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Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 1 of 109

EXHIBIT EE Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 2 of 109 US008183288B2

(12) United States Patent (10) Patent No.: US 8,183,288 B2 Kramer et al. (45) Date of Patent: May 22, 2012

(54) AMINO COMPOUNDS Maynard et al., J. Nutr. 131:287-290 (2001). Rytlewski et al., European Journal of Obstetrics & Gynecology and (75) Inventors: Ronald Kramer, Phoenix, AZ (US); Reproductive Biology 138:23-28 (2008). Alexander Nikolaidis, New Kallikratia Schwedheim et al., Br J Clin Pharmacol 65(1):51-59 (2007). Smith et al., J. Thorac Cardiovasc. Surg 132:58-65 (2006). (GR) Rytlewski et al., Eur J. Clin Invest 35 (1):32-37 (2005). (73) Assignee: Thermolife International, LLC, Ming et al., Circulation 110:3708-3714 (2004). Romero et al., Cardiovascular Drug Reviews 24(3-4):275-290 Phoenix, AZ (US) (2006). Oka et al., Vasc Med 10:265-274 (2005). (*) Notice: Subject to any disclaimer, the term of this Hayashi et al., PNAS 102(38): 13681-13686 (2005). patent is extended or adjusted under 35 Grasemann et al., Eur Respir J 25:62-68 (2005). U.S.C. 154(b) by 39 days. Boger, J. Nutr 137:1650S-1655S (2007). Beghettietal., J. Thorac Cardiovasc. Surg 132(6):1501-1502 (2006). (21) Appl. No.: 12/946,114 Larsen et al., B. Acta Physiol 191(1):59-66 (2007). Berge, Journal of Pharmaceutical Sciences, Jan. 1977, vol. 66, No. 1. (22) Filed: Nov. 15, 2010 Takahashi et al., “Characterization of the influence of donors on intestinal absorption of macromolecules.” International (65) Prior Publication Data Journal of Pharmaceutics vol. 286:89-97 (2004). |US 2011/0313011 A1 Dec. 22, 2011 Fetih et al., “Nitric oxide donors can enhance the intestinal transport and absorption of insulin and [Asu 1,7|-eel in rats,” Journal Related U.S. Application Data of Controlled Release vol. 106:287-297 (2005). Fetih et al., “Excellent Absorption Enhancing Characteristics of NO (63) Continuation of application No. 12/336,938, filed on Donors for Improving the Intestinal Absorption of Poorly Absorbable Dec. 17, 2008, now Pat. No. 8,034,836, which is a Compound Compared with Conventional Absorption Enhancers.” continuation of application No. 11/950,273, filed on Drug Metab. Pharmacokinet, vol. 21(3):222-229 (2006). Dec. 4, 2007, now Pat. No. 7,777,074. Aniya et al., “Evaluation of Nitric Oxide Formation from Nitrates in Pig Coronary Arteries,” Jpn. J. Pharmacal. vol. 71; 101-107 (1996). (60) Provisional application No. 60/973,229, filed on Sep. T.F. Luscher, “Endogenous and exogenous nitrates and their role in 18, 2007. myocardial ischaemia.” Br. J. Clin. Pharmacol. vol. 34:29S-35S (1992). (51) Int. Cl. Shiraki et al., “The hypotensive mechanisms of the new anti-anginal A6 IK 31/195 (2006.01) drug, N-(2-Hydroxyethyl) Nicotinamide Nitrate (SG-75) in beagle (52) U.S. Cl...... 514/561; 514/563 dogs,” Japan. J. Pharmacol. vol. 31:921-929 (1981). CFIndustries, “Material Safety Data Sheet for (58) Field of Classification Search ...... 514/561, Nitrate Solution (UAN),” available at www.cfindustries.com/pdf/ 514/563 UANMSDS.pdf Oct. 25, 2006. See application file for complete search history. Slart et al., “Nitrate Administration Increases Blood Flow in Dys functional but Viable Myocardium, Leading to Improved Assessment (56) References Cited of Myocardial Viability: A PET Study,” J. Nucl. Med. vol. 47: 1307 1311 (2006). |U.S. PATENT DOCUMENTS Fayers et al., “Nitrate tolerance and the links with endothelial dys 3,886,040 A. 5/1975 Chihata et al. function and oxidative stress.” Blackwell Publishing Ltd Br. J. Clin. 3,997,659 A. 12/1976 Knohl et al. Pharmacol. vol. 56:620-628 (2003). 4,146,611 A. 3/1979 Ondetti et al. Harm J. Knot. “Nitrate Tolerance in Hypertension New Insight Into a 4,379,177 A 4/1983 McCoy et al. Century-Old Problem.” Circulation Research vol. 93:799-801 4,743,614 A. 5/1988 Terano et al. (2003). 5,500,436 A. 3/1996 Schonafinger et al. 5,679,704 A. 10/1997 Schonafinger et al. (Continued) 7,235,237 B2 6/2007 Loscalzo et al. 7,777,074 B2 * 8/2010 Kramer et al...... 562/512 2005/0287210 A1 12/2005 Ron 2005/0288372 A1 12/2005 Ron Primary Examiner – Rei-tsang Shiao 2005/0288373 A1 12/2005 Ron (74) Attorney, Agent, or Firm – Booth Udall, PLC 2006/0029668 A1 2/2006 Ron 2006/01828.15 A1 8/2006 Gladwin et al. 2007/0154569 A1 7/2007 Gladwin et al. (57) ABSTRACT FOREIGN PATENT DOCUMENTS A method for increasing the bioabsorption of amino in CN 1631539 6/2005 a human or animal is disclosed. The method includes admin EP 1336602 8/2003 GB 2354441 3/2001 istering to the human or animal a pharmaceutically effective WO WO2006124,161 11/2006 amount of an compound consisting essentially of a nitrate or nitrite of an amino acid selected from the group OTHER PUBLICATIONS consisting of , , Beta , , Ramaswamy et al., J. Raman Spectrosc. 34:50-56 (2003). , , L-, , , Nor Rajkumar and Ramakrishnan, J. Raman Spectrosc. 31:1107-1112 , , and Valine. (2000). Petrosyan et at, J. Molecular Structure 794:160-167 (2006). Jablecka et al., MedSci Monit 10(I):CR29-32 (2004). 1 Claim, No Drawings Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 3 of 109

US 8,183,288 B2 Page 2

OTHER PUBLICATIONS Ahtee et al., J. Nutr 116:2555-2556 (1986). Bloomer et al., J Int Soc Sports Nutr 4(22): 1-6 (2007). Schulz et al., “Functional and Biochemical Analysis of Endothelial B. Sridhar, et al., “L- Nitrate-L-Aspartic Acid”, Acta (Dys)function and NO/cGMP Signaling in Human Blood Vessels Crystallographica Section, Dec. 2002, pp. 1372-1374, vol. 58. With and Without Nitroglycerin Pretreatment.” Circulation Research B. Sridhar, etal, “Bis(beta-alanine) Nitrate”, Acta Crystal vol. 105: 1170-1175 (2002). lographica Section, 2001, pp. 1004-1006, vol. 57. Hatanaka et al., “Stereoselective Pharmacokinetics and S. Narasinga Rao, et al., “Structure and Conformational Aspects of Pharmacodynamics of Organic Nitrates in Rats,” J Pharmacol Exp the Nitrates of Amino Acids and . I. Crystal Structure of Ther. vol. 298(1):346-53 (2001). Glycylglycine Nitrate”, Acta Crystallographica Section, 1973, pp. Chabot et al., “Characterization of the vasodilator properties of 2379-2388, vol. 29. peroxynitrite on rat pulmonary artery: role of poly ( Bauer JA, et al., “Photochemical Generation of Nitric Oxide from 5'-diphosphoribose) synthase.” British Journal of Pharmacology vol. Nitro-containing Compounds: Possible Relation to Vascular 121:485-490 (1997). Photorelaxation Phenomena”, Life Science, 1994, 54, 1, PL 1-4. Bauer et al., “Vascular and Hemodynamic Differences between Mostad et al., 1986, CAS: 104-197543. Organic Nitrates and Nitrites.” The Journal of Pharmacology and Pradhan et al. publication, Journal of Chemical and Engineering Experimental Therapeutics JPET vol. 280:326-331 (1997). Data, 2000, 45(1): 140-143. Niu et al., Eur J. Pharmacol 580:169-174 (2008). Tan et al., Vasc Pharmacol 46:338-345 (2007). * cited by examiner Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 4 of 109

US 8,183,288 B2 1 2 AMINO ACID COMPOUNDS Amino Acids typically differ from one another with respect to the structure of the R group. It is the structure of the R group CROSS REFERENCE TO RELATED that typically determines the individuality and character of APPLICATIONS each Amino Acid. For example, the R group for the Amino Acid Arginine is: This application is a continuation application of the earlier U.S. Utility patent application to Ronald Kramer, et. al. entitled “Amino Acid Compounds,” application Ser. No. 12/336,938, filed Dec. 17, 2008, now pending, which is a C=NH continuation application of the earlier U.S. Utility patent 10 application to Ronald Kramer, et al. entitled “Amino Acid NH2 Compounds,” application Ser. No. 11/950,273, filed Dec. 4, 2007, now U.S. Pat. No. 7,777,074, which application claims Arginine is characterized as a nonessential Amino Acid. Spe the benefit of the filing date of U.S. Provisional Patent Appli 15 cifically, Arginine can be independently manufactured by the cation 60/973,229 entitled “Amino Acid Compounds” to human body, and does not need to be obtained directly Ronald Kramer, et. al., filed on Sep. 18, 2007, the disclosures through dietary intake. Arginine plays a significant role in of all of which being hereby incorporated entirely herein by healing, cell division, immune function, the elimination of reference. from the body and the release of hormones. Argin 20 ine is presently used in the industry to BACKGROUND supplement Arginine production in the body. Arginine is also presently used in the dietary supplement industry to boost 1. Technical Field Human Growth Hormone (HGH) production, increase Aspects of this document relate generally to amino acid vasodilation, enhance blood circulation, increase oxygen compounds. 25 flow to the muscles, and boost Nitric Oxide (NO) production. 2. Background Various supplemental Arginine forms are available in the It is desirable to design new amino acid compounds that consumer marketplace. have properties lacking in conventional amino acids, conven The vasodilating effect of ingested Arginine takes consid tional nitrates, and conventional nitrites. erable time to manifest since Arginine requires extensive 30 to yield Nitric Oxide (NO). Additionally, consid SUMMARY erable amounts of Arginine are required to produce a signifi cant vasodilating effect, with common doses ranging from In one aspect, this document features a method for increas eight to twenty-four grams per day. ing the bioabsorption of amino acids in a human or animal is The R group for the Amino Acid Citrulline is: disclosed. The method includes administering to the human 35 or animal a pharmaceutically effective amount of an amino acid compound consisting essentially of a nitrate or nitrite of an amino acid selected from the group consisting of Arginine, O H Agmatine, Beta Alanine, Citrulline, Creatine, Glutamine, 40 L-Histidine, Isoleucine, Leucine, Norvaline, Ornithine, and Citrulline is an alpha-Amino Acid naturally occurring in the Valine. human body, and does not need to be obtained directly Implementations may comprise one or more of the follow through dietary intake. In vivo, Citrulline is made from the ing. The amino acid compound may further comprise a phar Amino Acid Ornithine, along with in maceutically acceptable additive, wherein the additive is one 45 one of the central reactions in the . Citrulline is of a carrier, excipient, binder, colorant, flavoring agent, pre also produced during the metabolism of Arginine in the body. servative, buffer, dilutant, and combinations thereof. The Citrulline is presently used in the dietary supplement industry amino acid compound may be in the form of a capsule, tablet, to supplement Citrulline production in the body. By itself, pill, liquid, liquid suspension, vapor, , powder, granulate Citrulline has no vasodilating properties. Citrulline is also or pulverulence. 50 water insoluble, which reduces its bioavailability and limits The foregoing and other aspects, features, and advantages the forms in which Citrulline may be effectively used. will be apparent to those artisans of ordinary skill in the art The R group for the Amino Acid Creatine is: from the DESCRIPTION and DRAWINGS, and from the CLAIMS. H2N H 55 / DESCRIPTION N Overview —N Compounds containing both a carboxyl group and an amino group are typically known as Amino Acids. Amino 60 Acids typically have the basic formula X-R, wherein X is: Creatine is a nonessential Amino Acid and is also a nitrog enous organic acid. Creatine is independently manufactured by the human body, and does not need to be obtained directly CH-COOH through dietary intake. Creatine plays a significant role in 65 providing muscles with energy. Creatine is presently used in the dietary supplement industry to supplement Creatine pro duction in the body. Creatine is also presently used in the Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 5 of 109

US 8,183,288 B2 3 4 dietary supplement industry to increase muscle-mass gains, The R group for the Amino Acid Ornithine is: improve athletic performance and strength. Creatine, by itself, has no vasodilating properties. Citrulline is also water insoluble, which reduces its bioavailability and limits the forms in which Citrulline may be effectively used. The R group for the Amino Acid Glutamine is: Holcº SNI,

10 Ornithine is a non-. That is, Ornithine is O independently manufactured by the human body, and does not need to be obtained directly through dietary intake. Orni Glutamine is a nonessential Amino Acid. Glutamine is the thine plays a significant role in the synthesis of polyamines, most abundant naturally occurring, non-essential amino acid specifically via the action of . Orni in the human body and is found circulating in the blood, as 15 thine is presently used in the dietary supplement industry to well as stored in the skeletal muscles. Glutamine plays a supplement dietary Ornithine sources. Ornithine is also pres significant role in synthesis, muscle growth, and ently used in the dietary supplement industry to enhance the wound healing. Glutamine is presently used in the dietary supplement industry to supplement Glutamine production in vasodilating properties in a series of products commonly the body. Glutamine is also presently used in the dietary 20 known as “NO Boosters.” Ornithine exerts its vasodilating supplement industry to maintain the body’s Glutamine pool. effect only by in vivo conversion to Arginine and then by Glutamine, by itself, has no vasodilating properties. following the pathway that converts Arginine to Nitric Acid Glutamine is also waterinsoluble, which reduces its bioavail (NO). Many grams of Ornithine, and a considerable amount ability and limits the forms in which Glutamine may be effec of time, are required in order to assert its vasodilating effect. tively used. Additionally, Glutamine inhibits Nitric Acid 25 The R group for the Amino Acid Histidine is: (NO) production through downregulation of eNOS synthase. The R group for the Amino Acid Leucine is: 30 &r Histidine is a naturally-occurring Amino Acid and is coded 35 Leucine is an essential Amino Acid, meaning that Leucine is for in DNA. Relatively small shifts in cellular pH will change not synthesized in vivo in animals. Accordingly, Leucine the electrical charge of Histidine. For this reason, Histidine must be ingested, usually as a component of con finds its way into considerable use as a coordinating in sumed directly through dietary intake. Leucine plays a sig , and also as a catalytic site in certain nificant role in muscle protein synthesis. Leucine can also 40 . Histidine is currently used in the dietary supple inhibit protein degradation in skeletal muscle, as well as in the ment industry to support carnosine production. Histidine, by liver. Leucine is presently used in the dietary supplement itself, has no vasodilating properties. Additionally, Histidine industry to supplement dietary Leucine sources. Leucine is is very poorly water soluble, a fact that limits its bioavailabil also presently used in the dietary supplement industry to ity and utility. Histidine is presently used in the dietary promote and stimulate muscle protein synthesis. 45 supplement industry in the forms of single administration Leucine, by itself, has no vasodilating properties. Leucine is Histidine and Histidine HC1. also water insoluble, which reduces its bioavailability and limits the forms in which Leucine may be effectively used. The R group for the Amino Acid Beta Alanine is: The R group for the Amino Acid Norvaline is: 50

Norvaline is a nonessential Amino Acid. Specifically, Norva 55 Beta Alanine is the only naturally-occurring Beta Amino line can be independently manufactured by the human body, Acid. A Beta Amino Acid is one in which the Amino group is and does not need to be obtained directly through dietary located at the beta position (i.e. two atoms away) from the intake. Norvaline is presently used in the dietary supplement Carboxyl group. Beta Alanine is formed in vivo through the industry to supplement Norvaline production in the body. degradation of dihydrouracil and carnosine. Beta Alanine is Norvaline is also presently used in the dietary supplement 60 the rate-limiting precursor of carnosine. Therefore, carnosine industry to inhibit the arginase and thus reduce the levels are limited by the amount of available Beta Alanine. conversion of Arginine to urea. Norvaline, by itself, has no Beta Alanine, by itself, has no vasodilating properties. Addi vasodilating properties, although it enhances the vasodilating tionally, Beat Alanine is poorly water soluble, which limits its properties of Arginine. Norvaline is also water insoluble, 65 bioavailability and utility. Beta Alanine is presently used in which reduces its bioavailability and limits the forms in the dietary supplement industry to support carnosine produc which Leucine may be effectively used. tion. Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 6 of 109

US 8,183,288 B2 5 6 The chemical structure of Agmatine is: exemplary purposes of this disclosure, Nitrate may comprise salts of Nitrate such as sodium nitrate, potassium nitrate, barium nitrate, nitrate, and the like. For the exem plary purposes of this disclosure, Nitrate may include mixed salts of Nitrate such as nitrate orotate, and the like. Addition ally, for the exemplary purposes of this disclosure, Nitrate may comprise nitrate esters such as nitroglycerine, and the Agmatine is the decarboxylation product of the Amino Acid like. As used herein, “Nitrite” is a term used in its broadest sense Arginine and is an intermediate in polyamine . 10 Agmatine is synthesized in the brain and stored in synaptic and may refer to an Nitrite in its many different chemical vesicles in regionally selective . Agmatine is released forms including a of Nitrous Acid, a single administration by depolarization and is inactivated by agnatinase. Agmatine Nitrite, its physiologically active salts or esters, its combina binds to alpha2-adrenoceptors and imidazoline binding sites. tions with its various salts, its tautomeric, polymeric and/or Agmatine likewise blocks N-methyl-D-aspartic acid 15 isomeric forms, its analog forms, and its derivative forms. (NMDA) channels and other ligand-gated cationic Nitrite comprises, by way of non-limiting example, many channels. Additionally, agnatine inhibits nitric oxide syn different chemical forms including dinitrite and trinitrite. thase, and induces the release of some hormones. Nitrites may be salts, or mixed salts, of Nitrous Acid and Agmatine modulates nitric oxide through various mecha comprise one Nitrogen atom and two Oxygen atoms. For the nisms. Agmatine stimulates some types of nitric oxide syn 20 exemplary purposes of this disclosure, Nitrite may comprise thase (NOS) while inhibiting others. Agmatine inhibits Nitric salts of Nitrite such as sodium nitrite, potassium nitrite, Oxide production by inhibiting NOS. Agmatine is presently barium nitrite, calcium nitrite, and the like. For the exemplary used in the dietary supplement industry in the forms of single purposes of this disclosure, Nitrite may comprise mixed salts administration Agmatine and Agmatine Sulfate. of Nitrite such as nitrite orotate, and the like. Additionally, for Nitrates are a class of compounds that are salts of Nitric 25 the exemplary purposes of this disclosure, Nitrite may com Acid (HNO3) and at least comprise one Nitrogen atoms and prise nitrite esters such as amyl nitrite, and the like. three Oxygen atoms (NOs). As used herein, “pharmaceutically acceptable additive” or Nitrites are a class of compounds that are salts of Nitrous “additive” are terms used in their broadest sense. Particular Acid (HNO2) and at least comprise one Nitrogen atom and implementations of the compositions described in this docu two Oxygen atoms (NO2). 30 ment may also comprise an additive (e.g. one of a solubilizer, Nitrates and Nitrites are commercially available in various an enzyme inhibiting agent, an anticoagulant, an antifoaming preparations and are used invarious commercial applications. In the case ofingestion by humans, Nitrate (NOs) is typically agent, an antioxidant, a coloring agent, a coolant, a cryopro reduced to Nitrite (NO2) in the epithelial cells of blood ves tectant, a hydrogen bonding agent; a flavoring agent, a plas sels. In vivo, Nitrite (NO2) reacts with a thiol donor, princi 35 ticizer, a preservative, a sweetener, a thickener, and combina pally , to yield Nitric Oxide (NO). tions thereof) and/or a carrier (e.g. one of an excipient, a Terminology and Definitions lubricant, a binder, a disintegrator, a diluent, an extender, a In describing implementations of an Amino Acid Com solvent, a suspending agent, a dissolution aid, an isotoniza pound, the following terminology will be used in accordance tion agent, a buffering agent, a soothing agent, an amphip with the definitions and explanations set out below. Notwith 40 athic delivery system, and combinations thereof). These standing, other terminology, definitions, and explanations additives may be solids or liquids, and the type of additive may be found throughout this document, as well. may be generally chosen based on the type of administration As used herein, “Amino Acid” is a term used in its broadest being used. Those of ordinary skill in the art will be able to sense and may refer to an Amino Acid in its many different readily select suitable pharmaceutically effective additives chemical forms including a single administration Amino 45 from the disclosure in this document. In particular implemen Acid, its physiologically active salts or esters, its combina tations, pharmaceutically acceptable additives may include, tions with its various salts, its tautomeric, polymeric and/or by non-limiting example, calcium phosphate, cellulose, isomeric forms, its analog forms, its derivative forms, and/or stearic acid, croscarmelose cellulose, stearate, its decarboxylation products. Amino Acids comprise, by way and silicon dioxide. of non-limiting example: Agmatine, Beta Alanine, Arginine, 50 As used in this document, “pharmaceutically effective” is a , Aspartic Acid, , Glutamine, Glutamic phrase used in its broadest sense, including, by non-limiting Acid, , Histidine, Isoleucine, Leucine, , example, effective in a clinical trial, for a specific patient, or , Phenylbeta Alanine, , , , only placebo-effective. , , and Valine. As used in this document, “Pharmaceutically acceptable” As used herein, “Compound” is a term used in its broadest 55 is a phrase used in its broadest sense and may describe ingre sense and may refer to an Amino Acid in combination with dients of a pharmaceutical composition that meet Food and one of a Nitrate and a Nitrite. Drug Administration (FDA) standards, United States Phar As used herein, “Nitrate” is a term used in its broadest macopeial Standards (USP), US Department of Agriculture sense and may refer to an Nitrate in its many different chemi (USDA) standards for food-grade materials, commonly cal forms including a salt of Nitric Acid, a single administra 60 accepted standards of the nutritional supplement industry, tion Nitrate, its physiologically active salts or esters, its com industry standards, botanical standards, or standards estab binations with its various salts, its tautomeric, polymeric lished by any individual. These standards may delineate and/or isomeric forms, its analog forms, and/or its derivative acceptable ranges of aspects of ingredients of a pharmaceu forms. Nitrate comprises, by way of non-limiting example, tical composition such as edibility, toxicity, pharmacological many different chemical forms including dinitrate and trini 65 effect, or any other aspect of a chemical, composition, or trate. Nitrates may be salts, or mixed salts, of Nitric Acid and preparation used in implementations of a pharmaceutical comprise one Nitrogenatom and three Oxygenatoms. For the composition. Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 7 of 109

US 8,183,288 B2 7 8 Compounds/Components place, yielding Creatine Dinitrate or Creatine Trinitrate. An A first implementation is an Arginine compound of the alternative implementation may comprise using Nitrous Acid formula: (HNO2) instead of Nitric Acid (HNO3), thus yielding Creat ine Nitrite. Creatine Nitrite has the same effects as Creatine Nitrate, the only difference being that it requires one less step to yield Nitric Oxide (NO—). Mixed salts may also be used, such as in the non-limiting example of Creatine Nitrate-Oro tate. A fourth implementation is a Glutamine compound of the wherein; 10 formula: R is the Arginine group identified and defined above; X is the Amino Acid base identified and defined above; and Y is selected from the group consisting of a Nitrate and a Nitrite. 15 Applicants have cost-effectively synthesized Arginine Nitrate by combining nitric acid and Arginine, mixing with water, and leaving to crystallize. Further nitratization can take wherein; place, yielding Arginine Dinitrate or Arginine Trinitrate. An R is the Glutamine group identified and defined above; alternative implementation may comprise using Nitrous Acid 20 X is the Amino Acid base identified and defined above; and (HNO2) instead of Nitric Acid (HNO3), thus yielding Argin Y is selected from the group consisting of a Nitrate and a ine Nitrite. Arginine Nitrite has the same effects as Arginine Nitrite. Nitrate, the only difference being that it requires one less step Applicants have cost-effectively synthesized Glutamine to yield Nitric Oxide (NO-). Mixed salts may also be used, Nitrate by combining nitric acid and Glutamine, mixing with such as in the non-limiting example of Arginine Nitrate 25 water, and leaving to crystallize. Further nitratization can take Orotate. place, yielding Glutamine Dinitrate or Glutamine Trinitrate. A second implementation is a Citrulline compound of the An alternative implementation comprises using Nitrous Acid formula: (HNO2) instead of Nitric Acid (HNO3), thus yielding Glutamine Nitrite. Glutamine Nitrite has the same effects as 30 Glutamine Nitrate, the only difference being that it requires one less step to yield Nitric Oxide (NO—). Mixed salts may also be used, such as in the non-limiting example of Glutamine Nitrate-Orotate. A fifth implementation is a Leucine compound of the for 35 mula: wherein; R is the Citrulline group identified and defined above; X is the Amino Acid base identified and defined above; and Y is selected from the group consisting of a Nitrate and a Nitrite. Applicants have cost-effectively synthesized Citrulline 40 Nitrate by combining nitric acid and Citrulline, mixing with water, and leaving to crystallize. Further nitratization can take wherein; place, yielding Citrulline Dinitrate or Citrulline Trinitrate. An R is the Leucine group identified and defined above; alternative implementation may comprise using Nitrous Acid X is the Amino Acid base identified and defined above; and (HNO2) instead of Nitric Acid (HNO3), thus yielding Citrul 45 Y is selected from the group consisting of a Nitrate and a line Nitrite. Citrulline Nitrite has the same effects as Citrul Nitrite. line Nitrate, the only difference being that it requires one less Applicants have cost-effectively synthesized Leucine step to yield Nitric Oxide (NO—). Mixed salts may also be Nitrate by combining nitric acid and Leucine, mixing with used, such as in the non-limiting example of Citrulline water, and leaving to crystallize. Further nitratization can take 50 place, yielding Leucine Dinitrate or Leucine Trinitrate. An Nitrate-Orotate. alternative implementation comprises substituting the Amino A third implementation is a Creatine compound of the Acids Valine or Isoleucine for Leucine. Another alternative formula: implementation comprises substituting Nitrous Acid (HNO2) for Nitric Acid (HNO3), thus yielding Leucine Nitrite. Leu 55 cine Nitrite has the same effects as Leucine Nitrate, the only difference being that it requires one less step to yield Nitric Oxide (NO—). Mixed salts may also be used, such as in the non-limiting example of Leucine Nitrate-Orotate. A sixth implementation is a Norvaline compound of the wherein; 60 formula: R is the Creatine group identified and defined above; X is the Amino Acid base identified and defined above; and Y is selected from the group consisting of a Nitrate and a Nitrite. Applicants have cost-effectively synthesized Creatine 65 Nitrate by combining nitric acid and Creatine, mixing with water, and leaving to crystallize. Further nitratization can take Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 8 of 109

US 8,183,288 B2 9 10 wherein; A ninth implementation is a Beta Alanine compound of the R is the Norvaline group identified and defined above; formula: X is the Amino Acid base identified and defined above; and Y is selected from the group consisting of a Nitrate and a Nitrite. Applicants have cost-effectively synthesized Norvaline Nitrate by combining nitric acid and Norvaline, mixing with water, and leaving to crystallize. Further nitratization can take place, yielding Norvaline Dinitrate or Norvaline Trinitrate. wherein; An alternative implementation comprises substituting 10 R is the Beta Alanine group identified and defined above; Nitrous Acid (HNO2) for Nitric Acid (HNO3), thus yielding X is the Amino Acid base identified and defined above; and Norvaline Nitrite. Norvaline Nitrite has the same effects as Y is selected from the group consisting of a Nitrate and a Norvaline Nitrate, the only difference being that it requires Nitrite. one less step to yield Nitric Oxide (NO—). Mixed salts may 15 Applicants have cost-effectively synthesized Beta Alanine also be used, such as in the non-limiting example of Norvaline Nitrate by combining nitric acid and Beta Alanine, mixing Nitrate-Orotate. with water, and leaving to crystallize. Further nitratization A seventh implementation is an Ornithine compound of the can take place, yielding Beta Alanine Dinitrate or Beta Ala formula: nine Trinitrate. An alternative implementation comprises 20 using Nitrous Acid (HNO2) instead of Nitric Acid (HNO3), thus yielding Beta Alanine Nitrite. Beta Alanine Nitrite has the same effects as Beta Alanine Nitrate, the only difference being that it requires one less step to yield Nitric Oxide (NO-). Mixed salts may also be used, such as in the non 25 limiting example of Beta Alanine Nitrate-Orotate. wherein; A tenth implementation is an Agmatine compound of the R is the Ornithine group identified and defined above; formula: X is the Amino Acid base identified and defined above; and Y is selected from the group consisting of a Nitrate and a Nitrite. 30 Applicants have cost-effectively synthesized Ornithine Nitrate by combining nitric acid and Ornithine, mixing with NH2 water, and leaving to crystallize. Further nitratization can take place, yielding Ornithine Dinitrate or Ornithine Trinitrate. An 35 wherein; alternative implementation comprises using Nitrous Acid Y is selected from the group consisting of a Nitrate and a (HNO2) instead of Nitric Acid (HNO3), thus yielding Orni Nitrite. thine Nitrite. Ornithine Nitrite has the same effects as Orni Applicants have cost-effectively synthesized Agmatine thine Nitrate, the only difference being that it requires one less Nitrate by combining nitric acid and Agmatine, mixing with step to yield Nitric Oxide (NO—). Mixed salts may also be 40 water, and leaving to crystallize. Further nitratization can take used, such as in the non-limiting example of Ornithine place, yielding Agmatine Dinitrate or Agmatine Trinitrate. An Nitrate-Orotate. alternative implementation comprises using Nitrous Acid An eighth implementation is a Histidine compound of the (HNO2) instead of Nitric Acid (HNO3), thus yielding Agma formula: tine Nitrite. Agmatine Nitrite has the same effects as Agma 45 tine Nitrate, the only difference being that it requires one less step to yield Nitric Oxide (NO—). Mixed salts may also be used, such as in the non-limiting example of Agmatine Nitrate-Orotate. Compositions and/or formulations may be administered in 50 any form, including one of a capsule, a cachet, a pill, a tablet, a powder, a granule, a pellet, a bead, a particle, a troche, a wherein; lozenge, a pastille, a solution, an elixir, a syrup, a tincture, a R is the Histidine group identified and defined above; suspension, an emulsion, a mouthwash, a spray, a drop, an X is the Amino Acid base identified and defined above; and ointment, a cream, a gel, a paste, a transdermal patch, a Y is selected from the group consisting of a Nitrate and a 55 suppository, a pessary, cream, a gel, a paste, a foam, and Nitrite. combinations thereof for example. Compositions and/or for Applicants have cost-effectively synthesized Histidine mulations may also include a acceptable additive (e.g. one of Nitrate by combining nitric acid and Histidine, mixing with a solubilizer, an enzyme inhibiting agent, an anticoagulant, an water, and leaving to crystallize. Further nitratization can take antifoaming agent, an antioxidant, a coloring agent, a coolant, place, yielding Histidine Dinitrate or Histidine Trinitrate. An 60 a cryoprotectant, a hydrogen bonding agent, a flavoring alternative implementation comprises using Nitrous Acid agent, a plasticizer, a preservative, a sweetener, a thickener, (HNO2) instead of Nitric Acid (HNO3), thus yielding Histi and combinations thereof) and/or a acceptable carrier (e.g. dine Nitrite. Histidine Nitrite has the same effects as Histidine one of an excipient, a lubricant, a binder, a disintegrator, a Nitrate, the only difference being that it requires one less step diluent, an extender, a solvent, a suspending agent, a disso to yield Nitric Oxide (NO-). Mixed salts may also be used, 65 lution aid, an isotonization agent, a buffering agent, a sooth such as in the non-limiting example of Histidine Nitrate ing agent, an amphipathic lipid delivery system, and combi Orotate. nations thereof). Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 9 of 109

US 8,183,288 B2 11 12 Implementations of Amino Acid Nitrate and/or Nitrite lyophilization, melting, mixed, molding, pan coating, solvent Compounds may also be synthesized or created in a wide dehydration, sonication, spheronization, spray chilling, spray variety of manners, and may be made from a wide variety of congealing, spray drying, or other processes known in the art materials. Those of ordinary skill in the art will readily be able depending in part on the dosage form desired. The various to select appropriate materials and methods to manufacture components may also be pre-coated or encapsulated as and use the compounds disclosed herein. known in the art. It will also be clear to one of ordinary skill Dosage Forms in the art that appropriate additives may also be introduced to Implementations of Amino Acid Compounds may conve the composition or during the processes to facilitate the niently be presented in unit dosage form. Unit dosage formu preparation of the dosage forms, depending on the need of the lations may be those containing a daily dose or unit, a daily 10 individual process. sub-dose, or an appropriate fraction thereof, of the adminis Mixing the measured quantities of Amino Acid, Nitric or tered components as described herein. Nitrous Acid and water, and pharmaceutically acceptable A dosage unit may include an Amino Acid Compound. In additives or inert ingredients, may involve any number of addition, a dosage unit may include an Amino Acid steps and implementing components, and may be accom Compound admixed with a pharmaceutically acceptable 15 plished readily from this disclosure. For the exemplary pur additive(s), and/or any combination thereof. poses of this disclosure, mixed the measured quantities of The dosage units may be in a form suitable for administra Amino Acid, Nitric or Nitrous Acid and water, and pharma tion by standard routes. In general, the dosage units may be ceutically acceptable additives orinertingredients, may com administered, by non-limiting example, by the topical (in prise combining the measured quantities of m Amino Acid, cluding buccaland sublingual), transdermal, oral, rectal, oph 20 Nitric or Nitrous Acid and water, and pharmaceutically thalmic (including intravitreal or intracameral), nasal, vagi acceptable additives or inert ingredients, under the influence nal, and/or parenteral (including subcutaneous, of physical, ultrasonic, or electrostatic forces to create a intramuscular, intravenous, intradermal, intratracheal, and desired degree of intermingling and/or chemical reaction of epidural) routes. the Amino Acid, Nitric or Nitrous Acid and water and any For the exemplary purposes of this disclosure, oral delivery 25 pharmaceutically acceptable ingredients. The mixed may be may be a particularly advantageous delivery route for admin accomplished when the Amino Acid, Nitric or Nitrous Acid istration to humans and animals of implementations of a and water and/or any pharmaceutically acceptable ingredi pharmaceutical composition, optionally formulated with ents are in a solid, liquid, or semisolid state. appropriate pharmaceutically acceptable additives to facili Separating the Amino Acid Compound into discrete quan tate administration. 30 tities for distribution may involve any number of steps and Manufacture implementing components, and separating the Amino Acid Implementations of an Amino Acid Compound may be Compound into discrete quantities for distribution may be made using conventional or other procedures. Accordingly, accomplished readily from this disclosure. For the exemplary although there are a variety of method implementations for purposes of this disclosure, separating the Amino Acid Com producing pharmaceutical compositions, for the exemplary 35 pound into discrete quantities for distribution may involve purposes of this disclosure, a method implementation for utilizing a specific piece of equipment, for example, a con producing an Amino Acid Compound may comprise: mea ventional tablet forming apparatus to shape the formed com suring specific quantities of Amino Acid, Nitric or Nitrous position into individual tablets, each containing a desired Acid and water mixed in a specific order the measured quan dose of Amino Acid Compound. The separating process may tities of Amino Acid, Nitric or Nitrous Acid and water, and 40 be accomplished when the Amino Acid Compound is in a any additional pharmaceutically acceptable additives or inert solid, liquid, or semisolid state. ingredients, and then separating the pharmaceutical compo Those of ordinary skill in the art will be able to readily sition into discrete quantities for distribution and/or admin select manufacturing equipment and pharmaceutically istration. acceptable additives or inert ingredients to manufacture Measuring specific quantities of Amino Acid, Nitric or 45 implementations of an Amino Acid Compound. For the Nitrous Acid and water, and pharmaceutically acceptable exemplary purposes of this disclosure, some examples of additives or inert ingredients, may involve any number of pharmaceutically acceptable additives or inert ingredients steps and implementing components, and measuring specific and manufacturing process are included below, particularly quantities of Amino Acid, Nitric or Nitrous Acid and water, those that relate to manufacture of implementations of an and pharmaceutically acceptable additives or inert ingredi 50 Amino Acid Compound in tablet form. Notwithstanding the ents, may be accomplished readily from this disclosure. For specific examples given, it will be understood that those of the exemplary purposes of this disclosure, measuring specific ordinary skill in the art will readily appreciate how to manu quantities of Amino Acid, Nitric or Nitrous Acid and water, facture implementations of an Amino Acid Compound and pharmaceutically acceptable additives or inert ingredi according to the other methods of administration and delivery ents, may comprise using a scale, a solid or liquid dispensing 55 disclosed in this document. apparatus, or othermeasurement device capable of measuring A particular implementation of an Amino Acid Compound solid mass or liquid volume to produce a desired quantity of may include a lubricant. Lubricants are any anti-sticking Amino Acid, Nitric or Nitrous Acid and water, and pharma agents, glidants, flow promoters, and the like materials that ceutically acceptable ingredient. perform a number of functions in tablet manufacture, for It should be appreciated that any of the components of 60 example, such as improving the rate of flow of the tablet particular implementations of an Amino Acid Compound granulation, preventing adhesion of the tablet material to the may be used as supplied commercially, or may be prepro surface of the dies and punches, reducing interparticle fric cessed by, by non-limiting example, any of the methods and tion, and facilitating the ejection of the tablets from the die techniques of agglomeration, air suspension chilling, air sus cavity. Lubricants may comprise, for example, magnesium pension drying, balling, coacervation, comminution, com 65 stearate, calcium stearate, talc, and colloidal silica. pression, pelletization, cryopelletization, extrusion, granula Particular implementations of an Amino Acid Compound tion, homogenization, inclusion Compoundation, may also include a binder. Binders are any agents used to Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 10 of 109

US 8,183,288 B2 13 14 impart cohesive qualities to powdered material through par Tablets and other orally discrete dosage forms, such as ticle-particle bonding. Binders may include, for example, capsules, cachets, pills, granules, pellets, beads, and particles, matrix binders (e.g. dry starch, dry sugars), film binders (e.g. for example, may optionally be coated with one or more celluloses, bentonite, sucrose), and chemical binders (e.g. enteric coatings, seal coatings, film coatings, barrier coatings, polymeric cellulose derivatives, such as methyl cellulose, compress coatings, fast disintegrating coatings, or enzyme carboxy methylcellulose, and hydroxy propyl cellulose); and degradable coatings for example. Multiple coatings may be other sugar, , non-cellulosic binders and the like. applied for desired performance. Further, dosage forms may Disintegrators may be used in particular implementations be designed for, by non-limiting example, immediate release, of an Amino Acid Compound to facilitate the breakup or pulsatile release, controlled release, extended release, 10 delayed release, targeted release, synchronized release, or disintegration of tablets after administration. Disintegrators targeted delayed release. For release/absorption control, car may include, for example, starch, starch derivatives, clays riers may be made of various component types and levels or (e.g. bentonite), algins, gums (e.g. guar gum), cellulose, cel thicknesses of coats. Such diverse carriers may be blended in lulose derivatives (e.g. methyl cellulose, carboxymethyl cel a dosage form to achieve a desired performance. In addition, lulose), croscarmellose sodium, croscarmellose cellulose, 15 the dosage form release profile may be effected by a poly and other organic and inorganic materials. meric matrix composition, a coated matrix composition, a Implementations of an Amino Acid Compound may multi-particulate composition, a coated multi-particulate include diluents, or any inert substances added to increase the composition, an ion-exchange resin-based composition, an bulk of the Amino Acid Compound to make a tablet a practi osmosis-based composition, or a biodegradable polymeric cal size for compression. Diluents may include, for example, 20 composition. calcium phosphate, calcium sulfate, lactose, mannitol, mag While manufacture of implementations of an Amino Acid nesium stearate, potassium chloride, and , among Compound have been described in particular sequences of other organic and inorganic materials. steps and/or in particular forms, it will be understood that Buffering agents may be included in an Amino Acid Com such manufacture is not limited to the specific order of steps pound and may be any one of an acid and a base, where the 25 or forms as disclosed. Any steps or sequences of steps of acid is, for example, , p-toluenesulfonic acid, manufacture of implementations of an Amino Acid Com salicylic acid, stearic acid, succinic acid, tannic acid, tartaric pound in any form are given as examples of possible steps or acid, thioglycolic acid, or toluenesulfonic acid, and the base sequences of steps or potential forms and not as limitations, is, for example, ammonium hydroxide, potassium hydroxide, since many possible manufacturing processes and sequences sodium hydroxide, sodium hydrogen carbonate, aluminum 30 of steps may be used to manufacture Amino Acid Compound hydroxide, calcium carbonate, and other organic and inor implementations in a wide variety of forms. ganic chemicals. Use Implementations of an Amino Acid Compound may also Implementations of an Amino Acid Compound are particu be administered through use of amphipathic lipid delivery larly useful in increasing vasodilation in humans and animals. systems (such as liposomes and unilamellar vesicles), caplet 35 However, implementations are not limited to uses relating to systems, oral liquid systems, parenteral and/or intravenous vasodilation modification, and the like. Rather, any descrip systems, topical systems (creams, gels, transdermal patches, tion relating to the foregoing is for the exemplary purposes of etc.), intranasal systems, rectal or vaginal systems, and many this disclosure. It will be understood that implementations of other delivery methods and/or systems known to those of an Amino Acid Compound may encompass a variety of uses ordinary skill in the art. Those of ordinary skill in the art will 40 and are not limited in their uses. For example, possible uses readily be able to select additional pharmaceutically accept may be, by non-limiting example, prevention of Nitrate tol able additives to enable delivery of implementations of a erance, enhanced water solubility, increased distribution to pharmaceutical composition from the disclosure in this docu muscles, and/or countering Nitric Oxide inhibiting effects of ment. certain Amino Acids. With respect to delivery of particular implementations of 45 In conventional preparations of Nitrate compounds, “tol an Amino Acid Compound, for the exemplary purposes of erance,” a particular side effect, has been observed in many this disclosure, tablets may be utilized. Tablets are any solid patients. This is unfortunate because the effectiveness of pharmaceutical dosage form containing a pharmaceutically Nitrate on vasodilation is well documented. “Tolerance” acceptable active agent or agents to be administered with or occurs when a subject’s reaction to Nitrate decreases so that without suitable pharmaceutically acceptable additives and 50 larger doses are required to achieve the same effect. A Mar. 3, prepared either by compression or molding methods well 2000 report in the British Journal of Pharmacology indicates known in the art. Tablets have been in widespread use and that “tolerance to the dilator effects of nitrates remains a remain popular as a dosage form because of the advantages persisting therapeutic problem.” Raymond J. MacAllister afforded both to the manufacturer (e.g., simplicity and “Arginine and Nitrate Tolerance” available at http://www.na economy of preparation, stability, and convenience in pack 55 ture.com/bjp/journal/v130/n2/full/0703340a.html, the con aging, shipping, and dispensing) and the patient (e.g., accu tents of which are hereby incorporated herein by reference. racy of dosage, compactness, portability, blandness of taste, Empirical studies indicate that Nitrates are useful for their and ease of administration). Although tablets are most fre vasolidating effects. Common Nitrates include nitroglycerin quently discoid in shape, they may also be round, oval, and isosorbide dinitrate. Nitrates exert their vasodilating oblong, cylindrical, rectangular or triangular, for example. 60 effect through their reduction to Nitrites. In vivo, Nitrates are The tablets may be optionally scored so that they may be reduced to Nitrites and, in the blood vessels’ epithelial cells, separated into different dosages. They may differ greatly in Nitrite reacts with a thiol donor (mainly glutathione) to yield size and weight depending on the amount of the pharmaceu Nitric Oxide. Louis J. Ignarro, “After 130 years, the Molecu tically acceptable active agent or agents present and the lar Mechanism of Action of Nitroglycerin is Revealed” (Jun. intended route of administration. They are divided into two 65 11, 2002) available at http://www.pnas.org/cgi/content/full/ general classes, (1) compressed tablets, and (2) molded tab 99/12/7816?ck=nck, the contents of which are hereby incor lets. porated herein by reference. Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 11 of 109

US 8,183,288 B2 15 16 The Nitric Oxide inhibiting characteristics of the Amino required for vasodilation to take place, compared to the single Acid Glutamine have been well documented in a number of administration of Arginine. Likewise, the development of studies. In particular, a Mar. 28, 2006 report in the American tolerance to the nitrate component of the molecule may be Journal of Physiology has found that Glutamine inhibits prevented with the presence of Arginine. Arginine Nitrate Nitric Oxide production by downregulation of eNOS syn 5 may promote vasodilation through production of Nitric thase. Masao Kakoki, et al. “Amino acids as Modulators of Oxide by two different pathways, the Arginine citrullization Endothelium-Derived Nitric Oxide.” available at http://ajpre pathway and the nitrate reduction pathway. Arginine Nitrate nal.physiology.org/cgi/content/full/291/2/F297, the contents may likewise be more water soluble than single administra of which are hereby incorporated by reference. tion Arginine. A January 2006 Journal of report indicates that 10 Accordingly, Applicants have discovered that the Citrul the Amino Acid Leucine promotes anabolism and stimulates line compound according to the second implementation, muscle protein synthesis. Michael J. Rennie, et al. when ingested, provides enhanced Nitric Oxide (NO—) pro “Branched-Chain Amino Acids as Fuels and Anabolic Sig duction while providing improved vasodilation effects over mals in Human Muscle” available at http://jn.nutrition.org/ single administration of Citrulline, the single administration cgi/content/full/136/1/264S, the contents of which are hereby 15 of Nitrates, or the single administration of Nitrites. Improved incorporated by reference. vasodilation may, in turn, provide better circulation and dis Empirical studies indicate that the Amino Acid Norvaline tribution of Citrulline in the body. Absorption may be inhibits the enzyme arginase and thus decreases the rate of improved since Amino Acid salts with inorganic acids are conversion of the Amino Acid Arginine to urea. Takeyori much more water soluble than single administration Amino Saheki, et al. “Regulation of Urea Synthesis in Rat Liver” 20 Acids. Additionally a much lesser dose may be required for available at http://jb.oxfordjournals.org/cgi/content/abstract/ vasodilation to take place, compared to the single adminis 86/3/745?ijkey=5d134456b7443ca36c809269462276eS325 tration of Citrulline or nitrates. Citrulline Nitrate is likewise 49798&keytype2=tf_ipsecsha, the contents of which are more water soluble than single administration Citrulline. hereby incorporated by reference. Accordingly, Applicants have discovered that the Creatine An October 2004 Journal of Nutrition report indicates that 25 compound according to the third implementation, when the Amino Acid Ornithine promotes anabolism and stimu ingested, provides enhanced Nitric Oxide (NO—) production lates muscle protein synthesis. Michael J. Rennie, et al. while providing improved vasodilation effects over single “Branched-Chain Amino Acids as Fuels and Anabolic Sig administration of Creatine, the single administration of mals in Human Muscle” available at http://jn.nutrition.org/ Nitrates, or the single administration of Nitrites. Improved cgi/content/full/136/1/264S, the contents of which are hereby 30 vasodilation may, in turn, provide better circulation and dis incorporated by reference. tribution of Creatine in the body. Absorption may be Empirical studies indicate that the Amino Acids Beta-Beta improved since Amino Acid salts with inorganic acids are Alanine and L-Histidine support carnosine production. M. much more water soluble than single administration Amino Dunnett, “Influence of Oral Beta-Beta Alanine and L-Histi Acids. Additionally a much lesser dose may be required for dine Supplementation on the Carnosine Content of the Glu 35 vasodilation to take place, compared to the single adminis teus Medius” Equine Veterinary Journal Supplement, avail tration of nitrates. Creatine Nitrate is likewise more water able at http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pub soluble than single administration Creatine. med&Cmd=ShowDetail View&Term'ToSearch=10659307& Accordingly, Applicants have discovered that the ordinalpos=4&itool=EntrezSystem 2.PEntrez.Pubmed. Glutamine compound according to the fourth implementa Pubmed, the contents of which are hereby incorporated by 40 tion, when ingested, counters the Nitric Oxide (NO—) inhib reference. iting characteristics of Glutamine. Absorption of Glutamine Empirical studies further indicate that the Amino Acids may be improved since Amino Acid salts withinorganic acids Beta Alanine and L-Histidine increase muscle power, recu are much more water soluble than single administration peration and stamina. Yoshihiro Suzuki “High Level of Skel Amino Acids. Additionally a much lesser dose may be etal Muscle Carnosine Contributes to the Latter Half of Exer 45 required for vasodilation to take place, compared to the single cise Performance During 30-S Maximal Cycle Ergometer administration of nitrates. Glutamine Nitrate may likewise be Sprinting” in the Japanese Journal of Physiology, available at more water soluble than single administration Glutamine. http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed& Accordingly, Applicants have discovered that the Leucine Cmd=ShowDetail View&Term'ToSearch=12139778& compound according to the fifth implementation, when ordinalpos=4&itool=EntrezSystem 2.PEntrez.Pubmed. Pub 50 ingested, provides enhanced Nitric Oxide (NO—) production med ResultsPanel. Pubmed RVDocSum, the contents of while providing improved vasodilation effects over single which are hereby incorporated by reference. administration of Leucine, the single administration of Accordingly, Applicants have discovered that the Arginine Nitrates, or the single administration of Nitrites. Improved compound according to the first implementation, when vasodilation may, in turn, provide better circulation and dis ingested, provides enhanced Nitric Oxide (NO—) production 55 tribution of Leucine in the body. Absorption may be improved while providing improved vasodilation effects over single since Amino Acid salts with inorganic acids are much more administration of Arginine, the single administration of water soluble than single administration Amino Acids. Addi Nitrates, or the single administration of Nitrites. Improved tionally a much lesser dose may be required for vasodilation vasodilation may, in turn, provide better circulation and dis to take place, compared to the single administration of tribution of Arginine in the body. Absorption may be 60 nitrates. Leucine Nitrate is likewise more water soluble than improved since Amino Acid salts with inorganic acids are single administration Leucine. much more water soluble than single administration Amino Accordingly, Applicants have discovered that the Norval Acids. Applicants have also discovered that the vasodilating ine compound according to the sixth implementation, when effect of Arginine Nitrate manifests faster than that of single ingested, promotes vasodilation through the inhibition of administration Arginine, and as fast as any nitrate, since the 65 arginase, while promoting Nitric Oxide formation via the NOs—group of the salt requires minimal conversion to yield nitrate mechanism. Improved vasodilation may, in turn, pro Nitric Oxide. Additionally a much lesser dose may be vide better circulation and distribution of Norvaline in the Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 12 of 109

US 8,183,288 B2 17 18 body. Absorption may be improved since Amino Acid salts Accordingly, Applicants have discovered that the Beta Ala with inorganic acids are much more water soluble than single nine compound according to the ninth implementation, when administration Amino Acids. Additionally a much lesser dose ingested, provides vasodilation. Vasodilation may, in turn, may be required for vasodilation to take place, compared to provide better circulation and distribution of Beta Alanine in the single administration of nitrates. Norvaline Nitrate may the body. Applicants have likewise discovered that the Beta likewise be more water soluble than single administration Alanine compound according to the tenth implementation, Norvaline. when ingested, promotes carnosine production, thus increas Accordingly, Applicants have discovered that the Orni thine compound according to the seventh implementation, ing muscle power, endurance and recuperation. Absorption when ingested, provides an additional vasodilation mecha may be improved since Amino Acid salts withinorganic acids nism, reducing the amount of Ornithine needed and the 10 are much more water soluble than single administration amount of time needed for the vasodilating properties to Amino Acids. Applicants have also discovered that Beta Ala manifest. Improved vasodilation may, in turn, provide better nine Nitrate begins acting as fast as any othernitrate, since the circulation and distribution of Ornithine in the body. Absorp NOs—group of the salt requires minimal conversion to yield tion may be improved since Amino Acid salts with inorganic Nitric Oxide. Additionally, a much lesser dose may be acids are much more water soluble than single administration 15 required for vasodilation to take place, compared to the single Amino Acids. Applicants have also discovered that Ornithine administration of nitrates. Beta Alanine Nitrate may likewise Nitrate begins acting as fast as any other nitrate, since the be more water soluble than single administration Beta Ala NOs—group of the salt requires minimal conversion to yield nine. Nitric Oxide. Additionally, a much lesser dose may be Accordingly, Applicants have discovered that the Agma required for vasodilation to take place, compared to the single 20 time compound according to the eighth implementation, when administration of nitrates. Ornithine Nitrate may likewise be ingested, counteracts the Nitric Oxide inhibiting effect of more water soluble than single administration Ornithine. single administration Agmatine. Absorption may be Accordingly, Applicants have discovered that the Histidine improved since Amino Acid salts with inorganic acids are compound according to the eighth implementation, when much more water soluble than single administration Amino ingested, provides a vasodilation mechanism. Vasodilation 25 Acids. Applicants have also discovered that Agmatine Nitrate may, in turn, provide better circulation and distribution of begins acting as fast as any other nitrate, since the NOs– Histidine in the body. Applicants have likewise discovered group of the salt requires minimal conversion to yield Nitric that the Histidine compound according to the ninth imple Oxide. Agmatine Nitrate may likewise be more water soluble mentation, when ingested, promotes carnosine production, than single administration Agmatine. thus increasing muscle power, endurance and recuperation. 30 The invention claimed is: Absorption may be improved since Amino Acid salts with 1. A method for increasing the bioabsorption of amino inorganic acids are much more water soluble than single acids in a human or animal, the method comprising adminis administration Amino Acids. Applicants have also discovered tering to the human or animal a pharmaceutically effective that Histidine Nitrate begins acting as fast as any othernitrate, amount of an amino acid compound consisting essentially of since the NOs– group of the salt requires minimal conver 35 a nitrate or nitrite of an amino acid selected from the group sion to yield Nitric Oxide. Additionally, a much lesser dose consisting of Arginine, Agmatine, Beta Alanine, Citrulline, may be required for vasodilation to take place, compared to Creatine, Glutamine, L-Histidine, Isoleucine, Leucine, Nor the single administration of nitrates. Histidine Nitrate may valine, Ornithine, and Valine. likewise be more water soluble than single administration Histidine. Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 13 of 109

EXHIBIT F Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 14 of 109 US008952046B1

(12) United States Patent (10) Patent No.: US 8,952,046 B1 Kramer et al. (45) Date of Patent: *Feb. 10, 2015

(54) AMINO ACID COMPOSITIONS 2004/0097.401 A1 5/2004 Datta 2005/0287210 A1 12/2005 Ron 2005/0288372 A1 12/2005 Ron (71) Applicant: Thermolife International, LLC, 2005/0288373 A1 12/2005 Ron Phoenix, AZ (US) 2006/0029668 A1 2/2006 Ron 2006/0142382 A1 6/2006 Morimoto et al. (72) Inventors: Ronald Kramer, Phoenix, AZ (US); 2006/01828.15 A1 8/2006 Gladwin et al. Alexander Nikolaidis, New Kallikratia 2007/0154569 A1 7/2007 Gladwin et al. (GR) FOREIGN PATENT DOCUMENTS

(73) Assignee: Thermolife International, LLC, CN 163 1539 6/2005 Phoenix, AZ (US) EP 1336602 8/2003 GB 2354441 3/2001 (*) Notice: Subject to any disclaimer, the term of this WO WO2006/124,161 11/2006 patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. OTHER PUBLICATIONS This patent is subject to a terminal dis Mostad et al., “Crystal and molecular structure of DL-methionine claimer. nitrate.” CAS 104:197543 (1986). Pradhan et al., “Effect of Anions on the Solubility of Zwitterionic (21) Appl. No.: 13/920,081 Amino Acids,” J. Chem. Eng. Data 45(1): 140-143 (2000). Terzyan et al., “L-Arginine Nitrates,” Journal of Molecular Structure (22) Filed: Jun. 17, 2013 687:111-117 (2004). Stryer, Lubert, Biochemistry, Third Edition, W. H. Freeman and Co.: New York, 1988, pp. 16-23, 500-502, and 934-936. Related U.S. Application Data Sastreet al., “Metabolism of agnatine in macrophages: modulation (63) Continuation of application No. 13/038,615, filed on by lipopolysaccharide and inhibitory cytokines.” Biochem. J. Mar. 2, 2011, now Pat. No. 8,466,187, which is a 330:1405-1409 (1998). continuation-in-part of application No. 12/336,938, Ishii et al., “High glucose augments arginase activity and nitric oxide production in the renal cortex,” Metabolism 53 (7):868-874 (2004). filed on Dec. 17, 2008, now Pat. No. 8,034,836, which Barger, G. (1914) The Simpler Natural Bases. In R.H.A. Plimmer & is a continuation of application No. 11/950,273, filed F.G. Hopkins (Eds.) Monographs on Biochemistry (pp. 157-163) on Dec. 4, 2007, now Pat. No. 7,777,074. Longmans, Green & Co., London. (60) Provisional application No. 60/973,229, filed on Sep. Larsen et al., “Effects of dietary nitrate on oxygen cost during exer 18, 2007. cise.” Acta Physiol 191:59-66 (2007). Berge et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sci (51) Int. Cl. ences 66(1):1-18 (1977). A6 IK 31/415 (2006.01) Jablecka et al., “The influence of two different doses of L-arginine (52) U.S. CI. oral supplementation on nitric oxide (NO) concentration and total USPC ..…. 514/400 antioxidant status (TAS) in atherosclerotic patients.” MedSci Monit 10(1):CR29-32 (2004). (58) Field of Classification Search Maynard et al. “High Levels of Dietary Carnosine Are Associated USPC ..…. 514/400 with Increased Concentrations of Carnosine and Histidine in Rat See application file for complete search history. Soleus Muscle,” J. Nutr. 131:287-290 (2001). Ruel et al., “Modulation in Angiogenic Therapy randomized con (56) References Cited trolled trial,” J Thorac Cardiovasc Surg 135:762-770 (2008). Rytlewski et al., “Effects of oral L-arginine on the pulsatility indices |U.S. PATENT DOCUMENTS of umbilical artery and middle cerebral artery in preterm labor.” 3,886,040 A 5/1975 Chibata et al. European Journal of Obstetrics & Gynecology and Reproductive 3,997,659 A 12/1976 Knohl et al. Biology 138:23-28 (2008). 4,146,611 A 3/1979 Ondetti et al. (Continued) 4,379,177 A 4/1983 McCoy et al. 4,743,614 A 5/1988 Terano et al. 4,996,067 A 2/1991 Kobayashi et al. Primary Examiner – Rei-tsang Shiao 5,500,436 A 3/1996 Schonafinger et al. (74) Attorney, Agent, or Firm – Booth Udall Fuller, PLC 5,543,430 A 8/1996 Kaesemeyer 5,679,704 A 10/1997 Schonafinger et al. 5,965,596 A 10/1999 Harris et al. (57) ABSTRACT 7,235,237 B2 6/2007 Loscalzo et al. A composition and a supplement formulation includes: at 7,777,074 B2 * 8/2010 Kramer et al...... 562/512 8,034,836 B2 * 10/2011 Kramer et al...... 514/400 least one constituent selected from the group consisting of a 8,048,921 B2 11/2011 Kramer et al. nitrate salt, a nitrite salt, and both; and at least one constituent 8,178,572 B2 5/2012 Kramer et al. amino acid selected from the group consisting of Arginine, 8,183,288 B2 5/2012 Kramer et al. Agmatine, Beta Alanine, Citrulline, Creatine, Glutamine, 8,455,531 B2 6/2013 Kramer et al. L-Histidine, Isoleucine, Leucine, Norvaline, Ornithine, 8,466,187 B2 6/2013 Kramer et al. 8,569,368 B2 10/2013 Kramer et al. Valine, Aspartic Acid, Cysteine, Glycine, Lysine, Methion 8,569,369 B2 10/2013 Kramer et al. ine, Proline, Tyrosine, and . 2002/01 19933 A1 8/2002 Butler et al. 2003/01 19888 A1 6/2003 Allen 14 Claims, No Drawings Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 15 of 109

US 8,952,046 B1 Page 2

(56) References Cited Knot, “Nitrate Tolerance in Hypertension: New Insight Into a Cen tury-Old Problem.” Circ Res 93:799-801 (2003). OTHER PUBLICATIONS Schulz et al., “Functional and Biochemical Analysis of Endothelial (Dys)function and NO/cGMP Signaling in Human Blood Vessels Schwedhelm et al., “Pharmacokinetic and pharmacodynamics prop with and without Nitroglycerin Pretreatment.” Circulation 105:1170 erties of oral L-citrulline and L-arginine: impact on nitric oxide 1175 (2002). metabolism.” Br J Clin Pharmacol 65(1):51-59 (2007). Hatanaka et al., “Stereoselective Pharmacokinetics and Smith et al., “Nitric oxide precursors and congenital heart surgery: A Pharmacodynamics of Organic Nitrates in Rats,” Journal of Pharma randomized controlled trial of oral citrulline,” J Thorac Cardioasc cology and Experimental Therapeutics 298:346-353 (2001). Surg 132:58-65 (2006). Chabot et al., “Characterization of the vasodilator properties of Rytlewski et al., “Effects of prolonged oral supplementation with peroxynitrite on rat pulmonary artery: role of poly (adenosine L-arginine on blood pressure and nitric oxide synthesis in 5'-diphosphoribose synthase.” British Journal of Pharmacology 121:485-490 (1997). preeclampsia.” Eur J Clin Invest 35(1):32-37 (2005). Bauer et al., “Vascular and Hemodynamic Differences between Ming et al., “Thrombin Stimulates Human Endothelial Arginase Organic Nitrates and Nitrites,” Journal of Pharmacology and Experi Enzymatic Activity via RhoA/ROCK Pathway.” Circulation mental Therapeutics 280:326-331 (1997). 110:3708-3714 (2004). Niu et al., “Vasorelaxant effect of is diminished by Romero et al., “Therapeutic Use of Citrulline in Cardiovascular Dis tetraethylammonium in rat isolated arteries.” European Journal of ease.” Cardiovascular Drug Reviews 24 (3-4):275-290 (2006). Pharmacology 580: 169-174 (2008). Oka et al., “A pilot study of L-arginine supplementation on functional Tan et al., “Taurine protects against low-density lipoprotein-induced capacity in peripheral arterial disease.” Vascular Medicine 10:265 endothelial dysfunction by the DDAH/ADMA pathway,” Vascular 274 (2005). Pharmacology 46:338-345 (2007). Hayashi et al., “L-citrulline and L-arginine supplementation retards Ahtee et al., “Taurine Biological Actions and Clinical Perspectives.” the progression of high-cholesterol--induced atherosclerosis in J. Nutr. 116:2555-2556 (1986). rabbits.” PNAS 102(38): 13681-13686 (2005). Bloomer et al., “Glycine propionyl-L-carnitine increases plasma Grasemann et al., “Oral L-arginine supplementation in cystic fibrosis nitrate/nitrite in resistance trained men.” Journal of the International patients: a placebo-controlled study.” Eur Respir J 25:62-68 (2005). Society of Sports Nutrition 4(22):1-6 (2007). Boger, “The Pharmacodynamics of L-Arginine,” J. Nutr. 137:1650S Ramaswamy et al., “Vibrational spectroscopic studies of 1655S (2007). L-argininium dinitrate,” J. Raman Spectrosc. 34:50-56 (2003). Beghetti et al., “Nitric oxide precursors and congenital cardiac sur Rajkumar et al., “Infrared and Raman spectra of L-valine nitrate and gery. A randomized controlled trial of oral citrulline. Definition of L-leucine nitrate,” J. Raman Spectrosc. 31:1107-1112 (2000). pulmonary hypertension in Fontan circulation?” J Thorac Cardioasc Petrosyan et al., “L-Histidine nitrates,” Journal of Molecular Struc Surg 132(6): 1501-1502 (2006). ture 794:160-167 (2006). Takahashi et al., “Characterization of the influence of nitric oxide Cromwell et al., “The Biosynthesis and Metabolism of Betaines in donors on intestinal absorption of macromolecules.” International Plants.” Biochem J. 55:189-192 (1953). Journal of Pharmaceutics 286:89-97 (2004). Basheva et al., “Role of Betaine as Foam Booster in the Presence of Fetih et al., “Nitric oxide donors can enhance the intestinal transport Silicone Oil Drops.” Langmuir 16:1000-1013 (2000). and absorption of insulin and [Asu 1,7|-eel calcitonin in rats,” Journal Danov et al., “Mixed Solutions of Anionic and Zwitterionic of Controlled Release 106:287-297 (2005). Surfactant (Betaine): Surface Tension Isotherms, Adsopr?ion, and Fetih et al., “Excellent Absorption Enhancing Characteristics of NO Relaxation Kinetics.” Langmuir 20:5445-5453 (2004). Donors for Improving the Intestinal Absorption of Poorly Absorbable Xu et al., “Composite medical preparation for promoting hair Compund Compared with Conventional Absorption Enhancers.” growth.” CAS; 143:103285 (2005). Drug Metab. Pharmacokinet. 21(3):222-229 (2006). Sridharetal, “L-Aspartic Acid Nitrate-L-Aspartic Acid.” Acta Cryst. Aniya et al., “Evaluation of Nitric Oxide Formation from Nitrates in E58:o 1372-ol374 (2002). Pig Coronary Arteries,” Jpn. J. Pharmacol. 71:101-107 (1996). Sridhar et al., “Bis (beta-alanine) hydrogen nitrate.” Acta Cryst. Luscher, “Endogenous and exogenous nitrates and their role in E57:o 1004-oloog (2001). myocardial ischaemia.” Br. J. Clin. Pharmacol. 34:29S-35S (1992). Rao et al., “Structure and Conformational Aspects of the Nitrates of Shiraki et al., “The Hypotensive Mechanisms of the New Anti-An Amino Acids and Peptides. I. Crystal Structure of Glycylglycine ginal Drug, N-(2-hydroxyethyl)nicotinamide nitrate (SG-75) in Nitrate.” Acta Cryst. B29:2379-2388 (1973). Beagle Dogs,” Japan J. Pharmacol. 31:921-929 (1981). Bauer et al., “Photochemical Generation of Nitric Oxide from Nitro Slart et al., “Nitrate Administration Increases Blood Flow in Dys containing Compounds: Possible Relation to Vascular functional but Viable Myocardium, Leading to Improved Assessment Photorelaxation Phenomena,” Life Science 54(1):PL1-PL4 (1994). of Myocardial Viability: A PET Study,” JNucl Med 47: 1307-1311 Magg et al., “Nitrogenous Compounds in Sugarbeet Juices,” Journal (2006). of the American Society of Technologists 17(2):154-164 Fayers et al., “Nitrate tolerance and the links with endothelial dys (1972). function and oxidative stress.” Br J Clin Pharmacol 56:620–628 (2003). * cited by examiner Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 16 of 109

US 8,952,046 B1 1 2 AMINO ACID COMPOSITIONS As used herein, “Amino Acid” is a term used in its broadest sense and may refer to an Amino Acid in its many different CROSS REFERENCE TO RELATED chemical forms including a single administration Amino APPLICATIONS Acid, its physiologically active salts or esters, its combina tions with its various salts, its tautomeric, polymeric and/or This application is a continuation application of the earlier isomeric forms, its analog forms, its derivative forms, its U.S. Utility Patent Application to Ronald Kramer, et al. products of biosynthesis, and/or its decarboxylation prod entitled “Amino Acid Compositions,” application Ser. No. ucts. Amino Acids comprise, by way of non-limiting 13/038,615, filed Mar. 2, 2011, now pending, which is a example: Agmatine, Beta Alanine, Arginine, Asparagine, continuation-in-part application of the earlier U.S. Utility 10 Aspartic Acid, Cysteine, Glutamine, , Glycine, Patent Application to Ronald Kramer, et. al. entitled “Amino Histidine, L-Histidine, Leucine, Isoleucine, Lysine, Methion Acid Compounds,” application Ser. No. 12/336,938, filed ine, Phenylbeta Alanine, Proline, Serine, Threonine, Tryp Dec. 17, 2008, now U.S. Pat. No. 8,034,836, which is a tophan, Tyrosine, Valine, Citrulline, Creatine, Glutamine, continuation application of the earlier U.S. Utility Patent 15 Norvaline, Ornithine, and Phenylalanine. Application to Ronald Kramer, et. al. entitled “Amino Acid Compounds containing both a carboxyl group and an Compounds,” application Ser. No. 11/950,273, filed Dec. 4, amino group are typically known as Amino Acids. Amino 2007, now U.S. Pat. No. 7,777,074, which application claims Acids typically have the basic formula X-R, wherein X is: the benefit of the filing date of U.S. Provisional Patent Appli cation 60/973,229 entitled “Amino Acid Compounds” to 20 Ronald Kramer, et. al., filed on Sep. 18, 2007, the disclosures CH – COOH of all of which being hereby incorporated entirely herein by reference.

BACKGROUND 25 Amino Acids typically differ from one another with respect to the structure of the R group. It is the structure of the R group 1. Technical Field that typically determines the individuality and character of Aspects of this document relate generally to amino acid each Amino Acid. compositions. For example, the R group for the Amino Acid Arginine is: 2. Background 30 It is desirable to design new amino acid compositions that have properties lacking in conventional amino acids, conven tional nitrates, and conventional nitrites alone. C=NH SUMMARY 35 NH2 In one aspect, a composition and a supplement formulation Arginine is characterized as a nonessential Amino Acid. are disclosed, both including: at least one constituent selected Specifically, Arginine can be independently manufactured by from the group consisting of a nitrate salt, a nitrite salt, and the human body, and does not need to be obtained directly both; and at least one constituent amino acid selected from the 40 through dietary intake. Arginine plays a significant role in group consisting of Arginine, Agmatine, Beta Alanine, Cit healing, cell division, immune function, the elimination of rulline, Creatine, Glutamine, L-Histidine, Isoleucine, Leu ammonia from the body and the release of hormones. Argin cine, Norvaline, Ornithine, Valine, Aspartic Acid, Cysteine, ine is presently used in the dietary supplement industry to Glycine, Lysine, Methionine, Proline, Tyrosine, and Pheny supplement Arginine production in the body. Arginine is also lalanine. 45 presently used in the dietary supplement industry to boost The composition or supplement formulation may further Human Growth Hormone (HGH) production, increase include an additive. The additive may be a carrier, an excipi vasodilation, enhance blood circulation, increase oxygen ent, a binder, a colorant, a flavoring agent, a preservative, a flow to the muscles, and boost Nitric Oxide (NO) production. buffer, a dilutant, and/or combinations thereof. Various supplemental Arginine forms are available in the The composition or supplement formulation may be in the 50 consumer marketplace. form of a capsule, a cachet, a pill, a tablet, a powder, a granule, The vasodilating effect of ingested Arginine takes consid a pellet, a bead, a particle, a troche, a lozenge, and a gel. erable time to manifest since Arginine requires extensive The foregoing and other aspects, features, and advantages metabolism to yield Nitric Oxide (NO). Additionally, consid will be apparent to those artisans of ordinary skill in the art erable amounts of Arginine are required to produce a signifi from the DESCRIPTION and DRAWINGS, and from the 55 cant vasodilating effect, with common doses ranging from CLAIMS. eight to twenty-four grams per day. The R group for the Amino Acid Citrulline is: DESCRIPTION

Overview, Terminology and Definitions 60 In describing implementations of an Amino Acid Com O H pound and Composition, the following terminology will be used in accordance with the definitions and explanations set Citrulline is an alpha-Amino Acid naturally occurring in out below. Notwithstanding, other terminology, definitions, 65 the human body, and does not need to be obtained directly and explanations may be found throughout this document, as through dietary intake. In vivo, Citrulline is made from the well. Amino Acid Ornithine, along with carbamoyl phosphate in Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 17 of 109

US 8,952,046 B1 3 4 one of the central reactions in the Urea Cycle. Citrulline is Leucine, by itself, has no vasodilating properties. Leucine is also produced during the metabolism of Arginine in the body. also water insoluble, which reduces its bioavailability and Citrulline is presently used in the dietary supplement industry limits the forms in which Leucine may be effectively used. to supplement Citrulline production in the body. By itself, The R group for the Amino Acid Norvaline is: Citrulline has no vasodilating properties. Citrulline is also water insoluble, which reduces its bioavailability and limits the forms in which Citrulline may be effectively used. The R group for the Amino Acid Creatine is: Svºs,

10 Norvaline is a nonessential Amino Acid. Specifically, Nor H2N H / valine can be independently manufactured by the human N body, and does not need to be obtained directly through dietary intake. Norvaline is presently used in the dietary —N supplement industry to supplement Norvaline production in 15 the body. Norvaline is also presently used in the dietary supplement industry to inhibit the enzyme arginase and thus Creatine is a nonessential Amino Acid and is also a nitrog reduce the conversion of Arginine to urea. Norvaline, by enous organic acid. Creatine is independently manufactured itself, has no vasodilating properties, although it enhances the by the human body, and does not need to be obtained directly vasodilating properties of Arginine. Norvaline is also water through dietary intake. Creatine plays a significant role in 20 providing muscles with energy. Creatine is presently used in insoluble, which reduces its bioavailability and limits the the dietary supplement industry to supplement Creatine pro forms in which Leucine may be effectively used. duction in the body. Creatine is also presently used in the The R group for the Amino Acid Omithine is: dietary supplement industry to increase muscle-mass gains, improve athletic performance and strength. Creatine, by 25 itself, has no vasodilating properties. Creatine is also water *NSp’s insoluble, which reduces its bioavailability and limits the forms in which Creatine may be effectively used. The R group for the Amino Acid Glutamine is: Holcº SNI, 30 Omithine is a non-essential Amino Acid. That is, Omithine | is independently manufactured by the human body, and does O not need to be obtained directly through dietary intake. Omithine plays a significant role in the synthesis of 35 Glutamine is a nonessential Amino Acid. Glutamine is the polyamines, specifically via the action of Ornithine decar most abundant naturally occurring, non-essential amino acid boxylase. Ornithine is presently used in the dietary supple in the human body and is found circulating in the blood, as ment industry to supplement dietary Omithine sources. well as stored in the skeletal muscles. Glutamine plays a Omithine is also presently used in the dietary supplement significant role in protein synthesis, muscle growth, and 40 industry to enhance the vasodilating properties in a series of wound healing. Glutamine is presently used in the dietary products commonly known as “NO Boosters.” Omithine supplement industry to supplement Glutamine production in exerts its vasodilating effect only by in vivo conversion to the body. Glutamine is also presently used in the dietary Arginine and then by following the pathway that converts supplement industry to maintain the body’s Glutamine pool. Arginine to Nitric Acid (NO). Many grams of Omithine, and Glutamine, by itself, has no vasodilating properties. 45 a considerable amount of time, are required in order to assert Glutamine is also waterinsoluble, which reduces its bioavail its vasodilating effect. ability and limits the forms in which Glutamine may be effec The R group for the Amino Acid Histidine is: tively used. Additionally, Glutamine inhibits Nitric Acid (NO) production through downregulation of eNOS synthase. The R group for the Amino Acid Leucine is: 50 or 55 Histidine is a naturally-occurring Amino Acid and is coded for in DNA. Relatively small shifts in cellular pH will change Leucine is an essential Amino Acid, meaning that Leucine the electrical charge of Histidine. For this reason, Histidine is not synthesized in vivo in animals. Accordingly, Leucine finds its way into considerable use as a coordinating ligand in must be ingested, usually as a component of proteins con 60 metalloproteins, and also as a catalytic site in certain sumed directly through dietary intake. Leucine plays a sig enzymes. Histidine is currently used in the dietary supple nificant role in muscle protein synthesis. Leucine can also ment industry to support carnosine production. Histidine, by inhibit protein degradation in skeletal muscle, as well as in the itself, has no vasodilating properties. Additionally, Histidine liver. Leucine is presently used in the dietary supplement is very poorly water soluble, a fact that limits its bioavailabil industry to supplement dietary Leucine sources. Leucine is 65 ity and utility. Histidine is presently used in the dietary also presently used in the dietary supplement industry to supplement industry in the forms of single administration promote anabolism and stimulate muscle protein synthesis. Histidine and Histidine HC1. Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 18 of 109

US 8,952,046 B1 5 6 The R group for the Amino Acid Beta Alanine is: interactions, ranging from covalent bonds to electrostatic forces inionic bonds. The physical and chemical properties of compounds are different from those of their constituent ele ments. This is one of the main criteria for distinguishing a compound from a mixture of elements or other substances because a mixture’s properties are generally closely related to and dependent on the properties of its constituents. However, Beta Alanine is the only naturally-occurring Beta Amino some mixtures are so intimately combined that they have Acid. A Beta Amino Acid is one in which the Amino group is some properties similar to compounds. Another criterion for located at the beta position (i.e. two atoms away) from the 10 distinguishing a compound from a mixture is that the con Carboxyl group. Beta Alanine is formed in vivo through the stituents of a mixture can usually be separated by simple, degradation of dihydrouracil and carnosine. Beta Alanine is mechanical means such as filtering, evaporation, or use of a the rate-limiting precursor of carnosine. Therefore, carnosine magnetic force, but the components of a compound can only levels are limited by the amount of available Beta Alanine. be separated by a chemical reaction. Conversely, mixtures Beta Alanine, by itself, has no vasodilating properties. Addi 15 can be created by mechanical means alone, but a compound tionally, Beat Alanine is somewhat water soluble, which lim can only be created (either from elements or from other com its its bioavailability and utility. Beta Alanine is presently pounds, or a combination of the two) by a chemical reaction. used in the dietary supplement industry to support carnosine Thus, for purposes of this disclosure, “Composition” may production. refer to a mixture of at least one Amino Acid in combination The chemical structure of Agmatine is: 20 with at least a Nitrate, a Nitrite, or both from any source. As used herein, “Nitrate” is a term used in its broadest sense and may refer to an Nitrate in its many different chemi cal forms including a salt of Nitric Acid, a single administra tion Nitrate, its physiologically active salts or esters, its com 25 binations with its various salts, its tautomeric, polymeric and/or isomeric forms, its analog forms, and/or its derivative forms. Nitrate comprises, by way of non-limiting example, Agmatine is the decarboxylation product of the Amino many different chemical forms including dinitrate and trini Acid Arginine and is an intermediate in polyamine biosyn trate. Nitrates may be salts, or mixed salts, of Nitric Acid thesis. Agmatine is synthesized in the brain and stored in 30 (HNOs) and comprise one Nitrogen atom and three Oxygen synaptic vesicles in regionally selective neurons. Agmatine is atoms (NOs). For the exemplary purposes of this disclosure, released by depolarization and is inactivated by agnatinase. Nitrate may comprise salts of Nitrate such as sodium nitrate, Agmatine binds to alpha2-adrenoceptors and imidazoline potassium nitrate, barium nitrate, calcium nitrate, and the binding sites. Agmatine likewise blocks N-methyl-D-aspartic like. For the exemplary purposes of this disclosure, Nitrate acid (NMDA) receptor channels and other ligand-gated cat 35 may include mixed salts of Nitrate such as nitrate orotate, and ionic channels. Additionally, agnatine inhibits nitric oxide the like. Furthermore, for the exemplary purposes of this synthase, and induces the release of some peptide hormones. disclosure, nitrates that are commonly used in supplement Agmatine modulates nitric oxide through various mecha industry are appropriate sources of nitrates, such as juice, nisms. Agmatine stimulates some types of nitric oxide syn extract, powder and the like of Cabbage, Spinach, Beetroot, thase (NOS) while inhibiting others. Agmatine inhibits Nitric 40 Artichoke, , Broad Bean, Eggplant, Garlic, Onion, Oxide production by inhibiting NOS. Agmatine is presently Green Bean, Mushroom, Pea, Pepper, Potato, Summer used in the dietary supplement industry in the forms of single Squash, Sweet Potato, Tomato, Watermelon, Broccoli, Car administration Agmatine and Agmatine Sulfate. rot, Cauliflower, Cucumber, Pumpkin, Chicory, Dill, Turnip, As used herein, “Composition” is a term used in its broad Savoy Cabbage, Celeriac, Chinese Cabbage, Endive, Fennel, est sense and may refer to a mixture of constituent substances 45 Kohlrabi, Leek, Parsley, Celery, Cress, Chervil, Lettuce, or ingredients. “Mixture” is a term used in its broadest sense Rocket (Rucola), and the like. and may refer to two or more constituent substances or ingre As used herein, “Nitrite” is a term used in its broadest sense dients (chemical species presentina system) which have been and may refer to an Nitrite in its many different chemical combined (not necessarily in fixed proportions and not nec forms including a salt of Nitrous Acid, a single administration essarily with chemical bonding and not necessarily so that 50 Nitrite, its physiologically active salts or esters, its combina each substance retains its own chemical identity). Mixtures tions with its various salts, its tautomeric, polymeric and/or can be the product of a blending or mixing of chemical sub isomeric forms, its analog forms, and its derivative forms. stances like elements and compounds, without chemical Nitrite comprises, by way of non-limiting example, many bonding or other chemical change, so that each ingredient different chemical forms including dinitrite and trinitrite. substance retains its own chemical properties and makeup. 55 Nitrites may be salts, or mixed salts, of Nitrous Acid (HNO2) Mixtures can be either homogeneous or heterogeneous. A and comprise one Nitrogen atom and two Oxygen atoms homogeneous mixture is a type of mixture in which the com (NO2). For the exemplary purposes of this disclosure, Nitrite position is uniform. A heterogeneous mixture is a type of may comprise salts of Nitrite such as sodium nitrite, potas mixture in which the composition can easily be identified, as sium nitrite, barium nitrite, calcium nitrite, and the like. For there are two or more phases present. A homogeneous mix 60 the exemplary purposes of this disclosure, Nitrite may com ture in which there is both a solute and solvent present is also prise mixed salts of Nitrite such as nitrite orotate, and the like. a solution. Additionally, for the exemplary purposes of this disclosure, A“Compound” is a term used in its broadest sense and may Nitrite may comprise nitrite esters such as amyl nitrite, and refer to a chemical substance comprising two or more differ the like. Furthermore, for the exemplary purposes of this ent chemically bonded chemical constituent elements or 65 disclosure, natural sources of Nitrites that are commonly used ingredients, with a fixed ratio or proportion by weight. The in supplement industry are appropriate sources of Nitrites, atoms within a compound can be held together by a variety of such as juice, extract, powder and the like of Cabbage, Spin Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 19 of 109

US 8,952,046 B1 7 8 ach, Beetroot, Artichoke, Asparagus, Broad Bean, Eggplant, Applicants have cost-effectively synthesized Arginine Garlic, Onion, Green Bean, Mushroom, Pea, Pepper, Potato, Nitrate by combining nitric acid and Arginine, mixing with Summer Squash, Sweet Potato, Tomato, Watermelon, Broc water or another polar, easily evaporated solvent like metha coli, Carrot, Cauliflower, Cucumber, Pumpkin, Chicory, Dill, nol, , , and the like, and leaving to crystallize. Turnip, Savoy Cabbage, Celeriac, Chinese Cabbage, Endive, Further nitratization can take place, yielding Arginine Dini Fennel, Kohlrabi, Leek, Parsley, Celery, Cress, Chervil, Let trate or Arginine Trinitrate. An alternative implementation tuce, Rocket (Rucola), and the like. may comprise using Nitrous Acid (HNO2) instead of Nitric Nitrates and Nitrites are commercially available in various Acid (HNO3), thus yielding Arginine Nitrite. Arginine Nitrite preparations, including natural preparations, and are used in has the same effects as Arginine Nitrate, the only difference various applications. In the case of ingestion by humans, 10 being that it requires one less step to yield Nitric Oxide (NO-). Mixed salts may also be used, such as in the non Nitrate (NOs) is typically reduced to Nitrite (NO2) in the limiting example of Arginine Nitrate-Orotate. epithelial cells of blood vessels. In vivo, Nitrite (NO2) reacts A second implementation is a Citrulline compound of the with a thiol donor, principally glutathione, to yield Nitric formula: Oxide (NO). 15 As used herein, “acceptable additive” or “additive” are terms used in their broadest sense. Particular implementa tions of the compositions described in this document may also comprise an additive (e.g. one of a solubilizer, an enzyme inhibiting agent, an anticoagulant, an antifoaming agent, an 20 antioxidant, a coloring agent, a coolant, a cryoprotectant, a hydrogen bonding agent, a flavoring agent, a plasticizer, a wherein; preservative, a sweetener, a thickener, and combinations R is the Citrulline group identified and defined above; thereof) and/or a carrier (e.g. one of an excipient, a lubricant, X is the Amino Acid base identified and defined above; and a binder, a disintegrator, a diluent, an extender, a solvent, a 25 Y is selected from the group consisting of a Nitrate and a suspending agent, a dissolution aid, an isotonization agent, a Nitrite. buffering agent, a soothing agent, an amphipathic lipid deliv Applicants have cost-effectively synthesized Citrulline ery system, and combinations thereof). These additives may Nitrate by combining nitric acid and Citrulline, mixing with be solids or liquids, and the type of additive may be generally water or another polar, easily evaporated solvent like metha chosen based on the type of administration being used. Those 30 nol, alcohol, pyridine, and the like, and leaving to crystallize. ofordinary skill in the art will be able to readily select suitable Further nitratization can take place, yielding Citrulline Dini pharmaceutically effective additives from the disclosure in trate or Citrulline Trinitrate. An alternative implementation this document. In particular implementations, acceptable may comprise using Nitrous Acid (HNO2) instead of Nitric additives may include, by non-limiting example, calcium 35 Acid (HNO3), thus yielding Citrulline Nitrite. Citrulline phosphate, cellulose, stearic acid, croscarmelose cellulose, Nitrite has the same effects as Citrulline Nitrate, the only magnesium stearate, and silicon dioxide. difference being that it requires one less step to yield Nitric As used in this document, “effective” is a phrase used in its Oxide (NO—). Mixed salts may also be used, such as in the broadest sense, including, by non-limiting example, effective non-limiting example of Citrulline Nitrate-Orotate. in a clinical trial, for a specific patient, or only placebo 40 A third implementation is a Creatine compound of the effective. formula: As used in this document, “acceptable” is a phrase used in its broadest sense and may describe ingredients of a compo sition that meet Food and Drug Administration (FDA) stan R dards, United States Pharmacopeial Standards (USP), US 45 || Y Department of Agriculture (USDA) standards for food-grade X materials, commonly accepted standards of the nutritional supplement industry, industry standards, botanical standards, wherein; or standards established by any individual. These standards R is the Creatine group identified and defined above; may delineate acceptable ranges of aspects of ingredients of a 50 composition such as edibility, toxicity, pharmacological X is the Amino Acid base identified and defined above; and effect, or any other aspect of a chemical, composition, or Y is selected from the group consisting of a Nitrate and a preparation used in implementations of a composition. Nitrite. Components/Compounds/Compositions Applicants have cost-effectively synthesized Creatine A first implementation is an Arginine compound of the 55 Nitrate by combining nitric acid and Creatine, mixing with formula: water or another polar, easily evaporated solvent like metha nol, alcohol, pyridine, and the like, and leaving to crystallize. Further nitratization can take place, yielding Creatine Dini trate or Creatine Trinitrate. An alternative implementation 60 may comprise using Nitrous Acid (HNO2) instead of Nitric Acid (HNO3), thus yielding Creatine Nitrite. Creatine Nitrite has the same effects as Creatine Nitrate, the only difference wherein; being that it requires one less step to yield Nitric Oxide R is the Arginine group identified and defined above; (NO-). Mixed salts may also be used, such as in the non X is the Amino Acid base identified and defined above; and 65 limiting example of Creatine Nitrate-Orotate. Y is selected from the group consisting of a Nitrate and a A fourth implementation is a Glutamine compound of the Nitrite. formula: Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 20 of 109

US 8,952,046 B1 10 Further nitratization can take place, yielding Norvaline Dini trate or Norvaline Trinitrate. An alternative implementation comprises substituting Nitrous Acid (HNO2) for Nitric Acid (HNOs), thus yielding Norvaline Nitrite. Norvaline Nitrite has the same effects as Norvaline Nitrate, the only difference wherein; being that it requires one less step to yield Nitric Oxide R is the Glutamine group identified and defined above; (NO-). Mixed salts may also be used, such as in the non X is the Amino Acid base identified and defined above; and limiting example of Norvaline Nitrate-Orotate. Y is selected from the group consisting of a Nitrate and a A seventh implementation is an Ornithine compound of the Nitrite. 10 formula: Applicants have cost-effectively synthesized Glutamine Nitrate by combining nitric acid and Glutamine, mixing with water or another polar, easily evaporated solvent like metha nol, alcohol, pyridine, and the like, and leaving to crystallize. 15 Further nitratization can take place, yielding Glutamine Dini trate or Glutamine Trinitrate. An alternative implementation comprises using Nitrous Acid (HNO2) instead of Nitric Acid wherein; R is the Ornithine group identified and defined above; (HNO3), thus yielding Glutamine Nitrite. Glutamine Nitrite X is the Amino Acid base identified and defined above; and has the same effects as Glutamine Nitrate, the only difference 20 being that it requires one less step to yield Nitric Oxide Y is selected from the group consisting of a Nitrate and a (NO-). Mixed salts may also be used, such as in the non Nitrite. limiting example of Glutamine Nitrate-Orotate. Applicants have cost-effectively synthesized Omithine A fifth implementation is a Leucine compound of the for Nitrate by combining nitric acid and Omithine, mixing with mula: water or another polar, easily evaporated solvent like metha 25 nol, alcohol, pyridine, and the like, and leaving to crystallize. Further nitratization can take place, yielding Omithine Dini trate or Omithine Trinitrate. An alternative implementation comprises using Nitrous Acid (HNO2) instead of Nitric Acid (HNO3), thus yielding Ornithine Nitrite. Omithine Nitrite has 30 the same effects as Omithine Nitrate, the only difference being that it requires one less step to yield Nitric Oxide wherein; (NO-). Mixed salts may also be used, such as in the non R is the Leucine group identified and defined above; limiting example of Ornithine Nitrate-Orotate. X is the Amino Acid base identified and defined above; and An eighth implementation is a Histidine compound of the Y is selected from the group consisting of a Nitrate and a 35 formula: Nitrite. Applicants have cost-effectively synthesized Leucine Nitrate by combining nitric acid and Leucine, mixing with water or another polar, easily evaporated solvent like metha nol, alcohol, pyridine, and the like, and leaving to crystallize. 40 Further nitratization can take place, yielding Leucine Dini trate or Leucine Trinitrate. An alternative implementation comprises substituting the Amino Acids Valine or Isoleucine wherein; for Leucine. Another alternative implementation comprises R is the Histidine group identified and defined above; substituting Nitrous Acid (HNO2) for Nitric Acid (HNO3), 45 X is the Amino Acid base identified and defined above; and thus yielding Leucine Nitrite. Leucine Nitrite has the same Y is selected from the group consisting of a Nitrate and a effects as Leucine Nitrate, the only difference being that it Nitrite. requires one less step to yield Nitric Oxide (NO—). Mixed Applicants have cost-effectively synthesized Histidine salts may also be used, such as in the non-limiting example of Nitrate by combining nitric acid and Histidine, mixing with Leucine Nitrate-Orotate. 50 water or another polar, easily evaporated solvent like metha A sixth implementation is a Norvaline compound of the nol, alcohol, pyridine, and the like, and leaving to crystallize. formula: Further nitratization can take place, yielding Histidine Dini trate or Histidine Trinitrate. An alternative implementation comprises using Nitrous Acid (HNO2) instead of Nitric Acid (HNO3), thus yielding Histidine Nitrite. Histidine Nitrite has 55 the same effects as Histidine Nitrate, the only difference being that it requires one less step to yield Nitric Oxide (NO-). Mixed salts may also be used, such as in the non limiting example of Histidine Nitrate-Orotate. wherein; A ninth implementation is a Beta Alanine compound of the R is the Norvaline group identified and defined above; 60 X is the Amino Acid base identified and defined above; and formula: Y is selected from the group consisting of a Nitrate and a Nitrite. Applicants have cost-effectively synthesized Norvaline Nitrate by combining nitric acid and Norvaline, mixing with 65 water or another polar, easily evaporated solvent like metha nol, alcohol, pyridine, and the like, and leaving to crystallize. Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 21 of 109

US 8,952,046 B1 11 12 wherein; Composition 5 (Tablets Containing Arginine and Potas R is the Beta Alanine group identified and defined above; sium Nitrate for Blood Pressure support). Per tablet: Arginine X is the Amino Acid base identified and defined above; and 250-700 mg. Potassium Nitrate 50-500 mg. Corn Starch till Y is selected from the group consisting of a Nitrate and a the desired volume for the tablet machine is obtained. Nitrite. Composition 6 (for healthy blood pressure support): 500 Applicants have cost-effectively synthesized Beta Alanine 1000 mg Arginine (As arginine nitrate)+250-500 mg Celery Nitrate by combining nitric acid and Beta Alanine, mixing Seed Extract-100-300 mg Dried Garlic Powder in airseal with water or another polar, easily evaporated solvent like Capsules. methanol, alcohol, pyridine, and the like, and leaving to crys Composition 7 (For improved Sexual Performance); 500 tallize. Further nitratization can take place, yielding Beta 10 1000 mg grams Agmatine--1-2 grams D-aspartic Acid (as Alanine Dinitrate or Beta Alanine Trinitrate. An alternative D-Aspartic Acid Nitrate)+1-2 grams dried onion powder (on implementation comprises using Nitrous Acid (HNO2) ion also increases testosterone) in capsules. instead of Nitric Acid (HNO3), thus yielding Beta Alanine Composition 8 (Improved Strength): Creatine (As Creatine Nitrite. Beta Alanine Nitrite has the same effects as Beta Malate) 2-3 grams and Calcium Nitrate 500 mg. Alanine Nitrate, the only difference being that it requires one 15 Composition 9 (Improved Muscle Endurance Sports less step to yield Nitric Oxide (NO—). Mixed salts may also Drink): Beta Alanine 1-2 grams+Citrulline (As Citrulline be used, such as in the non-limiting example of Beta Alanine Nitrate) 250-500 mg-Potassium Nitrate 100-200 mg-So Nitrate-Orotate. dium Nitrate 50-100 mg-Magnesium Nitrate 200 mg Artifi A tenth implementation is an Agmatine compound of the cial COlouring Sweetener and flavour Purified Water till 500 formula: 20 ml. Composition 10 (Improved Muscle anabolism and recov ery): Leucine 1-5 grams Isoleucine 1-2 grams Valine 1-2 N NH • Y grams Spinach Extract (Standarized for nitrate content and H2N ~~~ ~ 2 ecdysterone content minimum 1% and 10% respectively) 5 25 grams. Composition 11 (Improved Mental Performance): 500-1000 mg Tyrosine#250-500 mg Phenylalanine (as Phe wherein; nylalanine Nitrate)+1000-2000 mg Glycine-200-300 mg Y is selected from the group consisting of a Nitrate and a Lithium Nitrate+300-600mg Hystidine In Time Release Tab Nitrite. 30 lets. Applicants have cost-effectively synthesized Agmatine Composition 12 (Growth Hormone Support): Arginine 2-4 Nitrate by combining nitric acid and Agmatine, mixing with grams+Ornithine 1-2 grams+Magnesium Nitrate 500 mg. water or another polar, easily evaporated solvent like metha Composition 13 (Hair Growth Support As External Use nol, alcohol, pyridine, and the like, and leaving to crystallize. Cream): Lysine Nitrite 1 gram Hydroxyproline Nitrate 5 Further nitratization can take place, yielding Agmatine Dini 35 grams Methionine nitrate 5 grams Euserine Cream Base 100 trate or Agmatine Trinitrate. An alternative implementation grams. comprises using Nitrous Acid (HNO2) instead of Nitric Acid Composition 14 (Immune Support effervescent tabs): (HNO3), thus yielding Agmatine Nitrite. Agmatine Nitrite Glutamine 400-800 mg Hystidine (As histidine nitrate) 250 has the same effects as Agmatine Nitrate, the only difference 500 mg Cysteine (As N-Acetyl Cysteine) 200-300 mg PArs being that it requires one less step to yield Nitric Oxide 40 ley Powder (Standarized for C and nitrate) 125-250 (NO-). Mixed salts may also be used, such as in the non mg. limiting example of Agmatine Nitrate-Orotate. Administration and Dosage Forms Other implementations involve compositions instead of Compounds, Compositions and/or formulations may be compounds. Using an independent source of nitrates and/or administered in any form, including one of a capsule, a nitrites that is mixed with any of the amino acids disclosed in 45 cachet, a pill, a tablet, a powder, a granule, a pellet, a bead, a this document to form a composition can obtain substantially particle, a troche, a lozenge, a pastille, a solution, an elixir, a the same effects as the amino acid nitrate or nitrite com syrup, a tincture, a suspension, an emulsion, a mouthwash, a pounds discussed in this document. spray, a drop, an ointment, a cream, a gel, a paste, a transder Such an amino acid composition might be depicted by the mal patch, a suppository, a pessary, cream, a foam, and com formula X-R+Y. “X—R” represents an amino acid as dis 50 binations thereof for example. cussed previously and “Y” represents a Nitrate and/or Nitrite. Implementations of Amino Acid Compounds and Compo But instead of forming a compound, they are mixed together sitions may conveniently be presented in unit dosage form. (represented by the “4”) to form a composition. Unit dosage formulations may be those containing a daily For the exemplary purposes of this disclosure, following is dose or unit, a daily sub-dose, or an appropriate fraction a variety of specific examples of amino acid compositions. 55 thereof, of the administered components as described herein. Composition 1: Creatine Nitrate 100-1000 mg in capsules. A dosage unit may include an Amino Acid Compound or Dosage is 3 capsules twice daily. Composition. In addition, a dosage unit may include an Composition 2 (Powder Form): Serving Size: 4 grams. Amino Acid Compound or Composition admixed with a Creatine Nitrate 3-3.5 grams. Vitamin C 500-1000 mg. pharmaceutically acceptable additive(s), and/or any combi Composition 3 (Sports Drink): 0.5-3 Grams Arginine 60 nation thereof. Nitrate. 0.5-2 Grams Taurine. 1-3 grams Sugar or appropriate The dosage units may be in a form suitable for administra Sweetener. Artificial Coloring. Purified Water till 500 ml of tion by standard routes. In general, the dosage units may be total Volume. administered, by non-limiting example, by the topical (in Composition 4 (sublingual tablets; amounts are per tablet): cluding buccaland sublingual), transdermal, oral, rectal, oph Agmatine Nitrate 10-100 mg. Maltulose 200 mg. Artificial 65 thalmic (including intravitreal or intracameral), nasal, vagi Cherry Flavor. Melt Maltulose, add in slowly the Agmatine nal, and/or parenteral (including subcutaneous, Nitrate and the flavor, and pour in the tablet machine. intramuscular, intravenous, intradermal, intratracheal, and Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 22 of 109

US 8,952,046 B1 13 14 epidural) routes and many other delivery methods and/or the composition or during the processes to facilitate the systems known to those of ordinary skill in the art. Imple preparation of the dosage forms, depending on the need of the mentations of an Amino Acid Compound or Composition individual process. may also be administered through use of amphipathic lipid Mixing the measured quantities of Amino Acid, Nitric or delivery systems (such as liposomes and unilamellar Nitrous Acid and water or solvent, and pharmaceutically vesicles). Those of ordinary skill in the art will readily be able acceptable additives or inert ingredients for Compounds, or to select additional pharmaceutically acceptable additives to mixing the measured quantities of Amino Acid, Nitrate and/or enable delivery of implementations of a pharmaceutical com Nitrite sources, and pharmaceutically acceptable additives or position from the disclosure in this document. inert ingredients for Compositions, may involve any number For the exemplary purposes of this disclosure, oral delivery 10 of steps and implementing components, and may be accom may be a particularly advantageous delivery route for admin plished readily from this disclosure. istration to humans and animals of implementations of a For the exemplary purposes of this disclosure, mixing the pharmaceutical composition, optionally formulated with measured quantities of Amino Acid, Nitric or Nitrous Acid appropriate pharmaceutically acceptable additives to facili and water or solvent, and pharmaceutically acceptable addi tate administration. 15 tives or inert ingredients, may comprise combining the mea Manufacture sured quantities of m Amino Acid, Nitric or Nitrous Acid and Implementations of Amino Acid Nitrate and/or Nitrite water or solvent, and pharmaceutically acceptable additives Compounds or Compositions may be synthesized or created or inert ingredients, under the influence of physical, ultra in a wide variety of manners, and may be made from a wide sonic, or electrostatic forces to create a desired degree of variety of materials. Those of ordinary skill in the art will 20 intermingling and/or chemical reaction of the Amino Acid, readily be able to select appropriate materials and methods to Nitric or Nitrous Acid and water or solvent and any pharma manufacture and use the compounds and compositions dis ceutically acceptable ingredients. The mixed may be accom closed herein. plished when the Amino Acid, Nitric or Nitrous Acid and Accordingly, although there are a variety of method imple water or solvent and/or any pharmaceutically acceptable mentations for producing pharmaceutical compositions, for 25 ingredients are in a solid, liquid, or semisolid state. the exemplary purposes of this disclosure, a method imple Separating the Amino Acid Compound or Composition mentation for producing an Amino Acid Compound may into discrete quantities for distribution may involve any num comprise: measuring specific quantities of Amino Acid, ber of steps and implementing components, and separating Nitric or Nitrous Acid and water or any other polar, easily the Amino Acid Compound or Composition into discrete evaporated solvent such as methanol, alcohol, pyridine, and 30 quantities for distribution may be accomplished readily from the like mixed in a specific order the measured quantities of this disclosure. For the exemplary purposes of this disclosure, Amino Acid, Nitric or Nitrous Acid and water or solvent, and separating the Amino Acid Compound or Composition into any additional pharmaceutically acceptable additives or inert discrete quantities for distribution may involve utilizing a ingredients, and then separating the pharmaceutical compo specific piece of equipment, for example, a conventional tab sition into discrete quantities for distribution and/or admin 35 let forming apparatus to shape the formed composition into istration. individual tablets, each containing a desired dose of Amino Measuring specific quantities of Amino Acid, Nitric or Acid Compound or Composition. The separating process Nitrous Acid and water or solvent, and pharmaceutically may be accomplished when the Amino Acid Compound or acceptable additives or inert ingredients, may involve any Composition is in a solid, liquid, or semisolid state. number of steps and implementing components, and measur 40 Those of ordinary skill in the art will be able to readily ing specific quantities of Amino Acid, Nitric or Nitrous Acid select manufacturing equipment and pharmaceutically and water or solvent, and pharmaceutically acceptable addi acceptable additives or inert ingredients to manufacture tives or inert ingredients, may be accomplished readily from implementations of an Amino Acid Compound or Composi this disclosure. For the exemplary purposes of this disclosure, tion. For the exemplary purposes of this disclosure, some measuring specific quantities of Amino Acid, Nitric or 45 examples of pharmaceutically acceptable additives or inert Nitrous Acid and water or solvent, and pharmaceutically ingredients and manufacturing process are included below, acceptable additives or inertingredients, may comprise using particularly those that relate to manufacture of implementa a scale, a solid or liquid dispensing apparatus, or other mea tions of an Amino Acid Compound or Composition in tablet surement device capable of measuring solid mass or liquid form. Notwithstanding the specific examples given, it will be volume to produce a desired quantity of Amino Acid, Nitric or 50 understood that those of ordinary skill in the art will readily Nitrous Acid and water or solvent, and pharmaceutically appreciate how to manufacture implementations of an Amino acceptable ingredient. Acid Compound or Composition according to the other meth It should be appreciated that any of the components of ods of administration and delivery disclosed in this docu particular implementations of an Amino Acid Compound or ment. Composition may be used as supplied commercially, or may 55 Accordingly, compounds and Compositions may include a be preprocessed by, by non-limiting example, any of the acceptable additive (e.g. one of a solubilizer, an enzyme methods and techniques of agglomeration, air suspension inhibiting agent, an anticoagulant, an antifoaming agent, an chilling, air suspension drying, balling, coacervation, com antioxidant, a coloring agent, a coolant, a cryoprotectant, a minution, compression, pelletization, cryopelletization, hydrogen bonding agent, a flavoring agent, a plasticizer, a extrusion, granulation, homogenization, inclusion Compoun 60 preservative, a sweetener, a thickener, and combinations dation, lyophilization, melting, mixed, molding, pan coating, thereof) and/or a acceptable carrier (e.g. one of an excipient, solvent dehydration, sonication, spheronization, spray chill a lubricant, a binder, a disintegrator, a diluent, an extender, a ing, spray congealing, spray drying, or other processes known solvent, a suspending agent, a dissolution aid, an isotoniza in the art depending in part on the dosage form desired. The tion agent, a buffering agent, a soothing agent, an amphip various components may also be pre-coated or encapsulated 65 athic lipid delivery system, and combinations thereof). as known in the art. It will also be clear to one of ordinary skill For example, a particular implementation of an Amino in the art that appropriate additives may also be introduced to Acid Compound or Composition may include a lubricant. Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 23 of 109

US 8,952,046 B1 15 16 Lubricants are any anti-sticking agents, glidants, flow pro Tablets and other orally discrete dosage forms, such as moters, and the like materials that perform a number of func capsules, cachets, pills, granules, pellets, beads, and particles, tions in tablet manufacture, for example, such as improving for example, may optionally be coated with one or more the rate of flow of the tablet granulation, preventing adhesion enteric coatings, seal coatings, film coatings, barrier coatings, of the tablet material to the surface of the dies and punches, 5 compress coatings, fast disintegrating coatings, or enzyme reducing interparticle friction, and facilitating the ejection of degradable coatings for example. Multiple coatings may be the tablets from the die cavity. Lubricants may comprise, for applied for desired performance. Further, dosage forms may example, magnesium stearate, calcium stearate, talc, and col be designed for, by non-limiting example, immediate release, loidal silica. pulsatile release, controlled release, extended release, 10 delayed release, targeted release, synchronized release, or Particular implementations of an Amino Acid Compound targeted delayed release. For release/absorption control, car or Composition may also include a binder. Binders are any riers may be made of various component types and levels or agents used to impart cohesive qualities to powdered material thicknesses of coats. Such diverse carriers may be blended in through particle-particle bonding. Binders may include, for a dosage form to achieve a desired performance. In addition, example, matrix binders (e.g. dry starch, dry sugars), film 15 the dosage form release profile may be effected by a poly binders (e.g. celluloses, bentonite, sucrose), and chemical meric matrix composition, a coated matrix composition, a binders (e.g. polymeric cellulose derivatives, such as methyl multi-particulate composition, a coated multi-particulate cellulose, carboxy methyl cellulose, and hydroxy propyl cel composition, an ion-exchange resin-based composition, an lulose); and other sugar, gelatin, non-cellulosic binders and osmosis-based composition, or a biodegradable polymeric the like. 20 composition. Disintegrators may be used in particular implementations While manufacture of implementations of an Amino Acid of an Amino Acid Compound or Composition to facilitate the Compound and Composition have been described in particu breakup or disintegration of tablets after administration. Dis lar sequences of steps and/or in particular forms, it will be integrators may include, for example, starch, starch deriva understood that such manufacture is not limited to the specific tives, clays (e.g. bentonite), algins, gums (e.g. guar gum), 25 order of steps or forms as disclosed. Any steps or sequences of cellulose, cellulose derivatives (e.g. methyl cellulose, car steps of manufacture of implementations of an Amino Acid boxymethyl cellulose), croscarmellose sodium, croscarmel Compound and Composition in any form are given as lose cellulose, and other organic and inorganic materials. examples of possible steps or sequences of steps or potential Implementations of an Amino Acid Compound or Compo forms and not as limitations, since many possible manufac sition may include diluents, or any inert substances added to 30 turing processes and sequences of steps may be used to manu increase the bulk of the Amino Acid Compound to make a facture Amino Acid Compound and Composition implemen tablet a practical size for compression. Diluents may include, tations in a wide variety of forms. for example, calcium phosphate, calcium sulfate, lactose, Use mannitol, magnesium stearate, potassium chloride, and citric Implementations of an Amino Acid Compound or Compo acid, among other organic and inorganic materials. 35 sition are particularly useful in increasing bioabsorption and Buffering agents may be included in an Amino Acid Com vasodilation in humans and animals. However, implementa pound or Composition and may be any one of an acid and a tions are not limited to uses relating to bioabsorption or base, where the acid is, for example, propionic acid, p-tolu vasodilation modification, and the like. Rather, any descrip enesulfonic acid, salicylic acid, stearic acid, succinic acid, tion relating to the foregoing is for the exemplary purposes of tannic acid, tartaric acid, thioglycolic acid, ortoluenesulfonic 40 this disclosure. It will be understood that implementations of acid, and the base is, for example, ammonium hydroxide, an Amino Acid Compound or Composition may encompass a potassium hydroxide, sodium hydroxide, sodium hydrogen variety of uses and are not limited in their uses. For example, carbonate, aluminum hydroxide, calcium carbonate, and possible uses may be, by non-limiting example, prevention of other organic and inorganic chemicals. Nitrate tolerance, enhanced water solubility, increased distri With respect to delivery of particular implementations of 45 bution to muscles, increased athletic performance, and/or an Amino Acid Compound or Composition, for the exem countering Nitric Oxide inhibiting effects of certain Amino plary purposes of this disclosure, tablets may be utilized. Acids. Tablets are any solid pharmaceutical dosage form containing In conventional preparations of Nitrate compounds, “tol a pharmaceutically acceptable active agent or agents to be erance,” a particular side effect, has been observed in many administered with or without suitable pharmaceutically 50 patients. This is unfortunate because the effectiveness of acceptable additives and prepared either by compression or Nitrate on vasodilation is well documented. “Tolerance” molding methods well known in the art. Tablets have been in occurs when a subject’s reaction to Nitrate decreases so that widespread use and remain popular as a dosage form because larger doses are required to achieve the same effect. A Mar. 3, of the advantages afforded both to the manufacturer (e.g., 2000 report in the British Journal of Pharmacology indicates simplicity and economy of preparation, stability, and conve 55 that “tolerance to the dilator effects of nitrates remains a nience in packaging, shipping, and dispensing) and the persisting therapeutic problem.” Raymond J. MacAllister patient (e.g., accuracy of dosage, compactness, portability, “Arginine and Nitrate Tolerance” available at http://www.na blandness of taste, and ease of administration). Although ture.com/bjp/journal/v130/n2/full/0703340a.html, the con tablets are most frequently discoid in shape, they may also be tents of which are hereby incorporated herein by reference. round, oval, oblong, cylindrical, rectangular or triangular, for 60 Empirical studies indicate that Nitrates are useful for their example. The tablets may be optionally scored so that they vasolidating effects. Common Nitrates include nitroglycerin may be separated into different dosages. They may differ and isosorbide dinitrate. Nitrates exert their vasodilating greatly in size and weight depending on the amount of the effect through their reduction to Nitrites. In vivo, Nitrates are pharmaceutically acceptable active agent or agents present reduced to Nitrites and, in the blood vessels’ epithelial cells, and the intended route of administration. They are divided 65 Nitrite reacts with a thiol donor (mainly glutathione) to yield into two general classes, (1) compressed tablets, and (2) Nitric Oxide. Louis J. Ignarro, “After 130 years, the Molecu molded tablets. lar Mechanism of Action of Nitroglycerin is Revealed” (Jun. Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 24 of 109

US 8,952,046 B1 17 18 11, 2002) available at http://www.pnas.org/cgi/content/full/ administration Arginine, and as fast as any nitrate, since the 99/12/7816?ck=nck, the contents of which are hereby incor NOs—group of the salt requires minimal conversion to yield porated herein by reference. Nitric Oxide. Additionally a much lesser dose may be The Nitric Oxide inhibiting characteristics of the Amino required for vasodilation to take place, compared to the single Acid Glutamine have been well documented in a number of administration of Arginine. Likewise, the development of studies. In particular, a Mar. 28, 2006 report in the American tolerance to the nitrate component of the molecule may be Journal of Physiology has found that Glutamine inhibits prevented with the presence of Arginine. Arginine Nitrate Nitric Oxide production by downregulation of eNOS syn may promote vasodilation through production of Nitric thase. Masao Kakoki, et al. “Amino acids as Modulators of Oxide by two different pathways, the Arginine citrullization Endothelium-Derived Nitric Oxide.” available at http://ajpre 10 pathway and the nitrate reduction pathway. Arginine Nitrate nal.physiology.org/cgi/content/full/291/2/F297, the contents may likewise be more water soluble than single administra of which are hereby incorporated by reference. tion Arginine. A January 2006 Journal of Nutrition report indicates that Accordingly, Applicants have discovered that the Citrul the Amino Acid Leucine promotes anabolism and stimulates line compound according to the second implementation, muscle protein synthesis. Michael J. Rennie, et al. 15 when ingested, provides enhanced Nitric Oxide (NO—) pro “Branched-Chain Amino Acids as Fuels and Anabolic Sig duction while providing improved vasodilation effects over mals in Human Muscle” available at http://jn.nutrition.org/ single administration of Citrulline, the single administration cgi/content/full/136/1/264S, the contents of which are hereby of Nitrates, or the single administration of Nitrites. Improved incorporated by reference. vasodilation may, in turn, provide better circulation and dis Empirical studies indicate that the Amino Acid Norvaline 20 tribution of Citrulline in the body. Absorption may be inhibits the enzyme arginase and thus decreases the rate of improved since Amino Acid salts with inorganic acids are conversion of the Amino Acid Arginine to urea. Takeyori much more water soluble than single administration Amino Saheki, et al. “Regulation of Urea Synthesis in Rat Liver” Acids. Additionally a much lesser dose may be required for available at http://jb.oxfordjounals.org/cgi/con vasodilation to take place, compared to the single adminis tent/abstract/86/3/745 2ijkey=5d134456b7443ca36c809 25 tration of Citrulline or nitrates. Citrulline Nitrate is likewise 269462276e?32549798&keytype2=tf_ipsecsha, the con more water soluble than single administration Citrulline. tents of which are hereby incorporated by reference. Accordingly, Applicants have discovered that the Creatine An October 2004 Journal of Nutrition report indicates that compound according to the third implementation, when the Amino Acid Ornithine promotes anabolism and stimu ingested, provides enhanced Nitric Oxide (NO—) production lates muscle protein synthesis. Michael J. Rennie, et al. 30 while providing improved vasodilation effects over single “Branched-Chain Amino Acids as Fuels and Anabolic Sig administration of Creatine, the single administration of mals in Human Muscle” available at http://jn.nutrition.org/ Nitrates, or the single administration of Nitrites. Improved cgi/content/full/136/1/264S, the contents of which are hereby vasodilation may, in turn, provide better circulation and dis incorporated by reference. tribution of Creatine in the body. Absorption may be Empirical studies indicate that the Amino Acids Beta-Beta 35 improved since Amino Acid salts with inorganic acids are Alanine and L-Histidine support carnosine production. M. much more water soluble than single administration Amino Dunnett, “Influence of Oral Beta-Beta Alanine and L-Histi Acids. Additionally a much lesser dose may be required for dine Supplementation on the Camosine Content of the Glu vasodilation to take place, compared to the single adminis teus Medius” Equine Veterinary Journal Supplement, avail tration of nitrates. able at http://www.ncbi.nlm.nih.gov/sites/entrez?Db= 40 Enhancing a molecule’s solubility can enhance it’s bio pubmed&Cmd=ShowDetail View&Term ?oSearch=10659 availability, rate of absorption by the GI tract, and as a result, 307&ordinalpos=4&itool=EntrezSystem 2.PEntrez.Pub it’s concentration in the muscle tissue and it’s effectiveness. med.Pubmed, the contents of which are hereby incorporated As we have established, the nitrate salts of creatine and other by reference. molecules are exceptionally more soluble that their counter Empirical studies further indicate that the Amino Acids 45 parts. Recent studies on creatine nitrate show 1100% Beta Alanine and L-Histidine increase muscle power, recu improved solubility over creatine monohydrate. peration and stamina. Yoshihiro Suzuki “High Level of Skel Study 1 etal Muscle Carnosine Contributes to the Latter Half of Exer cise Performance During 30-S Maximal Cycle Ergometer Intrinsic Dissolution Profiles of Creatine Nitrate, Sprinting” in the Japanese Journal of Physiology, available at 50 Creatine Monohydrate and Buffered Creatine http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed& Cmd=ShowDetail View&Term'ToSearch=12139778&ordi Objective: The objective of this study was to determine the malpos=4&itool=EntrezSystem?.PEntrez.Pubmed. Pubmed_ dissolution characteristics of three different forms of com ResultsPanel. Pubmed RVDocSum, the contents of which mercially available creatine including creatine nitrate (CN), are hereby incorporated by reference. 55 creatine monohydrate (CM) and buffered creatine (BC) under Accordingly, Applicants have discovered that the Arginine different temperature and pH. Methods: Intrinsic dissolution compound according to the first implementation, when studies were carried out at 37°C. and room temperature in pH ingested, provides enhanced Nitric Oxide (NO—) production 2.5 and 7.4 buffer using modified Wood’s apparatus. CN, CM while providing improved vasodilation effects over single and BC samples (~0.5 g) were compressed in the dies with administration of Arginine, the single administration of 60 constant surface area of 1.21 cm2 using a Carver press at 2000 Nitrates, or the single administration of Nitrites. Improved psi with a dwell time of 10 sec. These dies were placed in the vasodilation may, in turn, provide better circulation and dis USP dissolution apparatus (type II) containing 140 ml of tribution of Arginine in the body. Absorption may be dissolution media, with paddle speed of 50 rpm. Dissolution improved since Amino Acid salts with inorganic acids are medium were collected at definite time intervals over a period much more water soluble than single administration Amino 65 of 3 hours for CN and 7 hours for both CM and BC and Acids. Applicants have also discovered that the vasodilating analyzed for creatine using a validated HPLC method. effect of Arginine Nitrate manifests faster than that of single Results: A plot of the amount of creatine dissolved (mg)/ Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 25 of 109

US 8,952,046 B1 19 20 surface area (cm2) versus time gives the slope (k’) which is Objective: The objective of this study was to determine the directly proportional to the dissolution rate constant. The k" equilibrium solubility of creatine nitrate (CN), creatine (mg/cm2 hr) values for CN, CM and BC in pH 2.5 buffer at monohydrate (CM) and buffered creatine (BC) in water at room temperature were 293.0+3.48, 59.1+2.06 and room temperature as well as in pH 2.5 buffer at room tem 71.1+0.59. At 37° C. these k' (mg/cm2 hr) values were 5 perature and 37° C. Methods: Excess amount of sample was 327.3+2.66, 97.940.88 and 117.9:1.12, respectively. In pH added to the appropriate solvent and temperature was main 7.4 buffer, the k' (mg/cm2.hr) values for CN, CM and BC were tained and agitated at 150 rpm. The supernatant was collected 278.9:14.6, 52.1+0.22 and 50.6+0.95 at room temperature after centrifugation at 24, 48, 72 hours till equilibration and and 319.5+14.3, 86.0+5.05 and 96.94.9.28 at 37°C., respec analyzed by a HPLC method. Equilibration was confirmed tively. Conclusions: The dissolution rates of all three creatine 10 forms were higher at 37°C. as compared to at room tempera when the solubility values of two consecutive time points ture. CM and BC showed a higher dissolution rate at pH 2.5 were identical. The pH of the solution was monitored and than that at pH 7.4, irrespective of temperature. However, the Differential scanning calorimetry (DSC) thermograms of the dissolution rate of CN was not affected by the pH of the solid samples before solubility and of the lyophilized sample dissolution media. Comparison of the dissolution profiles for 15 after solubility studies were compared. Results: The equilib these three creatine forms clearly indicated that CN has the rium solubility of CN, CM and BC in water at room tempera higher intrinsic dissolution rate constant as compared to CM ture was reached in 44 hours, and was 210.3+4.82 mg/ml, and BC irrespective of temperature and pH of the dissolution 19.1+0.40 mg/ml and 19.2+0.55 mg/ml, respectively. How media. Results of this study further predict a better bioavail ever, solubility for CN, CM and BC in pH 2.5 buffer at room ability of CN as compared to CM and BC. 20 temperature was 208.2+6.01 mg/ml, 23.8+0.33 mg/ml and Study 2 21.2+0.09 mg/ml and achieved within 72 hours for CN and in 48 hours for CM and BC samples, respectively. At 37°C. and Chemical Stability of Creatine Nitrate, Creatine in pH 2.5 buffer, the equilibrium solubility was reached Monohydrate and Buffered Creatine in Solution within 24 hours for all samples and was 325.9-6.10, 25 31.5+0.71 and 32.6+0.67 for CN, CM, and BC. The pH of Objective: The objective of this study was to determine the solutions of CN, CM and BC in water at room temperature chemical stability of creatine nitrate (CN), creatine monohy was 0.44+0.04, 8.24+0.14 and 10.03+0.02 respectively. drate (CM) and buffered creatine (BC) under two different However, these values in pH 2.5 buffer at room temperature storage conditions (37°C. in pH 2.5 buffer and 40°C. in pH were 1.31+0.02, 3.44+0.02 and 3.68+0.01 and at 37° C. this 6.8 buffer). Methods: A known concentration (~10 mg/ml) of 30 was 1.13+0.07, 3.86+0.47 and 4.42+0.05, respectively. DSC CN, CM and BC were prepared in both pH 2.5 and pH 6.8 thermograms of the original samples and lyophilized samples buffer and stored in stability chambers in screw capped bottles at 37° C. and 40° C., respectively. Samples were were identical. Conclusions: The solubility of creatine nitrate collected at predetermined time points and analyzed for cre was around 10 fold higher than that of CM or BC under these atine and degradation products if any, using a validated HPLC 35 experimental conditions studied, where as no significant dif method. Changes in the pH, clarity and color of the samples ference in the solubility of CM and BC were noticed. There were also determined. The order of degradation and rate was an increase in solubility of each of the creatine forms in constant were determined by graphical method. Results: The pH 2.5 at a higher temperature. DSC analysis confirmed that degradation rate constants (k) for CN, CM and BC at 37°C. no phase change was noticed during these solubility studies. in pH 2.5 buffer were 0.075+0.001, 0.1194-0.011 and 40 The effectiveness of creatine for increasing athletic perfor 0.108+0.002 (day-1) while that at 40°C. in pH 6.8 buffer were mance and improving body composition and muscle anabo 0.115+0.001, 0.015+0.001 and 0.013+0.002 (day-1), respec lism and performance is very well established. Such is also tively. The pH of CN samples at 40° C. in pH 6.8 buffer the case for BCAAs (leucine, isoleucine, and valine), taurine changed from 2.83+0.01 to 4.31+0.01 within a period of 12 and camitine. It is also well established that for these mol days. The pH changes noticed at 37° C. in pH 2.5 buffer 45 ecules to have these effects, like all drugs, they must reach the samples over the same period of time for CM, and BC were site of action, i.e. the muscle. 3.08+0.01 to 4.12+0.01 and 3.11+0.01 and 4.16+0.01, Creatine Nitrate & the Athlete respectively. No significant change in pH was observed for Creatine Nitrate excels beyond its superior solubility, sta the rest of the samples. No change in the color and the clarity bility, and dissolution. That’s because Creatine Nitrate over was noticed over 12 days. Conclusions: All the creatine 50 comes two primary drawbacks of creatine monohydrate. samples followed first order degradation kinetics under both First, creatine monohydrate results in extreme intra and extra these experimental conditions. The k value for CN was found cellular water and sodium retention. The intracellular water to be higher at 40°C. in pH 6.8 buffer as compared to at 37° retention is favorable. Cosmetically speaking however, the C. in pH 2.5 buffer. However, both CM and BC showed a extracellular water retention is an unfavorable effect, as an faster rate of degradation at 37°C. in pH 2.5 buffer than at 40° 55 athlete’s muscles develop a smooth, soft, and bloated appear C. in pH 6.8 buffer. The major degradation product detected ance. Second and most importantly, the extreme extracellular was . For CN the increase in pH was higher at 40°C. water retention may restrict muscle growth. Functionally in pH 6.8 buffer as compared to 37° C. in pH 2.5 buffer. speaking, the extracellular water retention may push back However, opposite effect was noticed for both CM and BC. against muscle cells that are attempting to expand in size. Study 3 60 Creatine Nitrate expels excess extracellular water and Equilibrium Solubility Studies of Creatine Nitrate, Creat sodium retention, while simultaneously hydrating and super ine Monohydrate and Buffered Creatine saturating muscle cells with creatine. This offers a HUGE Ambrish Panditl, Pinal Mistry1, Pat Dib2, Alexander benefit to athletes, encouraging muscle cells to expand in size Nikolaidis3 Alekha K. Dashl without resistance from extracellular fluid. In addition, ath Department of Pharmacy Sciences, Creighton University, 65 letes using Creatine Nitrate may achieve a leaner, drier, and Omaha, Nebr. 68178. Department of Physiological Science harder look to their muscle tissue; a stark contrast to the puffy UCLA. Aristotle University Of Thessaloniki. and bloated look created by creatine monohydrate. Creatine Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 26 of 109

US 8,952,046 B1 21 22 Nitrate however is more than “Creatine Nitrate,” as the nitrate For decades, the pharmaceutical industry has used nitrates component offers tremendous functional advantages to ath to induce direct and rapid vasodilation. And today, clinical letes. research is proving that nitrates may produce beneficial Nitrates provide substantial benefits to athletes and body effects on blood pressure and cardiovascular health (8). In builders, as supported by clinical research. Nitrates are fact, a recent clinical study investigated the effects of 5 times organic anions naturally occurring in the human diet, with the amount of nitrates (1,316 mg per day for a 70 kg adult) close to 80% of dietary nitrates found in vegetables. Fruits currently recommended by the World Health Organization and processed meats represent additional sources of nitrates (259 mg per day for a 70 kg adult) and showed no adverse in the human diet. In fact, researchers at Michigan State health or safety effects. The study results revealed an average University have suggested nitrates may be nutritious (13). So 10 reduction in diastolic blood pressure by 4.5 mmHg. Effects on what benefit does supplementation with nitrates offer to ath systolic blood pressure were not observed (14, 15). Nitrates themselves offer many benefits to athletes. Com letes? bined with the clinical research behind creatine supporting Today, nitric oxide and pre-workout nitric oxide perfor creatine’s positive benefits to athletes, Creatine Nitrate is the mance enhancing formulas have grown in popularity. Nitric 15 first creatine to solve to the solubility, stability, and dissolu oxide formulas are used to increase muscular “pumps,” tion challenges while simultaneously providing up to 8 hours vasodilation, and nutrient transport to the muscle to assist in of powerful vasodilation that workout enthusiasts demand! greater aerobic performance and recovery. However, most formulas utilize the amino acid L-arginine, a precursor to REFERENCES nitric oxide, as their base. Recently, L-arginine has been 20 proven to be ineffective for elevating nitric oxide levels. The following references are hereby incorporated herein L-arginine has also been proven ineffective at enhancing ath by reference. letic performance (9, 10, 11). Yet L-arginine is present in 1. Glucose- and arginine-induced insulin secretion by human nearly every single nitric oxide formula on the market. Con pancreatic B-cells: the role of HERG K+ channels in firing trary to popular belief, most of the “pump” feeling experi 25 and release enced by trainees is derived from an insulin increase follow 2. Does NO metabolism play a role in the effects of vegetables ing L-arginine supplementation (1). in health?Nitric oxide formation via the reduction of As recent clinical research confirms, the reduction of inor nitrites and nitrates. Dina Ralt.*Gertner Institute for Epide ganic nitrate (NO3-) and nitrite (NO2-) in vivo results in nitric miology and Health Policy Research, Tel Hashomer, Israel oxide production. Not only does nitrate generate nitric oxide, 30 3. Larsen FJ, Weitzberg E, Lundberg JO, Ekblom B. Effects but nitrate and nitrite are inert end-products of nitric oxide of dietary nitrate on oxygen cost during exercise. Acta oxidation. That is, nitrate converts into nitric oxide, and once Physiol (Oxf). 2007 September 191(1):59-66. Epub 2007 oxidized, nitric oxide is recycled back into nitrate, which then Jul. 17. has the potential to convert into nitric oxide once again. And 4. Stephen J. Bailey, 1 Paul Winyard, 2 Anni Vanhatalo, 1 Jamie the cycle continues to repeat itself. This creates an exciting 35 R. Blackwell,1 Fred J. DiMenna, 1 Daryl P. Wilkerson, 1 alternative to nitric oxide production, and carries profound Joanna Tarr,2 Nigel Benjamin,2 and Andrew M. Jones 1. implications for the bodybuilding community. Dietary nitrate supplementation reduces the 02 cost of low A critical problem with nitric oxide is the short lifespan it intensity exercise and enhances tolerance to high-intensity has in the body. In just a few seconds, the nitric oxide mol exercise in humans. 1 School of Sport and Health Sciences ecule can be metabolized, and the athlete loses any benefit 40 and; 2Peninsula College of Medicine and Dentistry, Uni he/she may have received. A pump however must be sus versity of Exeter, Exeter, United Kingdom tained for several minutes, if not hours, in order to result in 5. Fetih G, Habib F, Katsumi H, Okada N, Fujita T, Attia M. those biochemical conditions required to stimulate muscle Yamamoto A. Excellent absorption enhancing characteris hypertrophy. And nitrates are capable of elevating nitric oxide tics of NO donors for improving the intestinal absorption of production for up to 8 hours. 45 poorly absorbable compound compared with conventional Thus the use of nitrates represents an important alternative absorption enhancers. to the classical L-arginine-NO-synthase pathway (2) so com 6. Koichi Takahashia,” , Nanako Numataa, Natsumi Kinoshi monly attempted in various sports supplement formulations. taa, Naoki Utoguchib, The efficacy of nitrates in athletic performance is over Tadanori Mayumic, Nobuyasu Mizunoa. Characterization of whelming in the clinical research. Nitrate consumption sig 50 the influence of nitric oxide donors on intestinal absorption nificantly enhances nitric oxide production, resulting in of macromolecules. International Journal of Pharmaceu vasodilation, improved nutrient absorption, increased athletic tics 286 (2004) 89-97 performance (3), and improved energetic function in working 7. Fetih G, Habib F, Okada N, Fujita.T. Attia M. Yamamoto A. muscles during exercise (12). For example, during low and Nitric oxide donors can enhance the intestinal transport moderate intensity exercise by humans, supplementation 55 and absorption of insulin and [Asu(1,7)]-eel calcitonin in with nitrates has been reported to reduce the amount of oxy rats. gen required. During high intensity athletic exercise, nitrate 8. Supatra Porasuphatanaa, Pei Tsaib, Gerald M. Rosenb. The supplementation enhances tolerance to high intensity train generation of free radicals by nitric oxide synthase. Com ing, effectively extending the “time to exhaustion” (4). parative Biochemistry and Physiology Part C 134 (2003) Organic nitrates also function as permeation enhancers. 60 281–289 1532-0456/03/$–see front matter 2002 This is beneficial because enhanced permeation increases Elsevier Science Inc. All rights reserved. PII: S1532 intestinal absorption of all nutrients coingested. This may O456Z02.00271-5 Review. allow for a superior quantity of anabolic nutrients to be 9. Olek R A et al. A single oral intake of arginine does not absorbed and taken up into muscle cells, assisting athletes affect performance during repeated Wingate anaerobic with the growth and repair of muscle tissue. Nitrates are even 65 test. J Sports Med Phys Fitness. 2010 March; 50(1):52-6. able to allow absorption of large macromolecules such as 10. Liu TH, Wu CL, Chiang CW, Loy W, Tseng HF, Chang insulin (5, 6, 7). C K. No effect of shortterm arginine supplementation on Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 27 of 109

US 8,952,046 B1 23 24 nitric oxide production, metabolism and performance in circulation and distribution of Omithine in the body. Absorp intermittent exercise in athletes. J Nutr Biochem. 2008 tion may be improved since Amino Acid salts with inorganic Aug. 15. [Epub ahead of print acids are much more water soluble than single administration 11. Bescós R, Gonzalez-Haro C, Pujol P. Drobnic F. Alonso Amino Acids. Applicants have also discovered that Ornithine E, Santolaria ML, Ruiz O, Esteve M, Galilea P. Effects of 5 Nitrate begins acting as fast as any other nitrate, since the dietary L-arginine intake on cardiorespiratory and meta NOs—group of the salt requires minimal conversion to yield bolic adaptation in athletes. Int J Sport Nutr Exerc Metab. Nitric Oxide. Additionally, a much lesser dose may be 2009 August; 19(4):355-65. required for vasodilation to take place, compared to the single 12. Larsen F J, Weitzberg E, Lundberg J O, Ekblom B. administration of nitrates. Ornithine Nitrate may likewise be Dietary nitrate reduces maximal oxygen consumption 10 while maintaining work performance in maximal exercise. more water soluble than single administration Ornithine. Free Radic Biol Med. 2010 Jan. 15; 48(2):342–7. Epub Accordingly, Applicants have discovered that the Histidine 2009 Nov. 12. compound according to the eighth implementation, when 13. American Journal of Clinical Nutrition, doi:10.3945/ ingested, provides a vasodilation mechanism. Vasodilation ajcn.2008.27131 15 may, in turn, provide better circulation and distribution of 14. Tanja Sobko, Claude Marcus, Mirco Govoni, Shigeru Histidine in the body. Applicants have likewise discovered Kamiya. “Dietary nitrate in Japanese traditional foods low that the Histidine compound according to the ninth imple ers diastolic blood pressure in healthy volunteers.” Nitric mentation, when ingested, promotes carnosine production, Oxide Volume 22, Issue 2, Pages 136-140 thus increasing muscle power, endurance and recuperation. 15. http://www.foodnavigator.com/Product-Categories/Pre 20 Absorption may be improved since Amino Acid salts with servativesand-acidulants/Dietary-nitrates-maybe-benefi inorganic acids are much more water soluble than single cial-for-heart-health-Study/?utm_source=Newsletter_ administration Amino Acids. Applicants have also discovered Product&utm_medium=email&utm_campaign=Newslet that Histidine Nitrate begins acting as fast as any othernitrate, ter%2BProduct since the NOs– group of the salt requires minimal conver Accordingly, Applicants have discovered that the 25 sion to yield Nitric Oxide. Additionally, a much lesser dose Glutamine compound according to the fourth implementa may be required for vasodilation to take place, compared to tion, when ingested, counters the Nitric Oxide (NO—) inhib the single administration of nitrates. Histidine Nitrate may iting characteristics of Glutamine. Absorption of Glutamine likewise be more water soluble than single administration may be improved since Amino Acid salts withinorganic acids Histidine. are much more water soluble than single administration 30 Accordingly, Applicants have discovered that the Beta Ala Amino Acids. Additionally a much lesser dose may be nine compound according to the ninth implementation, when required for vasodilation to take place, compared to the single ingested, provides vasodilation. Vasodilation may, in turn, administration of nitrates. Glutamine Nitrate may likewise be provide better circulation and distribution of Beta Alanine in more water soluble than single administration Glutamine. the body. Applicants have likewise discovered that the Beta Accordingly, Applicants have discovered that the Leucine 35 Alanine compound according to the tenth implementation, compound according to the fifth implementation, when when ingested, promotes carnosine production, thus increas ingested, provides enhanced Nitric Oxide (NO—) production ing muscle power, endurance and recuperation. Absorption while providing improved vasodilation effects over single may be improved since Amino Acid salts withinorganic acids administration of Leucine, the single administration of are much more water soluble than single administration Nitrates, or the single administration of Nitrites. Improved 40 Amino Acids. Applicants have also discovered that Beta Ala vasodilation may, in turn, provide better circulation and dis nine Nitrate begins acting as fast as any othernitrate, since the tribution of Leucine in the body. Absorption may be improved NOs—group of the salt requires minimal conversion to yield since Amino Acid salts with inorganic acids are much more Nitric Oxide. Additionally, a much lesser dose may be water soluble than single administration Amino Acids. Addi required for vasodilation to take place, compared to the single tionally a much lesser dose may be required for vasodilation 45 administration of nitrates. Beta Alanine Nitrate may likewise to take place, compared to the single administration of be more water soluble than single administration Beta Ala nitrates. Leucine Nitrate is likewise more water soluble than nine. single administration Leucine. Accordingly, Applicants have discovered that the Agma Accordingly, Applicants have discovered that the Norval time compound according to the eighth implementation, when ine compound according to the sixth implementation, when 50 ingested, counteracts the Nitric Oxide inhibiting effect of ingested, promotes vasodilation through the inhibition of single administration Agmatine. Absorption may be arginase, while promoting Nitric Oxide formation via the improved since Amino Acid salts with inorganic acids are nitrate mechanism. Improved vasodilation may, in turn, pro much more water soluble than single administration Amino vide better circulation and distribution of Norvaline in the Acids. Applicants have also discovered that Agmatine Nitrate body. Absorption may be improved since Amino Acid salts 55 begins acting as fast as any other nitrate, since the NOs– with inorganic acids are much more water soluble than single group of the salt requires minimal conversion to yield Nitric administration Amino Acids. Additionally a much lesser dose Oxide. Agmatine Nitrate may likewise be more water soluble may be required for vasodilation to take place, compared to than single administration Agmatine. the single administration of nitrates. Norvaline Nitrate may Accordingly, Applicants have discovered that not only do likewise be more water soluble than single administration 60 the foregoing amino acid nitrate or nitrite compounds provide Norvaline. the effects discussed above, but that Amino Acid Composi Accordingly, Applicants have discovered that the Omith tions (amino acids mixed withindependent sources of nitrates ine compound according to the seventh implementation, and/or nitrites) enhance bioavailability, absorption, vasodila when ingested, provides an additional vasodilation mecha tion, water solubility, distribution to muscles, and the like of nism, reducing the amount of Ornithine needed and the 65 certain Amino Acids, as well as prevent Nitrate tolerance and amount of time needed for the vasodilating properties to counter Nitric Oxide inhibiting effects of certain Amino manifest. Improved vasodilation may, in turn, provide better Acids. Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 28 of 109

US 8,952,046 B1 25 26 As demonstrated by Anjali Pradhan and Juan Vera, “Effect valine, Ornithine and Taurine). In the case of Creatine, this is of Anions on the Solubility of Zwitterionic AImino Acids”, further enhanced by the nitrate’s ability to preserve muscle Journal of Chemical and Engineering data, Vol 45, 140-143 Creatine loads. (2000) (which is hereby incorporated herein by reference), Therefore, concomitant nitrate or nitrite administration in a the co-existence of the nitrate ion can enhance the solubility composition with an amino acid (just as with amino acid of various amino acids by 300-400%. Although the change in nitrate or nitrite compounds discussed previously) can solubility is significantly lower than that of the case of a salt improvemental focus, cognitive function, athletic and muscle with a nitrate, it is enough to make a difference in absorption performance, endurance, and strength, and produces much in-vivo. greater synergistic results than the use of only an amino acid Furthermore, the nitrate ion enhances absorption of com 10 alone or a nitrate and a nitrite alone. pounds by the intestine. Nitrates increase bioavailability by: The invention claimed is: increasing intestinal absorption of nutrients; and increasing 1. A composition comprising: vasodilation and blood flow and blood is the carrier of the at least one constituent selected from the group consisting nutrients to cells. See for example, the following references of a nitrate salt, a nitrite salt, and both; and which are hereby incorporated herein by reference: Takahashi 15 at least one constituent amino acid selected from the group K et al. “Characterization of the influence of nitric oxide consisting of Arginine, Agmatine, Beta Alanine, Citrul donors on intestinal absorption of macromolecules.” Int J line, Creatine, Glutamine, L-Histidine, Isoleucine, Leu Pharm 2004; 286:89–97; Fetih G. et al. “Nitric oxide donors cine, Norvaline, Ornithine, Valine, Aspartic Acid, Cys can enhance the intestinal transport and absorption of insulin teine, Glycine, Lysine, Methionine, Proline, Tyrosine, and [Asu(1,7)]-eel calcitonin in rats.” J Control Release 2005; 20 and Phenylalanine. 106:287-97; Fetih G et al. “Excellent absorption enhancing 2. The composition of claim 1 further comprising one or characteristics of NO donors for improving the intestinal more additional components selected from the group consist absorption of poorly absorbable compound compared with ing of a carrier, an excipient, a binder, a colorant, a flavoring conventional absorption enhancers.” Drug Metab Pharma agent, a preservative, a buffer, a dilutant, and any combination cokinet 2006; 21:222-9; and Mitchell, G. E., Little, C. O., Jr. 25 thereof. & Greathouse, T. R. (1964). “Influence of nitrate and nitrite, 3. The composition of claim 1 in a dosage form selected on carotene disappearance from the rat intestine.” Life Sci. 4, from the group consisting of a capsule, a cachet, a pill, a 385. tablet, a powder, a granule, a pellet, a bead, a particle, atroche, Also, the nitrate ion can cause vasodilatation after reduc a lozenge, and a gel. tion to nitrite and then nitric oxide, improve blood circulation, 30 4. The composition of claim 1, wherein the nitrate salt to the muscles and thus distribution of these compounds to the comprises sodium nitrate, potassium nitrate, barium nitrate, muscle, as well as oxygen distribution to the muscles. Muscle calcium nitrate, and any combination thereof, and the nitrite oxygen is needed to provide energy which is needed for all salt comprises sodium nitrite, potassium nitrite, barium muscle anabolic actions to take place as well as for the active nitrite, calcium nitrite, and any combination thereof. transport of above nutrients via the cell membrane. See the 35 5. The composition of claim 4, wherein the at least one following references which are hereby incorporated herein by constituent selected from the group consisting of a nitrate salt, reference—Bailey, Stephen G. et al., “Dietary nitrate supple a nitrite salt, and both comprises a nitrate salt. mentation reduces the 02 cost of low-intensity exercise and 6. The composition of claim 5, wherein the nitrate salt enhances tolerance to high-intensity exercise in humans”, comprises sodium nitrate. Press. J Appl Physiol (Aug. 6, 2009) and Bailey, Stephen G. 40 7. The composition of claim 5, wherein the nitrate salt et al., “Dietary nitrate supplementation enhances muscle con comprises potassium nitrate. tractile efficiency during knee-extensor exercise in humans”, 8. A supplement formulation comprising: JAppl Physiol 109:135-148, 2010). at least one constituent selected from the group consisting In these same references it is also very well described of a nitrate salt, a nitrite salt, and both; and nitrate’s positive effect on athletic endurance and muscle 45 at least one constituent amino acid selected from the group strength. Oxygen is needed by the body to produce energy consisting of Arginine, Agmatine, Beta Alanine, Citrul which by itself is needed for all the metabolic processes in the line, Creatine, Glutamine, L-Histidine, Isoleucine, Leu body, including those that Compositions of the present dis cine, Norvaline, Ornithine, Valine, Aspartic Acid, Cys closure are involved in. Thus co-administration of nitrate ion teine, Glycine, Lysine, Methionine, Proline, Tyrosine, with Compositions of the present disclosure furthermore 50 and Phenylalanine. increases their distribution to the muscle and their effective 9. The supplement formulation of claim 8 further compris IlêSS. ing one or more additional components selected from the Therefore, not only does the binding of nitrate salt with group consisting of a carrier, an excipient, a binder, a colo Compounds improve their bioavalability, absorption and rant, a flavoring agent, a preservative, a buffer, a dilutant, and effectiveness, but also the co-administration of nitrate 55 any combination thereof. through another nitrate salt, acid or a natural source of nitrate 10. The supplement formulation of claim 8 in a dosage in a Composition of the present disclosure shall have similar form selected from the group consisting of a capsule, a cachet, effects, albeit lower than in the case of nitrate bonded with the a pill, a tablet, a powder, a granule, a pellet, a bead, a particle, molecule. a troche, a lozenge, and a gel. Via all the above mechanisms, concomitant nitrate or 60 11. The supplement formulation claim 8, wherein the nitrite administration in a composition with an amino acid can nitrate salt comprises sodium nitrate, potassium nitrate, substantially increase the concentration of an amino acid in barium nitrate, calcium nitrate, and any combination thereof, the target muscles (e.g., cells for the cognitive and the nitrite salt comprises sodium nitrite, potassium nitrite, enhancement properties of phenylalanine, camitine, glycine, barium nitrite, calcium nitrite, and any combination thereof. and tyrosine, and Muscle cells for the performance enhancing 65 12. The supplement formulation of claim 11, wherein the at properties of Agmatine Arginine, Beta Alanine, Citrulline, least one constituent selected from the group consisting of a Creatine, Glutamine, L-Histidine, Isoleucine, Leucine, Nor nitrate salt, a nitrite salt, and both comprises a nitrate salt. Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 29 of 109

US 8,952,046 B1 27 28 13. The supplement formulation of claim 12, wherein the nitrate salt comprises sodium nitrate. 14. The supplement formulation of claim 12, wherein the nitrate salt comprises potassium nitrate. Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 30 of 109

EXHIBIT G Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 31 of 109 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 32 of 109

US 8,178,572 Cl 1 2 EXPARTE pharmaceutically effective amount of an amino acid com­ REEXAMINATION CERTIFICATE pound consisting essentially of a nitrate of Beta Alanine. 6. The method of claim 1, wherein administering to the THE PATENT IS HEREBY AMENDED AS human a pharmaceutically effective amount of an amino INDICATED BELOW. acid compound comprises administering to the human a pharmaceutically effective amount of an amino acid com­ Matter enclosed in heavybrackets [ ] appeared in the pound consisting essentially of a nitrate of Citrulline. patent, but has been deleted and is no longer a part of the 7. The method of claim 1, wherein administering to the patent; matter printed in italics indicates additions made human a pharmaceutically effective amount of an amino 10 to the patent. acid compound comprises administering to the human a pharmaceutically effective amount of an amino acid com­ AS A RESULT OF REEXAMINATION, IT HAS BEEN pound consisting essentially of a nitrate of Creatine. DETERMINED THAT: 8. The method of claim 1, wherein administering to the 15 human a pharmaceutically effective amount of an amino Claims 1 and 2 are determined to be patentable as acid compound comprises administering to the human a amended. pharmaceutically effective amount of an amino acid com­ New claims 3-13 are added and determined to be pound consisting essentially of a nitrate of Glutamine. patentable. 9. The method of claim 1, wherein administering to the 1. A method for increasing vasodilative characteristics in 20 human a pharmaceutically effective amount of an amino [ ] a human or animal , the method comprising administering acid compound comprises administering to the human a [ ] orally to the human or animal a pharmaceutically effective pharmaceutically effective amount of an amino acid com­ amount of an amino acid compound consisting essentially of pound consisting essentially of a nitrate of L-Histidine. a nitrate [or nitrite] of an amino acid selected from the group consisting of Arginine, Agmatine, Beta Alanine, Citrulline, 10. The method of claim 1, wherein administering to the 25 Creatine, Glutamine, L-Histidine, Isoleucine, Leucine, Nor­ human a pharmaceutically effective amount of an amino valine, Ornithine, and Valine. acid compound comprises administering to the human a 2. The method of claim 1, wherein administering to the pharmaceutically effective amount of an amino acid com­ human [or animal] a pharmaceutically effective amount of pound consisting essentially of a nitrate of Isoleucine. an amino acid compound comprises administering to the 30 11. The method of claim 1, wherein administering to the human or animal a pharmaceutically effective amount of an human a pharmaceutically effective amount of an amino amino acid compound consisting essentially of a nitrate [or acid compound comprises administering to the human a nitrite] of Ornithine. pharmaceutically effective amount of an amino acid com­ 3. The method of claim 1, wherein administering to the pound consisting essentially of a nitrate of Leucine. human a pharmaceutically effective amount of an amino 35 12. The method of claim 1, wherein administering to the acid compound comprises administering to the human a human a pharmaceutically effective amount of an amino pharmaceutically effective amount of an amino acid com­ acid compound comprises administering to the human a pound consisting essentially of a nitrate of Arginine. pharmaceutically effective amount of an amino acid com­ 4. The method of claim 1, wherein administering to the pound consisting essentially of a nitrate of Norvaline. human a pharmaceutically effective amount of an amino 40 acid compound comprises administering to the human a 13. The method of claim 1, wherein administering to the pharmaceutically effective amount of an amino acid com­ human a pharmaceutically effective amount of an amino pound consisting essentially of a nitrate of Agmatine. acid compound comprises administering to the human a 5. The method of claim 1, wherein administering to the pharmaceutically effective amount of an amino acid com­ human a pharmaceutically effective amount of an amino pound consisting essentially of a nitrate of Valine. acid compound comprises administering to the human a * * * * * Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 33 of 109

EXHIBIT H Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 34 of 109 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 35 of 109

US 8,455,531 Cl 1 2 EXPARTE 4. [An amino acid composition] A solid supplement formulation comprising: REEXAMINATION CERTIFICATE at least one [constituent selected from the group consist­ ing of a nitrate, a nitrite, and both] nitrate salt com­ THE PATEN T IS HEREBY AMENDED AS pound; and INDICATED BELOW. an isolated Agmatine compound, wherein the Agmatine compound is a separate compound than the at least one Matter enclosed in heavy brackets [ ] appeared in the nitrate salt compound. patent, but has been deleted and is no longer a part of the patent; matter printed in italics indicates additions made 5. [An amino acid composition] A solid supplement to the patent. lO formulation comprising: at least one [constituent selected from the group consist­ AS A RESULT OF REEXAMINATION, IT HAS BEEN ing of a nitrate, a nitrite, and both] nitrate salt com­ DETERMINED THAT: pound; and 15 an isolated Beta Alanine compound, wherein the Beta Claims 1-61 are determined to be patentable as amended. Alanine compound is a separate compound than the at New claims 62-122 are added and determined to be least one nitrate salt compound. patentable. 6. [An amino acid composition] A solid supplement formulation comprising: 1. [An amino acid composition] A solid supplement 20 at least one [constituent selected from the group consist- formulation comprising: ing of a nitrate, a nitrite, and both] nitrate salt com­ at least one [constituent selected from the group consist­ pound; and ing of a nitrate, a nitrite, and both] nitrate salt com­ an isolated Citrulline compound, wherein the Citrulline pound; and compound is a separate compound than the at least one at least one [constituent] isolated amino acid compound 25 nitrate salt compound. selected from the group consisting of{,]Agmatine, Beta 7. [An amino acid composition] A solid supplement Alanine, Citrulline, Creatine, Glutamine, L-Histidine, formulation comprising: Isoleucine, Leucine, Norvaline, Omithine, Valine, at least one [constituent selected from the group consist­ Aspartic Acid, Cysteine, Glycine, Lysine, Methionine, ing of a nitrate, a nitrite, and both] nitrate salt com­ Praline, Tyrosine, and Phenylalanine, 30 pound; and wherein the at least one isolated amino acid compound is an isolated Creatine compound, wherein the Creatine a separate compound than the at least one nitrate salt compound is a separate compound than the at least one compound. nitrate salt compound. 2. A method for increasing bioabsorption of Amino Acids 8. [An amino acid composition] A supplement formula- in a human [or animal], the method comprising administer­ 35 tion comprising: ing to the human [or animal] a pharmaceutically effective at least one [constituent selected from the group consist­ amount of [an amino acid composition] a solid supplement ing of a nitrate, a nitrite, and both] nitrate salt com­ formulation comprising: pound; and at least one [constituent selected from the group consist­ an isolated Glutamine compound, wherein the Glutamine ing of a nitrate, a nitrite, and both] nitrate salt com- 40 compound is a separate compound than the at least one pound; and nitrate salt compound. at least one [constituent] isolated amino acid compound 9. [An amino acid composition] A supplement formula­ selected from the group consisting of Arginine, Agma­ tion comprising: tine, Beta Alanine, Citrulline, Creatine, Glutamine, at least one [constituent selected from the group consist­ L-Histidine, Isoleucine, Leucine, Norvaline, Omithine, 45 ing of a nitrate, a nitrite, and both] nitrate salt com­ Valine, Aspartic Acid, Cysteine, Glycine, Lysine, pound; and Methionine, Praline, Tyrosine, and Phenylalanine, an isolated L-Histidine compound, wherein the L-Histi­ wherein the at least one isolated amino acid compound is dine compound is a separate compound than the at a separate compound than the at least one nitrate salt least one nitrate compound. compound. 50 10. [Anamino acid composition] A supplement formula­ 3. A method for increasing vasodilative characteristics in tion comprising: a human [or animal], the method comprising administering at least one [constituent selected from the group consist­ to the human [or animal] a pharmaceutically effective ing of a nitrate, a nitrite, and both] nitrate salt com­ amount of [an amino acid composition] a solid supplement pound; and formulation comprising: 55 an isolated Isoleucine compound, wherein the Isoleucine at least one [constituent selected from the group consist­ compound is a separate compound than the at least one ing of a nitrate, a nitrite, and both] nitrate salt com­ nitrate salt compound. pound; and 11. [An amino acid composition] A supplement formula­ at least one [constituent] isolated amino acid compound tion comprising: selected from the group consisting of Agmatine, Beta 60 at least one [constituent selected from the group consist­ Alanine, Citrulline, Creatine, Glutamine, L-Histidine, ing of a nitrate, a nitrite, and both] nitrate salt com­ Isoleucine, Leucine, Norvaline, Omithine, Valine, pound; and Aspartic Acid, Cysteine, Glycine, Lysine, Methionine, an isolated Leucine compound, wherein the Leucine com­ Praline, Tyrosine, and Phenylalanine, pound is a separate compound than the at least one wherein the at least one isolated amino acid compound is 65 nitrate salt compound. a separate compound than the at least one nitrate salt 12. [Anamino acid composition] A supplement formula­ compound. tion comprising: Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 36 of 109 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 37 of 109 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 38 of 109 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 39 of 109 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 40 of 109 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 41 of 109

EXHIBIT I Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 42 of 109 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 43 of 109 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 44 of 109 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 45 of 109 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 46 of 109 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 47 of 109 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 48 of 109

EXHIBIT II Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 49 of 109 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 50 of 109

US 8,183,288 Cl 1 2 EXPARTE 2. The method of claim 1, wherein the amino acid com­ pound consists essentially of a nitrate ofArginine. REEXAMINATION CERTIFICATE 3. The method of claim 1, wherein the amino acid com­ pound consists essentially of a nitrate ofAgmatine. THE PATENT IS HEREBY AMENDED AS 4. The method of claim 1, wherein the amino acid com­ INDICATED BELOW. pound consists essentially of a nitrate of Beta Alanine. Matter enclosed in heavybrackets [ ] appeared in the 5. The method of claim 1, wherein the amino acid com­ patent, but has been deleted and is no longer a part of the pound consists essentially of a nitrate of Citrulline. patent; matter printed in italics indicates additions made 6. The method of claim 1, wherein the amino acid com­ IO to the patent. pound consists essentially of a nitrate of Creatine. 7. The method of claim 1, wherein the amino acid com­ AS A RESULT OF REEXAMINATION, IT HAS BEEN pound consists essentially of a nitrate of Glutamine. DETERMINED THAT: 8. The method of claim 1, wherein the amino acid com­ pound consists essentially of a nitrate of L-Histidine. Claim 1 is determined to be patentable as amended. 15 9. The method of claim 1, wherein the amino acid com- New claims 2-13 are added and determined to be pound consists essentially of a nitrate of Isoleucine. patentable. 10. The method of claim 1, wherein the amino acid 1. A method for increasing the bioabsorption of amino compound consists essentially of a nitrate of Leucine. [ ] 11. The method of claim 1, wherein the amino acid acids in a human or animal , the method comprising admin­ 20 istering orally to the human [or animal] a pharmaceutically compound consists essentially of a nitrate of Norvaline. effective amount of an amino acid compound consisting 12. The method of claim 1, wherein the amino acid essentially of a nitrate [or nitrite] of an amino acid selected compound consists essentially of a nitrate of Ornithine. from the group consisting of Arginine, Agmatine, Beta 13. The method of claim 1, wherein the amino acid Alanine, Citrulline, Creatine, Glutamine, L-Histidine, Iso­ compound consists essentially of a nitrate of Valine. leucine, Leucine, Norvaline, Omithine, and Valine. * * * * * Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 51 of 109

EXHIBIT J Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 52 of 109 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 53 of 109

US 8,952,046 Cl 1 2 EXPARTE from the group consisting of a carrier,an excipient, a binder, a colorant, a flavoring agent, a preservative, a buffer, a REEXAMINATION CERTIFICATE dilutant, and any combination thereof. 10. The solid supplement formulation of claim 8 in a THE PATENT IS HEREBY AMENDED AS dosage form selected from the group consisting of a capsule, INDICATED BELOW. a cachet, a pill, a tablet, a powder, a granule, a pellet, a bead, Matter enclosed in heavybrackets [ ] appeared in the a particle, a troche, and a lozenge[, and a gel]. patent, but has been deleted and is no longer a part of the 11. The solid supplement formulationof claim 8, wherein at least one isolated nitrate salt comprises sodium nitrate, patent; matter printed in italics indicates additions made 10 to the patent. potassium nitrate, barium nitrate, calcium nitrate, and any combination thereof{, and the nitrite salt comprises sodium AS A RESULT OF REEXAMINATION, IT HAS BEEN nitrite, potassium nitrite, barium nitrite, calcium nitrite, and DETERMINED THAT: any combination thereof]. 15 13. The solid supplement formulation of claim [12] 11, Claims 5 and 12 are cancelled. wherein the isolated nitrate salt comprises sodium nitrate. Claims 1-4, 6-11 and 13-14 are determined to be 14. The solid supplement formulation of claim [12] 11, patentable as amended. wherein the isolated nitrate salt comprises potassium nitrate. New claims 15-54 are added and determined to be 15. The solid composition of claim 1, wherein the at least patentable. 20 one isolated amino acid compound is Arginine. 1. A solid composition comprising: 16. The solid composition of claim 1, wherein the at least at least one [constituent selected from the group consist­ one isolated amino acid compound is Agmatine. ing of a nitrate, a nitrite, and both] isolated nitrate salt 17. The solid composition of claim 1, wherein the at least compound; and one isolated amino acid compound is Beta Alanine. at least one [constituent] isolated amino acid compound 25 18. The solid composition of claim 1, wherein the at least selected from the group consisting of Arginine, Agma­ one isolated amino acid compound is Citrulline. tine, Beta Alanine, Citrulline, Creatine, Glutamine, 19. The solid composition of claim 1, wherein the at least L-Histidine, Isoleucine, Leucine, Norvaline, Omithine, one isolated amino acid compound is Creatine. Valine, Aspartic Acid, Cysteine, Glycine, Lysine, 20. The solid composition of claim 1, wherein the at least Methionine, Praline, Tyrosine, and Phenylalanine, 30 one isolated amino acid compound is Glutamine. wherein the at least one isolated amino acid compound is 21. The solid composition of claim 1, wherein the at least a separate compound than the at least one isolated one isolated amino acid compound is L-Histidine. nitrate salt compound. 22. The solid composition of claim 1, wherein the at least 2. The solid composition of claim 1 further comprising one isolated amino acid compound is Isoleucine. one or more additional components selected from the group 35 23. The solid composition of claim 1, wherein the at least consisting of a carrier, an excipient, a binder, a colorant, a one isolated amino acid compound is Leucine. flavoring agent, a preservative, a buffer, a dilutant, and any 24. The solid composition of claim 1, wherein the at least combination thereof. one isolated amino acid compound is Norvaline. 3. The solid composition of claim 1 in a dosage form 25. The solid composition of claim 1, wherein the at least selected from the group consisting of a capsule, a cachet, a 40 one isolated amino acid compound is Ornithine. pill, a tablet, a powder, a granule, a pellet, a bead, a particle, 26. The solid composition of claim 1, wherein the at least a troche, and a lozenge[, and a gel]. one isolated amino acid compound is Valine. 4. The solid composition of claim 1, wherein the at least 2 7. The solid composition of claim 1, wherein the at least one nitrate salt comprises sodium nitrate, potassium nitrate, one isolated amino acid compound is Aspartic Acid. barium nitrate, calcium nitrate, and any combination 45 28. The solid composition of claim 1, wherein the at least thereof{, and the nitrite salt comprises sodium nitrite, potas­ one isolated amino acid compound is Cysteine. sium nitrite, barium nitrite, calcium nitrite, and any combi­ 29. The solid composition of claim 1, wherein the at least nation thereof]. one isolated amino acid compound is Glycine. 6. The solid composition of claim [5] 4, wherein the at 30. The solid composition of claim 1, wherein the at least least one nitrate salt compound comprises sodium nitrate. 50 one isolated amino acid compound is Lysine. 7. The composition of claim [5] 4, wherein the at least one 31. The solid composition of claim 1, wherein the at least nitrate salt compound comprises potassium nitrate. one isolated amino acid compound is Methionine. 8. A solid supplement formulation comprising: 32. The solid composition of claim 1, wherein the at least at least one isolated nitrate salt compound [constituent one isolated amino acid compound is Praline. selected from the group consisting of a nitrate salt, a 55 33. The solid composition of claim 1, wherein the at least nitrite salt, and both]; and one isolated amino acid compound is Tyrosine. at least one [constituent] isolated amino acid compound 34. The solid composition of claim 1, wherein the at least selected from the group consisting of Arginine, Agma­ one isolated amino acid compound is Phenylalanine. tine, Beta Alanine, Citrulline, Creatine, Glutamine, 35. The solid supplement formulation of claim 8, wherein L-Histidine, Isoleucine, Leucine, Norvaline, Omithine, 60 the at least one isolated amino acid compound is Arginine. Valine, Aspartic Acid, Cysteine, Glycine, Lysine, 36. The solid supplement formulation of claim 8, wherein Methionine, Praline, Tyrosine, and Phenylalanine, the at least one isolated amino acid compound is Agmatine. wherein the at least one isolated amino acid compound is 3 7. The solid supplement formulation of claim 8, wherein a separate compound than the at least one isolated the at least one isolated amino acid compound is Beta nitrate salt compound. 65 Alanine. 9. The solid supplement formulation of claim 8 further 3 8. The solid supplement formulation of claim 8, wherein comprising one or more additional components selected the at least one isolated amino acid compound is Citrulline. Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 54 of 109 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 55 of 109

EXHIBIT K Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 56 of 109

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EXHIBIT L Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 79 of 109

Infringement of the ‘531 Patent

Claim Jack’d Up Mesomorph Mesomorph v. Anavar Phosphagen Creatine Nitrate TruePump, PWO-MAX Wicked 2.0 1. A solid Yes - Powder Yes – Powder Yes – Powder Yes – Tablet Yes – Powder Yes – Tablet Yes – Powder Yes – Powder Yes – Powder supplement formulation formulation formulation formulation formulation formulation formulation formulation formulation formulation comprising: at least one nitrate Includes at least Includes at least Includes at least Includes at least Includes at least Includes at least Includes at least Includes at least Includes at least salt compound; Creatine Nitrate, Creatine Nitrate, Creatine Nitrate, Creatine Nitrate, Creatine Nitrate, Creatine Nitrate, sodium nitrate, sodium nitrate, Creatine Nitrate, which is a nitrate which is a nitrate which is a nitrate which is a nitrate which is a nitrate which is a nitrate which is a nitrate which is a nitrate which is a nitrate salt compound. salt compound. salt compound. salt compound. salt compound. salt compound. salt compound. salt compound. salt compound. and at least one Includes at least Includes at least Includes at least Includes at least Includes at least Includes at least Includes at least Includes at least Includes at least isolated amino acid one isolated one isolated one isolated one isolated one isolated one isolated amino one isolated amino one isolated one isolated amino compound selected amino acid amino acid amino acid amino acid amino acid acid compound acid compound amino acid acid compound from the group compound compound compound compound compound comprising at least comprising at least compound comprising at least consisting of comprising at comprising at comprising at comprising at comprising at dicreatine malate, agmatine sulfate, comprising at agmatine silicate, Agmatine, Beta least agmatine least agmatine least agmatine least creatine least creatine HCl which is a histidine, L- least agmatine histidine, L- Alanine, Citrulline, sulfate and beta sulfate and beta sulfate and beta HCl and L- and beta alanine compound of malic citruline, L- sulfate and beta citruline silicate, Creatine, alanine alanine alanine cysteine HCl acid and creatine norvaline, and L- alanine and beta alanine Glutamine, L- valine Histidine, Isoleucine, Leucine, Norvaline, Omithine, Valine, Aspartic Acid, Cysteine, Glycine, Lysine, Methionine, Praline, Tyrosine, and Phenylalanine, wherein the at least The agmatine The agmatine The agmatine The creatine HCl The creatine HCl The dicreatine Includes agmatine The agmatine The agmatine one isolated amino sulfate and beta sulfate and beta sulfate and beta and L-cysteine and beta alanine malate is separate sulfate, histidine, sulfate and beta silicate, histidine, acid compound is a alanine are each alanine are each alanine are each HCl are each are each separate from the creatine L-citruline, L- alanine are each L-citruline silicate, separate compound separate from the separate from the separate from the separate from the from the creatine nitrate norvaline, and L- separate from the and beta alanine than the at least creatine nitrate creatine nitrate creatine nitrate creatine nitrate nitrate valine are each sodium nitrate are each separate one nitrate salt separate from the from the creatine compound. sodium nitrate nitrate

Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 80 of 109

Infringement of the ‘187 Patent

Claim Jack’d Up Mesomorph Mesomorph v. 2.0 TruePump PWO-MAX Wicked 4. A method for The product is designed The product is designed The product is designed and The product is designed and The product is designed and The product is designed and increasing and intended to and – on and intended to and – on intended to and – on intended to and – on intended to and – on intended to and – on athletic information and belief – information and belief – in information and belief – in information and belief – in information and belief – in fact information and belief – in fact performance in a in fact does increase fact does increase athletic fact does increase athletic fact does increase athletic does increase athletic does increase athletic human or athletic performance. performance. Defendants performance. Defendants tout performance. Defendants performance. Defendants tout performance. Defendants tout animal, Defendants tout this tout this advantage, this advantage, explaining that tout this advantage, this advantage, explaining that this advantage, explaining that advantage, explaining that explaining that - for - for example - the product has explaining that - for example - for example - the product will - for example - the product - for example - the example - the product is a “cutting edge preworkout - the product “enhances blood “[i]gnite each workout with a “provides explosive energy, product “Elevates Nitric “guaranteed to deliver eye formula that will cause you to flow to allow more nutrients highly potent dose beta long-lasting endurance, Oxide (NO) levels for opening energy, focus, and experience out of this world and oxygen to be shuttled into alanine, a widely researched increased strength and power, Extreme Muscle Pumps stamina like nothing you’ve pumps, and tons of extra your muscles. This results in lactic acid buffering molecule road-map vascularity, and Produces An Intense ever experienced before,” energy and unleash your true better pumps, increased proven to increase athletic razor-sharp mental focus,” and Sensation Of Energy,” “Will Help Athletes with muscle building and genetic endurance and quicker performance. You will be able “will help you to have the best “Increases Speed, Power the Following: potential,” and recovery.” to train longer and with more workouts of your life!” & Endurance,” and … Unleash Your True “Will Help Athletes with the intensity than you have ever “Experience Extreme Genetic Potential! Following: thought possible … [and] Pumps and Strength” Greater Muscle Gains and … Unleash Your True Genetic speed recovery time between Enhanced Athletic Potential! workouts and enhance muscle Performance.” Greater Muscle Gains and pump.” Enhanced Athletic Performance.”

the method Product is administered Product is administered Product is administered orally Product is administered orally Product is administered orally Product is administered orally comprising orally to a human. orally to a human. Product to a human. Product includes to a human. Product includes to a human. Product includes a to a human. orally Product includes a includes a pharmaceutically a pharmaceutically effective a pharmaceutically effective pharmaceutically effective administering to pharmaceutically effective amount of an amount of an amino acid amount of an amino acid amount of an amino acid Product further includes a the human or effective amount of an amino acid composition composition comprising composition comprising composition comprising pharmaceutically effective animal a amino acid composition comprising creatine nitrate, creatine nitrate, which is a salt sodium nitrate, which is a salt sodium nitrate, which is a salt amount of an amino acid pharmaceutically comprising creatine which is a salt of nitrate. of nitrate. of nitrate. of nitrate. composition comprising effective amount nitrate, which is a salt of creatine nitrate, which is a salt of an amino acid nitrate. The amino acid The amino acid composition The amino acid composition The amino acid composition of nitrate. composition composition further further includes agmatine in further includes agmatine in further includes agmatine in comprising at The amino acid includes agmatine in the the form of agmatine sulfate. the form of agmatine sulfate. the form of agmatine sulfate. The amino acid composition least one composition further form of agmatine sulfate. further includes agmatine constituent includes agmatine in the Product also includes beta The product further includes The product further includes silicate. Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 81 of 109

Claim Jack’d Up Mesomorph Mesomorph v. 2.0 TruePump PWO-MAX Wicked selected from the form of agmatine sulfate. Product also includes beta alanine, di-creatine malate, histidine, L-citruline, L- beta alanine. group consisting alanine, di-creatine malate, and arginine (Arginine Alpha- norvaline, and L-valine The product further includes of a salt of a Product also includes beta and arginine (Arginine Ketoglutarate). beta alanine, histidine, and L- nitrate (NO 3-), alanine and arginine Alpha-Ketoglutarate). citruline silicate a mixed salt of a (Arginine Alpha- nitrate (NO 3-), Ketoglutarate).. a salt of a nitrate (NO 2-), and a mixed salt of a nitrate (NO 2-); and agmatine.

Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 82 of 109

Infringement of the ‘187 Patent (cont.)

Claim Jack’d Up Mesomorph Mesomorph v. 2.0 Phosphagen PWO-MAX Wicked 5. A method for The product is designed The product is designed The product is designed and The product is designed and The product is designed and The product is designed and increasing and intended to and – on and intended to and – on intended to and – on intended to and – on intended to and – on intended to and – on athletic information and belief – information and belief – in information and belief – in information and belief – in fact information and belief – in fact information and belief – in performance in a in fact does increase fact does increase athletic fact does increase athletic does increase athletic does increase athletic fact does increase athletic human or athletic performance. performance. Defendants performance. Defendants tout performance. Defendants tout performance. Defendants tout performance. Defendants tout animal, Defendants tout this tout this advantage, this advantage, explaining that this advantage, explaining that this advantage, explaining that this advantage, explaining that advantage, explaining explaining that - for - for example - the product has - for example - the product - for example - the product - for example - the product that - for example - the example - the product is a “cutting edge preworkout encourages “enhanced muscle will “[i]gnite each workout “provides explosive energy, product “Elevates Nitric “guaranteed to deliver eye formula that will cause you to work performance and with a highly potent dose beta long-lasting endurance, Oxide (NO) levels for opening energy, focus, and experience out of this world muscular development,” and alanine, a widely researched increased strength and power, Extreme Muscle Pumps stamina like nothing you’ve pumps, and tons of extra “the bodybuilder … will have lactic acid buffering molecule road-map vascularity, and Produces An Intense ever experienced before,” energy and unleash your true the extra amount of muscle proven to increase athletic razor-sharp mental focus,” and Sensation Of Energy,” “Will Help Athletes with muscle building and genetic fuel available to complete the performance. You will be able “will help you to have the best “Increases Speed, Power the Following: potential,” and one additional rep required to to train longer and with more workouts of your life!” & Endurance,” and … Unleash Your True “Will Help Athletes … pull the trigger for muscles to intensity than you have ever “Experience Extreme Genetic Potential! Unleash Your True Genetic grow.” thought possible … [and] Pumps and Strength” Greater Muscle Gains and Potential! speed recovery time between Enhanced Athletic Greater Muscle Gains and workouts and enhance muscle Performance.” Enhanced Athletic pump.” Performance.” the method Product is administered Product is administered Product is administered orally Product is administered orally Product is administered orally Product is administered orally comprising orally to a human. orally to a human. Product to a human. Product includes to a human. Product includes to a human. Product includes a to a human. Product further orally Product includes a includes a pharmaceutically a pharmaceutically effective a pharmaceutically effective pharmaceutically effective includes a pharmaceutically administering to pharmaceutically effective amount of an amount of an amino acid amount of an amino acid amount of an amino acid effective amount of an amino the human or effective amount of an amino acid composition composition comprising composition comprising composition comprising acid composition comprising animal a amino acid composition comprising creatine nitrate, creatine nitrate, which is a salt creatine nitrate, which is a salt sodium nitrate, which is a salt creatine nitrate, which is a salt pharmaceutically comprising creatine which is a salt of nitrate. of nitrate. of nitrate. of nitrate. of nitrate. effective amount nitrate, which is a salt of of an amino acid nitrate. The amino acid The amino acid composition The amino acid composition The amino acid composition The amino acid composition composition composition further further includes beta alanine. further includes beta alanine. further includes beta alanine. further includes beta alanine. comprising at The amino acid includes beta alanine. least one composition further Product also includes Product further include The product further includes The product further includes constituent includes beta alanine. Product also includes agmatine sulfate, di-creatine creatine HCl. agmatine sulfate. agmatine silicate, histidine, selected from the agmatine sulfate, di- malate, and arginine (Arginine and L-citruline silicate group consisting Product also includes creatine malate, and Alpha-Ketoglutarate). Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 83 of 109

Claim Jack’d Up Mesomorph Mesomorph v. 2.0 Phosphagen PWO-MAX Wicked of a salt of a agmatine sulfate and arginine (Arginine Alpha- nitrate (NO 3-), arginine (Arginine Alpha- Ketoglutarate). a mixed salt of a Ketoglutarate).. nitrate (NO 3-), a salt of a nitrate (NO 2-), and a mixed salt of a nitrate (NO 2-); and beta alanine.

Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 84 of 109

Infringement of the ‘187 Patent (cont.)

Claim Jack’d Up Mesomorph Mesomorph v. 2.0 Anavar Phosphagen Creatine Nitrate 7. A method for The product is designed The product is designed The product is designed and The product is designed and The product is designed and The product is designed and increasing and intended to and – on and intended to and – on intended to and – on intended to and – on intended to and – on intended to and – on athletic information and belief – information and belief – in information and belief – in information and belief – in fact information and belief – in fact information and belief – in performance in a in fact does increase fact does increase athletic fact does increase athletic does increase athletic does increase athletic fact does increase athletic human or athletic performance. performance. Defendants performance. Defendants tout performance. Defendants tout performance. Defendants tout performance. Defendants animal, Defendants tout this tout this advantage, this advantage, explaining that this advantage, explaining that this advantage, explaining that tout this advantage, advantage, explaining that explaining that - for - for example - the product has - for example - the product has - for example - the product explaining that - for example - for example - the example - the product is a “cutting edge preworkout an “Extraordinary Profile of encourages “enhanced muscle - the product increases product “Elevates Nitric “guaranteed to deliver eye formula that will cause you to Muscle-Building Agents and work performance and “Vascularity, Strength, ATP Oxide (NO) levels for opening energy, focus, and experience out of this world Strength Increasing muscular development,” and Elevation And Recovery!” Extreme Muscle Pumps stamina like nothing you’ve pumps, and tons of extra Compounds,” and “the “the bodybuilder … will have and that the user “will Produces An Intense ever experienced before,” energy and unleash your true bodybuilder … will have the the extra amount of muscle experience full, swollen Sensation Of Energy,” “Will Help Athletes with muscle building and genetic extra amount of muscle fuel fuel available to complete the muscle bellies complimented “Increases Speed, Power the Following: potential,” and available to complete the one additional rep required to by road map vascularity.” & Endurance,” and … Unleash Your True “Will Help Athletes with the additional reps required to pull pull the trigger for muscles to “Experience Extreme Genetic Potential! Following: the trigger for muscles to grow.” Pumps and Strength” Greater Muscle Gains and … Unleash Your True Genetic grow.” Enhanced Athletic Potential! Performance.” Greater Muscle Gains and Enhanced Athletic Performance.”

Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 85 of 109

Claim Jack’d Up Mesomorph Mesomorph v. 2.0 Anavar Phosphagen Creatine Nitrate the method Product is administered Product is administered Product is administered orally Product is administered orally Product is administered orally Product is administered orally comprising orally to a human. orally to a human. Product to a human. Product includes to a human. Product includes a to a human. Product includes a to a human. Product includes orally Product includes a includes a pharmaceutically a pharmaceutically effective pharmaceutically effective pharmaceutically effective a pharmaceutically effective administering to pharmaceutically effective amount of an amount of an amino acid amount of an amino acid amount of an amino acid amount of an amino acid the human or effective amount of an amino acid composition composition comprising composition comprising composition comprising composition comprising animal a amino acid composition comprising creatine nitrate, creatine nitrate, which is a salt creatine nitrate, which is a salt creatine nitrate, which is a salt creatine nitrate, which is a pharmaceutically comprising creatine which is a salt of nitrate. of nitrate. of nitrate. of nitrate. salt of nitrate. effective amount nitrate, which is a salt of of an amino acid nitrate. The amino acid The amino acid composition The amino acid composition The amino acid composition The amino acid composition composition composition further further includes creatine in the further includes creatine in the further includes creatine in the further includes comprising at The amino acid includes creatine in the form of di-creatine malate form of creatine HCl. form of creatine HCl, creatine creatine in the form of di- least one composition further form of di-creatine malate phosphate, and disodium creatine malate. constituent includes creatine in the Product also includes beta Product further includes L- creatine phosphate selected from the form of creatine Product also includes beta alanine, agmatine sulfate, di- cysteine HCl tetrahydrate. group consisting monohydrate. alanine, agmatine sulfate, creatine malate, and arginine of a salt of a di-creatine malate, and (Arginine Alpha- Product further includes beta nitrate (NO 3-), Product also includes arginine (Arginine Alpha- Ketoglutarate). alanine a mixed salt of a agmatine sulfate and Ketoglutarate). nitrate (NO 3-), arginine (Arginine Alpha- a salt of a nitrate Ketoglutarate).. (NO 2-), and a mixed salt of a nitrate (NO 2-); and creatine.

Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 86 of 109

Infringement of the ‘187 Patent (cont.)

Claim Jack’d Up Mesomorph Mesomorph v. 2.0 Anavar 61. A method for The product is designed and The product is designed and intended to The product is designed and intended to and – on The product is designed and intended to and – on increasing athletic intended to and – on information and – on information and belief – in fact information and belief – in fact does increase information and belief – in fact does increase performance in a and belief – in fact does increase does increase athletic performance. athletic performance. Defendants tout this athletic performance. Defendants tout this human or animal, athletic performance. Defendants Defendants tout this advantage, explaining advantage, explaining that - for example - the advantage, explaining that - for example - the tout this advantage, explaining that that - for example - the product is product has a “cutting edge preworkout formula product has an “Extraordinary Profile of Muscle- - for example - the product “guaranteed to deliver eye opening energy, that will cause you to experience out of this world Building Agents and Strength Increasing “Elevates Nitric Oxide (NO) levels focus, and stamina like nothing you’ve pumps, and tons of extra energy and unleash your Compounds,” and “the bodybuilder who wisely for Extreme Muscle Pumps ever experienced before,” true muscle building and genetic potential,” and chooses Anavar® will have the extra amount of Produces An Intense Sensation Of “Will Help Athletes with the Following: “Will Help Athletes with the Following: muscle fuel available to complete the additional Energy,” “Increases Speed, Power … Unleash Your True Genetic Potential! … Unleash Your True Genetic Potential! reps required to pull the trigger for muscles to & Endurance,” and Greater Muscle Gains and Enhanced Greater Muscle Gains and Enhanced Athletic grow.” “Experience Extreme Pumps and Athletic Performance.” Performance.” Strength”

the method Product is administered orally to a Product is administered orally to a human. Product is administered orally to a human. Product is administered orally to a human. Product comprising orally human. Product includes a Product includes a pharmaceutically Product includes a pharmaceutically effective includes a pharmaceutically effective amount of an administering to the pharmaceutically effective amount effective amount of an amino acid amount of an amino acid composition comprising amino acid composition comprising Arginine in human or animal a of an amino acid composition composition comprising Arginine in the Arginine in the form of Arginine Alpha- the form of L-Arginine HCl. pharmaceutically comprising Arginine in the form of form of Arginine Alpha-Ketoglutarate. Ketoglutarate. effective amount of L-Arginine Alpha-Ketoglutarate. The amino acid composition also includes at least an amino acid The amino acid composition also includes The amino acid composition also includes at least Creatine Nitrate, which is a salt of Nitrate. composition The amino acid composition also at least Creatine Nitrate, which is a salt of Creatine Nitrate, which is a salt of Nitrate. comprising includes at least Creatine Nitrate, Nitrate. Arginine and at which is a salt of Nitrate. least one constituent selected from the group consisting of a salt of a nitrate (NO 3 -) and a mixed salt of a nitrate (NO 3 -).

Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 87 of 109

Infringement of the ‘046 Patent

Claim Jack’d Up Mesomorph Mesomorph v. 2.0 Anavar Phosphagen Creatine TruePump PWO-MAX Wicked Nitrate 1. A solid Yes - Powder Yes – Powder Yes – Powder Yes – Tablet Yes – Powder Yes – Tablet Yes – Powder Yes – Powder Yes – Powder composition formulation formulation formulation formulation formulation formulation formulation formulation formulation comprising: at least one Includes at least Includes at least Includes at least Includes at least Includes at least Includes at least Includes at least Includes at least Includes at least isolated nitrate Creatine Nitrate, Creatine Nitrate, Creatine Nitrate, Creatine Nitrate, Creatine Nitrate, Creatine Nitrate, sodium nitrate, sodium nitrate, Creatine Nitrate, salt compound; which is an isolated which is an isolated which is an isolated which is an which is an isolated which is an which is an which is an which is an nitrate salt nitrate salt nitrate salt isolated nitrate nitrate salt isolated nitrate isolated nitrate isolated nitrate isolated nitrate compound. compound. compound. salt compound. compound. salt compound. salt compound. salt compound. salt compound. and at least one Includes L-arginine Includes arginine Includes arginine Includes at least Includes creatine Includes Includes Includes N- Includes isolated amino alpha-ketoglutarate, alpha ketoglutarate, alpha ketoglutarate, creatine HCl, L- HCl, creatine dicreatine agmatine sulfate, acetyl L- agmatine acid compound creatine agmatine sulfate, l- agmatine sulfate, l- arginine HCl, phosphate, malate, which is histidine, L- tyrosine, silicate, selected from monohydrate, citrulline DL-malate, citrulline DL-malate, and L-cysteine disodium creatine a compound of citruline, L- agmatine histidine, L- the group agmatine sulfate, di-creatine malate, di-creatine malate, HCl phosphate and leucine, L- sulfate, and beta citruline silicate, consisting of and beta alanine and beta alanine and beta alanine tetrahydrate, and creatine norvaline, and L- alanine and beta alanine. Arginine, beta alanine valine Agmatine, Beta Alanine, Citrulline, Creatine, Glutamine, L- Histidine, Isoleucine, Leucine, Norvaline, Omithine, Valine, Aspartic Acid, Cysteine, Glycine, Lysine, Methionine, Praline, Tyrosine, and Phenylalanine,

Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 88 of 109

Infringement of the ‘572 Patent

Claim Jack’d Up Mesomorph Mesomorph v. Anavar Phosphagen Creatine TruePump PWO-MAX Wicked 2.0 Nitrate 1. A method for The product is The product is The product is The product is The product is The product is The product is The product is The product is designed increasing vasodilative designed and designed and designed and designed and designed and designed and designed and designed and and intended to and – on characteristics in a intended to and intended to and intended to and intended to and intended to and intended to and intended to and intended to and information and belief – human, – on information – on information – on information – on information – on information – on information – on information – on information in fact does increase and belief – in and belief – in and belief – in and belief – in and belief – in and belief – in and belief – in and belief – in athletic performance. fact does fact does fact does fact does fact does fact does fact does fact does Defendants tout this increase increase increase increase increase increase increase increase advantage, explaining vasodilative vasodilative vasodilative vasodilative vasodilative vasodilative vasodilative vasodilative that - for example - the characteristics in characteristics in characteristics in characteristics in characteristics in characteristics in characteristics in characteristics in product provides “road- a human. a human. a human. a human. a human. a human. a human. a human. map vascularity,” and Defendants tout Defendants tout Defendants tout Defendants tout Defendants tout Defendants tout Defendants tout Defendants tout “skin tearing pumps and this advantage, this advantage, this advantage, this advantage, this advantage, this advantage, this advantage, this advantage, freaky vascularity.” explaining that - explaining that - explaining that - explaining that - explaining that - explaining that - explaining that - explaining that - for example - the for example - the for example - the for example - the for example - the for example - the for example - the for example - the product product product product product product product product includes produces produces “vein produces “vein “Contains L- “volumize[s] “provide[s] more “increases a “scientifically “Extreme Pumps blasting” blasting” Arginine and the muscle cells,” vasodilation and training volume, backed dose of and Strength,” performance and performance, as Arginase and “enhance[s] vascularity than blood flow and Agmatine “muscle- “out of this well as “mind Inhibitors ABH the anabolic ANY current nitric oxide Sulfate, a engorging world pumps.” blowing” and and BEC for effect of greater Nitric production, vasodilator with pumps,” and “out of this Maximum muscle cell Oxide/pump leading to better the ability to “pumps and world pumps.” Muscle volumization.” product.” pumps,” and greatly expand vascularity are Vasodilation.” “promot[es] blood vessels, out of this blood flow allowing for world.” during resistance nutrients to flow training” fast and freely throughout the body … to speed recovery time between workouts and enhance muscle pump.”

Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 89 of 109

Claim Jack’d Up Mesomorph Mesomorph v. Anavar Phosphagen Creatine TruePump PWO-MAX Wicked 2.0 Nitrate the method comprising Product is Product is Product is Product is Product is Product is Product is Product is Product is administered administering orally to administered administered administered administered administered administered administered administered orally to a human. the human a orally to a orally to a orally to a orally to a orally to a orally to a orally to a orally to a Product includes a pharmaceutically human. Product human. Product human. Product human. Product human. Product human. Product human. Product human. Product pharmaceutically effective amount of an includes a includes a includes a includes a includes a includes a includes a includes a effective amount of an amino acid compound pharmaceutically pharmaceutically pharmaceutically pharmaceutically pharmaceutically pharmaceutically pharmaceutically pharmaceutically amino acid compound, consisting essentially of effective amount effective amount effective amount effective amount effective amount effective amount effective amount effective amount including at least a nitrate of an amino of an amino acid of an amino acid of an amino acid of an amino acid of an amino acid of an amino acid of an amino acid of an amino acid agmatine silicate, acid selected from the compound, compound, compound, compound, compound, compound, compound, compound, histidine, L-citrulline group consisting of including at least including at least including at least including at least including at least including at least including at least including at least silicate, and beta alanine. Arginine, Agmatine, L-arginine arginine alpha arginine alpha at least creatine creatine HCl, dicreatine agmatine sulfate, N-acetyl L- Beta Alanine, Citrulline, alpha- ketoglutarate, ketoglutarate, HCl, L-arginine creatine malate, which is histidine, L- tyrosine, Creatine, Glutamine, L- ketoglutarate, agmatine sulfate, agmatine sulfate, HCl, and L- phosphate, a compound of citrulline, L- agmatine sulfate, Histidine, Isoleucine, creatine l-citrulline DL- l-citrulline DL- cysteine HCl disodium malic acid and leucine, L- and beta alanine Leucine, Norvaline, monohydrate, malate, di- malate, di- creatine creatine norvaline, and Ornithine, and Valine. agmatine sulfate, creatine malate, creatine malate, phosphate L-valine and beta alanine and beta alanine and beta alanine tetrahydrate, and beta alanine

Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 90 of 109

Infringement of the ‘288 Patent

Claim Jack’d Up Mesomorph Mesomorph v. 2.0 Anavar Phosphagen Creatine Nitrate TruePump PWO-MAX Wicked 1. A The product is The product is The product is The product is The product is The product is The product is The product is The product is method designed and designed and designed and designed and designed and designed and designed and designed and designed and for intended to and – on intended to and – on intended to and – on intended to and – on intended to and – on intended to and – on intended to and – on intended to and – on intended to and – on increasi information and information and information and information and information and information and information and information and information and ng the belief – in fact does belief – in fact does belief – in fact does belief – in fact does belief – in fact does belief – in fact does belief – in fact does belief – in fact does belief – in fact does bioabso increase increase increase increase increase increase increase increase increase rption bioabsorption of bioabsorption of bioabsorption of bioabsorption of bioabsorption of bioabsorption of bioabsorption of bioabsorption of bioabsorption of of amino acids in a amino acids in a amino acids in a amino acids in a amino acids in a amino acids in a amino acids in a amino acids in a amino acids in a amino human. Indeed, this human. Indeed, this human. Indeed, this human. Indeed, this human. Indeed, this human. Indeed, this human. Indeed, this human. Indeed, this human. Indeed, this acids in specific benefit of specific benefit of specific benefit of specific benefit of specific benefit of specific benefit of specific benefit of specific benefit of specific benefit of a Plaintiff’s invention Plaintiff’s invention Plaintiff’s invention Plaintiff’s invention Plaintiff’s invention Plaintiff’s invention Plaintiff’s invention Plaintiff’s invention Plaintiff’s invention human, has recently become has recently become has recently become has recently become has recently become has recently become has recently become has recently become has recently become generally recognized generally recognized generally recognized generally recognized generally recognized generally recognized generally recognized generally recognized generally recognized by both Defendants by both Defendants by both Defendants by both Defendants by both Defendants by both Defendants by both Defendants by both Defendants by both Defendants as well as others in as well as others in as well as others in as well as others in as well as others in as well as others in as well as others in as well as others in as well as others in the industry. See, the industry. See, the industry. See, the industry. See, the industry. See, the industry. See, the industry. See, the industry. See, the industry. See, e.g., e.g., e.g., e.g., e.g., e.g., e.g., e.g., e.g., http://www.livestron http://www.livestron http://www.livestron http://www.livestron http://www.livestron http://www.livestron http://www.livestron http://www.livestron http://www.livestron g.com/article/51648 g.com/article/51648 g.com/article/51648 g.com/article/51648 g.com/article/51648 g.com/article/51648 g.com/article/51648 g.com/article/51648 g.com/article/51648 5-how-to-increase- 5-how-to-increase- 5-how-to-increase- 5-how-to-increase- 5-how-to-increase- 5-how-to-increase- 5-how-to-increase- 5-how-to-increase- 5-how-to-increase- your-absorption-of- your-absorption-of- your-absorption-of- your-absorption-of- your-absorption-of- your-absorption-of- your-absorption-of- your-absorption-of- your-absorption-of- arginine/ arginine/; see also arginine/; see also arginine/; see also arginine/; see also arginine/; see also arginine/; see also arginine/; see also arginine/; see also (“[s]upplements https://thefeed.com/ https://thefeed.com/ https://thefeed.com/ https://thefeed.com/ https://thefeed.com/ https://thefeed.com/ https://thefeed.com/ https://thefeed.com/ with a high quality blogs/news/10- blogs/news/10- blogs/news/10- blogs/news/10- blogs/news/10- blogs/news/10- blogs/news/10- blogs/news/10- L-glutamine product benefits-of-amino- benefits-of-amino- benefits-of-amino- benefits-of-amino- benefits-of-amino- benefits-of-amino- benefits-of-amino- benefits-of-amino- as this will enhance acid-supplements; acid-supplements; acid-supplements; acid-supplements; acid-supplements; acid-supplements; acid-supplements; acid-supplements; the absorption rate https://www.mysupp https://www.mysupp https://www.mysupp https://www.mysupp https://www.mysupp https://www.mysupp https://www.mysupp https://www.mysupp of nutrients in the lementstore.com/hi- lementstore.com/hi- lementstore.com/hi- lementstore.com/hi- lementstore.com/hi- lementstore.com/hi- lementstore.com/hi- lementstore.com/hi- small intestine tech- tech- tech- tech- tech- tech- tech- tech- where amino acids, pharmaceuticals- pharmaceuticals- pharmaceuticals- pharmaceuticals- pharmaceuticals- pharmaceuticals- pharmaceuticals- pharmaceuticals- including arginine is phosphagen-500- phosphagen-500- phosphagen-500- phosphagen-500- phosphagen-500- phosphagen-500- phosphagen-500- phosphagen-500- absorbed.”); see also grams.html grams.html grams.html grams.html grams.html grams.html grams.html grams.html https://thefeed.com/ blogs/news/10- benefits-of-amino- acid-supplements (“[A]mino acids Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 91 of 109

Claim Jack’d Up Mesomorph Mesomorph v. 2.0 Anavar Phosphagen Creatine Nitrate TruePump PWO-MAX Wicked compete for absorption with each other. To get the full benefit of BCAAs, then, a dedicated amino acid supplement, such as Klean BCAA, is needed.”); https://www.mysupp lementstore.com/hi- tech- pharmaceuticals- phosphagen-500- grams.html (Phosphagen “Increases Creatine Absorption”) the Product is Product is Product is Product is Product is Product is Product is Product is Product is method administered orally administered orally administered orally administered orally administered orally administered orally administered orally administered orally administered orally compris to a human. Product to a human. Product to a human. Product to a human. Product to a human. Product to a human. Product to a human. Product to a human. Product to a human. Product ing includes a includes a includes a includes a includes a includes a includes a includes a includes a adminis pharmaceutically pharmaceutically pharmaceutically pharmaceutically pharmaceutically pharmaceutically pharmaceutically pharmaceutically pharmaceutically tering effective amount of effective amount of effective amount of effective amount of effective amount of effective amount of effective amount of effective amount of effective amount of orally an amino acid an amino acid an amino acid an amino acid an amino acid an amino acid an amino acid an amino acid an amino acid to the compound, compound, compound, compound, compound, compound, compound, compound, compound, human including at least including at least including at least including at least including at least including at least including at least including at least including at least a L-arginine alpha- arginine alpha arginine alpha at least creatine creatine HCl, dicreatine malate, agmatine sulfate, N-acetyl L-tyrosine, agmatine silicate, pharma ketoglutarate, ketoglutarate, ketoglutarate, HCl, L-arginine creatine phosphate, which is a histidine, L- agmatine sulfate, histidine, L- ceutical creatine agmatine sulfate, l- agmatine sulfate, l- HCl, and L-cysteine disodium creatine compound of malic citrulline, L-leucine, and beta alanine citrulline silicate, ly monohydrate, citrulline DL- citrulline DL- HCl phosphate acid and creatine L-norvaline, and L- and beta alanine. effectiv agmatine sulfate, malate, di-creatine malate, di-creatine tetrahydrate, and valine e and beta alanine malate, and beta malate, and beta beta alanine amount alanine alanine of an amino acid compou nd Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 92 of 109

Claim Jack’d Up Mesomorph Mesomorph v. 2.0 Anavar Phosphagen Creatine Nitrate TruePump PWO-MAX Wicked consisti ng essentia lly of a nitrate of an amino acid selected from the group consisti ng of Arginin e, Agmati ne, Beta Alanine , Citrulli ne, Creatin e, Glutami ne, L- Histidin e, Isoleuci ne, Leucine , Norvali ne, Omithin e, and Valine.

Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 93 of 109

EXHIBIT M Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 94 of 109 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 95 of 109 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 96 of 109 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 97 of 109

EXHIBIT N Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 98 of 109

1 Gregory B. Collins (#023158) Jenessa G. B. Coccaro (#027090) 2 KERCSMAR & FELTUS PLLC 6263 North Scottsdale Road, Suite 320 3 Scottsdale, Arizona 85250 Telephone: (480) 421-1001 4 Fax: (480) 421-1002 [email protected] 5 [email protected] 6 Attorneys for Plaintiff ThermoLife International LLC 7 UNITED STATES DISTRICT COURT 8 FOR THE DISTRICT OF ARIZONA 9 ThermoLife International, LLC, an

10 Arizona limited liability company, No.

11 Plaintiff, COMPLAINT 85250 12 v. Road, Suite 320 Suite Road, 1001 - 13 Hi-Tech Pharmaceuticals, Inc. a Georgia corporation, 14 (480) 421 (Jury Trial Demanded) Defendant.

Scottsdale, Arizona 15 Kercsmar & Feltus PLLC Feltus & Kercsmar

6263 North Scottsdale 6263Scottsdale North 16 Plaintiff ThermoLife International LLC, for its complaint against defendant Hi- 17 Tech Pharmaceuticals Inc. (“Hi-Tech”) alleges upon personal knowledge with respect to 18 itself and its own acts, and upon information and belief with respect to all other matters, as 19 follows: 20 NATURE OF ACTION 21 1. Plaintiff ThermoLife International LLC (“ThermoLife”) brings claims for 22 patent infringement, inducement of patent infringement, and contributory patent 23 infringement against its competitor Hi-Tech. 24 2. Hi-Tech is openly violating ThermoLife’s U.S. Patent No. 7,777,074 (“the 25 ‘074 Patent”), which protects and covers amino acid compounds consisting a nitrate of an 26 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 99 of 109

1 amino acid, including Creatine Nitrate. See Exhibit A. As stated in the ‘074 Patent, 2 Creatine Nitrate effectively increases vasodilatation in humans, and is, therefore, a 3 desirable additive to dietary supplements for athletes and others. 4 3. Hi-Tech is also openly violating ThermoLife’s U.S. Patent No. 8,178,572 5 (“the ‘572 Patent”), which protects and covers “a method for increasing the vasodilative 6 characteristics of amino acids in a human or animal, the method comprising 7 administering to the human or animal a pharmaceutically effective amount of an amino 8 acid compound consisting essentially of a nitrate or nitrate of an amino acid selected from 9 the group consisting of Arginine, Armatine, Beta Alanine, Citrulline, Creatine,

10 Glutamine, L-Histidine, Isoleucine, Leucine, Norvaline, Ornithine, and Valine.” See

11 Exhibit B.

85250 12 4. Hi-Tech previously obtained its supply of ThermoLife’s patented Creatine 1001 - 13 Nitrate through ThermoLife’s authorized supplier, Prinova (formerly Premium 14 Ingredients International). Since April 2011, Hi-Tech has not purchased Creatine Nitrate (480) 421 Scottsdale, Arizona North Scottsdale Road, Suite 320 Road, Suite Scottsdale North 15 from Prinova; nonetheless, Hi-Tech continues to manufacture and distribute dietary Kercsmar & Feltus PLLC Feltus & Kercsmar

6263 16 supplements that include ThermoLife’s patented Creatine Nitrate. 17 5. In this case, Hi-Tech has violated ThermoLife’s ‘074 Patent and ‘572 Patent 18 by manufacturing and selling at least the following products: BodyFuse’s Torque 19 Reloaded, BodyFuse’s Cre-8, NLN’s N-Power, NZ Nutraceuticals’ Invincible, Unleashed 20 Muscle’s Creatine Nitrate, Unleashed Muscle’s Uprising. Each of these products rely on 21 Creatine Nitrate to increase the vasodilative characteristics of amino acids in a human. In 22 addition to the identified products, ThermoLife believers that Hi-Tech has manufactured 23 and sold other products that infringe ThermoLife’s ‘074 Patent and ‘572 Patent. 24 6. ThermoLife brings this action to enjoin Hi-Tech from continuing to violate 25 the ‘074 Patent and ‘572 Patent and to recover a reasonable royalty and treble damages for 26

2 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 100 of 109

1 its lost sales resulting from defendant’s willful infringement. In addition, Hi-Tech should 2 be made to disgorge its illegal profits made by violating ThermoLife’s valid patents. 3 PARTIES, JURISDICTION AND VENUE 4 7. Plaintiff ThermoLife is an Arizona limited liability company. ThermoLife’s 5 principal place of business is 3914 East Chandler Boulevard, Phoenix, Arizona 85048. 6 8. Hi-Tech is a Georgia corporation, with its principle place of business located 7 at 6015-B Unity Drive, Norcross, Georgia 30071. 8 9. Hi-Tech ships and sells products nationwide, including in Arizona. 9 10. Hi-Tech advertises its products nationwide, including in Arizona.

10 11. The Court has jurisdiction over Plaintiff’s federal claims under 28 U.S.C.

11 §§1331 and 1338 because this action, at least in part, is for patent infringement and arises

85250 12 under the patent laws of the United States, Title 35, Section 271 et seq. of the United 1001 - 13 States Code. 14 12. This Court also has jurisdiction over this matter pursuant to 28 U.S.C. §1332 (480) 421 Scottsdale, Arizona North Scottsdale Road, Suite 320 Road, Suite Scottsdale North 15 because ThermoLife and Hi-Tech are diverse in citizenship and the amount in Kercsmar & Feltus PLLC Feltus & Kercsmar

6263 16 controversy exceeds $75,000, exclusive of interests and costs. 17 13. Venue is proper in this District under 28 U.S.C. §1391(b)-(c), because a 18 substantial part of the events or omissions giving rise to ThermoLife’s claims occurred in 19 this District. Venue with respect to Hi-Tech is also proper in this district because Hi-Tech 20 is subject to personal jurisdiction in this district. 21 FACTUAL ALLEGATIONS 22 A. ThermoLife 23 14. Ron Kramer (“Kramer”) founded ThermoLife in 1998. Prior to founding 24 ThermoLife, Kramer was a gym owner who had competed in bodybuilding and later 25 promoted professional bodybuilding competitions for the International Federation of 26 Bodybuilders.

3 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 101 of 109

1 15. Between 1994 and 1997, Kramer opened and operated a Gold’s Gym in Santa 2 Cruz, California. 3 16. During his time as a bodybuilder, promoter, and gym owner, Kramer 4 discovered that many dietary supplements failed to meet any quality control standards. 5 Often supplements are spiked with hidden ingredients and labeled incorrectly. Many were 6 ineffective. 7 17. At the time ThermoLife was established, few supplements were clinically 8 researched or field tested. Even today, relatively few supplements have been proven to 9 work as advertised.

10 18. In 1998, Kramer founded ThermoLife in order to provide the public with

11 quality proven supplements. ThermoLife is committed to selling only the purest, most

85250 12 effective and innovative products. 1001 - 13 19. By relying on supposedly proprietary formulas, supplement companies often 14 hide the ingredients in their products from consumers. Unlike other supplement (480) 421 Scottsdale, Arizona North Scottsdale Road, Suite 320 Road, Suite Scottsdale North 15 companies, ThermoLife develops unique and novel products and formulas that it fully Kercsmar & Feltus PLLC Feltus & Kercsmar

6263 16 discloses to the public. In this way, ThermoLife allows consumers to know exactly what 17 products and raw materials they consume. 18 20. ThermoLife has been awarded patents on twenty individual compounds. 19 These patents protect ThermoLife’s innovative and proven products from being copied by 20 ThermoLife’s competitors. 21 21. By fully disclosing its formulas and relying on scientifically proven and 22 protected formulas and ingredients, ThermoLife has taken a lead role in ending the 23 deceptive business practices that have plagued the supplement industry. 24 22. One of the patents owned by ThermoLife is U.S. Patent 7,777,074. On 25 August 17, 2010, the ‘074 Patent was duly and legally issued to Kramer, et al. 26 ThermoLife is the assignee of all rights in and title to the ‘074 Patent. A true and correct

4 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 102 of 109

1 copy of the ‘074 Patent is attached as Exhibit A, and incorporated herein by this 2 reference. 3 23. ThermoLife also owns U.S. Patent No. 8,178,572. The ‘572 Patent was 4 issued on May 22, 2012. ThermoLife is the assignee of all rights in and title to the ‘572 5 Patent. A true and correct copy of the ‘572 Patent is attached as Exhibit B, and 6 incorporated herein by this reference. 7 24. ThermoLife’s supplements are sold nationwide on the internet and in vitamin 8 and dietary supplement stores such as The Vitamin Shoppe. 9 B. Hi-Tech’s Infringement

10 25. Hi-Tech manufactures and sells its own line of products under the label “Hi-

11 Tech Pharmaceuticals.”

85250 12 26. In addition to manufacturing and selling its own line of products, Hi-Tech 1001 - 13 formulates, manufactures and sells products for other dietary supplement companies. 14 27. Hi-Tech’s website advertises its formulation and manufacturing services, (480) 421 Scottsdale, Arizona North Scottsdale Road, Suite 320 Road, Suite Scottsdale North 15 stating, “Hi-Tech Nutraceuticals is one of the world’s leading suppliers of nutritional and Kercsmar & Feltus PLLC Feltus & Kercsmar

6263 16 dietary supplements because it consistently provides high-quality, bulk raw materials and 17 time proven, effective ingredients to its rapidly expanding customer base. Hi-Tech can 18 supply any custom herbal extracts and specialty ingredients on a timely basis and at 19 extremely competitive prices.” 20 28. Hi-Tech’s website also provides a list of the raw materials that Hi-Tech has 21 available to include in any dietary supplement. Hi-Tech’s website lists Creatine Nitrate 22 among its available raw materials. (Hi-Tech Website Printout, attached as Exhibit C.) 23 29. Hi-Tech began purchasing Creatine Nitrate from ThermoLife’s authorized 24 distributor in August 2010. Hi-Tech made its last purchase of Creatine Nitrate on April 7, 25 2011. The Creatine Nitrate that Premium Ingredients sold to Hi-Tech on April 7, 2011, is 26 identified by lot number 101209.

5 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 103 of 109

1 30. It is a regulatory requirement that the dietary supplement manufacturer 2 perform adequate identification tests on each lot of raw materials received, prior to 3 release of a dietary supplement. In order to meet this requirement, Creatine Nitrate is sold 4 with a Certificate of Analysis (“COA”). The Certificate of Analysis for lot number 5 101209, which Hi-Tech purchased on April 7, 2011, states that the Creatine Nitrate had 6 an expiration date of December 3, 3012. (COA attached as Exhibit D.) 7 31. Since the Creatine Nitrate that Hi-Tech purchased from Premium Ingredients 8 has an expiration date of December 3, 2012, any end product that includes this Creatine 9 Nitrate should expire on or before December 3, 2012. While there are potentially

10 incubation processes that could extend the expiration date of Creatine Nitrate, no known

11 incubation process could increase the expiration date by more than two years.

85250 12 32. In late May 2012, ThermoLife discovered that the following dietary 1001 - 13 supplements were being sold with labels that listed Creatine Nitrate as an ingredient: 14 BodyFuse’s Torque Reloaded, BodyFuse’s Cre-8, NLN’s N-Power, NZ Nutraceuticals’ (480) 421 Scottsdale, Arizona North Scottsdale Road, Suite 320 Road, Suite Scottsdale North 15 Invincible, Unleashed Muscle’s Creatine Nitrate, and Unleashed Muscle’s Uprising Kercsmar & Feltus PLLC Feltus & Kercsmar

6263 16 (hereinafter “the Infringing Products”). When ThermoLife purchased some of these 17 products, it learned at least some of these products purported to expire as late as July 18 2016. 19 33. Each of the Infringing Products are distributed by companies that are owned 20 or operated by Joe Eckstrom, Chief Executive Officer of Nutrition Zone Worldwide, Inc. 21 34. ThermoLife contacted Mr. Eckstrom in early June 2012, regarding these 22 products. 23 35. Mr. Eckstrom confirmed to ThermoLife that the Creatine Nitrate included in 24 the Infringing Products was purchased from Hi-Tech. 25 36. Because these products list an expiration date on or after December 3, 2012, 26 Hi-Tech could not have purchased the Creatine Nitrate included in these products from

6 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 104 of 109

1 ThermoLife’s authorized distributor. Even if Hi-Tech incubated the Creatine Nitrate 2 included in these products, none of the products should have an expiration date after 3 December 3, 2014. 4 37. As a member of the nutritional supplement and bodybuilding industries, Hi- 5 Tech appreciates the scope of the ‘572 and ‘074 Patents, as well as the other patents 6 assigned to ThermoLife. 7 38. As a result of its prior purchases of Creatine Nitrate, since at least April 7, 8 2010, Hi-Tech has had notice of the ‘074 Patent. 9 39. Notwithstanding Hi-Tech’s appreciation of the value and scope of the ‘074

10 Patent, Hi-Tech has obtained Creatine Nitrate from an unauthorized source and sold,

11 manufactured, imported and/or used infringing Creatine Nitrate compositions.

85250 12 40. The Infringing Products have at least one compositional feature corresponding 1001 - 13 to an Amino Acid Compound consisting essentially of a nitrate or nitrite of an Amino 14 Acid elected from the group consisting of Arginine Beta Alanine, Agmatine, Citrulline, (480) 421 Scottsdale, Arizona North Scottsdale Road, Suite 320 Road, Suite Scottsdale North 15 Creatine, Glutamine, L-Histidine, Isoleucine, Leucine, Norvaline, or Ornithine. Here, the Kercsmar & Feltus PLLC Feltus & Kercsmar

6263 16 Infringing Products includes Creatine Nitrate. 17 41. The Infringing Products also rely on Creatine Nitrate in order to increase the 18 vasodilative characteristics of amino acids in a human. 19 COUNT I – PATENT INFRINGEMENT 20 42. ThermoLife repeats and realleges each and every allegation contained in 21 Paragraphs 1 through 41 of this Complaint, as if fully set forth herein. 22 43. This cause of action arises under the Laws of the United States, Title 35, 23 United States Code, in particular under 35 U.S.C. § 271(a). 24 44. The ‘074 and ‘572 Patents are valid and enforceable. 25 45. Hi-Tech, acting through and by its respective officers and owners, has, 26 without authority, consent, right or license, and in direct infringement of the ‘074 Patent

7 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 105 of 109

1 and ‘572 Patent, imported, made, used, and/or sold the Infringing Products. In addition to 2 the Infringing Products, ThermoLife believers that Hi-Tech has manufactured and sold 3 other products that infringe ThermoLife’s ‘074 Patent and ‘572 Patent. 4 46. Hi-Tech’s infringing conduct is willful, intentional, unlawful and, upon 5 information and belief, will continue unless enjoined by this Court. 6 47. ThermoLife has no adequate remedy at law for the harm caused by 7 defendant’s acts. 8 48. By reason of Hi-Tech’s acts complained of herein, ThermoLife has suffered 9 monetary damages in an amount that has not yet been determined, but upon information

10 and belief, is substantially in excess of the sum or value of $75,000, exclusive of interest

11 and costs.

85250 12 49. Due to the intentional nature of Hi-Tech’s acts, this is an exceptional case in 1001 - 13 which ThermoLife is entitled to treble damages, attorneys’ fees and costs pursuant to 35 14 U.S.C. §§ 284 and 285. (480) 421 Scottsdale, Arizona North Scottsdale Road, Suite 320 Road, Suite Scottsdale North 15 50. Pursuant to 35 U.S.C. § 284, ThermoLife is entitled to: an accounting by Hi- Kercsmar & Feltus PLLC Feltus & Kercsmar

6263 16 Tech of funds comprising all revenues received through the commercial exploitation of 17 the Infringing Products; the imposition of a constructive trust for the benefit of 18 ThermoLife for all such funds in the custody or control of Hi-Tech; and to such other 19 damages to which ThermoLife may be determined to be entitled. 20 COUNT II – INDUCEMENT OF PATENT INFRINGEMENT 21 51. ThermoLife repeats and realleges each and every allegation contained in 22 Paragraphs 1 through 50 of this Complaint, as if fully set forth herein. 23 52. This cause of action arises under the Patent Laws of the United States, Title 24 35, United States Code, in particular under 35 U.S.C. § 271(b). 25 53. The ‘074 and ‘572 Patents are valid and enforceable. 26

8 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 106 of 109

1 54. To extent any of Hi-Tech’s actions do not constitute direct infringement of the 2 ‘074 and ‘572 Patents, Hi-Tech has induced each of the companies that sell the Infringing 3 Products to directly infringe the ‘074 and ‘572 Patents. 4 55. Hi-Tech’s infringing conduct is willful, intentional, unlawful and, upon 5 information and belief, will continue unless enjoined by this Court. 6 56. ThermoLife has no adequate remedy at law for the harm caused by Hi-Tech’s 7 acts. 8 57. By reason of Hi-Tech’s acts complained of herein, ThermoLife has suffered 9 monetary damages in an amount that has not yet been determined, but upon information

10 and belief, is substantially in excess of the sum or value of $75,000, exclusive of interest

11 and costs.

85250 12 58. Due to the intentional nature of Hi-Tech’s acts, this is an exceptional case in 1001 - 13 which ThermoLife is entitled to treble damages, attorneys’ fees and costs pursuant to 35 14 U.S.C. §§ 284 and 285. (480) 421 Scottsdale, Arizona North Scottsdale Road, Suite 320 Road, Suite Scottsdale North 15 COUNT III – CONTRIBUTORY PATENT INFRINGEMENT Kercsmar & Feltus PLLC Feltus & Kercsmar

6263 16 59. ThermoLife repeats and realleges each and every allegation contained in 17 Paragraphs 1 through 58 of this Complaint, as if fully set forth herein. 18 60. This cause of action arises under the Patent Laws of the United States, Title 19 35, United States Code, in particular under 35 U.S.C. § 271(c). 20 61. The ‘074 and ‘572 Patents are valid and enforceable. 21 62. To extent any of Hi-Tech’s actions do not constitute direct infringement of the 22 ‘074 and ‘572 Patents, Hi-Tech is liable for contributory infringement, pursuant to 35 23 U.S.C. § 271(c), in that Hi-Tech has imported, made, and/or sold within the United States 24 a component of a patented combination or composition, consisting of a material part of 25 the invention, knowing the same to be especially made or adapted for use in the 26

9 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 107 of 109

1 infringement of the ‘074 and ‘572 Patents and not a staple article or commodity of 2 commerce suitable for substantial non-infringing use. 3 63. Hi-Tech’s infringing conduct is willful, intentional, unlawful and, upon 4 information and belief, will continue unless enjoined by this Court. 5 64. ThermoLife has no adequate remedy at law for the harm caused by Hi-Tech’s 6 acts. 7 65. By reason of Hi-Tech’s acts complained of herein, ThermoLife has suffered 8 monetary damages in an amount that has not yet been determined, but upon information 9 and belief, is substantially in excess of the sum or value of $75,000, exclusive of interest

10 and costs.

11 66. Due to the intentional nature of Hi-Tech’s acts, this is an exceptional case in

85250 12 which ThermoLife is entitled to treble damages, attorneys’ fees and costs pursuant to 35 1001 - 13 U.S.C. §§ 284 and 285. 14 JURY TRIAL DEMAND (480) 421 Scottsdale, Arizona North Scottsdale Road, Suite 320 Road, Suite Scottsdale North 15 1. Plaintiff requests a trial by jury on all aspects of the Complaint. Kercsmar & Feltus PLLC Feltus & Kercsmar

6263 16 PRAYER FOR RELIEF 17 WHEREFORE, Plaintiff ThermoLife International, LLC prays for relief and 18 judgment against Defendant Hi-Tech as follows: 19 A. For a judicial determination and declaration that the ‘074 Patent is valid and 20 enforceable; 21 B. For a judicial determination and declaration that the ‘572 Patent is valid and 22 enforceable; 23 C. That a preliminary and permanent injunction issue against Hi-Tech, its agents, 24 officers, directors, employees, attorneys, successors and assigns, all parent and subsidiary 25 entities, and all those acting for or on the behalf of Hi-Tech, or in active concert, 26

10 Case 1:15-cv-00892-ELR Document 226-2 Filed 09/25/17 Page 108 of 109

1 participation, or combination with them, including customers and distributors, prohibiting 2 Hi-Tech from: 3 i. continuing acts of infringement of ThermoLife’s ‘074 and ‘572 Patents; 4 ii. making, using, selling and/or importing Infringing Products, to include any 5 colorable imitation thereof; and 6 iii. otherwise infringing upon ThermoLife’s patents. 7 D. That an Order issue from this Court requiring Hi-Tech, its officers, agents, 8 servants and employees, to deliver up to this Court for destruction all articles and 9 materials infringing upon the rights of ThermoLife and all formulations and other matter

10 or materials for reproducing such Infringing Products;

11 E. That defendant be required to file with the Court within thirty (30) days after

85250 12 entry of an injunctive order or final judgment a written statement under oath setting forth 1001 - 13 the manner in which defendant has complied with the order or final judgment; 14 F. Awarding ThermoLife its damages sustained due to Hi-Tech’s infringement (480) 421 Scottsdale, Arizona North Scottsdale Road, Suite 320 Road, Suite Scottsdale North 15 of the ‘074 and ‘572 Patents; Kercsmar & Feltus PLLC Feltus & Kercsmar

6263 16 G. In the alternative, ordering Hi-Tech to pay ThermoLife all profits, gains, and 17 advantages defendant has received or obtained from their unlawful conduct, in an amount 18 to be determined at trial; 19 H. In the alternative, that a reasonable royalty for defendant’s infringement be 20 awarded to ThermoLife pursuant to 35 U.S.C. § 284; 21 I. That, due to defendant’s willful infringement of ThermoLife’s patent rights, 22 defendant be ordered to pay ThermoLife treble damages pursuant to 35 U.S.C. §284; 23 J. An award of the costs of this action, including pre- and post-judgment 24 interest, pursuant to 35 U.S.C. § 284; 25 26

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1 K. That, due to defendant’s willful and flagrant disregard of ThermoLife’s patent 2 rights, defendant be ordered to pay ThermoLife its reasonable attorneys’ fees and experts’ 3 fees pursuant to 35 U.S.C. § 285; and 4 L. For such other and further relief as this Court deems necessary, just and 5 proper under the circumstances. 6 7 DATED this 6th day of July, 2012. 8 9 KERCSMAR & FELTUS PLLC

10

11 By s/ Gregory B. Collins Gregory B. Collins 85250 12 Jenessa G. B. Coccaro 1001 - 13 6263 North Scottsdale Road, Suite 320 Scottsdale, Arizona 85250 14 (480) 421 Attorneys for Plaintiff ThermoLife International LLC Scottsdale, Arizona North Scottsdale Road, Suite 320 Road, Suite Scottsdale North 15 Kercsmar & Feltus PLLC Feltus & Kercsmar

6263 16 17 18 19 20 21 22 23 24 25 26

12