounting 210 an electronic imaging device proximate the shelf assembly in an orientation to capture an image of the shelf assembly, the image configured to provide an indication of the number of products stocked on the upper shelf member.\",\n \"By several approaches, disposing 204 the compression member on the lower shelf member can include disposing the compression member on the lower shelf member such that a front edge of the compression member is recessed from a front edge of the lower shelf member and disposing the upper shelf member on the compression member can include disposing the upper shelf member on the compression member such that the front edge of the compression member is recessed from a front edge of the upper shelf member.\",\n \"By some approaches, the method can further include pivotably 212 coupling the upper and lower shelf members along at least a portion of rear edges thereof Those skilled in the art will recognize that a wide variety of other modifications, alterations, and combinations can also be made with respect to the above described embodiments without departing from the scope of the invention, and that such modifications, alterations, and combinations are to be viewed as being within the ambit of the inventive concept.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875834"}}},{"rowIdx":4494993,"cells":{"text":{"kind":"list like","value":[["Stent Graft With a Longitudinal Support Member","A delivery system for delivering and deploying stent grafts having a proximal stent includes a first lumen and a stent capture device including a capture portion fixedly connected adjacent a first lumen distal end.","An outer catheter has a catheter distal end and a catheter inner diameter.","A second lumen having a second distal end is slidably disposed about the first lumen and within the outer catheter.","A stent graft sheath has a sheath proximal end connected to the second distal end and disposed about the first lumen.","The sheath has a sheath distal end and a sheath inner diameter greater than the catheter inner diameter for holding a compressed stent graft.","A distal nose cone has a cone proximal end connected to either the capture portion or the first distal end.","The nose cone and the capture portion are movably adjustable to selectively capture the sheath distal end therebetween."],["1.A stent graft comprising: a) a luminal graft component defining a proximal end, a distal end, and a lumen therebetween, the luminal graft component defining a longitudinal axis; b) a proximal stent at the proximal end of the luminal graft component; c) a distal stent at the distal end of the luminal graft component; d) a plurality of intermediate stents along the luminal graft component between the proximal stent and the distal stent, wherein the intermediate stents define a circumferential proximal end that is distal to the proximal stent and a circumferential distal end that is proximal to the distal stent, wherein the circumferential proximal end lies in a plane distal to the proximal stent; and e) a curved longitudinal support member spanning at least a portion of the intermediate stents.","2.The stent graft of claim 1, wherein at least one of the proximal stent and distal stent includes a plurality of struts that are joined to each other at opposite ends to define proximal apices and distal apices.","3.The stent graft of claim 2, wherein the proximal apices of the proximal stent extend proximally from the proximal end of the luminal graft component.","4.The stent graft of claim 2, wherein at least a portion of the intermediate stents include a plurality of struts that are joined to each other at opposite ends to define proximal apices and distal apices.","5.The stent graft of claim 1, wherein the curved longitudinal support member is curvilinear.","6.The stent graft of claim 5, wherein the curved longitudinal support member defines a proximal end and a distal end that asymptomatically approach lines that extend parallel to a longitudinal axis of the stent graft when the stent graft is in a relaxed position.","7.The stent graft of claim 6, wherein proximal end and the distal end of the curved longitudinal support member are nested within proximal apices and distal apices, respectively, of the most proximal stent and most distal stent of the plurality of intermediate stents.","8.The stent graft of claim 7, wherein the proximal end and distal end of the curved longitudinal support member are looped.","9.The stent graft of claim 1, wherein the proximal stent includes nitinol.","10.The stent graft of claim 1, wherein the distal stent includes nitinol.","11.The stent graft of claim 1, wherein the intermediate stents include nitinol.","12.The stent graft of claim 1, wherein the curved longitudinal support member is on one side of a plane parallel to and bisecting the longitudinal axis of the luminal graft component, the other side of the plane the luminal graft component being free of the curved longitudinal support member.","13.The stent graft of claim 12, wherein the curved longitudinal support member being substantially reverse-mirror symmetrical with respect to the longitudinal axis of the luminal graft component.","14.The stent graft of claim 13, wherein the proximal end of the curved longitudinal support member is distal to a distal end of the proximal stent and the distal end of the curved longitudinal support member is proximal to a proximal end of the distal stent."],["<SOH> BACKGROUND OF THE INVENTION <EOH>"],["<SOH> SUMMARY OF THE INVENTION <EOH>The invention provides a sheath capture device for an endovascular stent graft delivery system and a method for operating the device that overcome the hereinafore-mentioned disadvantages of the heretofore-known devices and methods of this general type and that provides a vessel repair device that implants/conforms more efficiently within the natural or diseased course of the aorta by aligning with the natural curve of the aorta, decreases the likelihood of vessel puncture, increases the blood-tight vascular connection, retains the intraluminal wall of the vessel position, is more resistant to migration, and delivers the stent graft into a curved vessel while minimizing intraluminal forces imparted during delivery and while minimizing the forces needed for a user to deliver the stent graft into a curved vessel.","With the foregoing and other objects in view, there is provided, in accordance with the invention, a delivery system for delivering and deploying stent grafts having a proximal bare stent, the delivery system includes a hollow first lumen having a first distal end, a stent capture device including a capture portion fixedly connected adjacent said first distal end, a relatively rigid, hollow outer catheter having a catheter distal end and a catheter inner diameter, a hollow second lumen having a second distal end and being slidably disposed about said first lumen and slidably disposed in said outer catheter, a relatively flexible, hollow stent graft sheath having a sheath proximal end connected to said second distal end and disposed about said first lumen, said sheath having a sheath distal end and a sheath inner diameter greater than said catheter inner diameter to fit therein an at least partially compressed stent graft, and a distal nose cone having a cone proximal end connected to at least one of said capture portion and said first distal end, said nose cone and said capture portion being movably adjustable to selectively capture said sheath distal end therebetween.","In accordance with another feature of the invention, the nose cone and the capture portion define a cavity in which the sheath distal end is held releasably.","In accordance with a further feature of the invention, there is provided a handle, the outer catheter defining a longitudinal axis and being longitudinally fixedly connected to the handle about the second lumen, the first and second lumens being longitudinally movably connected to the handle.","In accordance with an added feature of the invention, the outer catheter has a length only long enough to be inserted in a patient's aorta to approximately the patient's celiac axis.","In accordance with an additional feature of the invention, there is provided a hollow third lumen disposed about the first lumen and within the second lumen, the third lumen having a third distal end, the capture portion being a first capture portion, the stent capture device including a second capture portion fixedly connected adjacent the third distal end and selectively movable with respect to the first capture portion to capture a stent therebetween.","With the objects of the invention in view, there is also provided a method of loading a stent graft in a prosthesis delivery system for implanting a stent graft in a patient at a treatment site, includes the steps of providing a prosthesis delivery system including a hollow first lumen having a first distal end, a stent capture device including a capture portion fixedly connected adjacent the first distal end, a relatively rigid, hollow outer catheter having a catheter distal end and a catheter inner diameter, and, a hollow second lumen having a second distal end and being slidably disposed about the first lumen and slidably disposed in the outer catheter, loading a stent graft inside a relatively flexible, hollow stent graft sheath having a sheath inner diameter greater than the catheter inner diameter to temporarily dispose the stent graft therein in an at least partially compressed state, the stent graft sheath being disposed about the first lumen and having a sheath distal end and a sheath proximal end connected to the second distal end, temporarily capturing a stent of the stent graft with the stent capture device, removably capturing the sheath distal end between the capture portion and a distal nose cone having a proximal end connected to at least one of the capture portion and the first distal end, and loading the sheath with the partially compressed stent graft into the outer catheter to compress the stent graft even further for subsequent implantation at the treatment site.","In accordance with yet another mode of the invention, the sheath capturing step is carried out by movably adjusting the nose cone and the capture portion to selectively secure the sheath distal end therebetween.","In accordance with yet a further mode of the invention, the outer catheter is extended with the loaded sheath up to a given position at a distance from the treatment site and the stent graft is implanted at the treatment site.","In accordance with yet an added mode of the invention, the implantation step is carried out by extending the first and second lumen in a patient towards the treatment site to move the sheath out from the outer catheter and return the stent graft to the partially compressed state in the sheath, extending the first and second lumen further towards the treatment site to place the loaded sheath at the treatment site, and releasing the sheath distal end from between the capture portion and the distal nose cone and unsheathing the stent graft from the sheath by retracting the second lumen away from the treatment site, and releasing the stent from the capture device to implant the stent graft at the treatment site.","In accordance with yet an additional mode of the invention, the outer catheter is advanced in a patient towards a treatment site up to a given position at a distance from the treatment site, and, while retaining the outer catheter in the given position, the stent graft sheath is advanced out from the outer catheter to the treatment site to align the stent graft with the treatment site, the sheath distal end of the sheath is released from between the capture portion and the distal nose cone and unsheathing the stent graft from the sheath by retracting the second lumen away from the treatment site to at least partially implant the stent graft at the treatment site, the stent is released from the capture device to implant the stent graft at the treatment site, and, upon completion of the stent graft implantation, both of the stent graft sheath and the outer catheter are retracted from the patient.","In accordance with again another mode of the invention, the advancing step is carried out by advancing the sheath out from the outer catheter to the treatment site to axially align the stent graft with the treatment site and rotating the stent graft sheath to circumferentially align the stent graft with the treatment site.","In accordance with again a further mode of the invention, the advancing step is carried out by advancing the outer catheter towards the treatment site only up to a point at a distance from the treatment site greater than a length of the stent graft.","In accordance with again an added mode of the invention, the advancing step is carried out by advancing the outer catheter in vasculature of a patient towards a vascular treatment site.","In accordance with again an additional mode of the invention, the advancing step is carried out by advancing the outer catheter in aortic vasculature of the patient to approximately a celiac axis of the patient.","In accordance with still another mode of the invention, the advancing step is carried out by advancing the outer catheter in aortic vasculature of the patient to approximately a celiac axis of the patient.","In accordance with yet another mode of the invention, the outer catheter is provided with a length sufficient to reach to approximately a celiac axis of a patient.","In accordance with yet a further mode of the invention, the outer catheter is provided with a length equal to approximately a distance from the patient's femoral arterial access site to the patient's celiac axis.","In accordance with yet an added mode of the invention, the retracting step is carried out upon completion of the stent graft implantation by retracting the stent graft sheath into the outer catheter and subsequently retracting the outer catheter containing the stent graft sheath from the patient.","In accordance with yet an additional mode of the invention, the stent graft sheath is of a material relatively more flexible than a material of the outer catheter.","With the objects of the invention in view, there is also provided a method of implanting a stent graft in a patient at a treatment site, including the steps of longitudinally locking a set of inner lumens and an inner sheath with respect to an outer lumen, at least a portion of the inner sheath constraining a stent graft, capturing a distal end of the inner sheath between a stent capture device and a distal nose cone, threading the lumens and the inner sheath onto a guidewire and into a patient to place the outer lumen into an aorta of the patient only up to a point at a distance from the treatment site greater than a length of the prosthesis, longitudinally unlocking the inner lumens with respect to the outer lumen, advancing the inner lumens and inner sheath distally out of the outer lumen in the aorta towards the patient's heart to transport the stent graft further upstream into the aorta, unlocking the inner sheath constraining the stent graft from at least one interior lumen of the inner lumens, and releasing the distal end of the inner sheath from between the capture portion and the distal nose cone by retracting the inner sheath in a proximal direction to at least partially implant the stent graft in a vessel.","In accordance with a concomitant mode of the invention, the stent graft is implanted in the vessel at the treatment site by retracting the second lumen away from the treatment site to unsheath the stent graft from the sheath and releasing the stent from the capture device.","Other features that are considered as characteristic for the invention are set forth in the appended claims.","Although the invention is illustrated and described herein as embodied in a sheath capture device for an endovascular stent graft delivery system and a method for operating the device, it is, nevertheless, not intended to be limited to the details shown because various modifications and structural changes may be made therein without departing from the spirit of the invention and within the scope and range of equivalents of the claims.","The construction and method of operation of the invention, however, together with additional objects and advantages thereof, will be best understood from the following description of specific embodiments when read in connection with the accompanying drawings."],["RELATED APPLICATIONS This application is a continuation of U.S. application Ser.","No.","14/675,102, filed Mar.","31, 2015, which is a continuation of U.S. application Ser.","No.","12/137,592, filed Jun.","12, 2008, abandoned.","U.S. application Ser.","No.","12/137,592 is a: continuation-in-part (CIP) application of U.S. patent application Ser.","No.","11/701,867, now U.S. Pat.","No.","9,198,786, filed Feb. 1, 2007, which claims the benefit under 35 U.S.C.","§ 119(e) of U.S.","Provisional Application Nos.","60/765,449, filed Feb. 3, 2006, and 60/833,533, filed Jul.","26, 2006; is a continuation-in-part of U.S. patent application Ser.","No.","11/828,653, filed Jul.","26, 2007, now abandoned, which claims the benefit under 35 U.S.C.","§ 119(e) of U.S.","Provisional Application Nos.","60/765,449, filed Feb. 3, 2006, and 60/833,533, filed Jul.","26, 2006; is a continuation-in-part of U.S. patent application Ser.","No.","11/828,675, now U.S. Pat.","No.","8,062,345, filed Jul.","26, 2007, which claims the benefit under 35 U.S.C.","§ 119(e) of U.S.","Provisional Application Nos.","60/765,449, filed Feb. 3, 2006, and 60/833,533, filed Jul.","26, 2006; is a continuation in part of U.S. patent application Ser.","No.","10/784,462, filed Feb. 23, 2004, now U.S. Pat.","No.","8,292,943, which claims the benefit under 35 U.S.C.","§ 119(e) of U.S.","Provisional Application Nos.","60/499,652, filed Sep. 3, 2003, and 60/500,155, filed Sep. 4, 2003; is a continuation-in-part of U.S. patent application Ser.","No.","10/884,136, filed Jul.","2, 2004, now U.S. Pat.","No.","7,763,063, which claims the benefit under 35 U.S.C.","§ 119(e) of U.S.","Provisional Application Nos.","60/499,652, filed Sep. 3, 2003, and 60/500,155, filed Sep. 4, 2003; is a continuation in part of U.S. patent application Ser.","No.","11/348,176, filed Feb. 6, 2006, now U.S. Pat.","No.","8,308,790; is a continuation-in-part of U.S. application Ser.","No.","11/353,927, filed Feb. 13, 2006, now U.S. Pat.","No.","8,070,790; is a continuation-in-part of U.S. application Ser.","No.","11/449,337, filed Jun.","8, 2006, now U.S. Pat.","No.","8,740,963; is a continuation-in-part of U.S. application Ser.","No.","11/699,700, filed Jan. 30, 2007, now abandoned; is a continuation-in-part of U.S. application Ser.","No.","11/699,701, filed Jan. 30, 2007, now U.S. Pat.","No.","8,007,605; is a continuation-in-part of U.S. application Ser.","No.","11/700,510, filed Jan. 31, 2007, now U.S. Pat.","No.","8,062,349; and a continuation-in-part of U.S. application Ser.","No.","11/700,609, filed Jan. 31, 2007, now U.S. Pat.","No.","9,320,631, the complete disclosures of the above-referenced applications are all hereby incorporated by reference herein in their entirety.","STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT n/a BACKGROUND OF THE INVENTION Field of the Invention The invention lies in the field of endoluminal blood vessel repairs.","The invention specifically relates to a delivery system, a kit, and method for endoluminally repairing a vessel, for example, an aneurysm and/or dissections of the thoracic transverse aortic arch, thoracic posterior aortic arch, and the descending thoracic portion of the aorta with a stent graft.","The present invention, in particular, relates to a sheath capture device for an endovascular stent graft delivery system and a method for operating the device.","Description of the Related Art A stent graft is an implantable device made of a tube-shaped surgical graft covering and an expanding or self-expanding frame.","The stent graft is placed inside a blood vessel to bridge, for example, an aneurismal, dissected, or other diseased segment of the blood vessel, and, thereby, exclude the hemodynamic pressures of blood flow from the diseased segment of the blood vessel.","In selected patients, a stent graft advantageously eliminates the need to perform open thoracic or abdominal surgical procedures to treat diseases of the aorta and eliminates the need for total aortic reconstruction.","Thus, the patient has less trauma and experiences a decrease in hospitalization and recovery times.","The time needed to insert a stent graft is substantially less than the typical anesthesia time required for open aortic bypass surgical repair, for example.","Use of surgical and/or endovascular grafts have widespread use throughout the world in vascular surgery.","There are many different kinds of vascular graft configurations.","Some have supporting framework over their entirety, some have only two stents as a supporting framework, and others simply have the tube-shaped graft material with no additional supporting framework, an example that is not relevant to the present invention.","One of the most commonly known supporting stent graft frameworks is that disclosed in U.S. Pat.","Nos.","5,282,824 and 5,507,771 to Gianturco (hereinafter collectively referred to as “Gianturco”).","Gianturco describes a zig-zag-shaped, self-expanding stent commonly referred to as a z-stent.","The stents are, preferably, made of nitinol, but also have been made from stainless steel and other biocompatible materials.","There are various features characterizing a stent graft.","The first significant feature is the tube of graft material.","This tube is commonly referred to as the graft and forms the tubular shape that will, ultimately, take the place of the diseased portion of the blood vessel.","The graft is, preferably, made of a woven sheet (tube) of polyester or PTFE.","The circumference of the graft tube is, typically, at least as large as the diameter and/or circumference of the vessel into which the graft will be inserted so that there is no possibility of blood flowing around the graft (also referred to as endoleak) to either displace the graft or to reapply hemodynamic pressure against the diseased portion of the blood vessel.","Accordingly, to so hold the graft, self-expanding frameworks are attached typically to the graft material, whether on the interior or exterior thereof.","Because blood flow within the lumen of the graft could be impaired if the framework was disposed on the interior wall of the graft, the framework is connected typically to the exterior wall of the graft.","The ridges formed by such an exterior framework help to provide a better fit in the vessel by providing a sufficiently uneven outer surface that naturally grips the vessel where it contacts the vessel wall and also provides areas around which the vessel wall can endothelialize to further secure the stent graft in place.","One of the significant dangers in endovascular graft technology is the possibility of the graft migrating from the desired position in which it is installed.","Therefore, various devices have been created to assist in anchoring the graft to the vessel wall.","One type of prior art prosthetic device is a stent graft made of a self-expanding metallic framework.","For delivery, the stent graft is, first, radially compressed and loaded into an introducer system that will deliver the device to the target area.","When the introducer system holding the stent graft positioned in an appropriate location in the vessel and allowed to open, the radial force imparted by the self-expanding framework is helpful, but, sometimes, not entirely sufficient, in endoluminally securing the stent graft within the vessel.","U.S. Pat.","No.","5,824,041 to Lenker et al.","(hereinafter “Lenker”) discloses an example of a stent graft delivery system.","Lenker discloses various embodiments in which a sheath is retractable proximally over a prosthesis to be released.","With regard to FIGS.","7 and 8 of Lenker, Lenker names components 72 and 76, respectively, as “sheath” and “prosthesis-containment sheath.” However, the latter is merely the catheter in which the prosthesis 74 and the sheath 72 are held.","With regard to FIGS.","9 and 10, the sheath 82 has inner and outer layers 91, 92 fluid-tightly connected to one another to form a ballooning structure around the prosthesis P. This ballooning structure inflates when liquid is inflated with a non-compressible fluid medium and flares radially outward when inflated.","With regard to FIGS.","13 to 15, Lenker discloses the “sheath” 120, which is merely the delivery catheter, and an eversible membrane 126 that “folds back over itself (everts) as the sheath 120 is retracted so that there are always two layers of the membrane between the distal end of the sheath [120] and the prosthesis P.” Lenker at col. 9, lines 63 to 66.The eversion (peeling back) is caused by direct connection of the distal end 130 to the sheath 120.The Lenker delivery system, shown in FIGS.","19A to 19D of Lenker, holds the prosthesis P at both ends 256, 258 while an outer catheter 254 is retracted over the prosthesis P and the inner sheath 260.The inner sheath 260 remains inside the outer catheter 254 before, during, and after retraction.","Another structure for holding the prosthesis P at both ends is illustrated in FIGS.","23A and 23B.","Therein, the proximal holder having resilient axial members 342 is connected to a proximal ring structure 346.FIGS.","24A to 24C also show an embodiment for holding the prosthesis at both ends inside thin-walled tube 362.To augment radial forces of stents, some prior art devices have added proximal and/or distal stents that are not entirely covered by the graft material.","By not covering with graft material a portion of the proximal/distal ends of the stent, these stents have the ability to expand further radially than those stents that are entirely covered by the graft material.","By expanding further, the proximal/distal stent ends better secure to the interior wall of the vessel and, in doing so, press the extreme cross-sectional surface of the graft ends into the vessel wall to create a fixated blood-tight seal.","One example of such a prior art exposed stent can be found in United States Patent Publication US 2002/0198587 to Greenberg et al.","The modular stent graft assembly therein has a three-part stent graft: a two-part graft having an aortic section 12 and an iliac section 14 (with four sizes for each) and a contralateral iliac occluder 80.FIGS.","1, 2, and 4 to 6 show the attachment stent 32.As illustrated in FIGS.","1, 2, and 4, the attachment stent 32, while rounded, is relatively sharp and, therefore, increases the probability of puncturing the vessel.","A second example of a prior art exposed stent can be found in U.S. Patent Publication 2003/0074049 to Hoganson et al.","(hereinafter “Hoganson”), which discloses a covered stent 10 in which the elongated portions or sections 24 of the ends 20a and 20b extend beyond the marginal edges of the cover 22.See Hoganson at FIGS.","1, 3, 9, 11a, 11b, 12a, 12b, and 13.However, these extending exposed edges are triangular, with sharp apices pointing both upstream and downstream with regard to a graft placement location.","Such a configuration of the exposed stent 20a, 20b increases the possibility of puncturing the vessel.","In various embodiments shown in FIGS.","6a, 6b, 6c; 10, 14a, Hoganson teaches completely covering the extended stent and, therefore, the absence of a stent extending from the cover 22.It is noted that the Hoganson stent is implanted by inflation of a balloon catheter.","Another example of a prior art exposed stent can be found in U.S. Pat.","No.","6,565,596 to White et al.","(hereinafter “White I”), which uses a proximally extending stent to prevent twisting or kinking and to maintain graft against longitudinal movement.","The extending stent is expanded by a balloon and has a sinusoidal amplitude greater than the next adjacent one or two sinusoidal wires.","White I indicates that it is desirable to space wires adjacent upstream end of graft as close together as is possible.","The stent wires of White I are actually woven into graft body by piercing the graft body at various locations.","See White I at FIGS.","6 and 7.Thus, the rips in the graft body can lead to the possibility of the exposed stent moving with respect to the graft and of the graft body ripping further.","Between the portions of the extending stent 17, the graft body has apertures.","The stent configuration of U.S. Pat.","No.","5,716,393 to Lindenberg et al.","is similar to White I in that the outermost portion of the one-piece stent—made from a sheet that is cut/punched and then rolled into cylinder—has a front end with a greater amplitude than the remaining body of the stent A further example of a prior art exposed stent can be found in U.S. Pat.","No.","6,524,335 to Hartley et al.","(hereinafter “Hartley”).","FIGS.","1 and 2 of Hartley particularly disclose a proximal first stent 1 extending proximally from graft proximal end 4 with both the proximal and distal apices narrowing to pointed ends.","Yet another example of a prior art exposed stent can be found in U.S. Pat.","No.","6,355,056 to Pinheiro (hereinafter “Pinheiro I”).","Like the Hartley exposed stent, Pinheiro discloses exposed stents having triangular, sharp proximal apices.","Still a further example of a prior art exposed stent can be found in U.S. Pat.","No.","6,099,558 to White et al.","(hereinafter “White II”).","The White II exposed stent is similar to the exposed stent of White I and also uses a balloon to expand the stent.","An added example of a prior art exposed stent can be found in U.S. Pat.","No.","5,871,536 to Lazarus, which discloses two support members 68 longitudinally extending from proximal end to a rounded point.","Such points, however, create a very significant possibility of piercing the vessel.","An additional example of a prior art exposed stent can be found in U.S. Pat.","No.","5,851,228 to Pinheiro (hereinafter “Pinheiro II”).","The Pinheiro II exposed stents are similar to the exposed stents of Pinheiro I and, as such, have triangular, sharp, proximal apices.","Still another example of a prior art exposed stent can be found in Lenker (U.S. Pat.","No.","5,824,041), which shows a squared-offend of the proximal and distal exposed band members 14.A portion of the exposed members 14 that is attached to the graft material 18, 20 is longitudinally larger than a portion of the exposed members 14 that is exposed and extends away from the graft material 18, 20.Lenker et al.","does not describe the members 14 in any detail.","Yet a further example of a prior art exposed stent can be found in U.S. Pat.","No.","5,824,036 to Lauterjung, which, of all of the prior art embodiments described herein, shows the most pointed of exposed stents.","Specifically, the proximal ends of the exposed stent are apices pointed like a minaret.","The minaret points are so shaped intentionally to allow forks 300 (see Lauterjung at FIG.","5) external to the stent 154 to pull the stent 154 from the sheath 302, as opposed to being pushed.","A final example of a prior art exposed stent can be found in U.S. Pat.","No.","5,755,778 to Kleshinski.","The Kleshinski exposed stents each have two different shaped portions, a triangular base portion and a looped end portion.","The totality of each exposed cycle resembles a castellation.","Even though the end-most portion of the stent is curved, because it is relatively narrow, it still creates the possibility of piercing the vessel wall.","All of these prior art stents suffer from the disadvantageous characteristic that the relatively sharp proximal apices of the exposed stents have a shape that is likely to puncture the vessel wall.","Devices other than exposed stents have been used to inhibit graft migration.","A second of such devices is the placement of a relatively stiff longitudinal support member longitudinally extending along the entirety of the graft.","The typical stent graft has a tubular body and a circumferential framework.","This framework is not usually continuous.","Rather, it typically takes the form of a series of rings along the tubular graft.","Some stent grafts have only one or two of such rings at the proximal and/or distal ends and some have many stents tandemly placed along the entirety of the graft material.","Thus, the overall stent graft has an “accordion” shape.","During the systolic phase of each cardiac cycle, the hemodynamic pressure within the vessel is substantially parallel with the longitudinal plane of the stent graft.","Therefore, a device having unsecured stents, could behave like an accordion or concertina with each systolic pulsation, and may have a tendency to migrate downstream.","(A downstream migration, to achieve forward motion, has a repetitive longitudinal compression and extension of its cylindrical body.)","Such movement is entirely undesirable.","Connecting the stents with support along the longitudinal extent of the device thereof can prevent such movement.","To provide such support, a second anti-migration device can be embodied as a relatively stiff longitudinal bar connected to the framework.","A clear example of a longitudinal support bar can be found in Pinheiro I (U.S. Pat.","No.","6,355,056) and Pinheiro II (U.S. Pat.","No.","5,851,228).","Each of these references discloses a plurality of longitudinally extending struts 40 extending between and directly interconnecting the proximal and distal exposed stents 20a, 20b.","These struts 40 are designed to extend generally parallel with the inner lumen 15 of the graft 10, in other words, they are straight.","Another example of a longitudinal support bar can be found in U.S. Pat.","No.","6,464,719 to Jayaraman.","The Jayaraman stent is formed from a graft tube 21 and a supporting sheet 1 made of nitinol.","This sheet is best shown in FIG.","3.The end pieces 11, 13 of the sheet are directly connected to one another by wavy longitudinal connecting pieces 15 formed by cutting the sheet 1.To form the stent graft, the sheet 1 is coiled with or around the cylindrical tube 21.See FIGS.","1 and 4.Alternatively, a plurality of connecting pieces 53 with holes at each end thereof can be attached to a cylindrical fabric tube 51 by stitching or sutures 57, as shown in FIG.","8.Jayaraman requires more than one of these serpentine shaped connecting pieces 53 to provide longitudinal support.","United States Patent Publication 2002/0016627 and U.S. Pat.","No.","6,312,458 to Golds each disclose a variation of a coiled securing member 20.A different kind of supporting member is disclosed in FIG.","8 of U.S. Pat.","No.","6,053,943 to Edwin et al.","Like Jayaraman, U.S. Pat.","No.","5,871,536 to Lazarus discloses a plurality of straight, longitudinal support structures 38 attached to the circumferential support structures 36, see FIGS.","1, 6, 7, 8, 10, 11, 12, 14.FIG.","8 of Lazarus illustrates the longitudinal support structures 38 attached to a distal structure 36 and extending almost all of the way to the proximal structure 36.The longitudinal structures 38, 84, 94 can be directly connected to the body 22, 80 and can be telescopic 38, 64.United States Patent Publication 2003/0088305 to Van Schie et al.","(hereinafter “Van Schie”) does not disclose a support bar.","Rather, it discloses a curved stent graft using an elastic material 8 connected to stents at a proximal end 2 and at a distal end 3 (see FIGS.","1, 2) thereof to create a curved stent graft.","Because Van Schie needs to create a flexible curved graft, the elastic material 8 is made of silicone rubber or another similar material.","Thus, the material 8 cannot provide support in the longitudinal extent of the stent graft.","Accordingly, an alternative to the elastic support material 8 is a suture material 25 shown in FIGS.","3 to 6.SUMMARY OF THE INVENTION The invention provides a sheath capture device for an endovascular stent graft delivery system and a method for operating the device that overcome the hereinafore-mentioned disadvantages of the heretofore-known devices and methods of this general type and that provides a vessel repair device that implants/conforms more efficiently within the natural or diseased course of the aorta by aligning with the natural curve of the aorta, decreases the likelihood of vessel puncture, increases the blood-tight vascular connection, retains the intraluminal wall of the vessel position, is more resistant to migration, and delivers the stent graft into a curved vessel while minimizing intraluminal forces imparted during delivery and while minimizing the forces needed for a user to deliver the stent graft into a curved vessel.","With the foregoing and other objects in view, there is provided, in accordance with the invention, a delivery system for delivering and deploying stent grafts having a proximal bare stent, the delivery system includes a hollow first lumen having a first distal end, a stent capture device including a capture portion fixedly connected adjacent said first distal end, a relatively rigid, hollow outer catheter having a catheter distal end and a catheter inner diameter, a hollow second lumen having a second distal end and being slidably disposed about said first lumen and slidably disposed in said outer catheter, a relatively flexible, hollow stent graft sheath having a sheath proximal end connected to said second distal end and disposed about said first lumen, said sheath having a sheath distal end and a sheath inner diameter greater than said catheter inner diameter to fit therein an at least partially compressed stent graft, and a distal nose cone having a cone proximal end connected to at least one of said capture portion and said first distal end, said nose cone and said capture portion being movably adjustable to selectively capture said sheath distal end therebetween.","In accordance with another feature of the invention, the nose cone and the capture portion define a cavity in which the sheath distal end is held releasably.","In accordance with a further feature of the invention, there is provided a handle, the outer catheter defining a longitudinal axis and being longitudinally fixedly connected to the handle about the second lumen, the first and second lumens being longitudinally movably connected to the handle.","In accordance with an added feature of the invention, the outer catheter has a length only long enough to be inserted in a patient's aorta to approximately the patient's celiac axis.","In accordance with an additional feature of the invention, there is provided a hollow third lumen disposed about the first lumen and within the second lumen, the third lumen having a third distal end, the capture portion being a first capture portion, the stent capture device including a second capture portion fixedly connected adjacent the third distal end and selectively movable with respect to the first capture portion to capture a stent therebetween.","With the objects of the invention in view, there is also provided a method of loading a stent graft in a prosthesis delivery system for implanting a stent graft in a patient at a treatment site, includes the steps of providing a prosthesis delivery system including a hollow first lumen having a first distal end, a stent capture device including a capture portion fixedly connected adjacent the first distal end, a relatively rigid, hollow outer catheter having a catheter distal end and a catheter inner diameter, and, a hollow second lumen having a second distal end and being slidably disposed about the first lumen and slidably disposed in the outer catheter, loading a stent graft inside a relatively flexible, hollow stent graft sheath having a sheath inner diameter greater than the catheter inner diameter to temporarily dispose the stent graft therein in an at least partially compressed state, the stent graft sheath being disposed about the first lumen and having a sheath distal end and a sheath proximal end connected to the second distal end, temporarily capturing a stent of the stent graft with the stent capture device, removably capturing the sheath distal end between the capture portion and a distal nose cone having a proximal end connected to at least one of the capture portion and the first distal end, and loading the sheath with the partially compressed stent graft into the outer catheter to compress the stent graft even further for subsequent implantation at the treatment site.","In accordance with yet another mode of the invention, the sheath capturing step is carried out by movably adjusting the nose cone and the capture portion to selectively secure the sheath distal end therebetween.","In accordance with yet a further mode of the invention, the outer catheter is extended with the loaded sheath up to a given position at a distance from the treatment site and the stent graft is implanted at the treatment site.","In accordance with yet an added mode of the invention, the implantation step is carried out by extending the first and second lumen in a patient towards the treatment site to move the sheath out from the outer catheter and return the stent graft to the partially compressed state in the sheath, extending the first and second lumen further towards the treatment site to place the loaded sheath at the treatment site, and releasing the sheath distal end from between the capture portion and the distal nose cone and unsheathing the stent graft from the sheath by retracting the second lumen away from the treatment site, and releasing the stent from the capture device to implant the stent graft at the treatment site.","In accordance with yet an additional mode of the invention, the outer catheter is advanced in a patient towards a treatment site up to a given position at a distance from the treatment site, and, while retaining the outer catheter in the given position, the stent graft sheath is advanced out from the outer catheter to the treatment site to align the stent graft with the treatment site, the sheath distal end of the sheath is released from between the capture portion and the distal nose cone and unsheathing the stent graft from the sheath by retracting the second lumen away from the treatment site to at least partially implant the stent graft at the treatment site, the stent is released from the capture device to implant the stent graft at the treatment site, and, upon completion of the stent graft implantation, both of the stent graft sheath and the outer catheter are retracted from the patient.","In accordance with again another mode of the invention, the advancing step is carried out by advancing the sheath out from the outer catheter to the treatment site to axially align the stent graft with the treatment site and rotating the stent graft sheath to circumferentially align the stent graft with the treatment site.","In accordance with again a further mode of the invention, the advancing step is carried out by advancing the outer catheter towards the treatment site only up to a point at a distance from the treatment site greater than a length of the stent graft.","In accordance with again an added mode of the invention, the advancing step is carried out by advancing the outer catheter in vasculature of a patient towards a vascular treatment site.","In accordance with again an additional mode of the invention, the advancing step is carried out by advancing the outer catheter in aortic vasculature of the patient to approximately a celiac axis of the patient.","In accordance with still another mode of the invention, the advancing step is carried out by advancing the outer catheter in aortic vasculature of the patient to approximately a celiac axis of the patient.","In accordance with yet another mode of the invention, the outer catheter is provided with a length sufficient to reach to approximately a celiac axis of a patient.","In accordance with yet a further mode of the invention, the outer catheter is provided with a length equal to approximately a distance from the patient's femoral arterial access site to the patient's celiac axis.","In accordance with yet an added mode of the invention, the retracting step is carried out upon completion of the stent graft implantation by retracting the stent graft sheath into the outer catheter and subsequently retracting the outer catheter containing the stent graft sheath from the patient.","In accordance with yet an additional mode of the invention, the stent graft sheath is of a material relatively more flexible than a material of the outer catheter.","With the objects of the invention in view, there is also provided a method of implanting a stent graft in a patient at a treatment site, including the steps of longitudinally locking a set of inner lumens and an inner sheath with respect to an outer lumen, at least a portion of the inner sheath constraining a stent graft, capturing a distal end of the inner sheath between a stent capture device and a distal nose cone, threading the lumens and the inner sheath onto a guidewire and into a patient to place the outer lumen into an aorta of the patient only up to a point at a distance from the treatment site greater than a length of the prosthesis, longitudinally unlocking the inner lumens with respect to the outer lumen, advancing the inner lumens and inner sheath distally out of the outer lumen in the aorta towards the patient's heart to transport the stent graft further upstream into the aorta, unlocking the inner sheath constraining the stent graft from at least one interior lumen of the inner lumens, and releasing the distal end of the inner sheath from between the capture portion and the distal nose cone by retracting the inner sheath in a proximal direction to at least partially implant the stent graft in a vessel.","In accordance with a concomitant mode of the invention, the stent graft is implanted in the vessel at the treatment site by retracting the second lumen away from the treatment site to unsheath the stent graft from the sheath and releasing the stent from the capture device.","Other features that are considered as characteristic for the invention are set forth in the appended claims.","Although the invention is illustrated and described herein as embodied in a sheath capture device for an endovascular stent graft delivery system and a method for operating the device, it is, nevertheless, not intended to be limited to the details shown because various modifications and structural changes may be made therein without departing from the spirit of the invention and within the scope and range of equivalents of the claims.","The construction and method of operation of the invention, however, together with additional objects and advantages thereof, will be best understood from the following description of specific embodiments when read in connection with the accompanying drawings.","BRIEF DESCRIPTION OF THE DRAWINGS The features of the present invention, which are believed to be novel, are set forth with particularity in the appended claims.","The invention, together with further objects and advantages thereof, may best be understood by reference to the following description, taken in conjunction with the accompanying drawings, in the several figures of which like reference numerals identify like elements, and in which: FIG.","1 is a side elevational view of a stent graft according to the invention; FIG.","2 is a side elevational view of a stent of the stent graft of FIG.","1; FIG.","3 is a cross-sectional view of the stent of FIG.","2 with different embodiments of protrusions; FIG.","4 is a perspective view of a prior art round mandrel for forming prior art stents; FIG.","5 is a fragmentary, side elevational view of a prior art stent in a portion of a vessel; FIG.","6 is a perspective view of a dodecahedral-shaped mandrel for forming stents in FIGS.","1 to 3; FIG.","7 is a fragmentary, side elevational view of the stent of FIGS.","1 to 3 in a portion of a vessel; FIG.","8 is a fragmentary, enlarged side elevational view of the proximal end of the stent graft of FIG.","1 illustrating movement of a gimbaled end; FIG.","9 is a side elevational view of a two-part stent graft according to the invention; FIG.","10 is a fragmentary, side elevational view of a delivery system according to the invention with a locking ring in a neutral position; FIG.","11 is a fragmentary, side elevational view of the delivery system of FIG.","10 with the locking ring in an advancement position and, as indicated by dashed lines, a distal handle and sheath assembly in an advanced position; FIG.","12 is a fragmentary, enlarged view of a sheath assembly of the delivery system of FIG.","10; FIG.","13 is a fragmentary, enlarged view of an apex capture device of the delivery system of FIG.","10 in a captured position; FIG.","14 is a fragmentary, enlarged view of the apex capture device of FIG.","13 in a released position; FIG.","15 is a fragmentary, enlarged view of an apex release assembly of the delivery system of FIG.","10 in the captured position; FIG.","16 is a fragmentary, enlarged view of the apex release assembly of FIG.","15 in the captured position with an intermediate part removed; FIG.","17 is a fragmentary, enlarged view of the apex release assembly of FIG.","16 in the released position; FIG.","18 is a fragmentary, side elevational view of the delivery system of FIG.","11 showing how a user deploys the prosthesis; FIG.","19 is a fragmentary cross-sectional view of human arteries including the aorta with the assembly of the present invention in a first step of a method for inserting the prosthesis according to the invention; FIG.","20 is a fragmentary cross-sectional view of the arteries of FIG.","19 with the assembly in a subsequent step of the method for inserting the prosthesis; FIG.","21 is a fragmentary cross-sectional view of the arteries of FIG.","20 with the assembly in a subsequent step of the method for inserting the prosthesis; FIG.","22 is a fragmentary cross-sectional view of the arteries of FIG.","21 with the assembly in a subsequent step of the method for inserting the prosthesis; FIG.","23 is a fragmentary cross-sectional view of the arteries of FIG.","22 with the assembly in a subsequent step of the method for inserting the prosthesis; FIG.","24 is a fragmentary cross-sectional view of the arteries of FIG.","23 with the assembly in a subsequent step of the method for inserting the prosthesis; FIG.","25 is a fragmentary, diagrammatic, perspective view of the coaxial relationship of delivery system lumen according to the invention; FIG.","26 is a fragmentary, cross-sectional view of the apex release assembly according to the invention; FIG.","27 is a fragmentary, side elevational view of the stent graft of FIG.","1 with various orientations of radiopaque markers according to the invention; FIG.","28 is a fragmentary perspective view of the stent graft of FIG.","1 with various orientations of radiopaque markers according to the invention; FIG.","29 is a perspective view of a distal apex head of the apex capture device of FIG.","13; FIG.","30 is a fragmentary side elevational view of the distal apex head of FIG.","29 and a proximal apex body of the apex capture device of FIG.","13 with portions of a bare stent in the captured position; FIG.","31 is a fragmentary, side elevational view of the distal apex head and proximal apex body of FIG.","30 with a portion of the proximal apex body cut away to illustrate the bare stent in the captured position; FIG.","32 is a fragmentary side elevational view of the distal apex head and proximal apex body of FIG.","30 in the released position; FIG.","33 is a fragmentary, cross-sectional view of an embodiment of handle assemblies according to the invention; FIG.","34 is a cross-sectional view of a pusher clasp rotator of the handle assembly of FIG.","33; FIG.","35 is a plan view of the pusher clasp rotator of FIG.","34 viewed along line C-C; FIG.","36 is a plan and partially hidden view of the pusher clasp rotator of FIG.","34 with a helix groove for a first embodiment of the handle assembly of FIGS.","10, 11, and 18; FIG.","37 is a cross-sectional view of the pusher clasp rotator of FIG.","36 along section line A-A; FIG.","38 is a plan and partially hidden view of the pusher clasp rotator of FIG.","36; FIG.","39 is a cross-sectional view of the pusher clasp rotator of FIG.","38 along section line B-B; FIG.","40 is a perspective view of a rotator body of the handle assembly of FIG.","33; FIG.","41 is an elevational and partially hidden side view of the rotator body of FIG.","40; FIG.","42 is a cross-sectional view of the rotator body of FIG.","41 along section line A-A; FIG.","43 is an elevational and partially hidden side view of the rotator body of FIG.","40; FIG.","44 is an elevational and partially hidden side view of a pusher clasp body of the handle assembly of FIG.","33; FIG.","45 is a cross-sectional view of the pusher clasp body of FIG.","44 along section line A-A; FIG.","46 is a cross-sectional view of the pusher clasp body of FIG.","44 along section line B-B; FIG.","47 is a fragmentary, side elevational view of a portion of the handle assembly of FIG.","33 with a sheath assembly according to the invention; FIG.","48 is an exploded side elevational view of a portion of the handle assembly of FIG.","47; FIG.","49 is a fragmentary elevational and partially hidden side view of a handle body of the handle assembly of FIG.","33; FIG.","50 is a fragmentary, exploded side elevational view of a portion of a second embodiment of the handle assembly according to the invention; FIG.","51 is a fragmentary, side elevational view of the portion of FIG.","50 in a neutral position; FIG.","52 is an exploded view of a first portion of the second embodiment of the handle assembly; FIG.","53 is a fragmentary, exploded view of a larger portion of the second embodiment of the handle assembly as compared to FIG.","52 with the first portion and the sheath assembly; FIG.","54 is perspective view of a clasp body of the second embodiment of the handle assembly; FIG.","55 is an elevational side view of the clasp body of FIG.","54; FIG.","56 is a cross-sectional view of the clasp body of FIG.","55 along section line A-A; FIG.","57 is a plan view of the clasp body of FIG.","54; FIG.","58 is a plan view of the clasp body of FIG.","57 viewed from section line B-B; FIG.","59 is a fragmentary and partially hidden side elevational view of a clasp sleeve of the second embodiment of the handle assembly; FIG.","60 is a fragmentary, cross-sectional view of a portion the clasp sleeve of FIG.","59 along section line A; FIG.","61 is a fragmentary, cross-sectional view of the clasp sleeve of FIG.","59 along section line C-C; FIG.","62 is a fragmentary and partially hidden side elevational view of the clasp sleeve of FIG.","59 rotated with respect to FIG.","59; FIG.","63 is a fragmentary, cross-sectional view of the nose cone and sheath assemblies of FIG.","10; FIG.","64 is a fragmentary, perspective view of a portion of self-alignment configuration according to the invention; FIG.","65 is a diagrammatic, fragmentary, cross-sectional view of a distal portion of the delivery system with the self-alignment configuration according to the invention inside the descending thoracic aorta and with the self-alignment configuration in an orientation opposite a desired orientation; FIG.","66 is a diagrammatic, fragmentary, cross-sectional view of the distal portion of the delivery system of FIG.","65 with the self-alignment configuration partially inside the descending thoracic aorta and partially inside the aortic arch and with the self-alignment configuration in an orientation closer to the desired orientation; FIG.","67 is a diagrammatic, fragmentary, cross-sectional view of the distal portion of the delivery system of FIG.","65 with the self-alignment configuration primarily inside the aortic arch and with the self-alignment configuration substantially in the desired orientation; FIG.","68 is a fragmentary, enlarged, partially exploded perspective view of an alternative embodiment of a distal end of the graft push lumen of FIG.","25; FIG.","69 is a photograph of a user bending a stent graft assembly around a curving device to impart a curve to a guidewire lumen therein; FIG.","70 is a side elevational view of a stent graft according to the invention; FIG.","71 is a side elevational view of an alternative embodiment of the stent graft with a clasping stent and a crown stent; FIG.","72 is a photograph depicting a side view of the stent graft of FIG.","71; FIG.","73 is a photograph of a perspective view from a side of a proximal end of the stent graft of FIGS.","1 and 70 with a bare stent protruding from the proximal end thereof; FIG.","74 is a photograph of an enlarged, perspective view from the interior of the proximal end of the stent graft of FIG.","71; FIG.","75 is a photograph of a perspective view from a distal end of the stent graft of FIG.","71 with an alternative embodiment of the crown stent where less of the stent is attached to the graft; FIG.","76 is a photograph of a side view of the stent graft of FIG.","71 partially withdrawn from a flexible sheath of the delivery system according to the invention with some of the capture stent apices releasably held within the apex capture device of the delivery system; FIG.","77 is a photograph of a perspective view of the captured stent graft of FIG.","76 from the proximal end thereof and with some of the capture stent apices releasably held within the apex capture device of the delivery system; FIG.","78 is a photograph of a perspective view from the proximal end of the stent graft of FIGS.","1 and 70 deployed in an exemplary vessel; FIG.","79 is a photograph of a perspective view from the proximal end of the stent graft of FIG.","71 deployed in an exemplary vessel; FIG.","80 is a cross-sectional view of the apex capture assembly of FIGS.","13, 14, 29 to 32, and 63 along a plane orthogonal to the longitudinal axis of the delivery system according to the invention without the inner sheath; FIG.","81 is a fragmentary, cross-sectional view of the apex capture assembly of FIG.","80 along a plane orthogonal to the view plane of FIG.","80 and through the longitudinal axis of the delivery system according to the invention without the inner sheath; FIG.","82 is a fragmentary, side elevational view of a distal end of the delivery system according to the invention with the inner sheath in a curved orientation and having an alternative embodiment of a D-shaped marker thereon; FIG.","83 is a fragmentary, plan view of the distal end of FIG.","82 viewed from above; FIG.","84 is a fragmentary, plan and partially hidden view of the distal end of FIG.","82 viewed from below with the D-shaped marker on the opposite top side; FIG.","85 is a fragmentary, elevational view of the distal end of FIG.","82 viewed from the top of FIG.","82 and parallel to the longitudinal axis of the catheter of the delivery system; FIG.","86 is a side elevational view of the delivery system according to the invention with an alternative embodiment of a rotating distal handle; FIG.","87 is a fragmentary, cross-sectional view of the rotating distal handle of FIG.","86; FIG.","88 is a is a fragmentary, cross-sectional view of an alternative embodiment of the rotating distal handle of FIG.","86; FIG.","89 is a fragmentary, perspective view of the distal end of the delivery system of FIG.","86; FIG.","90 is a perspective view from the distal side of another embodiment of the delivery system of the invention; FIG.","91 is a fragmentary, enlarged, exploded, side elevational view of the apex release assembly of the delivery system of FIG.","90; FIG.","92 is a fragmentary, enlarged, partially exploded, side elevational view of the locking knob assembly of the delivery system of FIG.","90; FIG.","93 is a perspective view of a clasp sleeve of a handle assembly of the delivery system of FIG.","90; FIG.","94 is an exploded, perspective view of a clasp body assembly of the handle assembly of FIG.","90; FIG.","95 is an exploded, perspective view of a rotator assembly of the handle assembly of FIG.","90; FIG.","96 is a perspective view of the rotator assembly of FIG.","95 in an assembled state; FIG.","97 is a fragmentary, exploded, side elevational view of a delivery sheath of the delivery system of FIG.","90; FIG.","98 is a fragmentary, exploded, side elevational view of the delivery sheath of FIG.","97 rotated approximately 90 degrees; FIG.","99 is an enlarged, side elevational view of a portion of the delivery sheath of FIG.","98; FIG.","100 is a fragmentary, enlarged, side elevational view of the distal end of the delivery system of FIG.","90; FIG.","101 is a fragmentary, partially hidden side elevational view and partially cross-sectional view of the proximal end of the handle assembly of FIG.","90 with the sheath lumen removed; FIG.","102 is a fragmentary, cross-sectional view of the proximal end of the handle assembly of FIG.","101; FIG.","103 is a fragmentary, enlarged, cross-sectional view of the actuation knob and clasp body assemblies of the handle assembly of FIG.","102; FIG.","104 is a fragmentary, enlarged, cross-sectional view of the rotator assembly of the handle assembly of FIG.","102; FIG.","105 is a fragmentary, further-enlarged, cross-sectional view of the rotator assembly of the handle assembly of FIG.","104; FIG.","106 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.","90; FIG.","107 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.","90; FIG.","108 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.","90; FIG.","109 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.","90; FIG.","110 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.","90; FIG.","111 is a fragmentary, enlarged, transverse cross-sectional view of the handle assembly of FIG.","110; FIG.","112 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.","90; FIG.","113 is a fragmentary, enlarged transverse cross-sectional view of the handle assembly of FIG.","112; FIG.","114 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.","90; FIG.","115 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.","90; FIG.","116 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.","90; FIG.","117 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.","90; FIG.","118 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.","90; FIG.","119 is a fragmentary, shaded, cross-sectional view of a distal portion of the handle assembly of FIG.","90 without the proximal handle.","DESCRIPTION OF EXEMPLARY EMBODIMENTS While the specification concludes with claims defining the features of the invention that are regarded as novel, it is believed that the invention will be better understood from a consideration of the following description in conjunction with the drawing figures, in which like reference numerals are carried forward.","The present invention provides a stent graft, delivery system, and method for implanting a prosthesis with a two-part expanding delivery system that treats, in particular, thoracic aortic defects from the brachiocephalic level of the aortic arch distally to a level just superior to the celiac axis and provides an endovascular foundation for an anastomosis with the thoracic aorta, while providing an alternative method for partial/total thoracic aortic repair by excluding the vessel defect and making surgical repair of the aorta unnecessary.","The stent graft of the present invention, however, is not limited to use in the aorta.","It can be endoluminally inserted in any accessible artery that could accommodate the stent graft's dimensions.","Stent Graft The stent graft according to the present invention provides various features that, heretofore, have not been applied in the art and, thereby, provide a vessel repair device that implants/conforms more efficiently within the natural or diseased course of the aorta, decreases the likelihood of vessel puncture, and increases the blood-tight vascular connection, and decreases the probability of graft mobility.","The stent graft is implanted endovascularly before or during or in place of an open repair of the vessel (i.e., an arch, in particular, the ascending and/or descending portion of the aorta) through a delivery system described in detail below.","The typical defects treated by the stent graft are aortic aneurysms, aortic dissections, and other diseases such as penetrating aortic ulcer, coarctation, and patent ductus arteriosus, related to the aorta.","When endovascularly placed in the aorta, the stent graft forms a seal in the vessel and automatically affixes itself to the vessel with resultant effacement of the pathological lesion.","Referring now to the figures of the drawings in detail and first, particularly to FIG.","1 thereof, there is shown an improved stent graft 1 having a graft sleeve 10 and a number of stents 20.These stents 20 are, preferably, made of nitinol, an alloy having particularly special properties allowing it to rebound to a set configuration after compression, the rebounding property being based upon the temperature at which the alloy exists.","For a detailed explanation of nitinol and its application with regard to stents, see, e.g., U.S. Pat.","Nos.","4,665,906, 5,067,957, and 5,597,378 to Jervis and to Gianturco.","The graft sleeve 10 is cylindrical in shape and is made of a woven graft material along its entire length.","The graft material is, preferably, polyester, in particular, polyester referred to under the name DACRON® or other material types like Expanded Polytetrafluoroethylene (“EPTFE”), or other polymeric based coverings.","The tubular graft sleeve 10 has a framework of individual lumen-supporting wires each referred to in the art as a stent 20.Connection of each stent 20 is, preferably, performed by sewing a polymeric (nylon, polyester) thread around an entirety of the stent 20 and through the graft sleeve 10.The stitch spacings are sufficiently close to prevent any edge of the stent 20 from extending substantially further from the outer circumference of the graft sleeve 10 than the diameter of the wire itself.","Preferably, the stitches have a 0.5 mm to 5 mm spacing.","The stents 20 are sewn either to the exterior or interior surfaces of the graft sleeve 10.FIG.","1 illustrates all stents 20, 30 on the exterior surface 16 of the graft sleeve 10.In an exemplary non-illustrated embodiment, the most proximal 23 and distal stents and a bare stent 30 are connected to the interior surface of the graft sleeve 10 and the remainder of the stents 20 are connected to the exterior surface 16.Another possible non-illustrated embodiment alternates connection of the stents 20, 30 to the graft sleeve 10 from the graft exterior surface to the graft interior surface, the alternation having any periodic sequence.","A stent 20, when connected to the graft sleeve 10, radially forces the graft sleeve 10 open to a predetermined diameter D. The released radial force creates a seal with the vessel wall and affixes the graft to the vessel wall when the graft is implanted in the vessel and is allowed to expand.","Typically, the stents 20 are sized to fully expand to the diameter D of the fully expanded graft sleeve 10.However, a characteristic of the present invention is that each of the stents 20 and 30 has a diameter larger than the diameter D of the fully expanded graft sleeve 10.Thus, when the stent graft 1 is fully expanded and resting on the internal surface of the vessel where it has been placed, each stent 20 is imparting independently a radially directed force to the graft sleeve 10.Such pre-compression, as it is referred to herein, is applied (1) to ensure that the graft covering is fully extended, (2) to ensure sufficient stent radial force to make sure sealing occurs, (3) to affix the stent graft and prevent it from kinking, and (4) to affix the stent graft and prevent migration.","Preferably, each of the stents 20 is formed with a single nitinol wire.","Of course other biocompatible materials can be used, for example, stainless steel, biopolymers, cobalt chrome, and titanium alloys.","An exemplary shape of each stent 20 corresponds to what is referred in the art as a Z-stent, see, e.g., Gianturco (although the shape of the stents 20 can be in any form that satisfies the functions of a self-expanding stent).","Thus, the wire forming the stent 20 is a ring having a wavy or sinusoidal shape.","In particular, an elevational view orthogonal to the center axis 21 of the stent 20 reveals a shape somewhere between a triangular wave and a sinusoidal wave as shown in FIG.","2.In other words, the view of FIG.","2 shows that the stents 20 each have alternating proximal 22 and distal 24 apices.","Preferably, the apices have a radius r that does not present too great of a point towards a vessel wall to prevent any possibility of puncturing the vessel, regardless of the complete circumferential connection to the graft sleeve 10.In particular, the radius r of curvature of the proximal 22 and distal 24 apices of the stent 20 are, preferably, equal.","The radius of curvature r is between approximately 0.1 mm and approximately 3.0 mm, in particular, approximately 0.5 mm.","Another advantageous feature of a stent lies in extending the longitudinal profile along which the stent contacts the inner wall of a vessel.","This longitudinal profile can be explained with reference to FIGS.","3 to 7.Prior art stents and stents according to the present invention are formed on mandrels 29, 29′ by winding the wire around the mandrel 29, 29′ and forming the apexes 22, 24, 32, 34 by wrapping the wire over non-illustrated pins that protrude perpendicular from the axis of the mandrel.","Such pins, if illustrated, would be located in the holes illustrated in the mandrels 29, 29′ of FIGS.","4 and 6.Prior art stents are formed on a round mandrel 29 (also referred to as a bar).","A stent 20′ formed on a round mandrel 29 has a profile that is rounded (see FIG.","5).","Because of the rounded profile, the stent 20′ does not conform evenly against the inner wall of the vessel 2 in which it is inserted.","This disadvantage is critical in the area of stent graft 1 seal zones—areas where the ends of the graft sleeve 10 need to be laid against the inner wall of the vessel 2.Clinical experience reveals that stents 20′ formed with the round mandrel 29 do not lie against the vessel 2; instead, only a mid-section of the stent 20′ rests against the vessel 2, as shown in FIG.","5.Accordingly, when such a stent 20′ is present at either of the proximal 12 or distal 14 ends of the stent graft 1, the graft material flares away from the wall of the vessel 2 into the lumen—a condition that is to be avoided.","An example of this flaring can be seen by comparing the upper and lower portions of the curved longitudinal profile of the stent 20′ in FIG.","5 with the linear longitudinal profile of the vessel 2.To remedy this problem and ensure co-columnar apposition of the stent and vessel, stents 20 of the present invention are formed on a multiple-sided mandrel.","In particular, the stents 20 are formed on a polygonal-shaped mandrel 29′.","The mandrel 29′ does not have sharp edges.","Instead, it has flat sections and rounded edge portions between the respective flat sections.","Thus, a stent formed on the mandrel 29′ will have a cross-section that is somewhat round but polygonal, as shown in FIG.","3.The cross-sectional view orthogonal to the center axis 21 of such a stent 20 will have beveled or rounded edges 31 (corresponding to the rounded edge portions of the mandrel 29′) disposed between flat sides or struts 33 (corresponding to the flat sections of the mandrel 29′).","With stents manufactured in this way, the apices remain on the circumference of the graft and do not bend into the graft interior like prior art stents—an undesirable condition as explained in the preceding paragraph.","Further, the struts of the stents so manufactured (the substantially linear portions of the stent between the apices) lie in the plane of the graft material when attached thereto as shown in FIG.","7.In contrast, prior art struts are curved (see FIG.","5) and, therefore, force the graft material inwards away from the vessel wall.","As used herein, substantially linear means that the struts are sufficiently straight and level to substantially prevent displacement of an apex (which lies between two adjacent struts) towards the interior of the graft material to which the struts and apices are attached.","To manufacture the stent 20, apexes of the stents 20 are formed by winding the wire over non-illustrated pins located on the rounded portions of the mandrel 29′.","Thus, the struts 33 lying between the apexes 22, 24, 32, 34 of the stents 20 lie flat against the flat sides of the mandrel 29′.","When so formed on the inventive mandrel 29′, the longitudinal profile is substantially less rounded than the profile of stent 20′ and, in practice, is substantially linear.","For stents 20 having six proximal 22 and six distal 24 apices, the stents 20 are formed on a dodecahedron-shaped mandrel 29′ (a mandrel having twelve sides), which mandrel 29′ is shown in FIG.","6.A stent 20 formed on such a mandrel 29′ will have the cross-section illustrated in FIG.","3.The fourteen-apex stent 20 shown in FIG.","7 illustrates a stent 20 that has been formed on a fourteen-sided mandrel.","The stent 20 in FIG.","7 is polygonal in cross-section (having fourteen sides) and, as shown in FIG.","7, has a substantially linear longitudinal profile.","Clinically, the linear longitudinal profile improves the stent's 20 ability to conform to the vessel 2 and press the graft sleeve 10 outward in the sealing zones at the extremities of the individual stent 20.Another way to improve the performance of the stent graft 1 is to provide the distal-most stent 25 on the graft sleeve 10 (i.e., downstream) with additional apices and to give it a longer longitudinal length (i.e., greater amplitude) and/or a longer circumferential length.","When a stent 25 having a longer circumferential length is sewn to a graft, the stent graft 1 will perform better clinically.","The improvement, in part, is due to a need for the distal portion of the graft material 10 to be pressed firmly against the wall of the vessel.","The additional apices result in additional points of contact between the stent graft 1 and vessel wall, thus ensuring better apposition to the wall of the vessel and better sealing of the graft material 10 to the vessel.","The increased apposition and sealing substantially improves the axial alignment of the distal end 14 of the stent graft 1 to the vessel.","As set forth above, each of the stents 20 and 30 has a diameter larger than the diameter D of the fully expanded graft sleeve 10.Thus, if the distal stent 25 also has a diameter larger than the diameter D, it will impart a greater radial bias on all 360 degrees of the corresponding section of the graft than stents not having such an oversized configuration.","A typical implanted stent graft 1 typically does not experience a lifting off at straight portions of a vessel because the radial bias of the stents acting upon the graft sleeve give adequate pressure to align the stent and graft sleeve with the vessel wall.","However, when a typical stent graft is implanted in a curved vessel (such as the aorta), the distal end of the stent graft 1 does experience a lift off from the vessel wall.","The increased apposition and sealing of the stent graft 1 according to the present invention substantially decreases the probability of lift off because the added height and additional apices enhance the alignment of the stent graft perpendicular to the vessel wall as compared to prior art stent grafts (no lift off occurs).","The number of total apices of a stent is dependent upon the diameter of the vessel in which the stent graft 1 is to be implanted.","Vessels having a smaller diameter have a smaller total number of apices than a stent to be implanted in a vessel having a larger diameter.","Table I below indicates exemplary stent embodiments for vessels having different diameters.","For example, if a vessel has a 26 or 27 mm diameter, then an exemplary diameter of the graft sleeve 10 is 30 mm.","For a 30 mm diameter graft sleeve, the intermediate stents 20 will have 5 apices on each side (proximal and distal) for a total of 10 apices.","In other words, the stent defines 5 periodic “waves.” The distal-most stent 25, in comparison, defines 6 periodic “waves” and, therefore, has 12 total apices.","It is noted that the distal-most stent 25 in FIG.","1 does not have the additional apex.","While Table 1 indicates exemplary embodiments, these configurations can be adjusted or changed as needed.","TABLE 1 Vessel Diameter Graft Diameter Stent Apices/Side (mm) (mm) (Distal-most Stent #) 19 22 5(5) 20-21 24 5(5) 22-23 26 5(5) 24-25 28 5(6) 26-27 30 5(6) 28-29 32 6(7) 30-31 34 6(7) 32-33 36 6(7) 34 38 6(7) 35-36 40 7(8) 37-38 42 7(8) 39-40 44 7(8) 41-42 46 7(8) To increase the security of the stent graft 1 in a vessel, an exposed or bare stent 30 is provided on the stent graft 1, preferably, only at the proximal end 12 of the graft sleeve 10—proximal meaning that it is attached to the portion of the graft sleeve 10 from which the blood flows into the sleeve, i.e., blood flows from the bare stent 30 and through the graft sleeve 10 to the left of FIG.","1.The bare stent 30 is not limited to being attached at the proximal end 12.Another non-illustrated bare stent can be attached similarly to the distal end 14 of the graft sleeve 10.Significantly, the bare stent 30 is only partially attached to the graft sleeve 10.Specifically, the bare stent 30 is fixed to the graft sleeve 10 only at the distal apices 34 of the bare stent 30.Thus, the bare stent 30 is partially free to extend the proximal apices 32 away from the proximal end of the graft sleeve 10.The bare stent 30 has various properties, the primary one being to improve the apposition of the graft material to the contour of the vessel wall and to align the proximal portion of the graft covering in the lumen of the arch and provide a blood-tight closure of the proximal end 12 of the graft sleeve 10 so that blood does not pass between the vascular inside wall and outer surface 16 of the graft sleeve 10 (endoleak).","An exemplary configuration for the radius of curvature a of the distal apices 34 is substantially equal to the radius r of the proximal 22 and distal 24 apices of the stent 20, in particular, it is equal at least to the radius of curvature r of the proximal apices of the stent 20 directly adjacent the bare stent 30.Thus, as shown in FIG.","8, a distance between the proximal apices 22 of the most proximal stent 23 and crossing points of the exposed portions of the bare stent 30 are substantially at a same distance from one another all the way around the circumference of the proximal end 12 of the graft sleeve 10.Preferably, this distance varies based upon the graft diameter.","Accordingly, the sinusoidal portion of the distal apices 34 connected to the graft sleeve 10 traverse substantially the same path as that of the stent 23 closest to the bare stent 30.Thus, the distance d between the stent 23 and all portions of the bare stent 30 connected to the graft sleeve 10 remain constant.","Such a configuration is advantageous because it maintains the symmetry of radial force of the device about the circumference of the vessel and also aids in the synchronous, simultaneous expansion of the device, thus increasing apposition of the graft material to the vessel wall to induce a proximal seal—and substantially improve the proximal seal—due to increasing outward force members in contact with the vessel wall.","Inter-positioning the stents 23, 30 in phase with one another, creates an overlap, i.e., the apices 34 of the bare stent 30 are positioned within the troughs of the stent 23.A further advantage of such a configuration is that the overlap provides twice as many points of contact between the proximal opening of the graft sleeve 10 and the vessel in which the stent graft 1 is implanted.","The additional apposition points keep the proximal opening of the graft sleeve 10 open against the vessel wall, which substantially reduces the potential for endoleaks.","In addition, the overlap of the stents 23, 30 increases the radial load or resistance to compression, which functionally increases fixation and reduces the potential for device migration.","In contrast to the distal apices 34 of the bare stent 30, the radius of curvature .beta.","of the proximal apices 32 (those apices that are not sewn into the graft sleeve 10) is significantly larger than the radius of curvature .alpha.","of the distal apices 34.An exemplary configuration for the bare stent apices has a radius approximately equal to 1.5 mm for the proximal apices 32 and approximately equal to 0.5 mm for the distal apices 34.Such a configuration substantially prevents perforation of the blood vessel by the proximal apices 32, or, at a minimum, makes is much less likely for the bare stent 30 to perforate the vessel because of the less-sharp curvature of the proximal apices 32.The bare stent 30 also has an amplitude greater than the other stents 20.Preferably, the peak-to-peak amplitude of the stents 20 is approximately 1.3 cm to 1.5 cm, whereas the peak-to-peak amplitude of the bare stent 30 is approximately 2.5 cm to 4.0 cm.","Accordingly, the force exerted by the bare stent 30 on the inner wall of the aorta (due to the bare stent 30 expanding to its native position) is spread over a larger surface area.","Thus, the bare stent 30 of the present invention presents a less traumatic radial stress to the interior of the vessel wall—a characteristic that, while less per square mm than an individual one of the stents 20 would be, is sufficient, nonetheless, to retain the proximal end 12 in position.","Simultaneously, the taller configuration of the bare stent 30 guides the proximal opening of the stent graft in a more “squared-off” manner.","Thus, the proximal opening of the stent graft is more aligned with the natural curvature of the vessel in the area of the proximal opening.","As set forth above, because the vessel moves constantly, and due to the constantly changing pressure imparted by blood flow, any stent graft placed in the vessel has the natural tendency to migrate downstream.","This is especially true when the stent graft 1 has graft sleeve segments 18 with lengths defined by the separation of the stents on either end of the segment 18, giving the stent graft 1 an accordion, concertina, or caterpillar-like shape.","When such a shape is pulsating with the vessel and while hemodynamic pressure is imparted in a pulsating manner along the stent graft from the proximal end 12 to the downstream distal end 14, the stent graft 1 has a tendency to migrate downstream in the vessel.","It is desired to have such motion be entirely prohibited.","Support along a longitudinal extent of the graft sleeve 10 assists in preventing such movement.","Accordingly, as set forth above, prior art stent grafts have provided longitudinal rods extending in a straight line from one stent to another.","The present invention, however, provides a longitudinal, spiraling/helical support member 40 that, while extending relatively parallel to the longitudinal axis 11 of the graft sleeve 10, is not aligned substantially parallel to a longitudinal extent of the entirety of the stent graft 1 as done in the prior art.","“Relatively parallel” is referred to herein as an extent that is more along the longitudinal axis 11 of the stent graft 1 than along an axis perpendicular thereto.","Specifically, the longitudinal support member 40 has a somewhat S-turn shape, in that, a proximal portion 42 is relatively parallel to the longitudinal axis 11 of the graft sleeve 10 at a first degree 41 (being defined as a degree of the 360 degrees of the circumference of the graft sleeve 10), and a distal portion 44 is, also, relatively parallel to the longitudinal axis 11 of the tube graft, but at a different second degree 43 on the circumference of the graft sleeve 10.The difference between the first and second degrees 41, 43 is dependent upon the length L of the graft sleeve 10.For an approximately 20 cm (approx.","8″) graft sleeve, for example, the second degree 43 is between 80 and 110 degrees away from the first degree 41, in particular, approximately 90 degrees away.","In comparison, for an approximately 9 cm (approx.","3.5″) graft sleeve, the second degree 43 is between 30 and 60 degrees away from the first degree 41, in particular, approximately 45 degrees away.","As set forth below, the distance between the first and second degrees 41, 43 is also dependent upon the curvature and the kind of curvature that the stent graft 1 will be exposed to when in vivo.","The longitudinal support member 40 has a curved intermediate portion 46 between the proximal and distal portions 42, 44.By using the word “portion” it is not intended to mean that the rod is in three separate parts (of course, in a particular configuration, a multi-part embodiment is possible).","An exemplary embodiment of the longitudinal support member 40 is a single, one-piece rod made of stainless steel, cobalt chrome, nitinol, or polymeric material that is shaped as a fully curved helix 42, 44, 46 without any straight portion.","In an alternative stent graft embodiment, the proximal and distal portions 42, 44 can be substantially parallel to the longitudinal axis 11 of the stent graft 1 and the central portion 46 can be helically curved.","One way to describe an exemplary curvature embodiment of the longitudinal support member 40 can be using an analogy of asymptotes.","If there are two asymptotes extending parallel to the longitudinal axis 11 of the graft sleeve 10 at the first and second degrees 41, 43 on the graft sleeve 10, then the proximal portion 42 can be on the first degree 41 or extend approximately asymptotically to the first degree 41 and the distal portion 44 can be on the second degree 43 or extend approximately asymptotically to the second degree 43.Because the longitudinal support member 40 is one piece in an exemplary embodiment, the curved portion 46 follows the natural curve formed by placing the proximal and distal portions 42, 44 as set forth herein.","In such a position, the curved longitudinal support member 40 has a centerline 45 (parallel to the longitudinal axis 11 of the graft sleeve 10 halfway between the first and second degrees 41, 43 on the graft sleeve 10).","In this embodiment, therefore, the curved portion intersects the centerline 45 at approximately 20 to 40 degrees in magnitude, preferably at approximately 30 to 35 degrees.","Another way to describe the curvature of the longitudinal support member can be with respect to the centerline 45.The portion of the longitudinal support member 40 between the first degree 41 and the centerline 45 is approximately a mirror image of the portion of the longitudinal support member 40 between the second degree 43 and the centerline 45, but rotated one-hundred eighty degrees (180.degree.)","around an axis orthogonal to the centerline 45.Such symmetry can be referred to herein as “reverse-mirror symmetrical.” The longitudinal support member 40 is, preferably, sewn to the graft sleeve 10 in the same way as the stents 20.However, the longitudinal support member 40 is not sewn directly to any of the stents 20 in the proximal portions of the graft.","In other words, the longitudinal support member 40 is independent of the proximal skeleton formed by the stents 20.Such a configuration is advantageous because an independent proximal end creates a gimbal that endows the stent graft with additional flexibility.","Specifically, the gimbaled proximal end allows the proximal end to align better to the proximal point of apposition, thus reducing the chance for endoleak.","The additional independence from the longitudinal support member allows the proximal fixation point to be independent from the distal section that is undergoing related motion due to the physiological motion of pulsatile flow of blood.","Also in an exemplary embodiment, the longitudinal support member 40 is pre-formed in the desired spiral/helical shape (counter-clockwise from proximal to distal), before being attached to the graft sleeve 10.Because vessels receiving the stent graft 1 are not typically straight (especially the aortic arch), the final implanted position of the stent graft 1 will, most likely, be curved in some way.","In prior art stent grafts (which only provide longitudinally parallel support rods), there exist, inherently, a force that urges the rod, and, thereby, the entire stent graft, to the straightened, natural shape of the rod.","This force is disadvantageous for stent grafts that are to be installed in an at least partly curved manner.","The curved shape of the longitudinal support member 40 according to the present invention eliminates at least a majority, or substantially all, of this disadvantage because the longitudinal support member's 40 natural shape is curved.","Therefore, the support member 40 imparts less of a force, or none at all, to straighten the longitudinal support member 40, and, thereby, move the implanted stent graft in an undesirable way.","At the same time, the curved longitudinal support member 40 negates the effect of the latent kinetic force residing in the aortic wall that is generated by the propagation of the pulse wave and systolic blood pressure in the cardiac cycle, which is, then, released during diastole.","As set forth in more detail below, the delivery system of the present invention automatically aligns the stent graft 1 to the most optimal position while traversing the curved vessel in which it is to be implanted, specifically, the longitudinal support member 40 is placed substantially at the superior longitudinal surface line of the curved aorta (with respect to anatomical position).","In an exemplary embodiment, the longitudinal support member 40 can be curved in a patient-customized way to accommodate the anticipated curve of the actual vessel in which the graft will be implanted.","Thus, the distance between the first and second degrees 41, 43 will be dependent upon the curvature and the kind of curvature that the stent graft 1 will be exposed to when in vivo.","As such, when implanted, the curved longitudinal support member 40 will, actually, exhibit an opposite force against any environment that would alter its conformance to the shape of its resident vessel's existing course(es).","Preferably, the support member 40 is sewn, in a similar manner as the stents 20, on the outside surface 16 of the graft sleeve 10.In prior art support rods, the ends thereof are merely a terminating end of a steel or nitinol rod and are, therefore, sharp.","Even though these ends are sewn to the tube graft in the prior art, the possibility of tearing the vessel wall still exists.","It is, therefore, desirable to not provide the support rod with sharp ends that could puncture the vessel in which the stent graft is placed.","The two ends of the longitudinal support member 40 of the present invention do not end abruptly.","Instead, each end of the longitudinal support member loops 47 back upon itself such that the end of the longitudinal support member along the axis of the stent graft is not sharp and, instead, presents an exterior of a circular or oval shape when viewed from the ends 12, 14 of the graft sleeve 10.Such a configuration substantially prevents the possibility of tearing the vessel wall and also provides additional longitudinal support at the oval shape by having two longitudinally extending sides of the oval 47.In addition, in another embodiment, the end of the longitudinal support member may be connected to the second proximal stent 28 and to the most distal stent.","This configuration would allow the longitudinal support member to be affixed to stent 28 (see FIG.","1) and the most distal stent for support while still allowing for the gimbaled feature of the proximal end of the stent graft to be maintained.","A significant feature of the longitudinal support member 40 is that the ends of the longitudinal support member 40 may not extend all the way to the two ends 12, 14 of the graft sleeve 10.Instead, the longitudinal support member 40 terminates at or prior to the second-to-last stent 28 at the proximal end 12, and, if desired, prior to the second-to-last stent 28′ at the distal end 14 of the graft sleeve 10.Such an ending configuration (whether proximal only or both proximal and distal) is chosen for a particular reason—when the longitudinal support member 40 ends before either of the planes defined by cross-sectional lines 52, 52′, the graft sleeve 10 and the stents 20 connected thereto respectively form gimbaled portions 50, 50′.","In other words, when a grasping force acting upon the gimbaled ends 50, 50′ moves or pivots the cross-sectional plane defining each end opening of the graft sleeve 10 about the longitudinal axis 11 starting from the planes defined by the cross-sectional lines 52, 52′, then the moving portions 50, 50′ can be oriented at any angle .gamma.","about the center of the circular opening in all directions (360 degrees), as shown in FIG.","8.The natural gimbal, thus, allows the ends 50, 50′ to be inclined in any radial direction away from the longitudinal axis 11.Among other things, the gimbaled ends 50, 50′ allow each end opening to dynamically align naturally to the curve of the vessel in which it is implanted.","A significant advantage of the gimbaled ends 50, 50′ is that they limit propagation of the forces acting upon the separate parts.","Specifically, a force that, previously, would act upon the entirety of the stent graft 1, in other words, both the end portions 50, 50′ and the middle portion of the stent graft 1 (i.e., between planes 52, 52′), now principally acts upon the portion in which the force occurs.","For example, a force that acts only upon one of the end portions 50, 50′ substantially does not propagate into the middle portion of the stent graft 1 (i.e., between planes 52, 52′).","More significantly, however, when a force acts upon the middle portion of the stent graft 1 (whether moving longitudinally, axially (dilation), or in a torqued manner), the ends 50, 50′, because they are gimbaled, remain relatively completely aligned with the natural contours of the vessel surrounding the respective end 50, 50′ and have virtually none of the force transferred thereto, which force could potentially cause the ends to grate, rub, or shift from their desired fixed position in the vessel.","Accordingly, the stent graft ends 50, 50′ remain fixed in the implanted position and extend the seating life of the stent graft 1.Another advantage of the longitudinal support member 40 is that it increases the columnar strength of the graft stent 1.Specifically, the material of the graft sleeve can be compressed easily along the longitudinal axis 11, a property that remains true even with the presence of the stents 20 so long as the stents 20 are attached to the graft sleeve 10 with a spacing between the distal apices 24 of one stent 20 and the proximal apices 22 of the next adjacent stent 20.This is especially true for the amount of force imparted by the flow of blood along the extent of the longitudinal axis 11.However, with the longitudinal support member 40 attached according to the present invention, longitudinal strength of the stent graft 1 increases to overcome the longitudinal forces imparted by blood flow.","Another benefit imparted by having such increased longitudinal strength is that the stent graft 1 is further prevented from migrating in the vessel because the tube graft is not compressing and expanding in an accordion-like manner—movement that would, inherently, cause graft migration.","A further measure for preventing migration of the stent graft 1 is to equip at least one of any of the individual stents 20, 30 or the longitudinal support member 40 with protuberances 60, such as barbs or hooks (FIG.","3).","See, e.g., United States Patent Publication 2002/0052660 to Greenhaigh.","In an exemplary embodiment of the present invention, the stents 20, 30 are secured to the outer circumferential surface 16 of the graft sleeve 10.Accordingly, if the stents 20 (or connected portions of stent 30) have protuberances 60 protruding outwardly, then such features would catch the interior wall of the vessel and add to the prevention of stent graft 1 migration.","Such an embodiment can be preferred for aneurysms but is not preferred for the fragile characteristics of dissections because such protuberances 60 can excoriate the inner layer(s) of the vessel and cause leaks between layers, for example.","As shown in FIG.","9, the stent graft 1 is not limited to a single graft sleeve 10.Instead, the entire stent graft can be a first stent graft 100 having all of the features of the stent graft 1 described above and a second stent graft 200 that, instead of having a circular extreme proximal end 12, as set forth above, has a proximal end 212 with a shape following the contour of the most proximal stent 220 and is slightly larger in circumference than the distal circumference of the first stent graft 100.Therefore, an insertion of the proximal end 212 of the second stent graft 200 into the distal end 114 of the first stent graft 100 results, in total, in a two-part stent graft.","Because blood flows from the proximal end 112 of the first stent graft 100 to the distal end 214 of the second stent graft 200, it is preferable to have the first stent graft 100 fit inside the second stent graft 200 to prevent blood from leaking out therebetween.","This configuration can be achieved by implanting the devices in reverse order (first implant graft 200 and, then, implant graft 100.Each of the stent grafts 100, 200 can have its own longitudinal support member 40 as needed.","It is not significant if the stent apices of the distal-most stent of the first stent graft 100 are not aligned with the stent apices of the proximal-most stent 220 of the second stent graft 200.What is important is the amount of junctional overlap between the two grafts 100, 200.Delivery System As set forth above, the prior art includes many different systems for endoluminally delivering a prosthesis, in particular, a stent graft, to a vessel.","Many of the delivery systems have similar parts and most are guided along a guidewire that is inserted, typically, through an insertion into the femoral artery near a patient's groin prior to use of the delivery system.","To prevent puncture of the arteries leading to and including the aorta, the delivery system is coaxially connected to the guidewire and tracks the course of the guidewire up to the aorta.","The parts of the delivery system that will track over the wire are, therefore, sized to have an outside diameter smaller than the inside diameter of the femoral artery of the patient.","The delivery system components that track over the guidewire include the stent graft and are made of a series of coaxial lumens referred to as catheters and sheaths.","The stent graft is constrained, typically, by an outer catheter, requiring the stent graft to be compressed to fit inside the outer catheter.","Doing so makes the portion of the delivery system that constrains the stent graft very stiff, which, therefore, reduces that portion's flexibility and makes it difficult for the delivery system to track over the guidewire, especially along curved vessels such as the aortic arch.","In addition, because the stent graft exerts very high radial forces on the constraining catheter due to the amount that it must be compressed to fit inside the catheter, the process of deploying the stent graft by sliding the constraining catheter off of the stent graft requires a very high amount of force, typically referred to as a deployment force.","Also, the catheter has to be strong enough to constrain the graft, requiring it to be made of a rigid material.","If the rigid material is bent, such as when tracking into the aortic arch, the rigid material tends to kink, making it difficult if not impossible to deploy the stent graft.","Common features of vascular prosthesis delivery systems include a tapered nose cone fixedly connected to a guidewire lumen, which has an inner diameter substantially corresponding to an outer diameter of the guidewire such that the guidewire lumen slides easily over and along the guidewire.","A removable, hollow catheter covers and holds a compressed prosthesis in its hollow and the catheter is fixedly connected to the guidewire lumen.","Thus, when the prosthesis is in a correct position for implantation, the physician withdraws the hollow catheter to gradually expose the self-expanding prosthesis from its proximal end towards its distal end.","When the catheter has withdrawn a sufficient distance from each portion of the expanding framework of the prosthesis, the framework can expand to its native position, preferably, a position that has a diameter at least as great as the inner diameter of the vessel wall to, thereby, tightly affix the prosthesis in the vessel.","When the catheter is entirely withdrawn from the prosthesis and, thereby, allows the prosthesis to expand to the diameter of the vessel, the prosthesis is fully expanded and connected endoluminally to the vessel along the entire extent of the prosthesis, e.g., to treat a dissection.","When treating an aneurysm, for example, the prosthesis is in contact with the vessel's proximal and distal landing zones when completely released from the catheter.","At such a point in the delivery, the delivery system can be withdrawn from the patient.","The prosthesis, however, cannot be reloaded in the catheter if implantation is not optimal.","The aorta usually has a relatively straight portion in the abdominal region and in a lower part of the thoracic region.","However, in the upper part of the thoracic region, the aorta is curved substantially, traversing an upside-down U-shape from the back of the heart over to the front of the heart.","As explained above, prior art delivery systems are relatively hard and inflexible (the guidewire/catheter portion of the prior art delivery systems).","Therefore, if the guidewire/catheter must traverse the curved portion of the aorta, it will kink as it is curved or it will press against the top portion of the aortic curve, possibly puncturing the aorta if the diseased portion is located where the guidewire/catheter is exerting its force.","Such a situation must be avoided at all costs because the likelihood of patient mortality is high.","The prior art does not provide any way for substantially reducing the stress on the curved portion of the aorta or for making the guidewire/catheter sufficiently flexible to traverse the curved portion without causing damage to the vessel.","The present invention, however, provides significant features not found in the prior art that assist in placing a stent graft in a curved portion of the aorta in a way that substantially reduces the stress on the curved portion of the aorta and substantially reduces the insertion forces needed to have the compressed graft traverse the curved portion of the aorta.","As set forth above, the longitudinal support member 40 is pre-formed in a desired spiral/helical shape before being attached to the graft sleeve 10 and, in an exemplary embodiment, is curved in a patient-customized way to accommodate the anticipated curve of the actual vessel in which the graft will be implanted.","As such, optimal positioning of the stent graft 1 occurs when the longitudinal support member 40 is placed substantially at the superior longitudinal surface line of the curved aorta (with respect to anatomical position).","Such placement can be effected in two ways.","First, the stent graft 1, the support member 40, or any portion of the delivery system that is near the target site can be provided with radiopaque markers that are monitored by the physician and used to manually align the support member 40 in what is perceived as an optimal position.","The success of this alignment technique, however, is dependent upon the skill of the physician.","Second, the delivery system can be made to automatically align the support member 40 at the optimal position.","No such system existed in the prior art.","However, the delivery system of the present invention provides such an alignment device, thereby, eliminating the need for physician guesswork as to the three-dimensional rotational position of the implanted stent graft 1.This alignment device is explained in further detail below with respect to FIGS.","64 to 67.The delivery system of the present invention also has a very simple to use handle assembly.","The handle assembly takes advantage of the fact that the inside diameter of the aorta is substantially larger that the inside diameter of the femoral arteries.","The present invention, accordingly, uses a two-stage approach in which, after the device is inserted in through the femoral artery and tracks up into the abdominal area of the aorta (having a larger diameter (see FIG.","19) than the femoral artery), a second stage is deployed (see FIG.","20) allowing a small amount of expansion of the stent graft while still constrained in a sheath; but this sheath, made of fabric/woven polymer or similar flexible material, is very flexible.","Such a configuration gives the delivery system greater flexibility for tracking, reduces deployment forces because of the larger sheath diameter, and easily overcome kinks because the sheath is made of fabric.","To describe the delivery system of the present invention, the method for operating the delivery assembly 600 will be described first in association with FIGS.","10, 11, and 12.Thereafter, the individual components will be described to allow a better understanding of how each step in the process is effected for delivering the stent graft 1 to any portion of the aorta 700 (see FIGS.","19 to 24), in particular, the curved portion 710 of the aorta.","Initially, the distal end 14 of the stent graft 1 is compressed and placed into a hollow, cup-shaped, or tubular-shaped graft holding device, in particular, the distal sleeve 644 (see, e.g., FIG.","25).","At this point, it is noted that the convention for indicating direction with respect to delivery systems is opposite that of the convention for indicating direction with respect to stent grafts.","Therefore, the proximal direction of the delivery system is that portion closest to the user/physician employing the system and the distal direction corresponds to the portion farthest away from the user/physician, i.e., towards the distal-most nose cone 632.The distal sleeve 644 is fixedly connected to the distal end of the graft push lumen 642, which lumen 642 provides an end face for the distal end 14 of the stent graft 1.Alternatively, the distal sleeve 644 can be removed entirely.","In such a configuration, as shown in FIG.","12, for example, the proximal taper of the inner sheath 652 can provide the measures for longitudinally holding the compressed distal end of the stent graft 1.If the sleeve 644 is removed, it is important to prevent the distal end 14 of the stent graft 1 from entering the space between the interior surface of the hollow sheath lumen 654 and the exterior surface of the graft push lumen 642 slidably disposed in the sheath lumen 654.Selecting a radial thickness of the space to be less than the diameter of the wire making up the stent 20, 30 (in particular, no greater than half a diameter thereof) insures reliable movement of the distal end 14 of the stent graft 1.In another alternative configuration shown in FIG.","68, the distal sleeve 644 can be a disk-shaped buttress 644 present at the distal end of the graft push lumen 642.An example configuration can provide the buttress 644 with a hollow proximal insertion peg 6442, a hollow distal stiffening tube 6444, and an intermediate buttress wall 6446.The buttress 644 is concentric to the center axis of the delivery system 600 and allows the co-axial guidewire lumen 620 and apex release lumen 640 to pass therethrough.","The peg 6442 allows for easy connection to the graft push lumen 643.The stiffening tube 64 creates a transition in stiffness from the graft push lumen 642 to the apex release lumen 640 and guidewire lumen 620 and provides support to the lumen 620, 640 located therein.","Such a transition in stiffness reduces any possibility of kinking at the distal end of the graft push lumen 642 and aids in transferring force from the graft push lumen 642 to the lumen therein 620, 640 when all are in a curved orientation.","The buttress wall 6446 provides a flat surface that will contact the distal-end-facing side of the stent graft 1 and can be used to push the stent graft distally when the graft push lumen 642 is moved distally.","The alternative configuration of the buttress 644 insures that the stent graft 1 does not become impinged within the graft push lumen 642 and the lumen therein 620, 640 when these components are moved relative to each other.","As set forth in more detail below, each apex 32 of the bare stent 30 is, then, loaded into the apex capture device 634 so that the stent graft 1 is held at both its proximal and distal ends.","The loaded distal end 14, along with the distal sleeve 644 and the graft push lumen 642, are, in turn, loaded into the inner sheath 652, thus, further compressing the entirety of the stent graft 1.The captured bare stent 30, along with the nose cone assembly 630 (including the apex capture device 634), is loaded until the proximal end of the nose cone 632 rests on the distal end of the inner sheath 652.The entire nose cone assembly 630 and sheath assembly 650 is, then, loaded proximally into the rigid outer catheter 660, further compressing the stent graft 1 (resting inside the inner sheath 652) to its fully compressed position for later insertion into a patient.","See FIG.","63.The stent graft 1 is, therefore, held both at its proximal and distal ends and, thereby, is both pushed and pulled when moving from a first position (shown in FIG.","19 and described below) to a second position (shown in FIG.","21 and described below).","Specifically, pushing is accomplished by the non-illustrated interior end face of the hollow distal sleeve 644 (or the taper 653 of the inner sheath 652) and pulling is accomplished by the hold that the apex capture device 634 has on the apices 32 of the bare stent 30.The assembly 600 according to the present invention tracks along a guidewire 610 already inserted in the patient and extending through the aorta and up to, but not into, the left ventricle of the heart 720.Therefore, a guidewire 610 is inserted through the guidewire lumen 620 starting from the nose cone assembly 630, through the sheath assembly 650, through the handle assembly 670, and through the apex release assembly 690.The guidewire 610 extends out the proximal-most end of the assembly 600.The guidewire lumen 620 is coaxial with the nose cone assembly 630, the sheath assembly 650, the handle assembly 670, and the apex release assembly 690 and is the innermost lumen of the assembly 600 immediately surrounding the guidewire 610.Before using the delivery system assembly 600, all air must be purged from inside the assembly 600.Therefore, a liquid, such as sterile U.S.P.","saline, is injected through a non-illustrated tapered luer fitting to flush the guidewire lumen at a non-illustrated purge port located near a proximal end of the guidewire lumen.","Second, saline is also injected through the luer fitting 612 of the lateral purge-port (see FIG.","11), which liquid fills the entire internal co-axial space of the delivery system assembly 600.It may be necessary to manipulate the system to facilitate movement of the air to be purged to the highest point of the system.","After purging all air, the system can be threaded onto the guidewire and inserted into the patient.","Because the outer catheter 660 has a predetermined length, the fixed front handle 672 can be disposed relatively close to the entry port of the femoral artery.","It is noted, however, that the length of the outer catheter 660 is sized such that it will not have the fixed proximal handle 672 directly contact the entry port of the femoral artery in a patient who has the longest distance between the entry port and the thoracic/abdominal junction 742, 732 of the aorta expected in a patient (this distance is predetermined).","Thus, the delivery assembly 600 of the present invention can be used with typical anatomy of the patient.","Of course, the assembly 600 can be sized to any usable length.","The nose cone assembly 630 is inserted into a patient's femoral artery and follows the guidewire 610 until the nose cone 632 reaches the first position at least to a level of the celiac axis and possibly further but not into the intended stent graft deployment site, which would prevent deployment of at least the downstream end of the stent graft.","The first position is shown in FIG.","19.The nose cone assembly 630 is radiopaque, whether wholly or partially, to enable the physician to determine fluoroscopically, for example, that the nose cone assembly 630 is in the first position.","For example, the nose cone 632 can have a radiopaque marker 631 anywhere thereon or the nose cone 632 can be entirely radiopaque.","FIGS.","19 to 24 illustrate the catheter 660 extending approximately up to the renal arteries.","However, the catheter 660 of the present invention is configured to travel up to at least the celiac axis (not shown in FIGS.","19 to 24).","As used herein, the celiac axis is to be defined according to common medical terms.","In a simplistic definition, the celiac axis is a plane that intersects and is parallel to a central axis of a patient's celiac at the intersection of the celiac and the aorta and, therefore, this plane is approximately orthogonal to the longitudinal axis of the abdominal/thoracic aorta at the point where the celiac intersects the aorta.","Therefore, with respect to extension of the catheter 660 into the aorta, it is extended into the aorta up to but not past the intended downstream end of the implant.","After arriving at this distal-most position, the distal end of the catheter 660 remains substantially steady along the longitudinal axis of the aorta until after the stent graft 1 is implanted (see FIG.","24) and the entire delivery system is to be removed from the patient.","While the delivery system of the present invention can be retracted in the orientation shown in FIG.","24 except for one difference (the bare stent 30 is open and the apex release device 634 is released from compressing the bare stent 30), the preferred embodiment for removal of the catheter 660 from the aorta after implantation of the stent graft 1 occurs with reference to the condition shown in FIG.","19—where all of the interior lumens 620, 640, 642, 654 are retracted inside the catheter 660 and the nose cone 632 is in contact with the distal end of the catheter 660.After the nose cone assembly 630 is in the first position shown in FIG.","19, the locking knob or ring 676 is placed from its neutral position into its advancement position.","As will be described below, placing the locking knob 676 into its advancement position A allows both the nose cone assembly 630 and the internal sheath assembly 650 to move as one when the proximal handle 678 is moved in either the proximal or distal directions because the locking knob 676 radially locks the graft push lumen 642 to the lumens of the apex release assembly 690 (including the guidewire lumen 620 and an apex release lumen 640).","The locking knob 676 is fixedly connected to a sheath lumen 654.Before describing how various embodiments of the handle assembly 670 function, a summary of the multi-lumen connectivity relationships, throughout the neutral, advancement, and deployment positions, is described.","When the locking ring is in the neutral position, the pusher clasp spring 298 shown in FIG.","48 and the distal clasp body spring 606 shown in FIG.","52 are both disengaged.","This allows free movement of the graft push lumen 642 with the guidewire lumen 620 and the apex release lumen 640 within the handle body 674.When the locking knob 676 is moved into the advancement position, the pusher clasp spring 298 shown in FIG.","48 is engaged and the distal clasp body spring 606 shown in FIG.","52 is disengaged.","The sheath lumen 654 (fixedly attached to the inner sheath 652) is, thereby, locked to the graft push lumen 642 (fixedly attached to the distal sleeve 644) so that, when the proximal handle 678 is moved toward the distal handle 672, both the sheath lumen 654 and the graft push lumen 642 move as one.","At this point, the graft push lumen 642 is also locked to both the guidewire lumen 620 and the apex release lumen 640 (which are locked to one another through the apex release assembly 690 as set forth in more detail below).","Accordingly, as the proximal handle 678 is moved to the second position, shown with dashed lines in FIG.","11, the sheath assembly 650 and the nose cone assembly 630 progress distally out of the outer catheter 660 as shown in FIGS.","20 and 21 and with dashed lines in FIG.","11.At this point, the sheath lumen 654 needs to be withdrawn from the stent graft 1 to, thereby, expose the stent graft 1 from its proximal end 12 to its distal end 14 and, ultimately, entirely off of its distal end 14.Therefore, movement of the locking knob 676 into the deployment position D will engage the distal clasp body spring 606 shown in FIG.","52 and disengage the pusher clasp spring 298 shown in FIG.","48.Accordingly, the graft push lumen 642 along with the guidewire lumen 620 and the apex release lumen 640 are locked to the handle body 674 so as not to move with respect to the handle body 674.The sheath lumen 654 is unlocked from the graft push lumen 642.Movement of the distal handle 678 back to the third position (proximally), therefore, pulls the sheath lumen 654 proximally, thus, proximally withdrawing the inner sheath 652 from the stent graft 1.At this point, the delivery assembly 600 only holds the bare stent 30 of the stent graft 1.Therefore, final release of the stent graft 1 occurs by releasing the bare stent 30 from the nose cone assembly 630, which is accomplished using the apex release assembly 690 as set forth below.","In order to explain how the locking and releasing of the lumen occur as set forth above, reference is made to FIGS.","33 to 62.FIG.","33 is a cross-sectional view of the proximal handle 678 and the locking knob 676.A pusher clasp rotator 292 is disposed between a clasp sleeve 614 and the graft push lumen 642.A specific embodiment of the pusher clasp rotator 292 is illustrated in FIGS.","34 through 39.Also disposed between the clasp rotator 292 and the graft push lumen 642 is a rotator body 294, which is directly adjacent the graft push lumen 642.A specific embodiment of the rotator body 294 is illustrated in FIGS.","40 through 43.Disposed between the rotator body 294 and the sheath lumen 654 is a pusher clasp body 296, which is fixedly connected to the rotator body 294 and to the locking knob 676.A specific embodiment of the pusher clasp body 296 is illustrated in FIGS.","44 through 46.A pusher clasp spring 298 operatively connects the pusher clasp rotator 292 to the rotator body 294 (and, thereby, the pusher clasp body 296).","An exploded view of these components is presented in FIG.","48, where an O-ring 293 is disposed between the rotator body 294 and the pusher clasp body 296.As shown in the plan view of FIG.","47, a crimp ring 295 connects the sheath lumen 654 to the distal projection 297 of the pusher clasp body 296.A hollow handle body 674 (see FIGS.","10, 11, and 33), on which the proximal handle 678 and the locking knob 676 are slidably mounted, holds the pusher clasp rotator 292, the rotator body 294, the pusher clasp body 296, and the pusher clasp spring 298 therein.","This entire assembly is rotationally mounted to the distal handle 672 for rotating the stent graft 1 into position (see FIGS.","23 and 24 and the explanations thereof below).","A specific embodiment of the handle body 674 is illustrated in FIG.","49.A setscrew 679 extends from the proximal handle 678 to contact a longitudinally helixed groove in the pusher clasp rotator 292 (shown in FIGS.","36 and 38).","Thus, when moving the proximal handle 678 proximally or distally, the pusher clasp rotator 292 rotates clockwise or counter-clockwise.","An alternative embodiment of the locking knob 676 is shown in FIG.","50 et seq.","in which, instead of applying a longitudinal movement to rotate the pusher clasp spring 298 through the cam/follower feature of the proximal handle 678 and pusher clasp rotator 292, a rotating locking knob 582 is located at the proximal end of the handle body 674.The knob 582 has three positions that are clearly shown in FIG.","51: a neutral position N, an advancement position A, and a deployment position D. The functions of these positions N, A, D correspond to the positions N, A, D of the locking knob 676 and the proximal handle 678 as set forth above.","In the alternative embodiment, a setscrew or pin 584 is threaded into the clasp sleeve 614 through a slot 675 in the handle body 674 and through a slot 583 in the knob 582 to engage the locking knob 582.The depth of the pin 584 in the clasp sleeve 614 is small because of the relatively small thickness of the clasp sleeve 614.To provide additional support to the pin 584 and prevent it from coming out of the clasp sleeve 614, an outer ring 6144 is disposed on the exterior surface of the proximal end of the clasp sleeve 614.Because of the x-axis orientation of the slot 583 in the knob 582 and the y-axis orientation of the slot 675 in the handle body 674, when the knob 582 is slid over the end of the handle body 674 and the setscrew 584 is screwed into the clasp sleeve 614, the knob 582 is connected fixedly to the handle body 674.When the locking knob 582 is, thereafter, rotated between the neutral N, advancement A, and deployment D positions, the clasp sleeve 614 rotates to actuate the spring lock (see FIGS.","48 and 52).","A setscrew 586, shown in FIG.","53, engages a groove 605 in the proximal clasp assembly 604 to connect the proximal clasp assembly 604 to the clasp sleeve 614 but allows the clasp sleeve 614 to rotate around the clasp body 602.The clasp sleeve 614 is shown in FIGS.","50 and 53 and, in particular, in FIGS.","59 to 62.The proximal clasp assembly 604 of FIG.","53 is more clearly shown in the exploded view of FIG.","52.The proximal clasp assembly 604 is made of the components including a distal clasp body spring 606, a locking washer 608, a fastener 603 (in particular, a screw fitting into internal threads of the proximal clasp body 602), and a proximal clasp body 602.The proximal clasp body 602 is shown, in particular, in FIGS.","54 through 58.The proximal clasp assembly 604 is connected fixedly to the handle body 674, preferably, with a screw 585 shown in FIG.","50 and hidden from view in FIG.","51 under knob 582.The handle body 674 has a position pin 592 for engaging in position openings at the distal end of the locking knob 582.The position pin 592 can be a setscrew that only engages the handle body 674.When the locking knob 582 is pulled slightly proximally, therefore, the knob can be rotated clockwise or counter-clockwise to place the pin 592 into the position openings corresponding to the advancement A, neutral N, and deployment D positions.","As shown in FIG.","18, to begin deployment of the stent graft 1, the user/physician grasps both the distal handle 672 and the proximal handle 678 and slides the proximal handle 678 towards the distal handle 672 in the direction indicated by arrow A.","This movement, as shown in FIGS.","19 to 21, causes the flexible inner sheath 652, holding the compressed stent graft 1 therein, to emerge progressively from inside the outer catheter 660.Such a process allows the stent graft 1, while constrained by the inner sheath 652, to expand to a larger diameter shown in FIG.","12, this diameter being substantially larger than the inner diameter of the outer catheter 660 but smaller than the inner diameter of the vessel in which it is to be inserted.","Preferably, the outer catheter 660 is made of a polymer (co-extrusions or teflons) and the inner sheath 652 is made of a material, such as a fabric/woven polymer or other similar material.","Therefore, the inner sheath 652 is substantially more flexible than the outer catheter 660.It is noted, at this point that the inner sheath 652 contains a taper 653 at its proximal end, distal to the sheath's 652 connection to the sheath lumen 654 (at which connection the inner sheath 652 has a similar diameter to the distal sleeve 644 and works in conjunction with the distal sleeve 644 to capture the distal end 14 of the stent graft 1.The taper 653 provides a transition that substantially prevents any kinking of the outer catheter 660 when the stent graft 1 is loaded into the delivery assembly 600 (as in the position illustrated in FIGS.","10 and 11) and, also, when the outer catheter 660 is navigating through the femoral and iliac vessels.","One specific embodiment of the sheath lumen 654 has a length between approximately 30 and approximately 40 inches, in particular, 36 inches, an outer diameter of between approximately 0.20 and approximately 0.25 inches, in particular 0.238 inches, and an inner diameter between approximately 0.18 and approximately 0.22 inches, in particular, 0.206 inches.","When the proximal handle 678 is moved towards its distal position, shown by the dashed lines in FIG.","11, the nose cone assembly 630 and the sheath assembly 650 move towards a second position where the sheath assembly 650 is entirely out of the outer catheter 660 as shown in FIGS.","20 and 21.As can be seen most particularly in FIGS.","20 and 21, as the nose cone assembly 630 and the sheath assembly 650 are emerging out of the outer catheter 660, they are traversing the curved portion 710 of the descending aorta.","The tracking is accomplished visually by viewing radiopaque markers on various portions of the delivery system and/or the stent graft 1 with fluoroscopic measures.","Such markers will be described in further detail below.","The delivery system can be made visible, for example, by the nose cone 632 being radiopaque or containing radiopaque materials.","It is noted that if the harder outer catheter 660 was to have been moved through the curved portion 710 of the aorta 700, there is a great risk of puncturing the aorta 700, and, particularly, a diseased portion 744 of the proximal descending aorta 710 because the outer catheter 660 is not as flexible as the inner sheath 652.But, because the inner sheath 652 is so flexible, the nose cone assembly 630 and the sheath assembly 650 can be extended easily into the curved portion 710 of the aorta 700 with much less force on the handle than previously needed with prior art systems while, at the same time, imparting harmless forces to the intraluminal surface of the curved aorta 710 due to the flexibility of the inner sheath 652.At the second position shown in FIG.","21, the user/physician, using fluoroscopic tracking of radiopaque markers (e.g., marker 631) on any portion of the nose cone or on the stent graft 1 and/or sheath assemblies 630, 650, for example, makes sure that the proximal end 112 of the stent graft 1 is in the correct longitudinal position proximal to the diseased portion 744 of the aorta 700.Because the entire inserted assembly 630, 650 in the aorta 700 is still rotationally connected to the portion of the handle assembly 670 except for the distal handle 672 (distal handle 672 is connected with the outer sheath 660 and rotates independently of the remainder of the handle assembly 670), the physician can rotate the entire inserted assembly 630, 650 clockwise or counterclockwise (indicated in FIG.","20 by arrow B) merely by rotating the proximal handle 678 in the desired direction.","Such a feature is extremely advantageous because the non-rotation of the outer catheter 660 while the inner sheath 652 is rotating eliminates stress on the femoral and iliac arteries when the rotation of the inner sheath 652 is needed and performed.","Accordingly, the stent graft 1 can be pre-aligned by the physician to place the stent graft 1 in the optimal circumferential position.","FIG.","23 illustrates the longitudinal support member 40 not in the correct superior position and FIG.","24 illustrates the longitudinal support member 40 in the correct superior position.","The optimal superior surface position is, preferably, near the longest superior longitudinal line along the circumference of the curved portion of the aorta as shown in FIGS.","23 and 24.As set forth above, when the longitudinal support member 40 extends along the superior longitudinal line of the curved aorta, the longitudinal support member 40 substantially eliminates any possibility of forming a kink in the inferior radial curve of the stent graft 1 during use and also allows transmission of longitudinal forces exerted along the inside lumen of the stent graft 1 to the entire longitudinal extent of the stent graft 1, thereby allowing the entire outer surface of the stent graft 1 to resist longitudinal migration.","Because of the predefined curvature of the support member 40, the support member 40 cannot align exactly and entirely along the superior longitudinal line of the curved aorta.","Accordingly, an optimal superior surface position of the support member 40 places as much of the central portion of the support member 40 (between the two ends 47 thereof) as possible close to the superior longitudinal line of the curved aorta.","A particularly desirable implantation position has the superior longitudinal line of the curved aorta intersecting the proximal half of the support member 40—the proximal half being defined as that portion of the support member 40 located between the centerline 45 and the proximal support member loop 47.However, for adequate implantation purposes, the centerline 45 of the support member 40 can be as much as seventy circumferential degrees away from either side of the superior longitudinal line of the curved aorta.","Adequate implantation can mean that the stent graft 1 is at least approximately aligned.","When implantation occurs with the stent graft 1 being less than seventy degrees, for example, less than forty degrees, away from either side of the superior longitudinal line of the curved aorta, then it is substantially aligned.","In prior art stent grafts and stent graft delivery systems, the stent graft is, typically, provided with symmetrically-shaped radiopaque markers along one longitudinal line and at least one other symmetrically-shaped radiopaque marker disposed along another longitudinal line on the opposite side (one-hundred eighty degrees (180.degree.))","of the stent graft.","Thus, using two-dimensional fluoroscopic techniques, the only way to determine if the stent graft is in the correct rotational position is by having the user/physician rotate the stent graft in both directions until it is determined that the first longitudinal line is superior and the other longitudinal line is anterior.","Such a procedure requires more work by the physician and is, therefore, undesirable.","According to an exemplary embodiment of the invention illustrated in FIGS.","27 and 28, unique radiopaque markers 232, 234 are positioned on the stent graft 1 to assist the user/physician in correctly positioning the longitudinal support member 40 in the correct aortic superior surface position with only one directional rotation, which corresponds to the minimal rotation needed to place the stent graft 1 in the rotationally correct position.","Specifically, the stent graft 1 is provided with a pair of symmetrically shaped but diametrically opposed markers 232, 234 indicating to the user/physician which direction the stent graft 1 needs to be rotated to align the longitudinal support member 40 to the superior longitudinal line of the curved aorta (with respect to anatomical position).","Preferably, the markers 232, 234 are placed at the proximal end 12 of the graft sleeve 10 on opposite sides (one-hundred eighty degrees (180.degree.))","of the graft sleeve 10.The angular position of the markers 232, 234 on the graft sleeve 10 is determined by the position of the longitudinal support member 40.In an exemplary embodiment, the support member 40 is between the two markers 232, 234.To explain such a position, if the marker 232 is at a 0 degree position on the graft sleeve 10 and the marker 234 is at a one-hundred eighty degree (180.degree.)","position, then the centerline 45 of the support member 40 is at a ninety degree position.","However, an alternative position of the markers can place the marker 234 ninety degrees away from the first degree 41 (see FIG.","1).","Such a positioning is dependent somewhat upon the way in which the implantation is to be viewed by the user/physician and can be varied based on other factors.","Thus, the position can be rotated in any beneficial way.","Exemplary ancillary equipment in endovascular placement of the stent graft 1 is a fluoroscope with a high-resolution image intensifier mounted on a freely angled C-arm.","The C-arm can be portable, ceiling, or pedestal mounted.","It is important that the C-arm have a complete range of motion to achieve AP to lateral projections without moving the patient or contaminating the sterile field.","Capabilities of the C-arm should include: Digital Subtraction Angiography, High-resolution Angiography, and Roadmapping.","For introduction of the delivery system into the groin access arteries, the patient is, first, placed in a sterile field in a supine position.","To determine the exact target area for placement of the stent graft 1, the C-arm is rotated to project the patient image into a left anterior oblique projection, which opens the radial curve of the thoracic aortic arch for optimal visualization without superimposition of structures.","The degree of patient rotation will vary, but is usually 40 to 50 degrees.","At this point, the C-arm is placed over the patient with the central ray of the fluoroscopic beam exactly perpendicular to the target area.","Such placement allows for the markers 232, 234 to be positioned for correct placement of the stent graft 1.Failure to have the central ray of the fluoroscopic beam perpendicular to the target area can result in parallax, leading to visual distortion to the patient anatomy due to the divergence of the fluoroscopic x-ray beam, with a resultant misplacement of the stent graft 1.An angiogram is performed and the proposed stent graft landing zones are marked on the visual monitor.","Once marked, neither the patient, the patient table, nor the fluoroscopic C-arm can be moved, otherwise, the reference markers become invalid.","The stent graft 1 is, then, placed at the marked landing zones.","In an exemplary embodiment, the markers 232, 234 are hemispherical, in other words, they have the approximate shape of a “D”.","This shape is chosen because it provides special, easy-to-read indicators that instantly direct the user/physician to the correct placement position for the longitudinal support member 40.FIG.","27, for example, illustrates a plan view of the markers 232, 234 when they are placed in the upper-most superior longitudinal line of the curved aorta.","The correct position is indicated clearly because the two hemispheres have the flat diameters aligned on top of or immediately adjacent to one another such that a substantially complete circle is formed by the two hemispherically rounded portions of the markers 232, 234.This position is also indicated in the perspective view of FIG.","28.Each of FIGS.","27 and 28 have been provided with examples where the markers 232, 234 are not aligned and, therefore, the stent graft 1 is not in the correct insertion position.","For example, in FIG.","27, two markers 232′, 234′ indicate a misaligned counter-clockwise-rotated stent graft 1 when viewed from the plane 236 at the right end of the stent graft 1 of FIG.","23 looking toward the left end thereof and down the longitudinal axis 11.Thus, to align the markers 232′, 234′ in the most efficient way possible (the shortest rotation), the user/physician sees that the distance between the two flat diameters is closer than the distance between the highest points of the hemispherical curves.","Therefore, it is known that the two flat diameters must be joined together by rotating the stent graft 1 clockwise.","FIG.","28 has also been provided with two markers 232″, 234″ indicating a misaligned clockwise-rotated stent graft 1 when viewed from the plane 236 at the right end of the stent graft 1 of FIG.","27 looking toward the left end thereof and down the longitudinal axis 11.Thus, to align the markers 232″, 234″ in the most efficient way possible (the shortest rotation), the user/physician sees that the distance between the highest points of the hemispherical curves is smaller than the distance between the two flat diameters.","Therefore, it is known that the two flat diameters must be joined together by rotating the stent graft 1 in the direction that the highest points of the hemispherical curves point; in other words, the stent graft 1 must be rotated counter-clockwise.","A significant advantage provided by the diametrically opposed symmetric markers 232, 234 is that they can be used for migration diagnosis throughout the remaining life of a patient after the stent graft 1 has been placed inside the patient's body.","If fluoroscopic or radiographic techniques are used any time after the stent graft 1 is inserted in the patient's body, and if the stent graft 1 is viewed from the same angle as it was viewed when placed therein, then the markers' 232, 234 relative positions observed should give the examining individual a very clear and instantaneous determination as to whether or not the stent graft 1 has migrated in a rotational manner.","The hemispherical shape of the markers 232, 234 are only provided as an example shape.","The markers 232, 234 can be any shape that allows a user/physician to distinguish alignment and direction of rotation for alignment.","For example, the markers 232, 234 can be triangular, in particular, an isosceles triangle having the single side be visibly longer or shorter than the two equal sides.","As set forth above, alignment to the optimal implantation position is dependent upon the skill of the physician(s) performing the implantation.","The present invention improves upon the embodiments having longitudinal and rotational radiopaque markers 232, 234 and substantially eliminates the need for rotational markers.","Specifically, it is noted that the guidewire 610 travels through a curve through the aortic arch towards the heart 720.It is, therefore, desirable to pre-shape the delivery system to match the aorta of the patient.","The guidewire lumen 620 is formed from a metal, preferably, stainless steel.","Thus, the guidewire lumen 620 can be deformed plastically into any given shape.","In contrast, the apex release lumen 640 is formed from a polymer, which tends to retain its original shape and cannot plastically deform without an external force, e.g., the use of heat.","Therefore, to effect the pre-shaping of the delivery assembly 600, the guidewire lumen 620, as shown in FIG.","64, is pre-shaped with a curve 622 at a distal-most area of the lumen 620.The pre-shape can be determined, for example, using the fluoroscopic pre-operative techniques described above, in which the guidewire lumen 620 can be customized to the individual patient's aortic shape.","Alternatively, the guidewire lumen 620 can be pre-shaped in a standard manner that is intended to fit an average patient.","Another alternative is to provide a kit that can be used to pre-shape the guidewire lumen 620 in a way that is somewhat tailored to the patient, for example, by providing a set of delivery systems 600 or a set of different guidewire lumens 620 that have different radii of curvature.","With the pre-curved guidewire lumen 620, when the nose cone 632 and inner sheath 652 exit the outer catheter 660 and begin to travel along the curved guidewire 610, the natural tendency of the pre-curved guidewire lumen 620 will be to move in a way that will best align the two curves to one another (see FIGS.","20 and 21).","The primary factor preventing the guidewire lumen 620 from rotating itself to cause such an alignment is the torque generated by rotating the guidewire lumen 620 around the guidewire 610.The friction between the aorta and the device also resists rotational motion.","The delivery system 600, however, is configured naturally to minimize such torque.","As set forth above with respect to FIGS.","15 to 17, the guidewire lumen 620 freely rotates within the apex release lumen 640 and is only connected to the apex release lumen 640 at the proximal-most area of both lumen 620, 640.While the inner sheath 652 advances through the aortic arch, the two lumen 620, 640 are rotationally connected only at the apex release assembly 690.This means that rotation of the guidewire lumen 620 about the guidewire 610 and within the apex release lumen 640 occurs along the entire length of the guidewire lumen 620.Because the metallic guidewire lumen 620 is relatively rotationally elastic along its length, rotation of the distal-most portion (near the nose cone assembly 630) with respect to the proximal-most portion (near the apex release assembly 690) requires very little force.","In other words, the torque resisting rotation of the distal-most portion to conform to the curve of the guidewire 610 is negligible.","Specifically, the torque is so low that the force resisting the alignment of the guidewire lumen 620 to the guidewire 610 causes little, negligible, or no damage to the inside of the aorta, especially to a dissecting inner wall of a diseased aorta.","Due to the configuration of the delivery system 600 of the present invention, when the guidewire lumen 620 is extended from the outer catheter 660 (along with the apex release lumen 640, the stent graft 1, the inner sheath 652 as shown in FIGS.","20 and 21, for example), the pre-shape of the guidewire lumen 620 causes automatic and natural rotation of the entire distal assembly—including the stent graft 1—along its longitudinal axis.","This means that the length and connectivity of the guidewire lumen 620, and the material from of which the guidewire lumen 620 is made, allow the entire distal assembly (1, 620, 630, 640, 650) to naturally rotate and align the pre-curved guidewire lumen 620 with the curve of the guidewire 610—this is true even if the guidewire lumen 620 is inserted into the aorta entirely opposite the curve of the aorta (one-hundred eighty degrees (180.degree.)).","In all circumstances, the curved guidewire lumen 620 will cause rotation of the stent graft 1 into an optimal implantation position, that is, aligning the desired portion of the support member 40 within .+−.70 degrees of the superior longitudinal line of the curved aorta.","Further, the torque forces acting against rotation of the guidewire lumen 620 will not be too high to cause damage to the aorta while carrying out the rotation.","The self-aligning feature of the invention begins with a strategic loading of the stent graft 1 in the inner sleeve 652.To describe the placement of the supporting member 40 of the stent graft 1 relative to the curve 622 of the guidewire lumen 620, an X-Y coordinate curve plane is defined and shown in FIG.","64.In particular, the guidewire lumen 620 is curved and that curve 622 defines the curve plane 624.To insure optimal implantation, when loading the stent graft 1 into the inner sheath 652, a desired point on the supporting member 40 between the centerline 45 of the stent graft 1 and the proximal support member loop 47 is aligned to intersect the curve plane 624.An exemplary, but not required, location of the desired point on the supporting member 40 is located forty-five (45) degrees around the circumference of the stent graft 1 shown in FIG.","1 beginning from the first degree 41 in line with the proximal support member loop 47.When the stent graft 1 is loaded in an exemplary orientation, it is ready for insertion into the inner sleeve 652.During the loading process, the stent graft 1 and the guidewire lumen 620 are held constant rotationally.","After such loading, the inner sleeve 652 is retracted into the outer catheter 660 and the delivery system 600 is ready for purging with saline and use with a patient.","FIGS.","65 to 67 illustrate self-alignment of the distal assembly 620, 630, 640, 650 after it is pushed out from the distal end of the outer catheter 660 (see FIGS.","20 and 21).","FIG.","65 shows an aorta 700 and the distal assembly after it has traversed the iliac arteries 802 and enters the descending thoracic portion 804 of the aorta.","The nose cone assembly 630 is positioned just before the aortic arch 806 and the stent graft 1 is contained within the inner sheath 652.A reference line 820 is placed on the stent graft 1 at a longitudinal line of the stent graft 1 that is intended to align with the superior longitudinal line 808 (indicated with dashes) of the aortic arch 806.In FIG.","65, the reference line 820 also lies on the curved plane 624 defined by the pre-curved guidewire lumen 620.As can be clearly seen from FIG.","65, the reference line 820 is positioned almost on or on the inferior longitudinal line of the curved aorta—thus, the stent graft 1 is one-hundred eighty degrees (180.degree.)","out of alignment.","FIG.","66 shows the nose cone assembly 630 fully in the aortic arch 806 and the inner sleeve 652 at the entrance of the aortic arch 806.With the self-aligning configuration of the pre-curved guidewire lumen 620, movement of the distal assembly from the position shown in FIG.","65 to the position shown in FIG.","66 causes a rotation of the reference line 820 almost ninety degrees (90.degree.)","clockwise (with respect to a view looking upward within the descending aorta) towards the superior longitudinal line 808.In FIG.","67, the nose cone assembly 630 has reached, approximately, the left subclavian artery 810.Rotational movement of the distal assembly is, now, complete, with the reference line 820 almost aligned with the superior longitudinal line 808 of the aortic arch 806.From the views of FIGS.","65 to 67, also shown is the fact that the pre-curved guidewire lumen 620 has not caused any portion of the inner sleeve 652 to push against the inner surface of the aortic arch 806 with force—force that might exacerbate an aortic dissection.","It is noted that the guidewire lumen 620 need not be rotationally fixedly connected to the apex release lumen 640 when the apex release assembly 690 is in the locked position shown in FIGS.","15 and 16.Instead, a non-illustrated, freely rotatable coupling can be interposed anywhere along the guidewire lumen 620 (but, preferably, closer to the apex release assembly 690).","This coupling would have a proximal portion rotationally fixedly connected to the to the apex release lumen 640 when the apex release assembly 690 is in the locked position shown in FIGS.","15 and 16 and a freely-rotatable distal portion that is fixedly connected to all of the guidewire lumen 620 disposed distal thereto.","Thus, the guidewire lumen 620 near the sheath assembly 650 will always be freely rotatable and, thereby, allow easy and torque-free rotation of the guidewire lumen 620 about the guidewire 610.It is also noted that the curved section 622 of the guidewire lumen need not be made at the manufacturer.","As shown in FIG.","69, a curving device can be provided with the delivery system 600 to allow the physician performing the implantation procedure to tailor-fit the curve 622 to the actual curve of the vessel in which the stent graft 1 is to be implanted.","Because different patients can have different aortic arch curves, a plurality of these curving devices can be provided with the delivery system 600, each of the curving devices having a different curved shape.","Each device can also have two sides with each side having a different curved shape, thus, reducing the number of devices if a large number of curves are required.","Further, the curving devices can all be rotationally connected on a common axle or spindle for each of transport, storage, and use.","For tailoring the curve to the patient's curved vessel, the physician can, for example, fluoroscopically view the vessel (e.g., aortic arch) and determine therefrom the needed curve by, for example, holding up the curving device to the display.","Any kind of curving device can be used to impart a bend to the guidewire lumen 620 when the guidewire lumen 620 is bent around the circumference.","Because of the predefined curvature of the support member 40, the support member 40 cannot align exactly and entirely along the superior longitudinal line of the curved aorta.","Accordingly, an optimal superior surface position of the support member 40 places as much of the central portion of the support member 40 (between the two ends 47 thereof) as possible close to the superior longitudinal line 808 of the curved aorta.","A particularly desirable implantation position has the superior longitudinal line 808 of the curved aorta intersecting the proximal half of the support member 40—the proximal half being defined as that portion of the support member 40 located between the centerline 45 and the proximal support member loop 47.However, for adequate implantation purposes, the centerline 45 of the support member 40 can be as much as seventy circumferential degrees away from either side of the superior longitudinal line of the curved aorta.","When the stent graft 1 is in place both longitudinally and circumferentially (FIG.","21), the stent graft 1 is ready to be removed from the inner sheath 652 and implanted in the vessel 700.Because relative movement of the stent graft 1 with respect to the vessel is no longer desired, the inner sheath 652 needs to be retracted while the stent graft 1 remains in place, i.e., no longitudinal or circumferential movement.","Such immovability of the stent graft 1 is insured by, first, the apex capture device 634 of the nose cone assembly 630 holding the front of the stent graft 1 by its bare stent 30 (see FIGS.","13, 22, and 23) and, second, by unlocking the locking knob 676/placing the locking ring/knob in the D position—which allows the sheath lumen 654 to move independently from the guidewire lumen 620, apex release lumen 640, and graft push lumen 642.The apex capture device 634, as shown in FIGS.","13, 14, 30 and 311 (and as will be described in more detail below), is holding each individual distal apex 32 of the bare stent 30 in a secure manner—both rotationally and longitudinally.","The nose cone assembly 630, along with the apex capture device 634, is securely attached to the guidewire lumen 620 (and the apex release lumen 640 at least until apex release occurs).","The inner sheath 652 is securely attached to a sheath lumen 654, which is coaxially disposed around the guidewire lumen 620 and fixedly attached to the proximal handle 678.The stent graft 1 is also supported at its distal end by the graft push lumen 642 and the distal sleeve 644 or the taper 653 of the inner sheath 652.","(The entire coaxial relationship of the various lumens 620, 640, 642, 654, and 660 is illustrated for exemplary purposes only in FIG.","25, and a portion of which can also be seen in the exploded view of the handle assembly in FIG.","50) Therefore, when the proximal handle 678 is moved proximally with the locking knob 676 in the deployment position D, the sheath lumen 654 moves proximally as shown in FIGS.","13, 22, and 23, taking the sheath 652 proximally along with it while the guidewire lumen 620, the apex release lumen 640, the graft push lumen 642, and the distal sleeve 644 remain substantially motionless and, therefore, the stent graft 1 remains both rotationally and longitudinally steady.","The stent graft 1 is, now, ready to be finally affixed to the aorta 700.To perform the implantation, the bare stent 30 must be released from the apex capture device 634.As will be described in more detail below, the apex capture device 634 shown in FIGS.","13, 14, and 29 to 32, holds the proximal apices 32 of the bare stent 30 between the distal apex head 636 and the proximal apex body 638.The distal apex head 636 is fixedly connected to the guidewire lumen 620.The proximal apex body 638, however, is fixedly connected to the apex release lumen 640, which is coaxial with both the guidewire lumen 620 and the sheath lumen 654 and disposed therebetween, as illustrated diagrammatically in FIG.","25.","(As will be described in more detail below, the graft push lumen 642 is also fixedly connected to the apex release lumen 640.)","Therefore, relative movement of the apex release lumen 640 and the guidewire lumen 620 separates the distal apex head 636 and a proximal apex body 638 from one another.","To cause such relative movement, the apex release assembly 690 has, in an exemplary embodiment, three parts, a distal release part 692, a proximal release part 694, and an intermediate part 696 (which is shown in the form of a clip in FIGS.","16 and 26).","To insure that the distal apex head 636 and the proximal apex body 638 always remain fixed with respect to one another until the bare stent 30 is ready to be released, the proximal release part 694 is formed with a distal surface 695, the distal release part 692 is formed with a proximal surface 693, and the intermediate part 696 has proximal and distal surfaces corresponding to the surfaces 695, 693 such that, when the intermediate part 696 is inserted removably between the distal surface 695 and the proximal surface 693, the intermediate part 696 fastens the distal release part 692 and the proximal release part 694 with respect to one another in a form-locking connection.","A form-locking connection is one that connects two elements together due to the shape of the elements themselves, as opposed to a force-locking connection, which locks the elements together by force external to the elements.","Specifically, as shown in FIG.","26, the clip 696 surrounds a distal plunger 699 of the proximal release part 694 that is inserted slidably within a hollow 698 of the distal release part 692.The plunger 699 of the proximal release part 694 can slide within the hollow 698, but a stop 697 inside the hollow 698 prevents the distal plunger 699 from withdrawing from the hollow 698 more than the longitudinal span of the clip 696.To allow relative movement between the distal apex head 636 and the proximal apex body 638, the intermediate part 696 is removed easily with one hand and, as shown from the position in FIG.","16 to the position in FIG.","17, the distal release part 692 and the proximal release part 694 are moved axially towards one another (preferably, the former is moved towards the latter).","Such movement separates the distal apex head 636 and the proximal apex body 638 as shown in FIG.","14.Accordingly, the distal apices 32 of the bare stent 30 are free to expand to their natural position in which the bare stent 30 is released against the vessel 700.Of course, the apex release assembly 690 can be formed with any kind of connector that moves the apex release lumen 640 and the guidewire lumen 620 relative to one another.","In an exemplary alternative embodiment, for example, the intermediate part 696 can be a selectable lever that is fixedly connected to either one of the distal release part 692 or the proximal release part 694 and has a length equal to the width of the clip 696 shown in FIG.","26.Thus, when engaged by pivoting the lever between the distal release part 692 and the proximal release part 694, for example, the parts 692, 694 cannot move with respect to one another and, when disengaged by pivoting the lever out from between the parts 692, 694, the distal release part 692 and the proximal release part 694 are free to move towards one another.","The apex capture device 634 is unique to the present invention in that it incorporates features that allow the longitudinal forces subjected on the stent graft 1 to be fully supported, through the bare stent 30, by both the guidewire lumen 620 and apex release lumen 640.Support occurs by providing the distal apex head 636 with a distal surface 639—which surface 639 supports the proximal apices 32 of the bare stent 30 (shown in the enlarged perspective view of the distal apex head 636 in FIG.","29).","When captured, each proximal apex 32 of the bare stent 30 separately rests on a distal surface 639, as more clearly shown in FIGS.","30 and 31.The proximal spokes of the distal apex head 636 slide within the fingers of the proximal apex body 638 as these parts moves towards one another.","A slight space, therefore, exists between the fingers and the outer circumferential surfaces of the spokes.","To insure that the bare stent 30 does not enter this space (which would prevent a proper release of the bare stent 30 from the apex capture device 634, a radial thickness of the space must be less than the diameter of the wire making up the bare stent 30.Preferably, the space is no greater than half a diameter of the wire.","Having the distal surface 639 be the load-bearing surface of the proximal apices 32 ensures expansion of each and every one of the distal apices 32 from the apex release assembly 690.The proximal surface 641 of the distal apex head 636 (see FIG.","30) meets with the interior surfaces of the proximal apex body 638 to help carry the apex load because the apices of the bare stent 30 are captured therebetween when the apex capture device 634 is closed.","Complete capture of the bare stent 30, therefore, fully transmits any longitudinal forces acting on the bare stent 30 to both the guidewire lumen 620 and apex release lumen 640, making the assembly much stronger.","Such capture can be clearly seen in the cut-away view of the proximal apex body 638 in FIG.","31.For release of the apices 32 of the bare stent 30, the proximal apex body 638 moves leftward with respect to FIGS.","30 to 33 (compare FIGS.","30 and 31 with FIG.","32).","Because friction exists between the apices 32 and the “teeth” of the proximal apex body 638 when the apices 32 are captured, the apices 32 will also try to move to the left along with the proximal apex body 638 and, if allowed to do so, possibly would never clear the “teeth” to allow each apex 32 to expand.","However, as the proximal apex body 638 disengages (moves in the direction of arrow C in FIG.","31), direct contact with the distal surface 639 entirely prevents the apices 32 from sliding in the direction of arrow C along with the proximal apex body 638 to ensure automatic release of every captured apex 32 of the bare stent 30.Because the proximal apex body 638 continues to move in the direction of arrow C, eventually the “teeth” will clear their respective capture of the apices 32 and the bare stent 30 will expand entirely.","The release position of the distal apex head 636 and the proximal apex body 638 is shown in FIGS.","14 and 32, and corresponds to the position of the apex release assembly 690 in FIG.","17.As can be seen, tapers on the distal outer surfaces of the proximal apex body 638 further assist in the prevention of catching the proximal apices 32 of the bare stent 30 on any part of the apex capture device 634.In this configuration, the distal surfaces 639 bear all the load upon the bare stent 30 and the fingers of the proximal apex body 638.Simply put, the apex capture device 634 provides support for load placed on the stent graft 1 during advancement A of the inner sheath 652 and during withdrawal of the inner sheath 652 (i.e., during deployment D).","Such a configuration benefits the apposition of the bare stent 30 by releasing the bare stent 30 after the entire graft sleeve 10 has been deployed, thus reducing the potential for vessel perforation at the point of initial deployment.","When the stent graft 1 is entirely free from the inner sheath 652 as shown in FIG.","24, the proximal handle 678 is, then, substantially at or near the third position (deployment position) shown in FIG.","10.The stent graft 1 is, now, securely placed within the vessel 700 and the entire portion 630, 650, 660 of the assembly 600 may be removed from the patient.","FIGS.","70 and 71 illustrate alternative configurations of the stent graft 1 of FIG.","1.The stent graft 1000 of FIG.","70 is similar to the stent graft 1 of FIG.","1.The stent graft 1000 has a graft 1010 and a number of stents 1020.The stents 1020 are attached either to the exterior or interior surfaces of the graft sleeve 1010.Preferably, the stents 1020 are sewn to the graft 1010.The stent graft 1000 shown in FIG.","70 has been discussed above with respect to FIG.","1, for example, and, therefore, the discussion relevant to features already discussed will not be repeated for the sake of brevity.","FIG.","70 shows an exemplary embodiment of the curved ends 1047 of the connecting rod 1040.In particular, the rod 1040 forms a loop (whether, polygonal, ovular, or circular) and has an end portion 1048 that continues back parallel and next to the rod 1040 for a short distance.","This end portion 1048, along with the adjacent portion of the rod 1040 allows, for example, connective stitching to cover two lengths of the rod 1040 and better secures the end portion 1048 to the graft sleeve 1010.In such configuration, there is limited or even no chance of a sharp end of the rod 1040 to be exposed to harm the graft sleeve 1010 or the vessel wall in which the stent graft 1000 is placed.","An alternative embodiment of the stent graft 1000 is shown as stent graft 1100 in FIG.","71.This stent graft 1100 contains a graft sleeve 1110 that completely covers the bare stent 30 shown in FIGS.","1 and 70 and is hereinafter referred to with respect to FIGS.","71 to 78 as a clasping stent 1130.As shown particularly well in FIGS.","72 and 74, the clasping stent 1130 is entirely covered by the graft 1110 but is not attached to the material of the graft 1110 along its entirety.","At least some of the proximal apices 1132, preferably, at least three or four, are left unconnected to permit a releasable connection with the fingers of the proximal apex body 638 when the fingers are extended through the apex openings 1134.Of course, in certain applications, it may be beneficial to only leave one apex 1132 unconnected.","The unconnected portion of each the apices 1132 has a minimal longitudinal length of about 10 percent of the longitudinal length of the stent and a maximum longitudinal length of up to approximately 90 percent of the length of the stent.","Preferably, the longitudinal length of the unconnected portion is between approximately 30 to 40 percent as shown in FIGS.","72 and 74, which show the clasping stent 1130 sewn to the interior of the graft 1110.For ease of comparison, FIG.","73 illustrating the proximal end of the stent graft of FIGS.","1 and 70 is included next to FIG.","74.The unconnected portions of apices 1132 need not have the same longitudinal lengths.","Depending on the application, one or some of the unconnected portions of apices 1132 can have a longitudinal length different from other ones of the unconnected portions of apices 1132.FIG.","75, for example, illustrates an embodiment near the maximum longitudinal length of the unconnected portion of the clasping stent 1130.FIGS.","76 and 77 illustrate a proximal end of the stent graft 1100 of FIG.","71 partially deployed from the flexible inner sheath 652.As can be seen in FIG.","76, the entire capturing assemblies of the apex capture device 634 reside inside the stent graft 1100 when the apices are captured.","Only the distal-most portion of the distal apex head 636 extends out from the interior of the stent graft 1100.With regard to the view of FIG.","77, it can be seen that only a few of the apices 1132 of the clasping stent 1130 are actually held by the apex capture device 634.It is noted at this point that implantation of the stent graft 1, 1000, 1100 of the present invention occurs while blood is flowing from the heart of the patient.","Accordingly, the stent graft 1100 cannot occlude the vessel in which it is to be implanted and, in order to do so, there must exist a lumen for passing blood throughout the time after the stent graft 1100 has partially or fully expanded within the vessel.","If all of the apices 1132 of the clasping stent 1130 were held within the apex capture device 634, then there is a possibility of occluding the vessel if the unattached portion of the apices 1132 are too short to provide such a lumen.","To avoid this condition, if only some apices 1132 of the clasping stent 1130 are captured, as illustrated in FIG.","77, then a sufficiently large lumen exists to allow blood flow through the vessel in which the stent graft is to be implanted.","Alternatively, if a large percentage of the apices 1132 are left unconnected, as shown, for example, in FIG.","75, then all of the apices 1132 can be releasably held by the apex capture device 634 while the graft sleeve 1110 remains entirely open to allow blood flow through the stent graft 1100 during the stent graft 1100 implantation process.","There exists a drawback to placing the clasping stent 1130 as the proximal stent of the stent graft 1100 because material of the graft 1110 is proximal of the clasping stent 1130.If unsupported, this material could move disadvantageously toward the interior of the stent graft 1100 after implantation and decrease or occlude blood flow.","To prevent such movement, the stent graft 1100 also includes a crown stent 1140.Like the clasping stent 1130, the crown stent 1140 is shown in FIGS.","71, 72, 74 to 76, and 78 as being attached to the inside of the graft 1120 and, in this exemplary embodiment, is sewn to the material of the graft using the same polyester suture as the other stents.","Of course, the crown stent 1140 can be attached to the exterior of the graft 1010.In such a configuration, the crown stent 1140 augments the rigidity of the material of the graft 1120 to reduce enfolding thereof at the proximal end of the stent graft 1100.Alternatively and/or additionally, a non-illustrated distal crown stent can be attached to the inside or outside of the graft 1120 at the opposite distal end of the stent graft 1100.In such a configuration, this distal crown stent 1140 augments the rigidity of the material at the distal end of the graft 1120 to reduce enfolding thereof.","The material of the graft 1120 can extend and bridge the entire distance between two proximal crown apices 1122.It is noted, however, that, alternatively or additionally, the material of the graft 1120 may be partially cut out between crown apices 1122 of the crown stent 1140 to define a plurality of a radially distensible flange portions 1124 at the proximal end of the stent graft 100, as shown in FIG.","74.There are various advantages provided by the stent graft 100 over the prior art.","First, the clasping and crown stents 1130, 1140 improve the apposition of the material of the graft to the intima of the vessel in which the stent graft 100 is placed, in particular, in the aorta.","Second, by better aligning the proximal portion of the stent graft 1110 in the lumen of the arch, the clasping and crown stents 1130, 1140 provide an improved blood-tight closure of the proximal end of the stent graft 1110 so that blood does not pass between the intima of the vasculature and the outer surface of the stent graft 1110.As set forth above, if the apex capture device 634 captures less than all of the apices of the clasping stent 1130.The resulting openings allow blood flow during implantation.","It is illustrated particularly well in FIGS.","1, 13, 14, and 70 that the material of the graft sleeve 10 of stent graft 1, 1000 begins only distal of the center of the bare stent 30.In comparison, as shown in FIGS.","71 and 73, the material of the graft 1120 begins well proximal of the proximal-most apices of the clasping stent 1130.Thus, this embodiment allows the material of the graft 1120 to extend much further into a vessel (i.e., further into the curved arch of the aorta).","Therefore, a physician can repair a vessel further upstream in the aorta than the embodiment of the stent graft 1, 1000 of FIGS.","1 and 70.In the prosthesis embodiment of FIGS.","1 and 70, there is direct contact between the metal of the bare stent 30 and the intima of the blood vessel.","In contrast thereto, the configuration of the stent graft 1100 with the clasping stent 1130 places material of the graft 1120 between the metal of the clasping stent 1130 and the intima.","Such a configuration provides a more atraumatic connection between the vessel and the proximal end of the stent graft 1100 than the configuration of FIGS.","1 and 70.This advantage is especially important for treating dissections—where the intima is in a weakened condition.","FIG.","63 illustrates interaction between the catheter 660, the inner sheath 652, and the nose cone assembly 630 (including the nose cone 632, the distal apex head 636, and the proximal apex body 638).","In this illustration, first, the catheter 660 is in a proximal position that does not cover the inner sheath 652 in any way.","For example, this position of the catheter 660 occurs when the inner sheath 652 has extended out of the catheter 660 as shown in FIGS.","20 and 21.Next, the inner sheath 652 is clearly shown in its expanded state (caused by the non-illustrated prosthesis disposed therein and expanding outward).","The distal-most end of the inner sheath 652 is disposed between the distal apex head 636 and the nose cone 632.In such an orientation, the inner sheath 652 is in the position that occurs during extension out of the catheter 660 as shown for example, in FIGS.","20 and 21.Because the nose cone 632 screws onto the distal end of the distal apex head 636, the distal-most end of the inner sheath 652 is releasably captured between the two parts 632, 636 until it is removed.","Retraction of the sheath lumen 654 proximally pulls the distal-most captured end of the inner sheath 652 out from the capturing interface.","Finally, the proximal apex body 638 is in a retracted position proximal of the distal apex head 636.This orientation is for illustrative purposes only to show the interaction of the distal apex head 636 and the proximal apex body 638 because the separation would not occur in use until, as set forth above, the inner sheath 652 is fully retracted from over the stent graft 1 and the proximal apices 32 of the stent 30 have been released as shown in FIG.","14.FIG.","80 is a cross-section through the catheter 660, the fingers of the proximal apex body 638, the distal apex body 636, the apex release lumen 640, and the guidewire lumen 620.FIG.","81 is a cross-section of the distal end of the delivery system along the longitudinal axis of the delivery system.","These two figures illustrate the space 662 that exists between the catheter 660 and both of the proximal apex body 638 and the distal apex body 636 to make room for the inner sheath 652 to surround the parts 636, 638 and pass between the nose cone 632 and the distal apex head 636 and enter the pass 664 that allows the inner sheath 652 to be releasably held there as shown in FIG.","63 until it is desired to remove the inner sheath 652 therefrom.","FIG.","82 shows a distal end of the delivery system according to the invention in the orientation of FIGS.","20 and 21, for example.","The inner sheath 652 is curved and has an alternative embodiment of a D-shaped marker 234 thereon.","In contrast to the configuration of two markers 234 on the stent graft 1 as shown in FIGS.","27 and 28, there is only one marker 234 on the inner sheath 652.As illustrated in the orientations of FIGS.","83, 84, and 85, the marker 234 allows the user to see how the inner sheath 652 should be oriented prior to implantation.","FIGS.","86, 87, 88, and 89 illustrate an alternative embodiment of the front handle 672 that is rotatably attached to the handle 674 and rotatably fixed to the catheter 660.FIGS.","90 to 119 depict another exemplary embodiment of various features of the delivery assembly 600.FIG.","90 shows the entire delivery assembly 600 with a portion of nose cone assembly 630 removed to reveal the distal apex head 636.On the proximal end of the delivery assembly 600, the enlarged view of FIG.","91 depicts an alternative embodiment of the apex release assembly 690.In FIG.","91, a proximal pusher support tube 645 surrounds two coaxial lumens, the guidewire lumen 620 and the apex release lumen 640.The proximal pusher support tube 645 is longitudinally fixed to the proximal end of the graft push lumen 642 and has substantially the same diameter as the graft push lumen 642.Because the proximal pusher support tube 645 is used for pushing/pulling the combination lumen 642, 645, and due to the fact that the proximal pusher support tube 645 only resides within the handle body or proximal thereof, the proximal pusher support tube 645 can be made of a relatively stiff material, such as stainless steel, for example.","In contrast, the graft push lumen 642 needs to flex and bend when extending out of the outer catheter 660 and into vasculature.","Thus, the graft push lumen 642 is made from a relatively flexible material, such as a plastic.","In FIG.","91, the proximal portion of the proximal pusher support tube 645 is cut away to reveal the features therein, including the guidewire lumen 620 and the apex release lumen 640.The apex release lumen 640 is axially fixed to the proximal apex body 638.The guidewire lumen 620, on the other hand, is axially fixed to the distal apex head 636.Thus, distal movement of the apex release lumen 640 with respect to the guidewire lumen 620 separates the tines of the proximal apex body 638 extending over the spokes of the distal apex head 636.To effect this relative movement, proximal and distal crimping devices 621 and 641 are respectively attached to the guidewire 620 and the apex release lumen 640.The distal release part 692 is connected, through a non-illustrated set screw, to the distal crimping device 641.The proximal release part 694 is connected, also through a non-illustrated set screw, to the proximal crimping device 621.Finally, a proximal luer connector 800 is connected to the proximal-most end of the proximal pusher support tube 645 so that all of the lumen 620, 640, 645 can be filled and/or drained with a liquid, such as saline.","FIG.","92 is an enlarged view of the alternative embodiment of the locking knob 582 first shown in FIGS.","50 and 51.To better explain the features of FIG.","92, reference is made to the separated clasp sleeve 614 of FIG.","93, which was first depicted in FIGS.","50, 53, and 59 to 62.This clasp sleeve 614 is longitudinally fixedly and rotationally freely connected to the handle body 674 through the setscrew 584 that protrudes into the slot 675 of the handle body 674.The setscrew 584 is screwed into but not through the proximal end of the clasp sleeve as shown in FIG.","93, for example.","This setscrew 584 protrudes into the slot 675 in the handle body 674.When so connected, the clasp sleeve 614 cannot move longitudinally with respect to the handle body 674 but can rotationally move along the arc defined by the length of the slot 675.The setscrew 584 protrudes from the outer circumference of the handle body 674 because it enters into the longitudinal slot 583 in the locking knob 582.Thus, the setscrew 584 also controls the longitudinal movement distance of the locking knob 582.When the knob 582 is at rest, the setscrew 584 resides in the distal end of the slot 583 because of the bias caused by spring 607 (see FIG.","94).","The second setscrew 592 (also referred to as a position pin) starts from the handle body 674 but does not extend inside the handle body 674.The setscrew 592 does, however, protrude out from the handle body 674 and into the three-position slot 587 of the locking knob 582.Thus, the setscrew 592 controls the rotation of the knob 582 within the three positions.","The third setscrew 585 is screwed through a threaded hole in the handle body 674 and into a co-axial threaded hole 6021 of the clasp body 602 until the setscrew 585 is even with the exterior surface of the handle body 674.Thus, the setscrew 585 does not protrude from the outer circumference of the handle body 674.The proximal clasp assembly 604 was first illustrated in FIG.","52.In FIG.","94, the proximal clasp assembly 604 is illustrated with different detail.","The clasp body 602 has a distal interior cavity 6023 shaped to receive therein the distal clasp body spring 606, which is a torsion spring in this exemplary embodiment.","The locking washer 608 is connected to the distal end of the clasp body 602 by a non-illustrated setscrew that, for example, runs through the bore illustrated at the 12 o'clock position on the locking washer 608 in FIG.","94.To keep the clasp body assembly pressed into the clasp sleeve 614, as shown in FIGS.","101 and 102 for example, a distal spring washer 611 and a proximal compression spring 607 are inserted into a proximal interior cavity 6024.Placement of the locking knob 676 onto the handle body 674, as shown in FIG.","92 for example, compresses the compression spring 607 between the locking knob 676 and the proximal surface of the spring washer 611 residing inside the proximal interior cavity 6023 of the clasp body 602.This compression forces the knob 676 proximally to keep the spring 592 inside the three-position slot 675.The spring washer 611 is present to prevent the spring 607 from binding when the locking knob 676 is rotated between the three rotational positions.","The smooth surface of the washer 611 does not catch the distal end of the compression spring 607 when the spring 607 rotates.","The rotator assembly includes the pusher clasp rotator 292, the pusher clasp spring 298, and the rotator body 294.These parts are first depicted in FIGS.","34 to 43 and 47 to 48 and are next depicted in FIGS.","95 and 96.In FIG.","95, the rotator assembly is illustrated in an exploded, unassembled state and FIG.","96 shows the assembly in an assembled state.","When assembled, the two protruding ends of the pusher clasp spring 298 are respectively inserted into the longitudinal slots 2942 and 2922 of each of the rotator body 294 and the pusher clasp rotator 292.Because the distal end of the rotator body 294 is smaller in diameter than the cavity of the pusher clasp rotator 292, the end of the spring that fits inside the slot 2922 must be longer than the end of the spring 298 that fits inside the slot 2942 of the rotator body 294.The rotator body 294 is secured inside the pusher clasp rotator 292 by two dowels 2926 that are press fit through a first orifice in the clasp rotator 292 after the rotator body 294 is inside the clasp rotator 292.These dowels 2926, then, pass through a circumferential groove 2944 substantially without touching the walls of the groove 2944 and, then, through a second orifice in the clasp rotator 292 directly opposite the first orifice.","In such a configuration, the rotator body 294 is longitudinally fixed but rotationally free inside the clasp rotator 292.The first and second orifices and the groove 2944 are clearly shown in FIG.","13 (with the dowels 2926 removed for clarity).","FIGS.","44 to 48 illustrated the pusher clasp body 296 and its relationship with the sheath lumen 654.FIGS.","97 and 98 further illustrate two views of the pusher clasp body 296 and its distal projection 297.The proximal end of the sheath lumen 654 passes through the crimp ring 295 and over the distal projection 297.Then, to secure the sheath lumen 654 to the pusher clasp body 296, the crimp ring 295 is compressed/crimped.","Such a connection both longitudinally and rotationally stabilizes the sheath lumen 654 with respect to the pusher clasp body 296.Two pins 2962 hold the pusher clasp body 296 to the proximal handle 678 so that longitudinal movement of the proximal handle 678 translates into a corresponding longitudinal movement of the pusher clasp body 296 within the handle body 674.These pins 2962 pass through a plug 2964, shown in FIG.","114, and then into the pusher clasp body 296.The length of the pins that exist through the plug 2964 and also through the pusher clasp body 296 gives enough support to prevent movement of the handle 678 from breaking the pins 2962, which might occur if the plug 2964 were not present.","It is noted that the conical expansion of the proximal end of the inner sheath 652 is different in FIGS.","97 and 98.This is because the embodiment shown in FIGS.","97 and 98 illustrates an expansion portion of the inner sheath 652 that is sutured on only one side thereof.","Accordingly, when viewed along the suture line (as in FIG.","98), the cone has one flat side.","In contrast, when viewed in an elevation 90 degrees turned from that suture line (as in FIG.","97), the expansion portion has a conical elevational view.","Also shown in FIG.","98 on the inner sheath 652 is a D-shaped radiopaque marker 232.This marker 232 is enlarged in FIG.","99 and can be, for example, secured to the inner sheath 652 by three sutures, diagrammatically indicated with an “X.” FIG.","100 is an enlarged view of the distal end of the handle assembly 670 shown in FIG.","90.This embodiment of the distal apex head 636 shows an alternative embodiment of the proximal portion that was first shown in FIG.","29.As can be seen in the drawing, the proximal side of the distal apex head 636 is tapered.","This tapered shape allows the distal apex head 636 to enter further into the interior cavity between the prongs of the proximal apex body 638 than the distal apex head 636 shown in FIG.","29.It is noted that the portion of the delivery system at the distal end is to be flexible so that this portion can traverse curved vessels.","Thus, it is desirable for the length of the distal apex head 636 and the proximal apex body 638 (semi-rigid parts) to be as short as possible.","By allowing the distal apex head 636 to travel further into the proximal apex body 638, the longitudinal length of the two parts 636 can be shorter.","Now that the various parts of the handle assembly 670 have been shown and described separately, the interactions and orientations when assembled can now be further understood with reference to the following description and to FIGS.","101 to 105.FIGS.","101 to 102 show the proximal half of the handle assembly 670 from just proximal of the locking knob 676 to just distal of the distal end of the proximal handle 678 (when the handle 678 is in a proximal position).","The hidden lines shown in FIG.","101 aid in the understanding of this portion.","It is noted that the sheath lumen 654 is not illustrated in FIG.","101 for clarity.","FIG.","102 clearly shows the components that are involved in the proximal half of the handle assembly 670.The handle body 674 is surrounded by the distal handle 678 and a portion of the locking knob 676.Inside the proximal end of the handle body 674 is the clasp body 602, which is surrounded by the proximal end of the clasp sleeve 614.The locking washer 608 is positioned inside the clasp sleeve 614 at the distal end of the clasp body 602.Separated at a distance from the distal end of the locking washer 608 is the rotator assembly, which, as set forth above, is longitudinally fixed to the proximal handle 678.The rotator assembly includes the pusher clasp rotator 292 surrounding the pusher clasp spring 298 and the rotator body 294.The pusher clasp body 296 is disposed on the distal end of the rotator body 294 and the crimp ring 295 secures the sheath lumen 654 on the distal projection 297 of the pusher clasp body 296.FIG.","103 is an enlarged view of the proximal portion of FIG.","102 by the locking knob 676.These figures show the alignment of the bores in the clasp body 602 and the locking washer 608 so that the non-illustrated setscrew can fasten the two parts to one another.","Also shown in FIG.","103 is the alignment between the groove 605 for receiving therein the setscrew 586 (see FIGS.","53 and 93) and connecting the proximal clasp assembly 604 to the clasp sleeve 614 so that the clasp sleeve 614 can still rotate around the clasp body 602.Also visible in the enlarged view of FIG.","103 are the three coaxial lumen 620, 640, 645 that pass through the clasp body 602.Like FIG.","103, FIG.","104 is an enlarged view of the distal portion of the handle assembly 670 around the pusher clasp rotator 292.This view not only shows the orientations of the rotator body 294 and the pusher clasp body 296 with respect to the pusher clasp rotator 292, but the three coaxial lumen passing therethrough are also evident.","The groove 2944 for receiving the non-illustrated dowels 2926 therein is also visible in this view.","As can be seen, the guidewire lumen 620 and the apex release lumen 640 each pass entirely through the pusher clasp body 296 but the proximal pusher support tube 645 ends just after the distal end of the rotator body 294 for hemostasis purposes.","It is at this end point that the proximal pusher support tube 645 is connected to the graft push lumen 642.This two-part structure of the proximal pusher support tube 645 and the graft push lumen 642 is, in an exemplary embodiment, a bonding of a proximal stainless steel lumen 645 and a plastic lumen 642, for example, a polyurethane-based extrusion.","As set forth above, a rigid lumen 645 in the handle portion keeps rigidity there and a flexible lumen 642 distal of the distal handle 672 allows the lumen to flex as needed.","The distal end of the rotator body 294 is also fluidically sealed off from the interior of the distal interior of the delivery system with a hemostasis o-ring 293.FIG.","105 is still a further enlarged view around the pusher clasp spring 298.A transverse cross-sectional view through the handle assembly 670 is illustrative of the interaction between and relationship of various components of this assembly 670.The cross-sections shown in FIGS.","106 to 118 progress from proximal to distal.","A first transverse cross-section through the longitudinal slot 583 of the locking knob 676 is illustrated in FIG.","106.In this cross-sectional plane, the clasp body 602 is shown as filling up most of the interior of the clasp sleeve 614.The anchoring bore in the clasp sleeve 614 for the setscrew 585 is shown aligned with the slot 583.A second transverse cross-section through the three-position slot 587 of the locking knob 676 is illustrated in FIG.","107.In this cross-sectional plane, the clasp body 602 still is shown as filling up most of the interior of the clasp sleeve 614.The slot 6022 of the clasp body 602 for receiving one end of the torsion spring 606 is also depicted in FIG.","107.A third transverse cross-section through the clasp body 602 before the locking washer 608 is illustrated in FIG.","108.In this cross-sectional plane, the slot 6022 of the clasp body 602 is aligned with a slot 6143 inside the proximal end of the clasp sleeve 614 that is not visible in FIG.","93 but is visible through the cutout in FIGS.","59 and 60.This alignment is merely shown in FIG.","108 for understanding the different depths of these slots 6022, 6143.Like the pusher clasp spring 298, the distal clasp body spring 606 has ends with different lengths.","The first, shorter, end is inserted into the inner slot 6022 of the clasp body 602 and the second, longer, end is inserted into the slot 6143 of the clasp sleeve 614.The fourth transverse cross-section between the proximal clasp assembly 604 and the rotator assembly shows, in FIG.","109, the spatial separation of these two assemblies that is depicted, for example, in FIGS.","101 to 102.Visible in these figures is the longitudinal slot 6141 that, as shown in the cross-sections of FIGS.","110 to 111, guides the movement of the pusher clasp rotator 292 by delimiting a space that corresponds to the width of the boss 2924 that extends out from the outer circumferences of the pusher clasp rotator 292.This slot 6141 allows the pusher clasp rotator 292 to move longitudinally freely with respect to the clasp sleeve 614; simultaneously, this connection prevents any rotation of the pusher clasp rotator 292 that is independent from rotation of the clasp sleeve 614.Accordingly, as the clasp sleeve 614 rotates about its longitudinal axis, the pusher clasp rotator 292 will rotate as well.","The further enlarged view of the center of the configuration illustrated in FIG.","110 is depicted in FIG.","111.Here, the rotator assembly portions are clearly shown with the pusher clasp spring 298 therebetween.","The sixth cross-section of FIG.","112, and the enlarged view of the sixth cross-section in FIG.","113, illustrate the longitudinally fixed but rotationally free connection between the pusher clasp rotator 292 and the rotator body 294.The two bores in the pusher clasp rotator 292 for receiving the dowels 2926 (not illustrated here) are clearly shown to intersect the open space in the groove 2944 of the rotator body 294.A seventh cross-section in FIG.","114 shows the connection of the pusher clasp body 296 and the proximal handle 678 through the plug 2964.This view also depicts the fluid communication between the interior of the handle assembly 670 and the luer fitting 612.When the luer 612 is connected to a fluid supply, the flushing liquid enters the interior cavity distal of the rotator body 294 and sealed off by the o-ring 293 and purges all air therein at the distal end of the delivery system.","FIG.","114 also shows the graft push lumen 642 extending through the handle body 674 beginning after the distal side of the o-ring 293.The eighth cross-section of FIG.","115 illustrates the distal projection 297 at which the crimp ring 295 holds the sheath lumen 654 onto the pusher clasp body 296.This figure also illustrates the open radial space between the clasp sleeve 614 and the graft push lumen 642.To keep the relatively long extent of the flexible inner lumen 620, 640, 642 passing through the open interior of the handle body 674 from moving out of a centered orientation (i.e., from bending out from the longitudinal axis of the handle body 674, sliding spacers 6142 are periodically provided along the clasp sleeve 614 as shown in FIGS.","93 and 116 to 118.These spacers 6142 are only needed while the proximal handle 678 is moving the rotator assembly and the pusher clasp body 296 in a distal direction to prevent bending of the interior flexible lumen 620, 640, 642.Accordingly, the spacers 6142 can slide within the groove 6141 of the clasp sleeve 614 up to and over the distal end of the clasp sleeve 614 (the right side of the clasp sleeve 614 as viewed in FIG.","93; see also FIG.","117).","Each of these spacers 6142 is self secured in a slidable manner to the clasp sleeve 614.FIG.","117 depicts a ninth cross-section through a distal end of the clasp sleeve 614 within the distal handle 672.The distal handle 672 freely rotates about the handle body 674 in an exemplary embodiment.","In such an embodiment, the outer catheter 660 will also freely rotate about all of the lumen 620, 640, 642 therein because of the fixation between the outer catheter 660 and the distal handle 672.See FIG.","118.The shaded parts in FIG.","119 are provided to show portions of the features around the clasp body 602.In this view, the rotator assembly is removed.","The following text describes the four movements for implanting a prosthesis with the delivery system and the relative connections between relevant lumens when in the three different settings of the locking knob 676.The first movement will be referred to as the advancement stage and utilizes position 1 of the locking knob 676.When in position 1, the distal spring 298 is engaged around and holds the pusher support tube 645 (and, therefore, graft push lumen 642) to the rotator assembly 292, 294.This assembly 292, 294 is fixed at the distal end of the rotator body 294 inside the pusher clasp body 296 (through a non-illustrated setscrew passing through the threaded bore 2966 shown in FIG.","98).","As set forth above, the pusher clasp body 296 is fixed to the proximal handle 678 and, therefore, the pusher support tube 245 moves with the proximal handle 678 in position 1.In this first movement, the entire distal assembly is advanced up to the implantation site using the proximal handle 678.Thus, when the handle 678 moves distally, all of the lumen, including the guidewire lumen 620, the apex release lumen 640, the graft push lumen 642/proximal pusher support tube 645, and the sheath lumen 654, are locked together and move distally with a corresponding movement of the proximal handle 678.As the outer catheter 660 is longitudinally fixed to the distal handle 672, it remains longitudinally fixed during the first movement.","The lumen displacement in the advancement stage is depicted in FIGS.","19 to 21.The second movement will be referred to as the primary deployment stage and utilizes position 2 of the locking knob 676.When in position 2, the distal spring 298 is disengaged from the pusher support tube 645 and the proximal spring 606 becomes engaged around the pusher support tube 645 to anchor only the push rod 642 (without lumen 620, 640) to the proximal handle 678 and allow retraction of sheath lumen 654 (and, thereby, the inner sheath 652) while all other lumens are disengaged and remain stationary.","In this second movement, the inner sheath 654 needs to be moved in the proximal direction, as shown in FIGS.","22 to 24.Accordingly, when the handle 678 moves distally, only the sheath lumen 654 moves with the handle 678.Thus, in position 2 of the locking knob 676, the sheath lumen 654 is locked to the proximal handle 678 and moves proximally with a corresponding movement of the proximal handle 678; all of the other lumen, including the guidewire lumen 620, the apex release lumen 640, and the graft push lumen 642/proximal pusher support tube 645, are unlocked and remain in the distally deployed position.","See FIGS.","22 to 24.The third movement will be referred to as the final deployment stage because, in this movement, the apex capture device 634 completely releases the distal end of the prosthesis as shown in FIG.","14.Here, the apex release lumen 640 is unlocked (using the release mechanism of FIG.","91) with respect to the guidewire lumen 620 and the graft push lumen 642/645.The fourth movement will be referred to as the extraction stage and utilizes position 4 of the locking knob (the third of the three positions in the slot 587 of the locking knob 676).","When in position 4, both the distal spring 298 and the proximal spring 606 are disengaged from the pusher support tube 645 to allow the user to pull the proximal end of the pusher support tube 645 and withdraw it from the implantation site.","The entire inner lumen assembly 620 and 640 travels with the proximal movement of the pusher support tube 645 because the release mechanism (see FIG.","91) is pulled with the support tube 645 as it moves proximally.","While exemplary embodiments of the invention have been illustrated and described, it will be clear that the invention is not so limited.","Numerous modifications, changes, variations, substitutions, and equivalents will occur to those skilled in the art without departing from the spirit and scope of the present invention as defined by the appended claims."]],"string":"[\n [\n \"Stent Graft With a Longitudinal Support Member\",\n \"A delivery system for delivering and deploying stent grafts having a proximal stent includes a first lumen and a stent capture device including a capture portion fixedly connected adjacent a first lumen distal end.\",\n \"An outer catheter has a catheter distal end and a catheter inner diameter.\",\n \"A second lumen having a second distal end is slidably disposed about the first lumen and within the outer catheter.\",\n \"A stent graft sheath has a sheath proximal end connected to the second distal end and disposed about the first lumen.\",\n \"The sheath has a sheath distal end and a sheath inner diameter greater than the catheter inner diameter for holding a compressed stent graft.\",\n \"A distal nose cone has a cone proximal end connected to either the capture portion or the first distal end.\",\n \"The nose cone and the capture portion are movably adjustable to selectively capture the sheath distal end therebetween.\"\n ],\n [\n \"1.A stent graft comprising: a) a luminal graft component defining a proximal end, a distal end, and a lumen therebetween, the luminal graft component defining a longitudinal axis; b) a proximal stent at the proximal end of the luminal graft component; c) a distal stent at the distal end of the luminal graft component; d) a plurality of intermediate stents along the luminal graft component between the proximal stent and the distal stent, wherein the intermediate stents define a circumferential proximal end that is distal to the proximal stent and a circumferential distal end that is proximal to the distal stent, wherein the circumferential proximal end lies in a plane distal to the proximal stent; and e) a curved longitudinal support member spanning at least a portion of the intermediate stents.\",\n \"2.The stent graft of claim 1, wherein at least one of the proximal stent and distal stent includes a plurality of struts that are joined to each other at opposite ends to define proximal apices and distal apices.\",\n \"3.The stent graft of claim 2, wherein the proximal apices of the proximal stent extend proximally from the proximal end of the luminal graft component.\",\n \"4.The stent graft of claim 2, wherein at least a portion of the intermediate stents include a plurality of struts that are joined to each other at opposite ends to define proximal apices and distal apices.\",\n \"5.The stent graft of claim 1, wherein the curved longitudinal support member is curvilinear.\",\n \"6.The stent graft of claim 5, wherein the curved longitudinal support member defines a proximal end and a distal end that asymptomatically approach lines that extend parallel to a longitudinal axis of the stent graft when the stent graft is in a relaxed position.\",\n \"7.The stent graft of claim 6, wherein proximal end and the distal end of the curved longitudinal support member are nested within proximal apices and distal apices, respectively, of the most proximal stent and most distal stent of the plurality of intermediate stents.\",\n \"8.The stent graft of claim 7, wherein the proximal end and distal end of the curved longitudinal support member are looped.\",\n \"9.The stent graft of claim 1, wherein the proximal stent includes nitinol.\",\n \"10.The stent graft of claim 1, wherein the distal stent includes nitinol.\",\n \"11.The stent graft of claim 1, wherein the intermediate stents include nitinol.\",\n \"12.The stent graft of claim 1, wherein the curved longitudinal support member is on one side of a plane parallel to and bisecting the longitudinal axis of the luminal graft component, the other side of the plane the luminal graft component being free of the curved longitudinal support member.\",\n \"13.The stent graft of claim 12, wherein the curved longitudinal support member being substantially reverse-mirror symmetrical with respect to the longitudinal axis of the luminal graft component.\",\n \"14.The stent graft of claim 13, wherein the proximal end of the curved longitudinal support member is distal to a distal end of the proximal stent and the distal end of the curved longitudinal support member is proximal to a proximal end of the distal stent.\"\n ],\n [\n \"<SOH> BACKGROUND OF THE INVENTION <EOH>\"\n ],\n [\n \"<SOH> SUMMARY OF THE INVENTION <EOH>The invention provides a sheath capture device for an endovascular stent graft delivery system and a method for operating the device that overcome the hereinafore-mentioned disadvantages of the heretofore-known devices and methods of this general type and that provides a vessel repair device that implants/conforms more efficiently within the natural or diseased course of the aorta by aligning with the natural curve of the aorta, decreases the likelihood of vessel puncture, increases the blood-tight vascular connection, retains the intraluminal wall of the vessel position, is more resistant to migration, and delivers the stent graft into a curved vessel while minimizing intraluminal forces imparted during delivery and while minimizing the forces needed for a user to deliver the stent graft into a curved vessel.\",\n \"With the foregoing and other objects in view, there is provided, in accordance with the invention, a delivery system for delivering and deploying stent grafts having a proximal bare stent, the delivery system includes a hollow first lumen having a first distal end, a stent capture device including a capture portion fixedly connected adjacent said first distal end, a relatively rigid, hollow outer catheter having a catheter distal end and a catheter inner diameter, a hollow second lumen having a second distal end and being slidably disposed about said first lumen and slidably disposed in said outer catheter, a relatively flexible, hollow stent graft sheath having a sheath proximal end connected to said second distal end and disposed about said first lumen, said sheath having a sheath distal end and a sheath inner diameter greater than said catheter inner diameter to fit therein an at least partially compressed stent graft, and a distal nose cone having a cone proximal end connected to at least one of said capture portion and said first distal end, said nose cone and said capture portion being movably adjustable to selectively capture said sheath distal end therebetween.\",\n \"In accordance with another feature of the invention, the nose cone and the capture portion define a cavity in which the sheath distal end is held releasably.\",\n \"In accordance with a further feature of the invention, there is provided a handle, the outer catheter defining a longitudinal axis and being longitudinally fixedly connected to the handle about the second lumen, the first and second lumens being longitudinally movably connected to the handle.\",\n \"In accordance with an added feature of the invention, the outer catheter has a length only long enough to be inserted in a patient's aorta to approximately the patient's celiac axis.\",\n \"In accordance with an additional feature of the invention, there is provided a hollow third lumen disposed about the first lumen and within the second lumen, the third lumen having a third distal end, the capture portion being a first capture portion, the stent capture device including a second capture portion fixedly connected adjacent the third distal end and selectively movable with respect to the first capture portion to capture a stent therebetween.\",\n \"With the objects of the invention in view, there is also provided a method of loading a stent graft in a prosthesis delivery system for implanting a stent graft in a patient at a treatment site, includes the steps of providing a prosthesis delivery system including a hollow first lumen having a first distal end, a stent capture device including a capture portion fixedly connected adjacent the first distal end, a relatively rigid, hollow outer catheter having a catheter distal end and a catheter inner diameter, and, a hollow second lumen having a second distal end and being slidably disposed about the first lumen and slidably disposed in the outer catheter, loading a stent graft inside a relatively flexible, hollow stent graft sheath having a sheath inner diameter greater than the catheter inner diameter to temporarily dispose the stent graft therein in an at least partially compressed state, the stent graft sheath being disposed about the first lumen and having a sheath distal end and a sheath proximal end connected to the second distal end, temporarily capturing a stent of the stent graft with the stent capture device, removably capturing the sheath distal end between the capture portion and a distal nose cone having a proximal end connected to at least one of the capture portion and the first distal end, and loading the sheath with the partially compressed stent graft into the outer catheter to compress the stent graft even further for subsequent implantation at the treatment site.\",\n \"In accordance with yet another mode of the invention, the sheath capturing step is carried out by movably adjusting the nose cone and the capture portion to selectively secure the sheath distal end therebetween.\",\n \"In accordance with yet a further mode of the invention, the outer catheter is extended with the loaded sheath up to a given position at a distance from the treatment site and the stent graft is implanted at the treatment site.\",\n \"In accordance with yet an added mode of the invention, the implantation step is carried out by extending the first and second lumen in a patient towards the treatment site to move the sheath out from the outer catheter and return the stent graft to the partially compressed state in the sheath, extending the first and second lumen further towards the treatment site to place the loaded sheath at the treatment site, and releasing the sheath distal end from between the capture portion and the distal nose cone and unsheathing the stent graft from the sheath by retracting the second lumen away from the treatment site, and releasing the stent from the capture device to implant the stent graft at the treatment site.\",\n \"In accordance with yet an additional mode of the invention, the outer catheter is advanced in a patient towards a treatment site up to a given position at a distance from the treatment site, and, while retaining the outer catheter in the given position, the stent graft sheath is advanced out from the outer catheter to the treatment site to align the stent graft with the treatment site, the sheath distal end of the sheath is released from between the capture portion and the distal nose cone and unsheathing the stent graft from the sheath by retracting the second lumen away from the treatment site to at least partially implant the stent graft at the treatment site, the stent is released from the capture device to implant the stent graft at the treatment site, and, upon completion of the stent graft implantation, both of the stent graft sheath and the outer catheter are retracted from the patient.\",\n \"In accordance with again another mode of the invention, the advancing step is carried out by advancing the sheath out from the outer catheter to the treatment site to axially align the stent graft with the treatment site and rotating the stent graft sheath to circumferentially align the stent graft with the treatment site.\",\n \"In accordance with again a further mode of the invention, the advancing step is carried out by advancing the outer catheter towards the treatment site only up to a point at a distance from the treatment site greater than a length of the stent graft.\",\n \"In accordance with again an added mode of the invention, the advancing step is carried out by advancing the outer catheter in vasculature of a patient towards a vascular treatment site.\",\n \"In accordance with again an additional mode of the invention, the advancing step is carried out by advancing the outer catheter in aortic vasculature of the patient to approximately a celiac axis of the patient.\",\n \"In accordance with still another mode of the invention, the advancing step is carried out by advancing the outer catheter in aortic vasculature of the patient to approximately a celiac axis of the patient.\",\n \"In accordance with yet another mode of the invention, the outer catheter is provided with a length sufficient to reach to approximately a celiac axis of a patient.\",\n \"In accordance with yet a further mode of the invention, the outer catheter is provided with a length equal to approximately a distance from the patient's femoral arterial access site to the patient's celiac axis.\",\n \"In accordance with yet an added mode of the invention, the retracting step is carried out upon completion of the stent graft implantation by retracting the stent graft sheath into the outer catheter and subsequently retracting the outer catheter containing the stent graft sheath from the patient.\",\n \"In accordance with yet an additional mode of the invention, the stent graft sheath is of a material relatively more flexible than a material of the outer catheter.\",\n \"With the objects of the invention in view, there is also provided a method of implanting a stent graft in a patient at a treatment site, including the steps of longitudinally locking a set of inner lumens and an inner sheath with respect to an outer lumen, at least a portion of the inner sheath constraining a stent graft, capturing a distal end of the inner sheath between a stent capture device and a distal nose cone, threading the lumens and the inner sheath onto a guidewire and into a patient to place the outer lumen into an aorta of the patient only up to a point at a distance from the treatment site greater than a length of the prosthesis, longitudinally unlocking the inner lumens with respect to the outer lumen, advancing the inner lumens and inner sheath distally out of the outer lumen in the aorta towards the patient's heart to transport the stent graft further upstream into the aorta, unlocking the inner sheath constraining the stent graft from at least one interior lumen of the inner lumens, and releasing the distal end of the inner sheath from between the capture portion and the distal nose cone by retracting the inner sheath in a proximal direction to at least partially implant the stent graft in a vessel.\",\n \"In accordance with a concomitant mode of the invention, the stent graft is implanted in the vessel at the treatment site by retracting the second lumen away from the treatment site to unsheath the stent graft from the sheath and releasing the stent from the capture device.\",\n \"Other features that are considered as characteristic for the invention are set forth in the appended claims.\",\n \"Although the invention is illustrated and described herein as embodied in a sheath capture device for an endovascular stent graft delivery system and a method for operating the device, it is, nevertheless, not intended to be limited to the details shown because various modifications and structural changes may be made therein without departing from the spirit of the invention and within the scope and range of equivalents of the claims.\",\n \"The construction and method of operation of the invention, however, together with additional objects and advantages thereof, will be best understood from the following description of specific embodiments when read in connection with the accompanying drawings.\"\n ],\n [\n \"RELATED APPLICATIONS This application is a continuation of U.S. application Ser.\",\n \"No.\",\n \"14/675,102, filed Mar.\",\n \"31, 2015, which is a continuation of U.S. application Ser.\",\n \"No.\",\n \"12/137,592, filed Jun.\",\n \"12, 2008, abandoned.\",\n \"U.S. application Ser.\",\n \"No.\",\n \"12/137,592 is a: continuation-in-part (CIP) application of U.S. patent application Ser.\",\n \"No.\",\n \"11/701,867, now U.S. Pat.\",\n \"No.\",\n \"9,198,786, filed Feb. 1, 2007, which claims the benefit under 35 U.S.C.\",\n \"§ 119(e) of U.S.\",\n \"Provisional Application Nos.\",\n \"60/765,449, filed Feb. 3, 2006, and 60/833,533, filed Jul.\",\n \"26, 2006; is a continuation-in-part of U.S. patent application Ser.\",\n \"No.\",\n \"11/828,653, filed Jul.\",\n \"26, 2007, now abandoned, which claims the benefit under 35 U.S.C.\",\n \"§ 119(e) of U.S.\",\n \"Provisional Application Nos.\",\n \"60/765,449, filed Feb. 3, 2006, and 60/833,533, filed Jul.\",\n \"26, 2006; is a continuation-in-part of U.S. patent application Ser.\",\n \"No.\",\n \"11/828,675, now U.S. Pat.\",\n \"No.\",\n \"8,062,345, filed Jul.\",\n \"26, 2007, which claims the benefit under 35 U.S.C.\",\n \"§ 119(e) of U.S.\",\n \"Provisional Application Nos.\",\n \"60/765,449, filed Feb. 3, 2006, and 60/833,533, filed Jul.\",\n \"26, 2006; is a continuation in part of U.S. patent application Ser.\",\n \"No.\",\n \"10/784,462, filed Feb. 23, 2004, now U.S. Pat.\",\n \"No.\",\n \"8,292,943, which claims the benefit under 35 U.S.C.\",\n \"§ 119(e) of U.S.\",\n \"Provisional Application Nos.\",\n \"60/499,652, filed Sep. 3, 2003, and 60/500,155, filed Sep. 4, 2003; is a continuation-in-part of U.S. patent application Ser.\",\n \"No.\",\n \"10/884,136, filed Jul.\",\n \"2, 2004, now U.S. Pat.\",\n \"No.\",\n \"7,763,063, which claims the benefit under 35 U.S.C.\",\n \"§ 119(e) of U.S.\",\n \"Provisional Application Nos.\",\n \"60/499,652, filed Sep. 3, 2003, and 60/500,155, filed Sep. 4, 2003; is a continuation in part of U.S. patent application Ser.\",\n \"No.\",\n \"11/348,176, filed Feb. 6, 2006, now U.S. Pat.\",\n \"No.\",\n \"8,308,790; is a continuation-in-part of U.S. application Ser.\",\n \"No.\",\n \"11/353,927, filed Feb. 13, 2006, now U.S. Pat.\",\n \"No.\",\n \"8,070,790; is a continuation-in-part of U.S. application Ser.\",\n \"No.\",\n \"11/449,337, filed Jun.\",\n \"8, 2006, now U.S. Pat.\",\n \"No.\",\n \"8,740,963; is a continuation-in-part of U.S. application Ser.\",\n \"No.\",\n \"11/699,700, filed Jan. 30, 2007, now abandoned; is a continuation-in-part of U.S. application Ser.\",\n \"No.\",\n \"11/699,701, filed Jan. 30, 2007, now U.S. Pat.\",\n \"No.\",\n \"8,007,605; is a continuation-in-part of U.S. application Ser.\",\n \"No.\",\n \"11/700,510, filed Jan. 31, 2007, now U.S. Pat.\",\n \"No.\",\n \"8,062,349; and a continuation-in-part of U.S. application Ser.\",\n \"No.\",\n \"11/700,609, filed Jan. 31, 2007, now U.S. Pat.\",\n \"No.\",\n \"9,320,631, the complete disclosures of the above-referenced applications are all hereby incorporated by reference herein in their entirety.\",\n \"STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT n/a BACKGROUND OF THE INVENTION Field of the Invention The invention lies in the field of endoluminal blood vessel repairs.\",\n \"The invention specifically relates to a delivery system, a kit, and method for endoluminally repairing a vessel, for example, an aneurysm and/or dissections of the thoracic transverse aortic arch, thoracic posterior aortic arch, and the descending thoracic portion of the aorta with a stent graft.\",\n \"The present invention, in particular, relates to a sheath capture device for an endovascular stent graft delivery system and a method for operating the device.\",\n \"Description of the Related Art A stent graft is an implantable device made of a tube-shaped surgical graft covering and an expanding or self-expanding frame.\",\n \"The stent graft is placed inside a blood vessel to bridge, for example, an aneurismal, dissected, or other diseased segment of the blood vessel, and, thereby, exclude the hemodynamic pressures of blood flow from the diseased segment of the blood vessel.\",\n \"In selected patients, a stent graft advantageously eliminates the need to perform open thoracic or abdominal surgical procedures to treat diseases of the aorta and eliminates the need for total aortic reconstruction.\",\n \"Thus, the patient has less trauma and experiences a decrease in hospitalization and recovery times.\",\n \"The time needed to insert a stent graft is substantially less than the typical anesthesia time required for open aortic bypass surgical repair, for example.\",\n \"Use of surgical and/or endovascular grafts have widespread use throughout the world in vascular surgery.\",\n \"There are many different kinds of vascular graft configurations.\",\n \"Some have supporting framework over their entirety, some have only two stents as a supporting framework, and others simply have the tube-shaped graft material with no additional supporting framework, an example that is not relevant to the present invention.\",\n \"One of the most commonly known supporting stent graft frameworks is that disclosed in U.S. Pat.\",\n \"Nos.\",\n \"5,282,824 and 5,507,771 to Gianturco (hereinafter collectively referred to as “Gianturco”).\",\n \"Gianturco describes a zig-zag-shaped, self-expanding stent commonly referred to as a z-stent.\",\n \"The stents are, preferably, made of nitinol, but also have been made from stainless steel and other biocompatible materials.\",\n \"There are various features characterizing a stent graft.\",\n \"The first significant feature is the tube of graft material.\",\n \"This tube is commonly referred to as the graft and forms the tubular shape that will, ultimately, take the place of the diseased portion of the blood vessel.\",\n \"The graft is, preferably, made of a woven sheet (tube) of polyester or PTFE.\",\n \"The circumference of the graft tube is, typically, at least as large as the diameter and/or circumference of the vessel into which the graft will be inserted so that there is no possibility of blood flowing around the graft (also referred to as endoleak) to either displace the graft or to reapply hemodynamic pressure against the diseased portion of the blood vessel.\",\n \"Accordingly, to so hold the graft, self-expanding frameworks are attached typically to the graft material, whether on the interior or exterior thereof.\",\n \"Because blood flow within the lumen of the graft could be impaired if the framework was disposed on the interior wall of the graft, the framework is connected typically to the exterior wall of the graft.\",\n \"The ridges formed by such an exterior framework help to provide a better fit in the vessel by providing a sufficiently uneven outer surface that naturally grips the vessel where it contacts the vessel wall and also provides areas around which the vessel wall can endothelialize to further secure the stent graft in place.\",\n \"One of the significant dangers in endovascular graft technology is the possibility of the graft migrating from the desired position in which it is installed.\",\n \"Therefore, various devices have been created to assist in anchoring the graft to the vessel wall.\",\n \"One type of prior art prosthetic device is a stent graft made of a self-expanding metallic framework.\",\n \"For delivery, the stent graft is, first, radially compressed and loaded into an introducer system that will deliver the device to the target area.\",\n \"When the introducer system holding the stent graft positioned in an appropriate location in the vessel and allowed to open, the radial force imparted by the self-expanding framework is helpful, but, sometimes, not entirely sufficient, in endoluminally securing the stent graft within the vessel.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,824,041 to Lenker et al.\",\n \"(hereinafter “Lenker”) discloses an example of a stent graft delivery system.\",\n \"Lenker discloses various embodiments in which a sheath is retractable proximally over a prosthesis to be released.\",\n \"With regard to FIGS.\",\n \"7 and 8 of Lenker, Lenker names components 72 and 76, respectively, as “sheath” and “prosthesis-containment sheath.” However, the latter is merely the catheter in which the prosthesis 74 and the sheath 72 are held.\",\n \"With regard to FIGS.\",\n \"9 and 10, the sheath 82 has inner and outer layers 91, 92 fluid-tightly connected to one another to form a ballooning structure around the prosthesis P. This ballooning structure inflates when liquid is inflated with a non-compressible fluid medium and flares radially outward when inflated.\",\n \"With regard to FIGS.\",\n \"13 to 15, Lenker discloses the “sheath” 120, which is merely the delivery catheter, and an eversible membrane 126 that “folds back over itself (everts) as the sheath 120 is retracted so that there are always two layers of the membrane between the distal end of the sheath [120] and the prosthesis P.” Lenker at col. 9, lines 63 to 66.The eversion (peeling back) is caused by direct connection of the distal end 130 to the sheath 120.The Lenker delivery system, shown in FIGS.\",\n \"19A to 19D of Lenker, holds the prosthesis P at both ends 256, 258 while an outer catheter 254 is retracted over the prosthesis P and the inner sheath 260.The inner sheath 260 remains inside the outer catheter 254 before, during, and after retraction.\",\n \"Another structure for holding the prosthesis P at both ends is illustrated in FIGS.\",\n \"23A and 23B.\",\n \"Therein, the proximal holder having resilient axial members 342 is connected to a proximal ring structure 346.FIGS.\",\n \"24A to 24C also show an embodiment for holding the prosthesis at both ends inside thin-walled tube 362.To augment radial forces of stents, some prior art devices have added proximal and/or distal stents that are not entirely covered by the graft material.\",\n \"By not covering with graft material a portion of the proximal/distal ends of the stent, these stents have the ability to expand further radially than those stents that are entirely covered by the graft material.\",\n \"By expanding further, the proximal/distal stent ends better secure to the interior wall of the vessel and, in doing so, press the extreme cross-sectional surface of the graft ends into the vessel wall to create a fixated blood-tight seal.\",\n \"One example of such a prior art exposed stent can be found in United States Patent Publication US 2002/0198587 to Greenberg et al.\",\n \"The modular stent graft assembly therein has a three-part stent graft: a two-part graft having an aortic section 12 and an iliac section 14 (with four sizes for each) and a contralateral iliac occluder 80.FIGS.\",\n \"1, 2, and 4 to 6 show the attachment stent 32.As illustrated in FIGS.\",\n \"1, 2, and 4, the attachment stent 32, while rounded, is relatively sharp and, therefore, increases the probability of puncturing the vessel.\",\n \"A second example of a prior art exposed stent can be found in U.S. Patent Publication 2003/0074049 to Hoganson et al.\",\n \"(hereinafter “Hoganson”), which discloses a covered stent 10 in which the elongated portions or sections 24 of the ends 20a and 20b extend beyond the marginal edges of the cover 22.See Hoganson at FIGS.\",\n \"1, 3, 9, 11a, 11b, 12a, 12b, and 13.However, these extending exposed edges are triangular, with sharp apices pointing both upstream and downstream with regard to a graft placement location.\",\n \"Such a configuration of the exposed stent 20a, 20b increases the possibility of puncturing the vessel.\",\n \"In various embodiments shown in FIGS.\",\n \"6a, 6b, 6c; 10, 14a, Hoganson teaches completely covering the extended stent and, therefore, the absence of a stent extending from the cover 22.It is noted that the Hoganson stent is implanted by inflation of a balloon catheter.\",\n \"Another example of a prior art exposed stent can be found in U.S. Pat.\",\n \"No.\",\n \"6,565,596 to White et al.\",\n \"(hereinafter “White I”), which uses a proximally extending stent to prevent twisting or kinking and to maintain graft against longitudinal movement.\",\n \"The extending stent is expanded by a balloon and has a sinusoidal amplitude greater than the next adjacent one or two sinusoidal wires.\",\n \"White I indicates that it is desirable to space wires adjacent upstream end of graft as close together as is possible.\",\n \"The stent wires of White I are actually woven into graft body by piercing the graft body at various locations.\",\n \"See White I at FIGS.\",\n \"6 and 7.Thus, the rips in the graft body can lead to the possibility of the exposed stent moving with respect to the graft and of the graft body ripping further.\",\n \"Between the portions of the extending stent 17, the graft body has apertures.\",\n \"The stent configuration of U.S. Pat.\",\n \"No.\",\n \"5,716,393 to Lindenberg et al.\",\n \"is similar to White I in that the outermost portion of the one-piece stent—made from a sheet that is cut/punched and then rolled into cylinder—has a front end with a greater amplitude than the remaining body of the stent A further example of a prior art exposed stent can be found in U.S. Pat.\",\n \"No.\",\n \"6,524,335 to Hartley et al.\",\n \"(hereinafter “Hartley”).\",\n \"FIGS.\",\n \"1 and 2 of Hartley particularly disclose a proximal first stent 1 extending proximally from graft proximal end 4 with both the proximal and distal apices narrowing to pointed ends.\",\n \"Yet another example of a prior art exposed stent can be found in U.S. Pat.\",\n \"No.\",\n \"6,355,056 to Pinheiro (hereinafter “Pinheiro I”).\",\n \"Like the Hartley exposed stent, Pinheiro discloses exposed stents having triangular, sharp proximal apices.\",\n \"Still a further example of a prior art exposed stent can be found in U.S. Pat.\",\n \"No.\",\n \"6,099,558 to White et al.\",\n \"(hereinafter “White II”).\",\n \"The White II exposed stent is similar to the exposed stent of White I and also uses a balloon to expand the stent.\",\n \"An added example of a prior art exposed stent can be found in U.S. Pat.\",\n \"No.\",\n \"5,871,536 to Lazarus, which discloses two support members 68 longitudinally extending from proximal end to a rounded point.\",\n \"Such points, however, create a very significant possibility of piercing the vessel.\",\n \"An additional example of a prior art exposed stent can be found in U.S. Pat.\",\n \"No.\",\n \"5,851,228 to Pinheiro (hereinafter “Pinheiro II”).\",\n \"The Pinheiro II exposed stents are similar to the exposed stents of Pinheiro I and, as such, have triangular, sharp, proximal apices.\",\n \"Still another example of a prior art exposed stent can be found in Lenker (U.S. Pat.\",\n \"No.\",\n \"5,824,041), which shows a squared-offend of the proximal and distal exposed band members 14.A portion of the exposed members 14 that is attached to the graft material 18, 20 is longitudinally larger than a portion of the exposed members 14 that is exposed and extends away from the graft material 18, 20.Lenker et al.\",\n \"does not describe the members 14 in any detail.\",\n \"Yet a further example of a prior art exposed stent can be found in U.S. Pat.\",\n \"No.\",\n \"5,824,036 to Lauterjung, which, of all of the prior art embodiments described herein, shows the most pointed of exposed stents.\",\n \"Specifically, the proximal ends of the exposed stent are apices pointed like a minaret.\",\n \"The minaret points are so shaped intentionally to allow forks 300 (see Lauterjung at FIG.\",\n \"5) external to the stent 154 to pull the stent 154 from the sheath 302, as opposed to being pushed.\",\n \"A final example of a prior art exposed stent can be found in U.S. Pat.\",\n \"No.\",\n \"5,755,778 to Kleshinski.\",\n \"The Kleshinski exposed stents each have two different shaped portions, a triangular base portion and a looped end portion.\",\n \"The totality of each exposed cycle resembles a castellation.\",\n \"Even though the end-most portion of the stent is curved, because it is relatively narrow, it still creates the possibility of piercing the vessel wall.\",\n \"All of these prior art stents suffer from the disadvantageous characteristic that the relatively sharp proximal apices of the exposed stents have a shape that is likely to puncture the vessel wall.\",\n \"Devices other than exposed stents have been used to inhibit graft migration.\",\n \"A second of such devices is the placement of a relatively stiff longitudinal support member longitudinally extending along the entirety of the graft.\",\n \"The typical stent graft has a tubular body and a circumferential framework.\",\n \"This framework is not usually continuous.\",\n \"Rather, it typically takes the form of a series of rings along the tubular graft.\",\n \"Some stent grafts have only one or two of such rings at the proximal and/or distal ends and some have many stents tandemly placed along the entirety of the graft material.\",\n \"Thus, the overall stent graft has an “accordion” shape.\",\n \"During the systolic phase of each cardiac cycle, the hemodynamic pressure within the vessel is substantially parallel with the longitudinal plane of the stent graft.\",\n \"Therefore, a device having unsecured stents, could behave like an accordion or concertina with each systolic pulsation, and may have a tendency to migrate downstream.\",\n \"(A downstream migration, to achieve forward motion, has a repetitive longitudinal compression and extension of its cylindrical body.)\",\n \"Such movement is entirely undesirable.\",\n \"Connecting the stents with support along the longitudinal extent of the device thereof can prevent such movement.\",\n \"To provide such support, a second anti-migration device can be embodied as a relatively stiff longitudinal bar connected to the framework.\",\n \"A clear example of a longitudinal support bar can be found in Pinheiro I (U.S. Pat.\",\n \"No.\",\n \"6,355,056) and Pinheiro II (U.S. Pat.\",\n \"No.\",\n \"5,851,228).\",\n \"Each of these references discloses a plurality of longitudinally extending struts 40 extending between and directly interconnecting the proximal and distal exposed stents 20a, 20b.\",\n \"These struts 40 are designed to extend generally parallel with the inner lumen 15 of the graft 10, in other words, they are straight.\",\n \"Another example of a longitudinal support bar can be found in U.S. Pat.\",\n \"No.\",\n \"6,464,719 to Jayaraman.\",\n \"The Jayaraman stent is formed from a graft tube 21 and a supporting sheet 1 made of nitinol.\",\n \"This sheet is best shown in FIG.\",\n \"3.The end pieces 11, 13 of the sheet are directly connected to one another by wavy longitudinal connecting pieces 15 formed by cutting the sheet 1.To form the stent graft, the sheet 1 is coiled with or around the cylindrical tube 21.See FIGS.\",\n \"1 and 4.Alternatively, a plurality of connecting pieces 53 with holes at each end thereof can be attached to a cylindrical fabric tube 51 by stitching or sutures 57, as shown in FIG.\",\n \"8.Jayaraman requires more than one of these serpentine shaped connecting pieces 53 to provide longitudinal support.\",\n \"United States Patent Publication 2002/0016627 and U.S. Pat.\",\n \"No.\",\n \"6,312,458 to Golds each disclose a variation of a coiled securing member 20.A different kind of supporting member is disclosed in FIG.\",\n \"8 of U.S. Pat.\",\n \"No.\",\n \"6,053,943 to Edwin et al.\",\n \"Like Jayaraman, U.S. Pat.\",\n \"No.\",\n \"5,871,536 to Lazarus discloses a plurality of straight, longitudinal support structures 38 attached to the circumferential support structures 36, see FIGS.\",\n \"1, 6, 7, 8, 10, 11, 12, 14.FIG.\",\n \"8 of Lazarus illustrates the longitudinal support structures 38 attached to a distal structure 36 and extending almost all of the way to the proximal structure 36.The longitudinal structures 38, 84, 94 can be directly connected to the body 22, 80 and can be telescopic 38, 64.United States Patent Publication 2003/0088305 to Van Schie et al.\",\n \"(hereinafter “Van Schie”) does not disclose a support bar.\",\n \"Rather, it discloses a curved stent graft using an elastic material 8 connected to stents at a proximal end 2 and at a distal end 3 (see FIGS.\",\n \"1, 2) thereof to create a curved stent graft.\",\n \"Because Van Schie needs to create a flexible curved graft, the elastic material 8 is made of silicone rubber or another similar material.\",\n \"Thus, the material 8 cannot provide support in the longitudinal extent of the stent graft.\",\n \"Accordingly, an alternative to the elastic support material 8 is a suture material 25 shown in FIGS.\",\n \"3 to 6.SUMMARY OF THE INVENTION The invention provides a sheath capture device for an endovascular stent graft delivery system and a method for operating the device that overcome the hereinafore-mentioned disadvantages of the heretofore-known devices and methods of this general type and that provides a vessel repair device that implants/conforms more efficiently within the natural or diseased course of the aorta by aligning with the natural curve of the aorta, decreases the likelihood of vessel puncture, increases the blood-tight vascular connection, retains the intraluminal wall of the vessel position, is more resistant to migration, and delivers the stent graft into a curved vessel while minimizing intraluminal forces imparted during delivery and while minimizing the forces needed for a user to deliver the stent graft into a curved vessel.\",\n \"With the foregoing and other objects in view, there is provided, in accordance with the invention, a delivery system for delivering and deploying stent grafts having a proximal bare stent, the delivery system includes a hollow first lumen having a first distal end, a stent capture device including a capture portion fixedly connected adjacent said first distal end, a relatively rigid, hollow outer catheter having a catheter distal end and a catheter inner diameter, a hollow second lumen having a second distal end and being slidably disposed about said first lumen and slidably disposed in said outer catheter, a relatively flexible, hollow stent graft sheath having a sheath proximal end connected to said second distal end and disposed about said first lumen, said sheath having a sheath distal end and a sheath inner diameter greater than said catheter inner diameter to fit therein an at least partially compressed stent graft, and a distal nose cone having a cone proximal end connected to at least one of said capture portion and said first distal end, said nose cone and said capture portion being movably adjustable to selectively capture said sheath distal end therebetween.\",\n \"In accordance with another feature of the invention, the nose cone and the capture portion define a cavity in which the sheath distal end is held releasably.\",\n \"In accordance with a further feature of the invention, there is provided a handle, the outer catheter defining a longitudinal axis and being longitudinally fixedly connected to the handle about the second lumen, the first and second lumens being longitudinally movably connected to the handle.\",\n \"In accordance with an added feature of the invention, the outer catheter has a length only long enough to be inserted in a patient's aorta to approximately the patient's celiac axis.\",\n \"In accordance with an additional feature of the invention, there is provided a hollow third lumen disposed about the first lumen and within the second lumen, the third lumen having a third distal end, the capture portion being a first capture portion, the stent capture device including a second capture portion fixedly connected adjacent the third distal end and selectively movable with respect to the first capture portion to capture a stent therebetween.\",\n \"With the objects of the invention in view, there is also provided a method of loading a stent graft in a prosthesis delivery system for implanting a stent graft in a patient at a treatment site, includes the steps of providing a prosthesis delivery system including a hollow first lumen having a first distal end, a stent capture device including a capture portion fixedly connected adjacent the first distal end, a relatively rigid, hollow outer catheter having a catheter distal end and a catheter inner diameter, and, a hollow second lumen having a second distal end and being slidably disposed about the first lumen and slidably disposed in the outer catheter, loading a stent graft inside a relatively flexible, hollow stent graft sheath having a sheath inner diameter greater than the catheter inner diameter to temporarily dispose the stent graft therein in an at least partially compressed state, the stent graft sheath being disposed about the first lumen and having a sheath distal end and a sheath proximal end connected to the second distal end, temporarily capturing a stent of the stent graft with the stent capture device, removably capturing the sheath distal end between the capture portion and a distal nose cone having a proximal end connected to at least one of the capture portion and the first distal end, and loading the sheath with the partially compressed stent graft into the outer catheter to compress the stent graft even further for subsequent implantation at the treatment site.\",\n \"In accordance with yet another mode of the invention, the sheath capturing step is carried out by movably adjusting the nose cone and the capture portion to selectively secure the sheath distal end therebetween.\",\n \"In accordance with yet a further mode of the invention, the outer catheter is extended with the loaded sheath up to a given position at a distance from the treatment site and the stent graft is implanted at the treatment site.\",\n \"In accordance with yet an added mode of the invention, the implantation step is carried out by extending the first and second lumen in a patient towards the treatment site to move the sheath out from the outer catheter and return the stent graft to the partially compressed state in the sheath, extending the first and second lumen further towards the treatment site to place the loaded sheath at the treatment site, and releasing the sheath distal end from between the capture portion and the distal nose cone and unsheathing the stent graft from the sheath by retracting the second lumen away from the treatment site, and releasing the stent from the capture device to implant the stent graft at the treatment site.\",\n \"In accordance with yet an additional mode of the invention, the outer catheter is advanced in a patient towards a treatment site up to a given position at a distance from the treatment site, and, while retaining the outer catheter in the given position, the stent graft sheath is advanced out from the outer catheter to the treatment site to align the stent graft with the treatment site, the sheath distal end of the sheath is released from between the capture portion and the distal nose cone and unsheathing the stent graft from the sheath by retracting the second lumen away from the treatment site to at least partially implant the stent graft at the treatment site, the stent is released from the capture device to implant the stent graft at the treatment site, and, upon completion of the stent graft implantation, both of the stent graft sheath and the outer catheter are retracted from the patient.\",\n \"In accordance with again another mode of the invention, the advancing step is carried out by advancing the sheath out from the outer catheter to the treatment site to axially align the stent graft with the treatment site and rotating the stent graft sheath to circumferentially align the stent graft with the treatment site.\",\n \"In accordance with again a further mode of the invention, the advancing step is carried out by advancing the outer catheter towards the treatment site only up to a point at a distance from the treatment site greater than a length of the stent graft.\",\n \"In accordance with again an added mode of the invention, the advancing step is carried out by advancing the outer catheter in vasculature of a patient towards a vascular treatment site.\",\n \"In accordance with again an additional mode of the invention, the advancing step is carried out by advancing the outer catheter in aortic vasculature of the patient to approximately a celiac axis of the patient.\",\n \"In accordance with still another mode of the invention, the advancing step is carried out by advancing the outer catheter in aortic vasculature of the patient to approximately a celiac axis of the patient.\",\n \"In accordance with yet another mode of the invention, the outer catheter is provided with a length sufficient to reach to approximately a celiac axis of a patient.\",\n \"In accordance with yet a further mode of the invention, the outer catheter is provided with a length equal to approximately a distance from the patient's femoral arterial access site to the patient's celiac axis.\",\n \"In accordance with yet an added mode of the invention, the retracting step is carried out upon completion of the stent graft implantation by retracting the stent graft sheath into the outer catheter and subsequently retracting the outer catheter containing the stent graft sheath from the patient.\",\n \"In accordance with yet an additional mode of the invention, the stent graft sheath is of a material relatively more flexible than a material of the outer catheter.\",\n \"With the objects of the invention in view, there is also provided a method of implanting a stent graft in a patient at a treatment site, including the steps of longitudinally locking a set of inner lumens and an inner sheath with respect to an outer lumen, at least a portion of the inner sheath constraining a stent graft, capturing a distal end of the inner sheath between a stent capture device and a distal nose cone, threading the lumens and the inner sheath onto a guidewire and into a patient to place the outer lumen into an aorta of the patient only up to a point at a distance from the treatment site greater than a length of the prosthesis, longitudinally unlocking the inner lumens with respect to the outer lumen, advancing the inner lumens and inner sheath distally out of the outer lumen in the aorta towards the patient's heart to transport the stent graft further upstream into the aorta, unlocking the inner sheath constraining the stent graft from at least one interior lumen of the inner lumens, and releasing the distal end of the inner sheath from between the capture portion and the distal nose cone by retracting the inner sheath in a proximal direction to at least partially implant the stent graft in a vessel.\",\n \"In accordance with a concomitant mode of the invention, the stent graft is implanted in the vessel at the treatment site by retracting the second lumen away from the treatment site to unsheath the stent graft from the sheath and releasing the stent from the capture device.\",\n \"Other features that are considered as characteristic for the invention are set forth in the appended claims.\",\n \"Although the invention is illustrated and described herein as embodied in a sheath capture device for an endovascular stent graft delivery system and a method for operating the device, it is, nevertheless, not intended to be limited to the details shown because various modifications and structural changes may be made therein without departing from the spirit of the invention and within the scope and range of equivalents of the claims.\",\n \"The construction and method of operation of the invention, however, together with additional objects and advantages thereof, will be best understood from the following description of specific embodiments when read in connection with the accompanying drawings.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS The features of the present invention, which are believed to be novel, are set forth with particularity in the appended claims.\",\n \"The invention, together with further objects and advantages thereof, may best be understood by reference to the following description, taken in conjunction with the accompanying drawings, in the several figures of which like reference numerals identify like elements, and in which: FIG.\",\n \"1 is a side elevational view of a stent graft according to the invention; FIG.\",\n \"2 is a side elevational view of a stent of the stent graft of FIG.\",\n \"1; FIG.\",\n \"3 is a cross-sectional view of the stent of FIG.\",\n \"2 with different embodiments of protrusions; FIG.\",\n \"4 is a perspective view of a prior art round mandrel for forming prior art stents; FIG.\",\n \"5 is a fragmentary, side elevational view of a prior art stent in a portion of a vessel; FIG.\",\n \"6 is a perspective view of a dodecahedral-shaped mandrel for forming stents in FIGS.\",\n \"1 to 3; FIG.\",\n \"7 is a fragmentary, side elevational view of the stent of FIGS.\",\n \"1 to 3 in a portion of a vessel; FIG.\",\n \"8 is a fragmentary, enlarged side elevational view of the proximal end of the stent graft of FIG.\",\n \"1 illustrating movement of a gimbaled end; FIG.\",\n \"9 is a side elevational view of a two-part stent graft according to the invention; FIG.\",\n \"10 is a fragmentary, side elevational view of a delivery system according to the invention with a locking ring in a neutral position; FIG.\",\n \"11 is a fragmentary, side elevational view of the delivery system of FIG.\",\n \"10 with the locking ring in an advancement position and, as indicated by dashed lines, a distal handle and sheath assembly in an advanced position; FIG.\",\n \"12 is a fragmentary, enlarged view of a sheath assembly of the delivery system of FIG.\",\n \"10; FIG.\",\n \"13 is a fragmentary, enlarged view of an apex capture device of the delivery system of FIG.\",\n \"10 in a captured position; FIG.\",\n \"14 is a fragmentary, enlarged view of the apex capture device of FIG.\",\n \"13 in a released position; FIG.\",\n \"15 is a fragmentary, enlarged view of an apex release assembly of the delivery system of FIG.\",\n \"10 in the captured position; FIG.\",\n \"16 is a fragmentary, enlarged view of the apex release assembly of FIG.\",\n \"15 in the captured position with an intermediate part removed; FIG.\",\n \"17 is a fragmentary, enlarged view of the apex release assembly of FIG.\",\n \"16 in the released position; FIG.\",\n \"18 is a fragmentary, side elevational view of the delivery system of FIG.\",\n \"11 showing how a user deploys the prosthesis; FIG.\",\n \"19 is a fragmentary cross-sectional view of human arteries including the aorta with the assembly of the present invention in a first step of a method for inserting the prosthesis according to the invention; FIG.\",\n \"20 is a fragmentary cross-sectional view of the arteries of FIG.\",\n \"19 with the assembly in a subsequent step of the method for inserting the prosthesis; FIG.\",\n \"21 is a fragmentary cross-sectional view of the arteries of FIG.\",\n \"20 with the assembly in a subsequent step of the method for inserting the prosthesis; FIG.\",\n \"22 is a fragmentary cross-sectional view of the arteries of FIG.\",\n \"21 with the assembly in a subsequent step of the method for inserting the prosthesis; FIG.\",\n \"23 is a fragmentary cross-sectional view of the arteries of FIG.\",\n \"22 with the assembly in a subsequent step of the method for inserting the prosthesis; FIG.\",\n \"24 is a fragmentary cross-sectional view of the arteries of FIG.\",\n \"23 with the assembly in a subsequent step of the method for inserting the prosthesis; FIG.\",\n \"25 is a fragmentary, diagrammatic, perspective view of the coaxial relationship of delivery system lumen according to the invention; FIG.\",\n \"26 is a fragmentary, cross-sectional view of the apex release assembly according to the invention; FIG.\",\n \"27 is a fragmentary, side elevational view of the stent graft of FIG.\",\n \"1 with various orientations of radiopaque markers according to the invention; FIG.\",\n \"28 is a fragmentary perspective view of the stent graft of FIG.\",\n \"1 with various orientations of radiopaque markers according to the invention; FIG.\",\n \"29 is a perspective view of a distal apex head of the apex capture device of FIG.\",\n \"13; FIG.\",\n \"30 is a fragmentary side elevational view of the distal apex head of FIG.\",\n \"29 and a proximal apex body of the apex capture device of FIG.\",\n \"13 with portions of a bare stent in the captured position; FIG.\",\n \"31 is a fragmentary, side elevational view of the distal apex head and proximal apex body of FIG.\",\n \"30 with a portion of the proximal apex body cut away to illustrate the bare stent in the captured position; FIG.\",\n \"32 is a fragmentary side elevational view of the distal apex head and proximal apex body of FIG.\",\n \"30 in the released position; FIG.\",\n \"33 is a fragmentary, cross-sectional view of an embodiment of handle assemblies according to the invention; FIG.\",\n \"34 is a cross-sectional view of a pusher clasp rotator of the handle assembly of FIG.\",\n \"33; FIG.\",\n \"35 is a plan view of the pusher clasp rotator of FIG.\",\n \"34 viewed along line C-C; FIG.\",\n \"36 is a plan and partially hidden view of the pusher clasp rotator of FIG.\",\n \"34 with a helix groove for a first embodiment of the handle assembly of FIGS.\",\n \"10, 11, and 18; FIG.\",\n \"37 is a cross-sectional view of the pusher clasp rotator of FIG.\",\n \"36 along section line A-A; FIG.\",\n \"38 is a plan and partially hidden view of the pusher clasp rotator of FIG.\",\n \"36; FIG.\",\n \"39 is a cross-sectional view of the pusher clasp rotator of FIG.\",\n \"38 along section line B-B; FIG.\",\n \"40 is a perspective view of a rotator body of the handle assembly of FIG.\",\n \"33; FIG.\",\n \"41 is an elevational and partially hidden side view of the rotator body of FIG.\",\n \"40; FIG.\",\n \"42 is a cross-sectional view of the rotator body of FIG.\",\n \"41 along section line A-A; FIG.\",\n \"43 is an elevational and partially hidden side view of the rotator body of FIG.\",\n \"40; FIG.\",\n \"44 is an elevational and partially hidden side view of a pusher clasp body of the handle assembly of FIG.\",\n \"33; FIG.\",\n \"45 is a cross-sectional view of the pusher clasp body of FIG.\",\n \"44 along section line A-A; FIG.\",\n \"46 is a cross-sectional view of the pusher clasp body of FIG.\",\n \"44 along section line B-B; FIG.\",\n \"47 is a fragmentary, side elevational view of a portion of the handle assembly of FIG.\",\n \"33 with a sheath assembly according to the invention; FIG.\",\n \"48 is an exploded side elevational view of a portion of the handle assembly of FIG.\",\n \"47; FIG.\",\n \"49 is a fragmentary elevational and partially hidden side view of a handle body of the handle assembly of FIG.\",\n \"33; FIG.\",\n \"50 is a fragmentary, exploded side elevational view of a portion of a second embodiment of the handle assembly according to the invention; FIG.\",\n \"51 is a fragmentary, side elevational view of the portion of FIG.\",\n \"50 in a neutral position; FIG.\",\n \"52 is an exploded view of a first portion of the second embodiment of the handle assembly; FIG.\",\n \"53 is a fragmentary, exploded view of a larger portion of the second embodiment of the handle assembly as compared to FIG.\",\n \"52 with the first portion and the sheath assembly; FIG.\",\n \"54 is perspective view of a clasp body of the second embodiment of the handle assembly; FIG.\",\n \"55 is an elevational side view of the clasp body of FIG.\",\n \"54; FIG.\",\n \"56 is a cross-sectional view of the clasp body of FIG.\",\n \"55 along section line A-A; FIG.\",\n \"57 is a plan view of the clasp body of FIG.\",\n \"54; FIG.\",\n \"58 is a plan view of the clasp body of FIG.\",\n \"57 viewed from section line B-B; FIG.\",\n \"59 is a fragmentary and partially hidden side elevational view of a clasp sleeve of the second embodiment of the handle assembly; FIG.\",\n \"60 is a fragmentary, cross-sectional view of a portion the clasp sleeve of FIG.\",\n \"59 along section line A; FIG.\",\n \"61 is a fragmentary, cross-sectional view of the clasp sleeve of FIG.\",\n \"59 along section line C-C; FIG.\",\n \"62 is a fragmentary and partially hidden side elevational view of the clasp sleeve of FIG.\",\n \"59 rotated with respect to FIG.\",\n \"59; FIG.\",\n \"63 is a fragmentary, cross-sectional view of the nose cone and sheath assemblies of FIG.\",\n \"10; FIG.\",\n \"64 is a fragmentary, perspective view of a portion of self-alignment configuration according to the invention; FIG.\",\n \"65 is a diagrammatic, fragmentary, cross-sectional view of a distal portion of the delivery system with the self-alignment configuration according to the invention inside the descending thoracic aorta and with the self-alignment configuration in an orientation opposite a desired orientation; FIG.\",\n \"66 is a diagrammatic, fragmentary, cross-sectional view of the distal portion of the delivery system of FIG.\",\n \"65 with the self-alignment configuration partially inside the descending thoracic aorta and partially inside the aortic arch and with the self-alignment configuration in an orientation closer to the desired orientation; FIG.\",\n \"67 is a diagrammatic, fragmentary, cross-sectional view of the distal portion of the delivery system of FIG.\",\n \"65 with the self-alignment configuration primarily inside the aortic arch and with the self-alignment configuration substantially in the desired orientation; FIG.\",\n \"68 is a fragmentary, enlarged, partially exploded perspective view of an alternative embodiment of a distal end of the graft push lumen of FIG.\",\n \"25; FIG.\",\n \"69 is a photograph of a user bending a stent graft assembly around a curving device to impart a curve to a guidewire lumen therein; FIG.\",\n \"70 is a side elevational view of a stent graft according to the invention; FIG.\",\n \"71 is a side elevational view of an alternative embodiment of the stent graft with a clasping stent and a crown stent; FIG.\",\n \"72 is a photograph depicting a side view of the stent graft of FIG.\",\n \"71; FIG.\",\n \"73 is a photograph of a perspective view from a side of a proximal end of the stent graft of FIGS.\",\n \"1 and 70 with a bare stent protruding from the proximal end thereof; FIG.\",\n \"74 is a photograph of an enlarged, perspective view from the interior of the proximal end of the stent graft of FIG.\",\n \"71; FIG.\",\n \"75 is a photograph of a perspective view from a distal end of the stent graft of FIG.\",\n \"71 with an alternative embodiment of the crown stent where less of the stent is attached to the graft; FIG.\",\n \"76 is a photograph of a side view of the stent graft of FIG.\",\n \"71 partially withdrawn from a flexible sheath of the delivery system according to the invention with some of the capture stent apices releasably held within the apex capture device of the delivery system; FIG.\",\n \"77 is a photograph of a perspective view of the captured stent graft of FIG.\",\n \"76 from the proximal end thereof and with some of the capture stent apices releasably held within the apex capture device of the delivery system; FIG.\",\n \"78 is a photograph of a perspective view from the proximal end of the stent graft of FIGS.\",\n \"1 and 70 deployed in an exemplary vessel; FIG.\",\n \"79 is a photograph of a perspective view from the proximal end of the stent graft of FIG.\",\n \"71 deployed in an exemplary vessel; FIG.\",\n \"80 is a cross-sectional view of the apex capture assembly of FIGS.\",\n \"13, 14, 29 to 32, and 63 along a plane orthogonal to the longitudinal axis of the delivery system according to the invention without the inner sheath; FIG.\",\n \"81 is a fragmentary, cross-sectional view of the apex capture assembly of FIG.\",\n \"80 along a plane orthogonal to the view plane of FIG.\",\n \"80 and through the longitudinal axis of the delivery system according to the invention without the inner sheath; FIG.\",\n \"82 is a fragmentary, side elevational view of a distal end of the delivery system according to the invention with the inner sheath in a curved orientation and having an alternative embodiment of a D-shaped marker thereon; FIG.\",\n \"83 is a fragmentary, plan view of the distal end of FIG.\",\n \"82 viewed from above; FIG.\",\n \"84 is a fragmentary, plan and partially hidden view of the distal end of FIG.\",\n \"82 viewed from below with the D-shaped marker on the opposite top side; FIG.\",\n \"85 is a fragmentary, elevational view of the distal end of FIG.\",\n \"82 viewed from the top of FIG.\",\n \"82 and parallel to the longitudinal axis of the catheter of the delivery system; FIG.\",\n \"86 is a side elevational view of the delivery system according to the invention with an alternative embodiment of a rotating distal handle; FIG.\",\n \"87 is a fragmentary, cross-sectional view of the rotating distal handle of FIG.\",\n \"86; FIG.\",\n \"88 is a is a fragmentary, cross-sectional view of an alternative embodiment of the rotating distal handle of FIG.\",\n \"86; FIG.\",\n \"89 is a fragmentary, perspective view of the distal end of the delivery system of FIG.\",\n \"86; FIG.\",\n \"90 is a perspective view from the distal side of another embodiment of the delivery system of the invention; FIG.\",\n \"91 is a fragmentary, enlarged, exploded, side elevational view of the apex release assembly of the delivery system of FIG.\",\n \"90; FIG.\",\n \"92 is a fragmentary, enlarged, partially exploded, side elevational view of the locking knob assembly of the delivery system of FIG.\",\n \"90; FIG.\",\n \"93 is a perspective view of a clasp sleeve of a handle assembly of the delivery system of FIG.\",\n \"90; FIG.\",\n \"94 is an exploded, perspective view of a clasp body assembly of the handle assembly of FIG.\",\n \"90; FIG.\",\n \"95 is an exploded, perspective view of a rotator assembly of the handle assembly of FIG.\",\n \"90; FIG.\",\n \"96 is a perspective view of the rotator assembly of FIG.\",\n \"95 in an assembled state; FIG.\",\n \"97 is a fragmentary, exploded, side elevational view of a delivery sheath of the delivery system of FIG.\",\n \"90; FIG.\",\n \"98 is a fragmentary, exploded, side elevational view of the delivery sheath of FIG.\",\n \"97 rotated approximately 90 degrees; FIG.\",\n \"99 is an enlarged, side elevational view of a portion of the delivery sheath of FIG.\",\n \"98; FIG.\",\n \"100 is a fragmentary, enlarged, side elevational view of the distal end of the delivery system of FIG.\",\n \"90; FIG.\",\n \"101 is a fragmentary, partially hidden side elevational view and partially cross-sectional view of the proximal end of the handle assembly of FIG.\",\n \"90 with the sheath lumen removed; FIG.\",\n \"102 is a fragmentary, cross-sectional view of the proximal end of the handle assembly of FIG.\",\n \"101; FIG.\",\n \"103 is a fragmentary, enlarged, cross-sectional view of the actuation knob and clasp body assemblies of the handle assembly of FIG.\",\n \"102; FIG.\",\n \"104 is a fragmentary, enlarged, cross-sectional view of the rotator assembly of the handle assembly of FIG.\",\n \"102; FIG.\",\n \"105 is a fragmentary, further-enlarged, cross-sectional view of the rotator assembly of the handle assembly of FIG.\",\n \"104; FIG.\",\n \"106 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.\",\n \"90; FIG.\",\n \"107 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.\",\n \"90; FIG.\",\n \"108 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.\",\n \"90; FIG.\",\n \"109 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.\",\n \"90; FIG.\",\n \"110 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.\",\n \"90; FIG.\",\n \"111 is a fragmentary, enlarged, transverse cross-sectional view of the handle assembly of FIG.\",\n \"110; FIG.\",\n \"112 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.\",\n \"90; FIG.\",\n \"113 is a fragmentary, enlarged transverse cross-sectional view of the handle assembly of FIG.\",\n \"112; FIG.\",\n \"114 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.\",\n \"90; FIG.\",\n \"115 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.\",\n \"90; FIG.\",\n \"116 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.\",\n \"90; FIG.\",\n \"117 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.\",\n \"90; FIG.\",\n \"118 is a fragmentary, transverse cross-sectional view of the handle assembly of the delivery system of FIG.\",\n \"90; FIG.\",\n \"119 is a fragmentary, shaded, cross-sectional view of a distal portion of the handle assembly of FIG.\",\n \"90 without the proximal handle.\",\n \"DESCRIPTION OF EXEMPLARY EMBODIMENTS While the specification concludes with claims defining the features of the invention that are regarded as novel, it is believed that the invention will be better understood from a consideration of the following description in conjunction with the drawing figures, in which like reference numerals are carried forward.\",\n \"The present invention provides a stent graft, delivery system, and method for implanting a prosthesis with a two-part expanding delivery system that treats, in particular, thoracic aortic defects from the brachiocephalic level of the aortic arch distally to a level just superior to the celiac axis and provides an endovascular foundation for an anastomosis with the thoracic aorta, while providing an alternative method for partial/total thoracic aortic repair by excluding the vessel defect and making surgical repair of the aorta unnecessary.\",\n \"The stent graft of the present invention, however, is not limited to use in the aorta.\",\n \"It can be endoluminally inserted in any accessible artery that could accommodate the stent graft's dimensions.\",\n \"Stent Graft The stent graft according to the present invention provides various features that, heretofore, have not been applied in the art and, thereby, provide a vessel repair device that implants/conforms more efficiently within the natural or diseased course of the aorta, decreases the likelihood of vessel puncture, and increases the blood-tight vascular connection, and decreases the probability of graft mobility.\",\n \"The stent graft is implanted endovascularly before or during or in place of an open repair of the vessel (i.e., an arch, in particular, the ascending and/or descending portion of the aorta) through a delivery system described in detail below.\",\n \"The typical defects treated by the stent graft are aortic aneurysms, aortic dissections, and other diseases such as penetrating aortic ulcer, coarctation, and patent ductus arteriosus, related to the aorta.\",\n \"When endovascularly placed in the aorta, the stent graft forms a seal in the vessel and automatically affixes itself to the vessel with resultant effacement of the pathological lesion.\",\n \"Referring now to the figures of the drawings in detail and first, particularly to FIG.\",\n \"1 thereof, there is shown an improved stent graft 1 having a graft sleeve 10 and a number of stents 20.These stents 20 are, preferably, made of nitinol, an alloy having particularly special properties allowing it to rebound to a set configuration after compression, the rebounding property being based upon the temperature at which the alloy exists.\",\n \"For a detailed explanation of nitinol and its application with regard to stents, see, e.g., U.S. Pat.\",\n \"Nos.\",\n \"4,665,906, 5,067,957, and 5,597,378 to Jervis and to Gianturco.\",\n \"The graft sleeve 10 is cylindrical in shape and is made of a woven graft material along its entire length.\",\n \"The graft material is, preferably, polyester, in particular, polyester referred to under the name DACRON® or other material types like Expanded Polytetrafluoroethylene (“EPTFE”), or other polymeric based coverings.\",\n \"The tubular graft sleeve 10 has a framework of individual lumen-supporting wires each referred to in the art as a stent 20.Connection of each stent 20 is, preferably, performed by sewing a polymeric (nylon, polyester) thread around an entirety of the stent 20 and through the graft sleeve 10.The stitch spacings are sufficiently close to prevent any edge of the stent 20 from extending substantially further from the outer circumference of the graft sleeve 10 than the diameter of the wire itself.\",\n \"Preferably, the stitches have a 0.5 mm to 5 mm spacing.\",\n \"The stents 20 are sewn either to the exterior or interior surfaces of the graft sleeve 10.FIG.\",\n \"1 illustrates all stents 20, 30 on the exterior surface 16 of the graft sleeve 10.In an exemplary non-illustrated embodiment, the most proximal 23 and distal stents and a bare stent 30 are connected to the interior surface of the graft sleeve 10 and the remainder of the stents 20 are connected to the exterior surface 16.Another possible non-illustrated embodiment alternates connection of the stents 20, 30 to the graft sleeve 10 from the graft exterior surface to the graft interior surface, the alternation having any periodic sequence.\",\n \"A stent 20, when connected to the graft sleeve 10, radially forces the graft sleeve 10 open to a predetermined diameter D. The released radial force creates a seal with the vessel wall and affixes the graft to the vessel wall when the graft is implanted in the vessel and is allowed to expand.\",\n \"Typically, the stents 20 are sized to fully expand to the diameter D of the fully expanded graft sleeve 10.However, a characteristic of the present invention is that each of the stents 20 and 30 has a diameter larger than the diameter D of the fully expanded graft sleeve 10.Thus, when the stent graft 1 is fully expanded and resting on the internal surface of the vessel where it has been placed, each stent 20 is imparting independently a radially directed force to the graft sleeve 10.Such pre-compression, as it is referred to herein, is applied (1) to ensure that the graft covering is fully extended, (2) to ensure sufficient stent radial force to make sure sealing occurs, (3) to affix the stent graft and prevent it from kinking, and (4) to affix the stent graft and prevent migration.\",\n \"Preferably, each of the stents 20 is formed with a single nitinol wire.\",\n \"Of course other biocompatible materials can be used, for example, stainless steel, biopolymers, cobalt chrome, and titanium alloys.\",\n \"An exemplary shape of each stent 20 corresponds to what is referred in the art as a Z-stent, see, e.g., Gianturco (although the shape of the stents 20 can be in any form that satisfies the functions of a self-expanding stent).\",\n \"Thus, the wire forming the stent 20 is a ring having a wavy or sinusoidal shape.\",\n \"In particular, an elevational view orthogonal to the center axis 21 of the stent 20 reveals a shape somewhere between a triangular wave and a sinusoidal wave as shown in FIG.\",\n \"2.In other words, the view of FIG.\",\n \"2 shows that the stents 20 each have alternating proximal 22 and distal 24 apices.\",\n \"Preferably, the apices have a radius r that does not present too great of a point towards a vessel wall to prevent any possibility of puncturing the vessel, regardless of the complete circumferential connection to the graft sleeve 10.In particular, the radius r of curvature of the proximal 22 and distal 24 apices of the stent 20 are, preferably, equal.\",\n \"The radius of curvature r is between approximately 0.1 mm and approximately 3.0 mm, in particular, approximately 0.5 mm.\",\n \"Another advantageous feature of a stent lies in extending the longitudinal profile along which the stent contacts the inner wall of a vessel.\",\n \"This longitudinal profile can be explained with reference to FIGS.\",\n \"3 to 7.Prior art stents and stents according to the present invention are formed on mandrels 29, 29′ by winding the wire around the mandrel 29, 29′ and forming the apexes 22, 24, 32, 34 by wrapping the wire over non-illustrated pins that protrude perpendicular from the axis of the mandrel.\",\n \"Such pins, if illustrated, would be located in the holes illustrated in the mandrels 29, 29′ of FIGS.\",\n \"4 and 6.Prior art stents are formed on a round mandrel 29 (also referred to as a bar).\",\n \"A stent 20′ formed on a round mandrel 29 has a profile that is rounded (see FIG.\",\n \"5).\",\n \"Because of the rounded profile, the stent 20′ does not conform evenly against the inner wall of the vessel 2 in which it is inserted.\",\n \"This disadvantage is critical in the area of stent graft 1 seal zones—areas where the ends of the graft sleeve 10 need to be laid against the inner wall of the vessel 2.Clinical experience reveals that stents 20′ formed with the round mandrel 29 do not lie against the vessel 2; instead, only a mid-section of the stent 20′ rests against the vessel 2, as shown in FIG.\",\n \"5.Accordingly, when such a stent 20′ is present at either of the proximal 12 or distal 14 ends of the stent graft 1, the graft material flares away from the wall of the vessel 2 into the lumen—a condition that is to be avoided.\",\n \"An example of this flaring can be seen by comparing the upper and lower portions of the curved longitudinal profile of the stent 20′ in FIG.\",\n \"5 with the linear longitudinal profile of the vessel 2.To remedy this problem and ensure co-columnar apposition of the stent and vessel, stents 20 of the present invention are formed on a multiple-sided mandrel.\",\n \"In particular, the stents 20 are formed on a polygonal-shaped mandrel 29′.\",\n \"The mandrel 29′ does not have sharp edges.\",\n \"Instead, it has flat sections and rounded edge portions between the respective flat sections.\",\n \"Thus, a stent formed on the mandrel 29′ will have a cross-section that is somewhat round but polygonal, as shown in FIG.\",\n \"3.The cross-sectional view orthogonal to the center axis 21 of such a stent 20 will have beveled or rounded edges 31 (corresponding to the rounded edge portions of the mandrel 29′) disposed between flat sides or struts 33 (corresponding to the flat sections of the mandrel 29′).\",\n \"With stents manufactured in this way, the apices remain on the circumference of the graft and do not bend into the graft interior like prior art stents—an undesirable condition as explained in the preceding paragraph.\",\n \"Further, the struts of the stents so manufactured (the substantially linear portions of the stent between the apices) lie in the plane of the graft material when attached thereto as shown in FIG.\",\n \"7.In contrast, prior art struts are curved (see FIG.\",\n \"5) and, therefore, force the graft material inwards away from the vessel wall.\",\n \"As used herein, substantially linear means that the struts are sufficiently straight and level to substantially prevent displacement of an apex (which lies between two adjacent struts) towards the interior of the graft material to which the struts and apices are attached.\",\n \"To manufacture the stent 20, apexes of the stents 20 are formed by winding the wire over non-illustrated pins located on the rounded portions of the mandrel 29′.\",\n \"Thus, the struts 33 lying between the apexes 22, 24, 32, 34 of the stents 20 lie flat against the flat sides of the mandrel 29′.\",\n \"When so formed on the inventive mandrel 29′, the longitudinal profile is substantially less rounded than the profile of stent 20′ and, in practice, is substantially linear.\",\n \"For stents 20 having six proximal 22 and six distal 24 apices, the stents 20 are formed on a dodecahedron-shaped mandrel 29′ (a mandrel having twelve sides), which mandrel 29′ is shown in FIG.\",\n \"6.A stent 20 formed on such a mandrel 29′ will have the cross-section illustrated in FIG.\",\n \"3.The fourteen-apex stent 20 shown in FIG.\",\n \"7 illustrates a stent 20 that has been formed on a fourteen-sided mandrel.\",\n \"The stent 20 in FIG.\",\n \"7 is polygonal in cross-section (having fourteen sides) and, as shown in FIG.\",\n \"7, has a substantially linear longitudinal profile.\",\n \"Clinically, the linear longitudinal profile improves the stent's 20 ability to conform to the vessel 2 and press the graft sleeve 10 outward in the sealing zones at the extremities of the individual stent 20.Another way to improve the performance of the stent graft 1 is to provide the distal-most stent 25 on the graft sleeve 10 (i.e., downstream) with additional apices and to give it a longer longitudinal length (i.e., greater amplitude) and/or a longer circumferential length.\",\n \"When a stent 25 having a longer circumferential length is sewn to a graft, the stent graft 1 will perform better clinically.\",\n \"The improvement, in part, is due to a need for the distal portion of the graft material 10 to be pressed firmly against the wall of the vessel.\",\n \"The additional apices result in additional points of contact between the stent graft 1 and vessel wall, thus ensuring better apposition to the wall of the vessel and better sealing of the graft material 10 to the vessel.\",\n \"The increased apposition and sealing substantially improves the axial alignment of the distal end 14 of the stent graft 1 to the vessel.\",\n \"As set forth above, each of the stents 20 and 30 has a diameter larger than the diameter D of the fully expanded graft sleeve 10.Thus, if the distal stent 25 also has a diameter larger than the diameter D, it will impart a greater radial bias on all 360 degrees of the corresponding section of the graft than stents not having such an oversized configuration.\",\n \"A typical implanted stent graft 1 typically does not experience a lifting off at straight portions of a vessel because the radial bias of the stents acting upon the graft sleeve give adequate pressure to align the stent and graft sleeve with the vessel wall.\",\n \"However, when a typical stent graft is implanted in a curved vessel (such as the aorta), the distal end of the stent graft 1 does experience a lift off from the vessel wall.\",\n \"The increased apposition and sealing of the stent graft 1 according to the present invention substantially decreases the probability of lift off because the added height and additional apices enhance the alignment of the stent graft perpendicular to the vessel wall as compared to prior art stent grafts (no lift off occurs).\",\n \"The number of total apices of a stent is dependent upon the diameter of the vessel in which the stent graft 1 is to be implanted.\",\n \"Vessels having a smaller diameter have a smaller total number of apices than a stent to be implanted in a vessel having a larger diameter.\",\n \"Table I below indicates exemplary stent embodiments for vessels having different diameters.\",\n \"For example, if a vessel has a 26 or 27 mm diameter, then an exemplary diameter of the graft sleeve 10 is 30 mm.\",\n \"For a 30 mm diameter graft sleeve, the intermediate stents 20 will have 5 apices on each side (proximal and distal) for a total of 10 apices.\",\n \"In other words, the stent defines 5 periodic “waves.” The distal-most stent 25, in comparison, defines 6 periodic “waves” and, therefore, has 12 total apices.\",\n \"It is noted that the distal-most stent 25 in FIG.\",\n \"1 does not have the additional apex.\",\n \"While Table 1 indicates exemplary embodiments, these configurations can be adjusted or changed as needed.\",\n \"TABLE 1 Vessel Diameter Graft Diameter Stent Apices/Side (mm) (mm) (Distal-most Stent #) 19 22 5(5) 20-21 24 5(5) 22-23 26 5(5) 24-25 28 5(6) 26-27 30 5(6) 28-29 32 6(7) 30-31 34 6(7) 32-33 36 6(7) 34 38 6(7) 35-36 40 7(8) 37-38 42 7(8) 39-40 44 7(8) 41-42 46 7(8) To increase the security of the stent graft 1 in a vessel, an exposed or bare stent 30 is provided on the stent graft 1, preferably, only at the proximal end 12 of the graft sleeve 10—proximal meaning that it is attached to the portion of the graft sleeve 10 from which the blood flows into the sleeve, i.e., blood flows from the bare stent 30 and through the graft sleeve 10 to the left of FIG.\",\n \"1.The bare stent 30 is not limited to being attached at the proximal end 12.Another non-illustrated bare stent can be attached similarly to the distal end 14 of the graft sleeve 10.Significantly, the bare stent 30 is only partially attached to the graft sleeve 10.Specifically, the bare stent 30 is fixed to the graft sleeve 10 only at the distal apices 34 of the bare stent 30.Thus, the bare stent 30 is partially free to extend the proximal apices 32 away from the proximal end of the graft sleeve 10.The bare stent 30 has various properties, the primary one being to improve the apposition of the graft material to the contour of the vessel wall and to align the proximal portion of the graft covering in the lumen of the arch and provide a blood-tight closure of the proximal end 12 of the graft sleeve 10 so that blood does not pass between the vascular inside wall and outer surface 16 of the graft sleeve 10 (endoleak).\",\n \"An exemplary configuration for the radius of curvature a of the distal apices 34 is substantially equal to the radius r of the proximal 22 and distal 24 apices of the stent 20, in particular, it is equal at least to the radius of curvature r of the proximal apices of the stent 20 directly adjacent the bare stent 30.Thus, as shown in FIG.\",\n \"8, a distance between the proximal apices 22 of the most proximal stent 23 and crossing points of the exposed portions of the bare stent 30 are substantially at a same distance from one another all the way around the circumference of the proximal end 12 of the graft sleeve 10.Preferably, this distance varies based upon the graft diameter.\",\n \"Accordingly, the sinusoidal portion of the distal apices 34 connected to the graft sleeve 10 traverse substantially the same path as that of the stent 23 closest to the bare stent 30.Thus, the distance d between the stent 23 and all portions of the bare stent 30 connected to the graft sleeve 10 remain constant.\",\n \"Such a configuration is advantageous because it maintains the symmetry of radial force of the device about the circumference of the vessel and also aids in the synchronous, simultaneous expansion of the device, thus increasing apposition of the graft material to the vessel wall to induce a proximal seal—and substantially improve the proximal seal—due to increasing outward force members in contact with the vessel wall.\",\n \"Inter-positioning the stents 23, 30 in phase with one another, creates an overlap, i.e., the apices 34 of the bare stent 30 are positioned within the troughs of the stent 23.A further advantage of such a configuration is that the overlap provides twice as many points of contact between the proximal opening of the graft sleeve 10 and the vessel in which the stent graft 1 is implanted.\",\n \"The additional apposition points keep the proximal opening of the graft sleeve 10 open against the vessel wall, which substantially reduces the potential for endoleaks.\",\n \"In addition, the overlap of the stents 23, 30 increases the radial load or resistance to compression, which functionally increases fixation and reduces the potential for device migration.\",\n \"In contrast to the distal apices 34 of the bare stent 30, the radius of curvature .beta.\",\n \"of the proximal apices 32 (those apices that are not sewn into the graft sleeve 10) is significantly larger than the radius of curvature .alpha.\",\n \"of the distal apices 34.An exemplary configuration for the bare stent apices has a radius approximately equal to 1.5 mm for the proximal apices 32 and approximately equal to 0.5 mm for the distal apices 34.Such a configuration substantially prevents perforation of the blood vessel by the proximal apices 32, or, at a minimum, makes is much less likely for the bare stent 30 to perforate the vessel because of the less-sharp curvature of the proximal apices 32.The bare stent 30 also has an amplitude greater than the other stents 20.Preferably, the peak-to-peak amplitude of the stents 20 is approximately 1.3 cm to 1.5 cm, whereas the peak-to-peak amplitude of the bare stent 30 is approximately 2.5 cm to 4.0 cm.\",\n \"Accordingly, the force exerted by the bare stent 30 on the inner wall of the aorta (due to the bare stent 30 expanding to its native position) is spread over a larger surface area.\",\n \"Thus, the bare stent 30 of the present invention presents a less traumatic radial stress to the interior of the vessel wall—a characteristic that, while less per square mm than an individual one of the stents 20 would be, is sufficient, nonetheless, to retain the proximal end 12 in position.\",\n \"Simultaneously, the taller configuration of the bare stent 30 guides the proximal opening of the stent graft in a more “squared-off” manner.\",\n \"Thus, the proximal opening of the stent graft is more aligned with the natural curvature of the vessel in the area of the proximal opening.\",\n \"As set forth above, because the vessel moves constantly, and due to the constantly changing pressure imparted by blood flow, any stent graft placed in the vessel has the natural tendency to migrate downstream.\",\n \"This is especially true when the stent graft 1 has graft sleeve segments 18 with lengths defined by the separation of the stents on either end of the segment 18, giving the stent graft 1 an accordion, concertina, or caterpillar-like shape.\",\n \"When such a shape is pulsating with the vessel and while hemodynamic pressure is imparted in a pulsating manner along the stent graft from the proximal end 12 to the downstream distal end 14, the stent graft 1 has a tendency to migrate downstream in the vessel.\",\n \"It is desired to have such motion be entirely prohibited.\",\n \"Support along a longitudinal extent of the graft sleeve 10 assists in preventing such movement.\",\n \"Accordingly, as set forth above, prior art stent grafts have provided longitudinal rods extending in a straight line from one stent to another.\",\n \"The present invention, however, provides a longitudinal, spiraling/helical support member 40 that, while extending relatively parallel to the longitudinal axis 11 of the graft sleeve 10, is not aligned substantially parallel to a longitudinal extent of the entirety of the stent graft 1 as done in the prior art.\",\n \"“Relatively parallel” is referred to herein as an extent that is more along the longitudinal axis 11 of the stent graft 1 than along an axis perpendicular thereto.\",\n \"Specifically, the longitudinal support member 40 has a somewhat S-turn shape, in that, a proximal portion 42 is relatively parallel to the longitudinal axis 11 of the graft sleeve 10 at a first degree 41 (being defined as a degree of the 360 degrees of the circumference of the graft sleeve 10), and a distal portion 44 is, also, relatively parallel to the longitudinal axis 11 of the tube graft, but at a different second degree 43 on the circumference of the graft sleeve 10.The difference between the first and second degrees 41, 43 is dependent upon the length L of the graft sleeve 10.For an approximately 20 cm (approx.\",\n \"8″) graft sleeve, for example, the second degree 43 is between 80 and 110 degrees away from the first degree 41, in particular, approximately 90 degrees away.\",\n \"In comparison, for an approximately 9 cm (approx.\",\n \"3.5″) graft sleeve, the second degree 43 is between 30 and 60 degrees away from the first degree 41, in particular, approximately 45 degrees away.\",\n \"As set forth below, the distance between the first and second degrees 41, 43 is also dependent upon the curvature and the kind of curvature that the stent graft 1 will be exposed to when in vivo.\",\n \"The longitudinal support member 40 has a curved intermediate portion 46 between the proximal and distal portions 42, 44.By using the word “portion” it is not intended to mean that the rod is in three separate parts (of course, in a particular configuration, a multi-part embodiment is possible).\",\n \"An exemplary embodiment of the longitudinal support member 40 is a single, one-piece rod made of stainless steel, cobalt chrome, nitinol, or polymeric material that is shaped as a fully curved helix 42, 44, 46 without any straight portion.\",\n \"In an alternative stent graft embodiment, the proximal and distal portions 42, 44 can be substantially parallel to the longitudinal axis 11 of the stent graft 1 and the central portion 46 can be helically curved.\",\n \"One way to describe an exemplary curvature embodiment of the longitudinal support member 40 can be using an analogy of asymptotes.\",\n \"If there are two asymptotes extending parallel to the longitudinal axis 11 of the graft sleeve 10 at the first and second degrees 41, 43 on the graft sleeve 10, then the proximal portion 42 can be on the first degree 41 or extend approximately asymptotically to the first degree 41 and the distal portion 44 can be on the second degree 43 or extend approximately asymptotically to the second degree 43.Because the longitudinal support member 40 is one piece in an exemplary embodiment, the curved portion 46 follows the natural curve formed by placing the proximal and distal portions 42, 44 as set forth herein.\",\n \"In such a position, the curved longitudinal support member 40 has a centerline 45 (parallel to the longitudinal axis 11 of the graft sleeve 10 halfway between the first and second degrees 41, 43 on the graft sleeve 10).\",\n \"In this embodiment, therefore, the curved portion intersects the centerline 45 at approximately 20 to 40 degrees in magnitude, preferably at approximately 30 to 35 degrees.\",\n \"Another way to describe the curvature of the longitudinal support member can be with respect to the centerline 45.The portion of the longitudinal support member 40 between the first degree 41 and the centerline 45 is approximately a mirror image of the portion of the longitudinal support member 40 between the second degree 43 and the centerline 45, but rotated one-hundred eighty degrees (180.degree.)\",\n \"around an axis orthogonal to the centerline 45.Such symmetry can be referred to herein as “reverse-mirror symmetrical.” The longitudinal support member 40 is, preferably, sewn to the graft sleeve 10 in the same way as the stents 20.However, the longitudinal support member 40 is not sewn directly to any of the stents 20 in the proximal portions of the graft.\",\n \"In other words, the longitudinal support member 40 is independent of the proximal skeleton formed by the stents 20.Such a configuration is advantageous because an independent proximal end creates a gimbal that endows the stent graft with additional flexibility.\",\n \"Specifically, the gimbaled proximal end allows the proximal end to align better to the proximal point of apposition, thus reducing the chance for endoleak.\",\n \"The additional independence from the longitudinal support member allows the proximal fixation point to be independent from the distal section that is undergoing related motion due to the physiological motion of pulsatile flow of blood.\",\n \"Also in an exemplary embodiment, the longitudinal support member 40 is pre-formed in the desired spiral/helical shape (counter-clockwise from proximal to distal), before being attached to the graft sleeve 10.Because vessels receiving the stent graft 1 are not typically straight (especially the aortic arch), the final implanted position of the stent graft 1 will, most likely, be curved in some way.\",\n \"In prior art stent grafts (which only provide longitudinally parallel support rods), there exist, inherently, a force that urges the rod, and, thereby, the entire stent graft, to the straightened, natural shape of the rod.\",\n \"This force is disadvantageous for stent grafts that are to be installed in an at least partly curved manner.\",\n \"The curved shape of the longitudinal support member 40 according to the present invention eliminates at least a majority, or substantially all, of this disadvantage because the longitudinal support member's 40 natural shape is curved.\",\n \"Therefore, the support member 40 imparts less of a force, or none at all, to straighten the longitudinal support member 40, and, thereby, move the implanted stent graft in an undesirable way.\",\n \"At the same time, the curved longitudinal support member 40 negates the effect of the latent kinetic force residing in the aortic wall that is generated by the propagation of the pulse wave and systolic blood pressure in the cardiac cycle, which is, then, released during diastole.\",\n \"As set forth in more detail below, the delivery system of the present invention automatically aligns the stent graft 1 to the most optimal position while traversing the curved vessel in which it is to be implanted, specifically, the longitudinal support member 40 is placed substantially at the superior longitudinal surface line of the curved aorta (with respect to anatomical position).\",\n \"In an exemplary embodiment, the longitudinal support member 40 can be curved in a patient-customized way to accommodate the anticipated curve of the actual vessel in which the graft will be implanted.\",\n \"Thus, the distance between the first and second degrees 41, 43 will be dependent upon the curvature and the kind of curvature that the stent graft 1 will be exposed to when in vivo.\",\n \"As such, when implanted, the curved longitudinal support member 40 will, actually, exhibit an opposite force against any environment that would alter its conformance to the shape of its resident vessel's existing course(es).\",\n \"Preferably, the support member 40 is sewn, in a similar manner as the stents 20, on the outside surface 16 of the graft sleeve 10.In prior art support rods, the ends thereof are merely a terminating end of a steel or nitinol rod and are, therefore, sharp.\",\n \"Even though these ends are sewn to the tube graft in the prior art, the possibility of tearing the vessel wall still exists.\",\n \"It is, therefore, desirable to not provide the support rod with sharp ends that could puncture the vessel in which the stent graft is placed.\",\n \"The two ends of the longitudinal support member 40 of the present invention do not end abruptly.\",\n \"Instead, each end of the longitudinal support member loops 47 back upon itself such that the end of the longitudinal support member along the axis of the stent graft is not sharp and, instead, presents an exterior of a circular or oval shape when viewed from the ends 12, 14 of the graft sleeve 10.Such a configuration substantially prevents the possibility of tearing the vessel wall and also provides additional longitudinal support at the oval shape by having two longitudinally extending sides of the oval 47.In addition, in another embodiment, the end of the longitudinal support member may be connected to the second proximal stent 28 and to the most distal stent.\",\n \"This configuration would allow the longitudinal support member to be affixed to stent 28 (see FIG.\",\n \"1) and the most distal stent for support while still allowing for the gimbaled feature of the proximal end of the stent graft to be maintained.\",\n \"A significant feature of the longitudinal support member 40 is that the ends of the longitudinal support member 40 may not extend all the way to the two ends 12, 14 of the graft sleeve 10.Instead, the longitudinal support member 40 terminates at or prior to the second-to-last stent 28 at the proximal end 12, and, if desired, prior to the second-to-last stent 28′ at the distal end 14 of the graft sleeve 10.Such an ending configuration (whether proximal only or both proximal and distal) is chosen for a particular reason—when the longitudinal support member 40 ends before either of the planes defined by cross-sectional lines 52, 52′, the graft sleeve 10 and the stents 20 connected thereto respectively form gimbaled portions 50, 50′.\",\n \"In other words, when a grasping force acting upon the gimbaled ends 50, 50′ moves or pivots the cross-sectional plane defining each end opening of the graft sleeve 10 about the longitudinal axis 11 starting from the planes defined by the cross-sectional lines 52, 52′, then the moving portions 50, 50′ can be oriented at any angle .gamma.\",\n \"about the center of the circular opening in all directions (360 degrees), as shown in FIG.\",\n \"8.The natural gimbal, thus, allows the ends 50, 50′ to be inclined in any radial direction away from the longitudinal axis 11.Among other things, the gimbaled ends 50, 50′ allow each end opening to dynamically align naturally to the curve of the vessel in which it is implanted.\",\n \"A significant advantage of the gimbaled ends 50, 50′ is that they limit propagation of the forces acting upon the separate parts.\",\n \"Specifically, a force that, previously, would act upon the entirety of the stent graft 1, in other words, both the end portions 50, 50′ and the middle portion of the stent graft 1 (i.e., between planes 52, 52′), now principally acts upon the portion in which the force occurs.\",\n \"For example, a force that acts only upon one of the end portions 50, 50′ substantially does not propagate into the middle portion of the stent graft 1 (i.e., between planes 52, 52′).\",\n \"More significantly, however, when a force acts upon the middle portion of the stent graft 1 (whether moving longitudinally, axially (dilation), or in a torqued manner), the ends 50, 50′, because they are gimbaled, remain relatively completely aligned with the natural contours of the vessel surrounding the respective end 50, 50′ and have virtually none of the force transferred thereto, which force could potentially cause the ends to grate, rub, or shift from their desired fixed position in the vessel.\",\n \"Accordingly, the stent graft ends 50, 50′ remain fixed in the implanted position and extend the seating life of the stent graft 1.Another advantage of the longitudinal support member 40 is that it increases the columnar strength of the graft stent 1.Specifically, the material of the graft sleeve can be compressed easily along the longitudinal axis 11, a property that remains true even with the presence of the stents 20 so long as the stents 20 are attached to the graft sleeve 10 with a spacing between the distal apices 24 of one stent 20 and the proximal apices 22 of the next adjacent stent 20.This is especially true for the amount of force imparted by the flow of blood along the extent of the longitudinal axis 11.However, with the longitudinal support member 40 attached according to the present invention, longitudinal strength of the stent graft 1 increases to overcome the longitudinal forces imparted by blood flow.\",\n \"Another benefit imparted by having such increased longitudinal strength is that the stent graft 1 is further prevented from migrating in the vessel because the tube graft is not compressing and expanding in an accordion-like manner—movement that would, inherently, cause graft migration.\",\n \"A further measure for preventing migration of the stent graft 1 is to equip at least one of any of the individual stents 20, 30 or the longitudinal support member 40 with protuberances 60, such as barbs or hooks (FIG.\",\n \"3).\",\n \"See, e.g., United States Patent Publication 2002/0052660 to Greenhaigh.\",\n \"In an exemplary embodiment of the present invention, the stents 20, 30 are secured to the outer circumferential surface 16 of the graft sleeve 10.Accordingly, if the stents 20 (or connected portions of stent 30) have protuberances 60 protruding outwardly, then such features would catch the interior wall of the vessel and add to the prevention of stent graft 1 migration.\",\n \"Such an embodiment can be preferred for aneurysms but is not preferred for the fragile characteristics of dissections because such protuberances 60 can excoriate the inner layer(s) of the vessel and cause leaks between layers, for example.\",\n \"As shown in FIG.\",\n \"9, the stent graft 1 is not limited to a single graft sleeve 10.Instead, the entire stent graft can be a first stent graft 100 having all of the features of the stent graft 1 described above and a second stent graft 200 that, instead of having a circular extreme proximal end 12, as set forth above, has a proximal end 212 with a shape following the contour of the most proximal stent 220 and is slightly larger in circumference than the distal circumference of the first stent graft 100.Therefore, an insertion of the proximal end 212 of the second stent graft 200 into the distal end 114 of the first stent graft 100 results, in total, in a two-part stent graft.\",\n \"Because blood flows from the proximal end 112 of the first stent graft 100 to the distal end 214 of the second stent graft 200, it is preferable to have the first stent graft 100 fit inside the second stent graft 200 to prevent blood from leaking out therebetween.\",\n \"This configuration can be achieved by implanting the devices in reverse order (first implant graft 200 and, then, implant graft 100.Each of the stent grafts 100, 200 can have its own longitudinal support member 40 as needed.\",\n \"It is not significant if the stent apices of the distal-most stent of the first stent graft 100 are not aligned with the stent apices of the proximal-most stent 220 of the second stent graft 200.What is important is the amount of junctional overlap between the two grafts 100, 200.Delivery System As set forth above, the prior art includes many different systems for endoluminally delivering a prosthesis, in particular, a stent graft, to a vessel.\",\n \"Many of the delivery systems have similar parts and most are guided along a guidewire that is inserted, typically, through an insertion into the femoral artery near a patient's groin prior to use of the delivery system.\",\n \"To prevent puncture of the arteries leading to and including the aorta, the delivery system is coaxially connected to the guidewire and tracks the course of the guidewire up to the aorta.\",\n \"The parts of the delivery system that will track over the wire are, therefore, sized to have an outside diameter smaller than the inside diameter of the femoral artery of the patient.\",\n \"The delivery system components that track over the guidewire include the stent graft and are made of a series of coaxial lumens referred to as catheters and sheaths.\",\n \"The stent graft is constrained, typically, by an outer catheter, requiring the stent graft to be compressed to fit inside the outer catheter.\",\n \"Doing so makes the portion of the delivery system that constrains the stent graft very stiff, which, therefore, reduces that portion's flexibility and makes it difficult for the delivery system to track over the guidewire, especially along curved vessels such as the aortic arch.\",\n \"In addition, because the stent graft exerts very high radial forces on the constraining catheter due to the amount that it must be compressed to fit inside the catheter, the process of deploying the stent graft by sliding the constraining catheter off of the stent graft requires a very high amount of force, typically referred to as a deployment force.\",\n \"Also, the catheter has to be strong enough to constrain the graft, requiring it to be made of a rigid material.\",\n \"If the rigid material is bent, such as when tracking into the aortic arch, the rigid material tends to kink, making it difficult if not impossible to deploy the stent graft.\",\n \"Common features of vascular prosthesis delivery systems include a tapered nose cone fixedly connected to a guidewire lumen, which has an inner diameter substantially corresponding to an outer diameter of the guidewire such that the guidewire lumen slides easily over and along the guidewire.\",\n \"A removable, hollow catheter covers and holds a compressed prosthesis in its hollow and the catheter is fixedly connected to the guidewire lumen.\",\n \"Thus, when the prosthesis is in a correct position for implantation, the physician withdraws the hollow catheter to gradually expose the self-expanding prosthesis from its proximal end towards its distal end.\",\n \"When the catheter has withdrawn a sufficient distance from each portion of the expanding framework of the prosthesis, the framework can expand to its native position, preferably, a position that has a diameter at least as great as the inner diameter of the vessel wall to, thereby, tightly affix the prosthesis in the vessel.\",\n \"When the catheter is entirely withdrawn from the prosthesis and, thereby, allows the prosthesis to expand to the diameter of the vessel, the prosthesis is fully expanded and connected endoluminally to the vessel along the entire extent of the prosthesis, e.g., to treat a dissection.\",\n \"When treating an aneurysm, for example, the prosthesis is in contact with the vessel's proximal and distal landing zones when completely released from the catheter.\",\n \"At such a point in the delivery, the delivery system can be withdrawn from the patient.\",\n \"The prosthesis, however, cannot be reloaded in the catheter if implantation is not optimal.\",\n \"The aorta usually has a relatively straight portion in the abdominal region and in a lower part of the thoracic region.\",\n \"However, in the upper part of the thoracic region, the aorta is curved substantially, traversing an upside-down U-shape from the back of the heart over to the front of the heart.\",\n \"As explained above, prior art delivery systems are relatively hard and inflexible (the guidewire/catheter portion of the prior art delivery systems).\",\n \"Therefore, if the guidewire/catheter must traverse the curved portion of the aorta, it will kink as it is curved or it will press against the top portion of the aortic curve, possibly puncturing the aorta if the diseased portion is located where the guidewire/catheter is exerting its force.\",\n \"Such a situation must be avoided at all costs because the likelihood of patient mortality is high.\",\n \"The prior art does not provide any way for substantially reducing the stress on the curved portion of the aorta or for making the guidewire/catheter sufficiently flexible to traverse the curved portion without causing damage to the vessel.\",\n \"The present invention, however, provides significant features not found in the prior art that assist in placing a stent graft in a curved portion of the aorta in a way that substantially reduces the stress on the curved portion of the aorta and substantially reduces the insertion forces needed to have the compressed graft traverse the curved portion of the aorta.\",\n \"As set forth above, the longitudinal support member 40 is pre-formed in a desired spiral/helical shape before being attached to the graft sleeve 10 and, in an exemplary embodiment, is curved in a patient-customized way to accommodate the anticipated curve of the actual vessel in which the graft will be implanted.\",\n \"As such, optimal positioning of the stent graft 1 occurs when the longitudinal support member 40 is placed substantially at the superior longitudinal surface line of the curved aorta (with respect to anatomical position).\",\n \"Such placement can be effected in two ways.\",\n \"First, the stent graft 1, the support member 40, or any portion of the delivery system that is near the target site can be provided with radiopaque markers that are monitored by the physician and used to manually align the support member 40 in what is perceived as an optimal position.\",\n \"The success of this alignment technique, however, is dependent upon the skill of the physician.\",\n \"Second, the delivery system can be made to automatically align the support member 40 at the optimal position.\",\n \"No such system existed in the prior art.\",\n \"However, the delivery system of the present invention provides such an alignment device, thereby, eliminating the need for physician guesswork as to the three-dimensional rotational position of the implanted stent graft 1.This alignment device is explained in further detail below with respect to FIGS.\",\n \"64 to 67.The delivery system of the present invention also has a very simple to use handle assembly.\",\n \"The handle assembly takes advantage of the fact that the inside diameter of the aorta is substantially larger that the inside diameter of the femoral arteries.\",\n \"The present invention, accordingly, uses a two-stage approach in which, after the device is inserted in through the femoral artery and tracks up into the abdominal area of the aorta (having a larger diameter (see FIG.\",\n \"19) than the femoral artery), a second stage is deployed (see FIG.\",\n \"20) allowing a small amount of expansion of the stent graft while still constrained in a sheath; but this sheath, made of fabric/woven polymer or similar flexible material, is very flexible.\",\n \"Such a configuration gives the delivery system greater flexibility for tracking, reduces deployment forces because of the larger sheath diameter, and easily overcome kinks because the sheath is made of fabric.\",\n \"To describe the delivery system of the present invention, the method for operating the delivery assembly 600 will be described first in association with FIGS.\",\n \"10, 11, and 12.Thereafter, the individual components will be described to allow a better understanding of how each step in the process is effected for delivering the stent graft 1 to any portion of the aorta 700 (see FIGS.\",\n \"19 to 24), in particular, the curved portion 710 of the aorta.\",\n \"Initially, the distal end 14 of the stent graft 1 is compressed and placed into a hollow, cup-shaped, or tubular-shaped graft holding device, in particular, the distal sleeve 644 (see, e.g., FIG.\",\n \"25).\",\n \"At this point, it is noted that the convention for indicating direction with respect to delivery systems is opposite that of the convention for indicating direction with respect to stent grafts.\",\n \"Therefore, the proximal direction of the delivery system is that portion closest to the user/physician employing the system and the distal direction corresponds to the portion farthest away from the user/physician, i.e., towards the distal-most nose cone 632.The distal sleeve 644 is fixedly connected to the distal end of the graft push lumen 642, which lumen 642 provides an end face for the distal end 14 of the stent graft 1.Alternatively, the distal sleeve 644 can be removed entirely.\",\n \"In such a configuration, as shown in FIG.\",\n \"12, for example, the proximal taper of the inner sheath 652 can provide the measures for longitudinally holding the compressed distal end of the stent graft 1.If the sleeve 644 is removed, it is important to prevent the distal end 14 of the stent graft 1 from entering the space between the interior surface of the hollow sheath lumen 654 and the exterior surface of the graft push lumen 642 slidably disposed in the sheath lumen 654.Selecting a radial thickness of the space to be less than the diameter of the wire making up the stent 20, 30 (in particular, no greater than half a diameter thereof) insures reliable movement of the distal end 14 of the stent graft 1.In another alternative configuration shown in FIG.\",\n \"68, the distal sleeve 644 can be a disk-shaped buttress 644 present at the distal end of the graft push lumen 642.An example configuration can provide the buttress 644 with a hollow proximal insertion peg 6442, a hollow distal stiffening tube 6444, and an intermediate buttress wall 6446.The buttress 644 is concentric to the center axis of the delivery system 600 and allows the co-axial guidewire lumen 620 and apex release lumen 640 to pass therethrough.\",\n \"The peg 6442 allows for easy connection to the graft push lumen 643.The stiffening tube 64 creates a transition in stiffness from the graft push lumen 642 to the apex release lumen 640 and guidewire lumen 620 and provides support to the lumen 620, 640 located therein.\",\n \"Such a transition in stiffness reduces any possibility of kinking at the distal end of the graft push lumen 642 and aids in transferring force from the graft push lumen 642 to the lumen therein 620, 640 when all are in a curved orientation.\",\n \"The buttress wall 6446 provides a flat surface that will contact the distal-end-facing side of the stent graft 1 and can be used to push the stent graft distally when the graft push lumen 642 is moved distally.\",\n \"The alternative configuration of the buttress 644 insures that the stent graft 1 does not become impinged within the graft push lumen 642 and the lumen therein 620, 640 when these components are moved relative to each other.\",\n \"As set forth in more detail below, each apex 32 of the bare stent 30 is, then, loaded into the apex capture device 634 so that the stent graft 1 is held at both its proximal and distal ends.\",\n \"The loaded distal end 14, along with the distal sleeve 644 and the graft push lumen 642, are, in turn, loaded into the inner sheath 652, thus, further compressing the entirety of the stent graft 1.The captured bare stent 30, along with the nose cone assembly 630 (including the apex capture device 634), is loaded until the proximal end of the nose cone 632 rests on the distal end of the inner sheath 652.The entire nose cone assembly 630 and sheath assembly 650 is, then, loaded proximally into the rigid outer catheter 660, further compressing the stent graft 1 (resting inside the inner sheath 652) to its fully compressed position for later insertion into a patient.\",\n \"See FIG.\",\n \"63.The stent graft 1 is, therefore, held both at its proximal and distal ends and, thereby, is both pushed and pulled when moving from a first position (shown in FIG.\",\n \"19 and described below) to a second position (shown in FIG.\",\n \"21 and described below).\",\n \"Specifically, pushing is accomplished by the non-illustrated interior end face of the hollow distal sleeve 644 (or the taper 653 of the inner sheath 652) and pulling is accomplished by the hold that the apex capture device 634 has on the apices 32 of the bare stent 30.The assembly 600 according to the present invention tracks along a guidewire 610 already inserted in the patient and extending through the aorta and up to, but not into, the left ventricle of the heart 720.Therefore, a guidewire 610 is inserted through the guidewire lumen 620 starting from the nose cone assembly 630, through the sheath assembly 650, through the handle assembly 670, and through the apex release assembly 690.The guidewire 610 extends out the proximal-most end of the assembly 600.The guidewire lumen 620 is coaxial with the nose cone assembly 630, the sheath assembly 650, the handle assembly 670, and the apex release assembly 690 and is the innermost lumen of the assembly 600 immediately surrounding the guidewire 610.Before using the delivery system assembly 600, all air must be purged from inside the assembly 600.Therefore, a liquid, such as sterile U.S.P.\",\n \"saline, is injected through a non-illustrated tapered luer fitting to flush the guidewire lumen at a non-illustrated purge port located near a proximal end of the guidewire lumen.\",\n \"Second, saline is also injected through the luer fitting 612 of the lateral purge-port (see FIG.\",\n \"11), which liquid fills the entire internal co-axial space of the delivery system assembly 600.It may be necessary to manipulate the system to facilitate movement of the air to be purged to the highest point of the system.\",\n \"After purging all air, the system can be threaded onto the guidewire and inserted into the patient.\",\n \"Because the outer catheter 660 has a predetermined length, the fixed front handle 672 can be disposed relatively close to the entry port of the femoral artery.\",\n \"It is noted, however, that the length of the outer catheter 660 is sized such that it will not have the fixed proximal handle 672 directly contact the entry port of the femoral artery in a patient who has the longest distance between the entry port and the thoracic/abdominal junction 742, 732 of the aorta expected in a patient (this distance is predetermined).\",\n \"Thus, the delivery assembly 600 of the present invention can be used with typical anatomy of the patient.\",\n \"Of course, the assembly 600 can be sized to any usable length.\",\n \"The nose cone assembly 630 is inserted into a patient's femoral artery and follows the guidewire 610 until the nose cone 632 reaches the first position at least to a level of the celiac axis and possibly further but not into the intended stent graft deployment site, which would prevent deployment of at least the downstream end of the stent graft.\",\n \"The first position is shown in FIG.\",\n \"19.The nose cone assembly 630 is radiopaque, whether wholly or partially, to enable the physician to determine fluoroscopically, for example, that the nose cone assembly 630 is in the first position.\",\n \"For example, the nose cone 632 can have a radiopaque marker 631 anywhere thereon or the nose cone 632 can be entirely radiopaque.\",\n \"FIGS.\",\n \"19 to 24 illustrate the catheter 660 extending approximately up to the renal arteries.\",\n \"However, the catheter 660 of the present invention is configured to travel up to at least the celiac axis (not shown in FIGS.\",\n \"19 to 24).\",\n \"As used herein, the celiac axis is to be defined according to common medical terms.\",\n \"In a simplistic definition, the celiac axis is a plane that intersects and is parallel to a central axis of a patient's celiac at the intersection of the celiac and the aorta and, therefore, this plane is approximately orthogonal to the longitudinal axis of the abdominal/thoracic aorta at the point where the celiac intersects the aorta.\",\n \"Therefore, with respect to extension of the catheter 660 into the aorta, it is extended into the aorta up to but not past the intended downstream end of the implant.\",\n \"After arriving at this distal-most position, the distal end of the catheter 660 remains substantially steady along the longitudinal axis of the aorta until after the stent graft 1 is implanted (see FIG.\",\n \"24) and the entire delivery system is to be removed from the patient.\",\n \"While the delivery system of the present invention can be retracted in the orientation shown in FIG.\",\n \"24 except for one difference (the bare stent 30 is open and the apex release device 634 is released from compressing the bare stent 30), the preferred embodiment for removal of the catheter 660 from the aorta after implantation of the stent graft 1 occurs with reference to the condition shown in FIG.\",\n \"19—where all of the interior lumens 620, 640, 642, 654 are retracted inside the catheter 660 and the nose cone 632 is in contact with the distal end of the catheter 660.After the nose cone assembly 630 is in the first position shown in FIG.\",\n \"19, the locking knob or ring 676 is placed from its neutral position into its advancement position.\",\n \"As will be described below, placing the locking knob 676 into its advancement position A allows both the nose cone assembly 630 and the internal sheath assembly 650 to move as one when the proximal handle 678 is moved in either the proximal or distal directions because the locking knob 676 radially locks the graft push lumen 642 to the lumens of the apex release assembly 690 (including the guidewire lumen 620 and an apex release lumen 640).\",\n \"The locking knob 676 is fixedly connected to a sheath lumen 654.Before describing how various embodiments of the handle assembly 670 function, a summary of the multi-lumen connectivity relationships, throughout the neutral, advancement, and deployment positions, is described.\",\n \"When the locking ring is in the neutral position, the pusher clasp spring 298 shown in FIG.\",\n \"48 and the distal clasp body spring 606 shown in FIG.\",\n \"52 are both disengaged.\",\n \"This allows free movement of the graft push lumen 642 with the guidewire lumen 620 and the apex release lumen 640 within the handle body 674.When the locking knob 676 is moved into the advancement position, the pusher clasp spring 298 shown in FIG.\",\n \"48 is engaged and the distal clasp body spring 606 shown in FIG.\",\n \"52 is disengaged.\",\n \"The sheath lumen 654 (fixedly attached to the inner sheath 652) is, thereby, locked to the graft push lumen 642 (fixedly attached to the distal sleeve 644) so that, when the proximal handle 678 is moved toward the distal handle 672, both the sheath lumen 654 and the graft push lumen 642 move as one.\",\n \"At this point, the graft push lumen 642 is also locked to both the guidewire lumen 620 and the apex release lumen 640 (which are locked to one another through the apex release assembly 690 as set forth in more detail below).\",\n \"Accordingly, as the proximal handle 678 is moved to the second position, shown with dashed lines in FIG.\",\n \"11, the sheath assembly 650 and the nose cone assembly 630 progress distally out of the outer catheter 660 as shown in FIGS.\",\n \"20 and 21 and with dashed lines in FIG.\",\n \"11.At this point, the sheath lumen 654 needs to be withdrawn from the stent graft 1 to, thereby, expose the stent graft 1 from its proximal end 12 to its distal end 14 and, ultimately, entirely off of its distal end 14.Therefore, movement of the locking knob 676 into the deployment position D will engage the distal clasp body spring 606 shown in FIG.\",\n \"52 and disengage the pusher clasp spring 298 shown in FIG.\",\n \"48.Accordingly, the graft push lumen 642 along with the guidewire lumen 620 and the apex release lumen 640 are locked to the handle body 674 so as not to move with respect to the handle body 674.The sheath lumen 654 is unlocked from the graft push lumen 642.Movement of the distal handle 678 back to the third position (proximally), therefore, pulls the sheath lumen 654 proximally, thus, proximally withdrawing the inner sheath 652 from the stent graft 1.At this point, the delivery assembly 600 only holds the bare stent 30 of the stent graft 1.Therefore, final release of the stent graft 1 occurs by releasing the bare stent 30 from the nose cone assembly 630, which is accomplished using the apex release assembly 690 as set forth below.\",\n \"In order to explain how the locking and releasing of the lumen occur as set forth above, reference is made to FIGS.\",\n \"33 to 62.FIG.\",\n \"33 is a cross-sectional view of the proximal handle 678 and the locking knob 676.A pusher clasp rotator 292 is disposed between a clasp sleeve 614 and the graft push lumen 642.A specific embodiment of the pusher clasp rotator 292 is illustrated in FIGS.\",\n \"34 through 39.Also disposed between the clasp rotator 292 and the graft push lumen 642 is a rotator body 294, which is directly adjacent the graft push lumen 642.A specific embodiment of the rotator body 294 is illustrated in FIGS.\",\n \"40 through 43.Disposed between the rotator body 294 and the sheath lumen 654 is a pusher clasp body 296, which is fixedly connected to the rotator body 294 and to the locking knob 676.A specific embodiment of the pusher clasp body 296 is illustrated in FIGS.\",\n \"44 through 46.A pusher clasp spring 298 operatively connects the pusher clasp rotator 292 to the rotator body 294 (and, thereby, the pusher clasp body 296).\",\n \"An exploded view of these components is presented in FIG.\",\n \"48, where an O-ring 293 is disposed between the rotator body 294 and the pusher clasp body 296.As shown in the plan view of FIG.\",\n \"47, a crimp ring 295 connects the sheath lumen 654 to the distal projection 297 of the pusher clasp body 296.A hollow handle body 674 (see FIGS.\",\n \"10, 11, and 33), on which the proximal handle 678 and the locking knob 676 are slidably mounted, holds the pusher clasp rotator 292, the rotator body 294, the pusher clasp body 296, and the pusher clasp spring 298 therein.\",\n \"This entire assembly is rotationally mounted to the distal handle 672 for rotating the stent graft 1 into position (see FIGS.\",\n \"23 and 24 and the explanations thereof below).\",\n \"A specific embodiment of the handle body 674 is illustrated in FIG.\",\n \"49.A setscrew 679 extends from the proximal handle 678 to contact a longitudinally helixed groove in the pusher clasp rotator 292 (shown in FIGS.\",\n \"36 and 38).\",\n \"Thus, when moving the proximal handle 678 proximally or distally, the pusher clasp rotator 292 rotates clockwise or counter-clockwise.\",\n \"An alternative embodiment of the locking knob 676 is shown in FIG.\",\n \"50 et seq.\",\n \"in which, instead of applying a longitudinal movement to rotate the pusher clasp spring 298 through the cam/follower feature of the proximal handle 678 and pusher clasp rotator 292, a rotating locking knob 582 is located at the proximal end of the handle body 674.The knob 582 has three positions that are clearly shown in FIG.\",\n \"51: a neutral position N, an advancement position A, and a deployment position D. The functions of these positions N, A, D correspond to the positions N, A, D of the locking knob 676 and the proximal handle 678 as set forth above.\",\n \"In the alternative embodiment, a setscrew or pin 584 is threaded into the clasp sleeve 614 through a slot 675 in the handle body 674 and through a slot 583 in the knob 582 to engage the locking knob 582.The depth of the pin 584 in the clasp sleeve 614 is small because of the relatively small thickness of the clasp sleeve 614.To provide additional support to the pin 584 and prevent it from coming out of the clasp sleeve 614, an outer ring 6144 is disposed on the exterior surface of the proximal end of the clasp sleeve 614.Because of the x-axis orientation of the slot 583 in the knob 582 and the y-axis orientation of the slot 675 in the handle body 674, when the knob 582 is slid over the end of the handle body 674 and the setscrew 584 is screwed into the clasp sleeve 614, the knob 582 is connected fixedly to the handle body 674.When the locking knob 582 is, thereafter, rotated between the neutral N, advancement A, and deployment D positions, the clasp sleeve 614 rotates to actuate the spring lock (see FIGS.\",\n \"48 and 52).\",\n \"A setscrew 586, shown in FIG.\",\n \"53, engages a groove 605 in the proximal clasp assembly 604 to connect the proximal clasp assembly 604 to the clasp sleeve 614 but allows the clasp sleeve 614 to rotate around the clasp body 602.The clasp sleeve 614 is shown in FIGS.\",\n \"50 and 53 and, in particular, in FIGS.\",\n \"59 to 62.The proximal clasp assembly 604 of FIG.\",\n \"53 is more clearly shown in the exploded view of FIG.\",\n \"52.The proximal clasp assembly 604 is made of the components including a distal clasp body spring 606, a locking washer 608, a fastener 603 (in particular, a screw fitting into internal threads of the proximal clasp body 602), and a proximal clasp body 602.The proximal clasp body 602 is shown, in particular, in FIGS.\",\n \"54 through 58.The proximal clasp assembly 604 is connected fixedly to the handle body 674, preferably, with a screw 585 shown in FIG.\",\n \"50 and hidden from view in FIG.\",\n \"51 under knob 582.The handle body 674 has a position pin 592 for engaging in position openings at the distal end of the locking knob 582.The position pin 592 can be a setscrew that only engages the handle body 674.When the locking knob 582 is pulled slightly proximally, therefore, the knob can be rotated clockwise or counter-clockwise to place the pin 592 into the position openings corresponding to the advancement A, neutral N, and deployment D positions.\",\n \"As shown in FIG.\",\n \"18, to begin deployment of the stent graft 1, the user/physician grasps both the distal handle 672 and the proximal handle 678 and slides the proximal handle 678 towards the distal handle 672 in the direction indicated by arrow A.\",\n \"This movement, as shown in FIGS.\",\n \"19 to 21, causes the flexible inner sheath 652, holding the compressed stent graft 1 therein, to emerge progressively from inside the outer catheter 660.Such a process allows the stent graft 1, while constrained by the inner sheath 652, to expand to a larger diameter shown in FIG.\",\n \"12, this diameter being substantially larger than the inner diameter of the outer catheter 660 but smaller than the inner diameter of the vessel in which it is to be inserted.\",\n \"Preferably, the outer catheter 660 is made of a polymer (co-extrusions or teflons) and the inner sheath 652 is made of a material, such as a fabric/woven polymer or other similar material.\",\n \"Therefore, the inner sheath 652 is substantially more flexible than the outer catheter 660.It is noted, at this point that the inner sheath 652 contains a taper 653 at its proximal end, distal to the sheath's 652 connection to the sheath lumen 654 (at which connection the inner sheath 652 has a similar diameter to the distal sleeve 644 and works in conjunction with the distal sleeve 644 to capture the distal end 14 of the stent graft 1.The taper 653 provides a transition that substantially prevents any kinking of the outer catheter 660 when the stent graft 1 is loaded into the delivery assembly 600 (as in the position illustrated in FIGS.\",\n \"10 and 11) and, also, when the outer catheter 660 is navigating through the femoral and iliac vessels.\",\n \"One specific embodiment of the sheath lumen 654 has a length between approximately 30 and approximately 40 inches, in particular, 36 inches, an outer diameter of between approximately 0.20 and approximately 0.25 inches, in particular 0.238 inches, and an inner diameter between approximately 0.18 and approximately 0.22 inches, in particular, 0.206 inches.\",\n \"When the proximal handle 678 is moved towards its distal position, shown by the dashed lines in FIG.\",\n \"11, the nose cone assembly 630 and the sheath assembly 650 move towards a second position where the sheath assembly 650 is entirely out of the outer catheter 660 as shown in FIGS.\",\n \"20 and 21.As can be seen most particularly in FIGS.\",\n \"20 and 21, as the nose cone assembly 630 and the sheath assembly 650 are emerging out of the outer catheter 660, they are traversing the curved portion 710 of the descending aorta.\",\n \"The tracking is accomplished visually by viewing radiopaque markers on various portions of the delivery system and/or the stent graft 1 with fluoroscopic measures.\",\n \"Such markers will be described in further detail below.\",\n \"The delivery system can be made visible, for example, by the nose cone 632 being radiopaque or containing radiopaque materials.\",\n \"It is noted that if the harder outer catheter 660 was to have been moved through the curved portion 710 of the aorta 700, there is a great risk of puncturing the aorta 700, and, particularly, a diseased portion 744 of the proximal descending aorta 710 because the outer catheter 660 is not as flexible as the inner sheath 652.But, because the inner sheath 652 is so flexible, the nose cone assembly 630 and the sheath assembly 650 can be extended easily into the curved portion 710 of the aorta 700 with much less force on the handle than previously needed with prior art systems while, at the same time, imparting harmless forces to the intraluminal surface of the curved aorta 710 due to the flexibility of the inner sheath 652.At the second position shown in FIG.\",\n \"21, the user/physician, using fluoroscopic tracking of radiopaque markers (e.g., marker 631) on any portion of the nose cone or on the stent graft 1 and/or sheath assemblies 630, 650, for example, makes sure that the proximal end 112 of the stent graft 1 is in the correct longitudinal position proximal to the diseased portion 744 of the aorta 700.Because the entire inserted assembly 630, 650 in the aorta 700 is still rotationally connected to the portion of the handle assembly 670 except for the distal handle 672 (distal handle 672 is connected with the outer sheath 660 and rotates independently of the remainder of the handle assembly 670), the physician can rotate the entire inserted assembly 630, 650 clockwise or counterclockwise (indicated in FIG.\",\n \"20 by arrow B) merely by rotating the proximal handle 678 in the desired direction.\",\n \"Such a feature is extremely advantageous because the non-rotation of the outer catheter 660 while the inner sheath 652 is rotating eliminates stress on the femoral and iliac arteries when the rotation of the inner sheath 652 is needed and performed.\",\n \"Accordingly, the stent graft 1 can be pre-aligned by the physician to place the stent graft 1 in the optimal circumferential position.\",\n \"FIG.\",\n \"23 illustrates the longitudinal support member 40 not in the correct superior position and FIG.\",\n \"24 illustrates the longitudinal support member 40 in the correct superior position.\",\n \"The optimal superior surface position is, preferably, near the longest superior longitudinal line along the circumference of the curved portion of the aorta as shown in FIGS.\",\n \"23 and 24.As set forth above, when the longitudinal support member 40 extends along the superior longitudinal line of the curved aorta, the longitudinal support member 40 substantially eliminates any possibility of forming a kink in the inferior radial curve of the stent graft 1 during use and also allows transmission of longitudinal forces exerted along the inside lumen of the stent graft 1 to the entire longitudinal extent of the stent graft 1, thereby allowing the entire outer surface of the stent graft 1 to resist longitudinal migration.\",\n \"Because of the predefined curvature of the support member 40, the support member 40 cannot align exactly and entirely along the superior longitudinal line of the curved aorta.\",\n \"Accordingly, an optimal superior surface position of the support member 40 places as much of the central portion of the support member 40 (between the two ends 47 thereof) as possible close to the superior longitudinal line of the curved aorta.\",\n \"A particularly desirable implantation position has the superior longitudinal line of the curved aorta intersecting the proximal half of the support member 40—the proximal half being defined as that portion of the support member 40 located between the centerline 45 and the proximal support member loop 47.However, for adequate implantation purposes, the centerline 45 of the support member 40 can be as much as seventy circumferential degrees away from either side of the superior longitudinal line of the curved aorta.\",\n \"Adequate implantation can mean that the stent graft 1 is at least approximately aligned.\",\n \"When implantation occurs with the stent graft 1 being less than seventy degrees, for example, less than forty degrees, away from either side of the superior longitudinal line of the curved aorta, then it is substantially aligned.\",\n \"In prior art stent grafts and stent graft delivery systems, the stent graft is, typically, provided with symmetrically-shaped radiopaque markers along one longitudinal line and at least one other symmetrically-shaped radiopaque marker disposed along another longitudinal line on the opposite side (one-hundred eighty degrees (180.degree.))\",\n \"of the stent graft.\",\n \"Thus, using two-dimensional fluoroscopic techniques, the only way to determine if the stent graft is in the correct rotational position is by having the user/physician rotate the stent graft in both directions until it is determined that the first longitudinal line is superior and the other longitudinal line is anterior.\",\n \"Such a procedure requires more work by the physician and is, therefore, undesirable.\",\n \"According to an exemplary embodiment of the invention illustrated in FIGS.\",\n \"27 and 28, unique radiopaque markers 232, 234 are positioned on the stent graft 1 to assist the user/physician in correctly positioning the longitudinal support member 40 in the correct aortic superior surface position with only one directional rotation, which corresponds to the minimal rotation needed to place the stent graft 1 in the rotationally correct position.\",\n \"Specifically, the stent graft 1 is provided with a pair of symmetrically shaped but diametrically opposed markers 232, 234 indicating to the user/physician which direction the stent graft 1 needs to be rotated to align the longitudinal support member 40 to the superior longitudinal line of the curved aorta (with respect to anatomical position).\",\n \"Preferably, the markers 232, 234 are placed at the proximal end 12 of the graft sleeve 10 on opposite sides (one-hundred eighty degrees (180.degree.))\",\n \"of the graft sleeve 10.The angular position of the markers 232, 234 on the graft sleeve 10 is determined by the position of the longitudinal support member 40.In an exemplary embodiment, the support member 40 is between the two markers 232, 234.To explain such a position, if the marker 232 is at a 0 degree position on the graft sleeve 10 and the marker 234 is at a one-hundred eighty degree (180.degree.)\",\n \"position, then the centerline 45 of the support member 40 is at a ninety degree position.\",\n \"However, an alternative position of the markers can place the marker 234 ninety degrees away from the first degree 41 (see FIG.\",\n \"1).\",\n \"Such a positioning is dependent somewhat upon the way in which the implantation is to be viewed by the user/physician and can be varied based on other factors.\",\n \"Thus, the position can be rotated in any beneficial way.\",\n \"Exemplary ancillary equipment in endovascular placement of the stent graft 1 is a fluoroscope with a high-resolution image intensifier mounted on a freely angled C-arm.\",\n \"The C-arm can be portable, ceiling, or pedestal mounted.\",\n \"It is important that the C-arm have a complete range of motion to achieve AP to lateral projections without moving the patient or contaminating the sterile field.\",\n \"Capabilities of the C-arm should include: Digital Subtraction Angiography, High-resolution Angiography, and Roadmapping.\",\n \"For introduction of the delivery system into the groin access arteries, the patient is, first, placed in a sterile field in a supine position.\",\n \"To determine the exact target area for placement of the stent graft 1, the C-arm is rotated to project the patient image into a left anterior oblique projection, which opens the radial curve of the thoracic aortic arch for optimal visualization without superimposition of structures.\",\n \"The degree of patient rotation will vary, but is usually 40 to 50 degrees.\",\n \"At this point, the C-arm is placed over the patient with the central ray of the fluoroscopic beam exactly perpendicular to the target area.\",\n \"Such placement allows for the markers 232, 234 to be positioned for correct placement of the stent graft 1.Failure to have the central ray of the fluoroscopic beam perpendicular to the target area can result in parallax, leading to visual distortion to the patient anatomy due to the divergence of the fluoroscopic x-ray beam, with a resultant misplacement of the stent graft 1.An angiogram is performed and the proposed stent graft landing zones are marked on the visual monitor.\",\n \"Once marked, neither the patient, the patient table, nor the fluoroscopic C-arm can be moved, otherwise, the reference markers become invalid.\",\n \"The stent graft 1 is, then, placed at the marked landing zones.\",\n \"In an exemplary embodiment, the markers 232, 234 are hemispherical, in other words, they have the approximate shape of a “D”.\",\n \"This shape is chosen because it provides special, easy-to-read indicators that instantly direct the user/physician to the correct placement position for the longitudinal support member 40.FIG.\",\n \"27, for example, illustrates a plan view of the markers 232, 234 when they are placed in the upper-most superior longitudinal line of the curved aorta.\",\n \"The correct position is indicated clearly because the two hemispheres have the flat diameters aligned on top of or immediately adjacent to one another such that a substantially complete circle is formed by the two hemispherically rounded portions of the markers 232, 234.This position is also indicated in the perspective view of FIG.\",\n \"28.Each of FIGS.\",\n \"27 and 28 have been provided with examples where the markers 232, 234 are not aligned and, therefore, the stent graft 1 is not in the correct insertion position.\",\n \"For example, in FIG.\",\n \"27, two markers 232′, 234′ indicate a misaligned counter-clockwise-rotated stent graft 1 when viewed from the plane 236 at the right end of the stent graft 1 of FIG.\",\n \"23 looking toward the left end thereof and down the longitudinal axis 11.Thus, to align the markers 232′, 234′ in the most efficient way possible (the shortest rotation), the user/physician sees that the distance between the two flat diameters is closer than the distance between the highest points of the hemispherical curves.\",\n \"Therefore, it is known that the two flat diameters must be joined together by rotating the stent graft 1 clockwise.\",\n \"FIG.\",\n \"28 has also been provided with two markers 232″, 234″ indicating a misaligned clockwise-rotated stent graft 1 when viewed from the plane 236 at the right end of the stent graft 1 of FIG.\",\n \"27 looking toward the left end thereof and down the longitudinal axis 11.Thus, to align the markers 232″, 234″ in the most efficient way possible (the shortest rotation), the user/physician sees that the distance between the highest points of the hemispherical curves is smaller than the distance between the two flat diameters.\",\n \"Therefore, it is known that the two flat diameters must be joined together by rotating the stent graft 1 in the direction that the highest points of the hemispherical curves point; in other words, the stent graft 1 must be rotated counter-clockwise.\",\n \"A significant advantage provided by the diametrically opposed symmetric markers 232, 234 is that they can be used for migration diagnosis throughout the remaining life of a patient after the stent graft 1 has been placed inside the patient's body.\",\n \"If fluoroscopic or radiographic techniques are used any time after the stent graft 1 is inserted in the patient's body, and if the stent graft 1 is viewed from the same angle as it was viewed when placed therein, then the markers' 232, 234 relative positions observed should give the examining individual a very clear and instantaneous determination as to whether or not the stent graft 1 has migrated in a rotational manner.\",\n \"The hemispherical shape of the markers 232, 234 are only provided as an example shape.\",\n \"The markers 232, 234 can be any shape that allows a user/physician to distinguish alignment and direction of rotation for alignment.\",\n \"For example, the markers 232, 234 can be triangular, in particular, an isosceles triangle having the single side be visibly longer or shorter than the two equal sides.\",\n \"As set forth above, alignment to the optimal implantation position is dependent upon the skill of the physician(s) performing the implantation.\",\n \"The present invention improves upon the embodiments having longitudinal and rotational radiopaque markers 232, 234 and substantially eliminates the need for rotational markers.\",\n \"Specifically, it is noted that the guidewire 610 travels through a curve through the aortic arch towards the heart 720.It is, therefore, desirable to pre-shape the delivery system to match the aorta of the patient.\",\n \"The guidewire lumen 620 is formed from a metal, preferably, stainless steel.\",\n \"Thus, the guidewire lumen 620 can be deformed plastically into any given shape.\",\n \"In contrast, the apex release lumen 640 is formed from a polymer, which tends to retain its original shape and cannot plastically deform without an external force, e.g., the use of heat.\",\n \"Therefore, to effect the pre-shaping of the delivery assembly 600, the guidewire lumen 620, as shown in FIG.\",\n \"64, is pre-shaped with a curve 622 at a distal-most area of the lumen 620.The pre-shape can be determined, for example, using the fluoroscopic pre-operative techniques described above, in which the guidewire lumen 620 can be customized to the individual patient's aortic shape.\",\n \"Alternatively, the guidewire lumen 620 can be pre-shaped in a standard manner that is intended to fit an average patient.\",\n \"Another alternative is to provide a kit that can be used to pre-shape the guidewire lumen 620 in a way that is somewhat tailored to the patient, for example, by providing a set of delivery systems 600 or a set of different guidewire lumens 620 that have different radii of curvature.\",\n \"With the pre-curved guidewire lumen 620, when the nose cone 632 and inner sheath 652 exit the outer catheter 660 and begin to travel along the curved guidewire 610, the natural tendency of the pre-curved guidewire lumen 620 will be to move in a way that will best align the two curves to one another (see FIGS.\",\n \"20 and 21).\",\n \"The primary factor preventing the guidewire lumen 620 from rotating itself to cause such an alignment is the torque generated by rotating the guidewire lumen 620 around the guidewire 610.The friction between the aorta and the device also resists rotational motion.\",\n \"The delivery system 600, however, is configured naturally to minimize such torque.\",\n \"As set forth above with respect to FIGS.\",\n \"15 to 17, the guidewire lumen 620 freely rotates within the apex release lumen 640 and is only connected to the apex release lumen 640 at the proximal-most area of both lumen 620, 640.While the inner sheath 652 advances through the aortic arch, the two lumen 620, 640 are rotationally connected only at the apex release assembly 690.This means that rotation of the guidewire lumen 620 about the guidewire 610 and within the apex release lumen 640 occurs along the entire length of the guidewire lumen 620.Because the metallic guidewire lumen 620 is relatively rotationally elastic along its length, rotation of the distal-most portion (near the nose cone assembly 630) with respect to the proximal-most portion (near the apex release assembly 690) requires very little force.\",\n \"In other words, the torque resisting rotation of the distal-most portion to conform to the curve of the guidewire 610 is negligible.\",\n \"Specifically, the torque is so low that the force resisting the alignment of the guidewire lumen 620 to the guidewire 610 causes little, negligible, or no damage to the inside of the aorta, especially to a dissecting inner wall of a diseased aorta.\",\n \"Due to the configuration of the delivery system 600 of the present invention, when the guidewire lumen 620 is extended from the outer catheter 660 (along with the apex release lumen 640, the stent graft 1, the inner sheath 652 as shown in FIGS.\",\n \"20 and 21, for example), the pre-shape of the guidewire lumen 620 causes automatic and natural rotation of the entire distal assembly—including the stent graft 1—along its longitudinal axis.\",\n \"This means that the length and connectivity of the guidewire lumen 620, and the material from of which the guidewire lumen 620 is made, allow the entire distal assembly (1, 620, 630, 640, 650) to naturally rotate and align the pre-curved guidewire lumen 620 with the curve of the guidewire 610—this is true even if the guidewire lumen 620 is inserted into the aorta entirely opposite the curve of the aorta (one-hundred eighty degrees (180.degree.)).\",\n \"In all circumstances, the curved guidewire lumen 620 will cause rotation of the stent graft 1 into an optimal implantation position, that is, aligning the desired portion of the support member 40 within .+−.70 degrees of the superior longitudinal line of the curved aorta.\",\n \"Further, the torque forces acting against rotation of the guidewire lumen 620 will not be too high to cause damage to the aorta while carrying out the rotation.\",\n \"The self-aligning feature of the invention begins with a strategic loading of the stent graft 1 in the inner sleeve 652.To describe the placement of the supporting member 40 of the stent graft 1 relative to the curve 622 of the guidewire lumen 620, an X-Y coordinate curve plane is defined and shown in FIG.\",\n \"64.In particular, the guidewire lumen 620 is curved and that curve 622 defines the curve plane 624.To insure optimal implantation, when loading the stent graft 1 into the inner sheath 652, a desired point on the supporting member 40 between the centerline 45 of the stent graft 1 and the proximal support member loop 47 is aligned to intersect the curve plane 624.An exemplary, but not required, location of the desired point on the supporting member 40 is located forty-five (45) degrees around the circumference of the stent graft 1 shown in FIG.\",\n \"1 beginning from the first degree 41 in line with the proximal support member loop 47.When the stent graft 1 is loaded in an exemplary orientation, it is ready for insertion into the inner sleeve 652.During the loading process, the stent graft 1 and the guidewire lumen 620 are held constant rotationally.\",\n \"After such loading, the inner sleeve 652 is retracted into the outer catheter 660 and the delivery system 600 is ready for purging with saline and use with a patient.\",\n \"FIGS.\",\n \"65 to 67 illustrate self-alignment of the distal assembly 620, 630, 640, 650 after it is pushed out from the distal end of the outer catheter 660 (see FIGS.\",\n \"20 and 21).\",\n \"FIG.\",\n \"65 shows an aorta 700 and the distal assembly after it has traversed the iliac arteries 802 and enters the descending thoracic portion 804 of the aorta.\",\n \"The nose cone assembly 630 is positioned just before the aortic arch 806 and the stent graft 1 is contained within the inner sheath 652.A reference line 820 is placed on the stent graft 1 at a longitudinal line of the stent graft 1 that is intended to align with the superior longitudinal line 808 (indicated with dashes) of the aortic arch 806.In FIG.\",\n \"65, the reference line 820 also lies on the curved plane 624 defined by the pre-curved guidewire lumen 620.As can be clearly seen from FIG.\",\n \"65, the reference line 820 is positioned almost on or on the inferior longitudinal line of the curved aorta—thus, the stent graft 1 is one-hundred eighty degrees (180.degree.)\",\n \"out of alignment.\",\n \"FIG.\",\n \"66 shows the nose cone assembly 630 fully in the aortic arch 806 and the inner sleeve 652 at the entrance of the aortic arch 806.With the self-aligning configuration of the pre-curved guidewire lumen 620, movement of the distal assembly from the position shown in FIG.\",\n \"65 to the position shown in FIG.\",\n \"66 causes a rotation of the reference line 820 almost ninety degrees (90.degree.)\",\n \"clockwise (with respect to a view looking upward within the descending aorta) towards the superior longitudinal line 808.In FIG.\",\n \"67, the nose cone assembly 630 has reached, approximately, the left subclavian artery 810.Rotational movement of the distal assembly is, now, complete, with the reference line 820 almost aligned with the superior longitudinal line 808 of the aortic arch 806.From the views of FIGS.\",\n \"65 to 67, also shown is the fact that the pre-curved guidewire lumen 620 has not caused any portion of the inner sleeve 652 to push against the inner surface of the aortic arch 806 with force—force that might exacerbate an aortic dissection.\",\n \"It is noted that the guidewire lumen 620 need not be rotationally fixedly connected to the apex release lumen 640 when the apex release assembly 690 is in the locked position shown in FIGS.\",\n \"15 and 16.Instead, a non-illustrated, freely rotatable coupling can be interposed anywhere along the guidewire lumen 620 (but, preferably, closer to the apex release assembly 690).\",\n \"This coupling would have a proximal portion rotationally fixedly connected to the to the apex release lumen 640 when the apex release assembly 690 is in the locked position shown in FIGS.\",\n \"15 and 16 and a freely-rotatable distal portion that is fixedly connected to all of the guidewire lumen 620 disposed distal thereto.\",\n \"Thus, the guidewire lumen 620 near the sheath assembly 650 will always be freely rotatable and, thereby, allow easy and torque-free rotation of the guidewire lumen 620 about the guidewire 610.It is also noted that the curved section 622 of the guidewire lumen need not be made at the manufacturer.\",\n \"As shown in FIG.\",\n \"69, a curving device can be provided with the delivery system 600 to allow the physician performing the implantation procedure to tailor-fit the curve 622 to the actual curve of the vessel in which the stent graft 1 is to be implanted.\",\n \"Because different patients can have different aortic arch curves, a plurality of these curving devices can be provided with the delivery system 600, each of the curving devices having a different curved shape.\",\n \"Each device can also have two sides with each side having a different curved shape, thus, reducing the number of devices if a large number of curves are required.\",\n \"Further, the curving devices can all be rotationally connected on a common axle or spindle for each of transport, storage, and use.\",\n \"For tailoring the curve to the patient's curved vessel, the physician can, for example, fluoroscopically view the vessel (e.g., aortic arch) and determine therefrom the needed curve by, for example, holding up the curving device to the display.\",\n \"Any kind of curving device can be used to impart a bend to the guidewire lumen 620 when the guidewire lumen 620 is bent around the circumference.\",\n \"Because of the predefined curvature of the support member 40, the support member 40 cannot align exactly and entirely along the superior longitudinal line of the curved aorta.\",\n \"Accordingly, an optimal superior surface position of the support member 40 places as much of the central portion of the support member 40 (between the two ends 47 thereof) as possible close to the superior longitudinal line 808 of the curved aorta.\",\n \"A particularly desirable implantation position has the superior longitudinal line 808 of the curved aorta intersecting the proximal half of the support member 40—the proximal half being defined as that portion of the support member 40 located between the centerline 45 and the proximal support member loop 47.However, for adequate implantation purposes, the centerline 45 of the support member 40 can be as much as seventy circumferential degrees away from either side of the superior longitudinal line of the curved aorta.\",\n \"When the stent graft 1 is in place both longitudinally and circumferentially (FIG.\",\n \"21), the stent graft 1 is ready to be removed from the inner sheath 652 and implanted in the vessel 700.Because relative movement of the stent graft 1 with respect to the vessel is no longer desired, the inner sheath 652 needs to be retracted while the stent graft 1 remains in place, i.e., no longitudinal or circumferential movement.\",\n \"Such immovability of the stent graft 1 is insured by, first, the apex capture device 634 of the nose cone assembly 630 holding the front of the stent graft 1 by its bare stent 30 (see FIGS.\",\n \"13, 22, and 23) and, second, by unlocking the locking knob 676/placing the locking ring/knob in the D position—which allows the sheath lumen 654 to move independently from the guidewire lumen 620, apex release lumen 640, and graft push lumen 642.The apex capture device 634, as shown in FIGS.\",\n \"13, 14, 30 and 311 (and as will be described in more detail below), is holding each individual distal apex 32 of the bare stent 30 in a secure manner—both rotationally and longitudinally.\",\n \"The nose cone assembly 630, along with the apex capture device 634, is securely attached to the guidewire lumen 620 (and the apex release lumen 640 at least until apex release occurs).\",\n \"The inner sheath 652 is securely attached to a sheath lumen 654, which is coaxially disposed around the guidewire lumen 620 and fixedly attached to the proximal handle 678.The stent graft 1 is also supported at its distal end by the graft push lumen 642 and the distal sleeve 644 or the taper 653 of the inner sheath 652.\",\n \"(The entire coaxial relationship of the various lumens 620, 640, 642, 654, and 660 is illustrated for exemplary purposes only in FIG.\",\n \"25, and a portion of which can also be seen in the exploded view of the handle assembly in FIG.\",\n \"50) Therefore, when the proximal handle 678 is moved proximally with the locking knob 676 in the deployment position D, the sheath lumen 654 moves proximally as shown in FIGS.\",\n \"13, 22, and 23, taking the sheath 652 proximally along with it while the guidewire lumen 620, the apex release lumen 640, the graft push lumen 642, and the distal sleeve 644 remain substantially motionless and, therefore, the stent graft 1 remains both rotationally and longitudinally steady.\",\n \"The stent graft 1 is, now, ready to be finally affixed to the aorta 700.To perform the implantation, the bare stent 30 must be released from the apex capture device 634.As will be described in more detail below, the apex capture device 634 shown in FIGS.\",\n \"13, 14, and 29 to 32, holds the proximal apices 32 of the bare stent 30 between the distal apex head 636 and the proximal apex body 638.The distal apex head 636 is fixedly connected to the guidewire lumen 620.The proximal apex body 638, however, is fixedly connected to the apex release lumen 640, which is coaxial with both the guidewire lumen 620 and the sheath lumen 654 and disposed therebetween, as illustrated diagrammatically in FIG.\",\n \"25.\",\n \"(As will be described in more detail below, the graft push lumen 642 is also fixedly connected to the apex release lumen 640.)\",\n \"Therefore, relative movement of the apex release lumen 640 and the guidewire lumen 620 separates the distal apex head 636 and a proximal apex body 638 from one another.\",\n \"To cause such relative movement, the apex release assembly 690 has, in an exemplary embodiment, three parts, a distal release part 692, a proximal release part 694, and an intermediate part 696 (which is shown in the form of a clip in FIGS.\",\n \"16 and 26).\",\n \"To insure that the distal apex head 636 and the proximal apex body 638 always remain fixed with respect to one another until the bare stent 30 is ready to be released, the proximal release part 694 is formed with a distal surface 695, the distal release part 692 is formed with a proximal surface 693, and the intermediate part 696 has proximal and distal surfaces corresponding to the surfaces 695, 693 such that, when the intermediate part 696 is inserted removably between the distal surface 695 and the proximal surface 693, the intermediate part 696 fastens the distal release part 692 and the proximal release part 694 with respect to one another in a form-locking connection.\",\n \"A form-locking connection is one that connects two elements together due to the shape of the elements themselves, as opposed to a force-locking connection, which locks the elements together by force external to the elements.\",\n \"Specifically, as shown in FIG.\",\n \"26, the clip 696 surrounds a distal plunger 699 of the proximal release part 694 that is inserted slidably within a hollow 698 of the distal release part 692.The plunger 699 of the proximal release part 694 can slide within the hollow 698, but a stop 697 inside the hollow 698 prevents the distal plunger 699 from withdrawing from the hollow 698 more than the longitudinal span of the clip 696.To allow relative movement between the distal apex head 636 and the proximal apex body 638, the intermediate part 696 is removed easily with one hand and, as shown from the position in FIG.\",\n \"16 to the position in FIG.\",\n \"17, the distal release part 692 and the proximal release part 694 are moved axially towards one another (preferably, the former is moved towards the latter).\",\n \"Such movement separates the distal apex head 636 and the proximal apex body 638 as shown in FIG.\",\n \"14.Accordingly, the distal apices 32 of the bare stent 30 are free to expand to their natural position in which the bare stent 30 is released against the vessel 700.Of course, the apex release assembly 690 can be formed with any kind of connector that moves the apex release lumen 640 and the guidewire lumen 620 relative to one another.\",\n \"In an exemplary alternative embodiment, for example, the intermediate part 696 can be a selectable lever that is fixedly connected to either one of the distal release part 692 or the proximal release part 694 and has a length equal to the width of the clip 696 shown in FIG.\",\n \"26.Thus, when engaged by pivoting the lever between the distal release part 692 and the proximal release part 694, for example, the parts 692, 694 cannot move with respect to one another and, when disengaged by pivoting the lever out from between the parts 692, 694, the distal release part 692 and the proximal release part 694 are free to move towards one another.\",\n \"The apex capture device 634 is unique to the present invention in that it incorporates features that allow the longitudinal forces subjected on the stent graft 1 to be fully supported, through the bare stent 30, by both the guidewire lumen 620 and apex release lumen 640.Support occurs by providing the distal apex head 636 with a distal surface 639—which surface 639 supports the proximal apices 32 of the bare stent 30 (shown in the enlarged perspective view of the distal apex head 636 in FIG.\",\n \"29).\",\n \"When captured, each proximal apex 32 of the bare stent 30 separately rests on a distal surface 639, as more clearly shown in FIGS.\",\n \"30 and 31.The proximal spokes of the distal apex head 636 slide within the fingers of the proximal apex body 638 as these parts moves towards one another.\",\n \"A slight space, therefore, exists between the fingers and the outer circumferential surfaces of the spokes.\",\n \"To insure that the bare stent 30 does not enter this space (which would prevent a proper release of the bare stent 30 from the apex capture device 634, a radial thickness of the space must be less than the diameter of the wire making up the bare stent 30.Preferably, the space is no greater than half a diameter of the wire.\",\n \"Having the distal surface 639 be the load-bearing surface of the proximal apices 32 ensures expansion of each and every one of the distal apices 32 from the apex release assembly 690.The proximal surface 641 of the distal apex head 636 (see FIG.\",\n \"30) meets with the interior surfaces of the proximal apex body 638 to help carry the apex load because the apices of the bare stent 30 are captured therebetween when the apex capture device 634 is closed.\",\n \"Complete capture of the bare stent 30, therefore, fully transmits any longitudinal forces acting on the bare stent 30 to both the guidewire lumen 620 and apex release lumen 640, making the assembly much stronger.\",\n \"Such capture can be clearly seen in the cut-away view of the proximal apex body 638 in FIG.\",\n \"31.For release of the apices 32 of the bare stent 30, the proximal apex body 638 moves leftward with respect to FIGS.\",\n \"30 to 33 (compare FIGS.\",\n \"30 and 31 with FIG.\",\n \"32).\",\n \"Because friction exists between the apices 32 and the “teeth” of the proximal apex body 638 when the apices 32 are captured, the apices 32 will also try to move to the left along with the proximal apex body 638 and, if allowed to do so, possibly would never clear the “teeth” to allow each apex 32 to expand.\",\n \"However, as the proximal apex body 638 disengages (moves in the direction of arrow C in FIG.\",\n \"31), direct contact with the distal surface 639 entirely prevents the apices 32 from sliding in the direction of arrow C along with the proximal apex body 638 to ensure automatic release of every captured apex 32 of the bare stent 30.Because the proximal apex body 638 continues to move in the direction of arrow C, eventually the “teeth” will clear their respective capture of the apices 32 and the bare stent 30 will expand entirely.\",\n \"The release position of the distal apex head 636 and the proximal apex body 638 is shown in FIGS.\",\n \"14 and 32, and corresponds to the position of the apex release assembly 690 in FIG.\",\n \"17.As can be seen, tapers on the distal outer surfaces of the proximal apex body 638 further assist in the prevention of catching the proximal apices 32 of the bare stent 30 on any part of the apex capture device 634.In this configuration, the distal surfaces 639 bear all the load upon the bare stent 30 and the fingers of the proximal apex body 638.Simply put, the apex capture device 634 provides support for load placed on the stent graft 1 during advancement A of the inner sheath 652 and during withdrawal of the inner sheath 652 (i.e., during deployment D).\",\n \"Such a configuration benefits the apposition of the bare stent 30 by releasing the bare stent 30 after the entire graft sleeve 10 has been deployed, thus reducing the potential for vessel perforation at the point of initial deployment.\",\n \"When the stent graft 1 is entirely free from the inner sheath 652 as shown in FIG.\",\n \"24, the proximal handle 678 is, then, substantially at or near the third position (deployment position) shown in FIG.\",\n \"10.The stent graft 1 is, now, securely placed within the vessel 700 and the entire portion 630, 650, 660 of the assembly 600 may be removed from the patient.\",\n \"FIGS.\",\n \"70 and 71 illustrate alternative configurations of the stent graft 1 of FIG.\",\n \"1.The stent graft 1000 of FIG.\",\n \"70 is similar to the stent graft 1 of FIG.\",\n \"1.The stent graft 1000 has a graft 1010 and a number of stents 1020.The stents 1020 are attached either to the exterior or interior surfaces of the graft sleeve 1010.Preferably, the stents 1020 are sewn to the graft 1010.The stent graft 1000 shown in FIG.\",\n \"70 has been discussed above with respect to FIG.\",\n \"1, for example, and, therefore, the discussion relevant to features already discussed will not be repeated for the sake of brevity.\",\n \"FIG.\",\n \"70 shows an exemplary embodiment of the curved ends 1047 of the connecting rod 1040.In particular, the rod 1040 forms a loop (whether, polygonal, ovular, or circular) and has an end portion 1048 that continues back parallel and next to the rod 1040 for a short distance.\",\n \"This end portion 1048, along with the adjacent portion of the rod 1040 allows, for example, connective stitching to cover two lengths of the rod 1040 and better secures the end portion 1048 to the graft sleeve 1010.In such configuration, there is limited or even no chance of a sharp end of the rod 1040 to be exposed to harm the graft sleeve 1010 or the vessel wall in which the stent graft 1000 is placed.\",\n \"An alternative embodiment of the stent graft 1000 is shown as stent graft 1100 in FIG.\",\n \"71.This stent graft 1100 contains a graft sleeve 1110 that completely covers the bare stent 30 shown in FIGS.\",\n \"1 and 70 and is hereinafter referred to with respect to FIGS.\",\n \"71 to 78 as a clasping stent 1130.As shown particularly well in FIGS.\",\n \"72 and 74, the clasping stent 1130 is entirely covered by the graft 1110 but is not attached to the material of the graft 1110 along its entirety.\",\n \"At least some of the proximal apices 1132, preferably, at least three or four, are left unconnected to permit a releasable connection with the fingers of the proximal apex body 638 when the fingers are extended through the apex openings 1134.Of course, in certain applications, it may be beneficial to only leave one apex 1132 unconnected.\",\n \"The unconnected portion of each the apices 1132 has a minimal longitudinal length of about 10 percent of the longitudinal length of the stent and a maximum longitudinal length of up to approximately 90 percent of the length of the stent.\",\n \"Preferably, the longitudinal length of the unconnected portion is between approximately 30 to 40 percent as shown in FIGS.\",\n \"72 and 74, which show the clasping stent 1130 sewn to the interior of the graft 1110.For ease of comparison, FIG.\",\n \"73 illustrating the proximal end of the stent graft of FIGS.\",\n \"1 and 70 is included next to FIG.\",\n \"74.The unconnected portions of apices 1132 need not have the same longitudinal lengths.\",\n \"Depending on the application, one or some of the unconnected portions of apices 1132 can have a longitudinal length different from other ones of the unconnected portions of apices 1132.FIG.\",\n \"75, for example, illustrates an embodiment near the maximum longitudinal length of the unconnected portion of the clasping stent 1130.FIGS.\",\n \"76 and 77 illustrate a proximal end of the stent graft 1100 of FIG.\",\n \"71 partially deployed from the flexible inner sheath 652.As can be seen in FIG.\",\n \"76, the entire capturing assemblies of the apex capture device 634 reside inside the stent graft 1100 when the apices are captured.\",\n \"Only the distal-most portion of the distal apex head 636 extends out from the interior of the stent graft 1100.With regard to the view of FIG.\",\n \"77, it can be seen that only a few of the apices 1132 of the clasping stent 1130 are actually held by the apex capture device 634.It is noted at this point that implantation of the stent graft 1, 1000, 1100 of the present invention occurs while blood is flowing from the heart of the patient.\",\n \"Accordingly, the stent graft 1100 cannot occlude the vessel in which it is to be implanted and, in order to do so, there must exist a lumen for passing blood throughout the time after the stent graft 1100 has partially or fully expanded within the vessel.\",\n \"If all of the apices 1132 of the clasping stent 1130 were held within the apex capture device 634, then there is a possibility of occluding the vessel if the unattached portion of the apices 1132 are too short to provide such a lumen.\",\n \"To avoid this condition, if only some apices 1132 of the clasping stent 1130 are captured, as illustrated in FIG.\",\n \"77, then a sufficiently large lumen exists to allow blood flow through the vessel in which the stent graft is to be implanted.\",\n \"Alternatively, if a large percentage of the apices 1132 are left unconnected, as shown, for example, in FIG.\",\n \"75, then all of the apices 1132 can be releasably held by the apex capture device 634 while the graft sleeve 1110 remains entirely open to allow blood flow through the stent graft 1100 during the stent graft 1100 implantation process.\",\n \"There exists a drawback to placing the clasping stent 1130 as the proximal stent of the stent graft 1100 because material of the graft 1110 is proximal of the clasping stent 1130.If unsupported, this material could move disadvantageously toward the interior of the stent graft 1100 after implantation and decrease or occlude blood flow.\",\n \"To prevent such movement, the stent graft 1100 also includes a crown stent 1140.Like the clasping stent 1130, the crown stent 1140 is shown in FIGS.\",\n \"71, 72, 74 to 76, and 78 as being attached to the inside of the graft 1120 and, in this exemplary embodiment, is sewn to the material of the graft using the same polyester suture as the other stents.\",\n \"Of course, the crown stent 1140 can be attached to the exterior of the graft 1010.In such a configuration, the crown stent 1140 augments the rigidity of the material of the graft 1120 to reduce enfolding thereof at the proximal end of the stent graft 1100.Alternatively and/or additionally, a non-illustrated distal crown stent can be attached to the inside or outside of the graft 1120 at the opposite distal end of the stent graft 1100.In such a configuration, this distal crown stent 1140 augments the rigidity of the material at the distal end of the graft 1120 to reduce enfolding thereof.\",\n \"The material of the graft 1120 can extend and bridge the entire distance between two proximal crown apices 1122.It is noted, however, that, alternatively or additionally, the material of the graft 1120 may be partially cut out between crown apices 1122 of the crown stent 1140 to define a plurality of a radially distensible flange portions 1124 at the proximal end of the stent graft 100, as shown in FIG.\",\n \"74.There are various advantages provided by the stent graft 100 over the prior art.\",\n \"First, the clasping and crown stents 1130, 1140 improve the apposition of the material of the graft to the intima of the vessel in which the stent graft 100 is placed, in particular, in the aorta.\",\n \"Second, by better aligning the proximal portion of the stent graft 1110 in the lumen of the arch, the clasping and crown stents 1130, 1140 provide an improved blood-tight closure of the proximal end of the stent graft 1110 so that blood does not pass between the intima of the vasculature and the outer surface of the stent graft 1110.As set forth above, if the apex capture device 634 captures less than all of the apices of the clasping stent 1130.The resulting openings allow blood flow during implantation.\",\n \"It is illustrated particularly well in FIGS.\",\n \"1, 13, 14, and 70 that the material of the graft sleeve 10 of stent graft 1, 1000 begins only distal of the center of the bare stent 30.In comparison, as shown in FIGS.\",\n \"71 and 73, the material of the graft 1120 begins well proximal of the proximal-most apices of the clasping stent 1130.Thus, this embodiment allows the material of the graft 1120 to extend much further into a vessel (i.e., further into the curved arch of the aorta).\",\n \"Therefore, a physician can repair a vessel further upstream in the aorta than the embodiment of the stent graft 1, 1000 of FIGS.\",\n \"1 and 70.In the prosthesis embodiment of FIGS.\",\n \"1 and 70, there is direct contact between the metal of the bare stent 30 and the intima of the blood vessel.\",\n \"In contrast thereto, the configuration of the stent graft 1100 with the clasping stent 1130 places material of the graft 1120 between the metal of the clasping stent 1130 and the intima.\",\n \"Such a configuration provides a more atraumatic connection between the vessel and the proximal end of the stent graft 1100 than the configuration of FIGS.\",\n \"1 and 70.This advantage is especially important for treating dissections—where the intima is in a weakened condition.\",\n \"FIG.\",\n \"63 illustrates interaction between the catheter 660, the inner sheath 652, and the nose cone assembly 630 (including the nose cone 632, the distal apex head 636, and the proximal apex body 638).\",\n \"In this illustration, first, the catheter 660 is in a proximal position that does not cover the inner sheath 652 in any way.\",\n \"For example, this position of the catheter 660 occurs when the inner sheath 652 has extended out of the catheter 660 as shown in FIGS.\",\n \"20 and 21.Next, the inner sheath 652 is clearly shown in its expanded state (caused by the non-illustrated prosthesis disposed therein and expanding outward).\",\n \"The distal-most end of the inner sheath 652 is disposed between the distal apex head 636 and the nose cone 632.In such an orientation, the inner sheath 652 is in the position that occurs during extension out of the catheter 660 as shown for example, in FIGS.\",\n \"20 and 21.Because the nose cone 632 screws onto the distal end of the distal apex head 636, the distal-most end of the inner sheath 652 is releasably captured between the two parts 632, 636 until it is removed.\",\n \"Retraction of the sheath lumen 654 proximally pulls the distal-most captured end of the inner sheath 652 out from the capturing interface.\",\n \"Finally, the proximal apex body 638 is in a retracted position proximal of the distal apex head 636.This orientation is for illustrative purposes only to show the interaction of the distal apex head 636 and the proximal apex body 638 because the separation would not occur in use until, as set forth above, the inner sheath 652 is fully retracted from over the stent graft 1 and the proximal apices 32 of the stent 30 have been released as shown in FIG.\",\n \"14.FIG.\",\n \"80 is a cross-section through the catheter 660, the fingers of the proximal apex body 638, the distal apex body 636, the apex release lumen 640, and the guidewire lumen 620.FIG.\",\n \"81 is a cross-section of the distal end of the delivery system along the longitudinal axis of the delivery system.\",\n \"These two figures illustrate the space 662 that exists between the catheter 660 and both of the proximal apex body 638 and the distal apex body 636 to make room for the inner sheath 652 to surround the parts 636, 638 and pass between the nose cone 632 and the distal apex head 636 and enter the pass 664 that allows the inner sheath 652 to be releasably held there as shown in FIG.\",\n \"63 until it is desired to remove the inner sheath 652 therefrom.\",\n \"FIG.\",\n \"82 shows a distal end of the delivery system according to the invention in the orientation of FIGS.\",\n \"20 and 21, for example.\",\n \"The inner sheath 652 is curved and has an alternative embodiment of a D-shaped marker 234 thereon.\",\n \"In contrast to the configuration of two markers 234 on the stent graft 1 as shown in FIGS.\",\n \"27 and 28, there is only one marker 234 on the inner sheath 652.As illustrated in the orientations of FIGS.\",\n \"83, 84, and 85, the marker 234 allows the user to see how the inner sheath 652 should be oriented prior to implantation.\",\n \"FIGS.\",\n \"86, 87, 88, and 89 illustrate an alternative embodiment of the front handle 672 that is rotatably attached to the handle 674 and rotatably fixed to the catheter 660.FIGS.\",\n \"90 to 119 depict another exemplary embodiment of various features of the delivery assembly 600.FIG.\",\n \"90 shows the entire delivery assembly 600 with a portion of nose cone assembly 630 removed to reveal the distal apex head 636.On the proximal end of the delivery assembly 600, the enlarged view of FIG.\",\n \"91 depicts an alternative embodiment of the apex release assembly 690.In FIG.\",\n \"91, a proximal pusher support tube 645 surrounds two coaxial lumens, the guidewire lumen 620 and the apex release lumen 640.The proximal pusher support tube 645 is longitudinally fixed to the proximal end of the graft push lumen 642 and has substantially the same diameter as the graft push lumen 642.Because the proximal pusher support tube 645 is used for pushing/pulling the combination lumen 642, 645, and due to the fact that the proximal pusher support tube 645 only resides within the handle body or proximal thereof, the proximal pusher support tube 645 can be made of a relatively stiff material, such as stainless steel, for example.\",\n \"In contrast, the graft push lumen 642 needs to flex and bend when extending out of the outer catheter 660 and into vasculature.\",\n \"Thus, the graft push lumen 642 is made from a relatively flexible material, such as a plastic.\",\n \"In FIG.\",\n \"91, the proximal portion of the proximal pusher support tube 645 is cut away to reveal the features therein, including the guidewire lumen 620 and the apex release lumen 640.The apex release lumen 640 is axially fixed to the proximal apex body 638.The guidewire lumen 620, on the other hand, is axially fixed to the distal apex head 636.Thus, distal movement of the apex release lumen 640 with respect to the guidewire lumen 620 separates the tines of the proximal apex body 638 extending over the spokes of the distal apex head 636.To effect this relative movement, proximal and distal crimping devices 621 and 641 are respectively attached to the guidewire 620 and the apex release lumen 640.The distal release part 692 is connected, through a non-illustrated set screw, to the distal crimping device 641.The proximal release part 694 is connected, also through a non-illustrated set screw, to the proximal crimping device 621.Finally, a proximal luer connector 800 is connected to the proximal-most end of the proximal pusher support tube 645 so that all of the lumen 620, 640, 645 can be filled and/or drained with a liquid, such as saline.\",\n \"FIG.\",\n \"92 is an enlarged view of the alternative embodiment of the locking knob 582 first shown in FIGS.\",\n \"50 and 51.To better explain the features of FIG.\",\n \"92, reference is made to the separated clasp sleeve 614 of FIG.\",\n \"93, which was first depicted in FIGS.\",\n \"50, 53, and 59 to 62.This clasp sleeve 614 is longitudinally fixedly and rotationally freely connected to the handle body 674 through the setscrew 584 that protrudes into the slot 675 of the handle body 674.The setscrew 584 is screwed into but not through the proximal end of the clasp sleeve as shown in FIG.\",\n \"93, for example.\",\n \"This setscrew 584 protrudes into the slot 675 in the handle body 674.When so connected, the clasp sleeve 614 cannot move longitudinally with respect to the handle body 674 but can rotationally move along the arc defined by the length of the slot 675.The setscrew 584 protrudes from the outer circumference of the handle body 674 because it enters into the longitudinal slot 583 in the locking knob 582.Thus, the setscrew 584 also controls the longitudinal movement distance of the locking knob 582.When the knob 582 is at rest, the setscrew 584 resides in the distal end of the slot 583 because of the bias caused by spring 607 (see FIG.\",\n \"94).\",\n \"The second setscrew 592 (also referred to as a position pin) starts from the handle body 674 but does not extend inside the handle body 674.The setscrew 592 does, however, protrude out from the handle body 674 and into the three-position slot 587 of the locking knob 582.Thus, the setscrew 592 controls the rotation of the knob 582 within the three positions.\",\n \"The third setscrew 585 is screwed through a threaded hole in the handle body 674 and into a co-axial threaded hole 6021 of the clasp body 602 until the setscrew 585 is even with the exterior surface of the handle body 674.Thus, the setscrew 585 does not protrude from the outer circumference of the handle body 674.The proximal clasp assembly 604 was first illustrated in FIG.\",\n \"52.In FIG.\",\n \"94, the proximal clasp assembly 604 is illustrated with different detail.\",\n \"The clasp body 602 has a distal interior cavity 6023 shaped to receive therein the distal clasp body spring 606, which is a torsion spring in this exemplary embodiment.\",\n \"The locking washer 608 is connected to the distal end of the clasp body 602 by a non-illustrated setscrew that, for example, runs through the bore illustrated at the 12 o'clock position on the locking washer 608 in FIG.\",\n \"94.To keep the clasp body assembly pressed into the clasp sleeve 614, as shown in FIGS.\",\n \"101 and 102 for example, a distal spring washer 611 and a proximal compression spring 607 are inserted into a proximal interior cavity 6024.Placement of the locking knob 676 onto the handle body 674, as shown in FIG.\",\n \"92 for example, compresses the compression spring 607 between the locking knob 676 and the proximal surface of the spring washer 611 residing inside the proximal interior cavity 6023 of the clasp body 602.This compression forces the knob 676 proximally to keep the spring 592 inside the three-position slot 675.The spring washer 611 is present to prevent the spring 607 from binding when the locking knob 676 is rotated between the three rotational positions.\",\n \"The smooth surface of the washer 611 does not catch the distal end of the compression spring 607 when the spring 607 rotates.\",\n \"The rotator assembly includes the pusher clasp rotator 292, the pusher clasp spring 298, and the rotator body 294.These parts are first depicted in FIGS.\",\n \"34 to 43 and 47 to 48 and are next depicted in FIGS.\",\n \"95 and 96.In FIG.\",\n \"95, the rotator assembly is illustrated in an exploded, unassembled state and FIG.\",\n \"96 shows the assembly in an assembled state.\",\n \"When assembled, the two protruding ends of the pusher clasp spring 298 are respectively inserted into the longitudinal slots 2942 and 2922 of each of the rotator body 294 and the pusher clasp rotator 292.Because the distal end of the rotator body 294 is smaller in diameter than the cavity of the pusher clasp rotator 292, the end of the spring that fits inside the slot 2922 must be longer than the end of the spring 298 that fits inside the slot 2942 of the rotator body 294.The rotator body 294 is secured inside the pusher clasp rotator 292 by two dowels 2926 that are press fit through a first orifice in the clasp rotator 292 after the rotator body 294 is inside the clasp rotator 292.These dowels 2926, then, pass through a circumferential groove 2944 substantially without touching the walls of the groove 2944 and, then, through a second orifice in the clasp rotator 292 directly opposite the first orifice.\",\n \"In such a configuration, the rotator body 294 is longitudinally fixed but rotationally free inside the clasp rotator 292.The first and second orifices and the groove 2944 are clearly shown in FIG.\",\n \"13 (with the dowels 2926 removed for clarity).\",\n \"FIGS.\",\n \"44 to 48 illustrated the pusher clasp body 296 and its relationship with the sheath lumen 654.FIGS.\",\n \"97 and 98 further illustrate two views of the pusher clasp body 296 and its distal projection 297.The proximal end of the sheath lumen 654 passes through the crimp ring 295 and over the distal projection 297.Then, to secure the sheath lumen 654 to the pusher clasp body 296, the crimp ring 295 is compressed/crimped.\",\n \"Such a connection both longitudinally and rotationally stabilizes the sheath lumen 654 with respect to the pusher clasp body 296.Two pins 2962 hold the pusher clasp body 296 to the proximal handle 678 so that longitudinal movement of the proximal handle 678 translates into a corresponding longitudinal movement of the pusher clasp body 296 within the handle body 674.These pins 2962 pass through a plug 2964, shown in FIG.\",\n \"114, and then into the pusher clasp body 296.The length of the pins that exist through the plug 2964 and also through the pusher clasp body 296 gives enough support to prevent movement of the handle 678 from breaking the pins 2962, which might occur if the plug 2964 were not present.\",\n \"It is noted that the conical expansion of the proximal end of the inner sheath 652 is different in FIGS.\",\n \"97 and 98.This is because the embodiment shown in FIGS.\",\n \"97 and 98 illustrates an expansion portion of the inner sheath 652 that is sutured on only one side thereof.\",\n \"Accordingly, when viewed along the suture line (as in FIG.\",\n \"98), the cone has one flat side.\",\n \"In contrast, when viewed in an elevation 90 degrees turned from that suture line (as in FIG.\",\n \"97), the expansion portion has a conical elevational view.\",\n \"Also shown in FIG.\",\n \"98 on the inner sheath 652 is a D-shaped radiopaque marker 232.This marker 232 is enlarged in FIG.\",\n \"99 and can be, for example, secured to the inner sheath 652 by three sutures, diagrammatically indicated with an “X.” FIG.\",\n \"100 is an enlarged view of the distal end of the handle assembly 670 shown in FIG.\",\n \"90.This embodiment of the distal apex head 636 shows an alternative embodiment of the proximal portion that was first shown in FIG.\",\n \"29.As can be seen in the drawing, the proximal side of the distal apex head 636 is tapered.\",\n \"This tapered shape allows the distal apex head 636 to enter further into the interior cavity between the prongs of the proximal apex body 638 than the distal apex head 636 shown in FIG.\",\n \"29.It is noted that the portion of the delivery system at the distal end is to be flexible so that this portion can traverse curved vessels.\",\n \"Thus, it is desirable for the length of the distal apex head 636 and the proximal apex body 638 (semi-rigid parts) to be as short as possible.\",\n \"By allowing the distal apex head 636 to travel further into the proximal apex body 638, the longitudinal length of the two parts 636 can be shorter.\",\n \"Now that the various parts of the handle assembly 670 have been shown and described separately, the interactions and orientations when assembled can now be further understood with reference to the following description and to FIGS.\",\n \"101 to 105.FIGS.\",\n \"101 to 102 show the proximal half of the handle assembly 670 from just proximal of the locking knob 676 to just distal of the distal end of the proximal handle 678 (when the handle 678 is in a proximal position).\",\n \"The hidden lines shown in FIG.\",\n \"101 aid in the understanding of this portion.\",\n \"It is noted that the sheath lumen 654 is not illustrated in FIG.\",\n \"101 for clarity.\",\n \"FIG.\",\n \"102 clearly shows the components that are involved in the proximal half of the handle assembly 670.The handle body 674 is surrounded by the distal handle 678 and a portion of the locking knob 676.Inside the proximal end of the handle body 674 is the clasp body 602, which is surrounded by the proximal end of the clasp sleeve 614.The locking washer 608 is positioned inside the clasp sleeve 614 at the distal end of the clasp body 602.Separated at a distance from the distal end of the locking washer 608 is the rotator assembly, which, as set forth above, is longitudinally fixed to the proximal handle 678.The rotator assembly includes the pusher clasp rotator 292 surrounding the pusher clasp spring 298 and the rotator body 294.The pusher clasp body 296 is disposed on the distal end of the rotator body 294 and the crimp ring 295 secures the sheath lumen 654 on the distal projection 297 of the pusher clasp body 296.FIG.\",\n \"103 is an enlarged view of the proximal portion of FIG.\",\n \"102 by the locking knob 676.These figures show the alignment of the bores in the clasp body 602 and the locking washer 608 so that the non-illustrated setscrew can fasten the two parts to one another.\",\n \"Also shown in FIG.\",\n \"103 is the alignment between the groove 605 for receiving therein the setscrew 586 (see FIGS.\",\n \"53 and 93) and connecting the proximal clasp assembly 604 to the clasp sleeve 614 so that the clasp sleeve 614 can still rotate around the clasp body 602.Also visible in the enlarged view of FIG.\",\n \"103 are the three coaxial lumen 620, 640, 645 that pass through the clasp body 602.Like FIG.\",\n \"103, FIG.\",\n \"104 is an enlarged view of the distal portion of the handle assembly 670 around the pusher clasp rotator 292.This view not only shows the orientations of the rotator body 294 and the pusher clasp body 296 with respect to the pusher clasp rotator 292, but the three coaxial lumen passing therethrough are also evident.\",\n \"The groove 2944 for receiving the non-illustrated dowels 2926 therein is also visible in this view.\",\n \"As can be seen, the guidewire lumen 620 and the apex release lumen 640 each pass entirely through the pusher clasp body 296 but the proximal pusher support tube 645 ends just after the distal end of the rotator body 294 for hemostasis purposes.\",\n \"It is at this end point that the proximal pusher support tube 645 is connected to the graft push lumen 642.This two-part structure of the proximal pusher support tube 645 and the graft push lumen 642 is, in an exemplary embodiment, a bonding of a proximal stainless steel lumen 645 and a plastic lumen 642, for example, a polyurethane-based extrusion.\",\n \"As set forth above, a rigid lumen 645 in the handle portion keeps rigidity there and a flexible lumen 642 distal of the distal handle 672 allows the lumen to flex as needed.\",\n \"The distal end of the rotator body 294 is also fluidically sealed off from the interior of the distal interior of the delivery system with a hemostasis o-ring 293.FIG.\",\n \"105 is still a further enlarged view around the pusher clasp spring 298.A transverse cross-sectional view through the handle assembly 670 is illustrative of the interaction between and relationship of various components of this assembly 670.The cross-sections shown in FIGS.\",\n \"106 to 118 progress from proximal to distal.\",\n \"A first transverse cross-section through the longitudinal slot 583 of the locking knob 676 is illustrated in FIG.\",\n \"106.In this cross-sectional plane, the clasp body 602 is shown as filling up most of the interior of the clasp sleeve 614.The anchoring bore in the clasp sleeve 614 for the setscrew 585 is shown aligned with the slot 583.A second transverse cross-section through the three-position slot 587 of the locking knob 676 is illustrated in FIG.\",\n \"107.In this cross-sectional plane, the clasp body 602 still is shown as filling up most of the interior of the clasp sleeve 614.The slot 6022 of the clasp body 602 for receiving one end of the torsion spring 606 is also depicted in FIG.\",\n \"107.A third transverse cross-section through the clasp body 602 before the locking washer 608 is illustrated in FIG.\",\n \"108.In this cross-sectional plane, the slot 6022 of the clasp body 602 is aligned with a slot 6143 inside the proximal end of the clasp sleeve 614 that is not visible in FIG.\",\n \"93 but is visible through the cutout in FIGS.\",\n \"59 and 60.This alignment is merely shown in FIG.\",\n \"108 for understanding the different depths of these slots 6022, 6143.Like the pusher clasp spring 298, the distal clasp body spring 606 has ends with different lengths.\",\n \"The first, shorter, end is inserted into the inner slot 6022 of the clasp body 602 and the second, longer, end is inserted into the slot 6143 of the clasp sleeve 614.The fourth transverse cross-section between the proximal clasp assembly 604 and the rotator assembly shows, in FIG.\",\n \"109, the spatial separation of these two assemblies that is depicted, for example, in FIGS.\",\n \"101 to 102.Visible in these figures is the longitudinal slot 6141 that, as shown in the cross-sections of FIGS.\",\n \"110 to 111, guides the movement of the pusher clasp rotator 292 by delimiting a space that corresponds to the width of the boss 2924 that extends out from the outer circumferences of the pusher clasp rotator 292.This slot 6141 allows the pusher clasp rotator 292 to move longitudinally freely with respect to the clasp sleeve 614; simultaneously, this connection prevents any rotation of the pusher clasp rotator 292 that is independent from rotation of the clasp sleeve 614.Accordingly, as the clasp sleeve 614 rotates about its longitudinal axis, the pusher clasp rotator 292 will rotate as well.\",\n \"The further enlarged view of the center of the configuration illustrated in FIG.\",\n \"110 is depicted in FIG.\",\n \"111.Here, the rotator assembly portions are clearly shown with the pusher clasp spring 298 therebetween.\",\n \"The sixth cross-section of FIG.\",\n \"112, and the enlarged view of the sixth cross-section in FIG.\",\n \"113, illustrate the longitudinally fixed but rotationally free connection between the pusher clasp rotator 292 and the rotator body 294.The two bores in the pusher clasp rotator 292 for receiving the dowels 2926 (not illustrated here) are clearly shown to intersect the open space in the groove 2944 of the rotator body 294.A seventh cross-section in FIG.\",\n \"114 shows the connection of the pusher clasp body 296 and the proximal handle 678 through the plug 2964.This view also depicts the fluid communication between the interior of the handle assembly 670 and the luer fitting 612.When the luer 612 is connected to a fluid supply, the flushing liquid enters the interior cavity distal of the rotator body 294 and sealed off by the o-ring 293 and purges all air therein at the distal end of the delivery system.\",\n \"FIG.\",\n \"114 also shows the graft push lumen 642 extending through the handle body 674 beginning after the distal side of the o-ring 293.The eighth cross-section of FIG.\",\n \"115 illustrates the distal projection 297 at which the crimp ring 295 holds the sheath lumen 654 onto the pusher clasp body 296.This figure also illustrates the open radial space between the clasp sleeve 614 and the graft push lumen 642.To keep the relatively long extent of the flexible inner lumen 620, 640, 642 passing through the open interior of the handle body 674 from moving out of a centered orientation (i.e., from bending out from the longitudinal axis of the handle body 674, sliding spacers 6142 are periodically provided along the clasp sleeve 614 as shown in FIGS.\",\n \"93 and 116 to 118.These spacers 6142 are only needed while the proximal handle 678 is moving the rotator assembly and the pusher clasp body 296 in a distal direction to prevent bending of the interior flexible lumen 620, 640, 642.Accordingly, the spacers 6142 can slide within the groove 6141 of the clasp sleeve 614 up to and over the distal end of the clasp sleeve 614 (the right side of the clasp sleeve 614 as viewed in FIG.\",\n \"93; see also FIG.\",\n \"117).\",\n \"Each of these spacers 6142 is self secured in a slidable manner to the clasp sleeve 614.FIG.\",\n \"117 depicts a ninth cross-section through a distal end of the clasp sleeve 614 within the distal handle 672.The distal handle 672 freely rotates about the handle body 674 in an exemplary embodiment.\",\n \"In such an embodiment, the outer catheter 660 will also freely rotate about all of the lumen 620, 640, 642 therein because of the fixation between the outer catheter 660 and the distal handle 672.See FIG.\",\n \"118.The shaded parts in FIG.\",\n \"119 are provided to show portions of the features around the clasp body 602.In this view, the rotator assembly is removed.\",\n \"The following text describes the four movements for implanting a prosthesis with the delivery system and the relative connections between relevant lumens when in the three different settings of the locking knob 676.The first movement will be referred to as the advancement stage and utilizes position 1 of the locking knob 676.When in position 1, the distal spring 298 is engaged around and holds the pusher support tube 645 (and, therefore, graft push lumen 642) to the rotator assembly 292, 294.This assembly 292, 294 is fixed at the distal end of the rotator body 294 inside the pusher clasp body 296 (through a non-illustrated setscrew passing through the threaded bore 2966 shown in FIG.\",\n \"98).\",\n \"As set forth above, the pusher clasp body 296 is fixed to the proximal handle 678 and, therefore, the pusher support tube 245 moves with the proximal handle 678 in position 1.In this first movement, the entire distal assembly is advanced up to the implantation site using the proximal handle 678.Thus, when the handle 678 moves distally, all of the lumen, including the guidewire lumen 620, the apex release lumen 640, the graft push lumen 642/proximal pusher support tube 645, and the sheath lumen 654, are locked together and move distally with a corresponding movement of the proximal handle 678.As the outer catheter 660 is longitudinally fixed to the distal handle 672, it remains longitudinally fixed during the first movement.\",\n \"The lumen displacement in the advancement stage is depicted in FIGS.\",\n \"19 to 21.The second movement will be referred to as the primary deployment stage and utilizes position 2 of the locking knob 676.When in position 2, the distal spring 298 is disengaged from the pusher support tube 645 and the proximal spring 606 becomes engaged around the pusher support tube 645 to anchor only the push rod 642 (without lumen 620, 640) to the proximal handle 678 and allow retraction of sheath lumen 654 (and, thereby, the inner sheath 652) while all other lumens are disengaged and remain stationary.\",\n \"In this second movement, the inner sheath 654 needs to be moved in the proximal direction, as shown in FIGS.\",\n \"22 to 24.Accordingly, when the handle 678 moves distally, only the sheath lumen 654 moves with the handle 678.Thus, in position 2 of the locking knob 676, the sheath lumen 654 is locked to the proximal handle 678 and moves proximally with a corresponding movement of the proximal handle 678; all of the other lumen, including the guidewire lumen 620, the apex release lumen 640, and the graft push lumen 642/proximal pusher support tube 645, are unlocked and remain in the distally deployed position.\",\n \"See FIGS.\",\n \"22 to 24.The third movement will be referred to as the final deployment stage because, in this movement, the apex capture device 634 completely releases the distal end of the prosthesis as shown in FIG.\",\n \"14.Here, the apex release lumen 640 is unlocked (using the release mechanism of FIG.\",\n \"91) with respect to the guidewire lumen 620 and the graft push lumen 642/645.The fourth movement will be referred to as the extraction stage and utilizes position 4 of the locking knob (the third of the three positions in the slot 587 of the locking knob 676).\",\n \"When in position 4, both the distal spring 298 and the proximal spring 606 are disengaged from the pusher support tube 645 to allow the user to pull the proximal end of the pusher support tube 645 and withdraw it from the implantation site.\",\n \"The entire inner lumen assembly 620 and 640 travels with the proximal movement of the pusher support tube 645 because the release mechanism (see FIG.\",\n \"91) is pulled with the support tube 645 as it moves proximally.\",\n \"While exemplary embodiments of the invention have been illustrated and described, it will be clear that the invention is not so limited.\",\n \"Numerous modifications, changes, variations, substitutions, and equivalents will occur to those skilled in the art without departing from the spirit and scope of the present invention as defined by the appended claims.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875835"}}},{"rowIdx":4494994,"cells":{"text":{"kind":"list like","value":[["Pressing of Wire Bond Wire Tips to Provide Bent-Over Tips","In a method for forming a microelectronic device, a substrate is loaded into a mold press.","The substrate has a first surface and a second surface.","The second surface is placed on an interior lower surface of the mold press.","The substrate has a plurality of wire bond wires extending from the first surface toward an interior upper surface of the mold press.","An upper surface of a mold film is indexed to the interior upper surface of the mold press.","A lower surface of the mold film is punctured with tips of the plurality of wire bond wires for having the tips of the plurality of wire bond wires extending above the lower surface of the mold film into the mold film.","The tips of the plurality of wire bond wires are pressed down toward the lower surface of the mold film to bend the tips over."],["1.A method for forming a microelectronic device, comprising: loading a substrate for the microelectronic device into a mold press; the substrate having a first surface and a second surface; the second surface being placed on an interior lower surface of the mold press; the substrate having a plurality of wire bond wires extending from the first surface toward an interior upper surface of the mold press; indexing an upper surface of a mold film to the interior upper surface of the mold press; puncturing a lower surface of the mold film with tips of the plurality of wire bond wires for having the tips of the plurality of wire bond wires located in the mold film between the upper surface and the lower surface; injecting a molding material between the first surface of the substrate and the lower surface of the mold film; curing the molding material to provide a molding layer; removing the mold film from the substrate; and pressing the tips of the plurality of wire bond wires down toward an upper surface of the molding layer to bend the tips over.","2.The method according to claim 1, wherein the puncturing further comprises embedding portions of arms of the wire bond wires adjacent to the tips in the mold film.","3.The method according to claim 1, wherein the pressing on the tips includes bending the tips over to provide bent over tips.","4.The method according to claim 3, wherein the bent over tips have trapezoidal front facing outlines prior to the pressing.","5.The method according to claim 3, wherein the bent over tips provide solder anchors after the pressing.","6.An apparatus for a microelectronic device, comprising: a substrate having a first surface and a second surface opposite the first surface; the substrate having a plurality of wire bond wires extending from the first surface; the substrate having a mold material layer on the first surface; wherein tips of the plurality of wire bond wires extend beyond an upper surface of the mold material layer; and wherein the tips are bent over.","7.The apparatus according to claim 6, wherein the tips are flattened.","8.The apparatus according to claim 6, wherein the tips have corresponding bends to provide bent over tips for solder anchors.","9.The apparatus according to claim 8, wherein the tips are bent over against the upper surface of the mold material layer.","10.The apparatus according to claim 8, wherein the tips are bent over toward and spaced-away from the upper surface of the mold material layer."],["<SOH> BACKGROUND <EOH>Microelectronic assemblies generally include one or more integrated circuit dies (“ICs”), such as for example one or more packaged ICs (“chips”).","One or more of such chips may be mounted on a circuit platform, such as on a wafer for wafer-level-packaging (“WLP”), a package substrate, an interposer, or a carrier.","Additionally, one chip may be mounted on another chip for a package-on-package (“PoP”) part.","A chip may include conductive elements, such as pathways, traces, tracks, vias, contacts, pads such as contact pads and bond pads, plugs, nodes, or terminals for example, that may be used for making electrical interconnections with another circuit platform.","These arrangements may facilitate electrical connections used to provide functionality of ICs.","A chip may be coupled to a circuit platform by bonding, such as bonding traces or terminals, for example, of such circuit platform to bond pads or exposed ends of pins or posts or the like of a chip.","Interconnecting of one chip to another chip or to a circuit platform is relevant to reliability.","Accordingly, it would be desirable and useful to provide interconnects that enhance reliability."],["<SOH> BRIEF SUMMARY <EOH>A method relates generally to forming a microelectronic device.","In such a method, a substrate for the microelectronic device is loaded into a mold press.","The substrate has a first surface and a second surface.","The second surface is placed on an interior lower surface of the mold press.","The substrate has a plurality of wire bond wires extending from the first surface toward an interior upper surface of the mold press.","An upper surface of a mold film is indexed to the interior upper surface of the mold press.","A lower surface of the mold film is punctured with tips of the plurality of wire bond wires for having the tips of the plurality of wire bond wires extending above the lower surface of the mold film into the mold film.","The tips of the plurality of wire bond wires are pressed down toward the lower surface of the mold film to bend the tips over.","Another method relates generally to forming a microelectronic device.","In such other method, a substrate for the microelectronic device is loaded into a mold press.","The substrate has a first surface and a second surface.","The second surface is placed on an interior lower surface of the mold press.","The substrate has a plurality of wire bond wires extending from the first surface toward an interior upper surface of the mold press.","An upper surface of a mold film is indexed to the interior upper surface of the mold press.","A lower surface of the mold film is punctured with tips of the plurality of wire bond wires for having the tips of the plurality of wire bond wires located in the mold film between the upper surface and the lower surface.","A molding material is injected between the first surface of the substrate and the lower surface of the mold film.","The molding material is cured to provide a molding layer.","The mold film is removed from the substrate.","The tips of the plurality of wire bond wires are pressed down toward an upper surface of the molding layer to bend the tips over.","An apparatus relates generally to a microelectronic device.","In such an apparatus, a substrate has a first surface and a second surface opposite the first surface.","The substrate has a plurality of wire bond wires extending from the first surface.","The substrate has a mold material layer on the first surface.","Tips of the plurality of wire bond wires extend beyond an upper surface of the mold material layer, and the tips are bent over.","Other features will be recognized from consideration of the Detailed Description and Claims, which follow."],["CROSS-REFERENCE TO RELATED APPLICATION(S) This application is a divisional of and hereby claims priority to U.S. patent application Ser.","No.","14/639,789, filed Mar.","5, 2015, the entirety of which is hereby incorporated by reference herein for all purposes.","FIELD The following description relates to microelectronic devices.","More particularly, the following description relates to pressing of wire bond wire tips to provide bent over tips for a microelectronic device.","BACKGROUND Microelectronic assemblies generally include one or more integrated circuit dies (“ICs”), such as for example one or more packaged ICs (“chips”).","One or more of such chips may be mounted on a circuit platform, such as on a wafer for wafer-level-packaging (“WLP”), a package substrate, an interposer, or a carrier.","Additionally, one chip may be mounted on another chip for a package-on-package (“PoP”) part.","A chip may include conductive elements, such as pathways, traces, tracks, vias, contacts, pads such as contact pads and bond pads, plugs, nodes, or terminals for example, that may be used for making electrical interconnections with another circuit platform.","These arrangements may facilitate electrical connections used to provide functionality of ICs.","A chip may be coupled to a circuit platform by bonding, such as bonding traces or terminals, for example, of such circuit platform to bond pads or exposed ends of pins or posts or the like of a chip.","Interconnecting of one chip to another chip or to a circuit platform is relevant to reliability.","Accordingly, it would be desirable and useful to provide interconnects that enhance reliability.","BRIEF SUMMARY A method relates generally to forming a microelectronic device.","In such a method, a substrate for the microelectronic device is loaded into a mold press.","The substrate has a first surface and a second surface.","The second surface is placed on an interior lower surface of the mold press.","The substrate has a plurality of wire bond wires extending from the first surface toward an interior upper surface of the mold press.","An upper surface of a mold film is indexed to the interior upper surface of the mold press.","A lower surface of the mold film is punctured with tips of the plurality of wire bond wires for having the tips of the plurality of wire bond wires extending above the lower surface of the mold film into the mold film.","The tips of the plurality of wire bond wires are pressed down toward the lower surface of the mold film to bend the tips over.","Another method relates generally to forming a microelectronic device.","In such other method, a substrate for the microelectronic device is loaded into a mold press.","The substrate has a first surface and a second surface.","The second surface is placed on an interior lower surface of the mold press.","The substrate has a plurality of wire bond wires extending from the first surface toward an interior upper surface of the mold press.","An upper surface of a mold film is indexed to the interior upper surface of the mold press.","A lower surface of the mold film is punctured with tips of the plurality of wire bond wires for having the tips of the plurality of wire bond wires located in the mold film between the upper surface and the lower surface.","A molding material is injected between the first surface of the substrate and the lower surface of the mold film.","The molding material is cured to provide a molding layer.","The mold film is removed from the substrate.","The tips of the plurality of wire bond wires are pressed down toward an upper surface of the molding layer to bend the tips over.","An apparatus relates generally to a microelectronic device.","In such an apparatus, a substrate has a first surface and a second surface opposite the first surface.","The substrate has a plurality of wire bond wires extending from the first surface.","The substrate has a mold material layer on the first surface.","Tips of the plurality of wire bond wires extend beyond an upper surface of the mold material layer, and the tips are bent over.","Other features will be recognized from consideration of the Detailed Description and Claims, which follow.","BRIEF DESCRIPTION OF THE DRAWING(S) Accompanying drawing(s) show exemplary embodiment(s) in accordance with one or more aspects of exemplary apparatus(es) or method(s).","However, the accompanying drawings should not be taken to limit the scope of the claims, but are for explanation and understanding only.","FIG.","1 is a respective block diagram of a cross-sectional side view depicting an implementation of a microelectronic device.","FIG.","2 is a respective block diagram of a cross-sectional side view depicting an implementation of a microelectronic device.","FIG.","3 is a respective block diagram of a cross-sectional side view depicting an implementation of a microelectronic device.","FIG.","4 is a block diagram of a top-down view of an exemplary microelectronic device.","FIG.","5 is a block diagram of a top-down view of an exemplary microelectronic device after tips have been bent over.","FIG.","6 is an enlarged side view depicting a pair of wire bond wires attached to an upper surface of carrier prior to formation of a molding layer.","FIGS.","7-1 through 7-6 are a progression of block diagrams of a side cutaway view depicting an exemplary manufacturing process having operations for forming a microelectronic device.","FIGS.","8-1 through 8-4 are a progression of block diagrams of a side cutaway view depicting another exemplary manufacturing process having operations for forming a microelectronic device.","FIG.","9 is a block diagram of a side cutaway view depicting another exemplary substrate after a manufacturing process having operations for forming a microelectronic device but with an uppermost portion of an arm of wire bond wires embedded in a mold film.","FIGS.","10-1 and 10-2 are block diagrams of a side cutaway view depicting yet another exemplary substrate after another manufacturing process having operations for forming a microelectronic device but with an upper portion of an arm of wire bond wires, longer than an uppermost portion thereof, embedded in mold film.","DETAILED DESCRIPTION In the following description, numerous specific details are set forth to provide a more thorough description of the specific examples described herein.","It should be apparent, however, to one skilled in the art, that one or more other examples or variations of these examples may be practiced without all the specific details given below.","In other instances, well known features have not been described in detail so as not to obscure the description of the examples herein.","For ease of illustration, the same number labels are used in different diagrams to refer to the same items; however, in alternative examples the items may be different.","As previously described, chip to chip or wiring platform interconnects are relevant to reliability.","As described below, wire bond wire tips may be pressed to provide bent over shaped tips for interconnects for a microelectronic device.","These bent over shaped tips may provide anchors for interconnecting a microelectronic device to an IC, a chip, and/or a wiring platform.","These anchors may be used to enhance reliability of such interconnects.","FIGS.","1 through 3 are respective block diagrams of cross-sectional side views depicting several implementations of a microelectronic device 100.In each implementation, a substrate 150 for a microelectronic device 100 may include an interposer or carrier 102 and a plurality of wire bond wires 110 generally extending from an upper surface 112 of such carrier 102.Wire bond wires 110 may be BVA™ wires.","Such a substrate 150 for a microelectronic device 100 may further include one or more integrated circuit dies 101.After processing, such substrate 150 may yet further include a molding material layer (“molding layer”) 103.After molding, a substrate 150 may have a lower surface 111 and a generally opposite or opposing upper surface 132 of a molding layer 103, and uppermost portions of wire bond wires 110 of such substrate 150 may extend above upper surface 132.Wire bond wires 110 may be attached to upper conductive pads 105.Upper conductive pads 105 may be in contact with upper surface 112 of carrier 102, in recesses of carrier 102 associated with upper surface 112, and/or in such recesses and extending above upper surface 112.Conductive interconnects 104, such as solder balls for example, may be attached to lower conductive pads 107.Lower conductive pads 107 may be in contact with lower surface 111 of carrier 102, in recesses of carrier 102 associated with lower surface 111, and/or in such recesses and extending below lower surface 111.Upper and lower conductive pads 105 and 107 may be coupled to one another through conductive vias 106.Wire bond wires 110 may have a lower portion (“base”) 125, a middle portion (“arm”) 127, and an upper portion (“tip”) 126.Bases 125 may be attached to conductive pads 105, including without limitation traces or other conductive structures associated with carrier 102.Arms 127 may extend from bases 125 to beyond an upper surface 122 of integrated circuit die 101 in molding layer 103.Tips 126 may extend from arms 127 to locations above upper surface 132 of molding layer 103.Molding layer 103 may be injected or otherwise deposited on upper surface 112 of carrier 102.Molding layer 103 may further be injected or otherwise deposited on upper surface 122 of integrated circuit die 101 for encapsulation of integrated circuit die 101.Bond pads 108 of carrier 102 may be used for wire bonds 109 of lower ends of arched lead-over chip wires 117 to wire bonds 119 of upper ends of wires 117 to bond pads 118 of integrated circuit die 101.In this configuration, a lower surface 121 of integrated circuit die 101 may rest on an upper surface 112 of carrier 102, and bond pads 108 and 118 may respectively be located on upper surfaces 112 and 122.In the implementation of FIG.","1, arms 127 are generally at a 90 degree angle 123 with respect to upper surface 112.However, in other implementations, such as generally indicated in FIG.","2, angle 123 may be less than or greater than 90 degrees.","Furthermore, in FIG.","2, integrated circuit die 101 is illustratively depicted as being coupled to carrier 102 with microbumps 133 and associated pads 134.Optionally, molding layer 103 may not completely encapsulate integrated circuit die 101, as an upper surface 122 may be exposed.","Optionally, as illustratively depicted in FIG.","3, attachment of wire bond wires 110 to carrier 102 may be reinforced with intermetallic compound (“IMC”) structures, such as soldered bases 135.For purposes of clarity and not limitation, many known details, as well as alternative and/or optional configurations, for microelectronic devices 100 have been omitted.","Along those lines, various configurations, other than those specifically described, may be used in accordance with the following description.","With reference to FIG.","4, a block diagram of a top-down view of an exemplary microelectronic device 100 is illustratively depicted.","In the example, there are two concentric rectangular rings of wire bond wires 110 forming an array 400.However, in other implementations, other numbers of wire bond wires 110, array shapes, array dimensions, and/or other patterns of wire bond wires 110 may be used to provide an array 400.Tips 126 extend above upper surface 132 of molding layer 103.At an interface between tips 126 and arms 127, there may be ledge 401.Ledges 401 may, though need not be, horizontal surfaces projecting from a wall of tips 126.In FIG.","4, tips 126 have any of four orientations.","However, these or other orientations of tips 126 may be used.","With reference to FIG.","5, a block diagram of a top-down view of an exemplary microelectronic device 100 is illustratively depicted, after tips 126 have been bent over.","Tips 126 may be bent over to have wall surfaces respectively thereof in contact with or at least proximal to corresponding ledges 401.This bending of tips 126 may be by placing substrate 150 into a molding press, as described below in additional detail.","Accordingly, during pressing, tips 126 may be bent over in any of a variety of orientations to provide bent over shapes for wire bond wires 110.Even though four orientations 501 through 504 are illustratively depicted by corresponding arrows for directions tips 126 point after bending, these and/or other orientations may be used.","Furthermore, even though orientations 501 through 504 point inwardly with respect to array 400, namely an open space in the center of array 400, in another implementation outwardly pointing tips 126, or a combination of inwardly and outwardly pointing tips 126, may be used.","FIG.","6 is an enlarged side view depicting a pair of wire bond wires 110-1 and 110-2 attached to an upper surface 112 of carrier 102 prior to formation of molding layer 103.Prior to formation of molding layer 103, wire bond wires 110-1 and 110-2 may be attached to pads (not shown in this FIG.)","along upper surface 112 via corresponding solder bases 135.Bases 125 of wire bond wires 110 may have j-like shapes, with bottoms thereof attached to upper surface 112 for forming wire bond wires 110.However, addition of solder bases 135 may provide additional support for enhanced reliability.","Wire bond wire 110-2 may have approximately a 90 rotation with respect to orientation of wire bond wire 110-1.Tips 126 may have a generally horizontal surface, namely ledge 401, extending away from a facing wall surface 602 extending above a corresponding ledge 401.Again, ledges 401 may, though need not be, parallel with upper surface 112.Moreover, wall surfaces 602 may, though need not be, orthogonal to corresponding ledges 401.Furthermore, a wall surface 602 may, though need not be, orthogonal to a plane of upper surface 112.In this example, front facing wall surface 602, as well as back facing wall surface 605, of a tip 126 is slightly tapered to narrow tip 126 toward a top surface 601 thereof.","Right and left side surfaces 604 of a tip 126 may both be tapered to widen tip 126 toward a top surface 601 thereof.","Along those lines, tip 126 may have a “shovelhead-like” or “fishtail-like” shape with a trapezoidal front facing outline being wider at a distal end than a proximal end to provide such a widened tip 126.This “fishtail-like” shape may be formed when pinching and pulling off a feed wire used to for forming wire bond wires 110.Wire bond wires 110 may be shaped in the formation thereof to provide such a “shovelhead-like” shape with a trapezoidal front facing outline.","While a shovelhead-like shape may be used to provide a greater surface area for attachment to an IMC structure, other shapes may likewise be used.","A bending locus may generally be at or slightly above the intersection of ledge 401 and wall surface 602 for a tip 126, namely where a bending radius or bending moment may likely occur when tips 126 are pressed, as described below in additional detail.","After pressing or bending of tips 126, such tips may have a bent over shape.","Such bent over shapes provided by bent tips 126 may be used as anchors for solder or other IMC structures.","FIGS.","7-1 through 7-6 are a progression of block diagrams of a side cutaway view depicting an exemplary manufacturing process having operations 801 through 806 for forming a microelectronic device 100.FIGS.","7-1 through 7-6 are further described with simultaneous reference to FIGS.","1 through 6, where the example of FIG.","6 is used in FIGS.","7-1 through 7-6 for purposes of clarity by way of example and not limitation.","At operation 801, a substrate 150 for microelectronic device 100 may be loaded or placed into a mold press 700.In this example, mold press 700 has a bottom platen 701 and top platen 702.In this example, bottom platen 701 is movable and top platen 702 is stationary.","Optionally, top platen 702 may optionally include a fixed plate 703 slightly raised or offset from lower surface 706 to define an upper interior region 705 within a cavity 710 between platens 701 and 702.Substrate 150 may be loaded into such cavity 710.However, in other implementations, no upper interior region 705 may be present, as bent over tips may be pressed into an upper surface of a deformable mold assist film, as described below in additional detail.","For purposes of clarity, known details of a mold press 700 are not described herein.","After loading at 801, wire bond wires 110 of substrate 150 may extend from upper surface 112 toward an interior upper surface of mold press 700, namely a lower surface 704 of plate 703.A lower surface 111 of substrate 150 may be placed on an interior lower surface defining cavity 710, namely an interior upper surface 709 of lower platen 701 of mold press 700.At operation 802, a mold assist film (“mold film”) 711 may be indexed to a lower surface 706 of top platen 702.Along those lines, an upper surface 712 of a mold film 711 may be brought into contact or conformed to a portion of an interior upper surface, such as lower surface 706 for example, of mold press 700 without leaving a gap between another portion of such interior upper surface, such as interior upper surface 706 for example, of mold press 700 and upper surface 712 of mold film 711.Again, there is no optional gap for upper interior region 705.At operation 803, mold film 711 may be punctured with tips 126 by moving bottom platen 701 in an upward direction 719.Along those lines, a lower surface 721 and an upper surface 712 of mold film 711 may be punctured with tips 126 of wire bond wires 110 for having tips 126 to have tips 126 bent over into upper surface 712 of mold film 711 deforming such upper surface 712 of mold film 711 into an upper interior region thereof, as generally indicated by arrow 723.In this position, substrate 150 is moved by moving lower platen 701 in an upward direction to cause tips 126 to bend toward and onto upper surface 712, as generally indicated by arrow 723.Optionally, upper platen 702 may be moved in a downward direction as generally indicated by arrow 725.Moreover, optionally both upper platen 702 and lower platen 701 may be moved in directions 719 and 725, respectively.","Furthermore, optionally a lateral movement 729 of upper platen 702 may be used to assist bending of tips 126 to reduce likelihood of cracking of wire bond wires 110 due to application of a compressive force.","For uses of a lateral movement 729, tips 126 may all have a same orientation.","At operation 804, tips 126 may continue to be pressed in a generally downward direction to provide shaped bent over tips 126 for wire bond wires 110.In this example, bent over tips 126 may be flattened between lower surface 706 of platen 702 and into a deformable upper surface 712 of mold film 711.This pressing of tips 126 may optionally include flattening or coining of tips 126.Furthermore, in this example, upper surface 712 of mold film 711 may be coplanar with ledges 401.However, in other examples, ledges 401 may extend to or just above upper surface 712, and thus tips 126 may be bent down for stopping on ledges 401 instead of being bent into upper surface 712.At operation 805, a molding material may be injected between upper surface 112 of substrate 150 and lower surface 721 of mold film 711 for molding layer 103.At operation 806, such molding material may be cured to form molding layer 103, and mold film 711 may be used to assist release of substrate 150 with such molding layer 103 from mold press 700.After formation and release of substrate 150 from mold press 700, including removal of mold film 711 from substrate 150, there may be a gap 730 between upper surface 132 of molding layer 103 and ledges 401, and this gap 730 may be associated with a partial thickness of mold film 711, namely a lower portion of a distance between surfaces 712 and 721 of mold film 711.Moreover, bent over tips 126 and uppermost portions of arms 127 corresponding to gap 730 may extend above upper surface 132.Thus, lower surfaces of shaped bent over tips 126 may be spaced-away from upper surface 132 of molding layer 103.In the above example, tips 126 were bent prior to forming a molding layer 103.However, in another implementation, tips 126 may be bent after forming a molding layer 103.In either order, tips 126 may be pressed down against an upper surface 712 of mold film 711, and such tips 126 may thus be bent over leaving a space between bottom surfaces of such tips 126 and upper surface 132 of molding layer 103 after removal of mold film 711.Again, tips 126 may be shaped prior to loading into mold press 700, and such shaped tips 126 may be to provide bending locations for bending.","The above process may generally be thought of as a pressing of tips prior to molding, namely a pressing-before-molding process.","The following description may generally be thought of as a pressing-after-molding process.","FIGS.","8-1 through 8-4 are a progression of block diagrams of a side cutaway view depicting an exemplary manufacturing process having operations 903 through 906 for forming a microelectronic device 100.FIGS.","8-1 through 8-4 are further described with simultaneous reference to FIGS.","1 through 7-6, where the example of FIG.","6 is used in FIGS.","8-1 through 8-4 for purposes of clarity by way of example and not limitation.","Prior to operation 903, operations 801 and 802 may be performed as previously described.","However, in operation 802 a thicker mold film 711 is indexed to a lower surface of upper platen 702.In the above example of a thinner mold film 711, such mold film thickness may be in a range of approximately 10 to 50 microns, and in the example of a thicker mold film 711, such mold film thickness may be in a range of approximately 50 to 150 microns.","In other implementations, these or other ranges may be used.","For example, for anchors using bent over tips 126, longer tips may be used and correspondingly thicker molding film to provide more surface area for anchoring at the expense of a larger pitch.","Bent over tips 126 may be used as anchors for soldering for example.","At operation 903, this thicker mold film 711 may be punctured with tips 126 by moving either or both lower platen 701 and upper platen 702, as previously described.","In this example, lower platen 701 is moved in an upward direction 719.Along those lines, a lower surface 721 and an upper surface 712 of mold film 711 may be punctured with tips 126 of wire bond wires 110 for having at least a substantial portion, if not all, of tips 126 extend above lower surface 721 of mold film 711 into an interior region of mold film 711, namely having such substantial portion of such tips 126 located in mold film 711 between upper surface 712 and lower surface 721 of such mold film 711 prior to molding.","Optionally, uppermost portions of arms 127 may likewise extend into mold film 711 prior to molding.","In this example, lower surface 721 is generally co-planar with ledges 401; however, ledges 401 may be above, equal with, and/or below lower surface 721 in this or other implementations.","At operation 904, a molding material may be injected between upper surface 112 of substrate 150 and lower surface 721 of mold film 711 for molding layer 103.At operation 905, such molding material may be cured to form molding layer 103, and mold film 711 may be used to assist release of substrate 150 from such molding layer 103 and then such mold film 711 may be removed from mold press 700.After formation of molding layer 103 and removal of mold film 711 from substrate 150 at operation 905, upper surface 132 of molding layer 103 and ledges 401 may optionally be co-planar, as in this example.","However, as previously indicated, such ledges 401 may be above or below upper surface 132.At 906, substrate 150 may be moved by having lower platen 701 moved in an upward direction 719 to cause tips 126 to be pressed into lower surface 706 of upper platen 702 to bend such tips 126 toward upper surface 132, as generally indicated by arrow 723 in FIG.","8-3.At operation 906, tips 126 may be pressed down against an upper surface 132 of molding layer 103, and such tips 126 may thus be bent over.","After bending, tips 126 may optionally be against upper surface 132 of molding layer 103, which optionally may leave no readily perceivable gap between bottom surfaces of such tips 126 and upper surface 132 of molding layer 103.Again, tips 126 may be shaped prior to loading into mold press 700, and such shaped tips 126 may be to provide bending locations.","Pressing of such tips 126 may optionally flatten such tips between upper surface 132 of molding layer 103 and lower surface 706 of upper platen 702.Again, though lower platen 701 may be raised for this pressing, either or both platens may be moved for pressing, as described elsewhere herein, to provide bent over tips 126.Such pressing may further flatten tips, which may spread out such tips 126.After such pressing operation at 906, substrate 150 may be removed from mold press 700.By pressing after molding, arms 127 may have some protection from compressive stresses by molding layer 103.As previously described an uppermost portion of an arm 127 may be embedded in mold film 711.Along those lines, FIG.","9 is a block diagram of a side cutaway view depicting another exemplary substrate 150 after a manufacturing process having operations for forming a microelectronic device as described above but with an uppermost portion 911 of an arm 127 of wire bond wires 110 embedded in mold film 711.Such uppermost portions 911 of arms 127 of wire bond wires 110 may be adjacent and integral with lowermost portions of such tips 126.Along those lines, a pressing after molding may be used to bend tips 126 over to have an uppermost portion of such tips bent down to be at least proximate to or touching upper surface 132.Such bent over tips 126 may define an underside through region or air gap 913, such as for a hook-like structure or shape for example.","Optionally, a solder ball 914 may be placed over tips 126, and such bent over tips 126 may be used to anchor such solder balls 914, namely solder anchors which may include completely or partially filing such air gaps 913 with solder to assist in anchoring.","As previously described an uppermost portion of an arm 127 may be embedded in mold film 711.Along those lines, FIGS.","10-1 and 10-2 are block diagrams of a side cutaway view depicting yet another exemplary substrate 150 after another manufacturing process having operations for forming a microelectronic device as described above but with an upper portion 912, longer than an uppermost portion 911, of an arm 127 of wire bond wires 110 embedded in mold film 711.Such upper portions 912 of arms 127 of wire bond wires 110 may include such uppermost portions 911 and thus may be adjacent and integral with lowermost portions of such tips 126.Along those lines, a pressing after molding may be used to bend tips 126 over to have an uppermost portion of such tips bent down to be at least proximate to or touching upper surface 132.Such bent over tips 126 may define an underside through region 913, such as for a hook-like structure or shape for example.","Optionally, a solder ball 914 may be placed over tips 126, and such bent over tips 126 may be used to anchor such solder balls 914, including completely or partially filing such air gaps 913 to assist in anchoring.","While the foregoing describes exemplary embodiment(s) in accordance with one or more aspects of the invention, other and further embodiment(s) in accordance with the one or more aspects of the invention may be devised without departing from the scope thereof, which is determined by the claim(s) that follow and equivalents thereof.","Claim(s) listing steps do not imply any order of the steps.","Trademarks are the property of their respective owners."]],"string":"[\n [\n \"Pressing of Wire Bond Wire Tips to Provide Bent-Over Tips\",\n \"In a method for forming a microelectronic device, a substrate is loaded into a mold press.\",\n \"The substrate has a first surface and a second surface.\",\n \"The second surface is placed on an interior lower surface of the mold press.\",\n \"The substrate has a plurality of wire bond wires extending from the first surface toward an interior upper surface of the mold press.\",\n \"An upper surface of a mold film is indexed to the interior upper surface of the mold press.\",\n \"A lower surface of the mold film is punctured with tips of the plurality of wire bond wires for having the tips of the plurality of wire bond wires extending above the lower surface of the mold film into the mold film.\",\n \"The tips of the plurality of wire bond wires are pressed down toward the lower surface of the mold film to bend the tips over.\"\n ],\n [\n \"1.A method for forming a microelectronic device, comprising: loading a substrate for the microelectronic device into a mold press; the substrate having a first surface and a second surface; the second surface being placed on an interior lower surface of the mold press; the substrate having a plurality of wire bond wires extending from the first surface toward an interior upper surface of the mold press; indexing an upper surface of a mold film to the interior upper surface of the mold press; puncturing a lower surface of the mold film with tips of the plurality of wire bond wires for having the tips of the plurality of wire bond wires located in the mold film between the upper surface and the lower surface; injecting a molding material between the first surface of the substrate and the lower surface of the mold film; curing the molding material to provide a molding layer; removing the mold film from the substrate; and pressing the tips of the plurality of wire bond wires down toward an upper surface of the molding layer to bend the tips over.\",\n \"2.The method according to claim 1, wherein the puncturing further comprises embedding portions of arms of the wire bond wires adjacent to the tips in the mold film.\",\n \"3.The method according to claim 1, wherein the pressing on the tips includes bending the tips over to provide bent over tips.\",\n \"4.The method according to claim 3, wherein the bent over tips have trapezoidal front facing outlines prior to the pressing.\",\n \"5.The method according to claim 3, wherein the bent over tips provide solder anchors after the pressing.\",\n \"6.An apparatus for a microelectronic device, comprising: a substrate having a first surface and a second surface opposite the first surface; the substrate having a plurality of wire bond wires extending from the first surface; the substrate having a mold material layer on the first surface; wherein tips of the plurality of wire bond wires extend beyond an upper surface of the mold material layer; and wherein the tips are bent over.\",\n \"7.The apparatus according to claim 6, wherein the tips are flattened.\",\n \"8.The apparatus according to claim 6, wherein the tips have corresponding bends to provide bent over tips for solder anchors.\",\n \"9.The apparatus according to claim 8, wherein the tips are bent over against the upper surface of the mold material layer.\",\n \"10.The apparatus according to claim 8, wherein the tips are bent over toward and spaced-away from the upper surface of the mold material layer.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>Microelectronic assemblies generally include one or more integrated circuit dies (“ICs”), such as for example one or more packaged ICs (“chips”).\",\n \"One or more of such chips may be mounted on a circuit platform, such as on a wafer for wafer-level-packaging (“WLP”), a package substrate, an interposer, or a carrier.\",\n \"Additionally, one chip may be mounted on another chip for a package-on-package (“PoP”) part.\",\n \"A chip may include conductive elements, such as pathways, traces, tracks, vias, contacts, pads such as contact pads and bond pads, plugs, nodes, or terminals for example, that may be used for making electrical interconnections with another circuit platform.\",\n \"These arrangements may facilitate electrical connections used to provide functionality of ICs.\",\n \"A chip may be coupled to a circuit platform by bonding, such as bonding traces or terminals, for example, of such circuit platform to bond pads or exposed ends of pins or posts or the like of a chip.\",\n \"Interconnecting of one chip to another chip or to a circuit platform is relevant to reliability.\",\n \"Accordingly, it would be desirable and useful to provide interconnects that enhance reliability.\"\n ],\n [\n \"<SOH> BRIEF SUMMARY <EOH>A method relates generally to forming a microelectronic device.\",\n \"In such a method, a substrate for the microelectronic device is loaded into a mold press.\",\n \"The substrate has a first surface and a second surface.\",\n \"The second surface is placed on an interior lower surface of the mold press.\",\n \"The substrate has a plurality of wire bond wires extending from the first surface toward an interior upper surface of the mold press.\",\n \"An upper surface of a mold film is indexed to the interior upper surface of the mold press.\",\n \"A lower surface of the mold film is punctured with tips of the plurality of wire bond wires for having the tips of the plurality of wire bond wires extending above the lower surface of the mold film into the mold film.\",\n \"The tips of the plurality of wire bond wires are pressed down toward the lower surface of the mold film to bend the tips over.\",\n \"Another method relates generally to forming a microelectronic device.\",\n \"In such other method, a substrate for the microelectronic device is loaded into a mold press.\",\n \"The substrate has a first surface and a second surface.\",\n \"The second surface is placed on an interior lower surface of the mold press.\",\n \"The substrate has a plurality of wire bond wires extending from the first surface toward an interior upper surface of the mold press.\",\n \"An upper surface of a mold film is indexed to the interior upper surface of the mold press.\",\n \"A lower surface of the mold film is punctured with tips of the plurality of wire bond wires for having the tips of the plurality of wire bond wires located in the mold film between the upper surface and the lower surface.\",\n \"A molding material is injected between the first surface of the substrate and the lower surface of the mold film.\",\n \"The molding material is cured to provide a molding layer.\",\n \"The mold film is removed from the substrate.\",\n \"The tips of the plurality of wire bond wires are pressed down toward an upper surface of the molding layer to bend the tips over.\",\n \"An apparatus relates generally to a microelectronic device.\",\n \"In such an apparatus, a substrate has a first surface and a second surface opposite the first surface.\",\n \"The substrate has a plurality of wire bond wires extending from the first surface.\",\n \"The substrate has a mold material layer on the first surface.\",\n \"Tips of the plurality of wire bond wires extend beyond an upper surface of the mold material layer, and the tips are bent over.\",\n \"Other features will be recognized from consideration of the Detailed Description and Claims, which follow.\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATION(S) This application is a divisional of and hereby claims priority to U.S. patent application Ser.\",\n \"No.\",\n \"14/639,789, filed Mar.\",\n \"5, 2015, the entirety of which is hereby incorporated by reference herein for all purposes.\",\n \"FIELD The following description relates to microelectronic devices.\",\n \"More particularly, the following description relates to pressing of wire bond wire tips to provide bent over tips for a microelectronic device.\",\n \"BACKGROUND Microelectronic assemblies generally include one or more integrated circuit dies (“ICs”), such as for example one or more packaged ICs (“chips”).\",\n \"One or more of such chips may be mounted on a circuit platform, such as on a wafer for wafer-level-packaging (“WLP”), a package substrate, an interposer, or a carrier.\",\n \"Additionally, one chip may be mounted on another chip for a package-on-package (“PoP”) part.\",\n \"A chip may include conductive elements, such as pathways, traces, tracks, vias, contacts, pads such as contact pads and bond pads, plugs, nodes, or terminals for example, that may be used for making electrical interconnections with another circuit platform.\",\n \"These arrangements may facilitate electrical connections used to provide functionality of ICs.\",\n \"A chip may be coupled to a circuit platform by bonding, such as bonding traces or terminals, for example, of such circuit platform to bond pads or exposed ends of pins or posts or the like of a chip.\",\n \"Interconnecting of one chip to another chip or to a circuit platform is relevant to reliability.\",\n \"Accordingly, it would be desirable and useful to provide interconnects that enhance reliability.\",\n \"BRIEF SUMMARY A method relates generally to forming a microelectronic device.\",\n \"In such a method, a substrate for the microelectronic device is loaded into a mold press.\",\n \"The substrate has a first surface and a second surface.\",\n \"The second surface is placed on an interior lower surface of the mold press.\",\n \"The substrate has a plurality of wire bond wires extending from the first surface toward an interior upper surface of the mold press.\",\n \"An upper surface of a mold film is indexed to the interior upper surface of the mold press.\",\n \"A lower surface of the mold film is punctured with tips of the plurality of wire bond wires for having the tips of the plurality of wire bond wires extending above the lower surface of the mold film into the mold film.\",\n \"The tips of the plurality of wire bond wires are pressed down toward the lower surface of the mold film to bend the tips over.\",\n \"Another method relates generally to forming a microelectronic device.\",\n \"In such other method, a substrate for the microelectronic device is loaded into a mold press.\",\n \"The substrate has a first surface and a second surface.\",\n \"The second surface is placed on an interior lower surface of the mold press.\",\n \"The substrate has a plurality of wire bond wires extending from the first surface toward an interior upper surface of the mold press.\",\n \"An upper surface of a mold film is indexed to the interior upper surface of the mold press.\",\n \"A lower surface of the mold film is punctured with tips of the plurality of wire bond wires for having the tips of the plurality of wire bond wires located in the mold film between the upper surface and the lower surface.\",\n \"A molding material is injected between the first surface of the substrate and the lower surface of the mold film.\",\n \"The molding material is cured to provide a molding layer.\",\n \"The mold film is removed from the substrate.\",\n \"The tips of the plurality of wire bond wires are pressed down toward an upper surface of the molding layer to bend the tips over.\",\n \"An apparatus relates generally to a microelectronic device.\",\n \"In such an apparatus, a substrate has a first surface and a second surface opposite the first surface.\",\n \"The substrate has a plurality of wire bond wires extending from the first surface.\",\n \"The substrate has a mold material layer on the first surface.\",\n \"Tips of the plurality of wire bond wires extend beyond an upper surface of the mold material layer, and the tips are bent over.\",\n \"Other features will be recognized from consideration of the Detailed Description and Claims, which follow.\",\n \"BRIEF DESCRIPTION OF THE DRAWING(S) Accompanying drawing(s) show exemplary embodiment(s) in accordance with one or more aspects of exemplary apparatus(es) or method(s).\",\n \"However, the accompanying drawings should not be taken to limit the scope of the claims, but are for explanation and understanding only.\",\n \"FIG.\",\n \"1 is a respective block diagram of a cross-sectional side view depicting an implementation of a microelectronic device.\",\n \"FIG.\",\n \"2 is a respective block diagram of a cross-sectional side view depicting an implementation of a microelectronic device.\",\n \"FIG.\",\n \"3 is a respective block diagram of a cross-sectional side view depicting an implementation of a microelectronic device.\",\n \"FIG.\",\n \"4 is a block diagram of a top-down view of an exemplary microelectronic device.\",\n \"FIG.\",\n \"5 is a block diagram of a top-down view of an exemplary microelectronic device after tips have been bent over.\",\n \"FIG.\",\n \"6 is an enlarged side view depicting a pair of wire bond wires attached to an upper surface of carrier prior to formation of a molding layer.\",\n \"FIGS.\",\n \"7-1 through 7-6 are a progression of block diagrams of a side cutaway view depicting an exemplary manufacturing process having operations for forming a microelectronic device.\",\n \"FIGS.\",\n \"8-1 through 8-4 are a progression of block diagrams of a side cutaway view depicting another exemplary manufacturing process having operations for forming a microelectronic device.\",\n \"FIG.\",\n \"9 is a block diagram of a side cutaway view depicting another exemplary substrate after a manufacturing process having operations for forming a microelectronic device but with an uppermost portion of an arm of wire bond wires embedded in a mold film.\",\n \"FIGS.\",\n \"10-1 and 10-2 are block diagrams of a side cutaway view depicting yet another exemplary substrate after another manufacturing process having operations for forming a microelectronic device but with an upper portion of an arm of wire bond wires, longer than an uppermost portion thereof, embedded in mold film.\",\n \"DETAILED DESCRIPTION In the following description, numerous specific details are set forth to provide a more thorough description of the specific examples described herein.\",\n \"It should be apparent, however, to one skilled in the art, that one or more other examples or variations of these examples may be practiced without all the specific details given below.\",\n \"In other instances, well known features have not been described in detail so as not to obscure the description of the examples herein.\",\n \"For ease of illustration, the same number labels are used in different diagrams to refer to the same items; however, in alternative examples the items may be different.\",\n \"As previously described, chip to chip or wiring platform interconnects are relevant to reliability.\",\n \"As described below, wire bond wire tips may be pressed to provide bent over shaped tips for interconnects for a microelectronic device.\",\n \"These bent over shaped tips may provide anchors for interconnecting a microelectronic device to an IC, a chip, and/or a wiring platform.\",\n \"These anchors may be used to enhance reliability of such interconnects.\",\n \"FIGS.\",\n \"1 through 3 are respective block diagrams of cross-sectional side views depicting several implementations of a microelectronic device 100.In each implementation, a substrate 150 for a microelectronic device 100 may include an interposer or carrier 102 and a plurality of wire bond wires 110 generally extending from an upper surface 112 of such carrier 102.Wire bond wires 110 may be BVA™ wires.\",\n \"Such a substrate 150 for a microelectronic device 100 may further include one or more integrated circuit dies 101.After processing, such substrate 150 may yet further include a molding material layer (“molding layer”) 103.After molding, a substrate 150 may have a lower surface 111 and a generally opposite or opposing upper surface 132 of a molding layer 103, and uppermost portions of wire bond wires 110 of such substrate 150 may extend above upper surface 132.Wire bond wires 110 may be attached to upper conductive pads 105.Upper conductive pads 105 may be in contact with upper surface 112 of carrier 102, in recesses of carrier 102 associated with upper surface 112, and/or in such recesses and extending above upper surface 112.Conductive interconnects 104, such as solder balls for example, may be attached to lower conductive pads 107.Lower conductive pads 107 may be in contact with lower surface 111 of carrier 102, in recesses of carrier 102 associated with lower surface 111, and/or in such recesses and extending below lower surface 111.Upper and lower conductive pads 105 and 107 may be coupled to one another through conductive vias 106.Wire bond wires 110 may have a lower portion (“base”) 125, a middle portion (“arm”) 127, and an upper portion (“tip”) 126.Bases 125 may be attached to conductive pads 105, including without limitation traces or other conductive structures associated with carrier 102.Arms 127 may extend from bases 125 to beyond an upper surface 122 of integrated circuit die 101 in molding layer 103.Tips 126 may extend from arms 127 to locations above upper surface 132 of molding layer 103.Molding layer 103 may be injected or otherwise deposited on upper surface 112 of carrier 102.Molding layer 103 may further be injected or otherwise deposited on upper surface 122 of integrated circuit die 101 for encapsulation of integrated circuit die 101.Bond pads 108 of carrier 102 may be used for wire bonds 109 of lower ends of arched lead-over chip wires 117 to wire bonds 119 of upper ends of wires 117 to bond pads 118 of integrated circuit die 101.In this configuration, a lower surface 121 of integrated circuit die 101 may rest on an upper surface 112 of carrier 102, and bond pads 108 and 118 may respectively be located on upper surfaces 112 and 122.In the implementation of FIG.\",\n \"1, arms 127 are generally at a 90 degree angle 123 with respect to upper surface 112.However, in other implementations, such as generally indicated in FIG.\",\n \"2, angle 123 may be less than or greater than 90 degrees.\",\n \"Furthermore, in FIG.\",\n \"2, integrated circuit die 101 is illustratively depicted as being coupled to carrier 102 with microbumps 133 and associated pads 134.Optionally, molding layer 103 may not completely encapsulate integrated circuit die 101, as an upper surface 122 may be exposed.\",\n \"Optionally, as illustratively depicted in FIG.\",\n \"3, attachment of wire bond wires 110 to carrier 102 may be reinforced with intermetallic compound (“IMC”) structures, such as soldered bases 135.For purposes of clarity and not limitation, many known details, as well as alternative and/or optional configurations, for microelectronic devices 100 have been omitted.\",\n \"Along those lines, various configurations, other than those specifically described, may be used in accordance with the following description.\",\n \"With reference to FIG.\",\n \"4, a block diagram of a top-down view of an exemplary microelectronic device 100 is illustratively depicted.\",\n \"In the example, there are two concentric rectangular rings of wire bond wires 110 forming an array 400.However, in other implementations, other numbers of wire bond wires 110, array shapes, array dimensions, and/or other patterns of wire bond wires 110 may be used to provide an array 400.Tips 126 extend above upper surface 132 of molding layer 103.At an interface between tips 126 and arms 127, there may be ledge 401.Ledges 401 may, though need not be, horizontal surfaces projecting from a wall of tips 126.In FIG.\",\n \"4, tips 126 have any of four orientations.\",\n \"However, these or other orientations of tips 126 may be used.\",\n \"With reference to FIG.\",\n \"5, a block diagram of a top-down view of an exemplary microelectronic device 100 is illustratively depicted, after tips 126 have been bent over.\",\n \"Tips 126 may be bent over to have wall surfaces respectively thereof in contact with or at least proximal to corresponding ledges 401.This bending of tips 126 may be by placing substrate 150 into a molding press, as described below in additional detail.\",\n \"Accordingly, during pressing, tips 126 may be bent over in any of a variety of orientations to provide bent over shapes for wire bond wires 110.Even though four orientations 501 through 504 are illustratively depicted by corresponding arrows for directions tips 126 point after bending, these and/or other orientations may be used.\",\n \"Furthermore, even though orientations 501 through 504 point inwardly with respect to array 400, namely an open space in the center of array 400, in another implementation outwardly pointing tips 126, or a combination of inwardly and outwardly pointing tips 126, may be used.\",\n \"FIG.\",\n \"6 is an enlarged side view depicting a pair of wire bond wires 110-1 and 110-2 attached to an upper surface 112 of carrier 102 prior to formation of molding layer 103.Prior to formation of molding layer 103, wire bond wires 110-1 and 110-2 may be attached to pads (not shown in this FIG.)\",\n \"along upper surface 112 via corresponding solder bases 135.Bases 125 of wire bond wires 110 may have j-like shapes, with bottoms thereof attached to upper surface 112 for forming wire bond wires 110.However, addition of solder bases 135 may provide additional support for enhanced reliability.\",\n \"Wire bond wire 110-2 may have approximately a 90 rotation with respect to orientation of wire bond wire 110-1.Tips 126 may have a generally horizontal surface, namely ledge 401, extending away from a facing wall surface 602 extending above a corresponding ledge 401.Again, ledges 401 may, though need not be, parallel with upper surface 112.Moreover, wall surfaces 602 may, though need not be, orthogonal to corresponding ledges 401.Furthermore, a wall surface 602 may, though need not be, orthogonal to a plane of upper surface 112.In this example, front facing wall surface 602, as well as back facing wall surface 605, of a tip 126 is slightly tapered to narrow tip 126 toward a top surface 601 thereof.\",\n \"Right and left side surfaces 604 of a tip 126 may both be tapered to widen tip 126 toward a top surface 601 thereof.\",\n \"Along those lines, tip 126 may have a “shovelhead-like” or “fishtail-like” shape with a trapezoidal front facing outline being wider at a distal end than a proximal end to provide such a widened tip 126.This “fishtail-like” shape may be formed when pinching and pulling off a feed wire used to for forming wire bond wires 110.Wire bond wires 110 may be shaped in the formation thereof to provide such a “shovelhead-like” shape with a trapezoidal front facing outline.\",\n \"While a shovelhead-like shape may be used to provide a greater surface area for attachment to an IMC structure, other shapes may likewise be used.\",\n \"A bending locus may generally be at or slightly above the intersection of ledge 401 and wall surface 602 for a tip 126, namely where a bending radius or bending moment may likely occur when tips 126 are pressed, as described below in additional detail.\",\n \"After pressing or bending of tips 126, such tips may have a bent over shape.\",\n \"Such bent over shapes provided by bent tips 126 may be used as anchors for solder or other IMC structures.\",\n \"FIGS.\",\n \"7-1 through 7-6 are a progression of block diagrams of a side cutaway view depicting an exemplary manufacturing process having operations 801 through 806 for forming a microelectronic device 100.FIGS.\",\n \"7-1 through 7-6 are further described with simultaneous reference to FIGS.\",\n \"1 through 6, where the example of FIG.\",\n \"6 is used in FIGS.\",\n \"7-1 through 7-6 for purposes of clarity by way of example and not limitation.\",\n \"At operation 801, a substrate 150 for microelectronic device 100 may be loaded or placed into a mold press 700.In this example, mold press 700 has a bottom platen 701 and top platen 702.In this example, bottom platen 701 is movable and top platen 702 is stationary.\",\n \"Optionally, top platen 702 may optionally include a fixed plate 703 slightly raised or offset from lower surface 706 to define an upper interior region 705 within a cavity 710 between platens 701 and 702.Substrate 150 may be loaded into such cavity 710.However, in other implementations, no upper interior region 705 may be present, as bent over tips may be pressed into an upper surface of a deformable mold assist film, as described below in additional detail.\",\n \"For purposes of clarity, known details of a mold press 700 are not described herein.\",\n \"After loading at 801, wire bond wires 110 of substrate 150 may extend from upper surface 112 toward an interior upper surface of mold press 700, namely a lower surface 704 of plate 703.A lower surface 111 of substrate 150 may be placed on an interior lower surface defining cavity 710, namely an interior upper surface 709 of lower platen 701 of mold press 700.At operation 802, a mold assist film (“mold film”) 711 may be indexed to a lower surface 706 of top platen 702.Along those lines, an upper surface 712 of a mold film 711 may be brought into contact or conformed to a portion of an interior upper surface, such as lower surface 706 for example, of mold press 700 without leaving a gap between another portion of such interior upper surface, such as interior upper surface 706 for example, of mold press 700 and upper surface 712 of mold film 711.Again, there is no optional gap for upper interior region 705.At operation 803, mold film 711 may be punctured with tips 126 by moving bottom platen 701 in an upward direction 719.Along those lines, a lower surface 721 and an upper surface 712 of mold film 711 may be punctured with tips 126 of wire bond wires 110 for having tips 126 to have tips 126 bent over into upper surface 712 of mold film 711 deforming such upper surface 712 of mold film 711 into an upper interior region thereof, as generally indicated by arrow 723.In this position, substrate 150 is moved by moving lower platen 701 in an upward direction to cause tips 126 to bend toward and onto upper surface 712, as generally indicated by arrow 723.Optionally, upper platen 702 may be moved in a downward direction as generally indicated by arrow 725.Moreover, optionally both upper platen 702 and lower platen 701 may be moved in directions 719 and 725, respectively.\",\n \"Furthermore, optionally a lateral movement 729 of upper platen 702 may be used to assist bending of tips 126 to reduce likelihood of cracking of wire bond wires 110 due to application of a compressive force.\",\n \"For uses of a lateral movement 729, tips 126 may all have a same orientation.\",\n \"At operation 804, tips 126 may continue to be pressed in a generally downward direction to provide shaped bent over tips 126 for wire bond wires 110.In this example, bent over tips 126 may be flattened between lower surface 706 of platen 702 and into a deformable upper surface 712 of mold film 711.This pressing of tips 126 may optionally include flattening or coining of tips 126.Furthermore, in this example, upper surface 712 of mold film 711 may be coplanar with ledges 401.However, in other examples, ledges 401 may extend to or just above upper surface 712, and thus tips 126 may be bent down for stopping on ledges 401 instead of being bent into upper surface 712.At operation 805, a molding material may be injected between upper surface 112 of substrate 150 and lower surface 721 of mold film 711 for molding layer 103.At operation 806, such molding material may be cured to form molding layer 103, and mold film 711 may be used to assist release of substrate 150 with such molding layer 103 from mold press 700.After formation and release of substrate 150 from mold press 700, including removal of mold film 711 from substrate 150, there may be a gap 730 between upper surface 132 of molding layer 103 and ledges 401, and this gap 730 may be associated with a partial thickness of mold film 711, namely a lower portion of a distance between surfaces 712 and 721 of mold film 711.Moreover, bent over tips 126 and uppermost portions of arms 127 corresponding to gap 730 may extend above upper surface 132.Thus, lower surfaces of shaped bent over tips 126 may be spaced-away from upper surface 132 of molding layer 103.In the above example, tips 126 were bent prior to forming a molding layer 103.However, in another implementation, tips 126 may be bent after forming a molding layer 103.In either order, tips 126 may be pressed down against an upper surface 712 of mold film 711, and such tips 126 may thus be bent over leaving a space between bottom surfaces of such tips 126 and upper surface 132 of molding layer 103 after removal of mold film 711.Again, tips 126 may be shaped prior to loading into mold press 700, and such shaped tips 126 may be to provide bending locations for bending.\",\n \"The above process may generally be thought of as a pressing of tips prior to molding, namely a pressing-before-molding process.\",\n \"The following description may generally be thought of as a pressing-after-molding process.\",\n \"FIGS.\",\n \"8-1 through 8-4 are a progression of block diagrams of a side cutaway view depicting an exemplary manufacturing process having operations 903 through 906 for forming a microelectronic device 100.FIGS.\",\n \"8-1 through 8-4 are further described with simultaneous reference to FIGS.\",\n \"1 through 7-6, where the example of FIG.\",\n \"6 is used in FIGS.\",\n \"8-1 through 8-4 for purposes of clarity by way of example and not limitation.\",\n \"Prior to operation 903, operations 801 and 802 may be performed as previously described.\",\n \"However, in operation 802 a thicker mold film 711 is indexed to a lower surface of upper platen 702.In the above example of a thinner mold film 711, such mold film thickness may be in a range of approximately 10 to 50 microns, and in the example of a thicker mold film 711, such mold film thickness may be in a range of approximately 50 to 150 microns.\",\n \"In other implementations, these or other ranges may be used.\",\n \"For example, for anchors using bent over tips 126, longer tips may be used and correspondingly thicker molding film to provide more surface area for anchoring at the expense of a larger pitch.\",\n \"Bent over tips 126 may be used as anchors for soldering for example.\",\n \"At operation 903, this thicker mold film 711 may be punctured with tips 126 by moving either or both lower platen 701 and upper platen 702, as previously described.\",\n \"In this example, lower platen 701 is moved in an upward direction 719.Along those lines, a lower surface 721 and an upper surface 712 of mold film 711 may be punctured with tips 126 of wire bond wires 110 for having at least a substantial portion, if not all, of tips 126 extend above lower surface 721 of mold film 711 into an interior region of mold film 711, namely having such substantial portion of such tips 126 located in mold film 711 between upper surface 712 and lower surface 721 of such mold film 711 prior to molding.\",\n \"Optionally, uppermost portions of arms 127 may likewise extend into mold film 711 prior to molding.\",\n \"In this example, lower surface 721 is generally co-planar with ledges 401; however, ledges 401 may be above, equal with, and/or below lower surface 721 in this or other implementations.\",\n \"At operation 904, a molding material may be injected between upper surface 112 of substrate 150 and lower surface 721 of mold film 711 for molding layer 103.At operation 905, such molding material may be cured to form molding layer 103, and mold film 711 may be used to assist release of substrate 150 from such molding layer 103 and then such mold film 711 may be removed from mold press 700.After formation of molding layer 103 and removal of mold film 711 from substrate 150 at operation 905, upper surface 132 of molding layer 103 and ledges 401 may optionally be co-planar, as in this example.\",\n \"However, as previously indicated, such ledges 401 may be above or below upper surface 132.At 906, substrate 150 may be moved by having lower platen 701 moved in an upward direction 719 to cause tips 126 to be pressed into lower surface 706 of upper platen 702 to bend such tips 126 toward upper surface 132, as generally indicated by arrow 723 in FIG.\",\n \"8-3.At operation 906, tips 126 may be pressed down against an upper surface 132 of molding layer 103, and such tips 126 may thus be bent over.\",\n \"After bending, tips 126 may optionally be against upper surface 132 of molding layer 103, which optionally may leave no readily perceivable gap between bottom surfaces of such tips 126 and upper surface 132 of molding layer 103.Again, tips 126 may be shaped prior to loading into mold press 700, and such shaped tips 126 may be to provide bending locations.\",\n \"Pressing of such tips 126 may optionally flatten such tips between upper surface 132 of molding layer 103 and lower surface 706 of upper platen 702.Again, though lower platen 701 may be raised for this pressing, either or both platens may be moved for pressing, as described elsewhere herein, to provide bent over tips 126.Such pressing may further flatten tips, which may spread out such tips 126.After such pressing operation at 906, substrate 150 may be removed from mold press 700.By pressing after molding, arms 127 may have some protection from compressive stresses by molding layer 103.As previously described an uppermost portion of an arm 127 may be embedded in mold film 711.Along those lines, FIG.\",\n \"9 is a block diagram of a side cutaway view depicting another exemplary substrate 150 after a manufacturing process having operations for forming a microelectronic device as described above but with an uppermost portion 911 of an arm 127 of wire bond wires 110 embedded in mold film 711.Such uppermost portions 911 of arms 127 of wire bond wires 110 may be adjacent and integral with lowermost portions of such tips 126.Along those lines, a pressing after molding may be used to bend tips 126 over to have an uppermost portion of such tips bent down to be at least proximate to or touching upper surface 132.Such bent over tips 126 may define an underside through region or air gap 913, such as for a hook-like structure or shape for example.\",\n \"Optionally, a solder ball 914 may be placed over tips 126, and such bent over tips 126 may be used to anchor such solder balls 914, namely solder anchors which may include completely or partially filing such air gaps 913 with solder to assist in anchoring.\",\n \"As previously described an uppermost portion of an arm 127 may be embedded in mold film 711.Along those lines, FIGS.\",\n \"10-1 and 10-2 are block diagrams of a side cutaway view depicting yet another exemplary substrate 150 after another manufacturing process having operations for forming a microelectronic device as described above but with an upper portion 912, longer than an uppermost portion 911, of an arm 127 of wire bond wires 110 embedded in mold film 711.Such upper portions 912 of arms 127 of wire bond wires 110 may include such uppermost portions 911 and thus may be adjacent and integral with lowermost portions of such tips 126.Along those lines, a pressing after molding may be used to bend tips 126 over to have an uppermost portion of such tips bent down to be at least proximate to or touching upper surface 132.Such bent over tips 126 may define an underside through region 913, such as for a hook-like structure or shape for example.\",\n \"Optionally, a solder ball 914 may be placed over tips 126, and such bent over tips 126 may be used to anchor such solder balls 914, including completely or partially filing such air gaps 913 to assist in anchoring.\",\n \"While the foregoing describes exemplary embodiment(s) in accordance with one or more aspects of the invention, other and further embodiment(s) in accordance with the one or more aspects of the invention may be devised without departing from the scope thereof, which is determined by the claim(s) that follow and equivalents thereof.\",\n \"Claim(s) listing steps do not imply any order of the steps.\",\n \"Trademarks are the property of their respective owners.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875842"}}},{"rowIdx":4494995,"cells":{"text":{"kind":"list like","value":[["AUTOMATED UN-MANNED AIR TRAFFIC CONTROL SYSTEM","A low flying unmanned vehicle is disclosed that may be able to determine whether a collision is possible and may take evasive action in response to the possible collision.","The vehicle may wirelessly communicate and may use a standard protocol such that a variety of additional objects may be taken into account when determining the possible collision risk."],["1-43.","(canceled) 44.An apparatus for in-flight collision avoidance in independently-operating unmanned aerial vehicles, the apparatus comprising: a processor and a memory, wherein the memory stores a set of machine-operable instructions operable, when executed by the processor, to: determine first flight operational data at a first computing system, wherein the first flight operational data corresponds to a first planned operation of a first unmanned aerial vehicle over a first area; receive second flight operational data at the first computing system from a second computing system, wherein the second computing system is remote from a second aerial vehicle, the second flight operational data corresponds to the second aerial vehicle, the second flight operational data for controlling the second aerial vehicle over a second area adjacent to the first area; and send a notification to the first computing system upon determining the second flight operational data crosses a threshold with respect to the first flight operational data.","45.The apparatus of claim 44, wherein the memory stores further machine-operable instructions that are operable, when executed by the processor, to allow modification of the first flight operational data at the first computing system based on the notification.","46.The apparatus of claim 44, wherein the memory stores further machine-operable instructions that are operable, when executed by the processor, to display the notification within a user interface of the first computing system.","47.The apparatus of claim 45, wherein the memory stores further machine-operable instructions that are operable, when executed by the processor, to wirelessly communicate the first flight operational data, a modified first flight operational data, and the second flight operational data to a remote collection site.","48.The apparatus of claim 47, wherein the memory stores further machine-operable instructions that are operable to wirelessly communicate the first flight operational data, the modified first flight operational data, and the second flight operational data in an ADS-b communication format when an altitude of the first unmanned aerial vehicle is equal to or greater than 1500 feet and in a cellular communication format when the altitude of the first unmanned aerial vehicle is less than 1500 feet.","49.The apparatus of claim 47, wherein the memory stores further machine-operable instructions that are operable, when executed by the processor, to determine relevant object data at the second computing device, wherein the relevant object data is within the second area and over the threshold.","50.The apparatus of claim 49, wherein the second flight operational data wirelessly communicated to the remote collection site includes the relevant object data.","51.The apparatus of claim 44, wherein the second flight operational data further corresponds to a manned aerial vehicle.","52.A system for in-flight collision avoidance in independently-operating unmanned aerial vehicles, the system comprising: a first computing system for operation of a first unmanned aerial vehicle over a first area, wherein the first computing system includes a first processor, a first memory, and a first communication device for sending and receiving wireless communication, the first memory includes, for the first unmanned aerial vehicle, first flight operational data corresponding to the first unmanned aerial vehicle within the first area; and a second computing system for operation of a second aerial vehicle over a second area, wherein the second area is adjacent to the first area, the second computing system is remote from the second aerial vehicle and includes a second processor, a second memory, and a second communication device for sending and receiving wireless communication, the second memory includes, for the second unmanned aerial vehicle, second flight operational data corresponding to the second unmanned aerial vehicle and for controlling the second aerial vehicle within the second area; wherein the first memory further stores a set of machine-operable instructions operable, when executed by the first processor, to: receive the second flight operational data at the first computing system; and send a notification to the first computing system upon determining the second flight operational data crosses a threshold with respect to the first flight operational data.","53.The system of claim 52, wherein the first memory stores further machine-operable instructions that are operable, when executed by the first processor, to allow modification of the first flight operational data at the first computing system based on the notification.","54.The system of claim 52, wherein the first memory stores further machine-operable instructions that are operable, when executed by the processor, to display the notification within a user interface of the first computing system.","55.The system of claim 53, wherein the second memory stores further machine-operable instructions that are operable, when executed by the second processor, to wirelessly communicate the first flight operational data, a modified first flight operational data, and the second flight operational data to a remote collection site.","56.The system of claim 55, wherein the second memory stores further machine-operable instructions that are operable, when executed by the second processor, to wirelessly communicate the first flight operational data, the modified first flight operational data, and the second flight operational data in an ADS-b communication format when an altitude of the first unmanned aerial vehicle is equal to or greater than 1500 feet and in a cellular communication format when the altitude of the first unmanned aerial vehicle is less than 1500 feet.","57.The system of claim 55, wherein the second memory stores further machine-operable instructions that are operable, when executed by the second processor, to determine relevant object data at the second computing device, wherein the relevant object data is within the second area and over the threshold.","58.The system of claim 57, wherein the second flight operational data wirelessly communicated to the remote collection site includes the relevant object data.","59.The system of claim 52, wherein the second flight operational data further corresponds to a manned aerial vehicle.","60.A computer-implemented method for in-flight collision avoidance in independently-operating aerial vehicles, the method comprising: determining first flight operational data at a first computing system, wherein the first flight operational data corresponds to a first planned operation of a first unmanned aerial vehicle over a first area; receiving second flight operational data at the first computing system from a second computing system, wherein the second computing system is remote from a second aerial vehicle, the second flight operational data corresponds to the second aerial vehicle, the second flight operational data for controlling the second aerial vehicle over a second area adjacent to the first area; and sending a notification to the first computing system upon determining the second flight operational data crosses a threshold with respect to the first flight operational data.","61.The computer-implemented method of claim 58, further comprising allowing modification of the first flight operational data at the first computing system based on the notification.","62.The computer-implemented method of claim 60, further comprising displaying the notification within a user interface of the first computing system.","63.The computer-implemented method of claim 61, further comprising wirelessly communicating the first flight operational data, a modified first flight operational data, and the second flight operational data to a remote collection site.","64.The computer-implemented method of claim 63, further comprising wirelessly communicating the first flight operational data, the modified first flight operational data, and the second flight operational data in an ADS-b communication format when an altitude of the first unmanned aerial vehicle is equal to or greater than 1500 feet and in a cellular communication format when the altitude of the first unmanned aerial vehicle is less than 1500 feet.","65.The computer-implemented method of claim 63, further comprising determining relevant object data at the second computing device, wherein the relevant object data is within the second area and over the threshold.","66.The computer-implemented method of claim 65, wherein the second flight operational data wirelessly communicated to the remote collection site includes the relevant object data.","67.The computer-implemented method of claim 60, wherein the second flight operational data further corresponds to a manned aerial vehicle."],["<SOH> BACKGROUND <EOH>Low flying unmanned vehicles have become more common and have more and more uses.","As low flying vehicles become more common, the likelihood of collisions with trees, commercial airliners, buildings, and other unmanned vehicles becomes more likely.","Trying to avoid collisions becomes more difficult as vehicles do not communicate with each other or FAA air traffic controllers and may take evasive action which made make collisions more probable rather than less likely."],["<SOH> SUMMARY <EOH>A low flying unmanned vehicle is disclosed that may be able to determine whether a collision is possible and may take evasive action in response to the possible collision.","The vehicle may wirelessly communicate (e.g., using cellular, satellite, WiFi, WiMax, etc.","communication) and may use a standard protocol such that a variety of additional objects may be taken into account when determining the possible collision risk.","In operation, the vehicle may receive flight data from one or more objects, may determine the location of the vehicles at a plurality of points in time in the future and may determine if a collision is probable.","If a collision is probable, evasive data may be communicated to the vehicle.","The flight data may be from a variety of vehicles, including commercial aircraft and other unmanned vehicles."],["CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of, and priority to, U.S. Non-Provisional application Ser.","No.","14/847,910, filed Sep. 8, 2015, titled “Automated Un-Manned Air Traffic Control System,” which claims benefit of, and priority to, U.S. Prov.","App.","Ser.","No.","62/046,619, filed Sep. 5, 2014, titled “Low Flying Collision Detection and Avoidance,” and U.S. Prov.","App.","Ser.","No.","62/139,272, filed Mar.","27, 2015, titled “Low Flying Collision Detection, Avoidance and Return System”, the content of each of which is incorporated herein by reference in its entirety.","BACKGROUND Low flying unmanned vehicles have become more common and have more and more uses.","As low flying vehicles become more common, the likelihood of collisions with trees, commercial airliners, buildings, and other unmanned vehicles becomes more likely.","Trying to avoid collisions becomes more difficult as vehicles do not communicate with each other or FAA air traffic controllers and may take evasive action which made make collisions more probable rather than less likely.","SUMMARY A low flying unmanned vehicle is disclosed that may be able to determine whether a collision is possible and may take evasive action in response to the possible collision.","The vehicle may wirelessly communicate (e.g., using cellular, satellite, WiFi, WiMax, etc.","communication) and may use a standard protocol such that a variety of additional objects may be taken into account when determining the possible collision risk.","In operation, the vehicle may receive flight data from one or more objects, may determine the location of the vehicles at a plurality of points in time in the future and may determine if a collision is probable.","If a collision is probable, evasive data may be communicated to the vehicle.","The flight data may be from a variety of vehicles, including commercial aircraft and other unmanned vehicles.","BRIEF DESCRIPTION OF THE DRAWINGS FIG.","1 may illustrate a method of information reporting and avoidance for a low flying unmanned vehicle; FIG.","2a may illustrate that a vehicle may have a processor and related computing equipment to control the path and course of the vehicle; FIG.","2b may illustrate that the vehicle may have a processor and related computing equipment to control the path and course of the vehicle; FIG.","3 may illustrate that the processor and memory may be mounted on a circuit board and the circuit board may be a load bearing member of the vehicle; FIG.","4a may illustrate a sample outbound packet; FIG.","4b may illustrate a sample inbound packet; FIG.","5a may illustrate a method of collecting and communicating additional data; FIG.","5b may illustrate equipment that may be used to collect the additional data; FIG.","6 may illustrate one way to determine whether an object is a relevant object worthy of reporting to a central collection point; FIG.","7 may illustrate a method of adjusting operational data of the vehicle; FIG.","8 may illustrate flight paths of vehicles; FIG.","9a may illustrate several aspects of a system; FIG.","9b may illustrate a backend of the system; FIG.","9c may illustrate elements of a user interface to the system; FIG.","10 may illustrate a device with a processor; and FIG.","11 may illustrate a user interface.","DETAILED DESCRIPTION At a high level, a low flying unmanned vehicle 100 is disclosed that may be able to determine whether a collision is possible and may take evasive action in response to the possible collision.","The vehicle 100 may wirelessly communicate (e.g., using cellular, satellite, WiFi, WiMax, etc.","communication) and may use a standard protocol such that a variety of additional objects 111 may be taken into account when determining the possible collision risk.","FIG.","1 may illustrate a method of information reporting and avoidance for a low flying unmanned vehicle 100.The vehicle 100 may be an airplane or flying vehicle 100 which is too small to contain an adult human but may be small and light enough to be carried by an adult human.","Further, the vehicle 100 may be of a size that it might fit into a standard van or the truck of a standard car.","In addition, the device may be modular such that parts of the device may be easily removed and reattached.","For example, the wings may be connected and disconnected in a manner that the wings are securely attached during flight but may be disconnected during travel to and from a location to make transporting the device easier.","Similarly, the tail or computing system may be removed to allow easier transportation.","Referring briefly to FIG.","3, the vehicle 100 may have a propulsion device such as a gas motor or an electric motor 305 which may be connected to a propeller 315.The vehicle 100 also may have height adjustments through adjustable wings 325 and directional adjustments through a rudder 335 on a rear stabilizer 345.It may have a payload bay 355 that may be able to accept a variety of different sensors such as cameras and video devices.","It may be able to land and, in some embodiments, the propellers may rotate to allow for vertical take-off and landing.","In other embodiments, the vehicle 100 may have landing gear which may be retractable or permanent.","A sample vehicle 100 may be described in U.S. patent application Ser.","No.","13/892,358 filed May 13, 2013, which is incorporated by reference in all aspects.","By low flying, the vehicle 100 may be designed to stay below 1,000 feet for example and not limitation.","The vehicle 100 may be designed to stay below the flight path of traditional aircraft in most situations.","In some embodiments, the vehicle 100 may fly higher depending on the purpose of the flight, the surrounding conditions and other environmental factors.","The vehicle 100 may be unmanned.","It may be flown be remote control or it may have intelligence and may fly according to a programmed flight path.","In addition, it may execute a combination of a preprogrammed flight path and remote control.","Further, in the described embodiment, the vehicle 100 may have intelligence to receive data and adjust its flight path in response to the received data.","As illustrated in FIG.","2, the vehicle 100 may have a processor 202 and related computing equipment to control the path and course of the vehicle.","The processor 202 may be physically configured to execute instructions that may be stored in a non-transitory memory.","As illustrated in FIG.","3, the processor 202 and memory may be mounted on a circuit board 365 and the circuit board 365 may be a load bearing member of the vehicle.","Referring again to FIG.","1, at block 110, flight operational data for the vehicle 100 may be determined.","Logically, a flying vehicle 100 may collect a significant amount of flight operational data.","In some embodiments, the flight operation data 250 may include a vehicle identifier, a present vehicle position, a present vehicle airspeed and a present vehicle heading.","Some sample operational data may be illustrated in FIG.","2b.","The operational data 250 described is merely exemplary and is not meant to be limiting.","The vehicle identifier may be a unique code used to identify the vehicle 100.Traditional aviation vehicle 100 may have unique identifiers such as serial numbers and serial numbers may also be used as part of the vehicle identifier.","In addition, vehicles often have a code name applied to them such as TWA 1456 and a similar naming function may be used to name the vehicles discussed herein.","Further, other combinations and naming conventions may be possible and are contemplated.","A present vehicle 100 position may be a location in space and may be reported using GPS coordinates.","In other embodiments, an aerospace coordinate system may be used such as the Aerospace Blockset coordinate system, other x, y, z coordinate systems such as north east down coordinates, Earth-centered inertial systems, systems used by AC3D systems, etc.","In yet another embodiment, the vehicle 100 position may be reported in relation to a set point such as a radio tower, a building, etc.","The present airspeed of vehicle 100 may simply be an indication of velocity such as in miles per hour.","In another embodiment, the airspeed may also include other measures such as kilometers per hour or meters per minute.","The present heading of vehicle 100 may indicate a heading or direction of the vehicle.","The heading may be in terms of degree off north or degrees from a fixed location.","In some embodiments, the heading may be user defined.","In some embodiments, there may be additional flight operational data 505 (FIG.","5b).","The additional data 505 may be communicated more infrequently, such as at the start of a flight or once a time period, such as once every ten minutes.","In other embodiments, the additional data 505 may be communicated just as frequently as the operational flight 250 data already described.","Some of the additional data 505 may be communicated more frequently than other additional data 505.The additional flight data 505 may include planned operation data, where the planned operation data may include a planned vehicle 100 position, a planned vehicle 100 airspeed and a planned heading.","Logically, the planned additional operational data may be for a limited time horizon as trying to communicate all future planned data may be difficult.","In addition, the additional data 505 may include an item containing planned waypoints.","Further, the planned route as it is stored onboard the aircraft may be viewed by an operator or remotely on a computer in communication with the vehicle 100 or the central storage device.","The additional operational data 505 may also include a pilot identifier.","The pilot may be the person that is monitoring the flight, may be the person that programmed the flight or may be the owner of the vehicle.","The pilot identifier may be a name, a number, an alpha-numeric combination or other code that may be used to identify a person responsible for the flight.","The additional operational data 505 may also include a flight plan identifier.","The flight plan identifier may be a code that is used to identify projected path of a flight.","The code may be unique for a time period and the other intended operational details of the flight may be accessed by accessing a database using the flight plan.","The additional operational data 505 may also include a current latitude and longitude of the device.","The latitude and longitude may be used to quickly identify the location of the device.","Further, the additional operational data 505 may include the present altitude of the device, a rate of climb or decent of the device, a roll, pitch and yaw of the device.","Such additional operational data 505 may be used to more finely track the location of the device and where the device will be in a point in time in the future.","Again, not all the additional operational data 505 may be communicated at all times and some of the additional operational data 505 may be communicated more often than other additional operational data 505.Finally, the additional operational data 505 may include any emergency status, an emergency type, an emergency description, whether an evasive maneuver has been performed and a packet checksum which may be used to ensure that a communication has been accurately communicated and accurately received.","Referring again to FIG.","1, at block 120 an outbound data packet may be created that may include the desired operational data.","The format of the outbound packet may follow a common pattern and the pattern may be predetermined.","In some embodiments, the outbound packet may be in the form of an application programming interface (API) that may be expected by a central collection service.","A sample outbound packet may be illustrated in FIG.","4a and may be described below.","Sample Packet (OutBound) 1.Randomized Packet ID (410) 2.Date/Time (420) 3.Flight ID (per flight identifier) (430) 4.Pilot Information (440) a.","Name (441) b.","Contact info (442) c. Credentials (443) 5.Aircraft Information (450) a.","Make (451) b.","Model (452) c. Weight (453) d. Category (454) e. Tail Number (455) 6.Flight Plan information (460) a.","Flight plan ID (461) b.","Planned altitudes (462) c. Planed flight path (463) 7.Live Telemetry Information (470) a.","Location (471) b.","Speed (472) c. Heading (473) d. Altitude (474) 8.Additional Information (480) a.","May contain a number of pre-defined optional parameters (Emergency information, etc.",".",".",". )","9.Checksum (490) A sample inbound packet may be illustrated in FIG.","4b and is described below.","1.Randomized Packet ID (4010) 2.Date/Time (4020) 3.Targeted flight number (4030) 4.Targeted tail number (4040) 5.Potential air vehicle obstacles (sent in array for scalability) (4050) a.","Location (4051) b.","Speed (4052) c. Altitude (4053) d. Heading (4054) e. Climb/decent rate (4055) f. Aircraft classification (4056) 6.Potential ground obstacle (sent in array for scalability) (4060) a.","Location (4061) b. Altitude (4062) 7.ATC instruction Information (4070) a.","Land (4071) b. Terminate Flight (4072) c. Adjust altitude (4073) 8.Additional Information (4080) a.","May contain a number of pre-defined optional parameters (Emergency information, etc.",".",".",". )","9.Checksum (4090) The length and format of the various elements of the inbound and outbound packets may be many and varied.","For example, element 440 may be an array of data or may be a given set of elements.","In addition, the order of the data elements may vary.","Further, not every packet may be the same format as an emergency packet may be short while a change of course packet may be large.","Of course, the outbound data packets may be encrypted.","The encryption may take on a variety of forms and may include key exchange encryption.","In some embodiments, the outbound packet may be formatted such that traditional aviation services may be able to receive and parse the packets if desired.","The outbound packet may contain additional information to indicate that the vehicle 100 is a low flying unmanned vehicle 100.In some embodiments, the vehicle 100 may have one or more sensors 375 that may collect sensor data.","FIG.","5a may illustrate a method of collecting and communicating additional data and FIG.","5b may illustrate the equipment that may be used to collect the sensor data 385.Similar to the operational data, the sensor data 385 may be collected at block 500, stored in a memory at block 510, packaged in a way to be easily communicated at block 520 and communicated to a center collection point at block 530.Sensor data 385 may be a variety of data.","As explained in U.S. patent application Ser.","No.","13/892,358, which is incorporated by reference, the sensors 375 may be plugged and exchanged into the circuit board 375 and a plurality of sensors 375 may be plugged into the same circuit board 365 at the same time.","The sensor 375 may be placed in the payload bay 355 or in other locations as needed.","Some sample sensors 375 (and not limitations) include traditional image sensors, sensors of ranges outside human vision such as infrared, sound sensors, light sensors, LIDAR sensors, ultrasound sensors, etc.","In some embodiments, the sensor data 385 may be communicated in the same format as the operational data 250.In other embodiments, the sensor data 385 may be communicated in a separate format than the operational data.","Logically, traditional air traffic networks may have little or no use for sensor data 385 meaning such data may be communicated in a different frequency in a different manner than operational data 250 to make it easier for the sensor data 385 to be ignored.","The sensor data 385 may be analyzed for relevant objects and the relevant objects may be communicated to a central collection point.","The relevant objects may be determined in a variety of ways.","In one embodiment, relevant objects may be determined to be over a threshold of relevance.","FIG.","6 may illustrate one way to determine whether an object is relevant object worthy of reporting to the central collection point and FIG.","8 may illustrate a plurality of objects.","At block 600, a location for the low flying unmanned vehicle 100 may be determined in a first time period.","At block 610, a radius 705 around the location of the low flying unmanned vehicle 100 in the first time period may be determined.","The radius 705 may vary depending on a variety of factors.","In some embodiments, the radius 705 may be greater if the vehicle 100 is traveling at a high rate of speed such that the vehicle 100 may encounter other vehicles in a short period of time.","Similarly, the radius 705 may be greater if other nearby objects 110 are moving at high rates of speed such that the vehicle 100 may encounter other vehicles 110 in a short period of time.","At block 620, it may be determined whether any additional vehicles 110 will be within the radius 705 around the location of the flying unmanned vehicle 100 in the first time period based on an intended operational data of the additional vehicles 110.For example, the additional time period may be 60 seconds.","Below is a pseudo code example of the vehicle 100 determining whether any additional vehicles will be within the radius 705.In an example, the vehicle 100 may search for nearby objects, referred to as “aggressors”, and list the aggressors in a table as set forth in the below pseudo code.","Receive Possible Aggressor Table getNearObjects( ) The vehicle 100 may use radar, GPS, or any other technology to locate vehicles that are within a predetermined distance (e.g., within 10 miles).","The vehicle 100 may perform a process similar to the below pseudo code to determine whether any of the identified nearby objects may be within the radius 705 in a particular time period.","For example, the vehicle 100 may determine the current location of itself relative to each object, determine a radial distance in latitude and longitude between itself and each object, and use the radial distance to determine a current distance between itself and each object considering the curvature of the earth.","Receive Possible Aggressor Table getNearObjects( ) For each Object in getNearObjects Data Input currentObject.Latitude=35.882234 currentObject.Longitude=−78.788222 currentObject.Altitude=30 # meters currentObject.Speed=16 # meters/sec currentObject.Track=93.6 currentObject.ID=4923 # Identifier assigned to Vehicle 100 AggressorObject.Latitude=35.866864 AggressorObject.Longitude=−78.799637 AggressorObject.Altitude=50 # meters AggressorObject.Speed=18 # meters/sec AggressorObject.Track=103.59 AggressorObject.ID=13830 # coded UAV ID uavFenceRadius.Critical=1437.38 # meters uavFenceRadius.Warning=2046.72 # meters Calculate_Distance (currentObject, AggressorObject) constR=6371000.0 # radius of earth in meters phi_1=radians(currentObject.Latitude) phi_2=radians(AggressorObject.Latitude) delta_phi=radians(AggressorObject.Latitude−currentObject.Latitude) delta_lambda=radians(AggressorObject.Longitude−currentObject.Longitude) The vehicle 100 may use delta_phi and delta_lambda to determine a distance between itself and each vehicle based on the curvature of the earth.","This distance is referenced as “ResultRange” in the below pseudo code.","At block 630, in response to the determination that the additional vehicles 110 will be within the radius around the location of the low flying unmanned vehicle 100 in the first time period based on the intended path of the additional vehicles 110, the relevant object may be determined as being over the threshold.","Below is a pseudo code example for determining whether an object is determined to be over the threshold.","For example, different thresholds may be set up based on how near an additional vehicle 110 is to vehicle 100.The different thresholds may be used by vehicle 100 to determine whether to issue a warning or whether to take evasive maneuvers.","Evasive maneuvers may include the vehicle 100 determining a safe location and causing the vehicle to move toward the safe location.","Check_Aggressor (ResultRange, uavFenceRadius) If ResultRange<uavFenceRadius.Critical safeLocation.Latitude=getSafeLocation.Latitude safeLocation.Longitude=getSafeLocation.Longtitude logOverrideEnabled( ) notifyOverrideEnabled( ) overrideToSafeLocation( ) If ResultRange<uavFenceRadius.Warning logOverrideWarning( ) notifyOverrideEnabled( ) At block 640, flight operational data 250 may be adjusted on the vehicle 100 based on the relevant objects 110.FIG.","7 may illustrate a method of adjusting the operational data of the vehicle.","At block 700, the flight path 805 of the additional vehicles 110 may be determined.","The flight path may be determined in a variety of ways.","In one embodiment, the operational data 250 may be analyzed to determine the location of a first additional vehicle 110 at a plurality of times in the future.","Similarly, the location of all the additional vehicles 110 at a plurality of times in the future may be determined.","The locations may be analyzed to determine if the additional vehicles 110 may be within the radius 705 of the unmanned vehicle 100 at a point in the future.","In some embodiments, other vehicles 110 may not be broadcasting their operational data 250.The sensors 375 on the vehicle 100 may observe the other vehicle 110.The locations and flight operation data 250 may be determined for the other vehicles 110.For example, the distance travel over a period of time may be used to determine a speed of the additional vehicle 110.Similarly, the height of the additional vehicle 110 and the changes in direction may be observed and changes may be determined to create a flight path 805 for the observed additional vehicle 110 at points in time in the future assuming the flight path stays the same.","Below is a pseudo code example for using sensors 375 to observe the other vehicle 110.The vehicle 100 may perform an algorithm similar to the pseudo code provided above, but instead may use sensor data to determine a current latitude, longitude, speed, and track for one or more additional vehicles 110.CheckUAVSensorArray getUAVSensorArray( ) For each Object in getUAVSensorArray SendUAVSensorArrayo Data Input currentObject.Latitude=35.882234 currentObject.Longitude=−78.788222 currentObject.Altitude=30 # meters currentObject.Speed=16 # meters/sec currentObject.Track=93.6 currentObject.ID=4923 # Identifier assigned to vehicle 100 AggressorObject.Latitude=35.866864 AggressorObject.Longitude=−78.799637 AggressorObject.Altitude=50 # meters AggressorObject.Speed=18 # meters/sec AggressorObject.Track=103.59 AgressorObject.ID=13830 # coded UAV ID uavFenceRadius.Critical=1437.38 # meters uavFenceRadius.Warning=2046.72 # meters Calculate_Distance (currentObject, uavFenceObject) constR=6371000.0 # meters phi_1=radians(currentObject.Latitude) phi_2=radians(AggressorObject.Latitude) delta_phi=radians(AggressorObject.Latitude−currentObject.Latitude) delta_lambda=radians(AggressorObject.Longitude−currentObject.Longitude) Similar to the example provided above, the vehicle 100 may use delta_phi and delta_lambda to determine a distance between itself and each additional vehicle 110 based on the curvature of the earth.","The vehicle 100 may use the calculated distance to determine whether to issue a warning and/or to determine that a distance is critical potentially requiring vehicle 100 to initiate evasive maneuvers.","Check_Aggressor (ResultRange, uavFenceRadius) If ResultRange<uavFenceRadius.Critical safeLocation.Latitude=getSafeLocation.Latitude safeLocation.Longitude=getSafeLocation.Longtitude logOverrideEnabled( ) notifyOverrideEnabled( ) overrideToSafeLocation( ) If ResultRange<uavFenceRadius.Warning logOverrideWarning( ) notifyOverrideEnabled( ) In some embodiments, operational data 250 may include fixed object data on fixed objects like radio antennas, large buildings, tall buildings, trees, power lines, mountains, cliffs, waypoints, etc.","The fixed object data may be known and may be communicated to the vehicle 100 from the central collection point 545.For example, small aircraft often use maps of known fixed objects to aid in navigation and these maps may be converted into digital data which may be useable by the vehicle 100.The communication may occur during set up for a flight based on an intended flight plan or may be communicated to the vehicle 100 in real time during the flight or traveling activity.","In any of the embodiments, the fixed object data may be used to assist in not interfering with any fixed objects.","Below is a pseudo code example of loading data on a geofence, which may correspond to a particular geographic location of a particular fixed object, for creating an intended flight plan to avoid fixed objects.","Receive GeoFence Table LoadGeoFence( ) For each Object in LoadGeoFence Data Input currentObject.Latitude=35.882234 currentObject.Longitude=−78.788222 currentObject.Altitude=30 # meters currentObject.Speed=16 # meters/sec currentObject.Track=93.6 currentObject.ID=4923 # Identifier assigned to vehicle 100 GeoFenceObject.Latitude=35.866864 GeoFenceObject.Longitude=−78.799637 GeoFenceObject.Height=20 # meters GeoFenceObject.ID=000483 # coded Airport code or Other Object geoFenceRadius.Critical=4437.38 # meters geoFenceRadius.Warning=5046.72 # meters Calculate_Distance (currentObject, GeoFenceObject) constR=6371000.0 # meters phi_1=radians(currentObject.Latitude) phi_2=radians(GeoFenceObject.Latitude) delta_phi=radians(GeoFenceObject.Latitude−currentObject.Latitude) delta_lambda=radians(GeoFenceObject.Longitude−currentObject.Longitude) Similar to the examples provided above, the vehicle 100 may use delta_phi and delta_lambda to determine a distance between itself and each fixed object based on the curvature of the earth.","The vehicle 100 may use the calculated distance to determine whether to issue a warning and/or to determine that a distance is critical potentially requiring vehicle 100 to initiate evasive maneuvers to avoid one or more objects.","Check_GeoFence (ResultRange, geoFenceRadius) If ResultRange<geoFenceRadius.Critical safeLocation.Latitude=getSafeLocation.Latitude safeLocation.Longitude=getSafeLocation.Longtitude logOverrideEnabled( ) notifyOverrideEnabled( ) overrideToSafeLocation( ) If ResultRange<geoFenceRadius.Warning logOverrideWarning( ) notifyOverrideEnabled( ) In addition, the vehicle 100 may use sensors 375 to sense fixed objects, including in areas where fixed objects have not been determined previously.","The data on the location, height and width of the fixed objects may be determined and may be communicated to the central collection point 545 where it may be added to the fixed object data.","In addition, the collected fixed object data may be used to verify the fixed object data store at the central server 545.Below is a pseudo code example where sensors 375 sense fixed objects for collision avoidance.","CheckGeoSensorArray getGeoSensorArray( ) For each Object in getGeoSensorArray SendGeoSensorArray( ) Data Input currentObject.Latitude=35.882234 currentObject.Longitude=−78.788222 currentObject.Altitude=30 # meters currentObject.Speed=16 # meters/sec currentObject.Track=93.6 currentObject.ID=4923 # Identifier assigned to vehicle 100 GeoFenceObject.Latitude=35.866864 GeoFenceObject.Longitude=−78.799637 GeoFenceObject.Height=22 # meters GeoFenceObject.ID=000483 # coded Airport code or Other Object geoFenceRadius.Critical=1437.38 # meters geoFenceRadius.Warning=2046.72 # meters Calculate_Distance (currentObject, GeoFenceObject) constR=6371000.0 # meters phi_1=radians(currentObject.Latitude) phi_2=radians(GeoFenceObject.Latitude) delta_phi=radians(GeoFenceObject.Latitude−currentObject.Latitude) delta_lambda=radians(GeoFenceObject.Longitude−currentObject.Longitude) Similar to the examples provided above, the vehicle 100 may use delta_phi and delta_lambda to determine a distance between itself and each sensed fixed object based on the curvature of the earth.","The vehicle 100 may use the calculated distance to determine whether to issue a warning and/or to determine that a distance is critical potentially requiring vehicle 100 to initiate evasive maneuvers.","Check_Aggressor (ResultRange, geoFenceRadius) If ResultRange<geoFenceRadius.Critical safeLocation.Latitude=getSafeLocation.Latitude safeLocation.Longitude=getSafeLocation.Longtitude logOverrideEnabled( ) notifyOverrideEnabled( ) overrideToSafeLocation( ) If ResultRange<geoFenceRadius.Warning logOverrideWarning( ) notifyOverrideEnabled( ) In yet some additional embodiments, weather conditions may also be communicated to the vehicle.","In many operating environments, the weather may not be a significant factor but in other embodiments, the weather may affect the flight or travel of the vehicle 100.For example, a steady crosswind may affect a proposed course and the trim of a flying vehicle 100 may be adjusted in advance to account for the cross wind.","Logically, the vehicle 100 may be able to adjust while in route but the adjustment may be less drastic if the weather is factored into operational data 250 in advance.","At block 710, it may be determined if the flight path of the additional vehicles 805 would interfere with the flight path 810 of the low flying unmanned vehicle 100.Logically, the location of the vehicles 110 at points in the future may be determined using the operation data 250 and it may be determined if the locations may be with a given radius 705.At block 720, in response to determining that the flight path of the additional vehicles 805 would interfere with the flight path 810 of the low flying unmanned vehicle 100, the flight path 810 of the low flying unmanned vehicle 100 may be adjusted to avoid the additional vehicle 110.At block 730, the flight path 810 of the low flying unmanned vehicle 100 may be adjusted to avoid the additional vehicle 100 by analyzing at least one of the low flying unmanned vehicle's performance ratings, roll, pitch yaw.","In addition, the determining may include analyzing at least one of the following of the additional vehicle's 110 classification, speed, altitude and climb/decent rate.","Below is a pseudo code example for determining that a flight path may interfere and adjusting the flight path.","Initially, the vehicle 100 may identify and calculate the distance to each nearby vehicle 110.Receive Possible Aggressor Table getNearObjects( ) For each Object in getNearObjects SendNearObjectCalculated Path( ) Data Input currentObject.Latitude=35.882234 currentObject.Longitude=−78.788222 currentObject.Altitude=30 # meters currentObject.Speed=16 # meters/sec currentObject.Track=93.6 currentObject.ID=4923 # Identifier assigned to vehicle 100 AggressorObject.Latitude=35.866864 AggressorObject.Longitude=−78.799637 AggressorObject.Altitude=50 # meters AggressorObject.Speed=18 # meters/sec AggressorObject.Track=103.59 AgressorObject.ID=13830 # coded UAV ID localUAVPerformance=getUAVCaps(currentObject.ID) AggressorCapabilities=getUAVCaps(AgressorObject.ID) After determining the location of each additional vehicle 110, vehicle 100 may determine if its flight path may overlap at some future point in time with a flight path for any additional vehicle 110.Calculate_Overlap (currentObject, AggressorObject) localUAVPerformace=getUAVPerformance( ) localX=cos(currentObject.Latitude)*cos(currentObject.Longitude) localY=sin(currentObject.Longitude)*cos(currentObject.Latitude) localZ=sin(currentObject.Latitude) AggressorX=cos(AggressorObject.Latitude)*cos(currentObject.Longitude) AggressorY=sin(AggressorObject.Longitude)*cos(currentObject.Latitude) AggressorZ=sin(AggressorObject.Latitude) solveProjection: intersectionObject=find Intersection Point(localX, localY, localZ, AggressorX, AggressorY, AggressorZ) centerObject=projectazimuth(intersectionObject) intersectionSolution=solveIntersection(centerObject, localXYZ, AggressorXYZ) if (intersectionSolution>intersectionSolution+Threshold) GoTo solveProjection: Else criticalPoint.Latitude=getLatitude(intersectionSolution.XYZ) critical Point.Longitude=getLongitude(intersectionSolution.XYZ) To determine whether at some time the flight path of an additional vehicle 110 potentially would intersect with the vehicle's flight path—referred to as the “critical point”—the vehicle 100 may periodically (or continuously) calculate the distance between itself and the critical point.","Calculate_Distance (currentObject, criticalPoint) constR=6371000.0 # meters phi_1=radians(currentObject.Latitude) phi_2=radians(criticalPoint.Latitude) delta_phi=radians(criticalPoint.Latitude−currentObject.Latitude) delta_lambda=radians(critical Point.Longitude−currentObject.Longitude) Similar to the examples provided above, the vehicle 100 may use delta_phi and delta_lambda to determine a distance between itself and the critical point based on the curvature of the earth.","The vehicle 100 may use the calculated distance to determine whether to issue a warning and/or to determine that a distance is critical potentially requiring vehicle 100 to initiate evasive maneuvers.","Below is example pseudo code for taking evasive maneuvers.","update_track (criticalPoint, localUAVPerformace, currentObject.Altitude, aggressorObject.Altitude, ResultRange) activateAvoidance(localUAVPerformance, ResultRange, currentObject.Altitude) escapeVector=optimizeFlightPath(criticalPoint) activateUpdatedTrack(escapeVector) In some examples, the additional vehicle 110 may be a commercial airliner and the flight path 805 of the additional vehicle 110 may be received from a traditional airline flight path data tracking system.","As is known, commercial aircraft broadcast their location to airline control systems.","This data may be used to determine operational data 250 about the commercial flights.","In yet another embodiment, the vehicle 100 may use sensors 375 that sense for commercial aircraft using known flight data, and determine operational data 250 about the sensed aircraft.","For example, apps exist for a portable computing device which may recognize commercial aircraft.","The data may then be matched with known flight plans to determine the likely path of the commercial airliner.","As an obvious example, the vehicle 100 may recognize a flight and determine if the flight is taking off (where it will likely rise) and if a flights is landing (where the flight will likely descend).","Referring again to FIG.","1, at block 130, the outbound data packet may be formatted to be wirelessly communicated, for example, over a mobile communication network 515 (FIG.","5).","The formatting may take on a variety of forms and other communication networks may also be used (e.g., a satellite, WiFi, WiMax, etc.","communication network).","In one embodiment, the formatting 515 may include creating at least one selected from the group of a SMS message, a cellular transmission 525, a satellite data transfer or an ADS-b communication 535.The choice of communication form may relate to the height of the vehicle 100.For example, if the vehicle 100 is above 1500 feet (532), ADS-b may be used and if the vehicle is below 1500 feet, cellular technology may be used.","In addition, the strength of the various communication forms may be analyzed and the strongest signal may be selected for communication.","At block 140, the outbound data packet may be wirelessly communicated (e.g., over the mobile communication network) to a collection site 545.The collection site 545 may include a communication device for receiving mobile communication.","The central collection point 545 may have a variety of forms.","In one embodiment, the central collection point 545 may be a plurality of computing systems which communicate with each other.","The central collection point 545 may accept communications that represent traditional airline flight paths and communicates unmanned flight data to the traditional airline flight path data tracking system.","At block 150, an inbound data packet may be received from the collection site.","The inbound data packet may include data regarding relevant objects 110 determined to be over a threshold as explained previously.","In some embodiments, receiving an inbound data packet from the collection site 545 may also require that the inbound data packet include data regarding relevant objects 110 where relevant objects 110 have been determined to be over a relevance threshold.","As mentioned previously, the relevance threshold may include determining if the object 110 will be in range of the unmanned flying object 100 within a time threshold or a distance threshold.","The collection site 545 may include a plurality of communication formats and the object 110 may be an immovable object or a moveable object.","At block 160, flight operational data 250 may be adjusted on the vehicle 100 based on the relevant objects 110.The method may take a variety of actions from changing direction, to changing height and to adjusting speed or a combination of any of the various adjustments.","For example, the vehicle 100 may speed up and turn right to avoid an incoming additional object 110.The device 100 may have a variety of hardware to implement the vehicle 100.Referring to FIG.","2, the vehicle 100 may have a GPS chip 215 which may collect location information which may be parsed by the CPU 160 for necessary information.","As mentioned previously, the GPS data may be communicated in its raw format at times received from various satellites, may be converted into latitude and longitude or may be converted into yet another form that may be helpful in determining locations and flight paths.","The vehicle 100 may also have a cellular network processing chip 525 which may accept commands from the CPU 160 to send encrypted data over a cellular network to a ground based server 545 and may receive and read information sent to the cellular chip 525 from the central server 545 and send to the CPU 160 for parsing.","The cellular network processing chip 525 may take the data to be communicated to and from the central point 545 and use an algorithm to allow the data to be communicated back and forth over the cellular network 525.A central processing unit (CPU) 160 may perform a variety of computing functions.","In one aspect, the CPU 160 may parse GPS information, may send encrypted messages to the cellular chip 525, may accept and parse incoming information from the cellular chip 525, and may communicate commands to any integrated autopilot system 225 or flight control servos.","The CPU 160 may be purpose built to meet the challenged created by the vehicle 100.For example, the CPU 160 may need to be efficient as the vehicle 100 may be powered by a battery 235 which may have a limited amount of power.","Similarly, the CPU 160 may be an off the shelf CPU 160 that is physically configured to computer executable instructions and is sufficiently efficient.","The vehicle 100 may also have connectivity ports (not shown) which may allow for a connection to other systems such as ADS-b Transmitter/Receiver Module 535 which may operate in the 1033 MHz band.","It should be noted that ADS-b coverage may only exist at 1500+ feet above ground level.","The modular additions may provide a means or manner to connect to different autopilot systems to send maneuver commands for detect and avoid needs in the case of possible collision.","For example, the device may operate using GPS coordinates and a second device may operate using height and direction vectors and an additional modular addition may be used to translate flight operations of the first device into direction vectors which may be used by the second device.","The ports may be standard ports such as USB ports or may be purpose built ports.","In addition, the CPU 160 may have instructions on what to do if an additional computing device is inserted into the ports such as how to communicate with the device, how to determine if the device is safe, which device has precedence, etc.","The vehicle 100 may also have a battery 235 and/or external power connections.","The battery may allow the system to be powered by a UAV independent battery or allow for connection directly into the UAV flight power system.","In some embodiments, the battery 235 may be used to provide additional power to the UAV if the UAV loses or runs low on power.","In some embodiments, the battery 235 supplies 5-24 volts but the vehicle 100 may operate with a variety of voltages and current ratings.","The vehicle 100 may also have roll, pitch, yaw, and accelerometer sensors 375.The sensors 375 may provide IMU data to assist in evasive maneuver planning calculations.","The current location of the device is only part of the data needed to determine if a flight collision may occur as the vehicle 100 may change course.","The roll, pitch, yaw and accelerometers sensors 375 may assist in determining a future course for the vehicle 100 and whether a collision is likely.","Below is a pseudo code example for determining evasive maneuver planning calculations.","Initially, the vehicle 100 may use sensors to identify each nearby vehicle 110 and then calculate the distance to each sensed nearby vehicle 110.CheckUAVSensorArray getNearObjects ( ) localUAVSensor=getUAVSensorArray( ) For each Object in getUAVSensorArray SendUAVSensorArrayo SendNearObjectCalculated Path( ) Data Input currentObject.Latitude=35.882234 currentObject.Longitude=−78.788222 currentObject.Altitude=30 # meters currentObject.Speed=16 # meters/sec currentObject.Track=93.6 currentObject.ID=4923 # identifier of vehicle 100 AggressorObject.Latitude=35.866864 AggressorObject.Longitude=−78.799637 AggressorObject.Altitude=50 # meters AggressorObject.Speed=18 # meters/sec AggressorObject.Track=103.59 AgressorObject.ID=13830 # coded UAV ID uavFenceRadius.Critical=1437.38 # meters uavFenceRadius.Warning=2046.72 # meters After determining the location of each additional vehicle 110, vehicle 100 may determine if its flight path may overlap at some future point in time with that of any additional vehicle 110.Calculate_Overlap (currentObject, AggressorObject) localUAVPerformace=getUAVPerformance( ) localX=cos(currentObject.Latitude)*cos(currentObject.Longitude) localY=sin(currentObject.Longitude)*cos(currentObject.Latitude) localZ=sin(currentObject.Latitude) AggressorX=cos(AggressorObject.Latitude)*cos(currentObject.Longitude) AggressorY=sin(AggressorObject.Longitude)*cos(currentObject.Latitude) AggressorZ=sin(AggressorObject.Latitude) solveProjection: intersectionObject=find Intersection Point(localX, localY, localZ, AggressorX, AggressorY, AggressorZ) centerObject=projectazimuth(intersectionObject) intersectionSolution=solveIntersection(centerObject, localXYZ, AggressorXYZ) if (intersectionSolution>intersectionSolution+Threshold) GoTo solveProjection: Else criticalPoint.Latitude=getLatitude(intersectionSolution.XYZ) critical Point.Longitude=getLongitude(intersectionSolution.XYZ) To determine whether at some time the flight path of an additional vehicle 110 potentially may intersect with the vehicle's flight path—referred to as the “critical point”—the vehicle 100 may calculate the distance between itself and the critical point.","Calculate_Distance (currentObject, criticalPoint) constR=6371000.0 # meters phi_1=radians(currentObject.Latitude) phi_2=radians(criticalPoint.Latitude) delta_phi=radians(criticalPoint.Latitude−currentObject.Latitude) delta_lambda=radians(critical Point.Longitude−currentObject.Longitude) Similar to the examples provided above, the vehicle 100 may use delta_phi and delta_lambda to determine a distance between itself and the critical point based on the curvature of the earth.","The vehicle 100 may use the calculated distance to determine whether to issue a warning and/or initiate evasive maneuvers.","Below is example pseudo code for initiating evasive maneuvers.","update_track (criticalPoint, localUAVPerformace, currentObject.Altitude, aggressorObject.Altitude, localUAVSensor, ResultRange) activateAvoidance(localUAVPerformance, localUAVSensor, ResultRange, currentObject.Altitude) escapeVector=optimizeFlightPath(criticalPoint) activateUpdatedTrack(escapeVector) The vehicle 100 may also have a localized wireless module 180.The localized wireless module 180 may allow for connection and configuration via a secondary handheld device such as a portable computing device (cellular phone) where one may access additional feature of the vehicle 100.The flight data may be loaded into or received from the vehicle 100 in a variety of ways and the wireless module 180 may allow additional computing devices to wirelessly communicate with the device.","The following may be an example of the device 100 in operation.","A low flying unmanned vehicle 100 may be flying over a farm field.","An airliner 100 may also be nearby, preparing to land.","The vehicle 100 may have an infrared camera to determine the water content of the crops in the field.","On a periodic basis, the vehicle 100 may report its operational data 250 to a nearby cellular tower.","The data may be encapsulated as an SMS message or in any other appropriate format or form such as cellular, satellite, WiFi, WiMax, etc., and may be directed to a central collection site 545.The central collection site 545 may receive and analyze the operational data 250 from the vehicles and aircraft which may be stored in a database or server 172.The analysis may quickly parse the vehicles into geographic areas.","As mentioned previously, the vehicle 100 may determine if any of the additional vehicles 110 will be in a radius around each other in a relevant range or radius 705 and the flights that are determined to be over a threshold or nearby may be stored as separate flights 174.The vehicle 100 may receive messages 525 from the cellular tower which also may be encapsulated as SMS messages or in any other appropriate format or form such as cellular, satellite, WiFi, WiMax, etc.","The messages may contain operational data 250 from a second low flying unmanned vehicle 110 working on an adjacent field.","In addition, the vehicle 100 may use GPS 215 to determine its current location which along with relevant location and flight parameters 176.The operational data 250 and operational data for the additional vehicle 110 may communicated to the CPU 160 where an algorithm 182 may have physically configured the CPU to determine the flight path of the vehicle 100 and the flight path of other relevant vehicles 110 and whether the paths may intersect.","The algorithm may take into account the current position and projected path at points in time in the future for vehicles 100, 110 to determine if a collision may occur.","If the algorithm 182 determines a collision is likely, evasive maneuver commands 184 may be created and made be communicated to the vehicle 100.If the vehicle 100 has auto pilot 225, the maneuver commands 184 may communicated to the autopilot system 225 on the vehicle 100 where it may be interpreted and communicated to the flight control servos 227 module which may execute the maneuver.","If the vehicle 100 does not have autopilot 225, the command may be communicated directly to the flight control servos 227.FIG.","9a may illustrate another embodiment of the system.","In this embodiment, the processor 160 may receive additional information.","In one aspect, a database with geofence data 931 may also be in communication with the processor 160.Geofence data may include data about location which the vehicle 100 should avoid such as restricted airspace, airport, congested area, buildings, tree lines, power lines, etc.","Geofence data may be known and may be created in advance of a flight.","In some embodiments, the geofence data may be targeted to the general area of the vehicle.","For example, data on geofences in China may not be relevant to a vehicle that is operating in the United States.","Different modules of geofence data may be available and loaded depending on the location of the vehicle.","In this arrangement, less data with have to be sifted to obtain the information that is most relevant.","The geofence data may come from a variety of sources.","As an example, the US government may publish a data on restricted regions.","In addition, the position of buildings which would interfere with vehicular travel may be obtained from a mapping data source.","The data may be aggregated into a single file for rapid access and ease of understanding.","In some embodiments, the geofence data may also include a “whitelist” or data about locations that are not subject to a geofence.","The whitelist data may be a useful double check to ensure that a vehicle is clear to travel.","Further, the data may be reviewed in advance of a session to ensure a vehicle is safe to travel.","Real time obstacle data may also be stored and used such that the obstacle data may be immediately shared with others.","For example, if a hot air balloon is unexpectedly preparing to land, the data on the location, direction and path of the balloon may be stored in the real time obstacle database 921.The data on the obstacles also may be shared through communication links to a central authority that may add the real time obstacle data to its database and it may communicate the obstacle data to other nearby vehicles.","Thus, other vehicles in the area may be promptly informed of the obstacle.","A tamper detection module 931 may also be part of the system.","The tamper detection module 931 may operate in a variety of ways.","In one embodiment, the module may monitor time differentials from the autopilot to determine if someone unauthorized has tampered with the processor 160.For example, if the time differentials are not as expected, the assumption may be made that someone has tampered with the processor 160.In yet another embodiment, the processor may be cemented in place in the circuit board may break if an attempt is made to modify or remove the processor 160.Similarly, the processor may periodically self-check itself to ensure it is operating as expected and if the self-check fails, the vehicle may render itself inoperable until the unexpected conditions are fixed.","Common self-checks including comparing the current surroundings to surrounds that should be expected based on the GPS signals and previous images from the GPS coordinates, checking battery life in comparison to an expected flight length, etc.","At block 2222, an external autopilot may also be used to assist the vehicle.","In the situation where the processor 160 determines that the current travel plan needs to be changed to avoid an obstacle, for example, the new travel plan may be communicated to an external autopilot 2222.The new travel plan may override the current travel mode.","The external autopilot 2222 may submit a new travel plan which the processor 160 may review to ensure the vehicle does not cross any geofences, cross into the flight path of any other known vehicles, does not hit any buildings, etc.","The external autopilot may be able to direct the vehicle from hitting a first obstacle, but the processor may be knowledge of even more obstacles than the outside autopilot.","Thus the new flight plan may be reviewed by the processor 160.In addition, the new flight plan may be communicated to traffic management for routing other vehicles and letting other vehicles know of the intended travel plan.","Below is a pseudo code example for determining whether to change a flight path to avoid an obstacle.","In an example, the vehicle 100 may periodically or continuously identify and calculate the distance to each nearby additional vehicle and/or obstacle.","Receive Possible Aggressor Table getNearObjects( ) LoadGeoFence( ) For each Object in getNearObjects SendNearObjectCalculated Path( ) Data Input currentObject.Latitude=35.882234 currentObject.Longitude=−78.788222 currentObject.Altitude=30 # meters currentObject.Speed=16 # meters/sec currentObject.Track=93.6 currentObject.ID=4923 # identifier of vehicle 100 AggressorObject.Latitude=35.866864 AgressorObject.Longitude=−78.799637 AggressorObject.Altitude=50 # meters AggressorObject.Speed=18 # meters/sec AggressorObject.Track=103.59 AggressorObject.ID=13830 # coded UAV ID GeoFenceObject.Latitude=35.866864 GeoFenceObject.Longitude=−78.799637 GeoFenceObject.Height=22 # meters GeoFenceObject.ID=000483 # coded Airport code or Other Object geoFenceRadius.Critical=1437.38 # meters geoFenceRadius.Warning=2046.72 # meters localUAVPerformance=getUAVCaps(currentObject.ID) AggressorCapabilities=getUAVCaps(AgressorObject.ID) After determining the location of each nearby additional vehicle and/or obstacle, vehicle 100 may determine if its flight path may overlap at some future point in time with either.","Calculate_Overlap (currentObject, AggressorObject) localUAVPerformace=getUAVPerformance( ) localX=cos(currentObject.Latitude)*cos(currentObject.Longitude) localY=sin(currentObject.Longitude)*cos(currentObject.Latitude) localZ=sin(currentObject.Latitude) AggressorX=cos(AggressorObject.Latitude)*cos(currentObject.Longitude) AggressorY=sin(AgressorObject.Longitude)*cos(currentObject.Latitude) AggressorZ=sin(AggressorObject.Latitude) solveProjection: intersectionObject=find Intersection Point(localX, localY, localZ, AggressorX, AggressorY, AggressorZ) centerObject=projectazimuth(intersectionObject) intersectionSolution=solveIntersection(centerObject, localXYZ, AggressorXYZ) if (intersectionSolution>intersectionSolution+Threshold) GoTo solveProjection: Else criticalPoint.Latitude=getLatitude(intersectionSolution.XYZ) critical Point.Longitude=getLongitude(intersectionSolution.XYZ) To determine whether at some time the flight path of an additional vehicle and/or obstacle potentially may intersect with the vehicle's flight path—referred to as the “critical point”—the vehicle 100 may periodically (or continuously) calculate the distance between itself and the critical point.","In some instances, there may be multiple critical points (e.g., one for a fixed object, one for an additional vehicle, and another for a geofence).","Calculate_Distance (currentObject, criticalPoint) constR=6371000.0 # meters phi_1=radians(currentObject.Latitude) phi_2=radians(criticalPoint.Latitude) delta_phi=radians(criticalPoint.Latitude−currentObject.Latitude) delta_lambda=radians(critical Point.Longitude−currentObject.Longitude) Calculate_Distance (currentObject, GeoFenceObject) constR=6371000.0 # meters phi_1=radians(currentObject.Latitude) phi_2=radians(GeoFenceObject.Latitude) delta_phi=radians(GeoFenceObject.Latitude−currentObject.Latitude) delta_lambda=radians(GeoFenceObject.Longitude−currentObject.Longitude) Similar to the examples provided above, the vehicle 100 may use delta_phi and delta_lambda to determine a distance between itself and each critical point based on the curvature of the earth.","The vehicle 100 may use the calculated distance to determine whether to issue a warning and/or initiate evasive maneuvers.","Below is example pseudo code for initiating evasive maneuvers.","update_track (criticalPoint, localUAVPerformace, currentObject.Altitude, aggressorObject.Altitude, ResultRange, GeoFenceResultRange) activateAvoidance(localUAVPerformance, ResultRange, currentObject.Altitude) escapeVector=optimizeFlightPath(criticalPoint) flightPlan=updateFlightPlan(escapeVector, GeoFenceObject, ResultRange, GeoFence ResultRange) activateUpdatedTrack(escapeVector, flightPlan) A Common Connector A “breadcrumb” system may also be used to ensure a vehicle 100 will be able to find its way even if traditional GPS systems stop working.","The breadcrumb systems may have a plurality of aspects and may work in a variety of ways, some of which may complement each other.","In one aspect, the vehicle may take images while following a flight plan.","If a GPS signal is lost, a vehicle may recall these images (e.g., from memory or other data storage device), compare the current image to the known images from the initial flight path and change its flight path toward the objects which are recognized.","In addition, if no objects are recognized, the vehicle may travel in ever increasing circles until it traverses terrain that is recognized.","Below is example pseudo code of this process.","In the below example, the vehicle 100 may capture images while flying and assign GPS coordinates to each image, prior to failure of a GPS system.","The captured images may be stored for later comparison should the GPS system stop working.","When using the breadcrumb system, the vehicle 100 may compare captured images to stored images looking for matches.","The vehicle 100 may also assign confidence scores based on the degree of matching.","Matches may be used to guide the vehicle in the absence of GPS data.","Finger Print Current Fly Over Image localUAVSensor=getUAVSensorArray( ) #9 Axis Accelerometer dead-reckoning=getPositionOffset(localUAVSensor) imageMatchThreshold=489 # configurable location Images=getLocationImages(lastGPS.Latitude+dead-reckoning, lastGPS.Longitude+dead-reckoning, gps.Altitude+dead-reckoning) #Land image fingerprints are small in size compared to actual images.","Images are stored in local memory and may be updated currentImage=captureImage( ) imagePrint=fingerprintImage(currentImage) For each searchimage in locationimages Data Input If (imageMatch (locationImages.fingerprint, imagePrint.fingerprintd)>485) proposedLocation=newLocation( ) assignedConfidence=newConfidence(previousConfidence) Continue to New Track Pathway In another aspect, the vehicle may review images related to the current location of the vehicle.","If there are existing images from past flights, the existing images may include additional such as GPS data related to the images.","Thus, the vehicle may traverse and take images and if the new images match past images, the GPS coordinated from the past image may be used to indicate the current GPS location.","Further, the vehicle may have noted its GPS position at the beginning of its flight.","By collecting addition GPS data from additional known sites with stored GPS locations, the vehicle may be able to triangulate its position and determine a path to its starting point or another stored rendezvous location.","In another aspect, the vehicle 100 may simply attempt to reverse its current path.","In some conditions such as when it is windy, the ability to retrace a path may be especially difficult but images from the initial flight path may be used to guide the vehicle back toward its starting point.","Below is example pseudo code applied by vehicle 100 to reverse its path using images.","Finger Print Current Fly Over Image reverseWaypoint=getWaypoint(atIndex) localUAVSensor=getUAVSensorArray( ) #9 Axis Accelerometer dead-reckoning=getPositionOffset(localUAVSensor) imageMatchThreshold=489 # configurable location Images=getLocationImages(lastGPS.Latitude+dead-reckoning, lastGPS.Longitude+dead-reckoning, gps.Altitude+dead-reckoning) #Land image fingerprints are small in size compared to actual images.","Images are stored in local memory and may be updated currentImage=captureImage( ) imagePrint=fingerprintImage(currentImage) For each searchimage in locationimages Data Input If (imageMatch (locationImages.fingerprint, imagePrint.fingerprintd)>485) proposedLocation=newLocation(reverseWaypoint) assignedConfidence=newConfidence(previousConfidence) Continue to New Track Pathway activateUpdatedTrack(proposedLocation, flightPlan) In another aspect, the vehicle 100 may make note of its starting point in a variety of ways and these starting point notations may be used to guide the vehicle back to its starting location or another desired location.","In one embodiment, the vehicle may receive and store cell phone tower information such as the tower identifier, a timing signal and the signal strength of the various cell towers.","The location of the cell towers may be fixed.","From analyzing the cell tower signal strength or timing signals, triangulation may be used to determine a starting location.","Assuming the cell tower and vehicle both have access to an accurate and consistent time reference, timing signals may be a very accurate indication of when a signal was sent.","The vehicle may receive the signal at a later time and the difference between the send time and the received time may be used to determine the distance from the cell tower as the velocity of the cell tower signal may be known.","Triangulation may be used to determine the location of the vehicle in relation to the various cell towers.","In addition, the GPS location of the cell towers may be known and the GPS location of the vehicle may be determined using the GPS coordinates of the cell towers and the timing signals.","Similarly, the timing signals from cellular towers may be used to determine a location of the vehicle if a GPS signal is lost in flight.","Using timing and known cell tower locations, triangulation may be used to determine a location of the vehicle.","Further, the cell tower signals may be used to guide the vehicle back to a start point or to an additional location.","Signal strength from various cell towers may be known and the received signal strength from a plurality of cell towers may be used to determine the location of the vehicle.","Similar to timing signals, the signal strength may be known at given locations and may be used to determine a location of a vehicle by comparing the observed signal strength to previously mapped signal strength measurements.","Other broadly available signals may be used to triangulate a location if GPS signals fail.","In some situations, traditional radio signals such as AM and FM may have known signal strengths in known locations.","At a minimum, the signal strengths may be used to narrow down the list of possible locations and at best, triangulation may be possible from a variety of signals from a variety of towers to establish either a starting location or a current location.","Signals from non-GPS satellites such as television satellites or wireless phone satellites, known WiFi signals also may be received and used to triangulate locations.","Finally, traditional method of observing sun, moon and stars and the time of day may be used.","As the location of the sun, moon, and certain star may be known at given times, locations may be determined.","The locations may not be as accurate as GPS signals but may provide useful guidance.","Of course, elements of these various aspects may be combined to create a more accurate location.","For example, if two cell phone towers signals may be received and a single FM signal, three signals may be combined to attempt to triangulate a location.","Further, the additional various signals may be used to verify a location in situations where a GPS signal may be in doubt.","In some embodiments, a homing signal may be communicated from a device at a point of origin or at another desired location.","The signal may be a low power, low frequency signal that may be heard from great distances.","The vehicle may execute a travel pattern such as a series of circles or squares which may be used to determine a general travel path and as the vehicle moves closer to the source of the signal, the path may be further improved to maximize the received signal which would indicate the beacon is near.","In some embodiments, the vehicle may contain the homing signal.","The homing signal may be used if there is a major failure and the launching vehicle may need to locate the vehicle.","For example, if GPS is lost, the vehicle may travel in a limited space that has been determined to be safe and may operate the homing signal.","If power drops to a predetermined level, the vehicle may take steps to determine a safe landing location and may continue to communicate the homing signal.","Of additional interest, the vehicle may be equipped with a flight control override intervention module 225.The module may sit between the autopilot and flight controls and may provide the processor 160 controlled manual override to the controls in case of no autopilot integration.","As a result, an authority such as the FAA may have the ability to override a vehicle travel plan.","The override may be for any purpose such as to avoid a collision or to free the area for an authority vehicle such as a police vehicle.","FIG.","9b may illustrate a backend 2222 of a traffic management system.","At a high level, numerous systems may feed data to the traffic management system backend 2222 including an analytics engine 1001, databases 1101, traffic management modules 1201 and various FAA data sources 1301, 1311, 1321.The analytics engine may review data collected on vehicles operations and operators and may attempt to come to some useful conclusions.","The data from all vehicles that use the system and method may be collected.","In addition, real time data on current systems may be collected.","From this collection of data, algorithms may attempt to review and quantify risk.","For example, the data may determine that pilot A is prone to errors while pilot B is extremely careful and has little risk.","The data may even show that certain pilot demographics are more risky than others.","For example, an algorithm may study the flight data and determine that pilots under the age of 25 may be riskier than pilots aged 34-43.Similarly, it may be determined that certain vehicles are riskier than others.","Logically, there may be a variety of conclusions that may be drawn from the data and may be used as part of the system.","As an example, if a risky pilot is flying a risky vehicle, a warning may be issued that the risk of this flight is over a predetermined threshold which may be a user threshold, a calculated threshold or a default threshold.","Below is pseudo code for determining whether to issue a warning.","Device Side: Update Analytics Engine Service sendGeoSensorArray(geoSearchData) sendImageFingerprint(imageFingerprintData) sendAudioGeoSensorData(audioData) sendRFSpectrumData(RFAnalysisData) sendNearObjectData(gpsData, Range, AgressorObject) Cloud Side: Aggregate Data Service updateGeoFenceData(geoSearchData) updateImageArchive(imageFingerprintData) updateAudioData(audioData) updateRFData(RFAnalysisData) updateNearObjectData(gpsData, Range, AggressorObject) Databases 1101 also may feed data to the traffic management system 2222.A first database 1111 may store real time data on aerial obstacles in the relevant area such as other vehicles.","A second database may store data on obstacles 1121 such as building, power lines, windmills, silos, trees, etc.","A third database 1131 may include pilot/aircraft registration data which may include information on pilots and planes which may be used to assess risk.","A flight log database 1141 may be used to store flight logs on past flights such that the flights may be replayed in the future.","A flight plan database 1151 may store all flight plans that are submitted by pilots which may be accessed and used to create additional flight paths in the future.","A traffic management module 1201 may be used to determine flight routing data to be communicated to the traffic management system backend 2222.The routing may pull in plans as they are submitted 1211 to the processor 160, may determine if a route collision is possible in comparison to other flight plans and geofences.","At block 1231, the system may determine if a collision is possible, and then a new flight path may be suggested to the processor 160 of the vehicle.","Other agencies related to tracking vehicles may also submit useful data.","NASA 1301 may submit flight plans which may need to be submitted to the traffic management system 2222.Similarly, FAA air traffic control 1311 may import and report real time information on manned aircraft from the FAA ATC system.","The FAA Air Traffic Control may escalate situations up to live traffic management personnel such as emergency or other situations that might require a manual override.","FIG.","9c may illustrate a user interface that interfaces with the traffic management system 2222.A flight planning module 1501 may make it easy for pilots of vehicles to submit flight plan 1511 through a variety of interfaces such as a web browser interface.","A variety of information may be collected 1521 such as a general area of the vehicle, the proposed vehicle path, the pilot information, the craft information and the operation type.","An interface may also allow easy access to review all the data on vehicle and vehicle travel plans.","Logically, the data may be restricted and a login may be required 1611.The login may be a traditional login or may be a secure electronic key exchange or may require biometric verification of the proposed users.","It may be web or cloud based or may be a purpose built computer.","A general user 1621 may be presented with a user interface tailored to that individual.","Accessible features to a general user 1621 may include personal flight logs, registration data for the local system, account settings, geo-fence information, option to see old flight logs, see meta data regarding flights, and performing algorithms to analyze the risk of a flight.","An administrator 1631 may be able to see more data 1651.For example, the administrator may see all known vehicles in real time, all vehicle travel logs, all current or past notifications or interventions, all geofence information, the option to update geofence data, the option to force a vehicle to undertake an action, communicate real-time notifications to user, perform risk analysis on flight data and research performance analysis.","The data may be in an easy to see graphical interface which may facilitate understanding by displaying the complicated data in an easy to understand and access format.","Below is example pseudo code for sending sense and avoid data to vehicle 100.Receive RealTime Sense and Avoid Data from UAV calculatePriority=processIncomingSenseData(currentObject) targetConfirmedNew=confirmNewTarget( ) addNewTarget(targetConfirmedNew) For each UAVRequest from currentObject sendRealTimeData( ) # send current live sense and avoid data to UAV The processor 160 may be integral to a vehicle 100 such as being on a circuit board that is a structural member.","In other embodiments, the processor 160 is a separate device which may be used to control virtually any vehicle via a standard protocol and interface, such as an Ethernet jack, Bluetooth, WiFi or fiber communication link.","The processor 160 also may be light weight and compact and may be designed to extend external power.","For example, processor sections which are not is use may be turned off when not needed.","As an example, a sound function may be useful during programming a flight path but may not be useful during flight.","FIG.","10 may be an illustration of a sample device.","The processor 160 may be placed on or integrated into existing small vehicles such as UAV platforms.","The processor 160 or chip may stand-alone, providing a framework which will allow real-time tracking of small vehicles at altitudes between 0-1000 ft above ground level.","The core framework may be expandable and modular to interface with numerous communication protocols.","The standard form of communication may be achieved over cellular networks even at their lowest bandwidth, however, the communication may be expanded to run on other networks such as wide-area WIFI and ADS-b.","The system hardware may be incorporated onto vehicles by three methods.","The hardware may be purchased stand-alone as a device which mounts onto any airframe without any autopilot integration, providing real time tracking information only.","The second method is a stand-alone unit which may plug into a number of pre-integrated autopilots (3dr, APM, DJI, etc.).","Providing real time tracking coupled with autopilot override functionality enabling sense-and-avoid capability.","The third integration solution may be provided by licensing build schematics of the hardware to vehicle manufacturers, allowing them to incorporate the system directly onto their integrated circuits.","The firmware may be strictly maintained by a single source, with updates provided over the cellular network infrastructure.","In another aspect, the vehicle 100 may attempt to use sound mitigation techniques to make the vehicle quieter.","As is known, a wave that is in opposite phase of a first wave may cancel out the first wave.","In the case of sound wave, the sound from a vehicle may be captured and a sound generator may create a sound in the opposite phase of the vehicle.","Further, the sound mitigation may review a flight plan and anticipate changes in sound such as a call for increased prop speed.","Such an increase may be anticipated and may be mitigated.","As a result, the “buzzing” of tradition unmanned aircraft may be reduced or eliminated.","Of course, other methods of reducing sound, such as insulation, are possible and are contemplated.","Below is a pseudo code example for determining whether to initiate audio suppression.","In the below example, the vehicle 100 may determine its distance relative to a geofence.","If too close, then the vehicle 100 may determine that a change in flight plan may be required that involves a change in prop speed and noise suppression to counteract noise generated due to the change in prop speed.","Receive AudioGeoFence Table LoadAudioGeoFence( ) For each Object in LoadGeoFence Data Input currentObject.Latitude=35.882234 currentObject.Longitude=−78.788222 currentObject.Altitude=30 # meters currentObject.Speed=16 # meters/sec currentObject.Track=93.6 currentObject.ID=4923 # identifier of vehicle 100 AudioGeoFenceObject.Latitude=35.866864 AudioGeoFenceObject.Longitude=−78.799637 AudioGeoFenceObject.Height=20 # meters AudioGeoFenceObject.ID=000483 # coded Airport code or Other Object AudiogeoFenceRadius.Critical=4437.38 # meters AudiogeoFenceRadius.Warning=5046.72 # meters Calculate_Distance (currentObject, AudioGeoFenceObject) constR=6371000.0 # meters phi_1=radians(currentObject.Latitude) phi_2=radians(AudioGeoFenceObject.Latitude) delta_phi=radians(AudioGeoFenceObject.Latitude−currentObject.Latitude) delta_lambda=radians(AudioGeoFenceObject.Longitude−currentObject.Longitude) Similar to the examples provided above, the vehicle 100 may use delta_phi and delta_lambda to determine a distance between itself and the geofence based on the curvature of the earth.","The vehicle 100 may use the calculated distance to determine whether to initiate audio suppression.","Check_GeoFence (ResultRange, AudiogeoFenceRadius) If ResultRange<AudiogeoFenceRadius.Critical AudioSuppresisonEnable(AudiogeoFenceRadius.NoiseCancellationLevel) FIG.","11 may be an illustration of a sample back end user interface 1701.It may have a plurality of input areas 1701 which may be different activities.","Flight plans may be submitted in a few clicks through a simple easy to use interface.","The user may define a block of airspace in which the vehicle is planning to conduct travel much like a pilot of a manned aircraft would.","This flight plan is received and parsed by the traffic management system servers 2222 and provides the user or pilot with an approval or denial for that flight based on a number of properties which are determined based upon nearby geofences and defined performance limitations for his/her certification and/or UAV platform.","The traffic management system 2222 may provide ground-based sense-and-avoid as a service to all vehicles such as small UAVs by informing each UAV of its surroundings both in the air and on the ground.","Transmitted items may include but are not limited to terrain, tree lines, infrastructure (e.g., power lines, towers, windmills, etc.","), buildings, manned aircraft, and other un-manned aircraft traffic.","This ability to teach the vehicle its surroundings allows the system to provide high fidelity sense-and-avoid at a low cost in a small, lightweight package.","Due to the type of information being ingested and parsed by the traffic management system 2222, the system may be able to classify various types of travel and conditions.","The system may automatically escalate specific situations to a manned controller who may then provide further instruction to the vehicle system or notifications to the pilot through the included mobile applications or over the system through ground control software.","Below is example pseudo code for providing ground-based sense-and-avoid as a service.","In an example, the traffic management system 2222 may populate a sense-and-avoid data table containing information on vehicles within a particular airspace.","Load RealTime Sense and Avoid Data Table realTimeData=LoadRealTimeData( ) sensorData=scanLocation( ) #Image based, Doppler, Infrared For each RealTimeObject in realTimeData Data Input currentObject.Latitude=35.882234 currentObject.Longitude=−78.788222 currentObject.Altitude=30 # meters currentObject.Speed=16 # meters/sec currentObject.Track=93.6 currentObject.ID=4923 # identifier for vehicle 100 RealTimeObject.Latitude=35.866864 RealTimeObject.Longitude=−78.799637 RealTimeObject.Height=18 # meters RealTimeObject.ID=000483 # coded Airport code or Other Object Calculate_Distance (currentObject, GeoFenceObject) constR=6371000.0 # meters phi_1=radians(currentObject.Latitude) phi_2=radians(GeoFenceObject.Latitude) delta_phi=radians(GeoFenceObject.Latitude−currentObject.Latitude) delta_lambda=radians(GeoFenceObject.Longitude−currentObject.Longitude) The traffic management system 2222 may use delta_phi and delta_lambda to determine a distance between vehicle 100 and each additional vehicle 110, object, or geofence based on the curvature of the earth.","This distance is referenced as “ResultRange” in the below pseudo code.","The traffic management system 2222 may generate and maintain data to track a current location of each vehicle in a particular airspace.","Verify_RealTimeData (ResultRange, RealTimeObject) For each sensorDataObject in SensorData If RealTimeObject=sensorDataObject notifyServerObjectVerifed(gps.Time, gps.Longitute,gps.Latitude) If RealTimeObject is not Found notifyServerNewObject(.Time, gps.Longitute,gps.Latitude, RealTimeObject) Notifications may be communicated to users of the registered active vehicles travel plan through mobile computing devices.","The notifications may alert the user in a number of travel situations.","Notifications may range from potential breach of allocated space to early notice that a travel path should be changed in order to miss an obstacle prior to the system providing commands to the autopilot to take corrective actions.","An interface may be provided which users or system managers may access to see and monitor flights in real time.","This portal is similar in display to an air traffic controller's radar scope as illustrated in FIG.","11 which may include an illustration of the relevant area 1721, other vehicles within given distances 1731 of the vehicle and any geofenced areas 1741.Certain embodiments are described herein as including logic or a number of components, modules, or mechanisms.","Modules may constitute either software modules (e.g., code embodied on a non-transitory machine-readable medium or in a transmission signal) or hardware modules.","A hardware module is tangible unit capable of performing certain operations and may be configured or arranged in a certain manner.","In example embodiments, one or more computer systems (e.g., a standalone, client or server computer system) or one or more hardware modules of a computer system (e.g., a processor or a group of processors) may be configured by software (e.g., an application or application portion) as a hardware module that operates to perform certain operations as described herein.","In various embodiments, a hardware module may be implemented mechanically or electronically.","For example, a hardware module may comprise dedicated circuitry or logic that is permanently configured (e.g., as a special-purpose processor, such as a field programmable gate array (FPGA) or an application-specific integrated circuit (ASIC)) to perform certain operations.","A hardware module may also comprise programmable logic or circuitry (e.g., as encompassed within a general-purpose processor or other programmable processor) that is temporarily configured by software to perform certain operations.","It will be appreciated that the decision to implement a hardware module mechanically, in dedicated and permanently configured circuitry, or in temporarily configured circuitry (e.g., configured by software) may be driven by cost and time considerations.","The various operations of example methods described herein may be performed, at least partially, by one or more processors that are temporarily configured (e.g., by software) or permanently configured to perform the relevant operations.","Whether temporarily or permanently configured, such processors may constitute processor-implemented modules that operate to perform one or more operations or functions.","The modules referred to herein may, in some example embodiments, may comprise processor-implemented modules.","Similarly, the methods or routines described herein may be at least partially processor-implemented.","For example, at least some of the operations of a method may be performed by one or more processors or processor-implemented hardware modules.","The performance of certain of the operations may be distributed among the one or more processors, not only residing within a single machine, but deployed across a number of machines.","In some example embodiments, the processor or processors may be located in a single location (e.g., within a home environment, an office environment or as a server farm), while in other embodiments the processors may be distributed across a number of locations.","The one or more processors may also operate to support performance of the relevant operations in a “cloud computing” environment or as a “software as a service” (SaaS).","For example, at least some of the operations may be performed by a group of computers (as examples of machines including processors), these operations being accessible via a network (e.g., the Internet) and via one or more appropriate interfaces (e.g., application program interfaces (APIs).)","The performance of certain of the operations may be distributed among the one or more processors, not only residing within a single machine, but deployed across a number of machines.","In some example embodiments, the one or more processors or processor-implemented modules may be located in a single geographic location (e.g., within a home environment, an office environment, or a server farm).","In other example embodiments, the one or more processors or processor-implemented modules may be distributed across a number of geographic locations.","Unless specifically stated otherwise, discussions herein using words such as “processing,” “computing,” “calculating,” “determining,” “presenting,” “displaying,” or the like may refer to actions or processes of a machine (e.g., a computer) that manipulates or transforms data represented as physical (e.g., electronic, magnetic, or optical) quantities within one or more memories (e.g., volatile memory, non-volatile memory, or a combination thereof), registers, or other machine components that receive, store, transmit, or display information.","Still further, the figures depict preferred embodiments of a vehicle control system for purposes of illustration only.","One skilled in the art will readily recognize from the foregoing discussion that alternative embodiments of the structures and methods illustrated herein may be employed without departing from the principles described herein.","Thus, upon reading this disclosure, those of skill in the art will appreciate still additional alternative structural and functional designs for a system and a process for a low flying unmanned vehicle automatically avoiding collisions through the disclosed principles herein.","Thus, while particular embodiments and applications have been illustrated and described, it is to be understood that the disclosed embodiments are not limited to the precise construction and components disclosed herein.","Various modifications, changes and variations, which will be apparent to those skilled in the art, may be made in the arrangement, operation and details of the method and apparatus disclosed herein without departing from the spirit and scope defined in the appended claims."]],"string":"[\n [\n \"AUTOMATED UN-MANNED AIR TRAFFIC CONTROL SYSTEM\",\n \"A low flying unmanned vehicle is disclosed that may be able to determine whether a collision is possible and may take evasive action in response to the possible collision.\",\n \"The vehicle may wirelessly communicate and may use a standard protocol such that a variety of additional objects may be taken into account when determining the possible collision risk.\"\n ],\n [\n \"1-43.\",\n \"(canceled) 44.An apparatus for in-flight collision avoidance in independently-operating unmanned aerial vehicles, the apparatus comprising: a processor and a memory, wherein the memory stores a set of machine-operable instructions operable, when executed by the processor, to: determine first flight operational data at a first computing system, wherein the first flight operational data corresponds to a first planned operation of a first unmanned aerial vehicle over a first area; receive second flight operational data at the first computing system from a second computing system, wherein the second computing system is remote from a second aerial vehicle, the second flight operational data corresponds to the second aerial vehicle, the second flight operational data for controlling the second aerial vehicle over a second area adjacent to the first area; and send a notification to the first computing system upon determining the second flight operational data crosses a threshold with respect to the first flight operational data.\",\n \"45.The apparatus of claim 44, wherein the memory stores further machine-operable instructions that are operable, when executed by the processor, to allow modification of the first flight operational data at the first computing system based on the notification.\",\n \"46.The apparatus of claim 44, wherein the memory stores further machine-operable instructions that are operable, when executed by the processor, to display the notification within a user interface of the first computing system.\",\n \"47.The apparatus of claim 45, wherein the memory stores further machine-operable instructions that are operable, when executed by the processor, to wirelessly communicate the first flight operational data, a modified first flight operational data, and the second flight operational data to a remote collection site.\",\n \"48.The apparatus of claim 47, wherein the memory stores further machine-operable instructions that are operable to wirelessly communicate the first flight operational data, the modified first flight operational data, and the second flight operational data in an ADS-b communication format when an altitude of the first unmanned aerial vehicle is equal to or greater than 1500 feet and in a cellular communication format when the altitude of the first unmanned aerial vehicle is less than 1500 feet.\",\n \"49.The apparatus of claim 47, wherein the memory stores further machine-operable instructions that are operable, when executed by the processor, to determine relevant object data at the second computing device, wherein the relevant object data is within the second area and over the threshold.\",\n \"50.The apparatus of claim 49, wherein the second flight operational data wirelessly communicated to the remote collection site includes the relevant object data.\",\n \"51.The apparatus of claim 44, wherein the second flight operational data further corresponds to a manned aerial vehicle.\",\n \"52.A system for in-flight collision avoidance in independently-operating unmanned aerial vehicles, the system comprising: a first computing system for operation of a first unmanned aerial vehicle over a first area, wherein the first computing system includes a first processor, a first memory, and a first communication device for sending and receiving wireless communication, the first memory includes, for the first unmanned aerial vehicle, first flight operational data corresponding to the first unmanned aerial vehicle within the first area; and a second computing system for operation of a second aerial vehicle over a second area, wherein the second area is adjacent to the first area, the second computing system is remote from the second aerial vehicle and includes a second processor, a second memory, and a second communication device for sending and receiving wireless communication, the second memory includes, for the second unmanned aerial vehicle, second flight operational data corresponding to the second unmanned aerial vehicle and for controlling the second aerial vehicle within the second area; wherein the first memory further stores a set of machine-operable instructions operable, when executed by the first processor, to: receive the second flight operational data at the first computing system; and send a notification to the first computing system upon determining the second flight operational data crosses a threshold with respect to the first flight operational data.\",\n \"53.The system of claim 52, wherein the first memory stores further machine-operable instructions that are operable, when executed by the first processor, to allow modification of the first flight operational data at the first computing system based on the notification.\",\n \"54.The system of claim 52, wherein the first memory stores further machine-operable instructions that are operable, when executed by the processor, to display the notification within a user interface of the first computing system.\",\n \"55.The system of claim 53, wherein the second memory stores further machine-operable instructions that are operable, when executed by the second processor, to wirelessly communicate the first flight operational data, a modified first flight operational data, and the second flight operational data to a remote collection site.\",\n \"56.The system of claim 55, wherein the second memory stores further machine-operable instructions that are operable, when executed by the second processor, to wirelessly communicate the first flight operational data, the modified first flight operational data, and the second flight operational data in an ADS-b communication format when an altitude of the first unmanned aerial vehicle is equal to or greater than 1500 feet and in a cellular communication format when the altitude of the first unmanned aerial vehicle is less than 1500 feet.\",\n \"57.The system of claim 55, wherein the second memory stores further machine-operable instructions that are operable, when executed by the second processor, to determine relevant object data at the second computing device, wherein the relevant object data is within the second area and over the threshold.\",\n \"58.The system of claim 57, wherein the second flight operational data wirelessly communicated to the remote collection site includes the relevant object data.\",\n \"59.The system of claim 52, wherein the second flight operational data further corresponds to a manned aerial vehicle.\",\n \"60.A computer-implemented method for in-flight collision avoidance in independently-operating aerial vehicles, the method comprising: determining first flight operational data at a first computing system, wherein the first flight operational data corresponds to a first planned operation of a first unmanned aerial vehicle over a first area; receiving second flight operational data at the first computing system from a second computing system, wherein the second computing system is remote from a second aerial vehicle, the second flight operational data corresponds to the second aerial vehicle, the second flight operational data for controlling the second aerial vehicle over a second area adjacent to the first area; and sending a notification to the first computing system upon determining the second flight operational data crosses a threshold with respect to the first flight operational data.\",\n \"61.The computer-implemented method of claim 58, further comprising allowing modification of the first flight operational data at the first computing system based on the notification.\",\n \"62.The computer-implemented method of claim 60, further comprising displaying the notification within a user interface of the first computing system.\",\n \"63.The computer-implemented method of claim 61, further comprising wirelessly communicating the first flight operational data, a modified first flight operational data, and the second flight operational data to a remote collection site.\",\n \"64.The computer-implemented method of claim 63, further comprising wirelessly communicating the first flight operational data, the modified first flight operational data, and the second flight operational data in an ADS-b communication format when an altitude of the first unmanned aerial vehicle is equal to or greater than 1500 feet and in a cellular communication format when the altitude of the first unmanned aerial vehicle is less than 1500 feet.\",\n \"65.The computer-implemented method of claim 63, further comprising determining relevant object data at the second computing device, wherein the relevant object data is within the second area and over the threshold.\",\n \"66.The computer-implemented method of claim 65, wherein the second flight operational data wirelessly communicated to the remote collection site includes the relevant object data.\",\n \"67.The computer-implemented method of claim 60, wherein the second flight operational data further corresponds to a manned aerial vehicle.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>Low flying unmanned vehicles have become more common and have more and more uses.\",\n \"As low flying vehicles become more common, the likelihood of collisions with trees, commercial airliners, buildings, and other unmanned vehicles becomes more likely.\",\n \"Trying to avoid collisions becomes more difficult as vehicles do not communicate with each other or FAA air traffic controllers and may take evasive action which made make collisions more probable rather than less likely.\"\n ],\n [\n \"<SOH> SUMMARY <EOH>A low flying unmanned vehicle is disclosed that may be able to determine whether a collision is possible and may take evasive action in response to the possible collision.\",\n \"The vehicle may wirelessly communicate (e.g., using cellular, satellite, WiFi, WiMax, etc.\",\n \"communication) and may use a standard protocol such that a variety of additional objects may be taken into account when determining the possible collision risk.\",\n \"In operation, the vehicle may receive flight data from one or more objects, may determine the location of the vehicles at a plurality of points in time in the future and may determine if a collision is probable.\",\n \"If a collision is probable, evasive data may be communicated to the vehicle.\",\n \"The flight data may be from a variety of vehicles, including commercial aircraft and other unmanned vehicles.\"\n ],\n [\n \"CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of, and priority to, U.S. Non-Provisional application Ser.\",\n \"No.\",\n \"14/847,910, filed Sep. 8, 2015, titled “Automated Un-Manned Air Traffic Control System,” which claims benefit of, and priority to, U.S. Prov.\",\n \"App.\",\n \"Ser.\",\n \"No.\",\n \"62/046,619, filed Sep. 5, 2014, titled “Low Flying Collision Detection and Avoidance,” and U.S. Prov.\",\n \"App.\",\n \"Ser.\",\n \"No.\",\n \"62/139,272, filed Mar.\",\n \"27, 2015, titled “Low Flying Collision Detection, Avoidance and Return System”, the content of each of which is incorporated herein by reference in its entirety.\",\n \"BACKGROUND Low flying unmanned vehicles have become more common and have more and more uses.\",\n \"As low flying vehicles become more common, the likelihood of collisions with trees, commercial airliners, buildings, and other unmanned vehicles becomes more likely.\",\n \"Trying to avoid collisions becomes more difficult as vehicles do not communicate with each other or FAA air traffic controllers and may take evasive action which made make collisions more probable rather than less likely.\",\n \"SUMMARY A low flying unmanned vehicle is disclosed that may be able to determine whether a collision is possible and may take evasive action in response to the possible collision.\",\n \"The vehicle may wirelessly communicate (e.g., using cellular, satellite, WiFi, WiMax, etc.\",\n \"communication) and may use a standard protocol such that a variety of additional objects may be taken into account when determining the possible collision risk.\",\n \"In operation, the vehicle may receive flight data from one or more objects, may determine the location of the vehicles at a plurality of points in time in the future and may determine if a collision is probable.\",\n \"If a collision is probable, evasive data may be communicated to the vehicle.\",\n \"The flight data may be from a variety of vehicles, including commercial aircraft and other unmanned vehicles.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS FIG.\",\n \"1 may illustrate a method of information reporting and avoidance for a low flying unmanned vehicle; FIG.\",\n \"2a may illustrate that a vehicle may have a processor and related computing equipment to control the path and course of the vehicle; FIG.\",\n \"2b may illustrate that the vehicle may have a processor and related computing equipment to control the path and course of the vehicle; FIG.\",\n \"3 may illustrate that the processor and memory may be mounted on a circuit board and the circuit board may be a load bearing member of the vehicle; FIG.\",\n \"4a may illustrate a sample outbound packet; FIG.\",\n \"4b may illustrate a sample inbound packet; FIG.\",\n \"5a may illustrate a method of collecting and communicating additional data; FIG.\",\n \"5b may illustrate equipment that may be used to collect the additional data; FIG.\",\n \"6 may illustrate one way to determine whether an object is a relevant object worthy of reporting to a central collection point; FIG.\",\n \"7 may illustrate a method of adjusting operational data of the vehicle; FIG.\",\n \"8 may illustrate flight paths of vehicles; FIG.\",\n \"9a may illustrate several aspects of a system; FIG.\",\n \"9b may illustrate a backend of the system; FIG.\",\n \"9c may illustrate elements of a user interface to the system; FIG.\",\n \"10 may illustrate a device with a processor; and FIG.\",\n \"11 may illustrate a user interface.\",\n \"DETAILED DESCRIPTION At a high level, a low flying unmanned vehicle 100 is disclosed that may be able to determine whether a collision is possible and may take evasive action in response to the possible collision.\",\n \"The vehicle 100 may wirelessly communicate (e.g., using cellular, satellite, WiFi, WiMax, etc.\",\n \"communication) and may use a standard protocol such that a variety of additional objects 111 may be taken into account when determining the possible collision risk.\",\n \"FIG.\",\n \"1 may illustrate a method of information reporting and avoidance for a low flying unmanned vehicle 100.The vehicle 100 may be an airplane or flying vehicle 100 which is too small to contain an adult human but may be small and light enough to be carried by an adult human.\",\n \"Further, the vehicle 100 may be of a size that it might fit into a standard van or the truck of a standard car.\",\n \"In addition, the device may be modular such that parts of the device may be easily removed and reattached.\",\n \"For example, the wings may be connected and disconnected in a manner that the wings are securely attached during flight but may be disconnected during travel to and from a location to make transporting the device easier.\",\n \"Similarly, the tail or computing system may be removed to allow easier transportation.\",\n \"Referring briefly to FIG.\",\n \"3, the vehicle 100 may have a propulsion device such as a gas motor or an electric motor 305 which may be connected to a propeller 315.The vehicle 100 also may have height adjustments through adjustable wings 325 and directional adjustments through a rudder 335 on a rear stabilizer 345.It may have a payload bay 355 that may be able to accept a variety of different sensors such as cameras and video devices.\",\n \"It may be able to land and, in some embodiments, the propellers may rotate to allow for vertical take-off and landing.\",\n \"In other embodiments, the vehicle 100 may have landing gear which may be retractable or permanent.\",\n \"A sample vehicle 100 may be described in U.S. patent application Ser.\",\n \"No.\",\n \"13/892,358 filed May 13, 2013, which is incorporated by reference in all aspects.\",\n \"By low flying, the vehicle 100 may be designed to stay below 1,000 feet for example and not limitation.\",\n \"The vehicle 100 may be designed to stay below the flight path of traditional aircraft in most situations.\",\n \"In some embodiments, the vehicle 100 may fly higher depending on the purpose of the flight, the surrounding conditions and other environmental factors.\",\n \"The vehicle 100 may be unmanned.\",\n \"It may be flown be remote control or it may have intelligence and may fly according to a programmed flight path.\",\n \"In addition, it may execute a combination of a preprogrammed flight path and remote control.\",\n \"Further, in the described embodiment, the vehicle 100 may have intelligence to receive data and adjust its flight path in response to the received data.\",\n \"As illustrated in FIG.\",\n \"2, the vehicle 100 may have a processor 202 and related computing equipment to control the path and course of the vehicle.\",\n \"The processor 202 may be physically configured to execute instructions that may be stored in a non-transitory memory.\",\n \"As illustrated in FIG.\",\n \"3, the processor 202 and memory may be mounted on a circuit board 365 and the circuit board 365 may be a load bearing member of the vehicle.\",\n \"Referring again to FIG.\",\n \"1, at block 110, flight operational data for the vehicle 100 may be determined.\",\n \"Logically, a flying vehicle 100 may collect a significant amount of flight operational data.\",\n \"In some embodiments, the flight operation data 250 may include a vehicle identifier, a present vehicle position, a present vehicle airspeed and a present vehicle heading.\",\n \"Some sample operational data may be illustrated in FIG.\",\n \"2b.\",\n \"The operational data 250 described is merely exemplary and is not meant to be limiting.\",\n \"The vehicle identifier may be a unique code used to identify the vehicle 100.Traditional aviation vehicle 100 may have unique identifiers such as serial numbers and serial numbers may also be used as part of the vehicle identifier.\",\n \"In addition, vehicles often have a code name applied to them such as TWA 1456 and a similar naming function may be used to name the vehicles discussed herein.\",\n \"Further, other combinations and naming conventions may be possible and are contemplated.\",\n \"A present vehicle 100 position may be a location in space and may be reported using GPS coordinates.\",\n \"In other embodiments, an aerospace coordinate system may be used such as the Aerospace Blockset coordinate system, other x, y, z coordinate systems such as north east down coordinates, Earth-centered inertial systems, systems used by AC3D systems, etc.\",\n \"In yet another embodiment, the vehicle 100 position may be reported in relation to a set point such as a radio tower, a building, etc.\",\n \"The present airspeed of vehicle 100 may simply be an indication of velocity such as in miles per hour.\",\n \"In another embodiment, the airspeed may also include other measures such as kilometers per hour or meters per minute.\",\n \"The present heading of vehicle 100 may indicate a heading or direction of the vehicle.\",\n \"The heading may be in terms of degree off north or degrees from a fixed location.\",\n \"In some embodiments, the heading may be user defined.\",\n \"In some embodiments, there may be additional flight operational data 505 (FIG.\",\n \"5b).\",\n \"The additional data 505 may be communicated more infrequently, such as at the start of a flight or once a time period, such as once every ten minutes.\",\n \"In other embodiments, the additional data 505 may be communicated just as frequently as the operational flight 250 data already described.\",\n \"Some of the additional data 505 may be communicated more frequently than other additional data 505.The additional flight data 505 may include planned operation data, where the planned operation data may include a planned vehicle 100 position, a planned vehicle 100 airspeed and a planned heading.\",\n \"Logically, the planned additional operational data may be for a limited time horizon as trying to communicate all future planned data may be difficult.\",\n \"In addition, the additional data 505 may include an item containing planned waypoints.\",\n \"Further, the planned route as it is stored onboard the aircraft may be viewed by an operator or remotely on a computer in communication with the vehicle 100 or the central storage device.\",\n \"The additional operational data 505 may also include a pilot identifier.\",\n \"The pilot may be the person that is monitoring the flight, may be the person that programmed the flight or may be the owner of the vehicle.\",\n \"The pilot identifier may be a name, a number, an alpha-numeric combination or other code that may be used to identify a person responsible for the flight.\",\n \"The additional operational data 505 may also include a flight plan identifier.\",\n \"The flight plan identifier may be a code that is used to identify projected path of a flight.\",\n \"The code may be unique for a time period and the other intended operational details of the flight may be accessed by accessing a database using the flight plan.\",\n \"The additional operational data 505 may also include a current latitude and longitude of the device.\",\n \"The latitude and longitude may be used to quickly identify the location of the device.\",\n \"Further, the additional operational data 505 may include the present altitude of the device, a rate of climb or decent of the device, a roll, pitch and yaw of the device.\",\n \"Such additional operational data 505 may be used to more finely track the location of the device and where the device will be in a point in time in the future.\",\n \"Again, not all the additional operational data 505 may be communicated at all times and some of the additional operational data 505 may be communicated more often than other additional operational data 505.Finally, the additional operational data 505 may include any emergency status, an emergency type, an emergency description, whether an evasive maneuver has been performed and a packet checksum which may be used to ensure that a communication has been accurately communicated and accurately received.\",\n \"Referring again to FIG.\",\n \"1, at block 120 an outbound data packet may be created that may include the desired operational data.\",\n \"The format of the outbound packet may follow a common pattern and the pattern may be predetermined.\",\n \"In some embodiments, the outbound packet may be in the form of an application programming interface (API) that may be expected by a central collection service.\",\n \"A sample outbound packet may be illustrated in FIG.\",\n \"4a and may be described below.\",\n \"Sample Packet (OutBound) 1.Randomized Packet ID (410) 2.Date/Time (420) 3.Flight ID (per flight identifier) (430) 4.Pilot Information (440) a.\",\n \"Name (441) b.\",\n \"Contact info (442) c. Credentials (443) 5.Aircraft Information (450) a.\",\n \"Make (451) b.\",\n \"Model (452) c. Weight (453) d. Category (454) e. Tail Number (455) 6.Flight Plan information (460) a.\",\n \"Flight plan ID (461) b.\",\n \"Planned altitudes (462) c. Planed flight path (463) 7.Live Telemetry Information (470) a.\",\n \"Location (471) b.\",\n \"Speed (472) c. Heading (473) d. Altitude (474) 8.Additional Information (480) a.\",\n \"May contain a number of pre-defined optional parameters (Emergency information, etc.\",\n \".\",\n \".\",\n \". )\",\n \"9.Checksum (490) A sample inbound packet may be illustrated in FIG.\",\n \"4b and is described below.\",\n \"1.Randomized Packet ID (4010) 2.Date/Time (4020) 3.Targeted flight number (4030) 4.Targeted tail number (4040) 5.Potential air vehicle obstacles (sent in array for scalability) (4050) a.\",\n \"Location (4051) b.\",\n \"Speed (4052) c. Altitude (4053) d. Heading (4054) e. Climb/decent rate (4055) f. Aircraft classification (4056) 6.Potential ground obstacle (sent in array for scalability) (4060) a.\",\n \"Location (4061) b. Altitude (4062) 7.ATC instruction Information (4070) a.\",\n \"Land (4071) b. Terminate Flight (4072) c. Adjust altitude (4073) 8.Additional Information (4080) a.\",\n \"May contain a number of pre-defined optional parameters (Emergency information, etc.\",\n \".\",\n \".\",\n \". )\",\n \"9.Checksum (4090) The length and format of the various elements of the inbound and outbound packets may be many and varied.\",\n \"For example, element 440 may be an array of data or may be a given set of elements.\",\n \"In addition, the order of the data elements may vary.\",\n \"Further, not every packet may be the same format as an emergency packet may be short while a change of course packet may be large.\",\n \"Of course, the outbound data packets may be encrypted.\",\n \"The encryption may take on a variety of forms and may include key exchange encryption.\",\n \"In some embodiments, the outbound packet may be formatted such that traditional aviation services may be able to receive and parse the packets if desired.\",\n \"The outbound packet may contain additional information to indicate that the vehicle 100 is a low flying unmanned vehicle 100.In some embodiments, the vehicle 100 may have one or more sensors 375 that may collect sensor data.\",\n \"FIG.\",\n \"5a may illustrate a method of collecting and communicating additional data and FIG.\",\n \"5b may illustrate the equipment that may be used to collect the sensor data 385.Similar to the operational data, the sensor data 385 may be collected at block 500, stored in a memory at block 510, packaged in a way to be easily communicated at block 520 and communicated to a center collection point at block 530.Sensor data 385 may be a variety of data.\",\n \"As explained in U.S. patent application Ser.\",\n \"No.\",\n \"13/892,358, which is incorporated by reference, the sensors 375 may be plugged and exchanged into the circuit board 375 and a plurality of sensors 375 may be plugged into the same circuit board 365 at the same time.\",\n \"The sensor 375 may be placed in the payload bay 355 or in other locations as needed.\",\n \"Some sample sensors 375 (and not limitations) include traditional image sensors, sensors of ranges outside human vision such as infrared, sound sensors, light sensors, LIDAR sensors, ultrasound sensors, etc.\",\n \"In some embodiments, the sensor data 385 may be communicated in the same format as the operational data 250.In other embodiments, the sensor data 385 may be communicated in a separate format than the operational data.\",\n \"Logically, traditional air traffic networks may have little or no use for sensor data 385 meaning such data may be communicated in a different frequency in a different manner than operational data 250 to make it easier for the sensor data 385 to be ignored.\",\n \"The sensor data 385 may be analyzed for relevant objects and the relevant objects may be communicated to a central collection point.\",\n \"The relevant objects may be determined in a variety of ways.\",\n \"In one embodiment, relevant objects may be determined to be over a threshold of relevance.\",\n \"FIG.\",\n \"6 may illustrate one way to determine whether an object is relevant object worthy of reporting to the central collection point and FIG.\",\n \"8 may illustrate a plurality of objects.\",\n \"At block 600, a location for the low flying unmanned vehicle 100 may be determined in a first time period.\",\n \"At block 610, a radius 705 around the location of the low flying unmanned vehicle 100 in the first time period may be determined.\",\n \"The radius 705 may vary depending on a variety of factors.\",\n \"In some embodiments, the radius 705 may be greater if the vehicle 100 is traveling at a high rate of speed such that the vehicle 100 may encounter other vehicles in a short period of time.\",\n \"Similarly, the radius 705 may be greater if other nearby objects 110 are moving at high rates of speed such that the vehicle 100 may encounter other vehicles 110 in a short period of time.\",\n \"At block 620, it may be determined whether any additional vehicles 110 will be within the radius 705 around the location of the flying unmanned vehicle 100 in the first time period based on an intended operational data of the additional vehicles 110.For example, the additional time period may be 60 seconds.\",\n \"Below is a pseudo code example of the vehicle 100 determining whether any additional vehicles will be within the radius 705.In an example, the vehicle 100 may search for nearby objects, referred to as “aggressors”, and list the aggressors in a table as set forth in the below pseudo code.\",\n \"Receive Possible Aggressor Table getNearObjects( ) The vehicle 100 may use radar, GPS, or any other technology to locate vehicles that are within a predetermined distance (e.g., within 10 miles).\",\n \"The vehicle 100 may perform a process similar to the below pseudo code to determine whether any of the identified nearby objects may be within the radius 705 in a particular time period.\",\n \"For example, the vehicle 100 may determine the current location of itself relative to each object, determine a radial distance in latitude and longitude between itself and each object, and use the radial distance to determine a current distance between itself and each object considering the curvature of the earth.\",\n \"Receive Possible Aggressor Table getNearObjects( ) For each Object in getNearObjects Data Input currentObject.Latitude=35.882234 currentObject.Longitude=−78.788222 currentObject.Altitude=30 # meters currentObject.Speed=16 # meters/sec currentObject.Track=93.6 currentObject.ID=4923 # Identifier assigned to Vehicle 100 AggressorObject.Latitude=35.866864 AggressorObject.Longitude=−78.799637 AggressorObject.Altitude=50 # meters AggressorObject.Speed=18 # meters/sec AggressorObject.Track=103.59 AggressorObject.ID=13830 # coded UAV ID uavFenceRadius.Critical=1437.38 # meters uavFenceRadius.Warning=2046.72 # meters Calculate_Distance (currentObject, AggressorObject) constR=6371000.0 # radius of earth in meters phi_1=radians(currentObject.Latitude) phi_2=radians(AggressorObject.Latitude) delta_phi=radians(AggressorObject.Latitude−currentObject.Latitude) delta_lambda=radians(AggressorObject.Longitude−currentObject.Longitude) The vehicle 100 may use delta_phi and delta_lambda to determine a distance between itself and each vehicle based on the curvature of the earth.\",\n \"This distance is referenced as “ResultRange” in the below pseudo code.\",\n \"At block 630, in response to the determination that the additional vehicles 110 will be within the radius around the location of the low flying unmanned vehicle 100 in the first time period based on the intended path of the additional vehicles 110, the relevant object may be determined as being over the threshold.\",\n \"Below is a pseudo code example for determining whether an object is determined to be over the threshold.\",\n \"For example, different thresholds may be set up based on how near an additional vehicle 110 is to vehicle 100.The different thresholds may be used by vehicle 100 to determine whether to issue a warning or whether to take evasive maneuvers.\",\n \"Evasive maneuvers may include the vehicle 100 determining a safe location and causing the vehicle to move toward the safe location.\",\n \"Check_Aggressor (ResultRange, uavFenceRadius) If ResultRange<uavFenceRadius.Critical safeLocation.Latitude=getSafeLocation.Latitude safeLocation.Longitude=getSafeLocation.Longtitude logOverrideEnabled( ) notifyOverrideEnabled( ) overrideToSafeLocation( ) If ResultRange<uavFenceRadius.Warning logOverrideWarning( ) notifyOverrideEnabled( ) At block 640, flight operational data 250 may be adjusted on the vehicle 100 based on the relevant objects 110.FIG.\",\n \"7 may illustrate a method of adjusting the operational data of the vehicle.\",\n \"At block 700, the flight path 805 of the additional vehicles 110 may be determined.\",\n \"The flight path may be determined in a variety of ways.\",\n \"In one embodiment, the operational data 250 may be analyzed to determine the location of a first additional vehicle 110 at a plurality of times in the future.\",\n \"Similarly, the location of all the additional vehicles 110 at a plurality of times in the future may be determined.\",\n \"The locations may be analyzed to determine if the additional vehicles 110 may be within the radius 705 of the unmanned vehicle 100 at a point in the future.\",\n \"In some embodiments, other vehicles 110 may not be broadcasting their operational data 250.The sensors 375 on the vehicle 100 may observe the other vehicle 110.The locations and flight operation data 250 may be determined for the other vehicles 110.For example, the distance travel over a period of time may be used to determine a speed of the additional vehicle 110.Similarly, the height of the additional vehicle 110 and the changes in direction may be observed and changes may be determined to create a flight path 805 for the observed additional vehicle 110 at points in time in the future assuming the flight path stays the same.\",\n \"Below is a pseudo code example for using sensors 375 to observe the other vehicle 110.The vehicle 100 may perform an algorithm similar to the pseudo code provided above, but instead may use sensor data to determine a current latitude, longitude, speed, and track for one or more additional vehicles 110.CheckUAVSensorArray getUAVSensorArray( ) For each Object in getUAVSensorArray SendUAVSensorArrayo Data Input currentObject.Latitude=35.882234 currentObject.Longitude=−78.788222 currentObject.Altitude=30 # meters currentObject.Speed=16 # meters/sec currentObject.Track=93.6 currentObject.ID=4923 # Identifier assigned to vehicle 100 AggressorObject.Latitude=35.866864 AggressorObject.Longitude=−78.799637 AggressorObject.Altitude=50 # meters AggressorObject.Speed=18 # meters/sec AggressorObject.Track=103.59 AgressorObject.ID=13830 # coded UAV ID uavFenceRadius.Critical=1437.38 # meters uavFenceRadius.Warning=2046.72 # meters Calculate_Distance (currentObject, uavFenceObject) constR=6371000.0 # meters phi_1=radians(currentObject.Latitude) phi_2=radians(AggressorObject.Latitude) delta_phi=radians(AggressorObject.Latitude−currentObject.Latitude) delta_lambda=radians(AggressorObject.Longitude−currentObject.Longitude) Similar to the example provided above, the vehicle 100 may use delta_phi and delta_lambda to determine a distance between itself and each additional vehicle 110 based on the curvature of the earth.\",\n \"The vehicle 100 may use the calculated distance to determine whether to issue a warning and/or to determine that a distance is critical potentially requiring vehicle 100 to initiate evasive maneuvers.\",\n \"Check_Aggressor (ResultRange, uavFenceRadius) If ResultRange<uavFenceRadius.Critical safeLocation.Latitude=getSafeLocation.Latitude safeLocation.Longitude=getSafeLocation.Longtitude logOverrideEnabled( ) notifyOverrideEnabled( ) overrideToSafeLocation( ) If ResultRange<uavFenceRadius.Warning logOverrideWarning( ) notifyOverrideEnabled( ) In some embodiments, operational data 250 may include fixed object data on fixed objects like radio antennas, large buildings, tall buildings, trees, power lines, mountains, cliffs, waypoints, etc.\",\n \"The fixed object data may be known and may be communicated to the vehicle 100 from the central collection point 545.For example, small aircraft often use maps of known fixed objects to aid in navigation and these maps may be converted into digital data which may be useable by the vehicle 100.The communication may occur during set up for a flight based on an intended flight plan or may be communicated to the vehicle 100 in real time during the flight or traveling activity.\",\n \"In any of the embodiments, the fixed object data may be used to assist in not interfering with any fixed objects.\",\n \"Below is a pseudo code example of loading data on a geofence, which may correspond to a particular geographic location of a particular fixed object, for creating an intended flight plan to avoid fixed objects.\",\n \"Receive GeoFence Table LoadGeoFence( ) For each Object in LoadGeoFence Data Input currentObject.Latitude=35.882234 currentObject.Longitude=−78.788222 currentObject.Altitude=30 # meters currentObject.Speed=16 # meters/sec currentObject.Track=93.6 currentObject.ID=4923 # Identifier assigned to vehicle 100 GeoFenceObject.Latitude=35.866864 GeoFenceObject.Longitude=−78.799637 GeoFenceObject.Height=20 # meters GeoFenceObject.ID=000483 # coded Airport code or Other Object geoFenceRadius.Critical=4437.38 # meters geoFenceRadius.Warning=5046.72 # meters Calculate_Distance (currentObject, GeoFenceObject) constR=6371000.0 # meters phi_1=radians(currentObject.Latitude) phi_2=radians(GeoFenceObject.Latitude) delta_phi=radians(GeoFenceObject.Latitude−currentObject.Latitude) delta_lambda=radians(GeoFenceObject.Longitude−currentObject.Longitude) Similar to the examples provided above, the vehicle 100 may use delta_phi and delta_lambda to determine a distance between itself and each fixed object based on the curvature of the earth.\",\n \"The vehicle 100 may use the calculated distance to determine whether to issue a warning and/or to determine that a distance is critical potentially requiring vehicle 100 to initiate evasive maneuvers to avoid one or more objects.\",\n \"Check_GeoFence (ResultRange, geoFenceRadius) If ResultRange<geoFenceRadius.Critical safeLocation.Latitude=getSafeLocation.Latitude safeLocation.Longitude=getSafeLocation.Longtitude logOverrideEnabled( ) notifyOverrideEnabled( ) overrideToSafeLocation( ) If ResultRange<geoFenceRadius.Warning logOverrideWarning( ) notifyOverrideEnabled( ) In addition, the vehicle 100 may use sensors 375 to sense fixed objects, including in areas where fixed objects have not been determined previously.\",\n \"The data on the location, height and width of the fixed objects may be determined and may be communicated to the central collection point 545 where it may be added to the fixed object data.\",\n \"In addition, the collected fixed object data may be used to verify the fixed object data store at the central server 545.Below is a pseudo code example where sensors 375 sense fixed objects for collision avoidance.\",\n \"CheckGeoSensorArray getGeoSensorArray( ) For each Object in getGeoSensorArray SendGeoSensorArray( ) Data Input currentObject.Latitude=35.882234 currentObject.Longitude=−78.788222 currentObject.Altitude=30 # meters currentObject.Speed=16 # meters/sec currentObject.Track=93.6 currentObject.ID=4923 # Identifier assigned to vehicle 100 GeoFenceObject.Latitude=35.866864 GeoFenceObject.Longitude=−78.799637 GeoFenceObject.Height=22 # meters GeoFenceObject.ID=000483 # coded Airport code or Other Object geoFenceRadius.Critical=1437.38 # meters geoFenceRadius.Warning=2046.72 # meters Calculate_Distance (currentObject, GeoFenceObject) constR=6371000.0 # meters phi_1=radians(currentObject.Latitude) phi_2=radians(GeoFenceObject.Latitude) delta_phi=radians(GeoFenceObject.Latitude−currentObject.Latitude) delta_lambda=radians(GeoFenceObject.Longitude−currentObject.Longitude) Similar to the examples provided above, the vehicle 100 may use delta_phi and delta_lambda to determine a distance between itself and each sensed fixed object based on the curvature of the earth.\",\n \"The vehicle 100 may use the calculated distance to determine whether to issue a warning and/or to determine that a distance is critical potentially requiring vehicle 100 to initiate evasive maneuvers.\",\n \"Check_Aggressor (ResultRange, geoFenceRadius) If ResultRange<geoFenceRadius.Critical safeLocation.Latitude=getSafeLocation.Latitude safeLocation.Longitude=getSafeLocation.Longtitude logOverrideEnabled( ) notifyOverrideEnabled( ) overrideToSafeLocation( ) If ResultRange<geoFenceRadius.Warning logOverrideWarning( ) notifyOverrideEnabled( ) In yet some additional embodiments, weather conditions may also be communicated to the vehicle.\",\n \"In many operating environments, the weather may not be a significant factor but in other embodiments, the weather may affect the flight or travel of the vehicle 100.For example, a steady crosswind may affect a proposed course and the trim of a flying vehicle 100 may be adjusted in advance to account for the cross wind.\",\n \"Logically, the vehicle 100 may be able to adjust while in route but the adjustment may be less drastic if the weather is factored into operational data 250 in advance.\",\n \"At block 710, it may be determined if the flight path of the additional vehicles 805 would interfere with the flight path 810 of the low flying unmanned vehicle 100.Logically, the location of the vehicles 110 at points in the future may be determined using the operation data 250 and it may be determined if the locations may be with a given radius 705.At block 720, in response to determining that the flight path of the additional vehicles 805 would interfere with the flight path 810 of the low flying unmanned vehicle 100, the flight path 810 of the low flying unmanned vehicle 100 may be adjusted to avoid the additional vehicle 110.At block 730, the flight path 810 of the low flying unmanned vehicle 100 may be adjusted to avoid the additional vehicle 100 by analyzing at least one of the low flying unmanned vehicle's performance ratings, roll, pitch yaw.\",\n \"In addition, the determining may include analyzing at least one of the following of the additional vehicle's 110 classification, speed, altitude and climb/decent rate.\",\n \"Below is a pseudo code example for determining that a flight path may interfere and adjusting the flight path.\",\n \"Initially, the vehicle 100 may identify and calculate the distance to each nearby vehicle 110.Receive Possible Aggressor Table getNearObjects( ) For each Object in getNearObjects SendNearObjectCalculated Path( ) Data Input currentObject.Latitude=35.882234 currentObject.Longitude=−78.788222 currentObject.Altitude=30 # meters currentObject.Speed=16 # meters/sec currentObject.Track=93.6 currentObject.ID=4923 # Identifier assigned to vehicle 100 AggressorObject.Latitude=35.866864 AggressorObject.Longitude=−78.799637 AggressorObject.Altitude=50 # meters AggressorObject.Speed=18 # meters/sec AggressorObject.Track=103.59 AgressorObject.ID=13830 # coded UAV ID localUAVPerformance=getUAVCaps(currentObject.ID) AggressorCapabilities=getUAVCaps(AgressorObject.ID) After determining the location of each additional vehicle 110, vehicle 100 may determine if its flight path may overlap at some future point in time with a flight path for any additional vehicle 110.Calculate_Overlap (currentObject, AggressorObject) localUAVPerformace=getUAVPerformance( ) localX=cos(currentObject.Latitude)*cos(currentObject.Longitude) localY=sin(currentObject.Longitude)*cos(currentObject.Latitude) localZ=sin(currentObject.Latitude) AggressorX=cos(AggressorObject.Latitude)*cos(currentObject.Longitude) AggressorY=sin(AggressorObject.Longitude)*cos(currentObject.Latitude) AggressorZ=sin(AggressorObject.Latitude) solveProjection: intersectionObject=find Intersection Point(localX, localY, localZ, AggressorX, AggressorY, AggressorZ) centerObject=projectazimuth(intersectionObject) intersectionSolution=solveIntersection(centerObject, localXYZ, AggressorXYZ) if (intersectionSolution>intersectionSolution+Threshold) GoTo solveProjection: Else criticalPoint.Latitude=getLatitude(intersectionSolution.XYZ) critical Point.Longitude=getLongitude(intersectionSolution.XYZ) To determine whether at some time the flight path of an additional vehicle 110 potentially would intersect with the vehicle's flight path—referred to as the “critical point”—the vehicle 100 may periodically (or continuously) calculate the distance between itself and the critical point.\",\n \"Calculate_Distance (currentObject, criticalPoint) constR=6371000.0 # meters phi_1=radians(currentObject.Latitude) phi_2=radians(criticalPoint.Latitude) delta_phi=radians(criticalPoint.Latitude−currentObject.Latitude) delta_lambda=radians(critical Point.Longitude−currentObject.Longitude) Similar to the examples provided above, the vehicle 100 may use delta_phi and delta_lambda to determine a distance between itself and the critical point based on the curvature of the earth.\",\n \"The vehicle 100 may use the calculated distance to determine whether to issue a warning and/or to determine that a distance is critical potentially requiring vehicle 100 to initiate evasive maneuvers.\",\n \"Below is example pseudo code for taking evasive maneuvers.\",\n \"update_track (criticalPoint, localUAVPerformace, currentObject.Altitude, aggressorObject.Altitude, ResultRange) activateAvoidance(localUAVPerformance, ResultRange, currentObject.Altitude) escapeVector=optimizeFlightPath(criticalPoint) activateUpdatedTrack(escapeVector) In some examples, the additional vehicle 110 may be a commercial airliner and the flight path 805 of the additional vehicle 110 may be received from a traditional airline flight path data tracking system.\",\n \"As is known, commercial aircraft broadcast their location to airline control systems.\",\n \"This data may be used to determine operational data 250 about the commercial flights.\",\n \"In yet another embodiment, the vehicle 100 may use sensors 375 that sense for commercial aircraft using known flight data, and determine operational data 250 about the sensed aircraft.\",\n \"For example, apps exist for a portable computing device which may recognize commercial aircraft.\",\n \"The data may then be matched with known flight plans to determine the likely path of the commercial airliner.\",\n \"As an obvious example, the vehicle 100 may recognize a flight and determine if the flight is taking off (where it will likely rise) and if a flights is landing (where the flight will likely descend).\",\n \"Referring again to FIG.\",\n \"1, at block 130, the outbound data packet may be formatted to be wirelessly communicated, for example, over a mobile communication network 515 (FIG.\",\n \"5).\",\n \"The formatting may take on a variety of forms and other communication networks may also be used (e.g., a satellite, WiFi, WiMax, etc.\",\n \"communication network).\",\n \"In one embodiment, the formatting 515 may include creating at least one selected from the group of a SMS message, a cellular transmission 525, a satellite data transfer or an ADS-b communication 535.The choice of communication form may relate to the height of the vehicle 100.For example, if the vehicle 100 is above 1500 feet (532), ADS-b may be used and if the vehicle is below 1500 feet, cellular technology may be used.\",\n \"In addition, the strength of the various communication forms may be analyzed and the strongest signal may be selected for communication.\",\n \"At block 140, the outbound data packet may be wirelessly communicated (e.g., over the mobile communication network) to a collection site 545.The collection site 545 may include a communication device for receiving mobile communication.\",\n \"The central collection point 545 may have a variety of forms.\",\n \"In one embodiment, the central collection point 545 may be a plurality of computing systems which communicate with each other.\",\n \"The central collection point 545 may accept communications that represent traditional airline flight paths and communicates unmanned flight data to the traditional airline flight path data tracking system.\",\n \"At block 150, an inbound data packet may be received from the collection site.\",\n \"The inbound data packet may include data regarding relevant objects 110 determined to be over a threshold as explained previously.\",\n \"In some embodiments, receiving an inbound data packet from the collection site 545 may also require that the inbound data packet include data regarding relevant objects 110 where relevant objects 110 have been determined to be over a relevance threshold.\",\n \"As mentioned previously, the relevance threshold may include determining if the object 110 will be in range of the unmanned flying object 100 within a time threshold or a distance threshold.\",\n \"The collection site 545 may include a plurality of communication formats and the object 110 may be an immovable object or a moveable object.\",\n \"At block 160, flight operational data 250 may be adjusted on the vehicle 100 based on the relevant objects 110.The method may take a variety of actions from changing direction, to changing height and to adjusting speed or a combination of any of the various adjustments.\",\n \"For example, the vehicle 100 may speed up and turn right to avoid an incoming additional object 110.The device 100 may have a variety of hardware to implement the vehicle 100.Referring to FIG.\",\n \"2, the vehicle 100 may have a GPS chip 215 which may collect location information which may be parsed by the CPU 160 for necessary information.\",\n \"As mentioned previously, the GPS data may be communicated in its raw format at times received from various satellites, may be converted into latitude and longitude or may be converted into yet another form that may be helpful in determining locations and flight paths.\",\n \"The vehicle 100 may also have a cellular network processing chip 525 which may accept commands from the CPU 160 to send encrypted data over a cellular network to a ground based server 545 and may receive and read information sent to the cellular chip 525 from the central server 545 and send to the CPU 160 for parsing.\",\n \"The cellular network processing chip 525 may take the data to be communicated to and from the central point 545 and use an algorithm to allow the data to be communicated back and forth over the cellular network 525.A central processing unit (CPU) 160 may perform a variety of computing functions.\",\n \"In one aspect, the CPU 160 may parse GPS information, may send encrypted messages to the cellular chip 525, may accept and parse incoming information from the cellular chip 525, and may communicate commands to any integrated autopilot system 225 or flight control servos.\",\n \"The CPU 160 may be purpose built to meet the challenged created by the vehicle 100.For example, the CPU 160 may need to be efficient as the vehicle 100 may be powered by a battery 235 which may have a limited amount of power.\",\n \"Similarly, the CPU 160 may be an off the shelf CPU 160 that is physically configured to computer executable instructions and is sufficiently efficient.\",\n \"The vehicle 100 may also have connectivity ports (not shown) which may allow for a connection to other systems such as ADS-b Transmitter/Receiver Module 535 which may operate in the 1033 MHz band.\",\n \"It should be noted that ADS-b coverage may only exist at 1500+ feet above ground level.\",\n \"The modular additions may provide a means or manner to connect to different autopilot systems to send maneuver commands for detect and avoid needs in the case of possible collision.\",\n \"For example, the device may operate using GPS coordinates and a second device may operate using height and direction vectors and an additional modular addition may be used to translate flight operations of the first device into direction vectors which may be used by the second device.\",\n \"The ports may be standard ports such as USB ports or may be purpose built ports.\",\n \"In addition, the CPU 160 may have instructions on what to do if an additional computing device is inserted into the ports such as how to communicate with the device, how to determine if the device is safe, which device has precedence, etc.\",\n \"The vehicle 100 may also have a battery 235 and/or external power connections.\",\n \"The battery may allow the system to be powered by a UAV independent battery or allow for connection directly into the UAV flight power system.\",\n \"In some embodiments, the battery 235 may be used to provide additional power to the UAV if the UAV loses or runs low on power.\",\n \"In some embodiments, the battery 235 supplies 5-24 volts but the vehicle 100 may operate with a variety of voltages and current ratings.\",\n \"The vehicle 100 may also have roll, pitch, yaw, and accelerometer sensors 375.The sensors 375 may provide IMU data to assist in evasive maneuver planning calculations.\",\n \"The current location of the device is only part of the data needed to determine if a flight collision may occur as the vehicle 100 may change course.\",\n \"The roll, pitch, yaw and accelerometers sensors 375 may assist in determining a future course for the vehicle 100 and whether a collision is likely.\",\n \"Below is a pseudo code example for determining evasive maneuver planning calculations.\",\n \"Initially, the vehicle 100 may use sensors to identify each nearby vehicle 110 and then calculate the distance to each sensed nearby vehicle 110.CheckUAVSensorArray getNearObjects ( ) localUAVSensor=getUAVSensorArray( ) For each Object in getUAVSensorArray SendUAVSensorArrayo SendNearObjectCalculated Path( ) Data Input currentObject.Latitude=35.882234 currentObject.Longitude=−78.788222 currentObject.Altitude=30 # meters currentObject.Speed=16 # meters/sec currentObject.Track=93.6 currentObject.ID=4923 # identifier of vehicle 100 AggressorObject.Latitude=35.866864 AggressorObject.Longitude=−78.799637 AggressorObject.Altitude=50 # meters AggressorObject.Speed=18 # meters/sec AggressorObject.Track=103.59 AgressorObject.ID=13830 # coded UAV ID uavFenceRadius.Critical=1437.38 # meters uavFenceRadius.Warning=2046.72 # meters After determining the location of each additional vehicle 110, vehicle 100 may determine if its flight path may overlap at some future point in time with that of any additional vehicle 110.Calculate_Overlap (currentObject, AggressorObject) localUAVPerformace=getUAVPerformance( ) localX=cos(currentObject.Latitude)*cos(currentObject.Longitude) localY=sin(currentObject.Longitude)*cos(currentObject.Latitude) localZ=sin(currentObject.Latitude) AggressorX=cos(AggressorObject.Latitude)*cos(currentObject.Longitude) AggressorY=sin(AggressorObject.Longitude)*cos(currentObject.Latitude) AggressorZ=sin(AggressorObject.Latitude) solveProjection: intersectionObject=find Intersection Point(localX, localY, localZ, AggressorX, AggressorY, AggressorZ) centerObject=projectazimuth(intersectionObject) intersectionSolution=solveIntersection(centerObject, localXYZ, AggressorXYZ) if (intersectionSolution>intersectionSolution+Threshold) GoTo solveProjection: Else criticalPoint.Latitude=getLatitude(intersectionSolution.XYZ) critical Point.Longitude=getLongitude(intersectionSolution.XYZ) To determine whether at some time the flight path of an additional vehicle 110 potentially may intersect with the vehicle's flight path—referred to as the “critical point”—the vehicle 100 may calculate the distance between itself and the critical point.\",\n \"Calculate_Distance (currentObject, criticalPoint) constR=6371000.0 # meters phi_1=radians(currentObject.Latitude) phi_2=radians(criticalPoint.Latitude) delta_phi=radians(criticalPoint.Latitude−currentObject.Latitude) delta_lambda=radians(critical Point.Longitude−currentObject.Longitude) Similar to the examples provided above, the vehicle 100 may use delta_phi and delta_lambda to determine a distance between itself and the critical point based on the curvature of the earth.\",\n \"The vehicle 100 may use the calculated distance to determine whether to issue a warning and/or initiate evasive maneuvers.\",\n \"Below is example pseudo code for initiating evasive maneuvers.\",\n \"update_track (criticalPoint, localUAVPerformace, currentObject.Altitude, aggressorObject.Altitude, localUAVSensor, ResultRange) activateAvoidance(localUAVPerformance, localUAVSensor, ResultRange, currentObject.Altitude) escapeVector=optimizeFlightPath(criticalPoint) activateUpdatedTrack(escapeVector) The vehicle 100 may also have a localized wireless module 180.The localized wireless module 180 may allow for connection and configuration via a secondary handheld device such as a portable computing device (cellular phone) where one may access additional feature of the vehicle 100.The flight data may be loaded into or received from the vehicle 100 in a variety of ways and the wireless module 180 may allow additional computing devices to wirelessly communicate with the device.\",\n \"The following may be an example of the device 100 in operation.\",\n \"A low flying unmanned vehicle 100 may be flying over a farm field.\",\n \"An airliner 100 may also be nearby, preparing to land.\",\n \"The vehicle 100 may have an infrared camera to determine the water content of the crops in the field.\",\n \"On a periodic basis, the vehicle 100 may report its operational data 250 to a nearby cellular tower.\",\n \"The data may be encapsulated as an SMS message or in any other appropriate format or form such as cellular, satellite, WiFi, WiMax, etc., and may be directed to a central collection site 545.The central collection site 545 may receive and analyze the operational data 250 from the vehicles and aircraft which may be stored in a database or server 172.The analysis may quickly parse the vehicles into geographic areas.\",\n \"As mentioned previously, the vehicle 100 may determine if any of the additional vehicles 110 will be in a radius around each other in a relevant range or radius 705 and the flights that are determined to be over a threshold or nearby may be stored as separate flights 174.The vehicle 100 may receive messages 525 from the cellular tower which also may be encapsulated as SMS messages or in any other appropriate format or form such as cellular, satellite, WiFi, WiMax, etc.\",\n \"The messages may contain operational data 250 from a second low flying unmanned vehicle 110 working on an adjacent field.\",\n \"In addition, the vehicle 100 may use GPS 215 to determine its current location which along with relevant location and flight parameters 176.The operational data 250 and operational data for the additional vehicle 110 may communicated to the CPU 160 where an algorithm 182 may have physically configured the CPU to determine the flight path of the vehicle 100 and the flight path of other relevant vehicles 110 and whether the paths may intersect.\",\n \"The algorithm may take into account the current position and projected path at points in time in the future for vehicles 100, 110 to determine if a collision may occur.\",\n \"If the algorithm 182 determines a collision is likely, evasive maneuver commands 184 may be created and made be communicated to the vehicle 100.If the vehicle 100 has auto pilot 225, the maneuver commands 184 may communicated to the autopilot system 225 on the vehicle 100 where it may be interpreted and communicated to the flight control servos 227 module which may execute the maneuver.\",\n \"If the vehicle 100 does not have autopilot 225, the command may be communicated directly to the flight control servos 227.FIG.\",\n \"9a may illustrate another embodiment of the system.\",\n \"In this embodiment, the processor 160 may receive additional information.\",\n \"In one aspect, a database with geofence data 931 may also be in communication with the processor 160.Geofence data may include data about location which the vehicle 100 should avoid such as restricted airspace, airport, congested area, buildings, tree lines, power lines, etc.\",\n \"Geofence data may be known and may be created in advance of a flight.\",\n \"In some embodiments, the geofence data may be targeted to the general area of the vehicle.\",\n \"For example, data on geofences in China may not be relevant to a vehicle that is operating in the United States.\",\n \"Different modules of geofence data may be available and loaded depending on the location of the vehicle.\",\n \"In this arrangement, less data with have to be sifted to obtain the information that is most relevant.\",\n \"The geofence data may come from a variety of sources.\",\n \"As an example, the US government may publish a data on restricted regions.\",\n \"In addition, the position of buildings which would interfere with vehicular travel may be obtained from a mapping data source.\",\n \"The data may be aggregated into a single file for rapid access and ease of understanding.\",\n \"In some embodiments, the geofence data may also include a “whitelist” or data about locations that are not subject to a geofence.\",\n \"The whitelist data may be a useful double check to ensure that a vehicle is clear to travel.\",\n \"Further, the data may be reviewed in advance of a session to ensure a vehicle is safe to travel.\",\n \"Real time obstacle data may also be stored and used such that the obstacle data may be immediately shared with others.\",\n \"For example, if a hot air balloon is unexpectedly preparing to land, the data on the location, direction and path of the balloon may be stored in the real time obstacle database 921.The data on the obstacles also may be shared through communication links to a central authority that may add the real time obstacle data to its database and it may communicate the obstacle data to other nearby vehicles.\",\n \"Thus, other vehicles in the area may be promptly informed of the obstacle.\",\n \"A tamper detection module 931 may also be part of the system.\",\n \"The tamper detection module 931 may operate in a variety of ways.\",\n \"In one embodiment, the module may monitor time differentials from the autopilot to determine if someone unauthorized has tampered with the processor 160.For example, if the time differentials are not as expected, the assumption may be made that someone has tampered with the processor 160.In yet another embodiment, the processor may be cemented in place in the circuit board may break if an attempt is made to modify or remove the processor 160.Similarly, the processor may periodically self-check itself to ensure it is operating as expected and if the self-check fails, the vehicle may render itself inoperable until the unexpected conditions are fixed.\",\n \"Common self-checks including comparing the current surroundings to surrounds that should be expected based on the GPS signals and previous images from the GPS coordinates, checking battery life in comparison to an expected flight length, etc.\",\n \"At block 2222, an external autopilot may also be used to assist the vehicle.\",\n \"In the situation where the processor 160 determines that the current travel plan needs to be changed to avoid an obstacle, for example, the new travel plan may be communicated to an external autopilot 2222.The new travel plan may override the current travel mode.\",\n \"The external autopilot 2222 may submit a new travel plan which the processor 160 may review to ensure the vehicle does not cross any geofences, cross into the flight path of any other known vehicles, does not hit any buildings, etc.\",\n \"The external autopilot may be able to direct the vehicle from hitting a first obstacle, but the processor may be knowledge of even more obstacles than the outside autopilot.\",\n \"Thus the new flight plan may be reviewed by the processor 160.In addition, the new flight plan may be communicated to traffic management for routing other vehicles and letting other vehicles know of the intended travel plan.\",\n \"Below is a pseudo code example for determining whether to change a flight path to avoid an obstacle.\",\n \"In an example, the vehicle 100 may periodically or continuously identify and calculate the distance to each nearby additional vehicle and/or obstacle.\",\n \"Receive Possible Aggressor Table getNearObjects( ) LoadGeoFence( ) For each Object in getNearObjects SendNearObjectCalculated Path( ) Data Input currentObject.Latitude=35.882234 currentObject.Longitude=−78.788222 currentObject.Altitude=30 # meters currentObject.Speed=16 # meters/sec currentObject.Track=93.6 currentObject.ID=4923 # identifier of vehicle 100 AggressorObject.Latitude=35.866864 AgressorObject.Longitude=−78.799637 AggressorObject.Altitude=50 # meters AggressorObject.Speed=18 # meters/sec AggressorObject.Track=103.59 AggressorObject.ID=13830 # coded UAV ID GeoFenceObject.Latitude=35.866864 GeoFenceObject.Longitude=−78.799637 GeoFenceObject.Height=22 # meters GeoFenceObject.ID=000483 # coded Airport code or Other Object geoFenceRadius.Critical=1437.38 # meters geoFenceRadius.Warning=2046.72 # meters localUAVPerformance=getUAVCaps(currentObject.ID) AggressorCapabilities=getUAVCaps(AgressorObject.ID) After determining the location of each nearby additional vehicle and/or obstacle, vehicle 100 may determine if its flight path may overlap at some future point in time with either.\",\n \"Calculate_Overlap (currentObject, AggressorObject) localUAVPerformace=getUAVPerformance( ) localX=cos(currentObject.Latitude)*cos(currentObject.Longitude) localY=sin(currentObject.Longitude)*cos(currentObject.Latitude) localZ=sin(currentObject.Latitude) AggressorX=cos(AggressorObject.Latitude)*cos(currentObject.Longitude) AggressorY=sin(AgressorObject.Longitude)*cos(currentObject.Latitude) AggressorZ=sin(AggressorObject.Latitude) solveProjection: intersectionObject=find Intersection Point(localX, localY, localZ, AggressorX, AggressorY, AggressorZ) centerObject=projectazimuth(intersectionObject) intersectionSolution=solveIntersection(centerObject, localXYZ, AggressorXYZ) if (intersectionSolution>intersectionSolution+Threshold) GoTo solveProjection: Else criticalPoint.Latitude=getLatitude(intersectionSolution.XYZ) critical Point.Longitude=getLongitude(intersectionSolution.XYZ) To determine whether at some time the flight path of an additional vehicle and/or obstacle potentially may intersect with the vehicle's flight path—referred to as the “critical point”—the vehicle 100 may periodically (or continuously) calculate the distance between itself and the critical point.\",\n \"In some instances, there may be multiple critical points (e.g., one for a fixed object, one for an additional vehicle, and another for a geofence).\",\n \"Calculate_Distance (currentObject, criticalPoint) constR=6371000.0 # meters phi_1=radians(currentObject.Latitude) phi_2=radians(criticalPoint.Latitude) delta_phi=radians(criticalPoint.Latitude−currentObject.Latitude) delta_lambda=radians(critical Point.Longitude−currentObject.Longitude) Calculate_Distance (currentObject, GeoFenceObject) constR=6371000.0 # meters phi_1=radians(currentObject.Latitude) phi_2=radians(GeoFenceObject.Latitude) delta_phi=radians(GeoFenceObject.Latitude−currentObject.Latitude) delta_lambda=radians(GeoFenceObject.Longitude−currentObject.Longitude) Similar to the examples provided above, the vehicle 100 may use delta_phi and delta_lambda to determine a distance between itself and each critical point based on the curvature of the earth.\",\n \"The vehicle 100 may use the calculated distance to determine whether to issue a warning and/or initiate evasive maneuvers.\",\n \"Below is example pseudo code for initiating evasive maneuvers.\",\n \"update_track (criticalPoint, localUAVPerformace, currentObject.Altitude, aggressorObject.Altitude, ResultRange, GeoFenceResultRange) activateAvoidance(localUAVPerformance, ResultRange, currentObject.Altitude) escapeVector=optimizeFlightPath(criticalPoint) flightPlan=updateFlightPlan(escapeVector, GeoFenceObject, ResultRange, GeoFence ResultRange) activateUpdatedTrack(escapeVector, flightPlan) A Common Connector A “breadcrumb” system may also be used to ensure a vehicle 100 will be able to find its way even if traditional GPS systems stop working.\",\n \"The breadcrumb systems may have a plurality of aspects and may work in a variety of ways, some of which may complement each other.\",\n \"In one aspect, the vehicle may take images while following a flight plan.\",\n \"If a GPS signal is lost, a vehicle may recall these images (e.g., from memory or other data storage device), compare the current image to the known images from the initial flight path and change its flight path toward the objects which are recognized.\",\n \"In addition, if no objects are recognized, the vehicle may travel in ever increasing circles until it traverses terrain that is recognized.\",\n \"Below is example pseudo code of this process.\",\n \"In the below example, the vehicle 100 may capture images while flying and assign GPS coordinates to each image, prior to failure of a GPS system.\",\n \"The captured images may be stored for later comparison should the GPS system stop working.\",\n \"When using the breadcrumb system, the vehicle 100 may compare captured images to stored images looking for matches.\",\n \"The vehicle 100 may also assign confidence scores based on the degree of matching.\",\n \"Matches may be used to guide the vehicle in the absence of GPS data.\",\n \"Finger Print Current Fly Over Image localUAVSensor=getUAVSensorArray( ) #9 Axis Accelerometer dead-reckoning=getPositionOffset(localUAVSensor) imageMatchThreshold=489 # configurable location Images=getLocationImages(lastGPS.Latitude+dead-reckoning, lastGPS.Longitude+dead-reckoning, gps.Altitude+dead-reckoning) #Land image fingerprints are small in size compared to actual images.\",\n \"Images are stored in local memory and may be updated currentImage=captureImage( ) imagePrint=fingerprintImage(currentImage) For each searchimage in locationimages Data Input If (imageMatch (locationImages.fingerprint, imagePrint.fingerprintd)>485) proposedLocation=newLocation( ) assignedConfidence=newConfidence(previousConfidence) Continue to New Track Pathway In another aspect, the vehicle may review images related to the current location of the vehicle.\",\n \"If there are existing images from past flights, the existing images may include additional such as GPS data related to the images.\",\n \"Thus, the vehicle may traverse and take images and if the new images match past images, the GPS coordinated from the past image may be used to indicate the current GPS location.\",\n \"Further, the vehicle may have noted its GPS position at the beginning of its flight.\",\n \"By collecting addition GPS data from additional known sites with stored GPS locations, the vehicle may be able to triangulate its position and determine a path to its starting point or another stored rendezvous location.\",\n \"In another aspect, the vehicle 100 may simply attempt to reverse its current path.\",\n \"In some conditions such as when it is windy, the ability to retrace a path may be especially difficult but images from the initial flight path may be used to guide the vehicle back toward its starting point.\",\n \"Below is example pseudo code applied by vehicle 100 to reverse its path using images.\",\n \"Finger Print Current Fly Over Image reverseWaypoint=getWaypoint(atIndex) localUAVSensor=getUAVSensorArray( ) #9 Axis Accelerometer dead-reckoning=getPositionOffset(localUAVSensor) imageMatchThreshold=489 # configurable location Images=getLocationImages(lastGPS.Latitude+dead-reckoning, lastGPS.Longitude+dead-reckoning, gps.Altitude+dead-reckoning) #Land image fingerprints are small in size compared to actual images.\",\n \"Images are stored in local memory and may be updated currentImage=captureImage( ) imagePrint=fingerprintImage(currentImage) For each searchimage in locationimages Data Input If (imageMatch (locationImages.fingerprint, imagePrint.fingerprintd)>485) proposedLocation=newLocation(reverseWaypoint) assignedConfidence=newConfidence(previousConfidence) Continue to New Track Pathway activateUpdatedTrack(proposedLocation, flightPlan) In another aspect, the vehicle 100 may make note of its starting point in a variety of ways and these starting point notations may be used to guide the vehicle back to its starting location or another desired location.\",\n \"In one embodiment, the vehicle may receive and store cell phone tower information such as the tower identifier, a timing signal and the signal strength of the various cell towers.\",\n \"The location of the cell towers may be fixed.\",\n \"From analyzing the cell tower signal strength or timing signals, triangulation may be used to determine a starting location.\",\n \"Assuming the cell tower and vehicle both have access to an accurate and consistent time reference, timing signals may be a very accurate indication of when a signal was sent.\",\n \"The vehicle may receive the signal at a later time and the difference between the send time and the received time may be used to determine the distance from the cell tower as the velocity of the cell tower signal may be known.\",\n \"Triangulation may be used to determine the location of the vehicle in relation to the various cell towers.\",\n \"In addition, the GPS location of the cell towers may be known and the GPS location of the vehicle may be determined using the GPS coordinates of the cell towers and the timing signals.\",\n \"Similarly, the timing signals from cellular towers may be used to determine a location of the vehicle if a GPS signal is lost in flight.\",\n \"Using timing and known cell tower locations, triangulation may be used to determine a location of the vehicle.\",\n \"Further, the cell tower signals may be used to guide the vehicle back to a start point or to an additional location.\",\n \"Signal strength from various cell towers may be known and the received signal strength from a plurality of cell towers may be used to determine the location of the vehicle.\",\n \"Similar to timing signals, the signal strength may be known at given locations and may be used to determine a location of a vehicle by comparing the observed signal strength to previously mapped signal strength measurements.\",\n \"Other broadly available signals may be used to triangulate a location if GPS signals fail.\",\n \"In some situations, traditional radio signals such as AM and FM may have known signal strengths in known locations.\",\n \"At a minimum, the signal strengths may be used to narrow down the list of possible locations and at best, triangulation may be possible from a variety of signals from a variety of towers to establish either a starting location or a current location.\",\n \"Signals from non-GPS satellites such as television satellites or wireless phone satellites, known WiFi signals also may be received and used to triangulate locations.\",\n \"Finally, traditional method of observing sun, moon and stars and the time of day may be used.\",\n \"As the location of the sun, moon, and certain star may be known at given times, locations may be determined.\",\n \"The locations may not be as accurate as GPS signals but may provide useful guidance.\",\n \"Of course, elements of these various aspects may be combined to create a more accurate location.\",\n \"For example, if two cell phone towers signals may be received and a single FM signal, three signals may be combined to attempt to triangulate a location.\",\n \"Further, the additional various signals may be used to verify a location in situations where a GPS signal may be in doubt.\",\n \"In some embodiments, a homing signal may be communicated from a device at a point of origin or at another desired location.\",\n \"The signal may be a low power, low frequency signal that may be heard from great distances.\",\n \"The vehicle may execute a travel pattern such as a series of circles or squares which may be used to determine a general travel path and as the vehicle moves closer to the source of the signal, the path may be further improved to maximize the received signal which would indicate the beacon is near.\",\n \"In some embodiments, the vehicle may contain the homing signal.\",\n \"The homing signal may be used if there is a major failure and the launching vehicle may need to locate the vehicle.\",\n \"For example, if GPS is lost, the vehicle may travel in a limited space that has been determined to be safe and may operate the homing signal.\",\n \"If power drops to a predetermined level, the vehicle may take steps to determine a safe landing location and may continue to communicate the homing signal.\",\n \"Of additional interest, the vehicle may be equipped with a flight control override intervention module 225.The module may sit between the autopilot and flight controls and may provide the processor 160 controlled manual override to the controls in case of no autopilot integration.\",\n \"As a result, an authority such as the FAA may have the ability to override a vehicle travel plan.\",\n \"The override may be for any purpose such as to avoid a collision or to free the area for an authority vehicle such as a police vehicle.\",\n \"FIG.\",\n \"9b may illustrate a backend 2222 of a traffic management system.\",\n \"At a high level, numerous systems may feed data to the traffic management system backend 2222 including an analytics engine 1001, databases 1101, traffic management modules 1201 and various FAA data sources 1301, 1311, 1321.The analytics engine may review data collected on vehicles operations and operators and may attempt to come to some useful conclusions.\",\n \"The data from all vehicles that use the system and method may be collected.\",\n \"In addition, real time data on current systems may be collected.\",\n \"From this collection of data, algorithms may attempt to review and quantify risk.\",\n \"For example, the data may determine that pilot A is prone to errors while pilot B is extremely careful and has little risk.\",\n \"The data may even show that certain pilot demographics are more risky than others.\",\n \"For example, an algorithm may study the flight data and determine that pilots under the age of 25 may be riskier than pilots aged 34-43.Similarly, it may be determined that certain vehicles are riskier than others.\",\n \"Logically, there may be a variety of conclusions that may be drawn from the data and may be used as part of the system.\",\n \"As an example, if a risky pilot is flying a risky vehicle, a warning may be issued that the risk of this flight is over a predetermined threshold which may be a user threshold, a calculated threshold or a default threshold.\",\n \"Below is pseudo code for determining whether to issue a warning.\",\n \"Device Side: Update Analytics Engine Service sendGeoSensorArray(geoSearchData) sendImageFingerprint(imageFingerprintData) sendAudioGeoSensorData(audioData) sendRFSpectrumData(RFAnalysisData) sendNearObjectData(gpsData, Range, AgressorObject) Cloud Side: Aggregate Data Service updateGeoFenceData(geoSearchData) updateImageArchive(imageFingerprintData) updateAudioData(audioData) updateRFData(RFAnalysisData) updateNearObjectData(gpsData, Range, AggressorObject) Databases 1101 also may feed data to the traffic management system 2222.A first database 1111 may store real time data on aerial obstacles in the relevant area such as other vehicles.\",\n \"A second database may store data on obstacles 1121 such as building, power lines, windmills, silos, trees, etc.\",\n \"A third database 1131 may include pilot/aircraft registration data which may include information on pilots and planes which may be used to assess risk.\",\n \"A flight log database 1141 may be used to store flight logs on past flights such that the flights may be replayed in the future.\",\n \"A flight plan database 1151 may store all flight plans that are submitted by pilots which may be accessed and used to create additional flight paths in the future.\",\n \"A traffic management module 1201 may be used to determine flight routing data to be communicated to the traffic management system backend 2222.The routing may pull in plans as they are submitted 1211 to the processor 160, may determine if a route collision is possible in comparison to other flight plans and geofences.\",\n \"At block 1231, the system may determine if a collision is possible, and then a new flight path may be suggested to the processor 160 of the vehicle.\",\n \"Other agencies related to tracking vehicles may also submit useful data.\",\n \"NASA 1301 may submit flight plans which may need to be submitted to the traffic management system 2222.Similarly, FAA air traffic control 1311 may import and report real time information on manned aircraft from the FAA ATC system.\",\n \"The FAA Air Traffic Control may escalate situations up to live traffic management personnel such as emergency or other situations that might require a manual override.\",\n \"FIG.\",\n \"9c may illustrate a user interface that interfaces with the traffic management system 2222.A flight planning module 1501 may make it easy for pilots of vehicles to submit flight plan 1511 through a variety of interfaces such as a web browser interface.\",\n \"A variety of information may be collected 1521 such as a general area of the vehicle, the proposed vehicle path, the pilot information, the craft information and the operation type.\",\n \"An interface may also allow easy access to review all the data on vehicle and vehicle travel plans.\",\n \"Logically, the data may be restricted and a login may be required 1611.The login may be a traditional login or may be a secure electronic key exchange or may require biometric verification of the proposed users.\",\n \"It may be web or cloud based or may be a purpose built computer.\",\n \"A general user 1621 may be presented with a user interface tailored to that individual.\",\n \"Accessible features to a general user 1621 may include personal flight logs, registration data for the local system, account settings, geo-fence information, option to see old flight logs, see meta data regarding flights, and performing algorithms to analyze the risk of a flight.\",\n \"An administrator 1631 may be able to see more data 1651.For example, the administrator may see all known vehicles in real time, all vehicle travel logs, all current or past notifications or interventions, all geofence information, the option to update geofence data, the option to force a vehicle to undertake an action, communicate real-time notifications to user, perform risk analysis on flight data and research performance analysis.\",\n \"The data may be in an easy to see graphical interface which may facilitate understanding by displaying the complicated data in an easy to understand and access format.\",\n \"Below is example pseudo code for sending sense and avoid data to vehicle 100.Receive RealTime Sense and Avoid Data from UAV calculatePriority=processIncomingSenseData(currentObject) targetConfirmedNew=confirmNewTarget( ) addNewTarget(targetConfirmedNew) For each UAVRequest from currentObject sendRealTimeData( ) # send current live sense and avoid data to UAV The processor 160 may be integral to a vehicle 100 such as being on a circuit board that is a structural member.\",\n \"In other embodiments, the processor 160 is a separate device which may be used to control virtually any vehicle via a standard protocol and interface, such as an Ethernet jack, Bluetooth, WiFi or fiber communication link.\",\n \"The processor 160 also may be light weight and compact and may be designed to extend external power.\",\n \"For example, processor sections which are not is use may be turned off when not needed.\",\n \"As an example, a sound function may be useful during programming a flight path but may not be useful during flight.\",\n \"FIG.\",\n \"10 may be an illustration of a sample device.\",\n \"The processor 160 may be placed on or integrated into existing small vehicles such as UAV platforms.\",\n \"The processor 160 or chip may stand-alone, providing a framework which will allow real-time tracking of small vehicles at altitudes between 0-1000 ft above ground level.\",\n \"The core framework may be expandable and modular to interface with numerous communication protocols.\",\n \"The standard form of communication may be achieved over cellular networks even at their lowest bandwidth, however, the communication may be expanded to run on other networks such as wide-area WIFI and ADS-b.\",\n \"The system hardware may be incorporated onto vehicles by three methods.\",\n \"The hardware may be purchased stand-alone as a device which mounts onto any airframe without any autopilot integration, providing real time tracking information only.\",\n \"The second method is a stand-alone unit which may plug into a number of pre-integrated autopilots (3dr, APM, DJI, etc.).\",\n \"Providing real time tracking coupled with autopilot override functionality enabling sense-and-avoid capability.\",\n \"The third integration solution may be provided by licensing build schematics of the hardware to vehicle manufacturers, allowing them to incorporate the system directly onto their integrated circuits.\",\n \"The firmware may be strictly maintained by a single source, with updates provided over the cellular network infrastructure.\",\n \"In another aspect, the vehicle 100 may attempt to use sound mitigation techniques to make the vehicle quieter.\",\n \"As is known, a wave that is in opposite phase of a first wave may cancel out the first wave.\",\n \"In the case of sound wave, the sound from a vehicle may be captured and a sound generator may create a sound in the opposite phase of the vehicle.\",\n \"Further, the sound mitigation may review a flight plan and anticipate changes in sound such as a call for increased prop speed.\",\n \"Such an increase may be anticipated and may be mitigated.\",\n \"As a result, the “buzzing” of tradition unmanned aircraft may be reduced or eliminated.\",\n \"Of course, other methods of reducing sound, such as insulation, are possible and are contemplated.\",\n \"Below is a pseudo code example for determining whether to initiate audio suppression.\",\n \"In the below example, the vehicle 100 may determine its distance relative to a geofence.\",\n \"If too close, then the vehicle 100 may determine that a change in flight plan may be required that involves a change in prop speed and noise suppression to counteract noise generated due to the change in prop speed.\",\n \"Receive AudioGeoFence Table LoadAudioGeoFence( ) For each Object in LoadGeoFence Data Input currentObject.Latitude=35.882234 currentObject.Longitude=−78.788222 currentObject.Altitude=30 # meters currentObject.Speed=16 # meters/sec currentObject.Track=93.6 currentObject.ID=4923 # identifier of vehicle 100 AudioGeoFenceObject.Latitude=35.866864 AudioGeoFenceObject.Longitude=−78.799637 AudioGeoFenceObject.Height=20 # meters AudioGeoFenceObject.ID=000483 # coded Airport code or Other Object AudiogeoFenceRadius.Critical=4437.38 # meters AudiogeoFenceRadius.Warning=5046.72 # meters Calculate_Distance (currentObject, AudioGeoFenceObject) constR=6371000.0 # meters phi_1=radians(currentObject.Latitude) phi_2=radians(AudioGeoFenceObject.Latitude) delta_phi=radians(AudioGeoFenceObject.Latitude−currentObject.Latitude) delta_lambda=radians(AudioGeoFenceObject.Longitude−currentObject.Longitude) Similar to the examples provided above, the vehicle 100 may use delta_phi and delta_lambda to determine a distance between itself and the geofence based on the curvature of the earth.\",\n \"The vehicle 100 may use the calculated distance to determine whether to initiate audio suppression.\",\n \"Check_GeoFence (ResultRange, AudiogeoFenceRadius) If ResultRange<AudiogeoFenceRadius.Critical AudioSuppresisonEnable(AudiogeoFenceRadius.NoiseCancellationLevel) FIG.\",\n \"11 may be an illustration of a sample back end user interface 1701.It may have a plurality of input areas 1701 which may be different activities.\",\n \"Flight plans may be submitted in a few clicks through a simple easy to use interface.\",\n \"The user may define a block of airspace in which the vehicle is planning to conduct travel much like a pilot of a manned aircraft would.\",\n \"This flight plan is received and parsed by the traffic management system servers 2222 and provides the user or pilot with an approval or denial for that flight based on a number of properties which are determined based upon nearby geofences and defined performance limitations for his/her certification and/or UAV platform.\",\n \"The traffic management system 2222 may provide ground-based sense-and-avoid as a service to all vehicles such as small UAVs by informing each UAV of its surroundings both in the air and on the ground.\",\n \"Transmitted items may include but are not limited to terrain, tree lines, infrastructure (e.g., power lines, towers, windmills, etc.\",\n \"), buildings, manned aircraft, and other un-manned aircraft traffic.\",\n \"This ability to teach the vehicle its surroundings allows the system to provide high fidelity sense-and-avoid at a low cost in a small, lightweight package.\",\n \"Due to the type of information being ingested and parsed by the traffic management system 2222, the system may be able to classify various types of travel and conditions.\",\n \"The system may automatically escalate specific situations to a manned controller who may then provide further instruction to the vehicle system or notifications to the pilot through the included mobile applications or over the system through ground control software.\",\n \"Below is example pseudo code for providing ground-based sense-and-avoid as a service.\",\n \"In an example, the traffic management system 2222 may populate a sense-and-avoid data table containing information on vehicles within a particular airspace.\",\n \"Load RealTime Sense and Avoid Data Table realTimeData=LoadRealTimeData( ) sensorData=scanLocation( ) #Image based, Doppler, Infrared For each RealTimeObject in realTimeData Data Input currentObject.Latitude=35.882234 currentObject.Longitude=−78.788222 currentObject.Altitude=30 # meters currentObject.Speed=16 # meters/sec currentObject.Track=93.6 currentObject.ID=4923 # identifier for vehicle 100 RealTimeObject.Latitude=35.866864 RealTimeObject.Longitude=−78.799637 RealTimeObject.Height=18 # meters RealTimeObject.ID=000483 # coded Airport code or Other Object Calculate_Distance (currentObject, GeoFenceObject) constR=6371000.0 # meters phi_1=radians(currentObject.Latitude) phi_2=radians(GeoFenceObject.Latitude) delta_phi=radians(GeoFenceObject.Latitude−currentObject.Latitude) delta_lambda=radians(GeoFenceObject.Longitude−currentObject.Longitude) The traffic management system 2222 may use delta_phi and delta_lambda to determine a distance between vehicle 100 and each additional vehicle 110, object, or geofence based on the curvature of the earth.\",\n \"This distance is referenced as “ResultRange” in the below pseudo code.\",\n \"The traffic management system 2222 may generate and maintain data to track a current location of each vehicle in a particular airspace.\",\n \"Verify_RealTimeData (ResultRange, RealTimeObject) For each sensorDataObject in SensorData If RealTimeObject=sensorDataObject notifyServerObjectVerifed(gps.Time, gps.Longitute,gps.Latitude) If RealTimeObject is not Found notifyServerNewObject(.Time, gps.Longitute,gps.Latitude, RealTimeObject) Notifications may be communicated to users of the registered active vehicles travel plan through mobile computing devices.\",\n \"The notifications may alert the user in a number of travel situations.\",\n \"Notifications may range from potential breach of allocated space to early notice that a travel path should be changed in order to miss an obstacle prior to the system providing commands to the autopilot to take corrective actions.\",\n \"An interface may be provided which users or system managers may access to see and monitor flights in real time.\",\n \"This portal is similar in display to an air traffic controller's radar scope as illustrated in FIG.\",\n \"11 which may include an illustration of the relevant area 1721, other vehicles within given distances 1731 of the vehicle and any geofenced areas 1741.Certain embodiments are described herein as including logic or a number of components, modules, or mechanisms.\",\n \"Modules may constitute either software modules (e.g., code embodied on a non-transitory machine-readable medium or in a transmission signal) or hardware modules.\",\n \"A hardware module is tangible unit capable of performing certain operations and may be configured or arranged in a certain manner.\",\n \"In example embodiments, one or more computer systems (e.g., a standalone, client or server computer system) or one or more hardware modules of a computer system (e.g., a processor or a group of processors) may be configured by software (e.g., an application or application portion) as a hardware module that operates to perform certain operations as described herein.\",\n \"In various embodiments, a hardware module may be implemented mechanically or electronically.\",\n \"For example, a hardware module may comprise dedicated circuitry or logic that is permanently configured (e.g., as a special-purpose processor, such as a field programmable gate array (FPGA) or an application-specific integrated circuit (ASIC)) to perform certain operations.\",\n \"A hardware module may also comprise programmable logic or circuitry (e.g., as encompassed within a general-purpose processor or other programmable processor) that is temporarily configured by software to perform certain operations.\",\n \"It will be appreciated that the decision to implement a hardware module mechanically, in dedicated and permanently configured circuitry, or in temporarily configured circuitry (e.g., configured by software) may be driven by cost and time considerations.\",\n \"The various operations of example methods described herein may be performed, at least partially, by one or more processors that are temporarily configured (e.g., by software) or permanently configured to perform the relevant operations.\",\n \"Whether temporarily or permanently configured, such processors may constitute processor-implemented modules that operate to perform one or more operations or functions.\",\n \"The modules referred to herein may, in some example embodiments, may comprise processor-implemented modules.\",\n \"Similarly, the methods or routines described herein may be at least partially processor-implemented.\",\n \"For example, at least some of the operations of a method may be performed by one or more processors or processor-implemented hardware modules.\",\n \"The performance of certain of the operations may be distributed among the one or more processors, not only residing within a single machine, but deployed across a number of machines.\",\n \"In some example embodiments, the processor or processors may be located in a single location (e.g., within a home environment, an office environment or as a server farm), while in other embodiments the processors may be distributed across a number of locations.\",\n \"The one or more processors may also operate to support performance of the relevant operations in a “cloud computing” environment or as a “software as a service” (SaaS).\",\n \"For example, at least some of the operations may be performed by a group of computers (as examples of machines including processors), these operations being accessible via a network (e.g., the Internet) and via one or more appropriate interfaces (e.g., application program interfaces (APIs).)\",\n \"The performance of certain of the operations may be distributed among the one or more processors, not only residing within a single machine, but deployed across a number of machines.\",\n \"In some example embodiments, the one or more processors or processor-implemented modules may be located in a single geographic location (e.g., within a home environment, an office environment, or a server farm).\",\n \"In other example embodiments, the one or more processors or processor-implemented modules may be distributed across a number of geographic locations.\",\n \"Unless specifically stated otherwise, discussions herein using words such as “processing,” “computing,” “calculating,” “determining,” “presenting,” “displaying,” or the like may refer to actions or processes of a machine (e.g., a computer) that manipulates or transforms data represented as physical (e.g., electronic, magnetic, or optical) quantities within one or more memories (e.g., volatile memory, non-volatile memory, or a combination thereof), registers, or other machine components that receive, store, transmit, or display information.\",\n \"Still further, the figures depict preferred embodiments of a vehicle control system for purposes of illustration only.\",\n \"One skilled in the art will readily recognize from the foregoing discussion that alternative embodiments of the structures and methods illustrated herein may be employed without departing from the principles described herein.\",\n \"Thus, upon reading this disclosure, those of skill in the art will appreciate still additional alternative structural and functional designs for a system and a process for a low flying unmanned vehicle automatically avoiding collisions through the disclosed principles herein.\",\n \"Thus, while particular embodiments and applications have been illustrated and described, it is to be understood that the disclosed embodiments are not limited to the precise construction and components disclosed herein.\",\n \"Various modifications, changes and variations, which will be apparent to those skilled in the art, may be made in the arrangement, operation and details of the method and apparatus disclosed herein without departing from the spirit and scope defined in the appended claims.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875845"}}},{"rowIdx":4494996,"cells":{"text":{"kind":"list like","value":[["MICROCHIP-TYPE OPTICAL MEASURING APPARATUS AND OPTICAL POSITION ADJUSTING METHOD THEREOF","To provide a microchip-type optical measuring apparatus which is able to automatically perform position adjustment of a microchip with respect to an optical axis of laser with high accuracy.","A microchip-type optical measuring apparatus includes an irradiation detection unit which detects light generated by irradiating a microchip with laser, a position adjustment unit which changes a relative position of the microchip with respect to the irradiation detection unit, and a control unit which outputs a movement signal for a position in which an integrated value or an average value of a detected intensity of the light in a preset region becomes high to the position adjustment unit."],["1.A microchip-type optical measuring apparatus, comprising: an irradiation detector configured to detect light generated by irradiating a microchip with a laser; a position adjustment unit comprising at least one motor, wherein the position adjustment unit is configured to change a relative position of the microchip with respect to the irradiation detector; and a processor configured to output a movement signal for a position selected based on an integrated value or an average value of a detected intensity of the light in at least one region.","2.The microchip-type optical measuring apparatus according to claim 1, wherein the processor is configured to: use a stochastic method to estimate a distribution parameter of a probability distribution for modeling a relationship between a detected position of the light and the integrated value or the average value of the detected intensity of the light in the at least one region associated with the detected position of the light; and generate the movement signal for the selected position based on a result of using the stochastic method to estimate the distribution parameter.","3.The microchip-type optical measuring apparatus according to claim 2, wherein the processor is configured to select the probability distribution according to an irradiation profile of the laser.","4.The microchip-type optical measuring apparatus according to claim 1, wherein the processor is configured to output the movement signal for the selected position based on a variation coefficient of the integrated value or the average value of the detected intensity of the light at a plurality of points.","5.The microchip-type optical measuring apparatus according to claim 4, wherein the processor is configured to output a movement signal for an area based on an area average of the integrated value of the detected intensity in a plurality of areas.","6.The microchip-type optical measuring apparatus according to claim 5, wherein the processor is configured to output the movement signal for the selected position based on the integrated value of the detected intensity at the plurality of points.","7.The microchip-type optical measuring apparatus according to claim 6, wherein the processor is configured to output a movement signal for a first position based on the integrated value of the detected intensity in the area, or for a second position based on the variation coefficient in the area.","8.The microchip-type optical measuring apparatus according to claim 7, wherein the processor is configured to output the movement signal for the second position to the position adjustment unit when the first position and the second position are different from each other.","9.The microchip-type optical measuring apparatus according to claim 8, wherein the microchip-type optical measuring apparatus is a microchip-type microparticle measuring apparatus.","10.An optical position adjusting method of a microchip-type optical measuring apparatus, comprising acts of: detecting light which is generated from a microchip by laser irradiation, from a plurality of positions on the microchip; and specifying a position based on an integrated value or an average value of a detected intensity of the light in at least one region.","11.The optical position adjusting method according to claim 10, wherein: the position is specified based on a probability distribution for modeling a relationship between a detected position of the light and the integrated value or the average value of the detected intensity of the light; a distribution parameter of the probability distribution is estimated on the basis of a stochastic method; and the position is specified based on a result of estimating the distribution parameter.","12.The optical position adjusting method according to claim 11, wherein the probability distribution comprises a two-dimensional distribution.","13.The optical position adjusting method according to claim 12, further comprising acts of: estimating the distribution parameter of the probability distribution on the basis of the stochastic method; and specifying the position based on the integrated value or the average value of the detected intensity of the light.","14.The optical position adjusting method according to claim 10, wherein the position is set to a position based on a variation coefficient of the integrated value or the average value of the detected intensity of the light at a plurality of points.","15.The optical position adjusting method according to claim 14, wherein: the position is specified further based on an area average of the integrated value of the detected intensity of the light in a plurality of areas.","16.The optical position adjusting method according to claim 15, further comprising an act of: specifying a first position based on the integrated value of the detected intensity in a selected area.","17.The optical position adjusting method according to claim 16, wherein the position is specified based on a second position specified based on the variation coefficient in the.","18.The optical position adjusting method according to claim 17, further comprising an act of: setting a relative position of the microchip with respect to the laser to the first position or the second position.","19.The optical position adjusting method according to claim 18, wherein the relative position is set to the second position when the first position and the second position are different from each other.","20.An optical position adjusting method of a microchip-type optical measuring apparatus, comprising acts of: detecting light which is generated from a microchip by laser irradiation, from a plurality of positions in an area on the microchip; specifying a position based on an area average of an integrated value of a detected intensity of the light; specifying a first position based on the integrated value or an average value of the detected intensity in the area; specifying a second position based on a variation coefficient of the integrated value or the average value of the detected intensity in the area; and a procedure for setting a relative position of the microchip with respect to the laser to the first position or the second position."],["<SOH> BACKGROUND ART <EOH>A microparticle measuring apparatus (for example, a flow cytometer) which optically measures characteristics of a microparticle such as a cell is known.","In the flow cytometer, sample liquid including the cell flows through a flow passage formed in a flow cell or a microchip, and a detector detects fluorescence or scattering light generated from the cell by irradiating the cell which through-flows inside the flow passage with laser, so that an optical characteristic of the cell is measured.","In addition, in the flow cytometer, as a measurement result of the optical characteristic, a population (a group) which is determined to satisfy a predetermined condition is separately collected from the cell.","For example, in PTL 1, as a microchip-type flow cytometer, “a microparticle splitting device including a microchip provided with a flow passage through which liquid including a microparticle flows, and an orifice which ejects the liquid flowing through the flow passage into a space outside the chip, an oscillating element for discharging the liquid to be liquid droplets in the orifice, a charging unit for applying an electric charge to the discharged liquid droplets, an optical detection unit which detects optical characteristic of the microparticle flowing through the flow passage, counter electrodes which are disposed to face each other and to interpose the liquid droplets moved along a movement direction of the liquid droplets which are discharged into the space outside the chip, and two or more containers which collect the liquid droplets passed between the counter electrodes” is disclosed."],["<SOH> SUMMARY OF INVENTION <EOH>"],["CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of and claims the benefit under 35 U.S.C.","§ 120 of U.S. patent application Ser.","No.","14/386,499, titled “MICROCHIP-TYPE OPTICAL MEASURING APPARATUS AND OPTICAL POSITION ADJUSTING METHOD THEREOF,” filed on Sep.19, 2014, which is a U.S. National Stage Entry under 35 U.S.C.","§ 371 of International Application No.","PCT/JP2013/051800, filed in the Japanese Patent Office as a Receiving Office on Jan. 28, 2013, which claims priority to Japanese Patent Application Number JP2012-080472, filed in the Japanese Patent Office on Mar.","30, 2012, each of which is hereby incorporated by reference in its entirety.","TECHNICAL FIELD The present technology relates to a microchip-type optical measuring apparatus and an optical position adjusting method thereof.","More specifically, the present technology relates to a microchip-type optical measuring apparatus or the like which allows an optical position of a microchip to be automatically optimized and to be measured with high accuracy.","BACKGROUND ART A microparticle measuring apparatus (for example, a flow cytometer) which optically measures characteristics of a microparticle such as a cell is known.","In the flow cytometer, sample liquid including the cell flows through a flow passage formed in a flow cell or a microchip, and a detector detects fluorescence or scattering light generated from the cell by irradiating the cell which through-flows inside the flow passage with laser, so that an optical characteristic of the cell is measured.","In addition, in the flow cytometer, as a measurement result of the optical characteristic, a population (a group) which is determined to satisfy a predetermined condition is separately collected from the cell.","For example, in PTL 1, as a microchip-type flow cytometer, “a microparticle splitting device including a microchip provided with a flow passage through which liquid including a microparticle flows, and an orifice which ejects the liquid flowing through the flow passage into a space outside the chip, an oscillating element for discharging the liquid to be liquid droplets in the orifice, a charging unit for applying an electric charge to the discharged liquid droplets, an optical detection unit which detects optical characteristic of the microparticle flowing through the flow passage, counter electrodes which are disposed to face each other and to interpose the liquid droplets moved along a movement direction of the liquid droplets which are discharged into the space outside the chip, and two or more containers which collect the liquid droplets passed between the counter electrodes” is disclosed.","CITATION LIST Patent Literature PTL 1: Japanese Unexamined Patent Application Publication No.","2010-190680 SUMMARY OF INVENTION Technical Problem The microparticle measuring apparatus is required to perform position adjustment of a through-flow position of the microparticle inside the flow passage formed in the flow cell or the microchip and an optical axis of the laser with high accuracy, in order to accurately measure the optical characteristic of the microparticle.","In the related art, since the position adjustment is manually performed by a user with particles for calibration (calibration beads), the position adjustment requires proficiency, and thus has a problem in reliability or stability.","Particularly, in the microchip-type microparticle measuring apparatus, the optical position adjustment is required whenever the microchip is exchanged or is analyzed, and thus the position adjustment is considerably cumbersome and complicated.","Therefore, an object of the present invention is to provide a microchip-type optical measuring apparatus which is able to automatically perform position adjustment of a microchip with respect to an optical axis of laser with high accuracy.","Solution to Problem In order to solve the problem described above, the present invention provides a microchip-type optical measuring apparatus including an irradiation detection unit which detects light generated by irradiating a microchip with laser, a position adjustment unit which changes a relative position of the microchip with respect to the irradiation detection unit, and a control unit which outputs a movement signal for a position in which an integrated value or an average value of a detected intensity of the light in a preset region becomes high to the position adjustment unit.","In this microchip-type optical measuring apparatus, the control unit may assume that a relationship between a detected position and the integrated value or the average value of the detected intensity of the light follows pre-stored probability distribution, may estimate a distribution parameter of the probability distribution on the basis of a stochastic method, and thus may create the movement signal for the position in which the integrated value or the average value of the detected intensity of the light becomes maximum according to the estimation.","The control unit may select the probability distribution according to an irradiation profile of the laser.","In addition, the control unit may output the movement signal for a position in which a variation coefficient of the integrated value or the average value of the detected intensity of the light in a plurality of preset points becomes minimum to the position adjustment unit.","In addition, the control unit may output the movement signal for an area in which an area average of the integrated value of the detected intensity in a plurality of preset areas becomes maximum to the position adjustment unit.","In addition, the control unit may output the movement signal for a position in which the integrated value of the detected intensity in the plurality of preset points becomes maximum to the position adjustment unit.","In addition, the control unit may output the movement signal for a first optimal position in which the integrated value of the detected intensity in the area of a maximum area average becomes maximum, or for a second optimal position in which the variation coefficient in the area of the maximum area average becomes minimum to the position adjustment unit.","In addition, the control unit may output the movement signal for the second optimal position to the position adjustment unit when the first optimal position and the second optimal position are different from each other.","This microchip-type optical measuring apparatus may be configured as a microchip-type microparticle measuring apparatus.","In addition, the present invention provides an optical position adjusting method including a procedure for detecting light which is generated from a microchip by laser irradiation, from a plurality of positions on the microchip, and a procedure for specifying a position in which an integrated value or an average value of a detected intensity of the light in a preset region becomes maximum.","In the procedure for specifying the position, a relationship between a detected position and the integrated value or the average value of the detected intensity of the light may be assumed to follow a pre-stored probability distribution, a distribution parameter of the probability distribution may be estimated on the basis of a stochastic method, and thus the position in which the integrated value or the average value of the detected intensity of the light becomes maximum may be specified by the estimation.","In addition, this optical position adjusting method may further include a procedure for assuming that the integrated value or the average value of the detected intensity of the light from the position in which the integrated value or the average value of the detected intensity of the light is estimated to be maximum by the probability distribution to a predetermined position is in a one-dimensional distribution, and thus for specifying a position in which the integrated value or the average value of the detected intensity of the light becomes maximum by the one-dimensional distribution.","In addition, in the procedure for specifying the position, the position may be set to a position in which a variation coefficient of the integrated value or the average value of the detected intensity of the light in a plurality of preset points becomes minimum.","In addition, this optical position adjusting method may further include a procedure for specifying a position in which an area average of the integrated value of the detected intensity of the light in a plurality of preset areas becomes maximum.","In addition, this optical position adjusting method may further include a procedure for specifying a first optimal position in which the integrated value of the detected intensity in the area of a maximum area average becomes maximum.","In addition, the procedure for specifying the position in which the variation coefficient becomes minimum may be a procedure for specifying a second optimal position in which the variation coefficient in the area of the maximum area average becomes minimum.","In addition, this optical position adjusting method may include a procedure for setting a relative position of the microchip with respect to the laser to the first optimal position or the second optimal position.","Further, the present invention provides an optical position adjusting method of a microchip-type optical measuring apparatus, including a procedure for detecting light which is generated from a microchip by laser irradiation, from a plurality of positions on the microchip, a procedure for specifying a position in which an area average of an integrated value of a detected intensity of the light becomes high, a procedure for specifying a first optimal position in which the integrated value or an average value of the detected intensity in an area where the area average becomes higher, becomes higher, a procedure for specifying a second optimal position in which a variation coefficient of the integrated value or the average value of the detected intensity in the area where the area average becomes higher, becomes smaller, and a procedure for setting a relative position of the microchip with respect to the laser to the first optimal position or the second optimal position.","In the present technology, a cell or a microbe, a biologically-relevant microparticle such as a liposome, or a latex particle or a gel particle, a synthetic particle such as an industrial particle, and the like are broadly included in the “microparticle”.","In the biologically-relevant microparticle, a chromosome, a liposome, a mitochondria, an organelle (a cell organelle), and the like which configure various cells are included.","In the cell, an animal cell (a blood cell or the like) and a plant cell are included.","In the microbe, a bacteria such as a bacteria coliform, a virus such as a tobacco mosaic virus, a fungus such as a Yeast fungus, and the like are included.","Further, in the biologically-relevant microparticle, a biologically-relevant polymer such as a nucleic acid or a protein, or a complex thereof is also able to be included.","In addition, the industrial particle may be, for example, an organic or inorganic polymeric material, a metal, and the like.","In the organic polymeric material, polystyrene, styrene-divinylbenzene, polymethylmethacrylate, and the like are included.","In the inorganic polymeric material, glass, silica, a magnetic body material, and the like are included.","In the metal, a gold colloid, aluminum, and the like are included.","Generally, it is ordinary that the shape of the microparticle is spherical, but the shape may also be non-spherical, and the size, mass, or the like is not particularly limited.","Advantageous Effects of Invention According to the present invention, a microchip-type optical measuring apparatus which is able to automatically perform position adjustment of a microchip with respect to an optical axis of laser with high accuracy is provided.","BRIEF DESCRIPTION OF DRAWINGS FIG.","1 is a diagram for describing a configuration of a microchip-type optical measuring apparatus 1 (a flow cytometer 1) according to the present invention which is configured as a microchip-type flow cytometer.","FIG.","2 is a diagram for describing a configuration of an example of a microchip 2 which is mountable on the flow cytometer 1.FIG.","3 is a diagram for describing a configuration of an orifice 21 of the microchip 2.FIG.","4 is a flowchart for describing a control step according to a first embodiment in order to optimize an optical position of the flow cytometer 1.FIG.","5 is a diagram for describing control of an original point-reference point movement step S1 to an area average value maximum position determination step S3 according to the first embodiment.","FIG.","6 is a diagram for describing control of an area average maximum position movement step S4 to an integrated value maximum position determination step S6 according to the first embodiment.","FIG.","7 is a diagram for describing control of a variation coefficient determination step S7 according to the first embodiment.","FIG.","8 is a flowchart for describing a control step according to a second embodiment in order to optimize the optical position of the flow cytometer 1.FIG.","9 is a diagram for describing control of a coarse adjustment step S21 according to the second embodiment.","FIG.","10 is a diagram for describing a fixed distribution assumed in the coarse adjustment step S21 according to the second embodiment.","FIG.","11 is a diagram for describing control of a first fine adjustment step S22 according to the second embodiment.","FIG.","12 is a diagram for describing control of a second fine adjustment step S23 according to the second embodiment.","FIG.","13 is a diagram for describing control of a finer adjustment step S24 according to the second embodiment.","DESCRIPTION OF EMBODIMENTS Hereinafter, best modes for carrying out the present invention will be described with reference to the drawings.","Furthermore, embodiments described below indicate an example of a representative embodiment of the present invention, and it is not construed as narrowing the range of the present invention by the embodiments.","The description will be provided according to the following order.","1.Microchip-Type Optical Measuring Apparatus (1) Irradiation Detection Unit (2) Position Adjustment Unit (3) Oscillating Element (4) Charging Unit (5) Deflection Plate (6) Collection Container (7) Control Unit or the like (8) Microchip 2.Optimization Control of Optical Position of Microchip-type Optical Measuring Apparatus according to First Embodiment of the Present Invention (1) Original Point-Reference Point Movement Step S1 (2) Signal Acquisition Step S2 (3) Area Average Value Maximum Position Determination Step S3 (4) Area Average Maximum Position Movement Step S4 (5) Signal Acquisition Step S5 (6) Integrated Value Maximum Position Determination Step S6 (7) Variation Coefficient Determination Step S7 (8) Position Optimization Step S8 3.Optimization Control of Optical Position of Microchip-type Optical Measuring Apparatus according to Second Embodiment of the Present Invention (1) Coarse Adjustment Step S21 (1-1) Grid-like Signal Acquisition Step S211 (1-2) Two-dimensional Distribution Parameter Estimation Step S212 (1-3) Maximum Position Movement Step S213 (2) First Fine Adjustment Step S22 (2-1) Linear Signal Acquisition Step S221 (2-2) One-dimensional Distribution Parameter Estimation Step S222 (2-3) Maximum Position Movement Step S223 (3) Second Fine Adjustment Step S23 (3-1) Linear Signal Acquisition Step S231 (3-2) One-dimensional Distribution Parameter Estimation Step S232 (3-3) Maximum Position Movement Step S233 (4) Finer Adjustment Step S24 1.Microchip-Type Optical Measuring Apparatus FIG.","1 is a schematic diagram for describing a configuration of a microchip-type optical measuring apparatus 1 (hereinafter, referred to as a “flow cytometer 1”) according to the present technology which is configured as a microchip-type flow cytometer.","In addition, FIG.","2 and FIG.","3 illustrate an example of a microchip 2 which is mountable on the flow cytometer 1.FIG.","2A illustrates a schematic upper surface view, and FIG.","2B illustrates a schematic sectional view corresponding to a cross-section cut along line P-P of FIG.","2A.","In addition, FIG.","3 is a diagram for schematically describing a configuration of an orifice 21 of the microchip 2, and FIG.","3A illustrates an upper surface view, FIG.","3B illustrates a sectional view, and FIG.","3C illustrates a front view.","FIG.","3B corresponds to the cross-section cut along line P-P of FIG.","2A.","(1) Irradiation Detection Unit The flow cytometer 1 is provided with an irradiation detection unit which includes a light source 61 for irradiating the microchip 2 with laser L1, and a detector 62 for detecting light to be detected which is generated by irradiation of the laser L1.An irradiation direction of the laser L1 with respect to the microchip 2 (an optical axis of the laser L1) is illustrated as a Z-axis forward direction of FIG.","1.The light source 61 may be an LD, an LED, or the like.","The laser L1 is applied into a cell which flows through a sample flow passage 22 of the microchip 2.The detector 62 detects scattering light of the laser L1 caused by the cell, and fluorescence generated by exciting the cell or fluorescent pigment marked on the cell with the laser L1.In FIG.","1, the fluorescence generated from the cell which flows through the sample flow passage 22 is indicated by a reference mark F1.The irradiation detection unit includes an irradiation system provided with a condensing lens for condensing light by guiding the laser L1 emitted from the light source 61 to the cell, a dichroic mirror, a band pass filter, or the like.","In addition, the irradiation detection unit is configured by a detection system for guiding the light to be detected which is generated from the cell by the irradiation of the laser L1 to the detector 62 by condensing the light.","The detection system is configured by, for example, a photo multiplier tube (PMT), an area imaging element such as a CCD or a CMOS element, or the like.","The light to be detected which is detected by the detection system of the irradiation detection unit is the light which is generated from the cell by the irradiation of the laser L1, and may be, for example, forward scattering light or lateral scattering light, scattering light such as Rayleigh scattering or Mie scattering, fluorescence, or the like.","The fluorescence may be generated from the cell or the fluorescent pigment marked on the cell.","The light to be detected is converted to an electric signal, and is used for optical characteristic determination of the cell and automatic adjustment of an optical position (described later).","(2) Position Adjustment Unit The flow cytometer 1 includes a position adjustment unit 9 which changes a relative position of the microchip 2 with respect to the irradiation detection unit.","The position adjustment unit 9 moves the position of the microchip 2 and/or the position of the irradiation detection unit on a plane (an XY plane) perpendicular to the optical axis of the laser L1.Accordingly, the position adjustment unit 9 adjusts the position of the microchip 2 with respect to the optical axis of the laser 1,1, and optimizes the laser L1 to be applied to a through-flow position of the cell inside the sample flow passage 22.The position adjustment unit 9 may move at least one of the position of the microchip 2 and the position of the irradiation detection unit including the light source 61 and the detector 62 to an X-axial direction and a Y-axial direction.","The position adjustment unit 9 is configured by, for example, a stepping motor or the like.","Furthermore, the position adjustment unit 9 may move the relative position of the microchip 2 with respect to the irradiation detection unit to a Z-axial direction (a focus direction of the laser L1).","(3) Oscillating Element The flow cytometer 1 includes an oscillating element 3 for discharging laminar flow of sample liquid and sheath liquid including the cell which is ejected from the orifice 21 to be liquid droplets by applying oscillation to the orifice 21 formed in the microchip 2.The oscillating element 3 may be, for example, a piezo element.","The discharged liquid droplets are injected to a Y-axis forward direction indicated by an arrow in the drawings as fluid stream S. Furthermore, in the flow cytometer 1, the microchip 2 is exchangeably mounted.","In the flow cytometer 1, the oscillating element 3 may be integrated with the microchip 2, and may be disposed on the apparatus side to be contactable with the mounted microchip 2.","(4) Charging Unit Positive or negative electric charges are applied to the liquid droplets discharged from the orifice 21 by a charging unit 41.The charging of the liquid droplets is performed by an electrode 42 which is electrically connected to the charging unit 41 and inserted into a sample inlet 23 disposed in the microchip 2.Furthermore, the electrode 42 may be inserted into any one portion of the microchip 2 to electrically come in contact with the sample liquid or the sheath liquid flowing through the flow passage.","In the flow cytometer 1, a frequency of a driving voltage of the oscillating element 3, and switching timing of a voltage (a charge voltage) of the charging unit 41 are synchronized, so that any one of plus and minus electric charges is applied to a part of the liquid droplets discharged from the orifice 21.The electric charge may not be applied to a part of the liquid droplets, and thus a part of the liquid droplets may be uncharged.","(5) Deflection Plate Further, the flow cytometer 1 includes a pair of deflection plates 51 and 52 which are disposed to face each other and to interpose the fluid stream S. The deflection plates 51 and 52 change a travelling direction of each of the liquid droplets in the fluid stream S by an electric force which acts with respect to the electric charges applied to the liquid droplets.","The deflection plates 51 and 52 may be an ordinary electrode.","In FIG.","1, a facing direction of the polarizing plates 51 and 52 is illustrated by the X-axial direction.","(6) Collection Container The fluid stream passed between the deflection plates 51 and 52 is received in any one of a collection container 81, a collection container 82, or a collection container 83.For example, when the deflection plate 51 is positively charged and the deflection plate 52 is negatively charged, the liquid droplets which are negatively charged by the charging unit 41 are collected in the collection container 82, and the positively charged liquid droplets are collected in the collection container 83, respectively.","In addition, the liquid droplets which are not charged by the charging unit 41 directly drop to be collected in the collection container 81 without receiving an electrical acting force from the deflection plates 51 and 52.In the flow cytometer 1, the travelling direction of the liquid droplets is controlled according to the characteristic of the cell included in each of the liquid droplets, thereby allowing a target cell having a desired characteristic and a non-target cell other than the target cell to be collected in separate collection containers.","The collection containers 81, 82, and 83 may be a general-purpose plastic tube or a glass tube for laboratory use.","It is preferable that the collection containers be exchangeably disposed in the flow cytometer 1.In addition, the collection container for receiving the non-target cell among the collection containers may be connected to a drainage route of the collected liquid droplets.","Furthermore, in the flow cytometer 1, the number of collection containers to be disposed is not particularly limited.","When more than 3 collection containers are disposed, the respective liquid droplets are induced toward any one of the collection containers according to presence or absence of the electrical acting force between the deflection plates 51 and 52, and the magnitude thereof, and collected in the collection container.","(7) Control Unit or the Like The flow cytometer 1 includes a data analysis unit for determining the optical characteristic of the cell, a tank unit for accumulating the sample liquid and the sheath liquid, a control unit 10 for controlling each configuration, and the like, which are provided in a usual flow cytometer, in addition to the configuration described above.","The control unit 10 is able to be configured by a general-purpose computer provided with a CPU, a memory, hard disk, and the like, and stores an OS, a program for executing a control step (described later), and the like in the hard disk.","The control unit 10 outputs a movement signal for a position in which a variation becomes small, that is, a position in which an integrated value or an average value of a detected intensity of the light generated from the microchip by the irradiation of the laser L1 becomes higher (preferably, becomes a maximum value) among regions set in advance to the position adjustment unit 9.","(8) Microchip The microchip 2 is configured by bonding substrate layers 2a and 2b in which the sample flow passage 22 is formed.","The sample flow passage 22 is able to be formed in the substrate layers 2a and 2b according to injection molding of a thermoplastic resin with a mold.","As the thermoplastic resin, plastics which are known as microchip material in the related art, such as polycarbonate, polymethylmethacrylate (PMMA) resin, cyclic polyolefin, polyethylene, polystyrene, polypropylene, and polydimethylsiloxane (PDMS) are able to be adopted.","The sample liquid is introduced to the sample inlet 23, merged into the sheath liquid introduced to a sheath inlet 24, and flows through the sample flow passage 22.The flow of the sheath liquid introduced from the sheath inlet 24 is divided into two directions, and then is merged into the sample liquid at a merging portion with the sample liquid introduced from the sample inlet 23, by sandwiching the sample liquid from the two directions.","Accordingly, three-dimensional laminar flow in which sample liquid laminar flow is positioned in the center of sheath liquid laminar flow is formed at the merging portion.","A reference numeral “25” indicates a suction flow passage for removing clogging or air bubbles by applying a negative pressure to the inside of the sample flow passage 22 and by temporarily regurgitating the flow when the clogging or the air bubbles is generated in the sample flow passage 22.One end of the suction flow passage 25 is provided with a suction outlet 251 which is connected to a negative pressure source such as a vacuum pump, and the other end is connected to the sample flow passage 22 at a communication port 252.A laminar flow width of the three-dimensional laminar flow is narrowed at a throttle portions 261 (refer to FIGS.","2) and 262 (refer to FIG.","3) which are formed such that the area of a cross section vertical to a flow direction gradually or progressively becomes smaller upstream to downstream in the flow direction.","Subsequently, the three-dimensional laminar flow is ejected from the orifice 21 disposed on one end of the flow passage.","The characteristic of the cell is detected between the throttle portion 261 and the throttle portion 262 of the sample flow passage 22.The cell which is arranged in line at the center of the three-dimensional laminar flow and flows through the sample flow passage 22 is irradiated with the laser L1 by the irradiation detection unit, and thus the fluorescence F1 and the scattering light which are generated from the cell are detected (refer to FIG.","2).","A connection portion with respect to the orifice 21 of the sample flow passage 22 is configured as a straight portion 27 which is linearly formed.","The straight portion 27 functions to directly inject the fluid stream S from the orifice 21 to the Y-axis forward direction.","The three-dimensional laminar flow ejected from the orifice 21 becomes the liquid droplets by the oscillation applied to the orifice 21 according to the oscillating element 31, and is injected as the fluid stream S (refer to FIG.","1).","The orifice 21 is open to an end surface direction of the substrate layers 2a and 2b, and a cutout portion 211 is formed between an opening position of the orifice and the end surfaces of the substrate layers.","The cutout portion 211 is formed by cutting out the substrate layers 2a and 2b between the opening position of the orifice 21 and the end surfaces of the substrates such that the diameter L of the cutout portion 221 is larger than the opening diameter 1 of the orifice 21 (refer to FIG.","3C).","It is preferable that the diameter L of the cutout portion 211 be equal to or greater than two times larger than the opening diameter 1 of the orifice 21 in order not to disturb the movement of the liquid droplets discharged from the orifice 21.2.Optimization Control of Optical Position of Microchip-type Optical Measuring Apparatus according to First Embodiment of the Present Technology FIG.","4 is a flowchart for describing a control step in order to optimize an optical position of the microchip 2 of the flow cytometer 1.The control step includes a procedure of an “original point-reference point movement step S1”, a “signal acquisition step S2”, an “area average value maximum position determination step S3”, an “area average maximum position movement step S4”, a “signal acquisition step S5”, an “integrated value maximum position determination step S6”, a “variation coefficient determination step S7”, and a “position optimization step S8”.","Hereinafter, each procedure will be described.","(1) Original Point-Reference Point Movement Step S1 When a starting signal of an analysis is input by a user, the control unit 10 outputs the movement signal to the position adjustment unit 9, and the position adjustment unit 9 moves the relative position of the microchip 2 with respect to the irradiation detection unit to an initial position (refer to an original point O of FIG.","5) set in advance.","When the relative position is at the original point O, the laser L1 emitted from the irradiation detection unit is applied to the original point O on the microchip 2.The relative position is changed by moving at least one of the position of the microchip 2 or the position of the irradiation detection unit including the light source 61 and the detector 62 to the X-axial direction and the Y-axial direction, and, hereinafter, a case where the relative position is changed by moving the position of the microchip 2 will be described as an example.","Next, the control unit 10 starts to allow the sample liquid and the sheath liquid to flow toward the sample inlet 23 and the sheath inlet 24 of the microchip 2 by driving a pump of the tank portion which accumulates the sample liquid and the sheath liquid.","It is preferable that the sample liquid include a calibration bead.","Further, the control unit 10 starts to apply the oscillation to the orifice 21 by the oscillating element 3.Accordingly, the three-dimensional laminar flow of the sample liquid and the sheath liquid injected from the orifice 21 is discharged to be the liquid droplets, and thus the fluid stream S is generated.","After starting the flow of the sample liquid and the sheath liquid, the control unit 10 outputs the movement signal to the position adjustment unit 9, and the position adjustment unit 9 moves the position of the microchip 2 to a reference point D0 from the original point O (refer to an arrow of FIG.","5).","When the relative position of the microchip 2 with respect to the irradiation detection unit is at the reference point D0, the laser L1 emitted from the irradiation detection unit is applied to the reference point D0 on the microchip 2.The reference point D0 is set in advance in the vicinity of the position in which the characteristic of the cell of the microchip 2 is able to be detected (that is, an optimal position which is determined by steps described later).","More specifically, the reference point D0 is the vicinity between the throttle portion 261 and the throttle portion 262 of the sample flow passage 22 (refer to FIG.","3).","(2) Signal Acquisition Step S2 In this step S2, the fluorescence or the scattering light (hereinafter, simply referred to as the “fluorescence”) generated from a plurality of positions on the microchip 2 which includes the reference point D0 is detected by the irradiation detection unit.","In this step S2, the position on the microchip 2 in which the fluorescence is detected is illustrated by a reference numeral D in FIG.","5.In the drawings, a case where 24 detected positions D including the reference point D0 are set, and the fluorescence is detected from the detected positions D in which the number of arrangements M1 of the X-axial direction is arranged in 8 rows, and the number of arrangements N1 of the Z-axial direction is arranged in 3 rows is illustrated as an example.","In a region in which the detected positions D are set, the sample flow passage 22 is included, and the number of detected positions D and an arrangement aspect are not particularly limited but arbitrarily set insofar as the sample flow passage 22 is included in the region.","It is preferable that the detected positions D be arranged in a reticular pattern in the X-axial direction and the Z-axial direction, as illustrated.","In this case, arrangement intervals W and H of the X-axial direction and the Z-axial direction of the detected positions D are able to be properly set according to a flow passage width (a flow passage diameter) of the sample flow passage 22 and the number of arrangements M1 and N1 of the detected positions D in the X-axial direction and the Z-axial direction.","The flow passage width of the sample flow passage 22 is approximately 70 to 100 μm, and when M1 is 8 and N1 is 3, the arrangement intervals W and H are set, for example, to 25 and 75 μm, respectively.","The detection of the fluorescence is performed with respect to one detected position D for a predetermined time.","The fluorescence detected for the predetermined time is integrated, converted to the electric signal, and output to the control unit 10.The fluorescence is able to be detected by performing scanning of the laser L1 in the X-axial direction and the Z-axial direction, by sequentially applying the laser to each detected position D, and by detecting the fluorescence to be generated.","Alternatively, the fluorescence from each of the detected positions D may be collectively detected by an area imaging element according to the irradiation of the laser L1.","(3) Area Average Value Maximum Position Determination Step S3 In this step S3, the control unit 10 calculates an area average of the integrated value of the detected intensity with respect to each of the detected positions D, and automatically determines the detected position D where the area average becomes higher, preferably, the detected position D where the area average is the maximum value.","The “area average” indicates an average of the integrated value of the detected intensity obtained by one detected position D, and a plurality of detected positions D within a predetermined distance range from the one detected position.","In FIG.","5, a case where the area average is an average of the integrated value of the detected intensity obtained by one detected position D1, and detected positions D2 to D9 within the distance range of 2W in the X-axial direction from the detected position D1 and 2H in the Z-axial direction from the detected position D1 is illustrated.","Setting how far the distance range is from the one detected position D as the area average is able to be properly determined according to the flow passage width (the flow passage diameter) of the sample flow passage 22, and the arrangement intervals W and H. The control unit 10 compares the calculated area average to each of the detected positions D, and determines the detected position D where the area average becomes higher, preferably, the detected position D where the area average is the maximum value.","Here, a case where the area average is the maximum value in the detected position D1 will be described.","Since the fluorescence is strongly generated in the sample flow passage 22 through which the calibration bead or the cell flows, it is possible to consider that the sample flow passage 22 is positioned within a region R1 where the detected positions D1 to D9 in which the area average is the maximum value are formed in conjunction.","(4) Area Average Maximum Position Movement Step S4 When the detected position D1 where the area average is the maximum value is specified, the control unit 10 outputs the movement signal to the position adjustment unit 9, and the position adjustment unit 9 moves the position of the microchip 2 to the detected position D1 from the reference point D0 (refer to an arrow of FIG.","6).","(5) Signal Acquisition Step S5 In this step S5, the detection of the fluorescence which is generated from a plurality of positions within the region R1 where the area average is the maximum value is performed by the irradiation detection unit.","The detected positions D of the fluorescence in this step S5 are illustrated in an enlarged view of FIG.","6.In the drawings, a case where the fluorescence is detected from the detected positions D of (M2×N2) in which M2 rows in the X-axial direction and N2 rows in the Z-axial direction are arranged, including the detected position D1 where the area average is the maximum value is illustrated as an example.","Arrangement intervals w and h of the detected positions D in the X-axial direction and the Z-axial direction are able to be properly set according to the flow passage width (the flow passage diameter) of the sample flow passage 22 and the number of arrangements M2 and N2 in the X-axial direction and the Z-axial direction.","The number of arrangements M2 and N2 are, for example, 11 and 7, respectively.","The row intervals w and h are set, for example, to 5 and 25 μm, respectively.","Furthermore, in this step S5, the number of detected positions D and the arrangement aspect are not particularly limited.","The detection of the fluorescence is performed with respect to the one detected position D for the predetermined time.","The fluorescence detected for the predetermined time is converted to the electric signal and output to the control unit 10.The fluorescence is detected by performing scanning of the laser L1 in the X-axial direction and the Z-axial direction to sequentially scan each detected position D, and by detecting the fluorescence to be generated.","Alternatively, the fluorescence from each of the detected positions D may be collectively detected by the irradiation of the laser L1 according to an area imaging element.","(6) Integrated Value Maximum Position Determination Step S6 In this step S6, the control unit 10 calculates either one or both of the integrated value and the average value of the detected intensity with respect to each of the detected positions D, and a variation coefficient (a CV value) thereof.","Hereinafter, a process using the integrated value of the detected intensity and the CV value thereof will be described as an example.","The control unit 10 compares the calculated integrated value of the detected intensity with respect to each of the detected positions D, and determines the detected position D where the integrated value becomes higher, preferably, the detected position D (a first optimal position) where the integrated value is the maximum value.","Here, a case where the integrated value is the maximum value in the detected position D11 will be described (refer to FIG.","6).","(7) Variation Coefficient Determination Step S7 Next, the control unit 10 compares the CV values between the detected position D11 where the integrated value is the maximum value and the adjacent detected positions D12 to D19, and automatically determines the presence or absence of the detected position D (a second optimal position) to which a CV value smaller than that of the detected position D11 is applied (refer to FIG.","7).","(8) Position Optimization Step S8 In step S2, when the detected position D to which the CV value smaller than that of the detected position D11 where the integrated value is the maximum value is applied is not found in any of the detected position D11 and the adjacent detected positions D12 to D19, the control unit 10 moves the position of the microchip 2 to the detected position D11 from the detected position D1.At this time, both the detected position (the first optimal position) where the integrated value is the maximum value and the detected position (the second optimal position) where the CV value is the minimum value are coincident with each other in the detected position D11.In addition, in step S7, when the detected position D to which the CV value smaller than that of the detected position D11 is applied is found in any one of the detected positions D12 to D19, the control unit 10 moves the position of the microchip 2 to the detected position D (for example, the detected position D18) from the detected position D1.At this time, the detected position (the first optimal position) where the integrated value is the maximum value and the detected position (the second optimal position) where the CV value is the minimum value are not coincident with each other.","The detected position D11 where the integrated value is the maximum value is a position where the fluorescence is most strongly generated, and is able to be considered as a through-flow position of the calibration bead or the cell in the sample flow passage 22.That is, when the relative position of the microchip 2 with respect to the irradiation detection unit is in the detected position D11, the laser L1 emitted from the irradiation detection unit is applied to the through-flow position of the calibration bead or the like in the sample flow passage 22.In some cases even though the detected position D11 where the integrated value is the maximum value is not the through-flow position of the calibration bead or the like in the sample flow passage 22, the integrated value of the fluorescence intensity may be the maximum value.","For example, when the detected position D11 is coincident with a flow passage wall of the micro-flow passage 22, the fluorescence intensity which is abnormally high due to reflecting, scattering, or the like of the fluorescence may be sporadically detected.","In this case, a variation is generated in the fluorescence intensity which is detected in the position, and the CV value of the integrated value of the fluorescence intensity becomes high.","When the detected position D11 is coincident with the flow passage wall of the micro-flow passage 22, or the like, it is possible to consider the detected position D18 to which a smaller CV value is applied among the detected position D11 and the adjacent detected positions as the through-flow position of the calibration bead or the like in the sample flow passage 22.That is, when the relative position of the microchip 2 with respect to the irradiation detection unit is in the detected position D18, the laser L1 emitted from the irradiation detection unit is applied to the through-flow position of the calibration bead or the like in the sample flow passage 22.As described above, in the flow cytometer 1, the relative position of the microchip 2 with respect to the laser L1 is set to the position where the integrated value or the average value of the detected intensity of the fluorescence generated from the microchip 2 by the irradiation of the laser L1 becomes higher or the position where the CV value becomes smaller.","Accordingly, in the flow cytometer 1, the through-flow position of the cell in the sample flow passage 22 of the microchip 2, and the optical axis of the laser L1 are automatically positioned with high accuracy, and thus it is possible to simply perform high accuracy measurement.","In addition, in the flow cytometer 1, the optical position of the microchip 2 is optimized by a two-staged procedure of a coarse adjustment for specifying the position where the area average of the integrated value of the detected intensity of the fluorescence becomes higher (steps S2 and S3), and a fine adjustment for specifying the position where the integrated value or the average value becomes higher within the region where the area average becomes higher or the position where the CV value becomes smaller (steps S5 to S7).","Accordingly, it is possible to rapidly perform the optimization of the optical position of the microchip 2 with a small processing load.","3.Optimization Control of Optical Position of Microchip-type Optical Measuring Apparatus according to Second Embodiment of the Present Technology FIG.","8 is a flowchart for describing a control step according to a second embodiment in order to optimize the optical position of the flow cytometer 1.The control step of this embodiment includes a procedure of an “original point-reference point movement step S1”, a “coarse adjustment step S21”, a “first fine adjustment step S22”, a “second fine adjustment step S23”, and a “finer adjustment step S24”.","Hereinafter, each procedure will be described.","Furthermore, since the original point-reference point movement step S1 is a process which is substantially identical to the original point-reference point movement step S1 of the first embodiment, except that the reference point D0 (refer to FIG.","5 again) corresponds to a reference point P0 illustrated in FIG.","9 (described later), the description thereof will be omitted.","(1) Coarse Adjustment Step S21 FIG.","9 is a diagram for describing control of a coarse adjustment step S21 according to this embodiment.","The coarse adjustment step S21 includes a procedure of a “grid-like signal acquisition step S211”, a “two-dimensional distribution parameter estimation step S212”, and a “maximum position movement step S213”.","Hereinafter, each procedure will be described.","(1-1) Grid-like Signal Acquisition Step S211 In this step 5211, the detection of the fluorescence from a plurality of detected positions D21 set in advance is performed by the irradiation detection unit (refer to FIG.","9A).","In this step S211, a position on the microchip 2 in which the detection of the fluorescence is performed is illustrated by a reference numeral D21 in FIG.","9A.","In FIG.","9A, a case where the fluorescence is detected from the detected positions D21 in which 6 rows in the X-axial direction and 7 rows in the Z-axial direction are arranged, centered on the reference point P0 is illustrated as an example.","In a region in which the detected positions D21 are set, the sample flow passage 22 is included, and the number of detected positions D21 and the arrangement aspect are not particularly limited but arbitrarily set insofar as the sample flow passage 22 is included in the region.","It is preferable that the detected positions D21 be arranged in a reticular pattern in the X-axial direction and the Z-axial direction, as illustrated in FIG.","9A.","In this case, arrangement intervals W2 and H2 of the detected positions D21 in the X-axial direction and the Z-axial direction are able to be properly set according to the flow passage width (the flow passage diameter) of the sample flow passage 22 and the number of arrangements M3 and N3 of the detected positions D21 in the X-axial direction and the Z-axial direction.","The arrangement intervals W2 and H2 are set, for example, to 62.5 and 125 μm, respectively.","The detection of the fluorescence is performed substantially similarly to the signal acquisition step S2 of the first embodiment.","(1-2) Two-Dimensional Distribution Parameter Estimation Step S212 In this step S212, the control unit 10 assumes that a relationship between each of the detected positions D21 and the integrated value or the average value of the detected intensity of the fluorescence follows two-dimensional probability distribution.","Further, for the detected position and the detected intensity acquired in step S211, and an irradiation profile of the laser indicating a relationship between an irradiation position and an irradiation intensity, the detected intensity of each of the detected positions has a correlative relationship with the irradiation intensity of a corresponding irradiation position.","For this reason, it is preferable that the assumed probability distribution be selected according to the irradiation profile of the laser.","For example, when the irradiation profile is in the shape of a top-hat beam as illustrated in FIG.","10A (described later), the control unit 10 is able to assume uniform distribution as a probability distribution model.","On the other hand, when the irradiation profile is in the shape of a Gaussian beam as illustrated in FIG.","10B (described later), normal distribution is able to be assumed as the probability distribution model.","Thus, it is possible to adjust the optical position according to the optical characteristic of the laser of the apparatus with high speed and high accuracy by selecting the probability distribution according to the irradiation profile of the laser.","In addition, when it is assumed that the relationship between each of the detected positions D21 and the integrated value or the average value of the detected intensity of the fluorescence follows the two-dimensional probability distribution, the control unit 10 estimates a distribution parameter of the probability distribution by a stochastic method, on the basis of stochastic information.","For example, the control unit 10 is able to estimate the distribution parameter (an average (a center position of the distribution), dispersion (spread of the distribution), or the like) with respect to each integrated value or average value by a maximum likelihood estimation method.","In this maximum likelihood estimation method, at the time of estimating the relationship between the detected intensity and the detected position to be in the two-dimensional normal distribution, it is possible to estimate where the center position (the position where the detected intensity is maximum) of the two-dimensional normal distribution is at the time of maximizing likelihood, on the basis of the probability distribution model stored in the control unit 10 in advance.","According to this maximum likelihood estimation method, it is possible to estimate the position (an optical axis center position of the laser L1) where the detected intensity is maximum with high accuracy even when data of the detected intensity is small.","(1-3) Maximum Position Movement Step S213 In this step S213, the control unit 10 outputs the movement signal for a position P1 where the integrated value or the average value of the detected intensity in the probability distribution estimated in the probability distribution estimation step S212 becomes higher, and preferably, becomes the maximum value to the position adjustment unit 9.Accordingly, as illustrated in FIG.","9C, the position adjustment unit 9 moves the position of the microchip 2 to the position P1 from the reference point P0.Here, a calculating method of the maximum position will be described with reference to FIG.","10.FIG.","10 is a diagram illustrating a state where the two-dimensional probability distribution is viewed from one direction.","In FIG.","10A, top-hat distribution (uniform distribution) is illustrated.","When the probability distribution is estimated to be the top-hat distribution, the control unit 10 determines a center position of an edge E1 and an edge E2 in FIG.","10A as the position where the detected intensity is maximum.","On the other hand, in FIG.","10B, Gaussian distribution is illustrated.","When the probability distribution is estimated as the Gaussian distribution, as illustrated in FIG.","10B, it is possible to set a position where the integrated value or the average value of the detected intensity has a maximum value b to a position where an inclination is 0 (an inclination a).","In the flow cytometer 1, it is preferable that the optical profile of the laser be the Gaussian distribution, and in this case, the distribution of the integrated value or the average value of a plurality of detected intensities may be the Gaussian distribution.","Thus, in the coarse adjustment step S21, the integrated value or the average value of the detected intensity of the light in a plurality of detected positions D21 is estimated as a specified two-dimensional probability distribution, and it is possible to move the microchip 2 to the position where the integrated value or the average value of the detected intensity of the light in the probability distribution becomes higher, and preferably, becomes the maximum value.","As described above, according to the optical position adjusting method of this embodiment, it is possible to improve position adjustment accuracy of the microchip 2 without increasing the number of detected positions D21, by estimating the probability distribution of the detected intensity of each of the detected positions D21.","(2) First Fine Adjustment Step S22 FIG.","11 is a diagram for describing control of a first fine adjustment step S22 according to this embodiment.","The first fine adjustment step S22 includes a procedure of a “linear signal acquisition step S221”, a “one-dimensional distribution parameter estimation step S222”, and a “maximum position movement step S223”.","Hereinafter, each procedure will be described.","(2-1) Linear Signal Acquisition Step S221 In this step S221, centered on the position P1 which is set in the coarse adjustment step S21, the detection of the fluorescence from a plurality of detected positions d22 which are arranged in the X-axial direction is performed (FIG.","11A).","An interval W22 to be detected and the number of arrangements of the detected positions d22 are able to be properly set.","In FIG.","11A, a case where 19 detected positions d22 are arranged in the X-axial direction, centered on the position P1 is illustrated as an example.","The detection of the fluorescence is performed substantially similarly to the signal acquisition step S2 of the first embodiment.","(2-2) One-Dimensional Distribution Parameter Estimation Step S222 In this step S222, the control unit 10 assumes that a relationship between each of the detected positions d22 and the integrated value or the average value of the detected intensity of the fluorescence follows a one-dimensional distribution stored in a memory or the like.","For example, when the data of the detected intensity illustrated in FIG.","11B is obtained, the control unit 10 sets the one-dimensional distribution to an Nth-order polynomial model, and thus it is possible to calculate a maximum value on the basis of a least-square method.","Setting the one-dimensional distribution to the Nth-order polynomial model allows a variation of the distribution of the optical profile due to a design variation or the like of each component configuring the flow cytometer 1 to be handled with high accuracy, compared to a case where the one-dimensional distribution is set to the normal distribution.","Here, at the time of setting the distribution to the Nth-order polynomial model, while accuracy increases as the order becomes higher, it is susceptible to an effect due to an error of the detected intensity of each of the detected positions d22 when the order is too high, and thus it is preferable that the order be, for example, fourth-order.","(2-3) Maximum Position Movement Step S223 In this step S223, the control unit 10 outputs the movement signal for the position P2 where the integrated value or the average value of the detected intensity in the one-dimensional distribution assumed in the one-dimensional parameter estimation step S222 becomes higher, and preferably, becomes the maximum value to the position adjustment unit 9.Accordingly, as illustrated in FIG.","11C, the position adjustment unit 9 moves the position of the microchip 2 to the position P2 from the position P1.Furthermore, a case where the position P2 illustrated in FIG.","11C is on the detected position d22 is illustrated as an example, but the position P2 may be between two detected positions d22.Thus, in the first fine adjustment step S22, it is possible to adjust the position of the microchip 2 adjusted in the coarse adjustment step S21 with high accuracy.","Particularly, the position adjustment of the microchip 2 is performed on the basis of the detected intensity of the detected positions d22 which are arranged in one direction.","For this reason, it is possible to reduce the number of data items to be detected, compared to a case where the position adjustment is performed on the basis of the intensity of the detected positions which are arranged in a plurality of directions, for example, in a reticular pattern.","Accordingly, even though the number of arrangements increases, and accuracy of the data increases, it is possible to inhibit data detection time from being increased by narrowing the interval of the detected positions d22, compared to a case where the data is two-dimensionally acquired.","(3) Second Fine Adjustment Step S23 FIG.","12 is a diagram for describing control of a second fine adjustment step S23 according to this embodiment.","The second fine adjustment step S23 includes a procedure of a “linear signal acquisition step S231”, a “one-dimensional parameter estimation step S232”, and a “maximum position movement step S233”.","As illustrated in FIGS.","12A to 12C, the control of this step S23 is substantially identical to the control of the first fine adjustment step S22 which is described with reference to FIGS.","11A to 11C, except that the microchip 2 is moved to the position P3 from the position P2 in the Y-axial direction on the basis of the detected intensity of detected positions d23 which are arranged in the Y-axial direction, centered on the position P2, instead of moving the microchip 2 to the position P2 from the position P1 in the X-axial direction on the basis of the detected intensity of the detected positions d22 which are arranged in the X-axial direction.","For this reason, the description thereof will be omitted here.","Here, in the first fine adjustment step S22, the position adjustment is performed in the X-axial direction (a flow width direction of the microchip 2), and in the second fine adjustment step S23, the position adjustment is performed in the Z-axial direction (a focus direction of the laser L1).","Since the Z-axial direction has a wider optical profile width (the detected intensity of the fluorescence is high in a wide range) compared to the X-axial direction, the position adjustment in the Z-axial direction is likely to be performed with high accuracy according to a process performed in the coarse adjustment step S21 described above, compared to the position adjustment in X-axial direction.","For this reason, in the coarse adjustment step S21, it is preferable that the Z-axial direction in which the position adjustment is performed with higher accuracy be fixed first, and then the position adjustment of the microchip 2 in the X-axial direction be performed.","Accordingly, it is preferable that the first fine adjustment step S21 and the second fine adjustment step S22 be performed in this order.","In the second fine adjustment step S23, the position adjustment of the microchip 2 is performed in a direction different from the direction of the fine adjustment in the first fine adjustment S22, thereby allowing the position adjustment to be performed with higher accuracy.","(4) Finer Adjustment Step S24 FIG.","13 is a diagram for describing control of the second fine adjustment step S23 according to this embodiment.","The finer adjustment step S24 includes a procedure of a “signal acquisition step S241”, an “integrated value maximum position determination step S6”, a “variation coefficient determination step S7”, and a “position optimization step S8”.","As illustrated in FIG.","13A, first, in the signal acquisition step S241, the detection of the fluorescence is performed in a plurality of detected positions d24, centered on the position P3 which is set in the second fine adjustment step S23.In FIG.","13A, a case where the number of arrangements M4 of the X-axial direction is 11 rows, and the number of arrangements N1 of the Z-axial direction is 3 rows is illustrated as an example.","The detection of the fluorescence is performed substantially similarly to the signal acquisition step S2 of the first embodiment.","Next, after performing the detection of the fluorescence in the signal acquisition step S241, the integrated value maximum position determination step S6, the variation coefficient determination step S2, and the position optimization step S8 are performed substantially similarly to the integrated value maximum position determination step S6, the variation coefficient determination step S2, and the position optimization step S8 of the control step of the first embodiment (refer to FIG.","13B and FIG.","13C).","Thus, the microchip 2 is moved to the most suitable position (moved to P4 from P3 in FIG.","13C).","Furthermore, in this embodiment, each process is described in an order of the “coarse adjustment step S21”, the “first fine adjustment step S22”, the “second fine adjustment step S23”, and the “finer adjustment step S24”, but, for example, the “coarse adjustment step S21”, the “first fine adjustment step S22”, and the “second fine adjustment step S23” may be repeated for a plurality of times.","In addition, only the “coarse adjustment step S21”, the “first fine adjustment step S22”, and the “second fine adjustment step S23” are performed at once or a plurality of times, and the “finer adjustment step S24” may be omitted.","As described above, according to the optical position adjusting method of this embodiment, the relationship between each of the detected positions and the detected intensity is assumed to follow the specified probability distribution model, and the distribution parameter is estimated on the basis of the stochastic method, thereby allowing the position adjustment of the microchip 2 to be performed with high accuracy in a rapid process, without increasing the number of detected positions.","In the microchip-type optical measuring apparatus according to the present technology, an apparatus for optically measuring an object to be measured which is introduced to a region having the microchip formed therein is broadly included in addition to the microparticle measuring apparatus (the flow cytometer).","In addition, the optical position adjusting method according to the present invention is able to be broadly applied to the entire apparatus for optically measuring an object to be measured which is introduced to a region having the microchip formed therein other than the microparticle measuring apparatus (the flow cytometer).","The microchip-type optical measuring apparatus according to the present technology is able to be configured as the following.","(1) A microchip-type optical measuring apparatus, including: an irradiation detection unit which detects light generated by irradiating a microchip with laser; a position adjustment unit which changes a relative position of the microchip with respect to the irradiation detection unit; and a control unit which outputs a movement signal for a position in which an integrated value or an average value of a detected intensity of the light in a preset region becomes high to the position adjustment unit.","(2) The microchip-type optical measuring apparatus according to (1), in which the control unit assumes that a relationship between a detected position of the light and the integrated value or the average value of the detected intensity of the light follows a pre-stored probability distribution, estimates a distribution parameter of the probability distribution on the basis of a pre-stored stochastic method, and thus creates the movement signal for the position in which the integrated value or the average value of the detected intensity of the light becomes maximum by the estimation.","(3) The microchip-type optical measuring apparatus according to (2), in which the control unit assumes the probability distribution according to an irradiation profile of the laser.","(4) The microchip-type optical measuring apparatus according to any one of (1) to (3), in which the control unit outputs the movement signal for a position in which a variation coefficient of the integrated value or the average value of the detected intensity of the light in a plurality of preset points becomes minimum to the position adjustment unit.","(5) The microchip-type optical measuring apparatus according to (4), in which the control unit outputs the movement signal for an area in which an area average of the integrated value of the detected intensity in a plurality of preset areas becomes maximum to the position adjustment unit.","(6) The microchip-type optical measuring apparatus according to (5), in which the control unit outputs the movement signal for a position in which the integrated value of the detected intensity in the plurality of preset points becomes maximum to the position adjustment unit.","(7) The microchip-type optical measuring apparatus according to (6), in which the control unit outputs the movement signal for a first optimal position in which the integrated value of the detected intensity in the area of a maximum area average becomes maximum, or for a second optimal position in which the variation coefficient in the area of the maximum area average becomes minimum to the position adjustment unit.","(8) The microchip-type optical measuring apparatus according to (7), in which the control unit outputs the movement signal for the second optimal position to the position adjustment unit when the first optimal position and the second optimal position are different from each other.","(9) The microchip-type optical measuring apparatus according to (1) to (8), in which the microchip-type optical measuring apparatus is a microchip-type microparticle measuring apparatus.","In addition, the optical position adjusting method of a microchip-type optical measuring apparatus according to the present technology is able to be configured as the following.","(1) An optical position adjusting method, including: a procedure for detecting light which is generated from a microchip by laser irradiation, from a plurality of positions on the microchip; and a procedure for specifying a position in which an integrated value or an average value of a detected intensity of the light in a region where a plurality of preset points exists becomes maximum.","(2) The optical position adjusting method according to (1), in which in the procedure for specifying the position, a relationship between a detected position of the light and the integrated value or the average value of the detected intensity of the light is assumed to follow a pre-stored probability distribution, a distribution parameter of the probability distribution is estimated on the basis of a pre-stored stochastic method, and thus the position in which the integrated value or the average value of the detected intensity of the light becomes maximum is specified by the estimation.","(3) The optical position adjusting method according to (2), in which in the procedure for specifying the position, the probability distribution is set to two-dimensional distribution.","(4) The optical position adjusting method according to (3), further including a procedure for assuming that a relationship of the integrated value or the average value of the detected intensity of the light from the position in which the integrated value or the average value of the detected intensity of the light is estimated to be maximum by the probability distribution to a predetermined position follows a one-dimensional distribution, and thus for specifying a position in which the integrated value or the average value of the detected intensity of the light becomes maximum by the one-dimensional distribution.","(5) The optical position adjusting method according to any one of (1) to (4), in which in the procedure for specifying the position, the position is set to a position in which a variation coefficient of the integrated value or the average value of the detected intensity of the light in a plurality of preset points becomes minimum.","(6) The optical position adjusting method according to (5), further including a procedure for specifying a position in which an area average of the integrated value of the detected intensity of the light in a plurality of preset areas becomes maximum.","(7) The optical position adjusting method according to (6), further including a procedure for specifying a first optimal position in which the integrated value of the detected intensity in the area of a maximum area average becomes maximum.","(8) The optical position adjusting method according to (7), in which the procedure for specifying the position in which the variation coefficient becomes minimum is a procedure for specifying a second optimal position in which the variation coefficient in the area of the maximum area average becomes minimum.","(9) The optical position adjusting method according to (8), further including a procedure for setting a relative position of the microchip with respect to the laser to the first optimal position or the second optimal position.","(10) The optical position adjusting method according to (9), in which the relative position is set to the second optimal position when the first optimal position and the second optimal position are different from each other.","(11) An optical position adjusting method of a microchip-type optical measuring apparatus, including: a procedure for detecting light which is generated from a microchip by laser irradiation, from a plurality of positions on the microchip; a procedure for specifying a position in which an area average of an integrated value of a detected intensity of the light becomes higher; a procedure for specifying a first optimal position in which the integrated value or an average value of the detected intensity in an area where the area average becomes higher, becomes higher; a procedure for specifying a second optimal position in which a variation coefficient of the integrated value or the average value of the detected intensity in the area where the area average becomes higher, becomes smaller; and a procedure for setting a relative position of the microchip with respect to the laser to the first optimal position or the second optimal position.","REFERENCE SIGNS LIST 1 microchip-type optical measuring apparatus 2 microchip 21 orifice 22 sample flow passage 23 sample inlet 3 oscillating element 41 charging unit 42 electrode 51, 52 deflection plate 61 light source 62 detector 81, 82, 83 collection container 9 position adjustment unit 10 control unit D detected position F1 fluorescence L1 laser"]],"string":"[\n [\n \"MICROCHIP-TYPE OPTICAL MEASURING APPARATUS AND OPTICAL POSITION ADJUSTING METHOD THEREOF\",\n \"To provide a microchip-type optical measuring apparatus which is able to automatically perform position adjustment of a microchip with respect to an optical axis of laser with high accuracy.\",\n \"A microchip-type optical measuring apparatus includes an irradiation detection unit which detects light generated by irradiating a microchip with laser, a position adjustment unit which changes a relative position of the microchip with respect to the irradiation detection unit, and a control unit which outputs a movement signal for a position in which an integrated value or an average value of a detected intensity of the light in a preset region becomes high to the position adjustment unit.\"\n ],\n [\n \"1.A microchip-type optical measuring apparatus, comprising: an irradiation detector configured to detect light generated by irradiating a microchip with a laser; a position adjustment unit comprising at least one motor, wherein the position adjustment unit is configured to change a relative position of the microchip with respect to the irradiation detector; and a processor configured to output a movement signal for a position selected based on an integrated value or an average value of a detected intensity of the light in at least one region.\",\n \"2.The microchip-type optical measuring apparatus according to claim 1, wherein the processor is configured to: use a stochastic method to estimate a distribution parameter of a probability distribution for modeling a relationship between a detected position of the light and the integrated value or the average value of the detected intensity of the light in the at least one region associated with the detected position of the light; and generate the movement signal for the selected position based on a result of using the stochastic method to estimate the distribution parameter.\",\n \"3.The microchip-type optical measuring apparatus according to claim 2, wherein the processor is configured to select the probability distribution according to an irradiation profile of the laser.\",\n \"4.The microchip-type optical measuring apparatus according to claim 1, wherein the processor is configured to output the movement signal for the selected position based on a variation coefficient of the integrated value or the average value of the detected intensity of the light at a plurality of points.\",\n \"5.The microchip-type optical measuring apparatus according to claim 4, wherein the processor is configured to output a movement signal for an area based on an area average of the integrated value of the detected intensity in a plurality of areas.\",\n \"6.The microchip-type optical measuring apparatus according to claim 5, wherein the processor is configured to output the movement signal for the selected position based on the integrated value of the detected intensity at the plurality of points.\",\n \"7.The microchip-type optical measuring apparatus according to claim 6, wherein the processor is configured to output a movement signal for a first position based on the integrated value of the detected intensity in the area, or for a second position based on the variation coefficient in the area.\",\n \"8.The microchip-type optical measuring apparatus according to claim 7, wherein the processor is configured to output the movement signal for the second position to the position adjustment unit when the first position and the second position are different from each other.\",\n \"9.The microchip-type optical measuring apparatus according to claim 8, wherein the microchip-type optical measuring apparatus is a microchip-type microparticle measuring apparatus.\",\n \"10.An optical position adjusting method of a microchip-type optical measuring apparatus, comprising acts of: detecting light which is generated from a microchip by laser irradiation, from a plurality of positions on the microchip; and specifying a position based on an integrated value or an average value of a detected intensity of the light in at least one region.\",\n \"11.The optical position adjusting method according to claim 10, wherein: the position is specified based on a probability distribution for modeling a relationship between a detected position of the light and the integrated value or the average value of the detected intensity of the light; a distribution parameter of the probability distribution is estimated on the basis of a stochastic method; and the position is specified based on a result of estimating the distribution parameter.\",\n \"12.The optical position adjusting method according to claim 11, wherein the probability distribution comprises a two-dimensional distribution.\",\n \"13.The optical position adjusting method according to claim 12, further comprising acts of: estimating the distribution parameter of the probability distribution on the basis of the stochastic method; and specifying the position based on the integrated value or the average value of the detected intensity of the light.\",\n \"14.The optical position adjusting method according to claim 10, wherein the position is set to a position based on a variation coefficient of the integrated value or the average value of the detected intensity of the light at a plurality of points.\",\n \"15.The optical position adjusting method according to claim 14, wherein: the position is specified further based on an area average of the integrated value of the detected intensity of the light in a plurality of areas.\",\n \"16.The optical position adjusting method according to claim 15, further comprising an act of: specifying a first position based on the integrated value of the detected intensity in a selected area.\",\n \"17.The optical position adjusting method according to claim 16, wherein the position is specified based on a second position specified based on the variation coefficient in the.\",\n \"18.The optical position adjusting method according to claim 17, further comprising an act of: setting a relative position of the microchip with respect to the laser to the first position or the second position.\",\n \"19.The optical position adjusting method according to claim 18, wherein the relative position is set to the second position when the first position and the second position are different from each other.\",\n \"20.An optical position adjusting method of a microchip-type optical measuring apparatus, comprising acts of: detecting light which is generated from a microchip by laser irradiation, from a plurality of positions in an area on the microchip; specifying a position based on an area average of an integrated value of a detected intensity of the light; specifying a first position based on the integrated value or an average value of the detected intensity in the area; specifying a second position based on a variation coefficient of the integrated value or the average value of the detected intensity in the area; and a procedure for setting a relative position of the microchip with respect to the laser to the first position or the second position.\"\n ],\n [\n \"<SOH> BACKGROUND ART <EOH>A microparticle measuring apparatus (for example, a flow cytometer) which optically measures characteristics of a microparticle such as a cell is known.\",\n \"In the flow cytometer, sample liquid including the cell flows through a flow passage formed in a flow cell or a microchip, and a detector detects fluorescence or scattering light generated from the cell by irradiating the cell which through-flows inside the flow passage with laser, so that an optical characteristic of the cell is measured.\",\n \"In addition, in the flow cytometer, as a measurement result of the optical characteristic, a population (a group) which is determined to satisfy a predetermined condition is separately collected from the cell.\",\n \"For example, in PTL 1, as a microchip-type flow cytometer, “a microparticle splitting device including a microchip provided with a flow passage through which liquid including a microparticle flows, and an orifice which ejects the liquid flowing through the flow passage into a space outside the chip, an oscillating element for discharging the liquid to be liquid droplets in the orifice, a charging unit for applying an electric charge to the discharged liquid droplets, an optical detection unit which detects optical characteristic of the microparticle flowing through the flow passage, counter electrodes which are disposed to face each other and to interpose the liquid droplets moved along a movement direction of the liquid droplets which are discharged into the space outside the chip, and two or more containers which collect the liquid droplets passed between the counter electrodes” is disclosed.\"\n ],\n [\n \"<SOH> SUMMARY OF INVENTION <EOH>\"\n ],\n [\n \"CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of and claims the benefit under 35 U.S.C.\",\n \"§ 120 of U.S. patent application Ser.\",\n \"No.\",\n \"14/386,499, titled “MICROCHIP-TYPE OPTICAL MEASURING APPARATUS AND OPTICAL POSITION ADJUSTING METHOD THEREOF,” filed on Sep.19, 2014, which is a U.S. National Stage Entry under 35 U.S.C.\",\n \"§ 371 of International Application No.\",\n \"PCT/JP2013/051800, filed in the Japanese Patent Office as a Receiving Office on Jan. 28, 2013, which claims priority to Japanese Patent Application Number JP2012-080472, filed in the Japanese Patent Office on Mar.\",\n \"30, 2012, each of which is hereby incorporated by reference in its entirety.\",\n \"TECHNICAL FIELD The present technology relates to a microchip-type optical measuring apparatus and an optical position adjusting method thereof.\",\n \"More specifically, the present technology relates to a microchip-type optical measuring apparatus or the like which allows an optical position of a microchip to be automatically optimized and to be measured with high accuracy.\",\n \"BACKGROUND ART A microparticle measuring apparatus (for example, a flow cytometer) which optically measures characteristics of a microparticle such as a cell is known.\",\n \"In the flow cytometer, sample liquid including the cell flows through a flow passage formed in a flow cell or a microchip, and a detector detects fluorescence or scattering light generated from the cell by irradiating the cell which through-flows inside the flow passage with laser, so that an optical characteristic of the cell is measured.\",\n \"In addition, in the flow cytometer, as a measurement result of the optical characteristic, a population (a group) which is determined to satisfy a predetermined condition is separately collected from the cell.\",\n \"For example, in PTL 1, as a microchip-type flow cytometer, “a microparticle splitting device including a microchip provided with a flow passage through which liquid including a microparticle flows, and an orifice which ejects the liquid flowing through the flow passage into a space outside the chip, an oscillating element for discharging the liquid to be liquid droplets in the orifice, a charging unit for applying an electric charge to the discharged liquid droplets, an optical detection unit which detects optical characteristic of the microparticle flowing through the flow passage, counter electrodes which are disposed to face each other and to interpose the liquid droplets moved along a movement direction of the liquid droplets which are discharged into the space outside the chip, and two or more containers which collect the liquid droplets passed between the counter electrodes” is disclosed.\",\n \"CITATION LIST Patent Literature PTL 1: Japanese Unexamined Patent Application Publication No.\",\n \"2010-190680 SUMMARY OF INVENTION Technical Problem The microparticle measuring apparatus is required to perform position adjustment of a through-flow position of the microparticle inside the flow passage formed in the flow cell or the microchip and an optical axis of the laser with high accuracy, in order to accurately measure the optical characteristic of the microparticle.\",\n \"In the related art, since the position adjustment is manually performed by a user with particles for calibration (calibration beads), the position adjustment requires proficiency, and thus has a problem in reliability or stability.\",\n \"Particularly, in the microchip-type microparticle measuring apparatus, the optical position adjustment is required whenever the microchip is exchanged or is analyzed, and thus the position adjustment is considerably cumbersome and complicated.\",\n \"Therefore, an object of the present invention is to provide a microchip-type optical measuring apparatus which is able to automatically perform position adjustment of a microchip with respect to an optical axis of laser with high accuracy.\",\n \"Solution to Problem In order to solve the problem described above, the present invention provides a microchip-type optical measuring apparatus including an irradiation detection unit which detects light generated by irradiating a microchip with laser, a position adjustment unit which changes a relative position of the microchip with respect to the irradiation detection unit, and a control unit which outputs a movement signal for a position in which an integrated value or an average value of a detected intensity of the light in a preset region becomes high to the position adjustment unit.\",\n \"In this microchip-type optical measuring apparatus, the control unit may assume that a relationship between a detected position and the integrated value or the average value of the detected intensity of the light follows pre-stored probability distribution, may estimate a distribution parameter of the probability distribution on the basis of a stochastic method, and thus may create the movement signal for the position in which the integrated value or the average value of the detected intensity of the light becomes maximum according to the estimation.\",\n \"The control unit may select the probability distribution according to an irradiation profile of the laser.\",\n \"In addition, the control unit may output the movement signal for a position in which a variation coefficient of the integrated value or the average value of the detected intensity of the light in a plurality of preset points becomes minimum to the position adjustment unit.\",\n \"In addition, the control unit may output the movement signal for an area in which an area average of the integrated value of the detected intensity in a plurality of preset areas becomes maximum to the position adjustment unit.\",\n \"In addition, the control unit may output the movement signal for a position in which the integrated value of the detected intensity in the plurality of preset points becomes maximum to the position adjustment unit.\",\n \"In addition, the control unit may output the movement signal for a first optimal position in which the integrated value of the detected intensity in the area of a maximum area average becomes maximum, or for a second optimal position in which the variation coefficient in the area of the maximum area average becomes minimum to the position adjustment unit.\",\n \"In addition, the control unit may output the movement signal for the second optimal position to the position adjustment unit when the first optimal position and the second optimal position are different from each other.\",\n \"This microchip-type optical measuring apparatus may be configured as a microchip-type microparticle measuring apparatus.\",\n \"In addition, the present invention provides an optical position adjusting method including a procedure for detecting light which is generated from a microchip by laser irradiation, from a plurality of positions on the microchip, and a procedure for specifying a position in which an integrated value or an average value of a detected intensity of the light in a preset region becomes maximum.\",\n \"In the procedure for specifying the position, a relationship between a detected position and the integrated value or the average value of the detected intensity of the light may be assumed to follow a pre-stored probability distribution, a distribution parameter of the probability distribution may be estimated on the basis of a stochastic method, and thus the position in which the integrated value or the average value of the detected intensity of the light becomes maximum may be specified by the estimation.\",\n \"In addition, this optical position adjusting method may further include a procedure for assuming that the integrated value or the average value of the detected intensity of the light from the position in which the integrated value or the average value of the detected intensity of the light is estimated to be maximum by the probability distribution to a predetermined position is in a one-dimensional distribution, and thus for specifying a position in which the integrated value or the average value of the detected intensity of the light becomes maximum by the one-dimensional distribution.\",\n \"In addition, in the procedure for specifying the position, the position may be set to a position in which a variation coefficient of the integrated value or the average value of the detected intensity of the light in a plurality of preset points becomes minimum.\",\n \"In addition, this optical position adjusting method may further include a procedure for specifying a position in which an area average of the integrated value of the detected intensity of the light in a plurality of preset areas becomes maximum.\",\n \"In addition, this optical position adjusting method may further include a procedure for specifying a first optimal position in which the integrated value of the detected intensity in the area of a maximum area average becomes maximum.\",\n \"In addition, the procedure for specifying the position in which the variation coefficient becomes minimum may be a procedure for specifying a second optimal position in which the variation coefficient in the area of the maximum area average becomes minimum.\",\n \"In addition, this optical position adjusting method may include a procedure for setting a relative position of the microchip with respect to the laser to the first optimal position or the second optimal position.\",\n \"Further, the present invention provides an optical position adjusting method of a microchip-type optical measuring apparatus, including a procedure for detecting light which is generated from a microchip by laser irradiation, from a plurality of positions on the microchip, a procedure for specifying a position in which an area average of an integrated value of a detected intensity of the light becomes high, a procedure for specifying a first optimal position in which the integrated value or an average value of the detected intensity in an area where the area average becomes higher, becomes higher, a procedure for specifying a second optimal position in which a variation coefficient of the integrated value or the average value of the detected intensity in the area where the area average becomes higher, becomes smaller, and a procedure for setting a relative position of the microchip with respect to the laser to the first optimal position or the second optimal position.\",\n \"In the present technology, a cell or a microbe, a biologically-relevant microparticle such as a liposome, or a latex particle or a gel particle, a synthetic particle such as an industrial particle, and the like are broadly included in the “microparticle”.\",\n \"In the biologically-relevant microparticle, a chromosome, a liposome, a mitochondria, an organelle (a cell organelle), and the like which configure various cells are included.\",\n \"In the cell, an animal cell (a blood cell or the like) and a plant cell are included.\",\n \"In the microbe, a bacteria such as a bacteria coliform, a virus such as a tobacco mosaic virus, a fungus such as a Yeast fungus, and the like are included.\",\n \"Further, in the biologically-relevant microparticle, a biologically-relevant polymer such as a nucleic acid or a protein, or a complex thereof is also able to be included.\",\n \"In addition, the industrial particle may be, for example, an organic or inorganic polymeric material, a metal, and the like.\",\n \"In the organic polymeric material, polystyrene, styrene-divinylbenzene, polymethylmethacrylate, and the like are included.\",\n \"In the inorganic polymeric material, glass, silica, a magnetic body material, and the like are included.\",\n \"In the metal, a gold colloid, aluminum, and the like are included.\",\n \"Generally, it is ordinary that the shape of the microparticle is spherical, but the shape may also be non-spherical, and the size, mass, or the like is not particularly limited.\",\n \"Advantageous Effects of Invention According to the present invention, a microchip-type optical measuring apparatus which is able to automatically perform position adjustment of a microchip with respect to an optical axis of laser with high accuracy is provided.\",\n \"BRIEF DESCRIPTION OF DRAWINGS FIG.\",\n \"1 is a diagram for describing a configuration of a microchip-type optical measuring apparatus 1 (a flow cytometer 1) according to the present invention which is configured as a microchip-type flow cytometer.\",\n \"FIG.\",\n \"2 is a diagram for describing a configuration of an example of a microchip 2 which is mountable on the flow cytometer 1.FIG.\",\n \"3 is a diagram for describing a configuration of an orifice 21 of the microchip 2.FIG.\",\n \"4 is a flowchart for describing a control step according to a first embodiment in order to optimize an optical position of the flow cytometer 1.FIG.\",\n \"5 is a diagram for describing control of an original point-reference point movement step S1 to an area average value maximum position determination step S3 according to the first embodiment.\",\n \"FIG.\",\n \"6 is a diagram for describing control of an area average maximum position movement step S4 to an integrated value maximum position determination step S6 according to the first embodiment.\",\n \"FIG.\",\n \"7 is a diagram for describing control of a variation coefficient determination step S7 according to the first embodiment.\",\n \"FIG.\",\n \"8 is a flowchart for describing a control step according to a second embodiment in order to optimize the optical position of the flow cytometer 1.FIG.\",\n \"9 is a diagram for describing control of a coarse adjustment step S21 according to the second embodiment.\",\n \"FIG.\",\n \"10 is a diagram for describing a fixed distribution assumed in the coarse adjustment step S21 according to the second embodiment.\",\n \"FIG.\",\n \"11 is a diagram for describing control of a first fine adjustment step S22 according to the second embodiment.\",\n \"FIG.\",\n \"12 is a diagram for describing control of a second fine adjustment step S23 according to the second embodiment.\",\n \"FIG.\",\n \"13 is a diagram for describing control of a finer adjustment step S24 according to the second embodiment.\",\n \"DESCRIPTION OF EMBODIMENTS Hereinafter, best modes for carrying out the present invention will be described with reference to the drawings.\",\n \"Furthermore, embodiments described below indicate an example of a representative embodiment of the present invention, and it is not construed as narrowing the range of the present invention by the embodiments.\",\n \"The description will be provided according to the following order.\",\n \"1.Microchip-Type Optical Measuring Apparatus (1) Irradiation Detection Unit (2) Position Adjustment Unit (3) Oscillating Element (4) Charging Unit (5) Deflection Plate (6) Collection Container (7) Control Unit or the like (8) Microchip 2.Optimization Control of Optical Position of Microchip-type Optical Measuring Apparatus according to First Embodiment of the Present Invention (1) Original Point-Reference Point Movement Step S1 (2) Signal Acquisition Step S2 (3) Area Average Value Maximum Position Determination Step S3 (4) Area Average Maximum Position Movement Step S4 (5) Signal Acquisition Step S5 (6) Integrated Value Maximum Position Determination Step S6 (7) Variation Coefficient Determination Step S7 (8) Position Optimization Step S8 3.Optimization Control of Optical Position of Microchip-type Optical Measuring Apparatus according to Second Embodiment of the Present Invention (1) Coarse Adjustment Step S21 (1-1) Grid-like Signal Acquisition Step S211 (1-2) Two-dimensional Distribution Parameter Estimation Step S212 (1-3) Maximum Position Movement Step S213 (2) First Fine Adjustment Step S22 (2-1) Linear Signal Acquisition Step S221 (2-2) One-dimensional Distribution Parameter Estimation Step S222 (2-3) Maximum Position Movement Step S223 (3) Second Fine Adjustment Step S23 (3-1) Linear Signal Acquisition Step S231 (3-2) One-dimensional Distribution Parameter Estimation Step S232 (3-3) Maximum Position Movement Step S233 (4) Finer Adjustment Step S24 1.Microchip-Type Optical Measuring Apparatus FIG.\",\n \"1 is a schematic diagram for describing a configuration of a microchip-type optical measuring apparatus 1 (hereinafter, referred to as a “flow cytometer 1”) according to the present technology which is configured as a microchip-type flow cytometer.\",\n \"In addition, FIG.\",\n \"2 and FIG.\",\n \"3 illustrate an example of a microchip 2 which is mountable on the flow cytometer 1.FIG.\",\n \"2A illustrates a schematic upper surface view, and FIG.\",\n \"2B illustrates a schematic sectional view corresponding to a cross-section cut along line P-P of FIG.\",\n \"2A.\",\n \"In addition, FIG.\",\n \"3 is a diagram for schematically describing a configuration of an orifice 21 of the microchip 2, and FIG.\",\n \"3A illustrates an upper surface view, FIG.\",\n \"3B illustrates a sectional view, and FIG.\",\n \"3C illustrates a front view.\",\n \"FIG.\",\n \"3B corresponds to the cross-section cut along line P-P of FIG.\",\n \"2A.\",\n \"(1) Irradiation Detection Unit The flow cytometer 1 is provided with an irradiation detection unit which includes a light source 61 for irradiating the microchip 2 with laser L1, and a detector 62 for detecting light to be detected which is generated by irradiation of the laser L1.An irradiation direction of the laser L1 with respect to the microchip 2 (an optical axis of the laser L1) is illustrated as a Z-axis forward direction of FIG.\",\n \"1.The light source 61 may be an LD, an LED, or the like.\",\n \"The laser L1 is applied into a cell which flows through a sample flow passage 22 of the microchip 2.The detector 62 detects scattering light of the laser L1 caused by the cell, and fluorescence generated by exciting the cell or fluorescent pigment marked on the cell with the laser L1.In FIG.\",\n \"1, the fluorescence generated from the cell which flows through the sample flow passage 22 is indicated by a reference mark F1.The irradiation detection unit includes an irradiation system provided with a condensing lens for condensing light by guiding the laser L1 emitted from the light source 61 to the cell, a dichroic mirror, a band pass filter, or the like.\",\n \"In addition, the irradiation detection unit is configured by a detection system for guiding the light to be detected which is generated from the cell by the irradiation of the laser L1 to the detector 62 by condensing the light.\",\n \"The detection system is configured by, for example, a photo multiplier tube (PMT), an area imaging element such as a CCD or a CMOS element, or the like.\",\n \"The light to be detected which is detected by the detection system of the irradiation detection unit is the light which is generated from the cell by the irradiation of the laser L1, and may be, for example, forward scattering light or lateral scattering light, scattering light such as Rayleigh scattering or Mie scattering, fluorescence, or the like.\",\n \"The fluorescence may be generated from the cell or the fluorescent pigment marked on the cell.\",\n \"The light to be detected is converted to an electric signal, and is used for optical characteristic determination of the cell and automatic adjustment of an optical position (described later).\",\n \"(2) Position Adjustment Unit The flow cytometer 1 includes a position adjustment unit 9 which changes a relative position of the microchip 2 with respect to the irradiation detection unit.\",\n \"The position adjustment unit 9 moves the position of the microchip 2 and/or the position of the irradiation detection unit on a plane (an XY plane) perpendicular to the optical axis of the laser L1.Accordingly, the position adjustment unit 9 adjusts the position of the microchip 2 with respect to the optical axis of the laser 1,1, and optimizes the laser L1 to be applied to a through-flow position of the cell inside the sample flow passage 22.The position adjustment unit 9 may move at least one of the position of the microchip 2 and the position of the irradiation detection unit including the light source 61 and the detector 62 to an X-axial direction and a Y-axial direction.\",\n \"The position adjustment unit 9 is configured by, for example, a stepping motor or the like.\",\n \"Furthermore, the position adjustment unit 9 may move the relative position of the microchip 2 with respect to the irradiation detection unit to a Z-axial direction (a focus direction of the laser L1).\",\n \"(3) Oscillating Element The flow cytometer 1 includes an oscillating element 3 for discharging laminar flow of sample liquid and sheath liquid including the cell which is ejected from the orifice 21 to be liquid droplets by applying oscillation to the orifice 21 formed in the microchip 2.The oscillating element 3 may be, for example, a piezo element.\",\n \"The discharged liquid droplets are injected to a Y-axis forward direction indicated by an arrow in the drawings as fluid stream S. Furthermore, in the flow cytometer 1, the microchip 2 is exchangeably mounted.\",\n \"In the flow cytometer 1, the oscillating element 3 may be integrated with the microchip 2, and may be disposed on the apparatus side to be contactable with the mounted microchip 2.\",\n \"(4) Charging Unit Positive or negative electric charges are applied to the liquid droplets discharged from the orifice 21 by a charging unit 41.The charging of the liquid droplets is performed by an electrode 42 which is electrically connected to the charging unit 41 and inserted into a sample inlet 23 disposed in the microchip 2.Furthermore, the electrode 42 may be inserted into any one portion of the microchip 2 to electrically come in contact with the sample liquid or the sheath liquid flowing through the flow passage.\",\n \"In the flow cytometer 1, a frequency of a driving voltage of the oscillating element 3, and switching timing of a voltage (a charge voltage) of the charging unit 41 are synchronized, so that any one of plus and minus electric charges is applied to a part of the liquid droplets discharged from the orifice 21.The electric charge may not be applied to a part of the liquid droplets, and thus a part of the liquid droplets may be uncharged.\",\n \"(5) Deflection Plate Further, the flow cytometer 1 includes a pair of deflection plates 51 and 52 which are disposed to face each other and to interpose the fluid stream S. The deflection plates 51 and 52 change a travelling direction of each of the liquid droplets in the fluid stream S by an electric force which acts with respect to the electric charges applied to the liquid droplets.\",\n \"The deflection plates 51 and 52 may be an ordinary electrode.\",\n \"In FIG.\",\n \"1, a facing direction of the polarizing plates 51 and 52 is illustrated by the X-axial direction.\",\n \"(6) Collection Container The fluid stream passed between the deflection plates 51 and 52 is received in any one of a collection container 81, a collection container 82, or a collection container 83.For example, when the deflection plate 51 is positively charged and the deflection plate 52 is negatively charged, the liquid droplets which are negatively charged by the charging unit 41 are collected in the collection container 82, and the positively charged liquid droplets are collected in the collection container 83, respectively.\",\n \"In addition, the liquid droplets which are not charged by the charging unit 41 directly drop to be collected in the collection container 81 without receiving an electrical acting force from the deflection plates 51 and 52.In the flow cytometer 1, the travelling direction of the liquid droplets is controlled according to the characteristic of the cell included in each of the liquid droplets, thereby allowing a target cell having a desired characteristic and a non-target cell other than the target cell to be collected in separate collection containers.\",\n \"The collection containers 81, 82, and 83 may be a general-purpose plastic tube or a glass tube for laboratory use.\",\n \"It is preferable that the collection containers be exchangeably disposed in the flow cytometer 1.In addition, the collection container for receiving the non-target cell among the collection containers may be connected to a drainage route of the collected liquid droplets.\",\n \"Furthermore, in the flow cytometer 1, the number of collection containers to be disposed is not particularly limited.\",\n \"When more than 3 collection containers are disposed, the respective liquid droplets are induced toward any one of the collection containers according to presence or absence of the electrical acting force between the deflection plates 51 and 52, and the magnitude thereof, and collected in the collection container.\",\n \"(7) Control Unit or the Like The flow cytometer 1 includes a data analysis unit for determining the optical characteristic of the cell, a tank unit for accumulating the sample liquid and the sheath liquid, a control unit 10 for controlling each configuration, and the like, which are provided in a usual flow cytometer, in addition to the configuration described above.\",\n \"The control unit 10 is able to be configured by a general-purpose computer provided with a CPU, a memory, hard disk, and the like, and stores an OS, a program for executing a control step (described later), and the like in the hard disk.\",\n \"The control unit 10 outputs a movement signal for a position in which a variation becomes small, that is, a position in which an integrated value or an average value of a detected intensity of the light generated from the microchip by the irradiation of the laser L1 becomes higher (preferably, becomes a maximum value) among regions set in advance to the position adjustment unit 9.\",\n \"(8) Microchip The microchip 2 is configured by bonding substrate layers 2a and 2b in which the sample flow passage 22 is formed.\",\n \"The sample flow passage 22 is able to be formed in the substrate layers 2a and 2b according to injection molding of a thermoplastic resin with a mold.\",\n \"As the thermoplastic resin, plastics which are known as microchip material in the related art, such as polycarbonate, polymethylmethacrylate (PMMA) resin, cyclic polyolefin, polyethylene, polystyrene, polypropylene, and polydimethylsiloxane (PDMS) are able to be adopted.\",\n \"The sample liquid is introduced to the sample inlet 23, merged into the sheath liquid introduced to a sheath inlet 24, and flows through the sample flow passage 22.The flow of the sheath liquid introduced from the sheath inlet 24 is divided into two directions, and then is merged into the sample liquid at a merging portion with the sample liquid introduced from the sample inlet 23, by sandwiching the sample liquid from the two directions.\",\n \"Accordingly, three-dimensional laminar flow in which sample liquid laminar flow is positioned in the center of sheath liquid laminar flow is formed at the merging portion.\",\n \"A reference numeral “25” indicates a suction flow passage for removing clogging or air bubbles by applying a negative pressure to the inside of the sample flow passage 22 and by temporarily regurgitating the flow when the clogging or the air bubbles is generated in the sample flow passage 22.One end of the suction flow passage 25 is provided with a suction outlet 251 which is connected to a negative pressure source such as a vacuum pump, and the other end is connected to the sample flow passage 22 at a communication port 252.A laminar flow width of the three-dimensional laminar flow is narrowed at a throttle portions 261 (refer to FIGS.\",\n \"2) and 262 (refer to FIG.\",\n \"3) which are formed such that the area of a cross section vertical to a flow direction gradually or progressively becomes smaller upstream to downstream in the flow direction.\",\n \"Subsequently, the three-dimensional laminar flow is ejected from the orifice 21 disposed on one end of the flow passage.\",\n \"The characteristic of the cell is detected between the throttle portion 261 and the throttle portion 262 of the sample flow passage 22.The cell which is arranged in line at the center of the three-dimensional laminar flow and flows through the sample flow passage 22 is irradiated with the laser L1 by the irradiation detection unit, and thus the fluorescence F1 and the scattering light which are generated from the cell are detected (refer to FIG.\",\n \"2).\",\n \"A connection portion with respect to the orifice 21 of the sample flow passage 22 is configured as a straight portion 27 which is linearly formed.\",\n \"The straight portion 27 functions to directly inject the fluid stream S from the orifice 21 to the Y-axis forward direction.\",\n \"The three-dimensional laminar flow ejected from the orifice 21 becomes the liquid droplets by the oscillation applied to the orifice 21 according to the oscillating element 31, and is injected as the fluid stream S (refer to FIG.\",\n \"1).\",\n \"The orifice 21 is open to an end surface direction of the substrate layers 2a and 2b, and a cutout portion 211 is formed between an opening position of the orifice and the end surfaces of the substrate layers.\",\n \"The cutout portion 211 is formed by cutting out the substrate layers 2a and 2b between the opening position of the orifice 21 and the end surfaces of the substrates such that the diameter L of the cutout portion 221 is larger than the opening diameter 1 of the orifice 21 (refer to FIG.\",\n \"3C).\",\n \"It is preferable that the diameter L of the cutout portion 211 be equal to or greater than two times larger than the opening diameter 1 of the orifice 21 in order not to disturb the movement of the liquid droplets discharged from the orifice 21.2.Optimization Control of Optical Position of Microchip-type Optical Measuring Apparatus according to First Embodiment of the Present Technology FIG.\",\n \"4 is a flowchart for describing a control step in order to optimize an optical position of the microchip 2 of the flow cytometer 1.The control step includes a procedure of an “original point-reference point movement step S1”, a “signal acquisition step S2”, an “area average value maximum position determination step S3”, an “area average maximum position movement step S4”, a “signal acquisition step S5”, an “integrated value maximum position determination step S6”, a “variation coefficient determination step S7”, and a “position optimization step S8”.\",\n \"Hereinafter, each procedure will be described.\",\n \"(1) Original Point-Reference Point Movement Step S1 When a starting signal of an analysis is input by a user, the control unit 10 outputs the movement signal to the position adjustment unit 9, and the position adjustment unit 9 moves the relative position of the microchip 2 with respect to the irradiation detection unit to an initial position (refer to an original point O of FIG.\",\n \"5) set in advance.\",\n \"When the relative position is at the original point O, the laser L1 emitted from the irradiation detection unit is applied to the original point O on the microchip 2.The relative position is changed by moving at least one of the position of the microchip 2 or the position of the irradiation detection unit including the light source 61 and the detector 62 to the X-axial direction and the Y-axial direction, and, hereinafter, a case where the relative position is changed by moving the position of the microchip 2 will be described as an example.\",\n \"Next, the control unit 10 starts to allow the sample liquid and the sheath liquid to flow toward the sample inlet 23 and the sheath inlet 24 of the microchip 2 by driving a pump of the tank portion which accumulates the sample liquid and the sheath liquid.\",\n \"It is preferable that the sample liquid include a calibration bead.\",\n \"Further, the control unit 10 starts to apply the oscillation to the orifice 21 by the oscillating element 3.Accordingly, the three-dimensional laminar flow of the sample liquid and the sheath liquid injected from the orifice 21 is discharged to be the liquid droplets, and thus the fluid stream S is generated.\",\n \"After starting the flow of the sample liquid and the sheath liquid, the control unit 10 outputs the movement signal to the position adjustment unit 9, and the position adjustment unit 9 moves the position of the microchip 2 to a reference point D0 from the original point O (refer to an arrow of FIG.\",\n \"5).\",\n \"When the relative position of the microchip 2 with respect to the irradiation detection unit is at the reference point D0, the laser L1 emitted from the irradiation detection unit is applied to the reference point D0 on the microchip 2.The reference point D0 is set in advance in the vicinity of the position in which the characteristic of the cell of the microchip 2 is able to be detected (that is, an optimal position which is determined by steps described later).\",\n \"More specifically, the reference point D0 is the vicinity between the throttle portion 261 and the throttle portion 262 of the sample flow passage 22 (refer to FIG.\",\n \"3).\",\n \"(2) Signal Acquisition Step S2 In this step S2, the fluorescence or the scattering light (hereinafter, simply referred to as the “fluorescence”) generated from a plurality of positions on the microchip 2 which includes the reference point D0 is detected by the irradiation detection unit.\",\n \"In this step S2, the position on the microchip 2 in which the fluorescence is detected is illustrated by a reference numeral D in FIG.\",\n \"5.In the drawings, a case where 24 detected positions D including the reference point D0 are set, and the fluorescence is detected from the detected positions D in which the number of arrangements M1 of the X-axial direction is arranged in 8 rows, and the number of arrangements N1 of the Z-axial direction is arranged in 3 rows is illustrated as an example.\",\n \"In a region in which the detected positions D are set, the sample flow passage 22 is included, and the number of detected positions D and an arrangement aspect are not particularly limited but arbitrarily set insofar as the sample flow passage 22 is included in the region.\",\n \"It is preferable that the detected positions D be arranged in a reticular pattern in the X-axial direction and the Z-axial direction, as illustrated.\",\n \"In this case, arrangement intervals W and H of the X-axial direction and the Z-axial direction of the detected positions D are able to be properly set according to a flow passage width (a flow passage diameter) of the sample flow passage 22 and the number of arrangements M1 and N1 of the detected positions D in the X-axial direction and the Z-axial direction.\",\n \"The flow passage width of the sample flow passage 22 is approximately 70 to 100 μm, and when M1 is 8 and N1 is 3, the arrangement intervals W and H are set, for example, to 25 and 75 μm, respectively.\",\n \"The detection of the fluorescence is performed with respect to one detected position D for a predetermined time.\",\n \"The fluorescence detected for the predetermined time is integrated, converted to the electric signal, and output to the control unit 10.The fluorescence is able to be detected by performing scanning of the laser L1 in the X-axial direction and the Z-axial direction, by sequentially applying the laser to each detected position D, and by detecting the fluorescence to be generated.\",\n \"Alternatively, the fluorescence from each of the detected positions D may be collectively detected by an area imaging element according to the irradiation of the laser L1.\",\n \"(3) Area Average Value Maximum Position Determination Step S3 In this step S3, the control unit 10 calculates an area average of the integrated value of the detected intensity with respect to each of the detected positions D, and automatically determines the detected position D where the area average becomes higher, preferably, the detected position D where the area average is the maximum value.\",\n \"The “area average” indicates an average of the integrated value of the detected intensity obtained by one detected position D, and a plurality of detected positions D within a predetermined distance range from the one detected position.\",\n \"In FIG.\",\n \"5, a case where the area average is an average of the integrated value of the detected intensity obtained by one detected position D1, and detected positions D2 to D9 within the distance range of 2W in the X-axial direction from the detected position D1 and 2H in the Z-axial direction from the detected position D1 is illustrated.\",\n \"Setting how far the distance range is from the one detected position D as the area average is able to be properly determined according to the flow passage width (the flow passage diameter) of the sample flow passage 22, and the arrangement intervals W and H. The control unit 10 compares the calculated area average to each of the detected positions D, and determines the detected position D where the area average becomes higher, preferably, the detected position D where the area average is the maximum value.\",\n \"Here, a case where the area average is the maximum value in the detected position D1 will be described.\",\n \"Since the fluorescence is strongly generated in the sample flow passage 22 through which the calibration bead or the cell flows, it is possible to consider that the sample flow passage 22 is positioned within a region R1 where the detected positions D1 to D9 in which the area average is the maximum value are formed in conjunction.\",\n \"(4) Area Average Maximum Position Movement Step S4 When the detected position D1 where the area average is the maximum value is specified, the control unit 10 outputs the movement signal to the position adjustment unit 9, and the position adjustment unit 9 moves the position of the microchip 2 to the detected position D1 from the reference point D0 (refer to an arrow of FIG.\",\n \"6).\",\n \"(5) Signal Acquisition Step S5 In this step S5, the detection of the fluorescence which is generated from a plurality of positions within the region R1 where the area average is the maximum value is performed by the irradiation detection unit.\",\n \"The detected positions D of the fluorescence in this step S5 are illustrated in an enlarged view of FIG.\",\n \"6.In the drawings, a case where the fluorescence is detected from the detected positions D of (M2×N2) in which M2 rows in the X-axial direction and N2 rows in the Z-axial direction are arranged, including the detected position D1 where the area average is the maximum value is illustrated as an example.\",\n \"Arrangement intervals w and h of the detected positions D in the X-axial direction and the Z-axial direction are able to be properly set according to the flow passage width (the flow passage diameter) of the sample flow passage 22 and the number of arrangements M2 and N2 in the X-axial direction and the Z-axial direction.\",\n \"The number of arrangements M2 and N2 are, for example, 11 and 7, respectively.\",\n \"The row intervals w and h are set, for example, to 5 and 25 μm, respectively.\",\n \"Furthermore, in this step S5, the number of detected positions D and the arrangement aspect are not particularly limited.\",\n \"The detection of the fluorescence is performed with respect to the one detected position D for the predetermined time.\",\n \"The fluorescence detected for the predetermined time is converted to the electric signal and output to the control unit 10.The fluorescence is detected by performing scanning of the laser L1 in the X-axial direction and the Z-axial direction to sequentially scan each detected position D, and by detecting the fluorescence to be generated.\",\n \"Alternatively, the fluorescence from each of the detected positions D may be collectively detected by the irradiation of the laser L1 according to an area imaging element.\",\n \"(6) Integrated Value Maximum Position Determination Step S6 In this step S6, the control unit 10 calculates either one or both of the integrated value and the average value of the detected intensity with respect to each of the detected positions D, and a variation coefficient (a CV value) thereof.\",\n \"Hereinafter, a process using the integrated value of the detected intensity and the CV value thereof will be described as an example.\",\n \"The control unit 10 compares the calculated integrated value of the detected intensity with respect to each of the detected positions D, and determines the detected position D where the integrated value becomes higher, preferably, the detected position D (a first optimal position) where the integrated value is the maximum value.\",\n \"Here, a case where the integrated value is the maximum value in the detected position D11 will be described (refer to FIG.\",\n \"6).\",\n \"(7) Variation Coefficient Determination Step S7 Next, the control unit 10 compares the CV values between the detected position D11 where the integrated value is the maximum value and the adjacent detected positions D12 to D19, and automatically determines the presence or absence of the detected position D (a second optimal position) to which a CV value smaller than that of the detected position D11 is applied (refer to FIG.\",\n \"7).\",\n \"(8) Position Optimization Step S8 In step S2, when the detected position D to which the CV value smaller than that of the detected position D11 where the integrated value is the maximum value is applied is not found in any of the detected position D11 and the adjacent detected positions D12 to D19, the control unit 10 moves the position of the microchip 2 to the detected position D11 from the detected position D1.At this time, both the detected position (the first optimal position) where the integrated value is the maximum value and the detected position (the second optimal position) where the CV value is the minimum value are coincident with each other in the detected position D11.In addition, in step S7, when the detected position D to which the CV value smaller than that of the detected position D11 is applied is found in any one of the detected positions D12 to D19, the control unit 10 moves the position of the microchip 2 to the detected position D (for example, the detected position D18) from the detected position D1.At this time, the detected position (the first optimal position) where the integrated value is the maximum value and the detected position (the second optimal position) where the CV value is the minimum value are not coincident with each other.\",\n \"The detected position D11 where the integrated value is the maximum value is a position where the fluorescence is most strongly generated, and is able to be considered as a through-flow position of the calibration bead or the cell in the sample flow passage 22.That is, when the relative position of the microchip 2 with respect to the irradiation detection unit is in the detected position D11, the laser L1 emitted from the irradiation detection unit is applied to the through-flow position of the calibration bead or the like in the sample flow passage 22.In some cases even though the detected position D11 where the integrated value is the maximum value is not the through-flow position of the calibration bead or the like in the sample flow passage 22, the integrated value of the fluorescence intensity may be the maximum value.\",\n \"For example, when the detected position D11 is coincident with a flow passage wall of the micro-flow passage 22, the fluorescence intensity which is abnormally high due to reflecting, scattering, or the like of the fluorescence may be sporadically detected.\",\n \"In this case, a variation is generated in the fluorescence intensity which is detected in the position, and the CV value of the integrated value of the fluorescence intensity becomes high.\",\n \"When the detected position D11 is coincident with the flow passage wall of the micro-flow passage 22, or the like, it is possible to consider the detected position D18 to which a smaller CV value is applied among the detected position D11 and the adjacent detected positions as the through-flow position of the calibration bead or the like in the sample flow passage 22.That is, when the relative position of the microchip 2 with respect to the irradiation detection unit is in the detected position D18, the laser L1 emitted from the irradiation detection unit is applied to the through-flow position of the calibration bead or the like in the sample flow passage 22.As described above, in the flow cytometer 1, the relative position of the microchip 2 with respect to the laser L1 is set to the position where the integrated value or the average value of the detected intensity of the fluorescence generated from the microchip 2 by the irradiation of the laser L1 becomes higher or the position where the CV value becomes smaller.\",\n \"Accordingly, in the flow cytometer 1, the through-flow position of the cell in the sample flow passage 22 of the microchip 2, and the optical axis of the laser L1 are automatically positioned with high accuracy, and thus it is possible to simply perform high accuracy measurement.\",\n \"In addition, in the flow cytometer 1, the optical position of the microchip 2 is optimized by a two-staged procedure of a coarse adjustment for specifying the position where the area average of the integrated value of the detected intensity of the fluorescence becomes higher (steps S2 and S3), and a fine adjustment for specifying the position where the integrated value or the average value becomes higher within the region where the area average becomes higher or the position where the CV value becomes smaller (steps S5 to S7).\",\n \"Accordingly, it is possible to rapidly perform the optimization of the optical position of the microchip 2 with a small processing load.\",\n \"3.Optimization Control of Optical Position of Microchip-type Optical Measuring Apparatus according to Second Embodiment of the Present Technology FIG.\",\n \"8 is a flowchart for describing a control step according to a second embodiment in order to optimize the optical position of the flow cytometer 1.The control step of this embodiment includes a procedure of an “original point-reference point movement step S1”, a “coarse adjustment step S21”, a “first fine adjustment step S22”, a “second fine adjustment step S23”, and a “finer adjustment step S24”.\",\n \"Hereinafter, each procedure will be described.\",\n \"Furthermore, since the original point-reference point movement step S1 is a process which is substantially identical to the original point-reference point movement step S1 of the first embodiment, except that the reference point D0 (refer to FIG.\",\n \"5 again) corresponds to a reference point P0 illustrated in FIG.\",\n \"9 (described later), the description thereof will be omitted.\",\n \"(1) Coarse Adjustment Step S21 FIG.\",\n \"9 is a diagram for describing control of a coarse adjustment step S21 according to this embodiment.\",\n \"The coarse adjustment step S21 includes a procedure of a “grid-like signal acquisition step S211”, a “two-dimensional distribution parameter estimation step S212”, and a “maximum position movement step S213”.\",\n \"Hereinafter, each procedure will be described.\",\n \"(1-1) Grid-like Signal Acquisition Step S211 In this step 5211, the detection of the fluorescence from a plurality of detected positions D21 set in advance is performed by the irradiation detection unit (refer to FIG.\",\n \"9A).\",\n \"In this step S211, a position on the microchip 2 in which the detection of the fluorescence is performed is illustrated by a reference numeral D21 in FIG.\",\n \"9A.\",\n \"In FIG.\",\n \"9A, a case where the fluorescence is detected from the detected positions D21 in which 6 rows in the X-axial direction and 7 rows in the Z-axial direction are arranged, centered on the reference point P0 is illustrated as an example.\",\n \"In a region in which the detected positions D21 are set, the sample flow passage 22 is included, and the number of detected positions D21 and the arrangement aspect are not particularly limited but arbitrarily set insofar as the sample flow passage 22 is included in the region.\",\n \"It is preferable that the detected positions D21 be arranged in a reticular pattern in the X-axial direction and the Z-axial direction, as illustrated in FIG.\",\n \"9A.\",\n \"In this case, arrangement intervals W2 and H2 of the detected positions D21 in the X-axial direction and the Z-axial direction are able to be properly set according to the flow passage width (the flow passage diameter) of the sample flow passage 22 and the number of arrangements M3 and N3 of the detected positions D21 in the X-axial direction and the Z-axial direction.\",\n \"The arrangement intervals W2 and H2 are set, for example, to 62.5 and 125 μm, respectively.\",\n \"The detection of the fluorescence is performed substantially similarly to the signal acquisition step S2 of the first embodiment.\",\n \"(1-2) Two-Dimensional Distribution Parameter Estimation Step S212 In this step S212, the control unit 10 assumes that a relationship between each of the detected positions D21 and the integrated value or the average value of the detected intensity of the fluorescence follows two-dimensional probability distribution.\",\n \"Further, for the detected position and the detected intensity acquired in step S211, and an irradiation profile of the laser indicating a relationship between an irradiation position and an irradiation intensity, the detected intensity of each of the detected positions has a correlative relationship with the irradiation intensity of a corresponding irradiation position.\",\n \"For this reason, it is preferable that the assumed probability distribution be selected according to the irradiation profile of the laser.\",\n \"For example, when the irradiation profile is in the shape of a top-hat beam as illustrated in FIG.\",\n \"10A (described later), the control unit 10 is able to assume uniform distribution as a probability distribution model.\",\n \"On the other hand, when the irradiation profile is in the shape of a Gaussian beam as illustrated in FIG.\",\n \"10B (described later), normal distribution is able to be assumed as the probability distribution model.\",\n \"Thus, it is possible to adjust the optical position according to the optical characteristic of the laser of the apparatus with high speed and high accuracy by selecting the probability distribution according to the irradiation profile of the laser.\",\n \"In addition, when it is assumed that the relationship between each of the detected positions D21 and the integrated value or the average value of the detected intensity of the fluorescence follows the two-dimensional probability distribution, the control unit 10 estimates a distribution parameter of the probability distribution by a stochastic method, on the basis of stochastic information.\",\n \"For example, the control unit 10 is able to estimate the distribution parameter (an average (a center position of the distribution), dispersion (spread of the distribution), or the like) with respect to each integrated value or average value by a maximum likelihood estimation method.\",\n \"In this maximum likelihood estimation method, at the time of estimating the relationship between the detected intensity and the detected position to be in the two-dimensional normal distribution, it is possible to estimate where the center position (the position where the detected intensity is maximum) of the two-dimensional normal distribution is at the time of maximizing likelihood, on the basis of the probability distribution model stored in the control unit 10 in advance.\",\n \"According to this maximum likelihood estimation method, it is possible to estimate the position (an optical axis center position of the laser L1) where the detected intensity is maximum with high accuracy even when data of the detected intensity is small.\",\n \"(1-3) Maximum Position Movement Step S213 In this step S213, the control unit 10 outputs the movement signal for a position P1 where the integrated value or the average value of the detected intensity in the probability distribution estimated in the probability distribution estimation step S212 becomes higher, and preferably, becomes the maximum value to the position adjustment unit 9.Accordingly, as illustrated in FIG.\",\n \"9C, the position adjustment unit 9 moves the position of the microchip 2 to the position P1 from the reference point P0.Here, a calculating method of the maximum position will be described with reference to FIG.\",\n \"10.FIG.\",\n \"10 is a diagram illustrating a state where the two-dimensional probability distribution is viewed from one direction.\",\n \"In FIG.\",\n \"10A, top-hat distribution (uniform distribution) is illustrated.\",\n \"When the probability distribution is estimated to be the top-hat distribution, the control unit 10 determines a center position of an edge E1 and an edge E2 in FIG.\",\n \"10A as the position where the detected intensity is maximum.\",\n \"On the other hand, in FIG.\",\n \"10B, Gaussian distribution is illustrated.\",\n \"When the probability distribution is estimated as the Gaussian distribution, as illustrated in FIG.\",\n \"10B, it is possible to set a position where the integrated value or the average value of the detected intensity has a maximum value b to a position where an inclination is 0 (an inclination a).\",\n \"In the flow cytometer 1, it is preferable that the optical profile of the laser be the Gaussian distribution, and in this case, the distribution of the integrated value or the average value of a plurality of detected intensities may be the Gaussian distribution.\",\n \"Thus, in the coarse adjustment step S21, the integrated value or the average value of the detected intensity of the light in a plurality of detected positions D21 is estimated as a specified two-dimensional probability distribution, and it is possible to move the microchip 2 to the position where the integrated value or the average value of the detected intensity of the light in the probability distribution becomes higher, and preferably, becomes the maximum value.\",\n \"As described above, according to the optical position adjusting method of this embodiment, it is possible to improve position adjustment accuracy of the microchip 2 without increasing the number of detected positions D21, by estimating the probability distribution of the detected intensity of each of the detected positions D21.\",\n \"(2) First Fine Adjustment Step S22 FIG.\",\n \"11 is a diagram for describing control of a first fine adjustment step S22 according to this embodiment.\",\n \"The first fine adjustment step S22 includes a procedure of a “linear signal acquisition step S221”, a “one-dimensional distribution parameter estimation step S222”, and a “maximum position movement step S223”.\",\n \"Hereinafter, each procedure will be described.\",\n \"(2-1) Linear Signal Acquisition Step S221 In this step S221, centered on the position P1 which is set in the coarse adjustment step S21, the detection of the fluorescence from a plurality of detected positions d22 which are arranged in the X-axial direction is performed (FIG.\",\n \"11A).\",\n \"An interval W22 to be detected and the number of arrangements of the detected positions d22 are able to be properly set.\",\n \"In FIG.\",\n \"11A, a case where 19 detected positions d22 are arranged in the X-axial direction, centered on the position P1 is illustrated as an example.\",\n \"The detection of the fluorescence is performed substantially similarly to the signal acquisition step S2 of the first embodiment.\",\n \"(2-2) One-Dimensional Distribution Parameter Estimation Step S222 In this step S222, the control unit 10 assumes that a relationship between each of the detected positions d22 and the integrated value or the average value of the detected intensity of the fluorescence follows a one-dimensional distribution stored in a memory or the like.\",\n \"For example, when the data of the detected intensity illustrated in FIG.\",\n \"11B is obtained, the control unit 10 sets the one-dimensional distribution to an Nth-order polynomial model, and thus it is possible to calculate a maximum value on the basis of a least-square method.\",\n \"Setting the one-dimensional distribution to the Nth-order polynomial model allows a variation of the distribution of the optical profile due to a design variation or the like of each component configuring the flow cytometer 1 to be handled with high accuracy, compared to a case where the one-dimensional distribution is set to the normal distribution.\",\n \"Here, at the time of setting the distribution to the Nth-order polynomial model, while accuracy increases as the order becomes higher, it is susceptible to an effect due to an error of the detected intensity of each of the detected positions d22 when the order is too high, and thus it is preferable that the order be, for example, fourth-order.\",\n \"(2-3) Maximum Position Movement Step S223 In this step S223, the control unit 10 outputs the movement signal for the position P2 where the integrated value or the average value of the detected intensity in the one-dimensional distribution assumed in the one-dimensional parameter estimation step S222 becomes higher, and preferably, becomes the maximum value to the position adjustment unit 9.Accordingly, as illustrated in FIG.\",\n \"11C, the position adjustment unit 9 moves the position of the microchip 2 to the position P2 from the position P1.Furthermore, a case where the position P2 illustrated in FIG.\",\n \"11C is on the detected position d22 is illustrated as an example, but the position P2 may be between two detected positions d22.Thus, in the first fine adjustment step S22, it is possible to adjust the position of the microchip 2 adjusted in the coarse adjustment step S21 with high accuracy.\",\n \"Particularly, the position adjustment of the microchip 2 is performed on the basis of the detected intensity of the detected positions d22 which are arranged in one direction.\",\n \"For this reason, it is possible to reduce the number of data items to be detected, compared to a case where the position adjustment is performed on the basis of the intensity of the detected positions which are arranged in a plurality of directions, for example, in a reticular pattern.\",\n \"Accordingly, even though the number of arrangements increases, and accuracy of the data increases, it is possible to inhibit data detection time from being increased by narrowing the interval of the detected positions d22, compared to a case where the data is two-dimensionally acquired.\",\n \"(3) Second Fine Adjustment Step S23 FIG.\",\n \"12 is a diagram for describing control of a second fine adjustment step S23 according to this embodiment.\",\n \"The second fine adjustment step S23 includes a procedure of a “linear signal acquisition step S231”, a “one-dimensional parameter estimation step S232”, and a “maximum position movement step S233”.\",\n \"As illustrated in FIGS.\",\n \"12A to 12C, the control of this step S23 is substantially identical to the control of the first fine adjustment step S22 which is described with reference to FIGS.\",\n \"11A to 11C, except that the microchip 2 is moved to the position P3 from the position P2 in the Y-axial direction on the basis of the detected intensity of detected positions d23 which are arranged in the Y-axial direction, centered on the position P2, instead of moving the microchip 2 to the position P2 from the position P1 in the X-axial direction on the basis of the detected intensity of the detected positions d22 which are arranged in the X-axial direction.\",\n \"For this reason, the description thereof will be omitted here.\",\n \"Here, in the first fine adjustment step S22, the position adjustment is performed in the X-axial direction (a flow width direction of the microchip 2), and in the second fine adjustment step S23, the position adjustment is performed in the Z-axial direction (a focus direction of the laser L1).\",\n \"Since the Z-axial direction has a wider optical profile width (the detected intensity of the fluorescence is high in a wide range) compared to the X-axial direction, the position adjustment in the Z-axial direction is likely to be performed with high accuracy according to a process performed in the coarse adjustment step S21 described above, compared to the position adjustment in X-axial direction.\",\n \"For this reason, in the coarse adjustment step S21, it is preferable that the Z-axial direction in which the position adjustment is performed with higher accuracy be fixed first, and then the position adjustment of the microchip 2 in the X-axial direction be performed.\",\n \"Accordingly, it is preferable that the first fine adjustment step S21 and the second fine adjustment step S22 be performed in this order.\",\n \"In the second fine adjustment step S23, the position adjustment of the microchip 2 is performed in a direction different from the direction of the fine adjustment in the first fine adjustment S22, thereby allowing the position adjustment to be performed with higher accuracy.\",\n \"(4) Finer Adjustment Step S24 FIG.\",\n \"13 is a diagram for describing control of the second fine adjustment step S23 according to this embodiment.\",\n \"The finer adjustment step S24 includes a procedure of a “signal acquisition step S241”, an “integrated value maximum position determination step S6”, a “variation coefficient determination step S7”, and a “position optimization step S8”.\",\n \"As illustrated in FIG.\",\n \"13A, first, in the signal acquisition step S241, the detection of the fluorescence is performed in a plurality of detected positions d24, centered on the position P3 which is set in the second fine adjustment step S23.In FIG.\",\n \"13A, a case where the number of arrangements M4 of the X-axial direction is 11 rows, and the number of arrangements N1 of the Z-axial direction is 3 rows is illustrated as an example.\",\n \"The detection of the fluorescence is performed substantially similarly to the signal acquisition step S2 of the first embodiment.\",\n \"Next, after performing the detection of the fluorescence in the signal acquisition step S241, the integrated value maximum position determination step S6, the variation coefficient determination step S2, and the position optimization step S8 are performed substantially similarly to the integrated value maximum position determination step S6, the variation coefficient determination step S2, and the position optimization step S8 of the control step of the first embodiment (refer to FIG.\",\n \"13B and FIG.\",\n \"13C).\",\n \"Thus, the microchip 2 is moved to the most suitable position (moved to P4 from P3 in FIG.\",\n \"13C).\",\n \"Furthermore, in this embodiment, each process is described in an order of the “coarse adjustment step S21”, the “first fine adjustment step S22”, the “second fine adjustment step S23”, and the “finer adjustment step S24”, but, for example, the “coarse adjustment step S21”, the “first fine adjustment step S22”, and the “second fine adjustment step S23” may be repeated for a plurality of times.\",\n \"In addition, only the “coarse adjustment step S21”, the “first fine adjustment step S22”, and the “second fine adjustment step S23” are performed at once or a plurality of times, and the “finer adjustment step S24” may be omitted.\",\n \"As described above, according to the optical position adjusting method of this embodiment, the relationship between each of the detected positions and the detected intensity is assumed to follow the specified probability distribution model, and the distribution parameter is estimated on the basis of the stochastic method, thereby allowing the position adjustment of the microchip 2 to be performed with high accuracy in a rapid process, without increasing the number of detected positions.\",\n \"In the microchip-type optical measuring apparatus according to the present technology, an apparatus for optically measuring an object to be measured which is introduced to a region having the microchip formed therein is broadly included in addition to the microparticle measuring apparatus (the flow cytometer).\",\n \"In addition, the optical position adjusting method according to the present invention is able to be broadly applied to the entire apparatus for optically measuring an object to be measured which is introduced to a region having the microchip formed therein other than the microparticle measuring apparatus (the flow cytometer).\",\n \"The microchip-type optical measuring apparatus according to the present technology is able to be configured as the following.\",\n \"(1) A microchip-type optical measuring apparatus, including: an irradiation detection unit which detects light generated by irradiating a microchip with laser; a position adjustment unit which changes a relative position of the microchip with respect to the irradiation detection unit; and a control unit which outputs a movement signal for a position in which an integrated value or an average value of a detected intensity of the light in a preset region becomes high to the position adjustment unit.\",\n \"(2) The microchip-type optical measuring apparatus according to (1), in which the control unit assumes that a relationship between a detected position of the light and the integrated value or the average value of the detected intensity of the light follows a pre-stored probability distribution, estimates a distribution parameter of the probability distribution on the basis of a pre-stored stochastic method, and thus creates the movement signal for the position in which the integrated value or the average value of the detected intensity of the light becomes maximum by the estimation.\",\n \"(3) The microchip-type optical measuring apparatus according to (2), in which the control unit assumes the probability distribution according to an irradiation profile of the laser.\",\n \"(4) The microchip-type optical measuring apparatus according to any one of (1) to (3), in which the control unit outputs the movement signal for a position in which a variation coefficient of the integrated value or the average value of the detected intensity of the light in a plurality of preset points becomes minimum to the position adjustment unit.\",\n \"(5) The microchip-type optical measuring apparatus according to (4), in which the control unit outputs the movement signal for an area in which an area average of the integrated value of the detected intensity in a plurality of preset areas becomes maximum to the position adjustment unit.\",\n \"(6) The microchip-type optical measuring apparatus according to (5), in which the control unit outputs the movement signal for a position in which the integrated value of the detected intensity in the plurality of preset points becomes maximum to the position adjustment unit.\",\n \"(7) The microchip-type optical measuring apparatus according to (6), in which the control unit outputs the movement signal for a first optimal position in which the integrated value of the detected intensity in the area of a maximum area average becomes maximum, or for a second optimal position in which the variation coefficient in the area of the maximum area average becomes minimum to the position adjustment unit.\",\n \"(8) The microchip-type optical measuring apparatus according to (7), in which the control unit outputs the movement signal for the second optimal position to the position adjustment unit when the first optimal position and the second optimal position are different from each other.\",\n \"(9) The microchip-type optical measuring apparatus according to (1) to (8), in which the microchip-type optical measuring apparatus is a microchip-type microparticle measuring apparatus.\",\n \"In addition, the optical position adjusting method of a microchip-type optical measuring apparatus according to the present technology is able to be configured as the following.\",\n \"(1) An optical position adjusting method, including: a procedure for detecting light which is generated from a microchip by laser irradiation, from a plurality of positions on the microchip; and a procedure for specifying a position in which an integrated value or an average value of a detected intensity of the light in a region where a plurality of preset points exists becomes maximum.\",\n \"(2) The optical position adjusting method according to (1), in which in the procedure for specifying the position, a relationship between a detected position of the light and the integrated value or the average value of the detected intensity of the light is assumed to follow a pre-stored probability distribution, a distribution parameter of the probability distribution is estimated on the basis of a pre-stored stochastic method, and thus the position in which the integrated value or the average value of the detected intensity of the light becomes maximum is specified by the estimation.\",\n \"(3) The optical position adjusting method according to (2), in which in the procedure for specifying the position, the probability distribution is set to two-dimensional distribution.\",\n \"(4) The optical position adjusting method according to (3), further including a procedure for assuming that a relationship of the integrated value or the average value of the detected intensity of the light from the position in which the integrated value or the average value of the detected intensity of the light is estimated to be maximum by the probability distribution to a predetermined position follows a one-dimensional distribution, and thus for specifying a position in which the integrated value or the average value of the detected intensity of the light becomes maximum by the one-dimensional distribution.\",\n \"(5) The optical position adjusting method according to any one of (1) to (4), in which in the procedure for specifying the position, the position is set to a position in which a variation coefficient of the integrated value or the average value of the detected intensity of the light in a plurality of preset points becomes minimum.\",\n \"(6) The optical position adjusting method according to (5), further including a procedure for specifying a position in which an area average of the integrated value of the detected intensity of the light in a plurality of preset areas becomes maximum.\",\n \"(7) The optical position adjusting method according to (6), further including a procedure for specifying a first optimal position in which the integrated value of the detected intensity in the area of a maximum area average becomes maximum.\",\n \"(8) The optical position adjusting method according to (7), in which the procedure for specifying the position in which the variation coefficient becomes minimum is a procedure for specifying a second optimal position in which the variation coefficient in the area of the maximum area average becomes minimum.\",\n \"(9) The optical position adjusting method according to (8), further including a procedure for setting a relative position of the microchip with respect to the laser to the first optimal position or the second optimal position.\",\n \"(10) The optical position adjusting method according to (9), in which the relative position is set to the second optimal position when the first optimal position and the second optimal position are different from each other.\",\n \"(11) An optical position adjusting method of a microchip-type optical measuring apparatus, including: a procedure for detecting light which is generated from a microchip by laser irradiation, from a plurality of positions on the microchip; a procedure for specifying a position in which an area average of an integrated value of a detected intensity of the light becomes higher; a procedure for specifying a first optimal position in which the integrated value or an average value of the detected intensity in an area where the area average becomes higher, becomes higher; a procedure for specifying a second optimal position in which a variation coefficient of the integrated value or the average value of the detected intensity in the area where the area average becomes higher, becomes smaller; and a procedure for setting a relative position of the microchip with respect to the laser to the first optimal position or the second optimal position.\",\n \"REFERENCE SIGNS LIST 1 microchip-type optical measuring apparatus 2 microchip 21 orifice 22 sample flow passage 23 sample inlet 3 oscillating element 41 charging unit 42 electrode 51, 52 deflection plate 61 light source 62 detector 81, 82, 83 collection container 9 position adjustment unit 10 control unit D detected position F1 fluorescence L1 laser\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875846"}}},{"rowIdx":4494997,"cells":{"text":{"kind":"list like","value":[["POLYPEPTIDE MODIFICATION METHOD FOR PURIFYING POLYPEPTIDE MULTIMERS","The present invention provides efficient methods based on alteration of the protein A-binding ability, for producing or purifying multispecific antibodies having the activity of binding to two or more types of antigens to high purity through a protein A-based purification step alone.","The methods of the present invention for producing or purifying multispecific antibodies which feature altering amino acid residues of antibody heavy chain constant region and/or variable region.","Multispecific antibodies with an altered protein A-binding ability, which exhibit plasma retention comparable or longer than that of human IgG1, can be efficiently prepared in high purity by introducing amino acid alterations of the present invention into antibodies."],["1.A method for producing a polypeptide multimer that comprises a first polypeptide having an antigen-binding activity and a second polypeptide having an antigen-binding activity or no antigen-binding activity, which comprises the steps of: (a) expressing a DNA that encodes the first polypeptide having an antigen-binding activity and a DNA that encodes the second polypeptide having an antigen-binding activity or no antigen-binding activity; and (b) collecting the expression product of step (a), wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.","2.The method of claim 1, wherein the expression product is collected using protein A affinity chromatography in step (b).","3.The method of claim 1, wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so that there is a larger difference between the solvent pH for eluting the first polypeptide having an antigen-binding activity from protein A and that for eluting the second polypeptide having an antigen-binding activity or no antigen-binding activity from protein A.","4.The method of claim 1, wherein one or more amino acid residues in the first polypeptide having an antigen-binding activity or the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so as to increase or reduce the protein A-binding ability of either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.","5.The method of claim 1, wherein one or more amino acid residues in the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so as to increase the protein A-binding ability of either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity, and reduce the protein A-binding ability of the other polypeptide.","6.The method of claim 1, wherein the purity of the collected polypeptide multimer is 95% or more.","7.The method of claim 1, wherein the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity comprise an amino acid sequence of an antibody Fc domain or an amino acid sequence of an antibody heavy-chain constant region.","8.The method of claim 7, wherein at least one amino acid residue selected from the amino acid residues of positions 250 to 255, 308 to 317, and 430 to 436 (EU numbering) in the amino acid sequence of the antibody Fc domain or antibody heavy-chain constant region has been modified.","9.The method of claim 1, wherein the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity comprise an amino acid sequence of an antibody heavy-chain variable region.","10.The method of claim 9, wherein at least one amino acid residue has been modified in the amino acid sequences of FR1, CDR2, and FR3 of the antibody heavy-chain variable region.","11.The method of claim 1, wherein the polypeptide multimer comprises one or two third polypeptides having an antigen-binding activity, and step (a) comprises expressing a DNA that encodes the third polypeptide having an antigen-binding activity.","12.The method of claim 11, wherein the third polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.","13.The method of claim 11, wherein the polypeptide multimer additionally comprises a fourth polypeptide having an antigen-binding activity, and step (a) comprises expressing a DNA that encodes the fourth polypeptide having an antigen-binding activity.","14.The method of claim 13, wherein at least one of the third and fourth polypeptides having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.","15.The method of claim 13, wherein the first polypeptide having an antigen-binding activity comprises amino acid sequences of an antibody light-chain variable region and an antibody heavy-chain constant region; the second polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody heavy chain; the third polypeptide having an antigen-binding activity comprises amino acid sequences of an antibody heavy-chain variable region and an antibody light-chain constant region; and the fourth polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.","16.The method of claim 1, wherein the polypeptide multimer is a multispecific antibody.","17.The method of claim 16, wherein the multispecific antibody is a bispecific antibody.","18.The method of claim 1, which comprises the first polypeptide having an antigen-binding activity and the second polypeptide having no antigen-binding activity, and wherein the first polypeptide having an antigen-binding activity comprises an amino acid sequence of an antigen-binding domain of a receptor and an amino acid sequence of an antibody Fc domain, and the second polypeptide having no antigen-binding activity comprises an amino acid sequence of an antibody Fc domain.","19.","(canceled) 20.A polypeptide multimer produced by the method of claim 1.21.-36.","(canceled) 37.A polypeptide multimer that comprises a first polypeptide having an antigen-binding activity and a second polypeptide having an antigen-binding activity or no antigen-binding activity, wherein the protein A-binding ability is different for the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.","38.-55.","(canceled)"],["<SOH> BACKGROUND ART <EOH>There are some previously reported methods for producing an IgG-type bispecific antibody having a human constant region (IgG-type antibody which has a human constant region and in which one of the arms has a specific binding activity to antigen A and the other has a specific binding activity to antigen B).","In general, an IgG-type bispecific antibody is composed of two types of H chains (i.e., H chain against antigen A and H chain against antigen B) and two types of L chains (i.e., L chain against antigen A and L chain against antigen B).","When such an IgG-type bispecific antibody is expressed, two types of H chains and two types of L chains are expressed, and there are ten possible combinations for the H2L2 combination.","Of these, only one combination has the specificity of interest (one arm has binding activity specific to antigen A and the other has binding activity specific to antigen B).","Thus, to obtain a bispecific antibody of interest, it is necessary to purify a single antibody of interest from the ten types of antibodies.","This is an extremely inefficient and difficult process.","There are reported methods for solving this problem which use a common L chain so that the L chain against antigen A and the L chain against antigen B have an identical amino acid sequence (Patent Documents 1 and 2).","When an IgG-type bispecific antibody having such a common L chain is expressed, two types of H chains and one type of common L chain are expressed, and there are three possible combinations for the H2L2 combination.","One of these combinations is a bispecific antibody of interest.","These three combinations are: monospecific antibody against antigen A (homomeric H chain antibody against antigen A), bispecific antibody against both antigen A and antigen B (heteromeric antibody with an H chain against antigen A and an H chain against antigen B), and monospecific antibody against antigen B (homomeric H chain antibody against antigen B).","Since their ratio is in general 1:2:1, the expression efficiency of the desired bispecific antibody is about 50%.","A method for further improving this efficiency has been reported which allows two types of H chains heteromerically associate (Patent Document 3).","This can increase the expression efficiency of the desired bispecific antibody up to about 90-95%.","Meanwhile, a method has been reported for efficiently removing the two types of homomeric antibodies which are impurities, in which amino acid substitutions are introduced into the variable regions of the two types of H chains to give them different isoelectric points so that the two types of homomeric antibodies and the bispecific antibody of interest (heteromeric antibody) can be purified by ion exchange chromatography (Patent Document 4).","A combination of the above-mentioned methods has made it possible to efficiently produce a bispecific antibody (heteromeric antibody) having an IgG-type human constant region.","On the other hand, in the industrial production of IgG-type antibodies, a purification step by protein A chromatography must be used, but ion exchange chromatography is not necessarily used in the purification step.","Therefore, the use of ion exchange chromatography for producing a highly pure bispecific antibody leads to an increase of production costs.","In addition, since ion exchange chromatography alone may not ensure a robust purification method for pharmaceuticals, it is preferable to perform more than one chromatographic step to remove impurities.","In any case, it is preferable that bispecific antibodies can also be highly purified by a chromatographic step that has a separation mode different from that of ion exchange chromatography.","It is desirable that as one of such separation modes, protein A chromatography, which must be used in the industrial production of IgG-type antibodies, could purify bispecific antibodies to high purity.","A previously reported method for purifying a bispecific antibody (heteromeric antibody) using protein A is to use a bispecific antibody having a mouse IgG2a H chain that binds to protein A and a rat IgG2b H chain that does not bind to protein A.","It has been reported that this method allows a bispecific antibody of interest to be purified to a purity of 95% by the protein A-based purification step alone (Non-patent Document 1 and Patent Document 5).","However, this method also uses ion exchange chromatography to improve the purity of the bispecific antibody.","In other words, purification of a highly pure bispecific antibody cannot be achieved by the purification step using protein A chromatography alone.","Moreover, catumaxomab, a bispecific antibody produced by the above-described method and having a mouse IgG2a H chain and a rat IgG2b H chain, has a half-life of about 2.1 days in human, which is extremely shorter than that of normal human IgG1 (2 to 3 weeks) (Non-patent Document 2).","In addition to having a short half-life, catumaxomab is highly immunogenic because of its mouse and rat constant regions (Non-patent Document 3).","Thus, a bispecific antibody obtained by such methods is considered inappropriate as a pharmaceutical.","On the other hand, it has been suggested that from the viewpoint of immunogenicity, a human IgG3 constant region may be used as a protein A-nonbinding constant region (Non-patent Document 1).","However, as it is known that the H chains of human IgG1 and human IgG3 hardly associate with each other (Non-patent Document 1), it is impossible to produce a bispecific antibody of interest using a human IgG1 H chain and a human IgG3 H chain by the same method used for the bispecific antibody having a mouse IgG2a H chain and a rat IgG2b H chain.","Furthermore, the half-life of human IgG3 in human has been reported to be generally shorter than that of human IgG1, human IgG2, and human IgG4 (Non-patent Documents 4 and 5).","Accordingly, like the bispecific antibody using a mouse IgG2a and a rat IgG2b, a bispecific antibody using human IgG3 might also have a short half-life in human.","The reason that H chain association rarely occurs between human IgG1 and human IgG3 is suggested to be the hinge sequence of human IgG3 (Non-patent Document 1).","Meanwhile, the reason for the short half-life of the human IgG3 constant region has not been fully elucidated yet.","Thus, there has been no report so far with regard to bispecific antibodies that use a human IgG3 constant region as a protein A-nonbinding constant region.","Moreover, there is also no report regarding methods for efficiently producing or purifying highly pure bispecific antibodies that have a human constant region and show a similarly long half-life as human IgG1."],["<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG.","1 is a graph showing an assessment of the plasma retention time of MRA-IgG1 and MRA-z106/z107k in human FcRn transgenic mice.","FIG.","2 is a diagram showing that the same region in the antibody Fc domain binds to protein A and FcRn.","FIG.","3 shows a time course of the plasma concentrations of Q499-z118/J339-z119/L377-k and Q499-z121/J339-z119/L377-k after administration to human FcRn transgenic mice.","FIG.","4 is a schematic diagram of a GC33-IgG1-CD3-scFv molecule which divalently binds to cancer specific antigen glypican-3 (GPC3) and monovalently binds to T cell antigen CD3.FIG.","5 shows the result of size exclusion chromatography analysis of protein A-purified NTA1L/NTA1R/GC33-k0 and NTA2L/NTA2R/GC33-k0.FIG.","6 is a schematic diagram of an anti-GPC3 IgG antibody molecule that monovalently binds to glypican-3.FIG.","7 shows the result of size exclusion chromatography analysis of protein A-purified NTA4L-cont/NTA4R-cont/GC33-k0, NTA4L-G3/NTA4R-cont/GC33-k0, and NTA4L/NTA4R/GC33-k0.FIG.","8 shows chromatograms of NTA4L-cont/NTA4R-cont/GC33-k0, NTA4L-G3/NTA4R-cont/GC33-k0, and NTA4L/NTA4R/GC33-k0 subjected to protein A column chromatography purification with pH gradient elution.","FIG.","9 is a schematic diagram of an Fc alpha receptor-Fc fusion protein molecule that monovalently binds to IgA.","FIG.","10 shows the result of size exclusion chromatography analysis of protein A-purified IAL-cont/IAR-cont and IAL/IAR.","FIG.","11 is a schematic diagram of no1, a naturally occurring anti-IL-6 receptor/anti-GPC3 bispecific antibody.","FIG.","12 is a schematic diagram of no2, which was obtained by interchanging the anti-GPC3 antibody VH domain and VL domain in no1.FIG.","13 is a schematic diagram of no3, which was obtained by modifying no2 to alter the isoelectric point of each chain.","FIG.","14 is a schematic diagram of no5, which was obtained by modifying no3 to enhance the heteromeric association of H chains and to purify the heteromerically associated antibody using protein A.","FIG.","15 is a schematic diagram of no6, which was obtained by modifying no5 to enhance the association between the H chain of interest and the L chain of interest.","FIG.","16 is chromatograms of anti-IL-6 receptor/anti-GPC3 bispecific antibodies no1, no2, no3, no5, and no6 in cation exchange chromatography to assess their expression patterns.","FIG.","17 is a chromatogram of no6 CM eluted with a pH gradient from a HiTrap protein A HP column (GE Healthcare).","FIG.","18 is a chromatogram of cation exchange chromatography analysis to assess a main peak fraction obtained by purification of a protein A-purified fraction of no6 using an SP Sepharose HP column (GE Healthcare).","detailed-description description=\"Detailed Description\" end=\"lead\"?"],["CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser.","No.","15/617,008, filed on Jun.","8, 2017, which is a continuation of U.S. application Ser.","No.","13/518,861, having a 371(c) date of Oct. 4, 2012, which is the National Stage of International Application Serial No.","PCT/JP2010/073361, filed on Dec. 24, 2010, which claims the benefit of Japanese Application Serial No.","2009-294391, filed on Dec. 25, 2009.The contents of the foregoing applications are incorporated by reference in their entireties in this application.","TECHNICAL FIELD The present invention relates to methods for producing or purifying polypeptide multimers, polypeptide multimers with an altered protein A-binding ability, and such.","BACKGROUND ART There are some previously reported methods for producing an IgG-type bispecific antibody having a human constant region (IgG-type antibody which has a human constant region and in which one of the arms has a specific binding activity to antigen A and the other has a specific binding activity to antigen B).","In general, an IgG-type bispecific antibody is composed of two types of H chains (i.e., H chain against antigen A and H chain against antigen B) and two types of L chains (i.e., L chain against antigen A and L chain against antigen B).","When such an IgG-type bispecific antibody is expressed, two types of H chains and two types of L chains are expressed, and there are ten possible combinations for the H2L2 combination.","Of these, only one combination has the specificity of interest (one arm has binding activity specific to antigen A and the other has binding activity specific to antigen B).","Thus, to obtain a bispecific antibody of interest, it is necessary to purify a single antibody of interest from the ten types of antibodies.","This is an extremely inefficient and difficult process.","There are reported methods for solving this problem which use a common L chain so that the L chain against antigen A and the L chain against antigen B have an identical amino acid sequence (Patent Documents 1 and 2).","When an IgG-type bispecific antibody having such a common L chain is expressed, two types of H chains and one type of common L chain are expressed, and there are three possible combinations for the H2L2 combination.","One of these combinations is a bispecific antibody of interest.","These three combinations are: monospecific antibody against antigen A (homomeric H chain antibody against antigen A), bispecific antibody against both antigen A and antigen B (heteromeric antibody with an H chain against antigen A and an H chain against antigen B), and monospecific antibody against antigen B (homomeric H chain antibody against antigen B).","Since their ratio is in general 1:2:1, the expression efficiency of the desired bispecific antibody is about 50%.","A method for further improving this efficiency has been reported which allows two types of H chains heteromerically associate (Patent Document 3).","This can increase the expression efficiency of the desired bispecific antibody up to about 90-95%.","Meanwhile, a method has been reported for efficiently removing the two types of homomeric antibodies which are impurities, in which amino acid substitutions are introduced into the variable regions of the two types of H chains to give them different isoelectric points so that the two types of homomeric antibodies and the bispecific antibody of interest (heteromeric antibody) can be purified by ion exchange chromatography (Patent Document 4).","A combination of the above-mentioned methods has made it possible to efficiently produce a bispecific antibody (heteromeric antibody) having an IgG-type human constant region.","On the other hand, in the industrial production of IgG-type antibodies, a purification step by protein A chromatography must be used, but ion exchange chromatography is not necessarily used in the purification step.","Therefore, the use of ion exchange chromatography for producing a highly pure bispecific antibody leads to an increase of production costs.","In addition, since ion exchange chromatography alone may not ensure a robust purification method for pharmaceuticals, it is preferable to perform more than one chromatographic step to remove impurities.","In any case, it is preferable that bispecific antibodies can also be highly purified by a chromatographic step that has a separation mode different from that of ion exchange chromatography.","It is desirable that as one of such separation modes, protein A chromatography, which must be used in the industrial production of IgG-type antibodies, could purify bispecific antibodies to high purity.","A previously reported method for purifying a bispecific antibody (heteromeric antibody) using protein A is to use a bispecific antibody having a mouse IgG2a H chain that binds to protein A and a rat IgG2b H chain that does not bind to protein A.","It has been reported that this method allows a bispecific antibody of interest to be purified to a purity of 95% by the protein A-based purification step alone (Non-patent Document 1 and Patent Document 5).","However, this method also uses ion exchange chromatography to improve the purity of the bispecific antibody.","In other words, purification of a highly pure bispecific antibody cannot be achieved by the purification step using protein A chromatography alone.","Moreover, catumaxomab, a bispecific antibody produced by the above-described method and having a mouse IgG2a H chain and a rat IgG2b H chain, has a half-life of about 2.1 days in human, which is extremely shorter than that of normal human IgG1 (2 to 3 weeks) (Non-patent Document 2).","In addition to having a short half-life, catumaxomab is highly immunogenic because of its mouse and rat constant regions (Non-patent Document 3).","Thus, a bispecific antibody obtained by such methods is considered inappropriate as a pharmaceutical.","On the other hand, it has been suggested that from the viewpoint of immunogenicity, a human IgG3 constant region may be used as a protein A-nonbinding constant region (Non-patent Document 1).","However, as it is known that the H chains of human IgG1 and human IgG3 hardly associate with each other (Non-patent Document 1), it is impossible to produce a bispecific antibody of interest using a human IgG1 H chain and a human IgG3 H chain by the same method used for the bispecific antibody having a mouse IgG2a H chain and a rat IgG2b H chain.","Furthermore, the half-life of human IgG3 in human has been reported to be generally shorter than that of human IgG1, human IgG2, and human IgG4 (Non-patent Documents 4 and 5).","Accordingly, like the bispecific antibody using a mouse IgG2a and a rat IgG2b, a bispecific antibody using human IgG3 might also have a short half-life in human.","The reason that H chain association rarely occurs between human IgG1 and human IgG3 is suggested to be the hinge sequence of human IgG3 (Non-patent Document 1).","Meanwhile, the reason for the short half-life of the human IgG3 constant region has not been fully elucidated yet.","Thus, there has been no report so far with regard to bispecific antibodies that use a human IgG3 constant region as a protein A-nonbinding constant region.","Moreover, there is also no report regarding methods for efficiently producing or purifying highly pure bispecific antibodies that have a human constant region and show a similarly long half-life as human IgG1.PRIOR ART DOCUMENTS Patent Documents Patent Document 1: WO98050431 Patent Document 2: WO2006109592 Patent Document 3: WO2006106905 Patent Document 4: WO2007114325 Patent Document 5: WO95033844 Non-Patent Documents Non-patent Document 1: The Journal of Immunology, 1995, 155:219-225 Non-patent Document 2: J Clin Oncol 26: 2008 (May 20 suppl; abstr 14006) Non-patent Document 3: Clin Cancer Res 2007 13:3899-3905 Non-patent Document 4: Nat Biotechnol.","2007 December; 25(12):1369-72 Non-patent Document 5: J. Clin Invest 1970; 49:673-80 DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention In general, an ordinary IgG-type antibody can be efficiently produced as a highly pure IgG through a protein A-based purification step.","However, the production of a highly pure bispecific antibody requires an additional purification step using ion exchange chromatography.","The addition of such a purification step by ion exchange chromatography can complicate the production and increase production cost.","Thus, it is preferable to produce a highly pure bispecific antibody by a protein A-based purification step alone.","An objective of the present invention is to provide methods that use only a protein A-based purification step for efficiently producing or purifying a highly pure IgG-type bispecific antibody having a human antibody heavy chain constant region.","Meanwhile, since the protein A binding site in the Fc domain is identical to the FcRn-binding site in the Fc domain, it is expected to be difficult to adjust the protein A-binding activity while retaining the binding to human FcRn.","Retaining the human FcRn-binding ability is very important for the long plasma retention (long half-life) in human which is characteristic of IgG-type antibodies.","The present invention provides methods that use only a protein A-based purification step to efficiently produce or purify a highly pure bispecific antibody that maintains a plasma retention time comparable to or longer than that of human IgG1.Means for Solving the Problems The present inventors discovered methods that use only a protein A-based purification step for efficiently purifying or producing a highly pure polypeptide multimer capable of binding to two or more antigens, in particular, a multispecific IgG-type antibody having a human constant region, by altering its protein A-binding ability.","Furthermore, these methods were combined with methods for regulating the association between a first polypeptide having an antigen-binding activity and a second polypeptide having an antigen-binding activity by modifying amino acids that constitute the interface formed upon association of the polypeptides.","By this combination, the present invention enables efficient production or purification of a highly pure polypeptide multimer of interest.","The present inventors also discovered that by modifying the amino acid residue at position 435 (EU numbering) in the heavy chain constant region, the protein A-binding ability could be adjusted while keeping its plasma retention comparable to or longer than that of human IgG1.Based on this finding, a highly pure bispecific antibody with plasma retention time comparable to or longer than that of human IgG1 can be produced or purified.","The present invention is based on the findings described above, and provides [1] to [55] below: [1] A method for producing a polypeptide multimer that comprises a first polypeptide having an antigen-binding activity and a second polypeptide having an antigen-binding activity or no antigen-binding activity, which comprises the steps of: (a) expressing a DNA that encodes the first polypeptide having an antigen-binding activity and a DNA that encodes the second polypeptide having an antigen-binding activity or no antigen-binding activity; and (b) collecting the expression product of step (a), wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.","[2] The method of [1], wherein the expression product is collected using protein A affinity chromatography in step (b).","[3] The method of [1] or [2], wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so that there is a larger difference between the solvent pH for eluting the first polypeptide having an antigen-binding activity from protein A and that for eluting the second polypeptide having an antigen-binding activity or no antigen-binding activity from protein A.","[4] The method of any one of [1] to [3], wherein one or more amino acid residues in the first polypeptide having an antigen-binding activity or the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so as to increase or reduce the protein A-binding ability of either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.","[5] The method of any one of [1] to [4], wherein one or more amino acid residues in the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so as to increase the protein A-binding ability of either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity, and reduce the protein A-binding ability of the other polypeptide.","[6] The method of any one of [1] to [5], wherein the purity of the collected polypeptide multimer is 95% or more.","[7] The method of any one of [1] to [6], wherein the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity comprise an amino acid sequence of an antibody Fc domain or an amino acid sequence of an antibody heavy-chain constant region.","[8] The method of [7], wherein at least one amino acid residue selected from the amino acid residues of positions 250 to 255, 308 to 317, and 430 to 436 (EU numbering) in the amino acid sequence of the antibody Fc domain or antibody heavy-chain constant region has been modified.","[9] The method of any one of [1] to [8], wherein the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity comprise an amino acid sequence of an antibody heavy-chain variable region.","[10] The method of [9], wherein at least one amino acid residue has been modified in the amino acid sequences of FR1, CDR2, and FR3 of the antibody heavy-chain variable region.","[11] The method of any one of [1] to [10], wherein the polypeptide multimer comprises one or two third polypeptides having an antigen-binding activity, and step (a) comprises expressing a DNA that encodes the third polypeptide having an antigen-binding activity.","[12] The method of [11], wherein the third polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.","[13] The method of [11] or [12], wherein the polypeptide multimer additionally comprises a fourth polypeptide having an antigen-binding activity, and step (a) comprises expressing a DNA that encodes the fourth polypeptide having an antigen-binding activity.","[14] The method of [13], wherein at least one of the third and fourth polypeptides having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.","[15] The method of [13], wherein the first polypeptide having an antigen-binding activity comprises amino acid sequences of an antibody light-chain variable region and an antibody heavy-chain constant region; the second polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody heavy chain; the third polypeptide having an antigen-binding activity comprises amino acid sequences of an antibody heavy-chain variable region and an antibody light-chain constant region; and the fourth polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.","[16] The method of any one of [1] to [15], wherein the polypeptide multimer is a multispecific antibody.","[17] The method of [16], wherein the multispecific antibody is a bispecific antibody.","[18] The method of any one of [1] to [8], which comprises the first polypeptide having an antigen-binding activity and the second polypeptide having no antigen-binding activity, and wherein the first polypeptide having an antigen-binding activity comprises an amino acid sequence of an antigen-binding domain of a receptor and an amino acid sequence of an antibody Fc domain, and the second polypeptide having no antigen-binding activity comprises an amino acid sequence of an antibody Fc domain.","[19] The method of any one of [7] to [18], wherein the antibody Fc domain or antibody heavy-chain constant region is derived from human IgG.","[20] A polypeptide multimer produced by the method of any one of [1] to [19].","[21] A method for purifying a polypeptide multimer that comprises a first polypeptide having an antigen-binding activity and a second polypeptide having an antigen-binding activity or no antigen-binding activity, which comprises the steps of: (a) expressing a DNA that encodes the first polypeptide having an antigen-binding activity and a DNA that encodes the second polypeptide having an antigen-binding activity or no antigen-binding activity; and (b) collecting the expression product of step (a) by protein A affinity chromatography, wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.","[22] The method of [21], wherein one or more amino acid residues in the first polypeptide having an antigen-binding activity or the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so as to increase or reduce the protein A-binding ability of the first polypeptide having an antigen-binding activity or the second polypeptide having an antigen-binding activity or no antigen-binding activity.","[23] The method of [20] or [21], wherein one or more amino acid residues in the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so as to increase the protein A-binding ability of either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity, and reduce the protein A-binding ability of the other polypeptide.","[24] The method of any one of [21] to [23], wherein the purity of the collected polypeptide multimer is 95% or more.","[25] The method of any one of [21] to [24], wherein the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity comprise an amino acid sequence of an antibody Fc domain or an amino acid sequence of an antibody heavy-chain constant region.","[26] The method of [25], wherein at least one amino acid residue selected from the amino acid residues of positions 250 to 255, 308 to 317, and 430 to 436 (EU numbering) in the amino acid sequence of the antibody Fc domain or antibody heavy-chain constant region has been modified.","[27] The method of any one of [21] to [26], wherein the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity comprise an amino acid sequence of an antibody heavy-chain variable region.","[28] The method of [27], wherein at least one amino acid residue has been modified in the amino acid sequences of FR1, CDR2, and FR3 of the antibody heavy-chain variable region.","[29] The method of any one of [21] to [28], wherein the polypeptide multimer comprises one or two third polypeptides having an antigen-binding activity, and step (a) comprises expressing a DNA that encodes the third polypeptide having an antigen-binding activity.","[30] The method of [29], wherein the third polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.","[31] The method of [29] or [30], wherein the polypeptide multimer additionally comprises a fourth polypeptide having an antigen-binding activity, and step (a) comprises expressing a DNA that encodes the fourth polypeptide having an antigen-binding activity.","[32] The method of [31], wherein at least one of the third and fourth polypeptides having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.","[33] The method of [31], wherein the first polypeptide having an antigen-binding activity comprises amino acid sequences of an antibody light-chain variable region and an antibody heavy-chain constant region; the second polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody heavy chain; the third polypeptide having an antigen-binding activity comprises amino acid sequences of an antibody heavy-chain variable region and an antibody light-chain constant region; and the fourth polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.","[34] The method of any one of [21] to [33], wherein the polypeptide multimer is a multispecific antibody.","[35] The method of [34], wherein the multispecific antibody is a bispecific antibody.","[36] The method of any one of [25] to [35], wherein the antibody Fc domain or antibody heavy-chain constant region is derived from human IgG.","[37] A polypeptide multimer that comprises a first polypeptide having an antigen-binding activity and a second polypeptide having an antigen-binding activity or no antigen-binding activity, wherein the protein A-binding ability is different for the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.","[38] The polypeptide multimer of [37], wherein there is a difference between the solvent pH for eluting the first polypeptide having an antigen-binding activity from protein A and that for eluting the second polypeptide having an antigen-binding activity or no antigen-binding activity from protein A.","[39] The polypeptide multimer of [37] or [38], wherein the first polypeptide having an antigen-binding activity or the second polypeptide having an antigen-binding activity or no antigen-binding activity comprises an amino acid sequence of an antibody Fc domain or an amino acid sequence of an antibody heavy-chain constant region, and wherein at least one amino acid residue selected from the amino acid residues of positions 250 to 255, 308 to 317, and 430 to 436 (EU numbering) in the amino acid sequence of the antibody Fc domain or antibody heavy-chain constant region has been modified.","[40] The polypeptide multimer of any one of [37] to [39], wherein the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity comprise an amino acid sequence of an antibody Fc domain or an amino acid sequence of an antibody heavy-chain constant region; wherein the amino acid residue of position 435 (EU numbering) in the amino acid sequence of the antibody Fc domain or antibody heavy-chain constant region is histidine or arginine in either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity; and wherein the amino acid residue of position 435 (EU numbering) in the amino acid sequence of the antibody Fc domain or antibody heavy-chain constant region in either one of said polypeptides is different from that in the other polypeptide.","[41] The polypeptide multimer of any one of [37] to [40], wherein the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity comprise an amino acid sequence of an antibody Fc domain or an amino acid sequence of an antibody heavy-chain constant region; wherein the amino acid residue of position 435 (EU numbering) in the amino acid sequence of the antibody Fc domain or antibody heavy-chain constant region is histidine in either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity; and wherein the amino acid residue of position 435 (EU numbering) in the amino acid sequence of the antibody Fc domain or antibody heavy-chain constant region is arginine in the other polypeptide.","[42] The polypeptide multimer of any one of [37] to [41], wherein the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity comprise an amino acid sequence of an antibody heavy-chain variable region, and at least one amino acid residue has been modified in the amino acid sequences of FR1, CDR2, and FR3 of the heavy-chain variable region.","[43] The polypeptide multimer of any one of [37] to [42], which additionally comprises one or two third polypeptides having an antigen-binding activity.","[44] The polypeptide multimer of [43], wherein the third polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.","[45] The polypeptide multimer of [43] or [44], which additionally comprises a fourth polypeptide having an antigen-binding activity.","[46] The polypeptide multimer of [45], wherein at least one of the third and fourth polypeptides having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.","[47] The polypeptide multimer of [45], wherein the first polypeptide having an antigen-binding activity comprises amino acid sequences of an antibody light-chain variable region and an antibody heavy-chain constant region; the second polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody heavy chain; the third polypeptide having an antigen-binding activity comprises amino acid sequences of an antibody heavy-chain variable region and an antibody light-chain constant region; and the fourth polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.","[48] The polypeptide multimer of any one of [37] to [47], which is a multispecific antibody.","[49] The polypeptide multimer of [48], wherein the multispecific antibody is a bispecific antibody.","[50] The polypeptide multimer of any one of [37] to [41], which comprises the first polypeptide having an antigen-binding activity and the second polypeptide having no antigen-binding activity, and wherein the first polypeptide having an antigen-binding activity comprises an amino acid sequence of an antigen-binding domain of a receptor and an amino acid sequence of an antibody Fc domain, and the second polypeptide having no antigen-binding activity comprises an amino acid sequence of an antibody Fc domain.","[51] The polypeptide multimer of any one of [39] to [50], wherein the antibody Fc domain or antibody heavy-chain constant region is derived from human IgG.","[52] A nucleic acid encoding a polypeptide that constitutes the polypeptide multimer of any one of [20] and [37] to [51].","[53] A vector inserted with the nucleic acid of [52].","[54] A cell comprising the nucleic acid of [52] or the vector of [53].","[55] A pharmaceutical composition comprising the polypeptide multimer of any one of [20] and [37] to [51] as active ingredient.","Effects of the Invention The present invention provides methods that use only a protein A-based purification step for efficiently purifying or producing a highly pure polypeptide multimer having binding activity against two or more antigens (multispecific antibody), by altering its protein A-binding ability.","The methods of the present invention enable efficient purification or production of a highly pure polypeptide multimer of interest without impairing the effects of other amino acid modifications of interest.","In particular, by combining these methods with a method for regulating the association between two protein domains, polypeptide multimers of interest can be more efficiently produced or purified to higher purity.","The methods of the present invention for producing or purifying multispecific antibodies are characterized in that amino acid residues in their antibody heavy chain constant region and/or antibody heavy chain variable region are modified.","The amino acid modifications of the present invention are introduced into these regions to modify their protein A-binding ability.","In addition, other effects of amino acid modification of interest, for example, comparable or longer plasma retention time than that of human IgG1 can also be obtained.","The methods of the present invention enable efficient preparation of highly pure multispecific antibodies having such amino acid modification effects.","In general, the production of highly pure IgG-type multispecific antibodies requires a purification step using ion exchange chromatography.","However, the addition of this purification step complicates the production and increases production cost.","On the other hand, purification that uses only ion exchange chromatography may not be robust enough as a purification method for pharmaceuticals.","Thus, it is a task to develop a method for producing an IgG-type bispecific antibody using only a protein A-based purification step, or develop a robust production method using a protein A-based purification step and an ion exchange chromatography step.","BRIEF DESCRIPTION OF THE DRAWINGS FIG.","1 is a graph showing an assessment of the plasma retention time of MRA-IgG1 and MRA-z106/z107k in human FcRn transgenic mice.","FIG.","2 is a diagram showing that the same region in the antibody Fc domain binds to protein A and FcRn.","FIG.","3 shows a time course of the plasma concentrations of Q499-z118/J339-z119/L377-k and Q499-z121/J339-z119/L377-k after administration to human FcRn transgenic mice.","FIG.","4 is a schematic diagram of a GC33-IgG1-CD3-scFv molecule which divalently binds to cancer specific antigen glypican-3 (GPC3) and monovalently binds to T cell antigen CD3.FIG.","5 shows the result of size exclusion chromatography analysis of protein A-purified NTA1L/NTA1R/GC33-k0 and NTA2L/NTA2R/GC33-k0.FIG.","6 is a schematic diagram of an anti-GPC3 IgG antibody molecule that monovalently binds to glypican-3.FIG.","7 shows the result of size exclusion chromatography analysis of protein A-purified NTA4L-cont/NTA4R-cont/GC33-k0, NTA4L-G3/NTA4R-cont/GC33-k0, and NTA4L/NTA4R/GC33-k0.FIG.","8 shows chromatograms of NTA4L-cont/NTA4R-cont/GC33-k0, NTA4L-G3/NTA4R-cont/GC33-k0, and NTA4L/NTA4R/GC33-k0 subjected to protein A column chromatography purification with pH gradient elution.","FIG.","9 is a schematic diagram of an Fc alpha receptor-Fc fusion protein molecule that monovalently binds to IgA.","FIG.","10 shows the result of size exclusion chromatography analysis of protein A-purified IAL-cont/IAR-cont and IAL/IAR.","FIG.","11 is a schematic diagram of no1, a naturally occurring anti-IL-6 receptor/anti-GPC3 bispecific antibody.","FIG.","12 is a schematic diagram of no2, which was obtained by interchanging the anti-GPC3 antibody VH domain and VL domain in no1.FIG.","13 is a schematic diagram of no3, which was obtained by modifying no2 to alter the isoelectric point of each chain.","FIG.","14 is a schematic diagram of no5, which was obtained by modifying no3 to enhance the heteromeric association of H chains and to purify the heteromerically associated antibody using protein A.","FIG.","15 is a schematic diagram of no6, which was obtained by modifying no5 to enhance the association between the H chain of interest and the L chain of interest.","FIG.","16 is chromatograms of anti-IL-6 receptor/anti-GPC3 bispecific antibodies no1, no2, no3, no5, and no6 in cation exchange chromatography to assess their expression patterns.","FIG.","17 is a chromatogram of no6 CM eluted with a pH gradient from a HiTrap protein A HP column (GE Healthcare).","FIG.","18 is a chromatogram of cation exchange chromatography analysis to assess a main peak fraction obtained by purification of a protein A-purified fraction of no6 using an SP Sepharose HP column (GE Healthcare).","MODE FOR CARRYING OUT THE INVENTION The present invention provides methods for producing a polypeptide multimer that comprises a first polypeptide having an antigen-binding activity and a second polypeptide having an antigen-binding activity or no antigen-binding activity.","The methods of the present invention for producing a polypeptide multimer comprise the steps of: (a) expressing a DNA encoding a first polypeptide having an antigen-binding activity and a DNA encoding a second polypeptide having an antigen-binding activity or no antigen-binding activity; and (b) collecting the expression products of step (a); wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.","The methods of the present invention for producing a polypeptide multimer may also be expressed as methods for producing a polypeptide multimer with an altered protein A-binding ability.","In the present invention, “a polypeptide having a first antigen-binding activity” may be referred to as “a first polypeptide having an antigen-binding activity”.","“A polypeptide having a second antigen-binding activity or no antigen-binding activity” may be referred to as “a second polypeptide having an antigen-binding activity or no antigen-binding activity”.","The same applies to “a polypeptide having a third antigen-binding activity” and “a polypeptide having a fourth antigen-binding activity” described below.","In the present invention, the term “comprise” means both “comprise” and “consist of”.","The present invention also provides methods for purifying a polypeptide multimer that comprises a first polypeptide having an antigen-binding activity and a second polypeptide having an antigen-binding activity or no antigen-binding activity.","The methods of the present invention for purifying a polypeptide multimer comprise the steps of: (a) expressing a DNA that encodes a first polypeptide having an antigen-binding activity and a DNA that encodes a second polypeptide having an antigen-binding activity or no antigen-binding activity; and (b) collecting the expression products of step (a) by protein A affinity chromatography; wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified so that the protein A-binding ability is different between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.","A polypeptide having an antigen-binding activity in which one or more amino acid residues have been modified can be obtained by: preparing a DNA that encodes a polypeptide having an antigen-binding activity or no antigen-binding activity, modifying one or more nucleotides in the DNA; introducing the resulting DNA into cells known to those skilled in the art; culturing the cells to express the DNA; and collecting the expression product.","Thus, the methods of the present invention for producing a polypeptide multimer can also be expressed as methods comprising the steps of: (a) providing a DNA that encodes a first polypeptide having an antigen-binding activity and a DNA that encodes a second polypeptide having an antigen-binding activity or no antigen-binding activity; (b) altering one or more nucleotides in either or both of the DNAs of step (a) that encode the first and second polypeptides so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity; (c) introducing the DNAs of step (b) into host cells and culturing the host cells to express the DNAs; and (d) collecting the expression products of step (c) from the culture of host cells.","The methods of the present invention for purifying a polypeptide multimer may also be expressed as methods comprising the step of: (a) providing a DNA that encodes a first polypeptide having an antigen-binding activity and a DNA that encodes a second polypeptide having an antigen-binding activity or no antigen-binding activity; (b) altering one or more nucleotides in either or both of the DNAs of step (a) that encode the first and second polypeptides so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity; (c) introducing the DNAs of step (b) into host cells and culturing the host cells to express the DNAs; and (d) collecting the expression products of step (c) from the culture of host cells by protein A affinity chromatography.","In the present invention, a polypeptide multimer refers to a heteromeric multimer containing first and second polypeptides.","It is preferable that the first and second polypeptides each have an activity of binding to a different antigen.","The first and second polypeptides each having a different antigen-binding activity are not particularly limited as long as one of the polypeptides has an antigen-binding domain (amino acid sequence) different from that of the other polypeptide.","For example, as shown in FIG.","4 described below, one polypeptide may be fused with an antigen-binding domain that is different from that of the other polypeptide.","Alternatively, as shown in FIGS.","4, 6, and 9 described below, one polypeptide may be a polypeptide that monovalently binds to an antigen and does not have the antigen-binding domain possessed by the other polypeptide.","Polypeptide multimers containing such first and second polypeptides are also included in the polypeptide multimers of the present invention.","The multimers include dimers, trimers, and tetramers, but are not limited thereto.","In present invention, a first polypeptide and/or a second polypeptide can form a multimer with one or two third polypeptides.","Thus, the present invention provides methods for producing a polypeptide multimer comprising a first polypeptide having an antigen-binding activity, a second polypeptide having an antigen-binding activity or no antigen-binding activity, and one or two third polypeptides having an antigen-binding activity, which comprise the steps of: (a) expressing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having an antigen-binding activity, and a DNA that encodes two third polypeptides having an antigen-binding activity; and (b) collecting the expression products of step (a); or (a) expressing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having no antigen-binding activity, and a DNA that encodes one third polypeptide having an antigen-binding activity; and (b) collecting the expression products of step (a); wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.","The above-described methods may also be expressed as methods comprising the steps of: (a) providing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having an antigen-binding activity, and a DNA that encodes two third polypeptides having an antigen-binding activity; (b) altering one or more nucleotides in either or both of the DNAs of step (a) that encode the first and second polypeptides so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity; (c) introducing the DNAs that encode the first, second, and two third polypeptides into host cells, and culturing the host cells to express the DNAs; and (d) collecting the expression products of step (c) from the culture of host cells; or (a) providing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having no antigen-binding activity, and a DNA that encodes one third polypeptide having an antigen-binding activity; (b) altering one or more nucleotides in either or both of the DNAs of step (a) that encode the first and second polypeptides so that there is a larger difference of protein A-binding activity between the first polypeptide having an antigen-binding activity and the second polypeptide having no antigen-binding activity; (c) introducing the DNAs that encode the first, second, and third polypeptides into host cells and culturing the host cells to express the DNAs; and (d) collecting the expression products of step (c) from the culture of host cells.","Furthermore, in the present invention, the first and second polypeptides can form a multimer with third and fourth polypeptides.","Thus, the present invention provides methods for producing a polypeptide multimer comprising a first polypeptide having an antigen-binding activity, a second polypeptide having an antigen-binding activity, a third polypeptide having an antigen-binding activity, and a fourth polypeptide having an antigen-binding activity, which comprise the steps of: (a) expressing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having an antigen-binding activity, and a DNA that encodes a third polypeptide having an antigen-binding activity and a fourth polypeptide having an antigen-binding activity; and (b) collecting the expression products of step (a); wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity have been modified so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity.","The above-described methods can also be expressed as methods comprising the steps of: (a) providing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having an antigen-binding activity, and a DNA that encodes a third polypeptide having an antigen-binding activity and a fourth polypeptide having an antigen-binding activity; (b) altering one or more nucleotides in either or both of the DNAs of step (a) that encode the first and second polypeptides so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity; (c) introducing the DNAs that encode the first, second, third, and fourth polypeptides into host cells and culturing the host cells to express the DNAs; and (d) collecting the expression products of step (c) from the culture of host cells.","The present invention provides methods for purifying a polypeptide multimer that comprises a first polypeptide having an antigen-binding activity, a second polypeptide having an antigen-binding activity or no antigen-binding activity, and one or two third polypeptides having an antigen-binding activity, which comprise the steps of: (a) expressing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having an antigen-binding activity, and a DNA that encodes two third polypeptides having an antigen-binding activity; and (b) collecting the expression products of step (a); or (a) expressing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having no antigen-binding activity, and a DNA that encodes one third polypeptide having an antigen-binding activity; and (b) collecting the expression products of step (a); wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.","The above-described methods can also be expressed as methods comprising the steps of: (a) providing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having an antigen-binding activity or no antigen-binding activity, and a DNA that encodes two third polypeptides having an antigen-binding activity; (b) altering one or more nucleotides in either or both of the DNAs of step (a) that encode the first and second polypeptides so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity; (c) introducing the DNAs that encode the first, second, and two third polypeptides into host cells and culturing the host cells to express the DNAs; and (d) collecting the expression products of step (c) from the culture of host cells; or (a) providing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having no antigen-binding activity, and a DNA that encodes one third polypeptide having an antigen-binding activity; (b) altering one or more nucleotides in either or both of the DNAs of step (a) that encode the first and second polypeptides so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having no antigen-binding activity; (c) introducing the DNAs that encode the first, second, and third polypeptides into host cells and culturing the host cells to express the DNAs; and (d) collecting the expression products of step (c) from the culture of host cells.","The present invention also provides methods for purifying a polypeptide multimer that comprises a first polypeptide having an antigen-binding activity, a second polypeptide having an antigen-binding activity, a third polypeptide having an antigen-binding activity, and a fourth polypeptide having an antigen-binding activity, which comprise the steps of: (a) expressing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having an antigen-binding activity, a DNA that encodes a third polypeptide having an antigen-binding activity, and a DNA that encodes a fourth polypeptide having an antigen-binding activity; and (b) collecting the expression products of step (a) by protein A affinity chromatography; wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity have been modified so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity.","The above-described methods can also be expressed as methods comprising the steps of: (a) providing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having an antigen-binding activity, a DNA that encodes a third polypeptide having an antigen-binding activity, and a DNA that encodes a fourth polypeptide having an antigen-binding activity; (b) altering one or more nucleotides in either or both of the DNAs of step (a) that encode the first and second polypeptides so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity; (c) introducing the DNAs that encode the first, second, third, and fourth polypeptides into host cells and culturing the host cells to express the DNAs; and (d) collecting the expression products of step (c) from the culture of host cells by protein A affinity chromatography.","In a polypeptide multimer of the present invention containing a first polypeptide, a second polypeptide, and one or two third polypeptides, the first and second polypeptides can each form a multimer (dimer) with the third polypeptide.","Furthermore, the resulting two dimers can form a multimer with each other.","The two third polypeptides may have completely the same amino acid sequence (may have a binding activity to the same antigen).","Alternatively, the third polypeptides may have the same amino acid sequence and two or more activities (for example, may have binding activities to two or more different antigens).","When only one third polypeptide is present, the third polypeptide can form a polypeptide multimer via dimerization with either the first polypeptide or the second polypeptide.","In a polypeptide multimer of the present invention, the first and second polypeptides preferably have binding activity to different antigens.","Meanwhile, the third polypeptide may have binding activity to the same antigen as that of either or both of the first and second polypeptides.","Alternatively, the third polypeptide may have binding activity to an antigen different from those of the first and second polypeptides.","Alternatively, a polypeptide multimer of the present invention may contain a first polypeptide, second polypeptide, third polypeptide, and fourth polypeptide.","In such a polypeptide multimer, the first polypeptide and second polypeptide can form a multimer (dimer) with the third polypeptide and fourth polypeptide, respectively.","For example, through formation of disulfide bonds in between, the first polypeptide and third polypeptide can form a dimer, and the second polypeptide and fourth polypeptide can form a dimer.","In a polypeptide multimer of the present invention, the first and second polypeptides preferably have binding activity to different antigens.","Meanwhile, the third polypeptide may have binding activity to the same antigen as that of either or both of the first and second polypeptides.","Alternatively, the third polypeptide may have binding activity to an antigen different from those of the first and second polypeptides.","Furthermore, the fourth polypeptide may have binding activity to the same antigen as that of either or both of the first and second polypeptides.","Alternatively, the fourth polypeptide may have binding activity to an antigen different from those of the first and second polypeptides.","Specifically, for example, when the first and second polypeptides contain the amino acid sequence of an antibody heavy chain against antigen A and the amino acid sequence of an antibody heavy chain against antigen B, respectively, the third and fourth polypeptides may contain the amino acid sequence of an antibody light chain against antigen A and the amino acid sequence of an antibody light chain against antigen B, respectively.","When a polypeptide multimer of the present invention has third and fourth polypeptides that contain two different antibody light chain amino acid sequences, a highly pure polypeptide multimer of interest can be efficiently produced or purified by making the pI values of the third and fourth polypeptide different using the methods described below, or by differentiating their protein L-binding ability, in addition to differentiating the protein A-binding ability between the first and second polypeptides.","Alternatively, for example, when the first polypeptide has the amino acid sequence of an antibody heavy chain against antigen A, the second polypeptide has the amino acid sequence of an antibody light chain variable region against antigen B and the amino acid sequence of an antibody heavy chain constant region, the third polypeptide has the amino acid sequence of an antibody light chain against antigen A, and the fourth polypeptide has the amino acid sequence of an antibody heavy chain variable region against antigen B and the amino acid sequence of an antibody light chain constant region, a highly pure polypeptide multimer of interest having the first, second, third, and fourth polypeptides can also be efficiently produced or purified by using the present invention.","In this case, as described in Example 12 below, introduction of amino acid mutations to alter the pI value of a polypeptide or introduction of amino acid mutations to promote the association of polypeptides of interest (WO2006/106905) enables more efficient purification or production of a polypeptide multimer of interest having the first, second, third, and fourth polypeptides to higher purity.","Amino acid mutations to be introduced to promote the association of polypeptides may be those used in the methods described in Protein Eng.","1996 July, 9(7):617-21; Protein Eng Des Sel.","2010 April, 23(4):195-202; J Biol Chem.","2010 Jun.","18, 285(25):19637-46; WO2009080254; and such, in which two polypeptides having a heavy chain constant region are heteromerically associated by modifying the CH3 domain of heavy chain constant region; and those used in the methods described in WO2009080251, WO2009080252, WO2009080253, and such, by which the association of a particular pair of heavy chain and light chain is promoted.","In the present invention, “polypeptide having an antigen-binding activity” refers to a peptide or protein of five or more amino acids in length having a domain (region) capable of binding to a protein or peptide such as an antigen or ligand, e.g., an antibody heavy chain or light chain variable region, receptor, receptor-Fc domain fusion peptide, scaffold, or a fragment thereof.","Specifically, a polypeptide having an antigen-binding activity can contain the amino acid sequence of an antibody variable region, receptor, receptor-Fc domain fusion peptide, scaffold, or a fragment thereof.","Scaffold may be any polypeptide as long as it is a conformationally stable polypeptide capable of binding to at least one antigen.","Such polypeptides include, but are not limited to, for example, antibody variable region fragments, fibronectin, protein A domains, LDL receptor A domains, lipocalins, and molecules mentioned in Nygren et al.","(Current Opinion in Structural Biology, 7:463-469 (1997); Journal of Immunol.","Methods, 290:3-28 (2004)), Binz et al.","(Nature Biotech 23:1257-1266 (2005)), and Hosse et al.","(Protein Science 15:14-27 (2006)).","Methods for obtaining antibody variable regions, receptors, receptor-Fc domain fusion peptides, scaffold, and fragments thereof are known to those skilled in the art.","Such polypeptides having an antigen-binding activity may be derived from a living organism or designed artificially.","The polypeptides may be derived from natural proteins, synthetic proteins, recombinant proteins, and such.","Furthermore, the polypeptides may be peptides or protein fragments of 10 or more amino acids in length which have a domain (region) capable of binding to a protein or peptide such as an antigen or ligand, as long as they have ability to bind to an antigen.","The polypeptides may have more than one domain capable of binding to an antigen (including ligand).","A polypeptide having an antigen-binding activity may also be referred to as a polypeptide having an antigen-binding protein domain(s).","In the present invention, “polypeptide having no antigen-binding activity” refers to a peptide or protein of five or more amino acids in length, such as an antibody fragment having no antigen-binding activity, Fc domain, scaffold, or a fragment thereof.","Specifically, a polypeptide having no antigen-binding activity may contain the amino acid sequence of an antibody constant region, Fc domain, scaffold, or fragment thereof, but the amino acid sequence is not limited to the above examples.","A polypeptide having no antigen-binding activity can be combined with a polypeptide having an antigen-binding activity to produce a polypeptide multimer that monovalently binds to an antigen.","In the present invention, the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity may contain the amino acid sequence of an antibody heavy chain constant region or the amino acid sequence of an antibody Fc domain.","The amino acid sequence of an antibody Fc domain or an antibody heavy chain constant region includes, but is not limited to, those of human IgG-type constant regions and Fc domains.","IgG-type constant regions or Fc domains may be of natural IgG1, IgG2, IgG3, or IgG4 isotype, or may be variants thereof.","Meanwhile, in the present invention, the third polypeptide having an antigen-binding activity and the fourth polypeptide having an antigen-binding activity may contain the amino acid sequence of an antibody light chain constant region.","The amino acid sequence of an antibody light chain constant region includes, but is not limited to, those of human kappa- and human lambda-type constant regions, and variants thereof.","Furthermore, in the present invention, polypeptides having an antigen-binding activity may contain the amino acid sequence of an antibody variable region (for example, the amino acid sequences of CDR1, CDR2, CDR3, FR1, FR2, FR3, and FR4).","Moreover, in the present invention, the polypeptides having an antigen-binding activity may contain the amino acid sequence of an antibody heavy chain or an antibody light chain.","More specifically, the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity may contain the amino acid sequence of an antibody heavy chain.","Meanwhile, the third polypeptide having an antigen-binding activity and the fourth polypeptide having an antigen-binding activity may contain the amino acid sequence of an antibody light chain.","When a polypeptide multimer of interest is a tetramer that is formed by multimerization between a dimer formed by the first and third polypeptides and a dimer formed by the second and fourth polypeptides, for example, a polypeptide in which the first and second polypeptides having an antigen-binding activity contain the amino acid sequence of an antibody heavy chain, and a polypeptide in which the third and fourth polypeptides having an antigen-binding activity contain the amino acid sequence of an antibody light chain, can be used for the polypeptide multimer of the present invention.","Alternatively, a polypeptide in which the first polypeptide having an antigen-binding activity contains the amino acid sequence of an antibody heavy chain, a polypeptide in which the second polypeptide having an antigen-binding activity contains the amino acid sequence of an antibody light chain variable region and the amino acid sequence of an antibody heavy chain constant region, a polypeptide in which the third polypeptide having an antigen-binding activity contains the amino acid sequence of an antibody light chain, and a polypeptide in which the fourth polypeptide having an antigen-binding activity contains the amino acid sequence of an antibody heavy chain variable region, can also be used.","Specifically, a polypeptide multimer of the present invention can be a multispecific antibody.","In the present invention, a “multispecific antibody” refers to an antibody capable of specifically binding to at least two different antigens.","In the present invention, “different antigens” refers not only to different antigen molecules per se, but also to different antigen determinants present in the same antigen molecules.","Accordingly, for example, different antigen determinants present within a single molecule are included in the “different antigens” of the present invention.","In the present invention, antibodies that recognize various different antigen determinants in a single molecule are regarded as “antibodies capable of specifically binding to different antigens”.","In the present invention, multispecific antibodies include, but are not limited to, bispecific antibodies capable of specifically binding to two types of antigens.","Preferred bispecific antibodies of the present invention include H2L2-type IgG antibodies (composed of two types of H chains and two types of L chains) having a human IgG constant region.","More specifically, such antibodies include, but are not limited to, for example, IgG-type chimeric antibodies, humanized antibodies, and human antibodies.","Moreover, a polypeptide having an antigen-binding activity may be, for example, a molecule in which at least two of a heavy chain variable region, light chain variable region, heavy chain constant region, and light chain constant region, are linked together as a single chain.","Alternatively, the polypeptide may be an antibody in which at least two of a heavy chain variable region, light chain variable region, Fc domain (constant region without CH1 domain), and light chain constant region, are linked together as a single chain.","In the present invention, the phrase “there is a larger difference of protein A-binding ability between polypeptides having an antigen-binding activity” means that the protein A-binding ability is not the same (is different) between two or more polypeptides as a result of amino acid modifications on the surface of polypeptides having an antigen-binding activity.","More specifically, this phrase means that, for example, the protein A-binding ability of the first polypeptide having an antigen-binding activity is different from that of the second polypeptide having an antigen-binding activity.","The difference of protein A-binding ability can be examined, for example, by using protein A affinity chromatography.","The strength of protein A-binding ability of a polypeptide having an antigen-binding activity is correlated with the pH of solvent used for elution.","The greater the protein A-binding ability of the polypeptide is, the lower the pH of the solvent used for elution becomes.","Thus, the phrase “there is a larger difference of protein A-binding ability between polypeptides having an antigen-binding activity” can also be expressed as “when two or more polypeptides having an antigen-binding activity are eluted using protein A affinity chromatography, each polypeptide is eluted at a different solvent pH”.","The difference in the pH of the elution solvent is 0.1 or more, preferably 0.5 or more, and still more preferably 1.0 or more, but is not limited thereto.","Furthermore, in the present invention, it is preferable to alter the protein A-binding ability without lowering other activities (for example, plasma retention) of the polypeptides having an antigen-binding activity.","A polypeptide multimer of interest that comprises the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity can be produced or purified using protein A affinity chromatography based on the difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.","Specifically, for example, when the polypeptide multimer of the present invention is a bispecific antibody that has a common L chain (i.e., same amino acid sequence in the third and fourth polypeptides), the polypeptide multimer can be produced or purified by the method described below.","First, host cells are introduced with the following: a nucleic acid that encodes the first polypeptide having an antigen-binding activity (more specifically, the first antibody heavy chain) whose amino acid at position 435 (EU numbering) in the amino acid sequence of the antibody heavy chain constant region is arginine (R); a nucleic acid that encodes the second polypeptide having an antigen-binding activity (more specifically, the second antibody heavy chain) whose amino acid at position 435 (EU numbering) in the amino acid sequence of the antibody heavy chain constant region is histidine (H); and a nucleic acid that encodes the third polypeptide having an antigen-binding activity (common L chain).","The cells are cultured to express the DNAs transiently.","Then, the resulting expression products are loaded onto a protein A column.","After washing, elution is performed first with a high pH elution solution and then with a low pH elution solution.","A homomeric antibody comprising two units of the first antibody heavy chain and two units of the common L chain does not have any protein A-binding site in its heavy chain constant region.","Meanwhile, a bispecific antibody comprising the first antibody heavy chain, the second antibody heavy chain, and two units of the common L chain has a single protein A-binding site in its heavy chain constant region.","A homomeric antibody comprising two units of the second antibody heavy chain and two units of the common L chain has two protein A-binding sites in its heavy chain constant region.","As described above, the protein A-binding ability of a polypeptide correlates with the solvent pH for eluting the polypeptide in protein A affinity chromatography.","The greater the protein A-binding ability is, the lower the solvent pH for elution becomes.","Thus, when elution is carried out first with a high pH elution solution and then with a low pH elution solution, the antibodies are eluted in the following order: a homomeric antibody comprising two units of the first antibody heavy chain and two units of the common L chain a bispecific antibody comprising the first antibody heavy chain, the second antibody heavy chain, and two units of the common L chain a homomeric antibody comprising two units of the second antibody heavy chain and two units of the common L chain This allows production or purification of the polypeptide multimers (bispecific antibodies) of interest.","The purity of the polypeptide multimers obtained by the production or purification methods of the present invention is at least 95% or higher (for example, 96%, 97%, 98%, 99% or higher).","Modifications of amino acid residues to create a difference in the protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity include, but are not limited to: (1) modification of one or more amino acid residues in the amino acid sequence of either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity, such that the protein A-binding ability of one of the polypeptides is increased; (2) modification of one or more amino acid residues in the amino acid sequence of either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity, such that the protein A-binding ability of one of the polypeptides is decreased; and (3) modification of one or more amino acid residues in the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity, such that the protein A-binding ability of either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity is increased, and the protein A-binding ability of the other polypeptide is decreased.","In the present invention, it is preferred that amino acids on the surface of a polypeptide having an antigen-binding activity or no antigen-binding activity are modified.","Furthermore, it is also preferred to consider reducing the influence of the modification on other activities of the polypeptide.","Accordingly, in the present invention, it is preferred to modify, for example, the amino acid residues at the following positions (EU numbering) in the antibody Fc domain or heavy chain constant region: TLMISR at positions 250-255, VLHQDWLNGK at positions 308-317, and EALHNHY at positions 430-436; preferably, TLMIS at positions 250-254, LHQD at positions 309-312, LN at positions 314 and 315, E at position 430, and LHNHY at positions 432-436; more preferably, LMIS at positions 251-254, LHQ at positions 309-311, L at position 314, and LHNH at positions 432-435; and in particular, MIS at positions 252-254, L at position 309, Q at position 311, and NHY at positions 434-436.As for amino acid modifications of the antibody heavy chain variable region, preferred mutation sites include FR1, CDR2, and FR3.More preferred mutation sites include, for example, positions H15-H23, H56-H59, H63-H72, and H79-H83 (EU numbering).","Of the above amino acid modifications, modifications that do not reduce the binding to FcRn or the plasma retention in human FcRn transgenic mice are more preferred.","More specifically, modifications that increase the protein A-binding ability of a polypeptide include, but are not limited to, substitution of histidine (His) for the amino acid residue at position 435 (EU numbering) in the amino acid sequence of an antibody Fc domain or an antibody heavy chain constant region.","Meanwhile, modifications that reduce the protein A-binding ability of a polypeptide include, but are not limited to, substitution of arginine for the amino acid residue at position 435 (EU numbering) in the amino acid sequence of an antibody Fc domain or an antibody heavy chain constant region.","As for the antibody heavy chain variable region, the heavy chain variable region of the VH3 subclass has protein A-binding activity.","Thus, to increase the protein A-binding ability, the amino acid sequences at the above modification sites are preferably identical to those of the heavy chain variable region of the VH3 subclass.","To reduce the protein A-binding ability, the amino acid sequences are preferably identical to those of the heavy chain variable region of another subclass.","As described below, modification of amino acid residues can be achieved by altering one or more nucleotides in a DNA encoding a polypeptide, and expressing the DNA in host cells.","Those skilled in the art can readily determine the number, site, and type of altered nucleotides depending on the type of amino acid residues after modification.","Herein, modification (alteration) refers to substitution, deletion, addition, or insertion, or combinations thereof.","The polypeptide having an antigen-binding activity may comprise other modifications in addition to the above modifications of amino acid residues.","Such additional modifications can be selected from, for example, substitutions, deletions, and modifications of amino acids, and combinations thereof.","Specifically, all polypeptides whose amino acid sequences comprise a modification described below are included in the present invention: amino acid modification for increasing the rate of heteromeric association of two types of H chains in a bispecific antibody amino acid modification for stabilizing the disulfide bonds between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity amino acid modification for improving the plasma retention of an antibody modification for increasing the stability under acidic conditions modification for reducing the heterogeneity modification for suppressing deamidation reaction modification for introducing a difference in between the isoelectric points of two types of polypeptides modification for altering the Fcγ receptor-binding ability These amino acid modifications are described below.","Amino Acid Modification for Increasing the Rate of Heteromeric Association Between the Two Types of H Chains in a Bispecific Antibody The amino acid modifications of the present invention can be combined with the amino acid modifications described in WO2006106905.There is no limitation on the modification sites as long as the amino acids form the interface between two polypeptides having an antigen-binding activity.","Specifically, for example, when a heavy chain constant region is modified, such modifications include modifications that make the amino acids of at least one of the combinations of positions 356 and 439, positions 357 and 370, and positions 399 and 409 (EU numbering) in the amino acid sequence of the heavy chain constant region of the first polypeptide having an antigen-binding activity have the same electric charge; and the amino acids of at least one of the combinations of positions 356 and 439, positions 357 and 370, and positions 399 and 409 (EU numbering) in the heavy chain constant region of the second polypeptide having an antigen-binding activity or no antigen-binding activity have electric charge opposite to that of the first polypeptide having an antigen-binding activity.","More specifically, such modifications include, for example, introduction of a mutation that substitutes Glu at position 356 (EU numbering) with Lys in the amino acid sequence of the heavy chain constant region of either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity, and a mutation that substitutes Lys at position 439 (EU numbering) with Glu in the amino acid sequence of the heavy chain constant region of the other polypeptide.","When these modifications are combined with the modifications of the present invention, the polypeptide of interest can be obtained with a higher purity by protein A-based purification alone.","Alternatively, the polypeptide multimer of interest that comprises the first, second, third, and fourth polypeptides having an antigen-binding activity can be efficiently produced or purified to a higher purity, when modification is performed to make the amino acids at position 39 (Kabat numbering) in the heavy chain variable region and/or at position 213 (EU numbering) in the heavy chain constant region of the first polypeptide having an antigen-binding activity have an electric charge opposite to that of the amino acid at position 39 (Kabat numbering) in the heavy chain variable region and/or the amino acid at position 213 (EU numbering) in the heavy chain constant region of the second polypeptide having an antigen-binding activity or no antigen-binding activity, and the amino acid at position 38 (Kabat numbering) and/or the amino acid at position 123 (EU numbering) in the light chain variable region of the third polypeptide having an antigen-binding activity have an electric charge opposite to that of the amino acid at position 38 (Kabat numbering) and/or the amino acid at position 123 (EU numbering) in the light chain variable region of the fourth polypeptide having an antigen-binding activity.","Amino Acid Modification for Stabilizing the Disulfide Bonds Between the First Polypeptide Having an Antigen-Binding Activity and the Second Polypeptide Having an Antigen-Binding Activity or No Antigen-Binding Activity As described in published documents (Mol.","Immunol.","1993, 30, 105-108; and Mol.","Immunol.","2001, 38, 1-8), the heterogeneity of IgG4 is eliminated and its stable structure can be maintained by substituting Pro for Ser at position 228 (EU numbering) in the amino acid sequence of the heavy chain constant region of IgG4.Amino Acid Modification for Improving the Plasma Retention of an Antibody In order to regulate plasma retention, it is possible to combine the amino acid modifications of the present invention with amino acid modifications that alter the antibody pI value.","Modifications to constant regions include, for example, amino acid modifications at positions 250 and 428 (EU numbering) and such described in published documents (J. Immunol.","2006, 176 (1):346-356; and Nat.","Biotechnol.","1997 15 (7):637-640).","Modifications to variable regions include the amino acid modifications described in WO2007/114319 and WO2009/041643.Amino acids to be modified are preferably exposed on the surface of a polypeptide having an antigen-binding activity.","The modifications include, for example, amino acid substitution at position 196 (EU numbering) in the amino acid sequence of a heavy chain constant region.","In the case of the heavy chain constant region of IgG4, the plasma retention can be enhanced, for example, by substituting glutamine for lysine at position 196 thereby reducing the pI value.","Furthermore, the plasma retention can be regulated by altering the FcRn-binding ability.","Amino acid modifications that alter the FcRn-binding ability include, for example, the amino acid substitutions in the antibody heavy chain constant region described in published documents (The Journal of Biological Chemistry vol.","276, No.","9 6591-6604, 2001; Molecular Cell, Vol.","7, 867-877, 2001; Curr Opin Biotechnol.","2009, 20 (6):685-91).","Such amino acid substitutions include, for example, substitutions at positions 233, 238, 253, 254, 255, 256, 258, 265, 272, 276, 280, 285, 288, 290, 292, 293, 295, 296, 297, 298, 301, 303, 305, 307, 309, 311, 312, 315, 317, 329, 331, 338, 360, 362, 376, 378, 380, 382, 415, 424, 433, 434, 435, and 436 (EU numbering).","Modification for Improving the Stability Under Acidic Conditions When the heavy chain constant region of IgG4 is used, the stable four-chain structure (H2L2 structure) is preferably maintained by suppressing the conversion of IgG4 into the half-molecule form under acidic conditions.","Thus, arginine at amino acid position 409 (EU numbering system) which plays an important role in the maintenance of the four-chain structure (Immunology 2002, 105, 9-19) is preferably substituted with lysine of the IgG1 type that maintains a stable four-chain structure even under acidic conditions.","Furthermore, to improve the acidic stability of IgG2, methionine at amino acid position 397 (EU numbering system) can be substituted with valine.","These modifications can be used in combination with the amino acid modifications of the present invention.","Modification for Reducing Heterogeneity The amino acid modifications of the present invention may be combined with the methods described in WO2009041613.Specifically, for example, the modification in which the two amino acids at the C-terminus of the IgG1 heavy chain constant region (i.e., glycine and lysine at positions 446 and 447 [EU numbering], respectively) are deleted can be combined with the amino acid modifications described in the Examples herein.","Modification for Suppressing Deamidation Reaction The amino acid modifications of the present invention may be combined with amino acid modifications for suppressing deamidation reaction.","Deamidation reaction has been reported to occur more frequently at a site where asparagine (N) and glycine (G) are adjacent to each other (- - -NG- - -) (Geiger et al., J. Bio.","Chem.","(1987) 262:785-794).","When a polypeptide multimer (multispecific antibody) of the present invention has a site where asparagine and glycine are adjacent to each other, deamidation reaction can be suppressed by modifying the amino acid sequence.","Specifically, for example, either or both of asparagine and glycine are substituted with other amino acids.","More specifically, for example, asparagine is substituted with aspartic acid.","Modification for Introducing a Difference in Isoelectric Point Between Two Types of Polypeptides The amino acid modifications of the present invention may be combined with amino acid modifications for introducing a difference in isoelectric point.","Specific methods are described, for example, in WO2007/114325.In addition to the modifications of the present invention, the amino acid sequences of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity are modified so that there is a larger difference in isoelectric point between these polypeptides.","This enables efficient production or purification of the polypeptide of interest to a higher purity.","Furthermore, a larger difference in isoelectric point can be produced between the third polypeptide having an antigen-binding activity and the fourth polypeptide having an antigen-binding activity.","This allows the polypeptide multimer of interest comprising the first, second, third, and fourth polypeptides to be efficiently produced or purified to a higher purity.","Specifically, when the first and second polypeptides each comprises an amino acid sequence of an antibody heavy chain, the modification sites include, for example, positions 1, 3, 5, 8, 10, 12, 13, 15, 16, 19, 23, 25, 26, 39, 42, 43, 44, 46, 68, 71, 72, 73, 75, 76, 81, 82b, 83, 85, 86, 105, 108, 110, and 112 (Kabat numbering).","When the third and fourth polypeptides each comprises an amino acid sequence of an antibody light chain, the modification sites include, for example, positions 1, 3, 7, 8, 9, 11, 12, 16, 17, 18, 20, 22, 38, 39, 41, 42, 43, 45, 46, 49, 57, 60, 63, 65, 66, 68, 69, 70, 74, 76, 77, 79, 80, 81, 85, 100, 103, 105, 106, 107, and 108 (Kabat numbering).","A larger difference in isoelectric point can be produced by modifying at least one of the amino acid residues at the above positions in one polypeptide to have an electric charge, and modifying at least one of the amino acid residues at the above positions in the other polypeptide to have no charge or opposite electric charge to the above.","Modification for Altering the Fcγ Receptor-Binding Ability The amino acid modifications of the present invention may be combined with amino acid modifications that alter (increase or reduce) the Fcγ receptor-binding ability.","Modifications for altering the Fcγ receptor-binding ability include, but are not limited to, the modifications described in Curr Opin Biotechnol.","2009, 20(6):685-91.Specifically, the Fcγ receptor-binding ability can be altered, for example, by combining the modifications of the present invention with a modification that substitutes leucine at positions 234 and 235 and asparagine at position 272 (EU numbering) of an IgG1 heavy chain constant region with other amino acids.","The amino acids after substitution include, but are not limited to, alanine.","Preparation of DNAs that encode polypeptides having an antigen-binding activity, modification of one or more nucleotides, DNA expression, and recovery of expression products are described below Preparation of DNAs that Encode Polypeptides Having an Antigen-Binding Activity In the present invention, a DNA that encodes a polypeptide having an antigen-binding activity or a polypeptide having no antigen-binding activity may be the whole or a portion of a known sequence (naturally-occurring or artificial sequence), or combinations thereof.","Such DNAs can be obtained by methods known to those skilled in the art.","The DNAs can be isolated, for example, from antibody libraries, or by cloning antibody-encoding genes from hybridomas producing monoclonal antibodies.","With regard to antibody libraries, many are already well known, and those skilled in the art can appropriately obtain antibody libraries since methods for producing antibody libraries are known.","For example, regarding antibody phage libraries, one can refer to the literature such as Clackson et al., Nature 1991, 352: 624-8; Marks et al., J. Mol.","Biol.","1991, 222: 581-97; Waterhouses et al., Nucleic Acids Res.","1993, 21: 2265-6; Griffiths et al., EMBO J.","1994, 13: 3245-60; Vaughan et al., Nature Biotechnology 1996, 14: 309-14; or Japanese Patent Kohyo Publication No.","(JP-A) H20-504970 (unexamined Japanese national phase publication corresponding to a non-Japanese international publication).","In addition, known methods such as methods that use eukaryotic cells as libraries (WO95/15393) and ribosome display methods may be used.","Furthermore, techniques to obtain human antibodies by panning using human antibody libraries are also known.","For example, variable regions of human antibodies can be expressed on the surface of phages as single chain antibodies (scFvs) using phage display methods, and phages that bind to antigens can be selected.","Genetic analysis of the selected phages can determine the DNA sequences encoding the variable regions of human antibodies that bind to the antigens.","Once the DNA sequences of scFvs that bind to the antigens is revealed, suitable expression vectors can be produced based on these sequences to obtain human antibodies.","These methods are already well known, and one can refer to WO92/01047, WO92/20791, WO93/06213, WO93/11236, WO93/19172, WO95/01438, and WO95/15388.As for methods for obtaining genes encoding antibodies from hybridomas, basically, known techniques may be used.","Specifically, desired antigens or cells expressing the desired antigens are used as sensitizing antigens for immunization according to conventional immunization methods.","The immune cells thus obtained are fused with known parent cells by ordinary cell fusion methods, and monoclonal antibody producing cells (hybridomas) are screened by ordinary screening methods.","cDNAs of antibody variable regions (V regions) can be obtained by reverse transcription of mRNAs of the obtained hybridomas using reverse transcriptase.","Antibody-encoding genes can be obtained by linking them with DNAs encoding the desired antibody constant regions (C regions).","More specifically, without limitations, the following methods are examples.","Sensitizing antigens for obtaining the antibody genes encoding the antibody heavy and light chains include both complete antigens with immunogenicity and incomplete antigens composed of haptens and such that do not show antigenicity.","For example, full length proteins and partial peptides of proteins of interest can be used.","In addition, it is known that substances composed of polysaccharides, nucleic acids, lipids, and such may become antigens.","Thus, there are no particular limitations on antigens in the present invention.","Antigens can be prepared by methods known to those skilled in the art, and they can be prepared, for example, by the following methods using baculoviruses (for example, WO98/46777).","Hybridomas can be produced, for example, the following methods of Milstein et al.","(G. Kohler and C. Milstein, Methods Enzymol.","1981, 73: 3-46), and such.","When the immunogenicity of an antigen is low, it can be linked to a macromolecule that has immunogenicity, such as albumin, and then used for immunization.","Furthermore, by linking antigens with other molecules if necessary, they can be converted into soluble antigens.","When transmembrane molecules such as receptors are used as antigens, portions of the extracellular regions of the receptors can be used as a fragment, or cells expressing transmembrane molecules on their cell surface may be used as immunogens.","Antibody-producing cells can be obtained by immunizing animals using suitable sensitizing antigens described above.","Alternatively, antibody-producing cells can be prepared by in vitro immunization of lymphocytes that can produce antibodies.","Various mammals can be used as the animals for immunization, where rodents, lagomorphas and primates are generally used.","Examples of such animals include mice, rats, and hamsters for rodents, rabbits for lagomorphas, and monkeys including the cynomolgus monkey, rhesus monkey, hamadryas, and chimpanzees for primates.","In addition, transgenic animals carrying human antibody gene repertoires are also known, and human antibodies can be obtained by using these animals (see WO96/34096; Mendez et al., Nat.","Genet.","1997, 15: 146-56).","Instead of using such transgenic animals, for example, desired human antibodies having binding activity against antigens can be obtained by in vitro sensitization of human lymphocytes with desired antigens or cells expressing the desired antigens, and then fusing the sensitized lymphocytes with human myeloma cells such as U266 (see Japanese Patent Application Kokoku Publication No.","(JP-B) H1-59878 (examined, approved Japanese patent application published for opposition)).","Furthermore, desired human antibodies can be obtained by immunizing transgenic animals carrying a complete repertoire of human antibody genes, with desired antigens (see WO93/12227, WO92/03918, WO94/02602, WO96/34096, and WO96/33735).","Animal immunization can be carried out by appropriately diluting and suspending a sensitizing antigen in Phosphate-Buffered Saline (PBS), physiological saline, or such, and forming an emulsion by mixing an adjuvant if necessary, followed by an intraperitoneal or subcutaneous injection into animals.","After that, the sensitizing antigen mixed with Freund's incomplete adjuvant is preferably administered several times every four to 21 days.","Antibody production can be confirmed by measuring the target antibody titer in animal sera using conventional methods.","Antibody-producing cells obtained from lymphocytes or animals immunized with a desired antigen can be fused with myeloma cells to generate hybridomas using conventional fusing agents (for example, polyethylene glycol) (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, 1986, 59-103).","When required, hybridoma cells can be cultured and grown, and the binding specificity of the antibody produced from these hybridomas can be measured using known analysis methods, such as immunoprecipitation, radioimmunoassay (RIA), and enzyme-linked immunosorbent assay (ELISA).","Thereafter, hybridomas that produce antibodies of interest whose specificity, affinity, or activity has been determined can be subcloned by methods such as limiting dilution.","Next, genes encoding the selected antibodies can be cloned from hybridomas or antibody-producing cells (sensitized lymphocytes, and such) using probes that may specifically bind to the antibodies (for example, oligonucleotides complementary to sequences encoding the antibody constant regions).","Cloning from mRNA using RT-PCR is also possible.","Immunoglobulins are classified into five different classes, IgA, IgD, IgE, IgG, and IgM.","These classes are further divided into several subclasses (isotypes) (for example, IgG-1, IgG-2, IgG-3, and IgG-4; IgA-1 and IgA-2; and such).","Heavy chains and light chains used in the present invention to produce antibodies are not particularly limited and may derive from antibodies belonging to any of these classes or subclasses; however, IgG is particularly preferred.","Herein, it is possible to modify heavy-chain-encoding genes and light-chain-encoding genes using genetic engineering techniques.","Genetically modified antibodies, such as chimeric antibodies, humanized antibodies that have been artificially modified for the purpose of decreasing heterologous antigenicity and such against humans, can be appropriately produced if necessary for antibodies such as mouse antibodies, rat antibodies, rabbit antibodies, hamster antibodies, sheep antibodies, and camel antibodies.","Chimeric antibodies are antibodies composed of a nonhuman mammal antibody heavy chain and light chain variable regions, such as mouse antibody, and the heavy chain and light chain constant regions of human antibody.","They can be obtained by ligating the DNA encoding a variable region of a mouse antibody to the DNA encoding a constant region of a human antibody, incorporating them into an expression vector, and introducing the vector into a host for production of the antibody.","A humanized antibody, which is also called a reshaped human antibody, can be synthesized by PCR from a number of oligonucleotides produced so that they have overlapping portions at the ends of DNA sequences designed to link the complementary determining regions (CDRs) of an antibody of a nonhuman mammal such as a mouse.","The obtained DNA can be ligated to a DNA encoding a human antibody constant region.","The ligated DNA can be incorporated into an expression vector, and the vector can be introduced into a host to produce the antibody (see EP239400 and WO96/02576).","Human antibody FRs that are ligated via the CDR are selected when the CDR forms a favorable antigen-binding site.","If necessary, amino acids in the framework region of an antibody variable region may be substituted such that the CDR of the reshaped human antibody forms an appropriate antigen-binding site (K. Sato et al., Cancer Res.","1993, 53: 851-856).","The monoclonal antibodies of the present invention include such humanized antibodies and chimeric antibodies.","When the antibodies of the present invention are chimeric antibodies or humanized antibodies, the constant regions of these antibodies are preferably derived from human antibodies.","For example, Cγ1, Cγ2, Cγ3, and Cγ4 can be used for the heavy chain, while Cκ and Cλ can be used for the light chain.","Furthermore, the human antibody constant region may be modified as necessary to improve antibody or its production stability.","A chimeric antibody of the present invention preferably comprises a variable region of an antibody derived from a nonhuman mammal and a constant region of a human antibody.","Meanwhile, a humanized antibody of the present invention preferably comprises CDRs of an antibody derived from a nonhuman mammal, and FRs and C regions of a human antibody.","The constant regions derived from human antibodies comprise specific amino acid sequences, which vary depending on the isotype such as IgG (IgG1, IgG2, IgG3, and IgG4), IgM, IgA, IgD, and IgE.","The constant regions used to prepare the humanized antibodies of the present invention may be constant regions of antibodies of any isotype.","A constant region of human IgG is preferably used, but the constant regions are not limited thereto.","Meanwhile, there is no particular limitation on the human antibody-derived FRs which are used to prepare humanized antibodies, and they may be derived from an antibody of any isotype.","The variable and constant regions of chimeric or humanized antibodies of the present invention may be modified by deletion, substitution, insertion, and/or addition, as long as the antibodies exhibit the same binding specificity as the original antibodies.","Chimeric and humanized antibodies that use human-derived sequences are expected to be useful when administered to humans for therapeutic purposes or such, since their antigenicity in the human body has been attenuated.","In the present invention, amino acids may be modified to alter the biological properties of an antibody.","Minibodies (low-molecular-weight antibodies) are useful as the antibodies because of their in vivo kinetic properties and low-cost production using E. coli, plant cells, or such.","Antibody fragments are one type of minibody.","Minibodies include antibodies that comprise an antibody fragment as their partial structure.","The minibodies of the present invention are not particularly limited by their structure or production method, as long as they have antigen-binding ability.","Some minibodies have an activity greater than that of a whole antibody (Orita et al., Blood (2005) 105: 562-566).","Herein, “antibody fragments” are not particularly limited as long as they are a portion of a whole antibody (for example, whole IgG).","However, the antibody fragments preferably comprise a heavy chain variable region (VH) or a light chain variable region (VL).","Preferred antibody fragments include, for example, Fab, F (ab′)2, Fab′, and Fv.","The amino acid sequence of a heavy chain variable region (VH) or light chain variable region (VL) in an antibody fragment may be modified by substitution, deletion, addition, and/or insertion.","Furthermore, some portions of a heavy chain variable region (VH) or light chain variable region (VL) may be deleted, as long as the fragments retain their antigen-binding ability.","For example, of the above antibody fragments, “Fv” is a minimal antibody fragment that comprises the complete antigen recognition and binding sites.","“Fv” is a dimer (VH-VL dimer) in which one heavy chain variable region (VH) and one light chain variable region (VL) are linked tightly by non-covalent bonding.","The three complementarity determining regions (CDRs) of each variable region form an antigen-binding site on the surface of the VH-VL dimer.","Six CDRs confer an antigen-binding site to the antibody.","However, even one variable region (or half of an Fv comprising only three antigen-specific CDRs) has the ability to recognize and bind to an antigen, although its affinity is lower than that of the complete binding site.","Thus, such molecules which are smaller than Fv are also included in the antibody fragments of the present invention.","Furthermore, the variable regions of an antibody fragment may be chimerized or humanized.","It is preferable that the minibodies comprise both a heavy chain variable region (VH) and a light chain variable region (VL).","The minibodies include, for example, antibody fragments such as Fab, Fab′, F(ab′)2, and Fv, and scFv (single-chain Fv) which can be prepared using antibody fragments (Huston et al., Proc.","Natl.","Acad.","Sci.","USA (1988) 85: 5879-83; Plickthun “The Pharmacology of Monoclonal Antibodies” Vol.","113, Resenburg and Moore (eds.","), Springer Verlag, New York, pp.","269-315, (1994)); diabodies (Holliger et al., Proc.","Natl.","Acad.","Sci.","USA (1993) 90:6444-8; EP 404097; WO93/11161; Johnson et al., Method in Enzymology (1991) 203: 88-98; Holliger et al., Protein Engineering (1996) 9:299-305; Perisic et al., Structure (1994) 2:1217-26; John et al., Protein Engineering (1999) 12(7):597-604; Atwell et al., Mol.","Immunol.","(1996) 33:1301-12); sc(Fv)2 (Hudson et al., J Immunol.","Methods (1999) 231:177-89; Orita et al., Blood (2005) 105:562-566); triabodies (Journal of Immunological Methods (1999) 231: 177-89); and tandem diabodies (Cancer Research (2000) 60:4336-41).","An antibody fragment can be prepared by treating an antibody with an enzyme, for example, a protease such as papain and pepsin (see Morimoto et al., J. Biochem.","Biophys.","Methods (1992) 24:107-17; Brennan et al., Science (1985) 229:81).","Alternatively, an antibody fragment can also be produced by genetic recombination based on its amino acid sequence.","A minibody comprising a structure that results from modification of an antibody fragment can be constructed using an antibody fragment obtained by enzyme treatment or genetic recombination.","Alternatively, after constructing a gene that encodes a whole minibody and introducing it into an expression vector, the minibody may be expressed in appropriate host cells (see, for example, Co et al., J. Immunol.","(1994) 152:2968-76; Better and Horwitz, Methods Enzymol.","(1989) 178:476-96; Pluckthun and Skerra, Methods Enzymol.","(1989) 178: 497-515; Lamoyi, Methods Enzymol.","(1986) 121:652-63; Rousseaux et al., Methods Enzymol.","(1986) 121:663-9; Bird and Walker, Trends Biotechnol.","(1991) 9:132-7).","The above scFv is a single-chain polypeptide comprising two variable regions linked together via a linker or such, as necessary.","The two variable regions contained in an scFv are typically one VH and one VL, but an scFv may have two VH or two VL.","In general, scFv polypeptides comprise a linker between the VH and VL domains, thereby forming a paired portion of VH and VL required for antigen binding.","A peptide linker of ten or more amino acids is typically used as the linker between VH and VL for forming an intramolecularly paired portion between VH and VL.","However, the linkers of the scFv of the present invention are not limited to such peptide linkers, as long as they do not inhibit scFv formation.","To review scFv, see Pluckthun “The Pharmacology of Monoclonal Antibody”, Vol.","113 (Rosenburg and Moore ed., Springer Verlag, NY, pp.","269-315 (1994)).","Meanwhile, “diabodies (Db)” refers to divalent antibody fragments constructed by gene fusion (P. Holliger et al., Proc.","Natl.","Acad.","Sci.","USA 90: 6444-6448 (1993); EP 404,097; WO93/11161; etc.).","Diabodies are dimers comprising two polypeptide chains, in which each polypeptide chain comprises within the same chain a light chain variable region (VL) and a heavy chain variable region (VH) linked via a linker short enough to prevent interaction of these two domains, for example, a linker of about five residues.","VL and VH encoded on the same polypeptide chain will form a dimer because the linker between VL and VH is too short to form a single-chain V region fragment.","Therefore, diabodies have two antigen-binding sites.","In this case, when VL and VH directed against two different epitopes (a and b) are expressed simultaneously as combinations of VLa-VHb and VLb-VHa connected with a linker of about five residues, they are secreted as bispecific Db.","Diabodies comprise two molecules of scFv and thus have four variable regions.","As a result, diabodies have two antigen binding sites.","Unlike situations in which scFv does not form dimers, in diabody formation, the length of the linker between the VH and VL in each scFv molecule is generally about five amino acids when the linker is a peptide linker.","However, the linker of scFv that forms a diabody is not limited to such a peptide linker, as long as it does not inhibit scFv expression and diabody formation.","Furthermore, it is preferable that minibodies and antibody fragments of the present invention additionally comprise an amino acid sequence of an antibody heavy chain constant region and/or an amino acid sequence of a light chain constant region.","Alteration of One or More Nucleotides Herein, “alteration of nucleotides” means that gene manipulation or mutagenesis is performed to insert, delete, or substitute at least one nucleotide in a DNA so that the polypeptide encoded by the DNA has amino acid residues of interest.","Specifically, this means that the codon encoding the original amino acid residue is substituted with a codon encoding the amino acid residue of interest.","Such nucleotide alterations can be introduced using methods such as site-directed mutagenesis (see, for example, Kunkel (1985) Proc.","Natl.","Acad.","Sci.","USA 82: 488), PCR mutagenesis, and cassette mutagenesis.","In general, mutant antibodies whose biological properties have been improved show an amino acid sequence homology and/or similarity of 70% or higher, more preferably 80% or higher, and even more preferably 90% or higher (for example, 95% or higher, 97%, 98%, 99%, etc.","), when compared to the amino acid sequence of the original antibody variable region.","Herein, the sequence homology and/or similarity is defined as the ratio of amino acid residues that are homologous (the same residue) or similar (amino acid residues classified into the same group based on the general properties of amino acid side chains) to the original amino acid residues, after maximizing the value of the sequence homology by performing sequence alignment and gap introduction as necessary.","In general, naturally-occurring amino acid residues are classified into the following groups based on the characteristics of their side chains: (1) hydrophobic: alanine, isoleucine, valine, methionine, and leucine; (2) neutral hydrophilic: asparagine, glutamine, cysteine, threonine, and serine; (3) acidic: aspartic acid and glutamic acid; (4) basic: arginine, histidine, and lysine; (5) residues that have an influence on the chain conformation: glycine and proline; and (6) aromatic: tyrosine, tryptophan, and phenylalanine.","The number of modified amino acids is, for example, ten, nine, eight, seven, six, five, four, three, two, or one, but is not limited thereto.","In general, a total of six complementarity determining regions (CDRs; hypervariable regions) present in the heavy chain and light chain variable regions interact to form the antigen binding site(s) of an antibody.","It is known that one of these variable regions has the ability to recognize and bind to the antigen, even though the affinity will be lower than when all binding sites are included.","Thus, polypeptides of the present invention having an antigen-binding activity may encode fragment portions containing the respective antigen binding sites of antibody heavy chain and light chain as long as they maintain the desired antigen-binding activity.","The methods of the present invention allow efficient preparation of, for example, desired polypeptide multimers that actually have the activity described above.","In a preferred embodiment of the present invention, appropriate amino acid residues to be “modified” can be selected from, for example, the amino acid sequences of antibody heavy chain and light chain variable regions and the amino acid sequences of antibody light chain and light chain variable region.","DNA Expression DNAs encoding the modified polypeptides are cloned (inserted) into an appropriate vector and then introduced into host cells.","There is no particular limitation on the vectors as long as they stably carry the inserted nucleic acids.","For example, when using E. coli as the host, the vectors include cloning vectors.","Preferred cloning vectors include pBluescript vectors (Stratagene).","It is possible to use various commercially available vectors.","Expression vectors are particularly useful as vectors for producing the polypeptide multimers or polypeptides of the present invention.","There is no particular limitation on the expression vectors as long as they express polypeptides in vitro, in E. coli, culture cells, or organisms.","Preferred vectors include, for example, pBEST vectors (Promega) for in vitro expression; pET vectors (Invitrogen) for expression in E. coli; the pME18S-FL3 vector (GenBank Accession No.","AB009864) for expression in culture cells; and the pME18S vector (Mol.","Cell.","Biol.","8:466-472 (1988)) for expression in organisms.","DNAs can be inserted into vectors by conventional methods such as ligase reaction using restriction enzyme sites (Current protocols in Molecular Biology edit.","Ausubel et al.","(1987) Publish.","John Wiley & Sons.","Section 11.4-11.11).","There is no particular limitation on the above host cells, and various host cells can be used depending on the purpose.","Cells for expressing polypeptides include, for example, bacterial cells (e.g., Streptococcus, Staphylococcus, E. coli, Streptomyces, and Bacillus subtilis), fungal cells (e.g., yeast and Aspergillus), insect cells (e.g., Drosophila S2 and Spodoptera SF9), animal cells (e.g., CHO, COS, HeLa, C127, 3T3, BHK, HEK293, Bowes melanoma cell), and plant cells.","Vectors can be introduced into host cells using known methods such as the calcium phosphate precipitation method, electroporation method (Current protocols in Molecular Biology edit.","Ausubel et al.","(1987) Publish.","John Wiley & Sons.","Section 9.1-9.9), lipofection method, and microinjection method.","In order to secrete host cell-expressed polypeptides into the lumen of the endoplasmic reticulum, periplasmic space, or extracellular environment, appropriate secretion signals can be incorporated into the polypeptides of interest.","These signals may be intrinsic or foreign to the polypeptides of interest.","Expression vectors for the first, second, third, and fourth polypeptides can be constructed by inserting DNAs encoding the polypeptides individually into separate vectors.","Alternatively, some of the DNAs encoding the first, second, third, and fourth polypeptides (for example, a DNA encoding the first polypeptide and a DNA encoding the second polypeptide) may be inserted into a single vector to construct expression vectors.","When an expression vector is constructed by inserting multiple DNAs into a single vector, there is no limitation on the combination of polypeptide-encoding DNAs to be inserted.","Recovery of Expression Products When polypeptides are secreted to a culture medium, the expression products are recovered by collecting the medium.","When polypeptides are produced in cells, the cells are first lysed and then the polypeptides are collected.","The polypeptides can be collected and purified from a culture of recombinant cells by known methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography, and lectin chromatography.","Protein A affinity chromatography is preferably used in the present invention.","Protein A columns include, but are not limited to, Hyper D (PALL), POROS (Applied Biosystems), Sepharose F.F.","(GE), and ProSep (Millipore).","Alternatively, protein A affinity chromatography can be performed using a resin bound by a ligand that mimics the IgG-binding ability of protein A.","Also when such a protein A mimic is used, polypeptide multimers of interest can be isolated and purified by creating a difference in the binding ability as a result of the amino acid modifications of the present invention.","Such protein A mimics include, but are not limited to, for example, mabSelect SuRE (GE Healthcare).","Furthermore, the present invention provides polypeptide multimers obtained by the production or purification methods of the present invention.","The present invention also provides polypeptide multimers comprising the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity, wherein the protein A-binding ability is different between the first and second polypeptides.","Such polypeptide multimers can be obtained by the methods described herein.","The structures and properties of the polypeptide multimers are as described above, and summarized below.","As compared to before modification of amino acids, the protein A-binding ability of the polypeptide multimers of the present invention has been altered.","More specifically, the protein A-binding ability has been altered in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.","In a polypeptide multimer of the present invention, the protein A-binding ability of the first polypeptide having an antigen-binding activity is different from that of the second polypeptide having an antigen-binding activity or no antigen-binding activity.","Accordingly, the solvent pH for protein A elution is different for the first polypeptide and the second polypeptide in affinity chromatography.","Furthermore, the first polypeptide and/or the second polypeptide can form a multimer with one or two third polypeptides.","Thus, the present invention relates to polypeptide multimers that comprise the first polypeptide having an antigen-binding activity, the second polypeptide having an antigen-binding activity or no antigen-binding activity, and one or two third polypeptides having an antigen-binding activity, wherein the protein A-binding ability is different for the first and second polypeptides.","Such polypeptide multimers can also be obtained by the methods described herein.","The polypeptide multimers may additionally comprise a fourth polypeptide.","Either one of the first polypeptide and the second polypeptide can form a multimer with the third polypeptide, while the other can form another multimer with the fourth polypeptide.","Thus, the present invention relates to polypeptide multimers that comprise the first polypeptide having an antigen-binding activity, the second polypeptide having an antigen-binding activity or no antigen-binding activity, the third polypeptide having an antigen-binding activity, and the fourth polypeptide having an antigen-binding activity, wherein the protein A-binding ability is different for the first and second polypeptides.","Such polypeptide multimers can also be obtained by the methods described herein.","The above first polypeptide having an antigen-binding activity and second polypeptide having an antigen-binding activity or no antigen-binding activity may comprise an amino acid sequence of an antibody heavy chain constant region or an amino acid sequence of an antibody Fc domain.","The amino acid sequence of an antibody heavy chain constant region or an antibody Fc domain includes, but is not limited to, an amino acid sequence of a human IgG-derived constant region.","Meanwhile, the above third polypeptide having an antigen-binding activity and fourth polypeptide having an antigen-binding activity may comprise an amino acid sequence of an antibody light chain constant region.","Furthermore, the polypeptides having an antigen-binding activity may comprise an amino acid sequence of an antibody variable region (for example, amino acid sequences of CDR1, CDR2, CDR3, FR1, FR2, FR3, and FR4).","The above first polypeptide having an antigen-binding activity and second polypeptide having an antigen-binding activity or no antigen-binding activity may comprise an amino acid sequence of an antibody heavy chain, or an amino acid sequence comprising an antibody light chain variable region and an antibody heavy chain constant region.","The above third polypeptide having an antigen-binding activity and fourth polypeptide having an antigen-binding activity may comprise an amino acid sequence of an antibody light chain, or an amino acid sequence comprising an antibody heavy chain variable region and an antibody light chain constant region.","A polypeptide multimer of the present invention can be a multispecific antibody.","Multispecific antibodies of the present invention include, but are not limited to, bispecific antibodies capable of specifically binding to two types of antigens.","In a polypeptide multimer of the present invention, one or more amino acid residues have been modified so that there is a (larger) difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.","As described above, the modification sites include, but are not limited to, for example, the following amino acid residues: TLMISR at positions 250-255, VLHQDWLNGK at positions 308-317, EALHNHY at positions 430-436, preferably TLMIS at positions 250-254, LHQD at positions 309-312, LN at positions 314-315, E at position 430, LHNHY at positions 432-436, more preferably LMIS at positions 251-254, LHQ at positions 309-311, L at position 314, LHNH at positions 432-435, and particularly LMIS at positions 252-254, L at position 309, Q at position 311, and NHY at positions 434-436 (EU numbering) in an antibody Fc domain or a heavy chain constant region.","Meanwhile, as for amino acid modifications of an antibody heavy chain variable region, preferred modification sites include FR1, CDR2, and FR3.More specifically, the polypeptide multimers of the present invention include, but are not limited to, polypeptide multimers in which the amino acid residue at position 435 (EU numbering) in the amino acid sequence of an antibody Fc domain or antibody heavy chain constant region is histidine or arginine in either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity, while the other polypeptide has a different amino acid residue at position 435 (EU numbering) in the amino acid sequence of an antibody Fc domain or antibody heavy chain constant region.","Furthermore, the polypeptide multimers of the present invention include, but are not limited to, polypeptide multimers in which the amino acid residue at position 435 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region is histidine in either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity, while the amino acid residue at position 435 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region is arginine in the other polypeptide.","Furthermore, the polypeptide multimers of the present invention comprising the first and second polypeptides include, but are not limited to the examples below.","(1) Polypeptide multimers that comprise the first or second polypeptide comprising an amino acid sequence in which the amino acid residues at positions 435 and 436 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region derived from a human IgG have been modified to histidine (His) and tyrosine (Tyr), respectively.","Such polypeptide multimers include, but are not limited to, for example, polypeptide multimers that comprise the first or second polypeptide comprising the amino acid sequence of SEQ ID NO: 9, 11, 13, or 15.","(2) Polypeptide multimers that comprise the first or second polypeptide comprising an amino acid sequence in which the amino acid residues at positions 435 and 436 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region derived from a human IgG have been modified to arginine (Arg) and phenylalanine (Phe), respectively.","Such polypeptide multimers include, but are not limited to, for example, polypeptide multimers that comprise the first or second polypeptide comprising the amino acid sequence of SEQ ID NO: 10 or 12.","(3) Polypeptide multimers that comprise the first or second polypeptide comprising an amino acid sequence in which the amino acid residues at positions 435 and 436 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region derived from a human IgG have been modified to arginine (Arg) and tyrosine (Tyr), respectively.","Such polypeptide multimers include, but are not limited to, for example, polypeptide multimers that comprise the first or second polypeptide comprising the amino acid sequence of SEQ ID NO: 14.","(4) Polypeptide multimers that comprise the first and second polypeptides, wherein either one of the polypeptides comprises an amino acid sequence in which the amino acid residues at positions 435 and 436 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region derived from a human IgG have been modified to histidine (His) and tyrosine (Tyr), respectively; and the other polypeptide comprises an amino acid sequence in which the amino acid residues at positions 435 and 436 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region have been modified to arginine (Arg) and phenylalanine (Phe), respectively.","Such polypeptide multimers include, but are not limited to, for example, polypeptide multimers that comprise the first polypeptide comprising the amino acid sequence of SEQ ID NO: 9, 11, 13, or 15 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 10 or 12.","(5) Polypeptide multimers that comprise the first and second polypeptides, wherein either one of the polypeptides comprises an amino acid sequence in which the amino acid residues at positions 435 and 436 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region derived from a human IgG have been modified to histidine (His) and tyrosine (Tyr), respectively; and the other polypeptide comprises an amino acid sequence in which the amino acid residues at positions 435 and 436 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region have been modified to arginine (Arg) and tyrosine (Tyr), respectively.","Such polypeptide multimers include, but are not limited to, for example, polypeptide multimers that comprise the first polypeptide comprising the amino acid sequence of SEQ ID NO: 9, 11, 13, or 15 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 14.","(6) Polypeptide multimers that comprise the first and second polypeptides, wherein either one of the polypeptides comprises an amino acid sequence in which the amino acid residues at positions 435 and 436 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region derived from a human IgG have been modified to arginine (Arg) and phenylalanine (Phe), respectively; and the other polypeptide comprises an amino acid sequence in which the amino acid residues at positions 435 and 436 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region have been modified to arginine (Arg) and tyrosine (Tyr), respectively.","Such polypeptide multimers include, but are not limited to, for example, polypeptide multimers that comprise the first polypeptide comprising the amino acid sequence of SEQ ID NO: 10 or 12 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 14.The above first and second polypeptides may additionally comprise an antibody heavy chain variable region.","The polypeptide multimers of (1) to (6) above may also comprise the third polypeptide and/or the fourth polypeptide.","Furthermore, the present invention provides polypeptide variants that comprise a polypeptide comprising a mutation in the amino acid residue at either position 435 or 436 (EU numbering).","Such polypeptide variants include, but are not limited to, polypeptide variants comprising a polypeptide described in the Examples.","Furthermore, the present invention provides nucleic acids encoding a polypeptide (polypeptide having an antigen-binding activity) that constitutes a polypeptide multimer of the present invention.","The present invention also provides vectors carrying such nucleic acids.","The present invention also provides host cells comprising the above nucleic acids or vectors.","There is no particular limitation on the host cells, and they include, for example, E. coli and various plant and animal cells.","The host cells may be used, for example, as a production system for producing and expressing the polypeptide multimers or polypeptides of the present invention.","There are in vitro and in vivo production systems for producing the polypeptide multimers or polypeptides.","In vitro production systems include those using eukaryotic cells and prokaryotic cells.","Eukaryotic cells that can be used as host cells include, for example, animal cells, plant cells, and fungal cells.","Animal cells include: mammalian cells, for example, CHO (J. Exp.","Med.","(1995) 108, 945), COS, HEK293, 3T3, myeloma, BHK (baby hamster kidney), HeLa, and Vero; amphibian cells such as Xenopus laevis oocytes (Valle, et al., Nature (1981) 291: 338-340); and insect cells such as Sf9, Sf21, and Tn5.For expressing the polypeptide multimers or polypeptides of the present invention, CHO-DG44, CHO-DX11B, COS7 cells, HEK293 cells, and BHK cells can be suitably used.","Of the animal cells, CHO cells are particularly preferable for large-scale expression.","Vectors can be introduced into a host cell by, for example, calcium phosphate methods, DEAE-dextran methods, methods using cationic liposome DOTAP (Boehringer-Mannheim), electroporation methods, or lipofection methods.","It is known that plant cells such as Nicotiana tabacum-derived cells and Lemna minor cells are protein production systems, and these cells can be used to produce polypeptide multimers or polypeptides of the present invention by methods that culture calluses from these cells.","Protein expression systems that use fungal cells including yeast cells, for example, cells of the genus Saccharomyces (Saccharomyces cerevisiae, Saccharomyces pombe, etc.","), and cells of filamentous fungi, for example, the genus Aspergillus (Aspergillus niger, etc.)","are known, and these cells can be used as a host to produce polypeptide multimers or polypeptides of the present invention.","When prokaryotic cells are used, production systems that use bacterial cells are available.","Production systems that use bacterial cells including Bacillus subtilis as well as E. coli described above are known, and they can be used to produce polypeptide multimers or polypeptides of the present invention.","When a polypeptide multimer or polypeptide is produced using a host cell of the present invention, a polynucleotide encoding the polypeptide multimer or polypeptide of the present invention may be expressed by culturing the host cell transformed with an expression vector comprising the polynucleotide.","Culturing can be performed according to known methods.","For example, when animal cells are used as a host, DMEM, MEM, RPMI 1640, or IMDM may be used as the culture medium.","The culture medium may be used with serum supplement solutions such as FBS or fetal calf serum (FCS).","Alternatively, cells can be cultured in serum-free cultures.","The preferred pH is about 6 to 8 during the course of culturing.","Incubation is carried out typically at about 30 to 40° C. for about 15 to 200 hours.","Medium is exchanged, aerated, or agitated, as necessary.","On the other hand, systems for producing polypeptides in vivo include, for example, those using animals and those using plants.","A polynucleotide of interest is introduced into an animal or plant to produce the polypeptide in the body of the animal or the plant, and then the polypeptide is collected.","The “host” of the present invention includes such animals and plants.","When animals are used, production systems that use mammals or insects are available.","Mammals such as goat, pig, sheep, mouse, and cattle may be used (Vicki Glaser, SPECTRUM Biotechnology Applications (1993)).","When mammals are used, transgenic animals may be used.","For example, a polynucleotide encoding a polypeptide multimer or polypeptide of the present invention may be prepared as a fusion gene with a gene encoding a polypeptide specifically produced in milk, such as goat β-casein.","Next, polynucleotide fragments containing this fusion gene are injected into goat embryos, which are then introduced back into female goats.","The antibody of interest can be obtained from milk produced by the transgenic goats, which are born from the goats that received the embryos, or by their offspring.","Appropriate hormones may be administered to the transgenic goats to increase the volume of milk containing the antibody produced by the transgenic goats (Ebert et al., Bio/Technology (1994) 12: 699-702).","Insects such as silkworms may be used for producing polypeptide multimers or polypeptides of the present invention.","When silkworms are used, baculoviruses carrying a polynucleotide encoding a polypeptide multimer or polypeptide of interest can be used to infect silkworms, so that the polypeptide multimer or polypeptide of interest can be obtained from the body fluids of these silkworms (Susumu et al., Nature (1985) 315:592-594).","Plants used for producing polypeptide multimers or polypeptides of the present invention include, for example, tobacco.","When tobacco is used, a polynucleotide encoding a polypeptide multimer or polypeptide of interest is inserted into a plant expression vector, for example, pMON 530, and then the vector is introduced into a bacterium such as Agrobacterium tumefaciens.","The bacteria are then used to infect tobacco such as Nicotiana tabacum, and the desired polypeptide multimer or polypeptide can be obtained from the leaves of the tobacco (Ma et al., Eur.","J. Immunol.","(1994) 24: 131-138).","Alternatively, the same bacteria can be used to infect Lemna minor, and after cloning, the desired polypeptide multimer or polypeptide can be obtained from the cells of Lemna minor (Cox K. M. et al., Nat.","Biotechnol.","2006 December; 24(12):1591-1597).","The polypeptide multimer or polypeptide thus obtained may be isolated from the inside or outside (such as the medium and milk) of host cells, and purified as a substantially pure and homogenous polypeptide multimer or polypeptide.","Methods used for separating and purifying a polypeptide multimer or polypeptide are not limited, and methods used in standard polypeptide purification may be applied.","Antibodies may be isolated and purified by selecting an appropriate combination of, for example, chromatographic columns, filtration, ultrafiltration, salting-out, solvent precipitation, solvent extraction, distillation, immunoprecipitation, SDS-polyacrylamide gel electrophoresis, isoelectric focusing, dialysis, recrystallization, and such.","Chromatographies include, for example, affinity chromatography, ion exchange chromatography, hydrophobic chromatography, gel filtration, reverse-phase chromatography, and adsorption chromatography (Strategies for Protein Purification and Characterization: A Laboratory Course Manual.","Ed Daniel R. Marshak et al., (1996) Cold Spring Harbor Laboratory Press).","These chromatographies can be carried out using liquid phase chromatography such as HPLC and FPLC.","Examples of columns for affinity chromatography include protein A columns and protein G columns.","Examples of the columns that use protein A include, but are not limited to, Hyper D, POROS, and Sepharose F. F. (Pharmacia).","As necessary, modifications can be added and peptides can be deleted from a polypeptide multimer or polypeptide arbitrarily by treatment with an appropriate protein modification enzyme before or after purification of the polypeptide multimer or polypeptide.","Such protein modification enzymes include, for example, trypsin, chymotrypsin, lysyl endopeptidase, protein kinase, and glucosidase.","Another preferred embodiment of the present invention includes a method for producing a polypeptide multimer or polypeptide of the present invention, which comprises the steps of culturing the host cells of the present invention as described above and collecting the polypeptide from the cell culture.","Furthermore, the present invention relates to pharmaceutical compositions (agents) comprising a polypeptide multimer or polypeptide of the present invention and a pharmaceutically acceptable carrier.","In the present invention, “pharmaceutical compositions” generally refers to agents for treating or preventing, or testing and diagnosing diseases.","The pharmaceutical compositions of the present invention can be formulated by methods known to those skilled in the art.","For example, such pharmaceutical compositions can be used parenterally in the form of injections, which are sterile solutions or suspensions prepared with water or another pharmaceutically acceptable liquid.","For example, such compositions may be formulated by appropriately combining with a pharmaceutically acceptable carrier or medium, specifically, sterile water, physiological saline, vegetable oil, emulsifier, suspension, surfactant, stabilizer, flavoring agent, excipient, vehicle, preservative, binder, or such, and mixed in a unit dose form that meets the generally accepted requirements for preparation of pharmaceuticals.","In such preparations, the amount of active ingredient is adjusted such that a suitable amount within a specified range is obtained.","Sterile compositions for injection can be formulated using vehicles such as distilled water for injection, according to standard protocols for formulation.","Aqueous solutions for injection include, for example, physiological saline and isotonic solutions containing glucose or other adjuvants (for example, D-sorbitol, D-mannose, D-mannitol, and sodium chloride).","Appropriate solubilizers, for example, alcohols (ethanol and such), polyalcohols (propylene glycol, polyethylene glycol, and such), non-ionic surfactants (polysorbate 80™, HCO-50, and such) may be used in combination.","Oils include sesame and soybean oils.","Benzyl benzoate and/or benzyl alcohol can be used as solubilizers in combination.","Buffers (for example, phosphate buffer and sodium acetate buffer), soothing agents (for example, procaine hydrochloride), stabilizers (for example, benzyl alcohol and phenol), and/or antioxidants can also be combined.","Prepared injections are generally filled into appropriate ampules.","The pharmaceutical compositions of the present invention are preferably administered parenterally.","For example, the compositions may be in the form of injections, transnasal agents, transpulmonary agents, or transdermal agents.","For example, such compositions can be administered systemically or locally by intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, or such.","The administration methods can be appropriately selected in consideration of a patient's age and symptoms.","The dosage of a pharmaceutical composition comprising a polypeptide multimer or polypeptide or a polynucleotide encoding a polypeptide multimer or polypeptide may be set, for example, within the range of 0.0001 to 1000 mg/kg weight for each administration.","Alternatively, the dosage may be, for example, from 0.001 to 100,000 mg per patient.","However, in the present invention, the dosage is not necessarily limited to the ranges described above.","Although the dosage and administration method vary depending on a patient's weight, age, symptoms, and such, those skilled in the art can select appropriate dosage and administration methods in consideration of these factors.","The multispecific antibodies of the present invention can be formulated by combining them with other pharmaceutical components as necessary.","All prior art references cited herein are incorporated by reference into this specification.","EXAMPLES Hereinbelow, the present invention will be specifically described with reference to the Examples, but it is not to be construed as being limited thereto.","[Example 1] Construction of Expression Vectors for Antibody Genes and Expression of Respective Antibodies The antibody H chain variable regions used were: Q153 (the H chain variable region of an anti-human F.IX antibody, SEQ ID NO: 1), Q407 (the H chain variable region of an anti-human F.IX antibody, SEQ ID NO: 2), J142 (the H chain variable region of an anti-human F.X antibody, SEQ ID NO: 3), J300 (the H chain variable region of an anti-human F.X antibody, SEQ ID NO: 4), and MRA-VH (the H chain variable region of an anti-human interleukin-6 receptor antibody, SEQ ID NO: 5).","The antibody L chain variable regions used were: L180-k (an L chain common to an anti-human F.IX antibody and an anti-human F.X antibody, SEQ ID NO: 6), L210-k (an L chain common to an anti-human F.IX antibody/anti-human F.X antibody, SEQ ID NO: 7), and MRA-k (the L chain of an anti-human interleukin-6 receptor antibody, SEQ ID NO: 8).","The antibody H chain constant regions used were: G4d (SEQ ID NO: 9), which was constructed from IgG4 by introducing a substitution mutation of Pro for Ser at position 228 (EU numbering) and deleting the C-terminal Gly and Lys; z72 (SEQ ID NO: 10), which was constructed from G4d by introducing the following mutations: a substitution mutation of Arg for His at position 435 (EU numbering); a substitution mutation of Phe for Tyr at position 436 (EU numbering); and a substitution mutation of Pro for Leu at position 445 (EU numbering); z7 (SEQ ID NO: 11), which was constructed from G4d by introducing a substitution mutation of Lys for Glu at position 356 (EU numbering); z73 (SEQ ID NO: 12), which was constructed from z72 by introducing a substitution mutation of Glu for Lys at position 439 (EU numbering); z106 (SEQ ID NO: 13), which was constructed from z7 by introducing the following mutations: a substitution mutation of Gln for Lys at position 196 (EU numbering); a substitution mutation of Tyr for Phe at position 296 (EU numbering); and a substitution mutation of Lys for Arg at position 409 (EU numbering); z107 (SEQ ID NO: 14), which was constructed from z73 by introducing the following mutations: a substitution mutation of Gln for Lys at position 196 (EU numbering); a substitution mutation of Tyr for Phe at position 296 (EU numbering); a substitution mutation of Lys for Arg at position 409 (EU numbering); and a substitution mutation of Tyr for Phe at position 436 (EU numbering); and Gld (SEQ ID NO: 15), which was constructed by deleting the C-terminal Gly and Lys from IgG1.Substitution mutations of Lys for Glu at position 356 (EU numbering) and Glu for Lys at position 439 (EU numbering) were introduced for efficient formation of heteromeric molecules from the respective H chains in the production of heteromeric antibodies ((WO 2006/106905) PROCESS FOR PRODUCTION OF POLYPEPTIDE BY REGULATION OF ASSEMBLY).","The anti-human F.IX antibody H chain genes Q153-G4d and Q153-z7 were constructed by linking respectively G4d and z7 downstream of Q153.The anti-human F.IX antibody H chain gene Q407-z106 was constructed by linking z106 downstream of Q407.The anti-human F.X antibody H chain genes J142-G4d, J142-z72, and J142-z73 were constructed by linking respectively G4d, z72, and z73 downstream of J142.The anti-human F.X antibody H chain gene J300-z107 was constructed by linking z107 downstream of J300.The anti-human interleukin-6 receptor antibody H chain genes MRA-G1d, MRA-z106, and MRA-z107 were constructed by linking respectively G1d, z106, and z107 downstream of MRA-VH.","The respective antibody genes (Q153-G4d, Q153-z7, Q407-z106, J142-G4d, J142-z72, J142-z73, J300-z106, MRA-G1d, MRA-z106, MRA-z107, L180-k, L210-k, and MRA-k) were inserted into animal cell expression vectors.","The following antibodies were expressed transiently in FreeStyle293 cells (Invitrogen) by transfection using the constructed expression vectors.","As shown below, antibodies were named using the combinations of transfected antibody genes.","MRA-G1d/MRA-k MRA-z106/MRA-z107/MRA-k Q153-G4d/J142-G4d/L180-k Q153-G4d/J142-z72/L180-k Q153-z7/J142-z73/L180-k Q407-z106/J300-z107/L210-k [Example 2] Assessment of the Elution Conditions for Protein a Affinity Chromatography Q153-G4d/J142-G4d/L180-k and Q153-G4d/J142-z72/L180-k were expressed transiently, and the medium of the resulting FreeStyle293 cell culture (hereinafter abbreviated as CM) was used as a sample for assessing the elution conditions for protein A affinity chromatography.","The CM samples were filtered through a filter with a pore size of 0.22 μm, and loaded onto an rProtein A Sepharose Fast Flow column (GE Healthcare) equilibrated with D-PBS.","The column was subjected to washes 1 and 2 and elutions 1 to 5 in a stepwise manner as shown in Table 1.The volume of CM to be loaded onto the column was adjusted to 20 mg antibody/ml resin.","Fractions eluted under each condition were collected, and the respective eluted fractions were analyzed by cation exchange chromatography to identify their components.","To prepare controls, each CM was loaded onto rProtein G Sepharose Fast Flow resin (GE Healthcare).","Samples purified by batchwise elution were used as controls.","Since protein G binds to the Fab domain of an antibody, all antibody species (a bispecific antibody of interest in which two types of H chains are associated in a heteromeric manner (heteromeric antibody) and as an impurity monospecific homomeric antibodies in which single-type H chains are homomerically associated) in CM can be purified by using protein G, regardless of their protein A-binding affinity.","TABLE 1 Equilibration D-PBS Wash 1 400 mM Arg-HCl/D-PBS Wash 2 20 mM NaCitrate, pH 5.0 Elution 1 20 mM NaCitrate, pH 4.0 Elution 2 20 mM NaCitrate, pH 3.8 Elution 3 20 mM NaCitrate, pH 3.6 Elution 4 20 mM NaCitrate, pH 3.4 Elution 5 20 mM NaCitrate, pH 3.2 CM in which Q153-G4d/J142-G4d/L180-k or Q153-G4d/J142-z72/L180-k had been expressed was eluted from a protein A column (elution 1 to 5), and the respective eluted fractions were analyzed by cation exchange chromatography.","As for Q153-G4d/J142-G4d/L180-k, the analysis revealed that as the elution condition was altered from 1 to 5, i.e., as the pH of the elution buffer was reduced, the antibody composition of the eluted fractions changed gradually in the order from the homomeric antibody J142-G4d/L180-k to the heteromeric antibody Q153-G4d/J142-G4d/L180-k, and then to the homomeric antibody Q153-G4d/L180-k.","The order of elution is understood to be in accordance with the binding ability for protein A.","This implies that the homomeric antibody Q153-G4d/L180-k, which remained bound until exposed to low pH, has a greater binding ability for protein A than the homomeric species J142-G4d/L180-k (a homomeric antibody against FX) eluted at a high pH.","It is known that the variable region J142 is a sequence incapable of binding to protein A.","Specifically, the homomeric species J142-G4d/L180-k (a homomeric antibody against FX) has two protein A-binding sites; the heteromeric antibody Q153-G4d/J142-G4d/L180-k has three; and the homomeric antibody Q153-G4d/L180-k (homomeric antibody against FX) has four protein A-binding sites.","Thus, it was revealed that more protein A-binding sites resulted in stronger protein A binding, and thus a lower pH was required for elution.","Meanwhile, as for Q153-G4d/J142-z72/L180-k, it was revealed that as the elution condition was altered from 1 to 5, the antibody composition in the eluted fraction changed from the heteromeric antibody Q153-G4d/J142-z72/L180-k to the homomeric antibody Q153-G4d/L180-k.","The homomeric antibody J142-z72/L180-k (a homomeric antibody against FX) was almost undetectable in any eluted fractions.","This suggests that J142-z72/L180-k has no protein A-binding ability.","It is thought that the lack of protein A-binding ability of J142-z72 might be due to the introduced substitution mutation of Arg for His at position 435 (EU numbering).","The homomeric antibody J142-z72/L180-k (a homomeric antibody against FX) has no protein A-binding site, while the heteromeric antibody Q153-G4d/J142-z72/L180-k has two protein A-binding sites and the homomeric antibody Q153-G4d/L180-k (a homomeric antibody against FIX) has four.","The homomeric antibody J142-z72/L180-k (a homomeric antibody against FX) passes through the column because it does not bind to protein A.","This is the reason why J142-z72/L180-k was undetectable in any eluted fractions.","Furthermore, in both cases of Q153-G4d/J142-G4d/L180-k and Q153-G4d/J142-z72/L180-k, it was suggested that the heteromeric antibody and homomeric antibody Q153-G4d/L180-k (a homomeric antibody against FIX) were separable from each other at pH 3.6 or a lower pH.","[Example 3] Isolation and Purification of Heteromeric Antibodies by Protein a Chromatography CM samples containing the following antibodies were used: Q153-G4d/J142-G4d/L180-k Q153-G4d/J142-z72/L180-k Q153-z7/J142-z73/L180-k Q407-z106/J300-z107/L210-k The CM samples were filtered through a filter with a pore size of 0.22 μm, and loaded onto an rProtein A Sepharose Fast Flow column (GE Healthcare) equilibrated with D-PBS.","The column was subjected to washes 1 and 2 and elutions 1 and 2 as shown in Table 2 (except that Q407-z106/J300-z107/L210-k was subjected to elution 1 only).","The elution conditions were determined based on the result described in Example 2.The volume of CM to be loaded onto the column was adjusted to 20 mg antibody/ml resin.","Respective fractions eluted under each condition were collected and analyzed by cation exchange chromatography to identify their components.","To prepare controls, each CM was loaded onto rProtein G Sepharose Fast Flow resin (GE Healthcare) in the same manner as described in Example 2.Samples purified by batchwise elution were used as controls.","TABLE 2 Equilibration D-PBS Wash 1 400 mM Arg-HCl/D-PBS Wash 2 20 mM NaCitrate, pH 5.0 Elution 1 20 mM NaCitrate, pH 3.6 Elution 2 20 mM NaCitrate, pH 2.7 The result of cation exchange chromatography analysis for each eluted fraction is shown in Table 3 below.","The values represent the area of elution peak expressed in percentage.","Except for the Q153-G4d/J142-G4d/L180-k antibody, homomeric antibodies against FX were almost undetectable in any fractions eluted.","Thus, it was revealed that not only the homomeric antibody J142-z72 (a homomeric antibody against FX) described in Example 2 but also the homomeric antibodies J142-z73 and J300-z107 (a homomeric antibody against FX) were incapable of binding to protein A.","It is thought that the lack of protein A-binding ability in the homomeric antibody against FX was due to the substitution mutation of Arg for His at position 435 (EU numbering), which was introduced into the H chain constant region of the antibody against FX.","The heteromeric antibody, which is a bispecific antibody of interest, was detected mostly in the fraction of elution 1.Meanwhile, the majority of homomeric antibodies against FIX were eluted by elution 2, although they were also detected at a very low level in the fraction of elution 1.As compared to Q153-G4d/J142-z72/L180-k, in the cases of Q153-z7/J142-z73/L180-k and Q407-z106/J300-z107/L210-k, the proportion of the heteromeric antibody (bispecific antibody of interest) was considerably increased in the fraction eluted at pH 3.6.Thus, it was demonstrated that when the substitution mutations of Lys for Glu at position 356 (EU numbering) and of Glu for Lys at position 439 (EU numbering) for efficient formation of heteromeric molecules from the respective H chains were introduced in combination with the substitution mutation of Arg for His at position 435 (EU numbering), the heteromeric antibody (bispecific antibody of interest) could be purified to a purity of 98% or higher through the protein A-based purification step alone.","As described above, the present inventors revealed that based on differences in the number of protein A-binding sites between the heteromeric antibody and homomeric antibodies, the heteromeric antibody could be isolated and purified to high purity through the protein A chromatography step alone.","TABLE 3 Q153-G4d/J142-G4d/L180-k Fraction eluted Fraction eluted Peak area (%) Control at pH 3.6 at pH 2.7 J142-G4d/L180-k 17.6 27.5 — Q153-G4d/J142-G4d/L180-k 48.3 58.4 9.0 Q153-G4d/L180-k 34.1 14.1 91.0 TABLE 4 Q153-G4d/J142-z72/L180-k Fraction Fraction eluted eluted Peak area (%) Control at pH 3.6 at pH 2.7 J142-z72/L180-k 8.4 0.9 — Q153-G4d/J142-z72/L180-k 50.8 81.0 2.2 Q153-G4d/L180-k 40.8 18.1 97.8 TABLE 5 Q153-z7/J142-z73/L180-k Fraction Fraction eluted eluted Peak area (%) Control at pH 3.6 at pH 2.7 J142-z73/L180-k 3.2 — — Q153-z7/J142-z73/L180-k 90.7 98.1 2.7 Q153-z7/L180-k 6.1 1.9 97.3 [Example 4] Assessment of Pharmacokinetics in Human FcRn Transgenic Mice As described in Example 3 above, the present inventors demonstrated that by using z106 (SEQ ID NO: 13) and z107 (SEQ ID NO: 14) for the respective H chain constant regions of the bispecific antibody, the heteromeric antibody (bispecific antibody of interest) could be purified to a purity of 98% or higher through the protein A step alone.","Meanwhile, the loss of protein A-binding affinity probably results in loss of human FcRn-binding activity because protein A and human FcRn recognize the same site in an IgG antibody (J Immunol.","2000, 164(10):5313-8).","Actually, there is a reported method for purifying a bispecific antibody to a purity of 95% using protein A.","The method uses a rat IgG2b H chain which does not bind to protein A. Catumaxomab (a bispecific antibody) purified by this method has a half-life of about 2.1 days in human.","Its half-life is significantly shorter than the half-life of a normal human IgG1 which is 2 to 3 weeks (Non-patent Document 2).","In this context, antibodies that have z106 (SEQ ID NO: 13) and z107 (SEQ ID NO: 14) described in Example 3 as constant regions were assessed for their pharmacokinetics.","In a pharmacokinetic experiment for calculating the half-life in human, the pharmacokinetics in human FcRn transgenic mice (B6.mFcRn−/−.hFcRn Tg line 276+/+mice, Jackson Laboratories) was assessed by the following procedure.","MRA-G1d/MRA-k (hereinafter abbreviated as MRA-IgG1) having the IgG1 constant region and MRA-z106/MRA-z107/MRA-k (hereinafter abbreviated as MRA-z106/z107) that has z106/z107 as constant region was each intravenously administered once at a dose of 1 mg/kg to mice, and blood was collected at appropriate time points.","The collected blood was immediately centrifuged at 15,000 rpm and 4° C. for 15 minutes to obtain blood plasma.","The separated plasma was stored in a freezer at −20° C. or below until use.","The plasma concentration was determined by ELISA.","MRA-IgG1 and MRA-z106/z107k were assessed for their plasma retention in human FcRn transgenic mice.","As shown in FIG.","1, the result indicates that the retention of MRA-z106/z107 in plasma was comparable to or longer than that of MRA-IgG1.As described above, z106/z107, a constant region that allows for efficient production or purification of the heteromeric antibody to high purity by the protein A-based purification step alone, was demonstrated to be comparable or superior to human IgG1 in terms of plasma retention.","[Example 5] Construction of Expression Vectors for Antibody Genes and Expression of Respective Antibodies The antibody H chain variable regions used were: Q499 (the H chain variable region of an anti-human F.IX antibody, SEQ ID NO: 16).","J339 (the H chain variable region of an anti-human F.X antibody, SEQ ID NO: 17).","The antibody L chain used was: L377-k (the L chain common to an anti-human F.IX antibody and an anti-human F.X antibody, SEQ ID NO: 18).","The antibody H chain constant regions used were: z118 (SEQ ID NO: 19), which was constructed from z106 described in Example 1, by introducing a substitution mutation of Phe for Leu at position 405 (EU numbering); z121 (SEQ ID NO: 20), which was constructed from z118 by introducing a substitution mutation of Arg for His at position 435 (EU numbering); and z119 (SEQ ID NO: 21), which was constructed from z118 by introducing substitution mutations of Glu for Lys at position 356 (EU numbering) and Lys for Glu at position 439 (EU numbering).","The anti-human F.IX antibody H chain genes Q499-z118 and Q499-z121 were constructed by linking respectively z118 and z121 downstream of Q499.The anti-human F. X antibody H chain gene J339-z119 was constructed by linking z119 downstream of J339.Each of the antibody genes (Q499-z118, Q499-z121, J339-z119, and L377-k) was inserted into an animal cell expression vector.","The following antibodies were expressed transiently in FreeStyle293 cells (Invitrogen) by transfection using the constructed expression vectors.","As shown below, antibodies were named using the combinations of transfected antibody genes.","Q499-z118/J339-z119/L377-k Q499-z121/J339-z119/L377-k The above two antibodies are only different at the amino acid of position 435 in the EU numbering system in the H chain of the anti-human F.IX antibody.","z118 has His at position 435 and it has protein A-binding affinity.","Meanwhile, z121 has Arg at position 435, and it is predicted to have no protein A-binding activity based on the finding described in Example 2.Q499 is predicted to bind to protein A based on its sequence.","Thus, as for Q499-z118/J339-z119/L377-k, the homomeric species J339-z119/L377-k (a homomeric antibody against FX) has two protein A-binding sites; the heteromeric antibody Q499-z118/J339-z119/L377-k has three; and the homomeric antibody Q499-z118/L377-k (homomeric antibody against FIX) has four protein A-binding sites.","Meanwhile, as for Q499-z121/J339-z119/L377-k introduced with a modification that leads to loss of protein A-binding affinity, the homomeric species J339-z119/L377-k has two protein A-binding sites; the heteromeric antibody Q499-z121/J339-z119/L377-k has two; and the homomeric antibody Q499-z121/L377-k has two.","Specifically, even if a modification that leads to loss of protein A-binding affinity (for example, a modification that substitutes Arg for the amino acid at position 435, EU numbering) was introduced into only the H chain which binds to protein A through its variable region, it would not produce the effect that allows for efficient isolation/purification of the heteromeric antibody to high purity by the protein A-based purification step alone.","However, the modification that leads to the loss of protein A-binding ability can produce the effect when MabSelct SuRe (GE Healthcare) is used.","MabSelect SuRe is a modified protein A incapable of binding to Q499 and a chromatographic carrier for use in the purification of antibodies.","The carrier was developed to meet industrial requirements.","The ligand is a recombinant protein A that has been modified by genetic engineering to be resistant to alkaline conditions.","The great pH stability enables efficient and low-cost NaOH wash.","Furthermore, the carrier is characteristic in that it does not bind to the heavy chain variable region of the VH3 subclass, such as Q499.With respect to Q499-z118/J339-z119/L377-k, the homomeric species J339-z119/L377-k has two MabSelect SuRe-binding sites; the heteromeric antibody Q499-z118/J339-z119/L377-k has two; and the homomeric antibody Q499-z118/L377-k has two.","Meanwhile, as for Q499-z121/J339-z119/L377-k, the homomeric species J339-z119/L377-k has two MabSelect SuRe-binding sites; the heteromeric antibody Q499-z121/J339-z119/L377-k has a single site; and the homomeric antibody Q499-z121/L377-k does not have any MabSelect SuRe-binding site.","Specifically, it is understood that by combining a modified protein A incapable of binding to the antibody variable region, such as MabSelect SuRe, with a modification that leads to loss of protein A-binding affinity, the heteromeric antibody can be efficiently isolated and purified to high purity by the protein A-based purification step alone regardless of the protein A-binding activity of the heavy chain variable region.","[Example 6] Isolation and Purification of Heteromeric Antibodies by Affinity Chromatography Using Modified Protein A CM in which Q499-z118/J339-z119/L377-k or Q499-z121/J339-z119/L377-k had been expressed was subjected to chromatography using modified protein A.","The CM samples were filtered through a filter with a pore size of 0.22 μm, and loaded onto a Mab Select SuRe column (GE Healthcare) equilibrated with D-PBS.","The column was subjected to washes 1 and 2 and elution as shown in Table 7.Recombinant protein A consists of five domains (A to E) which have IgG-binding activity.","In Mab Select SuRe, domain B has been modified by genetic engineering to have a tetrameric structure.","Mab Select SuRe lacks affinity for the antibody variable region, and is advantageous in that it allows for antibody elution even under milder conditions as compared to conventional recombinant protein A.","In addition, the resin has improved alkaline resistance and enables for cleaning in place using 0.1 to 0.5 M NaOH, and is thus more suitable for production.","In the experiment described in this Example as shown in Table 7, 50 mM acetic acid (the pH was not adjusted and the measured pH was around 3.0) was used for the elution instead of the stepwise elution at pH3.6 and pH 2.7 described in Example 3.The respective eluted fractions were collected and analyzed by cation exchange chromatography to identify their components.","To prepare controls, each CM was loaded onto rProtein G Sepharose Fast Flow resin (GE Healthcare) in the same manner as described in Example 2.Samples purified by batchwise elution were used as controls.","Next, the fractions eluted from protein A were subjected to ion exchange chromatography.","An SP Sepharose High Performance column (GE Healthcare) was equilibrated with an equilibration buffer (20 mM sodium phosphate buffer, pH 6.0).","Then, the fractions eluted from protein A were neutralized with 1.5 M Tris-HCl, (pH7.4), and diluted three times with equilibration buffer, and loaded.","Antibodies bound to the column were eluted with 25 column volumes (CV) of an NaCl concentration gradient of 50 to 350 mM.","The eluted fractions containing the heteromeric antibody were purified by gel filtration chromatography using superdex200.The resulting monomer fractions were collected, and used in the assessment of pharmacokinetics in human FcRn transgenic mice described in Example 7.TABLE 7 Equilibration D-PBS Wash 1 400 mM Arg-HCl/D-PBS Wash 2 50 mM NaAcetate buffer, pH 6.0 Elution 50 mM Acetic acid The result of cation exchange chromatography analysis of each eluted fraction is shown in Tables 8 and 9.As shown in Table 8, with respect to Q499-z118/J339-z119/L377-k, the component ratio of each eluted fraction is not much different from that of the control.","The reason is probably that all three species J339-z119/L377-k (a homomeric antibody against F.X), Q499-z118/L377-k (a homomeric antibody against F.IX), and Q499-z118/J339-z119/L377-k (a heteromeric antibody) had two binding sites for the modified protein, and thus there was no difference in terms of the association/dissociation during the protein A-based purification step.","Meanwhile, in the case of Q499-z121/J339-z119/L377-k, the ratio of Q499-z121/L377-k (a homomeric antibody against F.IX) in the eluted fraction was significantly reduced as compared to the control as shown in Table 9.In contrast, the ratios of J339-z119/L377-k (a homomeric antibody against F.X) and Q499-z121/J339-z119/L377-k (a heteromeric antibody) in the eluted fraction were relatively increased as compared to the control along with a decrease of Q499-z121/L377-k.","It was believed that this is because J339-z119/L377-k (a homomeric antibody against F.X) has two binding sites for the modified protein A and Q499-z121/J339-z119/L377-k (a heteromeric antibody) has one.","However, Q499-z121/L377-k (a homomeric antibody against F.IX) has no binding site, and accordingly the majority of Q499-z121/L377-k passed through the column without binding to the modified protein A.","As described above, the present invention also demonstrates that with respect to antibodies whose variable regions have protein A-binding activity, when the modified protein A is combined with a modification that leads to loss of protein A-binding affinity, one of the homomeric antibodies can be significantly decreased, and as a result the purity of the heteromeric antibody is increased by the protein A-based purification step alone.","TABLE 8 Q499-z118/J339-z119/L377-k Eluted Peak area (%) Control fraction J339-z119/L377-k 2.3 4.2 Q499-z118/J339-z119/L377-k 75.5 79.1 Q499-z118/L377-k 22.3 16.7 TABLE 9 Q499-z121/J339-z119/L377-k Eluted Peak area (%) Control fraction J339-z119/L377-k 3.2 5.9 Q499-z121/J339-z119/L377-k 76.6 91.6 Q499-z121/L377-k 20.2 2.5 [Example 7] Assessment of Pharmacokinetics in Human FcRn Transgenic Mice Q499-z118/J339-z119/L377-k and Q499-z121/J339-z119/L377-k prepared as described in Example 6 were assessed for their pharmacokinetics.","It is likely to be difficult to adjust the protein A-binding activity without loss of the human FcRn binding, because protein A and human FcRn recognize the same site in an antibody IgG (J Immunol.","2000 164 (10):5313-8) as shown in FIG.","2.To retain the binding affinity for human FcRn is very important for the long plasma retention (long half-life) in human, which is characteristic of IgG-type antibodies.","In this context, pharmacokinetics was compared between Q499-z118/J339-z119/L377-k and Q499-z121/J339-z119/L377-k prepared as described in Example 6.In a pharmacokinetic experiment to predict the half-life in human, the pharmacokinetics in human FcRn transgenic mice (B6.mFcRn−/−.hFcRn Tg line 276+/+mice, Jackson Laboratories) was assessed by the following procedure.","Q499-z118/J339-z119/L377-k and Q499-z121/J339-z119/L377-k were each intravenously administered once at a dose of 5 mg/kg to mice, and blood was collected at appropriate time points.","The collected blood was immediately centrifuged at 15,000 rpm and 4° C. for 15 minutes to obtain blood plasma.","The separated plasma was stored in a freezer at −20° C. or below until use.","The blood concentration was determined by ELISA.","As shown in FIG.","3, the result indicates that Q499-z118/J339-z119/L377-k and Q499-z121/J339-z119/L377-k were comparable to each other in terms of plasma retention.","Thus, z121/z119, a constant region in which either of the H chains is introduced with a modification that leads to loss of protein A-binding ability was demonstrated to be comparable in terms of plasma retention to z118/z119 which does not have the modification that leads to loss of protein A-binding affinity.","As described above, the present inventors revealed a modification (for example, a substitution mutation of Arg for the amino acid at position 435, EU numbering) that leads to loss of protein A-binding ability but has no influence on the pharmacokinetics, and which allows for efficient isolation/purification of the heteromeric antibody to high purity through the protein A-based purification step alone regardless of the variable region.","[Example 8] Introduction of Mutations into the CH3 Domain of GC33-IgG1-CD3-scFv and Preparation of Designed Molecules Through the Protein A-Based Purification Step Alone Introduction of Mutations for Protein A-Based Purification of the GC33-IgG1-CD3-scFv Molecule The inventors designed an anti-GPC3 IgG antibody molecule in which an anti-CD3 scFv antibody is linked to one of the two H chains (FIG.","4).","This molecule was expected to be capable of killing cancer cells by recruiting T cells to cancer cells through divalent binding to glypican-3 (GPC3), a cancer-specific antigen, and monovalent binding to CD3, a T-cell antigen.","An anti-CD3 scFv antibody must be linked to only one of the two H chains to achieve the monovalent binding to CD3.In this case, it is necessary to purify the molecule formed via heteromeric association of the two types of H chains.","Thus, using the same method described in Example 3, a substitution mutation of Arg for His at position 435 (EU numbering) was introduced into one of the H chains.","Furthermore, the above mutation was combined with the mutations (a substitution of Lys for Asp at position 356, EU numbering, is introduced into one H chain and a substitution of Glu for Lys at position 439, EU numbering, is introduced into the other H chain) described in WO 2006/106905 (PROCESS FOR PRODUCTION OF POLYPEPTIDE BY REGULATION OF ASSEMBLY) as a modification to enhance the heteromeric association of the two H chains.","The present inventors tested whether it was possible with the combined mutations to purify the molecule of interest by protein A chromatography alone.","Construction of Expression Vectors for Antibody Genes and Expression of Respective Antibodies The gene encoding GPC3 (anti-human Glypican-3 antibody H chain variable region, SEQ ID NO: 22) as an antibody H chain variable region was constructed by a method known to those skilled in the art.","Furthermore, the gene encoding GC33-k0 (anti-human Glypican-3 antibody L chain, SEQ ID NO: 23) as an antibody L chain was constructed by a method known to those skilled in the art.","In addition, the genes described below were constructed as an antibody H chain constant region by a method known to those skilled in the art.","LALA-G1d (SEQ ID NO: 24), which was constructed from IgG1 by substituting Ala for Leu at positions 234 and 235 (EU numbering), and Ala for Asn at position 297 (EU numbering), and deleting the C-terminal Gly and Lys LALA-G1d-CD3 (SEQ ID NO: 25), which was constructed from LALA-Gld by linking an anti-CD3 scFv (in which the anti-human CD3 antibody H chain variable region is linked via a peptide linker to the C terminus of the anti-human CD3 antibody L chain variable region) LALA-G3S3E-G1d (SEQ ID NO: 26), which was constructed from LALA-Gld by substituting Arg for His at position 435 (EU numbering) and Glu for Lys at position 439 (EU numbering); and LALA-S3K-G1d-CD3 (SEQ ID NO: 27), which was constructed from LALA-G1d-CD3 by substituting Lys for Asp at position 356 (EU numbering).","Anti-human GPC3 antibody H chain genes NTA1L and NTA1R were constructed by linking respectively LALA-G1d-CD3 (in which an anti-CD3 scFv antibody is linked to the H chain constant region) and LALA-Gld (an H chain constant region) downstream of GPC3, which is the H chain variable region of an anti-human Glypican-3 antibody.","Furthermore, anti-human GPC3 antibody H chain genes NTA2L and NTA2R were constructed by linking an anti-CD3 scFv antibody downstream of GPC3 as an H chain constant region, and linking LALA-S3K-G1d-CD3 introduced with a substitution mutation of Lys for Asp at position 356 (EU numbering) or LALA-G3S3E-G1d introduced with substitution mutations of Arg for His at position 435 (EU numbering) and of Glu for Lys at position 439 (EU numbering).","The constructed genes were listed below.","H chain NTA1L: GPC3-LALA-G1d-CD3 NTA1R: GPC3-LALA-G1d NTA2L: GPC3-LALA-S3K-G1d-CD3 NTA2R: GPC3-LALA-G3S3E-G1d L chain GC33-k0 Each of the antibody genes (H chains: NTA1L, NTA1R, NTA2L, and NTA2R; L chain: GC33-k0) was inserted into an animal cell expression vector.","Using a method known to those skilled in the art, the antibodies listed below were expressed transiently in FreeStyle293 cells (Invitrogen) by transfecting the cells with the constructed expression vectors.","As shown below, antibodies were named using the combinations of transfected antibody genes (first H chain/second H chain/L chain).","NTA1L/NTA1R/GC33-k0 NTA2L/NTA2R/GC33-k0 Protein Purification of the Expressed Samples and Assessment of Heterodimer Yield Culture supernatants of FreeStyle293 cells (CM) containing the following antibodies were used as a sample.","NTA1L/NTA1R/GC33-k0 NTA2L/NTA2R/GC33-k0 The CM samples were filtered through a filter with a pore size of 0.22 μm, and loaded onto an rProtein A Sepharose Fast Flow column (GE Healthcare) equilibrated with D-PBS.","The column was subjected to washes 1 and 2 and elution 1 as shown in Table 10.The volume of CM to be loaded onto the column was adjusted to 20 mg antibody/ml resin.","Respective fractions eluted under each condition were collected and analyzed by size exclusion chromatography to identify their components.","TABLE 10 Equilibration D-PBS Wash 1 1 mM sodium acetate, 150 mM NaCl, pH 6.5 Wash 2 0.3 mM HCl, 150 mM NaCl, pH 3.7 Elution 1 2 mM HCl, pH 2.7 The result of size exclusion chromatography of each eluted fraction is shown in FIG.","5 and Table 11 below.","The values represent the area of elution peak expressed in percentage.","For NTA1L/NTA1R/GC33-k0 and NTA2L/NTA2R/GC33-k0, the homomeric antibodies (antibodies with homomeric NTA1L or homomeric NTA2L) that have the anti-CD3 scFv antibody in both chains were almost undetectable.","This is thought to be caused by the extremely low expression level of the H chains containing the anti-CD3 scFv antibody because the expression level of an scFv molecule is generally low.","As for homomeric antibodies that do not contain the anti-CD3 scFv antibody in its two chains, about 76% of the NTA1R homomeric antibody was observed in the case of NTA1L/NTA1R/GC33-k0, while only about 2% of the homomeric NTA2R antibody was observed in the case of NTA2L/NTA2R/GC33-k0.Thus, the present invention demonstrated that when the substitution mutations of Lys for Glu at position 356 (EU numbering) and of Glu for Lys at position 439 (EU numbering) for efficient formation of heteromeric molecules from the respective H chains, was combined with the substitution mutation of Arg for His at position 435 (EU numbering), the heteromeric antibody (bispecific antibody of interest) could be efficiently purified to a purity of 98% or higher through the protein A-based purification step alone.","TABLE 11 NTA1R NTA1L/NTA1R NTA1R homodimer heterodimer homodimer NTA1L/NTA1R/GC33-k0 0.7 23.5 75.8 NTA2L/NTA2R/GC33-k0 1.8 98.2 — [Example 9] Introduction of Mutations into the CH3 Domain of Monovalent Antibodies and Preparation of Designed Molecules Through the Protein A-Based Purification Step Alone Introduction of Mutations for the Purification of Monovalent Antibody Molecules Using Protein A An ordinary anti-GPC3 IgG antibody binds divalently via the two H chains to glypican-3 (GPC3), a cancer-specific antigen.","In the experiment described in this Example, the inventors designed and assessed an anti-GPC3 IgG antibody molecule (FIG.","6) that monovalently binds to glypican-3.It is thought that when compared to ordinary divalent antibodies, the monovalent binding of the molecule to glypican-3 (GPC3), a cancer-specific antigen, was based on affinity and not avidity.","Thus, it was expected that the molecule was capable of binding to the antigen without crosslinking.","To achieve the monovalent binding of the two H chains to glypican-3 (GPC3), one has to be an H chain consisting of a hinge-Fc domain that lacks the variable region and CH1 domain, while the other is an ordinary H chain.","In this case, it is necessary to purify the molecule that results from heteromeric association of the two types of H chains.","Thus, using the same method as described in Example 3, a substitution mutation of Arg for His at position 435 (EU numbering) was introduced into one of the H chains.","Furthermore, the above mutation was combined with the mutations (a substitution of Lys for Asp at position 356, EU numbering, is introduced into one H chain and a substitution of Glu for Lys at position 439, EU numbering, is introduced into the other H chain) described in WO 2006/106905 (PROCESS FOR PRODUCTION OF POLYPEPTIDE BY REGULATION OF ASSEMBLY) as a modification to enhance the heteromeric association of the two H chains.","The present inventors assessed whether it was possible with the combined mutations to purify the molecule of interest by protein A chromatography alone.","Construction of Expression Vectors for Antibody Genes and Expression of Respective Antibodies The antibody H chain variable region used was: GPC3 (the H chain variable region of an anti-human Glypican-3 antibody, SEQ ID NO: 22).","The antibody L chain used was: GC33-k0 (the L chain of an anti-human Glypican-3 antibody, SEQ ID NO: 23).","The antibody H chain constant regions used were: LALA-Gld (SEQ ID NO: 24), which was constructed from IgG1 by introducing substitution mutations of Ala for Leu at positions 234 and 235 (EU numbering), and of Ala for Asn at position 297 (EU numbering), and deleting the C-terminal Gly and Lys; LALA-G3-G1d (SEQ ID NO: 28), which was constructed from LALA-Gld by introducing a substitution mutation of Arg for His at position 435 (EU numbering); LALA-G3S3E-G1d (SEQ ID NO: 26), which was constructed from LALA-G3-G1d by introducing a substitution mutation of Glu for Lys at position 439 (EU numbering); LALA-G1Fc (SEQ ID NO: 29), which was constructed from LALA-Gld by deleting the region of positions 1 to 215 (EU numbering); and LALA-G1Fc-S3K (SEQ ID NO: 30), which was constructed from G1Fc by introducing a substitution mutation of Lys for Asp at position 356 (EU numbering).","Anti-human GPC3 antibody H chain genes NTA4L-cont, NTL4L-G3, and NTA4L were constructed by linking downstream of GPC3 (the H chain variable region of an anti-human Glypican-3 antibody), respectively, LALA-Gld (an H chain constant region), LALA-G3-Gld introduced with a substitution mutation of Arg for His at position 435 (EU numbering), and LALA-G3S3E-Gld introduced with substitution mutations of Arg for His at position 435 (EU numbering) and of Glu for Lys at position 439 (EU numbering).","Furthermore, Fc genes NTA4R-cont and NTA4R were constructed by using LALA-G1Fc (an anti-human hinge Fc domain) and LALA-G1Fc-S3K (a hinge Fc domain introduced with a substitution mutation of Lys for Asp at position 356, EU numbering).","The constructed genes are: H chain NTA4L-cont: GPC3-LALA-G1 d NTA4L-G3: GPC3-LALA-G3-Gld NTA4L: GPC3-LALA-G3S3E-Gld NTA4R-cont: LALA-G1Fc NTA4R: LALA-G1Fc-S3K L chain GC33-k0 The antibody genes (NTA4L, NTA4L-cont, NTA4L-G3, NTA4R, NTA4R-cont, and GC33-k0) were each inserted into an animal cell expression vector.","The following antibodies were expressed transiently in FreeStyle293 cells (Invitrogen) by transfection using the constructed expression vectors.","As shown below, antibodies were named using the combinations of transfected antibody genes.","NTA4L-cont/NTA4R-cont/GC33-k0 NTA4L-G3/NTA4R-cont/GC33-k0 NTA4L/NTA4R/GC33-k0 Protein Purification of Expressed Samples and Assessment of Heterodimer Yield CM containing the following antibody was used as a sample: NTA4L-cont/NTA4R-cont/GC33-k0 NTA4L-G3/NTA4R-cont/GC33-k0 NTA4L/NTA4R/GC33-k0 The CM samples were filtered through a filter with a pore size of 0.22 μm, and loaded onto an rProtein A Sepharose Fast Flow column (GE Healthcare) equilibrated with D-PBS.","The column was subjected to washes 1 and 2 and elution 1 as shown in Table 12.The volume of CM to be loaded onto the column was adjusted to 20 mg antibody/ml resin.","Respective fractions eluted under each condition were collected and analyzed by size exclusion chromatography to identify their components.","TABLE 12 Equilibration D-PBS Wash 1 1 mM sodium acetate, 150 mM NaCl, pH 6.5 Wash 2 0.3 mM HCl, 150 mM NaCl, pH 3.7 Elution 1 2 mM HCl, pH 2.7 The result of size exclusion chromatography analysis of each eluted fraction is shown in FIG.","7 and Table 13 below.","The values represent the area of elution peak expressed in percentage.","As for NTA4L-cont/NTA4R-cont/GC33-k0, the homomeric antibody that divalently binds to GPC3 (homomeric antibody NTA4L-cont) and the homomeric molecule that has no GPC3-binding domain (homomeric antibody NTA4R-cont) were eluted, while the heteromeric antibody of interest, NTA4L-cont/NTA4R-cont, accounted for only 46.5%.","In the case of NTA4L-G3/NTA4R-cont/GC33-k0, the homomeric antibody that divalently binds to GPC3 (homomeric antibody NTA4L-G3) was almost undetectable, while the homomeric molecule having no GPC3-binding domain (homomeric antibody NTA4R-cont) was abundant.","The heteromeric antibody of interest, NTA4L-G3/NTA4R-cont, accounted for 66.7%.","In the case of NTA4L/NTA4R/GC33-k0, the homomeric antibody that divalently binds to GPC3 (homomeric antibody NTA4L) was almost undetectable, and the proportion of the homomeric molecule having no GPC3-binding domain (NTA4R) was considerably reduced, resulting in a significant increase of up to 93.0% in the proportion of the heteromeric antibody of interest, NTA4L/NTA4R.","Thus, the present invention demonstrated that when the substitution mutations of Lys for Asp at position 356 (EU numbering) and of Glu for Lys at position 439 (EU numbering) for efficient formation of heteromeric molecules from the respective H chains were introduced in combination with the substitution mutation of Arg for His at position 435 (EU numbering), the heteromeric antibody (a bispecific antibody of interest) could be efficiently purified to a purity of 93% or higher through the protein A-based purification step alone.","TABLE 13 Homomeric Hetero- Homomeric anti-GPC3 meric Fc antibody antibody molecule NTA4L-cont/NTA4R-cont/GC33-k0 30.0 46.5 23.5 NTA4L-63/NTA4R-cont/GC33-k0 — 66.7 33.3 NTA4L/NTA4R/GC33-k0 — 93.0 7.0 [Example 10] Preparation of Heteromeric Antibodies Through a Purification Step by Protein A Column Chromatography Using pH Gradient Elution As described in Example 9, the present inventors demonstrated that in the case of an antibody having the variable region only at one arm, the heteromeric antibody could be efficiently purified through the protein A-based purification step alone by combining the substitution mutation of Arg for His at position 435 (EU numbering) with the mutations (a substitution of Lys for Asp at position 356, EU numbering, is introduced into one H chain and a substitution of Glu for Lys at position 439, EU numbering, is introduced into the other H chain) described in WO 2006/106905 (PROCESS FOR PRODUCTION OF POLYPEPTIDE BY REGULATION OF ASSEMBLY).","However, the heteromeric antibody is not purified to a sufficiently high purity with elution 1 (elution buffer: 2 mM HCl, pH 2.7) alone.","An additional purification step is needed.","Then, in this Example, the present inventors assessed whether the heteromeric antibody can be isolated and purified to high purity by protein A column chromatography using elution with a pH gradient.","This was based on the assumption that more protein A-binding sites lead to stronger binding of the heteromeric antibody to protein A, and as a result lower pH is required for elution.","Purification can be achieved more efficiently at a lower cost when the purity of the heteromeric antibody can be increased to almost 100% by using such pH gradient elution.","CM samples containing the following antibodies were used: NTA4L-cont/NTA4R-cont/GC33-k0 NTA4L-G3/NTA4R-cont/GC33-k0 NTA4L/NTA4R/GC33-k0 The CM samples were filtered through a filter with a pore size of 0.22 μm, and loaded onto a HiTrap protein A HP column (GE Healthcare) equilibrated with D-PBS.","The column was sequentially subjected to washes 1 and 2, and then elution with a pH gradient using elution A and B as shown in Table 14.The pH gradient elution was achieved with the following linear gradient: elution A/elution B=(100:0)→(30:70) for 35 minutes.","Eluted fractions were collected and analyzed by size exclusion chromatography analysis to identify their components.","TABLE 14 Equilibration D-PBS Wash 1 D-PBS Wash 2 20 mM NaCitrate, pH 5.0 Elution A 20 mM NaCitrate, pH 5.0 Elution B 20 mM NaCitrate, pH 2.7 NTA4L-cont/NTA4R-cont/GC33-k0, NTA4L-G3/NTA4R-cont/GC33-k0, and NTA4L/NTA4R/GC33-k0 were purified by protein A column chromatography under the pH gradient elution condition.","The resulting chromatograms are shown in FIG.","8.The elution of NTA4L-cont/NTA4R-cont/GC33-k0 resulted in a broad peak.","Meanwhile, the pH gradient elution of NTA4L-G3/NTA4R-cont/GC33-k0 gave two elution peaks.","The peaks of high and low pHs were labeled as “elution 1” and “elution 2”, respectively.","The result for NTA4L/NTA4R/GC33-k0 was roughly the same as that for NTA4L-G3/NTA4R-cont/GC33-k0, except that the peak area of elution 2 was smaller.","The result of size exclusion chromatography analysis of each peak is shown in Table 15.NTA4L-cont/NTA4R-cont/GC33-k0 gave three components eluted in this order: a homomeric antibody that divalently binds to GPC3 (homomeric antibody NTA4L-cont), a heteromeric antibody that monovalently binds to GPC3 (heteromeric antibody NTA4L-cont/NTA4R-conc), and a homomeric molecule having no GPC3-binding domain (homomeric antibody NTA4R-cont).","It is thought that the reason why these components were not separated by pH gradient elution is that they have the same number (two) of protein A-binding sites.","Meanwhile, it was revealed that in elution 1 of NTA4L-G3/NTA4R-cont/GC33-k0, the levels of homomeric antibody that divalently binds to GPC3 (homomeric antibody NTA4L-G3) and homomeric molecule having no GPC3-binding domain (homomeric antibody NTA4R-cont) were below the detection limit, while the heteromeric antibody that monovalently binds to GPC3 (NTA4L-G3/NTA4R-conc heteromeric antibody) accounted for 99.6%.","In elution 2, the homomeric molecule having no GPC3-binding domain (homomeric antibody NTA4R-cont) was found to account for 98.8%.","The homomeric antibody NTA4L-G3 passes through the protein A column because it cannot bind to protein A due to the substitution mutation of Arg for His at position 435 (EU numbering).","Meanwhile, the heteromeric antibody NTA4L-G3/NTA4R-conc has a single protein A-binding site, while the homomeric antibody NTA4R-cont has two.","More protein A-binding sites means stronger protein A binding, and as a result lower pH was required for elution.","This is thought to be the reason why homomeric antibody NTA4R-cont was eluted at a lower pH than heteromeric antibody NTA4L-G3/NTA4R-conc.","Almost the same result was obtained for NTA4L/NTA4R/GC33-k0.The result of size exclusion chromatography analysis shows that the component ratio was comparable to that of NTA4L-G3/NTA4R-cont/GC33-k0.There was a difference between the protein A chromatograms, and the peak area ratio of elution 2 to elution 1 was smaller in NTA4L/NTA4R/GC33-k0.The expression ratio of the homomeric antibody NTA4R-cont, which is the major component of elution 2, was reduced due to the mutations introduced for efficient generation of the heteromeric antibody NTA4L-G3/NTA4R-conc.","The amino acid mutations described above improved the purification yield of the heteromeric antibody and the robustness of purification by protein A column chromatography with pH gradient elution.","As described above, the present inventors demonstrated that the heteromeric antibody could be efficiently isolated and purified to high purity through the purification step using protein A column chromatography alone with pH gradient elution.","TABLE 15 Homomeric Homomeric antibody Heteromeric molecule that antibody that having no divalently monovalently GPC3- binds to binds to binding Peak area (%) GPC3 GPC3 domain NTA4L-cont/NTA4R-cont/GC33-k0 Elution 25.4 54.4 20.2 NTA4L-G3/NTA4R-cont/GC33-k0 Elution 1 ND 99.6 ND Elution 2 — 1.2 98.8 NTA4L/NTA4R/GC33-k0 Elution 1 ND 99.6 ND Elution 2 — 1.4 98.6 [Example 11] Introduction of Mutation into the CH3 Domain of Monovalent Fcalpha Receptor-Fc Fusion Protein and Preparation of Designed Molecules Through the Protein A-Based Purification Step Alone Introduction of Mutation into CH3 Domain and Preparation of Monovalent Fcalpha Receptor-Fc Fusion Protein Through the Protein A-Based Purification Step Conventional Fc receptor-Fc fusion proteins such as Eternercept and Abatacept are homodimers that can divalently bind to ligands.","In the experiment described in this Example, the inventors designed and assessed an Fc receptor-Fc fusion protein that monovalently binds to IgA as a ligand (FIG.","9).","To achieve the monovalent binding of the Fcalpha receptor to IgA, one of the two Fc receptor-Fc fusion protein H chains must be the whole H chain having the hinge-Fc domain.","In this case, it is necessary to purify the molecule that results from heteromeric association of the two types of H chains Thus, using the same method described in Example 6, a substitution mutation of Arg for His at position 435 (EU numbering) was introduced into one of the two H chains.","Furthermore, the above mutation was combined with the mutations (a substitution of Lys for Asp at position 356, EU numbering, is introduced into one H chain and a substitution of Glu for Lys at position 439, EU numbering is introduced into the other H chain) described in WO 2006/106905 (PROCESS FOR PRODUCTION OF POLYPEPTIDE BY REGULATION OF ASSEMBLY) as a modification to enhance the heteromeric association of the two types of H chains.","The present inventors assessed whether it was possible with the combined mutations to purify the molecule of interest by protein A chromatography alone.","Construction of Expression Vectors for Antibody Genes and Expression of Respective Antibodies The Fc receptor used was FcalphaR (human IgA1 receptor, SEQ ID NO: 31).","The fusion H chain constant regions used were: G1Fc (SEQ ID NO: 32), which is a human hinge-Fc domain constructed from IgG1 by deleting the C-terminal Gly and Lys, and residues of positions 1 to 223 (EU numbering); G1Fc-G3S3K (SEQ ID NO: 33), which was constructed from G1Fc by introducing substitution mutations of Lys for Asp at position 356 (EU numbering) and of Arg for His at position 435 (EU numbering); and G1Fc-S3E (SEQ ID NO: 34), which was constructed from G1Fc by introducing a substitution mutation of Glu for Lys at position 439 (EU numbering).","FcalphaR-Fc fusion proteins IAL-cont and IAL were constructed by linking downstream of FcalphaR via a polypeptide linker (SEQ ID NO: 35), G1Fc (an H chain constant region) and G1Fc-G3S3K introduced with substitution mutations of Lys for Asp at position 356 (EU numbering) and of Arg for His at position 435 (EU numbering).","Furthermore, Fc genes IAR-cont and IAR were constructed to encode G1Fc (a human hinge-Fc domain) and G1Fc-S3E (a hinge Fc domain introduced with a substitution mutation of Glu for Lys at position 439, EU numbering), respectively.","The constructed genes were: H chain IAL-cont: FcalphaR-G1Fc IAL: FcalphaR-G1Fc-G3S3K IAR-cont: G1Fc IAR: G1Fc-S3E The antibody genes (IAL-cont, IAL, IAR-cont, and IAR) were each inserted into an animal cell expression vector.","The following antibodies were expressed transiently in FreeStyle293 cells (Invitrogen) by transfection using the constructed expression vectors.","As shown below, antibodies were named using the combinations of transfected antibody genes.","IAL-cont/IAR-cont IAL/IAR Protein Purification of Expressed Sample and Assessment of Heterodimer Yield CM samples containing the following antibody were used: IAL-cont/IAR-cont IAL/IAR The CM samples were filtered through a filter with a pore size of 0.22 μm, and loaded onto an rProtein A Sepharose Fast Flow column (GE Healthcare) equilibrated with D-PBS.","The column was subjected to washes 1 and 2 and elution 1 as shown in Table 16.The volume of CM to be loaded onto the column was adjusted to 20 mg antibody/ml resin.","Respective fractions eluted under each condition were collected and analyzed by size exclusion chromatography to identify their components.","TABLE 16 Equilibration D-PBS Wash 1 1 mM sodium acetate, 150 mM NaCl, pH 6.5 Wash 2 0.3 mM HCl, 150 mM NaCl, pH 3.7 Elution 1 2 mM HCl, pH 2.7 The result of size exclusion chromatography analysis of each eluted fraction is shown in FIG.","10 and Table 17 below.","The values represent the area of elution peak expressed in percentage.","As for IAL-cont/IAR-cont, a homomeric antibody that divalently binds to IgA (homomeric antibody IAL-cont) and a homomeric molecule having no IgA-binding site (homomeric antibody IAR-cont) were eluted, while the heteromeric antibody IAL-cont/IAR-cont of interest accounted for only 30%.","In the case of IAL/IAR, the homomeric antibody that divalently binds to IgA (homomeric antibody IAL) was not detectable, and the proportion of the homomeric molecule having no IgA-binding site (homomeric antibody IAR) was considerable reduced; thus, the heteromeric antibody IAL/IAR of interest was significantly increased up to about 96%.","Thus, the present invention demonstrated that when the substitution mutations of Lys for Asp at position 356 (EU numbering) and of Glu for Lys at position 439 (EU numbering) for efficient formation of heteromeric molecules from the respective H chains were introduced in combination with the substitution mutation of Arg for His at position 435 (EU numbering), the heteromeric antibody, a bispecific antibody of interest, could be efficiently purified to a purity of 95% or higher through the protein A-based purification step alone.","TABLE 17 Homomeric Heteromeric Homomeric IgA antibody antibody Fc molecule IAL-cont/IAR-cont 66.2% 30.0% 3.8% IAL/IAR — 95.8% 4.2% [Example 12] Construction of a Bispecific Antibody of the Four-Chain IgG Type Construction of Expression Vectors for Antibody Genes and Expression of Respective Antibodies The bispecific antibody against human F.IX and human F.X, which was designed as described in Example 1, consists of a common L chain and two types of H chains that each recognizes a different antigen.","Obtaining a bispecific antibody with such a common L chain is not easy, because it is difficult for a common L chain sequence to recognize two different types of antigens.","As described above, obtaining such a common L chain is extremely difficult.","Thus, one may suspect that a more preferred option is a bispecific antibody consisting of two types of H chains and two types of L chains that recognize two types of antigens.","If two types of H chains and two types of L chains are expressed, they form ten types of H2L2 IgG molecules in random combinations.","It is very difficult to purify the bispecific antibody of interest from the ten types of antibodies.","In the experiment described in this Example, the present inventors prepared and assessed bispecific antibodies consisting of two types of H chains and two types of L chains against human IL-6 receptor and human glypican-3 (GPC3).","To efficiently prepare bispecific antibodies consisting of two types of H chains and two types of L chains, it is necessary to enhance the association of H chains and L chains against the same antigen as well as the heteromeric association of two types of H chains.","In addition, it is essential that the bispecific antibody with the right combination can be purified from the obtained expression products.","To enhance the association between H chains and L chains against the same antigen, the variable region (VH) of H chain (GC33-VH-CH1-hinge-CH2-CH3) and the variable region (VL) of L chain (GC33-VL-CL) of GC33 (an anti-GPC3 antibody) were swapped with each other to produce H chain GC33-VL-CH1-hinge-CH2-CH3 and L chain (GC33-VH-CL) (the VH domain and VL domain were exchanged with each other).","GC33-VL-CH1-hinge-CH2-CH3 is associated with GC33-VH-CL; however, its association with the L chain (MRA-VL-CL) of the anti-IL-6 receptor antibody is inhibited due to the instability of VL/VL interaction.","Likewise, the H chain (MRA-VH-CH1-hinge-CH2-CH3) of the anti-IL-6 receptor antibody is associated with MRA-VL-CL; however, its association with the L chain (GC33-VH-CL) of the anti-GPC3 antibody is inhibited due to the instability of VH/VH interaction.","As described above, it is possible to enhance the association between H chains and L chains against the same antigen.","However, the VH/VH interaction and VL/VL interaction also occur although they are less stable than the VH/VL interaction (for VH/VH, see: FEBS Lett.","2003 Nov. 20, 554(3):323-9; J Mol Biol.","2003 Oct. 17, 333(2):355-65; for VL/VL, see: J Struct Biol.","2002 June, 138(3):171-86; Proc Natl Acad Sci USA.","1985 July, 82(14):4592-6), and thus although infrequently, unfavorable self association of H chains and L chains also occurs.","Hence, although the percentage of the bispecific antibody of interest is increased by simply swapping the VH domain and VL domain with each other, the expressed products still contain about ten types of combinations.","In general, it is extremely difficult to purify the bispecific antibody of interest from the ten types.","However, it is possible to improve the separation of the ten types of components in ion exchange chromatography by introducing a modification so that the ten types of components each have a different isoelectric point.","In this context, MRA-VH, which is the H chain variable region of an anti-IL-6 receptor antibody, was modified to lower the isoelectric point, and this yielded H54-VH with a lower isoelectric point.","In the same manner, MRA-VL, which is the L chain variable region of an anti-IL-6 receptor antibody, was modified to lower the isoelectric point, and this yielded L28-VL with a lower isoelectric point.","Furthermore, GC33-VH, which is the H chain variable region of an anti-GPC3 antibody, was modified to increase the isoelectric point.","This yielded Hu22-VH with an increased isoelectric point.","The combination of the H and L chains of interest was improved by swapping the VH and VL between the H chains and L chains of an anti-GPC3 antibody.","However, although infrequently, the unfavorable H chain/L chain association occurs because it is impossible to completely suppress the H54-VH/Hu22-VH interaction and L28-VL/GC33-VL interaction.","An ordinary antibody sequence has glutamine at position 39 in VH.","In VH/VH interaction, glutamines are believed to form hydrogen bonds at the VH/VH interface.","Then, lysine was substituted for the glutamine at position 39 (Kabat numbering) to impair the H54-VH/Hu22-VH interaction.","The VH/VH interaction was thus expected to be significantly impaired due to the electrostatic repulsion between two lysines at the VH/VH interface.","Next, H54-VH-Q39K and Hu22-VH-Q39K were constructed by substituting lysine for the glutamine at position 39 (Kabat numbering) in the sequences of H54-VH and Hu22-VH.","Likewise, an ordinary antibody sequence has glutamine at position 38 in VL.","In the VL/VL interaction, glutamines are expected to form hydrogen bonds at the VL/VL interface.","Then, glutamic acid was substituted for the glutamine at position 38 (Kabat numbering) to impair the L28-VL/GC33-VL interaction.","The VL/VL interaction was thus expected to be significantly impaired due to the electrostatic repulsion between two glutamic acids at the VL/VL interface.","Next, L28-VL-Q38E and GC33-VL-Q38E were constructed by substituting glutamic acid for the glutamine at position 39 (Kabat numbering) in the sequences of L28-VL and GC33-VL.","To further improve the efficiency of expression/purification of the bispecific antibody of interest, a substitution mutation of Arg for His at position 435 (EU numbering) was introduced into one H chain using the same method described in Example 3.Furthermore, the above mutation was combined with the mutations (a substitution of Lys for Asp at position 356, EU numbering, is introduced into one H chain and a substitution of Glu for Lys at position 439, EU numbering, is introduced into the other H chain) described in WO 2006/106905 (PROCESS FOR PRODUCTION OF POLYPEPTIDE BY REGULATION OF ASSEMBLY) as a modification to enhance the heteromeric association of the two types of H chains.","The combined mutations enable purification of the molecule resulting from heteromeric association of the two types of H chains by protein A chromatography alone.","Specifically, the antibody H chain variable regions used were: MRA-VH (the H chain variable region of an anti-human interleukin-6 receptor antibody, SEQ ID NO: 36); GC33-VH (the H chain variable region of an anti-GPC3 antibody, SEQ ID NO: 37); H54-VH (the H chain variable region of an anti-human interleukin-6 receptor antibody, SEQ ID NO: 38) with an isoelectric point lower than that of MRA-VH; Hu22-VH (the H chain variable region of an anti-GPC3 antibody, SEQ ID NO: 39) with an isoelectric point higher than that of GC33-VH; H54-VH-Q39K (SEQ ID NO: 40) where Lys is substituted for Gln at position 39 (Kabat numbering) in the sequence of H54-VH; and Hu22-VH-Q39K (SEQ ID NO: 41) where Lys is substituted for Gln at position 39 in the sequence of Hu22-VH.","The following antibody H chain constant regions were also used: IgG1-LALA-N297A-CH (SEQ ID NO: 42) where Ala is substituted for Leu at positions 234 and 235 (EU numbering), and Ala is substituted for Asn at position 297 (EU numbering), and the C-terminal Gly and Lys is deleted in the sequence of the H chain constant region of IgG1; IgG1-LALA-N297A-CHr (SEQ ID NO: 43) where the sequence of IgG1-LALA-N297A-CH has extra two residues of Ser at the N terminus; IgG1-LALA-N297A-s3-CH (SEQ ID NO: 44) where Glu is substituted for Lys at position 439 (EU numbering) in the sequence of IgG1-LALA-N297A-CH; and IgG1-LALA-N297A-G3s3-CHr (SEQ ID NO: 45) where Lys is substituted for Asp at position 356 (EU numbering) and Arg is substituted for His at position 435 (EU numbering) in the sequence of IgG1-LALA-N297A-CHr.","Meanwhile, the antibody L chain variable regions used were: MRA-VL (the L chain variable region of an anti-human interleukin-6 receptor antibody, SEQ ID NO: 46); GC33-VL (the L chain variable region of an anti-GPC3 antibody, SEQ ID NO: 47); L28-VL (the L chain variable region of an anti-human interleukin-6 receptor antibody, SEQ ID NO: 48) with an isoelectric point lower than that of MRA-VL; L28-VL-Q38E (SEQ ID NO: 49) where Glu is substituted for Gln at position 38 (Kabat numbering) in the sequence of L28-VL; and GC33-VL-Q38E (SEQ ID NO: 50) where Glu is substituted for Gln at position 38 (Kabat numbering) in the sequence of GC33-VL.","The following antibody L chain constant regions were also used.","IgG1-CL (the L chain constant region of IgG1, SEQ ID NO: 51).","IgG1-CLr (SEQ ID NO: 52), which was constructed by substituting Arg and Thr for the C-terminal Ala and Ser, respectively, in the sequence of IgG1-CL.","Gene no1-Mh-H was constructed by linking IgG1-LALA-N297A-CH downstream of MRA-VH.","Gene no1-Mh-L was constructed by linking IgG1-CL downstream of MRA-VL.","Gene no1-Gh-H was constructed by linking IgG1-LALA-N297A-CH downstream of GC33-VH.","Gene no1-Gh-L was constructed by linking IgG1-CL downstream of GC33-VL.","Gene no2-Gh-H was constructed by linking IgG1-LALA-N297A-CHr downstream of GC33-VL.","Gene no2-Gh-L was constructed by linking IgG1-CLr downstream of GC33-VH.","Gene no3-Ml-H was constructed by linking IgG1-LALA-N297A-CH downstream of H54-VH.","Gene no3-Ml-L was constructed by linking IgG1-CL downstream of L28-VL.","Gene no3-Ghh-L was constructed by linking IgG1-CLr downstream of Hu22-VH.","Gene no5-Ml-H was constructed by linking IgG1-LALA-N297A-s3-CH downstream of H54-VH.","Gene no5-Gh-H was constructed by linking IgG1-LALA-N297A-G3s3-CHr downstream of GC33-VL.","Gene no6-Ml-H was constructed by linking IgG1-LALA-N297A-s3-CH downstream of H54-VH-Q39K.","Gene no6-Ml-L was constructed by linking IgG1-CL downstream of L28-VL-Q38E.","Gene no6-Gh-H was constructed by linking IgG1-LALA-N297A-G3s3-CHr downstream of GC33-VL-Q38E.","Gene no6-Ghh-L was constructed by linking IgG1-CLr downstream of Hu22-VH-Q39K.","Respective genes (no1-Mh-H, no1-Mh-L, no1-Gh-H, no1-Gh-L, no2-Gh-H, no2-Gh-L, no3-Ml-H, no3-Ml-L, no3-Ghh-L, no5-Ml-H, no5-Gh-H, no6-Ml-H, no6-Ml-L, no6-Gh-H, and no6-Ghh-L) were inserted into animal cell expression vectors.","The following combinations of expression vectors were introduced into FreeStyle293-F cells to transiently express each designed molecule.","A.","Designed Molecule: No1 (FIG.","11) Description: natural anti-IL-6 receptor/anti-GPC3 bispecific antibody.","Polypeptides encoded by polynucleotides inserted into the expression vector: no1-Mh-H (SEQ ID NO: 53), no1-Mh-L (SEQ ID NO: 54), no1-Gh-H (SEQ ID NO: 55), and no1-Gh-L (SEQ ID NO: 56).","B.","Designed Molecule: No2 (FIG.","12) Description: constructed from no1 by swapping the VH and VL domains of the anti-GPC3 antibody.","Polypeptides encoded by polynucleotides inserted into the expression vector: no1-Mh-H, no1-Mh-L, no2-Gh-H (SEQ ID NO: 57), and no2-Gh-L (SEQ ID NO: 58).","C. Designed Molecule: No3 (FIG.","13) Description: constructed from no2 by introducing modifications to each chain to alter its isoelectric point.","Polypeptides encoded by polynucleotides inserted into the expression vector: no3-Ml-H (SEQ ID NO: 59), no3-Ml-L (SEQ ID NO: 60), and no2-Gh-H, and no3-Ghh-L (SEQ ID NO: 61).","D. Designed Molecule: No5 (FIG.","14) Description: constructed from no3 by introducing a modification to enhance heteromeric H chain association and a modification that enables protein A-based purification of antibody generated via heteromeric association.","Polypeptides encoded by polynucleotides inserted into the expression vector: no5-Ml-H (SEQ ID NO: 62), no3-Ml-L, no5-Gh-H (SEQ ID NO: 63), and no3-Ghh-L. E. Designed Molecule: No6 (FIG.","15) Description: constructed from no5 by introducing a modification to enhance the association between an H chain of interest and an L chain of interest.","Polypeptides encoded by polynucleotides inserted into the expression vector: no6-Ml-H (SEQ ID NO: 64), no6-Ml-L (SEQ ID NO: 65), no6-Gh-H (SEQ ID NO: 66), and no6-Ghh-L (SEQ ID NO: 67).","Culture supernatants filtered through a filter with a pore size of 0.22 μm were loaded onto rProtein A Sepharose Fast Flow resin (GE Healthcare) equilibrated with the medium.","The resin was eluted in a batchwise manner to purify the molecules.","Since protein G binds to the Fab domain of an antibody, all antibody species in CM can be purified with protein G regardless of the affinity for protein A.","The designed antibodies (no1, no2, no3, no5, and no6) were assessed for their expression by cation exchange chromatography (IEC) using a ProPac WCX-10 column (Dionex), an analytical column.","Cation exchange chromatography was performed at a flow rate of 0.5 ml/min with an adequate gradient using mobile phase A (20 mM MES-NaOH, pH 6.1) and mobile phase B (20 mM MES-NaOH, 250 mM NaCl, pH 6.1).","The result of IEC assessment of each antibody is shown in FIG.","16.Natural anti-IL-6 receptor/anti-GPC3 bispecific antibody no1 gave a number of peaks in close proximity to each other.","It was impossible to determine which peak corresponds to the bispecific antibody of interest.","The same applied to no2 which results from swapping the VH domain and VL domain of the anti-GPC3 antibody in no1.The peak for the bispecific antibody of interest could be isolated for the first time in no3 which was modified from no2 by introducing a modification to alter the isoelectric point of each chain of no2.The proportion of the peak corresponding to the bispecific antibody of interest was significantly increased in no5 which was constructed from no3 by introducing a modification to enhance the H-chain heteromeric association and a modification that allows for protein A-based purification of the antibody generated via heteromeric association.","The proportion of the peak corresponding to the bispecific antibody of interest was further increased in no6 which was constructed from no5 by introducing a modification that enhances the association between the H chain and L chain of interest.","Then, the present inventors assessed whether the bispecific antibody of interest could be purified from no6 CM to high purity using a purification column.","CM samples were filtered through a filter with a pore size of 0.22 μm and loaded onto a HiTrap protein A HP column (GE Healthcare) equilibrated with D-PBS.","The column was sequentially subjected to washes 1 and 2 and elution with a pH gradient using elution A and B as shown in Table 18.The pH gradient during elution was achieved with the following linear gradient: elution A/elution B=(100:0)->(35:65) for 40 minutes.","TABLE 18 Equilibration D-PBS Wash 1 D-PBS Wash 2 20 mM NaCitrate, pH 5.0 Elution A 20 mM NaCitrate, pH 5.0 Elution B 20 mM NaCitrate, pH 2.7 The result of pH gradient elution of No6 is shown in FIG.","17.The homomeric antibody having the H chain of the anti-GPC3 antibody which was incapable of binding to protein A passed through protein A; the first elution peak corresponded to the heteromeric antibody having the H chain of the anti-GPC3 antibody and the H chain of the anti-IL-6 receptor antibody; and the second elution peak corresponded to the homomeric antibody having the H chains of the anti-IL-6 receptor antibody.","Thus, the present inventors demonstrated that by substituting Arg for His at position 435 (EU numbering), the heteromeric antibody having the H chain of the anti-GPC3 antibody and the H chain of the anti-IL-6 receptor antibody could be purified by the protein A-based purification step alone.","The first elution fraction was loaded onto a HiTrap SP Sepharose HP column (GE Healthcare) equilibrated with 20 mM sodium acetate buffer (pH 5.5).","After washing with the same buffer, the column was eluted with a NaCl concentration gradient of 0 to 500 mM.","The resulting main peak was analyzed by cation exchange chromatography in the same manner as described above.","The result is shown in FIG.","18.The bispecific antibody of interest was demonstrated to be purified to a very high purity.","INDUSTRIAL APPLICABILITY The present invention provides efficient methods based on alteration of the protein A-binding ability, for producing or purifying to a high purity polypeptide multimers (multispecific antibodies) having the activity of binding to two or more types of antigens through the protein A-based purification step alone.","By using the methods of the present invention, polypeptide multimers of interest can be efficiently produced or purified to high purity without loss of other effects produced by amino acid mutations of interest.","In particular, when the methods are combined with a method for controlling the association between two types of protein domains, polypeptide multimers of interest can be more efficiently produced or purified to a higher purity."]],"string":"[\n [\n \"POLYPEPTIDE MODIFICATION METHOD FOR PURIFYING POLYPEPTIDE MULTIMERS\",\n \"The present invention provides efficient methods based on alteration of the protein A-binding ability, for producing or purifying multispecific antibodies having the activity of binding to two or more types of antigens to high purity through a protein A-based purification step alone.\",\n \"The methods of the present invention for producing or purifying multispecific antibodies which feature altering amino acid residues of antibody heavy chain constant region and/or variable region.\",\n \"Multispecific antibodies with an altered protein A-binding ability, which exhibit plasma retention comparable or longer than that of human IgG1, can be efficiently prepared in high purity by introducing amino acid alterations of the present invention into antibodies.\"\n ],\n [\n \"1.A method for producing a polypeptide multimer that comprises a first polypeptide having an antigen-binding activity and a second polypeptide having an antigen-binding activity or no antigen-binding activity, which comprises the steps of: (a) expressing a DNA that encodes the first polypeptide having an antigen-binding activity and a DNA that encodes the second polypeptide having an antigen-binding activity or no antigen-binding activity; and (b) collecting the expression product of step (a), wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.\",\n \"2.The method of claim 1, wherein the expression product is collected using protein A affinity chromatography in step (b).\",\n \"3.The method of claim 1, wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so that there is a larger difference between the solvent pH for eluting the first polypeptide having an antigen-binding activity from protein A and that for eluting the second polypeptide having an antigen-binding activity or no antigen-binding activity from protein A.\",\n \"4.The method of claim 1, wherein one or more amino acid residues in the first polypeptide having an antigen-binding activity or the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so as to increase or reduce the protein A-binding ability of either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.\",\n \"5.The method of claim 1, wherein one or more amino acid residues in the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so as to increase the protein A-binding ability of either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity, and reduce the protein A-binding ability of the other polypeptide.\",\n \"6.The method of claim 1, wherein the purity of the collected polypeptide multimer is 95% or more.\",\n \"7.The method of claim 1, wherein the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity comprise an amino acid sequence of an antibody Fc domain or an amino acid sequence of an antibody heavy-chain constant region.\",\n \"8.The method of claim 7, wherein at least one amino acid residue selected from the amino acid residues of positions 250 to 255, 308 to 317, and 430 to 436 (EU numbering) in the amino acid sequence of the antibody Fc domain or antibody heavy-chain constant region has been modified.\",\n \"9.The method of claim 1, wherein the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity comprise an amino acid sequence of an antibody heavy-chain variable region.\",\n \"10.The method of claim 9, wherein at least one amino acid residue has been modified in the amino acid sequences of FR1, CDR2, and FR3 of the antibody heavy-chain variable region.\",\n \"11.The method of claim 1, wherein the polypeptide multimer comprises one or two third polypeptides having an antigen-binding activity, and step (a) comprises expressing a DNA that encodes the third polypeptide having an antigen-binding activity.\",\n \"12.The method of claim 11, wherein the third polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.\",\n \"13.The method of claim 11, wherein the polypeptide multimer additionally comprises a fourth polypeptide having an antigen-binding activity, and step (a) comprises expressing a DNA that encodes the fourth polypeptide having an antigen-binding activity.\",\n \"14.The method of claim 13, wherein at least one of the third and fourth polypeptides having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.\",\n \"15.The method of claim 13, wherein the first polypeptide having an antigen-binding activity comprises amino acid sequences of an antibody light-chain variable region and an antibody heavy-chain constant region; the second polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody heavy chain; the third polypeptide having an antigen-binding activity comprises amino acid sequences of an antibody heavy-chain variable region and an antibody light-chain constant region; and the fourth polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.\",\n \"16.The method of claim 1, wherein the polypeptide multimer is a multispecific antibody.\",\n \"17.The method of claim 16, wherein the multispecific antibody is a bispecific antibody.\",\n \"18.The method of claim 1, which comprises the first polypeptide having an antigen-binding activity and the second polypeptide having no antigen-binding activity, and wherein the first polypeptide having an antigen-binding activity comprises an amino acid sequence of an antigen-binding domain of a receptor and an amino acid sequence of an antibody Fc domain, and the second polypeptide having no antigen-binding activity comprises an amino acid sequence of an antibody Fc domain.\",\n \"19.\",\n \"(canceled) 20.A polypeptide multimer produced by the method of claim 1.21.-36.\",\n \"(canceled) 37.A polypeptide multimer that comprises a first polypeptide having an antigen-binding activity and a second polypeptide having an antigen-binding activity or no antigen-binding activity, wherein the protein A-binding ability is different for the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.\",\n \"38.-55.\",\n \"(canceled)\"\n ],\n [\n \"<SOH> BACKGROUND ART <EOH>There are some previously reported methods for producing an IgG-type bispecific antibody having a human constant region (IgG-type antibody which has a human constant region and in which one of the arms has a specific binding activity to antigen A and the other has a specific binding activity to antigen B).\",\n \"In general, an IgG-type bispecific antibody is composed of two types of H chains (i.e., H chain against antigen A and H chain against antigen B) and two types of L chains (i.e., L chain against antigen A and L chain against antigen B).\",\n \"When such an IgG-type bispecific antibody is expressed, two types of H chains and two types of L chains are expressed, and there are ten possible combinations for the H2L2 combination.\",\n \"Of these, only one combination has the specificity of interest (one arm has binding activity specific to antigen A and the other has binding activity specific to antigen B).\",\n \"Thus, to obtain a bispecific antibody of interest, it is necessary to purify a single antibody of interest from the ten types of antibodies.\",\n \"This is an extremely inefficient and difficult process.\",\n \"There are reported methods for solving this problem which use a common L chain so that the L chain against antigen A and the L chain against antigen B have an identical amino acid sequence (Patent Documents 1 and 2).\",\n \"When an IgG-type bispecific antibody having such a common L chain is expressed, two types of H chains and one type of common L chain are expressed, and there are three possible combinations for the H2L2 combination.\",\n \"One of these combinations is a bispecific antibody of interest.\",\n \"These three combinations are: monospecific antibody against antigen A (homomeric H chain antibody against antigen A), bispecific antibody against both antigen A and antigen B (heteromeric antibody with an H chain against antigen A and an H chain against antigen B), and monospecific antibody against antigen B (homomeric H chain antibody against antigen B).\",\n \"Since their ratio is in general 1:2:1, the expression efficiency of the desired bispecific antibody is about 50%.\",\n \"A method for further improving this efficiency has been reported which allows two types of H chains heteromerically associate (Patent Document 3).\",\n \"This can increase the expression efficiency of the desired bispecific antibody up to about 90-95%.\",\n \"Meanwhile, a method has been reported for efficiently removing the two types of homomeric antibodies which are impurities, in which amino acid substitutions are introduced into the variable regions of the two types of H chains to give them different isoelectric points so that the two types of homomeric antibodies and the bispecific antibody of interest (heteromeric antibody) can be purified by ion exchange chromatography (Patent Document 4).\",\n \"A combination of the above-mentioned methods has made it possible to efficiently produce a bispecific antibody (heteromeric antibody) having an IgG-type human constant region.\",\n \"On the other hand, in the industrial production of IgG-type antibodies, a purification step by protein A chromatography must be used, but ion exchange chromatography is not necessarily used in the purification step.\",\n \"Therefore, the use of ion exchange chromatography for producing a highly pure bispecific antibody leads to an increase of production costs.\",\n \"In addition, since ion exchange chromatography alone may not ensure a robust purification method for pharmaceuticals, it is preferable to perform more than one chromatographic step to remove impurities.\",\n \"In any case, it is preferable that bispecific antibodies can also be highly purified by a chromatographic step that has a separation mode different from that of ion exchange chromatography.\",\n \"It is desirable that as one of such separation modes, protein A chromatography, which must be used in the industrial production of IgG-type antibodies, could purify bispecific antibodies to high purity.\",\n \"A previously reported method for purifying a bispecific antibody (heteromeric antibody) using protein A is to use a bispecific antibody having a mouse IgG2a H chain that binds to protein A and a rat IgG2b H chain that does not bind to protein A.\",\n \"It has been reported that this method allows a bispecific antibody of interest to be purified to a purity of 95% by the protein A-based purification step alone (Non-patent Document 1 and Patent Document 5).\",\n \"However, this method also uses ion exchange chromatography to improve the purity of the bispecific antibody.\",\n \"In other words, purification of a highly pure bispecific antibody cannot be achieved by the purification step using protein A chromatography alone.\",\n \"Moreover, catumaxomab, a bispecific antibody produced by the above-described method and having a mouse IgG2a H chain and a rat IgG2b H chain, has a half-life of about 2.1 days in human, which is extremely shorter than that of normal human IgG1 (2 to 3 weeks) (Non-patent Document 2).\",\n \"In addition to having a short half-life, catumaxomab is highly immunogenic because of its mouse and rat constant regions (Non-patent Document 3).\",\n \"Thus, a bispecific antibody obtained by such methods is considered inappropriate as a pharmaceutical.\",\n \"On the other hand, it has been suggested that from the viewpoint of immunogenicity, a human IgG3 constant region may be used as a protein A-nonbinding constant region (Non-patent Document 1).\",\n \"However, as it is known that the H chains of human IgG1 and human IgG3 hardly associate with each other (Non-patent Document 1), it is impossible to produce a bispecific antibody of interest using a human IgG1 H chain and a human IgG3 H chain by the same method used for the bispecific antibody having a mouse IgG2a H chain and a rat IgG2b H chain.\",\n \"Furthermore, the half-life of human IgG3 in human has been reported to be generally shorter than that of human IgG1, human IgG2, and human IgG4 (Non-patent Documents 4 and 5).\",\n \"Accordingly, like the bispecific antibody using a mouse IgG2a and a rat IgG2b, a bispecific antibody using human IgG3 might also have a short half-life in human.\",\n \"The reason that H chain association rarely occurs between human IgG1 and human IgG3 is suggested to be the hinge sequence of human IgG3 (Non-patent Document 1).\",\n \"Meanwhile, the reason for the short half-life of the human IgG3 constant region has not been fully elucidated yet.\",\n \"Thus, there has been no report so far with regard to bispecific antibodies that use a human IgG3 constant region as a protein A-nonbinding constant region.\",\n \"Moreover, there is also no report regarding methods for efficiently producing or purifying highly pure bispecific antibodies that have a human constant region and show a similarly long half-life as human IgG1.\"\n ],\n [\n \"<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG.\",\n \"1 is a graph showing an assessment of the plasma retention time of MRA-IgG1 and MRA-z106/z107k in human FcRn transgenic mice.\",\n \"FIG.\",\n \"2 is a diagram showing that the same region in the antibody Fc domain binds to protein A and FcRn.\",\n \"FIG.\",\n \"3 shows a time course of the plasma concentrations of Q499-z118/J339-z119/L377-k and Q499-z121/J339-z119/L377-k after administration to human FcRn transgenic mice.\",\n \"FIG.\",\n \"4 is a schematic diagram of a GC33-IgG1-CD3-scFv molecule which divalently binds to cancer specific antigen glypican-3 (GPC3) and monovalently binds to T cell antigen CD3.FIG.\",\n \"5 shows the result of size exclusion chromatography analysis of protein A-purified NTA1L/NTA1R/GC33-k0 and NTA2L/NTA2R/GC33-k0.FIG.\",\n \"6 is a schematic diagram of an anti-GPC3 IgG antibody molecule that monovalently binds to glypican-3.FIG.\",\n \"7 shows the result of size exclusion chromatography analysis of protein A-purified NTA4L-cont/NTA4R-cont/GC33-k0, NTA4L-G3/NTA4R-cont/GC33-k0, and NTA4L/NTA4R/GC33-k0.FIG.\",\n \"8 shows chromatograms of NTA4L-cont/NTA4R-cont/GC33-k0, NTA4L-G3/NTA4R-cont/GC33-k0, and NTA4L/NTA4R/GC33-k0 subjected to protein A column chromatography purification with pH gradient elution.\",\n \"FIG.\",\n \"9 is a schematic diagram of an Fc alpha receptor-Fc fusion protein molecule that monovalently binds to IgA.\",\n \"FIG.\",\n \"10 shows the result of size exclusion chromatography analysis of protein A-purified IAL-cont/IAR-cont and IAL/IAR.\",\n \"FIG.\",\n \"11 is a schematic diagram of no1, a naturally occurring anti-IL-6 receptor/anti-GPC3 bispecific antibody.\",\n \"FIG.\",\n \"12 is a schematic diagram of no2, which was obtained by interchanging the anti-GPC3 antibody VH domain and VL domain in no1.FIG.\",\n \"13 is a schematic diagram of no3, which was obtained by modifying no2 to alter the isoelectric point of each chain.\",\n \"FIG.\",\n \"14 is a schematic diagram of no5, which was obtained by modifying no3 to enhance the heteromeric association of H chains and to purify the heteromerically associated antibody using protein A.\",\n \"FIG.\",\n \"15 is a schematic diagram of no6, which was obtained by modifying no5 to enhance the association between the H chain of interest and the L chain of interest.\",\n \"FIG.\",\n \"16 is chromatograms of anti-IL-6 receptor/anti-GPC3 bispecific antibodies no1, no2, no3, no5, and no6 in cation exchange chromatography to assess their expression patterns.\",\n \"FIG.\",\n \"17 is a chromatogram of no6 CM eluted with a pH gradient from a HiTrap protein A HP column (GE Healthcare).\",\n \"FIG.\",\n \"18 is a chromatogram of cation exchange chromatography analysis to assess a main peak fraction obtained by purification of a protein A-purified fraction of no6 using an SP Sepharose HP column (GE Healthcare).\",\n \"detailed-description description=\\\"Detailed Description\\\" end=\\\"lead\\\"?\"\n ],\n [\n \"CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser.\",\n \"No.\",\n \"15/617,008, filed on Jun.\",\n \"8, 2017, which is a continuation of U.S. application Ser.\",\n \"No.\",\n \"13/518,861, having a 371(c) date of Oct. 4, 2012, which is the National Stage of International Application Serial No.\",\n \"PCT/JP2010/073361, filed on Dec. 24, 2010, which claims the benefit of Japanese Application Serial No.\",\n \"2009-294391, filed on Dec. 25, 2009.The contents of the foregoing applications are incorporated by reference in their entireties in this application.\",\n \"TECHNICAL FIELD The present invention relates to methods for producing or purifying polypeptide multimers, polypeptide multimers with an altered protein A-binding ability, and such.\",\n \"BACKGROUND ART There are some previously reported methods for producing an IgG-type bispecific antibody having a human constant region (IgG-type antibody which has a human constant region and in which one of the arms has a specific binding activity to antigen A and the other has a specific binding activity to antigen B).\",\n \"In general, an IgG-type bispecific antibody is composed of two types of H chains (i.e., H chain against antigen A and H chain against antigen B) and two types of L chains (i.e., L chain against antigen A and L chain against antigen B).\",\n \"When such an IgG-type bispecific antibody is expressed, two types of H chains and two types of L chains are expressed, and there are ten possible combinations for the H2L2 combination.\",\n \"Of these, only one combination has the specificity of interest (one arm has binding activity specific to antigen A and the other has binding activity specific to antigen B).\",\n \"Thus, to obtain a bispecific antibody of interest, it is necessary to purify a single antibody of interest from the ten types of antibodies.\",\n \"This is an extremely inefficient and difficult process.\",\n \"There are reported methods for solving this problem which use a common L chain so that the L chain against antigen A and the L chain against antigen B have an identical amino acid sequence (Patent Documents 1 and 2).\",\n \"When an IgG-type bispecific antibody having such a common L chain is expressed, two types of H chains and one type of common L chain are expressed, and there are three possible combinations for the H2L2 combination.\",\n \"One of these combinations is a bispecific antibody of interest.\",\n \"These three combinations are: monospecific antibody against antigen A (homomeric H chain antibody against antigen A), bispecific antibody against both antigen A and antigen B (heteromeric antibody with an H chain against antigen A and an H chain against antigen B), and monospecific antibody against antigen B (homomeric H chain antibody against antigen B).\",\n \"Since their ratio is in general 1:2:1, the expression efficiency of the desired bispecific antibody is about 50%.\",\n \"A method for further improving this efficiency has been reported which allows two types of H chains heteromerically associate (Patent Document 3).\",\n \"This can increase the expression efficiency of the desired bispecific antibody up to about 90-95%.\",\n \"Meanwhile, a method has been reported for efficiently removing the two types of homomeric antibodies which are impurities, in which amino acid substitutions are introduced into the variable regions of the two types of H chains to give them different isoelectric points so that the two types of homomeric antibodies and the bispecific antibody of interest (heteromeric antibody) can be purified by ion exchange chromatography (Patent Document 4).\",\n \"A combination of the above-mentioned methods has made it possible to efficiently produce a bispecific antibody (heteromeric antibody) having an IgG-type human constant region.\",\n \"On the other hand, in the industrial production of IgG-type antibodies, a purification step by protein A chromatography must be used, but ion exchange chromatography is not necessarily used in the purification step.\",\n \"Therefore, the use of ion exchange chromatography for producing a highly pure bispecific antibody leads to an increase of production costs.\",\n \"In addition, since ion exchange chromatography alone may not ensure a robust purification method for pharmaceuticals, it is preferable to perform more than one chromatographic step to remove impurities.\",\n \"In any case, it is preferable that bispecific antibodies can also be highly purified by a chromatographic step that has a separation mode different from that of ion exchange chromatography.\",\n \"It is desirable that as one of such separation modes, protein A chromatography, which must be used in the industrial production of IgG-type antibodies, could purify bispecific antibodies to high purity.\",\n \"A previously reported method for purifying a bispecific antibody (heteromeric antibody) using protein A is to use a bispecific antibody having a mouse IgG2a H chain that binds to protein A and a rat IgG2b H chain that does not bind to protein A.\",\n \"It has been reported that this method allows a bispecific antibody of interest to be purified to a purity of 95% by the protein A-based purification step alone (Non-patent Document 1 and Patent Document 5).\",\n \"However, this method also uses ion exchange chromatography to improve the purity of the bispecific antibody.\",\n \"In other words, purification of a highly pure bispecific antibody cannot be achieved by the purification step using protein A chromatography alone.\",\n \"Moreover, catumaxomab, a bispecific antibody produced by the above-described method and having a mouse IgG2a H chain and a rat IgG2b H chain, has a half-life of about 2.1 days in human, which is extremely shorter than that of normal human IgG1 (2 to 3 weeks) (Non-patent Document 2).\",\n \"In addition to having a short half-life, catumaxomab is highly immunogenic because of its mouse and rat constant regions (Non-patent Document 3).\",\n \"Thus, a bispecific antibody obtained by such methods is considered inappropriate as a pharmaceutical.\",\n \"On the other hand, it has been suggested that from the viewpoint of immunogenicity, a human IgG3 constant region may be used as a protein A-nonbinding constant region (Non-patent Document 1).\",\n \"However, as it is known that the H chains of human IgG1 and human IgG3 hardly associate with each other (Non-patent Document 1), it is impossible to produce a bispecific antibody of interest using a human IgG1 H chain and a human IgG3 H chain by the same method used for the bispecific antibody having a mouse IgG2a H chain and a rat IgG2b H chain.\",\n \"Furthermore, the half-life of human IgG3 in human has been reported to be generally shorter than that of human IgG1, human IgG2, and human IgG4 (Non-patent Documents 4 and 5).\",\n \"Accordingly, like the bispecific antibody using a mouse IgG2a and a rat IgG2b, a bispecific antibody using human IgG3 might also have a short half-life in human.\",\n \"The reason that H chain association rarely occurs between human IgG1 and human IgG3 is suggested to be the hinge sequence of human IgG3 (Non-patent Document 1).\",\n \"Meanwhile, the reason for the short half-life of the human IgG3 constant region has not been fully elucidated yet.\",\n \"Thus, there has been no report so far with regard to bispecific antibodies that use a human IgG3 constant region as a protein A-nonbinding constant region.\",\n \"Moreover, there is also no report regarding methods for efficiently producing or purifying highly pure bispecific antibodies that have a human constant region and show a similarly long half-life as human IgG1.PRIOR ART DOCUMENTS Patent Documents Patent Document 1: WO98050431 Patent Document 2: WO2006109592 Patent Document 3: WO2006106905 Patent Document 4: WO2007114325 Patent Document 5: WO95033844 Non-Patent Documents Non-patent Document 1: The Journal of Immunology, 1995, 155:219-225 Non-patent Document 2: J Clin Oncol 26: 2008 (May 20 suppl; abstr 14006) Non-patent Document 3: Clin Cancer Res 2007 13:3899-3905 Non-patent Document 4: Nat Biotechnol.\",\n \"2007 December; 25(12):1369-72 Non-patent Document 5: J. Clin Invest 1970; 49:673-80 DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention In general, an ordinary IgG-type antibody can be efficiently produced as a highly pure IgG through a protein A-based purification step.\",\n \"However, the production of a highly pure bispecific antibody requires an additional purification step using ion exchange chromatography.\",\n \"The addition of such a purification step by ion exchange chromatography can complicate the production and increase production cost.\",\n \"Thus, it is preferable to produce a highly pure bispecific antibody by a protein A-based purification step alone.\",\n \"An objective of the present invention is to provide methods that use only a protein A-based purification step for efficiently producing or purifying a highly pure IgG-type bispecific antibody having a human antibody heavy chain constant region.\",\n \"Meanwhile, since the protein A binding site in the Fc domain is identical to the FcRn-binding site in the Fc domain, it is expected to be difficult to adjust the protein A-binding activity while retaining the binding to human FcRn.\",\n \"Retaining the human FcRn-binding ability is very important for the long plasma retention (long half-life) in human which is characteristic of IgG-type antibodies.\",\n \"The present invention provides methods that use only a protein A-based purification step to efficiently produce or purify a highly pure bispecific antibody that maintains a plasma retention time comparable to or longer than that of human IgG1.Means for Solving the Problems The present inventors discovered methods that use only a protein A-based purification step for efficiently purifying or producing a highly pure polypeptide multimer capable of binding to two or more antigens, in particular, a multispecific IgG-type antibody having a human constant region, by altering its protein A-binding ability.\",\n \"Furthermore, these methods were combined with methods for regulating the association between a first polypeptide having an antigen-binding activity and a second polypeptide having an antigen-binding activity by modifying amino acids that constitute the interface formed upon association of the polypeptides.\",\n \"By this combination, the present invention enables efficient production or purification of a highly pure polypeptide multimer of interest.\",\n \"The present inventors also discovered that by modifying the amino acid residue at position 435 (EU numbering) in the heavy chain constant region, the protein A-binding ability could be adjusted while keeping its plasma retention comparable to or longer than that of human IgG1.Based on this finding, a highly pure bispecific antibody with plasma retention time comparable to or longer than that of human IgG1 can be produced or purified.\",\n \"The present invention is based on the findings described above, and provides [1] to [55] below: [1] A method for producing a polypeptide multimer that comprises a first polypeptide having an antigen-binding activity and a second polypeptide having an antigen-binding activity or no antigen-binding activity, which comprises the steps of: (a) expressing a DNA that encodes the first polypeptide having an antigen-binding activity and a DNA that encodes the second polypeptide having an antigen-binding activity or no antigen-binding activity; and (b) collecting the expression product of step (a), wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.\",\n \"[2] The method of [1], wherein the expression product is collected using protein A affinity chromatography in step (b).\",\n \"[3] The method of [1] or [2], wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so that there is a larger difference between the solvent pH for eluting the first polypeptide having an antigen-binding activity from protein A and that for eluting the second polypeptide having an antigen-binding activity or no antigen-binding activity from protein A.\",\n \"[4] The method of any one of [1] to [3], wherein one or more amino acid residues in the first polypeptide having an antigen-binding activity or the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so as to increase or reduce the protein A-binding ability of either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.\",\n \"[5] The method of any one of [1] to [4], wherein one or more amino acid residues in the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so as to increase the protein A-binding ability of either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity, and reduce the protein A-binding ability of the other polypeptide.\",\n \"[6] The method of any one of [1] to [5], wherein the purity of the collected polypeptide multimer is 95% or more.\",\n \"[7] The method of any one of [1] to [6], wherein the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity comprise an amino acid sequence of an antibody Fc domain or an amino acid sequence of an antibody heavy-chain constant region.\",\n \"[8] The method of [7], wherein at least one amino acid residue selected from the amino acid residues of positions 250 to 255, 308 to 317, and 430 to 436 (EU numbering) in the amino acid sequence of the antibody Fc domain or antibody heavy-chain constant region has been modified.\",\n \"[9] The method of any one of [1] to [8], wherein the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity comprise an amino acid sequence of an antibody heavy-chain variable region.\",\n \"[10] The method of [9], wherein at least one amino acid residue has been modified in the amino acid sequences of FR1, CDR2, and FR3 of the antibody heavy-chain variable region.\",\n \"[11] The method of any one of [1] to [10], wherein the polypeptide multimer comprises one or two third polypeptides having an antigen-binding activity, and step (a) comprises expressing a DNA that encodes the third polypeptide having an antigen-binding activity.\",\n \"[12] The method of [11], wherein the third polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.\",\n \"[13] The method of [11] or [12], wherein the polypeptide multimer additionally comprises a fourth polypeptide having an antigen-binding activity, and step (a) comprises expressing a DNA that encodes the fourth polypeptide having an antigen-binding activity.\",\n \"[14] The method of [13], wherein at least one of the third and fourth polypeptides having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.\",\n \"[15] The method of [13], wherein the first polypeptide having an antigen-binding activity comprises amino acid sequences of an antibody light-chain variable region and an antibody heavy-chain constant region; the second polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody heavy chain; the third polypeptide having an antigen-binding activity comprises amino acid sequences of an antibody heavy-chain variable region and an antibody light-chain constant region; and the fourth polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.\",\n \"[16] The method of any one of [1] to [15], wherein the polypeptide multimer is a multispecific antibody.\",\n \"[17] The method of [16], wherein the multispecific antibody is a bispecific antibody.\",\n \"[18] The method of any one of [1] to [8], which comprises the first polypeptide having an antigen-binding activity and the second polypeptide having no antigen-binding activity, and wherein the first polypeptide having an antigen-binding activity comprises an amino acid sequence of an antigen-binding domain of a receptor and an amino acid sequence of an antibody Fc domain, and the second polypeptide having no antigen-binding activity comprises an amino acid sequence of an antibody Fc domain.\",\n \"[19] The method of any one of [7] to [18], wherein the antibody Fc domain or antibody heavy-chain constant region is derived from human IgG.\",\n \"[20] A polypeptide multimer produced by the method of any one of [1] to [19].\",\n \"[21] A method for purifying a polypeptide multimer that comprises a first polypeptide having an antigen-binding activity and a second polypeptide having an antigen-binding activity or no antigen-binding activity, which comprises the steps of: (a) expressing a DNA that encodes the first polypeptide having an antigen-binding activity and a DNA that encodes the second polypeptide having an antigen-binding activity or no antigen-binding activity; and (b) collecting the expression product of step (a) by protein A affinity chromatography, wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.\",\n \"[22] The method of [21], wherein one or more amino acid residues in the first polypeptide having an antigen-binding activity or the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so as to increase or reduce the protein A-binding ability of the first polypeptide having an antigen-binding activity or the second polypeptide having an antigen-binding activity or no antigen-binding activity.\",\n \"[23] The method of [20] or [21], wherein one or more amino acid residues in the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified, so as to increase the protein A-binding ability of either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity, and reduce the protein A-binding ability of the other polypeptide.\",\n \"[24] The method of any one of [21] to [23], wherein the purity of the collected polypeptide multimer is 95% or more.\",\n \"[25] The method of any one of [21] to [24], wherein the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity comprise an amino acid sequence of an antibody Fc domain or an amino acid sequence of an antibody heavy-chain constant region.\",\n \"[26] The method of [25], wherein at least one amino acid residue selected from the amino acid residues of positions 250 to 255, 308 to 317, and 430 to 436 (EU numbering) in the amino acid sequence of the antibody Fc domain or antibody heavy-chain constant region has been modified.\",\n \"[27] The method of any one of [21] to [26], wherein the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity comprise an amino acid sequence of an antibody heavy-chain variable region.\",\n \"[28] The method of [27], wherein at least one amino acid residue has been modified in the amino acid sequences of FR1, CDR2, and FR3 of the antibody heavy-chain variable region.\",\n \"[29] The method of any one of [21] to [28], wherein the polypeptide multimer comprises one or two third polypeptides having an antigen-binding activity, and step (a) comprises expressing a DNA that encodes the third polypeptide having an antigen-binding activity.\",\n \"[30] The method of [29], wherein the third polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.\",\n \"[31] The method of [29] or [30], wherein the polypeptide multimer additionally comprises a fourth polypeptide having an antigen-binding activity, and step (a) comprises expressing a DNA that encodes the fourth polypeptide having an antigen-binding activity.\",\n \"[32] The method of [31], wherein at least one of the third and fourth polypeptides having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.\",\n \"[33] The method of [31], wherein the first polypeptide having an antigen-binding activity comprises amino acid sequences of an antibody light-chain variable region and an antibody heavy-chain constant region; the second polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody heavy chain; the third polypeptide having an antigen-binding activity comprises amino acid sequences of an antibody heavy-chain variable region and an antibody light-chain constant region; and the fourth polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.\",\n \"[34] The method of any one of [21] to [33], wherein the polypeptide multimer is a multispecific antibody.\",\n \"[35] The method of [34], wherein the multispecific antibody is a bispecific antibody.\",\n \"[36] The method of any one of [25] to [35], wherein the antibody Fc domain or antibody heavy-chain constant region is derived from human IgG.\",\n \"[37] A polypeptide multimer that comprises a first polypeptide having an antigen-binding activity and a second polypeptide having an antigen-binding activity or no antigen-binding activity, wherein the protein A-binding ability is different for the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.\",\n \"[38] The polypeptide multimer of [37], wherein there is a difference between the solvent pH for eluting the first polypeptide having an antigen-binding activity from protein A and that for eluting the second polypeptide having an antigen-binding activity or no antigen-binding activity from protein A.\",\n \"[39] The polypeptide multimer of [37] or [38], wherein the first polypeptide having an antigen-binding activity or the second polypeptide having an antigen-binding activity or no antigen-binding activity comprises an amino acid sequence of an antibody Fc domain or an amino acid sequence of an antibody heavy-chain constant region, and wherein at least one amino acid residue selected from the amino acid residues of positions 250 to 255, 308 to 317, and 430 to 436 (EU numbering) in the amino acid sequence of the antibody Fc domain or antibody heavy-chain constant region has been modified.\",\n \"[40] The polypeptide multimer of any one of [37] to [39], wherein the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity comprise an amino acid sequence of an antibody Fc domain or an amino acid sequence of an antibody heavy-chain constant region; wherein the amino acid residue of position 435 (EU numbering) in the amino acid sequence of the antibody Fc domain or antibody heavy-chain constant region is histidine or arginine in either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity; and wherein the amino acid residue of position 435 (EU numbering) in the amino acid sequence of the antibody Fc domain or antibody heavy-chain constant region in either one of said polypeptides is different from that in the other polypeptide.\",\n \"[41] The polypeptide multimer of any one of [37] to [40], wherein the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity comprise an amino acid sequence of an antibody Fc domain or an amino acid sequence of an antibody heavy-chain constant region; wherein the amino acid residue of position 435 (EU numbering) in the amino acid sequence of the antibody Fc domain or antibody heavy-chain constant region is histidine in either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity; and wherein the amino acid residue of position 435 (EU numbering) in the amino acid sequence of the antibody Fc domain or antibody heavy-chain constant region is arginine in the other polypeptide.\",\n \"[42] The polypeptide multimer of any one of [37] to [41], wherein the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity comprise an amino acid sequence of an antibody heavy-chain variable region, and at least one amino acid residue has been modified in the amino acid sequences of FR1, CDR2, and FR3 of the heavy-chain variable region.\",\n \"[43] The polypeptide multimer of any one of [37] to [42], which additionally comprises one or two third polypeptides having an antigen-binding activity.\",\n \"[44] The polypeptide multimer of [43], wherein the third polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.\",\n \"[45] The polypeptide multimer of [43] or [44], which additionally comprises a fourth polypeptide having an antigen-binding activity.\",\n \"[46] The polypeptide multimer of [45], wherein at least one of the third and fourth polypeptides having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.\",\n \"[47] The polypeptide multimer of [45], wherein the first polypeptide having an antigen-binding activity comprises amino acid sequences of an antibody light-chain variable region and an antibody heavy-chain constant region; the second polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody heavy chain; the third polypeptide having an antigen-binding activity comprises amino acid sequences of an antibody heavy-chain variable region and an antibody light-chain constant region; and the fourth polypeptide having an antigen-binding activity comprises an amino acid sequence of an antibody light chain.\",\n \"[48] The polypeptide multimer of any one of [37] to [47], which is a multispecific antibody.\",\n \"[49] The polypeptide multimer of [48], wherein the multispecific antibody is a bispecific antibody.\",\n \"[50] The polypeptide multimer of any one of [37] to [41], which comprises the first polypeptide having an antigen-binding activity and the second polypeptide having no antigen-binding activity, and wherein the first polypeptide having an antigen-binding activity comprises an amino acid sequence of an antigen-binding domain of a receptor and an amino acid sequence of an antibody Fc domain, and the second polypeptide having no antigen-binding activity comprises an amino acid sequence of an antibody Fc domain.\",\n \"[51] The polypeptide multimer of any one of [39] to [50], wherein the antibody Fc domain or antibody heavy-chain constant region is derived from human IgG.\",\n \"[52] A nucleic acid encoding a polypeptide that constitutes the polypeptide multimer of any one of [20] and [37] to [51].\",\n \"[53] A vector inserted with the nucleic acid of [52].\",\n \"[54] A cell comprising the nucleic acid of [52] or the vector of [53].\",\n \"[55] A pharmaceutical composition comprising the polypeptide multimer of any one of [20] and [37] to [51] as active ingredient.\",\n \"Effects of the Invention The present invention provides methods that use only a protein A-based purification step for efficiently purifying or producing a highly pure polypeptide multimer having binding activity against two or more antigens (multispecific antibody), by altering its protein A-binding ability.\",\n \"The methods of the present invention enable efficient purification or production of a highly pure polypeptide multimer of interest without impairing the effects of other amino acid modifications of interest.\",\n \"In particular, by combining these methods with a method for regulating the association between two protein domains, polypeptide multimers of interest can be more efficiently produced or purified to higher purity.\",\n \"The methods of the present invention for producing or purifying multispecific antibodies are characterized in that amino acid residues in their antibody heavy chain constant region and/or antibody heavy chain variable region are modified.\",\n \"The amino acid modifications of the present invention are introduced into these regions to modify their protein A-binding ability.\",\n \"In addition, other effects of amino acid modification of interest, for example, comparable or longer plasma retention time than that of human IgG1 can also be obtained.\",\n \"The methods of the present invention enable efficient preparation of highly pure multispecific antibodies having such amino acid modification effects.\",\n \"In general, the production of highly pure IgG-type multispecific antibodies requires a purification step using ion exchange chromatography.\",\n \"However, the addition of this purification step complicates the production and increases production cost.\",\n \"On the other hand, purification that uses only ion exchange chromatography may not be robust enough as a purification method for pharmaceuticals.\",\n \"Thus, it is a task to develop a method for producing an IgG-type bispecific antibody using only a protein A-based purification step, or develop a robust production method using a protein A-based purification step and an ion exchange chromatography step.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS FIG.\",\n \"1 is a graph showing an assessment of the plasma retention time of MRA-IgG1 and MRA-z106/z107k in human FcRn transgenic mice.\",\n \"FIG.\",\n \"2 is a diagram showing that the same region in the antibody Fc domain binds to protein A and FcRn.\",\n \"FIG.\",\n \"3 shows a time course of the plasma concentrations of Q499-z118/J339-z119/L377-k and Q499-z121/J339-z119/L377-k after administration to human FcRn transgenic mice.\",\n \"FIG.\",\n \"4 is a schematic diagram of a GC33-IgG1-CD3-scFv molecule which divalently binds to cancer specific antigen glypican-3 (GPC3) and monovalently binds to T cell antigen CD3.FIG.\",\n \"5 shows the result of size exclusion chromatography analysis of protein A-purified NTA1L/NTA1R/GC33-k0 and NTA2L/NTA2R/GC33-k0.FIG.\",\n \"6 is a schematic diagram of an anti-GPC3 IgG antibody molecule that monovalently binds to glypican-3.FIG.\",\n \"7 shows the result of size exclusion chromatography analysis of protein A-purified NTA4L-cont/NTA4R-cont/GC33-k0, NTA4L-G3/NTA4R-cont/GC33-k0, and NTA4L/NTA4R/GC33-k0.FIG.\",\n \"8 shows chromatograms of NTA4L-cont/NTA4R-cont/GC33-k0, NTA4L-G3/NTA4R-cont/GC33-k0, and NTA4L/NTA4R/GC33-k0 subjected to protein A column chromatography purification with pH gradient elution.\",\n \"FIG.\",\n \"9 is a schematic diagram of an Fc alpha receptor-Fc fusion protein molecule that monovalently binds to IgA.\",\n \"FIG.\",\n \"10 shows the result of size exclusion chromatography analysis of protein A-purified IAL-cont/IAR-cont and IAL/IAR.\",\n \"FIG.\",\n \"11 is a schematic diagram of no1, a naturally occurring anti-IL-6 receptor/anti-GPC3 bispecific antibody.\",\n \"FIG.\",\n \"12 is a schematic diagram of no2, which was obtained by interchanging the anti-GPC3 antibody VH domain and VL domain in no1.FIG.\",\n \"13 is a schematic diagram of no3, which was obtained by modifying no2 to alter the isoelectric point of each chain.\",\n \"FIG.\",\n \"14 is a schematic diagram of no5, which was obtained by modifying no3 to enhance the heteromeric association of H chains and to purify the heteromerically associated antibody using protein A.\",\n \"FIG.\",\n \"15 is a schematic diagram of no6, which was obtained by modifying no5 to enhance the association between the H chain of interest and the L chain of interest.\",\n \"FIG.\",\n \"16 is chromatograms of anti-IL-6 receptor/anti-GPC3 bispecific antibodies no1, no2, no3, no5, and no6 in cation exchange chromatography to assess their expression patterns.\",\n \"FIG.\",\n \"17 is a chromatogram of no6 CM eluted with a pH gradient from a HiTrap protein A HP column (GE Healthcare).\",\n \"FIG.\",\n \"18 is a chromatogram of cation exchange chromatography analysis to assess a main peak fraction obtained by purification of a protein A-purified fraction of no6 using an SP Sepharose HP column (GE Healthcare).\",\n \"MODE FOR CARRYING OUT THE INVENTION The present invention provides methods for producing a polypeptide multimer that comprises a first polypeptide having an antigen-binding activity and a second polypeptide having an antigen-binding activity or no antigen-binding activity.\",\n \"The methods of the present invention for producing a polypeptide multimer comprise the steps of: (a) expressing a DNA encoding a first polypeptide having an antigen-binding activity and a DNA encoding a second polypeptide having an antigen-binding activity or no antigen-binding activity; and (b) collecting the expression products of step (a); wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.\",\n \"The methods of the present invention for producing a polypeptide multimer may also be expressed as methods for producing a polypeptide multimer with an altered protein A-binding ability.\",\n \"In the present invention, “a polypeptide having a first antigen-binding activity” may be referred to as “a first polypeptide having an antigen-binding activity”.\",\n \"“A polypeptide having a second antigen-binding activity or no antigen-binding activity” may be referred to as “a second polypeptide having an antigen-binding activity or no antigen-binding activity”.\",\n \"The same applies to “a polypeptide having a third antigen-binding activity” and “a polypeptide having a fourth antigen-binding activity” described below.\",\n \"In the present invention, the term “comprise” means both “comprise” and “consist of”.\",\n \"The present invention also provides methods for purifying a polypeptide multimer that comprises a first polypeptide having an antigen-binding activity and a second polypeptide having an antigen-binding activity or no antigen-binding activity.\",\n \"The methods of the present invention for purifying a polypeptide multimer comprise the steps of: (a) expressing a DNA that encodes a first polypeptide having an antigen-binding activity and a DNA that encodes a second polypeptide having an antigen-binding activity or no antigen-binding activity; and (b) collecting the expression products of step (a) by protein A affinity chromatography; wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified so that the protein A-binding ability is different between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.\",\n \"A polypeptide having an antigen-binding activity in which one or more amino acid residues have been modified can be obtained by: preparing a DNA that encodes a polypeptide having an antigen-binding activity or no antigen-binding activity, modifying one or more nucleotides in the DNA; introducing the resulting DNA into cells known to those skilled in the art; culturing the cells to express the DNA; and collecting the expression product.\",\n \"Thus, the methods of the present invention for producing a polypeptide multimer can also be expressed as methods comprising the steps of: (a) providing a DNA that encodes a first polypeptide having an antigen-binding activity and a DNA that encodes a second polypeptide having an antigen-binding activity or no antigen-binding activity; (b) altering one or more nucleotides in either or both of the DNAs of step (a) that encode the first and second polypeptides so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity; (c) introducing the DNAs of step (b) into host cells and culturing the host cells to express the DNAs; and (d) collecting the expression products of step (c) from the culture of host cells.\",\n \"The methods of the present invention for purifying a polypeptide multimer may also be expressed as methods comprising the step of: (a) providing a DNA that encodes a first polypeptide having an antigen-binding activity and a DNA that encodes a second polypeptide having an antigen-binding activity or no antigen-binding activity; (b) altering one or more nucleotides in either or both of the DNAs of step (a) that encode the first and second polypeptides so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity; (c) introducing the DNAs of step (b) into host cells and culturing the host cells to express the DNAs; and (d) collecting the expression products of step (c) from the culture of host cells by protein A affinity chromatography.\",\n \"In the present invention, a polypeptide multimer refers to a heteromeric multimer containing first and second polypeptides.\",\n \"It is preferable that the first and second polypeptides each have an activity of binding to a different antigen.\",\n \"The first and second polypeptides each having a different antigen-binding activity are not particularly limited as long as one of the polypeptides has an antigen-binding domain (amino acid sequence) different from that of the other polypeptide.\",\n \"For example, as shown in FIG.\",\n \"4 described below, one polypeptide may be fused with an antigen-binding domain that is different from that of the other polypeptide.\",\n \"Alternatively, as shown in FIGS.\",\n \"4, 6, and 9 described below, one polypeptide may be a polypeptide that monovalently binds to an antigen and does not have the antigen-binding domain possessed by the other polypeptide.\",\n \"Polypeptide multimers containing such first and second polypeptides are also included in the polypeptide multimers of the present invention.\",\n \"The multimers include dimers, trimers, and tetramers, but are not limited thereto.\",\n \"In present invention, a first polypeptide and/or a second polypeptide can form a multimer with one or two third polypeptides.\",\n \"Thus, the present invention provides methods for producing a polypeptide multimer comprising a first polypeptide having an antigen-binding activity, a second polypeptide having an antigen-binding activity or no antigen-binding activity, and one or two third polypeptides having an antigen-binding activity, which comprise the steps of: (a) expressing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having an antigen-binding activity, and a DNA that encodes two third polypeptides having an antigen-binding activity; and (b) collecting the expression products of step (a); or (a) expressing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having no antigen-binding activity, and a DNA that encodes one third polypeptide having an antigen-binding activity; and (b) collecting the expression products of step (a); wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.\",\n \"The above-described methods may also be expressed as methods comprising the steps of: (a) providing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having an antigen-binding activity, and a DNA that encodes two third polypeptides having an antigen-binding activity; (b) altering one or more nucleotides in either or both of the DNAs of step (a) that encode the first and second polypeptides so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity; (c) introducing the DNAs that encode the first, second, and two third polypeptides into host cells, and culturing the host cells to express the DNAs; and (d) collecting the expression products of step (c) from the culture of host cells; or (a) providing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having no antigen-binding activity, and a DNA that encodes one third polypeptide having an antigen-binding activity; (b) altering one or more nucleotides in either or both of the DNAs of step (a) that encode the first and second polypeptides so that there is a larger difference of protein A-binding activity between the first polypeptide having an antigen-binding activity and the second polypeptide having no antigen-binding activity; (c) introducing the DNAs that encode the first, second, and third polypeptides into host cells and culturing the host cells to express the DNAs; and (d) collecting the expression products of step (c) from the culture of host cells.\",\n \"Furthermore, in the present invention, the first and second polypeptides can form a multimer with third and fourth polypeptides.\",\n \"Thus, the present invention provides methods for producing a polypeptide multimer comprising a first polypeptide having an antigen-binding activity, a second polypeptide having an antigen-binding activity, a third polypeptide having an antigen-binding activity, and a fourth polypeptide having an antigen-binding activity, which comprise the steps of: (a) expressing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having an antigen-binding activity, and a DNA that encodes a third polypeptide having an antigen-binding activity and a fourth polypeptide having an antigen-binding activity; and (b) collecting the expression products of step (a); wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity have been modified so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity.\",\n \"The above-described methods can also be expressed as methods comprising the steps of: (a) providing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having an antigen-binding activity, and a DNA that encodes a third polypeptide having an antigen-binding activity and a fourth polypeptide having an antigen-binding activity; (b) altering one or more nucleotides in either or both of the DNAs of step (a) that encode the first and second polypeptides so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity; (c) introducing the DNAs that encode the first, second, third, and fourth polypeptides into host cells and culturing the host cells to express the DNAs; and (d) collecting the expression products of step (c) from the culture of host cells.\",\n \"The present invention provides methods for purifying a polypeptide multimer that comprises a first polypeptide having an antigen-binding activity, a second polypeptide having an antigen-binding activity or no antigen-binding activity, and one or two third polypeptides having an antigen-binding activity, which comprise the steps of: (a) expressing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having an antigen-binding activity, and a DNA that encodes two third polypeptides having an antigen-binding activity; and (b) collecting the expression products of step (a); or (a) expressing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having no antigen-binding activity, and a DNA that encodes one third polypeptide having an antigen-binding activity; and (b) collecting the expression products of step (a); wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity have been modified so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.\",\n \"The above-described methods can also be expressed as methods comprising the steps of: (a) providing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having an antigen-binding activity or no antigen-binding activity, and a DNA that encodes two third polypeptides having an antigen-binding activity; (b) altering one or more nucleotides in either or both of the DNAs of step (a) that encode the first and second polypeptides so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity; (c) introducing the DNAs that encode the first, second, and two third polypeptides into host cells and culturing the host cells to express the DNAs; and (d) collecting the expression products of step (c) from the culture of host cells; or (a) providing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having no antigen-binding activity, and a DNA that encodes one third polypeptide having an antigen-binding activity; (b) altering one or more nucleotides in either or both of the DNAs of step (a) that encode the first and second polypeptides so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having no antigen-binding activity; (c) introducing the DNAs that encode the first, second, and third polypeptides into host cells and culturing the host cells to express the DNAs; and (d) collecting the expression products of step (c) from the culture of host cells.\",\n \"The present invention also provides methods for purifying a polypeptide multimer that comprises a first polypeptide having an antigen-binding activity, a second polypeptide having an antigen-binding activity, a third polypeptide having an antigen-binding activity, and a fourth polypeptide having an antigen-binding activity, which comprise the steps of: (a) expressing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having an antigen-binding activity, a DNA that encodes a third polypeptide having an antigen-binding activity, and a DNA that encodes a fourth polypeptide having an antigen-binding activity; and (b) collecting the expression products of step (a) by protein A affinity chromatography; wherein one or more amino acid residues in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity have been modified so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity.\",\n \"The above-described methods can also be expressed as methods comprising the steps of: (a) providing a DNA that encodes a first polypeptide having an antigen-binding activity, a DNA that encodes a second polypeptide having an antigen-binding activity, a DNA that encodes a third polypeptide having an antigen-binding activity, and a DNA that encodes a fourth polypeptide having an antigen-binding activity; (b) altering one or more nucleotides in either or both of the DNAs of step (a) that encode the first and second polypeptides so that there is a larger difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity; (c) introducing the DNAs that encode the first, second, third, and fourth polypeptides into host cells and culturing the host cells to express the DNAs; and (d) collecting the expression products of step (c) from the culture of host cells by protein A affinity chromatography.\",\n \"In a polypeptide multimer of the present invention containing a first polypeptide, a second polypeptide, and one or two third polypeptides, the first and second polypeptides can each form a multimer (dimer) with the third polypeptide.\",\n \"Furthermore, the resulting two dimers can form a multimer with each other.\",\n \"The two third polypeptides may have completely the same amino acid sequence (may have a binding activity to the same antigen).\",\n \"Alternatively, the third polypeptides may have the same amino acid sequence and two or more activities (for example, may have binding activities to two or more different antigens).\",\n \"When only one third polypeptide is present, the third polypeptide can form a polypeptide multimer via dimerization with either the first polypeptide or the second polypeptide.\",\n \"In a polypeptide multimer of the present invention, the first and second polypeptides preferably have binding activity to different antigens.\",\n \"Meanwhile, the third polypeptide may have binding activity to the same antigen as that of either or both of the first and second polypeptides.\",\n \"Alternatively, the third polypeptide may have binding activity to an antigen different from those of the first and second polypeptides.\",\n \"Alternatively, a polypeptide multimer of the present invention may contain a first polypeptide, second polypeptide, third polypeptide, and fourth polypeptide.\",\n \"In such a polypeptide multimer, the first polypeptide and second polypeptide can form a multimer (dimer) with the third polypeptide and fourth polypeptide, respectively.\",\n \"For example, through formation of disulfide bonds in between, the first polypeptide and third polypeptide can form a dimer, and the second polypeptide and fourth polypeptide can form a dimer.\",\n \"In a polypeptide multimer of the present invention, the first and second polypeptides preferably have binding activity to different antigens.\",\n \"Meanwhile, the third polypeptide may have binding activity to the same antigen as that of either or both of the first and second polypeptides.\",\n \"Alternatively, the third polypeptide may have binding activity to an antigen different from those of the first and second polypeptides.\",\n \"Furthermore, the fourth polypeptide may have binding activity to the same antigen as that of either or both of the first and second polypeptides.\",\n \"Alternatively, the fourth polypeptide may have binding activity to an antigen different from those of the first and second polypeptides.\",\n \"Specifically, for example, when the first and second polypeptides contain the amino acid sequence of an antibody heavy chain against antigen A and the amino acid sequence of an antibody heavy chain against antigen B, respectively, the third and fourth polypeptides may contain the amino acid sequence of an antibody light chain against antigen A and the amino acid sequence of an antibody light chain against antigen B, respectively.\",\n \"When a polypeptide multimer of the present invention has third and fourth polypeptides that contain two different antibody light chain amino acid sequences, a highly pure polypeptide multimer of interest can be efficiently produced or purified by making the pI values of the third and fourth polypeptide different using the methods described below, or by differentiating their protein L-binding ability, in addition to differentiating the protein A-binding ability between the first and second polypeptides.\",\n \"Alternatively, for example, when the first polypeptide has the amino acid sequence of an antibody heavy chain against antigen A, the second polypeptide has the amino acid sequence of an antibody light chain variable region against antigen B and the amino acid sequence of an antibody heavy chain constant region, the third polypeptide has the amino acid sequence of an antibody light chain against antigen A, and the fourth polypeptide has the amino acid sequence of an antibody heavy chain variable region against antigen B and the amino acid sequence of an antibody light chain constant region, a highly pure polypeptide multimer of interest having the first, second, third, and fourth polypeptides can also be efficiently produced or purified by using the present invention.\",\n \"In this case, as described in Example 12 below, introduction of amino acid mutations to alter the pI value of a polypeptide or introduction of amino acid mutations to promote the association of polypeptides of interest (WO2006/106905) enables more efficient purification or production of a polypeptide multimer of interest having the first, second, third, and fourth polypeptides to higher purity.\",\n \"Amino acid mutations to be introduced to promote the association of polypeptides may be those used in the methods described in Protein Eng.\",\n \"1996 July, 9(7):617-21; Protein Eng Des Sel.\",\n \"2010 April, 23(4):195-202; J Biol Chem.\",\n \"2010 Jun.\",\n \"18, 285(25):19637-46; WO2009080254; and such, in which two polypeptides having a heavy chain constant region are heteromerically associated by modifying the CH3 domain of heavy chain constant region; and those used in the methods described in WO2009080251, WO2009080252, WO2009080253, and such, by which the association of a particular pair of heavy chain and light chain is promoted.\",\n \"In the present invention, “polypeptide having an antigen-binding activity” refers to a peptide or protein of five or more amino acids in length having a domain (region) capable of binding to a protein or peptide such as an antigen or ligand, e.g., an antibody heavy chain or light chain variable region, receptor, receptor-Fc domain fusion peptide, scaffold, or a fragment thereof.\",\n \"Specifically, a polypeptide having an antigen-binding activity can contain the amino acid sequence of an antibody variable region, receptor, receptor-Fc domain fusion peptide, scaffold, or a fragment thereof.\",\n \"Scaffold may be any polypeptide as long as it is a conformationally stable polypeptide capable of binding to at least one antigen.\",\n \"Such polypeptides include, but are not limited to, for example, antibody variable region fragments, fibronectin, protein A domains, LDL receptor A domains, lipocalins, and molecules mentioned in Nygren et al.\",\n \"(Current Opinion in Structural Biology, 7:463-469 (1997); Journal of Immunol.\",\n \"Methods, 290:3-28 (2004)), Binz et al.\",\n \"(Nature Biotech 23:1257-1266 (2005)), and Hosse et al.\",\n \"(Protein Science 15:14-27 (2006)).\",\n \"Methods for obtaining antibody variable regions, receptors, receptor-Fc domain fusion peptides, scaffold, and fragments thereof are known to those skilled in the art.\",\n \"Such polypeptides having an antigen-binding activity may be derived from a living organism or designed artificially.\",\n \"The polypeptides may be derived from natural proteins, synthetic proteins, recombinant proteins, and such.\",\n \"Furthermore, the polypeptides may be peptides or protein fragments of 10 or more amino acids in length which have a domain (region) capable of binding to a protein or peptide such as an antigen or ligand, as long as they have ability to bind to an antigen.\",\n \"The polypeptides may have more than one domain capable of binding to an antigen (including ligand).\",\n \"A polypeptide having an antigen-binding activity may also be referred to as a polypeptide having an antigen-binding protein domain(s).\",\n \"In the present invention, “polypeptide having no antigen-binding activity” refers to a peptide or protein of five or more amino acids in length, such as an antibody fragment having no antigen-binding activity, Fc domain, scaffold, or a fragment thereof.\",\n \"Specifically, a polypeptide having no antigen-binding activity may contain the amino acid sequence of an antibody constant region, Fc domain, scaffold, or fragment thereof, but the amino acid sequence is not limited to the above examples.\",\n \"A polypeptide having no antigen-binding activity can be combined with a polypeptide having an antigen-binding activity to produce a polypeptide multimer that monovalently binds to an antigen.\",\n \"In the present invention, the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity may contain the amino acid sequence of an antibody heavy chain constant region or the amino acid sequence of an antibody Fc domain.\",\n \"The amino acid sequence of an antibody Fc domain or an antibody heavy chain constant region includes, but is not limited to, those of human IgG-type constant regions and Fc domains.\",\n \"IgG-type constant regions or Fc domains may be of natural IgG1, IgG2, IgG3, or IgG4 isotype, or may be variants thereof.\",\n \"Meanwhile, in the present invention, the third polypeptide having an antigen-binding activity and the fourth polypeptide having an antigen-binding activity may contain the amino acid sequence of an antibody light chain constant region.\",\n \"The amino acid sequence of an antibody light chain constant region includes, but is not limited to, those of human kappa- and human lambda-type constant regions, and variants thereof.\",\n \"Furthermore, in the present invention, polypeptides having an antigen-binding activity may contain the amino acid sequence of an antibody variable region (for example, the amino acid sequences of CDR1, CDR2, CDR3, FR1, FR2, FR3, and FR4).\",\n \"Moreover, in the present invention, the polypeptides having an antigen-binding activity may contain the amino acid sequence of an antibody heavy chain or an antibody light chain.\",\n \"More specifically, the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity may contain the amino acid sequence of an antibody heavy chain.\",\n \"Meanwhile, the third polypeptide having an antigen-binding activity and the fourth polypeptide having an antigen-binding activity may contain the amino acid sequence of an antibody light chain.\",\n \"When a polypeptide multimer of interest is a tetramer that is formed by multimerization between a dimer formed by the first and third polypeptides and a dimer formed by the second and fourth polypeptides, for example, a polypeptide in which the first and second polypeptides having an antigen-binding activity contain the amino acid sequence of an antibody heavy chain, and a polypeptide in which the third and fourth polypeptides having an antigen-binding activity contain the amino acid sequence of an antibody light chain, can be used for the polypeptide multimer of the present invention.\",\n \"Alternatively, a polypeptide in which the first polypeptide having an antigen-binding activity contains the amino acid sequence of an antibody heavy chain, a polypeptide in which the second polypeptide having an antigen-binding activity contains the amino acid sequence of an antibody light chain variable region and the amino acid sequence of an antibody heavy chain constant region, a polypeptide in which the third polypeptide having an antigen-binding activity contains the amino acid sequence of an antibody light chain, and a polypeptide in which the fourth polypeptide having an antigen-binding activity contains the amino acid sequence of an antibody heavy chain variable region, can also be used.\",\n \"Specifically, a polypeptide multimer of the present invention can be a multispecific antibody.\",\n \"In the present invention, a “multispecific antibody” refers to an antibody capable of specifically binding to at least two different antigens.\",\n \"In the present invention, “different antigens” refers not only to different antigen molecules per se, but also to different antigen determinants present in the same antigen molecules.\",\n \"Accordingly, for example, different antigen determinants present within a single molecule are included in the “different antigens” of the present invention.\",\n \"In the present invention, antibodies that recognize various different antigen determinants in a single molecule are regarded as “antibodies capable of specifically binding to different antigens”.\",\n \"In the present invention, multispecific antibodies include, but are not limited to, bispecific antibodies capable of specifically binding to two types of antigens.\",\n \"Preferred bispecific antibodies of the present invention include H2L2-type IgG antibodies (composed of two types of H chains and two types of L chains) having a human IgG constant region.\",\n \"More specifically, such antibodies include, but are not limited to, for example, IgG-type chimeric antibodies, humanized antibodies, and human antibodies.\",\n \"Moreover, a polypeptide having an antigen-binding activity may be, for example, a molecule in which at least two of a heavy chain variable region, light chain variable region, heavy chain constant region, and light chain constant region, are linked together as a single chain.\",\n \"Alternatively, the polypeptide may be an antibody in which at least two of a heavy chain variable region, light chain variable region, Fc domain (constant region without CH1 domain), and light chain constant region, are linked together as a single chain.\",\n \"In the present invention, the phrase “there is a larger difference of protein A-binding ability between polypeptides having an antigen-binding activity” means that the protein A-binding ability is not the same (is different) between two or more polypeptides as a result of amino acid modifications on the surface of polypeptides having an antigen-binding activity.\",\n \"More specifically, this phrase means that, for example, the protein A-binding ability of the first polypeptide having an antigen-binding activity is different from that of the second polypeptide having an antigen-binding activity.\",\n \"The difference of protein A-binding ability can be examined, for example, by using protein A affinity chromatography.\",\n \"The strength of protein A-binding ability of a polypeptide having an antigen-binding activity is correlated with the pH of solvent used for elution.\",\n \"The greater the protein A-binding ability of the polypeptide is, the lower the pH of the solvent used for elution becomes.\",\n \"Thus, the phrase “there is a larger difference of protein A-binding ability between polypeptides having an antigen-binding activity” can also be expressed as “when two or more polypeptides having an antigen-binding activity are eluted using protein A affinity chromatography, each polypeptide is eluted at a different solvent pH”.\",\n \"The difference in the pH of the elution solvent is 0.1 or more, preferably 0.5 or more, and still more preferably 1.0 or more, but is not limited thereto.\",\n \"Furthermore, in the present invention, it is preferable to alter the protein A-binding ability without lowering other activities (for example, plasma retention) of the polypeptides having an antigen-binding activity.\",\n \"A polypeptide multimer of interest that comprises the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity can be produced or purified using protein A affinity chromatography based on the difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.\",\n \"Specifically, for example, when the polypeptide multimer of the present invention is a bispecific antibody that has a common L chain (i.e., same amino acid sequence in the third and fourth polypeptides), the polypeptide multimer can be produced or purified by the method described below.\",\n \"First, host cells are introduced with the following: a nucleic acid that encodes the first polypeptide having an antigen-binding activity (more specifically, the first antibody heavy chain) whose amino acid at position 435 (EU numbering) in the amino acid sequence of the antibody heavy chain constant region is arginine (R); a nucleic acid that encodes the second polypeptide having an antigen-binding activity (more specifically, the second antibody heavy chain) whose amino acid at position 435 (EU numbering) in the amino acid sequence of the antibody heavy chain constant region is histidine (H); and a nucleic acid that encodes the third polypeptide having an antigen-binding activity (common L chain).\",\n \"The cells are cultured to express the DNAs transiently.\",\n \"Then, the resulting expression products are loaded onto a protein A column.\",\n \"After washing, elution is performed first with a high pH elution solution and then with a low pH elution solution.\",\n \"A homomeric antibody comprising two units of the first antibody heavy chain and two units of the common L chain does not have any protein A-binding site in its heavy chain constant region.\",\n \"Meanwhile, a bispecific antibody comprising the first antibody heavy chain, the second antibody heavy chain, and two units of the common L chain has a single protein A-binding site in its heavy chain constant region.\",\n \"A homomeric antibody comprising two units of the second antibody heavy chain and two units of the common L chain has two protein A-binding sites in its heavy chain constant region.\",\n \"As described above, the protein A-binding ability of a polypeptide correlates with the solvent pH for eluting the polypeptide in protein A affinity chromatography.\",\n \"The greater the protein A-binding ability is, the lower the solvent pH for elution becomes.\",\n \"Thus, when elution is carried out first with a high pH elution solution and then with a low pH elution solution, the antibodies are eluted in the following order: a homomeric antibody comprising two units of the first antibody heavy chain and two units of the common L chain a bispecific antibody comprising the first antibody heavy chain, the second antibody heavy chain, and two units of the common L chain a homomeric antibody comprising two units of the second antibody heavy chain and two units of the common L chain This allows production or purification of the polypeptide multimers (bispecific antibodies) of interest.\",\n \"The purity of the polypeptide multimers obtained by the production or purification methods of the present invention is at least 95% or higher (for example, 96%, 97%, 98%, 99% or higher).\",\n \"Modifications of amino acid residues to create a difference in the protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity include, but are not limited to: (1) modification of one or more amino acid residues in the amino acid sequence of either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity, such that the protein A-binding ability of one of the polypeptides is increased; (2) modification of one or more amino acid residues in the amino acid sequence of either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity, such that the protein A-binding ability of one of the polypeptides is decreased; and (3) modification of one or more amino acid residues in the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity, such that the protein A-binding ability of either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity is increased, and the protein A-binding ability of the other polypeptide is decreased.\",\n \"In the present invention, it is preferred that amino acids on the surface of a polypeptide having an antigen-binding activity or no antigen-binding activity are modified.\",\n \"Furthermore, it is also preferred to consider reducing the influence of the modification on other activities of the polypeptide.\",\n \"Accordingly, in the present invention, it is preferred to modify, for example, the amino acid residues at the following positions (EU numbering) in the antibody Fc domain or heavy chain constant region: TLMISR at positions 250-255, VLHQDWLNGK at positions 308-317, and EALHNHY at positions 430-436; preferably, TLMIS at positions 250-254, LHQD at positions 309-312, LN at positions 314 and 315, E at position 430, and LHNHY at positions 432-436; more preferably, LMIS at positions 251-254, LHQ at positions 309-311, L at position 314, and LHNH at positions 432-435; and in particular, MIS at positions 252-254, L at position 309, Q at position 311, and NHY at positions 434-436.As for amino acid modifications of the antibody heavy chain variable region, preferred mutation sites include FR1, CDR2, and FR3.More preferred mutation sites include, for example, positions H15-H23, H56-H59, H63-H72, and H79-H83 (EU numbering).\",\n \"Of the above amino acid modifications, modifications that do not reduce the binding to FcRn or the plasma retention in human FcRn transgenic mice are more preferred.\",\n \"More specifically, modifications that increase the protein A-binding ability of a polypeptide include, but are not limited to, substitution of histidine (His) for the amino acid residue at position 435 (EU numbering) in the amino acid sequence of an antibody Fc domain or an antibody heavy chain constant region.\",\n \"Meanwhile, modifications that reduce the protein A-binding ability of a polypeptide include, but are not limited to, substitution of arginine for the amino acid residue at position 435 (EU numbering) in the amino acid sequence of an antibody Fc domain or an antibody heavy chain constant region.\",\n \"As for the antibody heavy chain variable region, the heavy chain variable region of the VH3 subclass has protein A-binding activity.\",\n \"Thus, to increase the protein A-binding ability, the amino acid sequences at the above modification sites are preferably identical to those of the heavy chain variable region of the VH3 subclass.\",\n \"To reduce the protein A-binding ability, the amino acid sequences are preferably identical to those of the heavy chain variable region of another subclass.\",\n \"As described below, modification of amino acid residues can be achieved by altering one or more nucleotides in a DNA encoding a polypeptide, and expressing the DNA in host cells.\",\n \"Those skilled in the art can readily determine the number, site, and type of altered nucleotides depending on the type of amino acid residues after modification.\",\n \"Herein, modification (alteration) refers to substitution, deletion, addition, or insertion, or combinations thereof.\",\n \"The polypeptide having an antigen-binding activity may comprise other modifications in addition to the above modifications of amino acid residues.\",\n \"Such additional modifications can be selected from, for example, substitutions, deletions, and modifications of amino acids, and combinations thereof.\",\n \"Specifically, all polypeptides whose amino acid sequences comprise a modification described below are included in the present invention: amino acid modification for increasing the rate of heteromeric association of two types of H chains in a bispecific antibody amino acid modification for stabilizing the disulfide bonds between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity amino acid modification for improving the plasma retention of an antibody modification for increasing the stability under acidic conditions modification for reducing the heterogeneity modification for suppressing deamidation reaction modification for introducing a difference in between the isoelectric points of two types of polypeptides modification for altering the Fcγ receptor-binding ability These amino acid modifications are described below.\",\n \"Amino Acid Modification for Increasing the Rate of Heteromeric Association Between the Two Types of H Chains in a Bispecific Antibody The amino acid modifications of the present invention can be combined with the amino acid modifications described in WO2006106905.There is no limitation on the modification sites as long as the amino acids form the interface between two polypeptides having an antigen-binding activity.\",\n \"Specifically, for example, when a heavy chain constant region is modified, such modifications include modifications that make the amino acids of at least one of the combinations of positions 356 and 439, positions 357 and 370, and positions 399 and 409 (EU numbering) in the amino acid sequence of the heavy chain constant region of the first polypeptide having an antigen-binding activity have the same electric charge; and the amino acids of at least one of the combinations of positions 356 and 439, positions 357 and 370, and positions 399 and 409 (EU numbering) in the heavy chain constant region of the second polypeptide having an antigen-binding activity or no antigen-binding activity have electric charge opposite to that of the first polypeptide having an antigen-binding activity.\",\n \"More specifically, such modifications include, for example, introduction of a mutation that substitutes Glu at position 356 (EU numbering) with Lys in the amino acid sequence of the heavy chain constant region of either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity, and a mutation that substitutes Lys at position 439 (EU numbering) with Glu in the amino acid sequence of the heavy chain constant region of the other polypeptide.\",\n \"When these modifications are combined with the modifications of the present invention, the polypeptide of interest can be obtained with a higher purity by protein A-based purification alone.\",\n \"Alternatively, the polypeptide multimer of interest that comprises the first, second, third, and fourth polypeptides having an antigen-binding activity can be efficiently produced or purified to a higher purity, when modification is performed to make the amino acids at position 39 (Kabat numbering) in the heavy chain variable region and/or at position 213 (EU numbering) in the heavy chain constant region of the first polypeptide having an antigen-binding activity have an electric charge opposite to that of the amino acid at position 39 (Kabat numbering) in the heavy chain variable region and/or the amino acid at position 213 (EU numbering) in the heavy chain constant region of the second polypeptide having an antigen-binding activity or no antigen-binding activity, and the amino acid at position 38 (Kabat numbering) and/or the amino acid at position 123 (EU numbering) in the light chain variable region of the third polypeptide having an antigen-binding activity have an electric charge opposite to that of the amino acid at position 38 (Kabat numbering) and/or the amino acid at position 123 (EU numbering) in the light chain variable region of the fourth polypeptide having an antigen-binding activity.\",\n \"Amino Acid Modification for Stabilizing the Disulfide Bonds Between the First Polypeptide Having an Antigen-Binding Activity and the Second Polypeptide Having an Antigen-Binding Activity or No Antigen-Binding Activity As described in published documents (Mol.\",\n \"Immunol.\",\n \"1993, 30, 105-108; and Mol.\",\n \"Immunol.\",\n \"2001, 38, 1-8), the heterogeneity of IgG4 is eliminated and its stable structure can be maintained by substituting Pro for Ser at position 228 (EU numbering) in the amino acid sequence of the heavy chain constant region of IgG4.Amino Acid Modification for Improving the Plasma Retention of an Antibody In order to regulate plasma retention, it is possible to combine the amino acid modifications of the present invention with amino acid modifications that alter the antibody pI value.\",\n \"Modifications to constant regions include, for example, amino acid modifications at positions 250 and 428 (EU numbering) and such described in published documents (J. Immunol.\",\n \"2006, 176 (1):346-356; and Nat.\",\n \"Biotechnol.\",\n \"1997 15 (7):637-640).\",\n \"Modifications to variable regions include the amino acid modifications described in WO2007/114319 and WO2009/041643.Amino acids to be modified are preferably exposed on the surface of a polypeptide having an antigen-binding activity.\",\n \"The modifications include, for example, amino acid substitution at position 196 (EU numbering) in the amino acid sequence of a heavy chain constant region.\",\n \"In the case of the heavy chain constant region of IgG4, the plasma retention can be enhanced, for example, by substituting glutamine for lysine at position 196 thereby reducing the pI value.\",\n \"Furthermore, the plasma retention can be regulated by altering the FcRn-binding ability.\",\n \"Amino acid modifications that alter the FcRn-binding ability include, for example, the amino acid substitutions in the antibody heavy chain constant region described in published documents (The Journal of Biological Chemistry vol.\",\n \"276, No.\",\n \"9 6591-6604, 2001; Molecular Cell, Vol.\",\n \"7, 867-877, 2001; Curr Opin Biotechnol.\",\n \"2009, 20 (6):685-91).\",\n \"Such amino acid substitutions include, for example, substitutions at positions 233, 238, 253, 254, 255, 256, 258, 265, 272, 276, 280, 285, 288, 290, 292, 293, 295, 296, 297, 298, 301, 303, 305, 307, 309, 311, 312, 315, 317, 329, 331, 338, 360, 362, 376, 378, 380, 382, 415, 424, 433, 434, 435, and 436 (EU numbering).\",\n \"Modification for Improving the Stability Under Acidic Conditions When the heavy chain constant region of IgG4 is used, the stable four-chain structure (H2L2 structure) is preferably maintained by suppressing the conversion of IgG4 into the half-molecule form under acidic conditions.\",\n \"Thus, arginine at amino acid position 409 (EU numbering system) which plays an important role in the maintenance of the four-chain structure (Immunology 2002, 105, 9-19) is preferably substituted with lysine of the IgG1 type that maintains a stable four-chain structure even under acidic conditions.\",\n \"Furthermore, to improve the acidic stability of IgG2, methionine at amino acid position 397 (EU numbering system) can be substituted with valine.\",\n \"These modifications can be used in combination with the amino acid modifications of the present invention.\",\n \"Modification for Reducing Heterogeneity The amino acid modifications of the present invention may be combined with the methods described in WO2009041613.Specifically, for example, the modification in which the two amino acids at the C-terminus of the IgG1 heavy chain constant region (i.e., glycine and lysine at positions 446 and 447 [EU numbering], respectively) are deleted can be combined with the amino acid modifications described in the Examples herein.\",\n \"Modification for Suppressing Deamidation Reaction The amino acid modifications of the present invention may be combined with amino acid modifications for suppressing deamidation reaction.\",\n \"Deamidation reaction has been reported to occur more frequently at a site where asparagine (N) and glycine (G) are adjacent to each other (- - -NG- - -) (Geiger et al., J. Bio.\",\n \"Chem.\",\n \"(1987) 262:785-794).\",\n \"When a polypeptide multimer (multispecific antibody) of the present invention has a site where asparagine and glycine are adjacent to each other, deamidation reaction can be suppressed by modifying the amino acid sequence.\",\n \"Specifically, for example, either or both of asparagine and glycine are substituted with other amino acids.\",\n \"More specifically, for example, asparagine is substituted with aspartic acid.\",\n \"Modification for Introducing a Difference in Isoelectric Point Between Two Types of Polypeptides The amino acid modifications of the present invention may be combined with amino acid modifications for introducing a difference in isoelectric point.\",\n \"Specific methods are described, for example, in WO2007/114325.In addition to the modifications of the present invention, the amino acid sequences of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity are modified so that there is a larger difference in isoelectric point between these polypeptides.\",\n \"This enables efficient production or purification of the polypeptide of interest to a higher purity.\",\n \"Furthermore, a larger difference in isoelectric point can be produced between the third polypeptide having an antigen-binding activity and the fourth polypeptide having an antigen-binding activity.\",\n \"This allows the polypeptide multimer of interest comprising the first, second, third, and fourth polypeptides to be efficiently produced or purified to a higher purity.\",\n \"Specifically, when the first and second polypeptides each comprises an amino acid sequence of an antibody heavy chain, the modification sites include, for example, positions 1, 3, 5, 8, 10, 12, 13, 15, 16, 19, 23, 25, 26, 39, 42, 43, 44, 46, 68, 71, 72, 73, 75, 76, 81, 82b, 83, 85, 86, 105, 108, 110, and 112 (Kabat numbering).\",\n \"When the third and fourth polypeptides each comprises an amino acid sequence of an antibody light chain, the modification sites include, for example, positions 1, 3, 7, 8, 9, 11, 12, 16, 17, 18, 20, 22, 38, 39, 41, 42, 43, 45, 46, 49, 57, 60, 63, 65, 66, 68, 69, 70, 74, 76, 77, 79, 80, 81, 85, 100, 103, 105, 106, 107, and 108 (Kabat numbering).\",\n \"A larger difference in isoelectric point can be produced by modifying at least one of the amino acid residues at the above positions in one polypeptide to have an electric charge, and modifying at least one of the amino acid residues at the above positions in the other polypeptide to have no charge or opposite electric charge to the above.\",\n \"Modification for Altering the Fcγ Receptor-Binding Ability The amino acid modifications of the present invention may be combined with amino acid modifications that alter (increase or reduce) the Fcγ receptor-binding ability.\",\n \"Modifications for altering the Fcγ receptor-binding ability include, but are not limited to, the modifications described in Curr Opin Biotechnol.\",\n \"2009, 20(6):685-91.Specifically, the Fcγ receptor-binding ability can be altered, for example, by combining the modifications of the present invention with a modification that substitutes leucine at positions 234 and 235 and asparagine at position 272 (EU numbering) of an IgG1 heavy chain constant region with other amino acids.\",\n \"The amino acids after substitution include, but are not limited to, alanine.\",\n \"Preparation of DNAs that encode polypeptides having an antigen-binding activity, modification of one or more nucleotides, DNA expression, and recovery of expression products are described below Preparation of DNAs that Encode Polypeptides Having an Antigen-Binding Activity In the present invention, a DNA that encodes a polypeptide having an antigen-binding activity or a polypeptide having no antigen-binding activity may be the whole or a portion of a known sequence (naturally-occurring or artificial sequence), or combinations thereof.\",\n \"Such DNAs can be obtained by methods known to those skilled in the art.\",\n \"The DNAs can be isolated, for example, from antibody libraries, or by cloning antibody-encoding genes from hybridomas producing monoclonal antibodies.\",\n \"With regard to antibody libraries, many are already well known, and those skilled in the art can appropriately obtain antibody libraries since methods for producing antibody libraries are known.\",\n \"For example, regarding antibody phage libraries, one can refer to the literature such as Clackson et al., Nature 1991, 352: 624-8; Marks et al., J. Mol.\",\n \"Biol.\",\n \"1991, 222: 581-97; Waterhouses et al., Nucleic Acids Res.\",\n \"1993, 21: 2265-6; Griffiths et al., EMBO J.\",\n \"1994, 13: 3245-60; Vaughan et al., Nature Biotechnology 1996, 14: 309-14; or Japanese Patent Kohyo Publication No.\",\n \"(JP-A) H20-504970 (unexamined Japanese national phase publication corresponding to a non-Japanese international publication).\",\n \"In addition, known methods such as methods that use eukaryotic cells as libraries (WO95/15393) and ribosome display methods may be used.\",\n \"Furthermore, techniques to obtain human antibodies by panning using human antibody libraries are also known.\",\n \"For example, variable regions of human antibodies can be expressed on the surface of phages as single chain antibodies (scFvs) using phage display methods, and phages that bind to antigens can be selected.\",\n \"Genetic analysis of the selected phages can determine the DNA sequences encoding the variable regions of human antibodies that bind to the antigens.\",\n \"Once the DNA sequences of scFvs that bind to the antigens is revealed, suitable expression vectors can be produced based on these sequences to obtain human antibodies.\",\n \"These methods are already well known, and one can refer to WO92/01047, WO92/20791, WO93/06213, WO93/11236, WO93/19172, WO95/01438, and WO95/15388.As for methods for obtaining genes encoding antibodies from hybridomas, basically, known techniques may be used.\",\n \"Specifically, desired antigens or cells expressing the desired antigens are used as sensitizing antigens for immunization according to conventional immunization methods.\",\n \"The immune cells thus obtained are fused with known parent cells by ordinary cell fusion methods, and monoclonal antibody producing cells (hybridomas) are screened by ordinary screening methods.\",\n \"cDNAs of antibody variable regions (V regions) can be obtained by reverse transcription of mRNAs of the obtained hybridomas using reverse transcriptase.\",\n \"Antibody-encoding genes can be obtained by linking them with DNAs encoding the desired antibody constant regions (C regions).\",\n \"More specifically, without limitations, the following methods are examples.\",\n \"Sensitizing antigens for obtaining the antibody genes encoding the antibody heavy and light chains include both complete antigens with immunogenicity and incomplete antigens composed of haptens and such that do not show antigenicity.\",\n \"For example, full length proteins and partial peptides of proteins of interest can be used.\",\n \"In addition, it is known that substances composed of polysaccharides, nucleic acids, lipids, and such may become antigens.\",\n \"Thus, there are no particular limitations on antigens in the present invention.\",\n \"Antigens can be prepared by methods known to those skilled in the art, and they can be prepared, for example, by the following methods using baculoviruses (for example, WO98/46777).\",\n \"Hybridomas can be produced, for example, the following methods of Milstein et al.\",\n \"(G. Kohler and C. Milstein, Methods Enzymol.\",\n \"1981, 73: 3-46), and such.\",\n \"When the immunogenicity of an antigen is low, it can be linked to a macromolecule that has immunogenicity, such as albumin, and then used for immunization.\",\n \"Furthermore, by linking antigens with other molecules if necessary, they can be converted into soluble antigens.\",\n \"When transmembrane molecules such as receptors are used as antigens, portions of the extracellular regions of the receptors can be used as a fragment, or cells expressing transmembrane molecules on their cell surface may be used as immunogens.\",\n \"Antibody-producing cells can be obtained by immunizing animals using suitable sensitizing antigens described above.\",\n \"Alternatively, antibody-producing cells can be prepared by in vitro immunization of lymphocytes that can produce antibodies.\",\n \"Various mammals can be used as the animals for immunization, where rodents, lagomorphas and primates are generally used.\",\n \"Examples of such animals include mice, rats, and hamsters for rodents, rabbits for lagomorphas, and monkeys including the cynomolgus monkey, rhesus monkey, hamadryas, and chimpanzees for primates.\",\n \"In addition, transgenic animals carrying human antibody gene repertoires are also known, and human antibodies can be obtained by using these animals (see WO96/34096; Mendez et al., Nat.\",\n \"Genet.\",\n \"1997, 15: 146-56).\",\n \"Instead of using such transgenic animals, for example, desired human antibodies having binding activity against antigens can be obtained by in vitro sensitization of human lymphocytes with desired antigens or cells expressing the desired antigens, and then fusing the sensitized lymphocytes with human myeloma cells such as U266 (see Japanese Patent Application Kokoku Publication No.\",\n \"(JP-B) H1-59878 (examined, approved Japanese patent application published for opposition)).\",\n \"Furthermore, desired human antibodies can be obtained by immunizing transgenic animals carrying a complete repertoire of human antibody genes, with desired antigens (see WO93/12227, WO92/03918, WO94/02602, WO96/34096, and WO96/33735).\",\n \"Animal immunization can be carried out by appropriately diluting and suspending a sensitizing antigen in Phosphate-Buffered Saline (PBS), physiological saline, or such, and forming an emulsion by mixing an adjuvant if necessary, followed by an intraperitoneal or subcutaneous injection into animals.\",\n \"After that, the sensitizing antigen mixed with Freund's incomplete adjuvant is preferably administered several times every four to 21 days.\",\n \"Antibody production can be confirmed by measuring the target antibody titer in animal sera using conventional methods.\",\n \"Antibody-producing cells obtained from lymphocytes or animals immunized with a desired antigen can be fused with myeloma cells to generate hybridomas using conventional fusing agents (for example, polyethylene glycol) (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, 1986, 59-103).\",\n \"When required, hybridoma cells can be cultured and grown, and the binding specificity of the antibody produced from these hybridomas can be measured using known analysis methods, such as immunoprecipitation, radioimmunoassay (RIA), and enzyme-linked immunosorbent assay (ELISA).\",\n \"Thereafter, hybridomas that produce antibodies of interest whose specificity, affinity, or activity has been determined can be subcloned by methods such as limiting dilution.\",\n \"Next, genes encoding the selected antibodies can be cloned from hybridomas or antibody-producing cells (sensitized lymphocytes, and such) using probes that may specifically bind to the antibodies (for example, oligonucleotides complementary to sequences encoding the antibody constant regions).\",\n \"Cloning from mRNA using RT-PCR is also possible.\",\n \"Immunoglobulins are classified into five different classes, IgA, IgD, IgE, IgG, and IgM.\",\n \"These classes are further divided into several subclasses (isotypes) (for example, IgG-1, IgG-2, IgG-3, and IgG-4; IgA-1 and IgA-2; and such).\",\n \"Heavy chains and light chains used in the present invention to produce antibodies are not particularly limited and may derive from antibodies belonging to any of these classes or subclasses; however, IgG is particularly preferred.\",\n \"Herein, it is possible to modify heavy-chain-encoding genes and light-chain-encoding genes using genetic engineering techniques.\",\n \"Genetically modified antibodies, such as chimeric antibodies, humanized antibodies that have been artificially modified for the purpose of decreasing heterologous antigenicity and such against humans, can be appropriately produced if necessary for antibodies such as mouse antibodies, rat antibodies, rabbit antibodies, hamster antibodies, sheep antibodies, and camel antibodies.\",\n \"Chimeric antibodies are antibodies composed of a nonhuman mammal antibody heavy chain and light chain variable regions, such as mouse antibody, and the heavy chain and light chain constant regions of human antibody.\",\n \"They can be obtained by ligating the DNA encoding a variable region of a mouse antibody to the DNA encoding a constant region of a human antibody, incorporating them into an expression vector, and introducing the vector into a host for production of the antibody.\",\n \"A humanized antibody, which is also called a reshaped human antibody, can be synthesized by PCR from a number of oligonucleotides produced so that they have overlapping portions at the ends of DNA sequences designed to link the complementary determining regions (CDRs) of an antibody of a nonhuman mammal such as a mouse.\",\n \"The obtained DNA can be ligated to a DNA encoding a human antibody constant region.\",\n \"The ligated DNA can be incorporated into an expression vector, and the vector can be introduced into a host to produce the antibody (see EP239400 and WO96/02576).\",\n \"Human antibody FRs that are ligated via the CDR are selected when the CDR forms a favorable antigen-binding site.\",\n \"If necessary, amino acids in the framework region of an antibody variable region may be substituted such that the CDR of the reshaped human antibody forms an appropriate antigen-binding site (K. Sato et al., Cancer Res.\",\n \"1993, 53: 851-856).\",\n \"The monoclonal antibodies of the present invention include such humanized antibodies and chimeric antibodies.\",\n \"When the antibodies of the present invention are chimeric antibodies or humanized antibodies, the constant regions of these antibodies are preferably derived from human antibodies.\",\n \"For example, Cγ1, Cγ2, Cγ3, and Cγ4 can be used for the heavy chain, while Cκ and Cλ can be used for the light chain.\",\n \"Furthermore, the human antibody constant region may be modified as necessary to improve antibody or its production stability.\",\n \"A chimeric antibody of the present invention preferably comprises a variable region of an antibody derived from a nonhuman mammal and a constant region of a human antibody.\",\n \"Meanwhile, a humanized antibody of the present invention preferably comprises CDRs of an antibody derived from a nonhuman mammal, and FRs and C regions of a human antibody.\",\n \"The constant regions derived from human antibodies comprise specific amino acid sequences, which vary depending on the isotype such as IgG (IgG1, IgG2, IgG3, and IgG4), IgM, IgA, IgD, and IgE.\",\n \"The constant regions used to prepare the humanized antibodies of the present invention may be constant regions of antibodies of any isotype.\",\n \"A constant region of human IgG is preferably used, but the constant regions are not limited thereto.\",\n \"Meanwhile, there is no particular limitation on the human antibody-derived FRs which are used to prepare humanized antibodies, and they may be derived from an antibody of any isotype.\",\n \"The variable and constant regions of chimeric or humanized antibodies of the present invention may be modified by deletion, substitution, insertion, and/or addition, as long as the antibodies exhibit the same binding specificity as the original antibodies.\",\n \"Chimeric and humanized antibodies that use human-derived sequences are expected to be useful when administered to humans for therapeutic purposes or such, since their antigenicity in the human body has been attenuated.\",\n \"In the present invention, amino acids may be modified to alter the biological properties of an antibody.\",\n \"Minibodies (low-molecular-weight antibodies) are useful as the antibodies because of their in vivo kinetic properties and low-cost production using E. coli, plant cells, or such.\",\n \"Antibody fragments are one type of minibody.\",\n \"Minibodies include antibodies that comprise an antibody fragment as their partial structure.\",\n \"The minibodies of the present invention are not particularly limited by their structure or production method, as long as they have antigen-binding ability.\",\n \"Some minibodies have an activity greater than that of a whole antibody (Orita et al., Blood (2005) 105: 562-566).\",\n \"Herein, “antibody fragments” are not particularly limited as long as they are a portion of a whole antibody (for example, whole IgG).\",\n \"However, the antibody fragments preferably comprise a heavy chain variable region (VH) or a light chain variable region (VL).\",\n \"Preferred antibody fragments include, for example, Fab, F (ab′)2, Fab′, and Fv.\",\n \"The amino acid sequence of a heavy chain variable region (VH) or light chain variable region (VL) in an antibody fragment may be modified by substitution, deletion, addition, and/or insertion.\",\n \"Furthermore, some portions of a heavy chain variable region (VH) or light chain variable region (VL) may be deleted, as long as the fragments retain their antigen-binding ability.\",\n \"For example, of the above antibody fragments, “Fv” is a minimal antibody fragment that comprises the complete antigen recognition and binding sites.\",\n \"“Fv” is a dimer (VH-VL dimer) in which one heavy chain variable region (VH) and one light chain variable region (VL) are linked tightly by non-covalent bonding.\",\n \"The three complementarity determining regions (CDRs) of each variable region form an antigen-binding site on the surface of the VH-VL dimer.\",\n \"Six CDRs confer an antigen-binding site to the antibody.\",\n \"However, even one variable region (or half of an Fv comprising only three antigen-specific CDRs) has the ability to recognize and bind to an antigen, although its affinity is lower than that of the complete binding site.\",\n \"Thus, such molecules which are smaller than Fv are also included in the antibody fragments of the present invention.\",\n \"Furthermore, the variable regions of an antibody fragment may be chimerized or humanized.\",\n \"It is preferable that the minibodies comprise both a heavy chain variable region (VH) and a light chain variable region (VL).\",\n \"The minibodies include, for example, antibody fragments such as Fab, Fab′, F(ab′)2, and Fv, and scFv (single-chain Fv) which can be prepared using antibody fragments (Huston et al., Proc.\",\n \"Natl.\",\n \"Acad.\",\n \"Sci.\",\n \"USA (1988) 85: 5879-83; Plickthun “The Pharmacology of Monoclonal Antibodies” Vol.\",\n \"113, Resenburg and Moore (eds.\",\n \"), Springer Verlag, New York, pp.\",\n \"269-315, (1994)); diabodies (Holliger et al., Proc.\",\n \"Natl.\",\n \"Acad.\",\n \"Sci.\",\n \"USA (1993) 90:6444-8; EP 404097; WO93/11161; Johnson et al., Method in Enzymology (1991) 203: 88-98; Holliger et al., Protein Engineering (1996) 9:299-305; Perisic et al., Structure (1994) 2:1217-26; John et al., Protein Engineering (1999) 12(7):597-604; Atwell et al., Mol.\",\n \"Immunol.\",\n \"(1996) 33:1301-12); sc(Fv)2 (Hudson et al., J Immunol.\",\n \"Methods (1999) 231:177-89; Orita et al., Blood (2005) 105:562-566); triabodies (Journal of Immunological Methods (1999) 231: 177-89); and tandem diabodies (Cancer Research (2000) 60:4336-41).\",\n \"An antibody fragment can be prepared by treating an antibody with an enzyme, for example, a protease such as papain and pepsin (see Morimoto et al., J. Biochem.\",\n \"Biophys.\",\n \"Methods (1992) 24:107-17; Brennan et al., Science (1985) 229:81).\",\n \"Alternatively, an antibody fragment can also be produced by genetic recombination based on its amino acid sequence.\",\n \"A minibody comprising a structure that results from modification of an antibody fragment can be constructed using an antibody fragment obtained by enzyme treatment or genetic recombination.\",\n \"Alternatively, after constructing a gene that encodes a whole minibody and introducing it into an expression vector, the minibody may be expressed in appropriate host cells (see, for example, Co et al., J. Immunol.\",\n \"(1994) 152:2968-76; Better and Horwitz, Methods Enzymol.\",\n \"(1989) 178:476-96; Pluckthun and Skerra, Methods Enzymol.\",\n \"(1989) 178: 497-515; Lamoyi, Methods Enzymol.\",\n \"(1986) 121:652-63; Rousseaux et al., Methods Enzymol.\",\n \"(1986) 121:663-9; Bird and Walker, Trends Biotechnol.\",\n \"(1991) 9:132-7).\",\n \"The above scFv is a single-chain polypeptide comprising two variable regions linked together via a linker or such, as necessary.\",\n \"The two variable regions contained in an scFv are typically one VH and one VL, but an scFv may have two VH or two VL.\",\n \"In general, scFv polypeptides comprise a linker between the VH and VL domains, thereby forming a paired portion of VH and VL required for antigen binding.\",\n \"A peptide linker of ten or more amino acids is typically used as the linker between VH and VL for forming an intramolecularly paired portion between VH and VL.\",\n \"However, the linkers of the scFv of the present invention are not limited to such peptide linkers, as long as they do not inhibit scFv formation.\",\n \"To review scFv, see Pluckthun “The Pharmacology of Monoclonal Antibody”, Vol.\",\n \"113 (Rosenburg and Moore ed., Springer Verlag, NY, pp.\",\n \"269-315 (1994)).\",\n \"Meanwhile, “diabodies (Db)” refers to divalent antibody fragments constructed by gene fusion (P. Holliger et al., Proc.\",\n \"Natl.\",\n \"Acad.\",\n \"Sci.\",\n \"USA 90: 6444-6448 (1993); EP 404,097; WO93/11161; etc.).\",\n \"Diabodies are dimers comprising two polypeptide chains, in which each polypeptide chain comprises within the same chain a light chain variable region (VL) and a heavy chain variable region (VH) linked via a linker short enough to prevent interaction of these two domains, for example, a linker of about five residues.\",\n \"VL and VH encoded on the same polypeptide chain will form a dimer because the linker between VL and VH is too short to form a single-chain V region fragment.\",\n \"Therefore, diabodies have two antigen-binding sites.\",\n \"In this case, when VL and VH directed against two different epitopes (a and b) are expressed simultaneously as combinations of VLa-VHb and VLb-VHa connected with a linker of about five residues, they are secreted as bispecific Db.\",\n \"Diabodies comprise two molecules of scFv and thus have four variable regions.\",\n \"As a result, diabodies have two antigen binding sites.\",\n \"Unlike situations in which scFv does not form dimers, in diabody formation, the length of the linker between the VH and VL in each scFv molecule is generally about five amino acids when the linker is a peptide linker.\",\n \"However, the linker of scFv that forms a diabody is not limited to such a peptide linker, as long as it does not inhibit scFv expression and diabody formation.\",\n \"Furthermore, it is preferable that minibodies and antibody fragments of the present invention additionally comprise an amino acid sequence of an antibody heavy chain constant region and/or an amino acid sequence of a light chain constant region.\",\n \"Alteration of One or More Nucleotides Herein, “alteration of nucleotides” means that gene manipulation or mutagenesis is performed to insert, delete, or substitute at least one nucleotide in a DNA so that the polypeptide encoded by the DNA has amino acid residues of interest.\",\n \"Specifically, this means that the codon encoding the original amino acid residue is substituted with a codon encoding the amino acid residue of interest.\",\n \"Such nucleotide alterations can be introduced using methods such as site-directed mutagenesis (see, for example, Kunkel (1985) Proc.\",\n \"Natl.\",\n \"Acad.\",\n \"Sci.\",\n \"USA 82: 488), PCR mutagenesis, and cassette mutagenesis.\",\n \"In general, mutant antibodies whose biological properties have been improved show an amino acid sequence homology and/or similarity of 70% or higher, more preferably 80% or higher, and even more preferably 90% or higher (for example, 95% or higher, 97%, 98%, 99%, etc.\",\n \"), when compared to the amino acid sequence of the original antibody variable region.\",\n \"Herein, the sequence homology and/or similarity is defined as the ratio of amino acid residues that are homologous (the same residue) or similar (amino acid residues classified into the same group based on the general properties of amino acid side chains) to the original amino acid residues, after maximizing the value of the sequence homology by performing sequence alignment and gap introduction as necessary.\",\n \"In general, naturally-occurring amino acid residues are classified into the following groups based on the characteristics of their side chains: (1) hydrophobic: alanine, isoleucine, valine, methionine, and leucine; (2) neutral hydrophilic: asparagine, glutamine, cysteine, threonine, and serine; (3) acidic: aspartic acid and glutamic acid; (4) basic: arginine, histidine, and lysine; (5) residues that have an influence on the chain conformation: glycine and proline; and (6) aromatic: tyrosine, tryptophan, and phenylalanine.\",\n \"The number of modified amino acids is, for example, ten, nine, eight, seven, six, five, four, three, two, or one, but is not limited thereto.\",\n \"In general, a total of six complementarity determining regions (CDRs; hypervariable regions) present in the heavy chain and light chain variable regions interact to form the antigen binding site(s) of an antibody.\",\n \"It is known that one of these variable regions has the ability to recognize and bind to the antigen, even though the affinity will be lower than when all binding sites are included.\",\n \"Thus, polypeptides of the present invention having an antigen-binding activity may encode fragment portions containing the respective antigen binding sites of antibody heavy chain and light chain as long as they maintain the desired antigen-binding activity.\",\n \"The methods of the present invention allow efficient preparation of, for example, desired polypeptide multimers that actually have the activity described above.\",\n \"In a preferred embodiment of the present invention, appropriate amino acid residues to be “modified” can be selected from, for example, the amino acid sequences of antibody heavy chain and light chain variable regions and the amino acid sequences of antibody light chain and light chain variable region.\",\n \"DNA Expression DNAs encoding the modified polypeptides are cloned (inserted) into an appropriate vector and then introduced into host cells.\",\n \"There is no particular limitation on the vectors as long as they stably carry the inserted nucleic acids.\",\n \"For example, when using E. coli as the host, the vectors include cloning vectors.\",\n \"Preferred cloning vectors include pBluescript vectors (Stratagene).\",\n \"It is possible to use various commercially available vectors.\",\n \"Expression vectors are particularly useful as vectors for producing the polypeptide multimers or polypeptides of the present invention.\",\n \"There is no particular limitation on the expression vectors as long as they express polypeptides in vitro, in E. coli, culture cells, or organisms.\",\n \"Preferred vectors include, for example, pBEST vectors (Promega) for in vitro expression; pET vectors (Invitrogen) for expression in E. coli; the pME18S-FL3 vector (GenBank Accession No.\",\n \"AB009864) for expression in culture cells; and the pME18S vector (Mol.\",\n \"Cell.\",\n \"Biol.\",\n \"8:466-472 (1988)) for expression in organisms.\",\n \"DNAs can be inserted into vectors by conventional methods such as ligase reaction using restriction enzyme sites (Current protocols in Molecular Biology edit.\",\n \"Ausubel et al.\",\n \"(1987) Publish.\",\n \"John Wiley & Sons.\",\n \"Section 11.4-11.11).\",\n \"There is no particular limitation on the above host cells, and various host cells can be used depending on the purpose.\",\n \"Cells for expressing polypeptides include, for example, bacterial cells (e.g., Streptococcus, Staphylococcus, E. coli, Streptomyces, and Bacillus subtilis), fungal cells (e.g., yeast and Aspergillus), insect cells (e.g., Drosophila S2 and Spodoptera SF9), animal cells (e.g., CHO, COS, HeLa, C127, 3T3, BHK, HEK293, Bowes melanoma cell), and plant cells.\",\n \"Vectors can be introduced into host cells using known methods such as the calcium phosphate precipitation method, electroporation method (Current protocols in Molecular Biology edit.\",\n \"Ausubel et al.\",\n \"(1987) Publish.\",\n \"John Wiley & Sons.\",\n \"Section 9.1-9.9), lipofection method, and microinjection method.\",\n \"In order to secrete host cell-expressed polypeptides into the lumen of the endoplasmic reticulum, periplasmic space, or extracellular environment, appropriate secretion signals can be incorporated into the polypeptides of interest.\",\n \"These signals may be intrinsic or foreign to the polypeptides of interest.\",\n \"Expression vectors for the first, second, third, and fourth polypeptides can be constructed by inserting DNAs encoding the polypeptides individually into separate vectors.\",\n \"Alternatively, some of the DNAs encoding the first, second, third, and fourth polypeptides (for example, a DNA encoding the first polypeptide and a DNA encoding the second polypeptide) may be inserted into a single vector to construct expression vectors.\",\n \"When an expression vector is constructed by inserting multiple DNAs into a single vector, there is no limitation on the combination of polypeptide-encoding DNAs to be inserted.\",\n \"Recovery of Expression Products When polypeptides are secreted to a culture medium, the expression products are recovered by collecting the medium.\",\n \"When polypeptides are produced in cells, the cells are first lysed and then the polypeptides are collected.\",\n \"The polypeptides can be collected and purified from a culture of recombinant cells by known methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography, and lectin chromatography.\",\n \"Protein A affinity chromatography is preferably used in the present invention.\",\n \"Protein A columns include, but are not limited to, Hyper D (PALL), POROS (Applied Biosystems), Sepharose F.F.\",\n \"(GE), and ProSep (Millipore).\",\n \"Alternatively, protein A affinity chromatography can be performed using a resin bound by a ligand that mimics the IgG-binding ability of protein A.\",\n \"Also when such a protein A mimic is used, polypeptide multimers of interest can be isolated and purified by creating a difference in the binding ability as a result of the amino acid modifications of the present invention.\",\n \"Such protein A mimics include, but are not limited to, for example, mabSelect SuRE (GE Healthcare).\",\n \"Furthermore, the present invention provides polypeptide multimers obtained by the production or purification methods of the present invention.\",\n \"The present invention also provides polypeptide multimers comprising the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity, wherein the protein A-binding ability is different between the first and second polypeptides.\",\n \"Such polypeptide multimers can be obtained by the methods described herein.\",\n \"The structures and properties of the polypeptide multimers are as described above, and summarized below.\",\n \"As compared to before modification of amino acids, the protein A-binding ability of the polypeptide multimers of the present invention has been altered.\",\n \"More specifically, the protein A-binding ability has been altered in either or both of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.\",\n \"In a polypeptide multimer of the present invention, the protein A-binding ability of the first polypeptide having an antigen-binding activity is different from that of the second polypeptide having an antigen-binding activity or no antigen-binding activity.\",\n \"Accordingly, the solvent pH for protein A elution is different for the first polypeptide and the second polypeptide in affinity chromatography.\",\n \"Furthermore, the first polypeptide and/or the second polypeptide can form a multimer with one or two third polypeptides.\",\n \"Thus, the present invention relates to polypeptide multimers that comprise the first polypeptide having an antigen-binding activity, the second polypeptide having an antigen-binding activity or no antigen-binding activity, and one or two third polypeptides having an antigen-binding activity, wherein the protein A-binding ability is different for the first and second polypeptides.\",\n \"Such polypeptide multimers can also be obtained by the methods described herein.\",\n \"The polypeptide multimers may additionally comprise a fourth polypeptide.\",\n \"Either one of the first polypeptide and the second polypeptide can form a multimer with the third polypeptide, while the other can form another multimer with the fourth polypeptide.\",\n \"Thus, the present invention relates to polypeptide multimers that comprise the first polypeptide having an antigen-binding activity, the second polypeptide having an antigen-binding activity or no antigen-binding activity, the third polypeptide having an antigen-binding activity, and the fourth polypeptide having an antigen-binding activity, wherein the protein A-binding ability is different for the first and second polypeptides.\",\n \"Such polypeptide multimers can also be obtained by the methods described herein.\",\n \"The above first polypeptide having an antigen-binding activity and second polypeptide having an antigen-binding activity or no antigen-binding activity may comprise an amino acid sequence of an antibody heavy chain constant region or an amino acid sequence of an antibody Fc domain.\",\n \"The amino acid sequence of an antibody heavy chain constant region or an antibody Fc domain includes, but is not limited to, an amino acid sequence of a human IgG-derived constant region.\",\n \"Meanwhile, the above third polypeptide having an antigen-binding activity and fourth polypeptide having an antigen-binding activity may comprise an amino acid sequence of an antibody light chain constant region.\",\n \"Furthermore, the polypeptides having an antigen-binding activity may comprise an amino acid sequence of an antibody variable region (for example, amino acid sequences of CDR1, CDR2, CDR3, FR1, FR2, FR3, and FR4).\",\n \"The above first polypeptide having an antigen-binding activity and second polypeptide having an antigen-binding activity or no antigen-binding activity may comprise an amino acid sequence of an antibody heavy chain, or an amino acid sequence comprising an antibody light chain variable region and an antibody heavy chain constant region.\",\n \"The above third polypeptide having an antigen-binding activity and fourth polypeptide having an antigen-binding activity may comprise an amino acid sequence of an antibody light chain, or an amino acid sequence comprising an antibody heavy chain variable region and an antibody light chain constant region.\",\n \"A polypeptide multimer of the present invention can be a multispecific antibody.\",\n \"Multispecific antibodies of the present invention include, but are not limited to, bispecific antibodies capable of specifically binding to two types of antigens.\",\n \"In a polypeptide multimer of the present invention, one or more amino acid residues have been modified so that there is a (larger) difference of protein A-binding ability between the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity.\",\n \"As described above, the modification sites include, but are not limited to, for example, the following amino acid residues: TLMISR at positions 250-255, VLHQDWLNGK at positions 308-317, EALHNHY at positions 430-436, preferably TLMIS at positions 250-254, LHQD at positions 309-312, LN at positions 314-315, E at position 430, LHNHY at positions 432-436, more preferably LMIS at positions 251-254, LHQ at positions 309-311, L at position 314, LHNH at positions 432-435, and particularly LMIS at positions 252-254, L at position 309, Q at position 311, and NHY at positions 434-436 (EU numbering) in an antibody Fc domain or a heavy chain constant region.\",\n \"Meanwhile, as for amino acid modifications of an antibody heavy chain variable region, preferred modification sites include FR1, CDR2, and FR3.More specifically, the polypeptide multimers of the present invention include, but are not limited to, polypeptide multimers in which the amino acid residue at position 435 (EU numbering) in the amino acid sequence of an antibody Fc domain or antibody heavy chain constant region is histidine or arginine in either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity, while the other polypeptide has a different amino acid residue at position 435 (EU numbering) in the amino acid sequence of an antibody Fc domain or antibody heavy chain constant region.\",\n \"Furthermore, the polypeptide multimers of the present invention include, but are not limited to, polypeptide multimers in which the amino acid residue at position 435 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region is histidine in either one of the first polypeptide having an antigen-binding activity and the second polypeptide having an antigen-binding activity or no antigen-binding activity, while the amino acid residue at position 435 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region is arginine in the other polypeptide.\",\n \"Furthermore, the polypeptide multimers of the present invention comprising the first and second polypeptides include, but are not limited to the examples below.\",\n \"(1) Polypeptide multimers that comprise the first or second polypeptide comprising an amino acid sequence in which the amino acid residues at positions 435 and 436 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region derived from a human IgG have been modified to histidine (His) and tyrosine (Tyr), respectively.\",\n \"Such polypeptide multimers include, but are not limited to, for example, polypeptide multimers that comprise the first or second polypeptide comprising the amino acid sequence of SEQ ID NO: 9, 11, 13, or 15.\",\n \"(2) Polypeptide multimers that comprise the first or second polypeptide comprising an amino acid sequence in which the amino acid residues at positions 435 and 436 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region derived from a human IgG have been modified to arginine (Arg) and phenylalanine (Phe), respectively.\",\n \"Such polypeptide multimers include, but are not limited to, for example, polypeptide multimers that comprise the first or second polypeptide comprising the amino acid sequence of SEQ ID NO: 10 or 12.\",\n \"(3) Polypeptide multimers that comprise the first or second polypeptide comprising an amino acid sequence in which the amino acid residues at positions 435 and 436 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region derived from a human IgG have been modified to arginine (Arg) and tyrosine (Tyr), respectively.\",\n \"Such polypeptide multimers include, but are not limited to, for example, polypeptide multimers that comprise the first or second polypeptide comprising the amino acid sequence of SEQ ID NO: 14.\",\n \"(4) Polypeptide multimers that comprise the first and second polypeptides, wherein either one of the polypeptides comprises an amino acid sequence in which the amino acid residues at positions 435 and 436 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region derived from a human IgG have been modified to histidine (His) and tyrosine (Tyr), respectively; and the other polypeptide comprises an amino acid sequence in which the amino acid residues at positions 435 and 436 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region have been modified to arginine (Arg) and phenylalanine (Phe), respectively.\",\n \"Such polypeptide multimers include, but are not limited to, for example, polypeptide multimers that comprise the first polypeptide comprising the amino acid sequence of SEQ ID NO: 9, 11, 13, or 15 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 10 or 12.\",\n \"(5) Polypeptide multimers that comprise the first and second polypeptides, wherein either one of the polypeptides comprises an amino acid sequence in which the amino acid residues at positions 435 and 436 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region derived from a human IgG have been modified to histidine (His) and tyrosine (Tyr), respectively; and the other polypeptide comprises an amino acid sequence in which the amino acid residues at positions 435 and 436 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region have been modified to arginine (Arg) and tyrosine (Tyr), respectively.\",\n \"Such polypeptide multimers include, but are not limited to, for example, polypeptide multimers that comprise the first polypeptide comprising the amino acid sequence of SEQ ID NO: 9, 11, 13, or 15 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 14.\",\n \"(6) Polypeptide multimers that comprise the first and second polypeptides, wherein either one of the polypeptides comprises an amino acid sequence in which the amino acid residues at positions 435 and 436 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region derived from a human IgG have been modified to arginine (Arg) and phenylalanine (Phe), respectively; and the other polypeptide comprises an amino acid sequence in which the amino acid residues at positions 435 and 436 (EU numbering) in the amino acid sequence of an antibody heavy chain constant region have been modified to arginine (Arg) and tyrosine (Tyr), respectively.\",\n \"Such polypeptide multimers include, but are not limited to, for example, polypeptide multimers that comprise the first polypeptide comprising the amino acid sequence of SEQ ID NO: 10 or 12 and the second polypeptide comprising the amino acid sequence of SEQ ID NO: 14.The above first and second polypeptides may additionally comprise an antibody heavy chain variable region.\",\n \"The polypeptide multimers of (1) to (6) above may also comprise the third polypeptide and/or the fourth polypeptide.\",\n \"Furthermore, the present invention provides polypeptide variants that comprise a polypeptide comprising a mutation in the amino acid residue at either position 435 or 436 (EU numbering).\",\n \"Such polypeptide variants include, but are not limited to, polypeptide variants comprising a polypeptide described in the Examples.\",\n \"Furthermore, the present invention provides nucleic acids encoding a polypeptide (polypeptide having an antigen-binding activity) that constitutes a polypeptide multimer of the present invention.\",\n \"The present invention also provides vectors carrying such nucleic acids.\",\n \"The present invention also provides host cells comprising the above nucleic acids or vectors.\",\n \"There is no particular limitation on the host cells, and they include, for example, E. coli and various plant and animal cells.\",\n \"The host cells may be used, for example, as a production system for producing and expressing the polypeptide multimers or polypeptides of the present invention.\",\n \"There are in vitro and in vivo production systems for producing the polypeptide multimers or polypeptides.\",\n \"In vitro production systems include those using eukaryotic cells and prokaryotic cells.\",\n \"Eukaryotic cells that can be used as host cells include, for example, animal cells, plant cells, and fungal cells.\",\n \"Animal cells include: mammalian cells, for example, CHO (J. Exp.\",\n \"Med.\",\n \"(1995) 108, 945), COS, HEK293, 3T3, myeloma, BHK (baby hamster kidney), HeLa, and Vero; amphibian cells such as Xenopus laevis oocytes (Valle, et al., Nature (1981) 291: 338-340); and insect cells such as Sf9, Sf21, and Tn5.For expressing the polypeptide multimers or polypeptides of the present invention, CHO-DG44, CHO-DX11B, COS7 cells, HEK293 cells, and BHK cells can be suitably used.\",\n \"Of the animal cells, CHO cells are particularly preferable for large-scale expression.\",\n \"Vectors can be introduced into a host cell by, for example, calcium phosphate methods, DEAE-dextran methods, methods using cationic liposome DOTAP (Boehringer-Mannheim), electroporation methods, or lipofection methods.\",\n \"It is known that plant cells such as Nicotiana tabacum-derived cells and Lemna minor cells are protein production systems, and these cells can be used to produce polypeptide multimers or polypeptides of the present invention by methods that culture calluses from these cells.\",\n \"Protein expression systems that use fungal cells including yeast cells, for example, cells of the genus Saccharomyces (Saccharomyces cerevisiae, Saccharomyces pombe, etc.\",\n \"), and cells of filamentous fungi, for example, the genus Aspergillus (Aspergillus niger, etc.)\",\n \"are known, and these cells can be used as a host to produce polypeptide multimers or polypeptides of the present invention.\",\n \"When prokaryotic cells are used, production systems that use bacterial cells are available.\",\n \"Production systems that use bacterial cells including Bacillus subtilis as well as E. coli described above are known, and they can be used to produce polypeptide multimers or polypeptides of the present invention.\",\n \"When a polypeptide multimer or polypeptide is produced using a host cell of the present invention, a polynucleotide encoding the polypeptide multimer or polypeptide of the present invention may be expressed by culturing the host cell transformed with an expression vector comprising the polynucleotide.\",\n \"Culturing can be performed according to known methods.\",\n \"For example, when animal cells are used as a host, DMEM, MEM, RPMI 1640, or IMDM may be used as the culture medium.\",\n \"The culture medium may be used with serum supplement solutions such as FBS or fetal calf serum (FCS).\",\n \"Alternatively, cells can be cultured in serum-free cultures.\",\n \"The preferred pH is about 6 to 8 during the course of culturing.\",\n \"Incubation is carried out typically at about 30 to 40° C. for about 15 to 200 hours.\",\n \"Medium is exchanged, aerated, or agitated, as necessary.\",\n \"On the other hand, systems for producing polypeptides in vivo include, for example, those using animals and those using plants.\",\n \"A polynucleotide of interest is introduced into an animal or plant to produce the polypeptide in the body of the animal or the plant, and then the polypeptide is collected.\",\n \"The “host” of the present invention includes such animals and plants.\",\n \"When animals are used, production systems that use mammals or insects are available.\",\n \"Mammals such as goat, pig, sheep, mouse, and cattle may be used (Vicki Glaser, SPECTRUM Biotechnology Applications (1993)).\",\n \"When mammals are used, transgenic animals may be used.\",\n \"For example, a polynucleotide encoding a polypeptide multimer or polypeptide of the present invention may be prepared as a fusion gene with a gene encoding a polypeptide specifically produced in milk, such as goat β-casein.\",\n \"Next, polynucleotide fragments containing this fusion gene are injected into goat embryos, which are then introduced back into female goats.\",\n \"The antibody of interest can be obtained from milk produced by the transgenic goats, which are born from the goats that received the embryos, or by their offspring.\",\n \"Appropriate hormones may be administered to the transgenic goats to increase the volume of milk containing the antibody produced by the transgenic goats (Ebert et al., Bio/Technology (1994) 12: 699-702).\",\n \"Insects such as silkworms may be used for producing polypeptide multimers or polypeptides of the present invention.\",\n \"When silkworms are used, baculoviruses carrying a polynucleotide encoding a polypeptide multimer or polypeptide of interest can be used to infect silkworms, so that the polypeptide multimer or polypeptide of interest can be obtained from the body fluids of these silkworms (Susumu et al., Nature (1985) 315:592-594).\",\n \"Plants used for producing polypeptide multimers or polypeptides of the present invention include, for example, tobacco.\",\n \"When tobacco is used, a polynucleotide encoding a polypeptide multimer or polypeptide of interest is inserted into a plant expression vector, for example, pMON 530, and then the vector is introduced into a bacterium such as Agrobacterium tumefaciens.\",\n \"The bacteria are then used to infect tobacco such as Nicotiana tabacum, and the desired polypeptide multimer or polypeptide can be obtained from the leaves of the tobacco (Ma et al., Eur.\",\n \"J. Immunol.\",\n \"(1994) 24: 131-138).\",\n \"Alternatively, the same bacteria can be used to infect Lemna minor, and after cloning, the desired polypeptide multimer or polypeptide can be obtained from the cells of Lemna minor (Cox K. M. et al., Nat.\",\n \"Biotechnol.\",\n \"2006 December; 24(12):1591-1597).\",\n \"The polypeptide multimer or polypeptide thus obtained may be isolated from the inside or outside (such as the medium and milk) of host cells, and purified as a substantially pure and homogenous polypeptide multimer or polypeptide.\",\n \"Methods used for separating and purifying a polypeptide multimer or polypeptide are not limited, and methods used in standard polypeptide purification may be applied.\",\n \"Antibodies may be isolated and purified by selecting an appropriate combination of, for example, chromatographic columns, filtration, ultrafiltration, salting-out, solvent precipitation, solvent extraction, distillation, immunoprecipitation, SDS-polyacrylamide gel electrophoresis, isoelectric focusing, dialysis, recrystallization, and such.\",\n \"Chromatographies include, for example, affinity chromatography, ion exchange chromatography, hydrophobic chromatography, gel filtration, reverse-phase chromatography, and adsorption chromatography (Strategies for Protein Purification and Characterization: A Laboratory Course Manual.\",\n \"Ed Daniel R. Marshak et al., (1996) Cold Spring Harbor Laboratory Press).\",\n \"These chromatographies can be carried out using liquid phase chromatography such as HPLC and FPLC.\",\n \"Examples of columns for affinity chromatography include protein A columns and protein G columns.\",\n \"Examples of the columns that use protein A include, but are not limited to, Hyper D, POROS, and Sepharose F. F. (Pharmacia).\",\n \"As necessary, modifications can be added and peptides can be deleted from a polypeptide multimer or polypeptide arbitrarily by treatment with an appropriate protein modification enzyme before or after purification of the polypeptide multimer or polypeptide.\",\n \"Such protein modification enzymes include, for example, trypsin, chymotrypsin, lysyl endopeptidase, protein kinase, and glucosidase.\",\n \"Another preferred embodiment of the present invention includes a method for producing a polypeptide multimer or polypeptide of the present invention, which comprises the steps of culturing the host cells of the present invention as described above and collecting the polypeptide from the cell culture.\",\n \"Furthermore, the present invention relates to pharmaceutical compositions (agents) comprising a polypeptide multimer or polypeptide of the present invention and a pharmaceutically acceptable carrier.\",\n \"In the present invention, “pharmaceutical compositions” generally refers to agents for treating or preventing, or testing and diagnosing diseases.\",\n \"The pharmaceutical compositions of the present invention can be formulated by methods known to those skilled in the art.\",\n \"For example, such pharmaceutical compositions can be used parenterally in the form of injections, which are sterile solutions or suspensions prepared with water or another pharmaceutically acceptable liquid.\",\n \"For example, such compositions may be formulated by appropriately combining with a pharmaceutically acceptable carrier or medium, specifically, sterile water, physiological saline, vegetable oil, emulsifier, suspension, surfactant, stabilizer, flavoring agent, excipient, vehicle, preservative, binder, or such, and mixed in a unit dose form that meets the generally accepted requirements for preparation of pharmaceuticals.\",\n \"In such preparations, the amount of active ingredient is adjusted such that a suitable amount within a specified range is obtained.\",\n \"Sterile compositions for injection can be formulated using vehicles such as distilled water for injection, according to standard protocols for formulation.\",\n \"Aqueous solutions for injection include, for example, physiological saline and isotonic solutions containing glucose or other adjuvants (for example, D-sorbitol, D-mannose, D-mannitol, and sodium chloride).\",\n \"Appropriate solubilizers, for example, alcohols (ethanol and such), polyalcohols (propylene glycol, polyethylene glycol, and such), non-ionic surfactants (polysorbate 80™, HCO-50, and such) may be used in combination.\",\n \"Oils include sesame and soybean oils.\",\n \"Benzyl benzoate and/or benzyl alcohol can be used as solubilizers in combination.\",\n \"Buffers (for example, phosphate buffer and sodium acetate buffer), soothing agents (for example, procaine hydrochloride), stabilizers (for example, benzyl alcohol and phenol), and/or antioxidants can also be combined.\",\n \"Prepared injections are generally filled into appropriate ampules.\",\n \"The pharmaceutical compositions of the present invention are preferably administered parenterally.\",\n \"For example, the compositions may be in the form of injections, transnasal agents, transpulmonary agents, or transdermal agents.\",\n \"For example, such compositions can be administered systemically or locally by intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, or such.\",\n \"The administration methods can be appropriately selected in consideration of a patient's age and symptoms.\",\n \"The dosage of a pharmaceutical composition comprising a polypeptide multimer or polypeptide or a polynucleotide encoding a polypeptide multimer or polypeptide may be set, for example, within the range of 0.0001 to 1000 mg/kg weight for each administration.\",\n \"Alternatively, the dosage may be, for example, from 0.001 to 100,000 mg per patient.\",\n \"However, in the present invention, the dosage is not necessarily limited to the ranges described above.\",\n \"Although the dosage and administration method vary depending on a patient's weight, age, symptoms, and such, those skilled in the art can select appropriate dosage and administration methods in consideration of these factors.\",\n \"The multispecific antibodies of the present invention can be formulated by combining them with other pharmaceutical components as necessary.\",\n \"All prior art references cited herein are incorporated by reference into this specification.\",\n \"EXAMPLES Hereinbelow, the present invention will be specifically described with reference to the Examples, but it is not to be construed as being limited thereto.\",\n \"[Example 1] Construction of Expression Vectors for Antibody Genes and Expression of Respective Antibodies The antibody H chain variable regions used were: Q153 (the H chain variable region of an anti-human F.IX antibody, SEQ ID NO: 1), Q407 (the H chain variable region of an anti-human F.IX antibody, SEQ ID NO: 2), J142 (the H chain variable region of an anti-human F.X antibody, SEQ ID NO: 3), J300 (the H chain variable region of an anti-human F.X antibody, SEQ ID NO: 4), and MRA-VH (the H chain variable region of an anti-human interleukin-6 receptor antibody, SEQ ID NO: 5).\",\n \"The antibody L chain variable regions used were: L180-k (an L chain common to an anti-human F.IX antibody and an anti-human F.X antibody, SEQ ID NO: 6), L210-k (an L chain common to an anti-human F.IX antibody/anti-human F.X antibody, SEQ ID NO: 7), and MRA-k (the L chain of an anti-human interleukin-6 receptor antibody, SEQ ID NO: 8).\",\n \"The antibody H chain constant regions used were: G4d (SEQ ID NO: 9), which was constructed from IgG4 by introducing a substitution mutation of Pro for Ser at position 228 (EU numbering) and deleting the C-terminal Gly and Lys; z72 (SEQ ID NO: 10), which was constructed from G4d by introducing the following mutations: a substitution mutation of Arg for His at position 435 (EU numbering); a substitution mutation of Phe for Tyr at position 436 (EU numbering); and a substitution mutation of Pro for Leu at position 445 (EU numbering); z7 (SEQ ID NO: 11), which was constructed from G4d by introducing a substitution mutation of Lys for Glu at position 356 (EU numbering); z73 (SEQ ID NO: 12), which was constructed from z72 by introducing a substitution mutation of Glu for Lys at position 439 (EU numbering); z106 (SEQ ID NO: 13), which was constructed from z7 by introducing the following mutations: a substitution mutation of Gln for Lys at position 196 (EU numbering); a substitution mutation of Tyr for Phe at position 296 (EU numbering); and a substitution mutation of Lys for Arg at position 409 (EU numbering); z107 (SEQ ID NO: 14), which was constructed from z73 by introducing the following mutations: a substitution mutation of Gln for Lys at position 196 (EU numbering); a substitution mutation of Tyr for Phe at position 296 (EU numbering); a substitution mutation of Lys for Arg at position 409 (EU numbering); and a substitution mutation of Tyr for Phe at position 436 (EU numbering); and Gld (SEQ ID NO: 15), which was constructed by deleting the C-terminal Gly and Lys from IgG1.Substitution mutations of Lys for Glu at position 356 (EU numbering) and Glu for Lys at position 439 (EU numbering) were introduced for efficient formation of heteromeric molecules from the respective H chains in the production of heteromeric antibodies ((WO 2006/106905) PROCESS FOR PRODUCTION OF POLYPEPTIDE BY REGULATION OF ASSEMBLY).\",\n \"The anti-human F.IX antibody H chain genes Q153-G4d and Q153-z7 were constructed by linking respectively G4d and z7 downstream of Q153.The anti-human F.IX antibody H chain gene Q407-z106 was constructed by linking z106 downstream of Q407.The anti-human F.X antibody H chain genes J142-G4d, J142-z72, and J142-z73 were constructed by linking respectively G4d, z72, and z73 downstream of J142.The anti-human F.X antibody H chain gene J300-z107 was constructed by linking z107 downstream of J300.The anti-human interleukin-6 receptor antibody H chain genes MRA-G1d, MRA-z106, and MRA-z107 were constructed by linking respectively G1d, z106, and z107 downstream of MRA-VH.\",\n \"The respective antibody genes (Q153-G4d, Q153-z7, Q407-z106, J142-G4d, J142-z72, J142-z73, J300-z106, MRA-G1d, MRA-z106, MRA-z107, L180-k, L210-k, and MRA-k) were inserted into animal cell expression vectors.\",\n \"The following antibodies were expressed transiently in FreeStyle293 cells (Invitrogen) by transfection using the constructed expression vectors.\",\n \"As shown below, antibodies were named using the combinations of transfected antibody genes.\",\n \"MRA-G1d/MRA-k MRA-z106/MRA-z107/MRA-k Q153-G4d/J142-G4d/L180-k Q153-G4d/J142-z72/L180-k Q153-z7/J142-z73/L180-k Q407-z106/J300-z107/L210-k [Example 2] Assessment of the Elution Conditions for Protein a Affinity Chromatography Q153-G4d/J142-G4d/L180-k and Q153-G4d/J142-z72/L180-k were expressed transiently, and the medium of the resulting FreeStyle293 cell culture (hereinafter abbreviated as CM) was used as a sample for assessing the elution conditions for protein A affinity chromatography.\",\n \"The CM samples were filtered through a filter with a pore size of 0.22 μm, and loaded onto an rProtein A Sepharose Fast Flow column (GE Healthcare) equilibrated with D-PBS.\",\n \"The column was subjected to washes 1 and 2 and elutions 1 to 5 in a stepwise manner as shown in Table 1.The volume of CM to be loaded onto the column was adjusted to 20 mg antibody/ml resin.\",\n \"Fractions eluted under each condition were collected, and the respective eluted fractions were analyzed by cation exchange chromatography to identify their components.\",\n \"To prepare controls, each CM was loaded onto rProtein G Sepharose Fast Flow resin (GE Healthcare).\",\n \"Samples purified by batchwise elution were used as controls.\",\n \"Since protein G binds to the Fab domain of an antibody, all antibody species (a bispecific antibody of interest in which two types of H chains are associated in a heteromeric manner (heteromeric antibody) and as an impurity monospecific homomeric antibodies in which single-type H chains are homomerically associated) in CM can be purified by using protein G, regardless of their protein A-binding affinity.\",\n \"TABLE 1 Equilibration D-PBS Wash 1 400 mM Arg-HCl/D-PBS Wash 2 20 mM NaCitrate, pH 5.0 Elution 1 20 mM NaCitrate, pH 4.0 Elution 2 20 mM NaCitrate, pH 3.8 Elution 3 20 mM NaCitrate, pH 3.6 Elution 4 20 mM NaCitrate, pH 3.4 Elution 5 20 mM NaCitrate, pH 3.2 CM in which Q153-G4d/J142-G4d/L180-k or Q153-G4d/J142-z72/L180-k had been expressed was eluted from a protein A column (elution 1 to 5), and the respective eluted fractions were analyzed by cation exchange chromatography.\",\n \"As for Q153-G4d/J142-G4d/L180-k, the analysis revealed that as the elution condition was altered from 1 to 5, i.e., as the pH of the elution buffer was reduced, the antibody composition of the eluted fractions changed gradually in the order from the homomeric antibody J142-G4d/L180-k to the heteromeric antibody Q153-G4d/J142-G4d/L180-k, and then to the homomeric antibody Q153-G4d/L180-k.\",\n \"The order of elution is understood to be in accordance with the binding ability for protein A.\",\n \"This implies that the homomeric antibody Q153-G4d/L180-k, which remained bound until exposed to low pH, has a greater binding ability for protein A than the homomeric species J142-G4d/L180-k (a homomeric antibody against FX) eluted at a high pH.\",\n \"It is known that the variable region J142 is a sequence incapable of binding to protein A.\",\n \"Specifically, the homomeric species J142-G4d/L180-k (a homomeric antibody against FX) has two protein A-binding sites; the heteromeric antibody Q153-G4d/J142-G4d/L180-k has three; and the homomeric antibody Q153-G4d/L180-k (homomeric antibody against FX) has four protein A-binding sites.\",\n \"Thus, it was revealed that more protein A-binding sites resulted in stronger protein A binding, and thus a lower pH was required for elution.\",\n \"Meanwhile, as for Q153-G4d/J142-z72/L180-k, it was revealed that as the elution condition was altered from 1 to 5, the antibody composition in the eluted fraction changed from the heteromeric antibody Q153-G4d/J142-z72/L180-k to the homomeric antibody Q153-G4d/L180-k.\",\n \"The homomeric antibody J142-z72/L180-k (a homomeric antibody against FX) was almost undetectable in any eluted fractions.\",\n \"This suggests that J142-z72/L180-k has no protein A-binding ability.\",\n \"It is thought that the lack of protein A-binding ability of J142-z72 might be due to the introduced substitution mutation of Arg for His at position 435 (EU numbering).\",\n \"The homomeric antibody J142-z72/L180-k (a homomeric antibody against FX) has no protein A-binding site, while the heteromeric antibody Q153-G4d/J142-z72/L180-k has two protein A-binding sites and the homomeric antibody Q153-G4d/L180-k (a homomeric antibody against FIX) has four.\",\n \"The homomeric antibody J142-z72/L180-k (a homomeric antibody against FX) passes through the column because it does not bind to protein A.\",\n \"This is the reason why J142-z72/L180-k was undetectable in any eluted fractions.\",\n \"Furthermore, in both cases of Q153-G4d/J142-G4d/L180-k and Q153-G4d/J142-z72/L180-k, it was suggested that the heteromeric antibody and homomeric antibody Q153-G4d/L180-k (a homomeric antibody against FIX) were separable from each other at pH 3.6 or a lower pH.\",\n \"[Example 3] Isolation and Purification of Heteromeric Antibodies by Protein a Chromatography CM samples containing the following antibodies were used: Q153-G4d/J142-G4d/L180-k Q153-G4d/J142-z72/L180-k Q153-z7/J142-z73/L180-k Q407-z106/J300-z107/L210-k The CM samples were filtered through a filter with a pore size of 0.22 μm, and loaded onto an rProtein A Sepharose Fast Flow column (GE Healthcare) equilibrated with D-PBS.\",\n \"The column was subjected to washes 1 and 2 and elutions 1 and 2 as shown in Table 2 (except that Q407-z106/J300-z107/L210-k was subjected to elution 1 only).\",\n \"The elution conditions were determined based on the result described in Example 2.The volume of CM to be loaded onto the column was adjusted to 20 mg antibody/ml resin.\",\n \"Respective fractions eluted under each condition were collected and analyzed by cation exchange chromatography to identify their components.\",\n \"To prepare controls, each CM was loaded onto rProtein G Sepharose Fast Flow resin (GE Healthcare) in the same manner as described in Example 2.Samples purified by batchwise elution were used as controls.\",\n \"TABLE 2 Equilibration D-PBS Wash 1 400 mM Arg-HCl/D-PBS Wash 2 20 mM NaCitrate, pH 5.0 Elution 1 20 mM NaCitrate, pH 3.6 Elution 2 20 mM NaCitrate, pH 2.7 The result of cation exchange chromatography analysis for each eluted fraction is shown in Table 3 below.\",\n \"The values represent the area of elution peak expressed in percentage.\",\n \"Except for the Q153-G4d/J142-G4d/L180-k antibody, homomeric antibodies against FX were almost undetectable in any fractions eluted.\",\n \"Thus, it was revealed that not only the homomeric antibody J142-z72 (a homomeric antibody against FX) described in Example 2 but also the homomeric antibodies J142-z73 and J300-z107 (a homomeric antibody against FX) were incapable of binding to protein A.\",\n \"It is thought that the lack of protein A-binding ability in the homomeric antibody against FX was due to the substitution mutation of Arg for His at position 435 (EU numbering), which was introduced into the H chain constant region of the antibody against FX.\",\n \"The heteromeric antibody, which is a bispecific antibody of interest, was detected mostly in the fraction of elution 1.Meanwhile, the majority of homomeric antibodies against FIX were eluted by elution 2, although they were also detected at a very low level in the fraction of elution 1.As compared to Q153-G4d/J142-z72/L180-k, in the cases of Q153-z7/J142-z73/L180-k and Q407-z106/J300-z107/L210-k, the proportion of the heteromeric antibody (bispecific antibody of interest) was considerably increased in the fraction eluted at pH 3.6.Thus, it was demonstrated that when the substitution mutations of Lys for Glu at position 356 (EU numbering) and of Glu for Lys at position 439 (EU numbering) for efficient formation of heteromeric molecules from the respective H chains were introduced in combination with the substitution mutation of Arg for His at position 435 (EU numbering), the heteromeric antibody (bispecific antibody of interest) could be purified to a purity of 98% or higher through the protein A-based purification step alone.\",\n \"As described above, the present inventors revealed that based on differences in the number of protein A-binding sites between the heteromeric antibody and homomeric antibodies, the heteromeric antibody could be isolated and purified to high purity through the protein A chromatography step alone.\",\n \"TABLE 3 Q153-G4d/J142-G4d/L180-k Fraction eluted Fraction eluted Peak area (%) Control at pH 3.6 at pH 2.7 J142-G4d/L180-k 17.6 27.5 — Q153-G4d/J142-G4d/L180-k 48.3 58.4 9.0 Q153-G4d/L180-k 34.1 14.1 91.0 TABLE 4 Q153-G4d/J142-z72/L180-k Fraction Fraction eluted eluted Peak area (%) Control at pH 3.6 at pH 2.7 J142-z72/L180-k 8.4 0.9 — Q153-G4d/J142-z72/L180-k 50.8 81.0 2.2 Q153-G4d/L180-k 40.8 18.1 97.8 TABLE 5 Q153-z7/J142-z73/L180-k Fraction Fraction eluted eluted Peak area (%) Control at pH 3.6 at pH 2.7 J142-z73/L180-k 3.2 — — Q153-z7/J142-z73/L180-k 90.7 98.1 2.7 Q153-z7/L180-k 6.1 1.9 97.3 [Example 4] Assessment of Pharmacokinetics in Human FcRn Transgenic Mice As described in Example 3 above, the present inventors demonstrated that by using z106 (SEQ ID NO: 13) and z107 (SEQ ID NO: 14) for the respective H chain constant regions of the bispecific antibody, the heteromeric antibody (bispecific antibody of interest) could be purified to a purity of 98% or higher through the protein A step alone.\",\n \"Meanwhile, the loss of protein A-binding affinity probably results in loss of human FcRn-binding activity because protein A and human FcRn recognize the same site in an IgG antibody (J Immunol.\",\n \"2000, 164(10):5313-8).\",\n \"Actually, there is a reported method for purifying a bispecific antibody to a purity of 95% using protein A.\",\n \"The method uses a rat IgG2b H chain which does not bind to protein A. Catumaxomab (a bispecific antibody) purified by this method has a half-life of about 2.1 days in human.\",\n \"Its half-life is significantly shorter than the half-life of a normal human IgG1 which is 2 to 3 weeks (Non-patent Document 2).\",\n \"In this context, antibodies that have z106 (SEQ ID NO: 13) and z107 (SEQ ID NO: 14) described in Example 3 as constant regions were assessed for their pharmacokinetics.\",\n \"In a pharmacokinetic experiment for calculating the half-life in human, the pharmacokinetics in human FcRn transgenic mice (B6.mFcRn−/−.hFcRn Tg line 276+/+mice, Jackson Laboratories) was assessed by the following procedure.\",\n \"MRA-G1d/MRA-k (hereinafter abbreviated as MRA-IgG1) having the IgG1 constant region and MRA-z106/MRA-z107/MRA-k (hereinafter abbreviated as MRA-z106/z107) that has z106/z107 as constant region was each intravenously administered once at a dose of 1 mg/kg to mice, and blood was collected at appropriate time points.\",\n \"The collected blood was immediately centrifuged at 15,000 rpm and 4° C. for 15 minutes to obtain blood plasma.\",\n \"The separated plasma was stored in a freezer at −20° C. or below until use.\",\n \"The plasma concentration was determined by ELISA.\",\n \"MRA-IgG1 and MRA-z106/z107k were assessed for their plasma retention in human FcRn transgenic mice.\",\n \"As shown in FIG.\",\n \"1, the result indicates that the retention of MRA-z106/z107 in plasma was comparable to or longer than that of MRA-IgG1.As described above, z106/z107, a constant region that allows for efficient production or purification of the heteromeric antibody to high purity by the protein A-based purification step alone, was demonstrated to be comparable or superior to human IgG1 in terms of plasma retention.\",\n \"[Example 5] Construction of Expression Vectors for Antibody Genes and Expression of Respective Antibodies The antibody H chain variable regions used were: Q499 (the H chain variable region of an anti-human F.IX antibody, SEQ ID NO: 16).\",\n \"J339 (the H chain variable region of an anti-human F.X antibody, SEQ ID NO: 17).\",\n \"The antibody L chain used was: L377-k (the L chain common to an anti-human F.IX antibody and an anti-human F.X antibody, SEQ ID NO: 18).\",\n \"The antibody H chain constant regions used were: z118 (SEQ ID NO: 19), which was constructed from z106 described in Example 1, by introducing a substitution mutation of Phe for Leu at position 405 (EU numbering); z121 (SEQ ID NO: 20), which was constructed from z118 by introducing a substitution mutation of Arg for His at position 435 (EU numbering); and z119 (SEQ ID NO: 21), which was constructed from z118 by introducing substitution mutations of Glu for Lys at position 356 (EU numbering) and Lys for Glu at position 439 (EU numbering).\",\n \"The anti-human F.IX antibody H chain genes Q499-z118 and Q499-z121 were constructed by linking respectively z118 and z121 downstream of Q499.The anti-human F. X antibody H chain gene J339-z119 was constructed by linking z119 downstream of J339.Each of the antibody genes (Q499-z118, Q499-z121, J339-z119, and L377-k) was inserted into an animal cell expression vector.\",\n \"The following antibodies were expressed transiently in FreeStyle293 cells (Invitrogen) by transfection using the constructed expression vectors.\",\n \"As shown below, antibodies were named using the combinations of transfected antibody genes.\",\n \"Q499-z118/J339-z119/L377-k Q499-z121/J339-z119/L377-k The above two antibodies are only different at the amino acid of position 435 in the EU numbering system in the H chain of the anti-human F.IX antibody.\",\n \"z118 has His at position 435 and it has protein A-binding affinity.\",\n \"Meanwhile, z121 has Arg at position 435, and it is predicted to have no protein A-binding activity based on the finding described in Example 2.Q499 is predicted to bind to protein A based on its sequence.\",\n \"Thus, as for Q499-z118/J339-z119/L377-k, the homomeric species J339-z119/L377-k (a homomeric antibody against FX) has two protein A-binding sites; the heteromeric antibody Q499-z118/J339-z119/L377-k has three; and the homomeric antibody Q499-z118/L377-k (homomeric antibody against FIX) has four protein A-binding sites.\",\n \"Meanwhile, as for Q499-z121/J339-z119/L377-k introduced with a modification that leads to loss of protein A-binding affinity, the homomeric species J339-z119/L377-k has two protein A-binding sites; the heteromeric antibody Q499-z121/J339-z119/L377-k has two; and the homomeric antibody Q499-z121/L377-k has two.\",\n \"Specifically, even if a modification that leads to loss of protein A-binding affinity (for example, a modification that substitutes Arg for the amino acid at position 435, EU numbering) was introduced into only the H chain which binds to protein A through its variable region, it would not produce the effect that allows for efficient isolation/purification of the heteromeric antibody to high purity by the protein A-based purification step alone.\",\n \"However, the modification that leads to the loss of protein A-binding ability can produce the effect when MabSelct SuRe (GE Healthcare) is used.\",\n \"MabSelect SuRe is a modified protein A incapable of binding to Q499 and a chromatographic carrier for use in the purification of antibodies.\",\n \"The carrier was developed to meet industrial requirements.\",\n \"The ligand is a recombinant protein A that has been modified by genetic engineering to be resistant to alkaline conditions.\",\n \"The great pH stability enables efficient and low-cost NaOH wash.\",\n \"Furthermore, the carrier is characteristic in that it does not bind to the heavy chain variable region of the VH3 subclass, such as Q499.With respect to Q499-z118/J339-z119/L377-k, the homomeric species J339-z119/L377-k has two MabSelect SuRe-binding sites; the heteromeric antibody Q499-z118/J339-z119/L377-k has two; and the homomeric antibody Q499-z118/L377-k has two.\",\n \"Meanwhile, as for Q499-z121/J339-z119/L377-k, the homomeric species J339-z119/L377-k has two MabSelect SuRe-binding sites; the heteromeric antibody Q499-z121/J339-z119/L377-k has a single site; and the homomeric antibody Q499-z121/L377-k does not have any MabSelect SuRe-binding site.\",\n \"Specifically, it is understood that by combining a modified protein A incapable of binding to the antibody variable region, such as MabSelect SuRe, with a modification that leads to loss of protein A-binding affinity, the heteromeric antibody can be efficiently isolated and purified to high purity by the protein A-based purification step alone regardless of the protein A-binding activity of the heavy chain variable region.\",\n \"[Example 6] Isolation and Purification of Heteromeric Antibodies by Affinity Chromatography Using Modified Protein A CM in which Q499-z118/J339-z119/L377-k or Q499-z121/J339-z119/L377-k had been expressed was subjected to chromatography using modified protein A.\",\n \"The CM samples were filtered through a filter with a pore size of 0.22 μm, and loaded onto a Mab Select SuRe column (GE Healthcare) equilibrated with D-PBS.\",\n \"The column was subjected to washes 1 and 2 and elution as shown in Table 7.Recombinant protein A consists of five domains (A to E) which have IgG-binding activity.\",\n \"In Mab Select SuRe, domain B has been modified by genetic engineering to have a tetrameric structure.\",\n \"Mab Select SuRe lacks affinity for the antibody variable region, and is advantageous in that it allows for antibody elution even under milder conditions as compared to conventional recombinant protein A.\",\n \"In addition, the resin has improved alkaline resistance and enables for cleaning in place using 0.1 to 0.5 M NaOH, and is thus more suitable for production.\",\n \"In the experiment described in this Example as shown in Table 7, 50 mM acetic acid (the pH was not adjusted and the measured pH was around 3.0) was used for the elution instead of the stepwise elution at pH3.6 and pH 2.7 described in Example 3.The respective eluted fractions were collected and analyzed by cation exchange chromatography to identify their components.\",\n \"To prepare controls, each CM was loaded onto rProtein G Sepharose Fast Flow resin (GE Healthcare) in the same manner as described in Example 2.Samples purified by batchwise elution were used as controls.\",\n \"Next, the fractions eluted from protein A were subjected to ion exchange chromatography.\",\n \"An SP Sepharose High Performance column (GE Healthcare) was equilibrated with an equilibration buffer (20 mM sodium phosphate buffer, pH 6.0).\",\n \"Then, the fractions eluted from protein A were neutralized with 1.5 M Tris-HCl, (pH7.4), and diluted three times with equilibration buffer, and loaded.\",\n \"Antibodies bound to the column were eluted with 25 column volumes (CV) of an NaCl concentration gradient of 50 to 350 mM.\",\n \"The eluted fractions containing the heteromeric antibody were purified by gel filtration chromatography using superdex200.The resulting monomer fractions were collected, and used in the assessment of pharmacokinetics in human FcRn transgenic mice described in Example 7.TABLE 7 Equilibration D-PBS Wash 1 400 mM Arg-HCl/D-PBS Wash 2 50 mM NaAcetate buffer, pH 6.0 Elution 50 mM Acetic acid The result of cation exchange chromatography analysis of each eluted fraction is shown in Tables 8 and 9.As shown in Table 8, with respect to Q499-z118/J339-z119/L377-k, the component ratio of each eluted fraction is not much different from that of the control.\",\n \"The reason is probably that all three species J339-z119/L377-k (a homomeric antibody against F.X), Q499-z118/L377-k (a homomeric antibody against F.IX), and Q499-z118/J339-z119/L377-k (a heteromeric antibody) had two binding sites for the modified protein, and thus there was no difference in terms of the association/dissociation during the protein A-based purification step.\",\n \"Meanwhile, in the case of Q499-z121/J339-z119/L377-k, the ratio of Q499-z121/L377-k (a homomeric antibody against F.IX) in the eluted fraction was significantly reduced as compared to the control as shown in Table 9.In contrast, the ratios of J339-z119/L377-k (a homomeric antibody against F.X) and Q499-z121/J339-z119/L377-k (a heteromeric antibody) in the eluted fraction were relatively increased as compared to the control along with a decrease of Q499-z121/L377-k.\",\n \"It was believed that this is because J339-z119/L377-k (a homomeric antibody against F.X) has two binding sites for the modified protein A and Q499-z121/J339-z119/L377-k (a heteromeric antibody) has one.\",\n \"However, Q499-z121/L377-k (a homomeric antibody against F.IX) has no binding site, and accordingly the majority of Q499-z121/L377-k passed through the column without binding to the modified protein A.\",\n \"As described above, the present invention also demonstrates that with respect to antibodies whose variable regions have protein A-binding activity, when the modified protein A is combined with a modification that leads to loss of protein A-binding affinity, one of the homomeric antibodies can be significantly decreased, and as a result the purity of the heteromeric antibody is increased by the protein A-based purification step alone.\",\n \"TABLE 8 Q499-z118/J339-z119/L377-k Eluted Peak area (%) Control fraction J339-z119/L377-k 2.3 4.2 Q499-z118/J339-z119/L377-k 75.5 79.1 Q499-z118/L377-k 22.3 16.7 TABLE 9 Q499-z121/J339-z119/L377-k Eluted Peak area (%) Control fraction J339-z119/L377-k 3.2 5.9 Q499-z121/J339-z119/L377-k 76.6 91.6 Q499-z121/L377-k 20.2 2.5 [Example 7] Assessment of Pharmacokinetics in Human FcRn Transgenic Mice Q499-z118/J339-z119/L377-k and Q499-z121/J339-z119/L377-k prepared as described in Example 6 were assessed for their pharmacokinetics.\",\n \"It is likely to be difficult to adjust the protein A-binding activity without loss of the human FcRn binding, because protein A and human FcRn recognize the same site in an antibody IgG (J Immunol.\",\n \"2000 164 (10):5313-8) as shown in FIG.\",\n \"2.To retain the binding affinity for human FcRn is very important for the long plasma retention (long half-life) in human, which is characteristic of IgG-type antibodies.\",\n \"In this context, pharmacokinetics was compared between Q499-z118/J339-z119/L377-k and Q499-z121/J339-z119/L377-k prepared as described in Example 6.In a pharmacokinetic experiment to predict the half-life in human, the pharmacokinetics in human FcRn transgenic mice (B6.mFcRn−/−.hFcRn Tg line 276+/+mice, Jackson Laboratories) was assessed by the following procedure.\",\n \"Q499-z118/J339-z119/L377-k and Q499-z121/J339-z119/L377-k were each intravenously administered once at a dose of 5 mg/kg to mice, and blood was collected at appropriate time points.\",\n \"The collected blood was immediately centrifuged at 15,000 rpm and 4° C. for 15 minutes to obtain blood plasma.\",\n \"The separated plasma was stored in a freezer at −20° C. or below until use.\",\n \"The blood concentration was determined by ELISA.\",\n \"As shown in FIG.\",\n \"3, the result indicates that Q499-z118/J339-z119/L377-k and Q499-z121/J339-z119/L377-k were comparable to each other in terms of plasma retention.\",\n \"Thus, z121/z119, a constant region in which either of the H chains is introduced with a modification that leads to loss of protein A-binding ability was demonstrated to be comparable in terms of plasma retention to z118/z119 which does not have the modification that leads to loss of protein A-binding affinity.\",\n \"As described above, the present inventors revealed a modification (for example, a substitution mutation of Arg for the amino acid at position 435, EU numbering) that leads to loss of protein A-binding ability but has no influence on the pharmacokinetics, and which allows for efficient isolation/purification of the heteromeric antibody to high purity through the protein A-based purification step alone regardless of the variable region.\",\n \"[Example 8] Introduction of Mutations into the CH3 Domain of GC33-IgG1-CD3-scFv and Preparation of Designed Molecules Through the Protein A-Based Purification Step Alone Introduction of Mutations for Protein A-Based Purification of the GC33-IgG1-CD3-scFv Molecule The inventors designed an anti-GPC3 IgG antibody molecule in which an anti-CD3 scFv antibody is linked to one of the two H chains (FIG.\",\n \"4).\",\n \"This molecule was expected to be capable of killing cancer cells by recruiting T cells to cancer cells through divalent binding to glypican-3 (GPC3), a cancer-specific antigen, and monovalent binding to CD3, a T-cell antigen.\",\n \"An anti-CD3 scFv antibody must be linked to only one of the two H chains to achieve the monovalent binding to CD3.In this case, it is necessary to purify the molecule formed via heteromeric association of the two types of H chains.\",\n \"Thus, using the same method described in Example 3, a substitution mutation of Arg for His at position 435 (EU numbering) was introduced into one of the H chains.\",\n \"Furthermore, the above mutation was combined with the mutations (a substitution of Lys for Asp at position 356, EU numbering, is introduced into one H chain and a substitution of Glu for Lys at position 439, EU numbering, is introduced into the other H chain) described in WO 2006/106905 (PROCESS FOR PRODUCTION OF POLYPEPTIDE BY REGULATION OF ASSEMBLY) as a modification to enhance the heteromeric association of the two H chains.\",\n \"The present inventors tested whether it was possible with the combined mutations to purify the molecule of interest by protein A chromatography alone.\",\n \"Construction of Expression Vectors for Antibody Genes and Expression of Respective Antibodies The gene encoding GPC3 (anti-human Glypican-3 antibody H chain variable region, SEQ ID NO: 22) as an antibody H chain variable region was constructed by a method known to those skilled in the art.\",\n \"Furthermore, the gene encoding GC33-k0 (anti-human Glypican-3 antibody L chain, SEQ ID NO: 23) as an antibody L chain was constructed by a method known to those skilled in the art.\",\n \"In addition, the genes described below were constructed as an antibody H chain constant region by a method known to those skilled in the art.\",\n \"LALA-G1d (SEQ ID NO: 24), which was constructed from IgG1 by substituting Ala for Leu at positions 234 and 235 (EU numbering), and Ala for Asn at position 297 (EU numbering), and deleting the C-terminal Gly and Lys LALA-G1d-CD3 (SEQ ID NO: 25), which was constructed from LALA-Gld by linking an anti-CD3 scFv (in which the anti-human CD3 antibody H chain variable region is linked via a peptide linker to the C terminus of the anti-human CD3 antibody L chain variable region) LALA-G3S3E-G1d (SEQ ID NO: 26), which was constructed from LALA-Gld by substituting Arg for His at position 435 (EU numbering) and Glu for Lys at position 439 (EU numbering); and LALA-S3K-G1d-CD3 (SEQ ID NO: 27), which was constructed from LALA-G1d-CD3 by substituting Lys for Asp at position 356 (EU numbering).\",\n \"Anti-human GPC3 antibody H chain genes NTA1L and NTA1R were constructed by linking respectively LALA-G1d-CD3 (in which an anti-CD3 scFv antibody is linked to the H chain constant region) and LALA-Gld (an H chain constant region) downstream of GPC3, which is the H chain variable region of an anti-human Glypican-3 antibody.\",\n \"Furthermore, anti-human GPC3 antibody H chain genes NTA2L and NTA2R were constructed by linking an anti-CD3 scFv antibody downstream of GPC3 as an H chain constant region, and linking LALA-S3K-G1d-CD3 introduced with a substitution mutation of Lys for Asp at position 356 (EU numbering) or LALA-G3S3E-G1d introduced with substitution mutations of Arg for His at position 435 (EU numbering) and of Glu for Lys at position 439 (EU numbering).\",\n \"The constructed genes were listed below.\",\n \"H chain NTA1L: GPC3-LALA-G1d-CD3 NTA1R: GPC3-LALA-G1d NTA2L: GPC3-LALA-S3K-G1d-CD3 NTA2R: GPC3-LALA-G3S3E-G1d L chain GC33-k0 Each of the antibody genes (H chains: NTA1L, NTA1R, NTA2L, and NTA2R; L chain: GC33-k0) was inserted into an animal cell expression vector.\",\n \"Using a method known to those skilled in the art, the antibodies listed below were expressed transiently in FreeStyle293 cells (Invitrogen) by transfecting the cells with the constructed expression vectors.\",\n \"As shown below, antibodies were named using the combinations of transfected antibody genes (first H chain/second H chain/L chain).\",\n \"NTA1L/NTA1R/GC33-k0 NTA2L/NTA2R/GC33-k0 Protein Purification of the Expressed Samples and Assessment of Heterodimer Yield Culture supernatants of FreeStyle293 cells (CM) containing the following antibodies were used as a sample.\",\n \"NTA1L/NTA1R/GC33-k0 NTA2L/NTA2R/GC33-k0 The CM samples were filtered through a filter with a pore size of 0.22 μm, and loaded onto an rProtein A Sepharose Fast Flow column (GE Healthcare) equilibrated with D-PBS.\",\n \"The column was subjected to washes 1 and 2 and elution 1 as shown in Table 10.The volume of CM to be loaded onto the column was adjusted to 20 mg antibody/ml resin.\",\n \"Respective fractions eluted under each condition were collected and analyzed by size exclusion chromatography to identify their components.\",\n \"TABLE 10 Equilibration D-PBS Wash 1 1 mM sodium acetate, 150 mM NaCl, pH 6.5 Wash 2 0.3 mM HCl, 150 mM NaCl, pH 3.7 Elution 1 2 mM HCl, pH 2.7 The result of size exclusion chromatography of each eluted fraction is shown in FIG.\",\n \"5 and Table 11 below.\",\n \"The values represent the area of elution peak expressed in percentage.\",\n \"For NTA1L/NTA1R/GC33-k0 and NTA2L/NTA2R/GC33-k0, the homomeric antibodies (antibodies with homomeric NTA1L or homomeric NTA2L) that have the anti-CD3 scFv antibody in both chains were almost undetectable.\",\n \"This is thought to be caused by the extremely low expression level of the H chains containing the anti-CD3 scFv antibody because the expression level of an scFv molecule is generally low.\",\n \"As for homomeric antibodies that do not contain the anti-CD3 scFv antibody in its two chains, about 76% of the NTA1R homomeric antibody was observed in the case of NTA1L/NTA1R/GC33-k0, while only about 2% of the homomeric NTA2R antibody was observed in the case of NTA2L/NTA2R/GC33-k0.Thus, the present invention demonstrated that when the substitution mutations of Lys for Glu at position 356 (EU numbering) and of Glu for Lys at position 439 (EU numbering) for efficient formation of heteromeric molecules from the respective H chains, was combined with the substitution mutation of Arg for His at position 435 (EU numbering), the heteromeric antibody (bispecific antibody of interest) could be efficiently purified to a purity of 98% or higher through the protein A-based purification step alone.\",\n \"TABLE 11 NTA1R NTA1L/NTA1R NTA1R homodimer heterodimer homodimer NTA1L/NTA1R/GC33-k0 0.7 23.5 75.8 NTA2L/NTA2R/GC33-k0 1.8 98.2 — [Example 9] Introduction of Mutations into the CH3 Domain of Monovalent Antibodies and Preparation of Designed Molecules Through the Protein A-Based Purification Step Alone Introduction of Mutations for the Purification of Monovalent Antibody Molecules Using Protein A An ordinary anti-GPC3 IgG antibody binds divalently via the two H chains to glypican-3 (GPC3), a cancer-specific antigen.\",\n \"In the experiment described in this Example, the inventors designed and assessed an anti-GPC3 IgG antibody molecule (FIG.\",\n \"6) that monovalently binds to glypican-3.It is thought that when compared to ordinary divalent antibodies, the monovalent binding of the molecule to glypican-3 (GPC3), a cancer-specific antigen, was based on affinity and not avidity.\",\n \"Thus, it was expected that the molecule was capable of binding to the antigen without crosslinking.\",\n \"To achieve the monovalent binding of the two H chains to glypican-3 (GPC3), one has to be an H chain consisting of a hinge-Fc domain that lacks the variable region and CH1 domain, while the other is an ordinary H chain.\",\n \"In this case, it is necessary to purify the molecule that results from heteromeric association of the two types of H chains.\",\n \"Thus, using the same method as described in Example 3, a substitution mutation of Arg for His at position 435 (EU numbering) was introduced into one of the H chains.\",\n \"Furthermore, the above mutation was combined with the mutations (a substitution of Lys for Asp at position 356, EU numbering, is introduced into one H chain and a substitution of Glu for Lys at position 439, EU numbering, is introduced into the other H chain) described in WO 2006/106905 (PROCESS FOR PRODUCTION OF POLYPEPTIDE BY REGULATION OF ASSEMBLY) as a modification to enhance the heteromeric association of the two H chains.\",\n \"The present inventors assessed whether it was possible with the combined mutations to purify the molecule of interest by protein A chromatography alone.\",\n \"Construction of Expression Vectors for Antibody Genes and Expression of Respective Antibodies The antibody H chain variable region used was: GPC3 (the H chain variable region of an anti-human Glypican-3 antibody, SEQ ID NO: 22).\",\n \"The antibody L chain used was: GC33-k0 (the L chain of an anti-human Glypican-3 antibody, SEQ ID NO: 23).\",\n \"The antibody H chain constant regions used were: LALA-Gld (SEQ ID NO: 24), which was constructed from IgG1 by introducing substitution mutations of Ala for Leu at positions 234 and 235 (EU numbering), and of Ala for Asn at position 297 (EU numbering), and deleting the C-terminal Gly and Lys; LALA-G3-G1d (SEQ ID NO: 28), which was constructed from LALA-Gld by introducing a substitution mutation of Arg for His at position 435 (EU numbering); LALA-G3S3E-G1d (SEQ ID NO: 26), which was constructed from LALA-G3-G1d by introducing a substitution mutation of Glu for Lys at position 439 (EU numbering); LALA-G1Fc (SEQ ID NO: 29), which was constructed from LALA-Gld by deleting the region of positions 1 to 215 (EU numbering); and LALA-G1Fc-S3K (SEQ ID NO: 30), which was constructed from G1Fc by introducing a substitution mutation of Lys for Asp at position 356 (EU numbering).\",\n \"Anti-human GPC3 antibody H chain genes NTA4L-cont, NTL4L-G3, and NTA4L were constructed by linking downstream of GPC3 (the H chain variable region of an anti-human Glypican-3 antibody), respectively, LALA-Gld (an H chain constant region), LALA-G3-Gld introduced with a substitution mutation of Arg for His at position 435 (EU numbering), and LALA-G3S3E-Gld introduced with substitution mutations of Arg for His at position 435 (EU numbering) and of Glu for Lys at position 439 (EU numbering).\",\n \"Furthermore, Fc genes NTA4R-cont and NTA4R were constructed by using LALA-G1Fc (an anti-human hinge Fc domain) and LALA-G1Fc-S3K (a hinge Fc domain introduced with a substitution mutation of Lys for Asp at position 356, EU numbering).\",\n \"The constructed genes are: H chain NTA4L-cont: GPC3-LALA-G1 d NTA4L-G3: GPC3-LALA-G3-Gld NTA4L: GPC3-LALA-G3S3E-Gld NTA4R-cont: LALA-G1Fc NTA4R: LALA-G1Fc-S3K L chain GC33-k0 The antibody genes (NTA4L, NTA4L-cont, NTA4L-G3, NTA4R, NTA4R-cont, and GC33-k0) were each inserted into an animal cell expression vector.\",\n \"The following antibodies were expressed transiently in FreeStyle293 cells (Invitrogen) by transfection using the constructed expression vectors.\",\n \"As shown below, antibodies were named using the combinations of transfected antibody genes.\",\n \"NTA4L-cont/NTA4R-cont/GC33-k0 NTA4L-G3/NTA4R-cont/GC33-k0 NTA4L/NTA4R/GC33-k0 Protein Purification of Expressed Samples and Assessment of Heterodimer Yield CM containing the following antibody was used as a sample: NTA4L-cont/NTA4R-cont/GC33-k0 NTA4L-G3/NTA4R-cont/GC33-k0 NTA4L/NTA4R/GC33-k0 The CM samples were filtered through a filter with a pore size of 0.22 μm, and loaded onto an rProtein A Sepharose Fast Flow column (GE Healthcare) equilibrated with D-PBS.\",\n \"The column was subjected to washes 1 and 2 and elution 1 as shown in Table 12.The volume of CM to be loaded onto the column was adjusted to 20 mg antibody/ml resin.\",\n \"Respective fractions eluted under each condition were collected and analyzed by size exclusion chromatography to identify their components.\",\n \"TABLE 12 Equilibration D-PBS Wash 1 1 mM sodium acetate, 150 mM NaCl, pH 6.5 Wash 2 0.3 mM HCl, 150 mM NaCl, pH 3.7 Elution 1 2 mM HCl, pH 2.7 The result of size exclusion chromatography analysis of each eluted fraction is shown in FIG.\",\n \"7 and Table 13 below.\",\n \"The values represent the area of elution peak expressed in percentage.\",\n \"As for NTA4L-cont/NTA4R-cont/GC33-k0, the homomeric antibody that divalently binds to GPC3 (homomeric antibody NTA4L-cont) and the homomeric molecule that has no GPC3-binding domain (homomeric antibody NTA4R-cont) were eluted, while the heteromeric antibody of interest, NTA4L-cont/NTA4R-cont, accounted for only 46.5%.\",\n \"In the case of NTA4L-G3/NTA4R-cont/GC33-k0, the homomeric antibody that divalently binds to GPC3 (homomeric antibody NTA4L-G3) was almost undetectable, while the homomeric molecule having no GPC3-binding domain (homomeric antibody NTA4R-cont) was abundant.\",\n \"The heteromeric antibody of interest, NTA4L-G3/NTA4R-cont, accounted for 66.7%.\",\n \"In the case of NTA4L/NTA4R/GC33-k0, the homomeric antibody that divalently binds to GPC3 (homomeric antibody NTA4L) was almost undetectable, and the proportion of the homomeric molecule having no GPC3-binding domain (NTA4R) was considerably reduced, resulting in a significant increase of up to 93.0% in the proportion of the heteromeric antibody of interest, NTA4L/NTA4R.\",\n \"Thus, the present invention demonstrated that when the substitution mutations of Lys for Asp at position 356 (EU numbering) and of Glu for Lys at position 439 (EU numbering) for efficient formation of heteromeric molecules from the respective H chains were introduced in combination with the substitution mutation of Arg for His at position 435 (EU numbering), the heteromeric antibody (a bispecific antibody of interest) could be efficiently purified to a purity of 93% or higher through the protein A-based purification step alone.\",\n \"TABLE 13 Homomeric Hetero- Homomeric anti-GPC3 meric Fc antibody antibody molecule NTA4L-cont/NTA4R-cont/GC33-k0 30.0 46.5 23.5 NTA4L-63/NTA4R-cont/GC33-k0 — 66.7 33.3 NTA4L/NTA4R/GC33-k0 — 93.0 7.0 [Example 10] Preparation of Heteromeric Antibodies Through a Purification Step by Protein A Column Chromatography Using pH Gradient Elution As described in Example 9, the present inventors demonstrated that in the case of an antibody having the variable region only at one arm, the heteromeric antibody could be efficiently purified through the protein A-based purification step alone by combining the substitution mutation of Arg for His at position 435 (EU numbering) with the mutations (a substitution of Lys for Asp at position 356, EU numbering, is introduced into one H chain and a substitution of Glu for Lys at position 439, EU numbering, is introduced into the other H chain) described in WO 2006/106905 (PROCESS FOR PRODUCTION OF POLYPEPTIDE BY REGULATION OF ASSEMBLY).\",\n \"However, the heteromeric antibody is not purified to a sufficiently high purity with elution 1 (elution buffer: 2 mM HCl, pH 2.7) alone.\",\n \"An additional purification step is needed.\",\n \"Then, in this Example, the present inventors assessed whether the heteromeric antibody can be isolated and purified to high purity by protein A column chromatography using elution with a pH gradient.\",\n \"This was based on the assumption that more protein A-binding sites lead to stronger binding of the heteromeric antibody to protein A, and as a result lower pH is required for elution.\",\n \"Purification can be achieved more efficiently at a lower cost when the purity of the heteromeric antibody can be increased to almost 100% by using such pH gradient elution.\",\n \"CM samples containing the following antibodies were used: NTA4L-cont/NTA4R-cont/GC33-k0 NTA4L-G3/NTA4R-cont/GC33-k0 NTA4L/NTA4R/GC33-k0 The CM samples were filtered through a filter with a pore size of 0.22 μm, and loaded onto a HiTrap protein A HP column (GE Healthcare) equilibrated with D-PBS.\",\n \"The column was sequentially subjected to washes 1 and 2, and then elution with a pH gradient using elution A and B as shown in Table 14.The pH gradient elution was achieved with the following linear gradient: elution A/elution B=(100:0)→(30:70) for 35 minutes.\",\n \"Eluted fractions were collected and analyzed by size exclusion chromatography analysis to identify their components.\",\n \"TABLE 14 Equilibration D-PBS Wash 1 D-PBS Wash 2 20 mM NaCitrate, pH 5.0 Elution A 20 mM NaCitrate, pH 5.0 Elution B 20 mM NaCitrate, pH 2.7 NTA4L-cont/NTA4R-cont/GC33-k0, NTA4L-G3/NTA4R-cont/GC33-k0, and NTA4L/NTA4R/GC33-k0 were purified by protein A column chromatography under the pH gradient elution condition.\",\n \"The resulting chromatograms are shown in FIG.\",\n \"8.The elution of NTA4L-cont/NTA4R-cont/GC33-k0 resulted in a broad peak.\",\n \"Meanwhile, the pH gradient elution of NTA4L-G3/NTA4R-cont/GC33-k0 gave two elution peaks.\",\n \"The peaks of high and low pHs were labeled as “elution 1” and “elution 2”, respectively.\",\n \"The result for NTA4L/NTA4R/GC33-k0 was roughly the same as that for NTA4L-G3/NTA4R-cont/GC33-k0, except that the peak area of elution 2 was smaller.\",\n \"The result of size exclusion chromatography analysis of each peak is shown in Table 15.NTA4L-cont/NTA4R-cont/GC33-k0 gave three components eluted in this order: a homomeric antibody that divalently binds to GPC3 (homomeric antibody NTA4L-cont), a heteromeric antibody that monovalently binds to GPC3 (heteromeric antibody NTA4L-cont/NTA4R-conc), and a homomeric molecule having no GPC3-binding domain (homomeric antibody NTA4R-cont).\",\n \"It is thought that the reason why these components were not separated by pH gradient elution is that they have the same number (two) of protein A-binding sites.\",\n \"Meanwhile, it was revealed that in elution 1 of NTA4L-G3/NTA4R-cont/GC33-k0, the levels of homomeric antibody that divalently binds to GPC3 (homomeric antibody NTA4L-G3) and homomeric molecule having no GPC3-binding domain (homomeric antibody NTA4R-cont) were below the detection limit, while the heteromeric antibody that monovalently binds to GPC3 (NTA4L-G3/NTA4R-conc heteromeric antibody) accounted for 99.6%.\",\n \"In elution 2, the homomeric molecule having no GPC3-binding domain (homomeric antibody NTA4R-cont) was found to account for 98.8%.\",\n \"The homomeric antibody NTA4L-G3 passes through the protein A column because it cannot bind to protein A due to the substitution mutation of Arg for His at position 435 (EU numbering).\",\n \"Meanwhile, the heteromeric antibody NTA4L-G3/NTA4R-conc has a single protein A-binding site, while the homomeric antibody NTA4R-cont has two.\",\n \"More protein A-binding sites means stronger protein A binding, and as a result lower pH was required for elution.\",\n \"This is thought to be the reason why homomeric antibody NTA4R-cont was eluted at a lower pH than heteromeric antibody NTA4L-G3/NTA4R-conc.\",\n \"Almost the same result was obtained for NTA4L/NTA4R/GC33-k0.The result of size exclusion chromatography analysis shows that the component ratio was comparable to that of NTA4L-G3/NTA4R-cont/GC33-k0.There was a difference between the protein A chromatograms, and the peak area ratio of elution 2 to elution 1 was smaller in NTA4L/NTA4R/GC33-k0.The expression ratio of the homomeric antibody NTA4R-cont, which is the major component of elution 2, was reduced due to the mutations introduced for efficient generation of the heteromeric antibody NTA4L-G3/NTA4R-conc.\",\n \"The amino acid mutations described above improved the purification yield of the heteromeric antibody and the robustness of purification by protein A column chromatography with pH gradient elution.\",\n \"As described above, the present inventors demonstrated that the heteromeric antibody could be efficiently isolated and purified to high purity through the purification step using protein A column chromatography alone with pH gradient elution.\",\n \"TABLE 15 Homomeric Homomeric antibody Heteromeric molecule that antibody that having no divalently monovalently GPC3- binds to binds to binding Peak area (%) GPC3 GPC3 domain NTA4L-cont/NTA4R-cont/GC33-k0 Elution 25.4 54.4 20.2 NTA4L-G3/NTA4R-cont/GC33-k0 Elution 1 ND 99.6 ND Elution 2 — 1.2 98.8 NTA4L/NTA4R/GC33-k0 Elution 1 ND 99.6 ND Elution 2 — 1.4 98.6 [Example 11] Introduction of Mutation into the CH3 Domain of Monovalent Fcalpha Receptor-Fc Fusion Protein and Preparation of Designed Molecules Through the Protein A-Based Purification Step Alone Introduction of Mutation into CH3 Domain and Preparation of Monovalent Fcalpha Receptor-Fc Fusion Protein Through the Protein A-Based Purification Step Conventional Fc receptor-Fc fusion proteins such as Eternercept and Abatacept are homodimers that can divalently bind to ligands.\",\n \"In the experiment described in this Example, the inventors designed and assessed an Fc receptor-Fc fusion protein that monovalently binds to IgA as a ligand (FIG.\",\n \"9).\",\n \"To achieve the monovalent binding of the Fcalpha receptor to IgA, one of the two Fc receptor-Fc fusion protein H chains must be the whole H chain having the hinge-Fc domain.\",\n \"In this case, it is necessary to purify the molecule that results from heteromeric association of the two types of H chains Thus, using the same method described in Example 6, a substitution mutation of Arg for His at position 435 (EU numbering) was introduced into one of the two H chains.\",\n \"Furthermore, the above mutation was combined with the mutations (a substitution of Lys for Asp at position 356, EU numbering, is introduced into one H chain and a substitution of Glu for Lys at position 439, EU numbering is introduced into the other H chain) described in WO 2006/106905 (PROCESS FOR PRODUCTION OF POLYPEPTIDE BY REGULATION OF ASSEMBLY) as a modification to enhance the heteromeric association of the two types of H chains.\",\n \"The present inventors assessed whether it was possible with the combined mutations to purify the molecule of interest by protein A chromatography alone.\",\n \"Construction of Expression Vectors for Antibody Genes and Expression of Respective Antibodies The Fc receptor used was FcalphaR (human IgA1 receptor, SEQ ID NO: 31).\",\n \"The fusion H chain constant regions used were: G1Fc (SEQ ID NO: 32), which is a human hinge-Fc domain constructed from IgG1 by deleting the C-terminal Gly and Lys, and residues of positions 1 to 223 (EU numbering); G1Fc-G3S3K (SEQ ID NO: 33), which was constructed from G1Fc by introducing substitution mutations of Lys for Asp at position 356 (EU numbering) and of Arg for His at position 435 (EU numbering); and G1Fc-S3E (SEQ ID NO: 34), which was constructed from G1Fc by introducing a substitution mutation of Glu for Lys at position 439 (EU numbering).\",\n \"FcalphaR-Fc fusion proteins IAL-cont and IAL were constructed by linking downstream of FcalphaR via a polypeptide linker (SEQ ID NO: 35), G1Fc (an H chain constant region) and G1Fc-G3S3K introduced with substitution mutations of Lys for Asp at position 356 (EU numbering) and of Arg for His at position 435 (EU numbering).\",\n \"Furthermore, Fc genes IAR-cont and IAR were constructed to encode G1Fc (a human hinge-Fc domain) and G1Fc-S3E (a hinge Fc domain introduced with a substitution mutation of Glu for Lys at position 439, EU numbering), respectively.\",\n \"The constructed genes were: H chain IAL-cont: FcalphaR-G1Fc IAL: FcalphaR-G1Fc-G3S3K IAR-cont: G1Fc IAR: G1Fc-S3E The antibody genes (IAL-cont, IAL, IAR-cont, and IAR) were each inserted into an animal cell expression vector.\",\n \"The following antibodies were expressed transiently in FreeStyle293 cells (Invitrogen) by transfection using the constructed expression vectors.\",\n \"As shown below, antibodies were named using the combinations of transfected antibody genes.\",\n \"IAL-cont/IAR-cont IAL/IAR Protein Purification of Expressed Sample and Assessment of Heterodimer Yield CM samples containing the following antibody were used: IAL-cont/IAR-cont IAL/IAR The CM samples were filtered through a filter with a pore size of 0.22 μm, and loaded onto an rProtein A Sepharose Fast Flow column (GE Healthcare) equilibrated with D-PBS.\",\n \"The column was subjected to washes 1 and 2 and elution 1 as shown in Table 16.The volume of CM to be loaded onto the column was adjusted to 20 mg antibody/ml resin.\",\n \"Respective fractions eluted under each condition were collected and analyzed by size exclusion chromatography to identify their components.\",\n \"TABLE 16 Equilibration D-PBS Wash 1 1 mM sodium acetate, 150 mM NaCl, pH 6.5 Wash 2 0.3 mM HCl, 150 mM NaCl, pH 3.7 Elution 1 2 mM HCl, pH 2.7 The result of size exclusion chromatography analysis of each eluted fraction is shown in FIG.\",\n \"10 and Table 17 below.\",\n \"The values represent the area of elution peak expressed in percentage.\",\n \"As for IAL-cont/IAR-cont, a homomeric antibody that divalently binds to IgA (homomeric antibody IAL-cont) and a homomeric molecule having no IgA-binding site (homomeric antibody IAR-cont) were eluted, while the heteromeric antibody IAL-cont/IAR-cont of interest accounted for only 30%.\",\n \"In the case of IAL/IAR, the homomeric antibody that divalently binds to IgA (homomeric antibody IAL) was not detectable, and the proportion of the homomeric molecule having no IgA-binding site (homomeric antibody IAR) was considerable reduced; thus, the heteromeric antibody IAL/IAR of interest was significantly increased up to about 96%.\",\n \"Thus, the present invention demonstrated that when the substitution mutations of Lys for Asp at position 356 (EU numbering) and of Glu for Lys at position 439 (EU numbering) for efficient formation of heteromeric molecules from the respective H chains were introduced in combination with the substitution mutation of Arg for His at position 435 (EU numbering), the heteromeric antibody, a bispecific antibody of interest, could be efficiently purified to a purity of 95% or higher through the protein A-based purification step alone.\",\n \"TABLE 17 Homomeric Heteromeric Homomeric IgA antibody antibody Fc molecule IAL-cont/IAR-cont 66.2% 30.0% 3.8% IAL/IAR — 95.8% 4.2% [Example 12] Construction of a Bispecific Antibody of the Four-Chain IgG Type Construction of Expression Vectors for Antibody Genes and Expression of Respective Antibodies The bispecific antibody against human F.IX and human F.X, which was designed as described in Example 1, consists of a common L chain and two types of H chains that each recognizes a different antigen.\",\n \"Obtaining a bispecific antibody with such a common L chain is not easy, because it is difficult for a common L chain sequence to recognize two different types of antigens.\",\n \"As described above, obtaining such a common L chain is extremely difficult.\",\n \"Thus, one may suspect that a more preferred option is a bispecific antibody consisting of two types of H chains and two types of L chains that recognize two types of antigens.\",\n \"If two types of H chains and two types of L chains are expressed, they form ten types of H2L2 IgG molecules in random combinations.\",\n \"It is very difficult to purify the bispecific antibody of interest from the ten types of antibodies.\",\n \"In the experiment described in this Example, the present inventors prepared and assessed bispecific antibodies consisting of two types of H chains and two types of L chains against human IL-6 receptor and human glypican-3 (GPC3).\",\n \"To efficiently prepare bispecific antibodies consisting of two types of H chains and two types of L chains, it is necessary to enhance the association of H chains and L chains against the same antigen as well as the heteromeric association of two types of H chains.\",\n \"In addition, it is essential that the bispecific antibody with the right combination can be purified from the obtained expression products.\",\n \"To enhance the association between H chains and L chains against the same antigen, the variable region (VH) of H chain (GC33-VH-CH1-hinge-CH2-CH3) and the variable region (VL) of L chain (GC33-VL-CL) of GC33 (an anti-GPC3 antibody) were swapped with each other to produce H chain GC33-VL-CH1-hinge-CH2-CH3 and L chain (GC33-VH-CL) (the VH domain and VL domain were exchanged with each other).\",\n \"GC33-VL-CH1-hinge-CH2-CH3 is associated with GC33-VH-CL; however, its association with the L chain (MRA-VL-CL) of the anti-IL-6 receptor antibody is inhibited due to the instability of VL/VL interaction.\",\n \"Likewise, the H chain (MRA-VH-CH1-hinge-CH2-CH3) of the anti-IL-6 receptor antibody is associated with MRA-VL-CL; however, its association with the L chain (GC33-VH-CL) of the anti-GPC3 antibody is inhibited due to the instability of VH/VH interaction.\",\n \"As described above, it is possible to enhance the association between H chains and L chains against the same antigen.\",\n \"However, the VH/VH interaction and VL/VL interaction also occur although they are less stable than the VH/VL interaction (for VH/VH, see: FEBS Lett.\",\n \"2003 Nov. 20, 554(3):323-9; J Mol Biol.\",\n \"2003 Oct. 17, 333(2):355-65; for VL/VL, see: J Struct Biol.\",\n \"2002 June, 138(3):171-86; Proc Natl Acad Sci USA.\",\n \"1985 July, 82(14):4592-6), and thus although infrequently, unfavorable self association of H chains and L chains also occurs.\",\n \"Hence, although the percentage of the bispecific antibody of interest is increased by simply swapping the VH domain and VL domain with each other, the expressed products still contain about ten types of combinations.\",\n \"In general, it is extremely difficult to purify the bispecific antibody of interest from the ten types.\",\n \"However, it is possible to improve the separation of the ten types of components in ion exchange chromatography by introducing a modification so that the ten types of components each have a different isoelectric point.\",\n \"In this context, MRA-VH, which is the H chain variable region of an anti-IL-6 receptor antibody, was modified to lower the isoelectric point, and this yielded H54-VH with a lower isoelectric point.\",\n \"In the same manner, MRA-VL, which is the L chain variable region of an anti-IL-6 receptor antibody, was modified to lower the isoelectric point, and this yielded L28-VL with a lower isoelectric point.\",\n \"Furthermore, GC33-VH, which is the H chain variable region of an anti-GPC3 antibody, was modified to increase the isoelectric point.\",\n \"This yielded Hu22-VH with an increased isoelectric point.\",\n \"The combination of the H and L chains of interest was improved by swapping the VH and VL between the H chains and L chains of an anti-GPC3 antibody.\",\n \"However, although infrequently, the unfavorable H chain/L chain association occurs because it is impossible to completely suppress the H54-VH/Hu22-VH interaction and L28-VL/GC33-VL interaction.\",\n \"An ordinary antibody sequence has glutamine at position 39 in VH.\",\n \"In VH/VH interaction, glutamines are believed to form hydrogen bonds at the VH/VH interface.\",\n \"Then, lysine was substituted for the glutamine at position 39 (Kabat numbering) to impair the H54-VH/Hu22-VH interaction.\",\n \"The VH/VH interaction was thus expected to be significantly impaired due to the electrostatic repulsion between two lysines at the VH/VH interface.\",\n \"Next, H54-VH-Q39K and Hu22-VH-Q39K were constructed by substituting lysine for the glutamine at position 39 (Kabat numbering) in the sequences of H54-VH and Hu22-VH.\",\n \"Likewise, an ordinary antibody sequence has glutamine at position 38 in VL.\",\n \"In the VL/VL interaction, glutamines are expected to form hydrogen bonds at the VL/VL interface.\",\n \"Then, glutamic acid was substituted for the glutamine at position 38 (Kabat numbering) to impair the L28-VL/GC33-VL interaction.\",\n \"The VL/VL interaction was thus expected to be significantly impaired due to the electrostatic repulsion between two glutamic acids at the VL/VL interface.\",\n \"Next, L28-VL-Q38E and GC33-VL-Q38E were constructed by substituting glutamic acid for the glutamine at position 39 (Kabat numbering) in the sequences of L28-VL and GC33-VL.\",\n \"To further improve the efficiency of expression/purification of the bispecific antibody of interest, a substitution mutation of Arg for His at position 435 (EU numbering) was introduced into one H chain using the same method described in Example 3.Furthermore, the above mutation was combined with the mutations (a substitution of Lys for Asp at position 356, EU numbering, is introduced into one H chain and a substitution of Glu for Lys at position 439, EU numbering, is introduced into the other H chain) described in WO 2006/106905 (PROCESS FOR PRODUCTION OF POLYPEPTIDE BY REGULATION OF ASSEMBLY) as a modification to enhance the heteromeric association of the two types of H chains.\",\n \"The combined mutations enable purification of the molecule resulting from heteromeric association of the two types of H chains by protein A chromatography alone.\",\n \"Specifically, the antibody H chain variable regions used were: MRA-VH (the H chain variable region of an anti-human interleukin-6 receptor antibody, SEQ ID NO: 36); GC33-VH (the H chain variable region of an anti-GPC3 antibody, SEQ ID NO: 37); H54-VH (the H chain variable region of an anti-human interleukin-6 receptor antibody, SEQ ID NO: 38) with an isoelectric point lower than that of MRA-VH; Hu22-VH (the H chain variable region of an anti-GPC3 antibody, SEQ ID NO: 39) with an isoelectric point higher than that of GC33-VH; H54-VH-Q39K (SEQ ID NO: 40) where Lys is substituted for Gln at position 39 (Kabat numbering) in the sequence of H54-VH; and Hu22-VH-Q39K (SEQ ID NO: 41) where Lys is substituted for Gln at position 39 in the sequence of Hu22-VH.\",\n \"The following antibody H chain constant regions were also used: IgG1-LALA-N297A-CH (SEQ ID NO: 42) where Ala is substituted for Leu at positions 234 and 235 (EU numbering), and Ala is substituted for Asn at position 297 (EU numbering), and the C-terminal Gly and Lys is deleted in the sequence of the H chain constant region of IgG1; IgG1-LALA-N297A-CHr (SEQ ID NO: 43) where the sequence of IgG1-LALA-N297A-CH has extra two residues of Ser at the N terminus; IgG1-LALA-N297A-s3-CH (SEQ ID NO: 44) where Glu is substituted for Lys at position 439 (EU numbering) in the sequence of IgG1-LALA-N297A-CH; and IgG1-LALA-N297A-G3s3-CHr (SEQ ID NO: 45) where Lys is substituted for Asp at position 356 (EU numbering) and Arg is substituted for His at position 435 (EU numbering) in the sequence of IgG1-LALA-N297A-CHr.\",\n \"Meanwhile, the antibody L chain variable regions used were: MRA-VL (the L chain variable region of an anti-human interleukin-6 receptor antibody, SEQ ID NO: 46); GC33-VL (the L chain variable region of an anti-GPC3 antibody, SEQ ID NO: 47); L28-VL (the L chain variable region of an anti-human interleukin-6 receptor antibody, SEQ ID NO: 48) with an isoelectric point lower than that of MRA-VL; L28-VL-Q38E (SEQ ID NO: 49) where Glu is substituted for Gln at position 38 (Kabat numbering) in the sequence of L28-VL; and GC33-VL-Q38E (SEQ ID NO: 50) where Glu is substituted for Gln at position 38 (Kabat numbering) in the sequence of GC33-VL.\",\n \"The following antibody L chain constant regions were also used.\",\n \"IgG1-CL (the L chain constant region of IgG1, SEQ ID NO: 51).\",\n \"IgG1-CLr (SEQ ID NO: 52), which was constructed by substituting Arg and Thr for the C-terminal Ala and Ser, respectively, in the sequence of IgG1-CL.\",\n \"Gene no1-Mh-H was constructed by linking IgG1-LALA-N297A-CH downstream of MRA-VH.\",\n \"Gene no1-Mh-L was constructed by linking IgG1-CL downstream of MRA-VL.\",\n \"Gene no1-Gh-H was constructed by linking IgG1-LALA-N297A-CH downstream of GC33-VH.\",\n \"Gene no1-Gh-L was constructed by linking IgG1-CL downstream of GC33-VL.\",\n \"Gene no2-Gh-H was constructed by linking IgG1-LALA-N297A-CHr downstream of GC33-VL.\",\n \"Gene no2-Gh-L was constructed by linking IgG1-CLr downstream of GC33-VH.\",\n \"Gene no3-Ml-H was constructed by linking IgG1-LALA-N297A-CH downstream of H54-VH.\",\n \"Gene no3-Ml-L was constructed by linking IgG1-CL downstream of L28-VL.\",\n \"Gene no3-Ghh-L was constructed by linking IgG1-CLr downstream of Hu22-VH.\",\n \"Gene no5-Ml-H was constructed by linking IgG1-LALA-N297A-s3-CH downstream of H54-VH.\",\n \"Gene no5-Gh-H was constructed by linking IgG1-LALA-N297A-G3s3-CHr downstream of GC33-VL.\",\n \"Gene no6-Ml-H was constructed by linking IgG1-LALA-N297A-s3-CH downstream of H54-VH-Q39K.\",\n \"Gene no6-Ml-L was constructed by linking IgG1-CL downstream of L28-VL-Q38E.\",\n \"Gene no6-Gh-H was constructed by linking IgG1-LALA-N297A-G3s3-CHr downstream of GC33-VL-Q38E.\",\n \"Gene no6-Ghh-L was constructed by linking IgG1-CLr downstream of Hu22-VH-Q39K.\",\n \"Respective genes (no1-Mh-H, no1-Mh-L, no1-Gh-H, no1-Gh-L, no2-Gh-H, no2-Gh-L, no3-Ml-H, no3-Ml-L, no3-Ghh-L, no5-Ml-H, no5-Gh-H, no6-Ml-H, no6-Ml-L, no6-Gh-H, and no6-Ghh-L) were inserted into animal cell expression vectors.\",\n \"The following combinations of expression vectors were introduced into FreeStyle293-F cells to transiently express each designed molecule.\",\n \"A.\",\n \"Designed Molecule: No1 (FIG.\",\n \"11) Description: natural anti-IL-6 receptor/anti-GPC3 bispecific antibody.\",\n \"Polypeptides encoded by polynucleotides inserted into the expression vector: no1-Mh-H (SEQ ID NO: 53), no1-Mh-L (SEQ ID NO: 54), no1-Gh-H (SEQ ID NO: 55), and no1-Gh-L (SEQ ID NO: 56).\",\n \"B.\",\n \"Designed Molecule: No2 (FIG.\",\n \"12) Description: constructed from no1 by swapping the VH and VL domains of the anti-GPC3 antibody.\",\n \"Polypeptides encoded by polynucleotides inserted into the expression vector: no1-Mh-H, no1-Mh-L, no2-Gh-H (SEQ ID NO: 57), and no2-Gh-L (SEQ ID NO: 58).\",\n \"C. Designed Molecule: No3 (FIG.\",\n \"13) Description: constructed from no2 by introducing modifications to each chain to alter its isoelectric point.\",\n \"Polypeptides encoded by polynucleotides inserted into the expression vector: no3-Ml-H (SEQ ID NO: 59), no3-Ml-L (SEQ ID NO: 60), and no2-Gh-H, and no3-Ghh-L (SEQ ID NO: 61).\",\n \"D. Designed Molecule: No5 (FIG.\",\n \"14) Description: constructed from no3 by introducing a modification to enhance heteromeric H chain association and a modification that enables protein A-based purification of antibody generated via heteromeric association.\",\n \"Polypeptides encoded by polynucleotides inserted into the expression vector: no5-Ml-H (SEQ ID NO: 62), no3-Ml-L, no5-Gh-H (SEQ ID NO: 63), and no3-Ghh-L. E. Designed Molecule: No6 (FIG.\",\n \"15) Description: constructed from no5 by introducing a modification to enhance the association between an H chain of interest and an L chain of interest.\",\n \"Polypeptides encoded by polynucleotides inserted into the expression vector: no6-Ml-H (SEQ ID NO: 64), no6-Ml-L (SEQ ID NO: 65), no6-Gh-H (SEQ ID NO: 66), and no6-Ghh-L (SEQ ID NO: 67).\",\n \"Culture supernatants filtered through a filter with a pore size of 0.22 μm were loaded onto rProtein A Sepharose Fast Flow resin (GE Healthcare) equilibrated with the medium.\",\n \"The resin was eluted in a batchwise manner to purify the molecules.\",\n \"Since protein G binds to the Fab domain of an antibody, all antibody species in CM can be purified with protein G regardless of the affinity for protein A.\",\n \"The designed antibodies (no1, no2, no3, no5, and no6) were assessed for their expression by cation exchange chromatography (IEC) using a ProPac WCX-10 column (Dionex), an analytical column.\",\n \"Cation exchange chromatography was performed at a flow rate of 0.5 ml/min with an adequate gradient using mobile phase A (20 mM MES-NaOH, pH 6.1) and mobile phase B (20 mM MES-NaOH, 250 mM NaCl, pH 6.1).\",\n \"The result of IEC assessment of each antibody is shown in FIG.\",\n \"16.Natural anti-IL-6 receptor/anti-GPC3 bispecific antibody no1 gave a number of peaks in close proximity to each other.\",\n \"It was impossible to determine which peak corresponds to the bispecific antibody of interest.\",\n \"The same applied to no2 which results from swapping the VH domain and VL domain of the anti-GPC3 antibody in no1.The peak for the bispecific antibody of interest could be isolated for the first time in no3 which was modified from no2 by introducing a modification to alter the isoelectric point of each chain of no2.The proportion of the peak corresponding to the bispecific antibody of interest was significantly increased in no5 which was constructed from no3 by introducing a modification to enhance the H-chain heteromeric association and a modification that allows for protein A-based purification of the antibody generated via heteromeric association.\",\n \"The proportion of the peak corresponding to the bispecific antibody of interest was further increased in no6 which was constructed from no5 by introducing a modification that enhances the association between the H chain and L chain of interest.\",\n \"Then, the present inventors assessed whether the bispecific antibody of interest could be purified from no6 CM to high purity using a purification column.\",\n \"CM samples were filtered through a filter with a pore size of 0.22 μm and loaded onto a HiTrap protein A HP column (GE Healthcare) equilibrated with D-PBS.\",\n \"The column was sequentially subjected to washes 1 and 2 and elution with a pH gradient using elution A and B as shown in Table 18.The pH gradient during elution was achieved with the following linear gradient: elution A/elution B=(100:0)->(35:65) for 40 minutes.\",\n \"TABLE 18 Equilibration D-PBS Wash 1 D-PBS Wash 2 20 mM NaCitrate, pH 5.0 Elution A 20 mM NaCitrate, pH 5.0 Elution B 20 mM NaCitrate, pH 2.7 The result of pH gradient elution of No6 is shown in FIG.\",\n \"17.The homomeric antibody having the H chain of the anti-GPC3 antibody which was incapable of binding to protein A passed through protein A; the first elution peak corresponded to the heteromeric antibody having the H chain of the anti-GPC3 antibody and the H chain of the anti-IL-6 receptor antibody; and the second elution peak corresponded to the homomeric antibody having the H chains of the anti-IL-6 receptor antibody.\",\n \"Thus, the present inventors demonstrated that by substituting Arg for His at position 435 (EU numbering), the heteromeric antibody having the H chain of the anti-GPC3 antibody and the H chain of the anti-IL-6 receptor antibody could be purified by the protein A-based purification step alone.\",\n \"The first elution fraction was loaded onto a HiTrap SP Sepharose HP column (GE Healthcare) equilibrated with 20 mM sodium acetate buffer (pH 5.5).\",\n \"After washing with the same buffer, the column was eluted with a NaCl concentration gradient of 0 to 500 mM.\",\n \"The resulting main peak was analyzed by cation exchange chromatography in the same manner as described above.\",\n \"The result is shown in FIG.\",\n \"18.The bispecific antibody of interest was demonstrated to be purified to a very high purity.\",\n \"INDUSTRIAL APPLICABILITY The present invention provides efficient methods based on alteration of the protein A-binding ability, for producing or purifying to a high purity polypeptide multimers (multispecific antibodies) having the activity of binding to two or more types of antigens through the protein A-based purification step alone.\",\n \"By using the methods of the present invention, polypeptide multimers of interest can be efficiently produced or purified to high purity without loss of other effects produced by amino acid mutations of interest.\",\n \"In particular, when the methods are combined with a method for controlling the association between two types of protein domains, polypeptide multimers of interest can be more efficiently produced or purified to a higher purity.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875847"}}},{"rowIdx":4494998,"cells":{"text":{"kind":"list like","value":[["KISSPEPTIN-54 DETECTION BY TANDEM MASS SPECTROMETRY","Methods are described for measuring the amount of a kisspeptin-54-derived peptides in a sample.","More specifically, mass spectrometric methods are described for detecting and quantifying a kisspeptin-54 derived peptides in a sample utilizing on-line extraction methods coupled with tandem mass spectrometric techniques."],["1.A method for determining by mass spectrometry the amount in a sample of one or more kisspeptin-54-derived peptides, said method comprising: (a) subjecting the sample to acidification; (b) ionizing the enriched sample to produce one or more kisspeptin-54-derived peptide ions detectable by mass spectrometry; (c) determining the amount of one or more ions by mass spectrometry, wherein the amount of the ions is used to determine the amounts of the corresponding one or more kisspeptin-54-derived peptides in the sample.","2.The method in claim 1, wherein one or more kisspeptin-54-derived peptides is selected from the group consisting of kisspeptin-54, kisspeptin-53, kisspeptin-52, kisspeptin-54(R14P), kisspeptin-53(R14P), and kisspeptin-52(R14P).","3.The method in claim 1, wherein the sample comprises two or more kisspeptin-54-derived peptides selected from the group consisting of kisspeptin-54, kisspeptin-53, kisspeptin-52, kisspeptin-54(R14P), kisspeptin-53(R14P), and kisspeptin-52(R14P).","4.The method of claim 1, wherein said one or more ions are selected from the group of ions with a charge consisting of 4+, 5+, 6+, and 7+ from each of said one or more kisspeptin-54-derived peptides.","5.The method of claim 1, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-54, and said ions are selected from the group of ions with m/z of 1172.4±0.5, 977.2±0.5, and 837.7±0.5.6.The method of claim 1, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-54(R14P), and said ions are selected from the group of ions with m/z of 1450.5±0.5, 1160.6±0.5, and 967.3±0.5.7.The method of claim 1, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-53 and wherein said ions are selected from the group of ions with m/z of 1143.2±0.5, 952.7±0.5, and 816.9±0.5.8.The method of claim 1, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-52, and said ions are selected from the group of ions with m/z of 1112.0±0.5, and 926.6±0.5.9.The method of claim 1, wherein said mass spectrometry is tandem mass spectrometry, and said one or more ions are fragmented into kisspeptin-54-derived peptide fragment ions.","10.The method of claim 9, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-54, said ions comprise an ion with m/z of 977.2±0.5, and said fragment ions comprise one or more ions selected from the group consisting of ions with m/z of 1083.6±0.5 and 903.1±0.5.11.The method of claim 9, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-54, said ions comprise an ion with m/z of 837.7±0.5, and said fragment ions comprise an ion with m/z of 902.8±0.5.12.The method of claim 9, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-54(R14P), said ions comprise an ion with m/z of 1160.6±0.5, and said fragment ions comprise an ion with m/z of 1071.6±0.5.13.The method of claim 9, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-54(R14P), said ions comprise an ion with m/z of 967.3±0.5, and said fragment ions comprise an ion with m/z of 1071.6±0.5.14.The method of claim 9, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-53, said ions comprise an ion with m/z of 1143.2±0.5, and said fragment ions comprise an ion with m/z of 1053.9±0.5.15.The method of claim 9, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-53, said ions comprise an ion with m/z of 952.7±0.5, and said fragment ions comprise one or more ions selected from the group consisting of ions with m/z of 1054.1±0.5 and 878.5±0.5.16.The method of claim 9, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-53, said ions comprise an ion with m/z of 816.7±0.5, and said fragment ions comprise an ion with m/z of 878.3±0.5.17.The method of claim 9, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-52, said ions comprise an ion with m/z of 1112.0±0.5, and said fragment ions comprise one or more ions selected from the group consisting of ions with m/z of 1278.2±0.5 and 1022.9±0.5.18.The method of claim 9, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-52, said ions comprise an ion with m/z of 926.8±0.5, and said fragment ions comprise one or more ions selected from the group consisting of ions with m/z of 1022.9±0.5.19.The method of claim 1, further comprising adding one or more isotopically labeled kisspeptin-54-derived peptide to the sample before the ionization step.","20.The method of claim 1, wherein acidifying said body fluid sample comprises acidifying with aqueous formic acid.","21.The method of claim 1, further comprising subjecting the sample to precipitation with methanol.","22.The method of claim 1, further comprising purifying said sample with solid phase extraction (SPE) or high performance liquid chromatography (HPLC).","23.The method of claim 1, wherein the sample comprises plasma or serum.","24.The method of claim 1, further comprising determining the total amount of kisspeptin-54 in the sample before kisspeptin-54 is degraded in the sample by summing the determined amounts of kisspeptin-54-derived peptides in the sample."],["<SOH> BACKGROUND OF THE INVENTION <EOH>The following description of the background of the invention is provided simply as an aid in understanding the invention and is not admitted to describe or constitute prior art to the invention.","The kisspeptin-54 peptide is essential for sexual reproduction and it suppresses cancer metastasis.","It is also known as metastin, kisspeptin 1-54, KP-54, and KiSS-1 (68-121).","Kisspeptin-54 is the carboxamide fragment of residues 68-121 of the protein KISS-1, which in turn is encoded by the KiSS-1 gene.","Kisspeptin-54 potently and selectively stimulates the G-protein-coupled receptor 54 (GPR54) to signal secretion of gonadotropin-releasing hormone (GnRH).","Rhythmical secretions of GnRH initiate puberty, coordinate ovulation, and maintain overall reproductive function.","Kisspeptin-54 is known to suppress the progression of melanomas and breast cancers.","It is postulated that kisspeptin-54 suppresses metastasis by inhibiting chemotaxis and invasion of cancer cells.","Human kisspeptin-54 (CAS No: [374683-24-6]) consists of 54 amino acids with a molecular weight of about 5857.5 g/mol and a monoisotopic mass of about 5854.0 g/mol.","It is a peptide amide cleavage product containing the amino acid residues from 68 to 121 of the 138 amino acid KiSS-1 protein.","Other bioactive peptides that result from cleavage of KiSS-1 are kisspeptin-14 (KP-14, 41-54), kisspeptin-13 (KP-13, residues 42-54), and kisspeptin-10 (KP-10; residues 45-54).","Kisspeptin-54 has been identified using tandem mass spectrometry.","See e.g., Kotani, M., et al., J. Biol.","Chem.","2001, 276(37), 34631-6 (isolated); Dhillo, W., et al., J. Clin Endocrinol.","Metab.","2005, 90(12), 6609-15 (synthetic).","Kisspeptin-54 has been quantitated using immunoassays.","See e.g., Jayasena et al., J. Endocrinol.","Metab.","2009, 94(11), 4315-23 (measured immunoreactivity of antibody with kisspeptin-54).","Among the kisspeptin peptides, only kisspeptin-10 has been reported to be purified for and subjected to quantitative mass spectrometry.","Chan et al., J. Clin.","Endocrinol.","Metab., 2011, 96(6), E908-15."],["<SOH> SUMMARY OF THE INVENTION <EOH>In one aspect, the present invention provides methods of determining by mass spectrometry the amount in a sample of one or more kisspeptin-54-derived peptides selected from the group consisting of kisspeptin-54, kisspeptin-53, kisspeptin-52, kisspeptin-54(R14P), kisspeptin-53(R14P), and kisspeptin-52(R14P).","These methods include subjecting the sample to ionization under conditions suitable to produce one or more multiply charged kisspeptin-54-derived peptide ions detectable by mass spectrometry; determining by mass spectrometry the amount of one or more ions from each of the one or more kisspeptin-54-derived peptides; and using the amount of the determined ions to determine the amounts of the corresponding one or more kisspeptin-54-derived peptides in the sample.","In one aspect, the methods further include, prior to ionization, enriching the concentration of the kisspeptin-54-derived peptides with an antibody specific for the N-terminal portion of kisspeptin-54.In addition or alternatively, the methods further includes adding an organic solvent, such as methanol, to the sample in an amount sufficient to precipitate one or more components from said sample, so as to enrich the concentration of the kisspeptin-54-derived peptides.","In some embodiments, ions are determined from kisspeptin-54, kisspeptin-53, and kisspeptin-52.In some embodiments, ions are determined from kisspeptin-54(R14P), kisspeptin-53(R14P), and kisspeptin-52(R14P).","In some embodiments, kisspeptin-54-derived peptides from the sample are chemically modified prior to ionization.","In some embodiments, at least one of the multiply charged ions generated from the kisspeptin-54-derived peptides is selected from the group of ions with a charge consisting of 4+, 5+, 6+, or 7+.","In some embodiments, the determined kisspeptin-54-derived peptides are selected from the group consisting of kisspeptin-54, kisspeptin-53, kisspeptin-52.In embodiments where the one or more kisspeptin-54-derived peptides comprise kisspeptin-54, multiply charged kisspeptin-54 ions may be selected from the group of ions with m/z of 1172.4±0.5, 977.2±0.5, and 837.7±0.5.In embodiments where the one or more kisspeptin-54-derived peptides comprise kisspeptin-54(R14P), multiply charged kisspeptin-54(R14P) ions may be selected from the group of ions with m/z of 1450.5±0.5, 1160.6±0.5, and 967.3±0.5.In embodiments where the one or more kisspeptin-54-derived peptides comprise kisspeptin-53, multiply charged kisspeptin-53 ions may be selected from the group of ions with m/z of 1143.2±0.5, 952.7±0.5, and 816.9±0.5.In embodiments where the one or more kisspeptin-54-derived peptides comprise kisspeptin-52, multiply charged kisspeptin-52 ions may be selected from the group of ions with m/z of 1112.0±0.5, and 926.6±0.5.In some embodiments, mass spectrometry is tandem mass spectrometry.","Embodiments utilizing tandem mass spectrometry comprise fragmenting one or more of the multiply charged kisspeptin-54-derived peptide ions into kisspeptin-54-derived peptide fragment ions.","In embodiments where kisspeptin-54 is subjected to tandem mass spectrometry, multiply charged kisspeptin-54 ions with m/z of 977.2±0.5 may be fragmented into one or more ions selected from the group consisting of ions with m/z of 1083.6±0.5 and 903.1±0.5; multiply charged kisspeptin-54 ions with m/z of 837.7±0.5 may be fragmented into an ion with m/z of 977.2±0.5.In embodiments where kisspeptin-54(R14P) is subjected to tandem mass spectrometry, multiply charged kisspeptin-54(R14P) ions with m/z of 1160.6±0.5 may be fragmented into an ion with m/z of 1071.6±0.5; multiply charged kisspeptin-54(R14P) ions with m/z of 967.3±0.5 may be fragmented into an ion with m/z of 1071.6±0.5.In embodiments where kisspeptin-53 is subjected to tandem mass spectrometry, multiply charged kisspeptin-53 ions with m/z of 1143.2±0.5 may be fragmented into an ion with m/z of 1053.9±0.5; multiply charged kisspeptin-53 ions with m/z of 952.7±0.5 may be fragmented into one or more ions selected from the group of ions with m/z of 1054.1±0.5 and 878.5±0.5; and multiply charged kisspeptin-53 ions with m/z of 816.7±0.5 may be fragmented into an ion with m/z of 878.3±0.5.In embodiments where kisspeptin-52 is subjected to tandem mass spectrometry, multiply charged kisspeptin-52 ions with m/z of 1112.0±0.5 may be fragmented into one or more ions selected from the group consisting of ions with m/z of 1278.2±0.5 and 1022.9; multiply charged kisspeptin-52 ions with m/z of 926.8±0.5 may be fragmented into an ion with m/z of 1022.9±0.5.In some embodiments, a sample is subjected to one or more processing steps prior to ionization.","In some embodiments, the processing steps include one or more purification steps.","In some embodiments, the processing steps include adding aqueous formic acid to the sample.","In some embodiments, the processing steps include adding an organic solvent, such as methanol, to the sample in an amount sufficient to precipitate one or more components from said sample; centrifuging the organic solvent-sample mixture, wherein a portion of kisspeptin-54-derived peptides from the sample remain in the supernatant; and collecting the supernatant for further processing or ionization.","In some embodiments, the processing steps include applying the sample to an anion or cation exchange column under conditions suitable to retain kisspeptin-54-derived peptides on the column; eluting kisspeptin-54-derived peptides from the column; and collecting the eluted kisspeptin-54-derived peptides for further processing or ionization.","In some embodiments, the processing steps include immunopurification.","In some related embodiments, immunopurification comprises capture and extraction of one or more of kisspeptin-54-derived peptides using anti-kisspeptin-54-derived peptides antibodies specific for the N-terminus of kisspeptin-54.In some embodiments, the processing steps comprise solid phase extraction (SPE).","In some embodiments, the processing steps comprise high performance liquid chromatography (HPLC).","In a second aspect, the invention provides methods of reducing the degradation of kisspeptin-54-derived peptides in body fluid sample from a patient.","These methods include acidifying a body fluid sample, treating a body fluid sample with an agent under conditions sufficient to precipitate proteins from said body fluid sample, or both.","In some embodiments, acidifying said body fluid sample comprises acidifying with aqueous formic acid.","In some embodiments, the protein precipitation agent comprises an organic solvent, such as methanol.","In some related embodiments, the ratio of the volume of the organic solvent to the volume of the biological sample is about 3:1.In a third aspect, the invention provides methods of measuring degradation of kisspeptin-54 in a biological fluid sample from a patient.","These methods include subjecting a body fluid sample from a patient to ionization under conditions suitable to produce one or more multiply charged ions detectable by mass spectrometry from kisspeptin-54 and one or more kisspeptin-54 derivation products selected from the group consisting of kisspeptin-53 and kisspeptin-52; determining by mass spectrometry the amount of one or more ions of kisspeptin-54 and one or more kisspeptin-54 derivation products selected from the group consisting of kisspeptin-53 and kisspeptin-52; and using the amounts of ions determined in step b to determine the amounts of kisspeptin-54 and kisspeptin-54 derivation products in the sample.","Similar methods are provided for measuring degradation of kisspeptin-54(R14P) in a biological fluid sample from a patient.","These methods include subjecting a biological fluid sample from a patient to ionization under conditions suitable to produce one or more multiply charged ions detectable by mass spectrometry from kisspeptin-54(R14P) and one or more kisspeptin-54(R14P) derivation products selected from the group consisting of kisspeptin-53(R14P) and kisspeptin-52(R14P); determining by mass spectrometry the amount of one or more ions of kisspeptin-54(R14P) and one or more kisspeptin-54(R14P) derivation products selected from the group consisting of kisspeptin-53(R14P) and kisspeptin-52(R14P); and using the amounts of ions determined in step b to determine the amounts of kisspeptin-54(R14P) and kisspeptin-54(R14P) derivation products in the sample.","In another aspect, the invention provides methods of diagnosing or predicting risk of developing preeclampsia.","These methods include providing a body fluid or tissue sample obtained from a patient; subjecting the body fluid or tissue sample to one or more processing steps to generate a processed sample comprising one or more kisspeptin-54-derived peptides selected from the group consisting of kisspeptin-54, kisspeptin-53, kisspeptin-52, kisspeptin-54(R14P), kisspeptin-53(R14P), and kisspeptin-52(R14P); subjecting the processed sample to ionization under conditions suitable to produce one or more multiply charged ions detectable by mass spectrometry; determining by mass spectrometry the amount of one or more ions from one or more kisspeptin-54-derived peptides; and using the determined ion amounts to determine the amount of kisspeptin-54 or kisspeptin-54(R14P) in the sample.","In these methods, elevated kisspeptin-54 or kisspeptin-54(R14P) levels in the sample relative to normal indicate the presence of or risk of developing preeclampsia.","In another aspect, the invention provides one or more substantially isolated polypeptides with amino acid sequences consisting of the sequences identified as SEQ ID No.",":2 and SEQ ID No.",":3, or proline variants thereof.","In any of the methods provided herein which utilize tandem mass spectrometry, tandem mass spectrometry may be conducted by any method known in the art, including for example, multiple reaction monitoring, precursor ion scanning, or product ion scanning.","In any of the methods provided herein which utilize two or more of an extraction column, an analytical column, and an ionization source, two or more of these components may be connected in an on-line fashion to allow for automated sample processing and analysis.","In any of the methods provided herein which require ionization of a kisspeptin-54-derived peptide, mass spectrometry is preferably performed in positive ion mode.","Alternatively, mass spectrometry is performed in negative ion mode.","Various ionization sources, including for example atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI), and heated ESI, may be used in embodiments of the present invention.","In certain preferred embodiments, kisspeptin-54-derived peptides are ionized using heated ESI in positive ion mode.","In preferred embodiments of methods presented herein which determine the amount of one or more kisspeptin-54-derived peptides in a sample, a separately detectable internal standard is provided in the sample, the amount of which is also determined in the sample.","In these embodiments, all or a portion of both the analyte(s) of interest and the internal standard present in the sample is ionized to produce a plurality of ions detectable in a mass spectrometer, and one or more ions produced from each are detected by mass spectrometry.","In these embodiments, the presence or amount of ions generated from the analyte of interest may be related to the presence of amount of analyte of interest in the sample.","In other embodiments, the amount of one or more kisspeptin-54-derived peptides in a sample may be determined by comparison to one or more external reference standards.","Exemplary external reference standards include blank plasma or serum spiked with a kisspeptin-54-derived peptide or an isotopically labeled variant thereof (such as isotopically labeled kisspeptin-54 and isotopically labeled kisspeptin-54(R14P)).","As used herein, unless otherwise stated, the singular forms “a,” “an,” and “the” include plural reference.","Thus, for example, a reference to “a protein” includes a plurality of protein molecules.","As used herein, the term “kisspeptin-54-derived peptide” refers to intact kisspeptin-54 and peptide fragments whose amino acid sequence is found within the amino acid sequence of kisspeptin-54, and all polymorphs thereof.","One known polymorph of kisspeptin-54 includes a proline replacement for the arginine at position 14.This polymorph is described herein as kisspeptin-54 (proline variant) or kisspeptin-54(R14P).","Kisspeptin-54-derived peptides may possess one or more of the following attributes: naturally occurring, chemically synthesized, isotopically labeled, and chemically modified.","Isotopic labeling and/or chemical modification may be conducted by any of several techniques known by those of skill in the art.","Other exemplary kisspeptin-54 derived peptides include kisspeptin-53, kisspeptin-52, and their protein variants.","As used herein, the term “kisspeptin-54” refers to a 54 amino acid peptide with the sequence shown as SEQ ID No.",":1 in FIG.","1A .","As used herein, the term “kisspeptin-53” refers to a 53 amino acid peptide with the sequence shown as SEQ ID No.",":2 in FIG.","1B .","As used herein, the term “kisspeptin-52” refers to a 52 amino acid peptide with the sequence shown as SEQ ID No.",":3 in FIG.","1C .","As used herein, the term “isolated” as applied to a polypeptide means a polypeptide that has been separated from components that naturally accompany it.","Typically, the polypeptide is substantially isolated when it is at least 60%, by weight, free from the proteins and naturally occurring organic molecules with which it is naturally associated.","The definition also extends to a polypeptide separated from its flanking amino acids (e.g., for an amino acid sequence, isolated refers to a sequence that is free from the flanking amino acids with which the sequence is naturally associated in a polypeptide).","Preferably, the polypeptide is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight, isolated.","An isolated polypeptide may be obtained by standard techniques, for example, by extraction from a natural source (e.g., purification from a cell or body fluid), by expression of a recombinant nucleic acid encoding the peptide; or fusion protein thereof, by chemically synthesizing the polypeptide.","Purity can be measured by any appropriate method, e.g., by column chromatography, polyacrylamide gel electrophoresis, or HPLC analysis.","As used herein, the term “purification” or “purifying” does not refer to removing all materials from the sample other than the analyte(s) of interest.","Instead, purification refers to a procedure that enriches the amount of one or more analytes of interest relative to other components in the sample that may interfere with detection of the analyte of interest.","Purification of the sample by various means may allow relative reduction of one or more interfering substances, e.g., one or more substances that may or may not interfere with the detection of selected parent or daughter ions by mass spectrometry.","Relative reduction as this term is used does not require that any substance, present with the analyte of interest in the material to be purified, is entirely removed by purification.","As used herein, the term “immunopurification” or “immunopurify” refers to a purification procedure that utilizes antibodies, including polyclonal or monoclonal antibodies, to enrich the one or more analytes of interest.","Immunopurification can be performed using any of the immunopurification methods well known in the art.","Often the immunopurification procedure utilizes antibodies bound, conjugated or otherwise attached to a solid support, for example a column, well, tube, gel, capsule, particle or the like.","Immunopurification as used herein includes without limitation procedures often referred to in the art as immunoprecipitation, as well as procedures often referred to in the art as affinity chromatography.","As used herein, the term “immunoparticle” refers to a capsule, bead, gel particle or the like that has antibodies bound, conjugated or otherwise attached to its surface (either on and/or in the particle).","In certain preferred embodiments, immunoparticles are sepharose or agarose beads.","In alternative preferred embodiments, immunoparticles are glass, plastic or silica beads, or silica gel.","As used herein, the term “anti-kisspeptin-54-derived peptide antibody” refers to any polyclonal or monoclonal antibody that has an affinity for a kisspeptin-54-derived peptide.","In various embodiments the specificity of kisspeptin-54-derived peptide antibodies to chemical species other than the kisspeptin-54-derived peptide may vary; for example in certain preferred embodiments the anti-kisspeptin-54-derived peptide antibodies are specific for the kisspeptin-54-derived peptide and thus have little or no affinity for chemical species other than the kisspeptin-54-derived peptide, whereas in other preferred embodiments the anti-kisspeptin-54-derived peptide antibodies are non-specific and thus bind certain chemical species other than the kisspeptin-54-derived peptide.","As used herein, the term “sample” refers to any sample that may contain an analyte of interest.","As used herein, the term “body fluid” means any fluid that can be isolated from the body of an individual.","For example, “body fluid” may include blood, plasma, serum, bile, saliva, urine, tears, perspiration, and the like.","In some preferred embodiments, the sample comprises a body fluid sample; preferably plasma or serum, from a patient.","As used herein, the term “solid phase extraction” or “SPE” refers to a process in which a chemical mixture is separated into components as a result of the affinity of components dissolved or suspended in a solution (i.e., mobile phase) for a solid through or around which the solution is passed (i.e., solid phase).","In some instances, as the mobile phase passes through or around the solid phase, undesired components of the mobile phase may be retained by the solid phase resulting in a purification of the analyte in the mobile phase.","In other instances, the analyte may be retained by the solid phase, allowing undesired components of the mobile phase to pass through or around the solid phase.","In these instances, a second mobile phase is then used to elute the retained analyte off of the solid phase for further processing or analysis.","SPE, including TFLC, may operate via a unitary or mixed mode mechanism.","Mixed mode mechanisms utilize ion exchange and hydrophobic retention in the same column; for example, the solid phase of a mixed-mode SPE column may exhibit strong anion exchange and hydrophobic retention; or may exhibit column exhibit strong cation exchange and hydrophobic retention.","As used herein, the term “chromatography” refers to a process in which a chemical mixture carried by a liquid or gas is separated into components as a result of differential distribution of the chemical entities as they flow around or over a stationary liquid or solid phase.","As used herein, the term “liquid chromatography” or “LC” means a process of selective retardation of one or more components of a fluid solution as the fluid uniformly percolates through a column of a finely divided substance, or through capillary passageways.","The retardation results from the distribution of the components of the mixture between one or more stationary phases and the bulk fluid, (i.e., mobile phase), as this fluid moves relative to the stationary phase(s).","Examples of “liquid chromatography” include normal phase liquid chromatography (NPLC), reverse phase liquid chromatography (RPLC), high performance liquid chromatography (HPLC), ultra high performance liquid chromatography (UHPLC), and turbulent flow liquid chromatography (TFLC) (sometimes known as high turbulence liquid chromatography (HTLC) or high throughput liquid chromatography).","As used herein, the term “high performance liquid chromatography” or “HPLC” (sometimes known as “high pressure liquid chromatography”) refers to liquid chromatography in which the degree of separation is increased by forcing the mobile phase under pressure through a stationary phase, typically a densely packed column.","As used herein, the term “ultra high performance liquid chromatography” or “UHPLC” (sometimes known as “ultra high pressure liquid chromatography”) refers to liquid chromatography in which the degree of separation is increased by forcing the mobile phase under high pressure through a stationary phase, typically a densely packed column with a stationary phase comprising packing particles that have an average diameter of than 2 μM.","As used herein, the term “turbulent flow liquid chromatography” or “TFLC” (sometimes known as high turbulence liquid chromatography or high throughput liquid chromatography) refers to a form of chromatography that utilizes turbulent flow of the material being assayed through the column packing as the basis for performing the separation.","TFLC has been applied in the preparation of samples containing two unnamed drugs prior to analysis by mass spectrometry.","See, e.g., Zimmer et al., J Chromatogr A 854: 23-35 (1999); see also, U.S. Pat.","Nos.","5,968,367, 5,919,368, 5,795,469, and 5,772,874, which further explain TFLC.","Persons of ordinary skill in the art understand “turbulent flow”.","When fluid flows slowly and smoothly, the flow is called “laminar flow”.","For example, fluid moving through an HPLC column at low flow rates is laminar.","In laminar flow the motion of the particles of fluid is orderly with particles moving generally in straight lines.","At faster velocities, the inertia of the water overcomes fluid frictional forces and turbulent flow results.","Fluid not in contact with the irregular boundary “outruns” that which is slowed by friction or deflected by an uneven surface.","When a fluid is flowing turbulently, it flows in eddies and whirls (or vortices), with more “drag” than when the flow is laminar.","Many references are available for assisting in determining when fluid flow is laminar or turbulent (e.g., Turbulent Flow Analysis: Measurement and Prediction , P. S. Bernard & J. M. Wallace, John Wiley & Sons, Inc., (2000); An Introduction to Turbulent Flow , Jean Mathieu & Julian Scott, Cambridge University Press (2001)).","As used herein, the term “gas chromatography” or “GC” refers to chromatography in which the sample mixture is vaporized and injected into a stream of carrier gas (as nitrogen or helium) moving through a column containing a stationary phase composed of a liquid or a particulate solid and is separated into its component compounds according to the affinity of the compounds for the stationary phase.","As used herein, the term “large particle column” or “extraction column” refers to a chromatography column containing an average particle diameter greater than about 50 μm.","As used in this context, the term “about” means±10%.","As used herein, the term “analytical column” refers to a chromatography column having sufficient chromatographic plates to effect a separation of materials in a sample that elute from the column sufficient to allow a determination of the presence or amount of an analyte.","Such columns are often distinguished from “extraction columns”, which have the general purpose of separating or extracting retained material from non-retained materials in order to obtain a purified sample for further analysis.","As used in this context, the term “about” means±10%.","In a preferred embodiment the analytical column contains particles of about 5 μm in diameter.","As used herein, the terms “on-line” and “inline”, for example as used in “on-line automated fashion” or “on-line extraction” refers to a procedure performed without the need for operator intervention.","In contrast, the term “off-line” as used herein refers to a procedure requiring manual intervention of an operator.","Thus, if samples are subjected to precipitation, and the supernatants are then manually loaded into an autosampler, the precipitation and loading steps are off-line from the subsequent steps.","In various embodiments of the methods, one or more steps may be performed in an on-line automated fashion.","As used herein, the term “mass spectrometry” or “MS” refers to an analytical technique to identify compounds by their mass.","MS refers to methods of filtering, detecting, and measuring ions based on their mass-to-charge ratio, or “m/z”.","MS technology generally includes (1) ionizing the compounds to form charged compounds; and (2) detecting the molecular weight of the charged compounds and calculating a mass-to-charge ratio.","The compounds may be ionized and detected by any suitable means.","A “mass spectrometer” generally includes an ionizer and an ion detector.","In general, one or more molecules of interest are ionized, and the ions are subsequently introduced into a mass spectrometric instrument where, due to a combination of magnetic and electric fields, the ions follow a path in space that is dependent upon mass (“m”) and charge (“z”).","See, e.g., U.S. Pat.","No.","6,204,500, entitled “Mass Spectrometry From Surfaces;” U.S. Pat.","No.","6,107,623, entitled “Methods and Apparatus for Tandem Mass Spectrometry;” U.S. Pat.","No.","6,268,144, entitled “DNA Diagnostics Based On Mass Spectrometry;” U.S. Pat.","No.","6,124,137, entitled “Surface-Enhanced Photolabile Attachment And Release For Desorption And Detection Of Analytes;” Wright et al., Prostate Cancer and Prostatic Diseases 1999, 2: 264-76; and Merchant and Weinberger, Electrophoresis 2000, 21: 1164-67.As used herein, the term “operating in negative ion mode” refers to those mass spectrometry methods where negative ions are generated and detected.","The term “operating in positive ion mode” as used herein, refers to those mass spectrometry methods where positive ions are generated and detected.","As used herein, the term “ionization” or “ionizing” refers to the process of generating an analyte ion having a net electrical charge equal to one or more electron units.","Negative ions are those having a net negative charge of one or more electron units, while positive ions are those having a net positive charge of one or more electron units.","As used herein, the term “electron ionization” or “EI” refers to methods in which an analyte of interest in a gaseous or vapor phase interacts with a flow of electrons.","Impact of the electrons with the analyte produces analyte ions, which may then be subjected to a mass spectrometry technique.","As used herein, the term “chemical ionization” or “CI” refers to methods in which a reagent gas (e g ammonia) is subjected to electron impact, and analyte ions are formed by the interaction of reagent gas ions and analyte molecules.","As used herein, the term “fast atom bombardment” or “FAB” refers to methods in which a beam of high energy atoms (often Xe or Ar) impacts a non-volatile sample, desorbing and ionizing molecules contained in the sample.","Test samples are dissolved in a viscous liquid matrix such as glycerol, thioglycerol, m-nitrobenzyl alcohol, 18-crown-6 crown ether, 2-nitrophenyloctyl ether, sulfolane, diethanolamine, and triethanolamine.","The choice of an appropriate matrix for a compound or sample is an empirical process.","As used herein, the term “matrix-assisted laser desorption ionization” or “MALDI” refers to methods in which a non-volatile sample is exposed to laser irradiation, which desorbs and ionizes analytes in the sample by various ionization pathways, including photoionization, protonation, deprotonation, and cluster decay.","For MALDI, the sample is mixed with an energy-absorbing matrix, which facilitates desorption of analyte molecules.","As used herein, the term “surface enhanced laser desorption ionization” or “SELDI” refers to another method in which a non-volatile sample is exposed to laser irradiation, which desorbs and ionizes analytes in the sample by various ionization pathways, including photoionization, protonation, deprotonation, and cluster decay.","For SELDI, the sample is typically bound to a surface that preferentially retains one or more analytes of interest.","As in MALDI, this process may also employ an energy-absorbing material to facilitate ionization.","As used herein, the term “electrospray ionization” or “ESI,” refers to methods in which a solution is passed along a short length of capillary tube, to the end of which is applied a high positive or negative electric potential.","Solution reaching the end of the tube is vaporized (nebulized) into a jet or spray of very small droplets of solution in solvent vapor.","This mist of droplets flows through an evaporation chamber.","As the droplets get smaller the electrical surface charge density increases until such time that the natural repulsion between like charges causes ions as well as neutral molecules to be released.","Heated ESI is similar, but includes a heat source for heating the sample while in the capillary tube.","As used herein, the term “atmospheric pressure chemical ionization” or “APCI,” refers to mass spectrometry methods that are similar to ESI; however, APCI produces ions by ion-molecule reactions that occur within a plasma at atmospheric pressure.","The plasma is maintained by an electric discharge between the spray capillary and a counter electrode.","Then ions are typically extracted into the mass analyzer by use of a set of differentially pumped skimmer stages.","A counterflow of dry and preheated N 2 gas may be used to improve removal of solvent.","The gas-phase ionization in APCI can be more effective than ESI for analyzing less-polar species.","The term “atmospheric pressure photoionization” or “APPI” as used herein refers to the form of mass spectrometry where the mechanism for the photoionization of molecule M is photon absorption and electron ejection to form the molecular ion M+.","Because the photon energy typically is just above the ionization potential, the molecular ion is less susceptible to dissociation.","In many cases it may be possible to analyze samples without the need for chromatography, thus saving significant time and expense.","In the presence of water vapor or protic solvents, the molecular ion can extract H to form MH+.","This tends to occur if M has a high proton affinity.","This does not affect quantitation accuracy because the sum of M+ and MH+ is constant.","Drug compounds in protic solvents are usually observed as MH+, whereas nonpolar compounds such as naphthalene or testosterone usually form M+.","See, e.g., Robb et al., Anal.","Chem.","2000, 72(15): 3653-3659.As used herein, the term “inductively coupled plasma” or “ICP” refers to methods in which a sample interacts with a partially ionized gas at a sufficiently high temperature such that most elements are atomized and ionized.","As used herein, the term “field desorption” refers to methods in which a non-volatile test sample is placed on an ionization surface, and an intense electric field is used to generate analyte ions.","As used herein, the term “desorption” refers to the removal of an analyte from a surface and/or the entry of an analyte into a gaseous phase.","Laser desorption thermal desorption is a technique wherein a sample containing the analyte is thermally desorbed into the gas phase by a laser pulse.","The laser hits the back of a specially made 96-well plate with a metal base.","The laser pulse heats the base and the heat causes the sample to transfer into the gas phase.","The gas phase sample is then drawn into the mass spectrometer.","As used herein, the term “selective ion monitoring” is a detection mode for a mass spectrometric instrument in which only ions within a relatively narrow mass range, typically about one mass unit, are detected.","As used herein, “multiple reaction mode,” sometimes known as “selected reaction monitoring,” is a detection mode for a mass spectrometric instrument in which a precursor ion and one or more fragment ions are selectively detected.","As used herein, the term “lower limit of quantification”, “lower limit of quantitation” or “LLOQ” refers to the point where measurements become quantitatively meaningful.","The analyte response at this LOQ is identifiable, discrete and reproducible with a relative standard deviation (RSD %) of less than 20% and an accuracy of 85% to 115%.","As used herein, the term “limit of detection” or “LOD” is the point at which the measured value is larger than the uncertainty associated with it.","The LOD is the point at which a value is beyond the uncertainty associated with its measurement and is defined as three times the RSD of the mean at the zero concentration.","As used herein, an “amount” of an analyte in a body fluid sample refers generally to an absolute value reflecting the mass of the analyte detectable in volume of sample.","However, an amount also contemplates a relative amount in comparison to another analyte amount.","For example, an amount of an analyte in a sample can be an amount which is greater than a control or normal level of the analyte normally present in the sample.","The term “about” as used herein in reference to quantitative measurements not including the measurement of the mass of an ion, refers to the indicated value plus or minus 10%.","Mass spectrometry instruments can vary slightly in determining the mass of a given analyte.","The term “about” in the context of the mass of an ion or the mass/charge ratio of an ion refers to +/−0.5 atomic mass unit.","The summary of the invention described above is non-limiting and other features and advantages of the invention will be apparent from the following detailed description of the invention, and from the claims."],["CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation application of U.S. application Ser.","No.","15/443,645, filed Feb. 27, 2017, which is a continuation application of U.S. application Ser.","No.","14/565,805, filed Dec. 10, 2014, now U.S. Pat.","No.","9,583,322, which is a continuation application of U.S. application Ser.","No.","13/682,304, filed Nov. 20, 2012, now U.S. Pat.","No.","8,916,680, which claims the benefit under 35 U.S.C.","§ 119(e) of U.S.","Provisional Application Ser.","No.","61/563,435, filed Nov. 23, 2011, each of which is incorporated by reference in its entirety into the present disclosure.","FIELD OF THE INVENTION The invention relates to the quantitative measurement of kisspeptin-54 and kisspeptin-54-derived peptides.","In a particular aspect, the invention relates to methods for quantitative measurement of kisspeptin-54 and kisspeptin-54-derived peptides by HPLC-tandem mass spectrometry.","BACKGROUND OF THE INVENTION The following description of the background of the invention is provided simply as an aid in understanding the invention and is not admitted to describe or constitute prior art to the invention.","The kisspeptin-54 peptide is essential for sexual reproduction and it suppresses cancer metastasis.","It is also known as metastin, kisspeptin 1-54, KP-54, and KiSS-1 (68-121).","Kisspeptin-54 is the carboxamide fragment of residues 68-121 of the protein KISS-1, which in turn is encoded by the KiSS-1 gene.","Kisspeptin-54 potently and selectively stimulates the G-protein-coupled receptor 54 (GPR54) to signal secretion of gonadotropin-releasing hormone (GnRH).","Rhythmical secretions of GnRH initiate puberty, coordinate ovulation, and maintain overall reproductive function.","Kisspeptin-54 is known to suppress the progression of melanomas and breast cancers.","It is postulated that kisspeptin-54 suppresses metastasis by inhibiting chemotaxis and invasion of cancer cells.","Human kisspeptin-54 (CAS No: [374683-24-6]) consists of 54 amino acids with a molecular weight of about 5857.5 g/mol and a monoisotopic mass of about 5854.0 g/mol.","It is a peptide amide cleavage product containing the amino acid residues from 68 to 121 of the 138 amino acid KiSS-1 protein.","Other bioactive peptides that result from cleavage of KiSS-1 are kisspeptin-14 (KP-14, 41-54), kisspeptin-13 (KP-13, residues 42-54), and kisspeptin-10 (KP-10; residues 45-54).","Kisspeptin-54 has been identified using tandem mass spectrometry.","See e.g., Kotani, M., et al., J. Biol.","Chem.","2001, 276(37), 34631-6 (isolated); Dhillo, W., et al., J. Clin Endocrinol.","Metab.","2005, 90(12), 6609-15 (synthetic).","Kisspeptin-54 has been quantitated using immunoassays.","See e.g., Jayasena et al., J. Endocrinol.","Metab.","2009, 94(11), 4315-23 (measured immunoreactivity of antibody with kisspeptin-54).","Among the kisspeptin peptides, only kisspeptin-10 has been reported to be purified for and subjected to quantitative mass spectrometry.","Chan et al., J. Clin.","Endocrinol.","Metab., 2011, 96(6), E908-15.SUMMARY OF THE INVENTION In one aspect, the present invention provides methods of determining by mass spectrometry the amount in a sample of one or more kisspeptin-54-derived peptides selected from the group consisting of kisspeptin-54, kisspeptin-53, kisspeptin-52, kisspeptin-54(R14P), kisspeptin-53(R14P), and kisspeptin-52(R14P).","These methods include subjecting the sample to ionization under conditions suitable to produce one or more multiply charged kisspeptin-54-derived peptide ions detectable by mass spectrometry; determining by mass spectrometry the amount of one or more ions from each of the one or more kisspeptin-54-derived peptides; and using the amount of the determined ions to determine the amounts of the corresponding one or more kisspeptin-54-derived peptides in the sample.","In one aspect, the methods further include, prior to ionization, enriching the concentration of the kisspeptin-54-derived peptides with an antibody specific for the N-terminal portion of kisspeptin-54.In addition or alternatively, the methods further includes adding an organic solvent, such as methanol, to the sample in an amount sufficient to precipitate one or more components from said sample, so as to enrich the concentration of the kisspeptin-54-derived peptides.","In some embodiments, ions are determined from kisspeptin-54, kisspeptin-53, and kisspeptin-52.In some embodiments, ions are determined from kisspeptin-54(R14P), kisspeptin-53(R14P), and kisspeptin-52(R14P).","In some embodiments, kisspeptin-54-derived peptides from the sample are chemically modified prior to ionization.","In some embodiments, at least one of the multiply charged ions generated from the kisspeptin-54-derived peptides is selected from the group of ions with a charge consisting of 4+, 5+, 6+, or 7+.","In some embodiments, the determined kisspeptin-54-derived peptides are selected from the group consisting of kisspeptin-54, kisspeptin-53, kisspeptin-52.In embodiments where the one or more kisspeptin-54-derived peptides comprise kisspeptin-54, multiply charged kisspeptin-54 ions may be selected from the group of ions with m/z of 1172.4±0.5, 977.2±0.5, and 837.7±0.5.In embodiments where the one or more kisspeptin-54-derived peptides comprise kisspeptin-54(R14P), multiply charged kisspeptin-54(R14P) ions may be selected from the group of ions with m/z of 1450.5±0.5, 1160.6±0.5, and 967.3±0.5.In embodiments where the one or more kisspeptin-54-derived peptides comprise kisspeptin-53, multiply charged kisspeptin-53 ions may be selected from the group of ions with m/z of 1143.2±0.5, 952.7±0.5, and 816.9±0.5.In embodiments where the one or more kisspeptin-54-derived peptides comprise kisspeptin-52, multiply charged kisspeptin-52 ions may be selected from the group of ions with m/z of 1112.0±0.5, and 926.6±0.5.In some embodiments, mass spectrometry is tandem mass spectrometry.","Embodiments utilizing tandem mass spectrometry comprise fragmenting one or more of the multiply charged kisspeptin-54-derived peptide ions into kisspeptin-54-derived peptide fragment ions.","In embodiments where kisspeptin-54 is subjected to tandem mass spectrometry, multiply charged kisspeptin-54 ions with m/z of 977.2±0.5 may be fragmented into one or more ions selected from the group consisting of ions with m/z of 1083.6±0.5 and 903.1±0.5; multiply charged kisspeptin-54 ions with m/z of 837.7±0.5 may be fragmented into an ion with m/z of 977.2±0.5.In embodiments where kisspeptin-54(R14P) is subjected to tandem mass spectrometry, multiply charged kisspeptin-54(R14P) ions with m/z of 1160.6±0.5 may be fragmented into an ion with m/z of 1071.6±0.5; multiply charged kisspeptin-54(R14P) ions with m/z of 967.3±0.5 may be fragmented into an ion with m/z of 1071.6±0.5.In embodiments where kisspeptin-53 is subjected to tandem mass spectrometry, multiply charged kisspeptin-53 ions with m/z of 1143.2±0.5 may be fragmented into an ion with m/z of 1053.9±0.5; multiply charged kisspeptin-53 ions with m/z of 952.7±0.5 may be fragmented into one or more ions selected from the group of ions with m/z of 1054.1±0.5 and 878.5±0.5; and multiply charged kisspeptin-53 ions with m/z of 816.7±0.5 may be fragmented into an ion with m/z of 878.3±0.5.In embodiments where kisspeptin-52 is subjected to tandem mass spectrometry, multiply charged kisspeptin-52 ions with m/z of 1112.0±0.5 may be fragmented into one or more ions selected from the group consisting of ions with m/z of 1278.2±0.5 and 1022.9; multiply charged kisspeptin-52 ions with m/z of 926.8±0.5 may be fragmented into an ion with m/z of 1022.9±0.5.In some embodiments, a sample is subjected to one or more processing steps prior to ionization.","In some embodiments, the processing steps include one or more purification steps.","In some embodiments, the processing steps include adding aqueous formic acid to the sample.","In some embodiments, the processing steps include adding an organic solvent, such as methanol, to the sample in an amount sufficient to precipitate one or more components from said sample; centrifuging the organic solvent-sample mixture, wherein a portion of kisspeptin-54-derived peptides from the sample remain in the supernatant; and collecting the supernatant for further processing or ionization.","In some embodiments, the processing steps include applying the sample to an anion or cation exchange column under conditions suitable to retain kisspeptin-54-derived peptides on the column; eluting kisspeptin-54-derived peptides from the column; and collecting the eluted kisspeptin-54-derived peptides for further processing or ionization.","In some embodiments, the processing steps include immunopurification.","In some related embodiments, immunopurification comprises capture and extraction of one or more of kisspeptin-54-derived peptides using anti-kisspeptin-54-derived peptides antibodies specific for the N-terminus of kisspeptin-54.In some embodiments, the processing steps comprise solid phase extraction (SPE).","In some embodiments, the processing steps comprise high performance liquid chromatography (HPLC).","In a second aspect, the invention provides methods of reducing the degradation of kisspeptin-54-derived peptides in body fluid sample from a patient.","These methods include acidifying a body fluid sample, treating a body fluid sample with an agent under conditions sufficient to precipitate proteins from said body fluid sample, or both.","In some embodiments, acidifying said body fluid sample comprises acidifying with aqueous formic acid.","In some embodiments, the protein precipitation agent comprises an organic solvent, such as methanol.","In some related embodiments, the ratio of the volume of the organic solvent to the volume of the biological sample is about 3:1.In a third aspect, the invention provides methods of measuring degradation of kisspeptin-54 in a biological fluid sample from a patient.","These methods include subjecting a body fluid sample from a patient to ionization under conditions suitable to produce one or more multiply charged ions detectable by mass spectrometry from kisspeptin-54 and one or more kisspeptin-54 derivation products selected from the group consisting of kisspeptin-53 and kisspeptin-52; determining by mass spectrometry the amount of one or more ions of kisspeptin-54 and one or more kisspeptin-54 derivation products selected from the group consisting of kisspeptin-53 and kisspeptin-52; and using the amounts of ions determined in step b to determine the amounts of kisspeptin-54 and kisspeptin-54 derivation products in the sample.","Similar methods are provided for measuring degradation of kisspeptin-54(R14P) in a biological fluid sample from a patient.","These methods include subjecting a biological fluid sample from a patient to ionization under conditions suitable to produce one or more multiply charged ions detectable by mass spectrometry from kisspeptin-54(R14P) and one or more kisspeptin-54(R14P) derivation products selected from the group consisting of kisspeptin-53(R14P) and kisspeptin-52(R14P); determining by mass spectrometry the amount of one or more ions of kisspeptin-54(R14P) and one or more kisspeptin-54(R14P) derivation products selected from the group consisting of kisspeptin-53(R14P) and kisspeptin-52(R14P); and using the amounts of ions determined in step b to determine the amounts of kisspeptin-54(R14P) and kisspeptin-54(R14P) derivation products in the sample.","In another aspect, the invention provides methods of diagnosing or predicting risk of developing preeclampsia.","These methods include providing a body fluid or tissue sample obtained from a patient; subjecting the body fluid or tissue sample to one or more processing steps to generate a processed sample comprising one or more kisspeptin-54-derived peptides selected from the group consisting of kisspeptin-54, kisspeptin-53, kisspeptin-52, kisspeptin-54(R14P), kisspeptin-53(R14P), and kisspeptin-52(R14P); subjecting the processed sample to ionization under conditions suitable to produce one or more multiply charged ions detectable by mass spectrometry; determining by mass spectrometry the amount of one or more ions from one or more kisspeptin-54-derived peptides; and using the determined ion amounts to determine the amount of kisspeptin-54 or kisspeptin-54(R14P) in the sample.","In these methods, elevated kisspeptin-54 or kisspeptin-54(R14P) levels in the sample relative to normal indicate the presence of or risk of developing preeclampsia.","In another aspect, the invention provides one or more substantially isolated polypeptides with amino acid sequences consisting of the sequences identified as SEQ ID No.",":2 and SEQ ID No.",":3, or proline variants thereof.","In any of the methods provided herein which utilize tandem mass spectrometry, tandem mass spectrometry may be conducted by any method known in the art, including for example, multiple reaction monitoring, precursor ion scanning, or product ion scanning.","In any of the methods provided herein which utilize two or more of an extraction column, an analytical column, and an ionization source, two or more of these components may be connected in an on-line fashion to allow for automated sample processing and analysis.","In any of the methods provided herein which require ionization of a kisspeptin-54-derived peptide, mass spectrometry is preferably performed in positive ion mode.","Alternatively, mass spectrometry is performed in negative ion mode.","Various ionization sources, including for example atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI), and heated ESI, may be used in embodiments of the present invention.","In certain preferred embodiments, kisspeptin-54-derived peptides are ionized using heated ESI in positive ion mode.","In preferred embodiments of methods presented herein which determine the amount of one or more kisspeptin-54-derived peptides in a sample, a separately detectable internal standard is provided in the sample, the amount of which is also determined in the sample.","In these embodiments, all or a portion of both the analyte(s) of interest and the internal standard present in the sample is ionized to produce a plurality of ions detectable in a mass spectrometer, and one or more ions produced from each are detected by mass spectrometry.","In these embodiments, the presence or amount of ions generated from the analyte of interest may be related to the presence of amount of analyte of interest in the sample.","In other embodiments, the amount of one or more kisspeptin-54-derived peptides in a sample may be determined by comparison to one or more external reference standards.","Exemplary external reference standards include blank plasma or serum spiked with a kisspeptin-54-derived peptide or an isotopically labeled variant thereof (such as isotopically labeled kisspeptin-54 and isotopically labeled kisspeptin-54(R14P)).","As used herein, unless otherwise stated, the singular forms “a,” “an,” and “the” include plural reference.","Thus, for example, a reference to “a protein” includes a plurality of protein molecules.","As used herein, the term “kisspeptin-54-derived peptide” refers to intact kisspeptin-54 and peptide fragments whose amino acid sequence is found within the amino acid sequence of kisspeptin-54, and all polymorphs thereof.","One known polymorph of kisspeptin-54 includes a proline replacement for the arginine at position 14.This polymorph is described herein as kisspeptin-54 (proline variant) or kisspeptin-54(R14P).","Kisspeptin-54-derived peptides may possess one or more of the following attributes: naturally occurring, chemically synthesized, isotopically labeled, and chemically modified.","Isotopic labeling and/or chemical modification may be conducted by any of several techniques known by those of skill in the art.","Other exemplary kisspeptin-54 derived peptides include kisspeptin-53, kisspeptin-52, and their protein variants.","As used herein, the term “kisspeptin-54” refers to a 54 amino acid peptide with the sequence shown as SEQ ID No.",":1 in FIG.","1A.","As used herein, the term “kisspeptin-53” refers to a 53 amino acid peptide with the sequence shown as SEQ ID No.",":2 in FIG.","1B.","As used herein, the term “kisspeptin-52” refers to a 52 amino acid peptide with the sequence shown as SEQ ID No.",":3 in FIG.","1C.","As used herein, the term “isolated” as applied to a polypeptide means a polypeptide that has been separated from components that naturally accompany it.","Typically, the polypeptide is substantially isolated when it is at least 60%, by weight, free from the proteins and naturally occurring organic molecules with which it is naturally associated.","The definition also extends to a polypeptide separated from its flanking amino acids (e.g., for an amino acid sequence, isolated refers to a sequence that is free from the flanking amino acids with which the sequence is naturally associated in a polypeptide).","Preferably, the polypeptide is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight, isolated.","An isolated polypeptide may be obtained by standard techniques, for example, by extraction from a natural source (e.g., purification from a cell or body fluid), by expression of a recombinant nucleic acid encoding the peptide; or fusion protein thereof, by chemically synthesizing the polypeptide.","Purity can be measured by any appropriate method, e.g., by column chromatography, polyacrylamide gel electrophoresis, or HPLC analysis.","As used herein, the term “purification” or “purifying” does not refer to removing all materials from the sample other than the analyte(s) of interest.","Instead, purification refers to a procedure that enriches the amount of one or more analytes of interest relative to other components in the sample that may interfere with detection of the analyte of interest.","Purification of the sample by various means may allow relative reduction of one or more interfering substances, e.g., one or more substances that may or may not interfere with the detection of selected parent or daughter ions by mass spectrometry.","Relative reduction as this term is used does not require that any substance, present with the analyte of interest in the material to be purified, is entirely removed by purification.","As used herein, the term “immunopurification” or “immunopurify” refers to a purification procedure that utilizes antibodies, including polyclonal or monoclonal antibodies, to enrich the one or more analytes of interest.","Immunopurification can be performed using any of the immunopurification methods well known in the art.","Often the immunopurification procedure utilizes antibodies bound, conjugated or otherwise attached to a solid support, for example a column, well, tube, gel, capsule, particle or the like.","Immunopurification as used herein includes without limitation procedures often referred to in the art as immunoprecipitation, as well as procedures often referred to in the art as affinity chromatography.","As used herein, the term “immunoparticle” refers to a capsule, bead, gel particle or the like that has antibodies bound, conjugated or otherwise attached to its surface (either on and/or in the particle).","In certain preferred embodiments, immunoparticles are sepharose or agarose beads.","In alternative preferred embodiments, immunoparticles are glass, plastic or silica beads, or silica gel.","As used herein, the term “anti-kisspeptin-54-derived peptide antibody” refers to any polyclonal or monoclonal antibody that has an affinity for a kisspeptin-54-derived peptide.","In various embodiments the specificity of kisspeptin-54-derived peptide antibodies to chemical species other than the kisspeptin-54-derived peptide may vary; for example in certain preferred embodiments the anti-kisspeptin-54-derived peptide antibodies are specific for the kisspeptin-54-derived peptide and thus have little or no affinity for chemical species other than the kisspeptin-54-derived peptide, whereas in other preferred embodiments the anti-kisspeptin-54-derived peptide antibodies are non-specific and thus bind certain chemical species other than the kisspeptin-54-derived peptide.","As used herein, the term “sample” refers to any sample that may contain an analyte of interest.","As used herein, the term “body fluid” means any fluid that can be isolated from the body of an individual.","For example, “body fluid” may include blood, plasma, serum, bile, saliva, urine, tears, perspiration, and the like.","In some preferred embodiments, the sample comprises a body fluid sample; preferably plasma or serum, from a patient.","As used herein, the term “solid phase extraction” or “SPE” refers to a process in which a chemical mixture is separated into components as a result of the affinity of components dissolved or suspended in a solution (i.e., mobile phase) for a solid through or around which the solution is passed (i.e., solid phase).","In some instances, as the mobile phase passes through or around the solid phase, undesired components of the mobile phase may be retained by the solid phase resulting in a purification of the analyte in the mobile phase.","In other instances, the analyte may be retained by the solid phase, allowing undesired components of the mobile phase to pass through or around the solid phase.","In these instances, a second mobile phase is then used to elute the retained analyte off of the solid phase for further processing or analysis.","SPE, including TFLC, may operate via a unitary or mixed mode mechanism.","Mixed mode mechanisms utilize ion exchange and hydrophobic retention in the same column; for example, the solid phase of a mixed-mode SPE column may exhibit strong anion exchange and hydrophobic retention; or may exhibit column exhibit strong cation exchange and hydrophobic retention.","As used herein, the term “chromatography” refers to a process in which a chemical mixture carried by a liquid or gas is separated into components as a result of differential distribution of the chemical entities as they flow around or over a stationary liquid or solid phase.","As used herein, the term “liquid chromatography” or “LC” means a process of selective retardation of one or more components of a fluid solution as the fluid uniformly percolates through a column of a finely divided substance, or through capillary passageways.","The retardation results from the distribution of the components of the mixture between one or more stationary phases and the bulk fluid, (i.e., mobile phase), as this fluid moves relative to the stationary phase(s).","Examples of “liquid chromatography” include normal phase liquid chromatography (NPLC), reverse phase liquid chromatography (RPLC), high performance liquid chromatography (HPLC), ultra high performance liquid chromatography (UHPLC), and turbulent flow liquid chromatography (TFLC) (sometimes known as high turbulence liquid chromatography (HTLC) or high throughput liquid chromatography).","As used herein, the term “high performance liquid chromatography” or “HPLC” (sometimes known as “high pressure liquid chromatography”) refers to liquid chromatography in which the degree of separation is increased by forcing the mobile phase under pressure through a stationary phase, typically a densely packed column.","As used herein, the term “ultra high performance liquid chromatography” or “UHPLC” (sometimes known as “ultra high pressure liquid chromatography”) refers to liquid chromatography in which the degree of separation is increased by forcing the mobile phase under high pressure through a stationary phase, typically a densely packed column with a stationary phase comprising packing particles that have an average diameter of than 2 μM.","As used herein, the term “turbulent flow liquid chromatography” or “TFLC” (sometimes known as high turbulence liquid chromatography or high throughput liquid chromatography) refers to a form of chromatography that utilizes turbulent flow of the material being assayed through the column packing as the basis for performing the separation.","TFLC has been applied in the preparation of samples containing two unnamed drugs prior to analysis by mass spectrometry.","See, e.g., Zimmer et al., J Chromatogr A 854: 23-35 (1999); see also, U.S. Pat.","Nos.","5,968,367, 5,919,368, 5,795,469, and 5,772,874, which further explain TFLC.","Persons of ordinary skill in the art understand “turbulent flow”.","When fluid flows slowly and smoothly, the flow is called “laminar flow”.","For example, fluid moving through an HPLC column at low flow rates is laminar.","In laminar flow the motion of the particles of fluid is orderly with particles moving generally in straight lines.","At faster velocities, the inertia of the water overcomes fluid frictional forces and turbulent flow results.","Fluid not in contact with the irregular boundary “outruns” that which is slowed by friction or deflected by an uneven surface.","When a fluid is flowing turbulently, it flows in eddies and whirls (or vortices), with more “drag” than when the flow is laminar.","Many references are available for assisting in determining when fluid flow is laminar or turbulent (e.g., Turbulent Flow Analysis: Measurement and Prediction, P. S. Bernard & J. M. Wallace, John Wiley & Sons, Inc., (2000); An Introduction to Turbulent Flow, Jean Mathieu & Julian Scott, Cambridge University Press (2001)).","As used herein, the term “gas chromatography” or “GC” refers to chromatography in which the sample mixture is vaporized and injected into a stream of carrier gas (as nitrogen or helium) moving through a column containing a stationary phase composed of a liquid or a particulate solid and is separated into its component compounds according to the affinity of the compounds for the stationary phase.","As used herein, the term “large particle column” or “extraction column” refers to a chromatography column containing an average particle diameter greater than about 50 μm.","As used in this context, the term “about” means±10%.","As used herein, the term “analytical column” refers to a chromatography column having sufficient chromatographic plates to effect a separation of materials in a sample that elute from the column sufficient to allow a determination of the presence or amount of an analyte.","Such columns are often distinguished from “extraction columns”, which have the general purpose of separating or extracting retained material from non-retained materials in order to obtain a purified sample for further analysis.","As used in this context, the term “about” means±10%.","In a preferred embodiment the analytical column contains particles of about 5 μm in diameter.","As used herein, the terms “on-line” and “inline”, for example as used in “on-line automated fashion” or “on-line extraction” refers to a procedure performed without the need for operator intervention.","In contrast, the term “off-line” as used herein refers to a procedure requiring manual intervention of an operator.","Thus, if samples are subjected to precipitation, and the supernatants are then manually loaded into an autosampler, the precipitation and loading steps are off-line from the subsequent steps.","In various embodiments of the methods, one or more steps may be performed in an on-line automated fashion.","As used herein, the term “mass spectrometry” or “MS” refers to an analytical technique to identify compounds by their mass.","MS refers to methods of filtering, detecting, and measuring ions based on their mass-to-charge ratio, or “m/z”.","MS technology generally includes (1) ionizing the compounds to form charged compounds; and (2) detecting the molecular weight of the charged compounds and calculating a mass-to-charge ratio.","The compounds may be ionized and detected by any suitable means.","A “mass spectrometer” generally includes an ionizer and an ion detector.","In general, one or more molecules of interest are ionized, and the ions are subsequently introduced into a mass spectrometric instrument where, due to a combination of magnetic and electric fields, the ions follow a path in space that is dependent upon mass (“m”) and charge (“z”).","See, e.g., U.S. Pat.","No.","6,204,500, entitled “Mass Spectrometry From Surfaces;” U.S. Pat.","No.","6,107,623, entitled “Methods and Apparatus for Tandem Mass Spectrometry;” U.S. Pat.","No.","6,268,144, entitled “DNA Diagnostics Based On Mass Spectrometry;” U.S. Pat.","No.","6,124,137, entitled “Surface-Enhanced Photolabile Attachment And Release For Desorption And Detection Of Analytes;” Wright et al., Prostate Cancer and Prostatic Diseases 1999, 2: 264-76; and Merchant and Weinberger, Electrophoresis 2000, 21: 1164-67.As used herein, the term “operating in negative ion mode” refers to those mass spectrometry methods where negative ions are generated and detected.","The term “operating in positive ion mode” as used herein, refers to those mass spectrometry methods where positive ions are generated and detected.","As used herein, the term “ionization” or “ionizing” refers to the process of generating an analyte ion having a net electrical charge equal to one or more electron units.","Negative ions are those having a net negative charge of one or more electron units, while positive ions are those having a net positive charge of one or more electron units.","As used herein, the term “electron ionization” or “EI” refers to methods in which an analyte of interest in a gaseous or vapor phase interacts with a flow of electrons.","Impact of the electrons with the analyte produces analyte ions, which may then be subjected to a mass spectrometry technique.","As used herein, the term “chemical ionization” or “CI” refers to methods in which a reagent gas (e g ammonia) is subjected to electron impact, and analyte ions are formed by the interaction of reagent gas ions and analyte molecules.","As used herein, the term “fast atom bombardment” or “FAB” refers to methods in which a beam of high energy atoms (often Xe or Ar) impacts a non-volatile sample, desorbing and ionizing molecules contained in the sample.","Test samples are dissolved in a viscous liquid matrix such as glycerol, thioglycerol, m-nitrobenzyl alcohol, 18-crown-6 crown ether, 2-nitrophenyloctyl ether, sulfolane, diethanolamine, and triethanolamine.","The choice of an appropriate matrix for a compound or sample is an empirical process.","As used herein, the term “matrix-assisted laser desorption ionization” or “MALDI” refers to methods in which a non-volatile sample is exposed to laser irradiation, which desorbs and ionizes analytes in the sample by various ionization pathways, including photoionization, protonation, deprotonation, and cluster decay.","For MALDI, the sample is mixed with an energy-absorbing matrix, which facilitates desorption of analyte molecules.","As used herein, the term “surface enhanced laser desorption ionization” or “SELDI” refers to another method in which a non-volatile sample is exposed to laser irradiation, which desorbs and ionizes analytes in the sample by various ionization pathways, including photoionization, protonation, deprotonation, and cluster decay.","For SELDI, the sample is typically bound to a surface that preferentially retains one or more analytes of interest.","As in MALDI, this process may also employ an energy-absorbing material to facilitate ionization.","As used herein, the term “electrospray ionization” or “ESI,” refers to methods in which a solution is passed along a short length of capillary tube, to the end of which is applied a high positive or negative electric potential.","Solution reaching the end of the tube is vaporized (nebulized) into a jet or spray of very small droplets of solution in solvent vapor.","This mist of droplets flows through an evaporation chamber.","As the droplets get smaller the electrical surface charge density increases until such time that the natural repulsion between like charges causes ions as well as neutral molecules to be released.","Heated ESI is similar, but includes a heat source for heating the sample while in the capillary tube.","As used herein, the term “atmospheric pressure chemical ionization” or “APCI,” refers to mass spectrometry methods that are similar to ESI; however, APCI produces ions by ion-molecule reactions that occur within a plasma at atmospheric pressure.","The plasma is maintained by an electric discharge between the spray capillary and a counter electrode.","Then ions are typically extracted into the mass analyzer by use of a set of differentially pumped skimmer stages.","A counterflow of dry and preheated N2 gas may be used to improve removal of solvent.","The gas-phase ionization in APCI can be more effective than ESI for analyzing less-polar species.","The term “atmospheric pressure photoionization” or “APPI” as used herein refers to the form of mass spectrometry where the mechanism for the photoionization of molecule M is photon absorption and electron ejection to form the molecular ion M+.","Because the photon energy typically is just above the ionization potential, the molecular ion is less susceptible to dissociation.","In many cases it may be possible to analyze samples without the need for chromatography, thus saving significant time and expense.","In the presence of water vapor or protic solvents, the molecular ion can extract H to form MH+.","This tends to occur if M has a high proton affinity.","This does not affect quantitation accuracy because the sum of M+ and MH+ is constant.","Drug compounds in protic solvents are usually observed as MH+, whereas nonpolar compounds such as naphthalene or testosterone usually form M+.","See, e.g., Robb et al., Anal.","Chem.","2000, 72(15): 3653-3659.As used herein, the term “inductively coupled plasma” or “ICP” refers to methods in which a sample interacts with a partially ionized gas at a sufficiently high temperature such that most elements are atomized and ionized.","As used herein, the term “field desorption” refers to methods in which a non-volatile test sample is placed on an ionization surface, and an intense electric field is used to generate analyte ions.","As used herein, the term “desorption” refers to the removal of an analyte from a surface and/or the entry of an analyte into a gaseous phase.","Laser desorption thermal desorption is a technique wherein a sample containing the analyte is thermally desorbed into the gas phase by a laser pulse.","The laser hits the back of a specially made 96-well plate with a metal base.","The laser pulse heats the base and the heat causes the sample to transfer into the gas phase.","The gas phase sample is then drawn into the mass spectrometer.","As used herein, the term “selective ion monitoring” is a detection mode for a mass spectrometric instrument in which only ions within a relatively narrow mass range, typically about one mass unit, are detected.","As used herein, “multiple reaction mode,” sometimes known as “selected reaction monitoring,” is a detection mode for a mass spectrometric instrument in which a precursor ion and one or more fragment ions are selectively detected.","As used herein, the term “lower limit of quantification”, “lower limit of quantitation” or “LLOQ” refers to the point where measurements become quantitatively meaningful.","The analyte response at this LOQ is identifiable, discrete and reproducible with a relative standard deviation (RSD %) of less than 20% and an accuracy of 85% to 115%.","As used herein, the term “limit of detection” or “LOD” is the point at which the measured value is larger than the uncertainty associated with it.","The LOD is the point at which a value is beyond the uncertainty associated with its measurement and is defined as three times the RSD of the mean at the zero concentration.","As used herein, an “amount” of an analyte in a body fluid sample refers generally to an absolute value reflecting the mass of the analyte detectable in volume of sample.","However, an amount also contemplates a relative amount in comparison to another analyte amount.","For example, an amount of an analyte in a sample can be an amount which is greater than a control or normal level of the analyte normally present in the sample.","The term “about” as used herein in reference to quantitative measurements not including the measurement of the mass of an ion, refers to the indicated value plus or minus 10%.","Mass spectrometry instruments can vary slightly in determining the mass of a given analyte.","The term “about” in the context of the mass of an ion or the mass/charge ratio of an ion refers to +/−0.5 atomic mass unit.","The summary of the invention described above is non-limiting and other features and advantages of the invention will be apparent from the following detailed description of the invention, and from the claims.","BRIEF DESCRIPTION OF THE DRAWINGS FIGS.","1A-C show the amino acid sequences of kisspeptin-54 (SEQ ID NO.",":1), kisspeptin-53 (SEQ ID NO.",":2), and kisspeptin-52 (SEQ ID NO.",":3), respectively, including their respective proline variants (i.e., each having the R14P substitution).","FIG.","2 shows a full scan spectrum of Kisspeptin-54.This spectrum shows generation of KP-54 [M+7H]+7 and [M+6H]+6 ions with m/z of 837.5±0.5 and 977.0±0.5, respectively.","Details are discussed in Example 3.FIG.","3 shows an exemplary fragmentation spectrum of KP-54 [M+6H]+6 ion with m/z of 977.0±0.5.Exemplary fragment ions are observed at m/z of 1083.6±0.5 and 903.1±0.5.Details are discussed in Example 3.FIG.","4 shows an exemplary fragmentation spectrum of KP-54 [M+7H]+7 ion with m/z of 837.7±0.5.Exemplary fragment ions are observed at m/z of 902.8±0.5.Details are discussed in Example 3.FIG.","5 shows a full scan spectrum of Kisspeptin-54(R14P).","This spectrum shows generation of KP-54(R14P) [M+6H]+6, [M+5H]+5, and [M+4H]+4 ions with m/z of 967.3±0.5, 1160.6±0.5, and 1450.5±0.5, respectively.","Details are discussed in Example 3.FIG.","6 shows an exemplary fragmentation spectrum of KP-54(R14P) [M+5H]+ ion with m/z of 1160.6±0.5.Exemplary fragment ions are observed at m/z of 1071.6±0.5.Details are discussed in Example 3.FIG.","7 shows an exemplary fragmentation spectrum of KP-54(R14P) [M+6H]+6 ion with m/z of 967.3±0.5.Exemplary fragment ions are observed at m/z of 1071.6±0.5.Details are discussed in Example 3.FIG.","8 shows a full scan spectrum of Kisspeptin-53.This spectrum shows generation of KP-53 [M+7H]+7, [M+6H]+6, and [M+5H]+5 ions with m/z of 816.9±0.5, 952.7±0.5, and 1143.2±0.5, respectively.","Details are discussed in Example 3.FIG.","9 shows an exemplary fragmentation spectrum of KP-53 [M+5H]+5 ion with m/z of 1143.2±0.5.Exemplary fragment ions are observed at m/z of 1053.9±0.5.Details are discussed in Example 3.FIG.","10 shows an exemplary fragmentation spectrum of KP-53 [M+6H]+6 ion with m/z of 952.7±0.5.Exemplary fragment ions are observed at m/z of 1054.1±0.5 and 878.3±0.5.Details are discussed in Example 3.FIG.","11 shows an exemplary fragmentation spectrum of KP-53 [M+7H]+7 ion with m/z of 816.7±0.5.Exemplary fragment ions are observed at m/z of 878.3±0.5.Details are discussed in Example 3.FIG.","12 shows a full scan spectrum of Kisspeptin-52.This spectrum shows generation of KP-52 [M+6H]+6, [M+5H]+5, and [M+4H]+4 ions with m/z of 926.6±0.5, 1112.0±0.5, and 1389.5±0.5, respectively.","Details are discussed in Example 3.FIG.","13 shows an exemplary fragmentation spectrum of KP-52 [M+5H]+5 ion with m/z of 1111.9±0.5±0.5.Exemplary fragment ions are observed at m/z of 1278.2±0.5 and 1022.9±0.5.Details are discussed in Example 3.FIG.","14 shows an exemplary fragmentation spectrum of KP-52 [M+6H]+6 ion with m/z of 926.8±0.5.Exemplary fragment ions are observed at m/z of 1022.9±0.5.Details are discussed in Example 3.FIG.","15 shows the detection of KP-52, KP-53, KP-54, and KP-54(IS) in serum from pregnant woman #1 (28 years old, 25 weeks gestation).","Details are discussed in Example 4.FIG.","16 shows the detection of KP-52, KP-53, KP-54, and KP-54(IS) in EDTA plasma from pregnant woman #1 (28 years old, 25 weeks gestation).","Details are discussed in Example 4.FIG.","17 shows the detection of KP-52, KP-53, KP-54, and KP-54(IS) in serum from pregnant woman #2 (21 years old, 28 weeks gestation).","Details are discussed in Example 4.FIG.","18 shows the detection of KP-52, KP-53, KP-54, and KP-54(IS) in EDTA plasma from pregnant woman #2 (21 years old, 28 weeks gestation).","Details are discussed in Example 4.DETAILED DESCRIPTION OF THE INVENTION Methods are described for measuring the amount of one or more kisspeptin-54-derived peptides in a sample.","More specifically, mass spectrometric methods are described for detecting and quantifying one or more kisspeptin-54-derived peptides in a sample.","The methods may utilize solid phase extraction and/or liquid chromatography, to perform a purification of selected analytes, combined with methods of mass spectrometry (MS), thereby providing a high-throughput assay system for detecting and quantifying kisspeptin-54-derived peptides in a sample.","The preferred embodiments are particularly well suited for application in large clinical laboratories for automated kisspeptin-54-derived peptide quantification assay.","Suitable test samples for use in methods of the present invention include any test sample that may contain the analyte of interest.","In some preferred embodiments, a sample is a biological sample; that is, a sample obtained from any biological source, such as an animal, a cell culture, an organ culture, etc.","In certain preferred embodiments, samples are obtained from a mammalian animal, such as a dog, cat, horse, etc.","Particularly preferred mammalian animals are primates, most preferably male or female humans.","Preferred samples comprise bodily fluids such as blood, plasma, serum, saliva, cerebrospinal fluid, or tissue samples; preferably plasma and serum.","Such samples may be obtained, for example, from a patient; that is, a living person, male or female, presenting oneself in a clinical setting for diagnosis, prognosis, or treatment of a disease or condition, such as preeclampsia.","In embodiments where the sample comprises a biological sample, the methods may be used to determine the amount of one or more kisspeptin-54-derived peptides in the sample when the sample was obtained from the biological source (i.e., the amount of one or more endogenous kisspeptin-54-derived peptides in the sample).","Kisspeptin-54-derived peptides may be quantitated in patient samples from a pregnant female subject in order to diagnose or predict risk of developing preeclampsia.","In diagnosing or predicting risk of preeclampsia, levels of kisspeptin-54-derived peptides from the patient sample are compared to normal levels in pregnant female samples.","Elevated levels of kisspeptin-54-derived peptides in a patient sample relative to normal levels indicates the presence of or risk of developing preeclampsia.","The present invention also contemplates kits for a kisspeptin-54-derived peptide quantitation assay.","A kit for a kisspeptin-54-derived peptide quantitation assay may include a kit comprising the compositions provided herein.","For example, a kit may include packaging material and measured amounts of an isotopically labeled internal standard, in amounts sufficient for at least one assay.","Typically, the kits will also include instructions recorded in a tangible form (e.g., contained on paper or an electronic medium) for using the packaged reagents for use in a kisspeptin-54-derived peptide quantitation assay.","Calibration and QC pools for use in embodiments of the present invention are preferably prepared using a matrix similar to the intended sample matrix, provided that the kisspeptin-54-derived peptide is essentially absent.","Sample Preparation for Mass Spectrometric Analysis In some embodiments, samples are acidified prior to analysis.","Internal standard may be added to the samples prior or subsequent to acidification.","In preparation for mass spectrometric analysis, kisspeptin-54-derived peptides may be enriched relative to one or more other components in the sample (e.g.","protein) by various methods known in the art, including for example, liquid chromatography, filtration, centrifugation, thin layer chromatography (TLC), electrophoresis including capillary electrophoresis, affinity separations including immunoaffinity separations, extraction methods including ethyl acetate or methanol extraction, and the use of chaotropic agents or any combination of the above or the like.","Protein precipitation is one method of preparing a test sample, especially a biological test sample, such as serum or plasma.","Protein purification methods are well known in the art, for example, Polson et al., Journal of Chromatography B 2003, 785:263-275, describes protein precipitation techniques suitable for use in methods of the present invention.","Protein precipitation may be used to remove most of the protein from the sample leaving kisspeptin-54-derived peptides in the supernatant.","The samples may be centrifuged to separate the liquid supernatant from the precipitated proteins; alternatively the samples may be filtered to remove precipitated proteins.","The resultant supernatant or filtrate may then be applied directly to mass spectrometry analysis; or alternatively to further purification steps, such as liquid chromatography, and subsequent mass spectrometry analysis.","In certain embodiments, the use of protein precipitation such as, for example, formic acid protein precipitation, may obviate the need for TFLC or other on-line extraction prior to mass spectrometry or HPLC and mass spectrometry.","Another method of sample purification that may be used prior to mass spectrometry is liquid chromatography (LC).","Certain methods of liquid chromatography, including HPLC, rely on relatively slow, laminar flow technology.","Traditional HPLC analysis relies on column packing in which laminar flow of the sample through the column is the basis for separation of the analyte of interest from the sample.","The skilled artisan will understand that separation in such columns is a partition process and may select LC, including HPLC, instruments and columns that are suitable for use with kisspeptin-54-derived peptides.","The chromatographic column typically includes a medium (i.e., a packing material) to facilitate separation of chemical moieties (i.e., fractionation).","The medium may include minute particles.","The particles typically include a bonded surface that interacts with the various chemical moieties to facilitate separation of the chemical moieties.","One suitable bonded surface is a hydrophobic bonded surface such as an alkyl bonded or a cyano bonded surface.","Alkyl bonded surfaces may include C-4, C-8, C-12, or C-18 bonded alkyl groups.","In preferred embodiments, the column is a C-18 column.","The chromatographic column includes an inlet port for receiving a sample and an outlet port for discharging an effluent that includes the fractionated sample.","The sample may be supplied to the inlet port directly, or from a SPE column, such as an on-line extraction column or a TFLC column.","In some embodiments, an on-line filter may be used ahead of the SPE column and or HPLC column to remove particulates and phospholipids in the samples prior to the samples reaching the SPE and/or HPLC columns.","In preferred embodiments, a 0.2 μm or 0.45 μm micro-spin cellulose acetate delipidation filter is used as such an off-line filter.","In one embodiment, the sample may be applied to the LC column at the inlet port, eluted with a solvent or solvent mixture, and discharged at the outlet port.","Different solvent modes may be selected for eluting the analyte(s) of interest.","For example, liquid chromatography may be performed using a gradient mode, an isocratic mode, or a polytypic (i.e.","mixed) mode.","During chromatography, the separation of materials is effected by variables such as choice of eluent (also known as a “mobile phase”), elution mode, gradient conditions, temperature, etc.","In certain embodiments, an analyte may be purified by applying a sample to a column under conditions where the analyte of interest is reversibly retained by the column packing material, while one or more other materials are not retained.","In these embodiments, a first mobile phase condition can be employed where the analyte of interest is retained by the column, and a second mobile phase condition can subsequently be employed to remove retained material from the column, once the non-retained materials are washed through.","Alternatively, an analyte may be purified by applying a sample to a column under mobile phase conditions where the analyte of interest elutes at a differential rate in comparison to one or more other materials.","Such procedures may enrich the amount of one or more analytes of interest relative to one or more other components of the sample.","In one preferred embodiment, HPLC is conducted with a polar embedded analytical column chromatographic system.","In certain preferred embodiments, a C-18 BEH (ethylene bridged hybrid) analytical column (e.g., an XBridge C18 BEH analytical column from Waters Inc. (2.5×50 mm, 5 μm particle size), or equivalent) is used.","In certain preferred embodiments, HPLC is performed using HPLC Grade 0.2% aqueous formic acid as solvent A, and 0.2% formic acid in acetonitrile as solvent B.","By careful selection of valves and connector plumbing, two or more chromatography columns may be connected as needed such that material is passed from one to the next without the need for any manual steps.","In preferred embodiments, the selection of valves and plumbing is controlled by a computer pre-programmed to perform the necessary steps.","Most preferably, the chromatography system is also connected in such an on-line fashion to the detector system, e.g., an MS system.","Thus, an operator may place a tray of samples in an autosampler, and the remaining operations are performed under computer control, resulting in purification and analysis of all samples selected.","In some embodiments, TFLC may be used for purification of kisspeptin-54-derived peptides prior to mass spectrometry.","In such embodiments, samples may be extracted using a TFLC column which captures the analyte.","The analyte is then eluted and transferred on-line to an analytical HPLC column.","For example, sample extraction may be accomplished with a TFLC extraction cartridge may be accomplished with a large particle size (e.g., 25 μm or larger, such as 50 μm, particle size) packed column.","Sample eluted off of this column is then transferred on-line to an HPLC analytical column for further purification prior to mass spectrometry.","Because the steps involved in these chromatography procedures may be linked in an automated fashion, the requirement for operator involvement during the purification of the analyte can be minimized.","This feature may result in savings of time and costs, and eliminate the opportunity for operator error.","In some embodiments, the methods include immunopurifying kisspeptin-54-derived peptides prior to analysis.","The immunopurification step may be performed using any of the immunopurification methods well known in the art.","Often the immunopurification procedure utilizes antibodies bound, conjugated, immobilized or otherwise attached to a solid support, for example a column, well, tube, capsule, particle or the like.","Generally, immunopurification methods involve (1) incubating a sample containing the analyte of interest with antibodies such that the analyte binds to the antibodies, (2) performing one or more washing steps, and (3) eluting the analyte from the antibodies.","In certain embodiments the incubation step of the immunopurification is performed with the antibodies free in solution and the antibodies are subsequently bound or attached to a solid surface prior to the washing steps.","In certain embodiments this can be achieved using a primary antibody that is an anti-kisspeptin-54-derived peptide antibody and a secondary antibody attached to a solid surface that has an affinity to the primary anti-kisspeptin-54-derived peptide antibody.","In alternative embodiments, the primary antibody is bound to the solid surface prior to the incubation step.","Appropriate solid supports include without limitation tubes, slides, columns, beads, capsules, particles, gels, and the like.","In some preferred embodiments, the solid support is a multi-well plate, such as, for example, a 96 well plate, a 384-well plate or the like.","In certain preferred embodiments the solid support are sepharose or agarose beads or gels.","There are numerous methods well known in the art by which antibodies (for example, an anti-kisspeptin-54-derived peptide antibody or a secondary antibody) may be bound, attached, immobilized or coupled to a solid support, e.g., covalent or non-covalent linkages adsorption, affinity binding, ionic linkages and the like.","In some embodiments antibodies are coupled using CNBr, for example the antibodies may be coupled to CNBr activated sepharose.","In other embodiments, the antibody is attached to the solid support through an antibody binding protein such as protein A, protein G, protein A/G, or protein L. The washing step of the immunopurification methods generally involve washing the solid support such that one or more kisspeptin-54-derived peptides remain bound to the anti-kisspeptin-54-derived peptide antibodies on the solid support.","The elution step of the immunopurification generally involves the addition of a solution that disrupts the binding of kisspeptin-54-derived peptides to the anti-kisspeptin-54-derived peptide antibodies.","Exemplary elution solutions include organic solutions (such as ethanol), salt solutions, and high or low pH solutions.","In some embodiments, immunopurification is performed using immunoparticles having anti-kisspeptin-54-derived peptide antibodies.","In certain preferred embodiments the test sample possibly containing one or more kisspeptin-54-derived peptides and the immunoparticles are mixed in a tube for incubation and binding of kisspeptin-54-derived peptides to the anti-kisspeptin-54-derived peptide antibodies attached to the immunoparticles; the tube is centrifuged leaving the immunoparticles in a pellet; the supernatant is removed; the immunoparticles are washed one or more times by adding a solution to the pellet and recentrifuging; and the bound kisspeptin-54-derived peptides are eluted by adding an elution solution to the immunoparticles, the tube is centrifuged leaving the immunoparticles in a pellet; and the supernatant containing kisspeptin-54-derived peptides is collected.","In related preferred embodiments, the immunopurification is performed using a column or cartridge that contains immunoparticles having anti-kisspeptin-54-derived peptide antibodies.","Preferably, the such column or cartridge is configured and arranged in a manner to allow solutions to flow through while keeping the immunoparticles contained therein.","In certain preferred embodiments, the solution is forced through the column or cartridge by gravity, centrifugation or pressure.","The use of columns may improve the ease of performing the incubation, washing and elution steps.","In some embodiments, the immunopurification may be performed by affinity chromatography; preferably automated affinity chromatography.","It has been found that kisspeptin-54 in patient samples (i.e., serum or plasma) potentially degrades at the C-terminus to form shorter kisspeptin-54-derived peptides such as KP-53 and KP-52.This degradation, if not controlled or accounted for, could result in erroneously low analytical results.","For example, radioimmunoassays which rely on binding of the C-terminus of KP-54 would not account for that portion of KP-54 originally in the patient sample which has since degraded into KP-53 or KP-52.Thus, one aspect of the present invention utilizes antibodies specific for the N-terminus of kisspeptin-54-derived peptides for immunopurification and/or immunoassay.","By using N-terminus specific antibodies, KP-54 and its degradation products K-53 and K-52 are captured for further analysis.","Alternatively or in addition, patient samples may be treated with one or more agents or subject to physical conditions which inhibit or prevent KP-54 degradation prior to KP-54 purification and analysis.","For example, patient serum or plasma samples may be acidified, such as with formic acid, to inhibit or prevent degradation.","Alternatively, patient serum or plasma samples may be subject to any protein precipitation technique known in the art (such as treatment with methanol) to inhibit or prevent degradation.","Regardless of purification methods employed and/or steps taken to reduce or inhibit KP-54 degradation, methods of analyzing patient samples may be employed which account for KP-54 degradation by simultaneously analyzing the sample for other kisspeptin-54-derived peptides.","Specifically, patient samples can be simultaneously analyzed for KP-54, KP-53, and KP-52 (or their proline variants).","The combined amounts of KP-54 and one or both of KP-53 and KP-52 may provide a more diagnostically useful indication of KP-54 originally present in the patient sample.","Detection and Quantitation by Mass Spectrometry In various embodiments, kisspeptin-54-derived peptides may be ionized by any method known to the skilled artisan.","Mass spectrometry is performed using a mass spectrometer, which includes an ion source for ionizing the fractionated sample and creating charged molecules for further analysis.","For example ionization of the sample may be performed by electron ionization, chemical ionization, electrospray ionization (ESI), photon ionization, atmospheric pressure chemical ionization (APCI), photoionization, atmospheric pressure photoionization (APPI), Laser diode thermal desorption (LDTD), fast atom bombardment (FAB), liquid secondary ionization (LSI), matrix assisted laser desorption ionization (MALDI), field ionization, field desorption, thermospray/plasmaspray ionization, surface enhanced laser desorption ionization (SELDI), inductively coupled plasma (ICP) and particle beam ionization.","The skilled artisan will understand that the choice of ionization method may be determined based on the analyte to be measured, type of sample, the type of detector, the choice of positive versus negative mode, etc.","A kisspeptin-54-derived peptide may be ionized in positive or negative mode.","In some embodiments, kisspeptin-54-derived peptides are ionized by ESI (such as by heated ESI) in positive mode.","In mass spectrometry techniques generally, after the sample has been ionized, the positively or negatively charged ions thereby created may be analyzed to determine a mass-to-charge ratio.","Suitable analyzers for determining mass-to-charge ratios include quadrupole analyzers, ion traps analyzers, and time-of-flight analyzers.","Exemplary ion trap methods are described in Bartolucci, et al., Rapid Commun.","Mass Spectrom.","2000, 14:967-73.The ions may be detected using several detection modes.","For example, selected ions may be detected, i.e.","using a selective ion monitoring mode (SIM), or alternatively, mass transitions resulting from collision induced dissociation or neutral loss may be monitored, e.g., multiple reaction monitoring (MRM) or selected reaction monitoring (SRM).","Preferably, the mass-to-charge ratio is determined using a quadrupole analyzer.","For example, in a “quadrupole” or “quadrupole ion trap” instrument, ions in an oscillating radio frequency field experience a force proportional to the DC potential applied between electrodes, the amplitude of the RF signal, and the mass/charge ratio.","The voltage and amplitude may be selected so that only ions having a particular mass/charge ratio travel the length of the quadrupole, while all other ions are deflected.","Thus, quadrupole instruments may act as both a “mass filter” and as a “mass detector” for the ions injected into the instrument.","One may enhance the resolution of the MS technique by employing “tandem mass spectrometry,” or “MS/MS”.","In this technique, a precursor ion (also called a parent ion) generated from a molecule of interest can be filtered in an MS instrument, and the precursor ion subsequently fragmented to yield one or more fragment ions (also called daughter ions or product ions) that are then analyzed in a second MS procedure.","By careful selection of precursor ions, only ions produced by certain analytes are passed to the fragmentation chamber, where collisions with atoms of an inert gas produce the fragment ions.","Because both the precursor and fragment ions are produced in a reproducible fashion under a given set of ionization/fragmentation conditions, the MS/MS technique may provide an extremely powerful analytical tool.","For example, the combination of filtration/fragmentation may be used to eliminate interfering substances, and may be particularly useful in complex samples, such as biological samples.","Alternate modes of operating a tandem mass spectrometric instrument include product ion scanning and precursor ion scanning.","For a description of these modes of operation, see, e.g., E. Michael Thurman, et al., Chromatographic-Mass Spectrometric Food Analysis for Trace Determination of Pesticide Residues, Chapter 8 (Amadeo R. Fernandez-Alba, ed., Elsevier 2005) (387).","The results of an analyte assay may be related to the amount of the analyte in the original sample by numerous methods known in the art.","For example, given that sampling and analysis parameters are carefully controlled, the relative abundance of a given ion may be compared to a table that converts that relative abundance to an absolute amount of the original molecule.","Alternatively, external standards may be run with the samples, and a standard curve constructed based on ions generated from those standards.","Using such a standard curve, the relative abundance of a given ion may be converted into an absolute amount of the original molecule.","In certain preferred embodiments, an internal standard is used to generate a standard curve for calculating the quantity of a kisspeptin-54-derived peptide.","Methods of generating and using such standard curves are well known in the art and one of ordinary skill is capable of selecting an appropriate internal standard.","For example, in preferred embodiments one or more forms of isotopically labeled kisspeptin-54-derived peptides may be used as internal standards.","Numerous other methods for relating the amount of an ion to the amount of the original molecule will be well known to those of ordinary skill in the art.","As used herein, an “isotopic label” produces a mass shift in the labeled molecule relative to the unlabeled molecule when analyzed by mass spectrometric techniques.","Examples of suitable labels include deuterium (2H), 13C, and 15N.","One or more isotopic labels can be incorporated at one or more positions in the molecule and one or more kinds of isotopic labels can be used on the same isotopically labeled molecule.","One or more steps of the methods may be performed using automated machines.","In certain embodiments, one or more purification steps are performed on-line, and more preferably all of the purification and mass spectrometry steps may be performed in an on-line fashion.","In certain embodiments, such as MS/MS, where precursor ions are isolated for further fragmentation, collision activated dissociation (CAD) is often used to generate fragment ions for further detection.","In CAD, precursor ions gain energy through collisions with an inert gas, and subsequently fragment by a process referred to as “unimolecular decomposition.” Sufficient energy must be deposited in the precursor ion so that certain bonds within the ion can be broken due to increased vibrational energy.","In particularly preferred embodiments, one or more kisspeptin-54-derived peptides in a sample are detected and/or quantified using MS/MS as follows.","Samples are preferably subjected to SPE, then subjected to liquid chromatography, preferably HPLC; the flow of liquid solvent from a chromatographic column enters the heated nebulizer interface of an MS/MS analyzer; and the solvent/analyte mixture is converted to vapor in the heated charged tubing of the interface.","During these processes, one or more analytes (i.e., one or more kisspeptin-54-derived peptides) are analyzed.","The ions, e.g.","precursor ions, from a kisspeptin-54-derived peptide pass through the orifice of the instrument and enter the first quadrupole.","Quadrupoles 1 and 3 (Q1 and Q3) are mass filters, allowing selection of ions (i.e., selection of “precursor” and “fragment” ions in Q1 and Q3, respectively) based on their mass to charge ratio (m/z).","Quadrupole 2 (Q2) is the collision cell, where ions are fragmented.","The first quadrupole of the mass spectrometer (Q1) selects for molecules with the mass to charge ratios of a kisspeptin-54-derived peptide.","Precursor ions with the correct mass/charge ratios are allowed to pass into the collision chamber (Q2), while unwanted ions with any other mass/charge ratio collide with the sides of the quadrupole and are eliminated.","Precursor ions entering Q2 collide with neutral argon gas molecules and fragment.","The fragment ions generated are passed into quadrupole 3 (Q3), where the fragment ions of a kisspeptin-54-derived peptide are selected while other ions are eliminated.","This process can be repeated as often as necessary to analyze as many kisspeptin-54-derived peptides as desired.","Using standard methods well known in the art, one of ordinary skill is capable of identifying one or more fragment ions of a particular precursor ion of a kisspeptin-54-derived peptide that may be used for selection in quadrupole 3 (Q3).","As ions collide with the detector they produce a pulse of electrons that are converted to a digital signal.","The acquired data is relayed to a computer, which plots counts of the ions collected versus time.","The resulting mass chromatograms are similar to chromatograms generated in traditional HPLC-MS methods.","The areas under the peaks corresponding to particular ions, or the amplitude of such peaks, may be measured and correlated to the amount of the analyte of interest.","In certain embodiments, the area under the curves, or amplitude of the peaks, for fragment ion(s) and/or precursor ions are measured to determine the amount of a kisspeptin-54-derived peptide.","As described above, the relative abundance of a given ion may be converted into an absolute amount of the original analyte using calibration standard curves based on peaks of one or more ions of an internal molecular standard.","The following Examples serve to illustrate the invention.","These Examples are in no way intended to limit the scope of the methods.","EXAMPLES Example 1: Sample Preparation A 100 μL serum or EDTA plasma patient sample was mixed with 300 μL of methanol containing isotope labeled kisspeptin-54 as an internal standard.","The protein precipitate was removed via centrifugation and the supernatant was subjected to LC-MS and LC-MS/MS as described in the following Examples.","Example 2: Extraction of Kisspeptin-54-Derived Peptides from Samples Using Liquid Chromatography The on-line chromatographic separation of kisspeptin-54 and other kisspeptin-54-derived peptides from matrix components was performed with a Cohesive Technologies Aria TX-4 high throughput liquid chromatography (HTLC) system using Aria OS V 1.5 or newer software].","The analytes and internal standard were isolated from the serum extract using a Waters HLB C18 (2.1×20 mm, 25 μm particle size) solid phase extraction cartridge.","After injection of the extract, the cartridge was washed with 90% solvent A (water+0.2% formic acid) and 10% solvent B (acetonitrile+0.2% formic acid).","The extraction cartridge retained kisspeptin-54 while ions and very polar molecules flowed through.","The analytes were then back-flushed off the extraction cartridge over the analytical column using a pulse of 45% solvent A/55% solvent B, and 100 μL of the eluent was subjected to HPLC for analytical separation.","Analytical separation was performed with a Waters X-Bridge C18 BEH analytical column (2.5×50 mm, 5 μm particle size) using a fast, multiphase gradient of increasing solvent B in solvent A.","The HPLC gradient started with a 5% organic modifier which was ramped to 35% in approximately 180 seconds.","The separated analytes were then subjected to single and tandem mass spectrometry for identification and quantitation of kisspeptin-54-derived peptides.","Example 3: Detection of Kisspeptin-54-Derived Peptides by MS and MS/MS MS was performed using a Thermo-Fisher TSQ Quantum Ultra triple quadrupole.","Ionization was conducted with a heated electrospray ionization (HESI) probe.","Multiply charged ions of several kisspeptin-54-derived peptides were observed.","Single MS spectra showing multiply charged kisspeptin-54-related peptide ions are seen in FIG.","2 (KP-54), FIG.","5 (KP-54 (proline variant)), FIG.","8 (KP-53), and FIG.","12 (KP-52), respectively.","Several major ions, several of which are seen in these figures, are compiled in Table 1.TABLE 1 Exemplary ions observed for several Kisspeptin- 54-derived peptides (positive polarity) Peptide Charge state Ion (m/z) KP-54 (FIG.","1) 5+ 1172.4 ± 0.50 6+ 977.01 ± 0.50 7+ 837.50 ± 0.50 KP-54(R14P) (FIG.","4) 4+ 1450.49 ± 0.50 5+ 1160.60 ± 0.50 6+ 967.33 ± 0.50 KP-53 (FIG.","7) 5+ 1143.19 ± 0.50 6+ 952.66 ± 0.50 7+ 816.85 ± 0.50 KP-52 (FIG.","11) 4+ 1389.46 ± 0.50 5+ 1111.97 ± 0.50 6+ 926.64 ± 0.50 Various multiply charged precursor ions from each of the above listed kisspeptin-54-derived peptides were further subjected to MS/MS resulting in a plurality of fragment ions at various charge states.","For KP-54, 6+ and 7+ precursor ions were fragmented, with exemplary MS/MS spectra seen in FIGS.","3 and 4.For KP-54 (proline variant), 5+ and 6+ precursor ions were fragmented, with exemplary MS/MS spectra seen in FIGS.","6 and 7.For KP-53, 5+, 6+, and 7+ precursor ions were fragmented, with exemplary MS/MS spectra seen in FIGS.","9, 10, and 11.For KP-52, 5+ and 6+ precursor ions were fragmented, with exemplary MS/MS spectra seen in FIGS.","13 and 14.Additionally, isotopically labeled KP-54 were ionized and fragmented as discussed above (spectra not shown).","The m/z ratios of several of the observed major fragment ions are compiled and listed in Table 2.TABLE 2 Exemplary fragment ions observed for several Kisspeptin- 54-derived peptides (positive polarity) Exemplary Precursor Fragment Peptide Ion (m/z) Ions (m/z) KP-54 977.0 ± 0.50 1083.6 ± 0.50 (FIG.","2) 903.1 ± 0.50 837.7 ± 0.50 902.8 ± 0.50 (FIG.","3) KP-54(R14P) 1160.6 ± 0.50 1071.6 ± 0.50 (FIG.","5) 967.3 ± 0.50 1071.6 ± 0.50 (FIG.","6) KP-53 1143.0 ± 0.50 1053.9 ± 0.50 (FIG.","8) 952.8 ± 0.50 1054.1 ± 0.50 (FIG.","9) 878.5 ± 0.50 816.7 ± 0.50 878.3 ± 0.50 (FIG.","10) KP-52 1111.9 ± 0.50 1278.2 ± 0.50 (FIG.","12) 1022.9 ± 0.50 926.8 ± 0.50 1022.9 ± 0.50 (FIG.","13) Example 4: Detection and Quantitation of Kisspeptin-54-Derived Peptides by Tandem MS MS/MS was performed using a Thermo-Fisher TSQ Quantum Ultra triple quadrupole MS/MS system equipped with a heated electrospray ionization (HESI) probe (Thermo Electron Corporation).","The following software programs, all from Thermo Electron, were used in the Examples described herein: TSQ Ultra Quantum V 1.4.1 or newer, Xcalibur V 2.0 or newer, and LCQuan V 2.5 or newer.","Liquid solvent/analyte exiting the analytical column flowed to the heated nebulizer interface of the MS/MS analyzer.","The solvent/analyte mixture was converted to vapor in the heated tubing of the interface.","Analytes were ionized by HESI in positive polarity.","Kisspeptin-54-derived peptide ions passed to the first quadrupole (Q1), which selected KP-54 ions with a m/z of 977.0±0.5, KP-53 ions with a m/z of 952.9±0.5, KP-52 ions with a m/z of 926.9±0.5, or isotopically labeled KP-54 (IS) ions with a m/z of 980.3±0.5.Ions entering quadrupole 2 (Q2) collided with argon gas (at a collision cell energy of 28 V) to generate ion fragments, which were passed to quadrupole 3 (Q3) for further selection.","The following mass transitions were used for detection and quantitation during validation on positive polarity.","TABLE 3 Exemplary mass transitions used for quantitation of kisspeptin-54-derived peptides (positive polarity) Precursor Product Analyte Ion (m/z) Ions (m/z) KP 1-52 926.9 1022.9 KP 1-53 952.9 1054.2 KP 1-54 977.0 1083.6 KP 1-54(IS) 980.3 1087.3 The mass transitions listed in Table 3 are provided as examples only.","Additional precursor/product ion pairs may be selected (for example from ions seen in FIGS.","2 to 14) to replace or augment the pairs shown in Table 3.Exemplary mass chromatograms for the simultaneous quantitation of KP-52, KP-53, KP-54, and KP-54(IS) from analysis of two patient samples are shown in FIGS.","15 (patient #1-28 years old, 25 weeks gestation, serum) and 16 (patient #1-28 years old, 25 weeks gestation, EDTA plasma), 17 (patient #2-21 years old, 25 weeks gestation, serum), and 18 (patient #2-21 years old, 25 weeks gestation, EDTA plasma).","A comparison of the mass chromatograms from serum versus EDTA plasma samples shows that serum samples are more susceptible to formation of shorter forms of kisspeptin-54 derived peptides.","Example 5: Enrichment of Kisspeptin-54-Derived Peptides by Immunoassay In this Example, initial patient samples are enriched by capture and extraction of kisspeptin-54-derived peptides with antibodies highly specific for the N-terminal portion of Kisspeptin.","KP-54 has been found to degrade in samples at the C-terminus, thus allowing use of N-terminal specific antibodies for capture and enrichment of kisspeptin-54-derived peptides, including KP-54, KP-53, KP-52, and isotopic and chemically modified variants thereof.","Once captured on the N-terminus specific antibody, residual sample components are washed, and the captured peptides eluted for later analysis by any method known in the art, including mass spectrometric analysis as described above.","The contents of the articles, patents, and patent applications, and all other documents and electronically available information mentioned or cited herein, are hereby incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.","Applicants reserve the right to physically incorporate into this application any and all materials and information from any such articles, patents, patent applications, or other physical and electronic documents.","The methods illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein.","Thus, for example, the terms “comprising”, “including,” containing”, etc.","shall be read expansively and without limitation.","Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof.","It is recognized that various modifications are possible within the scope of the invention claimed.","Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the invention embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention.","The invention has been described broadly and generically herein.","Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the methods.","This includes the generic description of the methods with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.","Other embodiments are within the following claims.","In addition, where features or aspects of the methods are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group."]],"string":"[\n [\n \"KISSPEPTIN-54 DETECTION BY TANDEM MASS SPECTROMETRY\",\n \"Methods are described for measuring the amount of a kisspeptin-54-derived peptides in a sample.\",\n \"More specifically, mass spectrometric methods are described for detecting and quantifying a kisspeptin-54 derived peptides in a sample utilizing on-line extraction methods coupled with tandem mass spectrometric techniques.\"\n ],\n [\n \"1.A method for determining by mass spectrometry the amount in a sample of one or more kisspeptin-54-derived peptides, said method comprising: (a) subjecting the sample to acidification; (b) ionizing the enriched sample to produce one or more kisspeptin-54-derived peptide ions detectable by mass spectrometry; (c) determining the amount of one or more ions by mass spectrometry, wherein the amount of the ions is used to determine the amounts of the corresponding one or more kisspeptin-54-derived peptides in the sample.\",\n \"2.The method in claim 1, wherein one or more kisspeptin-54-derived peptides is selected from the group consisting of kisspeptin-54, kisspeptin-53, kisspeptin-52, kisspeptin-54(R14P), kisspeptin-53(R14P), and kisspeptin-52(R14P).\",\n \"3.The method in claim 1, wherein the sample comprises two or more kisspeptin-54-derived peptides selected from the group consisting of kisspeptin-54, kisspeptin-53, kisspeptin-52, kisspeptin-54(R14P), kisspeptin-53(R14P), and kisspeptin-52(R14P).\",\n \"4.The method of claim 1, wherein said one or more ions are selected from the group of ions with a charge consisting of 4+, 5+, 6+, and 7+ from each of said one or more kisspeptin-54-derived peptides.\",\n \"5.The method of claim 1, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-54, and said ions are selected from the group of ions with m/z of 1172.4±0.5, 977.2±0.5, and 837.7±0.5.6.The method of claim 1, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-54(R14P), and said ions are selected from the group of ions with m/z of 1450.5±0.5, 1160.6±0.5, and 967.3±0.5.7.The method of claim 1, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-53 and wherein said ions are selected from the group of ions with m/z of 1143.2±0.5, 952.7±0.5, and 816.9±0.5.8.The method of claim 1, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-52, and said ions are selected from the group of ions with m/z of 1112.0±0.5, and 926.6±0.5.9.The method of claim 1, wherein said mass spectrometry is tandem mass spectrometry, and said one or more ions are fragmented into kisspeptin-54-derived peptide fragment ions.\",\n \"10.The method of claim 9, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-54, said ions comprise an ion with m/z of 977.2±0.5, and said fragment ions comprise one or more ions selected from the group consisting of ions with m/z of 1083.6±0.5 and 903.1±0.5.11.The method of claim 9, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-54, said ions comprise an ion with m/z of 837.7±0.5, and said fragment ions comprise an ion with m/z of 902.8±0.5.12.The method of claim 9, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-54(R14P), said ions comprise an ion with m/z of 1160.6±0.5, and said fragment ions comprise an ion with m/z of 1071.6±0.5.13.The method of claim 9, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-54(R14P), said ions comprise an ion with m/z of 967.3±0.5, and said fragment ions comprise an ion with m/z of 1071.6±0.5.14.The method of claim 9, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-53, said ions comprise an ion with m/z of 1143.2±0.5, and said fragment ions comprise an ion with m/z of 1053.9±0.5.15.The method of claim 9, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-53, said ions comprise an ion with m/z of 952.7±0.5, and said fragment ions comprise one or more ions selected from the group consisting of ions with m/z of 1054.1±0.5 and 878.5±0.5.16.The method of claim 9, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-53, said ions comprise an ion with m/z of 816.7±0.5, and said fragment ions comprise an ion with m/z of 878.3±0.5.17.The method of claim 9, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-52, said ions comprise an ion with m/z of 1112.0±0.5, and said fragment ions comprise one or more ions selected from the group consisting of ions with m/z of 1278.2±0.5 and 1022.9±0.5.18.The method of claim 9, wherein said one or more kisspeptin-54-derived peptides comprise kisspeptin-52, said ions comprise an ion with m/z of 926.8±0.5, and said fragment ions comprise one or more ions selected from the group consisting of ions with m/z of 1022.9±0.5.19.The method of claim 1, further comprising adding one or more isotopically labeled kisspeptin-54-derived peptide to the sample before the ionization step.\",\n \"20.The method of claim 1, wherein acidifying said body fluid sample comprises acidifying with aqueous formic acid.\",\n \"21.The method of claim 1, further comprising subjecting the sample to precipitation with methanol.\",\n \"22.The method of claim 1, further comprising purifying said sample with solid phase extraction (SPE) or high performance liquid chromatography (HPLC).\",\n \"23.The method of claim 1, wherein the sample comprises plasma or serum.\",\n \"24.The method of claim 1, further comprising determining the total amount of kisspeptin-54 in the sample before kisspeptin-54 is degraded in the sample by summing the determined amounts of kisspeptin-54-derived peptides in the sample.\"\n ],\n [\n \"<SOH> BACKGROUND OF THE INVENTION <EOH>The following description of the background of the invention is provided simply as an aid in understanding the invention and is not admitted to describe or constitute prior art to the invention.\",\n \"The kisspeptin-54 peptide is essential for sexual reproduction and it suppresses cancer metastasis.\",\n \"It is also known as metastin, kisspeptin 1-54, KP-54, and KiSS-1 (68-121).\",\n \"Kisspeptin-54 is the carboxamide fragment of residues 68-121 of the protein KISS-1, which in turn is encoded by the KiSS-1 gene.\",\n \"Kisspeptin-54 potently and selectively stimulates the G-protein-coupled receptor 54 (GPR54) to signal secretion of gonadotropin-releasing hormone (GnRH).\",\n \"Rhythmical secretions of GnRH initiate puberty, coordinate ovulation, and maintain overall reproductive function.\",\n \"Kisspeptin-54 is known to suppress the progression of melanomas and breast cancers.\",\n \"It is postulated that kisspeptin-54 suppresses metastasis by inhibiting chemotaxis and invasion of cancer cells.\",\n \"Human kisspeptin-54 (CAS No: [374683-24-6]) consists of 54 amino acids with a molecular weight of about 5857.5 g/mol and a monoisotopic mass of about 5854.0 g/mol.\",\n \"It is a peptide amide cleavage product containing the amino acid residues from 68 to 121 of the 138 amino acid KiSS-1 protein.\",\n \"Other bioactive peptides that result from cleavage of KiSS-1 are kisspeptin-14 (KP-14, 41-54), kisspeptin-13 (KP-13, residues 42-54), and kisspeptin-10 (KP-10; residues 45-54).\",\n \"Kisspeptin-54 has been identified using tandem mass spectrometry.\",\n \"See e.g., Kotani, M., et al., J. Biol.\",\n \"Chem.\",\n \"2001, 276(37), 34631-6 (isolated); Dhillo, W., et al., J. Clin Endocrinol.\",\n \"Metab.\",\n \"2005, 90(12), 6609-15 (synthetic).\",\n \"Kisspeptin-54 has been quantitated using immunoassays.\",\n \"See e.g., Jayasena et al., J. Endocrinol.\",\n \"Metab.\",\n \"2009, 94(11), 4315-23 (measured immunoreactivity of antibody with kisspeptin-54).\",\n \"Among the kisspeptin peptides, only kisspeptin-10 has been reported to be purified for and subjected to quantitative mass spectrometry.\",\n \"Chan et al., J. Clin.\",\n \"Endocrinol.\",\n \"Metab., 2011, 96(6), E908-15.\"\n ],\n [\n \"<SOH> SUMMARY OF THE INVENTION <EOH>In one aspect, the present invention provides methods of determining by mass spectrometry the amount in a sample of one or more kisspeptin-54-derived peptides selected from the group consisting of kisspeptin-54, kisspeptin-53, kisspeptin-52, kisspeptin-54(R14P), kisspeptin-53(R14P), and kisspeptin-52(R14P).\",\n \"These methods include subjecting the sample to ionization under conditions suitable to produce one or more multiply charged kisspeptin-54-derived peptide ions detectable by mass spectrometry; determining by mass spectrometry the amount of one or more ions from each of the one or more kisspeptin-54-derived peptides; and using the amount of the determined ions to determine the amounts of the corresponding one or more kisspeptin-54-derived peptides in the sample.\",\n \"In one aspect, the methods further include, prior to ionization, enriching the concentration of the kisspeptin-54-derived peptides with an antibody specific for the N-terminal portion of kisspeptin-54.In addition or alternatively, the methods further includes adding an organic solvent, such as methanol, to the sample in an amount sufficient to precipitate one or more components from said sample, so as to enrich the concentration of the kisspeptin-54-derived peptides.\",\n \"In some embodiments, ions are determined from kisspeptin-54, kisspeptin-53, and kisspeptin-52.In some embodiments, ions are determined from kisspeptin-54(R14P), kisspeptin-53(R14P), and kisspeptin-52(R14P).\",\n \"In some embodiments, kisspeptin-54-derived peptides from the sample are chemically modified prior to ionization.\",\n \"In some embodiments, at least one of the multiply charged ions generated from the kisspeptin-54-derived peptides is selected from the group of ions with a charge consisting of 4+, 5+, 6+, or 7+.\",\n \"In some embodiments, the determined kisspeptin-54-derived peptides are selected from the group consisting of kisspeptin-54, kisspeptin-53, kisspeptin-52.In embodiments where the one or more kisspeptin-54-derived peptides comprise kisspeptin-54, multiply charged kisspeptin-54 ions may be selected from the group of ions with m/z of 1172.4±0.5, 977.2±0.5, and 837.7±0.5.In embodiments where the one or more kisspeptin-54-derived peptides comprise kisspeptin-54(R14P), multiply charged kisspeptin-54(R14P) ions may be selected from the group of ions with m/z of 1450.5±0.5, 1160.6±0.5, and 967.3±0.5.In embodiments where the one or more kisspeptin-54-derived peptides comprise kisspeptin-53, multiply charged kisspeptin-53 ions may be selected from the group of ions with m/z of 1143.2±0.5, 952.7±0.5, and 816.9±0.5.In embodiments where the one or more kisspeptin-54-derived peptides comprise kisspeptin-52, multiply charged kisspeptin-52 ions may be selected from the group of ions with m/z of 1112.0±0.5, and 926.6±0.5.In some embodiments, mass spectrometry is tandem mass spectrometry.\",\n \"Embodiments utilizing tandem mass spectrometry comprise fragmenting one or more of the multiply charged kisspeptin-54-derived peptide ions into kisspeptin-54-derived peptide fragment ions.\",\n \"In embodiments where kisspeptin-54 is subjected to tandem mass spectrometry, multiply charged kisspeptin-54 ions with m/z of 977.2±0.5 may be fragmented into one or more ions selected from the group consisting of ions with m/z of 1083.6±0.5 and 903.1±0.5; multiply charged kisspeptin-54 ions with m/z of 837.7±0.5 may be fragmented into an ion with m/z of 977.2±0.5.In embodiments where kisspeptin-54(R14P) is subjected to tandem mass spectrometry, multiply charged kisspeptin-54(R14P) ions with m/z of 1160.6±0.5 may be fragmented into an ion with m/z of 1071.6±0.5; multiply charged kisspeptin-54(R14P) ions with m/z of 967.3±0.5 may be fragmented into an ion with m/z of 1071.6±0.5.In embodiments where kisspeptin-53 is subjected to tandem mass spectrometry, multiply charged kisspeptin-53 ions with m/z of 1143.2±0.5 may be fragmented into an ion with m/z of 1053.9±0.5; multiply charged kisspeptin-53 ions with m/z of 952.7±0.5 may be fragmented into one or more ions selected from the group of ions with m/z of 1054.1±0.5 and 878.5±0.5; and multiply charged kisspeptin-53 ions with m/z of 816.7±0.5 may be fragmented into an ion with m/z of 878.3±0.5.In embodiments where kisspeptin-52 is subjected to tandem mass spectrometry, multiply charged kisspeptin-52 ions with m/z of 1112.0±0.5 may be fragmented into one or more ions selected from the group consisting of ions with m/z of 1278.2±0.5 and 1022.9; multiply charged kisspeptin-52 ions with m/z of 926.8±0.5 may be fragmented into an ion with m/z of 1022.9±0.5.In some embodiments, a sample is subjected to one or more processing steps prior to ionization.\",\n \"In some embodiments, the processing steps include one or more purification steps.\",\n \"In some embodiments, the processing steps include adding aqueous formic acid to the sample.\",\n \"In some embodiments, the processing steps include adding an organic solvent, such as methanol, to the sample in an amount sufficient to precipitate one or more components from said sample; centrifuging the organic solvent-sample mixture, wherein a portion of kisspeptin-54-derived peptides from the sample remain in the supernatant; and collecting the supernatant for further processing or ionization.\",\n \"In some embodiments, the processing steps include applying the sample to an anion or cation exchange column under conditions suitable to retain kisspeptin-54-derived peptides on the column; eluting kisspeptin-54-derived peptides from the column; and collecting the eluted kisspeptin-54-derived peptides for further processing or ionization.\",\n \"In some embodiments, the processing steps include immunopurification.\",\n \"In some related embodiments, immunopurification comprises capture and extraction of one or more of kisspeptin-54-derived peptides using anti-kisspeptin-54-derived peptides antibodies specific for the N-terminus of kisspeptin-54.In some embodiments, the processing steps comprise solid phase extraction (SPE).\",\n \"In some embodiments, the processing steps comprise high performance liquid chromatography (HPLC).\",\n \"In a second aspect, the invention provides methods of reducing the degradation of kisspeptin-54-derived peptides in body fluid sample from a patient.\",\n \"These methods include acidifying a body fluid sample, treating a body fluid sample with an agent under conditions sufficient to precipitate proteins from said body fluid sample, or both.\",\n \"In some embodiments, acidifying said body fluid sample comprises acidifying with aqueous formic acid.\",\n \"In some embodiments, the protein precipitation agent comprises an organic solvent, such as methanol.\",\n \"In some related embodiments, the ratio of the volume of the organic solvent to the volume of the biological sample is about 3:1.In a third aspect, the invention provides methods of measuring degradation of kisspeptin-54 in a biological fluid sample from a patient.\",\n \"These methods include subjecting a body fluid sample from a patient to ionization under conditions suitable to produce one or more multiply charged ions detectable by mass spectrometry from kisspeptin-54 and one or more kisspeptin-54 derivation products selected from the group consisting of kisspeptin-53 and kisspeptin-52; determining by mass spectrometry the amount of one or more ions of kisspeptin-54 and one or more kisspeptin-54 derivation products selected from the group consisting of kisspeptin-53 and kisspeptin-52; and using the amounts of ions determined in step b to determine the amounts of kisspeptin-54 and kisspeptin-54 derivation products in the sample.\",\n \"Similar methods are provided for measuring degradation of kisspeptin-54(R14P) in a biological fluid sample from a patient.\",\n \"These methods include subjecting a biological fluid sample from a patient to ionization under conditions suitable to produce one or more multiply charged ions detectable by mass spectrometry from kisspeptin-54(R14P) and one or more kisspeptin-54(R14P) derivation products selected from the group consisting of kisspeptin-53(R14P) and kisspeptin-52(R14P); determining by mass spectrometry the amount of one or more ions of kisspeptin-54(R14P) and one or more kisspeptin-54(R14P) derivation products selected from the group consisting of kisspeptin-53(R14P) and kisspeptin-52(R14P); and using the amounts of ions determined in step b to determine the amounts of kisspeptin-54(R14P) and kisspeptin-54(R14P) derivation products in the sample.\",\n \"In another aspect, the invention provides methods of diagnosing or predicting risk of developing preeclampsia.\",\n \"These methods include providing a body fluid or tissue sample obtained from a patient; subjecting the body fluid or tissue sample to one or more processing steps to generate a processed sample comprising one or more kisspeptin-54-derived peptides selected from the group consisting of kisspeptin-54, kisspeptin-53, kisspeptin-52, kisspeptin-54(R14P), kisspeptin-53(R14P), and kisspeptin-52(R14P); subjecting the processed sample to ionization under conditions suitable to produce one or more multiply charged ions detectable by mass spectrometry; determining by mass spectrometry the amount of one or more ions from one or more kisspeptin-54-derived peptides; and using the determined ion amounts to determine the amount of kisspeptin-54 or kisspeptin-54(R14P) in the sample.\",\n \"In these methods, elevated kisspeptin-54 or kisspeptin-54(R14P) levels in the sample relative to normal indicate the presence of or risk of developing preeclampsia.\",\n \"In another aspect, the invention provides one or more substantially isolated polypeptides with amino acid sequences consisting of the sequences identified as SEQ ID No.\",\n \":2 and SEQ ID No.\",\n \":3, or proline variants thereof.\",\n \"In any of the methods provided herein which utilize tandem mass spectrometry, tandem mass spectrometry may be conducted by any method known in the art, including for example, multiple reaction monitoring, precursor ion scanning, or product ion scanning.\",\n \"In any of the methods provided herein which utilize two or more of an extraction column, an analytical column, and an ionization source, two or more of these components may be connected in an on-line fashion to allow for automated sample processing and analysis.\",\n \"In any of the methods provided herein which require ionization of a kisspeptin-54-derived peptide, mass spectrometry is preferably performed in positive ion mode.\",\n \"Alternatively, mass spectrometry is performed in negative ion mode.\",\n \"Various ionization sources, including for example atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI), and heated ESI, may be used in embodiments of the present invention.\",\n \"In certain preferred embodiments, kisspeptin-54-derived peptides are ionized using heated ESI in positive ion mode.\",\n \"In preferred embodiments of methods presented herein which determine the amount of one or more kisspeptin-54-derived peptides in a sample, a separately detectable internal standard is provided in the sample, the amount of which is also determined in the sample.\",\n \"In these embodiments, all or a portion of both the analyte(s) of interest and the internal standard present in the sample is ionized to produce a plurality of ions detectable in a mass spectrometer, and one or more ions produced from each are detected by mass spectrometry.\",\n \"In these embodiments, the presence or amount of ions generated from the analyte of interest may be related to the presence of amount of analyte of interest in the sample.\",\n \"In other embodiments, the amount of one or more kisspeptin-54-derived peptides in a sample may be determined by comparison to one or more external reference standards.\",\n \"Exemplary external reference standards include blank plasma or serum spiked with a kisspeptin-54-derived peptide or an isotopically labeled variant thereof (such as isotopically labeled kisspeptin-54 and isotopically labeled kisspeptin-54(R14P)).\",\n \"As used herein, unless otherwise stated, the singular forms “a,” “an,” and “the” include plural reference.\",\n \"Thus, for example, a reference to “a protein” includes a plurality of protein molecules.\",\n \"As used herein, the term “kisspeptin-54-derived peptide” refers to intact kisspeptin-54 and peptide fragments whose amino acid sequence is found within the amino acid sequence of kisspeptin-54, and all polymorphs thereof.\",\n \"One known polymorph of kisspeptin-54 includes a proline replacement for the arginine at position 14.This polymorph is described herein as kisspeptin-54 (proline variant) or kisspeptin-54(R14P).\",\n \"Kisspeptin-54-derived peptides may possess one or more of the following attributes: naturally occurring, chemically synthesized, isotopically labeled, and chemically modified.\",\n \"Isotopic labeling and/or chemical modification may be conducted by any of several techniques known by those of skill in the art.\",\n \"Other exemplary kisspeptin-54 derived peptides include kisspeptin-53, kisspeptin-52, and their protein variants.\",\n \"As used herein, the term “kisspeptin-54” refers to a 54 amino acid peptide with the sequence shown as SEQ ID No.\",\n \":1 in FIG.\",\n \"1A .\",\n \"As used herein, the term “kisspeptin-53” refers to a 53 amino acid peptide with the sequence shown as SEQ ID No.\",\n \":2 in FIG.\",\n \"1B .\",\n \"As used herein, the term “kisspeptin-52” refers to a 52 amino acid peptide with the sequence shown as SEQ ID No.\",\n \":3 in FIG.\",\n \"1C .\",\n \"As used herein, the term “isolated” as applied to a polypeptide means a polypeptide that has been separated from components that naturally accompany it.\",\n \"Typically, the polypeptide is substantially isolated when it is at least 60%, by weight, free from the proteins and naturally occurring organic molecules with which it is naturally associated.\",\n \"The definition also extends to a polypeptide separated from its flanking amino acids (e.g., for an amino acid sequence, isolated refers to a sequence that is free from the flanking amino acids with which the sequence is naturally associated in a polypeptide).\",\n \"Preferably, the polypeptide is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight, isolated.\",\n \"An isolated polypeptide may be obtained by standard techniques, for example, by extraction from a natural source (e.g., purification from a cell or body fluid), by expression of a recombinant nucleic acid encoding the peptide; or fusion protein thereof, by chemically synthesizing the polypeptide.\",\n \"Purity can be measured by any appropriate method, e.g., by column chromatography, polyacrylamide gel electrophoresis, or HPLC analysis.\",\n \"As used herein, the term “purification” or “purifying” does not refer to removing all materials from the sample other than the analyte(s) of interest.\",\n \"Instead, purification refers to a procedure that enriches the amount of one or more analytes of interest relative to other components in the sample that may interfere with detection of the analyte of interest.\",\n \"Purification of the sample by various means may allow relative reduction of one or more interfering substances, e.g., one or more substances that may or may not interfere with the detection of selected parent or daughter ions by mass spectrometry.\",\n \"Relative reduction as this term is used does not require that any substance, present with the analyte of interest in the material to be purified, is entirely removed by purification.\",\n \"As used herein, the term “immunopurification” or “immunopurify” refers to a purification procedure that utilizes antibodies, including polyclonal or monoclonal antibodies, to enrich the one or more analytes of interest.\",\n \"Immunopurification can be performed using any of the immunopurification methods well known in the art.\",\n \"Often the immunopurification procedure utilizes antibodies bound, conjugated or otherwise attached to a solid support, for example a column, well, tube, gel, capsule, particle or the like.\",\n \"Immunopurification as used herein includes without limitation procedures often referred to in the art as immunoprecipitation, as well as procedures often referred to in the art as affinity chromatography.\",\n \"As used herein, the term “immunoparticle” refers to a capsule, bead, gel particle or the like that has antibodies bound, conjugated or otherwise attached to its surface (either on and/or in the particle).\",\n \"In certain preferred embodiments, immunoparticles are sepharose or agarose beads.\",\n \"In alternative preferred embodiments, immunoparticles are glass, plastic or silica beads, or silica gel.\",\n \"As used herein, the term “anti-kisspeptin-54-derived peptide antibody” refers to any polyclonal or monoclonal antibody that has an affinity for a kisspeptin-54-derived peptide.\",\n \"In various embodiments the specificity of kisspeptin-54-derived peptide antibodies to chemical species other than the kisspeptin-54-derived peptide may vary; for example in certain preferred embodiments the anti-kisspeptin-54-derived peptide antibodies are specific for the kisspeptin-54-derived peptide and thus have little or no affinity for chemical species other than the kisspeptin-54-derived peptide, whereas in other preferred embodiments the anti-kisspeptin-54-derived peptide antibodies are non-specific and thus bind certain chemical species other than the kisspeptin-54-derived peptide.\",\n \"As used herein, the term “sample” refers to any sample that may contain an analyte of interest.\",\n \"As used herein, the term “body fluid” means any fluid that can be isolated from the body of an individual.\",\n \"For example, “body fluid” may include blood, plasma, serum, bile, saliva, urine, tears, perspiration, and the like.\",\n \"In some preferred embodiments, the sample comprises a body fluid sample; preferably plasma or serum, from a patient.\",\n \"As used herein, the term “solid phase extraction” or “SPE” refers to a process in which a chemical mixture is separated into components as a result of the affinity of components dissolved or suspended in a solution (i.e., mobile phase) for a solid through or around which the solution is passed (i.e., solid phase).\",\n \"In some instances, as the mobile phase passes through or around the solid phase, undesired components of the mobile phase may be retained by the solid phase resulting in a purification of the analyte in the mobile phase.\",\n \"In other instances, the analyte may be retained by the solid phase, allowing undesired components of the mobile phase to pass through or around the solid phase.\",\n \"In these instances, a second mobile phase is then used to elute the retained analyte off of the solid phase for further processing or analysis.\",\n \"SPE, including TFLC, may operate via a unitary or mixed mode mechanism.\",\n \"Mixed mode mechanisms utilize ion exchange and hydrophobic retention in the same column; for example, the solid phase of a mixed-mode SPE column may exhibit strong anion exchange and hydrophobic retention; or may exhibit column exhibit strong cation exchange and hydrophobic retention.\",\n \"As used herein, the term “chromatography” refers to a process in which a chemical mixture carried by a liquid or gas is separated into components as a result of differential distribution of the chemical entities as they flow around or over a stationary liquid or solid phase.\",\n \"As used herein, the term “liquid chromatography” or “LC” means a process of selective retardation of one or more components of a fluid solution as the fluid uniformly percolates through a column of a finely divided substance, or through capillary passageways.\",\n \"The retardation results from the distribution of the components of the mixture between one or more stationary phases and the bulk fluid, (i.e., mobile phase), as this fluid moves relative to the stationary phase(s).\",\n \"Examples of “liquid chromatography” include normal phase liquid chromatography (NPLC), reverse phase liquid chromatography (RPLC), high performance liquid chromatography (HPLC), ultra high performance liquid chromatography (UHPLC), and turbulent flow liquid chromatography (TFLC) (sometimes known as high turbulence liquid chromatography (HTLC) or high throughput liquid chromatography).\",\n \"As used herein, the term “high performance liquid chromatography” or “HPLC” (sometimes known as “high pressure liquid chromatography”) refers to liquid chromatography in which the degree of separation is increased by forcing the mobile phase under pressure through a stationary phase, typically a densely packed column.\",\n \"As used herein, the term “ultra high performance liquid chromatography” or “UHPLC” (sometimes known as “ultra high pressure liquid chromatography”) refers to liquid chromatography in which the degree of separation is increased by forcing the mobile phase under high pressure through a stationary phase, typically a densely packed column with a stationary phase comprising packing particles that have an average diameter of than 2 μM.\",\n \"As used herein, the term “turbulent flow liquid chromatography” or “TFLC” (sometimes known as high turbulence liquid chromatography or high throughput liquid chromatography) refers to a form of chromatography that utilizes turbulent flow of the material being assayed through the column packing as the basis for performing the separation.\",\n \"TFLC has been applied in the preparation of samples containing two unnamed drugs prior to analysis by mass spectrometry.\",\n \"See, e.g., Zimmer et al., J Chromatogr A 854: 23-35 (1999); see also, U.S. Pat.\",\n \"Nos.\",\n \"5,968,367, 5,919,368, 5,795,469, and 5,772,874, which further explain TFLC.\",\n \"Persons of ordinary skill in the art understand “turbulent flow”.\",\n \"When fluid flows slowly and smoothly, the flow is called “laminar flow”.\",\n \"For example, fluid moving through an HPLC column at low flow rates is laminar.\",\n \"In laminar flow the motion of the particles of fluid is orderly with particles moving generally in straight lines.\",\n \"At faster velocities, the inertia of the water overcomes fluid frictional forces and turbulent flow results.\",\n \"Fluid not in contact with the irregular boundary “outruns” that which is slowed by friction or deflected by an uneven surface.\",\n \"When a fluid is flowing turbulently, it flows in eddies and whirls (or vortices), with more “drag” than when the flow is laminar.\",\n \"Many references are available for assisting in determining when fluid flow is laminar or turbulent (e.g., Turbulent Flow Analysis: Measurement and Prediction , P. S. Bernard & J. M. Wallace, John Wiley & Sons, Inc., (2000); An Introduction to Turbulent Flow , Jean Mathieu & Julian Scott, Cambridge University Press (2001)).\",\n \"As used herein, the term “gas chromatography” or “GC” refers to chromatography in which the sample mixture is vaporized and injected into a stream of carrier gas (as nitrogen or helium) moving through a column containing a stationary phase composed of a liquid or a particulate solid and is separated into its component compounds according to the affinity of the compounds for the stationary phase.\",\n \"As used herein, the term “large particle column” or “extraction column” refers to a chromatography column containing an average particle diameter greater than about 50 μm.\",\n \"As used in this context, the term “about” means±10%.\",\n \"As used herein, the term “analytical column” refers to a chromatography column having sufficient chromatographic plates to effect a separation of materials in a sample that elute from the column sufficient to allow a determination of the presence or amount of an analyte.\",\n \"Such columns are often distinguished from “extraction columns”, which have the general purpose of separating or extracting retained material from non-retained materials in order to obtain a purified sample for further analysis.\",\n \"As used in this context, the term “about” means±10%.\",\n \"In a preferred embodiment the analytical column contains particles of about 5 μm in diameter.\",\n \"As used herein, the terms “on-line” and “inline”, for example as used in “on-line automated fashion” or “on-line extraction” refers to a procedure performed without the need for operator intervention.\",\n \"In contrast, the term “off-line” as used herein refers to a procedure requiring manual intervention of an operator.\",\n \"Thus, if samples are subjected to precipitation, and the supernatants are then manually loaded into an autosampler, the precipitation and loading steps are off-line from the subsequent steps.\",\n \"In various embodiments of the methods, one or more steps may be performed in an on-line automated fashion.\",\n \"As used herein, the term “mass spectrometry” or “MS” refers to an analytical technique to identify compounds by their mass.\",\n \"MS refers to methods of filtering, detecting, and measuring ions based on their mass-to-charge ratio, or “m/z”.\",\n \"MS technology generally includes (1) ionizing the compounds to form charged compounds; and (2) detecting the molecular weight of the charged compounds and calculating a mass-to-charge ratio.\",\n \"The compounds may be ionized and detected by any suitable means.\",\n \"A “mass spectrometer” generally includes an ionizer and an ion detector.\",\n \"In general, one or more molecules of interest are ionized, and the ions are subsequently introduced into a mass spectrometric instrument where, due to a combination of magnetic and electric fields, the ions follow a path in space that is dependent upon mass (“m”) and charge (“z”).\",\n \"See, e.g., U.S. Pat.\",\n \"No.\",\n \"6,204,500, entitled “Mass Spectrometry From Surfaces;” U.S. Pat.\",\n \"No.\",\n \"6,107,623, entitled “Methods and Apparatus for Tandem Mass Spectrometry;” U.S. Pat.\",\n \"No.\",\n \"6,268,144, entitled “DNA Diagnostics Based On Mass Spectrometry;” U.S. Pat.\",\n \"No.\",\n \"6,124,137, entitled “Surface-Enhanced Photolabile Attachment And Release For Desorption And Detection Of Analytes;” Wright et al., Prostate Cancer and Prostatic Diseases 1999, 2: 264-76; and Merchant and Weinberger, Electrophoresis 2000, 21: 1164-67.As used herein, the term “operating in negative ion mode” refers to those mass spectrometry methods where negative ions are generated and detected.\",\n \"The term “operating in positive ion mode” as used herein, refers to those mass spectrometry methods where positive ions are generated and detected.\",\n \"As used herein, the term “ionization” or “ionizing” refers to the process of generating an analyte ion having a net electrical charge equal to one or more electron units.\",\n \"Negative ions are those having a net negative charge of one or more electron units, while positive ions are those having a net positive charge of one or more electron units.\",\n \"As used herein, the term “electron ionization” or “EI” refers to methods in which an analyte of interest in a gaseous or vapor phase interacts with a flow of electrons.\",\n \"Impact of the electrons with the analyte produces analyte ions, which may then be subjected to a mass spectrometry technique.\",\n \"As used herein, the term “chemical ionization” or “CI” refers to methods in which a reagent gas (e g ammonia) is subjected to electron impact, and analyte ions are formed by the interaction of reagent gas ions and analyte molecules.\",\n \"As used herein, the term “fast atom bombardment” or “FAB” refers to methods in which a beam of high energy atoms (often Xe or Ar) impacts a non-volatile sample, desorbing and ionizing molecules contained in the sample.\",\n \"Test samples are dissolved in a viscous liquid matrix such as glycerol, thioglycerol, m-nitrobenzyl alcohol, 18-crown-6 crown ether, 2-nitrophenyloctyl ether, sulfolane, diethanolamine, and triethanolamine.\",\n \"The choice of an appropriate matrix for a compound or sample is an empirical process.\",\n \"As used herein, the term “matrix-assisted laser desorption ionization” or “MALDI” refers to methods in which a non-volatile sample is exposed to laser irradiation, which desorbs and ionizes analytes in the sample by various ionization pathways, including photoionization, protonation, deprotonation, and cluster decay.\",\n \"For MALDI, the sample is mixed with an energy-absorbing matrix, which facilitates desorption of analyte molecules.\",\n \"As used herein, the term “surface enhanced laser desorption ionization” or “SELDI” refers to another method in which a non-volatile sample is exposed to laser irradiation, which desorbs and ionizes analytes in the sample by various ionization pathways, including photoionization, protonation, deprotonation, and cluster decay.\",\n \"For SELDI, the sample is typically bound to a surface that preferentially retains one or more analytes of interest.\",\n \"As in MALDI, this process may also employ an energy-absorbing material to facilitate ionization.\",\n \"As used herein, the term “electrospray ionization” or “ESI,” refers to methods in which a solution is passed along a short length of capillary tube, to the end of which is applied a high positive or negative electric potential.\",\n \"Solution reaching the end of the tube is vaporized (nebulized) into a jet or spray of very small droplets of solution in solvent vapor.\",\n \"This mist of droplets flows through an evaporation chamber.\",\n \"As the droplets get smaller the electrical surface charge density increases until such time that the natural repulsion between like charges causes ions as well as neutral molecules to be released.\",\n \"Heated ESI is similar, but includes a heat source for heating the sample while in the capillary tube.\",\n \"As used herein, the term “atmospheric pressure chemical ionization” or “APCI,” refers to mass spectrometry methods that are similar to ESI; however, APCI produces ions by ion-molecule reactions that occur within a plasma at atmospheric pressure.\",\n \"The plasma is maintained by an electric discharge between the spray capillary and a counter electrode.\",\n \"Then ions are typically extracted into the mass analyzer by use of a set of differentially pumped skimmer stages.\",\n \"A counterflow of dry and preheated N 2 gas may be used to improve removal of solvent.\",\n \"The gas-phase ionization in APCI can be more effective than ESI for analyzing less-polar species.\",\n \"The term “atmospheric pressure photoionization” or “APPI” as used herein refers to the form of mass spectrometry where the mechanism for the photoionization of molecule M is photon absorption and electron ejection to form the molecular ion M+.\",\n \"Because the photon energy typically is just above the ionization potential, the molecular ion is less susceptible to dissociation.\",\n \"In many cases it may be possible to analyze samples without the need for chromatography, thus saving significant time and expense.\",\n \"In the presence of water vapor or protic solvents, the molecular ion can extract H to form MH+.\",\n \"This tends to occur if M has a high proton affinity.\",\n \"This does not affect quantitation accuracy because the sum of M+ and MH+ is constant.\",\n \"Drug compounds in protic solvents are usually observed as MH+, whereas nonpolar compounds such as naphthalene or testosterone usually form M+.\",\n \"See, e.g., Robb et al., Anal.\",\n \"Chem.\",\n \"2000, 72(15): 3653-3659.As used herein, the term “inductively coupled plasma” or “ICP” refers to methods in which a sample interacts with a partially ionized gas at a sufficiently high temperature such that most elements are atomized and ionized.\",\n \"As used herein, the term “field desorption” refers to methods in which a non-volatile test sample is placed on an ionization surface, and an intense electric field is used to generate analyte ions.\",\n \"As used herein, the term “desorption” refers to the removal of an analyte from a surface and/or the entry of an analyte into a gaseous phase.\",\n \"Laser desorption thermal desorption is a technique wherein a sample containing the analyte is thermally desorbed into the gas phase by a laser pulse.\",\n \"The laser hits the back of a specially made 96-well plate with a metal base.\",\n \"The laser pulse heats the base and the heat causes the sample to transfer into the gas phase.\",\n \"The gas phase sample is then drawn into the mass spectrometer.\",\n \"As used herein, the term “selective ion monitoring” is a detection mode for a mass spectrometric instrument in which only ions within a relatively narrow mass range, typically about one mass unit, are detected.\",\n \"As used herein, “multiple reaction mode,” sometimes known as “selected reaction monitoring,” is a detection mode for a mass spectrometric instrument in which a precursor ion and one or more fragment ions are selectively detected.\",\n \"As used herein, the term “lower limit of quantification”, “lower limit of quantitation” or “LLOQ” refers to the point where measurements become quantitatively meaningful.\",\n \"The analyte response at this LOQ is identifiable, discrete and reproducible with a relative standard deviation (RSD %) of less than 20% and an accuracy of 85% to 115%.\",\n \"As used herein, the term “limit of detection” or “LOD” is the point at which the measured value is larger than the uncertainty associated with it.\",\n \"The LOD is the point at which a value is beyond the uncertainty associated with its measurement and is defined as three times the RSD of the mean at the zero concentration.\",\n \"As used herein, an “amount” of an analyte in a body fluid sample refers generally to an absolute value reflecting the mass of the analyte detectable in volume of sample.\",\n \"However, an amount also contemplates a relative amount in comparison to another analyte amount.\",\n \"For example, an amount of an analyte in a sample can be an amount which is greater than a control or normal level of the analyte normally present in the sample.\",\n \"The term “about” as used herein in reference to quantitative measurements not including the measurement of the mass of an ion, refers to the indicated value plus or minus 10%.\",\n \"Mass spectrometry instruments can vary slightly in determining the mass of a given analyte.\",\n \"The term “about” in the context of the mass of an ion or the mass/charge ratio of an ion refers to +/−0.5 atomic mass unit.\",\n \"The summary of the invention described above is non-limiting and other features and advantages of the invention will be apparent from the following detailed description of the invention, and from the claims.\"\n ],\n [\n \"CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation application of U.S. application Ser.\",\n \"No.\",\n \"15/443,645, filed Feb. 27, 2017, which is a continuation application of U.S. application Ser.\",\n \"No.\",\n \"14/565,805, filed Dec. 10, 2014, now U.S. Pat.\",\n \"No.\",\n \"9,583,322, which is a continuation application of U.S. application Ser.\",\n \"No.\",\n \"13/682,304, filed Nov. 20, 2012, now U.S. Pat.\",\n \"No.\",\n \"8,916,680, which claims the benefit under 35 U.S.C.\",\n \"§ 119(e) of U.S.\",\n \"Provisional Application Ser.\",\n \"No.\",\n \"61/563,435, filed Nov. 23, 2011, each of which is incorporated by reference in its entirety into the present disclosure.\",\n \"FIELD OF THE INVENTION The invention relates to the quantitative measurement of kisspeptin-54 and kisspeptin-54-derived peptides.\",\n \"In a particular aspect, the invention relates to methods for quantitative measurement of kisspeptin-54 and kisspeptin-54-derived peptides by HPLC-tandem mass spectrometry.\",\n \"BACKGROUND OF THE INVENTION The following description of the background of the invention is provided simply as an aid in understanding the invention and is not admitted to describe or constitute prior art to the invention.\",\n \"The kisspeptin-54 peptide is essential for sexual reproduction and it suppresses cancer metastasis.\",\n \"It is also known as metastin, kisspeptin 1-54, KP-54, and KiSS-1 (68-121).\",\n \"Kisspeptin-54 is the carboxamide fragment of residues 68-121 of the protein KISS-1, which in turn is encoded by the KiSS-1 gene.\",\n \"Kisspeptin-54 potently and selectively stimulates the G-protein-coupled receptor 54 (GPR54) to signal secretion of gonadotropin-releasing hormone (GnRH).\",\n \"Rhythmical secretions of GnRH initiate puberty, coordinate ovulation, and maintain overall reproductive function.\",\n \"Kisspeptin-54 is known to suppress the progression of melanomas and breast cancers.\",\n \"It is postulated that kisspeptin-54 suppresses metastasis by inhibiting chemotaxis and invasion of cancer cells.\",\n \"Human kisspeptin-54 (CAS No: [374683-24-6]) consists of 54 amino acids with a molecular weight of about 5857.5 g/mol and a monoisotopic mass of about 5854.0 g/mol.\",\n \"It is a peptide amide cleavage product containing the amino acid residues from 68 to 121 of the 138 amino acid KiSS-1 protein.\",\n \"Other bioactive peptides that result from cleavage of KiSS-1 are kisspeptin-14 (KP-14, 41-54), kisspeptin-13 (KP-13, residues 42-54), and kisspeptin-10 (KP-10; residues 45-54).\",\n \"Kisspeptin-54 has been identified using tandem mass spectrometry.\",\n \"See e.g., Kotani, M., et al., J. Biol.\",\n \"Chem.\",\n \"2001, 276(37), 34631-6 (isolated); Dhillo, W., et al., J. Clin Endocrinol.\",\n \"Metab.\",\n \"2005, 90(12), 6609-15 (synthetic).\",\n \"Kisspeptin-54 has been quantitated using immunoassays.\",\n \"See e.g., Jayasena et al., J. Endocrinol.\",\n \"Metab.\",\n \"2009, 94(11), 4315-23 (measured immunoreactivity of antibody with kisspeptin-54).\",\n \"Among the kisspeptin peptides, only kisspeptin-10 has been reported to be purified for and subjected to quantitative mass spectrometry.\",\n \"Chan et al., J. Clin.\",\n \"Endocrinol.\",\n \"Metab., 2011, 96(6), E908-15.SUMMARY OF THE INVENTION In one aspect, the present invention provides methods of determining by mass spectrometry the amount in a sample of one or more kisspeptin-54-derived peptides selected from the group consisting of kisspeptin-54, kisspeptin-53, kisspeptin-52, kisspeptin-54(R14P), kisspeptin-53(R14P), and kisspeptin-52(R14P).\",\n \"These methods include subjecting the sample to ionization under conditions suitable to produce one or more multiply charged kisspeptin-54-derived peptide ions detectable by mass spectrometry; determining by mass spectrometry the amount of one or more ions from each of the one or more kisspeptin-54-derived peptides; and using the amount of the determined ions to determine the amounts of the corresponding one or more kisspeptin-54-derived peptides in the sample.\",\n \"In one aspect, the methods further include, prior to ionization, enriching the concentration of the kisspeptin-54-derived peptides with an antibody specific for the N-terminal portion of kisspeptin-54.In addition or alternatively, the methods further includes adding an organic solvent, such as methanol, to the sample in an amount sufficient to precipitate one or more components from said sample, so as to enrich the concentration of the kisspeptin-54-derived peptides.\",\n \"In some embodiments, ions are determined from kisspeptin-54, kisspeptin-53, and kisspeptin-52.In some embodiments, ions are determined from kisspeptin-54(R14P), kisspeptin-53(R14P), and kisspeptin-52(R14P).\",\n \"In some embodiments, kisspeptin-54-derived peptides from the sample are chemically modified prior to ionization.\",\n \"In some embodiments, at least one of the multiply charged ions generated from the kisspeptin-54-derived peptides is selected from the group of ions with a charge consisting of 4+, 5+, 6+, or 7+.\",\n \"In some embodiments, the determined kisspeptin-54-derived peptides are selected from the group consisting of kisspeptin-54, kisspeptin-53, kisspeptin-52.In embodiments where the one or more kisspeptin-54-derived peptides comprise kisspeptin-54, multiply charged kisspeptin-54 ions may be selected from the group of ions with m/z of 1172.4±0.5, 977.2±0.5, and 837.7±0.5.In embodiments where the one or more kisspeptin-54-derived peptides comprise kisspeptin-54(R14P), multiply charged kisspeptin-54(R14P) ions may be selected from the group of ions with m/z of 1450.5±0.5, 1160.6±0.5, and 967.3±0.5.In embodiments where the one or more kisspeptin-54-derived peptides comprise kisspeptin-53, multiply charged kisspeptin-53 ions may be selected from the group of ions with m/z of 1143.2±0.5, 952.7±0.5, and 816.9±0.5.In embodiments where the one or more kisspeptin-54-derived peptides comprise kisspeptin-52, multiply charged kisspeptin-52 ions may be selected from the group of ions with m/z of 1112.0±0.5, and 926.6±0.5.In some embodiments, mass spectrometry is tandem mass spectrometry.\",\n \"Embodiments utilizing tandem mass spectrometry comprise fragmenting one or more of the multiply charged kisspeptin-54-derived peptide ions into kisspeptin-54-derived peptide fragment ions.\",\n \"In embodiments where kisspeptin-54 is subjected to tandem mass spectrometry, multiply charged kisspeptin-54 ions with m/z of 977.2±0.5 may be fragmented into one or more ions selected from the group consisting of ions with m/z of 1083.6±0.5 and 903.1±0.5; multiply charged kisspeptin-54 ions with m/z of 837.7±0.5 may be fragmented into an ion with m/z of 977.2±0.5.In embodiments where kisspeptin-54(R14P) is subjected to tandem mass spectrometry, multiply charged kisspeptin-54(R14P) ions with m/z of 1160.6±0.5 may be fragmented into an ion with m/z of 1071.6±0.5; multiply charged kisspeptin-54(R14P) ions with m/z of 967.3±0.5 may be fragmented into an ion with m/z of 1071.6±0.5.In embodiments where kisspeptin-53 is subjected to tandem mass spectrometry, multiply charged kisspeptin-53 ions with m/z of 1143.2±0.5 may be fragmented into an ion with m/z of 1053.9±0.5; multiply charged kisspeptin-53 ions with m/z of 952.7±0.5 may be fragmented into one or more ions selected from the group of ions with m/z of 1054.1±0.5 and 878.5±0.5; and multiply charged kisspeptin-53 ions with m/z of 816.7±0.5 may be fragmented into an ion with m/z of 878.3±0.5.In embodiments where kisspeptin-52 is subjected to tandem mass spectrometry, multiply charged kisspeptin-52 ions with m/z of 1112.0±0.5 may be fragmented into one or more ions selected from the group consisting of ions with m/z of 1278.2±0.5 and 1022.9; multiply charged kisspeptin-52 ions with m/z of 926.8±0.5 may be fragmented into an ion with m/z of 1022.9±0.5.In some embodiments, a sample is subjected to one or more processing steps prior to ionization.\",\n \"In some embodiments, the processing steps include one or more purification steps.\",\n \"In some embodiments, the processing steps include adding aqueous formic acid to the sample.\",\n \"In some embodiments, the processing steps include adding an organic solvent, such as methanol, to the sample in an amount sufficient to precipitate one or more components from said sample; centrifuging the organic solvent-sample mixture, wherein a portion of kisspeptin-54-derived peptides from the sample remain in the supernatant; and collecting the supernatant for further processing or ionization.\",\n \"In some embodiments, the processing steps include applying the sample to an anion or cation exchange column under conditions suitable to retain kisspeptin-54-derived peptides on the column; eluting kisspeptin-54-derived peptides from the column; and collecting the eluted kisspeptin-54-derived peptides for further processing or ionization.\",\n \"In some embodiments, the processing steps include immunopurification.\",\n \"In some related embodiments, immunopurification comprises capture and extraction of one or more of kisspeptin-54-derived peptides using anti-kisspeptin-54-derived peptides antibodies specific for the N-terminus of kisspeptin-54.In some embodiments, the processing steps comprise solid phase extraction (SPE).\",\n \"In some embodiments, the processing steps comprise high performance liquid chromatography (HPLC).\",\n \"In a second aspect, the invention provides methods of reducing the degradation of kisspeptin-54-derived peptides in body fluid sample from a patient.\",\n \"These methods include acidifying a body fluid sample, treating a body fluid sample with an agent under conditions sufficient to precipitate proteins from said body fluid sample, or both.\",\n \"In some embodiments, acidifying said body fluid sample comprises acidifying with aqueous formic acid.\",\n \"In some embodiments, the protein precipitation agent comprises an organic solvent, such as methanol.\",\n \"In some related embodiments, the ratio of the volume of the organic solvent to the volume of the biological sample is about 3:1.In a third aspect, the invention provides methods of measuring degradation of kisspeptin-54 in a biological fluid sample from a patient.\",\n \"These methods include subjecting a body fluid sample from a patient to ionization under conditions suitable to produce one or more multiply charged ions detectable by mass spectrometry from kisspeptin-54 and one or more kisspeptin-54 derivation products selected from the group consisting of kisspeptin-53 and kisspeptin-52; determining by mass spectrometry the amount of one or more ions of kisspeptin-54 and one or more kisspeptin-54 derivation products selected from the group consisting of kisspeptin-53 and kisspeptin-52; and using the amounts of ions determined in step b to determine the amounts of kisspeptin-54 and kisspeptin-54 derivation products in the sample.\",\n \"Similar methods are provided for measuring degradation of kisspeptin-54(R14P) in a biological fluid sample from a patient.\",\n \"These methods include subjecting a biological fluid sample from a patient to ionization under conditions suitable to produce one or more multiply charged ions detectable by mass spectrometry from kisspeptin-54(R14P) and one or more kisspeptin-54(R14P) derivation products selected from the group consisting of kisspeptin-53(R14P) and kisspeptin-52(R14P); determining by mass spectrometry the amount of one or more ions of kisspeptin-54(R14P) and one or more kisspeptin-54(R14P) derivation products selected from the group consisting of kisspeptin-53(R14P) and kisspeptin-52(R14P); and using the amounts of ions determined in step b to determine the amounts of kisspeptin-54(R14P) and kisspeptin-54(R14P) derivation products in the sample.\",\n \"In another aspect, the invention provides methods of diagnosing or predicting risk of developing preeclampsia.\",\n \"These methods include providing a body fluid or tissue sample obtained from a patient; subjecting the body fluid or tissue sample to one or more processing steps to generate a processed sample comprising one or more kisspeptin-54-derived peptides selected from the group consisting of kisspeptin-54, kisspeptin-53, kisspeptin-52, kisspeptin-54(R14P), kisspeptin-53(R14P), and kisspeptin-52(R14P); subjecting the processed sample to ionization under conditions suitable to produce one or more multiply charged ions detectable by mass spectrometry; determining by mass spectrometry the amount of one or more ions from one or more kisspeptin-54-derived peptides; and using the determined ion amounts to determine the amount of kisspeptin-54 or kisspeptin-54(R14P) in the sample.\",\n \"In these methods, elevated kisspeptin-54 or kisspeptin-54(R14P) levels in the sample relative to normal indicate the presence of or risk of developing preeclampsia.\",\n \"In another aspect, the invention provides one or more substantially isolated polypeptides with amino acid sequences consisting of the sequences identified as SEQ ID No.\",\n \":2 and SEQ ID No.\",\n \":3, or proline variants thereof.\",\n \"In any of the methods provided herein which utilize tandem mass spectrometry, tandem mass spectrometry may be conducted by any method known in the art, including for example, multiple reaction monitoring, precursor ion scanning, or product ion scanning.\",\n \"In any of the methods provided herein which utilize two or more of an extraction column, an analytical column, and an ionization source, two or more of these components may be connected in an on-line fashion to allow for automated sample processing and analysis.\",\n \"In any of the methods provided herein which require ionization of a kisspeptin-54-derived peptide, mass spectrometry is preferably performed in positive ion mode.\",\n \"Alternatively, mass spectrometry is performed in negative ion mode.\",\n \"Various ionization sources, including for example atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI), and heated ESI, may be used in embodiments of the present invention.\",\n \"In certain preferred embodiments, kisspeptin-54-derived peptides are ionized using heated ESI in positive ion mode.\",\n \"In preferred embodiments of methods presented herein which determine the amount of one or more kisspeptin-54-derived peptides in a sample, a separately detectable internal standard is provided in the sample, the amount of which is also determined in the sample.\",\n \"In these embodiments, all or a portion of both the analyte(s) of interest and the internal standard present in the sample is ionized to produce a plurality of ions detectable in a mass spectrometer, and one or more ions produced from each are detected by mass spectrometry.\",\n \"In these embodiments, the presence or amount of ions generated from the analyte of interest may be related to the presence of amount of analyte of interest in the sample.\",\n \"In other embodiments, the amount of one or more kisspeptin-54-derived peptides in a sample may be determined by comparison to one or more external reference standards.\",\n \"Exemplary external reference standards include blank plasma or serum spiked with a kisspeptin-54-derived peptide or an isotopically labeled variant thereof (such as isotopically labeled kisspeptin-54 and isotopically labeled kisspeptin-54(R14P)).\",\n \"As used herein, unless otherwise stated, the singular forms “a,” “an,” and “the” include plural reference.\",\n \"Thus, for example, a reference to “a protein” includes a plurality of protein molecules.\",\n \"As used herein, the term “kisspeptin-54-derived peptide” refers to intact kisspeptin-54 and peptide fragments whose amino acid sequence is found within the amino acid sequence of kisspeptin-54, and all polymorphs thereof.\",\n \"One known polymorph of kisspeptin-54 includes a proline replacement for the arginine at position 14.This polymorph is described herein as kisspeptin-54 (proline variant) or kisspeptin-54(R14P).\",\n \"Kisspeptin-54-derived peptides may possess one or more of the following attributes: naturally occurring, chemically synthesized, isotopically labeled, and chemically modified.\",\n \"Isotopic labeling and/or chemical modification may be conducted by any of several techniques known by those of skill in the art.\",\n \"Other exemplary kisspeptin-54 derived peptides include kisspeptin-53, kisspeptin-52, and their protein variants.\",\n \"As used herein, the term “kisspeptin-54” refers to a 54 amino acid peptide with the sequence shown as SEQ ID No.\",\n \":1 in FIG.\",\n \"1A.\",\n \"As used herein, the term “kisspeptin-53” refers to a 53 amino acid peptide with the sequence shown as SEQ ID No.\",\n \":2 in FIG.\",\n \"1B.\",\n \"As used herein, the term “kisspeptin-52” refers to a 52 amino acid peptide with the sequence shown as SEQ ID No.\",\n \":3 in FIG.\",\n \"1C.\",\n \"As used herein, the term “isolated” as applied to a polypeptide means a polypeptide that has been separated from components that naturally accompany it.\",\n \"Typically, the polypeptide is substantially isolated when it is at least 60%, by weight, free from the proteins and naturally occurring organic molecules with which it is naturally associated.\",\n \"The definition also extends to a polypeptide separated from its flanking amino acids (e.g., for an amino acid sequence, isolated refers to a sequence that is free from the flanking amino acids with which the sequence is naturally associated in a polypeptide).\",\n \"Preferably, the polypeptide is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight, isolated.\",\n \"An isolated polypeptide may be obtained by standard techniques, for example, by extraction from a natural source (e.g., purification from a cell or body fluid), by expression of a recombinant nucleic acid encoding the peptide; or fusion protein thereof, by chemically synthesizing the polypeptide.\",\n \"Purity can be measured by any appropriate method, e.g., by column chromatography, polyacrylamide gel electrophoresis, or HPLC analysis.\",\n \"As used herein, the term “purification” or “purifying” does not refer to removing all materials from the sample other than the analyte(s) of interest.\",\n \"Instead, purification refers to a procedure that enriches the amount of one or more analytes of interest relative to other components in the sample that may interfere with detection of the analyte of interest.\",\n \"Purification of the sample by various means may allow relative reduction of one or more interfering substances, e.g., one or more substances that may or may not interfere with the detection of selected parent or daughter ions by mass spectrometry.\",\n \"Relative reduction as this term is used does not require that any substance, present with the analyte of interest in the material to be purified, is entirely removed by purification.\",\n \"As used herein, the term “immunopurification” or “immunopurify” refers to a purification procedure that utilizes antibodies, including polyclonal or monoclonal antibodies, to enrich the one or more analytes of interest.\",\n \"Immunopurification can be performed using any of the immunopurification methods well known in the art.\",\n \"Often the immunopurification procedure utilizes antibodies bound, conjugated or otherwise attached to a solid support, for example a column, well, tube, gel, capsule, particle or the like.\",\n \"Immunopurification as used herein includes without limitation procedures often referred to in the art as immunoprecipitation, as well as procedures often referred to in the art as affinity chromatography.\",\n \"As used herein, the term “immunoparticle” refers to a capsule, bead, gel particle or the like that has antibodies bound, conjugated or otherwise attached to its surface (either on and/or in the particle).\",\n \"In certain preferred embodiments, immunoparticles are sepharose or agarose beads.\",\n \"In alternative preferred embodiments, immunoparticles are glass, plastic or silica beads, or silica gel.\",\n \"As used herein, the term “anti-kisspeptin-54-derived peptide antibody” refers to any polyclonal or monoclonal antibody that has an affinity for a kisspeptin-54-derived peptide.\",\n \"In various embodiments the specificity of kisspeptin-54-derived peptide antibodies to chemical species other than the kisspeptin-54-derived peptide may vary; for example in certain preferred embodiments the anti-kisspeptin-54-derived peptide antibodies are specific for the kisspeptin-54-derived peptide and thus have little or no affinity for chemical species other than the kisspeptin-54-derived peptide, whereas in other preferred embodiments the anti-kisspeptin-54-derived peptide antibodies are non-specific and thus bind certain chemical species other than the kisspeptin-54-derived peptide.\",\n \"As used herein, the term “sample” refers to any sample that may contain an analyte of interest.\",\n \"As used herein, the term “body fluid” means any fluid that can be isolated from the body of an individual.\",\n \"For example, “body fluid” may include blood, plasma, serum, bile, saliva, urine, tears, perspiration, and the like.\",\n \"In some preferred embodiments, the sample comprises a body fluid sample; preferably plasma or serum, from a patient.\",\n \"As used herein, the term “solid phase extraction” or “SPE” refers to a process in which a chemical mixture is separated into components as a result of the affinity of components dissolved or suspended in a solution (i.e., mobile phase) for a solid through or around which the solution is passed (i.e., solid phase).\",\n \"In some instances, as the mobile phase passes through or around the solid phase, undesired components of the mobile phase may be retained by the solid phase resulting in a purification of the analyte in the mobile phase.\",\n \"In other instances, the analyte may be retained by the solid phase, allowing undesired components of the mobile phase to pass through or around the solid phase.\",\n \"In these instances, a second mobile phase is then used to elute the retained analyte off of the solid phase for further processing or analysis.\",\n \"SPE, including TFLC, may operate via a unitary or mixed mode mechanism.\",\n \"Mixed mode mechanisms utilize ion exchange and hydrophobic retention in the same column; for example, the solid phase of a mixed-mode SPE column may exhibit strong anion exchange and hydrophobic retention; or may exhibit column exhibit strong cation exchange and hydrophobic retention.\",\n \"As used herein, the term “chromatography” refers to a process in which a chemical mixture carried by a liquid or gas is separated into components as a result of differential distribution of the chemical entities as they flow around or over a stationary liquid or solid phase.\",\n \"As used herein, the term “liquid chromatography” or “LC” means a process of selective retardation of one or more components of a fluid solution as the fluid uniformly percolates through a column of a finely divided substance, or through capillary passageways.\",\n \"The retardation results from the distribution of the components of the mixture between one or more stationary phases and the bulk fluid, (i.e., mobile phase), as this fluid moves relative to the stationary phase(s).\",\n \"Examples of “liquid chromatography” include normal phase liquid chromatography (NPLC), reverse phase liquid chromatography (RPLC), high performance liquid chromatography (HPLC), ultra high performance liquid chromatography (UHPLC), and turbulent flow liquid chromatography (TFLC) (sometimes known as high turbulence liquid chromatography (HTLC) or high throughput liquid chromatography).\",\n \"As used herein, the term “high performance liquid chromatography” or “HPLC” (sometimes known as “high pressure liquid chromatography”) refers to liquid chromatography in which the degree of separation is increased by forcing the mobile phase under pressure through a stationary phase, typically a densely packed column.\",\n \"As used herein, the term “ultra high performance liquid chromatography” or “UHPLC” (sometimes known as “ultra high pressure liquid chromatography”) refers to liquid chromatography in which the degree of separation is increased by forcing the mobile phase under high pressure through a stationary phase, typically a densely packed column with a stationary phase comprising packing particles that have an average diameter of than 2 μM.\",\n \"As used herein, the term “turbulent flow liquid chromatography” or “TFLC” (sometimes known as high turbulence liquid chromatography or high throughput liquid chromatography) refers to a form of chromatography that utilizes turbulent flow of the material being assayed through the column packing as the basis for performing the separation.\",\n \"TFLC has been applied in the preparation of samples containing two unnamed drugs prior to analysis by mass spectrometry.\",\n \"See, e.g., Zimmer et al., J Chromatogr A 854: 23-35 (1999); see also, U.S. Pat.\",\n \"Nos.\",\n \"5,968,367, 5,919,368, 5,795,469, and 5,772,874, which further explain TFLC.\",\n \"Persons of ordinary skill in the art understand “turbulent flow”.\",\n \"When fluid flows slowly and smoothly, the flow is called “laminar flow”.\",\n \"For example, fluid moving through an HPLC column at low flow rates is laminar.\",\n \"In laminar flow the motion of the particles of fluid is orderly with particles moving generally in straight lines.\",\n \"At faster velocities, the inertia of the water overcomes fluid frictional forces and turbulent flow results.\",\n \"Fluid not in contact with the irregular boundary “outruns” that which is slowed by friction or deflected by an uneven surface.\",\n \"When a fluid is flowing turbulently, it flows in eddies and whirls (or vortices), with more “drag” than when the flow is laminar.\",\n \"Many references are available for assisting in determining when fluid flow is laminar or turbulent (e.g., Turbulent Flow Analysis: Measurement and Prediction, P. S. Bernard & J. M. Wallace, John Wiley & Sons, Inc., (2000); An Introduction to Turbulent Flow, Jean Mathieu & Julian Scott, Cambridge University Press (2001)).\",\n \"As used herein, the term “gas chromatography” or “GC” refers to chromatography in which the sample mixture is vaporized and injected into a stream of carrier gas (as nitrogen or helium) moving through a column containing a stationary phase composed of a liquid or a particulate solid and is separated into its component compounds according to the affinity of the compounds for the stationary phase.\",\n \"As used herein, the term “large particle column” or “extraction column” refers to a chromatography column containing an average particle diameter greater than about 50 μm.\",\n \"As used in this context, the term “about” means±10%.\",\n \"As used herein, the term “analytical column” refers to a chromatography column having sufficient chromatographic plates to effect a separation of materials in a sample that elute from the column sufficient to allow a determination of the presence or amount of an analyte.\",\n \"Such columns are often distinguished from “extraction columns”, which have the general purpose of separating or extracting retained material from non-retained materials in order to obtain a purified sample for further analysis.\",\n \"As used in this context, the term “about” means±10%.\",\n \"In a preferred embodiment the analytical column contains particles of about 5 μm in diameter.\",\n \"As used herein, the terms “on-line” and “inline”, for example as used in “on-line automated fashion” or “on-line extraction” refers to a procedure performed without the need for operator intervention.\",\n \"In contrast, the term “off-line” as used herein refers to a procedure requiring manual intervention of an operator.\",\n \"Thus, if samples are subjected to precipitation, and the supernatants are then manually loaded into an autosampler, the precipitation and loading steps are off-line from the subsequent steps.\",\n \"In various embodiments of the methods, one or more steps may be performed in an on-line automated fashion.\",\n \"As used herein, the term “mass spectrometry” or “MS” refers to an analytical technique to identify compounds by their mass.\",\n \"MS refers to methods of filtering, detecting, and measuring ions based on their mass-to-charge ratio, or “m/z”.\",\n \"MS technology generally includes (1) ionizing the compounds to form charged compounds; and (2) detecting the molecular weight of the charged compounds and calculating a mass-to-charge ratio.\",\n \"The compounds may be ionized and detected by any suitable means.\",\n \"A “mass spectrometer” generally includes an ionizer and an ion detector.\",\n \"In general, one or more molecules of interest are ionized, and the ions are subsequently introduced into a mass spectrometric instrument where, due to a combination of magnetic and electric fields, the ions follow a path in space that is dependent upon mass (“m”) and charge (“z”).\",\n \"See, e.g., U.S. Pat.\",\n \"No.\",\n \"6,204,500, entitled “Mass Spectrometry From Surfaces;” U.S. Pat.\",\n \"No.\",\n \"6,107,623, entitled “Methods and Apparatus for Tandem Mass Spectrometry;” U.S. Pat.\",\n \"No.\",\n \"6,268,144, entitled “DNA Diagnostics Based On Mass Spectrometry;” U.S. Pat.\",\n \"No.\",\n \"6,124,137, entitled “Surface-Enhanced Photolabile Attachment And Release For Desorption And Detection Of Analytes;” Wright et al., Prostate Cancer and Prostatic Diseases 1999, 2: 264-76; and Merchant and Weinberger, Electrophoresis 2000, 21: 1164-67.As used herein, the term “operating in negative ion mode” refers to those mass spectrometry methods where negative ions are generated and detected.\",\n \"The term “operating in positive ion mode” as used herein, refers to those mass spectrometry methods where positive ions are generated and detected.\",\n \"As used herein, the term “ionization” or “ionizing” refers to the process of generating an analyte ion having a net electrical charge equal to one or more electron units.\",\n \"Negative ions are those having a net negative charge of one or more electron units, while positive ions are those having a net positive charge of one or more electron units.\",\n \"As used herein, the term “electron ionization” or “EI” refers to methods in which an analyte of interest in a gaseous or vapor phase interacts with a flow of electrons.\",\n \"Impact of the electrons with the analyte produces analyte ions, which may then be subjected to a mass spectrometry technique.\",\n \"As used herein, the term “chemical ionization” or “CI” refers to methods in which a reagent gas (e g ammonia) is subjected to electron impact, and analyte ions are formed by the interaction of reagent gas ions and analyte molecules.\",\n \"As used herein, the term “fast atom bombardment” or “FAB” refers to methods in which a beam of high energy atoms (often Xe or Ar) impacts a non-volatile sample, desorbing and ionizing molecules contained in the sample.\",\n \"Test samples are dissolved in a viscous liquid matrix such as glycerol, thioglycerol, m-nitrobenzyl alcohol, 18-crown-6 crown ether, 2-nitrophenyloctyl ether, sulfolane, diethanolamine, and triethanolamine.\",\n \"The choice of an appropriate matrix for a compound or sample is an empirical process.\",\n \"As used herein, the term “matrix-assisted laser desorption ionization” or “MALDI” refers to methods in which a non-volatile sample is exposed to laser irradiation, which desorbs and ionizes analytes in the sample by various ionization pathways, including photoionization, protonation, deprotonation, and cluster decay.\",\n \"For MALDI, the sample is mixed with an energy-absorbing matrix, which facilitates desorption of analyte molecules.\",\n \"As used herein, the term “surface enhanced laser desorption ionization” or “SELDI” refers to another method in which a non-volatile sample is exposed to laser irradiation, which desorbs and ionizes analytes in the sample by various ionization pathways, including photoionization, protonation, deprotonation, and cluster decay.\",\n \"For SELDI, the sample is typically bound to a surface that preferentially retains one or more analytes of interest.\",\n \"As in MALDI, this process may also employ an energy-absorbing material to facilitate ionization.\",\n \"As used herein, the term “electrospray ionization” or “ESI,” refers to methods in which a solution is passed along a short length of capillary tube, to the end of which is applied a high positive or negative electric potential.\",\n \"Solution reaching the end of the tube is vaporized (nebulized) into a jet or spray of very small droplets of solution in solvent vapor.\",\n \"This mist of droplets flows through an evaporation chamber.\",\n \"As the droplets get smaller the electrical surface charge density increases until such time that the natural repulsion between like charges causes ions as well as neutral molecules to be released.\",\n \"Heated ESI is similar, but includes a heat source for heating the sample while in the capillary tube.\",\n \"As used herein, the term “atmospheric pressure chemical ionization” or “APCI,” refers to mass spectrometry methods that are similar to ESI; however, APCI produces ions by ion-molecule reactions that occur within a plasma at atmospheric pressure.\",\n \"The plasma is maintained by an electric discharge between the spray capillary and a counter electrode.\",\n \"Then ions are typically extracted into the mass analyzer by use of a set of differentially pumped skimmer stages.\",\n \"A counterflow of dry and preheated N2 gas may be used to improve removal of solvent.\",\n \"The gas-phase ionization in APCI can be more effective than ESI for analyzing less-polar species.\",\n \"The term “atmospheric pressure photoionization” or “APPI” as used herein refers to the form of mass spectrometry where the mechanism for the photoionization of molecule M is photon absorption and electron ejection to form the molecular ion M+.\",\n \"Because the photon energy typically is just above the ionization potential, the molecular ion is less susceptible to dissociation.\",\n \"In many cases it may be possible to analyze samples without the need for chromatography, thus saving significant time and expense.\",\n \"In the presence of water vapor or protic solvents, the molecular ion can extract H to form MH+.\",\n \"This tends to occur if M has a high proton affinity.\",\n \"This does not affect quantitation accuracy because the sum of M+ and MH+ is constant.\",\n \"Drug compounds in protic solvents are usually observed as MH+, whereas nonpolar compounds such as naphthalene or testosterone usually form M+.\",\n \"See, e.g., Robb et al., Anal.\",\n \"Chem.\",\n \"2000, 72(15): 3653-3659.As used herein, the term “inductively coupled plasma” or “ICP” refers to methods in which a sample interacts with a partially ionized gas at a sufficiently high temperature such that most elements are atomized and ionized.\",\n \"As used herein, the term “field desorption” refers to methods in which a non-volatile test sample is placed on an ionization surface, and an intense electric field is used to generate analyte ions.\",\n \"As used herein, the term “desorption” refers to the removal of an analyte from a surface and/or the entry of an analyte into a gaseous phase.\",\n \"Laser desorption thermal desorption is a technique wherein a sample containing the analyte is thermally desorbed into the gas phase by a laser pulse.\",\n \"The laser hits the back of a specially made 96-well plate with a metal base.\",\n \"The laser pulse heats the base and the heat causes the sample to transfer into the gas phase.\",\n \"The gas phase sample is then drawn into the mass spectrometer.\",\n \"As used herein, the term “selective ion monitoring” is a detection mode for a mass spectrometric instrument in which only ions within a relatively narrow mass range, typically about one mass unit, are detected.\",\n \"As used herein, “multiple reaction mode,” sometimes known as “selected reaction monitoring,” is a detection mode for a mass spectrometric instrument in which a precursor ion and one or more fragment ions are selectively detected.\",\n \"As used herein, the term “lower limit of quantification”, “lower limit of quantitation” or “LLOQ” refers to the point where measurements become quantitatively meaningful.\",\n \"The analyte response at this LOQ is identifiable, discrete and reproducible with a relative standard deviation (RSD %) of less than 20% and an accuracy of 85% to 115%.\",\n \"As used herein, the term “limit of detection” or “LOD” is the point at which the measured value is larger than the uncertainty associated with it.\",\n \"The LOD is the point at which a value is beyond the uncertainty associated with its measurement and is defined as three times the RSD of the mean at the zero concentration.\",\n \"As used herein, an “amount” of an analyte in a body fluid sample refers generally to an absolute value reflecting the mass of the analyte detectable in volume of sample.\",\n \"However, an amount also contemplates a relative amount in comparison to another analyte amount.\",\n \"For example, an amount of an analyte in a sample can be an amount which is greater than a control or normal level of the analyte normally present in the sample.\",\n \"The term “about” as used herein in reference to quantitative measurements not including the measurement of the mass of an ion, refers to the indicated value plus or minus 10%.\",\n \"Mass spectrometry instruments can vary slightly in determining the mass of a given analyte.\",\n \"The term “about” in the context of the mass of an ion or the mass/charge ratio of an ion refers to +/−0.5 atomic mass unit.\",\n \"The summary of the invention described above is non-limiting and other features and advantages of the invention will be apparent from the following detailed description of the invention, and from the claims.\",\n \"BRIEF DESCRIPTION OF THE DRAWINGS FIGS.\",\n \"1A-C show the amino acid sequences of kisspeptin-54 (SEQ ID NO.\",\n \":1), kisspeptin-53 (SEQ ID NO.\",\n \":2), and kisspeptin-52 (SEQ ID NO.\",\n \":3), respectively, including their respective proline variants (i.e., each having the R14P substitution).\",\n \"FIG.\",\n \"2 shows a full scan spectrum of Kisspeptin-54.This spectrum shows generation of KP-54 [M+7H]+7 and [M+6H]+6 ions with m/z of 837.5±0.5 and 977.0±0.5, respectively.\",\n \"Details are discussed in Example 3.FIG.\",\n \"3 shows an exemplary fragmentation spectrum of KP-54 [M+6H]+6 ion with m/z of 977.0±0.5.Exemplary fragment ions are observed at m/z of 1083.6±0.5 and 903.1±0.5.Details are discussed in Example 3.FIG.\",\n \"4 shows an exemplary fragmentation spectrum of KP-54 [M+7H]+7 ion with m/z of 837.7±0.5.Exemplary fragment ions are observed at m/z of 902.8±0.5.Details are discussed in Example 3.FIG.\",\n \"5 shows a full scan spectrum of Kisspeptin-54(R14P).\",\n \"This spectrum shows generation of KP-54(R14P) [M+6H]+6, [M+5H]+5, and [M+4H]+4 ions with m/z of 967.3±0.5, 1160.6±0.5, and 1450.5±0.5, respectively.\",\n \"Details are discussed in Example 3.FIG.\",\n \"6 shows an exemplary fragmentation spectrum of KP-54(R14P) [M+5H]+ ion with m/z of 1160.6±0.5.Exemplary fragment ions are observed at m/z of 1071.6±0.5.Details are discussed in Example 3.FIG.\",\n \"7 shows an exemplary fragmentation spectrum of KP-54(R14P) [M+6H]+6 ion with m/z of 967.3±0.5.Exemplary fragment ions are observed at m/z of 1071.6±0.5.Details are discussed in Example 3.FIG.\",\n \"8 shows a full scan spectrum of Kisspeptin-53.This spectrum shows generation of KP-53 [M+7H]+7, [M+6H]+6, and [M+5H]+5 ions with m/z of 816.9±0.5, 952.7±0.5, and 1143.2±0.5, respectively.\",\n \"Details are discussed in Example 3.FIG.\",\n \"9 shows an exemplary fragmentation spectrum of KP-53 [M+5H]+5 ion with m/z of 1143.2±0.5.Exemplary fragment ions are observed at m/z of 1053.9±0.5.Details are discussed in Example 3.FIG.\",\n \"10 shows an exemplary fragmentation spectrum of KP-53 [M+6H]+6 ion with m/z of 952.7±0.5.Exemplary fragment ions are observed at m/z of 1054.1±0.5 and 878.3±0.5.Details are discussed in Example 3.FIG.\",\n \"11 shows an exemplary fragmentation spectrum of KP-53 [M+7H]+7 ion with m/z of 816.7±0.5.Exemplary fragment ions are observed at m/z of 878.3±0.5.Details are discussed in Example 3.FIG.\",\n \"12 shows a full scan spectrum of Kisspeptin-52.This spectrum shows generation of KP-52 [M+6H]+6, [M+5H]+5, and [M+4H]+4 ions with m/z of 926.6±0.5, 1112.0±0.5, and 1389.5±0.5, respectively.\",\n \"Details are discussed in Example 3.FIG.\",\n \"13 shows an exemplary fragmentation spectrum of KP-52 [M+5H]+5 ion with m/z of 1111.9±0.5±0.5.Exemplary fragment ions are observed at m/z of 1278.2±0.5 and 1022.9±0.5.Details are discussed in Example 3.FIG.\",\n \"14 shows an exemplary fragmentation spectrum of KP-52 [M+6H]+6 ion with m/z of 926.8±0.5.Exemplary fragment ions are observed at m/z of 1022.9±0.5.Details are discussed in Example 3.FIG.\",\n \"15 shows the detection of KP-52, KP-53, KP-54, and KP-54(IS) in serum from pregnant woman #1 (28 years old, 25 weeks gestation).\",\n \"Details are discussed in Example 4.FIG.\",\n \"16 shows the detection of KP-52, KP-53, KP-54, and KP-54(IS) in EDTA plasma from pregnant woman #1 (28 years old, 25 weeks gestation).\",\n \"Details are discussed in Example 4.FIG.\",\n \"17 shows the detection of KP-52, KP-53, KP-54, and KP-54(IS) in serum from pregnant woman #2 (21 years old, 28 weeks gestation).\",\n \"Details are discussed in Example 4.FIG.\",\n \"18 shows the detection of KP-52, KP-53, KP-54, and KP-54(IS) in EDTA plasma from pregnant woman #2 (21 years old, 28 weeks gestation).\",\n \"Details are discussed in Example 4.DETAILED DESCRIPTION OF THE INVENTION Methods are described for measuring the amount of one or more kisspeptin-54-derived peptides in a sample.\",\n \"More specifically, mass spectrometric methods are described for detecting and quantifying one or more kisspeptin-54-derived peptides in a sample.\",\n \"The methods may utilize solid phase extraction and/or liquid chromatography, to perform a purification of selected analytes, combined with methods of mass spectrometry (MS), thereby providing a high-throughput assay system for detecting and quantifying kisspeptin-54-derived peptides in a sample.\",\n \"The preferred embodiments are particularly well suited for application in large clinical laboratories for automated kisspeptin-54-derived peptide quantification assay.\",\n \"Suitable test samples for use in methods of the present invention include any test sample that may contain the analyte of interest.\",\n \"In some preferred embodiments, a sample is a biological sample; that is, a sample obtained from any biological source, such as an animal, a cell culture, an organ culture, etc.\",\n \"In certain preferred embodiments, samples are obtained from a mammalian animal, such as a dog, cat, horse, etc.\",\n \"Particularly preferred mammalian animals are primates, most preferably male or female humans.\",\n \"Preferred samples comprise bodily fluids such as blood, plasma, serum, saliva, cerebrospinal fluid, or tissue samples; preferably plasma and serum.\",\n \"Such samples may be obtained, for example, from a patient; that is, a living person, male or female, presenting oneself in a clinical setting for diagnosis, prognosis, or treatment of a disease or condition, such as preeclampsia.\",\n \"In embodiments where the sample comprises a biological sample, the methods may be used to determine the amount of one or more kisspeptin-54-derived peptides in the sample when the sample was obtained from the biological source (i.e., the amount of one or more endogenous kisspeptin-54-derived peptides in the sample).\",\n \"Kisspeptin-54-derived peptides may be quantitated in patient samples from a pregnant female subject in order to diagnose or predict risk of developing preeclampsia.\",\n \"In diagnosing or predicting risk of preeclampsia, levels of kisspeptin-54-derived peptides from the patient sample are compared to normal levels in pregnant female samples.\",\n \"Elevated levels of kisspeptin-54-derived peptides in a patient sample relative to normal levels indicates the presence of or risk of developing preeclampsia.\",\n \"The present invention also contemplates kits for a kisspeptin-54-derived peptide quantitation assay.\",\n \"A kit for a kisspeptin-54-derived peptide quantitation assay may include a kit comprising the compositions provided herein.\",\n \"For example, a kit may include packaging material and measured amounts of an isotopically labeled internal standard, in amounts sufficient for at least one assay.\",\n \"Typically, the kits will also include instructions recorded in a tangible form (e.g., contained on paper or an electronic medium) for using the packaged reagents for use in a kisspeptin-54-derived peptide quantitation assay.\",\n \"Calibration and QC pools for use in embodiments of the present invention are preferably prepared using a matrix similar to the intended sample matrix, provided that the kisspeptin-54-derived peptide is essentially absent.\",\n \"Sample Preparation for Mass Spectrometric Analysis In some embodiments, samples are acidified prior to analysis.\",\n \"Internal standard may be added to the samples prior or subsequent to acidification.\",\n \"In preparation for mass spectrometric analysis, kisspeptin-54-derived peptides may be enriched relative to one or more other components in the sample (e.g.\",\n \"protein) by various methods known in the art, including for example, liquid chromatography, filtration, centrifugation, thin layer chromatography (TLC), electrophoresis including capillary electrophoresis, affinity separations including immunoaffinity separations, extraction methods including ethyl acetate or methanol extraction, and the use of chaotropic agents or any combination of the above or the like.\",\n \"Protein precipitation is one method of preparing a test sample, especially a biological test sample, such as serum or plasma.\",\n \"Protein purification methods are well known in the art, for example, Polson et al., Journal of Chromatography B 2003, 785:263-275, describes protein precipitation techniques suitable for use in methods of the present invention.\",\n \"Protein precipitation may be used to remove most of the protein from the sample leaving kisspeptin-54-derived peptides in the supernatant.\",\n \"The samples may be centrifuged to separate the liquid supernatant from the precipitated proteins; alternatively the samples may be filtered to remove precipitated proteins.\",\n \"The resultant supernatant or filtrate may then be applied directly to mass spectrometry analysis; or alternatively to further purification steps, such as liquid chromatography, and subsequent mass spectrometry analysis.\",\n \"In certain embodiments, the use of protein precipitation such as, for example, formic acid protein precipitation, may obviate the need for TFLC or other on-line extraction prior to mass spectrometry or HPLC and mass spectrometry.\",\n \"Another method of sample purification that may be used prior to mass spectrometry is liquid chromatography (LC).\",\n \"Certain methods of liquid chromatography, including HPLC, rely on relatively slow, laminar flow technology.\",\n \"Traditional HPLC analysis relies on column packing in which laminar flow of the sample through the column is the basis for separation of the analyte of interest from the sample.\",\n \"The skilled artisan will understand that separation in such columns is a partition process and may select LC, including HPLC, instruments and columns that are suitable for use with kisspeptin-54-derived peptides.\",\n \"The chromatographic column typically includes a medium (i.e., a packing material) to facilitate separation of chemical moieties (i.e., fractionation).\",\n \"The medium may include minute particles.\",\n \"The particles typically include a bonded surface that interacts with the various chemical moieties to facilitate separation of the chemical moieties.\",\n \"One suitable bonded surface is a hydrophobic bonded surface such as an alkyl bonded or a cyano bonded surface.\",\n \"Alkyl bonded surfaces may include C-4, C-8, C-12, or C-18 bonded alkyl groups.\",\n \"In preferred embodiments, the column is a C-18 column.\",\n \"The chromatographic column includes an inlet port for receiving a sample and an outlet port for discharging an effluent that includes the fractionated sample.\",\n \"The sample may be supplied to the inlet port directly, or from a SPE column, such as an on-line extraction column or a TFLC column.\",\n \"In some embodiments, an on-line filter may be used ahead of the SPE column and or HPLC column to remove particulates and phospholipids in the samples prior to the samples reaching the SPE and/or HPLC columns.\",\n \"In preferred embodiments, a 0.2 μm or 0.45 μm micro-spin cellulose acetate delipidation filter is used as such an off-line filter.\",\n \"In one embodiment, the sample may be applied to the LC column at the inlet port, eluted with a solvent or solvent mixture, and discharged at the outlet port.\",\n \"Different solvent modes may be selected for eluting the analyte(s) of interest.\",\n \"For example, liquid chromatography may be performed using a gradient mode, an isocratic mode, or a polytypic (i.e.\",\n \"mixed) mode.\",\n \"During chromatography, the separation of materials is effected by variables such as choice of eluent (also known as a “mobile phase”), elution mode, gradient conditions, temperature, etc.\",\n \"In certain embodiments, an analyte may be purified by applying a sample to a column under conditions where the analyte of interest is reversibly retained by the column packing material, while one or more other materials are not retained.\",\n \"In these embodiments, a first mobile phase condition can be employed where the analyte of interest is retained by the column, and a second mobile phase condition can subsequently be employed to remove retained material from the column, once the non-retained materials are washed through.\",\n \"Alternatively, an analyte may be purified by applying a sample to a column under mobile phase conditions where the analyte of interest elutes at a differential rate in comparison to one or more other materials.\",\n \"Such procedures may enrich the amount of one or more analytes of interest relative to one or more other components of the sample.\",\n \"In one preferred embodiment, HPLC is conducted with a polar embedded analytical column chromatographic system.\",\n \"In certain preferred embodiments, a C-18 BEH (ethylene bridged hybrid) analytical column (e.g., an XBridge C18 BEH analytical column from Waters Inc. (2.5×50 mm, 5 μm particle size), or equivalent) is used.\",\n \"In certain preferred embodiments, HPLC is performed using HPLC Grade 0.2% aqueous formic acid as solvent A, and 0.2% formic acid in acetonitrile as solvent B.\",\n \"By careful selection of valves and connector plumbing, two or more chromatography columns may be connected as needed such that material is passed from one to the next without the need for any manual steps.\",\n \"In preferred embodiments, the selection of valves and plumbing is controlled by a computer pre-programmed to perform the necessary steps.\",\n \"Most preferably, the chromatography system is also connected in such an on-line fashion to the detector system, e.g., an MS system.\",\n \"Thus, an operator may place a tray of samples in an autosampler, and the remaining operations are performed under computer control, resulting in purification and analysis of all samples selected.\",\n \"In some embodiments, TFLC may be used for purification of kisspeptin-54-derived peptides prior to mass spectrometry.\",\n \"In such embodiments, samples may be extracted using a TFLC column which captures the analyte.\",\n \"The analyte is then eluted and transferred on-line to an analytical HPLC column.\",\n \"For example, sample extraction may be accomplished with a TFLC extraction cartridge may be accomplished with a large particle size (e.g., 25 μm or larger, such as 50 μm, particle size) packed column.\",\n \"Sample eluted off of this column is then transferred on-line to an HPLC analytical column for further purification prior to mass spectrometry.\",\n \"Because the steps involved in these chromatography procedures may be linked in an automated fashion, the requirement for operator involvement during the purification of the analyte can be minimized.\",\n \"This feature may result in savings of time and costs, and eliminate the opportunity for operator error.\",\n \"In some embodiments, the methods include immunopurifying kisspeptin-54-derived peptides prior to analysis.\",\n \"The immunopurification step may be performed using any of the immunopurification methods well known in the art.\",\n \"Often the immunopurification procedure utilizes antibodies bound, conjugated, immobilized or otherwise attached to a solid support, for example a column, well, tube, capsule, particle or the like.\",\n \"Generally, immunopurification methods involve (1) incubating a sample containing the analyte of interest with antibodies such that the analyte binds to the antibodies, (2) performing one or more washing steps, and (3) eluting the analyte from the antibodies.\",\n \"In certain embodiments the incubation step of the immunopurification is performed with the antibodies free in solution and the antibodies are subsequently bound or attached to a solid surface prior to the washing steps.\",\n \"In certain embodiments this can be achieved using a primary antibody that is an anti-kisspeptin-54-derived peptide antibody and a secondary antibody attached to a solid surface that has an affinity to the primary anti-kisspeptin-54-derived peptide antibody.\",\n \"In alternative embodiments, the primary antibody is bound to the solid surface prior to the incubation step.\",\n \"Appropriate solid supports include without limitation tubes, slides, columns, beads, capsules, particles, gels, and the like.\",\n \"In some preferred embodiments, the solid support is a multi-well plate, such as, for example, a 96 well plate, a 384-well plate or the like.\",\n \"In certain preferred embodiments the solid support are sepharose or agarose beads or gels.\",\n \"There are numerous methods well known in the art by which antibodies (for example, an anti-kisspeptin-54-derived peptide antibody or a secondary antibody) may be bound, attached, immobilized or coupled to a solid support, e.g., covalent or non-covalent linkages adsorption, affinity binding, ionic linkages and the like.\",\n \"In some embodiments antibodies are coupled using CNBr, for example the antibodies may be coupled to CNBr activated sepharose.\",\n \"In other embodiments, the antibody is attached to the solid support through an antibody binding protein such as protein A, protein G, protein A/G, or protein L. The washing step of the immunopurification methods generally involve washing the solid support such that one or more kisspeptin-54-derived peptides remain bound to the anti-kisspeptin-54-derived peptide antibodies on the solid support.\",\n \"The elution step of the immunopurification generally involves the addition of a solution that disrupts the binding of kisspeptin-54-derived peptides to the anti-kisspeptin-54-derived peptide antibodies.\",\n \"Exemplary elution solutions include organic solutions (such as ethanol), salt solutions, and high or low pH solutions.\",\n \"In some embodiments, immunopurification is performed using immunoparticles having anti-kisspeptin-54-derived peptide antibodies.\",\n \"In certain preferred embodiments the test sample possibly containing one or more kisspeptin-54-derived peptides and the immunoparticles are mixed in a tube for incubation and binding of kisspeptin-54-derived peptides to the anti-kisspeptin-54-derived peptide antibodies attached to the immunoparticles; the tube is centrifuged leaving the immunoparticles in a pellet; the supernatant is removed; the immunoparticles are washed one or more times by adding a solution to the pellet and recentrifuging; and the bound kisspeptin-54-derived peptides are eluted by adding an elution solution to the immunoparticles, the tube is centrifuged leaving the immunoparticles in a pellet; and the supernatant containing kisspeptin-54-derived peptides is collected.\",\n \"In related preferred embodiments, the immunopurification is performed using a column or cartridge that contains immunoparticles having anti-kisspeptin-54-derived peptide antibodies.\",\n \"Preferably, the such column or cartridge is configured and arranged in a manner to allow solutions to flow through while keeping the immunoparticles contained therein.\",\n \"In certain preferred embodiments, the solution is forced through the column or cartridge by gravity, centrifugation or pressure.\",\n \"The use of columns may improve the ease of performing the incubation, washing and elution steps.\",\n \"In some embodiments, the immunopurification may be performed by affinity chromatography; preferably automated affinity chromatography.\",\n \"It has been found that kisspeptin-54 in patient samples (i.e., serum or plasma) potentially degrades at the C-terminus to form shorter kisspeptin-54-derived peptides such as KP-53 and KP-52.This degradation, if not controlled or accounted for, could result in erroneously low analytical results.\",\n \"For example, radioimmunoassays which rely on binding of the C-terminus of KP-54 would not account for that portion of KP-54 originally in the patient sample which has since degraded into KP-53 or KP-52.Thus, one aspect of the present invention utilizes antibodies specific for the N-terminus of kisspeptin-54-derived peptides for immunopurification and/or immunoassay.\",\n \"By using N-terminus specific antibodies, KP-54 and its degradation products K-53 and K-52 are captured for further analysis.\",\n \"Alternatively or in addition, patient samples may be treated with one or more agents or subject to physical conditions which inhibit or prevent KP-54 degradation prior to KP-54 purification and analysis.\",\n \"For example, patient serum or plasma samples may be acidified, such as with formic acid, to inhibit or prevent degradation.\",\n \"Alternatively, patient serum or plasma samples may be subject to any protein precipitation technique known in the art (such as treatment with methanol) to inhibit or prevent degradation.\",\n \"Regardless of purification methods employed and/or steps taken to reduce or inhibit KP-54 degradation, methods of analyzing patient samples may be employed which account for KP-54 degradation by simultaneously analyzing the sample for other kisspeptin-54-derived peptides.\",\n \"Specifically, patient samples can be simultaneously analyzed for KP-54, KP-53, and KP-52 (or their proline variants).\",\n \"The combined amounts of KP-54 and one or both of KP-53 and KP-52 may provide a more diagnostically useful indication of KP-54 originally present in the patient sample.\",\n \"Detection and Quantitation by Mass Spectrometry In various embodiments, kisspeptin-54-derived peptides may be ionized by any method known to the skilled artisan.\",\n \"Mass spectrometry is performed using a mass spectrometer, which includes an ion source for ionizing the fractionated sample and creating charged molecules for further analysis.\",\n \"For example ionization of the sample may be performed by electron ionization, chemical ionization, electrospray ionization (ESI), photon ionization, atmospheric pressure chemical ionization (APCI), photoionization, atmospheric pressure photoionization (APPI), Laser diode thermal desorption (LDTD), fast atom bombardment (FAB), liquid secondary ionization (LSI), matrix assisted laser desorption ionization (MALDI), field ionization, field desorption, thermospray/plasmaspray ionization, surface enhanced laser desorption ionization (SELDI), inductively coupled plasma (ICP) and particle beam ionization.\",\n \"The skilled artisan will understand that the choice of ionization method may be determined based on the analyte to be measured, type of sample, the type of detector, the choice of positive versus negative mode, etc.\",\n \"A kisspeptin-54-derived peptide may be ionized in positive or negative mode.\",\n \"In some embodiments, kisspeptin-54-derived peptides are ionized by ESI (such as by heated ESI) in positive mode.\",\n \"In mass spectrometry techniques generally, after the sample has been ionized, the positively or negatively charged ions thereby created may be analyzed to determine a mass-to-charge ratio.\",\n \"Suitable analyzers for determining mass-to-charge ratios include quadrupole analyzers, ion traps analyzers, and time-of-flight analyzers.\",\n \"Exemplary ion trap methods are described in Bartolucci, et al., Rapid Commun.\",\n \"Mass Spectrom.\",\n \"2000, 14:967-73.The ions may be detected using several detection modes.\",\n \"For example, selected ions may be detected, i.e.\",\n \"using a selective ion monitoring mode (SIM), or alternatively, mass transitions resulting from collision induced dissociation or neutral loss may be monitored, e.g., multiple reaction monitoring (MRM) or selected reaction monitoring (SRM).\",\n \"Preferably, the mass-to-charge ratio is determined using a quadrupole analyzer.\",\n \"For example, in a “quadrupole” or “quadrupole ion trap” instrument, ions in an oscillating radio frequency field experience a force proportional to the DC potential applied between electrodes, the amplitude of the RF signal, and the mass/charge ratio.\",\n \"The voltage and amplitude may be selected so that only ions having a particular mass/charge ratio travel the length of the quadrupole, while all other ions are deflected.\",\n \"Thus, quadrupole instruments may act as both a “mass filter” and as a “mass detector” for the ions injected into the instrument.\",\n \"One may enhance the resolution of the MS technique by employing “tandem mass spectrometry,” or “MS/MS”.\",\n \"In this technique, a precursor ion (also called a parent ion) generated from a molecule of interest can be filtered in an MS instrument, and the precursor ion subsequently fragmented to yield one or more fragment ions (also called daughter ions or product ions) that are then analyzed in a second MS procedure.\",\n \"By careful selection of precursor ions, only ions produced by certain analytes are passed to the fragmentation chamber, where collisions with atoms of an inert gas produce the fragment ions.\",\n \"Because both the precursor and fragment ions are produced in a reproducible fashion under a given set of ionization/fragmentation conditions, the MS/MS technique may provide an extremely powerful analytical tool.\",\n \"For example, the combination of filtration/fragmentation may be used to eliminate interfering substances, and may be particularly useful in complex samples, such as biological samples.\",\n \"Alternate modes of operating a tandem mass spectrometric instrument include product ion scanning and precursor ion scanning.\",\n \"For a description of these modes of operation, see, e.g., E. Michael Thurman, et al., Chromatographic-Mass Spectrometric Food Analysis for Trace Determination of Pesticide Residues, Chapter 8 (Amadeo R. Fernandez-Alba, ed., Elsevier 2005) (387).\",\n \"The results of an analyte assay may be related to the amount of the analyte in the original sample by numerous methods known in the art.\",\n \"For example, given that sampling and analysis parameters are carefully controlled, the relative abundance of a given ion may be compared to a table that converts that relative abundance to an absolute amount of the original molecule.\",\n \"Alternatively, external standards may be run with the samples, and a standard curve constructed based on ions generated from those standards.\",\n \"Using such a standard curve, the relative abundance of a given ion may be converted into an absolute amount of the original molecule.\",\n \"In certain preferred embodiments, an internal standard is used to generate a standard curve for calculating the quantity of a kisspeptin-54-derived peptide.\",\n \"Methods of generating and using such standard curves are well known in the art and one of ordinary skill is capable of selecting an appropriate internal standard.\",\n \"For example, in preferred embodiments one or more forms of isotopically labeled kisspeptin-54-derived peptides may be used as internal standards.\",\n \"Numerous other methods for relating the amount of an ion to the amount of the original molecule will be well known to those of ordinary skill in the art.\",\n \"As used herein, an “isotopic label” produces a mass shift in the labeled molecule relative to the unlabeled molecule when analyzed by mass spectrometric techniques.\",\n \"Examples of suitable labels include deuterium (2H), 13C, and 15N.\",\n \"One or more isotopic labels can be incorporated at one or more positions in the molecule and one or more kinds of isotopic labels can be used on the same isotopically labeled molecule.\",\n \"One or more steps of the methods may be performed using automated machines.\",\n \"In certain embodiments, one or more purification steps are performed on-line, and more preferably all of the purification and mass spectrometry steps may be performed in an on-line fashion.\",\n \"In certain embodiments, such as MS/MS, where precursor ions are isolated for further fragmentation, collision activated dissociation (CAD) is often used to generate fragment ions for further detection.\",\n \"In CAD, precursor ions gain energy through collisions with an inert gas, and subsequently fragment by a process referred to as “unimolecular decomposition.” Sufficient energy must be deposited in the precursor ion so that certain bonds within the ion can be broken due to increased vibrational energy.\",\n \"In particularly preferred embodiments, one or more kisspeptin-54-derived peptides in a sample are detected and/or quantified using MS/MS as follows.\",\n \"Samples are preferably subjected to SPE, then subjected to liquid chromatography, preferably HPLC; the flow of liquid solvent from a chromatographic column enters the heated nebulizer interface of an MS/MS analyzer; and the solvent/analyte mixture is converted to vapor in the heated charged tubing of the interface.\",\n \"During these processes, one or more analytes (i.e., one or more kisspeptin-54-derived peptides) are analyzed.\",\n \"The ions, e.g.\",\n \"precursor ions, from a kisspeptin-54-derived peptide pass through the orifice of the instrument and enter the first quadrupole.\",\n \"Quadrupoles 1 and 3 (Q1 and Q3) are mass filters, allowing selection of ions (i.e., selection of “precursor” and “fragment” ions in Q1 and Q3, respectively) based on their mass to charge ratio (m/z).\",\n \"Quadrupole 2 (Q2) is the collision cell, where ions are fragmented.\",\n \"The first quadrupole of the mass spectrometer (Q1) selects for molecules with the mass to charge ratios of a kisspeptin-54-derived peptide.\",\n \"Precursor ions with the correct mass/charge ratios are allowed to pass into the collision chamber (Q2), while unwanted ions with any other mass/charge ratio collide with the sides of the quadrupole and are eliminated.\",\n \"Precursor ions entering Q2 collide with neutral argon gas molecules and fragment.\",\n \"The fragment ions generated are passed into quadrupole 3 (Q3), where the fragment ions of a kisspeptin-54-derived peptide are selected while other ions are eliminated.\",\n \"This process can be repeated as often as necessary to analyze as many kisspeptin-54-derived peptides as desired.\",\n \"Using standard methods well known in the art, one of ordinary skill is capable of identifying one or more fragment ions of a particular precursor ion of a kisspeptin-54-derived peptide that may be used for selection in quadrupole 3 (Q3).\",\n \"As ions collide with the detector they produce a pulse of electrons that are converted to a digital signal.\",\n \"The acquired data is relayed to a computer, which plots counts of the ions collected versus time.\",\n \"The resulting mass chromatograms are similar to chromatograms generated in traditional HPLC-MS methods.\",\n \"The areas under the peaks corresponding to particular ions, or the amplitude of such peaks, may be measured and correlated to the amount of the analyte of interest.\",\n \"In certain embodiments, the area under the curves, or amplitude of the peaks, for fragment ion(s) and/or precursor ions are measured to determine the amount of a kisspeptin-54-derived peptide.\",\n \"As described above, the relative abundance of a given ion may be converted into an absolute amount of the original analyte using calibration standard curves based on peaks of one or more ions of an internal molecular standard.\",\n \"The following Examples serve to illustrate the invention.\",\n \"These Examples are in no way intended to limit the scope of the methods.\",\n \"EXAMPLES Example 1: Sample Preparation A 100 μL serum or EDTA plasma patient sample was mixed with 300 μL of methanol containing isotope labeled kisspeptin-54 as an internal standard.\",\n \"The protein precipitate was removed via centrifugation and the supernatant was subjected to LC-MS and LC-MS/MS as described in the following Examples.\",\n \"Example 2: Extraction of Kisspeptin-54-Derived Peptides from Samples Using Liquid Chromatography The on-line chromatographic separation of kisspeptin-54 and other kisspeptin-54-derived peptides from matrix components was performed with a Cohesive Technologies Aria TX-4 high throughput liquid chromatography (HTLC) system using Aria OS V 1.5 or newer software].\",\n \"The analytes and internal standard were isolated from the serum extract using a Waters HLB C18 (2.1×20 mm, 25 μm particle size) solid phase extraction cartridge.\",\n \"After injection of the extract, the cartridge was washed with 90% solvent A (water+0.2% formic acid) and 10% solvent B (acetonitrile+0.2% formic acid).\",\n \"The extraction cartridge retained kisspeptin-54 while ions and very polar molecules flowed through.\",\n \"The analytes were then back-flushed off the extraction cartridge over the analytical column using a pulse of 45% solvent A/55% solvent B, and 100 μL of the eluent was subjected to HPLC for analytical separation.\",\n \"Analytical separation was performed with a Waters X-Bridge C18 BEH analytical column (2.5×50 mm, 5 μm particle size) using a fast, multiphase gradient of increasing solvent B in solvent A.\",\n \"The HPLC gradient started with a 5% organic modifier which was ramped to 35% in approximately 180 seconds.\",\n \"The separated analytes were then subjected to single and tandem mass spectrometry for identification and quantitation of kisspeptin-54-derived peptides.\",\n \"Example 3: Detection of Kisspeptin-54-Derived Peptides by MS and MS/MS MS was performed using a Thermo-Fisher TSQ Quantum Ultra triple quadrupole.\",\n \"Ionization was conducted with a heated electrospray ionization (HESI) probe.\",\n \"Multiply charged ions of several kisspeptin-54-derived peptides were observed.\",\n \"Single MS spectra showing multiply charged kisspeptin-54-related peptide ions are seen in FIG.\",\n \"2 (KP-54), FIG.\",\n \"5 (KP-54 (proline variant)), FIG.\",\n \"8 (KP-53), and FIG.\",\n \"12 (KP-52), respectively.\",\n \"Several major ions, several of which are seen in these figures, are compiled in Table 1.TABLE 1 Exemplary ions observed for several Kisspeptin- 54-derived peptides (positive polarity) Peptide Charge state Ion (m/z) KP-54 (FIG.\",\n \"1) 5+ 1172.4 ± 0.50 6+ 977.01 ± 0.50 7+ 837.50 ± 0.50 KP-54(R14P) (FIG.\",\n \"4) 4+ 1450.49 ± 0.50 5+ 1160.60 ± 0.50 6+ 967.33 ± 0.50 KP-53 (FIG.\",\n \"7) 5+ 1143.19 ± 0.50 6+ 952.66 ± 0.50 7+ 816.85 ± 0.50 KP-52 (FIG.\",\n \"11) 4+ 1389.46 ± 0.50 5+ 1111.97 ± 0.50 6+ 926.64 ± 0.50 Various multiply charged precursor ions from each of the above listed kisspeptin-54-derived peptides were further subjected to MS/MS resulting in a plurality of fragment ions at various charge states.\",\n \"For KP-54, 6+ and 7+ precursor ions were fragmented, with exemplary MS/MS spectra seen in FIGS.\",\n \"3 and 4.For KP-54 (proline variant), 5+ and 6+ precursor ions were fragmented, with exemplary MS/MS spectra seen in FIGS.\",\n \"6 and 7.For KP-53, 5+, 6+, and 7+ precursor ions were fragmented, with exemplary MS/MS spectra seen in FIGS.\",\n \"9, 10, and 11.For KP-52, 5+ and 6+ precursor ions were fragmented, with exemplary MS/MS spectra seen in FIGS.\",\n \"13 and 14.Additionally, isotopically labeled KP-54 were ionized and fragmented as discussed above (spectra not shown).\",\n \"The m/z ratios of several of the observed major fragment ions are compiled and listed in Table 2.TABLE 2 Exemplary fragment ions observed for several Kisspeptin- 54-derived peptides (positive polarity) Exemplary Precursor Fragment Peptide Ion (m/z) Ions (m/z) KP-54 977.0 ± 0.50 1083.6 ± 0.50 (FIG.\",\n \"2) 903.1 ± 0.50 837.7 ± 0.50 902.8 ± 0.50 (FIG.\",\n \"3) KP-54(R14P) 1160.6 ± 0.50 1071.6 ± 0.50 (FIG.\",\n \"5) 967.3 ± 0.50 1071.6 ± 0.50 (FIG.\",\n \"6) KP-53 1143.0 ± 0.50 1053.9 ± 0.50 (FIG.\",\n \"8) 952.8 ± 0.50 1054.1 ± 0.50 (FIG.\",\n \"9) 878.5 ± 0.50 816.7 ± 0.50 878.3 ± 0.50 (FIG.\",\n \"10) KP-52 1111.9 ± 0.50 1278.2 ± 0.50 (FIG.\",\n \"12) 1022.9 ± 0.50 926.8 ± 0.50 1022.9 ± 0.50 (FIG.\",\n \"13) Example 4: Detection and Quantitation of Kisspeptin-54-Derived Peptides by Tandem MS MS/MS was performed using a Thermo-Fisher TSQ Quantum Ultra triple quadrupole MS/MS system equipped with a heated electrospray ionization (HESI) probe (Thermo Electron Corporation).\",\n \"The following software programs, all from Thermo Electron, were used in the Examples described herein: TSQ Ultra Quantum V 1.4.1 or newer, Xcalibur V 2.0 or newer, and LCQuan V 2.5 or newer.\",\n \"Liquid solvent/analyte exiting the analytical column flowed to the heated nebulizer interface of the MS/MS analyzer.\",\n \"The solvent/analyte mixture was converted to vapor in the heated tubing of the interface.\",\n \"Analytes were ionized by HESI in positive polarity.\",\n \"Kisspeptin-54-derived peptide ions passed to the first quadrupole (Q1), which selected KP-54 ions with a m/z of 977.0±0.5, KP-53 ions with a m/z of 952.9±0.5, KP-52 ions with a m/z of 926.9±0.5, or isotopically labeled KP-54 (IS) ions with a m/z of 980.3±0.5.Ions entering quadrupole 2 (Q2) collided with argon gas (at a collision cell energy of 28 V) to generate ion fragments, which were passed to quadrupole 3 (Q3) for further selection.\",\n \"The following mass transitions were used for detection and quantitation during validation on positive polarity.\",\n \"TABLE 3 Exemplary mass transitions used for quantitation of kisspeptin-54-derived peptides (positive polarity) Precursor Product Analyte Ion (m/z) Ions (m/z) KP 1-52 926.9 1022.9 KP 1-53 952.9 1054.2 KP 1-54 977.0 1083.6 KP 1-54(IS) 980.3 1087.3 The mass transitions listed in Table 3 are provided as examples only.\",\n \"Additional precursor/product ion pairs may be selected (for example from ions seen in FIGS.\",\n \"2 to 14) to replace or augment the pairs shown in Table 3.Exemplary mass chromatograms for the simultaneous quantitation of KP-52, KP-53, KP-54, and KP-54(IS) from analysis of two patient samples are shown in FIGS.\",\n \"15 (patient #1-28 years old, 25 weeks gestation, serum) and 16 (patient #1-28 years old, 25 weeks gestation, EDTA plasma), 17 (patient #2-21 years old, 25 weeks gestation, serum), and 18 (patient #2-21 years old, 25 weeks gestation, EDTA plasma).\",\n \"A comparison of the mass chromatograms from serum versus EDTA plasma samples shows that serum samples are more susceptible to formation of shorter forms of kisspeptin-54 derived peptides.\",\n \"Example 5: Enrichment of Kisspeptin-54-Derived Peptides by Immunoassay In this Example, initial patient samples are enriched by capture and extraction of kisspeptin-54-derived peptides with antibodies highly specific for the N-terminal portion of Kisspeptin.\",\n \"KP-54 has been found to degrade in samples at the C-terminus, thus allowing use of N-terminal specific antibodies for capture and enrichment of kisspeptin-54-derived peptides, including KP-54, KP-53, KP-52, and isotopic and chemically modified variants thereof.\",\n \"Once captured on the N-terminus specific antibody, residual sample components are washed, and the captured peptides eluted for later analysis by any method known in the art, including mass spectrometric analysis as described above.\",\n \"The contents of the articles, patents, and patent applications, and all other documents and electronically available information mentioned or cited herein, are hereby incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.\",\n \"Applicants reserve the right to physically incorporate into this application any and all materials and information from any such articles, patents, patent applications, or other physical and electronic documents.\",\n \"The methods illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein.\",\n \"Thus, for example, the terms “comprising”, “including,” containing”, etc.\",\n \"shall be read expansively and without limitation.\",\n \"Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof.\",\n \"It is recognized that various modifications are possible within the scope of the invention claimed.\",\n \"Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the invention embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention.\",\n \"The invention has been described broadly and generically herein.\",\n \"Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the methods.\",\n \"This includes the generic description of the methods with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.\",\n \"Other embodiments are within the following claims.\",\n \"In addition, where features or aspects of the methods are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.\"\n ]\n]","isConversational":false},"source":{"kind":"string","value":"Patent_15875850"}}},{"rowIdx":4494999,"cells":{"text":{"kind":"list like","value":[["ADJUVANT AND VACCINE COMPOSITIONS","Methods are provided for preparing and delivering an adjuvant for vaccines including lecithin, polymer and one or more additives.","The polymer is preferably polyacrylic acid-based.","The additive is preferably one or more of a glycoside and a sterol.","The method of preparation includes hydrating lecithin and a polymer in saline or water and mixing the lecithin and polymer to form the adjuvant.","Additives can be included prior to or after hydration of the lecithin and polymer."],["1.An adjuvant composition comprising a lecithin, a polymer, Quil A and cholesterol wherein the lecithin to polymer ratio is 1:10 to 10:1 by weight and wherein the weight of the Quil A and cholesterol combined is up to about 10% of the weight of the lecithin and polymer combined.","2.The adjuvant composition of claim 1 wherein the polymer is an acrylic polymer selected from the group consisting of polyacrylic acid, methacrylic acid, methacrylate, acrylamide, acrylate, poly (acrylamide-co butyl, methacrylate), acrylic-methacrylic acid, acrylic-acrylamide, poly (methacrylate) and alkyl-esters of poly acrylic acid.","3.The adjuvant composition of claim 1 further comprising an antigen.","4.The adjuvant composition of claim 3 wherein the antigen is DNA based.","5.The adjuvant composition of claim 1 further comprising calcium phosphate.","6.An adjuvant composition consisting of a lecithin, a polymer, Quil A and cholesterol, wherein the lecithin to polymer ratio is 1:10 to 10:1 by weight and wherein the weight of the Quil A and cholesterol combined is up to about 10% of the weight of the lecithin and polymer combined.","7.The adjuvant composition of claim 6 wherein the polymer is an acrylic polymer.","8.A vaccine composition consisting of a lecithin, a polymer, a glycoside, a sterol, and a DNA based antigen, wherein the lecithin to polymer ratio is 1:10 to 10:1 by weight and wherein the weight of the glycoside and sterol combined is up to about 10% of the weight of the lecithin and polymer combined.","9.A vaccine composition consisting of a lecithin, a polymer, a glycoside, a sterol, a DNA based antigen and calcium phosphate, wherein the lecithin to polymer ratio is 1:10 to 10:1 by weight and wherein the weight of the glycoside and sterol combined is up to about 10% of the weight of the lecithin and polymer combined.","10.A method for preparing a vaccine comprising: combining a dry lecithin, an acrylic polymer, a glycoside and a sterol, wherein the dry lecithin to acrylic polymer are at a ratio of 1:10 to 10:1 by weight and wherein the weight of the glycoside and sterol combined is up to about 10% of the weight of the lecithin and polymer combined; suspending the combined lecithin, acrylic polymer, glycoside and sterol in saline or water; and mixing the lecithin, acrylic polymer, glycoside and sterol sufficiently to form a netlike structure; wherein an antigen is added before or after suspension of the dry lecithin, acrylic polymer, glycoside and sterol such that a vaccine is formed and wherein the vaccine is used to elicit an immune response against an infectious agent, cancer, hormone, or autoimmune disease; and wherein the glycoside is Quil A and the sterol is cholesterol.","11.The method of claim 10 wherein the antigen is DNA based and further comprising addition of calcium phosphate prior to or after mixing of the lecithin, acrylic polymer, glycoside and sterol."],["<SOH> BACKGROUND <EOH>Mucosal delivery of vaccines has been underutilized because of the problems associated with effectively delivering the vaccine antigens to the mucosal surface and to the underlying mucosal lymphoid tissue.","Since mucosal surfaces are the port of entry of the majority of the infectious agents (Sabin, A.","B., Vaccination at the portal of entry of infectious agents.","Dev Biol Stand 33:3-9, 1976) it is important to the health of an animal to have developed a strong protective antibody and cell-mediated immune response at the portal of entry.","This is best done with an adjuvant and delivery system that targets vaccine antigens to either the mucous membranes of the oral cavity, gut, nose, rectum, or vagina.","Because this is not commonly done with an injectable vaccine, it would be advantageous to have a vaccine adjuvant delivery composition that would adsorb the vaccine onto the mucosal surface, and then, following absorption, be brought in contact with mucosal-associated lymphoid tissue.","For example, oral administration of a vaccine against a gut pathogen may engender a stronger immune response against such pathogens by eliciting the production of secretory immunoglobulin A antibodies at the mucosal site.","This happens when the vaccine is presented to the gut-associated lymphoid tissue (O'Hagen, D, Oral Delivery of Vaccines: Formulation and Clinical Pharmacokinetic Considerations 1992, Clin.","Pharmacokinet.","22 (1): 1-10).","Likewise, administration of vaccine against an upper respiratory pathogen may be most effective if delivered to the mucosal-associated lymphoid tissue in the oral cavity or nasal passages.","Interestingly, administration of antigens induces a mucosal immune response not only at the site of antigen application, for example the oral mucosa, but also at other mucosal sites such as the nasal mucosal (Mestecky, J I, The Common Mucosal Immune System and Current Strategies for Induction of Immune Responses in External Secretions.","J Clin Immunol.","7 (4): 265-76).","Vaccinating large numbers of animals, such as cattle, swine and poultry, is extremely labor intensive and expensive.","Each individual animal has to be handled at the time of vaccination in order to inject the animal with the vaccine.","Most often the vaccine must be administered to the animal at least twice, and sometimes three or more times.","It would be advantageous in terms of time and expense if the vaccine could be administered, simultaneously, with feed or water to a large number of animals.","Another advantage of targeting the vaccine to mucosal surfaces is that the vaccine can stimulate a protective immune response in the presence of circulating antibody that interferes with parenterally injected vaccines (Periwal, S B, et.","al., Orally administered microencapsulated reovirus can bypass suckled, neutralizing maternal antibody that inhibits active immunization of neonates.","J Virol 1997 (April 71(4): 2844-50)).","Adjuvant systems to enhance an animal's immune response to a vaccine antigen are well known.","Likewise, systems for the delivery of vaccine and drugs to mucosal surfaces are known.","Different methods have been described to protect the vaccine antigen and drugs from degradation by stomach acid and digestive enzymes and to adsorb the antigen to the mucosal surface.","Often these adjuvants and delivery systems include mixing the antigen with one or more components.","Exemplary adjuvants include the following: U.S. Pat.","No.","4,917,892, Speaker et al, issued Apr.","17, 1990, describes a topical delivery system comprising a viscous carrier containing a dissolved or dispersed active agent and active agent microencapsulated within a semi permeable anisotropic salt film which is the emulsion reaction product of a) a partially lipophilic, partially hydrophilic, polyfunctional Lewis acid or salt thereof in aqueous medium, such as carboxymethylcellulose, an alkali metal salt of polyacrylic acid or cross linked polyacrylic acid/polyoxyethylene, with b) a Lewis base or salt thereof in a water-immiscible, slightly polar organic solvent for the base, such as benzalkonium chloride, and piperidine.","U.S. Pat.","No.","5,132,117, Speaker et al., issued Jul.","21, 1992, discloses a microcapsule with an aqueous core, capsular, ionic stabilized anisotropic Lewis salt membrane formed from the interfacial reaction product of an emulsion of an aqueous solution of a water-soluble, hydrophilic polymeric Lewis acid or salt thereof with a non-aqueous solution of a lipophilic Lewis base or salt thereof.","The Lewis base may be stearylamine, piperidine, or benzalkonium chloride and the Lewis acid may be carboxymethylcellulose, polyacrylic acid, or polyacrylic acid/polyoxyethylene copolymer, for example.","U.S. Pat.","No.","4,740,365, Yukimatsu et al., issued Apr.","26, 1988 describes a sustained-release preparation applicable to mucous membranes in the oral cavity.","The preparation consists of an active ingredient in a mixture of a polymer component (A) comprising one or more polymers selected from polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, alginic acid or a salt thereof, and an alternating copolymer of maleic anhydride and methyl vinyl ether and a polymer component (B) comprising one or more polymers selected from polyacrylic acid and a salt thereof.","Polymer component (A) and (B) are in a ratio of 95:5 to 5:95 by weight.","The preparation is layered with the active ingredient and may have optional conventional carriers and additives.","U.S. Pat.","No.","5,451,411, Gombotz et al., issued Sep. 19, 1995, describes a delivery system for a cationic therapeutic agent whereupon alginate has been cross-linked in the presence of the therapeutic agent and polyacrylic acid to obtain a sustained release composition for oral delivery.","U.S. Pat.","No.","5,352,448, Bowersock et al., issued Oct. 4, 1994, describes an oral vaccine formulation comprising an enzymatically degradable antigen in a hydrogel matrix for stimulation of an immune response in gut-associated lymphoid tissues.","The hydrogel pellets are preferably synthesized by polymerizing methacrylic acid, in the presence of methylene bis-acrylamide and ammonium persulfate and sodium bisulfite.","U.S. Pat.","No.","5,674,495, Bowersock et al., issued Oct. 7, 1997, describes a vaccine composition for oral administration comprising an alginate gel in the form of discrete particles.","The alginate gel may contain a polymer coating such a poly-1-lysine to enhance stability and to add a positive charge to the surface.","U.S. Pat.","No.","4,944,942, Brown et al., issued Jul.","31, 1990, describes an intranasal vaccine for horses, which may comprise polyacrylic acid cross linked polyallyl sucrose combined with polyoxyethylene sorbitan mono-oleate and sorbitan monolaurate, preferably at 7.5 to 15 volume percent based on the total volume of the formulation, as an adjuvant.","U.S. Pat.","No.","5,500,161, Andrianov et al., issued Mar.","19, 1996, describes a method for the preparation of microparticles, and the product thereof, that includes dispersing a substantially water insoluble non-ionic or ionic polymer in a aqueous solution in which the substance to be delivered is also dissolved, dispersed or suspended, and then coagulating the polymer together with the substance by impact forces to form a microparticle.","Alternatively, the microparticle is formed by coagulation of an aqueous polymeric dispersion through the use of electrolytes, pH changes, organic solvents in low concentrations, or temperature changes to form polymer matrices encapsulating biological materials.","U.S. Pat.","No.","6,015,576, See et al., issued Jan. 18, 2000, describes a method that comprises orally administering lyophilized multilamellar liposomes containing the antigen wherein the liposome preparation is contained in a pill form or within an enterically coated capsule.","Such an enteric coating may be composed of acrylic polymers and copolymers.","U.S. Pat.","No.","5,811,128, Tice et al., issued Sep. 22, 1998, describes a method, and compositions for delivering a bioactive agent to an animal entailing the steps of encapsulating effective amounts of the agent in a biocompatible excipient to form microcapsules having a size less than approximately ten micrometers and administering effective amounts of the microcapsules to the animal.","A pulsatile response is obtained, as well as mucosal and systemic immunity.","The biocompatible excipient is selected from the group consisting of poly (DL-lactide-co-glycolide), poly (lactide), poly (glycolide), copolyoxalates, polycaprolactone, polyorthoesters and poly (beta-hydroxybutyric acid), polyanhydrides and mixtures thereof.","U.S. Pat.","No.","5,565,209, Rijke, issued Oct. 15, 1996, describes oil-free vaccines comprising polyoxypropylene-polyoxyethylene polyols and an acrylic acid polymer as adjuvant constituents for injectable vaccines.","U.S. Pat.","No.","5,084,269, Kullenberg, issued Jan. 28, 1992, describes an adjuvant, comprised of lecithin in combination with a carrier which may be selected from the group consisting of non-edible oil such as mineral oil and edible triglyceride oils such as soybean oil, for an injectable vaccine.","U.S. Pat.","No.","5,026,543, Rijke, issued Jun.","25, 1991, discloses oil-free vaccines which contain polyoxypropylene-polyoxyethylene polyols as well as an acrylic acid polymer as adjuvanting constituents.","U.S. Pat.","No.","5,451,411, Gombotz et al, issued Sep. 19, 1995, discloses alginate beads as a site specific oral delivery system for cationic therapeutic agents designed to target the agents to the luminal side of the small intestine.","Enhanced bioactivity of therapeutic agents released from the alginate is attributed to the ability of polyacrylic acid to shield the agents from interaction with lower molecular weight fragments of acid treated alginate.","U.S. Pat.","No.","5,567,433, Collins, issued Oct. 22, 1996, discloses a method of producing liposomes useful for encapsulating and delivering a wide variety of biologically active materials.","The method involves the formation of a liposome dispersion in the absence of an organic solvent or detergent, one or several cycles of freezing and thawing, and dehydration to form a lipid powder.","The powder is hydrated in the presence of a biologically active material to encapsulate it in the liposomes.","U.S. Pat.","No.","5,091,188, Haynes, issued Feb. 25, 1992, discloses water-insoluble drugs rendered injectable by formulation as aqueous suspensions of phospholipid-coated microcrystals."],["<SOH> SUMMARY <EOH>The present invention concerns an adjuvant composition that includes lecithin and a polymer that is preferably an acrylic polymer or copolymer.","An exemplary acrylic polymer is a polyacrylic acid polymer.","Any lecithin is contemplated herein, including individual phospholipid components of lecithin or any combination thereof.","In some embodiments, the present invention also concerns lecithin and polymer adjuvant compositions that include one or more additives that facilitate an immune response, including glycosides, sterols, ISCOMS, muramyl dipeptide and analogues, pluronic polyols, trehalose dimycolate, amine containing compounds, cytokines, calcium and lipopolysaccharide derivatives.","Exemplary additives are glycosides and sterols, where the glycoside can be Quil A and the sterol can be cholesterol.","The present invention also includes an adjuvant composition that consists of only a lecithin and polymer, and does not include additional lipid components.","Typical polymers are acrylic polymer or copolymer.","In one particular embodiment the adjuvant consists of lecithin and polyacrylic acid polymer.","The present invention also includes an adjuvant composition that consists of a lecithin and polymer adjuvant composition in combination with one or more glycosides and/or one or more sterols.","In some embodiments the adjuvant composition consists of lecithin, polymer, a glycoside and a sterol, where the glycoside can be a saponin or any fraction thereof and the sterol can be, for example, cholesterol.","In some embodiments the polymer is an acrylic polymer or copolymer, for example, polyacrylic acid polymer.","In general, the lecithin and polymer adjuvants herein form a matrix or net-like structure which is effective in trapping or encapsulating vaccine antigen.","In some cases, the lecithin and polymer adjuvant combination form an “oil-free” net-like structure, being composed predominately (and in some cases entirely) by phospholipids and acrylic polymer.","In other cases, the lecithin and polymer adjuvant includes additives directed toward further facilitating the adjuvant's capacity to elicit an immune response.","The strong mucoadhesive and adsorptive properties of the polymer and lecithin combination enhances the adsorption of vaccine antigen onto mucosal surfaces.","Further, the lecithin composition enhances absorption (Swenson, E S and W J Curatolo, ©Means to Enhance Penetration (2) Intestinal permeability enhancement for proteins, peptides and other polar drugs: mechanisms and potential toxicity.","Advanced Drug Delivery Reviews.","1992.8:39-92) that helps bring the antigen in contact with the underlying lymphoid tissue.","Embodiments herein provide a significant improvement over conventional vaccines for delivery of an antigen to a mucosal surface, particularly where the adjuvant does not include the significant proportion or ratio of polymer, as shown in the inventive embodiments herein.","The adjuvant compositions of this invention make it possible to vaccinate via a mucosal surface, such as oral cavity, gut, nasal, rectal, or vaginal surfaces.","The vaccine may be administered by pill or tablet form, a paste form or in fluid form using a dropper or needleless syringe.","This adjuvant composition allows a method of vaccination via food and/or water.","In addition, the adjuvant compositions herein facilitate robust mucosal immunity, an advancement over conventional administration techniques for a number of antigens.","In an alternative embodiment the composition can be used traditionally as an injectable.","Thus, there is provided a method for preparing an adjuvant composition comprising: hydrating lecithin and a polymer in saline or water; and mixing the lecithin and polymer to form an adjuvant.","In some embodiments, the lecithin and the polymer can be mixed by placing the lecithin and the polymer in a blender.","Advantageously, the lecithin and the polymer can be mixed in the presence of surfactants.","In some instances the lecithin and polymer are mixed in the presence of other additives, for example: a glycoside and/or sterol.","In some embodiments, the method further includes the step of microwaving or autoclaving the adjuvant.","In some embodiments, the method further includes the step of not filtering the adjuvant.","In one embodiment, from about 0.001-10% by weight dry lecithin and from about 0.001-10% by weight polymer are hydrated.","In some implementations the polymer is also dry and the lecithin and polymer are mixed dry prior to hydration.","In this implementation, the method further includes the step of adding an antigen.","Advantageously, the antigen is added during the hydration step.","In another advantageous embodiment, the antigen is added to the adjuvant.","The lecithin and the polymer can be mixed in the presence of an oil.","Adjuvants of the invention can be mixed by placing the lecithin and the polymer in a microfluidizer.","Alternative implementations include adding a calcium based compound to the adjuvants described herein where a DNA based antigen is implemented in the vaccine.","Further features and advantages of the present invention will be set forth in, or apparent from, the detailed description which follows."],["This application is a Continuation of U.S. patent application Ser.","No.","14/385,144, entitled “Adjuvant and Vaccine Compositions,” filed Sep. 12, 2014, which is a 371 of International PCT Application No.","PCT/US2013/030515, filed Mar.","12, 2013, entitled “Adjuvant and Vaccine Compositions,” and claims priority under 35 U.S.C.","119(e) to U.S.","Provisional Patent Application Ser.","No.","61/609,783, entitled “Adjuvant and Vaccine Compositions,” filed Mar.","12, 2012, the disclosures of which are hereby incorporated by reference in their entirety.","FIELD Provided herein are compositions and methods for preparing and delivering vaccine to a patient or animal in need thereof and in particular, to compositions and methods for preparing novel adjuvant compositions and delivering vaccines that include these novel adjuvant compositions to a patient or animal in need thereof.","BACKGROUND Mucosal delivery of vaccines has been underutilized because of the problems associated with effectively delivering the vaccine antigens to the mucosal surface and to the underlying mucosal lymphoid tissue.","Since mucosal surfaces are the port of entry of the majority of the infectious agents (Sabin, A.","B., Vaccination at the portal of entry of infectious agents.","Dev Biol Stand 33:3-9, 1976) it is important to the health of an animal to have developed a strong protective antibody and cell-mediated immune response at the portal of entry.","This is best done with an adjuvant and delivery system that targets vaccine antigens to either the mucous membranes of the oral cavity, gut, nose, rectum, or vagina.","Because this is not commonly done with an injectable vaccine, it would be advantageous to have a vaccine adjuvant delivery composition that would adsorb the vaccine onto the mucosal surface, and then, following absorption, be brought in contact with mucosal-associated lymphoid tissue.","For example, oral administration of a vaccine against a gut pathogen may engender a stronger immune response against such pathogens by eliciting the production of secretory immunoglobulin A antibodies at the mucosal site.","This happens when the vaccine is presented to the gut-associated lymphoid tissue (O'Hagen, D, Oral Delivery of Vaccines: Formulation and Clinical Pharmacokinetic Considerations 1992, Clin.","Pharmacokinet.","22 (1): 1-10).","Likewise, administration of vaccine against an upper respiratory pathogen may be most effective if delivered to the mucosal-associated lymphoid tissue in the oral cavity or nasal passages.","Interestingly, administration of antigens induces a mucosal immune response not only at the site of antigen application, for example the oral mucosa, but also at other mucosal sites such as the nasal mucosal (Mestecky, J I, The Common Mucosal Immune System and Current Strategies for Induction of Immune Responses in External Secretions.","J Clin Immunol.","7 (4): 265-76).","Vaccinating large numbers of animals, such as cattle, swine and poultry, is extremely labor intensive and expensive.","Each individual animal has to be handled at the time of vaccination in order to inject the animal with the vaccine.","Most often the vaccine must be administered to the animal at least twice, and sometimes three or more times.","It would be advantageous in terms of time and expense if the vaccine could be administered, simultaneously, with feed or water to a large number of animals.","Another advantage of targeting the vaccine to mucosal surfaces is that the vaccine can stimulate a protective immune response in the presence of circulating antibody that interferes with parenterally injected vaccines (Periwal, S B, et.","al., Orally administered microencapsulated reovirus can bypass suckled, neutralizing maternal antibody that inhibits active immunization of neonates.","J Virol 1997 (April 71(4): 2844-50)).","Adjuvant systems to enhance an animal's immune response to a vaccine antigen are well known.","Likewise, systems for the delivery of vaccine and drugs to mucosal surfaces are known.","Different methods have been described to protect the vaccine antigen and drugs from degradation by stomach acid and digestive enzymes and to adsorb the antigen to the mucosal surface.","Often these adjuvants and delivery systems include mixing the antigen with one or more components.","Exemplary adjuvants include the following: U.S. Pat.","No.","4,917,892, Speaker et al, issued Apr.","17, 1990, describes a topical delivery system comprising a viscous carrier containing a dissolved or dispersed active agent and active agent microencapsulated within a semi permeable anisotropic salt film which is the emulsion reaction product of a) a partially lipophilic, partially hydrophilic, polyfunctional Lewis acid or salt thereof in aqueous medium, such as carboxymethylcellulose, an alkali metal salt of polyacrylic acid or cross linked polyacrylic acid/polyoxyethylene, with b) a Lewis base or salt thereof in a water-immiscible, slightly polar organic solvent for the base, such as benzalkonium chloride, and piperidine.","U.S. Pat.","No.","5,132,117, Speaker et al., issued Jul.","21, 1992, discloses a microcapsule with an aqueous core, capsular, ionic stabilized anisotropic Lewis salt membrane formed from the interfacial reaction product of an emulsion of an aqueous solution of a water-soluble, hydrophilic polymeric Lewis acid or salt thereof with a non-aqueous solution of a lipophilic Lewis base or salt thereof.","The Lewis base may be stearylamine, piperidine, or benzalkonium chloride and the Lewis acid may be carboxymethylcellulose, polyacrylic acid, or polyacrylic acid/polyoxyethylene copolymer, for example.","U.S. Pat.","No.","4,740,365, Yukimatsu et al., issued Apr.","26, 1988 describes a sustained-release preparation applicable to mucous membranes in the oral cavity.","The preparation consists of an active ingredient in a mixture of a polymer component (A) comprising one or more polymers selected from polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, alginic acid or a salt thereof, and an alternating copolymer of maleic anhydride and methyl vinyl ether and a polymer component (B) comprising one or more polymers selected from polyacrylic acid and a salt thereof.","Polymer component (A) and (B) are in a ratio of 95:5 to 5:95 by weight.","The preparation is layered with the active ingredient and may have optional conventional carriers and additives.","U.S. Pat.","No.","5,451,411, Gombotz et al., issued Sep. 19, 1995, describes a delivery system for a cationic therapeutic agent whereupon alginate has been cross-linked in the presence of the therapeutic agent and polyacrylic acid to obtain a sustained release composition for oral delivery.","U.S. Pat.","No.","5,352,448, Bowersock et al., issued Oct. 4, 1994, describes an oral vaccine formulation comprising an enzymatically degradable antigen in a hydrogel matrix for stimulation of an immune response in gut-associated lymphoid tissues.","The hydrogel pellets are preferably synthesized by polymerizing methacrylic acid, in the presence of methylene bis-acrylamide and ammonium persulfate and sodium bisulfite.","U.S. Pat.","No.","5,674,495, Bowersock et al., issued Oct. 7, 1997, describes a vaccine composition for oral administration comprising an alginate gel in the form of discrete particles.","The alginate gel may contain a polymer coating such a poly-1-lysine to enhance stability and to add a positive charge to the surface.","U.S. Pat.","No.","4,944,942, Brown et al., issued Jul.","31, 1990, describes an intranasal vaccine for horses, which may comprise polyacrylic acid cross linked polyallyl sucrose combined with polyoxyethylene sorbitan mono-oleate and sorbitan monolaurate, preferably at 7.5 to 15 volume percent based on the total volume of the formulation, as an adjuvant.","U.S. Pat.","No.","5,500,161, Andrianov et al., issued Mar.","19, 1996, describes a method for the preparation of microparticles, and the product thereof, that includes dispersing a substantially water insoluble non-ionic or ionic polymer in a aqueous solution in which the substance to be delivered is also dissolved, dispersed or suspended, and then coagulating the polymer together with the substance by impact forces to form a microparticle.","Alternatively, the microparticle is formed by coagulation of an aqueous polymeric dispersion through the use of electrolytes, pH changes, organic solvents in low concentrations, or temperature changes to form polymer matrices encapsulating biological materials.","U.S. Pat.","No.","6,015,576, See et al., issued Jan. 18, 2000, describes a method that comprises orally administering lyophilized multilamellar liposomes containing the antigen wherein the liposome preparation is contained in a pill form or within an enterically coated capsule.","Such an enteric coating may be composed of acrylic polymers and copolymers.","U.S. Pat.","No.","5,811,128, Tice et al., issued Sep. 22, 1998, describes a method, and compositions for delivering a bioactive agent to an animal entailing the steps of encapsulating effective amounts of the agent in a biocompatible excipient to form microcapsules having a size less than approximately ten micrometers and administering effective amounts of the microcapsules to the animal.","A pulsatile response is obtained, as well as mucosal and systemic immunity.","The biocompatible excipient is selected from the group consisting of poly (DL-lactide-co-glycolide), poly (lactide), poly (glycolide), copolyoxalates, polycaprolactone, polyorthoesters and poly (beta-hydroxybutyric acid), polyanhydrides and mixtures thereof.","U.S. Pat.","No.","5,565,209, Rijke, issued Oct. 15, 1996, describes oil-free vaccines comprising polyoxypropylene-polyoxyethylene polyols and an acrylic acid polymer as adjuvant constituents for injectable vaccines.","U.S. Pat.","No.","5,084,269, Kullenberg, issued Jan. 28, 1992, describes an adjuvant, comprised of lecithin in combination with a carrier which may be selected from the group consisting of non-edible oil such as mineral oil and edible triglyceride oils such as soybean oil, for an injectable vaccine.","U.S. Pat.","No.","5,026,543, Rijke, issued Jun.","25, 1991, discloses oil-free vaccines which contain polyoxypropylene-polyoxyethylene polyols as well as an acrylic acid polymer as adjuvanting constituents.","U.S. Pat.","No.","5,451,411, Gombotz et al, issued Sep. 19, 1995, discloses alginate beads as a site specific oral delivery system for cationic therapeutic agents designed to target the agents to the luminal side of the small intestine.","Enhanced bioactivity of therapeutic agents released from the alginate is attributed to the ability of polyacrylic acid to shield the agents from interaction with lower molecular weight fragments of acid treated alginate.","U.S. Pat.","No.","5,567,433, Collins, issued Oct. 22, 1996, discloses a method of producing liposomes useful for encapsulating and delivering a wide variety of biologically active materials.","The method involves the formation of a liposome dispersion in the absence of an organic solvent or detergent, one or several cycles of freezing and thawing, and dehydration to form a lipid powder.","The powder is hydrated in the presence of a biologically active material to encapsulate it in the liposomes.","U.S. Pat.","No.","5,091,188, Haynes, issued Feb. 25, 1992, discloses water-insoluble drugs rendered injectable by formulation as aqueous suspensions of phospholipid-coated microcrystals.","SUMMARY The present invention concerns an adjuvant composition that includes lecithin and a polymer that is preferably an acrylic polymer or copolymer.","An exemplary acrylic polymer is a polyacrylic acid polymer.","Any lecithin is contemplated herein, including individual phospholipid components of lecithin or any combination thereof.","In some embodiments, the present invention also concerns lecithin and polymer adjuvant compositions that include one or more additives that facilitate an immune response, including glycosides, sterols, ISCOMS, muramyl dipeptide and analogues, pluronic polyols, trehalose dimycolate, amine containing compounds, cytokines, calcium and lipopolysaccharide derivatives.","Exemplary additives are glycosides and sterols, where the glycoside can be Quil A and the sterol can be cholesterol.","The present invention also includes an adjuvant composition that consists of only a lecithin and polymer, and does not include additional lipid components.","Typical polymers are acrylic polymer or copolymer.","In one particular embodiment the adjuvant consists of lecithin and polyacrylic acid polymer.","The present invention also includes an adjuvant composition that consists of a lecithin and polymer adjuvant composition in combination with one or more glycosides and/or one or more sterols.","In some embodiments the adjuvant composition consists of lecithin, polymer, a glycoside and a sterol, where the glycoside can be a saponin or any fraction thereof and the sterol can be, for example, cholesterol.","In some embodiments the polymer is an acrylic polymer or copolymer, for example, polyacrylic acid polymer.","In general, the lecithin and polymer adjuvants herein form a matrix or net-like structure which is effective in trapping or encapsulating vaccine antigen.","In some cases, the lecithin and polymer adjuvant combination form an “oil-free” net-like structure, being composed predominately (and in some cases entirely) by phospholipids and acrylic polymer.","In other cases, the lecithin and polymer adjuvant includes additives directed toward further facilitating the adjuvant's capacity to elicit an immune response.","The strong mucoadhesive and adsorptive properties of the polymer and lecithin combination enhances the adsorption of vaccine antigen onto mucosal surfaces.","Further, the lecithin composition enhances absorption (Swenson, E S and W J Curatolo, ©Means to Enhance Penetration (2) Intestinal permeability enhancement for proteins, peptides and other polar drugs: mechanisms and potential toxicity.","Advanced Drug Delivery Reviews.","1992.8:39-92) that helps bring the antigen in contact with the underlying lymphoid tissue.","Embodiments herein provide a significant improvement over conventional vaccines for delivery of an antigen to a mucosal surface, particularly where the adjuvant does not include the significant proportion or ratio of polymer, as shown in the inventive embodiments herein.","The adjuvant compositions of this invention make it possible to vaccinate via a mucosal surface, such as oral cavity, gut, nasal, rectal, or vaginal surfaces.","The vaccine may be administered by pill or tablet form, a paste form or in fluid form using a dropper or needleless syringe.","This adjuvant composition allows a method of vaccination via food and/or water.","In addition, the adjuvant compositions herein facilitate robust mucosal immunity, an advancement over conventional administration techniques for a number of antigens.","In an alternative embodiment the composition can be used traditionally as an injectable.","Thus, there is provided a method for preparing an adjuvant composition comprising: hydrating lecithin and a polymer in saline or water; and mixing the lecithin and polymer to form an adjuvant.","In some embodiments, the lecithin and the polymer can be mixed by placing the lecithin and the polymer in a blender.","Advantageously, the lecithin and the polymer can be mixed in the presence of surfactants.","In some instances the lecithin and polymer are mixed in the presence of other additives, for example: a glycoside and/or sterol.","In some embodiments, the method further includes the step of microwaving or autoclaving the adjuvant.","In some embodiments, the method further includes the step of not filtering the adjuvant.","In one embodiment, from about 0.001-10% by weight dry lecithin and from about 0.001-10% by weight polymer are hydrated.","In some implementations the polymer is also dry and the lecithin and polymer are mixed dry prior to hydration.","In this implementation, the method further includes the step of adding an antigen.","Advantageously, the antigen is added during the hydration step.","In another advantageous embodiment, the antigen is added to the adjuvant.","The lecithin and the polymer can be mixed in the presence of an oil.","Adjuvants of the invention can be mixed by placing the lecithin and the polymer in a microfluidizer.","Alternative implementations include adding a calcium based compound to the adjuvants described herein where a DNA based antigen is implemented in the vaccine.","Further features and advantages of the present invention will be set forth in, or apparent from, the detailed description which follows.","BRIEF DESCRIPTION OF THE FIGURES FIG.","1 is a bar graph showing mean HAI titer for various antigen concentrations and adjuvants.","FIG.","2A and FIG.","2B are micrographs at 30,000× magnification of an embodiment adjuvant composition of the present invention (2A) and a competitor's adjuvant composition (2B).","FIG.","3 shows data from HAI GMT serum titers for various adjuvant embodiments of the present invention.","FIG.","4 shows the results of Adenovirus vector-based FMD vaccine alone or in combination with adjuvant embodiments described herein.","FIG.","5, FIG.","6 and FIG.","7 are cell viability bar graphs having a starting cell density of 1×106/ml, percent reduction of Alamar Blue at 42 hrs (5), 50 hrs (6) and 68 hrs (7) from treatment.","FIG.","8, FIG.","9 and FIG.","10 are cell viability bar graphs having a starting cell density of 10×106/ml, percent reduction of Alamar Blue at 42 hrs (8), 50 hrs (9) and 68 hrs (10) from treatment.","FIG.","11 and FIG.","12 show Log 10 TCID50 of adjuvant options with Ad5bIFNalpha-adjuvant mixtures after incubation (11) and Log 10 TCID50 of adjuvant options with Ad501-adjuvant mixtures after incubation) (12).","FIG.","13A and FIG.","13B are graphs showing group average of IL-4 expression at 24 and 48 hours normalized to ARBP.","FIG.","14 is a graph showing average IL-4 expression at 48 hours normalized to HPRT.","FIGS.","15A and 15B are graphs showing a group average of IFN-Y expression at 25 and 48 hours normalized to ARBP or HPRT.","FIGS.","16A and 16B are graphs showing a group average of TNF-alpha expression at 24 and 48 hours normalized to HPRT.","FIG.","17 is a graph showing average IL-4 expression at 24 and 48 hours treatment with LAP+OVA or LAP/QAC+OVA normalized to HPRT.","DETAILED DESCRIPTION The present invention provides a vaccine adjuvant which, when admixed with an antigen or hapten and administered into a human or animal, will induce a more intense immune response to the antigen than when the antigen is administered alone.","The present invention also provides vaccines comprising an antigen or group of antigens and a novel adjuvant herein described which comprises a combination of lecithin and a polymer.","As will appear, the present invention also specifically provides methods of making and using the foregoing adjuvants and vaccines.","Such adjuvants offer the advantage of allowing application of a vaccine directly to a mucosal surface.","In doing so, the vaccine stimulates a protective immune response which helps prevent interference from circulating maternal antibodies that may be present in a newborn or infant, for example.","Direct administration of a vaccine herein to a mucosal surface, i.e., mucosal vaccination, provides mucosal immunity and systemic immunity, an advantage over most systemic only based vaccines.","Unlike other vaccines developed for mucosal vaccination, embodiments of the present invention provide unexpected improvement for immunogenic response by improving the vaccine's contact time on the mucosal surface.","“Antigen” is herein defined as a compound which, when introduced into an animal or a human, will result in the formation of antibodies and cell-mediated immunity.","“Adjuvant” is herein defined as a compound or compounds that, when used in combination with specific vaccine antigens in formulations, augment or otherwise alter or modify the resultant immune responses.","“Vaccine” is herein defined as a composition of antigenic moieties, usually consisting of modified-live (attenuated) or inactivated infectious agents, or some part of the infectious agents, that is administered, most often with an adjuvant, into the body to produce active immunity.","The antigen can be any desired antigen falling within the definition set forth above.","Antigens are commercially available or one of skill in the art is capable of producing them.","The antigenic moiety making up the vaccine can be either a modified-live or killed microorganism, or a natural product purified from a microorganism or other cell including, but not limited to, tumor cells, a synthetic product, a genetically engineered protein, peptide, polysaccharide or similar product, or an allergen.","The antigenic moiety can also be a subunit of a protein, peptide, polysaccharide or similar product.","The antigen may also be the genetic antigens, i.e., the DNA or RNA that engenders an immune response.","Representative of the antigens that can be used according to the present invention include, but are not limited to, natural, recombinant or synthetic products derived from viruses, bacteria, fungi, parasites and other infectious agents in addition to autoimmune diseases, hormones, or tumor antigens which might be used in prophylactic or therapeutic vaccines and allergens.","The viral or bacterial products can be components which the organism produced by enzymatic cleavage or can be components of the organism that were produced by recombinant DNA techniques that are well known to those of ordinary skill in the art.","Because of the nature of the invention and its mode of delivery it is very conceivable that the invention would also function as a delivery system for drugs, such as hormones, antibiotics and antivirals.","The lecithin can be any lecithin or, for instance, lecithin lipoidal material, such as phospholipids, lysophospholipids, glycolipids and neutral lipids that comprise the typical composition of lecithin.","Lecithins are molecules that, when completely hydrolyzed, yield two molecules of fatty acid, and one molecule each of glycerol, phosphoric acid, and a basic nitrogenous compound, such as choline.","The fatty acids obtained from lecithins on hydrolysis are usually, but not limited to, oleic, palmitic, and stearic acids.","The phosphoric acid may be attached to the glycerol in either an α- or the β-position, forming α-glycerophosphoric acid or β-glycerophosphoric acid, respectively, and producing the corresponding series of lecithins which are known as α- and β-lecithins.","Commercial lecithin is obtained by extraction processes from egg yolk, brain tissue, or soybeans.","Ovolecithin (vitelin) from eggs and vegilecithin from soybeans, as well as purified lecithin from calf s brains have been used as emulsifiers, antioxidants, and stabilizers in foods and pharmaceutical preparations.","Commercial lecithin may be obtained from a variety of sources.","One of ordinary skill in the art would be able to determine an appropriate lecithin for a desired application.","The polymer is preferably an acrylic polymer, which is any polymer or copolymer that contains an acrylic moiety.","Examples of suitable acrylic polymers include, but are not limited to polyacrylic acid, methacrylic acid, methacrylate, acrylamide, acrylate, acryinitrile, and alkyl-esters of poly acrylic acid.","Examples of acrylic copolymers are poly (acrylamide-co butyl, methacrylate), acrylic-methacrylic acid, acrylic-acrylamide and poly (methacrylate).","Commercial polymers may be obtained from a variety of sources.","In some embodiments, acrylic polymers may benefit from the inclusion of a cross linker, such as a polyalkenyl polyether, an alkyl sucrose, or an allyl ether of penta-erythirtol, for example, which is effective in binding the polymers.","An exemplary acrylic polymer for use in this invention is polyacrylic acid with or without a polyalkenyl polyether cross linker.","One of ordinary skill in the art would be able to determine an appropriate acrylic polymer for a desired application.","Likewise, one of ordinary skill in the art would be able to determine an appropriate cross linker for a given acrylic polymer.","Examples of non-acrylic polymers that are suitable for use herein are polyvinyl acetate phthalate, cellulose acetate phthalate, methylcellulose, polyethylene glycol, polyvinyl alcohol, and polyoxyethylene.","The method of manufacturing the adjuvant of this invention first involves hydrating the lecithin and polymer by suspending from about 0.0001-10% by weight/volume dry lecithin and from about 0.0001-10% by weight polymer in saline or water.","In some cases the polymer is also dry prior to suspension in saline or water.","The preferred concentrations of lecithin and polymer are 0.001-1.0% each by weight/volume.","The two components may be mixed together using conventional methods, such as, for example, a Waring Blender, emulsification equipment or a microfluidizer.","Surfactants (emulsifiers) may be added to aid in the mixing or emulsification of the lecithin and polymer.","Suitable synthetic detergents are well known to those of ordinary skill in the art.","Examples of appropriate surfactants include polyoxyethylene sorbitan monooleate, sorbitan monolaurate, sodium stearate, non-ionic ether-linked surfactants such as Laureth®4 and Laureth®23, alkyl sulfate surfactants, alkyl alkoxylated sulfate surfactants, alkylbenzenesulphonates, alkanesulphonates, olefinsulphonates, sulphonated polycarboxylic acids, alkyl glycerol sulfonates, fatty acyl glycerol sulfonates, fatty oleyl glycerol sulfates, alkyl phenol ethylene oxide ether sulfates, paraffin sulfonates, alkyl phosphates, isothionates such as the acyl isothionates, N-acyl taurates, fatty acid amides of methyl tauride, alkyl succinamates and sulfosuccinates, mono- and diesters of sulfosuccinate, N-acyl sarcosinates, sulfates of alkylpolysaccharides, branched primary alkyl sulfates, alkyl polyethoxy carboxylates, and fatty acids esterified with isethionic acid and neutralized with sodium hydroxide.","Further examples are given in Surface Active Agents and Detergents (Vol.","I and II by Schwartz, Perry and Berch), the disclosure of which is expressly incorporated herein by reference.","Suitable nonionic detergent surfactants are generally disclosed in U.S. Pat.","No.","3,929,678, Laughlin et al., issued Dec. 30, 1975, at column 13, line 14 through column 16, line 6, incorporated herein by reference.","If included, the emulsifier should be added in a concentration ranging from about 0.001-0.05% by volume of the mixture.","Lecithin and polymer embodiments herein may also be used in combination with other additives such as, but not limited to, glycosides such as saponins, fractions of saponins, or synthesized components of saponins, sterols, ISCOMS, muramyl dipeptide and analogues, pluronic polyols, trehalose dimycolate, amine containing compounds, cytokines, calcium and lipopolysaccharide derivatives.","The addition of another additive may aid in the stimulation of an immune response and in particular a mucosal immune response.","If included, additional additives may be present in a concentration of up to about 10% by weight of the composition, for example, less than about 1% by weight of the composition.","In most cases, additives of the invention are included in adjuvant embodiments herein in an amount to cause an induction of an immune response.","In some instances, additives herein provide additional stimulation of TH1 (T helper cell 1), an important mediator in mucosal immunity.","Typical additives for inclusion with lecithin/polymer adjuvants described herein include one or more of a glycoside and/or a sterol.","In some embodiments, the glycosides are saponins, fractions of saponins or synthesized components of saponins.","Exemplary saponins can be derived from plant sources including, but not limited to Quillaja Saponaria Molina, Polygala senega, and Astragalus species.","In one instance the saponin is a triterpensaponin, such as Quil A (a saponin preparation isolated from the South American tree Quillaja Saponaria Molina).","Purified fractions of Quil A include QS7 and QS21 (also known as QA7 and QA21).","Nonetheless, any saponins are contemplated as useful herein.","Preferred sterols are cholesterol, lanosterol, lumisterol, stigmasterol and sitosterol.","In some instances, Quil A is combined with cholesterol and added to adjuvant embodiments described herein.","This particular additive combination provides an unexpected enhancement in immune response over similarly prepared lecithin and polymer adjuvants described herein.","Note that QS7 and/or QS21 can be substituted and/or added to the Quil A.","Typical additives for inclusion with lecithin/polymer adjuvants described herein also include calcium compounds, for example, calcium phosphate, as described in U.S. patent application Ser.","No.","12/125,577, incorporated herein by reference for all purposes.","Calcium additives are most appropriate for DNA virus based antigens, although it is envisioned that other antigen types can be used.","In some instances, calcium compounds can be combined with Quil A and/or cholesterol, and included in a lecithin/polymer based adjuvant.","The invention may also include one or more probiotics.","Probiotics are bacteria or microorganisms that are beneficial to the health of the individual or animal.","Examples of commonly used probiotics include, but are not limited to, various beneficial strains of Lactobacillus, Bifidobacterium, Streptococcus, etc.","If present, each of the organisms should be administered in a concentration ranging from about 103 to 108 CFU each (per vaccination).","In addition to all of the above, as is well understood by those skilled in the art, other minors can be employed to make the composition more pharmaceutically and/or cosmetically elegant.","For example, dyes can be added at very minor levels as can diluents such as alcohol, buffers, stabilizers, wetting agents, dissolving agents, colors, etc.","With the exception of diluents such as alcohols which are used at higher levels, the levels of these minors are generally not more than 0.001% to 1.0% by weight.","If desired, the adjuvant components may be sterilized by autoclaving prior to the hydration step.","It has also been found that autoclaving and/or microwaving the components may improve their suspending ability.","The vaccine antigen may be added after formation of the adjuvant, or at the time of hydration of the adjuvant components.","If in tablet form, the antigen may be mixed with dry components of the adjuvant invention along with other excipients necessary for tablet formation.","Examples of appropriate types of vaccine antigens include killed or attenuated bacterial, viral, parasitic, or subunits of these organisms, or genomic vaccine antigens, for example, DNA.","Applicant believes that the capacity to be autoclaved/microwaved provides a significant benefit over other conventional adjuvants which require filtration.","Initially, structural analysis of embodiments herein before and after autoclaving illustrated that the structure of the autoclaved composition(s) was not significantly affected.","However, the more costly filtration method for sterilizing an adjuvant removes and/or modifies structural aspects of the composition.","As such, the embodiments herein are relatively less costly and avoid structural alterations found in other adjuvant materials that require filtration.","This is an unexpected finding of the present formulations.","The relative concentration of the components, including the antigen, may be determined by testing the formulations in animals starting with a low dose of the formulation and then increasing the dosage while monitoring the immune response.","The following considerations should be made when determining an optimal dose, e.g., breed, age, size and the presence or absence of interfering maternal antibodies.","A concentration of an attenuated viral vaccine will comprise about 103 to 109 TCID50 per animal.","In some embodiments, the amount will be from about 104 to 107 TCID50 per animal.","The concentration of killed antigen or subunit antigen may range from nanogram to milligram quantities of antigen with about 1 microgram to 1 milligram preferred.","When the acrylic polymer and lecithin are combined, a matrix, or net-like structure is formed.","In some instances the net-like structure is “oil free,” i.e., not having additional oils or lipids added to the adjuvant.","The ratio of lecithin to polymer include ratios between 1:1000 and 1000:1.In some embodiments, the ratios of lecithin to polymer include ratios between 1:10 and 10 to 1.The relative proportions of lecithin and acrylic polymer may be found to be important to the efficiency of delivery of different antigens, i.e., bacterial, viral, parasitic or sub-units of these organisms.","The optimum ratio may be determined by the conventional means of testing the different ratios of lecithin to polymer with the desired antigen in animals.","The adjuvant composition can be used for the delivery of vaccine antigens such as whole killed or attenuated virus, bacteria, or parasite vaccine antigens or sub-unit(s) of such organisms to mucosal surfaces, such as oral cavity, gut, nasal, vaginal and rectal surfaces.","Electron microscopic evaluation shows that there exists a physical and/or chemical affinity between lecithin and polymer.","This affinity or association appears as a matrix, or net-like structure.","Without intending to be bound by any particular theory, it is believed that a structure such as this can function as a means of physically trapping or encapsulating vaccine antigen.","Such binding of antigen is further enhanced by the electrical charge and the hydrophilic and hydrophobic properties of lecithin and the acrylic polymers of this invention.","To facilitate this, a polymer of different electrical charge may be selected depending on the anionic or cationic properties of the antigen.","Likewise a polymer and lecithin of different hydrophobicity may be selected depending on the lipophilic or hydrophilic properties of the antigen.","If necessary or desired, the antigen can be coupled to the lecithin-acrylic polymer matrix with a cross-linker such as glutaraldehyde in a concentration of from about 1 to 50 mM, for example, about 15 mM.","Further, the antigen can be coupled using water-soluble carbodiimide in a concentration ranging from about 0.05-0.5 M, for example, about 0.1 M, or a coupling method using a heterofunctional reagent such as N-hydroxysuccinimidyl 3-(2-pyridyldithio) propionate (SPDP) in a concentration ranging from about 0.1-1.0 mM, and preferably about 0.2 mM.","Other appropriate coupling agents include mixed anhydride and bisdiazotized benzidene.","The cross-linker is used to improve the binding affinities of the components of the adjuvant composition, for example, where the components are not electrically attracted to each other.","The strong mucoadhesive and adsorptive properties of the polymer, e.g., acrylic acid and lecithin combination also make it an excellent mechanism to aid in the adsorption of vaccine antigen onto mucosal surfaces.","The adjuvant delivery system's absorption enhancement properties help bring the vaccine antigen in contact with mucosal associated lymphoid tissue.","Thus, an immune response is engendered that will aid in the protection of an animal from infections and/or disease process.","A robust mucosal immune response is critical since most infectious disease-causing organisms gain entry to the animal at mucosal surfaces.","The invention can also be used as an adjuvant for injectable vaccines and provides improvement for facilitating an immune response over other conventional injectable adjuvant materials.","The vaccine comprising the adjuvant is delivered to a mucosal surface by direct application, ingestion through the oral cavity, insertion, injection, and through other conventional means known in the art.","Alternatively, the adjuvant may also be administered as a conventional injectable, which is typically either a liquid solutions or suspension.","When administered in a food or beverage carrier, the adjuvant/vaccine composition of this invention is generally included in the carrier composition in a concentration ranging from about 0.0001-10% by weight/volume (w/v) in case of a beverage carrier and weight/weight (w/w) in case of a food carrier, for example, about 0.01-1.0% w/v or w/w respectively.","When administered in an injectable, the adjuvant/vaccine composition should be present in a concentration ranging from about 0.02-2.0% by weight, for example, about 0.1-0.5% by weight.","The adjuvant/vaccine may also be administered in other conventional solid dosage forms, such as in tablets, capsules, granules, troches, and vaginal or rectal suppositories.","If administered in a solid dosage form, the adjuvant/vaccine composition should constitute between 0.0001-10% by weight of the dosage form, for example, about 0.01-1.0% by weight.","In addition to the active compounds, the pharmaceutical compositions of this invention may contain suitable excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.","Oral dosage forms encompass tablets, capsules, and granules.","Preparations which can be administered rectally include suppositories.","Other dosage forms include suitable solutions for administration parenterally or orally, and compositions which can be administered buccally or sublingually.","The pharmaceutical preparations of the present invention are manufactured in a manner which is itself well known in the art.","For example the pharmaceutical preparations may be made by means of conventional mixing, granulating, dissolving, lyophilizing processes.","The processes to be used will depend ultimately on the physical properties of the active ingredient used.","Suitable excipients are, in particular, fillers such as sugars for example, lactose or sucrose mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch, paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.","If desired, disintegrating agents may be added, such as the above-mentioned starches as well as carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.","Auxiliaries are flow-regulating agents and lubricants, for example, such as silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate and/or polyethylene glycol.","Oral dosage forms may be provided with suitable coatings which, if desired, may be resistant to gastric juices.","For this purpose concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.","In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, dyestuffs and pigments may be added to the tablet coatings, for example, for identification or in order to characterize different combination of compound doses.","Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.","The push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.","In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.","In addition stabilizers may be added.","Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of the active compounds with the suppository base.","Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols, or higher alkanols.","In addition, it is also possible to use gelatin rectal capsules which consist of a combination of the active compounds with a base.","Possible base material includes, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.","Suitable formulations for parenteral administration include aqueous solutions of active compounds in water-soluble or water-dispersible form.","In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered.","Suitable lipophilic solvents or vehicles include fatty oils for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides.","Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, including for example, sodium carboxymethyl cellulose, sorbitol and/or dextran.","Such compositions may also comprise adjuvants such as preserving, wetting, emulsifying, and dispensing agents.","They may also be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents into the compositions.","They can also be manufactured in the form of sterile solid compositions which can be dissolved or suspended in sterile water, saline, or other injectable medium prior to administration.","In addition to administration with conventional carriers, active ingredients may be administered by a variety of specialized delivery drug techniques which are known to those of skill in the art, such as portable infusion pumps.","The lecithin/polymer adjuvant serves multiple functions when it is delivered orally in food and water: 1) it protects the vaccine antigen from degradation by the stomach acid and digestive enzymes; 2) transports the antigen to the mucosal surfaces; 3) facilitates adsorption of the antigen onto the mucosal surfaces; 4) enhances absorption of the antigen; and 5) enhances the immune response to the antigen due to the adjuvant properties of the two components.","In the case of delivery to nasal, oral cavity, vaginal and rectal mucosa, the lecithin/acrylic polymer complex functions as a system to deliver and adsorb the antigen to the mucosal surface.","Once adsorbed onto the mucosal surface and absorbed, an immune response is engendered.","The combination of polymer and lecithin unexpectedly provides an improved vaccine delivery system for vaccine antigens.","It is apparent that the invention is also an improved delivery system for drugs, such as hormones, antibiotics, probiotics and antivirals.","The current invention provides a more simple and efficient method of incorporation of antigen into a delivery system with no, or minimal damage, to vaccine epitopes.","The vaccine formulation can be done at low cost and can be easily commercialized as a feed or water additive or as an oral paste or tablet.","It is to be understood that these formulations also would be effective in delivering antigen onto other mucosal surfaces, such as nasal, rectal and vaginal surfaces, and would be effective as an adjuvant for an injectable vaccine.","In addition, the hydrophobic properties that aid in the adsorption of the adjuvant and vaccine antigen to mucosal surfaces also provides a means of applying to animal feeds, whether it be plant foliage or seeds, both which have a hydrophobic wax surface.","The combination of polymer, lecithin and additives (in particular Quil A and cholesterol) provides an unexpected enhancement of an adjuvant to induce an immune response.","This benefit is present for multiple delivery routes, which includes when the adjuvant is delivered as an injectable.","The composition with which the current invention is concerned differs from the prior art in that it comprises a mixture of lecithin and, in some embodiments, an acrylic polymer or copolymer.","The invention provides certain advantages over other vaccine delivery systems described in the prior art.","It is not prepared under harsh conditions that adversely affect the substance such as the use of organic solvents.","It does not require elevated temperatures to manufacture and does not require a stabilization step.","The invention provides a simpler method of incorporation of antigen with minimal damage to vaccine epitopes.","Using this simpler method of manufacturing results in low cost and ease of commercialization.","The following examples are intended to further illustrate the invention and its preferred embodiments.","They are not intended to limit the invention in any manner.","Example 1 Vaccine Plus Adjuvant Effectiveness An experimental vaccine was made comprising bovine serum albumin Fraction 5 (BSA) as a non-living model antigen, lecithin, and an acrylic acid polymer.","A second vaccine was made comprising only BSA.","The lecithin and acrylic polymer were suspended together in 150 milliliters (ml) phosphate buffered saline (PBS), each at a concentration of 4 milligrams (mg) per milliliter (ml).","The components were first dispersed by stirring with a magnetic stir bar and then mixed further in a Waring Blender using an emulsification head.","The mixture was then autoclaved to sterilize the adjuvant mixture.","Bovine serum albumin was dissolved in PBS at a concentration of 2 mg/ml and filter sterilized.","One part lecithin/acrylic polymer adjuvant was then combined with one part of BSA.","Merthiolate (0.01%) was added as a preservative.","The final concentration of the vaccine components was 2 mg/ml of the lecithin/acrylic polymer and 1 mg/ml of BSA.","CF-1 female mice, approximately 18 grams, from Charles River Laboratories (Willmington, Mich.), were injected subcutaneously in the groin area with 0.1 ml of vaccine (0.1 mg. of BSA/dose) on days 0 and 21.Mice were bled on day 45, 24 days after the second vaccination.","Mice were bled by cutting the brachial artery following euthanasia by cervical dislocation.","Blood serum Immunoglobulin G (IgG) anti-BSA antibody titers were determined by an enzyme linked immunosorbant assay (ELISA).","Results are shown in Table 1.TABLE 1 Results of Antibody Titers Reciprocal of Number of Geometric Adjuvant Group Mice Mean Titer None 8 51,200 Lecithin/Acrylic 8 157,916 Polymer Results show that the adjuvant comprising a combination of lecithin and acrylic polymer does indeed enhance the immune response to an antigen.","Example 2 Comparison of Individual Vaccine Adjuvants Administered Orally Experimental vaccines, for delivery by the oral route, were prepared in PBS.","The vaccines comprised the antigen, BSA Fraction 5, at a concentration of 400 micrograms (μg) per ml.","Vaccine 1 contained no adjuvant only BSA.","Vaccine 2 was comprised of BSA mixed with 3 mg/ml of lecithin.","Vaccine 3 was comprised of BSA mixed with 3 mg/ml of the acrylic polymer.","Vaccine 4 was comprised of BSA mixed with 3 mg/ml of lecithin and 3 mg/ml of acrylic polymer.","Mixing was first done with a laboratory bench top magnetic stir bar and then in a Waring blender using an emulsification head.","Lactobacillus culture was added to all vaccines just prior to vaccination.","The final concentration of Lactobacillus was 0.01 μg/ml of vaccine.","On days 0, 4, 29 and 33 the groups of CF-1 female mice from Charles-River Laboratories and weighing approximately 18 grams, were administered 0.5 ml of vaccine orally by feeding needle.","On day 53, 20 days post fourth vaccination, mice were euthanized and bled by the brachial artery.","End-point anti-BSA serum IgG antibody titers were determined by ELISA.","A 1/100 starting dilution of serum was used due to non-specific background color development at dilutions less than 1/100.Results are recorded in Table 2: TABLE 2 Effect of Adjuvant Composition on the Anti-BSA Antibody Response Reciprocal of No.","of Mice Geometric Adjuvant with Titer >/= Mean of Mice Composition 1/100 (%) with Titers None 3/9 (33) 158 Lecithin 4/6 (67) 141 Acrylic Polymer 6/9 (67) 8,063 Lecithin and Acrylic 6/9 (67) 45,614 Polymer Anti-BSA IgG antibody titers were over five times higher when a combination of lecithin and acrylic polymer was used as adjuvant than when acrylic polymer was used alone and 323 times higher than when lecithin was used alone.","This demonstrates that the combination of lecithin and acrylic polymer is far more effective at delivering the antigen orally to the mucosal surface for uptake by lymphoid tissue than either lecithin or acrylic polymer alone.","Although, not all of the mice showed a serum anti-BSA IgG antibody response the results clearly show a synergistic adjuvant effect of lecithin combined with the acrylic polymer.","However, the mice that did not seroconvert may have had a secretory IgA antibody response.","Indeed, oral vaccination, and mucosal vaccination in general, stimulates IgA secreting cells at mucosal surfaces.","Example 3 Second Test of Lecithin/Polymer Adjuvant by the Oral Route Two vaccines were prepared in PBS that comprised the antigen, BSA Fraction 5, at a concentration of 400 μg per ml.","One vaccine contained no adjuvant only BSA.","The other vaccine was comprised of BSA adjuvanted with 3 mg/ml of lecithin and 3 mg/ml of acrylic polymer.","The vaccine was assembled as described in Example 2.On days 0, 4, 27, and 31 groups of CF-1 female mice from Charles-River Laboratories and weighing approximately 18 grams, were administered 0.5 ml of vaccine orally by feeding needle.","On day 52, 21 days post vaccination, mice were euthanized and bled by the brachial artery.","End-point anti-BSA serum IgG antibody titers were determined by ELISA.","A 1/100 starting dilution of serum was used due to non-specific background color development at dilutions less than 1/100.Results are recorded in Table 3: TABLE 3 Comparative Results of Adjuvant Versus Control Reciprocal of No.","of Mice Geometric Adjuvant with Titer >/= Mean of Mice Composition 1/100 (%) with Titers None 1/12 (8) 100 Lecithin and 9/11 (82) 18,812 Acrylic Polymer This study again demonstrates that the combination of lecithin and acrylic polymer is effective in delivering antigen to oral mucosal surfaces.","In a separate study, 4/10 mice that received this same vaccine had a geometric mean titer of 1/1,345 six weeks after only a single vaccination.","This demonstrates the potential of the adjuvant composition, when once optimized, to engender an immune response of long duration.","Example 4 Administration of Vaccine Intranasally Two experimental vaccines for delivery by the intranasal route were prepared in PBS comprising the antigen, BSA, at a concentration of 500 μg/ml.","One vaccine was comprised of BSA alone.","The second vaccine was comprised of BSA adjuvanted with a combination of 3 mg/ml of lecithin and 3 mg/ml of the acrylic polymer.","The lecithin and acrylic polymer were first mixed with a laboratory bench top magnetic stir bar and then in a Waring blender using an emulsification head.","BSA was then added and mixed again using the emulsification head.","Mice were vaccinated on days 0 and 20.Forty μl containing 20 μg of BSA antigen were placed on the nose while the mouth was held shut.","The vaccine entered the nose when the mouse inhaled.","On day 41, 21 days post second vaccination, the mice were euthanized and bled by cutting the brachial artery.","Anti-BSA antibody titers were determined by ELISA.","The starting dilution of serum was at 1/100 due to non-specific background color development at lower dilutions.","Results are shown in Table 4: TABLE 4 Comparative Results of Adjuvant Versus Control Reciprocal of No.","of Mice Geometric Adjuvant with Titer >/= Mean of Mice Composition 1/100 (%) with Titers None 0/11 (0%) 0 Lecithin and 7/12 (58%) 269 Acrylic Polymer None of the mice (0/11) vaccinated with BSA alone seroconverted.","The BSA antigen alone, when administered intranasally, failed to stimulate a serum antibody response in any of the mice.","In contrast, 7 of 12 mice, or 58%, developed serum anti-BSA IgG antibody titers as high as 1/3200 following intranasal vaccination with BSA in combination with the invention comprised of lecithin and acrylic polymer.","The fact that not all mice seroconverted suggests that not enough, or perhaps none of the vaccine was inhaled by those mice that did not have an antibody titer greater than 1/100.Indeed, some, perhaps most, of the vaccine was observed to run off the nose or was blown off the nose when the mouse exhaled.","Still, the results of this study show that the invention, comprised of lecithin and acrylic polymer, functions effectively as an adjuvant for the intranasal delivery of a vaccine antigen.","Example 5 Use of Adjuvant with Vaccine in Swine The adjuvant invention comprising a combination of 2 mg/ml of lecithin and 2 mg/ml of acrylic polymer was used as a diluent for modified-live pseudorabies virus (ML-PRV) for swine.","This adjuvant diluent and a control diluent consisting of sterile water were used to rehydrate lyophilized (ML-PRV).","The ML-PRV was rehydrated immediately prior to vaccination.","Groups of 10 weaned piglets, 6 weeks of age, were vaccinated on days 0 and 21.Blood serum was collected on days 2, 20, 28, and 48 for serological testing for anti-PRV serum neutralizing antibodies.","The anti-PRV antibody responses of piglets in the different vaccine groups are shown in Table 5.TABLE 5 Results in Pigs Geometric Mean Virus Neutralizing Antibody Titer on Days Post Adjuvant First Vaccination Diluent Day 2 Day 20 Day 28 Day 48 Non-Vaccinated 0 0 0 0 Control Water 0 4 34 21 Lecithin/ 0 6 69 52 Acrylic Polymer This study showed that the invention comprising a lecithin and acrylic polymer combination functions as an adjuvant for a ML-virus vaccine adjuvant, in this case swine ML Pseudorabies vaccine virus.","The virus neutralizing anti-PRV antibody titer to ML-PRV, which by itself is a very good antigen without an adjuvant and is used commercially without an adjuvant, was over twice as high when the lecithin/acrylic polymer was used instead of water.","Example 6 Lecithin and Acrylic Copolymer Adjuvant Supports H1N1 and H3N2 Vaccine Responses Lecithin and acrylic copolymer adjuvant as described and prepared herein was analyzed for its effectiveness at supporting the immunization of swine against H1N1 and H2N2 viral antigens.","Inventive adjuvants herein were compared to a commercially available adjuvant, 5% Amphigen®, to identify the capacity of adjuvants as described herein to support viral antigen based vaccines.","Each adjuvant was combined with H1N1 and H3N2 antigens (derived from a released lyophilized commercial product (FluSure™, Pfizer Animal Group).","Test groups for vaccination included 29 to 35 day old piglets.","Four treatment groups were observed (each group having 15 piglets, except the negative control group which had 5 piglets): T1, 5% Amphigen, positive control; T2, Quil A alone adjuvant; T3, lecithin and acrylic copolymer of the invention, intramuscular; and T4, lecithin and acrylic copolymer of the invention, intranasal.","T5 was a control group that was un-vaccinated.","T1, T2 and T3 received one intramuscular dose on day 0, T4 received one intranasal dose on day 0.Blood samples were obtained from each animal participating in the study on days 0, 21 and 35.Table 6 shows data from H1N1 titer, Table 7 shows data from the H3N2 titer: TABLE 6 Number of Piglets with H1N1 Swine Influenza Titers and Geometric Mean Titers No.","of Piglets With H1N1 H1N1 Geometric Titers/Total Piglets Mean Titers Treat Test Treat.","Day Day Day Day No.","Art Group Day 0 21 35 Day 0 21 35 T1 1 SIV-Kill 0/15 15/15 11/15 5.0 24.1 11.5 Amphigen T2 2 SIV-Kill 0/15 6/15 0/15 5.0 6.9 5.0 Quil A T3 3 SIV-Kill 0/15 15/15 13/15 5.0 24.1 14.5 LAP T4 4 SIV-Kill 0/15 0/15 0/15 5.0 5.0 5.0 LAP T5 5 Neg.","0/5 0/5 0/5 5.0 5.0 5.0 Control No.","of piglets with H1N1 Titers - Piglets with titers of 10 or higher were determined as positive.","Geometric Mean Titers - A titer of 5 was assigned to negative titers for calculation of geometric mean.","SIV—Lyophilized swine influenza (H1N1, H3N2) virus killed viral vaccine (FluSure ™, Pfizer Animal Health).","LAP—Lecithin acrylic polymer as described in Examples 1-5.TABLE 7 Number of piglets with H3N2 Swine Influenza Titers and Geometric Mean Titers No.","of Piglets With H3N2 H3N2 Geometric Titers/Total Piglets Mean Titers Treat Test Treat.","Day Day Day Day No.","Art Group Day 0 21 35 Day 0 21 35 T1 1 SIV-Kill 11/15 15/15 15/15 14.5 20.9 16.6 Amphigen T2 2 SIV-Kill 10/15 10/15 3/15 15.2 8.3 5.7 Quil A T3 3 SIV-Kill 10/15 15/15 15/15 13.8 28.9 17.4 LAP T4 4 SIV-Kill 12/15 6/15 1/15 16.6 6.9 5.2 LAP T5 5 Neg.","4/5 3/5 1/5 17.4 8.7 5.7 Control No.","of piglets with H3N2 titers - Piglets with titers of 10 or higher were designated as positive for titers.","Geometric Mean Titers - A titer of 5 was assigned a negative titer for calculations of geometric mean titers.","SIV—Lyophilzed swine influenza (H1N1, H3N2) virus killed viral vaccine (FluSure ™, Pfizer Animal Health).","Amphigen ®—Amphigen ® adjuvant (Pfizer Animal Health) LAP—Lecithin acrylic polymer as described in Examples 1-5.Referring to Tables 6 and 7, the results indicate lecithin and acrylic copolymer adjuvants of the invention induce significant serological responses to H1N1 and H3N2 swine influenza viruses in piglets.","The responses were similar to conventional commercial adjuvants and significantly better than a Quil A alone adjuvant.","The data in Example 6 further show the utility of the lecithin/acrylic polymer adjuvants of the invention and show that additives alone, for example Quil A, provide for a minimal immunological response under identical conditions.","Example 7 Immune Response to Vaccine Enhanced by Inclusion of Additives The immunogenecity of a lecithin, acrylic polymer, Quil A and cholesterol adjuvant of the invention was tested against Amphigen, a commercial adjuvant.","The study was performed to determine the effectiveness of eliciting an enhanced immune response through inclusion of cholesterol and Quil A in adjuvant embodiments described herein.","Adjuvant was prepared as described above, except in this Example, 15 mg/ml lecithin was combined with 10 mg/ml acrylic polymer.","Each vaccine dose included 1.25 mg of adjuvant (as compared to 5 mg of Amphigen).","The adjuvant samples were spiked with 0.5 mg/ml of Quil A/cholesterol.","All adjuvant samples further received 50 μg, 5 μg or 0.5 μg AIV-HA antigen.","Ingredients described above were combined as discussed herein to provide 3 different antigen concentrations for each lecithin/acrylic polymer/additive sample and Amphigen sample.","All samples were stored at 4° C. Twenty-nine to thirty-five day old piglets were vaccinated and bleeds taken on days one, fourteen and twenty eight.","Titers were determined for each condition and mean HAI titer determined.","As shown in FIG.","1, the study showed a surprising increase in mean HAI titer with cholesterol and Quil A included in the adjuvant and therefore vaccine preparation.","In each case, the increase in titer was antigen concentration dependent and showed a significant increase comparable to corresponding antigen spiked Amphigen samples.","It is noted that the amount of lecithin and acrylic polymer was limited (1.25 mg) to provide a more sensitive platform for identifying effects of the inventive adjuvants described herein.","The low dose lecithin/acrylic polymer/additive adjuvant provided an adequate platform for analyzing the adjuvant's capacity to elicit an immune response, which was comparable to a full dose Amphigen based adjuvant.","Example 8 Lecithin and Acrylic Polymer Adjuvant is Facilitated by Inclusion of Additives The immunogenecity of a lecithin, acrylic polymer, cholesterol, and Quil A adjuvant was tested in chickens.","Cell line based antigen was tested in this manner in order to determine utility of adjuvants (additive based) in accordance with the present invention.","Adjuvant was prepared using 33.5 μg/dose Quil A, 32.4 μg/dose cholesterol, 800 μg/dose lecithin and 500 μg/dose acrylic copolymer 974PNF.","Vaccine antigen was a stably transfected cell line using a H5 HA expressing plasmid (CHO-HA-10).","In some vaccines, an antigen stabilizing agent was added to the material, i.e., Nicotiana tabacum cell line lysate.","Sixty five pathogen-free Leghorn chickens (10 day old) were obtained and quarantined for nine days prior to start-up of the experiment.","Birds were split into eleven groups (six birds per group for groups T1 through T10 and five birds for T11).","Each group was housed together.","Treatment group T11 birds were a baseline group and used to obtain a Day 0 bleed.","Study design is provided in Table 8: TABLE 8 Example 8 study design Treatment Processing No.","of Vacination No.","Group Method Birds Days Dose Route Bleed Days* T1 CHO lys.","Mixing 6 0, 14 0.5 ml SQ 14, 28 NT-1 ext Adjuvant T2 CHOHA0102 Mixing 6 on 0, 14 0.5 ml SQ 14, 28 Adjuvant zero 5 on 14 T3 CHOHA0102 Microfluid.","6 0, 14 0.5 ml SQ 14, 28 Adjuvant Non- Clarified T4 CHOHA0102 Microfluid.","6 0, 14 0.5 ml SQ 14, 28 Adjuvant Clarified T5 CHOHA0102 Silverson 6 0, 14 0.5 ml SQ 14, 28 Adjuvant Non- Clarified T6 CHOHA0102 Mixing 6 0, 14 0.5 ml SQ 14, 28 NT-1 ext Adjuvant T7 CHOHA0102 Microfluid.","6 0, 14 0.5 ml SQ 14, 28 NT-1 ext Non- Adjuvant Clarified T8 CHOHA0102 Microfluid.","6 0, 14 0.5 ml SQ 14, 28 NT-1 ext Clarified Adjuvant T9 CHOHA0102 Silverson 6 0, 14 0.5 ml SQ 14, 28 NT-1 ext Non- Adjuvant Clarified T10 H5N9 AIV Mixing 6 0, 14 0.5 ml SQ 14, 28 Adjuvant T11 Baseline NA 5 NA NA NA 0 Bleed Bleed days - serum evaluated by hemagglutination inhibition with A/Turkey/Wisconsin/68 (H5N9) CHO lysate - Non-transfected CHO cells NT-1 extract - Nicotiana tabacum, lyophilized, non-transformed clarified cell lysate Adjuvant - Lecithin, acrylic copolymer, Quil A, and cholesterol SQ—subcutaneous administration CHOHA0102—CHO cells transfected with H5 hemagglutinin H5N9 AIV—Inactivated H5N9 avian influenza virus A/Turkey/Wisconsin/68 NA—not applicable As shown in Table 9, all vaccinated treatment groups (T2-T9) were clearly different from the negative control (T1).","Although slight differences were observed, little differentiation was discernable between treatment groups that did or did not receive the Nicotiana tabacum cell line lysate or between the various processing methods.","TABLE 9 Seroconversion rates and avian influenza hemagglutination inhibition geometric mean titer results Avian Influenza No.","of Birds Geometric Seroconverting/ Mean Treat- Tot.","Birds Titers ment Treatment Group Day Day group Antigen Ad Processing 14 Day 28 14 Day 28 T1 CHO lys.","Mixing 0/6 0/6 4.0 4.0 NT-1 ext Adjuvant T2 CHOHA0102 Mixing 2/6 5/5 8.0 48.5 Adjuvant T3 CHOHA0102 Microfluid.","5/6 5/6 11.3 22.6 Adjuvant Non- Clarified T4 CHOHA0102 Microfluid.","3/6 5/6 9.0 28.5 Adjuvant Clarified T5 CHOHA0102 Silverson 4/6 4/6 14.3 22.6 Adjuvant Non- Clarified T6 CHOHA0102 Mixing 4/6 5/6 10.1 32.0 NT-1 ext Adjuvant T7 CHOHA0102 Microfluid.","3/6 5/6 10.1 18.0 NT-1 ext Non- Adjuvant Clarified T8 CHOHA0102 Microfluid.","3/6 6/6 9.0 20.2 NT-1 ext Clarified Adjuvant T9 CHOHA0102 Silverson 2/6 5/6 5.7 25.4 NT-1 ext Non- Adjuvant Clarified T10 H5N9 AIV Mixing 3/6 6/6 8.0 228.1 Adjuvant Results from the Example show that additive based adjuvants of the invention support a cell line based antigen, i.e., a cell line that expresses the antigen, and provided excellent immunogenicity in chickens.","This data further supports the conclusion that Quil A and cholesterol when used in combination with other adjuvant based embodiments described herein have surprising utility in the context of the present invention.","Example 9 Micrograph Data: Embodiments of the Present Invention have Net-Like Structure Inventive adjuvant compositions were as prepared and described in previous Examples.","Adjuvant samples were visualized by transmission electron microscopy.","Adjuvants included lecithin and polymer, no additives, and were sterilized by autoclaving.","An illustrative micrograph at 30,000× magnification is shown in FIG.","2A.","For comparison, an illustrative emulsion as prepared by the methods described in U.S. Pat.","No.","5,716,637 (Anselem et al.","), and visualized via transmission electron microscopy at the same magnification (30,000×) is shown in FIG.","2B.","As described in the description of the Anselem patent, the adjuvant was microfiltered and not autoclaved.","The adjuvant prepared via the methods of U.S. Pat.","No.","5,716,637, show an expected emulsion structure of lipid droplets in an aqueous phase.","In contrast, the micrograph shown in FIG.","2 A illustrates that adjuvants of the present invention have a significantly different physical structure or distribution than the adjuvants described in Anselem.","Adjuvants of the present invention show a diffuse net-like structure with significant polymer content combining with the lecithin (phospholipids) to provide the unexpected structure of the present invention.","This is a surprising given the significant difference is structure between the two adjuvant compositions.","Example 10 Calcium Phosphate Facilitates Immunity of DNA-Based Vaccine Lecithin and acrylic copolymer adjuvant as described and prepared herein was analyzed alone and in combination with calcium phosphate (CaPO4) to determine effectiveness at supporting the immunization of chicks against an avian influenza DNA antigen (H5N9 AIV HA DNA).","Inventive adjuvants herein were compared to a commercially available adjuvant, having the same antigen.","The commercially available adjuvant was also tested with CaPO4.Chick treatment groups were immunized on day 0 and day 16.Serum testing was performed on each treatment group and HAI titers determined using standard assays.","FIG.","3 shows data from HAI GMT serum titers for adjuvant only, no antigen (Amphigen®); antigen only, no adjuvant; Amphigen®; Amphigen® with CaPO4; Lecithin and Copolymer; and Lecithin, Copolymer and CaPO4.The results in FIG.","3 indicate that the lecithin, copolymer and calcium phosphate group vaccine provided significantly higher levels of immunity than lecithin and copolymer alone or Amphigen with or without calcium phosphate.","This combination of lecithin, copolymer and calcium phosphate shows an unexpected capacity to transform poorly immunogenic DNA vaccines into highly effective vaccines.","Example 11 Enhanced Potency of FMD Vaccine Experimental design: Second generation human adenovirus type 5 (Ad5) vector for FMDV serotype A24 Cruzeiro administered to pigs subcutaneously at two sites with or without adjuvant.","The animals were challenged 21 days post-vaccination at doses 10-fold higher than recommended.","FIG.","4 shows the results of the experimental Adenovirus vector-based FMD vaccine alone or in combination with one of two adjuvants: a DNA plasmid called plCLC or Adjuvant E (Adjuplex/Vetplex with Quil A and Cholesterol).","Adjuvant E increased potency by at least 5-fold whereas the plCLC adjuvant was less effective.","This data further supports the conclusion that Quil A and cholesterol when used in combination with other adjuvant based embodiments described herein have surprising utility in the context of the present invention.","Example 12 Effect of Vaccine Adjuvants on Adeno-Vector Viruses The overarching goal of this research was to produce and evaluate Foot-and-mouth disease (FMD) single or combinational vaccines comprising replication-defective recombinant human adenovirus carrying (a) the FMD VP1 capsid and 3C protease coding regions and/or (b) bovine or porcine type 1 interferon genes.","This strategy is being used to develop next generation molecular FMD licensed vaccines for stock piling by the National Veterinary Stockpile Program for use as an FMD countermeasure in emergency outbreaks.","One research area of this project was the addition of vaccine adjuvants to the adeno-based vector vaccines for enhancement of their immunogenecity and efficacy.","Two adjuvants (Adjuplex-LAP and Adjuplex-LE) were evaluated in vitro for virucidal effects on the vaccine vectors under different time and temperature conditions.","The conclusion drawn from this study was that Adjuplex LAP did not have any virucidal effect on Ad5bIFNα virus at the recommended or 4-fold concentration level.","The incubation temperatures and times for these studies were 20° C., or 39° C., and 1 or 24 hours, respectively.","However, similar results were not observed for Adjuplex-LE.","No titer reductions were observed at 39° C. and one hour incubation; however when the incubation was increased to 24 hours, there were significant reductions in virus titers at both concentrations.","Results from this study would suggest that Adjuplex-LE adjuvant produced a virucidal effect on Ad5-bIFNα virus at both the recommended and two-fold higher concentration levels.","Similar results were obtained with Ad5-O1 virus when it was mixed with both Adjuplex LAP and LE, respectively, at the recommended quantity and when the amount was increased two- or four-fold.","Furthermore, there were no significant titer reductions even when the mixtures were incubated at 39° C. for 24 hours.","The 39° C. incubation temperature was selected because that is the average cattle rectal body temperature.","It is recommended that Adjuplex LAP should be the adjuvant of choice to be combined with the Ad5-bIFNα, Ad5-O1 and other Ad5 based FMD sub unit vaccines for clinical evaluation in cattle and pigs.","Foot-and-mouth disease (FMD) is an economically important and highly contagious viral disease of cloven-hoofed livestock and wildlife including cattle, swine, sheep, goats, and deer.","The recent re-emergence of FMD in both developing and developed nations has refocused world's attention on universe control strategies particularly in the USA.","In many countries the control and eradication of FMD are by immunization of susceptible animals using commercially available FMD vaccines, which are based on conventional chemically inactivated vaccines emulsified with adjuvants.","Failure to completely inactivate the vaccine has led to outbreaks of the disease.","There is no approved diagnostic test available to reliably differentiate vaccinated from infected animals.","Furthermore vaccinated animals can become disease carriers following contact with FMD virus.","These disadvantages of inactivated whole FMD vaccine have made FMD-free countries to be reluctant to vaccinate their livestock during outbreaks.","In order to overcome some of the problems associated with convectional FMD vaccines, many approaches have been utilized to develop alternative FMD vaccines, including construction of modified live-virus, biosynthetic proteins, synthetic peptides, naked DNA vectors, and recombinant viruses.","The use of human adenovirus as a vector for FMD vaccines has been met with variable results, sometimes resulting in incomplete protection or failure of vaccinated animals to develop a neutralizing antibody.","In this study, two adjuvants viz Adjuplex-LAP and Adjuplex-LE were investigated in vitro as possible adjuvants for Ad5 FMD subunit vaccines.","This was a preliminary investigation prior to in vivo studies.","Experiments were set up to determine both their cytotoxic effect on 293 cells and their virucidal effects on Ad5-FMD viruses.","Adjuplex-LAP is a mucosal vaccine adjuvant as well as an adjuvant for parenterally administered vaccines.","The adjuvant is a lecithin phospholipid/acrylic polymer combination.","The combination forms a mucoadhesive matrix that facilitates the adsorption of vaccine antigens to mucosal surfaces and subsequent absorption and presentation of antigen to cells of the immune system.","Both adjuvant components are used in the pharmaceutical and biological industries and thus have value as a delivery and adjuvant system for vaccine antigens.","Adjuplex-LE is a 5%, or less, oil-in-water emulsion, the oil droplets which are covered by lecithin derived phospholipid vesicles.","The lipid vesicles act as a carrier for vaccine antigens and make them accessible to cells of the immune system.","The lipid vesicles on the surface of the oil droplets is also a safety feature making the oil less irritable or not irritable at all to tissue at the injection site.","The adjuvant is also non-virucidal.","Therefore the formulation can be, and is, used to adjuvant modified-live virus vaccines.","The adjuvant can be mixed directly with vaccine antigens without further emulsification or the antigens can be added at the time of emulsification.","The redox indicator Alamar Blue™ (AB), a fluorescent dye, which has been used in mammalian cell culture cytotoxicity assays.","AB is a safe, nontoxic aqueous dye, which is used to assess cell viability and cell proliferation because it is stable in cell culture.","It has also been shown to be a rapid and simple non-radioactive assay alternative to the [3H] thymidine incorporation assay.","AB both fluoresces and changes color in response to chemical reduction, and the extent of the conversion is a reflection of cell viability.","AB assay is a simple, one-step procedure.","Alamar Blue™ assay was set up to study the cytotoxicity effects of two vaccine adjuvants 293 cells.","There were two objectives: (a) evaluate the relative 293 cell cytotoxity of vaccine adjuvants in combination with Ad5-bovine interferon alpha (Ad5bIFN α) and Ad5O1 vectors, and (b) establish if the vaccine adjuvants are virucidal for Ad5bIFNα vector.","Alamar Blue™ assay was set up to study the cytotoxicity effect of vaccine adjuvants on 293 cells.","Alamar Blue™ is a safe, nontoxic aqueous dye which is used to assess cell viability and cell proliferation.","Materials and Methods 293 Cells Human embryonic kidney (293) cells were obtained from Dr. Patrick Hearing, Department of Microbiology, Stony Brook University, Stony Brook, N.Y., and were propagated in minimum essential medium (MEM) containing 10% fetal bovine serum (FBS), 1% antibiotic-antimycotic solution, and 1% MEM non essential amino acid (NEAA).","293 cells of passages 15 and 36 were used for transfection, propagation of viruses, virus titrations and performing of cytotoxicity assays.","Ad5bIFNα and Ad5O1 Plasmids The two plasmids were provided by Dr. Laszlo Zsak from US Department of Homeland Security, Targeted Advanced Development, Plum Island Animal Diseases Center, Orient Point, N.Y. Transfection of Ad5bIFNα and Ad5O1 Plasmids in 293 Cells The pAd5bIFNα and pAd5O1 were linearized by digestion with restriction enzyme Pad and transfected in 293 cells using Lipofectamin™ 2000.Production and Purification of Ad5bIFNα and Ad5O1 Viruses (Vaccine Vectors) The 2 viruses were harvested with the appearance of the initial plaques, which were then grown in large quantities in 293 cells, and purified utilizing a nonlinear followed by a linear CsCl gradient centrifugation.","Dilutions of Vaccine Viruses (Ad5bIFNα and Ad5O1) 1:10, 1:100 and 1:100 dilutions of both Ad5bIFNα and Ad5O1 vaccine viruses were prepared respectively in EMEM containing 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA.","Dilutions of Adjuvants (Adjuplex-LAP and Adjuplex-LE) 1:20, 1:200, 1:2000, and 1:20,000 dilutions of both Adjuplex-LAP and Adjuplex-LE adjuvants were prepared respectively in EMEM containing 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA.","Alamar Blue (AB) AB was aliquoted and stored at −80° C. Prior to each experiment, AB was brought to room temperature and vortexed.","Exposure of AB to light was minimized throughout the experiments.","Alamar Blue (AB) Cytotoxicity Assay (Cell Viability Assay) Cell viability of 293 cells was assessed by AB cytotoxicity assay.","293 cells in EMEM containing 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA were seeded at a density of 1×106 viable cells/ml (1×105/well) in a 96 well Treatment (BD Falcon* Primaria* Tissue culture Treatments, Fisher Scientific Company, Suwanee, Ga.).","In a second plate, cells were seeded at a density of 10×106 viable cells/ml (1×106/well) to determine the optimal cell concentration for the cytotoxicity study.","Table 10 shows the addition of diluted Ad5bIFNα, Ad5O1, Adjuplex-LAP and Adjuplex-LE to the cells.","Briefly, 0.1 ml of each of the dilutions of Ad5bIFNα and Ad5O1 (1:10, 1:100, 1:100) was added to each well respectively in triplicates.","0.1 ml of each of the dilutions of the adjuvants (1:20, 1:200, 1:2000, and 1:20,000) was added to each well respectively in triplicates.","EMEM containing 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA was added to wells A1, A2, A3, D1, D2 and D3 as negative controls.","The two treatments were incubated at 37° C. in a 5% CO2 atmosphere for approximately 18 hours, after which 20 μl AB was added to each well.","The treatments were returned to the incubator.","Optical densities (OD) at 570 nm and 600 nm were measured with the ELX808 ultra microplate reader (BioTek Instruments, Inc., Winooski, Vt.) at approximately 42 hours, 50 hours, and 68 hours (total culture times).","The OD data were analyzed as follows: (a).","determine % difference in reduction of AB (between media growth control wells and treatment wells); this will indicate the amount inhibition (or stimulation) of cell growth in treatment wells with respect to media control wells, and (b).","determine % reduction of AB in media control and in treatment wells; this will indicate the amount of cell growth in media control and treatment wells.","Treatments with higher % reduction than media controls are considered to stimulate cell growth.","Treatments with lower % reduction than media controls are considered cytotoxic.","Treatments with the same % reduction are neither cytotoxic nor stimulatory.","Calculation of Alamar Blue (AB) Reduction Percent reduction of AB was calculated using the manufacturer's formula (33).","In monitoring AB reduction spectrophotometrically, reduction is expressed as a percentage (% reduced).","The calculation of % Reduced is as follows when the samples are read at λ1 = 570 nm λ2 = 600 nm % Reduced = ( ɛ ox λ2 ) ( A λ1 ) - ( ɛ ox λ1 ) ( A λ2 ) ( ɛ red λ1 ) ( A ’ λ2 ) - ( ɛ red λ2 ) ( A ’ λ1 ) × 100 Where: (εred λ1)=155,677 (Molar extinction coefficient of reduced AlamarBlue™ at 570 nm) (εred λ2)=14,652 (Molar extinction coefficient of reduced AlamarBlue™ at 600 nm) (εox λ1)=80,586 (Molar extinction coefficient of oxidized AlamarBlue™ at 570 nm) (εox λ2)=117,216 (Molar extinction coefficient of oxidized AlamarBlue™ at 600 nm) (Aλ1)=Absorbance of test wells at 570 nm (Aλ2)=Absorbance of test wells at 600 nm (A′λ1)=Absorbance of negative control wells which contain medium plus AlamarBlue™ but to which no cells have been added at 570 nm.","(A′λ2)=Absorbance of negative control wells which contain medium plus AlamarBlue™ but to which no cells have been added at 600 nm.","In reporting AlamarBlue™ reduction by monitoring absorbance, data are expressed as percent AlamarBlue™ reduced as a function of time of incubation.","The AB assay was used to determine viability of 293 cells to vaccine adjuvants.","Virucidal Assay (TCID50 Assay) The TCID50 assay was employed to ascertain and measure if there were virucidal effects of Adjuplex-LAP and Adjuplex-LE adjuvants on Ad5bIFNα and Ad5O1 viruses.","293 cells were harvested from a T-150 flask of fresh 293 cells, and counted on a hemocytometer.","A dilution of the cell suspension at 1×105/ml in MEM containing 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA was made, and at least 10 ml was prepared for each 96 flat-bottomed well tissue culture plate.","Using a 12-channel pipette and a multichannel pipetter basin, 100 μl of the cell dilution (104 cells/per well) was seeded into 96-well tissue culture plates, and covered.","They were incubated at 37° C. in a CO2 incubator until used.","Frozen vials of Ad5bIFNα and Ad5O1 viruses were thawed and kept on ice at all times.","MEM supplemented with 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA was used to make virus dilutions of 10−1 to 10−13.The 10 fold dilutions were made in 5 ml sterile, disposable tubes.","The cells were infected by adding 0.1 ml per well of each virus-adjuvant dilution immediately after the dilutions were made.","AB assay with a cell concentration of 10×106/ml was also set up.","Preparation of Antigen-Adjuvant Mixtures Ad5bIFNα Virus-Adjuvant Mixtures Each of the two adjuvants was mixed with Ad5bIFNα according to the manufacturer recommended ratios (LAP:virus ratio, 1:4; LE:virus ratio, 1:1).","In addition to the recommended ratios, additional ratios (LAP:antigen ratio, 4:1; LE:antigen ratio, 2:1) were also tested to increase the chances of having virucidal effects.","Each mixture was made in a sterile 1 ml microtube and vortexed three times to ensure adequate mixing before use, and was incubated according to the appropriate conditions.","The media-virus mixture served as a control.","The media consisted of MEM supplemented with 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA.","The ratios tested were as follows: Experiment 1 Treatment A: 25 μl Media+100 μL Ad5bIFNα Treatment B: 25 μL LAP+100 μL Ad5bIFNα Treatment C: 100 μL Media+100 μL Ad5bIFNα Treatment D: 100 μL LE+100 μL Ad5bIFNα The mixtures were not incubated before dilutions were made.","Experiment 2 Treatment A: 25 μl Media+100 μL Ad5bIFNα Treatment B: 25 μL LAP+100 μL Ad5bIFNα Treatment C: 100 μL Media+100 μL Ad5bIFNα Treatment D: 100 μL LE+100 μL Ad5bIFNα The mixtures were incubated at room temperature (20-25° C.) for one hour before dilutions were made.","Experiment 3 Treatment A: 100 μl Media+100 μL Ad5bIFNα Treatment B: 100 μL LAP (4×)+100 μL d5bIFNα Treatment C: 100 μL LE+100 μL Ad5bIFNα Treatment D: 200 μL Media+100 μL Ad5bIFNα Treatment E: 200 μL LE (2×)+100 μL Ad5bIFNα The mixtures were incubated at 39° C. for one hour before dilutions were made.","Experiment 4 Treatment A: 100 μl Media+100 μL Ad5bIFNα Treatment B: 100 μL LAP (4×)+100 μL Ad5bIFNα Treatment C: 100 μL LE+100 μL Ad5bIFNα Treatment D: 200 μL Media+100 μL Ad5bIFNα Treatment E: 0.200 μL LE (2×)+100 μL Ad5bIFNα The mixtures were incubated at 39° C. for 24 hours before dilutions were made.","Ad5O1-Adjuvant Mixtures Each of the two adjuvants was mixed with Ad5O1 according to the manufacturer recommended ratios (LAP:virus ratio, 1:4; LE:virus ratio, 1:1).","In addition to the recommended ratios, additional ratios (LAP:virus ratio, 4:1; LE:virus ratio, 2:1) were also tested to increase the chances of having virucidal effects.","Each mixture was made in a sterile 1 ml microtube and vortexed three times to ensure adequate mixing before use.","The media-virus mixture served as a control.","The media consisted of MEM supplemented with 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA.","The ratios tested were as follows: Experiment 1 Treatment A: 25 μl Media+100 μL Ad5O1 Treatment B: 25 μL LAP+100 μL Ad5O1 Treatment C: 100 μL Media+100 μL Ad5O1 Treatment D: 100 μL LE+100 μL Ad5O1 The mixtures were not incubated before being dilutions were made.","Experiment 2 Treatment A: 25 μl Media+100 μL Ad5O1 Treatment B: 25 μL LAP+100 μL Ad5O1 Treatment C: 100 μL Media+100 μL Ad5O1 Treatment D: 100 μL LE+100 μL Ad5O1 The mixtures were incubated at room temperature (20-25° C.) for one hour dilutions were made.","Experiment 3 Treatment A: 100 μl Media+100 μL Ad5O1 Treatment B: 100 μL LAP (4×)+100 μL Ad5O1 Treatment C: 100 μL LE+100 μL Ad5O1 Treatment D: 200 μL Media+100 μL Ad5O1 Treatment E: 200 μL LE (2×)+100 μL Ad5O1 The mixtures were incubated at 39° C. for one hour before dilutions were made.","Experiment 4 Treatment A: 100 μl Media+100 μL Ad5O1 Treatment B: 100 μL LAP (4×)+100 μL Ad5O1 Treatment C: 100 μL LE+100 μL Ad5O1 Treatment D: 200 μL Media+100 μL AdO1 Treatment E: 0.200 μL LE (2×)+100 μL Ad5O1 The mixtures were incubated at 39° C. for 24 hours before dilutions were made.","Preparation of Virus-Adjuvant Dilutions From each treatment, serial 10 fold dilutions of adjuvant-virus mixtures were prepared in 5 ml sterile, disposable tubes using MEM supplemented with 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA to prepare adjuvant-virus dilutions of 10−1 to 10−13.0.9 ml MEM supplemented with 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA was dispensed into the first two tubes.","To each of the eleven other tubes was added 1.8 ml.","0.1 ml of each adjuvant-virus mixture from each treatment was added to the first tube and mixed by votexing.","Filtered pipette tips were changed between dilutions.","0.1 ml of the 10−1 dilution was withdrawn and transferred to the second tube containing MEM supplemented with 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA.","0.2 ml of the 10−2 dilution was withdrawn and transferred to the third tube containing MEM supplemented with 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA, and this became 10−3 virus dilution.","The above steps were repeated to prepare the next virus dilutions (10−4 to 10−13).","Infection of Cells with Virus-Adjuvant Dilutions One 96-well plate was used for infection per treatment.","Immediately after the dilutions were made, the cells were infected by adding 0.1 ml per well of each virus-adjuvant dilution.","0.1 ml of the virus-adjuvant suspension with the highest dilution was dispensed in column 1 wells to infect the cells in the 8 wells of this column.","The cells in the 8 wells of the next column; column 2 of the 96-well were infected with 0.1 ml of the next adjuvant-virus dilution (10−12).","The cells in the 8 wells of columns 3 through 11 were infected with 0.1 ml of the remaining virus-adjuvant dilutions (10−11-10−13).","Pipette tips were changed between dilutions.","To test the cell viability and as a negative control (no adjuvant-virus control), 0.1 ml/well of MEM containing 2% FBS, 1% antibiotic-antimycotic solution and 1% MEM-NEAA was added to each well in column 12.Each plate was covered and incubated at 37° C. in a CO2 incubator for 10 days.","Cells in each plate were observed daily by an inverted microscope for cytopathic effects (CPE) over the next 10 days.","Observable CPE per column were counted and recorded.","Final reading of each plate was done on the 10th day post incubation to determine the titer.","A well was counted as positive even if only a small spot or a few cells showed CPE.","The negative control wells were used for comparison.","The test was valid if the negative controls did not show any CPE or cell growth problems, and the lowest dilution showed 100% infection (8/8) while the highest dilutions showed 0% infection (0/8).","The results were recorded for day 10, scoring wells “+” (CPE positive) or “−” (CPE negative) using the CPE scoring form in appendix A, and the ratio of positive wells per column was determined, and recorded it as in appendix A.","After recording the assay data, the plates were placed in a biohazard bag and autoclaved and discarded as biohazardous waste.","For each plate (treatment), TCID50/ml titer was calculated using the KÄRBER statistical method.","Compare the TCID50/ml between the treatments in each experiment to determine if there was a difference.","A difference in titers between treatments in each experiment that is greater than 0.7 log was considered to be significant, which means the adjuvant in that experiment was virucidal to the tested virus.","Results Alamar Blue (AB) Cytotoxicity Assay (Cell Viability Assay) Alamar Blue™ was used to measure 293 cell viability at two densities There was cell clumping at a density of 10×106/ml for all treatments.","The 1×106/ml density was better than the higher density.","Cell Viability Assay on Exposure to Ad5bIFNα At a cell concentration of 1×106/ml, the 1:100 dilution of Ad5bIFNα produced the higher % AB reduction than the media controls at 42 and 50 hours post exposure (FIGS.","5 and 6).","However, there was a % AB reduction at 68 hours post exposure (FIG.","7).","Similar results were obtained at a cell density of 10×106/ml (FIGS.","8-10).","Cell Viability Assay on Exposure to Adjuplex LAP Cell exposure at a cell density of 1×106/ml to Adjuplex LAP at a dilution of 1:20 gave the higher % AB reduction than the media controls at 42 and 50 hours post exposure (FIGS.","5 and 6) but with a % AB reduction at 68 hours post exposure (FIG.","7).","Similar results were obtained at a cell density of 10×106/ml (FIGS.","8-10).","Cell Viability Assay on Exposure to Adjuplex LE When 293 cells at a cell density 1×106/ml were treated with Adjuplex LE at a dilution of 1:20, higher % AB reductions were obtained compared to the media controls at 42 and 50 hours post exposure (FIGS.","5 and 6) but with a % AB reduction at 68 hours post exposure (FIG.","7).","Similar results were obtained at a cell density of 10×106/ml (FIGS.","8-10).","Cell Viability Assay on Exposure to Emulsigen Treatment of 293 cells at a cell density 1×106/ml with Emulsigen at 1:20 dilution resulted in higher % AB reductions relative to the media controls at 42 and 50 hours post exposure (FIGS.","5 and 6) but with lower % AB reductions at 68 hours post exposure (FIG.","7).","Similar results were obtained at a cell density of 10×106/ml (FIGS.","8-10).","Virucidal Assay (TCID50 Assay) Ad5bIFNα Virus-Adjuvant Mixtures Experiment 1 The log 10 titers of treatments in this group were 10.0, 9.9, 9.5, and 9.6 (Table 11, FIG.","11).","The differences between them were lower than log 0.7 (34), therefore there were no significant differences within this treatment group (34).","This indicates that the two adjuvants did not produce any virucidal effect on the virus when combined at room temperature.","Experiment 2 As in the first experiment, leaving the virus-adjuvant mixtures at 24° C. for one hour of incubation, the two adjuvants did not produce any virucidal effect on the virus because the differences between log 10 titers were less than log 10 0.7 (34), (Table 11, FIG.","11).","Experiment 3 The adjuvants in these treatment groups did not exhibit any virucidal effect on the virus when incubated for one hour at 39° C. (Table 11, FIG.","11).","Experiment 4 Incubating the two first treatment groups at 39° C. for 24 hours did not produce any virucidal effect by Adjuplex-LAP adjuvant on the virus (Table 11, FIG.","11).","However, treatments at these incubation time and temperature conditions significantly reduced titers by 3.3- and 1.9-log 10 TCID50 (34) when compared to the control treatment groups at the recommended amount and when the amount of Adjuplex LE was doubled, respectively.","Ad5O1 Virus-Adjuvant Mixtures Experiment 1 There were no significant differences in virus titers of treatments A and B.","The reduction in titer between treatments C and D was 0.2 log 10 TCID50 and this was not significant (34) (Table 12, FIG.","12).","Virus-adjuvant mixtures in this experiment were not incubated.","Experiment 2 There was no significant titer reduction between treatments A and B incubated for 1 hour at 20° C. The adjuvants did not produce any significant titer reduction (34) in treatments C and D (Table 12, FIG.","12).","Experiment 3 In a similar fashion, all the groups in this experiment did not show any significant differences in log 10 titer reduction.","Experiment 4 There was a significant reduction (1.0 log 10) in titers between treatments A and B.","The titer reduction (0.3 log) between treatments 3 and 4 was not significant (34) (Table 12, FIG.","12).","TABLE 10 Alamar Blue Cytoxicity Assay Setup 1 2 3 4 5 6 7 8 9 10 11 12 Plate 1: 1 × 10{circumflex over ( )}5 cells per well A #1 media + cells #1 Ad5-bIFNα 1:10 #1 Ad5-bIFNα 1:100 Media NO CELLS B #1 Adjuplex-LAP 1:20 #1 Adjuplex-LAP 1:200 #1 Adjuplex-LAP 1:2000 #1 Adjuplex-LAP 1:20000 C #1 Adjuplex-LE 1:20 #1 Adjuplex-LE 1:200 #1 Adjuplex-LE 1:2000 #1 Adjuplex-LE 1:20000 D #2 media + cells #1 Ad5-bIFNα 1:10 #1 Ad5-bIFNα 1:100 Media NO CELLS E #2 Adjucplex-LAP 1:20 #2 Adjuplex-LAP 1:200 #2 Adjuplex-LAP 1:2000 #2 Adjuplex-LAP 1:20000 F #2 Adjuplex-LE 1:20 #2 Adjuplex-LE 1:200 #2 Adjuplex-LE 1:2000 #1 Adjuplex-LE 1:20000 G #2 Adjucplex-LAP 1:20 #2 Adjuplex-LAP 1:200 #2 Adjuplex-LAP 1:2000 #2 Adjuplex-LAP 1:20000 H #2 Adjuplex-LE 1:20 #2 Adjuplex-LE 1:200 #2 Adjuplex-LE 1:2000 #1 Adjuplex-LE 1:20000 Plate 2: 1 × 10{circumflex over ( )}5 cells per well A #1 media + cells #1 Ad5-bIFNα 1:10 #1 Ad5-bIFNα 1:100 Media NO CELLS B #1 Adjuplex-LAP 1:20 #1 Adjuplex-LAP 1:200 #1 Adjuplex-LAP 1:2000 #1 Adjuplex-LAP 1:20000 C #1 Adjuplex-LE 1:20 #1 Adjuplex-LE 1:200 #1 Adjuplex-LE 1:2000 #1 Adjuplex-LE 1:20000 D #2 media + cells #1 Ad5-bIFNα 1:10 #1 Ad5-bIFNα 1:100 Media NO CELLS E #2 Adjucplex-LAP 1:20 #2 Adjuplex-LAP 1:200 #2 Adjuplex-LAP 1:2000 #2 Adjuplex-LAP 1:20000 F #2 Adjuplex-LE 1:20 #2 Adjuplex-LE 1:200 #2 Adjuplex-LE 1:2000 #1 Adjuplex-LE 1:20000 G #2 Adjucplex-LAP 1:20 #2 Adjuplex-LAP 1:200 #2 Adjuplex-LAP 1:2000 #2 Adjuplex-LAP 1:20000 TABLE 11 Ad5bIFNα virus-Adjuvant Mixture Titers Expressed in Log10 TCID50 Experiment Temperature Incubation Log10 Number Treatment ° C. Time (hrs) TCID50 1 A.","25 μl Media + 100 μl Ad5bIFNα None 10.0 B.","25 μl LAP + 100 μl Ad5bIFNα None 9.9 C. 100 μl LE + 100 μl Ad5bIFNα None 9.5 D. 100 μl Media + 100 μl Ad5bIFNα None 9.6 2 A.","25 μl Media + 100 μl Ad5bIFNα 20 1 10.6 B.","25 μl LAP + 100 μl Ad5bIFNα 20 1 10.5 C. 100 μl Media + 100 μl Ad5bIFNα 20 1 10.4 D. 100 μl LE + 100 μl Ad5bIFNα 20 1 10.3 3 A.","100 μl Media + 100 μl Ad5bIFNα 39 1 10.0 B.","100 μl LAP (4X)* + 100 μl Ad5bIFNα 39 1 9.9 C. 100 μl LE + 100 μl Ad5bIFNα 39 1 9.9 D. 200 μl Media + 100 μl Ad5bIFNα 39 1 9.8 E. 200 μl LE (2X)** + 100 μl Ad5bIFNα 39 1 9.9 4 A.","100 μl Media + 100 μl Ad5bIFNα 39 24 9.9 B.","100 μl LAP (4X)* + 100 μl Ad5bIFNα 39 24 9.9 3.100 μl LE + 100 μl Ad5bIFNα 39 24 6.6 4.200 μl Media + 100 μl Ad5bIFNα 39 24 7.5 5.200 μl LE (2X)** + 100 μl Ad5bIFNα 39 24 5.6 Ad5bIFNα virus (without adjuvants) titer expressed in Log10 TCID50 = 10.5 *= Indicates four-fold in the amount of recommended concentration **= Indicates twice the amount of recommended concentration TABLE 12 Ad5O1 virus-Adjuvant Mixture Titers Expressed in Log10 TCID50 Experiment Temperature Incubation Log10 Number Treatment ° C. Time (hrs) TCID50 1 A.","25 μl Media + 100 μl Ad5O1 None 10.6 B.","25 μl LAP + 100 μl Ad5O1 None 10.8 C. 100 μl Media + 100 μl Ad5O1 None 9.6 D. 100 μl LE + 100 μl Ad5O1 None 9.8 2 A.","25 μl Media + 100 μl Ad5O1 20 1 10.8 B.","25 μl LAP + 100 μl Ad5O1 20 1 11.1 C. 100 μl Media + 100 μl Ad5O1 20 1 10.4 D. 100 μl LE + 100 μl Ad5O1 20 1 10.6 3 A.","100 μl Media + 100 μl Ad5O1 39 1 10.0 B.","100 μl LAP (4X)* + 100 μl Ad5O1 39 1 10.1 C. 200 μl Media + 100 μl Ad5O1 39 1 9.5 D. 200 μl LE (2X)** + 100 μl Ad5O1 39 1 9.5 4 A.","100 μl Media + 100 μl Ad5O1 39 24 9.9 B.","100 μl LAP (4X)* + 100 μl Ad5O1 39 24 10.9 C. 100 μl LE + 100 μl Ad5O1 39 24 10.0 D. 200 μl Media + 100 μl Ad5O1 39 24 8.3 E. 200 μl LE (2X)** + 100 μl Ad5O1 39 24 8.0 Ad5O1 virus (without adjuvants) titer expressed in Log10 TCID50 = 11.8 *= Indicates four-fold in the amount of recommended concentration **= Indicates twice the amount of recommended concentration Discussion Alamar Blue is a redox indicator of viable cell number.","At cell density of 10×106/ml, cell clumping was observed, which indicated that there were too many cells in each well at this concentration.","There was no clumping at a cell concentration of 1×106/ml.","Based on this observation, the cell concentration 1×106/ml was employed in the study.","In this study AB was employed to measure 293 cell viability at two cell concentrations.","Optical densities were measured at 570 nm and 600 nm at approximately 42 hours (total culture time), 50 hours, and 68 hours.","The OD data obtained were analyzed using the formula provided by the AB manufacturer.","The % difference in reduction of AB (between media growth control wells and treatment wells) indicated the amount inhibition (or stimulation) of cell growth in treatment wells with respect to media control wells.","Treatments with higher % reductions than media controls are considered to stimulate cell growth.","Treatments with lower % reduction than media controls are considered cytotoxic.","Treatments with the same % reduction are neither cytotoxic nor stimulatory.","A dilution of 1:100 of Ad5bIFNα virus gave the higher % reduction of AB at 42 and 50 hours post exposure to the 293 cells at both 1×106/ml and 10×106/ml.","The 1×106/ml cell concentration would be the best concentration because there was no cell clumping observed at a cell concentration of 1×106/ml.","The 1:100 dilution would be the optimal dilution of Ad5bIFNα virus for 293 cells.","Adjuplex LAP, LE, and emulsigen adjuvants at dilutions of 1:20 gave the highest percent reduction of AB at 42 and 50 hours post exposure to 293 cells.","When LAP and LE were mixed at room temperature with Ad5bIFNα virus and immediately assayed for virus titer, there was no significant reduction in log titer.","A similar result was obtained when the virus-adjuvant mixtures were incubated for one hour.","There was no significant virus titer reduction in the virus-adjuvant mixtures when incubated for one hour at room temperature.","The adjuvant contents of LAP and LE of the mixtures were increased four-fold and two fold, respectively, in order to increase the possibility of these adjuvants having a virucidal effect on the viruses.","However, the reduction in titer was very little.","When the incubation temperature was raised to 39° C. but incubation time remaining the same, there was no appreciable reduction in titer.","The virus-adjuvant mixtures were incubated with 4- and 2-fold in the LAP and LE contents, respectively, for 24 hours (previously it was one hour), there was no reduction in titer of the virus-adjuvant LAP mixture.","However, there was a 1.9 log 10 reduction in titer of the virus-LE mixture.","This reduction was significant (35).","The titer reduction 3.3 log 10 was even greater when the amount of LE in the virus-adjuvant mixture was not increased.","The conclusion drawn from this study was that adjuplex LAP did not have any virucidal effect on Ad5bIFNα virus at the recommended amount and even when the amount was increased by 4.The incubation temperatures and times for this observation were 20° C., 39° C., 1 and 24 hours.","However, the same could not be said for adjuplex LE because although there were no titer reductions when the incubation temperature and time were 39° C. and one hour, when the time of incubation was increased to 24 hours there were significant reductions in virus titers at both concentrations.","Results from this study would suggest that Adjuplex-LE adjuvant produced a virucidal effect on Ad5bIFNα virus when the adjuvant concentration in the mixture was increased two-fold., and also at the recommended concentration.","Similar results were obtained for Ad5O1 virus was mixed with both adjuplex LAP and LE at the recommended quantity and when the amount was increased by 4 fold and 2 fold, respectively.","Furthermore, there were no significant titer reductions even when the mixtures were incubated at 39° C. for 24 hours.","The 39° incubation temperature was selected because that is the average rectal temperature of cattle.","It is recommended that adjuplex LAP should be the adjuvant to be combined with the Ad5bIFNα, Ad5O1 and other Ad5 based FMD sub unit vaccines for clinical evaluation in cattle.","Example 13 Vaccination of Chickens with H5 HA-Transfected Cells and its Effect on Detectable Shedding of Low Pathogenic Avian Influenza Virus Following Challenge by Real-Time Reverse Transcriptase Polymerase Chain Reaction Objective The objective of this study was to challenge chickens vaccinated with H5N2 low pathogenic avian influenza (LPAI) virus and evaluate effect by measuring virus shed from the oropharynx and the cloaca by real-time reverse transcriptase polymerase chain reaction.","Background A further purpose was to evaluate if Chinese Hamster Ovary (CHO) cells, stably transfected with H5 HA expressing plasmid, would stimulate an immune response in birds.","Following one vaccination, seroconversion to H5 HA was noted in a few birds.","The birds were subsequently administered a second dose.","Since the birds seroconverted following one dose, the birds were challenged with H5N2 LPAI virus to determine if the detectable serological response had any effect on virus shed.","Test/Control Articles 1.Generic Name: Media/Lecithin acrylic copolymer plus Quil A cholesterol Formulation: Media—DMEM, fetal calf serum, non-essential amino acids, L-glutamine 2.Generic Name: Control Cells/Lecithin acrylic copolymer plus Quil A cholesterol Formulation: Control cells—CHO cells not expressing HA 3.Generic Name: CHO-HA-10 cells freeze/thaw/Lecithin acrylic copolymer plus Quil A cholesterol Formulation: CHO-HA-10—CHO cells transfected to express HA with a freeze/thaw application 4.Generic Name: CHO-HA-10 cells fresh/Lecithin acrylic copolymer plus Quil A cholesterol Formulation: CHO-HA-10—CHO cells transfected to express HA prepared fresh Challenge Organism Description: LPAI* virus isolate A/TK/CA/209092/02 (H5N2) Origin: National Veterinary Services Laboratory Dosage: Challenge dose of 105.5 ELD50** per 0.1 ml dose Route of Infection: Intranasal *LPAI—Low pathogenic avian influenza**ELD50—Embryo lethal dose 50 TABLE 13 STUDY ANIMALS Species: Chickens Type: SPF Breed/Strain: Leghorn Sex: Male and Female Description: Individually identified Age: 64 days at challenge Origin (chicks) Hy-Vac Total: 15 21459 Old Hwy 6 Adel, Iowa 50003 Birds were transferred from IACUC request BEDA 1197-06-06 for challenge.","TABLE 14 STUDY DESIGN Trt.","Treatment Group Bird LPAI IN* Challenge Sample** No.","Antigen Adjuvant Numbers Day 0 Days T1 None None 3 H5N2 105.5 ELD50# 0 through 6 T2 Media## LAP/QAC† 3 H5N2 105.5 ELD50# 0 through 6 T3 Control cells†† LAP/QAC† 3 H5N2 105.5 ELD50# 0 through 6 T4 CHO-HA-10 cells‡ LAP/QAC† 3 H5N2 105.5 ELD50# 0 through 6 freeze/thaw T5 CHO-HA-10 cells‡ LAP/QAC† 3 H5N2 105.5 ELD50# 0 through 6 fresh *LPAI IN—Low pathogenic avian influenza virus isolate A/TK/CA/209092/02 (H5N2), intranasal administration with 0.1 ml.","**Sample Days—Oropharyngeal and cloacal samples collected.","Samples were evaluated by real-time reverse transcriptase polymerase chain reaction.","On Day 0, blood samples were also collected that were evaluated by hemagglutination inhibition.","#H5N2 105.5 ELD50—Low pathogenic avian influenza isolate A/TK/CA/209092/02 administered intranasally at a dose of 105.5 embryo lethal dose 50 per 0.1 ml challenge inoculum.","##Media—DMEM, fetal calf serum, non-essential amino acids, L-glutamine.","†LAP/QAC—Lecithin acrylic copolymer plus Quil A cholesterol.","††Control cells—CHO cells not expressing HA.","‡CHO-HA-10 cells—CHO cells transfected to express HA.","Procedures Prior to Day 0 Leghorn specific-pathogen-free chicks used in the study were derived from IACUC request BEDA 1197-06-06.Birds were placed in five isolators, three birds per isolator with each isolator housing a treatment group.","Day 0 On Day 0, a blood sample, an oropharyngeal swab, and a cloacal swab were collected from each bird.","Oropharyngeal and cloacal swabs were placed into one ml of culture medium and frozen at approximately −80° C. until processed for viral detection.","Also on Day 0, all birds were exposed by the intranasal route to 0.1 ml of challenge inoculum of LPAI H5N2 isolate according to the table under STUDY DESIGN.","The titer of the inoculum was 105.5 ELD50 per 0.1-ml dose.","Days 1 Through 6 On Days 1 through 6, an oropharyngeal swab and a cloacal swab were collected from each bird in all treatment groups and processed as described previously.","All birds were euthanized and disposed of according to standard operating procedures following sample collection on Day 6.Serum Testing Serum samples collected from birds on Day 0 were analyzed for hemagglutination inhibition (HAI) titers against H5 avian influenza virus (A/Turkey/Wisconsin/68 [H5N9]).","Results of serological testing on serum samples collected from birds while on the BEDA 1197-06-06 IACUC Request Study have been incorporated into this report.","Virus Detection Oropharyngeal swabs collected on Days 0 through 6 and cloacal swabs collected on Days 2 through 6 from birds in treatment groups T1, T3, T4, and T5 were analyzed for viral RNA by RT-rtPCR.","Samples collected from birds in treatment group T2 were not analyzed and cloacal samples collected on Days 0 and 1 from the remaining treatment groups were also not analyzed.","RNA extraction for the RT-rtPCR assay was conducted in the laboratory at 2321 30 Road, Brainard, Nebr.","The RT-rtPCR assay was conducted in the laboratory at 521 West Industrial Lake Drive, Lincoln, Nebr.","Deviations to the Protocol According to the Benchmark Biolabs IACUC proposal (BEDA 1197-06-06) under the direction of standard operating procedure AC-019-01, first vaccination was to take place when birds were four to six weeks of age.","Birds were approximately 26 days of age at time of first vaccination.","This deviation had no impact on the study.","According to the Benchmark Biolabs IACUC proposal (BEDA 1197-06-06) under the direction of standard operating procedure AC-019-01, the media used in treatment group 2 (T2) was to contain fetal calf serum.","However, due to the cost of serum and the fact that the cells used for inoculation in T3, T4, and T5 groups were rinsed, serum was not added as it was determined that the addition or elimination of serum would not effect the antibody response to the test antigen in this study.","Therefore, this deviation had no impact on the study.","Leghorn specific-pathogen-free chicks were used in the study and were derived from IACUC request BEDA 1197-06-06.Birds were to be placed in five isolators, three birds per isolator; however, birds were placed into individual isolators by treatment group rather than by placement of birds from different treatment groups in each isolator.","In addition, the documentation for placement into the isolators was not done.","This deviation impacted the study in that there was no effort to control for isolator effect on individual treatment groups which could have had undetected consequences on one or more treatment groups.","Data Analysis Descriptive statistics were conducted on data collected.","Results and Discussion Table 15.Avian influenza hemagglutination inhibition (HAI) assay titers Table 16.Geometric mean titers for real-time reverse transcriptase polymerase chain reaction assay results on oropharyngeal swab samples Table 17.Geometric mean titers for real-time reverse transcriptase polymerase chain reaction assay results on cloacal swab samples Table 18.Real-time reverse transcriptase polymerase chain reaction assay results on oro-pharyngeal swab samples Table 19.Real-time reverse transcriptase polymerase chain reaction assay results on cloacal swab samples Table 15 lists the results of the avian influenza H5 HAI serological testing.","Following first vaccination on Day −25 on the BEDA 1197-06-06 IACUC Request Study, one of three birds in treatment group T4 and two of three birds in treatment group T5 had detectable H5 serological titers of either 8 or 16.On Day 0, all birds in treatment groups T4 and T5 had seroconverted to H5 with titers ranging from 8 to 128.No birds in treatment groups T1 through T3 had detectable H5 serological titers on either sampling day.","These detectable titers were considered substantial due to the fact that the CHO cells were transfected with H5 (A/Chicken/Scotland 59 [H5N1]) that was heterologous to the H5 antigen in the serological assay (A/Turkey/Wisconsin 68 [H5N9]).","Table 16 lists the geometric mean titer (GMT) results of the oropharyngeal swab testing.","No viral RNA was detected on Day 0 from any treatment groups.","For Days 1 through 6, virus levels were detected by RT-rtPCR in all three T1 birds (negative controls) with the peak mean titer occurring on Day 1 (GMT of 7.00×107 viral copy number) and a secondary peak titer occurring on Day 4 (GMT of 3.37×107 viral copy number).","The viral copy number of the three T1 birds declined to a GMT of 7.55×104 by Day 6.In birds that were administered only non-transfected CHO cells (T3) or CHO cells transfected to express H5 HA (T4 and T5), similar levels of viral copy number were detected on Days 1 through 6 when compared to treatment group T1.This indicates that vaccination with either fresh H5-transfected CHO cells or frozen and thawed H5-transfected CHO cells had no effect on A/TK/CA/209092/02 (H5N2) oropharyngeal viral shedding.","Table 17 lists the geometric mean titer (GMT) results of the cloacal swab testing.","For Days 2 through 6, virus levels were detected by RT-rtPCR in all three T1 birds (negative controls) with the peak mean titer occurring on Day 5 (GMT of 4.78×106 viral copy number).","In general, the shedding was more variable than that detected in oropharyngeal swabs from the same birds.","In birds that were administered only non-transfected CHO cells (T3) or CHO cells transfected to express H5 HA (T4 and T5), generally lower levels of viral copy number were detected on Days 2 through 6 when compared to treatment group T1; however, the results varied greatly from bird to bird and day to day.","This suggests that measuring vaccine effects on fecal shedding via cloacal swabs may be difficult with A/TK/CA/209092/02 (H5N2) and the effect of vaccination in this trial could not be evaluated.","Conclusion It is concluded that vaccination with fresh H5-transfected CHO cells or frozen and thawed H5-transfected CHO cells induced detectable titers in a heterologous H5 antigen serological assay but had no effect on A/TK/CA/209092/02 (H5N2) oropharyngeal viral shedding.","Fecal shedding of A/TK/CA/209092/02 (H5N2) could not be evaluated due to highly variable shedding detected in cloacal swabs.","It is also concluded that Quil A and cholesterol when used in combination with other adjuvant based embodiments described herein have surprising utility in the context of the present invention.","TABLE 15 Avian influenza hemagglutination inhibition (HAI) assay titers H5 HAI H5 HAI Trt.","Treatment Group Bird titer titer No.","Antigen Adjuvant Number Day −25* Day 0** T1 None None 67 <8 <2 68 <8 <2 69 <8 <2 T2 Media# LAP/ 70 <8 <2 QAC## 71 <8 <2 72 <8 <2 T3 Control cells† LAP/ 73 <8 <2 QAC## 74 <8 <2 75 <8 <2 T4 CHO-HA-10 LAP/ 76 8 64 cells†† QAC## 77 <8 64 freeze/thaw 78 <8 128 T5 CHO-HA-10 LAP/ 79 <8 8 cells†† fresh QAC## 80 8 128 81 16 128 *H5 HAI titer Day −25—Hemagglutination inhibition titer to H5N9 avian influenza virus.","**H5 HAI titer Day 0—Hemagglutination inhibition titer to H5N9 avian influenza virus.","#Media—DMEM, non-essential amino acids, L-glutamine.","##LAP/QAC—Lecithin acrylic copolymer plus Quil A cholesterol.","†Control cells—CHO cells not expressing HA.","††CHO-HA-10 cells—CHO cells transfected to express HA.","TABLE 16 Geometric mean titers for real-time reverse transcriptase polymerase chain reaction assay results on oropharyngeal swab samples RT-rtPCR* Number of GMT Trt.","Treatment Group Study birds positive/ viral copy No.","Antigen Adjuvant Day total birds number** T1 None None 0 0/3 0.00 × 100 1 3/3 7.00 × 107 2 3/3 8.32 × 106 3 3/3 1.40 × 107 4 3/3 3.37 × 107 5 3/3 6.64 × 106 6 3/3 7.55 × 104 T2 Media# LAP/ 0 Not done Not done QAC## 1 Not done Not done 2 Not done Not done 3 Not done Not done 4 Not done Not done 5 Not done Not done 6 Not done Not done T3 Control LAP/ 0 0/3 0.00 × 100 cells† QAC## 1 3/3 5.79 × 106 2 3/3 2.37 × 107 3 3/3 6.70 × 106 4 3/3 1.15 × 107 5 3/3 3.80 × 106 6 3/3 1.03 × 106 T4 CHO-HA-10 LAP/ 0 0/3 0.00 × 100 cells†† QAC## 1 3/3 9.33 × 106 freeze/thaw 2 3/3 4.55 × 106 3 3/3 6.46 × 106 4 3/3 4.46 × 107 5 3/3 5.91 × 106 6 3/3 4.39 × 106 T5 CHO-HA-10 LAP/ 0 0/3 0.00 × 100 cells†† fresh QAC## 1 3/3 9.23 × 106 2 3/3 8.17 × 106 3 3/3 1.04 × 107 4 3/3 9.58 × 107 5 3/3 7.87 × 106 6 3/3 2.95 × 106 *RT-rtPCR—Real-time reverse transcriptase polymerase chain reaction assay.","**GMT viral copy number—Geometric mean titer viral copy number.","Samples where no copies were detected were factored as 1 for calculation of GMT.","#Media—DMEM, non-essential amino acids, L-glutamine.","##LAP/QAC—Lecithin acrylic copolymer plus Quil A cholesterol.","†Control cells—CHO cells not expressing HA.","††CHO-HA-10 cells—CHO cells transfected to express HA.","TABLE 17 Geometric mean titers for real-time reverse transcriptase polymerase chain reaction assay results on cloacal swab samples RT-rtPCR* Number of GMT Trt.","Treatment Group Study birds positive/ viral copy No.","Antigen Adjuvant Day total birds number** T1 None None 0 Not done Not done 1 Not done Not done 2 3/3 5.46 × 105 3 3/3 1.34 × 105 4 3/3 5.66 × 105 5 3/3 4.78 × 106 6 3/3 2.03 × 106 T2 Media# LAP/ 0 Not done Not done QAC## 1 Not done Not done 2 Not done Not done 3 Not done Not done 4 Not done Not done 5 Not done Not done 6 Not done Not done T3 Control LAP/ 0 Not done Not done cells† QAC## 1 Not done Not done 2 1/3 3.64 × 101 3 2/3 4.90 × 102 4 3/3 1.13 × 105 5 3/3 3.35 × 105 6 2/3 6.86 × 104 T4 CHO-HA-10 LAP/ 0 Not done Not done cells†† QAC## 1 Not done Not done freeze/thaw 2 2/3 1.05 × 103 3 2/3 1.06 × 104 4 3/3 8.55 × 105 5 3/3 1.12 × 106 6 1/3 1.95 × 102 T5 CHO-HA-10 LAP/ 0 Not done Not done cells†† fresh QAC## 1 Not done Not done 2 3/3 3.31 × 104 3 3/3 5.15 × 104 4 3/3 7.19 × 105 5 3/3 1.39 × 105 6 3/3 1.01 × 106 *RT-rtPCR—Real-time reverse transcriptase polymerase chain reaction assay.","**GMT viral copy number—Geometric mean titer viral copy number.","Samples where no copies were detected were factored as 1 for calculation of GMT.","#Media—DMEM, non-essential amino acids, L-glutamine.","##LAP/QAC—Lecithin acrylic copolymer plus Quil A cholesterol.","†Control cells—CHO cells not expressing HA.","††CHO-HA-10 cells—CHO cells transfected to express HA.","TABLE 18 Real-time reverse transcriptase polymerase chain reaction assay results on oropharyngeal swab samples Bird RT-rtPCR* (Mean viral copy number)** on oropharyngeal swabs Trt.","Group number Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 T1 67 0.00 × 100 2.07 × 108 7.87 × 106 1.67 × 107 2.54 × 107 6.48 × 106 1.91 × 105 Antigen - 68 0.00 × 100 3.70 × 107 7.94 × 106 7.03 × 107 2.00 × 107 3.48 × 106 2.38 × 104 none 69 0.00 × 100 4.48 × 107 9.22 × 106 2.36 × 106 7.56 × 107 1.30 × 107 9.47 × 104 Adjuvant - none T2 70 Not done Not done Not done Not done Not done Not done Not done Media# 71 Not done Not done Not done Not done Not done Not done Not done LAP/QAC## 72 Not done Not done Not done Not done Not done Not done Not done T3 73 0.00 × 100 1.20 × 107 7.44 × 105 1.63 × 107 1.70 × 107 2.19 × 106 4.03 × 106 Control 74 0.00 × 100 9.39 × 106 4.92 × 106 1.25 × 107 5.66 × 106 1.10 × 107 1.40 × 106 cells† 75 0.00 × 100 1.72 × 106 3.63 × 109 1.48 × 106 1.59 × 107 2.26 × 106 1.92 × 105 LAP/QAC## T4 76 0.00 × 100 3.04 × 107 5.57 × 106 1.50 × 107 6.04 × 107 2.86 × 106 1.43 × 106 CHO-HA-10 77 0.00 × 100 1.87 × 107 3.04 × 106 3.86 × 106 6.16 × 107 6.67 × 106 1.05 × 107 cells†† freeze 78 0.00 × 100 1.43 × 106 5.55 × 106 4.65 × 106 2.38 × 107 1.08 × 107 5.63 × 106 thaw LAP/QAC## T5 79 0.00 × 100 4.41 × 106 7.06 × 107 3.05 × 106 1.61 × 107 1.07 × 107 4.65 × 106 CHO-HA-10 80 0.00 × 100 1.51 × 107 5.32 × 106 1.07 × 107 1.23 × 108 1.86 × 107 4.11 × 106 cells†† fresh 81 0.00 × 100 1.18 × 107 1.45 × 106 3.42 × 107 4.43 × 108 2.45 × 106 1.34 × 106 LAP/QAC## *RT-rtPCR—Real-time reverse transcriptase polymerase chain reaction assay.","**Mean titer viral copy number - Samples where no copies were detected were factored as 0 for calculation of means.","#Media - DMEM, non-essential amino acids, L-glutamine ##LAP/QAC—Lecithin acrylic copolymer plus Quil A cholesterol.","†Control cells - CHO cells not expressing HA.","††CHO-HA-10 cells—CHO cells transfected to express HA TABLE 19 Real-time reverse transcriptase polymerase chain reaction assay results on cloacal swab samples Bird RT-rtPCR* (Mean viral copy number)** on cloacal swabs Trt.","Group number Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 T1 67 Not done Not done 2.81 × 108 1.29 × 106 4.42 × 107 6.58 × 108 4.99 × 107 Antigen - 68 Not done Not done 4.34 × 104 5.51 × 104 6.07 × 104 3.94 × 104 1.37 × 104 none 69 Not done Not done 1.34 × 104 3.41 × 104 6.74 × 104 4.21 × 106 1.23 × 107 Adjuvant - none T2 70 Not done Not done Not done Not done Not done Not done Not done Media# 71 Not done Not done Not done Not done Not done Not done Not done LAP/QAC## 72 Not done Not done Not done Not done Not done Not done Not done T3 73 Not done Not done 4.81 × 104 1.48 × 104 8.33 × 104 1.89 × 104 0.00 × 100 Control 74 Not done Not done 0.00 × 100 0.00 × 100 1.75 × 105 8.54 × 106 5.43 × 107 cells† 75 Not done Not done 0.00 × 100 7.96 × 103 9.93 × 104 2.33 × 105 5.95 × 106 LAP/QAC## T4 76 Not done Not done 2.65 × 104 2.61 × 104 2.42 × 105 8.58 × 104 0.00 × 100 CHO-HA-10 77 Not done Not done 0.00 × 100 0.00 × 100 4.69 × 104 2.46 × 105 0.00 × 100 cells†† freeze 78 Not done Not done 4.34 × 104 4.57 × 107 5.51 × 107 6.69 × 107 7.41 × 106 thaw LAP/QAC## T5 79 Not done Not done 2.66 × 104 3.83 × 105 2.02 × 106 2.85 × 106 1.30 × 106 CHO-HA-10 80 Not done Not done 5.84 × 104 1.50 × 104 4.23 × 104 3.90 × 104 1.08 × 107 cells†† fresh 81 Not done Not done 2.34 × 104 2.38 × 104 4.33 × 106 2.44 × 104 7.34 × 104 LAP/QAC## *RT-rtPCR—Real-time reverse transcriptase polymerase chain reaction assay.","**Mean titer viral copy number - Samples where no copies were detected were factored as 0 for calculation of means.","#Media - DMEM, non-essential amino acids, L-glutamine ##LAP/QAC—Lecithin acrylic copolymer plus Quil A cholesterol.","†Control cells - CHO cells not expressing HA.","††CHO-HA-10 cells—CHO cells transfected to express HA.","Example 14 Summary Vaccines prepared with LAP or LAP/QAC adjuvants stimulate serologic responses in poultry, mice, swine, and elicit protection from live NDV challenge in poultry; however, the mechanism of immune response development to these vaccines has not been studied.","The present study was designed to investigate the cytokine profiles of splenic lymphocytes from mice after a prime and boost regimen with LAP or LAP/QAC adjuvant, with and without antigen.","After in vitro stimulation, splenic lymphocytes from some animals vaccinated with LAP+OVA or LAP/QAC+OVA produced increased levels of IL-4 mRNA relative to media controls.","Large variations in IL-4 mRNA expression were observed between animals in each treatments group, suggesting that further optimization of sampling times is required.","Samples were also evaluated for relative expression if IFN-γ and TNF-α; however, increase in expression of these cytokine mRNAs were not observed.","Introduction Cytokine responses that develop after vaccination with LAP or LAP/QAC adjuvants, alone or in combination with antigen, are not well characterized.","Polarized cytokine responses, classified as T-helper 1 (Th1) or T-helper 2 (Th2), are initiated within hours of vaccination.","The nature of the cytokine profile predicts whether the immune response favors cellular (Th1) or humoral (Th2) immunity.","Identification of the cytokines produced after vaccination with LAP or LAP/QAC-adjuvanted vaccines can provide clues about the mechanism of immune induction.","Methods developed through this study facilitate investigation into Th1 and Th2 cytokine responses associated with LAP- and LAP/QAC-adjuvanted vaccines.","TABLE 1 Study Design Bleed/ Vaccination Necropsy Treatment Route of Day Group Vaccine No.","Mice Days Dose Administration Day 16 T1 None 4 N/A N/A N/A 4 mice T2 LAP* 4 0, 14 0.2 ml Subcutaneous 4 mice T3 LAP/QAC† 4 0, 14 0.2 ml Subcutaneous 4 mice T4 Ovalbumin in 4 0, 14 0.2 ml Subcutaneous 4 mice LAP* T5 Ovalbumin in 4 0, 14 0.2 ml Subcutaneous 4 mice LAP/QAC* T6 Ovalbumin 4 0, 14 0.2 ml Subcutaneous 4 mice *Lecithin Acrylic Polymer †Lecithin Acrylic Polymer/Quil A Cholesterol TABLE 2 Treatment Group Vaccine Components: μg per 0.2 ml Dose Treatment Group LAP* QAC** Ovalbumin T1 — — — T2 10001 — — T3 1000 502 — T4 1000 — 50 T5 1000 50 50 T6 — — 50 *Lecithin Acrylic Polymer **Quil A Cholesterol 1600 μg CP; 400 μg Carbopol 934P 225 μg Quil A; 25 μg Cholesterol Methods Study animals were subjected to vaccines at days 0 and 14, and spleens were harvested 48 hours after the second vaccination (day 15) (Table 20).","Concentrations of treatment group vaccines are shown in Table 21.Splenic lymphocytes from each animal were isolated by gradient centrifugation and cultured in vitro with media, ConA (10 μm/ml), LAP (6.2 μg/ml), LAP/QAC (6.2/0.062 μg/ml), or OVA (10 μg/ml).","Additional in vitro treatments (culture with LAP+OVA and LAP/QAC+OVA) were performed if there were sufficient numbers of lymphocytes.","For the additional treatments, OVA was added to cells first, and LAP or LAP/QAC was added to cells last.","At approximately 24 and 48 hours in culture, samples were collected and RNA was isolated.","RNA samples were analyzed by real time RT-PCR assays for expression of cytokine genes (TNF-α, IL-4, IFN-γ).","Levels of cytokine gene expression were normalized to expression of one housekeeping gene: hypoxanthine guanine phosphoribosyl transferase (HPRT) or acidic ribosomal phosphoprotein PO (ARBP).","Relative levels of cytokine gene expression were calculated, using the normalized values, for in vitro treatments with respect to the media controls.","A positive result is indicated by a relative expression ratio greater than 2, which shows cytokine gene expression for in vitro treated samples that is at least twice the level of expression observed in media control samples.","Results Relative expression of IL-4 mRNA was evaluated for samples from all treatment groups after 24 to 48 hours in culture (FIG.","13A, B).","Samples collected after 24 hours in culture with treatments as listed above (see Methods) using ARBP as the housekeeping gene for normalization purposes.","The highest relative expression levels of IL-4 were observed in samples from vaccine treatment groups T4 (LAP+OVA) and T5 (LAP/QAC+OVA).","Samples from vaccine treatment groups T1 (no vaccine), T3 (LAP/QAC), and T6 (OVA) were also evaluated at 48 hours in culture using ARBP as the housekeeping gene.","Increased IL-4 expression was observed for some animals in each group after 48 hours in culture with LPA, LAP/QAC or OVA.","Unexpectedly, ConA-treated samples did not have increased levels of IL-4 expression with respect to media controls; however, increases observed in samples from T4 and T5 indicate that cells were viable and were able to produce cytokines.","In order to determine whether relative expression ratios would be greater if an alternative housekeeping gene were used, samples collected after 48 hours in culture were assayed using HPRT as the housekeeping gene for normalization purposes (FIG.","14).","Increased relative expression of IL-4 was observed for vaccine treatment groups T4 (LAP+OVA) and T5 (LAP/QAC+OVA) after in vitro stimulation with LAP.","In vitro treatment with LAP/QAC stimulated IL-4 mRNA production in samples from T2 (LAP) and T5 (LAP/QAC+OVA).","Increases in relative IL-4 mRNA expression were also seen in cells from vaccine treatment groups T1 (no vaccine), T2 (LAP), and T5 (LAP/QAC+OVA) after incubation with OVA.","Relative expression levels of IFN-γ and TNF-α were also evaluated for in vitro stimulated samples (FIG.","15 A, B; FIG.","16 A, B).","No significant increases in these cytokines were observed.","Positive control samples (ConA stimulated) were evaluated for selected samples; however, these control samples did not have increased levels of either cytokine in comparison to negative control samples (media treated).","Samples from some animals were treated in vitro with LAP+OVA or LAP/QAC+OVA and relative expression of IL-4 mRNA was evaluated (FIG.","17).","Increases in IL-4 expression were observed for 48 hour samples from one animal (1-3) from treatment group T1 after in vitro stimulation with LAP+OVA and LAP/QAC+OVA.","Analysis of samples treated in vitro with LAP+OVA or LAP/QAC were also analyzed for relative expression of IFNγ with HPRT as the housekeeping gene.","Relative expression ratios for these samples were all less than 1, indicating that IFNγ expression levels in treated cells were lower than the levels observed for media controls (data not shown).","CONCLUSION The highest average relative expression ratios were observed for IL-4/ARBP in samples collected at 24 hours of culture.","Samples from treatment groups T4 (LAP+OVA) and T5 (LAP/QAC+OVA) showed the greatest increases in relative expression of IL-4 message (FIG.","1A, B).","Analysis of samples from individual animals showed that there were large variations in IL-4 expression ratios among animals in these treatment groups.","Cells from one animal in treatment group T1 had increased IL-4 mRNA expression after 48 hours in vitro stimulation with LAP+OVA and LAP/QAC+OVA.","Positive control samples (ConA stimulated) did not show increased cytokine expression as expected.","Increases observed in IL-4 expression in some samples indicate that cells were capable of producing cytokines; however, further optimization of assay conditions is needed to determine culture times at which cytokine expression is at a maximum.","No significant increases in relative expression levels of IFN-γ or TNF-α were observed.","Because ConA positive controls did not show increased expression of IFN-γ or TNF-α, further optimization of assays for detection of these cytokines may be warranted.","Having described the invention with reference to particular compositions, theories of effectiveness, and the like, it will be apparent to those of skill in the art that it is not intended that the invention be limited by such illustrative embodiments or mechanisms, and that modifications can be made without departing from the scope or spirit of the invention, as defined by the appended claims.","It is intended that all such obvious modifications and variations be included within the scope of the present invention as defined in the appended claims.","The claims are meant to cover the claimed components and steps in any sequence which is effective to meet the objectives there intended, unless the context specifically indicates to the contrary."]],"string":"[\n [\n \"ADJUVANT AND VACCINE COMPOSITIONS\",\n \"Methods are provided for preparing and delivering an adjuvant for vaccines including lecithin, polymer and one or more additives.\",\n \"The polymer is preferably polyacrylic acid-based.\",\n \"The additive is preferably one or more of a glycoside and a sterol.\",\n \"The method of preparation includes hydrating lecithin and a polymer in saline or water and mixing the lecithin and polymer to form the adjuvant.\",\n \"Additives can be included prior to or after hydration of the lecithin and polymer.\"\n ],\n [\n \"1.An adjuvant composition comprising a lecithin, a polymer, Quil A and cholesterol wherein the lecithin to polymer ratio is 1:10 to 10:1 by weight and wherein the weight of the Quil A and cholesterol combined is up to about 10% of the weight of the lecithin and polymer combined.\",\n \"2.The adjuvant composition of claim 1 wherein the polymer is an acrylic polymer selected from the group consisting of polyacrylic acid, methacrylic acid, methacrylate, acrylamide, acrylate, poly (acrylamide-co butyl, methacrylate), acrylic-methacrylic acid, acrylic-acrylamide, poly (methacrylate) and alkyl-esters of poly acrylic acid.\",\n \"3.The adjuvant composition of claim 1 further comprising an antigen.\",\n \"4.The adjuvant composition of claim 3 wherein the antigen is DNA based.\",\n \"5.The adjuvant composition of claim 1 further comprising calcium phosphate.\",\n \"6.An adjuvant composition consisting of a lecithin, a polymer, Quil A and cholesterol, wherein the lecithin to polymer ratio is 1:10 to 10:1 by weight and wherein the weight of the Quil A and cholesterol combined is up to about 10% of the weight of the lecithin and polymer combined.\",\n \"7.The adjuvant composition of claim 6 wherein the polymer is an acrylic polymer.\",\n \"8.A vaccine composition consisting of a lecithin, a polymer, a glycoside, a sterol, and a DNA based antigen, wherein the lecithin to polymer ratio is 1:10 to 10:1 by weight and wherein the weight of the glycoside and sterol combined is up to about 10% of the weight of the lecithin and polymer combined.\",\n \"9.A vaccine composition consisting of a lecithin, a polymer, a glycoside, a sterol, a DNA based antigen and calcium phosphate, wherein the lecithin to polymer ratio is 1:10 to 10:1 by weight and wherein the weight of the glycoside and sterol combined is up to about 10% of the weight of the lecithin and polymer combined.\",\n \"10.A method for preparing a vaccine comprising: combining a dry lecithin, an acrylic polymer, a glycoside and a sterol, wherein the dry lecithin to acrylic polymer are at a ratio of 1:10 to 10:1 by weight and wherein the weight of the glycoside and sterol combined is up to about 10% of the weight of the lecithin and polymer combined; suspending the combined lecithin, acrylic polymer, glycoside and sterol in saline or water; and mixing the lecithin, acrylic polymer, glycoside and sterol sufficiently to form a netlike structure; wherein an antigen is added before or after suspension of the dry lecithin, acrylic polymer, glycoside and sterol such that a vaccine is formed and wherein the vaccine is used to elicit an immune response against an infectious agent, cancer, hormone, or autoimmune disease; and wherein the glycoside is Quil A and the sterol is cholesterol.\",\n \"11.The method of claim 10 wherein the antigen is DNA based and further comprising addition of calcium phosphate prior to or after mixing of the lecithin, acrylic polymer, glycoside and sterol.\"\n ],\n [\n \"<SOH> BACKGROUND <EOH>Mucosal delivery of vaccines has been underutilized because of the problems associated with effectively delivering the vaccine antigens to the mucosal surface and to the underlying mucosal lymphoid tissue.\",\n \"Since mucosal surfaces are the port of entry of the majority of the infectious agents (Sabin, A.\",\n \"B., Vaccination at the portal of entry of infectious agents.\",\n \"Dev Biol Stand 33:3-9, 1976) it is important to the health of an animal to have developed a strong protective antibody and cell-mediated immune response at the portal of entry.\",\n \"This is best done with an adjuvant and delivery system that targets vaccine antigens to either the mucous membranes of the oral cavity, gut, nose, rectum, or vagina.\",\n \"Because this is not commonly done with an injectable vaccine, it would be advantageous to have a vaccine adjuvant delivery composition that would adsorb the vaccine onto the mucosal surface, and then, following absorption, be brought in contact with mucosal-associated lymphoid tissue.\",\n \"For example, oral administration of a vaccine against a gut pathogen may engender a stronger immune response against such pathogens by eliciting the production of secretory immunoglobulin A antibodies at the mucosal site.\",\n \"This happens when the vaccine is presented to the gut-associated lymphoid tissue (O'Hagen, D, Oral Delivery of Vaccines: Formulation and Clinical Pharmacokinetic Considerations 1992, Clin.\",\n \"Pharmacokinet.\",\n \"22 (1): 1-10).\",\n \"Likewise, administration of vaccine against an upper respiratory pathogen may be most effective if delivered to the mucosal-associated lymphoid tissue in the oral cavity or nasal passages.\",\n \"Interestingly, administration of antigens induces a mucosal immune response not only at the site of antigen application, for example the oral mucosa, but also at other mucosal sites such as the nasal mucosal (Mestecky, J I, The Common Mucosal Immune System and Current Strategies for Induction of Immune Responses in External Secretions.\",\n \"J Clin Immunol.\",\n \"7 (4): 265-76).\",\n \"Vaccinating large numbers of animals, such as cattle, swine and poultry, is extremely labor intensive and expensive.\",\n \"Each individual animal has to be handled at the time of vaccination in order to inject the animal with the vaccine.\",\n \"Most often the vaccine must be administered to the animal at least twice, and sometimes three or more times.\",\n \"It would be advantageous in terms of time and expense if the vaccine could be administered, simultaneously, with feed or water to a large number of animals.\",\n \"Another advantage of targeting the vaccine to mucosal surfaces is that the vaccine can stimulate a protective immune response in the presence of circulating antibody that interferes with parenterally injected vaccines (Periwal, S B, et.\",\n \"al., Orally administered microencapsulated reovirus can bypass suckled, neutralizing maternal antibody that inhibits active immunization of neonates.\",\n \"J Virol 1997 (April 71(4): 2844-50)).\",\n \"Adjuvant systems to enhance an animal's immune response to a vaccine antigen are well known.\",\n \"Likewise, systems for the delivery of vaccine and drugs to mucosal surfaces are known.\",\n \"Different methods have been described to protect the vaccine antigen and drugs from degradation by stomach acid and digestive enzymes and to adsorb the antigen to the mucosal surface.\",\n \"Often these adjuvants and delivery systems include mixing the antigen with one or more components.\",\n \"Exemplary adjuvants include the following: U.S. Pat.\",\n \"No.\",\n \"4,917,892, Speaker et al, issued Apr.\",\n \"17, 1990, describes a topical delivery system comprising a viscous carrier containing a dissolved or dispersed active agent and active agent microencapsulated within a semi permeable anisotropic salt film which is the emulsion reaction product of a) a partially lipophilic, partially hydrophilic, polyfunctional Lewis acid or salt thereof in aqueous medium, such as carboxymethylcellulose, an alkali metal salt of polyacrylic acid or cross linked polyacrylic acid/polyoxyethylene, with b) a Lewis base or salt thereof in a water-immiscible, slightly polar organic solvent for the base, such as benzalkonium chloride, and piperidine.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,132,117, Speaker et al., issued Jul.\",\n \"21, 1992, discloses a microcapsule with an aqueous core, capsular, ionic stabilized anisotropic Lewis salt membrane formed from the interfacial reaction product of an emulsion of an aqueous solution of a water-soluble, hydrophilic polymeric Lewis acid or salt thereof with a non-aqueous solution of a lipophilic Lewis base or salt thereof.\",\n \"The Lewis base may be stearylamine, piperidine, or benzalkonium chloride and the Lewis acid may be carboxymethylcellulose, polyacrylic acid, or polyacrylic acid/polyoxyethylene copolymer, for example.\",\n \"U.S. Pat.\",\n \"No.\",\n \"4,740,365, Yukimatsu et al., issued Apr.\",\n \"26, 1988 describes a sustained-release preparation applicable to mucous membranes in the oral cavity.\",\n \"The preparation consists of an active ingredient in a mixture of a polymer component (A) comprising one or more polymers selected from polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, alginic acid or a salt thereof, and an alternating copolymer of maleic anhydride and methyl vinyl ether and a polymer component (B) comprising one or more polymers selected from polyacrylic acid and a salt thereof.\",\n \"Polymer component (A) and (B) are in a ratio of 95:5 to 5:95 by weight.\",\n \"The preparation is layered with the active ingredient and may have optional conventional carriers and additives.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,451,411, Gombotz et al., issued Sep. 19, 1995, describes a delivery system for a cationic therapeutic agent whereupon alginate has been cross-linked in the presence of the therapeutic agent and polyacrylic acid to obtain a sustained release composition for oral delivery.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,352,448, Bowersock et al., issued Oct. 4, 1994, describes an oral vaccine formulation comprising an enzymatically degradable antigen in a hydrogel matrix for stimulation of an immune response in gut-associated lymphoid tissues.\",\n \"The hydrogel pellets are preferably synthesized by polymerizing methacrylic acid, in the presence of methylene bis-acrylamide and ammonium persulfate and sodium bisulfite.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,674,495, Bowersock et al., issued Oct. 7, 1997, describes a vaccine composition for oral administration comprising an alginate gel in the form of discrete particles.\",\n \"The alginate gel may contain a polymer coating such a poly-1-lysine to enhance stability and to add a positive charge to the surface.\",\n \"U.S. Pat.\",\n \"No.\",\n \"4,944,942, Brown et al., issued Jul.\",\n \"31, 1990, describes an intranasal vaccine for horses, which may comprise polyacrylic acid cross linked polyallyl sucrose combined with polyoxyethylene sorbitan mono-oleate and sorbitan monolaurate, preferably at 7.5 to 15 volume percent based on the total volume of the formulation, as an adjuvant.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,500,161, Andrianov et al., issued Mar.\",\n \"19, 1996, describes a method for the preparation of microparticles, and the product thereof, that includes dispersing a substantially water insoluble non-ionic or ionic polymer in a aqueous solution in which the substance to be delivered is also dissolved, dispersed or suspended, and then coagulating the polymer together with the substance by impact forces to form a microparticle.\",\n \"Alternatively, the microparticle is formed by coagulation of an aqueous polymeric dispersion through the use of electrolytes, pH changes, organic solvents in low concentrations, or temperature changes to form polymer matrices encapsulating biological materials.\",\n \"U.S. Pat.\",\n \"No.\",\n \"6,015,576, See et al., issued Jan. 18, 2000, describes a method that comprises orally administering lyophilized multilamellar liposomes containing the antigen wherein the liposome preparation is contained in a pill form or within an enterically coated capsule.\",\n \"Such an enteric coating may be composed of acrylic polymers and copolymers.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,811,128, Tice et al., issued Sep. 22, 1998, describes a method, and compositions for delivering a bioactive agent to an animal entailing the steps of encapsulating effective amounts of the agent in a biocompatible excipient to form microcapsules having a size less than approximately ten micrometers and administering effective amounts of the microcapsules to the animal.\",\n \"A pulsatile response is obtained, as well as mucosal and systemic immunity.\",\n \"The biocompatible excipient is selected from the group consisting of poly (DL-lactide-co-glycolide), poly (lactide), poly (glycolide), copolyoxalates, polycaprolactone, polyorthoesters and poly (beta-hydroxybutyric acid), polyanhydrides and mixtures thereof.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,565,209, Rijke, issued Oct. 15, 1996, describes oil-free vaccines comprising polyoxypropylene-polyoxyethylene polyols and an acrylic acid polymer as adjuvant constituents for injectable vaccines.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,084,269, Kullenberg, issued Jan. 28, 1992, describes an adjuvant, comprised of lecithin in combination with a carrier which may be selected from the group consisting of non-edible oil such as mineral oil and edible triglyceride oils such as soybean oil, for an injectable vaccine.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,026,543, Rijke, issued Jun.\",\n \"25, 1991, discloses oil-free vaccines which contain polyoxypropylene-polyoxyethylene polyols as well as an acrylic acid polymer as adjuvanting constituents.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,451,411, Gombotz et al, issued Sep. 19, 1995, discloses alginate beads as a site specific oral delivery system for cationic therapeutic agents designed to target the agents to the luminal side of the small intestine.\",\n \"Enhanced bioactivity of therapeutic agents released from the alginate is attributed to the ability of polyacrylic acid to shield the agents from interaction with lower molecular weight fragments of acid treated alginate.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,567,433, Collins, issued Oct. 22, 1996, discloses a method of producing liposomes useful for encapsulating and delivering a wide variety of biologically active materials.\",\n \"The method involves the formation of a liposome dispersion in the absence of an organic solvent or detergent, one or several cycles of freezing and thawing, and dehydration to form a lipid powder.\",\n \"The powder is hydrated in the presence of a biologically active material to encapsulate it in the liposomes.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,091,188, Haynes, issued Feb. 25, 1992, discloses water-insoluble drugs rendered injectable by formulation as aqueous suspensions of phospholipid-coated microcrystals.\"\n ],\n [\n \"<SOH> SUMMARY <EOH>The present invention concerns an adjuvant composition that includes lecithin and a polymer that is preferably an acrylic polymer or copolymer.\",\n \"An exemplary acrylic polymer is a polyacrylic acid polymer.\",\n \"Any lecithin is contemplated herein, including individual phospholipid components of lecithin or any combination thereof.\",\n \"In some embodiments, the present invention also concerns lecithin and polymer adjuvant compositions that include one or more additives that facilitate an immune response, including glycosides, sterols, ISCOMS, muramyl dipeptide and analogues, pluronic polyols, trehalose dimycolate, amine containing compounds, cytokines, calcium and lipopolysaccharide derivatives.\",\n \"Exemplary additives are glycosides and sterols, where the glycoside can be Quil A and the sterol can be cholesterol.\",\n \"The present invention also includes an adjuvant composition that consists of only a lecithin and polymer, and does not include additional lipid components.\",\n \"Typical polymers are acrylic polymer or copolymer.\",\n \"In one particular embodiment the adjuvant consists of lecithin and polyacrylic acid polymer.\",\n \"The present invention also includes an adjuvant composition that consists of a lecithin and polymer adjuvant composition in combination with one or more glycosides and/or one or more sterols.\",\n \"In some embodiments the adjuvant composition consists of lecithin, polymer, a glycoside and a sterol, where the glycoside can be a saponin or any fraction thereof and the sterol can be, for example, cholesterol.\",\n \"In some embodiments the polymer is an acrylic polymer or copolymer, for example, polyacrylic acid polymer.\",\n \"In general, the lecithin and polymer adjuvants herein form a matrix or net-like structure which is effective in trapping or encapsulating vaccine antigen.\",\n \"In some cases, the lecithin and polymer adjuvant combination form an “oil-free” net-like structure, being composed predominately (and in some cases entirely) by phospholipids and acrylic polymer.\",\n \"In other cases, the lecithin and polymer adjuvant includes additives directed toward further facilitating the adjuvant's capacity to elicit an immune response.\",\n \"The strong mucoadhesive and adsorptive properties of the polymer and lecithin combination enhances the adsorption of vaccine antigen onto mucosal surfaces.\",\n \"Further, the lecithin composition enhances absorption (Swenson, E S and W J Curatolo, ©Means to Enhance Penetration (2) Intestinal permeability enhancement for proteins, peptides and other polar drugs: mechanisms and potential toxicity.\",\n \"Advanced Drug Delivery Reviews.\",\n \"1992.8:39-92) that helps bring the antigen in contact with the underlying lymphoid tissue.\",\n \"Embodiments herein provide a significant improvement over conventional vaccines for delivery of an antigen to a mucosal surface, particularly where the adjuvant does not include the significant proportion or ratio of polymer, as shown in the inventive embodiments herein.\",\n \"The adjuvant compositions of this invention make it possible to vaccinate via a mucosal surface, such as oral cavity, gut, nasal, rectal, or vaginal surfaces.\",\n \"The vaccine may be administered by pill or tablet form, a paste form or in fluid form using a dropper or needleless syringe.\",\n \"This adjuvant composition allows a method of vaccination via food and/or water.\",\n \"In addition, the adjuvant compositions herein facilitate robust mucosal immunity, an advancement over conventional administration techniques for a number of antigens.\",\n \"In an alternative embodiment the composition can be used traditionally as an injectable.\",\n \"Thus, there is provided a method for preparing an adjuvant composition comprising: hydrating lecithin and a polymer in saline or water; and mixing the lecithin and polymer to form an adjuvant.\",\n \"In some embodiments, the lecithin and the polymer can be mixed by placing the lecithin and the polymer in a blender.\",\n \"Advantageously, the lecithin and the polymer can be mixed in the presence of surfactants.\",\n \"In some instances the lecithin and polymer are mixed in the presence of other additives, for example: a glycoside and/or sterol.\",\n \"In some embodiments, the method further includes the step of microwaving or autoclaving the adjuvant.\",\n \"In some embodiments, the method further includes the step of not filtering the adjuvant.\",\n \"In one embodiment, from about 0.001-10% by weight dry lecithin and from about 0.001-10% by weight polymer are hydrated.\",\n \"In some implementations the polymer is also dry and the lecithin and polymer are mixed dry prior to hydration.\",\n \"In this implementation, the method further includes the step of adding an antigen.\",\n \"Advantageously, the antigen is added during the hydration step.\",\n \"In another advantageous embodiment, the antigen is added to the adjuvant.\",\n \"The lecithin and the polymer can be mixed in the presence of an oil.\",\n \"Adjuvants of the invention can be mixed by placing the lecithin and the polymer in a microfluidizer.\",\n \"Alternative implementations include adding a calcium based compound to the adjuvants described herein where a DNA based antigen is implemented in the vaccine.\",\n \"Further features and advantages of the present invention will be set forth in, or apparent from, the detailed description which follows.\"\n ],\n [\n \"This application is a Continuation of U.S. patent application Ser.\",\n \"No.\",\n \"14/385,144, entitled “Adjuvant and Vaccine Compositions,” filed Sep. 12, 2014, which is a 371 of International PCT Application No.\",\n \"PCT/US2013/030515, filed Mar.\",\n \"12, 2013, entitled “Adjuvant and Vaccine Compositions,” and claims priority under 35 U.S.C.\",\n \"119(e) to U.S.\",\n \"Provisional Patent Application Ser.\",\n \"No.\",\n \"61/609,783, entitled “Adjuvant and Vaccine Compositions,” filed Mar.\",\n \"12, 2012, the disclosures of which are hereby incorporated by reference in their entirety.\",\n \"FIELD Provided herein are compositions and methods for preparing and delivering vaccine to a patient or animal in need thereof and in particular, to compositions and methods for preparing novel adjuvant compositions and delivering vaccines that include these novel adjuvant compositions to a patient or animal in need thereof.\",\n \"BACKGROUND Mucosal delivery of vaccines has been underutilized because of the problems associated with effectively delivering the vaccine antigens to the mucosal surface and to the underlying mucosal lymphoid tissue.\",\n \"Since mucosal surfaces are the port of entry of the majority of the infectious agents (Sabin, A.\",\n \"B., Vaccination at the portal of entry of infectious agents.\",\n \"Dev Biol Stand 33:3-9, 1976) it is important to the health of an animal to have developed a strong protective antibody and cell-mediated immune response at the portal of entry.\",\n \"This is best done with an adjuvant and delivery system that targets vaccine antigens to either the mucous membranes of the oral cavity, gut, nose, rectum, or vagina.\",\n \"Because this is not commonly done with an injectable vaccine, it would be advantageous to have a vaccine adjuvant delivery composition that would adsorb the vaccine onto the mucosal surface, and then, following absorption, be brought in contact with mucosal-associated lymphoid tissue.\",\n \"For example, oral administration of a vaccine against a gut pathogen may engender a stronger immune response against such pathogens by eliciting the production of secretory immunoglobulin A antibodies at the mucosal site.\",\n \"This happens when the vaccine is presented to the gut-associated lymphoid tissue (O'Hagen, D, Oral Delivery of Vaccines: Formulation and Clinical Pharmacokinetic Considerations 1992, Clin.\",\n \"Pharmacokinet.\",\n \"22 (1): 1-10).\",\n \"Likewise, administration of vaccine against an upper respiratory pathogen may be most effective if delivered to the mucosal-associated lymphoid tissue in the oral cavity or nasal passages.\",\n \"Interestingly, administration of antigens induces a mucosal immune response not only at the site of antigen application, for example the oral mucosa, but also at other mucosal sites such as the nasal mucosal (Mestecky, J I, The Common Mucosal Immune System and Current Strategies for Induction of Immune Responses in External Secretions.\",\n \"J Clin Immunol.\",\n \"7 (4): 265-76).\",\n \"Vaccinating large numbers of animals, such as cattle, swine and poultry, is extremely labor intensive and expensive.\",\n \"Each individual animal has to be handled at the time of vaccination in order to inject the animal with the vaccine.\",\n \"Most often the vaccine must be administered to the animal at least twice, and sometimes three or more times.\",\n \"It would be advantageous in terms of time and expense if the vaccine could be administered, simultaneously, with feed or water to a large number of animals.\",\n \"Another advantage of targeting the vaccine to mucosal surfaces is that the vaccine can stimulate a protective immune response in the presence of circulating antibody that interferes with parenterally injected vaccines (Periwal, S B, et.\",\n \"al., Orally administered microencapsulated reovirus can bypass suckled, neutralizing maternal antibody that inhibits active immunization of neonates.\",\n \"J Virol 1997 (April 71(4): 2844-50)).\",\n \"Adjuvant systems to enhance an animal's immune response to a vaccine antigen are well known.\",\n \"Likewise, systems for the delivery of vaccine and drugs to mucosal surfaces are known.\",\n \"Different methods have been described to protect the vaccine antigen and drugs from degradation by stomach acid and digestive enzymes and to adsorb the antigen to the mucosal surface.\",\n \"Often these adjuvants and delivery systems include mixing the antigen with one or more components.\",\n \"Exemplary adjuvants include the following: U.S. Pat.\",\n \"No.\",\n \"4,917,892, Speaker et al, issued Apr.\",\n \"17, 1990, describes a topical delivery system comprising a viscous carrier containing a dissolved or dispersed active agent and active agent microencapsulated within a semi permeable anisotropic salt film which is the emulsion reaction product of a) a partially lipophilic, partially hydrophilic, polyfunctional Lewis acid or salt thereof in aqueous medium, such as carboxymethylcellulose, an alkali metal salt of polyacrylic acid or cross linked polyacrylic acid/polyoxyethylene, with b) a Lewis base or salt thereof in a water-immiscible, slightly polar organic solvent for the base, such as benzalkonium chloride, and piperidine.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,132,117, Speaker et al., issued Jul.\",\n \"21, 1992, discloses a microcapsule with an aqueous core, capsular, ionic stabilized anisotropic Lewis salt membrane formed from the interfacial reaction product of an emulsion of an aqueous solution of a water-soluble, hydrophilic polymeric Lewis acid or salt thereof with a non-aqueous solution of a lipophilic Lewis base or salt thereof.\",\n \"The Lewis base may be stearylamine, piperidine, or benzalkonium chloride and the Lewis acid may be carboxymethylcellulose, polyacrylic acid, or polyacrylic acid/polyoxyethylene copolymer, for example.\",\n \"U.S. Pat.\",\n \"No.\",\n \"4,740,365, Yukimatsu et al., issued Apr.\",\n \"26, 1988 describes a sustained-release preparation applicable to mucous membranes in the oral cavity.\",\n \"The preparation consists of an active ingredient in a mixture of a polymer component (A) comprising one or more polymers selected from polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, alginic acid or a salt thereof, and an alternating copolymer of maleic anhydride and methyl vinyl ether and a polymer component (B) comprising one or more polymers selected from polyacrylic acid and a salt thereof.\",\n \"Polymer component (A) and (B) are in a ratio of 95:5 to 5:95 by weight.\",\n \"The preparation is layered with the active ingredient and may have optional conventional carriers and additives.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,451,411, Gombotz et al., issued Sep. 19, 1995, describes a delivery system for a cationic therapeutic agent whereupon alginate has been cross-linked in the presence of the therapeutic agent and polyacrylic acid to obtain a sustained release composition for oral delivery.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,352,448, Bowersock et al., issued Oct. 4, 1994, describes an oral vaccine formulation comprising an enzymatically degradable antigen in a hydrogel matrix for stimulation of an immune response in gut-associated lymphoid tissues.\",\n \"The hydrogel pellets are preferably synthesized by polymerizing methacrylic acid, in the presence of methylene bis-acrylamide and ammonium persulfate and sodium bisulfite.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,674,495, Bowersock et al., issued Oct. 7, 1997, describes a vaccine composition for oral administration comprising an alginate gel in the form of discrete particles.\",\n \"The alginate gel may contain a polymer coating such a poly-1-lysine to enhance stability and to add a positive charge to the surface.\",\n \"U.S. Pat.\",\n \"No.\",\n \"4,944,942, Brown et al., issued Jul.\",\n \"31, 1990, describes an intranasal vaccine for horses, which may comprise polyacrylic acid cross linked polyallyl sucrose combined with polyoxyethylene sorbitan mono-oleate and sorbitan monolaurate, preferably at 7.5 to 15 volume percent based on the total volume of the formulation, as an adjuvant.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,500,161, Andrianov et al., issued Mar.\",\n \"19, 1996, describes a method for the preparation of microparticles, and the product thereof, that includes dispersing a substantially water insoluble non-ionic or ionic polymer in a aqueous solution in which the substance to be delivered is also dissolved, dispersed or suspended, and then coagulating the polymer together with the substance by impact forces to form a microparticle.\",\n \"Alternatively, the microparticle is formed by coagulation of an aqueous polymeric dispersion through the use of electrolytes, pH changes, organic solvents in low concentrations, or temperature changes to form polymer matrices encapsulating biological materials.\",\n \"U.S. Pat.\",\n \"No.\",\n \"6,015,576, See et al., issued Jan. 18, 2000, describes a method that comprises orally administering lyophilized multilamellar liposomes containing the antigen wherein the liposome preparation is contained in a pill form or within an enterically coated capsule.\",\n \"Such an enteric coating may be composed of acrylic polymers and copolymers.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,811,128, Tice et al., issued Sep. 22, 1998, describes a method, and compositions for delivering a bioactive agent to an animal entailing the steps of encapsulating effective amounts of the agent in a biocompatible excipient to form microcapsules having a size less than approximately ten micrometers and administering effective amounts of the microcapsules to the animal.\",\n \"A pulsatile response is obtained, as well as mucosal and systemic immunity.\",\n \"The biocompatible excipient is selected from the group consisting of poly (DL-lactide-co-glycolide), poly (lactide), poly (glycolide), copolyoxalates, polycaprolactone, polyorthoesters and poly (beta-hydroxybutyric acid), polyanhydrides and mixtures thereof.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,565,209, Rijke, issued Oct. 15, 1996, describes oil-free vaccines comprising polyoxypropylene-polyoxyethylene polyols and an acrylic acid polymer as adjuvant constituents for injectable vaccines.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,084,269, Kullenberg, issued Jan. 28, 1992, describes an adjuvant, comprised of lecithin in combination with a carrier which may be selected from the group consisting of non-edible oil such as mineral oil and edible triglyceride oils such as soybean oil, for an injectable vaccine.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,026,543, Rijke, issued Jun.\",\n \"25, 1991, discloses oil-free vaccines which contain polyoxypropylene-polyoxyethylene polyols as well as an acrylic acid polymer as adjuvanting constituents.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,451,411, Gombotz et al, issued Sep. 19, 1995, discloses alginate beads as a site specific oral delivery system for cationic therapeutic agents designed to target the agents to the luminal side of the small intestine.\",\n \"Enhanced bioactivity of therapeutic agents released from the alginate is attributed to the ability of polyacrylic acid to shield the agents from interaction with lower molecular weight fragments of acid treated alginate.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,567,433, Collins, issued Oct. 22, 1996, discloses a method of producing liposomes useful for encapsulating and delivering a wide variety of biologically active materials.\",\n \"The method involves the formation of a liposome dispersion in the absence of an organic solvent or detergent, one or several cycles of freezing and thawing, and dehydration to form a lipid powder.\",\n \"The powder is hydrated in the presence of a biologically active material to encapsulate it in the liposomes.\",\n \"U.S. Pat.\",\n \"No.\",\n \"5,091,188, Haynes, issued Feb. 25, 1992, discloses water-insoluble drugs rendered injectable by formulation as aqueous suspensions of phospholipid-coated microcrystals.\",\n \"SUMMARY The present invention concerns an adjuvant composition that includes lecithin and a polymer that is preferably an acrylic polymer or copolymer.\",\n \"An exemplary acrylic polymer is a polyacrylic acid polymer.\",\n \"Any lecithin is contemplated herein, including individual phospholipid components of lecithin or any combination thereof.\",\n \"In some embodiments, the present invention also concerns lecithin and polymer adjuvant compositions that include one or more additives that facilitate an immune response, including glycosides, sterols, ISCOMS, muramyl dipeptide and analogues, pluronic polyols, trehalose dimycolate, amine containing compounds, cytokines, calcium and lipopolysaccharide derivatives.\",\n \"Exemplary additives are glycosides and sterols, where the glycoside can be Quil A and the sterol can be cholesterol.\",\n \"The present invention also includes an adjuvant composition that consists of only a lecithin and polymer, and does not include additional lipid components.\",\n \"Typical polymers are acrylic polymer or copolymer.\",\n \"In one particular embodiment the adjuvant consists of lecithin and polyacrylic acid polymer.\",\n \"The present invention also includes an adjuvant composition that consists of a lecithin and polymer adjuvant composition in combination with one or more glycosides and/or one or more sterols.\",\n \"In some embodiments the adjuvant composition consists of lecithin, polymer, a glycoside and a sterol, where the glycoside can be a saponin or any fraction thereof and the sterol can be, for example, cholesterol.\",\n \"In some embodiments the polymer is an acrylic polymer or copolymer, for example, polyacrylic acid polymer.\",\n \"In general, the lecithin and polymer adjuvants herein form a matrix or net-like structure which is effective in trapping or encapsulating vaccine antigen.\",\n \"In some cases, the lecithin and polymer adjuvant combination form an “oil-free” net-like structure, being composed predominately (and in some cases entirely) by phospholipids and acrylic polymer.\",\n \"In other cases, the lecithin and polymer adjuvant includes additives directed toward further facilitating the adjuvant's capacity to elicit an immune response.\",\n \"The strong mucoadhesive and adsorptive properties of the polymer and lecithin combination enhances the adsorption of vaccine antigen onto mucosal surfaces.\",\n \"Further, the lecithin composition enhances absorption (Swenson, E S and W J Curatolo, ©Means to Enhance Penetration (2) Intestinal permeability enhancement for proteins, peptides and other polar drugs: mechanisms and potential toxicity.\",\n \"Advanced Drug Delivery Reviews.\",\n \"1992.8:39-92) that helps bring the antigen in contact with the underlying lymphoid tissue.\",\n \"Embodiments herein provide a significant improvement over conventional vaccines for delivery of an antigen to a mucosal surface, particularly where the adjuvant does not include the significant proportion or ratio of polymer, as shown in the inventive embodiments herein.\",\n \"The adjuvant compositions of this invention make it possible to vaccinate via a mucosal surface, such as oral cavity, gut, nasal, rectal, or vaginal surfaces.\",\n \"The vaccine may be administered by pill or tablet form, a paste form or in fluid form using a dropper or needleless syringe.\",\n \"This adjuvant composition allows a method of vaccination via food and/or water.\",\n \"In addition, the adjuvant compositions herein facilitate robust mucosal immunity, an advancement over conventional administration techniques for a number of antigens.\",\n \"In an alternative embodiment the composition can be used traditionally as an injectable.\",\n \"Thus, there is provided a method for preparing an adjuvant composition comprising: hydrating lecithin and a polymer in saline or water; and mixing the lecithin and polymer to form an adjuvant.\",\n \"In some embodiments, the lecithin and the polymer can be mixed by placing the lecithin and the polymer in a blender.\",\n \"Advantageously, the lecithin and the polymer can be mixed in the presence of surfactants.\",\n \"In some instances the lecithin and polymer are mixed in the presence of other additives, for example: a glycoside and/or sterol.\",\n \"In some embodiments, the method further includes the step of microwaving or autoclaving the adjuvant.\",\n \"In some embodiments, the method further includes the step of not filtering the adjuvant.\",\n \"In one embodiment, from about 0.001-10% by weight dry lecithin and from about 0.001-10% by weight polymer are hydrated.\",\n \"In some implementations the polymer is also dry and the lecithin and polymer are mixed dry prior to hydration.\",\n \"In this implementation, the method further includes the step of adding an antigen.\",\n \"Advantageously, the antigen is added during the hydration step.\",\n \"In another advantageous embodiment, the antigen is added to the adjuvant.\",\n \"The lecithin and the polymer can be mixed in the presence of an oil.\",\n \"Adjuvants of the invention can be mixed by placing the lecithin and the polymer in a microfluidizer.\",\n \"Alternative implementations include adding a calcium based compound to the adjuvants described herein where a DNA based antigen is implemented in the vaccine.\",\n \"Further features and advantages of the present invention will be set forth in, or apparent from, the detailed description which follows.\",\n \"BRIEF DESCRIPTION OF THE FIGURES FIG.\",\n \"1 is a bar graph showing mean HAI titer for various antigen concentrations and adjuvants.\",\n \"FIG.\",\n \"2A and FIG.\",\n \"2B are micrographs at 30,000× magnification of an embodiment adjuvant composition of the present invention (2A) and a competitor's adjuvant composition (2B).\",\n \"FIG.\",\n \"3 shows data from HAI GMT serum titers for various adjuvant embodiments of the present invention.\",\n \"FIG.\",\n \"4 shows the results of Adenovirus vector-based FMD vaccine alone or in combination with adjuvant embodiments described herein.\",\n \"FIG.\",\n \"5, FIG.\",\n \"6 and FIG.\",\n \"7 are cell viability bar graphs having a starting cell density of 1×106/ml, percent reduction of Alamar Blue at 42 hrs (5), 50 hrs (6) and 68 hrs (7) from treatment.\",\n \"FIG.\",\n \"8, FIG.\",\n \"9 and FIG.\",\n \"10 are cell viability bar graphs having a starting cell density of 10×106/ml, percent reduction of Alamar Blue at 42 hrs (8), 50 hrs (9) and 68 hrs (10) from treatment.\",\n \"FIG.\",\n \"11 and FIG.\",\n \"12 show Log 10 TCID50 of adjuvant options with Ad5bIFNalpha-adjuvant mixtures after incubation (11) and Log 10 TCID50 of adjuvant options with Ad501-adjuvant mixtures after incubation) (12).\",\n \"FIG.\",\n \"13A and FIG.\",\n \"13B are graphs showing group average of IL-4 expression at 24 and 48 hours normalized to ARBP.\",\n \"FIG.\",\n \"14 is a graph showing average IL-4 expression at 48 hours normalized to HPRT.\",\n \"FIGS.\",\n \"15A and 15B are graphs showing a group average of IFN-Y expression at 25 and 48 hours normalized to ARBP or HPRT.\",\n \"FIGS.\",\n \"16A and 16B are graphs showing a group average of TNF-alpha expression at 24 and 48 hours normalized to HPRT.\",\n \"FIG.\",\n \"17 is a graph showing average IL-4 expression at 24 and 48 hours treatment with LAP+OVA or LAP/QAC+OVA normalized to HPRT.\",\n \"DETAILED DESCRIPTION The present invention provides a vaccine adjuvant which, when admixed with an antigen or hapten and administered into a human or animal, will induce a more intense immune response to the antigen than when the antigen is administered alone.\",\n \"The present invention also provides vaccines comprising an antigen or group of antigens and a novel adjuvant herein described which comprises a combination of lecithin and a polymer.\",\n \"As will appear, the present invention also specifically provides methods of making and using the foregoing adjuvants and vaccines.\",\n \"Such adjuvants offer the advantage of allowing application of a vaccine directly to a mucosal surface.\",\n \"In doing so, the vaccine stimulates a protective immune response which helps prevent interference from circulating maternal antibodies that may be present in a newborn or infant, for example.\",\n \"Direct administration of a vaccine herein to a mucosal surface, i.e., mucosal vaccination, provides mucosal immunity and systemic immunity, an advantage over most systemic only based vaccines.\",\n \"Unlike other vaccines developed for mucosal vaccination, embodiments of the present invention provide unexpected improvement for immunogenic response by improving the vaccine's contact time on the mucosal surface.\",\n \"“Antigen” is herein defined as a compound which, when introduced into an animal or a human, will result in the formation of antibodies and cell-mediated immunity.\",\n \"“Adjuvant” is herein defined as a compound or compounds that, when used in combination with specific vaccine antigens in formulations, augment or otherwise alter or modify the resultant immune responses.\",\n \"“Vaccine” is herein defined as a composition of antigenic moieties, usually consisting of modified-live (attenuated) or inactivated infectious agents, or some part of the infectious agents, that is administered, most often with an adjuvant, into the body to produce active immunity.\",\n \"The antigen can be any desired antigen falling within the definition set forth above.\",\n \"Antigens are commercially available or one of skill in the art is capable of producing them.\",\n \"The antigenic moiety making up the vaccine can be either a modified-live or killed microorganism, or a natural product purified from a microorganism or other cell including, but not limited to, tumor cells, a synthetic product, a genetically engineered protein, peptide, polysaccharide or similar product, or an allergen.\",\n \"The antigenic moiety can also be a subunit of a protein, peptide, polysaccharide or similar product.\",\n \"The antigen may also be the genetic antigens, i.e., the DNA or RNA that engenders an immune response.\",\n \"Representative of the antigens that can be used according to the present invention include, but are not limited to, natural, recombinant or synthetic products derived from viruses, bacteria, fungi, parasites and other infectious agents in addition to autoimmune diseases, hormones, or tumor antigens which might be used in prophylactic or therapeutic vaccines and allergens.\",\n \"The viral or bacterial products can be components which the organism produced by enzymatic cleavage or can be components of the organism that were produced by recombinant DNA techniques that are well known to those of ordinary skill in the art.\",\n \"Because of the nature of the invention and its mode of delivery it is very conceivable that the invention would also function as a delivery system for drugs, such as hormones, antibiotics and antivirals.\",\n \"The lecithin can be any lecithin or, for instance, lecithin lipoidal material, such as phospholipids, lysophospholipids, glycolipids and neutral lipids that comprise the typical composition of lecithin.\",\n \"Lecithins are molecules that, when completely hydrolyzed, yield two molecules of fatty acid, and one molecule each of glycerol, phosphoric acid, and a basic nitrogenous compound, such as choline.\",\n \"The fatty acids obtained from lecithins on hydrolysis are usually, but not limited to, oleic, palmitic, and stearic acids.\",\n \"The phosphoric acid may be attached to the glycerol in either an α- or the β-position, forming α-glycerophosphoric acid or β-glycerophosphoric acid, respectively, and producing the corresponding series of lecithins which are known as α- and β-lecithins.\",\n \"Commercial lecithin is obtained by extraction processes from egg yolk, brain tissue, or soybeans.\",\n \"Ovolecithin (vitelin) from eggs and vegilecithin from soybeans, as well as purified lecithin from calf s brains have been used as emulsifiers, antioxidants, and stabilizers in foods and pharmaceutical preparations.\",\n \"Commercial lecithin may be obtained from a variety of sources.\",\n \"One of ordinary skill in the art would be able to determine an appropriate lecithin for a desired application.\",\n \"The polymer is preferably an acrylic polymer, which is any polymer or copolymer that contains an acrylic moiety.\",\n \"Examples of suitable acrylic polymers include, but are not limited to polyacrylic acid, methacrylic acid, methacrylate, acrylamide, acrylate, acryinitrile, and alkyl-esters of poly acrylic acid.\",\n \"Examples of acrylic copolymers are poly (acrylamide-co butyl, methacrylate), acrylic-methacrylic acid, acrylic-acrylamide and poly (methacrylate).\",\n \"Commercial polymers may be obtained from a variety of sources.\",\n \"In some embodiments, acrylic polymers may benefit from the inclusion of a cross linker, such as a polyalkenyl polyether, an alkyl sucrose, or an allyl ether of penta-erythirtol, for example, which is effective in binding the polymers.\",\n \"An exemplary acrylic polymer for use in this invention is polyacrylic acid with or without a polyalkenyl polyether cross linker.\",\n \"One of ordinary skill in the art would be able to determine an appropriate acrylic polymer for a desired application.\",\n \"Likewise, one of ordinary skill in the art would be able to determine an appropriate cross linker for a given acrylic polymer.\",\n \"Examples of non-acrylic polymers that are suitable for use herein are polyvinyl acetate phthalate, cellulose acetate phthalate, methylcellulose, polyethylene glycol, polyvinyl alcohol, and polyoxyethylene.\",\n \"The method of manufacturing the adjuvant of this invention first involves hydrating the lecithin and polymer by suspending from about 0.0001-10% by weight/volume dry lecithin and from about 0.0001-10% by weight polymer in saline or water.\",\n \"In some cases the polymer is also dry prior to suspension in saline or water.\",\n \"The preferred concentrations of lecithin and polymer are 0.001-1.0% each by weight/volume.\",\n \"The two components may be mixed together using conventional methods, such as, for example, a Waring Blender, emulsification equipment or a microfluidizer.\",\n \"Surfactants (emulsifiers) may be added to aid in the mixing or emulsification of the lecithin and polymer.\",\n \"Suitable synthetic detergents are well known to those of ordinary skill in the art.\",\n \"Examples of appropriate surfactants include polyoxyethylene sorbitan monooleate, sorbitan monolaurate, sodium stearate, non-ionic ether-linked surfactants such as Laureth®4 and Laureth®23, alkyl sulfate surfactants, alkyl alkoxylated sulfate surfactants, alkylbenzenesulphonates, alkanesulphonates, olefinsulphonates, sulphonated polycarboxylic acids, alkyl glycerol sulfonates, fatty acyl glycerol sulfonates, fatty oleyl glycerol sulfates, alkyl phenol ethylene oxide ether sulfates, paraffin sulfonates, alkyl phosphates, isothionates such as the acyl isothionates, N-acyl taurates, fatty acid amides of methyl tauride, alkyl succinamates and sulfosuccinates, mono- and diesters of sulfosuccinate, N-acyl sarcosinates, sulfates of alkylpolysaccharides, branched primary alkyl sulfates, alkyl polyethoxy carboxylates, and fatty acids esterified with isethionic acid and neutralized with sodium hydroxide.\",\n \"Further examples are given in Surface Active Agents and Detergents (Vol.\",\n \"I and II by Schwartz, Perry and Berch), the disclosure of which is expressly incorporated herein by reference.\",\n \"Suitable nonionic detergent surfactants are generally disclosed in U.S. Pat.\",\n \"No.\",\n \"3,929,678, Laughlin et al., issued Dec. 30, 1975, at column 13, line 14 through column 16, line 6, incorporated herein by reference.\",\n \"If included, the emulsifier should be added in a concentration ranging from about 0.001-0.05% by volume of the mixture.\",\n \"Lecithin and polymer embodiments herein may also be used in combination with other additives such as, but not limited to, glycosides such as saponins, fractions of saponins, or synthesized components of saponins, sterols, ISCOMS, muramyl dipeptide and analogues, pluronic polyols, trehalose dimycolate, amine containing compounds, cytokines, calcium and lipopolysaccharide derivatives.\",\n \"The addition of another additive may aid in the stimulation of an immune response and in particular a mucosal immune response.\",\n \"If included, additional additives may be present in a concentration of up to about 10% by weight of the composition, for example, less than about 1% by weight of the composition.\",\n \"In most cases, additives of the invention are included in adjuvant embodiments herein in an amount to cause an induction of an immune response.\",\n \"In some instances, additives herein provide additional stimulation of TH1 (T helper cell 1), an important mediator in mucosal immunity.\",\n \"Typical additives for inclusion with lecithin/polymer adjuvants described herein include one or more of a glycoside and/or a sterol.\",\n \"In some embodiments, the glycosides are saponins, fractions of saponins or synthesized components of saponins.\",\n \"Exemplary saponins can be derived from plant sources including, but not limited to Quillaja Saponaria Molina, Polygala senega, and Astragalus species.\",\n \"In one instance the saponin is a triterpensaponin, such as Quil A (a saponin preparation isolated from the South American tree Quillaja Saponaria Molina).\",\n \"Purified fractions of Quil A include QS7 and QS21 (also known as QA7 and QA21).\",\n \"Nonetheless, any saponins are contemplated as useful herein.\",\n \"Preferred sterols are cholesterol, lanosterol, lumisterol, stigmasterol and sitosterol.\",\n \"In some instances, Quil A is combined with cholesterol and added to adjuvant embodiments described herein.\",\n \"This particular additive combination provides an unexpected enhancement in immune response over similarly prepared lecithin and polymer adjuvants described herein.\",\n \"Note that QS7 and/or QS21 can be substituted and/or added to the Quil A.\",\n \"Typical additives for inclusion with lecithin/polymer adjuvants described herein also include calcium compounds, for example, calcium phosphate, as described in U.S. patent application Ser.\",\n \"No.\",\n \"12/125,577, incorporated herein by reference for all purposes.\",\n \"Calcium additives are most appropriate for DNA virus based antigens, although it is envisioned that other antigen types can be used.\",\n \"In some instances, calcium compounds can be combined with Quil A and/or cholesterol, and included in a lecithin/polymer based adjuvant.\",\n \"The invention may also include one or more probiotics.\",\n \"Probiotics are bacteria or microorganisms that are beneficial to the health of the individual or animal.\",\n \"Examples of commonly used probiotics include, but are not limited to, various beneficial strains of Lactobacillus, Bifidobacterium, Streptococcus, etc.\",\n \"If present, each of the organisms should be administered in a concentration ranging from about 103 to 108 CFU each (per vaccination).\",\n \"In addition to all of the above, as is well understood by those skilled in the art, other minors can be employed to make the composition more pharmaceutically and/or cosmetically elegant.\",\n \"For example, dyes can be added at very minor levels as can diluents such as alcohol, buffers, stabilizers, wetting agents, dissolving agents, colors, etc.\",\n \"With the exception of diluents such as alcohols which are used at higher levels, the levels of these minors are generally not more than 0.001% to 1.0% by weight.\",\n \"If desired, the adjuvant components may be sterilized by autoclaving prior to the hydration step.\",\n \"It has also been found that autoclaving and/or microwaving the components may improve their suspending ability.\",\n \"The vaccine antigen may be added after formation of the adjuvant, or at the time of hydration of the adjuvant components.\",\n \"If in tablet form, the antigen may be mixed with dry components of the adjuvant invention along with other excipients necessary for tablet formation.\",\n \"Examples of appropriate types of vaccine antigens include killed or attenuated bacterial, viral, parasitic, or subunits of these organisms, or genomic vaccine antigens, for example, DNA.\",\n \"Applicant believes that the capacity to be autoclaved/microwaved provides a significant benefit over other conventional adjuvants which require filtration.\",\n \"Initially, structural analysis of embodiments herein before and after autoclaving illustrated that the structure of the autoclaved composition(s) was not significantly affected.\",\n \"However, the more costly filtration method for sterilizing an adjuvant removes and/or modifies structural aspects of the composition.\",\n \"As such, the embodiments herein are relatively less costly and avoid structural alterations found in other adjuvant materials that require filtration.\",\n \"This is an unexpected finding of the present formulations.\",\n \"The relative concentration of the components, including the antigen, may be determined by testing the formulations in animals starting with a low dose of the formulation and then increasing the dosage while monitoring the immune response.\",\n \"The following considerations should be made when determining an optimal dose, e.g., breed, age, size and the presence or absence of interfering maternal antibodies.\",\n \"A concentration of an attenuated viral vaccine will comprise about 103 to 109 TCID50 per animal.\",\n \"In some embodiments, the amount will be from about 104 to 107 TCID50 per animal.\",\n \"The concentration of killed antigen or subunit antigen may range from nanogram to milligram quantities of antigen with about 1 microgram to 1 milligram preferred.\",\n \"When the acrylic polymer and lecithin are combined, a matrix, or net-like structure is formed.\",\n \"In some instances the net-like structure is “oil free,” i.e., not having additional oils or lipids added to the adjuvant.\",\n \"The ratio of lecithin to polymer include ratios between 1:1000 and 1000:1.In some embodiments, the ratios of lecithin to polymer include ratios between 1:10 and 10 to 1.The relative proportions of lecithin and acrylic polymer may be found to be important to the efficiency of delivery of different antigens, i.e., bacterial, viral, parasitic or sub-units of these organisms.\",\n \"The optimum ratio may be determined by the conventional means of testing the different ratios of lecithin to polymer with the desired antigen in animals.\",\n \"The adjuvant composition can be used for the delivery of vaccine antigens such as whole killed or attenuated virus, bacteria, or parasite vaccine antigens or sub-unit(s) of such organisms to mucosal surfaces, such as oral cavity, gut, nasal, vaginal and rectal surfaces.\",\n \"Electron microscopic evaluation shows that there exists a physical and/or chemical affinity between lecithin and polymer.\",\n \"This affinity or association appears as a matrix, or net-like structure.\",\n \"Without intending to be bound by any particular theory, it is believed that a structure such as this can function as a means of physically trapping or encapsulating vaccine antigen.\",\n \"Such binding of antigen is further enhanced by the electrical charge and the hydrophilic and hydrophobic properties of lecithin and the acrylic polymers of this invention.\",\n \"To facilitate this, a polymer of different electrical charge may be selected depending on the anionic or cationic properties of the antigen.\",\n \"Likewise a polymer and lecithin of different hydrophobicity may be selected depending on the lipophilic or hydrophilic properties of the antigen.\",\n \"If necessary or desired, the antigen can be coupled to the lecithin-acrylic polymer matrix with a cross-linker such as glutaraldehyde in a concentration of from about 1 to 50 mM, for example, about 15 mM.\",\n \"Further, the antigen can be coupled using water-soluble carbodiimide in a concentration ranging from about 0.05-0.5 M, for example, about 0.1 M, or a coupling method using a heterofunctional reagent such as N-hydroxysuccinimidyl 3-(2-pyridyldithio) propionate (SPDP) in a concentration ranging from about 0.1-1.0 mM, and preferably about 0.2 mM.\",\n \"Other appropriate coupling agents include mixed anhydride and bisdiazotized benzidene.\",\n \"The cross-linker is used to improve the binding affinities of the components of the adjuvant composition, for example, where the components are not electrically attracted to each other.\",\n \"The strong mucoadhesive and adsorptive properties of the polymer, e.g., acrylic acid and lecithin combination also make it an excellent mechanism to aid in the adsorption of vaccine antigen onto mucosal surfaces.\",\n \"The adjuvant delivery system's absorption enhancement properties help bring the vaccine antigen in contact with mucosal associated lymphoid tissue.\",\n \"Thus, an immune response is engendered that will aid in the protection of an animal from infections and/or disease process.\",\n \"A robust mucosal immune response is critical since most infectious disease-causing organisms gain entry to the animal at mucosal surfaces.\",\n \"The invention can also be used as an adjuvant for injectable vaccines and provides improvement for facilitating an immune response over other conventional injectable adjuvant materials.\",\n \"The vaccine comprising the adjuvant is delivered to a mucosal surface by direct application, ingestion through the oral cavity, insertion, injection, and through other conventional means known in the art.\",\n \"Alternatively, the adjuvant may also be administered as a conventional injectable, which is typically either a liquid solutions or suspension.\",\n \"When administered in a food or beverage carrier, the adjuvant/vaccine composition of this invention is generally included in the carrier composition in a concentration ranging from about 0.0001-10% by weight/volume (w/v) in case of a beverage carrier and weight/weight (w/w) in case of a food carrier, for example, about 0.01-1.0% w/v or w/w respectively.\",\n \"When administered in an injectable, the adjuvant/vaccine composition should be present in a concentration ranging from about 0.02-2.0% by weight, for example, about 0.1-0.5% by weight.\",\n \"The adjuvant/vaccine may also be administered in other conventional solid dosage forms, such as in tablets, capsules, granules, troches, and vaginal or rectal suppositories.\",\n \"If administered in a solid dosage form, the adjuvant/vaccine composition should constitute between 0.0001-10% by weight of the dosage form, for example, about 0.01-1.0% by weight.\",\n \"In addition to the active compounds, the pharmaceutical compositions of this invention may contain suitable excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.\",\n \"Oral dosage forms encompass tablets, capsules, and granules.\",\n \"Preparations which can be administered rectally include suppositories.\",\n \"Other dosage forms include suitable solutions for administration parenterally or orally, and compositions which can be administered buccally or sublingually.\",\n \"The pharmaceutical preparations of the present invention are manufactured in a manner which is itself well known in the art.\",\n \"For example the pharmaceutical preparations may be made by means of conventional mixing, granulating, dissolving, lyophilizing processes.\",\n \"The processes to be used will depend ultimately on the physical properties of the active ingredient used.\",\n \"Suitable excipients are, in particular, fillers such as sugars for example, lactose or sucrose mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch, paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.\",\n \"If desired, disintegrating agents may be added, such as the above-mentioned starches as well as carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.\",\n \"Auxiliaries are flow-regulating agents and lubricants, for example, such as silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate and/or polyethylene glycol.\",\n \"Oral dosage forms may be provided with suitable coatings which, if desired, may be resistant to gastric juices.\",\n \"For this purpose concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.\",\n \"In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, dyestuffs and pigments may be added to the tablet coatings, for example, for identification or in order to characterize different combination of compound doses.\",\n \"Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.\",\n \"The push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.\",\n \"In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.\",\n \"In addition stabilizers may be added.\",\n \"Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of the active compounds with the suppository base.\",\n \"Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols, or higher alkanols.\",\n \"In addition, it is also possible to use gelatin rectal capsules which consist of a combination of the active compounds with a base.\",\n \"Possible base material includes, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.\",\n \"Suitable formulations for parenteral administration include aqueous solutions of active compounds in water-soluble or water-dispersible form.\",\n \"In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered.\",\n \"Suitable lipophilic solvents or vehicles include fatty oils for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides.\",\n \"Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, including for example, sodium carboxymethyl cellulose, sorbitol and/or dextran.\",\n \"Such compositions may also comprise adjuvants such as preserving, wetting, emulsifying, and dispensing agents.\",\n \"They may also be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents into the compositions.\",\n \"They can also be manufactured in the form of sterile solid compositions which can be dissolved or suspended in sterile water, saline, or other injectable medium prior to administration.\",\n \"In addition to administration with conventional carriers, active ingredients may be administered by a variety of specialized delivery drug techniques which are known to those of skill in the art, such as portable infusion pumps.\",\n \"The lecithin/polymer adjuvant serves multiple functions when it is delivered orally in food and water: 1) it protects the vaccine antigen from degradation by the stomach acid and digestive enzymes; 2) transports the antigen to the mucosal surfaces; 3) facilitates adsorption of the antigen onto the mucosal surfaces; 4) enhances absorption of the antigen; and 5) enhances the immune response to the antigen due to the adjuvant properties of the two components.\",\n \"In the case of delivery to nasal, oral cavity, vaginal and rectal mucosa, the lecithin/acrylic polymer complex functions as a system to deliver and adsorb the antigen to the mucosal surface.\",\n \"Once adsorbed onto the mucosal surface and absorbed, an immune response is engendered.\",\n \"The combination of polymer and lecithin unexpectedly provides an improved vaccine delivery system for vaccine antigens.\",\n \"It is apparent that the invention is also an improved delivery system for drugs, such as hormones, antibiotics, probiotics and antivirals.\",\n \"The current invention provides a more simple and efficient method of incorporation of antigen into a delivery system with no, or minimal damage, to vaccine epitopes.\",\n \"The vaccine formulation can be done at low cost and can be easily commercialized as a feed or water additive or as an oral paste or tablet.\",\n \"It is to be understood that these formulations also would be effective in delivering antigen onto other mucosal surfaces, such as nasal, rectal and vaginal surfaces, and would be effective as an adjuvant for an injectable vaccine.\",\n \"In addition, the hydrophobic properties that aid in the adsorption of the adjuvant and vaccine antigen to mucosal surfaces also provides a means of applying to animal feeds, whether it be plant foliage or seeds, both which have a hydrophobic wax surface.\",\n \"The combination of polymer, lecithin and additives (in particular Quil A and cholesterol) provides an unexpected enhancement of an adjuvant to induce an immune response.\",\n \"This benefit is present for multiple delivery routes, which includes when the adjuvant is delivered as an injectable.\",\n \"The composition with which the current invention is concerned differs from the prior art in that it comprises a mixture of lecithin and, in some embodiments, an acrylic polymer or copolymer.\",\n \"The invention provides certain advantages over other vaccine delivery systems described in the prior art.\",\n \"It is not prepared under harsh conditions that adversely affect the substance such as the use of organic solvents.\",\n \"It does not require elevated temperatures to manufacture and does not require a stabilization step.\",\n \"The invention provides a simpler method of incorporation of antigen with minimal damage to vaccine epitopes.\",\n \"Using this simpler method of manufacturing results in low cost and ease of commercialization.\",\n \"The following examples are intended to further illustrate the invention and its preferred embodiments.\",\n \"They are not intended to limit the invention in any manner.\",\n \"Example 1 Vaccine Plus Adjuvant Effectiveness An experimental vaccine was made comprising bovine serum albumin Fraction 5 (BSA) as a non-living model antigen, lecithin, and an acrylic acid polymer.\",\n \"A second vaccine was made comprising only BSA.\",\n \"The lecithin and acrylic polymer were suspended together in 150 milliliters (ml) phosphate buffered saline (PBS), each at a concentration of 4 milligrams (mg) per milliliter (ml).\",\n \"The components were first dispersed by stirring with a magnetic stir bar and then mixed further in a Waring Blender using an emulsification head.\",\n \"The mixture was then autoclaved to sterilize the adjuvant mixture.\",\n \"Bovine serum albumin was dissolved in PBS at a concentration of 2 mg/ml and filter sterilized.\",\n \"One part lecithin/acrylic polymer adjuvant was then combined with one part of BSA.\",\n \"Merthiolate (0.01%) was added as a preservative.\",\n \"The final concentration of the vaccine components was 2 mg/ml of the lecithin/acrylic polymer and 1 mg/ml of BSA.\",\n \"CF-1 female mice, approximately 18 grams, from Charles River Laboratories (Willmington, Mich.), were injected subcutaneously in the groin area with 0.1 ml of vaccine (0.1 mg. of BSA/dose) on days 0 and 21.Mice were bled on day 45, 24 days after the second vaccination.\",\n \"Mice were bled by cutting the brachial artery following euthanasia by cervical dislocation.\",\n \"Blood serum Immunoglobulin G (IgG) anti-BSA antibody titers were determined by an enzyme linked immunosorbant assay (ELISA).\",\n \"Results are shown in Table 1.TABLE 1 Results of Antibody Titers Reciprocal of Number of Geometric Adjuvant Group Mice Mean Titer None 8 51,200 Lecithin/Acrylic 8 157,916 Polymer Results show that the adjuvant comprising a combination of lecithin and acrylic polymer does indeed enhance the immune response to an antigen.\",\n \"Example 2 Comparison of Individual Vaccine Adjuvants Administered Orally Experimental vaccines, for delivery by the oral route, were prepared in PBS.\",\n \"The vaccines comprised the antigen, BSA Fraction 5, at a concentration of 400 micrograms (μg) per ml.\",\n \"Vaccine 1 contained no adjuvant only BSA.\",\n \"Vaccine 2 was comprised of BSA mixed with 3 mg/ml of lecithin.\",\n \"Vaccine 3 was comprised of BSA mixed with 3 mg/ml of the acrylic polymer.\",\n \"Vaccine 4 was comprised of BSA mixed with 3 mg/ml of lecithin and 3 mg/ml of acrylic polymer.\",\n \"Mixing was first done with a laboratory bench top magnetic stir bar and then in a Waring blender using an emulsification head.\",\n \"Lactobacillus culture was added to all vaccines just prior to vaccination.\",\n \"The final concentration of Lactobacillus was 0.01 μg/ml of vaccine.\",\n \"On days 0, 4, 29 and 33 the groups of CF-1 female mice from Charles-River Laboratories and weighing approximately 18 grams, were administered 0.5 ml of vaccine orally by feeding needle.\",\n \"On day 53, 20 days post fourth vaccination, mice were euthanized and bled by the brachial artery.\",\n \"End-point anti-BSA serum IgG antibody titers were determined by ELISA.\",\n \"A 1/100 starting dilution of serum was used due to non-specific background color development at dilutions less than 1/100.Results are recorded in Table 2: TABLE 2 Effect of Adjuvant Composition on the Anti-BSA Antibody Response Reciprocal of No.\",\n \"of Mice Geometric Adjuvant with Titer >/= Mean of Mice Composition 1/100 (%) with Titers None 3/9 (33) 158 Lecithin 4/6 (67) 141 Acrylic Polymer 6/9 (67) 8,063 Lecithin and Acrylic 6/9 (67) 45,614 Polymer Anti-BSA IgG antibody titers were over five times higher when a combination of lecithin and acrylic polymer was used as adjuvant than when acrylic polymer was used alone and 323 times higher than when lecithin was used alone.\",\n \"This demonstrates that the combination of lecithin and acrylic polymer is far more effective at delivering the antigen orally to the mucosal surface for uptake by lymphoid tissue than either lecithin or acrylic polymer alone.\",\n \"Although, not all of the mice showed a serum anti-BSA IgG antibody response the results clearly show a synergistic adjuvant effect of lecithin combined with the acrylic polymer.\",\n \"However, the mice that did not seroconvert may have had a secretory IgA antibody response.\",\n \"Indeed, oral vaccination, and mucosal vaccination in general, stimulates IgA secreting cells at mucosal surfaces.\",\n \"Example 3 Second Test of Lecithin/Polymer Adjuvant by the Oral Route Two vaccines were prepared in PBS that comprised the antigen, BSA Fraction 5, at a concentration of 400 μg per ml.\",\n \"One vaccine contained no adjuvant only BSA.\",\n \"The other vaccine was comprised of BSA adjuvanted with 3 mg/ml of lecithin and 3 mg/ml of acrylic polymer.\",\n \"The vaccine was assembled as described in Example 2.On days 0, 4, 27, and 31 groups of CF-1 female mice from Charles-River Laboratories and weighing approximately 18 grams, were administered 0.5 ml of vaccine orally by feeding needle.\",\n \"On day 52, 21 days post vaccination, mice were euthanized and bled by the brachial artery.\",\n \"End-point anti-BSA serum IgG antibody titers were determined by ELISA.\",\n \"A 1/100 starting dilution of serum was used due to non-specific background color development at dilutions less than 1/100.Results are recorded in Table 3: TABLE 3 Comparative Results of Adjuvant Versus Control Reciprocal of No.\",\n \"of Mice Geometric Adjuvant with Titer >/= Mean of Mice Composition 1/100 (%) with Titers None 1/12 (8) 100 Lecithin and 9/11 (82) 18,812 Acrylic Polymer This study again demonstrates that the combination of lecithin and acrylic polymer is effective in delivering antigen to oral mucosal surfaces.\",\n \"In a separate study, 4/10 mice that received this same vaccine had a geometric mean titer of 1/1,345 six weeks after only a single vaccination.\",\n \"This demonstrates the potential of the adjuvant composition, when once optimized, to engender an immune response of long duration.\",\n \"Example 4 Administration of Vaccine Intranasally Two experimental vaccines for delivery by the intranasal route were prepared in PBS comprising the antigen, BSA, at a concentration of 500 μg/ml.\",\n \"One vaccine was comprised of BSA alone.\",\n \"The second vaccine was comprised of BSA adjuvanted with a combination of 3 mg/ml of lecithin and 3 mg/ml of the acrylic polymer.\",\n \"The lecithin and acrylic polymer were first mixed with a laboratory bench top magnetic stir bar and then in a Waring blender using an emulsification head.\",\n \"BSA was then added and mixed again using the emulsification head.\",\n \"Mice were vaccinated on days 0 and 20.Forty μl containing 20 μg of BSA antigen were placed on the nose while the mouth was held shut.\",\n \"The vaccine entered the nose when the mouse inhaled.\",\n \"On day 41, 21 days post second vaccination, the mice were euthanized and bled by cutting the brachial artery.\",\n \"Anti-BSA antibody titers were determined by ELISA.\",\n \"The starting dilution of serum was at 1/100 due to non-specific background color development at lower dilutions.\",\n \"Results are shown in Table 4: TABLE 4 Comparative Results of Adjuvant Versus Control Reciprocal of No.\",\n \"of Mice Geometric Adjuvant with Titer >/= Mean of Mice Composition 1/100 (%) with Titers None 0/11 (0%) 0 Lecithin and 7/12 (58%) 269 Acrylic Polymer None of the mice (0/11) vaccinated with BSA alone seroconverted.\",\n \"The BSA antigen alone, when administered intranasally, failed to stimulate a serum antibody response in any of the mice.\",\n \"In contrast, 7 of 12 mice, or 58%, developed serum anti-BSA IgG antibody titers as high as 1/3200 following intranasal vaccination with BSA in combination with the invention comprised of lecithin and acrylic polymer.\",\n \"The fact that not all mice seroconverted suggests that not enough, or perhaps none of the vaccine was inhaled by those mice that did not have an antibody titer greater than 1/100.Indeed, some, perhaps most, of the vaccine was observed to run off the nose or was blown off the nose when the mouse exhaled.\",\n \"Still, the results of this study show that the invention, comprised of lecithin and acrylic polymer, functions effectively as an adjuvant for the intranasal delivery of a vaccine antigen.\",\n \"Example 5 Use of Adjuvant with Vaccine in Swine The adjuvant invention comprising a combination of 2 mg/ml of lecithin and 2 mg/ml of acrylic polymer was used as a diluent for modified-live pseudorabies virus (ML-PRV) for swine.\",\n \"This adjuvant diluent and a control diluent consisting of sterile water were used to rehydrate lyophilized (ML-PRV).\",\n \"The ML-PRV was rehydrated immediately prior to vaccination.\",\n \"Groups of 10 weaned piglets, 6 weeks of age, were vaccinated on days 0 and 21.Blood serum was collected on days 2, 20, 28, and 48 for serological testing for anti-PRV serum neutralizing antibodies.\",\n \"The anti-PRV antibody responses of piglets in the different vaccine groups are shown in Table 5.TABLE 5 Results in Pigs Geometric Mean Virus Neutralizing Antibody Titer on Days Post Adjuvant First Vaccination Diluent Day 2 Day 20 Day 28 Day 48 Non-Vaccinated 0 0 0 0 Control Water 0 4 34 21 Lecithin/ 0 6 69 52 Acrylic Polymer This study showed that the invention comprising a lecithin and acrylic polymer combination functions as an adjuvant for a ML-virus vaccine adjuvant, in this case swine ML Pseudorabies vaccine virus.\",\n \"The virus neutralizing anti-PRV antibody titer to ML-PRV, which by itself is a very good antigen without an adjuvant and is used commercially without an adjuvant, was over twice as high when the lecithin/acrylic polymer was used instead of water.\",\n \"Example 6 Lecithin and Acrylic Copolymer Adjuvant Supports H1N1 and H3N2 Vaccine Responses Lecithin and acrylic copolymer adjuvant as described and prepared herein was analyzed for its effectiveness at supporting the immunization of swine against H1N1 and H2N2 viral antigens.\",\n \"Inventive adjuvants herein were compared to a commercially available adjuvant, 5% Amphigen®, to identify the capacity of adjuvants as described herein to support viral antigen based vaccines.\",\n \"Each adjuvant was combined with H1N1 and H3N2 antigens (derived from a released lyophilized commercial product (FluSure™, Pfizer Animal Group).\",\n \"Test groups for vaccination included 29 to 35 day old piglets.\",\n \"Four treatment groups were observed (each group having 15 piglets, except the negative control group which had 5 piglets): T1, 5% Amphigen, positive control; T2, Quil A alone adjuvant; T3, lecithin and acrylic copolymer of the invention, intramuscular; and T4, lecithin and acrylic copolymer of the invention, intranasal.\",\n \"T5 was a control group that was un-vaccinated.\",\n \"T1, T2 and T3 received one intramuscular dose on day 0, T4 received one intranasal dose on day 0.Blood samples were obtained from each animal participating in the study on days 0, 21 and 35.Table 6 shows data from H1N1 titer, Table 7 shows data from the H3N2 titer: TABLE 6 Number of Piglets with H1N1 Swine Influenza Titers and Geometric Mean Titers No.\",\n \"of Piglets With H1N1 H1N1 Geometric Titers/Total Piglets Mean Titers Treat Test Treat.\",\n \"Day Day Day Day No.\",\n \"Art Group Day 0 21 35 Day 0 21 35 T1 1 SIV-Kill 0/15 15/15 11/15 5.0 24.1 11.5 Amphigen T2 2 SIV-Kill 0/15 6/15 0/15 5.0 6.9 5.0 Quil A T3 3 SIV-Kill 0/15 15/15 13/15 5.0 24.1 14.5 LAP T4 4 SIV-Kill 0/15 0/15 0/15 5.0 5.0 5.0 LAP T5 5 Neg.\",\n \"0/5 0/5 0/5 5.0 5.0 5.0 Control No.\",\n \"of piglets with H1N1 Titers - Piglets with titers of 10 or higher were determined as positive.\",\n \"Geometric Mean Titers - A titer of 5 was assigned to negative titers for calculation of geometric mean.\",\n \"SIV—Lyophilized swine influenza (H1N1, H3N2) virus killed viral vaccine (FluSure ™, Pfizer Animal Health).\",\n \"LAP—Lecithin acrylic polymer as described in Examples 1-5.TABLE 7 Number of piglets with H3N2 Swine Influenza Titers and Geometric Mean Titers No.\",\n \"of Piglets With H3N2 H3N2 Geometric Titers/Total Piglets Mean Titers Treat Test Treat.\",\n \"Day Day Day Day No.\",\n \"Art Group Day 0 21 35 Day 0 21 35 T1 1 SIV-Kill 11/15 15/15 15/15 14.5 20.9 16.6 Amphigen T2 2 SIV-Kill 10/15 10/15 3/15 15.2 8.3 5.7 Quil A T3 3 SIV-Kill 10/15 15/15 15/15 13.8 28.9 17.4 LAP T4 4 SIV-Kill 12/15 6/15 1/15 16.6 6.9 5.2 LAP T5 5 Neg.\",\n \"4/5 3/5 1/5 17.4 8.7 5.7 Control No.\",\n \"of piglets with H3N2 titers - Piglets with titers of 10 or higher were designated as positive for titers.\",\n \"Geometric Mean Titers - A titer of 5 was assigned a negative titer for calculations of geometric mean titers.\",\n \"SIV—Lyophilzed swine influenza (H1N1, H3N2) virus killed viral vaccine (FluSure ™, Pfizer Animal Health).\",\n \"Amphigen ®—Amphigen ® adjuvant (Pfizer Animal Health) LAP—Lecithin acrylic polymer as described in Examples 1-5.Referring to Tables 6 and 7, the results indicate lecithin and acrylic copolymer adjuvants of the invention induce significant serological responses to H1N1 and H3N2 swine influenza viruses in piglets.\",\n \"The responses were similar to conventional commercial adjuvants and significantly better than a Quil A alone adjuvant.\",\n \"The data in Example 6 further show the utility of the lecithin/acrylic polymer adjuvants of the invention and show that additives alone, for example Quil A, provide for a minimal immunological response under identical conditions.\",\n \"Example 7 Immune Response to Vaccine Enhanced by Inclusion of Additives The immunogenecity of a lecithin, acrylic polymer, Quil A and cholesterol adjuvant of the invention was tested against Amphigen, a commercial adjuvant.\",\n \"The study was performed to determine the effectiveness of eliciting an enhanced immune response through inclusion of cholesterol and Quil A in adjuvant embodiments described herein.\",\n \"Adjuvant was prepared as described above, except in this Example, 15 mg/ml lecithin was combined with 10 mg/ml acrylic polymer.\",\n \"Each vaccine dose included 1.25 mg of adjuvant (as compared to 5 mg of Amphigen).\",\n \"The adjuvant samples were spiked with 0.5 mg/ml of Quil A/cholesterol.\",\n \"All adjuvant samples further received 50 μg, 5 μg or 0.5 μg AIV-HA antigen.\",\n \"Ingredients described above were combined as discussed herein to provide 3 different antigen concentrations for each lecithin/acrylic polymer/additive sample and Amphigen sample.\",\n \"All samples were stored at 4° C. Twenty-nine to thirty-five day old piglets were vaccinated and bleeds taken on days one, fourteen and twenty eight.\",\n \"Titers were determined for each condition and mean HAI titer determined.\",\n \"As shown in FIG.\",\n \"1, the study showed a surprising increase in mean HAI titer with cholesterol and Quil A included in the adjuvant and therefore vaccine preparation.\",\n \"In each case, the increase in titer was antigen concentration dependent and showed a significant increase comparable to corresponding antigen spiked Amphigen samples.\",\n \"It is noted that the amount of lecithin and acrylic polymer was limited (1.25 mg) to provide a more sensitive platform for identifying effects of the inventive adjuvants described herein.\",\n \"The low dose lecithin/acrylic polymer/additive adjuvant provided an adequate platform for analyzing the adjuvant's capacity to elicit an immune response, which was comparable to a full dose Amphigen based adjuvant.\",\n \"Example 8 Lecithin and Acrylic Polymer Adjuvant is Facilitated by Inclusion of Additives The immunogenecity of a lecithin, acrylic polymer, cholesterol, and Quil A adjuvant was tested in chickens.\",\n \"Cell line based antigen was tested in this manner in order to determine utility of adjuvants (additive based) in accordance with the present invention.\",\n \"Adjuvant was prepared using 33.5 μg/dose Quil A, 32.4 μg/dose cholesterol, 800 μg/dose lecithin and 500 μg/dose acrylic copolymer 974PNF.\",\n \"Vaccine antigen was a stably transfected cell line using a H5 HA expressing plasmid (CHO-HA-10).\",\n \"In some vaccines, an antigen stabilizing agent was added to the material, i.e., Nicotiana tabacum cell line lysate.\",\n \"Sixty five pathogen-free Leghorn chickens (10 day old) were obtained and quarantined for nine days prior to start-up of the experiment.\",\n \"Birds were split into eleven groups (six birds per group for groups T1 through T10 and five birds for T11).\",\n \"Each group was housed together.\",\n \"Treatment group T11 birds were a baseline group and used to obtain a Day 0 bleed.\",\n \"Study design is provided in Table 8: TABLE 8 Example 8 study design Treatment Processing No.\",\n \"of Vacination No.\",\n \"Group Method Birds Days Dose Route Bleed Days* T1 CHO lys.\",\n \"Mixing 6 0, 14 0.5 ml SQ 14, 28 NT-1 ext Adjuvant T2 CHOHA0102 Mixing 6 on 0, 14 0.5 ml SQ 14, 28 Adjuvant zero 5 on 14 T3 CHOHA0102 Microfluid.\",\n \"6 0, 14 0.5 ml SQ 14, 28 Adjuvant Non- Clarified T4 CHOHA0102 Microfluid.\",\n \"6 0, 14 0.5 ml SQ 14, 28 Adjuvant Clarified T5 CHOHA0102 Silverson 6 0, 14 0.5 ml SQ 14, 28 Adjuvant Non- Clarified T6 CHOHA0102 Mixing 6 0, 14 0.5 ml SQ 14, 28 NT-1 ext Adjuvant T7 CHOHA0102 Microfluid.\",\n \"6 0, 14 0.5 ml SQ 14, 28 NT-1 ext Non- Adjuvant Clarified T8 CHOHA0102 Microfluid.\",\n \"6 0, 14 0.5 ml SQ 14, 28 NT-1 ext Clarified Adjuvant T9 CHOHA0102 Silverson 6 0, 14 0.5 ml SQ 14, 28 NT-1 ext Non- Adjuvant Clarified T10 H5N9 AIV Mixing 6 0, 14 0.5 ml SQ 14, 28 Adjuvant T11 Baseline NA 5 NA NA NA 0 Bleed Bleed days - serum evaluated by hemagglutination inhibition with A/Turkey/Wisconsin/68 (H5N9) CHO lysate - Non-transfected CHO cells NT-1 extract - Nicotiana tabacum, lyophilized, non-transformed clarified cell lysate Adjuvant - Lecithin, acrylic copolymer, Quil A, and cholesterol SQ—subcutaneous administration CHOHA0102—CHO cells transfected with H5 hemagglutinin H5N9 AIV—Inactivated H5N9 avian influenza virus A/Turkey/Wisconsin/68 NA—not applicable As shown in Table 9, all vaccinated treatment groups (T2-T9) were clearly different from the negative control (T1).\",\n \"Although slight differences were observed, little differentiation was discernable between treatment groups that did or did not receive the Nicotiana tabacum cell line lysate or between the various processing methods.\",\n \"TABLE 9 Seroconversion rates and avian influenza hemagglutination inhibition geometric mean titer results Avian Influenza No.\",\n \"of Birds Geometric Seroconverting/ Mean Treat- Tot.\",\n \"Birds Titers ment Treatment Group Day Day group Antigen Ad Processing 14 Day 28 14 Day 28 T1 CHO lys.\",\n \"Mixing 0/6 0/6 4.0 4.0 NT-1 ext Adjuvant T2 CHOHA0102 Mixing 2/6 5/5 8.0 48.5 Adjuvant T3 CHOHA0102 Microfluid.\",\n \"5/6 5/6 11.3 22.6 Adjuvant Non- Clarified T4 CHOHA0102 Microfluid.\",\n \"3/6 5/6 9.0 28.5 Adjuvant Clarified T5 CHOHA0102 Silverson 4/6 4/6 14.3 22.6 Adjuvant Non- Clarified T6 CHOHA0102 Mixing 4/6 5/6 10.1 32.0 NT-1 ext Adjuvant T7 CHOHA0102 Microfluid.\",\n \"3/6 5/6 10.1 18.0 NT-1 ext Non- Adjuvant Clarified T8 CHOHA0102 Microfluid.\",\n \"3/6 6/6 9.0 20.2 NT-1 ext Clarified Adjuvant T9 CHOHA0102 Silverson 2/6 5/6 5.7 25.4 NT-1 ext Non- Adjuvant Clarified T10 H5N9 AIV Mixing 3/6 6/6 8.0 228.1 Adjuvant Results from the Example show that additive based adjuvants of the invention support a cell line based antigen, i.e., a cell line that expresses the antigen, and provided excellent immunogenicity in chickens.\",\n \"This data further supports the conclusion that Quil A and cholesterol when used in combination with other adjuvant based embodiments described herein have surprising utility in the context of the present invention.\",\n \"Example 9 Micrograph Data: Embodiments of the Present Invention have Net-Like Structure Inventive adjuvant compositions were as prepared and described in previous Examples.\",\n \"Adjuvant samples were visualized by transmission electron microscopy.\",\n \"Adjuvants included lecithin and polymer, no additives, and were sterilized by autoclaving.\",\n \"An illustrative micrograph at 30,000× magnification is shown in FIG.\",\n \"2A.\",\n \"For comparison, an illustrative emulsion as prepared by the methods described in U.S. Pat.\",\n \"No.\",\n \"5,716,637 (Anselem et al.\",\n \"), and visualized via transmission electron microscopy at the same magnification (30,000×) is shown in FIG.\",\n \"2B.\",\n \"As described in the description of the Anselem patent, the adjuvant was microfiltered and not autoclaved.\",\n \"The adjuvant prepared via the methods of U.S. Pat.\",\n \"No.\",\n \"5,716,637, show an expected emulsion structure of lipid droplets in an aqueous phase.\",\n \"In contrast, the micrograph shown in FIG.\",\n \"2 A illustrates that adjuvants of the present invention have a significantly different physical structure or distribution than the adjuvants described in Anselem.\",\n \"Adjuvants of the present invention show a diffuse net-like structure with significant polymer content combining with the lecithin (phospholipids) to provide the unexpected structure of the present invention.\",\n \"This is a surprising given the significant difference is structure between the two adjuvant compositions.\",\n \"Example 10 Calcium Phosphate Facilitates Immunity of DNA-Based Vaccine Lecithin and acrylic copolymer adjuvant as described and prepared herein was analyzed alone and in combination with calcium phosphate (CaPO4) to determine effectiveness at supporting the immunization of chicks against an avian influenza DNA antigen (H5N9 AIV HA DNA).\",\n \"Inventive adjuvants herein were compared to a commercially available adjuvant, having the same antigen.\",\n \"The commercially available adjuvant was also tested with CaPO4.Chick treatment groups were immunized on day 0 and day 16.Serum testing was performed on each treatment group and HAI titers determined using standard assays.\",\n \"FIG.\",\n \"3 shows data from HAI GMT serum titers for adjuvant only, no antigen (Amphigen®); antigen only, no adjuvant; Amphigen®; Amphigen® with CaPO4; Lecithin and Copolymer; and Lecithin, Copolymer and CaPO4.The results in FIG.\",\n \"3 indicate that the lecithin, copolymer and calcium phosphate group vaccine provided significantly higher levels of immunity than lecithin and copolymer alone or Amphigen with or without calcium phosphate.\",\n \"This combination of lecithin, copolymer and calcium phosphate shows an unexpected capacity to transform poorly immunogenic DNA vaccines into highly effective vaccines.\",\n \"Example 11 Enhanced Potency of FMD Vaccine Experimental design: Second generation human adenovirus type 5 (Ad5) vector for FMDV serotype A24 Cruzeiro administered to pigs subcutaneously at two sites with or without adjuvant.\",\n \"The animals were challenged 21 days post-vaccination at doses 10-fold higher than recommended.\",\n \"FIG.\",\n \"4 shows the results of the experimental Adenovirus vector-based FMD vaccine alone or in combination with one of two adjuvants: a DNA plasmid called plCLC or Adjuvant E (Adjuplex/Vetplex with Quil A and Cholesterol).\",\n \"Adjuvant E increased potency by at least 5-fold whereas the plCLC adjuvant was less effective.\",\n \"This data further supports the conclusion that Quil A and cholesterol when used in combination with other adjuvant based embodiments described herein have surprising utility in the context of the present invention.\",\n \"Example 12 Effect of Vaccine Adjuvants on Adeno-Vector Viruses The overarching goal of this research was to produce and evaluate Foot-and-mouth disease (FMD) single or combinational vaccines comprising replication-defective recombinant human adenovirus carrying (a) the FMD VP1 capsid and 3C protease coding regions and/or (b) bovine or porcine type 1 interferon genes.\",\n \"This strategy is being used to develop next generation molecular FMD licensed vaccines for stock piling by the National Veterinary Stockpile Program for use as an FMD countermeasure in emergency outbreaks.\",\n \"One research area of this project was the addition of vaccine adjuvants to the adeno-based vector vaccines for enhancement of their immunogenecity and efficacy.\",\n \"Two adjuvants (Adjuplex-LAP and Adjuplex-LE) were evaluated in vitro for virucidal effects on the vaccine vectors under different time and temperature conditions.\",\n \"The conclusion drawn from this study was that Adjuplex LAP did not have any virucidal effect on Ad5bIFNα virus at the recommended or 4-fold concentration level.\",\n \"The incubation temperatures and times for these studies were 20° C., or 39° C., and 1 or 24 hours, respectively.\",\n \"However, similar results were not observed for Adjuplex-LE.\",\n \"No titer reductions were observed at 39° C. and one hour incubation; however when the incubation was increased to 24 hours, there were significant reductions in virus titers at both concentrations.\",\n \"Results from this study would suggest that Adjuplex-LE adjuvant produced a virucidal effect on Ad5-bIFNα virus at both the recommended and two-fold higher concentration levels.\",\n \"Similar results were obtained with Ad5-O1 virus when it was mixed with both Adjuplex LAP and LE, respectively, at the recommended quantity and when the amount was increased two- or four-fold.\",\n \"Furthermore, there were no significant titer reductions even when the mixtures were incubated at 39° C. for 24 hours.\",\n \"The 39° C. incubation temperature was selected because that is the average cattle rectal body temperature.\",\n \"It is recommended that Adjuplex LAP should be the adjuvant of choice to be combined with the Ad5-bIFNα, Ad5-O1 and other Ad5 based FMD sub unit vaccines for clinical evaluation in cattle and pigs.\",\n \"Foot-and-mouth disease (FMD) is an economically important and highly contagious viral disease of cloven-hoofed livestock and wildlife including cattle, swine, sheep, goats, and deer.\",\n \"The recent re-emergence of FMD in both developing and developed nations has refocused world's attention on universe control strategies particularly in the USA.\",\n \"In many countries the control and eradication of FMD are by immunization of susceptible animals using commercially available FMD vaccines, which are based on conventional chemically inactivated vaccines emulsified with adjuvants.\",\n \"Failure to completely inactivate the vaccine has led to outbreaks of the disease.\",\n \"There is no approved diagnostic test available to reliably differentiate vaccinated from infected animals.\",\n \"Furthermore vaccinated animals can become disease carriers following contact with FMD virus.\",\n \"These disadvantages of inactivated whole FMD vaccine have made FMD-free countries to be reluctant to vaccinate their livestock during outbreaks.\",\n \"In order to overcome some of the problems associated with convectional FMD vaccines, many approaches have been utilized to develop alternative FMD vaccines, including construction of modified live-virus, biosynthetic proteins, synthetic peptides, naked DNA vectors, and recombinant viruses.\",\n \"The use of human adenovirus as a vector for FMD vaccines has been met with variable results, sometimes resulting in incomplete protection or failure of vaccinated animals to develop a neutralizing antibody.\",\n \"In this study, two adjuvants viz Adjuplex-LAP and Adjuplex-LE were investigated in vitro as possible adjuvants for Ad5 FMD subunit vaccines.\",\n \"This was a preliminary investigation prior to in vivo studies.\",\n \"Experiments were set up to determine both their cytotoxic effect on 293 cells and their virucidal effects on Ad5-FMD viruses.\",\n \"Adjuplex-LAP is a mucosal vaccine adjuvant as well as an adjuvant for parenterally administered vaccines.\",\n \"The adjuvant is a lecithin phospholipid/acrylic polymer combination.\",\n \"The combination forms a mucoadhesive matrix that facilitates the adsorption of vaccine antigens to mucosal surfaces and subsequent absorption and presentation of antigen to cells of the immune system.\",\n \"Both adjuvant components are used in the pharmaceutical and biological industries and thus have value as a delivery and adjuvant system for vaccine antigens.\",\n \"Adjuplex-LE is a 5%, or less, oil-in-water emulsion, the oil droplets which are covered by lecithin derived phospholipid vesicles.\",\n \"The lipid vesicles act as a carrier for vaccine antigens and make them accessible to cells of the immune system.\",\n \"The lipid vesicles on the surface of the oil droplets is also a safety feature making the oil less irritable or not irritable at all to tissue at the injection site.\",\n \"The adjuvant is also non-virucidal.\",\n \"Therefore the formulation can be, and is, used to adjuvant modified-live virus vaccines.\",\n \"The adjuvant can be mixed directly with vaccine antigens without further emulsification or the antigens can be added at the time of emulsification.\",\n \"The redox indicator Alamar Blue™ (AB), a fluorescent dye, which has been used in mammalian cell culture cytotoxicity assays.\",\n \"AB is a safe, nontoxic aqueous dye, which is used to assess cell viability and cell proliferation because it is stable in cell culture.\",\n \"It has also been shown to be a rapid and simple non-radioactive assay alternative to the [3H] thymidine incorporation assay.\",\n \"AB both fluoresces and changes color in response to chemical reduction, and the extent of the conversion is a reflection of cell viability.\",\n \"AB assay is a simple, one-step procedure.\",\n \"Alamar Blue™ assay was set up to study the cytotoxicity effects of two vaccine adjuvants 293 cells.\",\n \"There were two objectives: (a) evaluate the relative 293 cell cytotoxity of vaccine adjuvants in combination with Ad5-bovine interferon alpha (Ad5bIFN α) and Ad5O1 vectors, and (b) establish if the vaccine adjuvants are virucidal for Ad5bIFNα vector.\",\n \"Alamar Blue™ assay was set up to study the cytotoxicity effect of vaccine adjuvants on 293 cells.\",\n \"Alamar Blue™ is a safe, nontoxic aqueous dye which is used to assess cell viability and cell proliferation.\",\n \"Materials and Methods 293 Cells Human embryonic kidney (293) cells were obtained from Dr. Patrick Hearing, Department of Microbiology, Stony Brook University, Stony Brook, N.Y., and were propagated in minimum essential medium (MEM) containing 10% fetal bovine serum (FBS), 1% antibiotic-antimycotic solution, and 1% MEM non essential amino acid (NEAA).\",\n \"293 cells of passages 15 and 36 were used for transfection, propagation of viruses, virus titrations and performing of cytotoxicity assays.\",\n \"Ad5bIFNα and Ad5O1 Plasmids The two plasmids were provided by Dr. Laszlo Zsak from US Department of Homeland Security, Targeted Advanced Development, Plum Island Animal Diseases Center, Orient Point, N.Y. Transfection of Ad5bIFNα and Ad5O1 Plasmids in 293 Cells The pAd5bIFNα and pAd5O1 were linearized by digestion with restriction enzyme Pad and transfected in 293 cells using Lipofectamin™ 2000.Production and Purification of Ad5bIFNα and Ad5O1 Viruses (Vaccine Vectors) The 2 viruses were harvested with the appearance of the initial plaques, which were then grown in large quantities in 293 cells, and purified utilizing a nonlinear followed by a linear CsCl gradient centrifugation.\",\n \"Dilutions of Vaccine Viruses (Ad5bIFNα and Ad5O1) 1:10, 1:100 and 1:100 dilutions of both Ad5bIFNα and Ad5O1 vaccine viruses were prepared respectively in EMEM containing 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA.\",\n \"Dilutions of Adjuvants (Adjuplex-LAP and Adjuplex-LE) 1:20, 1:200, 1:2000, and 1:20,000 dilutions of both Adjuplex-LAP and Adjuplex-LE adjuvants were prepared respectively in EMEM containing 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA.\",\n \"Alamar Blue (AB) AB was aliquoted and stored at −80° C. Prior to each experiment, AB was brought to room temperature and vortexed.\",\n \"Exposure of AB to light was minimized throughout the experiments.\",\n \"Alamar Blue (AB) Cytotoxicity Assay (Cell Viability Assay) Cell viability of 293 cells was assessed by AB cytotoxicity assay.\",\n \"293 cells in EMEM containing 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA were seeded at a density of 1×106 viable cells/ml (1×105/well) in a 96 well Treatment (BD Falcon* Primaria* Tissue culture Treatments, Fisher Scientific Company, Suwanee, Ga.).\",\n \"In a second plate, cells were seeded at a density of 10×106 viable cells/ml (1×106/well) to determine the optimal cell concentration for the cytotoxicity study.\",\n \"Table 10 shows the addition of diluted Ad5bIFNα, Ad5O1, Adjuplex-LAP and Adjuplex-LE to the cells.\",\n \"Briefly, 0.1 ml of each of the dilutions of Ad5bIFNα and Ad5O1 (1:10, 1:100, 1:100) was added to each well respectively in triplicates.\",\n \"0.1 ml of each of the dilutions of the adjuvants (1:20, 1:200, 1:2000, and 1:20,000) was added to each well respectively in triplicates.\",\n \"EMEM containing 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA was added to wells A1, A2, A3, D1, D2 and D3 as negative controls.\",\n \"The two treatments were incubated at 37° C. in a 5% CO2 atmosphere for approximately 18 hours, after which 20 μl AB was added to each well.\",\n \"The treatments were returned to the incubator.\",\n \"Optical densities (OD) at 570 nm and 600 nm were measured with the ELX808 ultra microplate reader (BioTek Instruments, Inc., Winooski, Vt.) at approximately 42 hours, 50 hours, and 68 hours (total culture times).\",\n \"The OD data were analyzed as follows: (a).\",\n \"determine % difference in reduction of AB (between media growth control wells and treatment wells); this will indicate the amount inhibition (or stimulation) of cell growth in treatment wells with respect to media control wells, and (b).\",\n \"determine % reduction of AB in media control and in treatment wells; this will indicate the amount of cell growth in media control and treatment wells.\",\n \"Treatments with higher % reduction than media controls are considered to stimulate cell growth.\",\n \"Treatments with lower % reduction than media controls are considered cytotoxic.\",\n \"Treatments with the same % reduction are neither cytotoxic nor stimulatory.\",\n \"Calculation of Alamar Blue (AB) Reduction Percent reduction of AB was calculated using the manufacturer's formula (33).\",\n \"In monitoring AB reduction spectrophotometrically, reduction is expressed as a percentage (% reduced).\",\n \"The calculation of % Reduced is as follows when the samples are read at λ1 = 570 nm λ2 = 600 nm % Reduced = ( ɛ ox λ2 ) ( A λ1 ) - ( ɛ ox λ1 ) ( A λ2 ) ( ɛ red λ1 ) ( A ’ λ2 ) - ( ɛ red λ2 ) ( A ’ λ1 ) × 100 Where: (εred λ1)=155,677 (Molar extinction coefficient of reduced AlamarBlue™ at 570 nm) (εred λ2)=14,652 (Molar extinction coefficient of reduced AlamarBlue™ at 600 nm) (εox λ1)=80,586 (Molar extinction coefficient of oxidized AlamarBlue™ at 570 nm) (εox λ2)=117,216 (Molar extinction coefficient of oxidized AlamarBlue™ at 600 nm) (Aλ1)=Absorbance of test wells at 570 nm (Aλ2)=Absorbance of test wells at 600 nm (A′λ1)=Absorbance of negative control wells which contain medium plus AlamarBlue™ but to which no cells have been added at 570 nm.\",\n \"(A′λ2)=Absorbance of negative control wells which contain medium plus AlamarBlue™ but to which no cells have been added at 600 nm.\",\n \"In reporting AlamarBlue™ reduction by monitoring absorbance, data are expressed as percent AlamarBlue™ reduced as a function of time of incubation.\",\n \"The AB assay was used to determine viability of 293 cells to vaccine adjuvants.\",\n \"Virucidal Assay (TCID50 Assay) The TCID50 assay was employed to ascertain and measure if there were virucidal effects of Adjuplex-LAP and Adjuplex-LE adjuvants on Ad5bIFNα and Ad5O1 viruses.\",\n \"293 cells were harvested from a T-150 flask of fresh 293 cells, and counted on a hemocytometer.\",\n \"A dilution of the cell suspension at 1×105/ml in MEM containing 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA was made, and at least 10 ml was prepared for each 96 flat-bottomed well tissue culture plate.\",\n \"Using a 12-channel pipette and a multichannel pipetter basin, 100 μl of the cell dilution (104 cells/per well) was seeded into 96-well tissue culture plates, and covered.\",\n \"They were incubated at 37° C. in a CO2 incubator until used.\",\n \"Frozen vials of Ad5bIFNα and Ad5O1 viruses were thawed and kept on ice at all times.\",\n \"MEM supplemented with 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA was used to make virus dilutions of 10−1 to 10−13.The 10 fold dilutions were made in 5 ml sterile, disposable tubes.\",\n \"The cells were infected by adding 0.1 ml per well of each virus-adjuvant dilution immediately after the dilutions were made.\",\n \"AB assay with a cell concentration of 10×106/ml was also set up.\",\n \"Preparation of Antigen-Adjuvant Mixtures Ad5bIFNα Virus-Adjuvant Mixtures Each of the two adjuvants was mixed with Ad5bIFNα according to the manufacturer recommended ratios (LAP:virus ratio, 1:4; LE:virus ratio, 1:1).\",\n \"In addition to the recommended ratios, additional ratios (LAP:antigen ratio, 4:1; LE:antigen ratio, 2:1) were also tested to increase the chances of having virucidal effects.\",\n \"Each mixture was made in a sterile 1 ml microtube and vortexed three times to ensure adequate mixing before use, and was incubated according to the appropriate conditions.\",\n \"The media-virus mixture served as a control.\",\n \"The media consisted of MEM supplemented with 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA.\",\n \"The ratios tested were as follows: Experiment 1 Treatment A: 25 μl Media+100 μL Ad5bIFNα Treatment B: 25 μL LAP+100 μL Ad5bIFNα Treatment C: 100 μL Media+100 μL Ad5bIFNα Treatment D: 100 μL LE+100 μL Ad5bIFNα The mixtures were not incubated before dilutions were made.\",\n \"Experiment 2 Treatment A: 25 μl Media+100 μL Ad5bIFNα Treatment B: 25 μL LAP+100 μL Ad5bIFNα Treatment C: 100 μL Media+100 μL Ad5bIFNα Treatment D: 100 μL LE+100 μL Ad5bIFNα The mixtures were incubated at room temperature (20-25° C.) for one hour before dilutions were made.\",\n \"Experiment 3 Treatment A: 100 μl Media+100 μL Ad5bIFNα Treatment B: 100 μL LAP (4×)+100 μL d5bIFNα Treatment C: 100 μL LE+100 μL Ad5bIFNα Treatment D: 200 μL Media+100 μL Ad5bIFNα Treatment E: 200 μL LE (2×)+100 μL Ad5bIFNα The mixtures were incubated at 39° C. for one hour before dilutions were made.\",\n \"Experiment 4 Treatment A: 100 μl Media+100 μL Ad5bIFNα Treatment B: 100 μL LAP (4×)+100 μL Ad5bIFNα Treatment C: 100 μL LE+100 μL Ad5bIFNα Treatment D: 200 μL Media+100 μL Ad5bIFNα Treatment E: 0.200 μL LE (2×)+100 μL Ad5bIFNα The mixtures were incubated at 39° C. for 24 hours before dilutions were made.\",\n \"Ad5O1-Adjuvant Mixtures Each of the two adjuvants was mixed with Ad5O1 according to the manufacturer recommended ratios (LAP:virus ratio, 1:4; LE:virus ratio, 1:1).\",\n \"In addition to the recommended ratios, additional ratios (LAP:virus ratio, 4:1; LE:virus ratio, 2:1) were also tested to increase the chances of having virucidal effects.\",\n \"Each mixture was made in a sterile 1 ml microtube and vortexed three times to ensure adequate mixing before use.\",\n \"The media-virus mixture served as a control.\",\n \"The media consisted of MEM supplemented with 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA.\",\n \"The ratios tested were as follows: Experiment 1 Treatment A: 25 μl Media+100 μL Ad5O1 Treatment B: 25 μL LAP+100 μL Ad5O1 Treatment C: 100 μL Media+100 μL Ad5O1 Treatment D: 100 μL LE+100 μL Ad5O1 The mixtures were not incubated before being dilutions were made.\",\n \"Experiment 2 Treatment A: 25 μl Media+100 μL Ad5O1 Treatment B: 25 μL LAP+100 μL Ad5O1 Treatment C: 100 μL Media+100 μL Ad5O1 Treatment D: 100 μL LE+100 μL Ad5O1 The mixtures were incubated at room temperature (20-25° C.) for one hour dilutions were made.\",\n \"Experiment 3 Treatment A: 100 μl Media+100 μL Ad5O1 Treatment B: 100 μL LAP (4×)+100 μL Ad5O1 Treatment C: 100 μL LE+100 μL Ad5O1 Treatment D: 200 μL Media+100 μL Ad5O1 Treatment E: 200 μL LE (2×)+100 μL Ad5O1 The mixtures were incubated at 39° C. for one hour before dilutions were made.\",\n \"Experiment 4 Treatment A: 100 μl Media+100 μL Ad5O1 Treatment B: 100 μL LAP (4×)+100 μL Ad5O1 Treatment C: 100 μL LE+100 μL Ad5O1 Treatment D: 200 μL Media+100 μL AdO1 Treatment E: 0.200 μL LE (2×)+100 μL Ad5O1 The mixtures were incubated at 39° C. for 24 hours before dilutions were made.\",\n \"Preparation of Virus-Adjuvant Dilutions From each treatment, serial 10 fold dilutions of adjuvant-virus mixtures were prepared in 5 ml sterile, disposable tubes using MEM supplemented with 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA to prepare adjuvant-virus dilutions of 10−1 to 10−13.0.9 ml MEM supplemented with 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA was dispensed into the first two tubes.\",\n \"To each of the eleven other tubes was added 1.8 ml.\",\n \"0.1 ml of each adjuvant-virus mixture from each treatment was added to the first tube and mixed by votexing.\",\n \"Filtered pipette tips were changed between dilutions.\",\n \"0.1 ml of the 10−1 dilution was withdrawn and transferred to the second tube containing MEM supplemented with 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA.\",\n \"0.2 ml of the 10−2 dilution was withdrawn and transferred to the third tube containing MEM supplemented with 2% FBS, 1% antibiotic-antimycotic solution, and 1% MEM-NEAA, and this became 10−3 virus dilution.\",\n \"The above steps were repeated to prepare the next virus dilutions (10−4 to 10−13).\",\n \"Infection of Cells with Virus-Adjuvant Dilutions One 96-well plate was used for infection per treatment.\",\n \"Immediately after the dilutions were made, the cells were infected by adding 0.1 ml per well of each virus-adjuvant dilution.\",\n \"0.1 ml of the virus-adjuvant suspension with the highest dilution was dispensed in column 1 wells to infect the cells in the 8 wells of this column.\",\n \"The cells in the 8 wells of the next column; column 2 of the 96-well were infected with 0.1 ml of the next adjuvant-virus dilution (10−12).\",\n \"The cells in the 8 wells of columns 3 through 11 were infected with 0.1 ml of the remaining virus-adjuvant dilutions (10−11-10−13).\",\n \"Pipette tips were changed between dilutions.\",\n \"To test the cell viability and as a negative control (no adjuvant-virus control), 0.1 ml/well of MEM containing 2% FBS, 1% antibiotic-antimycotic solution and 1% MEM-NEAA was added to each well in column 12.Each plate was covered and incubated at 37° C. in a CO2 incubator for 10 days.\",\n \"Cells in each plate were observed daily by an inverted microscope for cytopathic effects (CPE) over the next 10 days.\",\n \"Observable CPE per column were counted and recorded.\",\n \"Final reading of each plate was done on the 10th day post incubation to determine the titer.\",\n \"A well was counted as positive even if only a small spot or a few cells showed CPE.\",\n \"The negative control wells were used for comparison.\",\n \"The test was valid if the negative controls did not show any CPE or cell growth problems, and the lowest dilution showed 100% infection (8/8) while the highest dilutions showed 0% infection (0/8).\",\n \"The results were recorded for day 10, scoring wells “+” (CPE positive) or “−” (CPE negative) using the CPE scoring form in appendix A, and the ratio of positive wells per column was determined, and recorded it as in appendix A.\",\n \"After recording the assay data, the plates were placed in a biohazard bag and autoclaved and discarded as biohazardous waste.\",\n \"For each plate (treatment), TCID50/ml titer was calculated using the KÄRBER statistical method.\",\n \"Compare the TCID50/ml between the treatments in each experiment to determine if there was a difference.\",\n \"A difference in titers between treatments in each experiment that is greater than 0.7 log was considered to be significant, which means the adjuvant in that experiment was virucidal to the tested virus.\",\n \"Results Alamar Blue (AB) Cytotoxicity Assay (Cell Viability Assay) Alamar Blue™ was used to measure 293 cell viability at two densities There was cell clumping at a density of 10×106/ml for all treatments.\",\n \"The 1×106/ml density was better than the higher density.\",\n \"Cell Viability Assay on Exposure to Ad5bIFNα At a cell concentration of 1×106/ml, the 1:100 dilution of Ad5bIFNα produced the higher % AB reduction than the media controls at 42 and 50 hours post exposure (FIGS.\",\n \"5 and 6).\",\n \"However, there was a % AB reduction at 68 hours post exposure (FIG.\",\n \"7).\",\n \"Similar results were obtained at a cell density of 10×106/ml (FIGS.\",\n \"8-10).\",\n \"Cell Viability Assay on Exposure to Adjuplex LAP Cell exposure at a cell density of 1×106/ml to Adjuplex LAP at a dilution of 1:20 gave the higher % AB reduction than the media controls at 42 and 50 hours post exposure (FIGS.\",\n \"5 and 6) but with a % AB reduction at 68 hours post exposure (FIG.\",\n \"7).\",\n \"Similar results were obtained at a cell density of 10×106/ml (FIGS.\",\n \"8-10).\",\n \"Cell Viability Assay on Exposure to Adjuplex LE When 293 cells at a cell density 1×106/ml were treated with Adjuplex LE at a dilution of 1:20, higher % AB reductions were obtained compared to the media controls at 42 and 50 hours post exposure (FIGS.\",\n \"5 and 6) but with a % AB reduction at 68 hours post exposure (FIG.\",\n \"7).\",\n \"Similar results were obtained at a cell density of 10×106/ml (FIGS.\",\n \"8-10).\",\n \"Cell Viability Assay on Exposure to Emulsigen Treatment of 293 cells at a cell density 1×106/ml with Emulsigen at 1:20 dilution resulted in higher % AB reductions relative to the media controls at 42 and 50 hours post exposure (FIGS.\",\n \"5 and 6) but with lower % AB reductions at 68 hours post exposure (FIG.\",\n \"7).\",\n \"Similar results were obtained at a cell density of 10×106/ml (FIGS.\",\n \"8-10).\",\n \"Virucidal Assay (TCID50 Assay) Ad5bIFNα Virus-Adjuvant Mixtures Experiment 1 The log 10 titers of treatments in this group were 10.0, 9.9, 9.5, and 9.6 (Table 11, FIG.\",\n \"11).\",\n \"The differences between them were lower than log 0.7 (34), therefore there were no significant differences within this treatment group (34).\",\n \"This indicates that the two adjuvants did not produce any virucidal effect on the virus when combined at room temperature.\",\n \"Experiment 2 As in the first experiment, leaving the virus-adjuvant mixtures at 24° C. for one hour of incubation, the two adjuvants did not produce any virucidal effect on the virus because the differences between log 10 titers were less than log 10 0.7 (34), (Table 11, FIG.\",\n \"11).\",\n \"Experiment 3 The adjuvants in these treatment groups did not exhibit any virucidal effect on the virus when incubated for one hour at 39° C. (Table 11, FIG.\",\n \"11).\",\n \"Experiment 4 Incubating the two first treatment groups at 39° C. for 24 hours did not produce any virucidal effect by Adjuplex-LAP adjuvant on the virus (Table 11, FIG.\",\n \"11).\",\n \"However, treatments at these incubation time and temperature conditions significantly reduced titers by 3.3- and 1.9-log 10 TCID50 (34) when compared to the control treatment groups at the recommended amount and when the amount of Adjuplex LE was doubled, respectively.\",\n \"Ad5O1 Virus-Adjuvant Mixtures Experiment 1 There were no significant differences in virus titers of treatments A and B.\",\n \"The reduction in titer between treatments C and D was 0.2 log 10 TCID50 and this was not significant (34) (Table 12, FIG.\",\n \"12).\",\n \"Virus-adjuvant mixtures in this experiment were not incubated.\",\n \"Experiment 2 There was no significant titer reduction between treatments A and B incubated for 1 hour at 20° C. The adjuvants did not produce any significant titer reduction (34) in treatments C and D (Table 12, FIG.\",\n \"12).\",\n \"Experiment 3 In a similar fashion, all the groups in this experiment did not show any significant differences in log 10 titer reduction.\",\n \"Experiment 4 There was a significant reduction (1.0 log 10) in titers between treatments A and B.\",\n \"The titer reduction (0.3 log) between treatments 3 and 4 was not significant (34) (Table 12, FIG.\",\n \"12).\",\n \"TABLE 10 Alamar Blue Cytoxicity Assay Setup 1 2 3 4 5 6 7 8 9 10 11 12 Plate 1: 1 × 10{circumflex over ( )}5 cells per well A #1 media + cells #1 Ad5-bIFNα 1:10 #1 Ad5-bIFNα 1:100 Media NO CELLS B #1 Adjuplex-LAP 1:20 #1 Adjuplex-LAP 1:200 #1 Adjuplex-LAP 1:2000 #1 Adjuplex-LAP 1:20000 C #1 Adjuplex-LE 1:20 #1 Adjuplex-LE 1:200 #1 Adjuplex-LE 1:2000 #1 Adjuplex-LE 1:20000 D #2 media + cells #1 Ad5-bIFNα 1:10 #1 Ad5-bIFNα 1:100 Media NO CELLS E #2 Adjucplex-LAP 1:20 #2 Adjuplex-LAP 1:200 #2 Adjuplex-LAP 1:2000 #2 Adjuplex-LAP 1:20000 F #2 Adjuplex-LE 1:20 #2 Adjuplex-LE 1:200 #2 Adjuplex-LE 1:2000 #1 Adjuplex-LE 1:20000 G #2 Adjucplex-LAP 1:20 #2 Adjuplex-LAP 1:200 #2 Adjuplex-LAP 1:2000 #2 Adjuplex-LAP 1:20000 H #2 Adjuplex-LE 1:20 #2 Adjuplex-LE 1:200 #2 Adjuplex-LE 1:2000 #1 Adjuplex-LE 1:20000 Plate 2: 1 × 10{circumflex over ( )}5 cells per well A #1 media + cells #1 Ad5-bIFNα 1:10 #1 Ad5-bIFNα 1:100 Media NO CELLS B #1 Adjuplex-LAP 1:20 #1 Adjuplex-LAP 1:200 #1 Adjuplex-LAP 1:2000 #1 Adjuplex-LAP 1:20000 C #1 Adjuplex-LE 1:20 #1 Adjuplex-LE 1:200 #1 Adjuplex-LE 1:2000 #1 Adjuplex-LE 1:20000 D #2 media + cells #1 Ad5-bIFNα 1:10 #1 Ad5-bIFNα 1:100 Media NO CELLS E #2 Adjucplex-LAP 1:20 #2 Adjuplex-LAP 1:200 #2 Adjuplex-LAP 1:2000 #2 Adjuplex-LAP 1:20000 F #2 Adjuplex-LE 1:20 #2 Adjuplex-LE 1:200 #2 Adjuplex-LE 1:2000 #1 Adjuplex-LE 1:20000 G #2 Adjucplex-LAP 1:20 #2 Adjuplex-LAP 1:200 #2 Adjuplex-LAP 1:2000 #2 Adjuplex-LAP 1:20000 TABLE 11 Ad5bIFNα virus-Adjuvant Mixture Titers Expressed in Log10 TCID50 Experiment Temperature Incubation Log10 Number Treatment ° C. Time (hrs) TCID50 1 A.\",\n \"25 μl Media + 100 μl Ad5bIFNα None 10.0 B.\",\n \"25 μl LAP + 100 μl Ad5bIFNα None 9.9 C. 100 μl LE + 100 μl Ad5bIFNα None 9.5 D. 100 μl Media + 100 μl Ad5bIFNα None 9.6 2 A.\",\n \"25 μl Media + 100 μl Ad5bIFNα 20 1 10.6 B.\",\n \"25 μl LAP + 100 μl Ad5bIFNα 20 1 10.5 C. 100 μl Media + 100 μl Ad5bIFNα 20 1 10.4 D. 100 μl LE + 100 μl Ad5bIFNα 20 1 10.3 3 A.\",\n \"100 μl Media + 100 μl Ad5bIFNα 39 1 10.0 B.\",\n \"100 μl LAP (4X)* + 100 μl Ad5bIFNα 39 1 9.9 C. 100 μl LE + 100 μl Ad5bIFNα 39 1 9.9 D. 200 μl Media + 100 μl Ad5bIFNα 39 1 9.8 E. 200 μl LE (2X)** + 100 μl Ad5bIFNα 39 1 9.9 4 A.\",\n \"100 μl Media + 100 μl Ad5bIFNα 39 24 9.9 B.\",\n \"100 μl LAP (4X)* + 100 μl Ad5bIFNα 39 24 9.9 3.100 μl LE + 100 μl Ad5bIFNα 39 24 6.6 4.200 μl Media + 100 μl Ad5bIFNα 39 24 7.5 5.200 μl LE (2X)** + 100 μl Ad5bIFNα 39 24 5.6 Ad5bIFNα virus (without adjuvants) titer expressed in Log10 TCID50 = 10.5 *= Indicates four-fold in the amount of recommended concentration **= Indicates twice the amount of recommended concentration TABLE 12 Ad5O1 virus-Adjuvant Mixture Titers Expressed in Log10 TCID50 Experiment Temperature Incubation Log10 Number Treatment ° C. Time (hrs) TCID50 1 A.\",\n \"25 μl Media + 100 μl Ad5O1 None 10.6 B.\",\n \"25 μl LAP + 100 μl Ad5O1 None 10.8 C. 100 μl Media + 100 μl Ad5O1 None 9.6 D. 100 μl LE + 100 μl Ad5O1 None 9.8 2 A.\",\n \"25 μl Media + 100 μl Ad5O1 20 1 10.8 B.\",\n \"25 μl LAP + 100 μl Ad5O1 20 1 11.1 C. 100 μl Media + 100 μl Ad5O1 20 1 10.4 D. 100 μl LE + 100 μl Ad5O1 20 1 10.6 3 A.\",\n \"100 μl Media + 100 μl Ad5O1 39 1 10.0 B.\",\n \"100 μl LAP (4X)* + 100 μl Ad5O1 39 1 10.1 C. 200 μl Media + 100 μl Ad5O1 39 1 9.5 D. 200 μl LE (2X)** + 100 μl Ad5O1 39 1 9.5 4 A.\",\n \"100 μl Media + 100 μl Ad5O1 39 24 9.9 B.\",\n \"100 μl LAP (4X)* + 100 μl Ad5O1 39 24 10.9 C. 100 μl LE + 100 μl Ad5O1 39 24 10.0 D. 200 μl Media + 100 μl Ad5O1 39 24 8.3 E. 200 μl LE (2X)** + 100 μl Ad5O1 39 24 8.0 Ad5O1 virus (without adjuvants) titer expressed in Log10 TCID50 = 11.8 *= Indicates four-fold in the amount of recommended concentration **= Indicates twice the amount of recommended concentration Discussion Alamar Blue is a redox indicator of viable cell number.\",\n \"At cell density of 10×106/ml, cell clumping was observed, which indicated that there were too many cells in each well at this concentration.\",\n \"There was no clumping at a cell concentration of 1×106/ml.\",\n \"Based on this observation, the cell concentration 1×106/ml was employed in the study.\",\n \"In this study AB was employed to measure 293 cell viability at two cell concentrations.\",\n \"Optical densities were measured at 570 nm and 600 nm at approximately 42 hours (total culture time), 50 hours, and 68 hours.\",\n \"The OD data obtained were analyzed using the formula provided by the AB manufacturer.\",\n \"The % difference in reduction of AB (between media growth control wells and treatment wells) indicated the amount inhibition (or stimulation) of cell growth in treatment wells with respect to media control wells.\",\n \"Treatments with higher % reductions than media controls are considered to stimulate cell growth.\",\n \"Treatments with lower % reduction than media controls are considered cytotoxic.\",\n \"Treatments with the same % reduction are neither cytotoxic nor stimulatory.\",\n \"A dilution of 1:100 of Ad5bIFNα virus gave the higher % reduction of AB at 42 and 50 hours post exposure to the 293 cells at both 1×106/ml and 10×106/ml.\",\n \"The 1×106/ml cell concentration would be the best concentration because there was no cell clumping observed at a cell concentration of 1×106/ml.\",\n \"The 1:100 dilution would be the optimal dilution of Ad5bIFNα virus for 293 cells.\",\n \"Adjuplex LAP, LE, and emulsigen adjuvants at dilutions of 1:20 gave the highest percent reduction of AB at 42 and 50 hours post exposure to 293 cells.\",\n \"When LAP and LE were mixed at room temperature with Ad5bIFNα virus and immediately assayed for virus titer, there was no significant reduction in log titer.\",\n \"A similar result was obtained when the virus-adjuvant mixtures were incubated for one hour.\",\n \"There was no significant virus titer reduction in the virus-adjuvant mixtures when incubated for one hour at room temperature.\",\n \"The adjuvant contents of LAP and LE of the mixtures were increased four-fold and two fold, respectively, in order to increase the possibility of these adjuvants having a virucidal effect on the viruses.\",\n \"However, the reduction in titer was very little.\",\n \"When the incubation temperature was raised to 39° C. but incubation time remaining the same, there was no appreciable reduction in titer.\",\n \"The virus-adjuvant mixtures were incubated with 4- and 2-fold in the LAP and LE contents, respectively, for 24 hours (previously it was one hour), there was no reduction in titer of the virus-adjuvant LAP mixture.\",\n \"However, there was a 1.9 log 10 reduction in titer of the virus-LE mixture.\",\n \"This reduction was significant (35).\",\n \"The titer reduction 3.3 log 10 was even greater when the amount of LE in the virus-adjuvant mixture was not increased.\",\n \"The conclusion drawn from this study was that adjuplex LAP did not have any virucidal effect on Ad5bIFNα virus at the recommended amount and even when the amount was increased by 4.The incubation temperatures and times for this observation were 20° C., 39° C., 1 and 24 hours.\",\n \"However, the same could not be said for adjuplex LE because although there were no titer reductions when the incubation temperature and time were 39° C. and one hour, when the time of incubation was increased to 24 hours there were significant reductions in virus titers at both concentrations.\",\n \"Results from this study would suggest that Adjuplex-LE adjuvant produced a virucidal effect on Ad5bIFNα virus when the adjuvant concentration in the mixture was increased two-fold., and also at the recommended concentration.\",\n \"Similar results were obtained for Ad5O1 virus was mixed with both adjuplex LAP and LE at the recommended quantity and when the amount was increased by 4 fold and 2 fold, respectively.\",\n \"Furthermore, there were no significant titer reductions even when the mixtures were incubated at 39° C. for 24 hours.\",\n \"The 39° incubation temperature was selected because that is the average rectal temperature of cattle.\",\n \"It is recommended that adjuplex LAP should be the adjuvant to be combined with the Ad5bIFNα, Ad5O1 and other Ad5 based FMD sub unit vaccines for clinical evaluation in cattle.\",\n \"Example 13 Vaccination of Chickens with H5 HA-Transfected Cells and its Effect on Detectable Shedding of Low Pathogenic Avian Influenza Virus Following Challenge by Real-Time Reverse Transcriptase Polymerase Chain Reaction Objective The objective of this study was to challenge chickens vaccinated with H5N2 low pathogenic avian influenza (LPAI) virus and evaluate effect by measuring virus shed from the oropharynx and the cloaca by real-time reverse transcriptase polymerase chain reaction.\",\n \"Background A further purpose was to evaluate if Chinese Hamster Ovary (CHO) cells, stably transfected with H5 HA expressing plasmid, would stimulate an immune response in birds.\",\n \"Following one vaccination, seroconversion to H5 HA was noted in a few birds.\",\n \"The birds were subsequently administered a second dose.\",\n \"Since the birds seroconverted following one dose, the birds were challenged with H5N2 LPAI virus to determine if the detectable serological response had any effect on virus shed.\",\n \"Test/Control Articles 1.Generic Name: Media/Lecithin acrylic copolymer plus Quil A cholesterol Formulation: Media—DMEM, fetal calf serum, non-essential amino acids, L-glutamine 2.Generic Name: Control Cells/Lecithin acrylic copolymer plus Quil A cholesterol Formulation: Control cells—CHO cells not expressing HA 3.Generic Name: CHO-HA-10 cells freeze/thaw/Lecithin acrylic copolymer plus Quil A cholesterol Formulation: CHO-HA-10—CHO cells transfected to express HA with a freeze/thaw application 4.Generic Name: CHO-HA-10 cells fresh/Lecithin acrylic copolymer plus Quil A cholesterol Formulation: CHO-HA-10—CHO cells transfected to express HA prepared fresh Challenge Organism Description: LPAI* virus isolate A/TK/CA/209092/02 (H5N2) Origin: National Veterinary Services Laboratory Dosage: Challenge dose of 105.5 ELD50** per 0.1 ml dose Route of Infection: Intranasal *LPAI—Low pathogenic avian influenza**ELD50—Embryo lethal dose 50 TABLE 13 STUDY ANIMALS Species: Chickens Type: SPF Breed/Strain: Leghorn Sex: Male and Female Description: Individually identified Age: 64 days at challenge Origin (chicks) Hy-Vac Total: 15 21459 Old Hwy 6 Adel, Iowa 50003 Birds were transferred from IACUC request BEDA 1197-06-06 for challenge.\",\n \"TABLE 14 STUDY DESIGN Trt.\",\n \"Treatment Group Bird LPAI IN* Challenge Sample** No.\",\n \"Antigen Adjuvant Numbers Day 0 Days T1 None None 3 H5N2 105.5 ELD50# 0 through 6 T2 Media## LAP/QAC† 3 H5N2 105.5 ELD50# 0 through 6 T3 Control cells†† LAP/QAC† 3 H5N2 105.5 ELD50# 0 through 6 T4 CHO-HA-10 cells‡ LAP/QAC† 3 H5N2 105.5 ELD50# 0 through 6 freeze/thaw T5 CHO-HA-10 cells‡ LAP/QAC† 3 H5N2 105.5 ELD50# 0 through 6 fresh *LPAI IN—Low pathogenic avian influenza virus isolate A/TK/CA/209092/02 (H5N2), intranasal administration with 0.1 ml.\",\n \"**Sample Days—Oropharyngeal and cloacal samples collected.\",\n \"Samples were evaluated by real-time reverse transcriptase polymerase chain reaction.\",\n \"On Day 0, blood samples were also collected that were evaluated by hemagglutination inhibition.\",\n \"#H5N2 105.5 ELD50—Low pathogenic avian influenza isolate A/TK/CA/209092/02 administered intranasally at a dose of 105.5 embryo lethal dose 50 per 0.1 ml challenge inoculum.\",\n \"##Media—DMEM, fetal calf serum, non-essential amino acids, L-glutamine.\",\n \"†LAP/QAC—Lecithin acrylic copolymer plus Quil A cholesterol.\",\n \"††Control cells—CHO cells not expressing HA.\",\n \"‡CHO-HA-10 cells—CHO cells transfected to express HA.\",\n \"Procedures Prior to Day 0 Leghorn specific-pathogen-free chicks used in the study were derived from IACUC request BEDA 1197-06-06.Birds were placed in five isolators, three birds per isolator with each isolator housing a treatment group.\",\n \"Day 0 On Day 0, a blood sample, an oropharyngeal swab, and a cloacal swab were collected from each bird.\",\n \"Oropharyngeal and cloacal swabs were placed into one ml of culture medium and frozen at approximately −80° C. until processed for viral detection.\",\n \"Also on Day 0, all birds were exposed by the intranasal route to 0.1 ml of challenge inoculum of LPAI H5N2 isolate according to the table under STUDY DESIGN.\",\n \"The titer of the inoculum was 105.5 ELD50 per 0.1-ml dose.\",\n \"Days 1 Through 6 On Days 1 through 6, an oropharyngeal swab and a cloacal swab were collected from each bird in all treatment groups and processed as described previously.\",\n \"All birds were euthanized and disposed of according to standard operating procedures following sample collection on Day 6.Serum Testing Serum samples collected from birds on Day 0 were analyzed for hemagglutination inhibition (HAI) titers against H5 avian influenza virus (A/Turkey/Wisconsin/68 [H5N9]).\",\n \"Results of serological testing on serum samples collected from birds while on the BEDA 1197-06-06 IACUC Request Study have been incorporated into this report.\",\n \"Virus Detection Oropharyngeal swabs collected on Days 0 through 6 and cloacal swabs collected on Days 2 through 6 from birds in treatment groups T1, T3, T4, and T5 were analyzed for viral RNA by RT-rtPCR.\",\n \"Samples collected from birds in treatment group T2 were not analyzed and cloacal samples collected on Days 0 and 1 from the remaining treatment groups were also not analyzed.\",\n \"RNA extraction for the RT-rtPCR assay was conducted in the laboratory at 2321 30 Road, Brainard, Nebr.\",\n \"The RT-rtPCR assay was conducted in the laboratory at 521 West Industrial Lake Drive, Lincoln, Nebr.\",\n \"Deviations to the Protocol According to the Benchmark Biolabs IACUC proposal (BEDA 1197-06-06) under the direction of standard operating procedure AC-019-01, first vaccination was to take place when birds were four to six weeks of age.\",\n \"Birds were approximately 26 days of age at time of first vaccination.\",\n \"This deviation had no impact on the study.\",\n \"According to the Benchmark Biolabs IACUC proposal (BEDA 1197-06-06) under the direction of standard operating procedure AC-019-01, the media used in treatment group 2 (T2) was to contain fetal calf serum.\",\n \"However, due to the cost of serum and the fact that the cells used for inoculation in T3, T4, and T5 groups were rinsed, serum was not added as it was determined that the addition or elimination of serum would not effect the antibody response to the test antigen in this study.\",\n \"Therefore, this deviation had no impact on the study.\",\n \"Leghorn specific-pathogen-free chicks were used in the study and were derived from IACUC request BEDA 1197-06-06.Birds were to be placed in five isolators, three birds per isolator; however, birds were placed into individual isolators by treatment group rather than by placement of birds from different treatment groups in each isolator.\",\n \"In addition, the documentation for placement into the isolators was not done.\",\n \"This deviation impacted the study in that there was no effort to control for isolator effect on individual treatment groups which could have had undetected consequences on one or more treatment groups.\",\n \"Data Analysis Descriptive statistics were conducted on data collected.\",\n \"Results and Discussion Table 15.Avian influenza hemagglutination inhibition (HAI) assay titers Table 16.Geometric mean titers for real-time reverse transcriptase polymerase chain reaction assay results on oropharyngeal swab samples Table 17.Geometric mean titers for real-time reverse transcriptase polymerase chain reaction assay results on cloacal swab samples Table 18.Real-time reverse transcriptase polymerase chain reaction assay results on oro-pharyngeal swab samples Table 19.Real-time reverse transcriptase polymerase chain reaction assay results on cloacal swab samples Table 15 lists the results of the avian influenza H5 HAI serological testing.\",\n \"Following first vaccination on Day −25 on the BEDA 1197-06-06 IACUC Request Study, one of three birds in treatment group T4 and two of three birds in treatment group T5 had detectable H5 serological titers of either 8 or 16.On Day 0, all birds in treatment groups T4 and T5 had seroconverted to H5 with titers ranging from 8 to 128.No birds in treatment groups T1 through T3 had detectable H5 serological titers on either sampling day.\",\n \"These detectable titers were considered substantial due to the fact that the CHO cells were transfected with H5 (A/Chicken/Scotland 59 [H5N1]) that was heterologous to the H5 antigen in the serological assay (A/Turkey/Wisconsin 68 [H5N9]).\",\n \"Table 16 lists the geometric mean titer (GMT) results of the oropharyngeal swab testing.\",\n \"No viral RNA was detected on Day 0 from any treatment groups.\",\n \"For Days 1 through 6, virus levels were detected by RT-rtPCR in all three T1 birds (negative controls) with the peak mean titer occurring on Day 1 (GMT of 7.00×107 viral copy number) and a secondary peak titer occurring on Day 4 (GMT of 3.37×107 viral copy number).\",\n \"The viral copy number of the three T1 birds declined to a GMT of 7.55×104 by Day 6.In birds that were administered only non-transfected CHO cells (T3) or CHO cells transfected to express H5 HA (T4 and T5), similar levels of viral copy number were detected on Days 1 through 6 when compared to treatment group T1.This indicates that vaccination with either fresh H5-transfected CHO cells or frozen and thawed H5-transfected CHO cells had no effect on A/TK/CA/209092/02 (H5N2) oropharyngeal viral shedding.\",\n \"Table 17 lists the geometric mean titer (GMT) results of the cloacal swab testing.\",\n \"For Days 2 through 6, virus levels were detected by RT-rtPCR in all three T1 birds (negative controls) with the peak mean titer occurring on Day 5 (GMT of 4.78×106 viral copy number).\",\n \"In general, the shedding was more variable than that detected in oropharyngeal swabs from the same birds.\",\n \"In birds that were administered only non-transfected CHO cells (T3) or CHO cells transfected to express H5 HA (T4 and T5), generally lower levels of viral copy number were detected on Days 2 through 6 when compared to treatment group T1; however, the results varied greatly from bird to bird and day to day.\",\n \"This suggests that measuring vaccine effects on fecal shedding via cloacal swabs may be difficult with A/TK/CA/209092/02 (H5N2) and the effect of vaccination in this trial could not be evaluated.\",\n \"Conclusion It is concluded that vaccination with fresh H5-transfected CHO cells or frozen and thawed H5-transfected CHO cells induced detectable titers in a heterologous H5 antigen serological assay but had no effect on A/TK/CA/209092/02 (H5N2) oropharyngeal viral shedding.\",\n \"Fecal shedding of A/TK/CA/209092/02 (H5N2) could not be evaluated due to highly variable shedding detected in cloacal swabs.\",\n \"It is also concluded that Quil A and cholesterol when used in combination with other adjuvant based embodiments described herein have surprising utility in the context of the present invention.\",\n \"TABLE 15 Avian influenza hemagglutination inhibition (HAI) assay titers H5 HAI H5 HAI Trt.\",\n \"Treatment Group Bird titer titer No.\",\n \"Antigen Adjuvant Number Day −25* Day 0** T1 None None 67 <8 <2 68 <8 <2 69 <8 <2 T2 Media# LAP/ 70 <8 <2 QAC## 71 <8 <2 72 <8 <2 T3 Control cells† LAP/ 73 <8 <2 QAC## 74 <8 <2 75 <8 <2 T4 CHO-HA-10 LAP/ 76 8 64 cells†† QAC## 77 <8 64 freeze/thaw 78 <8 128 T5 CHO-HA-10 LAP/ 79 <8 8 cells†† fresh QAC## 80 8 128 81 16 128 *H5 HAI titer Day −25—Hemagglutination inhibition titer to H5N9 avian influenza virus.\",\n \"**H5 HAI titer Day 0—Hemagglutination inhibition titer to H5N9 avian influenza virus.\",\n \"#Media—DMEM, non-essential amino acids, L-glutamine.\",\n \"##LAP/QAC—Lecithin acrylic copolymer plus Quil A cholesterol.\",\n \"†Control cells—CHO cells not expressing HA.\",\n \"††CHO-HA-10 cells—CHO cells transfected to express HA.\",\n \"TABLE 16 Geometric mean titers for real-time reverse transcriptase polymerase chain reaction assay results on oropharyngeal swab samples RT-rtPCR* Number of GMT Trt.\",\n \"Treatment Group Study birds positive/ viral copy No.\",\n \"Antigen Adjuvant Day total birds number** T1 None None 0 0/3 0.00 × 100 1 3/3 7.00 × 107 2 3/3 8.32 × 106 3 3/3 1.40 × 107 4 3/3 3.37 × 107 5 3/3 6.64 × 106 6 3/3 7.55 × 104 T2 Media# LAP/ 0 Not done Not done QAC## 1 Not done Not done 2 Not done Not done 3 Not done Not done 4 Not done Not done 5 Not done Not done 6 Not done Not done T3 Control LAP/ 0 0/3 0.00 × 100 cells† QAC## 1 3/3 5.79 × 106 2 3/3 2.37 × 107 3 3/3 6.70 × 106 4 3/3 1.15 × 107 5 3/3 3.80 × 106 6 3/3 1.03 × 106 T4 CHO-HA-10 LAP/ 0 0/3 0.00 × 100 cells†† QAC## 1 3/3 9.33 × 106 freeze/thaw 2 3/3 4.55 × 106 3 3/3 6.46 × 106 4 3/3 4.46 × 107 5 3/3 5.91 × 106 6 3/3 4.39 × 106 T5 CHO-HA-10 LAP/ 0 0/3 0.00 × 100 cells†† fresh QAC## 1 3/3 9.23 × 106 2 3/3 8.17 × 106 3 3/3 1.04 × 107 4 3/3 9.58 × 107 5 3/3 7.87 × 106 6 3/3 2.95 × 106 *RT-rtPCR—Real-time reverse transcriptase polymerase chain reaction assay.\",\n \"**GMT viral copy number—Geometric mean titer viral copy number.\",\n \"Samples where no copies were detected were factored as 1 for calculation of GMT.\",\n \"#Media—DMEM, non-essential amino acids, L-glutamine.\",\n \"##LAP/QAC—Lecithin acrylic copolymer plus Quil A cholesterol.\",\n \"†Control cells—CHO cells not expressing HA.\",\n \"††CHO-HA-10 cells—CHO cells transfected to express HA.\",\n \"TABLE 17 Geometric mean titers for real-time reverse transcriptase polymerase chain reaction assay results on cloacal swab samples RT-rtPCR* Number of GMT Trt.\",\n \"Treatment Group Study birds positive/ viral copy No.\",\n \"Antigen Adjuvant Day total birds number** T1 None None 0 Not done Not done 1 Not done Not done 2 3/3 5.46 × 105 3 3/3 1.34 × 105 4 3/3 5.66 × 105 5 3/3 4.78 × 106 6 3/3 2.03 × 106 T2 Media# LAP/ 0 Not done Not done QAC## 1 Not done Not done 2 Not done Not done 3 Not done Not done 4 Not done Not done 5 Not done Not done 6 Not done Not done T3 Control LAP/ 0 Not done Not done cells† QAC## 1 Not done Not done 2 1/3 3.64 × 101 3 2/3 4.90 × 102 4 3/3 1.13 × 105 5 3/3 3.35 × 105 6 2/3 6.86 × 104 T4 CHO-HA-10 LAP/ 0 Not done Not done cells†† QAC## 1 Not done Not done freeze/thaw 2 2/3 1.05 × 103 3 2/3 1.06 × 104 4 3/3 8.55 × 105 5 3/3 1.12 × 106 6 1/3 1.95 × 102 T5 CHO-HA-10 LAP/ 0 Not done Not done cells†† fresh QAC## 1 Not done Not done 2 3/3 3.31 × 104 3 3/3 5.15 × 104 4 3/3 7.19 × 105 5 3/3 1.39 × 105 6 3/3 1.01 × 106 *RT-rtPCR—Real-time reverse transcriptase polymerase chain reaction assay.\",\n \"**GMT viral copy number—Geometric mean titer viral copy number.\",\n \"Samples where no copies were detected were factored as 1 for calculation of GMT.\",\n \"#Media—DMEM, non-essential amino acids, L-glutamine.\",\n \"##LAP/QAC—Lecithin acrylic copolymer plus Quil A cholesterol.\",\n \"†Control cells—CHO cells not expressing HA.\",\n \"††CHO-HA-10 cells—CHO cells transfected to express HA.\",\n \"TABLE 18 Real-time reverse transcriptase polymerase chain reaction assay results on oropharyngeal swab samples Bird RT-rtPCR* (Mean viral copy number)** on oropharyngeal swabs Trt.\",\n \"Group number Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 T1 67 0.00 × 100 2.07 × 108 7.87 × 106 1.67 × 107 2.54 × 107 6.48 × 106 1.91 × 105 Antigen - 68 0.00 × 100 3.70 × 107 7.94 × 106 7.03 × 107 2.00 × 107 3.48 × 106 2.38 × 104 none 69 0.00 × 100 4.48 × 107 9.22 × 106 2.36 × 106 7.56 × 107 1.30 × 107 9.47 × 104 Adjuvant - none T2 70 Not done Not done Not done Not done Not done Not done Not done Media# 71 Not done Not done Not done Not done Not done Not done Not done LAP/QAC## 72 Not done Not done Not done Not done Not done Not done Not done T3 73 0.00 × 100 1.20 × 107 7.44 × 105 1.63 × 107 1.70 × 107 2.19 × 106 4.03 × 106 Control 74 0.00 × 100 9.39 × 106 4.92 × 106 1.25 × 107 5.66 × 106 1.10 × 107 1.40 × 106 cells† 75 0.00 × 100 1.72 × 106 3.63 × 109 1.48 × 106 1.59 × 107 2.26 × 106 1.92 × 105 LAP/QAC## T4 76 0.00 × 100 3.04 × 107 5.57 × 106 1.50 × 107 6.04 × 107 2.86 × 106 1.43 × 106 CHO-HA-10 77 0.00 × 100 1.87 × 107 3.04 × 106 3.86 × 106 6.16 × 107 6.67 × 106 1.05 × 107 cells†† freeze 78 0.00 × 100 1.43 × 106 5.55 × 106 4.65 × 106 2.38 × 107 1.08 × 107 5.63 × 106 thaw LAP/QAC## T5 79 0.00 × 100 4.41 × 106 7.06 × 107 3.05 × 106 1.61 × 107 1.07 × 107 4.65 × 106 CHO-HA-10 80 0.00 × 100 1.51 × 107 5.32 × 106 1.07 × 107 1.23 × 108 1.86 × 107 4.11 × 106 cells†† fresh 81 0.00 × 100 1.18 × 107 1.45 × 106 3.42 × 107 4.43 × 108 2.45 × 106 1.34 × 106 LAP/QAC## *RT-rtPCR—Real-time reverse transcriptase polymerase chain reaction assay.\",\n \"**Mean titer viral copy number - Samples where no copies were detected were factored as 0 for calculation of means.\",\n \"#Media - DMEM, non-essential amino acids, L-glutamine ##LAP/QAC—Lecithin acrylic copolymer plus Quil A cholesterol.\",\n \"†Control cells - CHO cells not expressing HA.\",\n \"††CHO-HA-10 cells—CHO cells transfected to express HA TABLE 19 Real-time reverse transcriptase polymerase chain reaction assay results on cloacal swab samples Bird RT-rtPCR* (Mean viral copy number)** on cloacal swabs Trt.\",\n \"Group number Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 T1 67 Not done Not done 2.81 × 108 1.29 × 106 4.42 × 107 6.58 × 108 4.99 × 107 Antigen - 68 Not done Not done 4.34 × 104 5.51 × 104 6.07 × 104 3.94 × 104 1.37 × 104 none 69 Not done Not done 1.34 × 104 3.41 × 104 6.74 × 104 4.21 × 106 1.23 × 107 Adjuvant - none T2 70 Not done Not done Not done Not done Not done Not done Not done Media# 71 Not done Not done Not done Not done Not done Not done Not done LAP/QAC## 72 Not done Not done Not done Not done Not done Not done Not done T3 73 Not done Not done 4.81 × 104 1.48 × 104 8.33 × 104 1.89 × 104 0.00 × 100 Control 74 Not done Not done 0.00 × 100 0.00 × 100 1.75 × 105 8.54 × 106 5.43 × 107 cells† 75 Not done Not done 0.00 × 100 7.96 × 103 9.93 × 104 2.33 × 105 5.95 × 106 LAP/QAC## T4 76 Not done Not done 2.65 × 104 2.61 × 104 2.42 × 105 8.58 × 104 0.00 × 100 CHO-HA-10 77 Not done Not done 0.00 × 100 0.00 × 100 4.69 × 104 2.46 × 105 0.00 × 100 cells†† freeze 78 Not done Not done 4.34 × 104 4.57 × 107 5.51 × 107 6.69 × 107 7.41 × 106 thaw LAP/QAC## T5 79 Not done Not done 2.66 × 104 3.83 × 105 2.02 × 106 2.85 × 106 1.30 × 106 CHO-HA-10 80 Not done Not done 5.84 × 104 1.50 × 104 4.23 × 104 3.90 × 104 1.08 × 107 cells†† fresh 81 Not done Not done 2.34 × 104 2.38 × 104 4.33 × 106 2.44 × 104 7.34 × 104 LAP/QAC## *RT-rtPCR—Real-time reverse transcriptase polymerase chain reaction assay.\",\n \"**Mean titer viral copy number - Samples where no copies were detected were factored as 0 for calculation of means.\",\n \"#Media - DMEM, non-essential amino acids, L-glutamine ##LAP/QAC—Lecithin acrylic copolymer plus Quil A cholesterol.\",\n \"†Control cells - CHO cells not expressing HA.\",\n \"††CHO-HA-10 cells—CHO cells transfected to express HA.\",\n \"Example 14 Summary Vaccines prepared with LAP or LAP/QAC adjuvants stimulate serologic responses in poultry, mice, swine, and elicit protection from live NDV challenge in poultry; however, the mechanism of immune response development to these vaccines has not been studied.\",\n \"The present study was designed to investigate the cytokine profiles of splenic lymphocytes from mice after a prime and boost regimen with LAP or LAP/QAC adjuvant, with and without antigen.\",\n \"After in vitro stimulation, splenic lymphocytes from some animals vaccinated with LAP+OVA or LAP/QAC+OVA produced increased levels of IL-4 mRNA relative to media controls.\",\n \"Large variations in IL-4 mRNA expression were observed between animals in each treatments group, suggesting that further optimization of sampling times is required.\",\n \"Samples were also evaluated for relative expression if IFN-γ and TNF-α; however, increase in expression of these cytokine mRNAs were not observed.\",\n \"Introduction Cytokine responses that develop after vaccination with LAP or LAP/QAC adjuvants, alone or in combination with antigen, are not well characterized.\",\n \"Polarized cytokine responses, classified as T-helper 1 (Th1) or T-helper 2 (Th2), are initiated within hours of vaccination.\",\n \"The nature of the cytokine profile predicts whether the immune response favors cellular (Th1) or humoral (Th2) immunity.\",\n \"Identification of the cytokines produced after vaccination with LAP or LAP/QAC-adjuvanted vaccines can provide clues about the mechanism of immune induction.\",\n \"Methods developed through this study facilitate investigation into Th1 and Th2 cytokine responses associated with LAP- and LAP/QAC-adjuvanted vaccines.\",\n \"TABLE 1 Study Design Bleed/ Vaccination Necropsy Treatment Route of Day Group Vaccine No.\",\n \"Mice Days Dose Administration Day 16 T1 None 4 N/A N/A N/A 4 mice T2 LAP* 4 0, 14 0.2 ml Subcutaneous 4 mice T3 LAP/QAC† 4 0, 14 0.2 ml Subcutaneous 4 mice T4 Ovalbumin in 4 0, 14 0.2 ml Subcutaneous 4 mice LAP* T5 Ovalbumin in 4 0, 14 0.2 ml Subcutaneous 4 mice LAP/QAC* T6 Ovalbumin 4 0, 14 0.2 ml Subcutaneous 4 mice *Lecithin Acrylic Polymer †Lecithin Acrylic Polymer/Quil A Cholesterol TABLE 2 Treatment Group Vaccine Components: μg per 0.2 ml Dose Treatment Group LAP* QAC** Ovalbumin T1 — — — T2 10001 — — T3 1000 502 — T4 1000 — 50 T5 1000 50 50 T6 — — 50 *Lecithin Acrylic Polymer **Quil A Cholesterol 1600 μg CP; 400 μg Carbopol 934P 225 μg Quil A; 25 μg Cholesterol Methods Study animals were subjected to vaccines at days 0 and 14, and spleens were harvested 48 hours after the second vaccination (day 15) (Table 20).\",\n \"Concentrations of treatment group vaccines are shown in Table 21.Splenic lymphocytes from each animal were isolated by gradient centrifugation and cultured in vitro with media, ConA (10 μm/ml), LAP (6.2 μg/ml), LAP/QAC (6.2/0.062 μg/ml), or OVA (10 μg/ml).\",\n \"Additional in vitro treatments (culture with LAP+OVA and LAP/QAC+OVA) were performed if there were sufficient numbers of lymphocytes.\",\n \"For the additional treatments, OVA was added to cells first, and LAP or LAP/QAC was added to cells last.\",\n \"At approximately 24 and 48 hours in culture, samples were collected and RNA was isolated.\",\n \"RNA samples were analyzed by real time RT-PCR assays for expression of cytokine genes (TNF-α, IL-4, IFN-γ).\",\n \"Levels of cytokine gene expression were normalized to expression of one housekeeping gene: hypoxanthine guanine phosphoribosyl transferase (HPRT) or acidic ribosomal phosphoprotein PO (ARBP).\",\n \"Relative levels of cytokine gene expression were calculated, using the normalized values, for in vitro treatments with respect to the media controls.\",\n \"A positive result is indicated by a relative expression ratio greater than 2, which shows cytokine gene expression for in vitro treated samples that is at least twice the level of expression observed in media control samples.\",\n \"Results Relative expression of IL-4 mRNA was evaluated for samples from all treatment groups after 24 to 48 hours in culture (FIG.\",\n \"13A, B).\",\n \"Samples collected after 24 hours in culture with treatments as listed above (see Methods) using ARBP as the housekeeping gene for normalization purposes.\",\n \"The highest relative expression levels of IL-4 were observed in samples from vaccine treatment groups T4 (LAP+OVA) and T5 (LAP/QAC+OVA).\",\n \"Samples from vaccine treatment groups T1 (no vaccine), T3 (LAP/QAC), and T6 (OVA) were also evaluated at 48 hours in culture using ARBP as the housekeeping gene.\",\n \"Increased IL-4 expression was observed for some animals in each group after 48 hours in culture with LPA, LAP/QAC or OVA.\",\n \"Unexpectedly, ConA-treated samples did not have increased levels of IL-4 expression with respect to media controls; however, increases observed in samples from T4 and T5 indicate that cells were viable and were able to produce cytokines.\",\n \"In order to determine whether relative expression ratios would be greater if an alternative housekeeping gene were used, samples collected after 48 hours in culture were assayed using HPRT as the housekeeping gene for normalization purposes (FIG.\",\n \"14).\",\n \"Increased relative expression of IL-4 was observed for vaccine treatment groups T4 (LAP+OVA) and T5 (LAP/QAC+OVA) after in vitro stimulation with LAP.\",\n \"In vitro treatment with LAP/QAC stimulated IL-4 mRNA production in samples from T2 (LAP) and T5 (LAP/QAC+OVA).\",\n \"Increases in relative IL-4 mRNA expression were also seen in cells from vaccine treatment groups T1 (no vaccine), T2 (LAP), and T5 (LAP/QAC+OVA) after incubation with OVA.\",\n \"Relative expression levels of IFN-γ and TNF-α were also evaluated for in vitro stimulated samples (FIG.\",\n \"15 A, B; FIG.\",\n \"16 A, B).\",\n \"No significant increases in these cytokines were observed.\",\n \"Positive control samples (ConA stimulated) were evaluated for selected samples; however, these control samples did not have increased levels of either cytokine in comparison to negative control samples (media treated).\",\n \"Samples from some animals were treated in vitro with LAP+OVA or LAP/QAC+OVA and relative expression of IL-4 mRNA was evaluated (FIG.\",\n \"17).\",\n \"Increases in IL-4 expression were observed for 48 hour samples from one animal (1-3) from treatment group T1 after in vitro stimulation with LAP+OVA and LAP/QAC+OVA.\",\n \"Analysis of samples treated in vitro with LAP+OVA or LAP/QAC were also analyzed for relative expression of IFNγ with HPRT as the housekeeping gene.\",\n \"Relative expression ratios for these samples were all less than 1, indicating that IFNγ expression levels in treated cells were lower than the levels observed for media controls (data not shown).\",\n \"CONCLUSION The highest average relative expression ratios were observed for IL-4/ARBP in samples collected at 24 hours of culture.\",\n \"Samples from treatment groups T4 (LAP+OVA) and T5 (LAP/QAC+OVA) showed the greatest increases in relative expression of IL-4 message (FIG.\",\n \"1A, B).\",\n \"Analysis of samples from individual animals showed that there were large variations in IL-4 expression ratios among animals in these treatment groups.\",\n \"Cells from one animal in treatment group T1 had increased IL-4 mRNA expression after 48 hours in vitro stimulation with LAP+OVA and LAP/QAC+OVA.\",\n \"Positive control samples (ConA stimulated) did not show increased cytokine expression as expected.\",\n \"Increases observed in IL-4 expression in some samples indicate that cells were capable of producing cytokines; however, further optimization of assay conditions is needed to determine culture times at which cytokine expression is at a maximum.\",\n \"No significant increases in relative expression levels of IFN-γ or TNF-α were observed.\",\n \"Because ConA positive controls did not show increased expression of IFN-γ or TNF-α, further optimization of assays for detection of these cytokines may be warranted.\",\n \"Having described the invention with reference to particular compositions, theories of effectiveness, and the like, it will be apparent to those of skill in the art that it is not intended that the invention be limited by such illustrative embodiments or mechanisms, and that modifications can be made without departing from the scope or spirit of the invention, as defined by the appended claims.\",\n \"It is intended that all such obvious modifications and variations be included within the scope of the present invention as defined in the appended claims.\",\n \"The claims are meant to cover the claimed components and steps in any sequence which is effective to meet the objectives there intended, unless the context specifically indicates to the contrary.\"\n 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"COMPUTER SYSTEM AND METHOD FOR DETERMINING STAY PERIODS OF A ROAD VEHICLE",
"A computer system, method, and computer program product, for detecting a stay of a vehicle.",
"The computer system includes an interface component configured to periodically receive location data sets (211-1 to 211-n) from o... | Patent_15875544 |
[
[
"VEHICLE SPEED CONTROL SYSTEM AND METHOD",
"A vehicle speed control system operable to cause a vehicle to operate in accordance with a target speed value, the system being further operable automatically to control cross-axle locking means of an axle of the vehicle to cause an increase in resistance to rel... | Patent_15875545 |
[
[
"METHOD FOR OPERATING AND INVERTER, INVERTER, AND PHOTOVOLTAIC SYSTEM",
"A method for operating an inverter, the DC voltage input of which is connected to a positive pole (PV+) and to a negative pole (PV−) of a PV generator and the AC voltage output of which is connected to an AC grid via a transformer, i... | Patent_15875546 |
[
[
"METHODS FOR CONTROLLING TOWED MARINE SENSOR ARRAY GEOMETRY",
"A method for towing a streamer array includes moving a vessel along a body of water.",
"Streamers are towed by vessel.",
"A relative position is determined at selected points along each streamer with respect to the vessel.",
"At le... | Patent_15875547 |
[
[
"MAGNETIC MEMORY",
"A magnetic memory of an embodiment includes: a first terminal to third terminals; a first nonmagnetic layer, which is conductive, including a first portion, a second portion, and a third portion, the first portion being disposed between the second portion and the third portion, the sec... | Patent_15875549 |
[
[
"COMPUTER SYSTEM AND METHOD FOR MULTI-PROCESSOR COMMUNICATION",
"A compiler system, computer-implemented method and computer program product for optimizing a program for multi-processor system execution.",
"The compiler includes an interface component configured to load from a storage component progra... | Patent_15875553 |
[
[
"SYSTEM AND METHOD FOR SUPPLYING SECURITY INFORMATION",
"A wearable device having one or more processors configured to receive one or more signals representative of biometric parameter(s) and sensed presence of a user.",
"The one or more processors configured to compare the biometric parameter to a st... | Patent_15875558 |
[
[
"ELECTRICAL ARCHITECTURE FOR CONVERTING DC VOLTAGE INTO AC VOLTAGE, AND VICE VERSA",
"An electrical architecture (1) for converting DC voltage into AC voltage, and vice versa, comprising:—a DC/AC voltage converter (2), comprising a plurality of arms mounted in parallel, each arm comprising two controllabl... | Patent_15875560 |
[
[
"SYSTEMS AND METHODS TO MANAGE AND CONTROL RENEWABLE DISTRIBUTED ENERGY RESOURCES",
"A system for analyzing energy usage measures one or more parameters indicative of energy usage for a plurality of sub-circuits, where the sampling rate for the measuring is substantially continuous, and automatically tran... | Patent_15875562 |
[
[
"FIBER OPTIC ENCLOSURE WITH INTERNAL CABLE SPOOL",
"A fiber optic enclosure assembly includes a housing having an interior region and a bearing mount disposed in the interior region of the housing.",
"A cable spool is connectedly engaged with the bearing mount such that the cable spool selectively rot... | Patent_15875564 |
[
[
"METHOD FOR PREPARING AZOXYSTROBIN AND ITS INTERMEDIATES",
"The present invention discloses a method for preparing azoxystrobin intermediates represented by formulae (1) and (2), comprising: controlling a compound represented by formula (3) to contact with sodium methoxide and 4,6-dichloropyrimidine, to o... | Patent_15875569 |
[
[
"SEMICONDUCTOR DEVICE HAVING CAL LATENCY FUNCTION",
"One controller for controlling operation of a memory device includes an output circuit configured to supply a chip select signal, an address signal, a command signal, and a clock signal to the memory device, and a data processing circuit configured to p... | Patent_15875574 |
[
[
"Dual Irrigating Bipolar Forceps",
"Bipolar electrosurgical forceps are provided with dual irrigating tubes that deliver irrigating liquid to the opposed surfaces of the tips of the forceps to prevent the sticking of body tissue to the tips.",
"To reduce the manufacturing costs of the forceps and enab... | Patent_15875576 |
[
[
"INFORMATION PROCESSING APPARATUS, INFORMATION PROCESSING METHOD, AND INFORMATION PROCESSING PROGRAM",
"There is provided an image processing apparatus including an input device configured to receive a stroke input, and a display controller configured to control a displaying of a modified stroke, wherein ... | Patent_15875582 |
[
[
"SELECTIVE PER-CYCLE MASKING OF SCAN CHAINS FOR SYSTEM LEVEL TEST",
"Built-in self-test techniques for integrated circuits that address the issue of unknown states.",
"Some implementations use a specialized scan chain selector coupled to a time compactor.",
"The presence of the specialized scan ch... | Patent_15875589 |
[
[
"NEURAL MODEL-BASED CONTROLLER",
"Described is a system for memory improvement intervention.",
"Based on both real-time EEG data and a neural model, the system simulates replay of a person's specific memory during a sleep state.",
"Using the neural model, a prediction of behavioral performance of ... | Patent_15875591 |
[
[
"PIGMENT IDENTIFICATION OF COMPLEX COATING MIXTURES WITH SPARKLE COLOR",
"Using an image capturing device, multiple images can be obtained at different angles with respect to a surface of a target coating.",
"In one computer-implemented embodiment, a method involves using a filtering technique to perf... | Patent_15875593 |
[
[
"DAMASCENE OXYGEN BARRIER AND HYDROGEN BARRIER FOR FERROELECTRIC RANDOM-ACCESS MEMORY",
"Disclosed herein is an apparatus that includes a ferrocapacitor disposed on a damascene barrier film.",
"The damascene barrier film includes a hydrogen barrier region and an oxygen barrier region, with each being ... | Patent_15875594 |
[
[
"Enhanced Network Performance Monitoring",
"There are disclosed measures for enhancing network performance monitoring.",
"Such measures may for example comprise receiving a report on measurements of terminal-related network performance parameters from a terminal, acquiring information of access networ... | Patent_15875595 |
[
[
"SEMICONDUCTOR INTEGRATED CIRCUIT, COMMUNICATION MODULE, AND SMART METER",
"A semiconductor integrated circuit includes a transformer that includes a first winding and a second winding, a low-noise amplifier circuit that includes an input terminal in which at least one end of the second winding of the tra... | Patent_15875602 |
[
[
"FIBER OPTIC ENCLOSURE WITH INTERNAL CABLE SPOOL",
"A fiber optic enclosure assembly includes a housing having an interior region and a bearing mount disposed in the interior region of the housing.",
"A cable spool is connectedly engaged with the bearing mount such that the cable spool selectively rot... | Patent_15875605 |
[
[
"SYSTEMS & METHODS FOR AUTOMATED ASSESSMENT FOR REMEDIATION AND/OR REDEVELOPMENT OF BROWNFIELD REAL ESTATE",
"Systems and methods for distributed, automated management of brownfield real estate asset remediation and/or redevelopment, including at least one server computer for analyzing and providing recom... | Patent_15875608 |
[
[
"METHOD, APPARATUS, AND SYSTEM HAVING SUPER STEEP RETROGRADE WELL WITH ENGINEERED DOPANT PROFILES",
"Generally, in one embodiment, the present disclosure is directed to a method for forming a transistor.",
"The method includes: implanting a substrate to form at least one of an n and p doped region; de... | Patent_15875609 |
[
[
"PROPSHAFT DAMPER AND METHOD OF ASSEMBLY",
"A propshaft damper for a vehicle is provided.",
"The propshaft damper includes an inertia ring where the inertia ring having an inner ring.",
"A rubber track is positioned on inner ring, the rubber track having an first inner surface.",
"A transmissi... | Patent_15875610 |
[
[
"SPONDYLISTHESIS REDUCTION SYSTEM",
"A system for reducing deformities of the vertebrae in the spine includes a first reduction assembly, a second reduction assembly, and a reduction drive assembly.",
"The first reduction assembly is configured for attachment to a first reduction tower that attaches t... | Patent_15875612 |
[
[
"METHOD AND APPARATUS FOR COUNTING DEVICES RELATED TO BROADCAST DATA SERVICES",
"Methods and apparatuses are provided that include counting devices for broadcast data services.",
"The devices can be counted based on registrations received from the devices.",
"This registration count can additional... | Patent_15875613 |
[
[
"ACCESS GUARDS FOR MULTI-TENANT LOGGING",
"A multi-tenant logging system that allows a user to have an individual profile that controls the user's access to tenant logs is provided.",
"The system includes a plugin that adds features of an access control list (ACL) to indexes of a logging stack based o... | Patent_15875614 |
[
[
"AIRCRAFT SYSTEM",
"An aircraft capable of operating at a variety of speeds includes a power plant and an auxiliary turbine.",
"The auxiliary turbine can be a ram air turbine used to expand and cool an airflow and provide work.",
"The cooled airflow from the auxiliary turbine can be used in a heat... | Patent_15875616 |
[
[
"FIBER OPTIC ENCLOSURE WITH INTERNAL CABLE SPOOL",
"A fiber optic enclosure assembly includes a housing having an interior region and a bearing mount disposed in the interior region of the housing.",
"A cable spool is connectedly engaged with the bearing mount such that the cable spool selectively rot... | Patent_15875620 |
[
[
"ANTIMICROBIAL COMPOUNDS AND COMPOSITIONS, AND USES THEREOF",
"A method of enhancing the growth of an animal is provided.",
"The method includes causing the animal to ingest or absorb an effective amount of one or more Fe III complex compounds, including but not limited to Fe III complexes comprising ... | Patent_15875623 |
[
[
"TACTILE TOUCH SENSOR SYSTEM AND METHOD",
"A tactile touch sensor (TTS) system and method allowing physical augmentation of a high-resolution touch sensor array (TSA) is disclosed.",
"Physical augmentation is accomplished using a TSA physical overlay (TPO) placed on top of the TSA.",
"The TPO is c... | Patent_15875625 |
[
[
"INKJET RECORDING INK AND RECORDED MATTER",
"An inkjet recording ink is used for an inkjet recording device that includes a silicone rubber having a solubility parameter at 25° C. of 6 to 8 as a member with which an ink comes in contact, the inkjet recording ink including water, a disperse dye, and an ani... | Patent_15875631 |
[
[
"PHYSIOLOGIC SIMULATOR SYSTEM",
"Systems for the simulation of percutaneous medical procedures are disclosed.",
"The systems can include a simulated vasculature including a first component configured to allow for introduction of a medical device into the system through an introductory port, a second c... | Patent_15875636 |
[
[
"PROVIDING 3D LOOK-UP TABLE (LUT) ESTIMATION FOR COLOR GAMUT SCALABILITY",
"Systems and/or methods for estimating color conversion components.",
"A video coding device may receive a picture associated with a first color space.",
"The picture may comprise a first component at a first sampling locat... | Patent_15875638 |
[
[
"BICYCLE POWER METER",
"A power meter for a bicycle includes a body having a torque input section and a torque output section, the body configured to transmit power between the torque input section and the torque output section.",
"The power meter also includes a printed circuit board (“PCB”) having a... | Patent_15875642 |
[
[
"SYSTEM AND METHOD FOR CREATING CUSTOM FINGERNAIL ART",
"Systems and methods are provided for a creating nail polish art by providing an image, providing a hand pose stencil, including image coordinates for the fingernails of the hand pose stencil, allowing the hand pose stencil to be positioned on the im... | Patent_15875643 |
[
[
"VEHICLE MANIPULATION USING OCCUPANT IMAGE ANALYSIS",
"Vehicle manipulation is performed using occupant image analysis.",
"A camera within a vehicle is used to collect cognitive state data including facial data, on an occupant of a vehicle.",
"A cognitive state profile is learned, on a first compu... | Patent_15875644 |
[
[
"REAL-TIME OR JUST-IN-TIME ONLINE ASSISTANCE FOR INDIVIDUALS TO HELP THEM IN ACHIEVING PERSONALIZED HEALTH GOALS",
"A method and a system for providing real-time assistance to users in achieving their personalized health goals through a mobile phone with an integrated software application by uploading the... | Patent_15875653 |
[
[
"METHOD FOR SETTING A GEAR RATIO OF A FAN DRIVE GEAR SYSTEM OF A GAS TURBINE ENGINE",
"A gas turbine engine includes a fan with a plurality of fan blades rotatable about an engine centerline longitudinal axis.",
"The fan has a low corrected fan tip speed less than 1400 ft/sec.",
"A bypass ratio is... | Patent_15875656 |
[
[
"MULTI-PROCESS INTERACTIVE SYSTEMS AND METHODS",
"A multi-process interactive system is described.",
"The system includes numerous processes running on a processing device.",
"The processes include separable program execution contexts of application programs, such that each application program com... | Patent_15875661 |
[
[
"PEPTIDE FOR SUPPRESSING OSTEOCLAST DIFFERENTIATION AND USE THEREOF",
"The peptide of the present invention performs a function, which is the same as or similar to that of natural interleukin (IL)-3, and has superior skin permeability due to the small size thereof.",
"In addition, the peptide of the p... | Patent_15875669 |
[
[
"Method and Apparatus for Storing Increment Values Without Using an Increment Counter",
"Electronic systems, such as printing systems, often use components that have integral memory.",
"The integral memory can be used to store information about the component.",
"In some printing systems this memor... | Patent_15875671 |
[
[
"NET BUILD PROCESS FOR SEATING SUBASSEMBLY",
"A vehicle seat subassembly includes a first bracket and a second bracket rotatably coupled with the first bracket.",
"First and second pins are welded to the first bracket, and an alignment plate is welded to the second bracket.",
"First and second dat... | Patent_15875672 |
[
[
"VEHICLE AIR CONDITIONER",
"There is disclosed a vehicle air conditioner of a heat pump system in which there is prevented or inhibited frosting to an outdoor heat exchanger when heating in a vehicle interior is beforehand performed during plug-in, thereby realizing comfortable heating in the vehicle inte... | Patent_15875674 |
[
[
"COMMUNICATION SYSTEM, COMMUNICATION APPARATUS AND COMMUNICATION METHOD AS WELL AS PROGRAM",
"A communication system, a communication apparatus, a communication method, and a program for acquiring the advantage of a plurality of communication protocols is provided.",
"A random number and a first commu... | Patent_15875677 |
[
[
"NOVEL BICYCLIC BROMODOMAIN INHIBITORS",
"The invention relates to substituted bicyclic compounds, which are useful for inhibition of BET protein function by binding to bromodomains, pharmaceutical compositions comprising these compounds, and use of the compounds and compositions in therapy."
],
[
... | Patent_15875678 |
[
[
"METHOD AND APPARATUS FOR MANAGING A FAULT IN A DISTRIBUTED ANTENNA SYSTEM",
"Aspects of the subject disclosure may include, for example, receiving, by a first antenna system of a distributed antenna system, a first wireless signal from a second antenna system of the distributed antenna system, the second... | Patent_15875680 |
[
[
"ACTIVITY RECOGNITION SYSTEMS AND METHODS",
"An activity recognition system is disclosed.",
"A plurality of temporal features is generated from a digital representation of an observed activity using a feature detection algorithm.",
"An observed activity graph comprising one or more clusters of tem... | Patent_15875681 |
[
[
"Geofence Information Delivery Systems and Methods",
"The present invention is directed to methods and systems for querying a database of geofences.",
"A method for querying a database of geofences in the present invention includes generating at a device a first request comprising an Internet Protocol... | Patent_15875682 |
[
[
"GANTRY IMAGE GUIDED RADIOTHERAPY SYSTEM AND RELATED TREATMENT DELIVERY METHODS",
"A radiation treatment apparatus, comprising a gantry structure comprising a beam member extending between first and second ends of the gantry structure.",
"The radiation treatment apparatus also includes a radiation tre... | Patent_15875683 |
[
[
"DISPLAY DEVICE AND BACKLIGHT UNIT INCLUDED THEREIN",
"A display device includes a light source to emit light, a light guide plate on which the light emitted from the light source is incident and which irradiates light through a first and a second surface of the light guide plate, a quantum dot sheet on w... | Patent_15875691 |
[
[
"Method of Treating Substance Addictions",
"A pharmaceutical composition containing isomyosmine or a pharmaceutically acceptable salt thereof is administered to an individual in need thereof for treating a substance addiction, inclusive of addiction to heroin (diacetylmorphine), cocaine, opioids, methadon... | Patent_15875692 |
[
[
"Display Device with Integrated Touch Screen and Method for Driving the Same",
"Discussed are a display device with an integrated touch screen and a method of operating the same.",
"The display device according to an embodiment includes a display panel including a plurality of pixel electrodes; a touc... | Patent_15875696 |
[
[
"HETEROJUNCTION BIPOLAR TRANSISTOR",
"A heterojunction bipolar transistor, comprising an elongated base mesa, an elongated base electrode, two elongated emitters, an elongated collector, and two elongated collector electrodes.",
"The elongated base electrode is formed on the base mesa along the long a... | Patent_15875700 |
[
[
"METHOD FOR DETERMINING AMPLITUDE OF STICK-SLIP ON A VALVE ASSEMBLY AND IMPLEMENTATION THEREOF",
"A method for processing operating data (e.g., position, setpoint, and pressure) for a valve assembly.",
"The method is configured to associate characteristics of operation for the valve assembly with a ro... | Patent_15875702 |
[
[
"TREATMENT INSTRUMENT FOR ENDOSCOPE",
"A treatment instrument for an endoscope is equipped with a sheath; and a balloon which is provided at the sheath, the balloon being configured to be expandable to an unfolded inflated shape from a folded initial shape by supplying a fluid, the balloon having a first ... | Patent_15875707 |
[
[
"ENGINE GOVERNOR",
"An electronic governor system includes a motor, a transmission coupled to the motor, a throttle plate coupled to the transmission, the throttle plate movable to multiple positions between closed and wide-open, wherein power is supplied to the motor to move the throttle pate to a desire... | Patent_15875712 |
[
[
"Neural Progenitor Cell Differentiation",
"Differentiation and stability of neural stem cells can be enhanced by in vitro or in vivo culturing with one or more extracellular matrix (ECM) compositions, such as collagen I, IV, laminin and/or a heparan sulfate proteoglycan.",
"In one aspect of the invent... | Patent_15875717 |
[
[
"SYSTEMS AND METHODS FOR PROCESSING AUDIO SIGNALS BASED ON USER DEVICE PARAMETERS",
"In various applications, the system provides a method for processing audio signals, including: receiving a request for audio content; receiving an identifier encoded in a personal audio device comprising a transducer for ... | Patent_15875721 |
[
[
"RECURSIVE PUMPING FOR SYMMETRICAL GAS EXHAUST TO CONTROL CRITICAL DIMENSION UNIFORMITY IN PLASMA REACTORS",
"Embodiments of the present invention provide apparatus and methods for reducing non-uniformity and/or skews during substrate processing.",
"One embodiment of the present invention provides a f... | Patent_15875726 |
[
[
"EXTRACTION OF LIPID FROM CELLS AND PRODUCTS THEREFROM",
"The present invention relates to processes for obtaining a lipid from a cell by lysing the cell, contacting the cell with a base and/or salt, and separating the lipid.",
"The present invention is also directed to a lipid prepared by the process... | Patent_15875733 |
[
[
"DEVICES, SYSTEMS AND METHODS FOR PAIN MANAGEMENT AND BONE HEALING",
"Systems and methods disclosed herein provide efficacious therapies based on delivery of combinations of thermoceuticals, electroceuticals, ultrasound via computer-implemented systems.",
"Sensors coupled to the device are configured ... | Patent_15875743 |
[
[
"IMAGE-FORMING APPARATUS PROVIDED WITH URGING MEMBER FOR URGING PROCESS CARTRIDGE",
"An image-forming apparatus includes: a main body; a toner cartridge having a first opening; a process cartridge having a photosensitive drum and a second opening; a positioning part; a transfer unit; and an urging member.... | Patent_15875746 |
[
[
"PROJECTION EXPOSURE METHODS AND SYSTEMS",
"Projection exposure methods, systems, sub-systems and components are disclosed.",
"Methods can include performing a first exposure to image a first sub-pattern of the pattern, where the first sub-pattern includes a plurality of first features extending in a ... | Patent_15875752 |
[
[
"SYSTEM AND METHOD FOR IDENTIFYING, INDEXING, AND NAVIGATING TO DEEP STATES OF MOBILE APPLICATIONS",
"A mobile application development system includes a developer portal that receives an application from a developer and provides a routing library to the developer to augment the application.",
"An offl... | Patent_15875753 |
[
[
"EMBEDDING DEBUGGING INFORMATION VIA WATERMARKS",
"Debugging information for content rendered for display on a client device can be included in one or more watermarks inserted into the content.",
"Performance, state, configuration, debugging, and other information can be encoded into a watermark and p... | Patent_15875754 |
[
[
"FIBER TERMINATION ENCLOSURE WITH MODULAR PLATE ASSEMBLIES",
"Certain types of fiber termination enclosures include an enclosure and at least one of a plurality of plate module mounting assemblies.",
"Example plate module mounting assemblies include a termination panel plate assembly; a splice tray pl... | Patent_15875756 |
[
[
"OUT OF STOCK ITEM TRACKING AT RETAIL SALES FACILITIES",
"In some embodiments, methods and systems of locating overstock items at a retail sales facility include receiving an indication that a product at the retail sales facility is out of stock and determining whether the product is located on a sales fl... | Patent_15875760 |
[
[
"Electronic Method and System that Improves Efficiencies for Rendering Diagnosis of Radiology Procedures",
"An electronic method and system for improving radiologists' efficiencies when viewing radiology procedures and rendering diagnosis in a manner that emulates current methods and apparatus.",
"The... | Patent_15875763 |
[
[
"ELECTRICALLY HEATED GARMENT",
"An article of clothing including a garment body and a heating system coupled to the garment body.",
"The heating system includes a plurality of heating zones configured to heat different portions of the garment body.",
"A battery pack supplies power to the heating s... | Patent_15875768 |
[
[
"REAL-TIME OR JUST-IN-TIME ONLINE ASSISTANCE FOR INDIVIDUALS TO HELP THEM IN ACHIEVING PERSONALIZED HEALTH GOALS",
"A method and a system for providing real-time assistance to users in achieving their personalized health goals through a mobile phone with an integrated software application by uploading the... | Patent_15875771 |
[
[
"COATED COMPRESSIVE SUBPAD FOR CHEMICAL MECHANICAL POLISHING",
"Coated compressive subpads for polishing pad stacks and methods of fabricating coated compressive subpads for polishing pad stacks are described.",
"In an example, a polishing pad stack for polishing a substrate includes a polishing pad h... | Patent_15875773 |
[
[
"BI-FOLD DOOR LATCH ASSEMBLY",
"A latch assembly connected to the drive unit of a bi-fold door retains the bi-fold door in engagement with upright columns of a building with elongated straps attached to the upright columns and rotatable latch drums mounted on a drive shaft of a drive unit.",
"Lift dev... | Patent_15875776 |
[
[
"GARDEN FOUNTAIN",
"The garden fountain includes a lower container, a middle container and an upper container.",
"A water pump positioned in the lower container pumps water up into the middle container.",
"The upper container rests in the middle container.",
"Using a combination of the water l... | Patent_15875778 |
[
[
"METHODS AND DEVICES FOR STIMULATING CELL PROLIFERATION",
"Embodiments of the present disclosure are directed to devices and methods for stimulating cell proliferation.",
"In one implementation, a method for increasing cell proliferation is provided.",
"The method includes providing a vibrational ... | Patent_15875779 |
[
[
"TRANSFORMABLE SPEECH PROCESSOR MODULE FOR A HEARING PROSTHESIS",
"A method for operating an external component of a cochlear implant hearing system.",
"The external component includes a speech processor module operable in a stand-alone mode of operation and a body-worn mode of operation, and a protec... | Patent_15875780 |
[
[
"Wide Swath Offset Concrete Screed",
"Methods and systems for making and using a wide swath offset concrete screed apparatus for screeding wet concrete slurry.",
"The apparatus includes a cross support bar, an attachment mechanism for attaching the cross support bar to a liftable arm of a motorized ve... | Patent_15875785 |
[
[
"Orientation Layer for Directed Self-Assembly Patterning Process",
"Disclosed is a method of forming a semiconductor device using a self-assembly (DSA) patterning process.",
"The method includes forming a patterned feature over a substrate; applying an orientation material that includes a first polyme... | Patent_15875788 |
[
[
"OPERATION METHOD OF ELECTRIC POWER SOURCE DEVICE, ELECTRIC POWER SOURCE DEVICE, AND HIGH-FREQUENCY TREATMENT SYSTEM",
"A method of operating a power source device for a high-frequency treatment instrument adapted to perform high-frequency treatment for biological tissue includes causing a high-frequency ... | Patent_15875791 |
[
[
"Method for improving the dissolution profile of a biologically active material",
"A method for improving the dissolution profile of a biologically active material"
],
[
"1.A method for improving the dissolution profile of a biologically active material, comprising the steps of: dry milling a soli... | Patent_15875794 |
[
[
"NON-TRANSITORY COMPUTER-READABLE STORAGE MEDIUM, ENCODING APPARATUS, AND ENCODING METHOD",
"A non-transitory computer-readable storage medium storing a program that causes a computer to execute a process including detecting, from a text, one of a plurality of first strings included in first information, ... | Patent_15875802 |
[
[
"SYSTEM AND METHOD FOR THE DISPLAY OF RESTRICTED INFORMATION ON PRIVATE DISPLAYS",
"The present invention is directed to a system and method for restricting data, or portions thereof, to specific display devices when accessed by a user.",
"Furthermore, the system and method of the invention are direct... | Patent_15875805 |
[
[
"IDENTIFYING RELATIONSHIPS OF INTEREST OF ENTITIES",
"A method, system and computer program product for identifying relationships of interest of entities in a data modeling environment, where the data modeling environment represents objects as entities with links representing relationships between the ent... | Patent_15875806 |
[
[
"FTM PROTOCOL WITH ANGLE OF ARRIVAL AND ANGLE OF DEPARTURE",
"Apparatuses and methods are disclosed for performing ranging operations between a first device and a second device.",
"The first device may receive, from the second device, a fine timing measurement (FTM) request frame including a request t... | Patent_15875807 |
[
[
"SYSTEMS, APPARATUSES, AND METHODS FOR MEASURING SUBMERGED SURFACES",
"The present disclosure provides systems, apparatuses, and methods for measuring submerged surfaces.",
"Embodiments include a measurement apparatus including a main frame, a source positioned outside a pipe and connected to the main... | Patent_15875810 |
[
[
"REAL-TIME OR JUST-IN-TIME ONLINE ASSISTANCE FOR INDIVIDUALS TO HELP THEM IN ACHIEVING PERSONALIZED HEALTH GOALS",
"A method and a system for providing real-time assistance to users in achieving their personalized health goals through a mobile phone with an integrated software application by uploading the... | Patent_15875812 |
[
[
"Slim Booster Bars for Electronic Devices",
"A wireless device includes at least one slim radiating system having a slim radiating structure and a radio-frequency system.",
"The slim radiating structure includes one or more booster bars.",
"The booster bar has slim width and height factors that fa... | Patent_15875817 |
[
[
"ROTARY KNIFE FIXTURE FOR CUTTING SPIRAL, TEXTURED POTATO PIECES",
"A rotary knife fixture for cutting vegetable products such as raw potatoes into spiral shapes.",
"The knife fixture includes a ring-shaped blade holder driven rotatably within a hydraulic product flow path.",
"The blade holder inc... | Patent_15875819 |
[
[
"Dynamic Configuration of Touch Sensor Electrode Clusters",
"An apparatus of one embodiment includes a sensor having a plurality of electrodes and a controller having a processor and a memory.",
"The memory includes logic operable to configure the plurality of electrodes of the sensor to form a first ... | Patent_15875827 |
[
[
"WEARABLE RECORDING SYSTEM WITH MEMORY DESIGNATION",
"A surveillance apparatus continuously records imaged data from a camera into a circular buffer in a local memory.",
"When a record signal is received, the system records the video stream that was recorded before the record signal was received, and ... | Patent_15875828 |
[
[
"Interlaced Multiband Antenna Arrays",
"Antenna arrays which can work simultaneously in various frequency bands thanks to the physical disposition of the elements which constitute them, and also the multiband behavior of some elements situated strategically in the array.",
"The configuration of the ar... | Patent_15875831 |
[
[
"Treatment of Glaucoma Using Laquinimod",
"The subject invention provides a method of treating a subject afflicted with glaucoma, suffering from retinal ganglion cell (RGC) loss or damage, or elevated intraocular pressure (IOP), or of reducing RGC loss or damage, or reducing IOP in a subject, comprising a... | Patent_15875833 |
[
[
"STOCKING LEVEL INDICATION APPARATUS AND METHOD",
"In some embodiments, systems, apparatuses, and methods are described herein including a shelf assembly that utilizes the accumulated weight of products stocked thereon to compress a compression member disposed within the assembly.",
"An electronic ima... | Patent_15875834 |
[
[
"Stent Graft With a Longitudinal Support Member",
"A delivery system for delivering and deploying stent grafts having a proximal stent includes a first lumen and a stent capture device including a capture portion fixedly connected adjacent a first lumen distal end.",
"An outer catheter has a catheter ... | Patent_15875835 |
[
[
"Pressing of Wire Bond Wire Tips to Provide Bent-Over Tips",
"In a method for forming a microelectronic device, a substrate is loaded into a mold press.",
"The substrate has a first surface and a second surface.",
"The second surface is placed on an interior lower surface of the mold press.",
... | Patent_15875842 |
[
[
"AUTOMATED UN-MANNED AIR TRAFFIC CONTROL SYSTEM",
"A low flying unmanned vehicle is disclosed that may be able to determine whether a collision is possible and may take evasive action in response to the possible collision.",
"The vehicle may wirelessly communicate and may use a standard protocol such ... | Patent_15875845 |
[
[
"MICROCHIP-TYPE OPTICAL MEASURING APPARATUS AND OPTICAL POSITION ADJUSTING METHOD THEREOF",
"To provide a microchip-type optical measuring apparatus which is able to automatically perform position adjustment of a microchip with respect to an optical axis of laser with high accuracy.",
"A microchip-typ... | Patent_15875846 |
[
[
"POLYPEPTIDE MODIFICATION METHOD FOR PURIFYING POLYPEPTIDE MULTIMERS",
"The present invention provides efficient methods based on alteration of the protein A-binding ability, for producing or purifying multispecific antibodies having the activity of binding to two or more types of antigens to high purity ... | Patent_15875847 |
[
[
"KISSPEPTIN-54 DETECTION BY TANDEM MASS SPECTROMETRY",
"Methods are described for measuring the amount of a kisspeptin-54-derived peptides in a sample.",
"More specifically, mass spectrometric methods are described for detecting and quantifying a kisspeptin-54 derived peptides in a sample utilizing on... | Patent_15875850 |
[
[
"ADJUVANT AND VACCINE COMPOSITIONS",
"Methods are provided for preparing and delivering an adjuvant for vaccines including lecithin, polymer and one or more additives.",
"The polymer is preferably polyacrylic acid-based.",
"The additive is preferably one or more of a glycoside and a sterol.",
... | Patent_15875860 |