`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner
`
`
`Inter Partes Review No.: IPR2021-00881
`
`
`U.S. Patent No. 9,254,338 B2
`Filed: July 12, 2013
`Issued: February 9, 2016
`Inventor: George D. Yancopoulos
`
`Title: USE OF A VEGF ANTAGONIST TO TREAT
`ANGIOGENIC EYE DISORDERS
`
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 9,254,338 B2
`
`
`

`

`TABLE OF CONTENTS
`TABLE OF AUTHORITIES ................................................................................... iv
`EXHIBIT LIST ...................................................................................................... viii
`I.
`INTRODUCTION. .......................................................................................... 1
`II. MANDATORY NOTICES (37 C.F.R. § 42.8). .............................................. 3
`REAL PARTIES-IN-INTEREST (37 C.F.R. § 42.8(b)(1)). ........................... 3
`RELATED MATTERS (37 C.F.R. § 42.8(b)(2)). ........................................ 3
`LEAD AND BACK-UP COUNSEL AND SERVICE INFORMATION (37
`C.F.R. § 42.8(b)(3)-(4)). ........................................................................ 4
`PAYMENT UNDER 37 C.F.R. § 42.15(a) AND § 42.103. ........................... 5
`III.
`IV. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)). ................................ 5
`V.
`THRESHOLD REQUIREMENT FOR INTER PARTES REVIEW. .............. 5
`VI. OVERVIEW OF CHALLENGE AND PRECISE RELIEF
`REQUESTED. ................................................................................................. 6
`CHALLENGED CLAIMS. ........................................................................... 6
`STATUTORY GROUNDS OF CHALLENGE. ................................................. 6
`VII. OVERVIEW OF THE ’338 PATENT. ........................................................... 7
`THE ’338 PATENT. .................................................................................. 7
`EUROPEAN EQUIVALENT, EP-325. ........................................................ 10
`VIII. CLAIM CONSTRUCTION (37 C.F.R. § 42.104(b)(3)). .............................. 11
`“INITIAL DOSE,” “SECONDARY DOSE,” AND “TERTIARY DOSE.” ............. 12
`1.
`Regeneron’s contradictory construction for “tertiary
`dose,” if presented here, must be rejected. ............................... 13
`“4 WEEKS” AND “8 WEEKS,” AFTER THE IMMEDIATELY PRECEDING
`DOSE. .................................................................................................... 16
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`i
`
`

`

`3.
`
`
`
`
`
`
`
`2.
`
`“VEGFR1 COMPONENT,” “VEGFR2 COMPONENT” AND THE
`“MULTIMERIZATION COMPONENT.” ..................................................... 16
`“TREATING.” ........................................................................................ 17
`1.
`The “method for treating” element of the preamble is not
`a limitation of the Challenged Claims, and therefore does
`not require construction. ........................................................... 17
`Regeneron’s anticipated argument that the “method for
`treating” preamble is a positive limitation should be
`rejected. ..................................................................................... 19
`If construed to be a limitation, the preamble’s plain and
`ordinary meaning—which does not provide any specific
`efficacy requirement—must govern. ........................................ 21
`IX. PERSON OF ORDINARY SKILL IN THE ART. ....................................... 22
`X.
`THE SCOPE AND CONTENT OF THE PRIOR ART. ............................... 23
` VEGF TRAP-EYE/AFLIBERCEPT BACKGROUND. .................................. 23
`PETITIONER’S PRIOR ART REFERENCES. ............................................... 26
`1.
`Dixon (Ex.1006)........................................................................ 27
`2.
`Adis (Ex.1007). ......................................................................... 30
`3.
`Regeneron (8-May-2008) (Ex.1013). ....................................... 31
`4.
`NCT-795 (Ex.1014). ................................................................. 32
`5.
`NCT-377 (Ex.1015). ................................................................. 35
`6.
`The ’758 patent (Ex.1010). ....................................................... 36
`7.
`Dix (Ex.1033). ........................................................................... 37
`XI. GROUNDS FOR UNPATENTABILITY—DETAILED ANALYSIS. ....... 37
` ANTICIPATION. ..................................................................................... 37
`1.
`Legal standards. ........................................................................ 37
`
`ii
`
`

`

`5.
`
`
`
`2.
`3.
`4.
`
`Ground 1: Dixon anticipates the Challenged Claims. .............. 39
`Ground 2: Adis anticipates the Challenged Claims. ................. 44
`Ground 3: Regeneron (8-May-2008) anticipates the
`Challenged Claims. ................................................................... 49
`Grounds 4 and 5: NCT-795 and NCT-377 each anticipate
`the Challenged Claims. ............................................................. 54
`Obviousness. ........................................................................................ 61
`1.
`Legal standard. .......................................................................... 61
`2.
`Ground 6: The Challenged Claims are obvious over Dixon
`(either alone or in combination with the ’758 patent or
`Dix). .......................................................................................... 62
`No secondary considerations. ................................................... 66
`3.
`XII. CONCLUSION. ............................................................................................. 69
`
`
`
`
`
`iii
`
`

`

`TABLE OF AUTHORITIES
`Cases
`Advanced Display Sys., Inc. v. Kent State Univ.,
`212 F.3d 1272 (Fed. Cir. 2000) ............................................................................ 28
`Arctic Cat Inc. v. GEP Power Prods., Inc.,
`919 F.3d 1320 (Fed. Cir. 2019) ............................................................................ 17
`Ariosa Diagnostics v. Verinata Health, Inc.,
`805 F.3d 1359 (Fed. Cir. 2015) ............................................................................ 23
`Bayer Healthcare Pharm., Inc. v. Watson Pharm., Inc.,
`713 F.3d 1369 (Fed. Cir. 2013) ............................................................................ 64
`Bayer Schering Pharma AG v. Barr Lab’ys, Inc.,
`575 F.3d 1341 (Fed. Cir. 2009) ............................................................................ 65
`Bio-Rad Lab’ys, Inc. v. 10X Genomics Inc.,
`967 F.3d 1353 (Fed. Cir. 2020) ............................................................................ 17
`Bristol-Myers Squibb Co. v. Ben Venue Lab’ys, Inc.,
`246 F.3d 1368 (Fed. Cir. 2001) .................................................................... passim
`Cubist Pharms., Inc. v. Hospira, Inc.,
`75 F. Supp. 3d 641 (D. Del. 2014) ....................................................................... 59
`GlaxoSmithKline LLC v. Glenmark Pharms., Inc.,
`C.A. No. 14-877-LPS-CJB, 2016 WL 3186657 (D. Del. June 3, 2016) .............. 20
`Grünenthal GMBH v. Antecip Bioventures II LLC,
`PGR2019-00026, 2020 WL 4341822 (P.T.A.B. May 5, 2020) .................... 33, 35
`Hulu, LLC v. Sound View Innovations,
`IPR2018-01039, 2019 WL 7000067 (P.T.A.B. Dec. 20, 2019) .................... 32, 35
`In re Antor Media Corp.,
`689 F.3d 1282 (Fed. Cir. 2012) ............................................................................ 59
`In re Baxter Travenol Labs,
`952 F.2d 388 (Fed. Cir. 1991) .............................................................................. 41
`
`iv
`
`

`

`In re Cruciferous Sprout Litig.,
`301 F.3d 1343 (Fed. Cir. 2002) ............................................................................ 38
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) ..................................................................... 62, 66
`In re O’Farrell,
`853 F.2d 894 (Fed. Cir. 1988) .............................................................................. 64
`In re Omeprazole Patent Litig.,
`483 F.3d 1364 (Fed. Cir. 2007) ............................................................................ 38
`In Re: Copaxone Consol. Cases,
`906 F.3d 1013 (Fed. Cir. 2018) ..................................................................... 18, 20
`King Pharms., Inc. v. Eon Labs, Inc.,
`616 F.3d 1267 (Fed. Cir. 2010) ............................................................................ 38
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .......................................................................... 23, 61, 62, 63
`Merck & Co. v. Teva Pharms. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) ............................................................................ 15
`Motorola Mobility LLC v. Arnouse,
`IPR2013-00010, 2013 WL 12349001 (P.T.A.B. Jan. 30, 2013) ............................ 5
`Multiform Desiccants, Inc. v. Medzam, Ltd.,
`133 F.3d 1473 (Fed. Cir. 1998) ............................................................................ 15
`Mylan Lab’ys Ltd. v. Aventis Pharma S.A.,
`IPR2016-00712, 2016 WL 5753968, Paper 9 (P.T.A.B. Sept. 22, 2016) ............ 19
`Ormco Corp. v. Align Tech., Inc.,
`463 F.3d 1299 (Fed. Cir. 2006) ..................................................................... 62, 66
`Perricone v. Medicis Pharm. Corp.,
`432 F.3d 1368 (Fed. Cir. 2005) ............................................................................ 38
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) ............................................................................ 64
`
`v
`
`

`

`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) ............................................................... 11, 14, 21
`Purdue Pharma L.P. v. Endo Pharms. Inc.,
`438 F.3d 1123 (Fed. Cir. 2006) ........................................................................... 18
`Rasmusson v. SmithKline Beecham Corp.,
`413 F.3d 1318 (Fed. Cir. 2005) ............................................................................ 38
`Rosco, Inc. v. Mirror Lite Co.,
`304 F.3d 1373 (Fed. Cir. 2002) ............................................................................ 25
`Ruckus Wireless, Inc. v. Innovative Wireless Sols., LLC,
`824 F.3d 999 (Fed. Cir. 2016) .............................................................................. 15
`Samsung Elecs. Co. v. Elm 3DS Innovations, LLC,
`925 F.3d 1373 (Fed. Cir. 2019) ............................................................................ 14
`Sandoz Inc. v. Abbvie Biotechnology Ltd.,
`IPR2018-00156, 2018 WL 2735468 (P.T.A.B. June 5, 2018) ...................... 33, 35
`Sinorgchem Co., Shandong v. Int’l Trade Comm’n,
`511 F.3d 1132 (Fed. Cir. 2007) ............................................................................ 13
`TomTom, Inc. v. Adolph,
`790 F.3d 1315 (Fed. Cir. 2015) ............................................................................ 17
`Vizio, Inc. v. Int'l Trade Comm'n,
`605 F.3d 1330 (Fed. Cir. 2010) ............................................................................ 17
`Wyers v. Master Lock Co.,
`616 F.3d 1231 (Fed. Cir. 2010) ............................................................................ 66
`Statutes
`35 U.S.C. § 102 ................................................................................................ passim
`35 U.S.C. § 103 ........................................................................................................ 64
`35 U.S.C. § 103(a) ................................................................................................... 61
`35 U.S.C. § 314(a) ..................................................................................................... 5
`35 U.S.C. §§ 311-119 ................................................................................................ 1
`
`vi
`
`

`

`Other Authorities
`83 Fed. Reg. 197, 51340-51359 (Oct. 11, 2018) ..................................................... 11
`MANUAL OF PATENT EXAMINING PROCEDURE § 2128 ............................................. 33
`Trial Practice Guide,
`77 Fed. Reg. 48759-60 ........................................................................................... 3
`Regulations
`37 C.F.R. § 42.10(b) .................................................................................................. 4
`37 C.F.R. § 42.100(b) .............................................................................................. 11
`37 C.F.R. § 42.8(a)(1) ................................................................................................ 3
`37 C.F.R. § 42.8(b) .................................................................................................... 3
`37 C.F.R. §§ 42 et seq. ............................................................................................... 1
`
`
`
`
`
`
`vii
`
`

`

`Exhibit
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`1009
`1010
`
`1011
`
`1012
`
`1013
`
`EXHIBIT LIST
`
`Description
`U.S. Patent No. 9,254,338 B2 (“’338 patent”)
`Expert Declaration of Dr. Thomas A. Albini in Support of Petition
`for Inter Partes Review of Patent No. 9,254,338 B2, dated May 4,
`2021 (“Albini”)
`Expert Declaration of Mary Gerritsen, Ph.D. in Support of Petition
`for Inter Partes Review of U.S. Patent No. 9,254,338 B2, dated Apr.
`26, 2021 (“Gerritsen”)
`Jocelyn Holash et al., VEGF-Trap: A VEGF Blocker with Potent
`Antitumor Effects, 99 PROC. NAT’L ACAD. SCI. 11393 (2002)
`(“Holash”)
`Quan Dong Nguyen et al., A Phase I Study of Intravitreal Vascular
`Endothelial Growth Factor Trap-Eye in Patients with Neovascular
`Age-Related Macular Degeneration, 116 OPHTHALMOLOGY 2141
`(2009) (“Nguyen-2009”)
`James A Dixon et al., VEGF Trap-Eye for the Treatment of
`Neovascular Age-Related Macular Degeneration, 18 EXPERT
`OPINION ON INVESTIGATIONAL DRUGS 1573 (2009) (“Dixon”)
`Adis R&D Profile, Aflibercept: AVE 0005, AVE 005, AVE0005,
`VEGF Trap – Regeneron, VEGF Trap (R1R2), VEGF Trap-Eye, 9
`DRUGS R&D 261 (2008) (“Adis”)
`U.S. Patent No. 7,531,173 B2 (“’173 patent”)
`U.S. Patent No. 7,396,664 B2 (“’664 patent”)
`U.S. Patent No. 7,374,758 B2 (“’758 patent”)
`F Semeraro et al., Aflibercept in Wet AMD: Specific Role and
`Optimal Use, 7 DRUG DESIGN, DEV. & THERAPY 711 (2013)
`(“Semeraro”)
`Press Release, Regeneron, Regeneron and Bayer Health Care
`Announce Encouraging 32-Week Follow-Up Results from a Phase 2
`Study of VEGF Trap-Eye in Age-Related Macular Degeneration
`(Apr. 28, 2008),
`http://investor.regeneron.com/releasedetail.cfm?releaseid=394066
`(“Regeneron (28-April-2008)”)
`Press Release, Regeneron, Bayer and Regeneron Dose First Patient
`in Second Phase 3 Study for VEGF Trap-Eye in Wet Age-Related
`Macular Degeneration (May 8, 2008),
`
`viii
`
`

`

`http://investor.regeneron.com/releasedetail.cfm?ReleaseID=394065
`(“Regeneron (8-May-2008)”)
`Vascular Endothelial Growth Factor (VEGF) Trap-Eye:
`Investigation of Efficacy and Safety in Wet Age-Related Macular
`Degeneration (AMD) (VIEW1), NCT00509795, ClinicalTrials.gov
`(Apr. 28, 2009), https://clinicaltrials.gov/ct2/show/NCT00509795
`(“NCT-795”)
`VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD
`(VIEW 2), NCT00637377, ClinicalTrials.gov (Mar. 17, 2008),
`https://clinicaltrials.gov/ct2/show/NCT00637377 (“NCT-377”)
`U.S. Patent Nos. 7,303,746 B2; 7,303,747 B2; 7,306,799 B2; and
`7,521,049 B2 (“Monthly-Dosing-Patents”)
`File History of U.S. Patent No. 9,254,338 B2 (“’338 FH”)
`Jeffrey S. Heier et al., Intravitreal Aflibercept (VEGF Trap-Eye) in
`Wet Age-Related Macular Degeneration, 119 OPHTHALMOLOGY
`2537 (2012) (“Heier-2012”)
`U.S. Patent No. 9,669,069 B2 (“’069 patent”)
`Jeffrey S. Heier, Intravitreal VEGF Trap for AMD: An Update,
`RETINA TODAY, Oct. 2009, 44 (“Heier-2009”)
`Regeneron Pharm., Inc., Quarterly Report (Form 10-Q) (Sept. 30,
`2009) (“2009 10-Q”)
`U.S. Patent No. 7,374,757 B2 (“’757 patent”)
`U.S. Patent No. 7,070,959 B1 (“’959 patent”)
`File History of U.S. Patent No. 7,374,758 B2, 12/22/2011 Patent
`Term Extension Application (“’758 FH, 12/22/2011 PTE”)
`Michael Engelbert et al., Long-Term Follow-Up For Type 1
`(Subretinal Pigment Epithelium) Neovascularization Using A
`Modified “Treat And Extend” Dosing Regimen of Intravitreal
`Antivascular Endothelial Growth Factor Therapy, 30 RETINA, J.
`RETINAL & VITREOUS DISEASES 1368 (2010) (“Engelbert-2010”)
`Michael Engelbert et al., “Treat and Extend” Dosing of Intravitreal
`Antivascular Endothelial Growth Factor Therapy For Type 3
`Neovascularization/Retinal Angiomatous Proliferation, 29 J.
`RETINAL & VITREOUS DISEASES 1424 (2009) (“Engelbert-2009”)
`Richard F. Spaide et al., Prospective Study of Intravitreal
`Ranibizumab as a Treatment for Decreased Visual Acuity
`Secondary to Central Retinal Vein Occlusion, 147 AM. J.
`OPHTHALMOLOGY 298 (2009) (“Spaide”)
`
`1014
`
`1015
`
`1016
`1017
`
`1018
`
`1019
`1020
`
`1021
`1022
`1023
`1024
`
`1025
`
`1026
`
`1027
`
`ix
`
`

`

`Press Release, Regeneron, Bayer and Regeneron Extend
`Development Program for VEGF Trap-Eye to Include Central
`Retinal Vein Occlusion (Apr. 30, 2009),
`https://investor.regeneron.com/news-releases/news-release-
`details/bayer-and-regeneron-extend-development-program-vegf-
`trap-eye (“Regeneron (30-April-2009)”)
`Vascular Endothelial Growth Factor (VEGF) Trap-Eye:
`Investigation of Efficacy and Safety in Central Retinal Vein
`Occlusion (CRVO), NCT01012973, ClinicalTrials.gov (Nov. 12,
`2009), https://clinicaltrials.gov/ct2/show/NCT01012973 (“NCT-
`973”)
`P Mitchell et al., Ranibizumab (Lucentis) in Neovascular Age-
`Related Macular Degeneration: Evidence from Clinical Trials, 94
`BRIT. J. OPHTHALMOLOGY 2 (2009) (date of online publication)
`(“Mitchell”)
`Pascale G. Massin, Anti-VEGF Therapy for Diabetic Macular
`Edema: An Update, RETINA TODAY, SEPT./Oct. 2008, 54 (“Massin”)
`Press Release, Bayer AG, Bayer and Regeneron Start Additional
`Phase 3 Study for VEGF Trap-Eye in Wet Age-Related Macular
`Degeneration (May 8, 2008) (“Bayer (8-May-2008)”)
`U.S. Patent Application Publication No. 2006/0217311 A1 (“Dix”)
`Anne E. Fung et al., An Optical Coherence Tomography-Guided,
`Variable Dosing Regimen with Intravitreal Ranibizumab (Lucentis)
`for Neovascular Age-related Macular Degeneration, 143 AM. J.
`OPHTHALMOLOGY 566 (2007) (“Fung”)
`Geeta A. Lalwani et al., A Variable-dosing Regimen with
`Intravitreal Ranibizumab for Neovascular Age-Related Macular
`Degeneration: Year 2 of the PrONTO Study, 148 AM. J.
`OPHTHALMOLOGY 43 (2009) (“Lalwani”)
`Peter A Campochiaro et al., Ranibizumab for Macular Edema Due
`to Retinal Vein Occlusions: Implication of VEGF as a Critical
`Stimulator, 16 MOLECULAR THERAPY 791 (2008) (“Campochiaro”)
`Robert Steinbrook, The Price of Sight — Ranibizumab,
`Bevacizumab, and the Treatment of Macular Degeneration, 355 N.
`ENG. J. MED. 1409 (2006) (“Steinbrook”)
`Curriculum Vitae of Dr. Thomas Albini (“Albini CV”)
`U.S. Patent No. 7,378,095 B2 (“’095 patent”)
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`1039
`
`x
`
`

`

`1040
`
`1041
`
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`1048
`
`1049
`
`1050
`
`International Nonproprietary Names for Pharmaceutical
`Substances (INN), 20 WHO DRUG INFORMATION 115 (2006)
`(“WHO Drug Info”)
`Press Release, Regeneron, Regeneron Reports Full Year and Fourth
`Quarter 2008 Financial and Operating Results (Feb. 26, 2009),
`https://investor.regeneron.com/news-releases/news-release-
`details/regeneron-reports-full-year-and-fourth-quarter-2008-
`financial (“Regeneron (26-February-2009)”)
`U.S. DEP’T HEALTH & HUMAN SERVS., NAT’L INST. HEALTH, NAT’L
`EYE INST., Age-Related Macular Degeneration: What You Should
`Know (Sept. 2015),
`https://www.nei.nih.gov/sites/default/files/health-
`pdfs/WYSK AMD English Sept2015 PRINT.pdf (“NIH AMD”)
`David M. Brown & Carl D. Regillo, Anti-VEGF Agents in the
`Treatment of Neovascular Age-Related Macular Degeneration:
`Applying Clinical Trial Results to the Treatment of Everyday
`Patients, 144 AM. J. OPHTHALMOLOGY 627 (2007) (“Brown”)
`U.S. DEP’T HEALTH & HUMAN SERVS., NAT’L INST. HEALTH, NAT’L
`EYE INST., Diabetic Retinopathy: What You Should Know (Sept.
`2015), https://www.nei.nih.gov/sites/default/files/2019-06/Diabetic-
`Retinopathy-What-You-Should-Know-508.pdf (“NIH DR”)
`Napoleone Ferrara & Kari Alitalo, Clinical Applications of
`Angiogenic Growth Factors and Their Inhibitors, 5 NATURE MED.
`1359 (1999) (“Ferrara-1999”)
`Napoleone Ferrara & Robert S. Kerbel, Angiogenesis as a
`Therapeutic Target, 438 NATURE 967 (2005) (“Ferrara-2005”)
`Ziad F. Bashshur et al., Intravitreal Bevacizumab for the
`Management of Choroidal Neovascularization in Age-Related
`Macular Degeneration, 142 AM. J. OPHTHALMOLOGY 1 (2006)
`(“Bashshur”)
`LUCENTIS® Prescribing Information (2006) (“Lucentis”)
`L. Spielberg & A. Leys, Intravitreal Bevacizumab for Myopic
`Choroidal Neovascularization: Short-Term and 1-Year Results, 312
`BULLETIN SOCIETE BELGE D’OPHTALMOLOGIE 17 (2009)
`(“Spielberg”)
`Ursula Schmidt-Erfurth, Current Concepts in the Management of
`Diabetic Macular Edema, 7 PROCEEDINGS 52 (2010) (“Schmidt-
`Erfurth”)
`
`xi
`
`

`

`1051
`
`1052
`
`1053
`
`1054
`
`1055
`
`1056
`
`1057
`
`1058
`
`Pearse A. Keane et al., Effect of Ranibizumab Retreatment
`Frequency on Neurosensory Retinal Volume in Neovascular AMD,
`29 RETINA 592 (2009) (“Keane”)
`J.S. Rudge et al., VEGF Trap as a Novel Antiangiogenic Treatment
`Currently in Clinical Trials for Cancer and Eye Diseases, and
`VelociGene®-Based Discovery of the Next Generation of
`Angiogenesis Targets, 70 COLD SPRING HARBOR SYMPOSIA
`QUANTITATIVE BIOLOGY 411 (2005) (“Rudge”)
`Press Release, Regeneron, Positive Interim Phase 2 Data Reported
`for VEGF Trap-Eye in Age-Related Macular Degeneration (Mar.
`27, 2007), https://newsroom.regeneron.com/news-releases/news-
`release-details/positive-interim-phase-2-data-reported-vegf-trap-
`eye-age-related?releaseid=394105 (“Regeneron (27-March-2007)”)
`Press Release, Regeneron, Regeneron and Bayer Healthcare Initiate
`Phase 3 Global Development Program for VEGF Trap-Eye in Wet
`Age-Related Macular Degeneration (AMD) (Aug. 2, 2007),
`https://investor.regeneron.com/news-releases/news-release-
`details/regeneron-and-bayer-healthcare-initiate-phase-3-global
`(“Regeneron (2-August-2007)”)
`Retina Society, VEGF Trap-Eye in Wet AMD CLEAR-IT 2:
`Summary of One-Year Key Results, A Phase 2, Randomized,
`Controlled Dose-and Interval-Ranging Study of Intravitreal VEGF
`Trap-Eye in Patients With Neovascular, Age-Related Macular
`Degeneration (Sept. 28, 2008) (“Retina Society Meeting
`Presentation”)
`Press Release, Regeneron, VEGF Trap-Eye Final Phase 2 Results in
`Age-related Macular Degeneration Presented at 2008 Retina Society
`Meeting (Sept. 28, 2008), https://investor.regeneron.com/news-
`releases/news-release-details/vegf-trap-eye-final-phase-2-results-
`age-related-macular?ReleaseID=393906 (“Regeneron (28-
`September-2008)”)
`Press Release, Regeneron, VEGF Trap-Eye Shows Positive Results
`in a Phase 2 Study in Patients with Diabetic Macular Edema (Feb.
`18, 2010), https://investor.regeneron.com/news-releases/news-
`release-details/vegf-trap-eye-shows-positive-results-phase-2-study-
`patients?releaseid=445521 (“Regeneron (18-February-2010)”)
`ASS’N FOR RES. VISION & OPHTHALMOLOGY, ARVO® News
`(Winter/Spring 2008) (“ARVONews Winter/Spring 2008”)
`
`xii
`
`

`

`1059
`
`1060
`
`1061
`1062
`1063
`
`1064
`
`1065
`
`1066
`
`1067
`
`1068
`
`1069
`
`1070
`
`ASS’N FOR RES. VISION & OPHTHALMOLOGY, ARVO® News
`(Summer 2007) (“ARVONews Summer 2007”)
`Jean-François Korobelnik et al., Intravitreal Aflibercept Injection
`for Macular Edema Resulting from Central Retinal Vein Occlusion,
`121 OPHTHALMOLOGY 202 (2014) (“Korobelnik”)
`Curriculum Vitae of Dr. Mary Gerritsen (“Gerritsen CV”)
`EP 2 663 325 (published as WO 2012/097019 A1) (“EP-325”)
`File History of EP 2 663 325 (“EP-325-FH”)
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`2009), https://bjo.bmj.com/onlinefirst.dtl
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`Press Release, Bayer, VEGF Trap-Eye Shows Positive Results in
`Phase II Study in Patients with Diabetic Macular Edema (Feb. 18,
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`Press Release, Bayer, Bayer Health Care and Regeneron Announce
`Encouraging 32-Week Follow Up Results From A Phase 2 Study of
`VEGF Trap-Eye in Age-Related Macular Degeneration (Apr. 28,
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`Bayer HealthCare Phase 3 Studies of VEGF Trap-Eye in
`Neovascular Age-Related Macular Degeneration (Wet AMD) (Sept.
`14, 2009), https://investor.regeneron.com/news-releases/news-
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`healthcare-phase-3?ReleaseID=408872 (“Regeneron (14-
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`Processor) Regarding Vascular Endothelial Growth Factor (VEGF)
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`Vein Occlusion (CRVO) (GALILEO), NCT01012973,
`ClinicalTrials.gov (Apr. 8, 2011); Vascular Endothelial Growth
`
`xiii
`
`

`

`Factor (VEGF) Trap-Eye: Investigation of Efficacy and Safety in
`Wet Age-Related Macular Degeneration (AMD) (VIEW1),
`NCT00509795, ClinicalTrials.gov (Apr. 8, 2011); and VEGF Trap-
`Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW 2),
`NCT00637377, ClinicalTrials.gov (Aug. 13, 2009), dated January
`20, 2021 (“Wayback-Affidavit-069”)
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`Secondary to Central Retinal Vein Occlusion: 6-Month Results of
`the Phase III GALILEO Study, 97 BRITISH J. OPHTHALMOLOGY 278
`(2013) (“Holz”)
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`xiv
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`1083
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`with SEQ ID NO:16 of the ’758 patent and SEQ ID NO:4 of Dix
`(“’069 Amino Acid Sequences”)
`Nucleotide sequence alignment of SEQ ID NO:1 of the ’069 patent
`with SEQ ID NO:15 of the ’758 patent and SEQ ID NO:3 of Dix
`(“’069 Nucleotide Sequences”)
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`(“Shams”)
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`Trap-Eye: Investigation of Efficacy and Safety in Wet Age-Related
`Macular Degeneration (AMD) (VIEW1), NCT00509795,
`ClinicalTrials.gov (Apr. 28, 2009) and VEGF Trap-Eye:
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`
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`Press Release, Bayer, Bayer HealthCare and Regeneron Announce
`VEGF Trap-Eye Achieved Durable Improvement in Vision Over 52
`Weeks in a Phase 2 Study in Patients with Age-Related Macular
`Degeneration (Aug. 19, 2008) (“Bayer (19-August-2008)”)
`Amino acid sequence alignment of SEQ ID NO:2 of the ’338 patent
`with SEQ ID NO:16 of the ’758 patent and SEQ ID NO:4 of Dix
`(“’338 Amino Acid Sequences”)
`Nucleotide sequence alignment of SEQ ID NO:1 of the ’338 patent
`with SEQ ID NO:15 of the ’758 patent and SEQ ID NO:3 of Dix
`(“’338 Nucleotide Sequences”)
`
`
`
`xvi
`
`

`

`Mylan Pharmaceuticals Inc. (“Petitioner”) petitions for inter partes review
`
`(“IPR”) under 35 U.S.C. §§ 311–319 and 37 C.F.R. §§ 42 et seq., seeking
`
`cancellation of claims 1, 3-11, 13-14, 16-24, and 26 (the “Challenged Claims”) of
`
`U.S. Patent No. 9,254,338 (“’338 patent”) (Ex.1001), assigned to Regeneron
`
`Pharmaceuticals, Inc. (“Regeneron” or “Patent Owner”).
`
`I.
`
`INTRODUCTION.
`The Challenged Claims should have never issued. They are drawn to “VEGF
`
`Trap-Eye” dosing regimens known to persons of ordinary skill in the art (hereafter,
`
`“skilled artisans”) long before the patent’s alleged 2011 priority date. Regeneron’s
`
`age-related macular degeneration (“AMD”) clinical trials (VIEW1/VIEW2) with
`
`EYLEA® (a/k/a VEGF Trap-Eye or aflibercept) were designed to use the precise
`
`dosing regimens now covered by the Challenged Claims. The problem: Regeneron
`
`publicly disclosed these exact dosing regimens to skilled artisans as early as 2008,
`
`three years prior to filing its patent application. Regeneron then withheld those
`
`publications from the Examiner, allowing the ’338 patent to issue. For at least these
`
`reasons, the Challenged Claims are unpatentable.
`
`Petitioner thus files this Petition, supported by expert declarations from Dr.
`
`Thomas Albini—a renowned ophthalmologist (Ex.1002), and Dr. Mary Gerritsen—
`
`a pharmacologist with over thirty years’ experience (Ex.1003).
`
`Anticipation. Each Challenged Claim is anticipated. VEGF Trap-Eye was a
`
`1
`
`

`

`known blocker of vascular endothelial growth factor (“VEGF”) independently
`
`disclosed in the scientific literature, (see Ex.1004, Holash; Ex.1005, Nguyen-2009;
`
`Ex.1006, Dixon; Ex.1007, Adis) and patented (see Ex.1008, ’173 patent; Ex.1009,
`
`’664 patent; Ex.1010, ’758 patent) well before the alleged priority date.
`
`At least two VEGF Trap-Eye clinical trials—“VIEW1” and “VIEW2” and the
`
`dosing