`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`HIKMA PHARMACEUTICALS USA INC.,
`HIKMA PHARMACEUTICALS PLC,
`Petitioner,
`
`v.
`
`AMARIN PHARMACEUTICALS IRELAND LIMITED,
`Patent Owner.
`
`
`Case IPR2022-00215
`Patent 8,642,077 B2
`Issued: February 4, 2014
`
`Title: STABLE PHARMACEUTICAL
`COMPOSITION AND METHODS OF USING SAME
`
`
`PETITION FOR INTER PARTES REVIEW
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`IPR2022-00215 (8,642,077 B2)
`
`TABLE OF CONTENTS
`
`Page
`
`
`LIST OF EXHIBITS ............................................................................................... vii
`I.
`INTRODUCTION ........................................................................................... 1
`II. MANDATORY NOTICES .............................................................................. 3
`III. REQUIREMENTS FOR REVIEW ................................................................. 4
`IV. THE ʼ077 PATENT .......................................................................................... 5
`V.
`LEVEL OF ORDINARY SKILL .................................................................... 7
`VI. TECHNICAL BACKGROUND ..................................................................... 8
`VII. CLAIM CONSTRUCTION .......................................................................... 10
`VIII. PRIOR-ART REFERENCES ........................................................................ 13
`A. Yokoyama I ......................................................................................... 14
`B. Mori ..................................................................................................... 14
`C.
`Yokoyama II ........................................................................................ 15
`D.
`Satoh .................................................................................................... 16
`E.
`Grimsgaard .......................................................................................... 16
`IX. ANALYSIS OF GROUNDS FOR TRIAL .................................................... 17
`A. Grounds based on Yokoyama I ............................................................ 17
`1.
`Ground A.1: Yokoyama I anticipates claims 1, 8, and 19. ........ 17
`a.
`Independent claim 1 ........................................................ 17
`b.
`Dependent claim 8 .......................................................... 25
`c.
`Dependent claim 19 ........................................................ 27
`Ground A.2: Dependent claim 8 would have been obvious over
`Yokoyama I in view of Satoh. .................................................. 28
`Ground A.3: Dependent claims 14–18 would have been obvious
`over Yokoyama I in view of Grimsgaard. ................................ 31
`a.
`Dependent claims 14, 16, 17 .......................................... 31
`b.
`Dependent claims 15 and 18 ........................................... 34
`Grounds based on Mori and Yokoyama II .......................................... 34
`1.
`Ground B.1: Claims 1, 8, and 19 would have been obvious over
`Mori in view of Yokoyama II. .................................................. 34
`
`B.
`
`2.
`
`3.
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`-i-
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`

`

`IPR2022-00215 (8,642,077 B2)
`
`2.
`
`3.
`
`C.
`
`Independent claim 1 ........................................................ 34
`a.
`Dependent claim 8 .......................................................... 40
`b.
`Dependent claim 19 ........................................................ 42
`c.
`Ground B.2: Dependent claim 8 would have been obvious over
`Mori in view of Yokoyama II and Satoh. ................................. 42
`Ground B.3: Dependent claims 14–18 would have been obvious
`over Mori in view of Yokoyama II and Grimsgaard. ............... 44
`a.
`Dependent claims 14, 16, 17 .......................................... 44
`b.
`Dependent claims 15 and 18 ........................................... 46
`There are no secondary considerations of nonobviousness. ............... 46
`1.
`The claimed method does not produce unexpected results. ..... 47
`2.
`Patent Owner’s Vascepa lacks a nexus to the claims. .............. 55
`3.
`Any alleged secondary considerations would be discounted by
`the blocking effect of existing and expected patents. ............... 56
`X. DISCRETIONARY FACTORS ..................................................................... 57
`A.
`The Board should not deny review under § 314(a). ............................ 57
`1.
`Fintiv factors 2–4 and 6 strongly favor institution. .................. 58
`2.
`The remaining Fintiv factors do not warrant denial. ................ 59
`The Board should not deny review under § 325(d). ........................... 60
`B.
`XI. CONCLUSION .............................................................................................. 62
`CERTIFICATE OF COMPLIANCE WITH TYPE-VOLUME LIMITATION ....... 63
`CERTIFICATE OF SERVICE ................................................................................. 64
`
`
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`-ii-
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`IPR2022-00215 (8,642,077 B2)
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Acorda Therapeutics, Inc. v. Roxane Labs., Inc.,
`903 F.3d 1310 (Fed. Cir. 2018) .......................................................................... 57
`
`Advanced Bionics, LLC v. MED-EL Elektromedizinische Geräte
`GmbH,
`IPR2019-01469, Paper 6 (PTAB Feb. 13, 2020) ................................................ 60
`Alcon Research, Ltd. v. Apotex Inc.,
`687 F.3d 1362 (Fed. Cir. 2012) .......................................................................... 30
`Amarin Pharma, Inc. v. Hikma Pharm. USA Inc.,
`449 F. Supp. 3d 967 (D. Nev. 2020) ............................................................. 35, 37
`Amarin Pharma, Inc. v. Hikma Pharm. USA Inc.,
`No. 1:20-cv-01630 (D. Del.) ................................................................................. 3
`Amgen Inc. v. Alexion Pharm., Inc.,
`IPR2019-00740, Paper 15 (PTAB Aug. 30, 2019) ............................................. 61
`Apple Inc. v. Fintiv, Inc.,
`IPR2020-00019, Paper 11 (PTAB Mar. 20, 2020) ....................................... 57, 59
`Asyst Techs., Inc. v. Emtrak, Inc.,
`544 F.3d 1310 (Fed. Cir. 2008) .......................................................................... 52
`Atlas Powder Co. v. Ireco Inc.,
`190 F.3d 1342 (Fed. Cir. 1999) .......................................................................... 26
`Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc.,
`246 F.3d 1368 (Fed. Cir. 2001) .............................................................. 25, 26, 40
`ClearValue, Inc. v. Pearl River Polymers, Inc.,
`668 F.3d 1340 (Fed. Cir. 2012) .......................................................................... 23
`In re Cruciferous Sprout Litig.,
`301 F.3d 1343 (Fed. Cir. 2002) .......................................................................... 26
`
`-iii-
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`

`IPR2022-00215 (8,642,077 B2)
`
`In re Dillon,
`919 F.2d 688 (Fed. Cir. 1990) ............................................................................ 41
`Eli Lilly & Co. v. Perrigo Co.,
`718 F. App’x 953 (Fed. Cir. 2017) ..................................................................... 48
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ...................................................................... 51, 52
`Gen. Hosp. Corp. v. Sienna Biopharmaceuticals, Inc.,
`888 F.3d 1368 (Fed. Cir. 2018) .................................................................... 32, 44
`Hoffmann-La Roche Inc. v. Apotex Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) .......................................................................... 30
`Inc. v. Netlist, Inc.,
`IPR2020-01421, Paper 10 (PTAB Mar. 16, 2021) ............................................. 59
`Ineos USA LLC v. Berry Plastics Corp.,
`783 F.3d 865 (Fed. Cir. 2015) ............................................................................ 23
`Kao Corp. v. Unilever U.S., Inc.,
`441 F.3d 963 (Fed. Cir. 2006) ............................................................................ 50
`In re Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .................................................................... 41, 51
`In re Kubin,
`561 F.3d 1351 (Fed. Cir. 2009) .......................................................................... 41
`Lego Sys., Inc. v. MQ Gaming LLC,
`IPR2020-01445, Paper 12 (PTAB Feb. 16, 2021) .............................................. 59
`McNeil-PPC, Inc. v. L. Perrigo Co.,
`337 F.3d 1362 (Fed. Cir. 2003) .......................................................................... 48
`Medichem, S.A. v. Rolabo, S.L.,
`353 F.3d 928 (Fed. Cir. 2003) ............................................................................ 23
`Merck & Co. v. Teva Pharm. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) .................................................................... 30, 43
`
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`

`IPR2022-00215 (8,642,077 B2)
`
`Minton v. Nat’l Ass’n of Sec. Dealers, Inc.,
`336 F.3d 1373 (Fed. Cir. 2003) .......................................................................... 26
`Monsanto Tech. LLC v. E.I. DuPont de Nemours & Co.,
`878 F.3d 1336 (Fed. Cir. 2018) .................................................................... 26, 27
`In re Napier,
`55 F.3d 610 (Fed. Cir. 1995) .............................................................................. 41
`Ormco Corp. v. Align Tech., Inc.,
`463 F.3d 1299 (Fed. Cir. 2006) .......................................................................... 55
`Oticon Med. AB v. Cochlear Ltd.,
`IPR2019-00975, Paper 15 (PTAB Oct. 16, 2019) .............................................. 61
`PAR Pharm., Inc. v. TWI Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .......................................................................... 41
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .................................................................... 47, 54
`Pfizer, Inc. v. Genentech, Inc.,
`IPR2017-01923, Paper 14 (PTAB April 4, 2018) .............................................. 61
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) .......................................................................... 53
`Richardson-Vicks Inc. v. Upjohn Co.,
`122 F.3d 1476 (Fed. Cir. 1997) .......................................................................... 54
`Sand Revolution II, LLC v. Cont’l Intermodal Grp. – Trucking LLC,
`IPR2019-01393, Paper 24 (PTAB June 16, 2020) ............................................. 60
`Santarus, Inc. v. Par Pharm., Inc.,
`694 F.3d 1344 (Fed. Cir. 2012) .......................................................................... 41
`Schering Corp. v. Geneva Pharm., Inc.,
`339 F.3d 1373 (Fed. Cir. 2003) .......................................................................... 26
`Sotera Wireless, Inc. v. Masimo Corp.,
`IPR2020-01019, Paper 12 (PTAB Dec. 1, 2020) ......................................... 59, 60
`
`-v-
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`

`

`IPR2022-00215 (8,642,077 B2)
`
`Wyeth v. Lupin Ltd.,
`579 F. Supp. 2d 711 (D. Md. 2008) .................................................................... 32
`Statutes
`35 U.S.C. § 102(b) ............................................................................................passim
`35 U.S.C. § 314(a) ................................................................................................... 57
`35 U.S.C. § 314(b)(1)............................................................................................... 58
`35 U.S.C. § 316(a)(11) ............................................................................................. 58
`35 U.S.C. § 325(d) ....................................................................................... 57, 60, 61
`Other Authorities
`37 C.F.R. § 42.8(b) .................................................................................................... 3
`37 C.F.R. § 42.104 ..................................................................................................... 4
`
`
`
`
`
`-vi-
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`

`IPR2022-00215 (8,642,077 B2)
`
`LIST OF EXHIBITS
`
`Description
`U.S. Patent No. 8,642,077 B2 to Manku et al. (the “ʼ077 patent”)
`Expert Declaration of Edward A. Fisher, M.D., Ph.D., M.P.H.
`WO 2007/142118 to Yokoyama et al. (2007) (certified English
`translation) (“Yokoyama I”)
`Trevor A. Mori et al., Purified Eicosapentaenoic and
`Docosahexaenoic Acids Have Differential Effects on Serum Lipids
`and Lipoproteins, LDL Particle Size, Glucose, and Insulin in Mildly
`Hyperlipidemic Men, 71 AM. J. CLINICAL NUTRI. 1085 (2000)
`(“Mori”)
`Mitsuhiro Yokoyama et al., Effects of Eicosapentaenoic Acid on
`Major Coronary Events in Hypercholesterolaemic Patients (JELIS):
`a Randomized Open- Label, Blinded Endpoint Analysis, 369
`LANCET 1090 (2007) (“Yokoyama II”)
`Noriko Satoh et al., Purified Eicosapentaenoic Acid Reduces Small
`Dense LDL, Remnant Lipoprotein Particles, and C-Reactive Protein
`in Metabolic Syndrome, 30 DIABETES CARE 144 (2007) (“Satoh”)
`Sameline Grimsgaard et al., Highly Purified Eicosapentaenoic Acid
`and Docosahexaenoic Acid in Humans Have Similar
`Triacylglycerol-Lowering Effects but Divergent Effects on Serum
`Fatty Acids, 66 AM. J. CLINICAL NUTRI. 649 (1997) (“Grimsgaard”)
`Third Report of the National Cholesterol Education Program
`(NCEP) Expert Panel on Detection, Evaluation, and Treatment of
`High Blood Cholesterol in Adults (Adult Treatment Panel 111)
`Final Report, 106 CIRCULATION 3143 (2002) (“ATP-III”)
`Plaintiffs’ Corrected Post-Trial Proposed Findings of Fact and
`Conclusions of Law (Feb. 27, 2020) from Amarin Pharma, Inc. v.
`Hikma Pharm. USA Inc., No. 16-2525, D.I. 377, ¶ 510 (D. Nev.)
`(“Amarin FFCL”)
`Day 2 (Jan. 14, 2020) Trial Transcript from Amarin Pharma, Inc. v.
`Hikma Pharm. USA Inc., No. 16-2525 (D. Nev.) (Testimony of Dr.
`Budoff) (“Bufoff Tr.”)
`Margaret Carroll, et al., Serum Lipids of Adults 20–74 Years: United
`States, 1976–80, Nat’l Ctr for Health Statistics, Vital & Health
`Statistics, 11(242) (1993) (“Nat’l Health Survey”)
`
`No.
`1001
`1002
`1003
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
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`IPR2022-00215 (8,642,077 B2)
`
`No.
`1012
`
`1013
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`Description
`Hartmut H-J Schmidt et al., Lipid Evaluation in HIV-1-Positive
`Patients Treated with Protease Inhibitors, 4 ANTIVIRAL THER. 163
`(1999) (“Schmidt”)
`Expert Declaration of Sylvia Hall-Ellis, Ph.D.
`Lovaza®, PHYSICIANS’ DESK REFERENCE 2699 (62d ed. 2007)
`(“Lovaza PDR”)
`Shuichi Nozaki et al., Effects of Purified Eicosapentaenoic Acid
`Ethyl Ester on Plasma Lipoproteins in Primary
`Hypercholesterolemia, 62 INT’L J. VITAMIN & NUTR. RES.
`256(1992) (“Nozaki”)
`Koji Shinozaki et al., The Long-Term Effect of Eicosapentaenoic
`Acid on Serum Levels of Lipoprotein (a) and Lipids in Patients with
`Vascular Disease, 2(2) J. ATHEROSCL. THROMB. 107 (1996)
`(“Shinozaki”)
`Joint Stipulations of Fact from Amarin Pharma, Inc. v. Hikma
`Pharm. USA Inc., No. 16-2525, D.I. 324 (D. Nev.)
`Day 7 (Jan. 28, 2020) Trial Transcript from Amarin Pharma, Inc. v.
`Hikma Pharm. USA Inc., No. 16-2525 (D. Nev.) (Testimony of Dr.
`Toth) (“Toth Tr.”)
`Plaintiffs’ Validity Contentions from Amarin Pharma, Inc. v. Hikma
`Pharm. USA Inc., No. 16-2525 (D. Nev.)
`Plaintiffs’ Infringement Contentions from Amarin Pharma, Inc. et
`al. v. Hikma Pharm. USA Inc. et al., C.A. No. 20-1630 (D. Del.)
`Plaintiffs’ Opposition to Motion to Dismiss from Amarin Pharma,
`Inc. et al. v. Hikma Pharm. USA Inc. et al., C.A. No. 20-1630 (D.
`Del.)
`Plaintiffs’ First Amended Complaint from Amarin Pharma, Inc. et
`al. v. Hikma Pharm. USA Inc. et al., C.A. No. 20-1630, D.I. 17 (D.
`Del.) (“Complaint”)
`Exhibit U to Plaintiffs’ First Amended Complaint from Amarin
`Pharma, Inc. et al. v. Hikma Pharm. USA Inc. et al., C.A. No. 20-
`1630, D.I. 17-22 (D. Del.) (Christie Ballantyne et al., Efficacy and
`Safety of Eicosapentaenoic Acid Ethyl Ester (AMR101) Therapy in
`Statin-Treated Patients with Persistent High Triglycerides, AM. J.
`CARDIOL. 1 (2012)) (“Ballantyne”)
`Exhibit V to Plaintiffs’ First Amended Complaint from Amarin
`Pharma, Inc. et al. v. Hikma Pharm. USA Inc. et al., C.A. No. 20-
`
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`IPR2022-00215 (8,642,077 B2)
`
`No.
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`1034
`
`1035
`
`1036
`
`1037
`
`Description
`1630, D.I. 17-23 (D. Del.) (Deepak L. Bhatt et al., Cardiovascular
`Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia, 380
`N. ENGL. J. MED. 11 (2018)) (“Bhatt”)
`Amarin Response to U.S. Patent Office re U.S. Patent Application
`No. 13/768,906 (Aug. 26, 2013)
`Michael H. Davidson et al., Efficacy and Tolerability of Adding
`Prescription Omega-3 Fatty Acids 4 g/d to Simvastatin 40 mg/d in
`Hypertriglyceridemic Patients: An 8-Week, Randomized, Double-
`Blind, Placebo-Controlled Study, 29 CLIN. THERAPEUTICS 1354
`(2007) (“Davidson”)
`Yasushi Saito et al., Effects of EPA on Coronary Artery Disease in
`Hypercholesterolemic Patients with Multiple Risk Factors: Sub-
`Analysis of Primary Prevention Cases from the Japan EPA Lipid
`Intervention Study (JELIS), 200 ATHEROSCLEROSIS 135 (2008)
`(“Saito”)
`Notice of Allowability from U.S. Patent Office re U.S. Patent
`Application No. 13/768,906 (Sept. 30, 2013)
`FDA Briefing Document, Endocrinologic and Metabolic Drugs,
`Advisory Committee Meeting regarding ANCHOR trial (Oct. 16,
`2013)
`U.S. Patent Office Interview Summary re U.S. Patent Application
`No. 13/614,111 (Dec. 12, 2012)
`Amarin Supplemental Response to U.S. Patent Office re U.S. Patent
`Application No. 13/614,111 (Jan. 11, 2013)
`Notice of Allowability from U.S. Patent Office re U.S. Patent
`Application No. 13/614,111 (Feb. 11, 2013)
`Vascepa® Label (rev. Dec. 2019)
`World Health Organization Memorandum, Classification of
`Hyperlipoproteinemias and Hyperlipoproteinemias, 43
`CIRCULATION 501 (1972) (“WHO Memo”)
`Declaration of C. Rosebraugh from Amarin Pharma, Inc. et al. v.
`U.S. F.D.A. et al., No. 15-3588, D.I. 54 (S.D.N.Y.)
`Scheduling Order from Amarin Pharma, Inc. et al. v. Hikma Pharm.
`USA Inc. et al., C.A. No. 20-1630, D.I. 50 (D. Del.)
`Hikma’s Motion to Dismiss from Amarin Pharma, Inc. et al. v.
`Hikma Pharm. USA Inc. et al., C.A. No. 20-1630, D.I. 19 (D. Del.)
`
`-ix-
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`IPR2022-00215 (8,642,077 B2)
`
`No.
`1038
`
`1039
`1040
`1041
`1042
`1043
`1044
`
`1045
`
`1046
`
`1047
`1048
`1049
`
`Description
`Office Action from U.S. Patent Office re U.S. Patent Application
`No. 13/768,906 (May 24, 2013)
`Original Japanese version of WO 2007/142118 to Yokoyama et al.
`U.S. Patent No. 6,384,077 to Peet et al.
`U.S. Patent No. 6,479,544 to Horrobin
`U.S. Patent No. 7,119,118 to Peet et al.
`Amarin Reports Fourth Quarter and Full Year 2004 Results Report
`U.S. Patent Application Publication No. 2007/0021504 A1 to
`Yokoyama et al.
`Mitsuhiro Yokoyama et al., Effects of Eicosapentaenoic Acid on
`Cardiovascular Events in Japanese Patients with
`Hypercholesterolemia: Rationale, Design, and Baseline
`Characteristics of the Japan EPA Lipid Intervention Study (JELIS),
`146 AM. HEART J. 613 (2003)
`Joint Claim Construction Chart from Amarin Pharma, Inc. et al. v.
`Hikma Pharm. USA Inc. et al., C.A. No. 20-1630, D.I. 94 (D. Del.)
`Curriculum vitae of Edward A. Fisher
`Lipitor® (atorvastatin calcium) tablets, labeling (rev. Sept. 2007)
`Crestor® (rosuvastatin calcium) tablets, labeling (rev. Nov. 2007)
`
`-x-
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`

`

`IPR2022-00215 (8,642,077 B2)
`
`I.
`
`INTRODUCTION
`Petitioner requests inter partes review of claims 1, 8, and 14–19 of U.S.
`
`Patent No. 8,642,077 (the “’077 patent”). These claims are directed to “[a] method
`
`of reducing triglycerides in a subject with mixed dyslipidemia on statin therapy”
`
`by administering “about 2500 mg to 5000 mg per day of ethyl eicosapentaenoate”
`
`(Ex. 1001, claim 1), a purified form of eicosapentaenoic acid (“EPA”) that, along
`
`with docosahexaenoic acid (“DHA”), is an omega-3 fatty acid found naturally in
`
`fish oil. Ex. 1002 ¶ 1. As shown below, under two sets of grounds, the challenged
`
`claims are anticipated or would have been obvious to a person of ordinary skill in
`
`the art (“POSA”) by the ’077 patent’s critical date in April 2008.
`
`First, all claims are anticipated or would have been obvious based on
`
`Yokoyama I (Ex. 1003), an international patent publication that disclosed methods
`
`of treating patients with both hypercholesterolemia and hypertriglyceridemia (i.e.,
`
`mixed dyslipidemia) by administering purified EPA with a statin. Ex. 1003, 9–11.
`
`In addition to dosing ranges that overlap with the claimed range, Yokoyama I
`
`disclosed that administering “high purity” EPA at “900 mg per dose, three times a
`
`day” (i.e., 2,700 mg/day) reduces triglycerides “by 14 to 20%.” Ex. 1003, 6–7.
`
`Thus, as confirmed by Petitioner’s declarant, Dr. Edward Fisher, Yokoyama I
`
`disclosed the claimed method of reducing triglycerides in a subject on statin
`
`therapy with mixed dyslipidemia using purified EPA. Ex. 1002 ¶ 93.
`
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`

`

`IPR2022-00215 (8,642,077 B2)
`
`Second, all claims would have been obvious based on Mori (Ex. 1004) in
`
`view of Yokoyama II (Ex. 1005). Both of these references disclosed clinical trials
`
`on purified EPA in patients with mixed dyslipidemia. Ex. 1002 ¶¶ 151, 157. Mori
`
`disclosed the use of 4 g/day of purified EPA to reduce triglycerides (Ex. 1004, 1–
`
`3), and Yokoyama II disclosed the combination of purified EPA with statin therapy
`
`(Ex. 1005, 1–2). As discussed below, a POSA would have been motivated to add
`
`statin therapy to Mori’s treatment method because it was the standard of care for
`
`patients with mixed dyslipidemia, and Yokoyama II taught that the combination of
`
`purified EPA with statin therapy significantly reduced both triglycerides and the
`
`risk of major coronary events. Together, therefore, these references taught the
`
`method of treatment claimed by the ’077 patent. Ex. 1002 ¶ 148.
`
`The challenged dependent claims add only minor details that were either
`
`disclosed in these same references or in two other clinical trials on purified EPA—
`
`Satoh (Ex. 1006) and Grimsgaard (Ex. 1007)—which a POSA would have been
`
`motivated to combine with the primary references above to arrive at the claimed
`
`subject matter with a reasonable expectation of success. Ex. 1002 ¶¶ 177, 179.
`
`During prosecution, the claims were repeatedly rejected as prima facie
`
`obvious over other prior art—a finding the examiner never retracted. The ’077
`
`patent issued only after Patent Owner alleged unexpected results based on a
`
`purported reduction in low-density-lipoprotein-cholesterol (“LDL-C”), which is
`
`-2-
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`

`

`IPR2022-00215 (8,642,077 B2)
`
`not recited in any challenged claim. But Patent Owner’s arguments were incorrect.
`
`As shown below, any reduction in LDL-C was expected and, regardless, lacks a
`
`nexus to the challenged claims and is not commensurate with their scope. Infra
`
`IX.C.1–2. Moreover, while Yokoyama I, Mori, Yokoyama II, and Grimsgaard
`
`were disclosed during prosecution (among thousands of other references), they
`
`were never substantively considered in any office action.
`
` The Board should institute IPR and cancel claims 1, 8, and 14–19.
`
`II. MANDATORY NOTICES
`Pursuant to 37 C.F.R. § 42.8(b), Petitioner states as follows:
`
`1.
`
`Real parties-in-interest. Petitioner’s real parties-in-interest are
`
`Hikma Pharmaceuticals USA Inc. and Hikma Pharmaceuticals PLC. No other
`
`parties exercised or could have exercised control over this Petition, and no other
`
`parties funded or directed this Petition.
`
`2.
`
`Related matters. The ’077 patent has been asserted in the following
`
`civil action: Amarin Pharma, Inc. v. Hikma Pharmaceuticals USA Inc., No. 1:20-
`
`cv-01630 (D. Del.). No prior IPR petition for the ʼ077 patent has been filed.
`
`3.
`
`Lead and back-up counsel. Petitioner identifies the following:
`
` Lead counsel:
`
`Jovial Wong (Reg. No. 60,115)
`
` Back-up counsel:
`
`Charles B. Klein*
`
` Back-up counsel:
`
`Eimeric Reig-Plessis*
`
`-3-
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`

`

`IPR2022-00215 (8,642,077 B2)
`
` Back-up counsel:
`
`Claire A. Fundakowski
`
` Back-up counsel:
`
`Alison M. King (Reg. No. 76,897)
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`* Counsel to seek pro hac vice admission.
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`4.
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`Service information. Petitioner identifies the following:
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` Email address:
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`HikmaIPR@winston.com
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` Mailing address:
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`Winston & Strawn LLP
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`1901 L Street NW
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`Washington, DC 20036
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` Telephone number:
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`202-282-5867
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` Fax number:
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`
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`202-282-5100
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`Please address all correspondence to lead counsel at the address shown above.
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`Petitioner consents to electronic service at the above-listed email address.
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`III. REQUIREMENTS FOR REVIEW
`Pursuant to 37 C.F.R. § 42.104, Petitioner certifies:
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`a. Grounds for standing. The ’077 patent is available for IPR.
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`Petitioner is not barred or estopped from requesting review of any claim on any
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`ground. All fees may be charged to Deposit Account No. 50-1814.
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`b.
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`Identification of challenge. Petitioner challenges claims 1, 8, and
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`14–19 under the following statement of precise relief requested:
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`IPR2022-00215 (8,642,077 B2)
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`Ground Claims Basis
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`Reference(s)
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`A.1
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`A.2
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`A.3
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`B.1
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`B.2
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`1, 8, 19 102(b) Yokoyama I (Ex. 1003)
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`8
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`103(a) Yokoyama I (Ex. 1003), Satoh (Ex. 1006)
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`14–18
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`103(a) Yokoyama I (Ex. 1003), Grimsgaard (Ex. 1007)
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`1, 8, 19 103(a) Mori (Ex. 1004), Yokoyama II (Ex. 1005)
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`8
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`103(a) Mori (Ex. 1004), Yokoyama II (Ex. 1005),
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`Satoh (Ex. 1006)
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`B.3
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`14–18
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`103(a) Mori (Ex. 1004), Yokoyama II (Ex. 1005),
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`Grimsgaard (Ex. 1007)
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`IV. THE ʼ077 PATENT
`The ’077 patent relates to EPA compositions and methods of using them to
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`treat patients. Ex. 1001, 1:1–3, 1:41–59. Claim 1 is the sole independent claim:
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`1. A method of reducing triglycerides in a subject with mixed
`dyslipidemia on statin therapy comprising, administering to the
`subject a pharmaceutical composition comprising about 2500 mg to
`5000 mg per day of ethyl eicosapentaenoate and not more than about
`5%, by weight of all fatty acids, docosahexaenoic acid or its esters to
`effect a reduction in fasting triglyceride levels in the subject.
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`Id., claim 1.
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`IPR2022-00215 (8,642,077 B2)
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`Dependent claim 8 is “[t]he method of claim 1 wherein the subject exhibits a
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`reduction in hs-CRP compared to placebo control.” Id., claim 8. The specification
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`defines “hs-CRP” as “high sensitivity C-reactive protein.” Id., 18:11–12.
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`Dependent claims 14, 16, and 17 specify that EPA is administered in “dosage
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`units” and progressively narrow the amount of EPA in such units, with the
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`narrowest of these claims—claim 17—reciting “dosage units each comprising
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`about 1 g of ethyl eicosapentaenoate.” Id., claims 14, 16–17.
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`Dependent claims 15 and 18 depend from these claims and specify that “the
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`dosage units are capsules.” Id., claims 15, 18.
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`Dependent claim 19 specifies that the EPA in claim 1 “comprises at least
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`about 90%, by weight, of all fatty acids.” Id., claim 19.
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`The specification does not recite any clinical data, let alone data on the
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`effects recited in the claims—e.g., “a reduction in fasting triglyceride levels in the
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`subject” (claim 1) and “a reduction in hs-CRP compared to placebo control” (claim
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`8). Nor does the specification recite any data on patients with “mixed
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`dyslipidemia” (claim 1) or the effects of “about 2500 mg to 5000 mg per day of
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`ethyl eicosapentaenoate” (claim 1). The only disclosed data relate to the stability,
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`dissolution, and bioavailability of a particular composition that is not claimed. Id.,
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`Figs. 1–2, 23:13–25:32 (Examples 1–4). These data have nothing to do with the
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`claimed treatment methods. Ex. 1002 ¶ 41.
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`IPR2022-00215 (8,642,077 B2)
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`The specification asserts without evidence that, “upon treatment in
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`accordance with the present invention, for example over a period of about 1 to
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`about 200 weeks, … the subject or subject group exhibits one or more of the
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`following outcomes,” followed by a laundry list of 23 hypothetical effects. Ex.
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`1001, 17:27–18:21. The specification speculates that reductions to lipids and
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`markers could range anywhere from 5–100%, without any data or other evidence.
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`Id. at 18:46–21:14. As Dr. Fisher explains, the specification adds nothing to the
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`prior art with respect to the claimed methods. Ex. 1002 ¶ 43.
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`V. LEVEL OF ORDINARY SKILL
`The ʼ077 patent claims priority to April 29, 2009. Ex. 1001. Without
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`conceding entitlement to this priority date, Petitioner and Dr. Fisher have used it to
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`analyze a POSA’s knowledge and level of skill. Ex. 1002 ¶¶ 17–18. Arguments in
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`this Petition and opinions in Dr. Fisher’s declaration would not change if the
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`relevant date were one year before the claimed priority date—i.e., April 29, 2008—
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`the earliest possible critical date under pre-AIA 35 U.S.C. § 102(b). Id.
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`A POSA at the time of the relevant priority date would have had (1) a
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`medical degree; (2) several years of experience in the development and/or clinical
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`use of fatty acids to treat cardiovascular, endocrine, and/or lipid disorders,
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`including fish-oil-based fatty acids, i.e., EPA and/or DHA, and their dosage forms;
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`IPR2022-00215 (8,642,077 B2)
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`and (3) access to a team including one or more of an analytical chemist,
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`pharmaceutical chemist, formulator, or biostatistician. Id. ¶ 21.
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`Dr. Fisher meets this definition of a POSA and met this definition at all
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`times between April 2008 and April 2009. Id. ¶ 22.
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`VI. TECHNICAL BACKGROUND
`The challenged claims relate to blood-lipid disorders, generally called
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`dyslipidemia. Id. ¶ 44. As of the priority date, the prevailing clinical guidelines
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`for dyslipidemia were the Third Report of the National Cholesterol Education
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`Program’s Adult Treatment Panel, or “ATP-III.” Id.; Ex. 1008. In prior litigation
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`involving a similar priority date (March 2008), Patent Owner called ATP-III “an
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`authoritative source for treating lipid disorders.” Ex. 1009 ¶ 21. For this petition,
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`two lipids addressed in ATP-III are important: triglycerides and LDL-C.
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`Triglycerides, sometimes called “triacylglycerols” or abbreviated “TG,” are
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`a type of fat in the blood used as an energy source. Ex. 1002 ¶ 45; Ex. 1009 ¶ 12.
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`Having elevated triglycerides is “hypertriglyceridemia.” Id. As of the priority
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`date, triglycerides were considered normal if below 150 mg/dL, with all levels
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`above this threshold considered elevated to varying degrees. Ex. 1008, 28 (Table
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`II.3-1); Ex. 1010, 27 (Budoff Tr. 329:5–17). Doctors were motivated to keep
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`triglycerides in the normal range (below 150 mg/dL) because, as stated in ATP-III,
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`IPR2022-00215 (8,642,077 B2)
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`“[e]levated triglycerides are widely recognized as a marker for increased risk” of
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`coronary heart disease (“CHD”). Ex. 1008, 27.
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`Controlling LDL-C—known as “bad cholesterol”—was recognized as even
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`more important for reducing the risk of CHD. Ex. 1002 ¶ 46. ATP-III
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`characterized LDL-C-lowering as “the primary target of cholesterol-lowering
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`therapy.” Ex. 1008, 16. ATP-III explained that “[t]his focus on LDL has been
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`strongly validated by recent clinical trials, which show the efficacy of LDL-
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`lowering therapy for reducing risk for CHD.” Id., 22. ATP-III characterized
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`elevated LDL-C as at least 100 mg/dL. Id., 23, 26 (Table II.2-4). Patients with
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`elevated LDL-C were known as having “hypercholesterolemia.” Ex. 1002 ¶ 46.
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`For patients with hypercholesterolemia, ATP-III taught that “the first
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`priority of drug therapy is to achieve the goal for LDL cholesterol.” Ex. 1008, 162.
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`Specifically, “an LDL-lowering drug should be started,” and “[t]he usual drug will
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`be a statin.” Id. “Statin” is a common term for “HMG CoA reductase inhibitors.”
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`Id., 168. ATP-III explained that statins “are the most effective and practical class
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`of drugs for reducing LDL-cholesterol concentrations.” Id. “Statin therapy [has]
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`proved remarkably safe, with no major or unexpected adverse effects,” and is
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`“highly effective in lowering LDL-cholesterol levels (the primary target of
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`therapy).” Id. ATP-III thus reflected that statin therapy for patients with elevated
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`LDL-C was the standard of care: “Statin therapy reduces the risk of essentially
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`IPR2022-00215 (8,642,077 B2)
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`every clinical manifestation of the atherosclerotic process; they are easy to
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`administer with good patient acceptance. They have few drug-drug interactions,
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`and they have a good record for safety.” Id.; Ex. 1002 ¶ 47.
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`Along with other U.S. medical references, ATP-III used mg/dL (milligrams
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`per deciliter) as the unit of measurement for lipid levels.