`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`MYLAN PHARMACEUTICALS INC., CELLTRION, INC., and
`APOTEX, INC.,
`Petitioners,
`
`v.
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner.
`
`
`Inter Partes Review No.: IPR2021-008811
`
`
`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
`
`
`PETITIONER REPLY
`
`
`
`
`
`
`
`
`
`1 IPR2022-00258 and IPR2022-00298 have been joined with this proceeding.
`
`

`

`
`
`
`
`
`
`
`
`2.
`
`TABLE OF CONTENTS
`INTRODUCTION. .......................................................................................... 1
`I.
`PERSON OF ORDINARY SKILL IN THE ART (“POSA”). ........................ 4
`II.
`III. CLAIM CONSTRUCTION. ........................................................................... 6
`PREAMBLE: “A METHOD FOR TREATING AN ANGIOGENIC EYE
`DISORDER IN A PATIENT.” ..................................................................... 7
`1.
`If Limiting, The Board Should Apply Its Preamble
`Construction. ............................................................................... 7
`PO Reads In Multiple Unsupported and Undefined
`Limitations. ................................................................................. 7
`PO’s “high level of efficacy” is unsupported. .................. 8
`PO’s “high level of efficacy” is undefined (and
`inconsistent with the intrinsic evidence). ....................... 10
`PO’s “standard of care” claim meaning also is
`undefined, variable and subjective. ................................ 13
`“INITIAL DOSE,” “SECONDARY DOSE(S)” AND “TERTIARY
`DOSE(S).” ............................................................................................. 14
`1.
`All Are Defined As The Temporal Sequence Of Doses. .......... 15
`2.
`PO’s Current Construction Fundamentally Differs From
`Its Last Proposal For The Same Term (In The Same
`Family). ..................................................................................... 16
`PO’s Construction Eliminates the Notice Function. ................. 17
`3.
`IV. ANTICIPATION AND OBVIOUSNESS. .................................................... 18
`THE ASSERTED REFERENCES HAVE UTILITY AND ARE NOT
`SUBJECT TO THE EXPERIMENTAL USE EXCEPTION............................... 18
`THE ASSERTED REFERENCES DISCLOSE EVERY-8-WEEK VEGF
`TRAP-EYE ADMINISTRATION. ............................................................... 21
`
`
`
`
`
`
`
`i
`
`

`

`VEGF TRAP-EYE/AFLIBERCEPT WAS DISCLOSED IN EACH
`ASSERTED REFERENCE. ........................................................................ 21
`1.
`VEGF Trap-Eye/Aflibercept sequence is a prior art,
`necessary feature. ...................................................................... 22
`VEGF Trap-Eye/Aflibercept sequence is inherent. .................. 23
`2.
`THERE WAS NEVER CONFUSION OVER THE IDENTITY OF VEGF
`TRAP-EYE/AFLIBERCEPT. ..................................................................... 23
`1.
`“VEGF Trap-Eye” and “aflibercept” were known as the
`same molecular structure. ......................................................... 23
`“VEGF Trap-Eye” and “aflibercept” molecular weight
`reports were, in fact, consistent................................................. 24
`VEGF Trap-Eye is not a genus of proteins. .............................. 26
`VEGF Trap-Eye/Aflibercept was known in the prior art as
`VEGFR1R2-FcΔC1(a), “VEGF TrapR1R2” for short. ............... 27
`PO’s confidentiality claims are irrelevant. ............................... 28
`5.
`VEGF TRAP-EYE/AFLIBERCEPT ADMINISTRATION RESULTED IN
`EFFECTIVE TREATMENT. ...................................................................... 29
`THE CLAIMS WOULD HAVE BEEN OBVIOUS. ....................................... 32
` NO EVIDENCE OF “SURPRISING” / “UNEXPECTED” RESULTS OR
`“LONG-FELT, UNMET NEED”. .............................................................. 34
` NO NEXUS / NO COMMERCIAL SUCCESS. ............................................. 35
`CONCLUSION. ............................................................................................. 38
`
`2.
`
`3.
`4.
`
`
`
`
`
`
`
`
`
`V.
`
`
`
`
`
`
`ii
`
`

`

`TABLE OF AUTHORITIES
`Cases
`Abbott Lab’ys v. Geneva Pharms., Inc.,
`182 F.3d 1315 (Fed. Cir. 1999) ............................................................................ 22
`Al-Site Corp. v. VSI Int’l Inc.,
`174 F.3d 1308 (Fed. Cir. 1999) .............................................................................. 4
`Amgen Inc. v. Alexion Pharms., Inc.,
`IPR2019-00740, Paper 15 (P.T.A.B. Aug. 30, 2019) .......................................... 29
`Beckman Instruments v. LKB Produkter AB,
`892 F.2d 1547 (Fed. Cir. 1989) ............................................................................ 20
`Byrne v. Wood, Herron & Evans, LLP,
`450 F. App’x 956 (Fed. Cir. 2011) ......................................................................... 5
`Celltrion, Inc. v. Genentech, Inc.,
`IPR2016-01667, Paper No. 15 (P.T.A.B. Mar. 2, 2017) ...................................... 31
`Continental Circuits LLC v. Intel Corp.,
`915 F.3d 788 (Fed. Cir. 2019) .............................................................................. 10
`Elan Microelectronics Corp. v. Apple, Inc.,
`No. 09-01531, 2010 WL 4510909 (N.D. Cal. Nov. 1, 2010) .............................. 18
`Ex Parte Urban Weber,
`Appeal 2020-005142, 2021 WL 4319420 (P.T.A.B. Sept. 21, 2021) .................. 21
`Extreme Networks, Inc. v. Enterasys Networks, Inc.,
`395 F. App’x 709 (2010) ........................................................................................ 6
`Gilead Scis., Inc. v. United States,
`IPR2019-01455, Paper No. 16 (P.T.A.B. Feb. 5, 2020) ...................................... 31
`Helsinn Healthcare S.A. v. Dr. Reddy's Lab’ys, Ltd.,
`No. CV 14-4274 (SRC), 2018 WL 623642 (D.N.J. Jan. 30, 2018) ..................... 19
`Hoffmann-La Roche Inc. v. Apotex Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) ............................................................... 32, 33, 34
`
`iii
`
`

`

`HVLPO2, LLC v. Oxygen Frog, LLC,
`949 F.3d 685 (Fed. Cir. 2020) ................................................................................ 6
`
`Impax Labs. Inc. v. Aventis Pharm.Inc.,
`468 F.3d 1366 (Fed. Cir. 2006) ............................................................................ 19
`In re Baxter Travenol Labs.,
`952 F.2d 388 (Fed. Cir. 1991) .............................................................................. 21
`In re Omeprazole Pat. Litig.,
`483 F.3d 1364 (Fed. Cir. 2007) ............................................................................ 21
`In re Omeprazole Patent Litig.,
`536 F.3d 1361 (Fed. Cir. 2008) ............................................................................ 20
`In Re: Copaxone Consol. Cases,
`906 F.3d 1013 (Fed. Cir. 2018) ..................................................................... 2, 7, 8
`Intellectual Ventures I LLC v. T-Mobile USA, Inc.,
`902 F.3d 1372 (Fed. Cir. 2018) .............................................................................. 9
`Kaneka Corp. v. Xiamen Kingdomway Grp. Co.,
`790 F.3d 1298 (Fed. Cir. 2015) ..........................................................................2, 8
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................... 6
`Merck & Co., Inc. v. Teva Pharms. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005) ..................................................................... 30, 36
`Microsoft Corp. v. Synkloud Techs., LLC,
`IPR2020-01316, Paper 43 (P.T.A.B. Jun. 14, 2021) ............................................ 35
`Nautilus, Inc. v. Biosig Instruments, Inc.,
`572 U.S. 898 (2014) ............................................................................................. 17
`Oatey Co. v. IPS Corp.,
`514 F.3d 1271 (Fed. Cir. 2008) ..................................................................... 13, 16
`Paragon Podiatry Lab. v. KLM Labs. Inc.,
`984 F.2d 1182 (Fed. Cir. 1993) ............................................................................ 20
`
`iv
`
`

`

`Pfaff v. Wells Elecs., Inc.,
`525 U.S. 55 (1998) ............................................................................................... 20
`Pfizer Inc. v. Sanofi-Aventis Deutschland GmbH,
`IPR2019-00979, POR, 93 (P.T.A.B. Aug. 11, 2020) ........................................... 37
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) .................................................................... passim
`Profectus Tech. LLC v. Huawei Techs. Co.,
`823 F.3d 1375 (Fed. Cir. 2016) .............................................................................. 1
`Prometheus Lab’ys, Inc. v. Roxane Lab’ys,
`805 F.3d 1092 (Fed. Cir. 2015) ............................................................................ 36
`Rapoport v. Dement,
`254 F.3d 1053 (Fed. Cir. 2001) ............................................................................ 31
`Rhine v. Casio, Inc.,
`183 F.3d 1342 (Fed. Cir. 1999) ............................................................................ 12
`Samsung Elecs. Co. v. Elm 3DS Innovations, LLC,
`925 F.3d 1373 (Fed. Cir. 2019) ............................................................................ 16
`Schering Corp. v. Geneva Pharms.,
`339 F.3d 1373 (Fed. Cir. 2003) ............................................................................ 21
`SciMed Life Sys., Inc. v. Advanced Cardiovascular Sys., Inc.,
`242 F.3d 1337 (Fed. Cir. 2001) .............................................................................. 8
`Scott v. Finney,
`34 F.3d 1058 (Fed. Cir. 1994) .............................................................................. 20
`Seabed Geosolutions (US) Inc. v. Magseis FF LLC,
`8 F.4th 1285 (Fed. Cir. 2021) ...................................................................... 1, 6, 16
`Sinorgchem Co., Shandong v. Int’l Trade Comm’n,
`511 F.3d 1132 (Fed. Cir. 2007) ........................................................... 2, 11, 15, 16
`Southwall Techs., Inc. v. Cardinal IG Co.,
`54 F.3d 1570 (Fed. Cir. 1995) .............................................................................. 12
`
`v
`
`

`

`Standard Oil Co. v. Am. Cyanamid Co.,
`774 F.2d 448 (Fed. Cir. 1985) ................................................................................ 5
`Sundance, Inc. v. DeMonte Fabricating Ltd.,
`550 F.3d 1356 (Fed. Cir. 2008) ..........................................................................5, 6
`Tate Access Floors, Inc. v. Interface Architectural Res., Inc.,
`279 F.3d 1357 (Fed. Cir. 2002) .............................................................................. 1
`Toro Co. v. Deere & Co.,
`355 F.3d 1313 (Fed. Cir. 2004) ............................................................................ 21
`Vitronics Corp. v. Conceptronic, Inc.,
`90 F.3d 1576 (Fed. Cir. 1996) .............................................................................. 16
`Statutes
`35 U.S.C. § 102 ................................................................................................. 19, 20
`35 U.S.C. § 112 ............................................................................................. 3, 19, 32
`Other Authorities
`MANUAL OF PATENT EXAMINING PROCEDURE § 2121 ............................ 19
`
`
`
`
`
`
`vi
`
`

`

`
`
`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),
`
`vii
`
`

`

`Exhibit
`
`1014
`
`1015
`
`1016
`1017
`
`1018
`
`1019
`1020
`
`1021
`1022
`1023
`1024
`
`1025
`
`1026
`
`1027
`
`Description
`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”)
`
`viii
`
`

`

`Exhibit
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`1039
`
`Description
`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”)
`
`ix
`
`

`

`Exhibit
`
`1040
`
`1041
`
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`1048
`
`1049
`
`1050
`
`Description
`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”)
`
`x
`
`

`

`Exhibit
`
`1051
`
`1052
`
`1053
`
`1054
`
`1055
`
`1056
`
`1057
`
`1058
`
`Description
`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”)
`
`xi
`
`

`

`Exhibit
`1059
`
`1060
`
`1061
`1062
`1063
`
`1064
`
`1065
`
`1066
`
`1067
`
`1068
`
`1069
`
`1070
`
`Description
`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”)
`BMJ Publishing Group Ltd., Online First, BJO ONLINE, (Feb. 11,
`2009), https://bjo.bmj.com/onlinefirst.dtl
`[http://web.archive.org/web/20090212162702/https://bjo.bmj.com/on
`linefirst.dtl] (“Wayback-BJO-Online First”)
`BMJ Publishing Group Ltd., Review: Ranibizumab (Lucentis) In
`Neovascular Age-Related Macular Degeneration: Evidence From
`Clinical Trials, BRITISH J. OPHTHALMOLOGY (Dec. 2020),
`https://bjo.bmj.com/content/94/1/2.altmetrics (“BJO-Article
`Metrics”)
`Press Release, Bayer, VEGF Trap-Eye Shows Positive Results in
`Phase II Study in Patients with Diabetic Macular Edema (Feb. 18,
`2010) (“Bayer (18-February-2010)”)
`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,
`2008) (“Bayer (28-April-2008)”)
`Press Release, Regeneron, Enrollment Completed in Regeneron and
`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-
`release-details/enrollment-completed-regeneron-and-bayer-
`healthcare-phase-3?ReleaseID=408872 (“Regeneron (14-September-
`2009)”)
`ClinicalTrials.gov, What Is ClinicalTrials.gov?, U.S. NAT’L LIBRARY
`MED. (Jan. 2018), https://www.clinicaltrials.gov/ct2/about-
`site/background (“Background-ClinicalTrials.gov”)
`Affidavit of Duncan Hall (Internet Archive Records Request
`Processor) Regarding Vascular Endothelial Growth Factor (VEGF)
`Trap-Eye: Investigation of Efficacy and Safety in Central Retinal
`Vein Occlusion (CRVO) (GALILEO), NCT01012973,
`
`xii
`
`

`

`Exhibit
`
`1071
`
`1072
`
`1073
`
`1074
`
`1075
`
`1076
`
`1077
`
`1078
`
`1079
`
`Description
`ClinicalTrials.gov (Apr. 8, 2011); Vascular Endothelial Growth
`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”)
`Frank G Holz et al., VEGF Trap-Eye for Macular Oedema
`Secondary to Central Retinal Vein Occlusion: 6-Month Results of the
`Phase III GALILEO Study, 97 BRITISH J. OPHTHALMOLOGY 278
`(2013) (“Holz”)
`Janice M. Reichert, Antibody-Based Therapeutics To Watch In 2011,
`3 MABS 76 (2011) (“Reichert”)
`Owen A. Anderson et al., Delivery of Anti-Angiogenic Molecular
`Therapies for Retinal Disease, 15 DRUG DISCOVERY TODAY 272
`(2010) (“Anderson”)
`Thomas A. Ciulla & Philip J. Rosenfeld, Antivascular Endothelial
`Growth Factor Therapy For Neovascular Age-Related Macular
`Degeneration, 20 CURRENT OPINION OPHTHALMOLOGY 158 (2009)
`(“Ciulla”)
`Zhang Ni & Peng Hui, Emerging Pharmacologic Therapies for Wet
`Age-Related Macular Degeneration, 223 OPHTHALMOLOGICA 401
`(2009) (“Ni”)
`Marco A. Zarbin & Philip J. Rosenfeld, Pathway-Based Therapies
`for Age-Related Macular Degeneration: An Integrated Survey of
`Emerging Treatment Alternatives, 30 RETINA 1350 (2010) (“Zarbin”)
`Corporate Finance Institute, SEC Filings: Public Disclosures About
`Public Companies,
`https://corporatefinanceinstitute.com/resources/data/public-
`filings/sec-filings/ (last visited May 5, 2021) (“Corporate Finance
`Institute”)
`Carl W. Schneider, Nits, Grits, and Soft Information in SEC Filings,
`121 U. PA. L. REV. 254 (1972) (“Schneider”)
`Justin Kuepper, The Best Investment Information Sources: Using
`SEC Filings, Analyst Reports, and Company Websites, BALANCE
`(Jan. 13, 2021), https://www.thebalance.com/top-best-sources-of-
`investor-information-1979207 (“Kuepper”)
`
`xiii
`
`

`

`Exhibit
`
`1080
`
`1081
`
`1082
`
`1083
`
`1084
`
`1085
`
`1086
`
`1087
`
`1088
`
`1089
`
`Description
`Kristina Zucchi, EDGAR: Investors’ One-Stop-Shop For Company
`Filings, YAHOO!LIFE (Jan. 31, 2014),
`https://www.yahoo.com/lifestyle/tagged/health/edgar-investors-one-
`stop-shop-170000800.html (“Zucchi”)
`Adam Hayes, SEC Filings: Forms You Need To Know,
`INVESTOPEDIA (Jan. 18, 2021),
`https://www.investopedia.com/articles/fundamental-analysis/08/sec-
`forms.asp (“Hayes”)
`Amino acid sequence alignment of SEQ ID NO:2 of the ’069 patent
`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”)
`U.S. Patent Application Publication No. 2006/0172944 A1
`(“Wiegand”)
`U.S. Patent Application Publication No. 2007/0190058 A1
`(“Shams”)
`ClinicalTrials.gov, 1997: Congress Passes Law (FDAMA) Requiring
`Trial Registration, U.S. NAT’L LIBRARY MED. (Oct. 2020),
`https://clinicaltrials.gov/ct2/about-site/history (“History-
`ClinicalTrials.gov”)
`Affidavit of Duncan Hill (Internet Archive Records Request
`Processor) Regarding 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) and VEGF Trap-Eye:
`Investigation of Efficacy and Safety in Wet AMD (VIEW 2),
`NCT00637377, ClinicalTrials.gov (Mar. 17, 2008), dated January
`27, 2021 (“Wayback-Affidavit-038”)
`Quan Dong Nguyen et al., A Phase I Trial of an IV-Administered
`Vascular Endothelial Growth Factor Trap for Treatment in Patients
`with Choroidal Neovascularization due to Age-Related Macular
`Degeneration, 113 OPHTHALMOLOGY 1522 (2006) (“Nguyen-2006”)
`Press Release, Regeneron, Regeneron and Bayer Healthcare
`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),
`
`xiv
`
`

`

`Exhibit
`
`1090
`
`1091
`
`1092
`
`1093
`
`1094
`
`1095
`
`1096
`
`1097
`
`1098
`
`1099
`
`Description
`https://investor.regeneron.com/news-releases/news-release-
`details/regeneron-and-bayer-healthcare-announce-vegf-trap-eye-
`achieved?ReleaseID=394056 (“Regeneron (19-August-2008)”)
`Eugene S. Kim et al., Potent VEGF Blockade Causes Regression of
`Coopted Vessels in a Model of Neuroblastoma, 99 PROC. NAT’L
`ACAD. SCI. 11399 (2002) (“Kim”)
`EYLEA® Prescribing Information (“Eylea PI”)
`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”)
`Declaration of William A. Rakoczy in support of Mylan
`Pharmaceuticals Inc.’s Unopposed Motion for Pro Hac Vice
`Admission (dated June 18, 2021) (“Rakoczy Decl.”)
`Declaration of Heinz J. Salmen in support of Mylan Pharmaceuticals
`Inc.’s Unopposed Motion for Pro Hac Vice Admission (dated June
`18, 2021) (“Salmen Decl.”)
`Transcript of the Teleconference before the United States Patent
`Trial and Appeal Board on September 8, 2021 (“Transcript (8-
`September-2021)”)
`Redline Text Comparison Petitioner’s Exhibit 1056, 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 and Patent Owner’s Exhibit 2007,
`Thompson Reuters Integrity, Biomedical Literature List: “Regeneron
`Pharmaceuticals Press Release 2008, September 28” (dated 18-04-
`2012) (“Redline Compare”)
`Excerpted File History of U.S. Patent No. 8,115,597 (NXP) (“’597
`FH Excerpts (NXP)”)
`
`xv
`
`

`

`Exhibit
`
`1100
`
`
`1101
`
`1102
`
`1103
`
`1104
`
`1105
`
`1106
`
`1107
`
`1108
`
`1109
`
`1110
`
`1111
`
`Description
`Transcript of the Teleconference before the United States Patent
`Trial and Appeal Board on February 23, 2022 (“Transcript (23-
`February-2022)”)
`Declaration of Eric R. Hunt in support of Mylan Pharmaceuticals
`Inc.’s Unopposed Motion for Pro Hac Vice Admission (dated April
`20, 2022) (“Hunt Decl.”)
`File History for U.S. Patent No. 7,070,959, , 12/22/2011 Patent Term
`Extension Application (“’959 FH, 12/22/2011 PTE”)
`Klibanov Dep. Ex. 3, Amgen v. F. Hoffman-La Roche, Ltd., Case No.
`05-cv-12237 (D. Mass.), ECF 610-3, Declaration of Alexander M.
`Klibanov, Ph.D. in Support of Defendants’ Opposition to Amgen’s
`Motion for Summary Judgment of Infringement of ‘422 Claim
`1,’933 Claim 3, and ‘698 Claim 6 (June 28, 2007) (“Klibanov Dep.
`Ex. 3, Klibanov Amgen Decl.”)
`Klibanov Dep. Ex. 18, J. Hanhart & I. Chowers, Correspondence
`regarding Fellow Eye Effect of Unilateral Intravitreal Anti-VEGF
`Injections in Eyes with Diabetic Macular Edema, 29 EYE 292 (2015)
`(“Klibanov Dep. Ex. 18, Hanhart”)
`Klibanov Dep. Ex. 19, Marianne O. Stefanini et al., Increase of
`Plasma VEGF after Intravenous Administration of Bevacizumab Is
`Predicted by a Pharmacokinetic Model, 70 CANCER RESEARCH 9886
`(2010) (“Klibanov Dep. Ex. 19, Stefanini”)
`Klibanov Dep. Ex. 20, Jihong Yang, Comparison of Binding
`Characteristics and In Vitro Activities of Three Inhibitors of
`Vascular Endothelial Growth Factor A, 11 Molecular Pharmaceutics
`3421 (2014) (“Klibanov Dep. Ex. 20, Yang”)
`Klibanov Dep. Ex. 22, International Nonproprietary Names for
`Pharmaceutical Substances (INN), 20 WHO DRUG INFORMATION
`118 (2006) (“Klibanov Dep. Ex. 22, WHO Drug Info”)
`Alexander Klibanov Deposition Transcript (March 24, 2022)
`CONFIDENTIAL MATERIAL - SUBJECT TO PROTECTIVE
`ORDER (“Klibanov Dep. Tr.”)
`Diana V. Do Deposition Transcript (April 21, 2022) (“Do Dep. Tr.”)
`
`David M. Brown Deposition Transcript (April 26, 2022) (“Brown
`Dep. Tr.”)
`Lucian V. Del Priore Deposition Transcript (April 29, 2022)
`CONFIDENTIAL MATERIAL - SUBJECT TO PROTE