Case 1:22-cv-00061-TSK-JPM Document 576 Filed 07/07/23 Page 1 of 45 PageID #: 44588
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE NORTHERN DISTRICT OF WEST VIRGINIA
`AT CLARKSBURG
`
`
`Plaintiff,
`
`
`v.
`
`
`REGENERON PHARMACEUTICALS, INC.,
`
`
`
`
`MYLAN PHARMACEUTICALS INC.
`and BIOCON BIOLOGICS INC.,
`
`
`
`
`
`
`
`
`Civil Action No. 1:22-cv-00061-TSK
`
`
`
`
`
`
`Defendants.
`
`
`
`
`
`DEFENDANTS’ OPENING POST TRIAL BRIEF – ISSUES
`WHERE DEFENDANTS BEAR THE BURDEN OF PROOF
`
`
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 576 Filed 07/07/23 Page 2 of 45 PageID #: 44589
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`III.
`
`IV.
`
`INTRODUCTION. ............................................................................................................. 1
`
`GENERAL BACKGROUND. ............................................................................................ 2
`
`CLAIM CONSTRUCTION. ............................................................................................... 2
`
`THE SCOPE, CONTENT, AND STATE OF THE ART. .................................................. 2
`
`A.
`
`B.
`
`C.
`
`Anti-VEGF targets, and the anti-VEGF aflibercept molecule. ............................... 3
`
`Formulating anti-VEGF compounds....................................................................... 3
`
`The utility of anti-VEGF compounds. .................................................................... 4
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Genentech—preclinical Lucentis (ranibizumab). ....................................... 4
`
`Regeneron—preclinical aflibercept. ........................................................... 4
`
`Avastin (bevacizumab)—approved anti-VEGF cancer drug; used
`by physicians intravitreally to target wet AMD and DME. ........................ 5
`
`Lucentis (ranibizumab) human clinical trials. ............................................ 6
`
`Aflibercept human clinical trials. ................................................................ 6
`
`V.
`
`LEGAL STANDARDS ...................................................................................................... 7
`
`VI.
`
`THE ASSERTED DOSING CLAIMS ARE INVALID. .................................................... 8
`
`A.
`
`Claim 6 of the ‘572 patent is both anticipated and obvious. ................................... 9
`
`1.
`
`2.
`
`The level of ordinary skill; the scope and content of the prior art. ............. 9
`
`The differences, if any, between the claims and the prior art. .................... 9
`
`a.
`
`b.
`
`c.
`
`Claim 6 is anticipated by Dixon (DTX 204). ................................ 10
`
`Claim 6 was obvious over Dixon (DTX 204) alone or
`combined with Hecht (DTX 3588). .............................................. 11
`
`Secondary considerations do not save claim 6. ............................ 12
`
`B.
`
`Claim 25 of the ‘572 patent and claims 11 and 19 of the ‘601 patent are
`anticipated and obvious......................................................................................... 12
`
`1.
`
`The level of ordinary skill; the scope and content of the prior art. ........... 12
`
`i
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 576 Filed 07/07/23 Page 3 of 45 PageID #: 44590
`
`2.
`
`The differences (if any) between the claims and the prior art. ................. 13
`
`a.
`
`b.
`
`The Regeneron Press Release (DTX 3198) anticipates
`claim 25 of the ‘572 patent and claims 11 and 19 of the
`‘601 patent. ................................................................................... 14
`
`Any differences between claim 25 of the ‘572 patent and
`claims 11 and 19 of the ‘601 patent would have been
`obvious. ......................................................................................... 15
`
`3.
`
`Secondary considerations do not save the claims here. ............................ 17
`
`C.
`
`The Asserted Dosing Claims fail to comply with Section 112
`requirements. ......................................................................................................... 18
`
`1.
`
`2.
`
`Claim 6 of the ‘572 patent fails to comply with Section 112. .................. 18
`
`The 5 starting dose elements lack written description and
`enablement. ............................................................................................... 19
`
`a.
`
`b.
`
`There are no blaze marks as written description requires. ............ 19
`
`Regeneron’s obviousness arguments undermine both the
`“blaze marks” and enablement. ..................................................... 19
`
`3.
`
`The “approximately” term is indefinite. ................................................... 20
`
`VII. THE ASSERTED FORMULATION CLAIMS ARE INVALID; THEY COVER
`KNOWN AND OBVIOUS FORMULATIONS, AND CLAIMED TOO
`BROADLY. ...................................................................................................................... 21
`
`A.
`
`The Asserted Formulation Claims Are Anticipated.............................................. 22
`
`1.
`
`Dix ‘226 (or iterations thereof) anticipates. .............................................. 22
`
`B.
`
`The claims cover formulations that follow the Genentech Lucentis and/or
`Liu’s established pathways, which would have been obvious to a POSA............ 23
`
`1.
`
`2.
`
`Level of ordinary skill; scope and content of the prior art. ....................... 23
`
`The differences, if any, between the claims and the prior art. .................. 24
`
`a.
`
`b.
`
`c.
`
`Aflibercept (Fraser) + Lucentis formulation ................................. 24
`
`Aflibercept (Fraser) + Liu to optimize the formulation. ............... 24
`
`Dix ‘226, alone or in view of the knowledge of a POSA. ............ 25
`
`3.
`
`Secondary considerations.......................................................................... 26
`
`ii
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 576 Filed 07/07/23 Page 4 of 45 PageID #: 44591
`
`C.
`
`The Asserted Formulation Claims Are Invalid Under Section 112. ..................... 28
`
`1.
`
`2.
`
`3.
`
`“Suitable for intravitreal administration” is indefinite. ............................. 28
`
`The written description fails to show possession of the full claim
`scope. ........................................................................................................ 29
`
`Practicing the full claim scope imposes undue burdens on the
`POSA. ....................................................................................................... 30
`
`VIII. CONCLUSION. ................................................................................................................ 30
`
`
`
`
`
`
`
`iii
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 576 Filed 07/07/23 Page 5 of 45 PageID #: 44592
`
`TABLE OF AUTHORITIES
`
`Cases
`
`Abbott Lab’ys v. Andrx Pharms., Inc.,
`452 F.3d 1331 (Fed. Cir. 2006) ................................................................................................ 17
`
`Abbott Lab’ys v. Sandoz, Inc.,
`566 F.3d 1282 (Fed. Cir. 2009) ................................................................................................ 10
`
`AK Steel Corp. v. Sollac & Ugine,
`344 F.3d 1234 (Fed. Cir. 2003) .................................................................................................. 1
`
`Almirall, LLC v. Amneal Pharms. LLC,
`28 F.4th 265 (Fed. Cir. 2022) ................................................................................................... 26
`
`Amgen Inc. v. Sanofi,
`143 S. Ct. 1243 (2023) ...................................................................................................... 1, 8, 18
`
`Ariad Pharms., Inc. v. Eli Lilly & Co.,
`598 F.3d 1336 (Fed. Cir. 2010) ............................................................................................ 8, 29
`
`Auto. Techs. Int’l, Inc. v. BMW of N. Am., Inc.,
`501 F.3d 1274 (Fed. Cir. 2007) ................................................................................................ 30
`
`Bayer Pharma AG v. Watson Lab’ys, Inc.,
`874 F.3d 1316 (Fed. Cir. 2017) ................................................................................................ 12
`
`Blue Calypso, LLC v. Groupon, Inc.,
`815 F.3d 1331 (Fed. Cir. 2016) ................................................................................................ 15
`
`Brenner v. Manson,
`383 U.S. 519 (1966) .................................................................................................................... 8
`
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc.,
`752 F.3d 967 (Fed. Cir. 2014) .................................................................................................... 8
`
`Connell v. Sears, Roebuck & Co.,
`722 F.2d 1542 (Fed. Cir. 1983) .......................................................................................... 11, 25
`
`Datamize, LLC v. Plumtree Software, Inc.,
`417 F.3d 1342 (Fed. Cir. 2005) .......................................................................................... 28, 29
`
`E.I. DuPont de Nemours & Co. v. Synvina C.V.,
`904 F.3d 996 (Fed. Cir. 2018) ............................................................................................ 25, 26
`
`Eli Lilly & Co. v. Barr Lab’ys, Inc.,
`251 F.3d 955 (Fed. Cir. 2001) .................................................................................................. 15
`
`iv
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 576 Filed 07/07/23 Page 6 of 45 PageID #: 44593
`
`Galderma Lab’ys, L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................................ 12, 16
`
`Genentech, Inc. v. Hospira, Inc.,
`946 F.3d 1333 (Fed. Cir. 2020) .................................................................................... 15, 16, 22
`
`Genentech, Inc. v. Novo Nordisk A/S,
`108 F.3d 1361 (Fed. Cir. 1997) ................................................................................................ 30
`
`Guangdong Alison Hi-Tech Co. v. Int’l Trade Comm’n,
`936 F.3d 1353 (Fed. Cir. 2019) ................................................................................................ 28
`
`Hoffmann-La Roche Inc. v. Apotex Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) .................................................................................... 16, 17, 26
`
`HZNP Meds. LLC v. Actavis Lab’ys UT, Inc.,
`940 F.3d 680 (Fed. Cir. 2019) .................................................................................................. 20
`
`In re Aller,
`220 F.2d 454 (C.C.P.A. 1955) .................................................................................................. 26
`
`In re Baxter Travenol Labs,
`952 F.2d 388 (Fed. Cir. 1991) .................................................................................................. 10
`
`In re Copaxone Consol. Cases,
`906 F.3d 1013 (Fed. Cir. 2018) ............................................................................................ 8, 15
`
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .................................................................................................. 8
`
`In re Wands,
`858 F.2d 731 (Fed. Cir. 1988) .................................................................................................. 30
`
`Ineos USA LLC v. Berry Plastics Corp.,
`783 F.3d 865 (Fed. Cir. 2015) ............................................................................................ 15, 22
`
`Interval Licensing LLC v. AOL, Inc.,
`766 F.3d 1364 (Fed. Cir. 2014) ................................................................................................ 28
`
`Kao Corp. v. Unilever U.S., Inc.,
`441 F.3d 963 (Fed. Cir. 2006) .................................................................................................. 17
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .................................................................................................... 2, 8, 12, 16
`
`Liebel-Flarsheim Co. v. Medrad, Inc.,
`481 F.3d 1371 (Fed. Cir. 2007) ................................................................................................ 20
`
`v
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 576 Filed 07/07/23 Page 7 of 45 PageID #: 44594
`
`Merck & Co., Inc. v. Teva Pharms. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) ................................................................................................ 27
`
`Microsoft Corp. v. i4i Ltd. P’ship,
`564 U.S. 91 (2011) ...................................................................................................................... 7
`
`Nautilus, Inc. v. Biosig Instruments, Inc.,
`572 U.S. 898 (2014) ............................................................................................................ 20, 28
`
`Novo Nordisk A/S v. Caraco Pharm. Lab’ys, Ltd.,
`719 F.3d 1346 (Fed. Cir. 2013) ................................................................................................ 12
`
`PAR Pharm., Inc. v. TWI Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) ................................................................................................ 12
`
`PharmaStem Therapeutics, Inc. v. ViaCell, Inc.,
`491 F.3d 1342 (Fed. Cir. 2007) ................................................................................................ 11
`
`Purdue Pharma L.P. v. Faulding Inc.,
`230 F.3d 1320 (Fed. Cir. 2000) ............................................................................................ 8, 19
`
`Rasmusson v. SmithKline Beecham Corp.,
`413 F.3d 1318 (Fed. Cir. 2005) ................................................................................................ 30
`
`Richardson-Vicks Inc. v. Upjohn Co.,
`122 F.3d 1476 (Fed. Cir. 1997) ................................................................................................ 24
`
`Schering Corp. v. Geneva Pharms.,
`339 F.3d 1373 (Fed. Cir. 2003) .................................................................................................. 8
`
`Scripps Clinic & Rsch. Found. v. Genentech, Inc.,
`927 F.2d 1565 (Fed. Cir. 1991) ................................................................................................ 10
`
`Senju Pharm. Co. v. Lupin Ltd.,
`780 F.3d 1337 (Fed. Cir. 2015) ................................................................................................ 24
`
`UCB, Inc. v. Actavis Lab’ys UT, Inc.,
`65 F.4th 679 (Fed. Cir. 2023) ................................................................................................... 26
`
`Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC,
`683 F.3d 1356 (Fed. Cir. 2012) ................................................................................................ 14
`
`Statutes
`
`35 U.S.C. § 102 ....................................................................................................................... 1, 2, 8
`
`35 U.S.C. § 102(b) ........................................................................................................................ 24
`
`35 U.S.C. § 102(e) ........................................................................................................................ 25
`
`vi
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 576 Filed 07/07/23 Page 8 of 45 PageID #: 44595
`
`35 U.S.C. § 103 ....................................................................................................................... 1, 2, 8
`
`35 U.S.C. § 103(c) ........................................................................................................................ 25
`
`35 U.S.C. § 112 ...................................................................................................................... passim
`
`
`
`
`
`
`
`vii
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 576 Filed 07/07/23 Page 9 of 45 PageID #: 44596
`
`TABLE OF ABREVIATIONS
`
`Abbreviation
`
`Description
`
`‘572 patent
`
`‘601 patent
`
`‘747 patent
`
`‘865 patent
`
`‘959 patent
`
`µL
`
`AIA
`
`AMD
`
`ARVO
`
`ASRS
`
`Asserted Claims
`
`Asserted Dosing Claims
`
`Asserted Formulation Claims
`
`Asserted Patents
`
`Avery
`
`Bashshur
`
`BCVA
`
`Chang
`
`U.S. Patent No. 11,253,572 B2 (PTX 3)
`
`U.S. Patent No. 10,888,601 B2 (PTX 1)
`
`U.S. Patent No. 7,303,474 B2 (DTX 2730)
`
`U.S. Patent No. 11,084,865 B2 (PTX 2)
`
`U.S. Patent No. 7,070,959 B1 (DTX 7)
`
`Microliter
`
`Leahy-Smith America Invents Act
`
`Age-related macular degeneration
`
`Association for Research in Vision and Ophthalmology
`
`American Society of Retinal Specialists
`
`Claims 11 and 19 of the ‘601 patent, claims 6 and 25 of the ‘572
`patent, and claims 4, 7, 9, 11, and 14-17 of the ‘865 patent
`Claims 11 and 19 of the ‘601 patent and claims 6 and 25 of the
`‘572 patent
`Claims 4, 7, 9, 11, and 14-17 of the ‘865 patent
`
`U.S. Patent No. 10,888,601 B2 (PTX 1), U.S. Patent No.
`11,084,865 B2 (PTX 2), and U.S. Patent No. 11,253,572 B2 (PTX
`3)
`
`Robert L. Avery et al., Intravitreal Bevacizumab (Avastin) for
`Neovascular Age-Related Macular Degeneration, 113
`OPHTHALMOLOGY 363 (2006) (DTX 9036)
`
`Ziad F. Bashshur et al., Intravitreal Bevacizumab for Treatment of
`Neovascular Age-related Macular Degeneration: A One-year
`Prospective Study, 145 AMERICAN J. OPHTHALMOLOGY 249 (2008)
`(DTX 4013)
`
`Best corrected visual acuity
`
`Byeong S. Chang & Susan Hershenson, Practical Approaches to
`Protein Formulation Development, in RATIONAL DESIGN OF
`STABLE PROTEIN FORMULATIONS, 1 (John F. Carpenter & Mark C.
`Manning eds., 2002) (PTX 1832)
`
`viii
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 576 Filed 07/07/23 Page 10 of 45 PageID #:
`44597
`
`Abbreviation
`
`Description
`
`CLEAR-IT 1
`
`CLEAR-IT 2
`
`CRVO
`
`Defendants
`
`Defs.’ FOF
`
`Dix ‘226
`
`Dixon
`
`DME
`
`Do 2009
`
`DR
`
`FDA
`
`Fraser
`
`Gaudreault
`
`Hecht
`
`Regeneron, Phase I Study, Aflibercept in AMD, An Exploratory
`Study of the Safety, Tolerability and Biological Effect of
`Intravitreal Administration of VEGF Trap in Patients With
`Neovascular Age-Related Macular Degeneration
`
`Regeneron, Phase II Study, Aflibercept in AMD, A Randomized,
`Controlled Study of the Safety, Tolerability and Biological Effect
`of Repeated Intravitreal Administration of VEGF Trap in Patients
`With Neovascular Age-Related Macular Degeneration
`
`Central retinal vein occlusion
`
`Biocon Biologics Inc. and Mylan Pharmaceuticals Inc.
`
`Defendants’ Proposed Findings of Fact and Conclusions of Law
`
`U.S. Patent No. 10,406,226 B2 (DTX 13)
`
`James A. Dixon et al., VEGF Trap-Eye for the Treatment
`of Neovascular Age-Related Macular Degeneration, 18 EXPERT
`OPINION INVESTIGATIONAL DRUGS 1573 (2009) (DTX 204)
`
`Diabetic macular edema
`
`D.V. Do et al., An Exploratory Study of the Safety, Tolerability and
`Bioactivity of a Single Intravitreal Injection of Vascular
`Endothelial Growth Factor Trap-Eye in Patients with Diabetic
`Macular Oedema, 93 J. OPHTHALMOLOGY 144 (2009) (DTX 3102)
`
`Diabetic retinopathy
`
`United States Food and Drug Administration
`
`Hamish M. Fraser et al., Single Injections of Vascular Endothelial
`Growth Factor Trap Block Ovulation in the Macaque and
`Produce a Prolonged, Dose-Related Suppression of
`Ovarian Function, 90 CLINICAL ENDOCRINOLOGY & METABOLISM
`1114 (2005) (DTX 729)
`
`Jacques Gaudreault et al., Preclinical Pharmacokinetics of
`Ranibizumab (rhuFabV2) after a Single Intravitreal
`Administration, 46 INVESTIGATIVE OPHTHALMOLOGY & VISUAL
`SCIENCE 726 (2005) (DTX 2265/PTX 1839)
`
`Gerald Hecht, Ophthalmic Preparations, in 2 REMINGTON: THE
`SCIENCE AND PRACTICE OF PHARMACY, 1563 (Alfonso R. Gennaro
`et al. eds.,19th ed. 1995) (DTX 3588)
`
`ix
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 576 Filed 07/07/23 Page 11 of 45 PageID #:
`44598
`
`Abbreviation
`
`Description
`
`Holash
`
`Lalwani
`
`Liu
`
`mg
`
`mL
`
`PANORAMA
`
`PBS
`
`Peyman
`
`POSA
`
`PRN
`
`PrONTO
`
`PTAB
`
`PTO
`
`PVR
`
`Jocelyn Holash et al., VEGF-Trap: A VEGF Blocker with Potent
`Antitumor Effects, 99 PNAS 11393 (2002) (DTX 3549)
`
`Geeta A. Lalwani, Anti-VEGF Therapy in Diabetic Macular
`Edema, RETINA TODAY 45 (Sept. 2009) (DTX 2733)
`
`US. Patent Application Publication No. 2004/0197324 A1 (DTX
`730)
`
`Milligram
`
`Milliliter
`
`Regeneron, Phase III Study, Aflibercept in DR, A Phase 3, Double-
`Masked, Randomized Study of the Efficacy and Safety of
`Intravitreal Aflibercept Injection in Patients With Moderately
`Severe to Severe Nonproliferative Diabetic Retinopathy
`
`Phosphate buffered saline
`
`International Patent Publication No. WO 2005/102303 A2 (PTX
`1758)
`
`Person of ordinary skill in the art
`
`Pro re nata or as-needed dosing
`
`Genentech, Phase II Study, Ranibizumab in AMD, Prospective
`Optical Coherence Tomography (OCT) Imaging of Patients With
`Neovascular Age-Related Macular Degeneration (AMD) Treated
`With Intra-Ocular Lucentis™ (Ranibizumab): PrONTO Study
`
`Patent Trial and Appeal Board
`
`United States Patent and Trademark Office
`
`Proliferative vitreoretinopathy
`
`Regeneron
`
`Regeneron Pharmaceuticals, Inc.
`
`Regeneron Press Release
`
`Regeneron Press Release, Enrollment Completed in Regeneron and
`Bayer HealthCare Phase 3 Studies of VEGF Trap-Eye in
`Neovascular Age-Related Macular Degeneration (Wet AMD)
`(September 14, 2009) (DTX 3198)
`
`RVO
`
`Tr.
`
`VEGF
`
`Retinal vein occlusion
`
`Trial Transcript
`
`Vascular endothelial growth factor
`
`VEGF Trap
`
`Regeneron development name for aflibercept
`
`x
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 576 Filed 07/07/23 Page 12 of 45 PageID #:
`44599
`
`Abbreviation
`
`Description
`
`VISTA
`
`VIVID
`
`
`
`Regeneron, Phase III Study, Aflibercept in DME, A Double-
`Masked, Randomized, Active-Controlled, Phase 3 Study of the
`Efficacy and Safety of Intravitreal Administration of VEGF Trap-
`Eye in Patients With Diabetic Macular Edema
`
`Regeneron, Phase III Study, Aflibercept in DME, A Randomized,
`Double Masked, Active Controlled, Phase III Study of the Efficacy
`and Safety of Repeated Doses of Intravitreal VEGF Trap-Eye in
`Subjects With Diabetic Macular Edema
`
`
`
`xi
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 576 Filed 07/07/23 Page 13 of 45 PageID #:
`44600
`
`TABLE OF RECORD CITATIONS
`
`Abbreviation
`
`Description
`
`Dkt. 427
`
`Dkt. 494-9
`
`Dkt. 494-12
`
`Order on Claim Construction (April 19, 2023)
`
`Joint Pretrial Order Memorandum, Exhibit 5P, Plaintiff’s Brief Summary
`of Material Facts and Theories of Liability or Defense (May 26, 2023)
`
`Joint Pretrial Order Memorandum, Exhibit 7, Stipulated Facts (May 26,
`2023)
`
`Dkt. 553
`
`Joint Stipulation Regarding Commercial Success (June 22, 2023)
`
`xii
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 576 Filed 07/07/23 Page 14 of 45 PageID #:
`44601
`
`I.
`
`INTRODUCTION.
`
`A patent’s “term of ‘protection from competitive exploitation’” is limited. Amgen Inc. v.
`
`Sanofi, 143 S. Ct. 1243, 1251 (2023). Regeneron had a huge family of patents that covered the
`
`aflibercept molecule and its anti-VEGF use. On June 16, 2023, the last of those patents officially
`
`expired,1 placing aflibercept in the public domain—the final exchange in the quid pro quo that
`
`Regeneron agreed to for U.S. patent protection over its molecule. The Asserted Claims here will
`
`renege on that bargain, because they cover aflibercept in dosing regimens that also were in the
`
`public domain (claims 6 and 25 of the ‘572 patent, claims 11 and 19 of the ‘601 patent); and putting
`
`aflibercept in known formulations (one that is “isotonic” for the ‘572 patent claim 6; the one for
`
`Lucentis, or the one for high concentrations that are stable in Liu, for the ‘865 patent claims).
`
`The Asserted Claims also cover steps to achieve known and routine goals, such as
`
`administering monthly starting doses sufficient to dry the macula (the claimed number of 5 falls
`
`within that range), before moving to extended 8-week dosing intervals; making a formulation
`
`isotonic (to be comfortable and non-irritating to the eye as in Dixon); ensuring a stable formulation
`
`(which Lucentis was, and which was Liu’s stated goal); measuring native conformation using size
`
`exclusion chromatography; and optimizing concentrations (the industry standard).
`
`Work building on a prior invention, to be patentable, must be novel, non-obvious, and give
`
`the public a new quid pro quo benefit. AK Steel Corp. v. Sollac & Ugine, 344 F.3d 1234, 1244
`
`(Fed. Cir. 2003); 35 U.S.C. §§ 102, 103, 112. The claims cover what was old and obvious; and
`
`the specifications don’t solve the issues that Regeneron’s witnesses argued made what is claimed
`
`non-routine (e.g., show that more monthly doses or formulations with high concentrations work in
`
`humans). (Tr. 498:2-16, 499:8-11 (Furfine); Tr. 2155:11-13, 2155:21-2156:11, 2167:13-2168:21,
`
`
`1 DTX 3501.12 (‘959 PTE); DTX 7 (‘959 patent), among others; Tr. 1432:8-1438:24 (MacMichael).
`
`1
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 576 Filed 07/07/23 Page 15 of 45 PageID #:
`44602
`
`2176:18-20 (Trout); Tr. 1927:6-25, 1933:21-25 (Csaky)). The Asserted Claims are invalid.
`
`II.
`
`GENERAL BACKGROUND.
`
`Patents are assessed from the perspective of a POSA. KSR Int’l Co. v. Teleflex Inc., 550
`
`U.S. 398, 420 (2007). The parties’ few POSA differences do not alter the ultimate outcome of
`
`those analyses. (Tr. 1372:15-1374:4 (MacMichael); Tr. 1008:25-1012:13 (Rabinow); Tr. 752:5-
`
`753:21, 755:22-756:6 (Albini); Tr. 1270:19-1271:11 (Stewart); Tr. 2011:5-2012:6 (Trout); Tr.
`
`1815:20-1816:3 (Csaky)).
`
`Aflibercept was a known, potent, VEGF blocker. (Tr. 114:16-17 (Yancopoulos); DTX
`
`3549 (Holash)). But it was Genentech’s prior anti-VEGF work with bevacizumab (Avastin) in
`
`2003, and ranibizumab (Lucentis) in 2005, that were the “game changers” that blazed a trail that
`
`aflibercept followed. (Tr. 185:23-186:15 (Yancopoulos)). Once FDA approved Avastin in 2003,
`
`and Genentech reported ranibizumab human clinical data in 2005, physicians injected intravenous
`
`bevacizumab to treat AMD and DME without a specific intravitreal formulation, and without Phase
`
`III clinical safety and efficacy data. (Tr. 764:5-17 (Albini); Tr. 1030:13-1031:2 (Rabinow); DTX
`
`3058 (Rosenfeld); DTX 9036 (Avery); DTX 4041 (Ferrara 2005)). The dosing and formulation
`
`art rapidly advanced without regard to Regeneron’s patents. (See, e.g., Tr. 515:19-25 (Furfine);
`
`Tr. 2138:2-24 (Trout); DTX 3058; DTX 9036; DTX 2265 (Gaudreault); DTX 726 (Shams)).
`
`III. CLAIM CONSTRUCTION.
`
`The Court has correctly construed the claims. (Dkt. 427). The parties presented their cases
`
`at trial in reliance thereon. (See, e.g., Tr. 16, 18-19, 40, 59, 72 (opening statements), 316, 353-54,
`
`588, 591, 600, 602, 615, 626, 630, 649, 696-97, 810-11, 813, 829, 1008 (experts’ opinions)).
`
`IV.
`
`THE SCOPE, CONTENT, AND STATE OF THE ART.
`
`Pre-AIA 35 U.S.C. §§ 102 and 103 apply here. Detailed legal standards; what prior art and
`
`conception contentions were timely raised; and the references that are prior art across Regeneron’s
`
`2
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 576 Filed 07/07/23 Page 16 of 45 PageID #:
`44603
`
`multiple proposed invention dates shall be set forth in Defs.’ FOF. Defendants mainly focus on
`
`art stipulated as prior art to the Asserted Patents. (Dkt. 494-12).
`
`A.
`
`Anti-VEGF targets, and the anti-VEGF aflibercept molecule.
`
`By 2005, the literature confirmed that “[i]nhibiting angiogenesis” was “a promising
`
`strategy” to treat cancer and “age-related macular degeneration,” with “the first antiangiogenic
`
`agents … recently approved for use in several countries.” (DTX 4041.1). Regeneron’s prior art
`
`patents and publications also tout anti-VEGFs as “useful” to treat “VEGF-induced pathological
`
`angiogenesis” and “eye disorders such as age related macular degeneration and diabetic
`
`retinopathy.” (DTX 3619.6, ll. 8-13; see also DTX 3619.36-37). VEGF was a known target.
`
`Regeneron tried to argue a POSA didn’t know aflibercept’s exact structure. Regeneron
`
`disclosed VEGFR1R2FcΔCl(a), its full sequence, and better properties before 2006. (See DTX
`
`3619.60; DTX 3619.139-141; DTX 7.1; DTX 7.42-44; DTX 7.63, 9:65-67; DTX 7.73, 29:13:29;
`
`Tr. 1432:19-1433:23 (MacMichael)). A POSA thus knew aflibercept’s structure and sequence,
`
`whatever the name. (DTX 3549; DTX 3619; DTX 4008; DTX 7; DTX 728; Tr. 1227:9-12 (Chu
`
`30(b)(6)); Tr. 110:11-22 (Yancopoulos); Tr. 762:2-8 (Albini); Tr. 1014:18-1015:8 (Rabinow)).
`
`B.
`
`Formulating anti-VEGF compounds.
`
`Regeneron’s early aflibercept injection formulations used an aqueous PBS vehicle that the
`
`art called isotonic. (DTX 3549.2; DTX 8180 (calling it isotonic)). Regeneron’s animal studies
`
`had recipes for high aflibercept concentrations, in a formulation with the classic buffer, surfactant,
`
`and stabilizer ingredients. (DTX 728.2; DTX 718.1). Fraser’s animal studies also used a high
`
`concentration aflibercept formulation, also with a buffer, surfactant, and stabilizer, using “buffer
`
`composed of 5 mM phosphate, 5 mM citrate, 100 mM NaCl (pH 6.0), and 0.1% wt/vol Tween 20
`
`[surfactant], with either 20% glycerol or 20% sucrose [stabilizer].” (DTX 729.2).
`
`Regeneron filed patents to more stable anti-VEGF formulations, such as Dix ‘226 (DTX
`
`3
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 576 Filed 07/07/23 Page 17 of 45 PageID #:
`44604
`
`13.4, 1:39 (“pharmaceutical formulations having increased stability.”)). Stable formulation
`
`Examples used high concentration aflibercept, phosphate buffer, polysorbate, and sucrose as a
`
`stabilizer; the specification also discussed formulations with a “a buffer, a co-solvent, and one or
`
`more stabilizers,” a “preferred” range of 10-50 mg/mL; and a “40 mg/mL” embodiment. (DTX
`
`13.5, 3:60-61; 13.7, 7:1-10, 7:60-8:40). The original application and publication also had, among
`
`others, 40 mg/mL liquid aflibercept with a buffer, polysorbate 20, and stabilizer. (DTX 4121.1, 3
`
`[0017], 5 [0036]; Tr. 1788:8-13, 1789:18-1790:1, 1790:14-17 (Graham)).
`
`The art also included ranibizumab formulations (including a clinical trial formulation stable
`
`and suitable for human intravitreal use), also with the classic buffer, surfactant, and stabilizer.
`
`(DTX 2265; DTX 726; Tr. 1034:21-1037:21, 1042:9-1044:9, 1045:9-14 (Rabinow)).
`
`C.
`
`The utility of anti-VEGF compounds.
`
`By 2005, clinicians used anti-VEGF strategies to treat their patients, including with
`
`intravitreal injections, for the clinical indications of AMD, DME, and DR.
`
`1.
`
`Genentech—preclinical Lucentis (ranibizumab).
`
`Regeneron monitored how Genentech dosed ranibizumab for eye diseases, and by March
`
`1, 2004, knew that Genentech had reported that the “highest levels [of ranibizumab were] observed
`
`for ITV,” intravitreal doses. (See, e.g., DTX 710.1-2; DTX 2265.1 (Genentech comparing how
`
`ranibizumab performed intravitreally and intravenously in monkeys, and reporting ranibizumab
`
`would be “favorable for its clinical use in treating neovascular AMD by monthly ITV injection.”);
`
`Tr. 247:16-248:12 (Furfine); Tr. 1605:19-22 (Graham)). In February 2005, Gaudreault published
`
`a primate study comparing intravitreal and intravenous ranibizumab formulations, including 10
`
`mg/mL and 40 mg/mL in 50 µLs dosed intravitreally. (DTX 2265.2).
`
`2.
`
`Regeneron—preclinical aflibercept.
`
`By 2002, Regeneron published that the “combination of high-affinity and improved
`
`4
`
`

`

`Case 1:22-cv-00061-TSK-JPM Document 576 Filed 07/07/23 Page 18 of 45 PageID #:
`44605
`
`pharmacokinetics” made “VEGF-TrapR1R2 one of the most, if not the most, potent and efficacious
`
`VEGF blocker available.” (DTX 3549.5; Tr. 1252:4-14 (Chu)). In 2003, Regeneron published
`
`studies on aflibercept injected into mice eyes. (DTX 2751.1; Tr. 1050:21-1052:3, 1090:5-1092:3
`
`(Rabinow)). One intravitreal injection of VEGF-TrapR1R2 “markedly suppressed the development
`
`of choroidal neovascularization.” (DTX 2751.7). In 2005, Regeneron published Fraser, a dose-
`
`ranging study to find “the minimal dose of VEGF TrapRlR2” producing the anti-VEGF effect.
`
`(DTX 729.2). VEGF TrapR1R2 “was well tolerated.” (DTX 729.3). The 4 mg/kg and the 1 mg/kg
`
`doses “resulted in a significantly longer” period of activity. (DTX 729.5).
`
`Regeneron also praised aflibercept’s performance in animal studies for showing
`
`“impressive efficacy in an assortment of animal models of these eye diseases,” including diabetic
`
`edema, retinopathy, and AMD. (DTX 3592.4; see also DTX 2730 (Regeneron ‘747 patent
`
`emphasizing efficacy of VEGFR1R2FcΔCl(a), collecting animal testing data, and discussing
`
`treating AMD with intravitreal injections of aflibercept in human patients); DTX 4229.24 [0031]
`
`(published patent application reporting results of intravitreal aflibercept injections)).
`
`3.
`
`Avastin (bevacizumab)—approved anti-VEGF cancer drug; used by
`physicians intravitreally to target wet AMD and DME.
`
`FDA approve