Paper No. 1
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`Human Power of N Company
`
`Petitioner
`
`
`v.
`
`Heartbeet Ltd.
`
`Patent Owner
`
`______________
`
`Post Grant Review No. PGR2021-00110
`Patent 10,835,555
`______________
`
`
`PETITION FOR POST GRANT REVIEW UNDER 35 U.S.C. §321
`
`
`

`

`PGR2021-00110
`Patent 10,835,555
`
`V.
`
`TABLE OF CONTENTS
`INTRODUCTION ............................................................................... 1
`I.
`II. MANDATORY NOTICES ................................................................... 1
`A.
`Real Party in Interest (37 C.F.R. §42.8(b)(1)) ................................. 1
`B.
`Related Matters (§42.8(b)(2)) ....................................................... 1
`C.
`Lead and Back-Up Counsel (§42.8(b)(3))....................................... 2
`D.
`Service Information (§42.8(b)(4)) ................................................. 2
`III. GROUNDS FOR STANDING (§42.204(A)) ........................................... 2
`IV. STATEMENT OF PRECISE RELIEF REQUESTED FOR EACH
`CLAIM CHALLENGED ...................................................................... 3
`A.
`Claims for Which Review Is Requested (§42.204(b)(1)) .................. 3
`B.
`Statutory Grounds of Challenge (§42.204(b)(2)) ............................. 3
`FIELD OF TECHNOLOGY.................................................................. 4
`A.
`Fitness, Exercise, and Associated Benefits ..................................... 5
`B. Nitric Oxide As Vasodilator, Performance Enhancer, and Blood
`Pressure Regulator ...................................................................... 8
`Ingested Nitrate As a Known Precursor for NO............................. 10
`C.
`D. Natural Sources of Nitrates ........................................................ 12
`E.
`Possible Nitrate and Nitrite Side Effects....................................... 14
`VI. LEVEL OF ORDINARY SKILL IN THE ART ..................................... 16
`VII. THE ’555 PATENT ........................................................................... 17
`A. Admitted Prior Art and Perceived Shortcomings ........................... 18
`B. Asserted Improvement to the Prior Art ........................................ 21
`C.
`Prosecution History................................................................... 21
`D. Claim Construction (§42.204(b)(3)) ............................................ 23
`“inorganic nitrate” .......................................................... 23
`1.
`VIII. THE ’555 PATENT IS SUBJECT TO POST GRANT REVIEW ............. 24
`
`
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`

`2.
`3.
`
`2.
`
`PGR2021-00110
`Patent 10,835,555
`IX. REASONS FOR THE RELIEF REQUESTED UNDER 37 C.F.R.
`§§42.22(A)(2) AND 42.204(B)(4)........................................................ 29
`A.
`Ground 1: NIH2 and Brunton Rendered Obvious Claims 1-5, 11-
`13, and 17-19............................................................................. 29
`1.
`Inorganic Nitrate Administration Before Exercise Was
`Obvious for Preventing and Treating Hypertension .............. 29
`The ’555 Patent’s Weight-Normalized Doses Were Obvious .. 32
`Nitrate Administration Increases and Obviously Would Have
`Increased Physical Endurance During Exercise ................... 37
`B. Ground 2: NIH2, Brunton, & Brunton2 Rendered Obvious
`Claims 11-12............................................................................ 49
`C. Grounds 3 and 4: NIH2, Brunton, Shevach, and Optionally
`Brunton2 Rendered Obvious Claims 6-10 and 31 .......................... 51
`1.
`Including an Additive in a DASH Diet Juice or Brunton’s
`Hypertension Treatment Was Obvious (Grounds 3 and 4) ..... 51
`The ’555 Patent’s Claimed Inorganic Nitrate Sources Are
`Product-By-Process Limitations and Were Obvious (Grounds
`3 and 4) .......................................................................... 58
`D. Grounds 5 and 6: NIH2, Brunton, & Chevaux Rendered
`Obvious Claims 14-16 and 25 and NIH2, Brunton, Chevaux, &
`Brunton2 Rendered Obvious Claim 16......................................... 61
`1.
`It Was Obvious To Include a Polyphenol In the DASH Diet or
`In Brunton’s Treatment (Ground 5) .................................... 61
`It Was Obvious For the Inorganic Nitrate to Be At Least 50%
`of the Composition (Grounds 5 and 6) ................................ 64
`E. Grounds 7 and 8: NIH2, Brunton, & Prinkkilä Rendered
`Obvious Claims 19-20 and NIH2, Brunton, Prinkkilä, and
`Chevaux Rendered Obvious Claims 25-26 ................................... 67
`1.
`It Was Obvious to Administer Brunton’s Treatment in a Sport
`Drink (Ground 7) ............................................................. 67
`Including the Polyphenol in the Sport Drink Was Obvious
`(Ground 8) ...................................................................... 70
`
`2.
`
`2.
`
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`

`F.
`
`PGR2021-00110
`Patent 10,835,555
`Grounds 9 and 10: NIH2, Brunton, & Mäyrä-Mäkinen
`Rendered Obvious Claims 19 and 21-24 and NIH2, Brunton,
`Mäyrä-Mäkinen, and Chevaux Rendered Obvious Claims 25
`and 27-30................................................................................. 71
`1.
`It Was Obvious to Administer Brunton’s Treatment in a
`Bacteria-Containing Functional Food (Ground 9) ............... 71
`Including the Polyphenol in the Functional Food Product Was
`Obvious (Ground 10) ....................................................... 75
`G. Grounds 11 and 12: Claims 1-11 and 13-31 Are Invalid Under
`35 U.S.C. § 112 for Lack of Written Description and
`Enablement .............................................................................. 77
`X. CONCLUSION ................................................................................ 78
`
`
`2.
`
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`- iv -
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`

`

`Petitioner’s Exhibit List
`
`PGR2021-00110
`Patent 10,835,555
`
`Description
`Short Title
`No.
`U.S. Patent No. 10,835,555 (the ’555 Patent)
`’555 Patent
`1001
`Excerpts of Prosecution History of the ‘555 Patent
`1002 File History
`Declaration of Jeff Volek, Ph.D.
`1003 Volek
`’629 Application U.S. Patent Application No. 15/966,629
`1004
`1005 Swedish1
`Swedish Patent Application No. 0700520-0
`1006 Provisional
`U.S. Provisional Application No. 60/919,709
`1007 PCT1
`PCT Application No. PCT/SE08/50212
`1008 Parent1
`U.S. Patent Application No. 12/528,794
`1009 Swedish2
`Swedish Patent Application No. 0700729-7
`1010 PCT2
`PCT Application No. PCT/SE08/50211
`1011 Parent2
`U.S. Patent Application No. 12/528,798
`1012 Parent3
`U.S. Patent Application No. 14/830,937
`1013 Archer
`Archer, Douglas L., Evidence that Ingested Nitrate
`and Nitrite Are Beneficial to Health, Journal of Food
`Protection, Vol. 65, No. 5, pp. 872-875 (2002)
`C. Oldreive, et al., The Mechanisms for Nitration and
`Nitrotyrosine Formation in vitro and in vivo: Impact
`of Diet, Free Rad. Res., Vol. 35, pp. 215-231 (2001)
`Omitted
`Benjamin, Nigel, Nitrates in the Human Diet – good
`or bad?, Ann. Zootech. Vol. 49, pp. 207-216 (2000)
`G. Richardson, et al., The ingestion of inorganic
`nitrate increases gastric S-nitrosothiol levels and
`inhibits platelet function in humans, Nitric Oxide,
`Vol. 7, pp. 24-29 (2002)
`F. Murad, Cyclic Guanosine Monophosphate as a
`Mediator of Vasodilation, J. Clin. Invest., Vol. 78,
`pp. 1-5 (July 1986)
`
`1018 Murad
`
`
`
`
`
`- v -
`
`
`
`1014 Oldreive
`
`1015 N/A
`1016 Benjamin
`
`1017 Richardson
`
`

`

`PGR2021-00110
`Patent 10,835,555
`
`Short Title
`No.
`1019 Abrams
`
`1020 Butler
`
`1021 Page
`1022 Pickering
`
`1023 Stokes
`
`Description
`J. Abrams, MD, Beneficial Actions of Nitrates in
`Cardiovascular Disease, The American Journal of
`Cardiology, Vol. 77, pp. 31C-37C (May 30, 1996)
`A Butler, et al., Medieval Chinese Medicine: The
`Dunhuang Medical Manuscripts (Chapter 16: A
`treatment for cardiovascular dysfunction in a
`Dunhuang medical manuscript), Routledge (2005)
`U.S. Patent Application Pub. No. US 2007/0105817
`Pickering, MD, DPhil, Thomas G., Why Don’t We
`Use Nitrates to Treat Older Hypertensive Patients?,
`Journal of Clinical Hypertension, Vol. 7, No. 11, pp.
`685-690 (Nov. 2005)
`G. S. Stokes, et al., Long-Term Effectiveness of
`Extended-Release Nitrate for the Treatment of
`Systolic Hypertension, Hypertension Vol. 45, pp.
`380-384 (2005)
`P. Santamaria, Nitrate in vegetables: toxicity, content,
`intake and EC regulation, Journal of the Science of
`Food and Agriculture, 86:10-17 (2006)
`E. G. Heisler, et al., Changes in Nitrate and Nitrite
`Content, and Search for Nitrosamines in Storage-
`Abused Spinach and Beets, J. Agr. Food Chem., Vol.
`22, No. 6, pp. 1029-1032 (1974)
`1026 Smiechowska M. Smiechowska, The Content of Nitrates V and III
`and Vitamin C In Juices Obtained from Organic and
`Conventional Raw Materials, Polish Journal of Food
`and Nutrition Sciences, Vol. 12/53, No. 2, pp. 57-61
`(2003)
`International Patent Application Publication No.
`WO 2005/062713
`Hungarian Patent Application No. HU0401219A2 &
`Certified Translation
`
`1024 Santamaria
`
`1025 Heisler
`
`1027 Shevach
`
`1028 Petri
`
`
`
`
`
`- vi -
`
`
`
`

`

`Short Title
`No.
`1029 Warner
`
`1030 McKnight99
`
`1031 Challis
`
`1032 Brunton
`
`1033 Brunton2
`
`1034 Brunton3
`
`1035 Symonds
`
`1036 Alka Seltzer
`
`1037 Robinson
`
`PGR2021-00110
`Patent 10,835,555
`
`Description
`J. Warner, Nitrates Lower Blood Pressure: Nutrient
`Found in Spinach, Other Vegetables Keeps Blood
`Vessels Healthy, WebMD Medical News (Dec. 27,
`2006) (available at https://web.archive.org/web/
`20070119154017/http://www.webmd.com/content/
`article/131/117916)
`G.M. McKnight, et al., Dietary nitrate in man: friend
`or foe?, British Journal of Nutrition, Vol. 81, pp. 349-
`358 (1999)
`B. C. Challis, Nutrition and nitrosamine formation,
`Proceeds of the Nutrition Society, Vol. 44, pp. 95-100
`(1985)
`L. Brunton, An Address on Blood Pressure In Man:
`Its estimation and indications for treatment, The
`British Medical Journal, pp. 64-67 (July 10, 1909)
`L. Brunton, et al., An Address on Longevity and the
`Means of Attaining It, The Lancet, Vol. 168, Issue
`4342, pp. 1330-1335 (Nov. 17, 1906)
`L. Brunton, Therapeutics of the Circulation, Second
`Edition (1914)
`B. Symonds, The Influence of Overweight and
`Underweight on Vitality, Journal of the Medical
`Society of New Jersey, Vol. V, No. 4, pp. 159-167
`(Sep. 1908))
`Extra Strength Alka Seltzer Drug Facts (2004)
`(available at https://web.archive.org/web/
`20040422223603/http://www.alka-seltzer.com/as/
`images/Alka-Extra-Strength.gif
`M. Robinson, et al., Effects of antacid formulation on
`postprandial oesophageal acidity in patients with a
`history of episodic heartburn, Ailment Pharmacol.
`Therm., Vol. 16, pp. 435-443 (2002)
`
`
`
`
`
`- vii -
`
`
`
`

`

`Short Title
`No.
`1038 McKnight97
`
`1039 Cosby
`
`1040 Larsen
`
`1041 Moncada
`
`1042 Webb
`
`1043 Chevaux
`
`1044 Whisonant
`
`1045 RediBeets
`
`1046 DASH
`
`1047 Mukerji
`
`1048 Thatcher
`
`PGR2021-00110
`Patent 10,835,555
`
`Description
`G. M. McKnight, et al., Chemical synthesis of nitric
`oxide in the stomach from dietary nitrate in humans,
`Gut, Vol. 40, pp. 211-214 (1997)
`K. Cosby, et al., Nitrite reduction to nitric oxide by
`deoxyhemoglobin vasodilates the human circulation,
`Nature Medicine, Vol. 9, No. 12, pp. 1498-1505
`(Dec. 2003).
`F. J. Larsen, et al., Effects of Dietary Nitrate on Blood
`Pressure in Healthy Volunteers, N. Engl. J. Med.,
`355:26, pp. 2792-2793 (Dec. 28, 2006)
`S. Moncada, et al., The L-Arginine:Nitric Oxide
`Pathway, Journal of Cardiovascular Pharmacology,
`17(Suppl. 3):S1-S9 (1991)
`AJ Webb, et al., BHS Abstracts, Journal of Human
`Hypertension, Vol. 21, pp. 828-850 (Sep. 20, 2007)
`International Patent Application Publication
`No. 99/45797
`R. C. Whisonant, et al., Geology and History of
`Confederate Saltpeter Cave Operations in Western
`Virginia, Virginia Minerals (Nov. 2001)
`RediBeetsTM Webpage (2006) (available at
`https://web.archive.org/web/20060206221752/https://
`allonhealth.com/health-products/redibeets.htm)
`L. Appel, et al., A Clinical Trial of the Effects of
`Dietary Patterns on Blood Pressure, N. Engl. J.
`Med., 336:16, pp. 1117-1124 (Apr. 17, 1997)
`U.S. Patent Application Publication No.
`US 2003/0104596
`G. R. J. Thatcher, Serial Review: Mechanisms and
`Novel Directions in the Biological Applications of
`Nitric Oxide Donors, Free Radical Biology &
`Medicine, Vol. 37, No. 8, pp. 1122-1143 (2004)
`
`
`
`
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`- viii -
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`

`

`Short Title
`No.
`1049 Millar
`
`1050 N/A
`1051 Fryer
`
`1052 Rees
`
`1053 Lundberg
`
`1054 Tsuchiya
`
`1055 NIH1
`
`1056 NIH2
`
`1057 Spiegelhalder
`
`PGR2021-00110
`Patent 10,835,555
`
`Description
`T. M. Millar, et al., Xanthine oxidoreductase
`catalyses the reduction of nitrates and nitrite to nitric
`oxide under hypoxic conditions, FEBS Letters, Vol.
`427, pp. 225-228 (1998)
`Omitted
`C. D. Fryer, National Health Statistic Reports: Mean
`Body Weight, Height, Waist Circumference, and Body
`Mass Index Among Adults: United States, 1999–2000
`Through 2015–2016, U.S. Dept. of Health and
`Human Services, Centers for Disease Control and
`Prevention National Center for Health Statistics (Dec.
`20, 2018)
`D. D. Rees, et al., Role of endothelium-derived nitric
`oxide in the regulation of blood pressure, Proc. Natl.
`Acad. Sci. USA, Vol. 86, pp. 3375-3378 (May 1989)
`J. O. Lundberg, et al., NO Generation From Nitrite
`and Its Role in Vascular Control, Arterioscler
`Thromb Vasc Biol., Vol. 25, pp. 915-922 (2005)
`K. Tsuchiya, et al., Malfunction of Vascular Control
`in Lifestyle-Related Diseases: Formation of Systemic
`Hemoglobin-Nitric Oxide Complex (HbNO) From
`Dietary Nitrite, J. Pharmacol Sci, Vol. 96, pp. 395-
`400 (2004)
`Facts About The DASH Diet, U.S. Dept. of Health
`and Human Services; National Institutes of Health;
`National Heart, Lung, and Blood Institute (2001)
`The Seventh Report of the Joint National Committee
`on Prevention, Detection, Evaluation, and Treatment
`of High Blood Pressure, U.S. Dept. of Health and
`Human Services; National Institutes of Health;
`National Heart, Lung, and Blood Institute (2004)
`B. Spiegelhalder, et al., Influence of Dietary Nitrate
`On Nitrate Content of Human Saliva: Possible
`Relevance of N-Nitroso Compounds, Fd. Cosmet.
`Toxicol., Vol. 14, pp. 545-548 (1976)
`
`
`
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`

`Short Title
`No.
`1058 N/A
`1059
`ISO 3091
`1060
`
`1061
`
`
`1062
`1063
`1064
`
`1065
`
`
`
`
`
`
`
`1066
`
`INCHEM
`
`1067 Rigby
`
`1068 Hall-Ellis
`
`1069
`
`
`
`1070 Gardiner
`
`1071 Boguslavskiy
`
`PGR2021-00110
`Patent 10,835,555
`
`Description
`
`Omitted
`ISO Standard ISO 3091:1975
`British Medical Journal Webpage for EX1032 Article
`British Medical Journal Webpage for EX1032 Journal
`Issue
`The Lancet Webpage for EX1033
`ScienceDirect Webpage for EX1033
`Wayback Machine Webpage for EX1042 archived
`Oct. 11, 2007
`Journal of Human Hypertension Webpage for
`EX1042
`Wayback Machine Archive of INCHEM Webpage
`entitled Nitrates and nitrites (archived Dec. 15, 2006)
`U.S. Patent Application Publication No. US
`2003/0104596
`Declaration of Sylvia Hall-Ellis, Ph.D. re EX1026,
`EX1032, EX1033, EX1034, , EX1035, EX1037,
`EX1038, EX1039, EX1042, EX1044, EX1046
`NIH Webpage showing availability of EX1056
`(NIH2) as of February 12, 2006 (available at
`https://web.archive.org/web/20060212100027/http://
`www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.
`htm)
`U.S. Patent Application Publication No.
`US 2005/0256192
`Effect of nitric oxide on the efficiency of oxygen usage
`by a working skeletal muscle under fatigue, Fiziol.
`Zhurn., Vol. 51, No. 1, pp. 33-42 (2005) & Certified
`Translation
`
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`

`Short Title
`No.
`1072 Burtscher
`
`PGR2021-00110
`Patent 10,835,555
`
`Description
`The Proonged Intake of L-Arginine-L-Aspartate
`Reduces Blood Lactate Accumulation and Oxygen
`Consumption During Submaximal Exercise, Journal
`of Sports Science and Medicine, Vol. 4, pp. 314-322
`(2005)
`The Nitrovasodilators; New Ideas About Old Drugs,
`Circulation, Vol. 87, No. 5, pp. 1461-1467 (May
`1993)
`Effects of L-Arginine on Forearm Vessels and
`Responses to Acetylcholine, Hypertension, Vol. 20,
`No. 4, pp. 511-517 (October 1992)
`Sharkey, B. J., Fitness and Work Capacity, Second
`Edition, USDA Forest Service, Technology &
`Development Program (April 1997)
`21 CFR §101.12 Reference amounts customarily
`consumed per eating occasion (4-1-3 Edition)
`U.S. Patent No. 4,853,237
`Roy, D., Insulin stimulation of glucose uptake in
`skeletal muscles and adipose tissues in vivo is NO
`dependent, Am. J. Physiology, Vol. 274, No. 4, pp.
`E692-E699 (April 1998).
`Shen, W., Nitric oxide production and NO synthase
`gene expression contribute to vascular regulation
`during exercise, Med. Sci. Sports Exerc., Vol. 27, No.
`8, pp. 1125-1134 (August 1995)
`1080 Mäyrä-Mäkinen U.S. Patent No. 6,890,529
`1081 Sobko
`Sobko, T., Gastrointestinal nitric oxide generation in
`germ-free and conventional rats, Am. J. Gastrointest.
`Liver Physiol., Vol. 287, pp. G993-G997 (2004)
`U.S. Patent Publication No. US 2007/0071871
`
`1073 Harrison
`
`1074
`
`Imaizumi
`
`1075 Sharkey
`
`1076 FDA Servings
`
`1077 Prinkkilä
`1078 Roy
`
`1079 Shen
`
`1082 Shrikhande
`
`
`
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`- xi -
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`PGR2021-00110
`Patent 10,835,555
`
`I.
`
`INTRODUCTION
`The ’555 Patent claims administering inorganic nitrate, which was already
`
`known to be beneficial for reducing blood pressure. As its invention, the ’555 Patent
`
`purports to extend that link to exercise performance. But the claims do not recite
`
`exercise performance in a limiting way. Even if they had, exercise-related benefits
`
`of administering inorganic nitrate necessarily occurred and were obvious.
`
`II. MANDATORY NOTICES
`A. Real Party in Interest (37 C.F.R. §42.8(b)(1))
`The real party-in-interest is Human Power of N Company.
`
`B. Related Matters (§42.8(b)(2))
`The following matters could affect, or be affected by, a decision in the
`
`proceeding:
`
`(1) U.S. Patent No. 10,555,968 (the ’968 Patent), of which the ’555 Patent
`
`is a continuation-in-part.
`
`(2) U.S. Patent No. 9,180,140 (the ’140 Patent), of which the ’968 Patent
`
`is a continuation.
`
`(3) U.S. Patent No. 10,406,118 (the ’118 Patent), of which the ’555 Patent
`
`is a continuation-in-part.
`
`(4) Reexamination No. 90/013,759, which is a reexamination of the
`
`’140 Patent.
`
`
`
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`

`PGR2021-00110
`Patent 10,835,555
`
`(5) PGR2021-00094 against the ’813 Patent.
`
`(6) Thermolife International, LLC v. Human Power of N Company,
`
`6-21-CV-00144-ADA (W.D. Tex.), in which the ’140 Patent and the
`
`’968 Patent are asserted.
`
`C. Lead and Back-Up Counsel (§42.8(b)(3))
`Lead counsel: Eagle H. Robinson (Reg. No. 61,361)
`
`Back-up counsel: Michael Pohl (Reg. No. 72,871)
`
`Service Information (§42.8(b)(4))
`D.
`Email:
`eagle.robinson@nortonrosefulbright.com
`
`
`
`
`
`michael.pohl@nortonrosefulbright.com
`
`Post: Eagle H. Robinson, Norton Rose Fulbright US LLP, 98 San Jacinto
`
`Boulevard, Suite 1100, Austin, TX 78701
`
`Phone: 512.536.3083 Fax: 512.536.4598
`
`Petitioner consents to electronic service.
`
`III. GROUNDS FOR STANDING (§42.204(A))
`Petitioner certifies that the ’555 Patent is available for post grant review, and
`
`that Petitioner is not barred or estopped from requesting a post grant review on the
`
`grounds identified in this Petition.
`
`
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`

`PGR2021-00110
`Patent 10,835,555
`The ’555 Patent (a) issued November 17, 2020, nine or fewer months prior to
`
`this Petition’s filing (EX1001 at 1/31), and (b) is subject to the AIA’s first-inventor-
`
`to-file provisions because at least one claim has a post-2013 priority date (see
`
`Section VIII). Leahy-Smith America Invents Act, Pub. L. No. 112-29, 125 Stat. 284
`
`(2011) (“AIA”) at §§3(n)(1), 6(d), 6(f)(2)(A); 35 U.S.C. §321; US Endodontics, LLC
`
`v. Gold Standard Instruments, LLC, PGR2015-00019, slip op. at 6-8 (P.T.A.B. Dec.
`
`28, 2016) (Paper 54).
`
`The ’555 Patent has not been subject to a previous final written decision in an
`
`estoppel-based AIA proceeding.
`
`IV. STATEMENT OF PRECISE RELIEF REQUESTED FOR EACH
`CLAIM CHALLENGED
`A. Claims for Which Review Is Requested (§42.204(b)(1))
`Petitioner requests review and cancellation of claims 1-31.
`
`Statutory Grounds of Challenge (§42.204(b)(2))
`B.
`All claims are invalid under Sections 103 and 112 as follows:
`
`Ground
`
`Claims
`
`Statutory
`Basis
`
`Prior Art/Basis
`
`1
`
`1-5, 11-13,
`17-19
`
`§103(a)
`
`NIH2 (EX1056), which published in
`2004 (EX1003 at ¶¶81-82; EX1069;
`EX1082 at ¶[0008], 1/15), and Brunton
`(EX1032), which published in 1909
`(EX1003 at ¶84; EX1060; EX1061;
`EX1068 at ¶¶55-61).
`
`
`
`
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`- 3 -
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`
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`

`

`Ground
`
`Claims
`
`Statutory
`Basis
`
`PGR2021-00110
`Patent 10,835,555
`Prior Art/Basis
`
`11-12
`
`6-10, 31
`
`6-10, 31
`
`14-16, 25
`
`16
`
`19-20
`
`25-26
`
`19, 21-24
`
`25, 27-30
`
`1-11, 13-21
`1-11, 13-21
`
`§103(a)
`
`NIH2, Brunton, and Brunton2 (EX1033),
`which published in 1906. EX1003 at
`¶125; EX1062; EX1063; EX1068 at
`¶¶62-68.
`§103(a) NIH2, Brunton, and Shevach (EX1027),
`which published in 2005.
`§103(a) NIH2, Brunton, Shevach, and Brunton2.
`§103(a) NIH2, Brunton, and Chevaux (EX1043),
`which published in 1999.
`§103(a) NIH2, Brunton, Chevaux, and Brunton2.
`§103(a) NIH2, Brunton, and Prinkkilä (EX1077),
`which published in 1989.
`
`§103(a) NIH2, Brunton, Prinkkilä, and Chevaux.
`§103(a) NIH2, Brunton, and Mäyrä-Mäkinen
`(EX1080), which published in 2005.
`§103(a) NIH2, Brunton, Mäyrä-Mäkinen, and
`Chevaux.
`§112(a) No written description.
`§112(a) Not enabled.
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`2
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`3
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`4
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`5
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`6
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`7
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`8
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`9
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`10
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`11
`12
`
`V.
`
`FIELD OF TECHNOLOGY
`The ’555 Patent “relates to the field of performance enhancing nutritional
`
`foods and food supplements” and “medicine and pharmaceuticals,” all comprising
`
`“nitrates and/or nitrites.” EX1001 at 1:32-42; EX1003 at ¶26. Its claims each recite
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`PGR2021-00110
`Patent 10,835,555
`“[a] method of increasing exercise endurance in a human subject” by administering
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`inorganic nitrate to the subject. EX1001 at Claim 1.
`
`Fitness, Exercise, and Associated Benefits
`A.
`Aerobic fitness “indicates the functional capacity of the respiratory system
`
`(take in oxygen), the circulatory system (transport oxygen), and the muscles (utilize
`
`oxygen),” as reflected by “maximal oxygen intake (VO2 max).” EX1075 at 9; EX1003
`
`at ¶27. VO2 max is the amount of oxygen the body can consume during maximal
`
`effort and “defines the maximal intensity of effort that can be accomplished.” See
`
`EX1075 at 9-11; EX1003 at ¶27.
`
`Other dimensions of fitness include “the aerobic and anaerobic thresholds.”
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`EX1075 at 10-11; EX1003 at ¶28. “When work is too strenuous to be met with
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`aerobic metabolism,” the body turns to “anaerobic energy sources [which] rapidly
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`leads to fatigue” due to the production of “lactic acid (a metabolic byproduct)” that
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`“interferes with muscles’ contractile force and energy production.” EX1075 at 10;
`
`EX1003 at ¶28. The aerobic and anaerobic thresholds—“often defined as a
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`percentage of the VO2 max” (see, e.g., EX1075 at FIG. 2.1 (below))—mark when the
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`lactic acid initially and rapidly, respectively, rises and thus “define duration or how
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`long an effort can be sustained.” Id. at 10-11; EX1003 at ¶28. Those who were
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`more fit had higher aerobic and anaerobic thresholds, and thus had greater endurance
`
`and needed to consume less oxygen for a given submaximal workload. See EX1075
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`PGR2021-00110
`Patent 10,835,555
`at 10-11, FIG. 2.1, Table 2.1 (with a higher aerobic threshold, “slow-oxidative”
`
`muscles fibers “that use oxygen efficiently” are used over more work capacity);
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`EX1003 at ¶28.
`
`
`Exercise “can improve aerobic fitness by 20 to 25%, or more if accompanied
`
`by significant weight loss,” such as by increasing VO2 max and “improv[ing] the
`
`submaximal work capacity[ and] the aerobic threshold.” EX1075 at 11-12, Table
`
`2.1; EX1003 at ¶28. The improved fitness provides “many health benefits.”
`
`EX1075 at 11-12; EX1003 at ¶28.
`
`One health benefit of exercise is reducing blood pressure—which was “the
`
`force of blood against artery walls”—and cardiovascular risk. EX1055 at 1-2;
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`EX1056 at 25, 42, Tables 9, 16 (“aerobic fitness may negate much of the
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`cardiovascular risk associated with obesity”); EX1003 at ¶29. Those having a
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`PGR2021-00110
`Patent 10,835,555
`sustained systolic blood pressure of at least 140 mmHg and/or a sustained diastolic
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`blood of at least 90 mmHg had “high blood pressure” or “hypertension.” EX1055
`
`at 1-2, Box 1; EX1046 at 1117; EX1003 at ¶29. About “1 in 4[] adult Americans”
`
`had hypertension, and it was more prevalent “among older Americans.” EX1055 at
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`2; EX1056 at 8; EX1046 at 1117; EX1003 at ¶29.
`
`Hypertension was “dangerous” and could “lead to heart and kidney disease,
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`and stroke.” EX1055 at 2; EX1056 at 1, 9-10 (“suboptimal BP is the number one
`
`attributable risk factor for death”); EX1003 at ¶29. Blood pressure reductions were
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`desirable to prevent disease and mortality. EX1056 at 16, 25 (“a 5 mmHg reduction
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`of SBP in the population” would yield a 14%-reduction in stroke mortality, 9%
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`reduction in CHD mortality, and a 7%-reduction in all-cause mortality); EX1003 at
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`¶30. And anti-hypertensive regimens were recommended not only for those with
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`hypertension, but also for the general population “[t]o prevent BP levels from
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`rising.” EX1056 at 16; EX1003 at ¶30.
`
`The first step for reducing blood pressure to prevent and mitigate hypertension
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`was “[l]ifestyle [m]odifications,” which were “indispensable.” EX1056 at 25-26,
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`30-31; EX1003 at ¶31. Suggested lifestyle modifications included “[e]xercise
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`programs,” as well “a diet rich in fruits, vegetables, and lowfat dairy products” and
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`“[w]eight loss.” EX1056 at 25, 42; EX1003 at ¶31. If an individual did not meet a
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`“BP goal” with lifestyle changes, medications were prescribed. EX1056 at 30-31;
`
`EX1003 at ¶31; see also EX1056 at 26-29 (describing medications).
`
`B. Nitric Oxide As Vasodilator, Performance Enhancer, and Blood
`Pressure Regulator
`Nitric oxide (NO) production in the body was known to have “profound
`
`physiologic effects” relevant for both exercise performance and preventing and
`
`treating hypertension, including “promoting[ and] enhancing the metabolic
`
`vasodilation,” “regulat[ing] oxygen consumption,” and “control[ling] [] blood
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`pressure.” EX1013 at 873; EX1079 at Abstract; EX1014 at 220; EX1003 at ¶32.
`
`NO causes vasodilation and, thus, “increase[s] flow of blood” to increase
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`“delivery of nutrients, oxygen, and hormones” to the muscles and “help[] remove
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`undesirable byproducts of metabolism that fatigue muscles,” thereby increasing
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`exercise performance and endurance. See EX1070 at Abstract, ¶ [0019]; EX1003 at
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`¶32. Such NO-based vasodilation also reduces blood pressure. See EX1016 at 210;
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`EX1041 at S2 (“[T]he marked rise in blood pressure obtained after inhibition of NO
`
`synthesis confirms … that NO is the endogenous nitrovasodilator” and inhibiting its
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`production “may contribute to … hypertension”); EX1039 at 1503 (“[N]itrite-
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`induced vasodilation in humans is associated with reduction of nitrite to NO” which
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`“decrease[s] blood pressure”); EX1003 at ¶32.
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`PGR2021-00110
`Patent 10,835,555
`NO production enhances exercise performance in other ways too. EX1003 at
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`¶33. For example, “NO may enhance glucose uptake” to increase energy availability
`
`and may “inhibit glycolysis” to yield “lower lactate levels” during exercise, thereby
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`improving endurance. EX1072 at 318; EX1003 at ¶33. Furthermore, the opening
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`of the mitochondrial permeability transition pore (mPTP) with continued exercise
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`“can cause a distinct suppression of the muscular contraction strength and a
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`significant reduction in the efficiency of oxygen usage by working muscle,” which
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`NO suppresses to “prevent[] the development of muscle fatigue” and mitigate the
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`“decrease … [in] the efficiency of oxygen usage by the working muscle.” EX1071
`
`at 35-38, 41; EX1003 at ¶33; see, e.g., EX1071 at 38 (inhibiting NO production
`
`caused “a decrease in the muscular contraction strength and a significant reduction
`
`in the efficiency of oxygen usage”); EX1072 at 318 (“L-arginine-L-aspartate
`
`supplementation resulted in lower … oxygen consumption,” and NO “derived from
`
`L-arginine ingestion, may be speculated to be responsible”).
`
`With this understanding, enhancing NO production was viewed as a way to
`
`increase exercise performance and mitigate hypertension. See, e.g., EXSHEN at
`
`1131-32 (training increases “NOS gene expression” to enhance “NO production,”
`
`indicating “truly outstanding levels of exercise performance in animals or man is
`
`due to an enhanced production of NO”); EX1070 at ¶ [0019]; EX1053 at 916;
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`EX1003 at ¶34.
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`PGR2021-00110
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`Ingested Nitrate As a Known Precursor for NO
`C.
`While vascular endothelial cells produced NO endogenously from L-arginine
`
`(EX1052 at 3375; EX1041 at S1-S2), ingesting organic or inorganic nitrates also
`
`resulted in NO production (EX1018 at 1; EX1038 at 211). EX1003 at ¶35; see, e.g.,
`
`EX1019 at 32C (“The nitrovasodilators … result in the formation and release of
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`nitric oxide (NO).”); EX1018 at 1 (“[Nitrovasodilators] include the organic nitrates
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`such as nitroglycerine[ and] the inorganic nitrates and nitrites.”); EX1022 at 686.
`
`Organic and inorganic nitrates produced NO differently. Organic nitrates did
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`so via “[a]ctivation of guanylate cyclase,” although “the precise mechanism of
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`activation” was “not [] understood.” EX1018 at 1; EX1053 at 919-20; EX1003 at
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`¶36.
`
`Ingesting inorganic nitrate resulted in NO production via the nitrate-nitrite-
`
`NO pathway (EX1038 at 211), which was well-understood. EX1003 at ¶37. A mid-
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`1970’s study found inorganic nitrate “was handled in a peculiar way in the human
`
`body.” EX1016 at 210 (citing EX1057). “Approximately 25% of dietary nitrate”
`
`that was “absorbed from the stomach and proximal small intestine” was recirculated
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`into the saliva. EX1038 at 211; EX1003 at ¶37; see also EX1017 at 24 (“When
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`inorganic nitrate is swallowed, it is rapidly absorbed and concentrated in the salivary
`
`glands.”). Bacteria under the tongue “rapidly reduce[d the recirculated] nitrate to
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`nitrite,” resulting in “a high concentration of nitrite in saliva.” EX1038 at 211;
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`EX1003 at ¶37.
`
`The nitrite, when swallowed, undergoes reactions “under the acidic conditions
`
`of the stomach” to yield NO or “enter[ed] the circulation” for systemic NO
`
`generation. EX1038 at 211; EX1053 at 916-19 and Fig. 1 (“reduction of nitrite [to
`
`NO] can occur … in the stomach” via “[a]cidic reduction” and “also systemically in
`
`blood and tissues,” such as via “[r]eduction by [d]eoxyhemoglobin” in blood);
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`EX1003 at ¶38; see also EX1038 at 211 (acidic reduction); EX1039 at 1502-03
`
`(deoxyhemoglobin reduction). A POSITA would have understood that the resulting
`
`NO yielded the physiological responses described in Section V.B, including
`
`vasodilation that reduces blood pressure and increases blood flow to improve
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`nutrient delivery and mitigate fatigue during exercise. See EX1019 at ¶ [0019];
`
`EX1053 at 916-17, 919, Fig. 1 (“systemic nitrite generation from inorganic nitrate”
`
`rendered nitrate “a major vascular storage pool for NO” to influence the “activity of
`
`NO in the cardiovascular system,” which included “reduc[ing] blood pressure”);
`
`EX1054 at 395-96 (nitrite-nitrate-NO pathway), 397-98 (blood pressure reduction
`
`from ingesting nitrite); EX1039 at 1503; EX1003 at ¶38.
`
`Indeed, inorganic nitrates have long been administered to achieve such
`
`physiological responses, such as improving blood flow. See EX1018 at 1; EX1003
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`at ¶39. For example, an ancient Chinese manuscript described placing “saltpetre”—
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`potassium nitrate, an inorganic nitrate—under the tongue “to cause the heart [] to
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`flow freely.” EX1020 at 363-64; EX1003 at ¶39. In 1906, physicians similarly
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`administered “nitrate of potash [potassium nitrate] with nitrite of soda [sodium
`
`nitrite] to reduce the blood pressure.” EX1033 at 1335; EX1003 at ¶39; see also
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`EX1032 at 66 (“potassium nitrate” with “bicarbonate” and “sodium nitrite …
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`keep[s] [blood] pressure down”). And by February 2006, “nitrates (organic or
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`inorganic)” were recognized as “preferred treatments for isolated systolic
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`hypertension.” EX1021 at ¶[0030]; see also EX1022 at 686; EX1023 at 380;
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`EX1003 at ¶39; EX1040 at 2791-92.
`
`D. Natural Sources of Nitr