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.: IPR2021-00881
`
`
`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
`
`
`PETITIONER’S UPDATED EXHIBIT LIST
`
`
`
`
`
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`Petitioner submits this Updated Exhibit List to accompany submission of
`
`Exhibit No. 1180.
`
`PETITIONER’S UPDATED 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),
`
`2
`
`
`
`Exhibit
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`1009
`1010
`
`1011
`
`1012
`
`
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`
`Exhibit
`
`1013
`
`1014
`
`1015
`
`1016
`1017
`
`1018
`
`1019
`1020
`
`1021
`1022
`1023
`1024
`
`1025
`
`1026
`
`
`
`Description
`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),
`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
`
`3
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`
`Exhibit
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`
`
`Description
`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”)
`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”)
`
`4
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`
`Exhibit
`
`1037
`
`1038
`1039
`
`1040
`
`1041
`
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`1047
`
`1048
`
`
`
`Description
`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”)
`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”)
`
`5
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`
`Exhibit
`
`1049
`
`1050
`
`1051
`
`1052
`
`1053
`
`1054
`
`1055
`
`1056
`
`
`
`Description
`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”)
`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-
`
`6
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`
`Exhibit
`
`1057
`
`1058
`
`1059
`
`1060
`
`1061
`1062
`1063
`
`1064
`
`1065
`
`1066
`
`1067
`
`1068
`
`
`
`Description
`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”)
`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-
`
`7
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`
`Description
`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,
`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”)
`
`8
`
`Exhibit
`
`1069
`
`1070
`
`1071
`
`1072
`
`1073
`
`1074
`
`1075
`
`1076
`
`
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`
`Exhibit
`
`1077
`
`1078
`
`1079
`
`1080
`
`1081
`
`1082
`
`1083
`
`1084
`
`1085
`
`1086
`
`1087
`
`
`
`Description
`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”)
`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,
`
`9
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`
`Description
`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),
`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.”)
`
`10
`
`Exhibit
`
`1088
`
`1089
`
`1090
`
`1091
`
`1092
`
`1093
`
`1094
`
`1095
`
`1096
`
`
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`
`Description
`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)”)
`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”)
`
`11
`
`Exhibit
`
`1097
`
`1098
`
`1099
`
`1100
`
`
`1101
`
`1102
`
`1103
`
`1104
`
`1105
`
`
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`
`Exhibit
`1106
`
`1107
`
`1108
`
`1109
`
`1110
`
`1111
`
`1112
`
`1113
`
`1114
`
`1115
`
`1116
`
`1117
`
`
`
`Description
`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 PROTECTIVE
`ORDER (“Del Priore Dep. Tr.”)
`Klibanov Dep. Ex. 14, W. Colin Duncan et al., Inhibition of Vascular
`Endothelial Growth Factor in the Primate Ovary Up-Regulates
`Hypoxia-Inducible Factor-1α in the Follicle and Corpus Luteum,
`149 ENDOCRINOLOGY 3313 (2008) (“Klibanov Dep. Ex. 14,
`Duncan”)
`Del Priore Dep. Ex. 10, John S. Rudge et al., CLINCAL
`DEVELOPMENT OF VEGF TRAP, in ANGIOGENESIS (William D. Figg
`& Judah Folkman eds. 2008) (“Del Priore Dep. Ex. 10, Rudge
`2008”)
`Expert Declaration of Dr. Thomas A. Albini in Support of
`Petitioner’s Reply, dated May 27, 2022 (“Albini Reply Decl.”)
`Expert Declaration of Mary Gerritsen, Ph.D. in Support of
`Petitioner’s Reply, dated May 26, 2022 (“Gerritsen Reply Decl.”)
`Transcript of the Teleconference before the United States Patent
`Trial and Appeal Board on May 19, 2022 (“Transcript (19-May-
`2022)”)
`Klibanov Dep. Ex. 6, amino acid sequence alignment of SEQ ID
`NO:2 of the ’338 patent, aflibercept amino acid sequence from WHO
`2006, and SEQ ID NO:2 of the ’173 patent (“Klibanov Dep. Ex. 6,
`’173 patent SEQ. ID No:2”)
`
`12
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`
`Exhibit
`1118
`
`1119
`
`1120
`
`1121
`
`1122
`
`
`
`1123
`
`1124
`
`
`1125
`
`1126
`
`1127
`
`1128
`
`1129
`
`
`
`Description
`Klibanov Dep. Ex. 9, CAS registry for No. 862111-32-8 (“Klibanov
`Dep. Ex. 9, CAS”)
`Klibanov Dep. Ex. 12, John S. Rudge et al., VEGF Trap Complex
`Formation Measures Production Rates of VEGF, Providing a
`Biomarker for Predicting Efficacious Angiogenic Blockade, 104
`PNAS 18363 (2007) (“Klibanov Dep. Ex. 12, Rudge 2007”)
`Klibanov Dep. Ex. 13, Candelaria Gomez-Manzano et al., VEGF
`Trap Induces Antiglioma Effect at Different Stages of Disease, 10
`NEURO-ONCOLOGY 940 (2008) (“Klibanov Dep. Ex. 13, Gomez-
`Manzano”)
`Klibanov Dep. Ex. 21, Lily Liu et al., A Novel Engineered VEGF
`Blocker with an Excellent Pharmacokinetic Profile and Robust Anti-
`Tumor Activity, 15 BMC CANCER 1 (2015) (“Klibanov Dep. Ex. 21,
`Liu”)
`Amino acid sequence alignment of SEQ ID NO:2 of the ’338 and
`’069 patents with aflibercept amino acid sequence from WHO 2006,
`SEQ ID NO:16 of the ’758 patent, and SEQ ID NO:16 of the ’959
`patent (“AA Alignment”)
`Polly A. Quiram & Yahui Song, Exudative Age-Related Macular
`Degeneration: Current Therapies and Potential Treatments, 1
`CLINICAL MEDICINE: THERAPEUTICS 1003 (2009) (“Quiram”)
`Nucleic acid sequence alignment of SEQ ID NO:1 of the ’338 and
`’069 patents with SEQ ID NO:15 of the ’758 patent and SEQ ID
`NO:15 of the ’959 patent (“NA Alignment”)
`HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (5th ed. 2006) (“HPE
`2006”)
`D.B. Volkin & A.M. Klibanov, Alterations in the Structure of
`Proteins that Cause Their Irreversible Inactivation, 74
`DEVELOPMENTS BIOLOGICAL STANDARDIZATION 73 (1992) (“Volkin
`& Klibanov 1992”)
`File History for U.S. Patent No. 7,070,959, 4/5/2016 Election for
`Patent Term Extension (“959 FH, Election re PTE”)
`File History for U.S. Patent No. 7,070,959, 5/25/2016 Patent Term
`Extension Certificate (“959 FH, PTE Certificate”)
`Christine Wulff et al., Prevention of Thecal Angiogenesis, Antral
`Follicular Growth, and Ovulation in the Primate by Treatment
`
`13
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`
`Exhibit
`
`1130
`
`1131
`
`1132
`1133
`1134
`1135
`
`1136
`1137
`
`1138
`
`1139
`
`1140
`
`1141
`
`1142
`
`1143
`
`
`
`Description
`with Vascular Endothelial Growth Factor Trap R1R2, 143
`ENDOCRINOLOGY 2797 (2002) (“Wulff”)
`Do Dep. Ex. 2, Regeneron’s Yancopoulos Receives Columbia
`College’s Alexander Hamilton Award (Nov. 22, 2019)
`(https://www.prnewswire.com/news-releases/regenerons-
`yancopoulos-receives-columbia-colleges-alexander-hamilton-award-
`300963506.html) (“Do Dep. Ex. 2, Regeneron (22-Nov-2019)”)
`Do Dep. Ex. 3, Laura Vanderkam, George Yancopoulos: Doing Well
`by Trying to Do Good, SCIENTIFIC AMERICAN (Oct. 6, 2008)
`(https://www.scientificamerican.com/article/george-yancopoulos-
`westinghouse/) (“Do Dep. Ex. 3, Vanderkam”)
`Exhibit Number Unused
`U.S. Patent No.: 10,828,345 B2 (“’345 patent”)
`U.S. Patent No.: 10,888,601 B2 (“’601 patent”)
`U.S. Patent Application Publication No. 2007 /0190058 A1 (“’058
`publication”)
`Ivan T. Hofmann CV and Testimony (“Hofmann CV”)
`Expert Declaration of Ivan T. Hofmann Support of Petitioner’s
`Reply, dated May 27, 2022 (“Hofmann Reply Decl.”)
`Do Dep. Ex. 4, annotated version of ’338 patent claim 1 (“Do Dep.
`Ex. 4, ’338 patent claim 1”)
`Brown Dep. Ex. 10, ASRS Clinical Updates, ASRS Fights Novitas
`Decision to Interpret Eylea Usage More Frequently than q8 as “Off
`Label” (May 24, 2016) (“Brown Dep. Ex. 10, ASRS Clinical
`Update”)
`Brown Dep. Ex. 11, L36962: Medicare Part A/B Local Coverage
`Determination (LCD) Comment Summary (May 2, 2014) (“Brown
`Dep. Ex. 11, Medicare Comment Summary”)
`Chengdu Kanghong Biotechnology Co. v. Regeneron
`Pharmaceuticals, Inc., PGR20221-00035, Paper 6 (April 15, 2021)
`(“PGR20221-00035, Paper 6”)
`Sascha Fauser et al., Suppression of Intraocular Vascular
`Endothelial Growth Factor During Aflibercept Treatment of Age-
`Related Macular Degeneration, 158 AM. J. OPHTHALMOLOGY 532
`(2014) (“Fauser”)
`Diana V. Do, Pharmacokinetic Study of Intravitreal Aflibercept In
`
`14
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`
`Exhibit
`
`1144
`1145
`1146
`
`1147
`
`1148
`1149
`
`1150
`
`1151
`
`1152
`
`1153
`
`1154
`
`1155
`
`1156
`1157
`1158
`1159
`1160
`
`
`
`Description
`Humans with Neovascular Age-Related Macular Degeneration, 00
`RETINA 1 (2019) (“Do”)
`U.S. Patent No.: 7,300,563 B2 (“’563 patent”)
`U.S. Patent No.: 7,300,653 B2 (“’653 patent”)
`DRUGS@FDA: FDA-APPROVED DRUGS, EYELA, BIOLOGIC LICENSE
`APPLICATION (BLA) NO.: 125387
`(https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=o
`verview.process&ApplNo=125387), accessed May 18, 2022
`(“Drugs@FDA Eylea”)
`Regeneron Form 10-K for the year ended December 31, 2005
`(“Regeneron 2005 10-K”)
`U.S. Patent No.: 7,303,748 B2 (“’748 patent”)
`Regeneron Form 10-K for the year ended December 31, 2011
`(“Regeneron 2011 10-K”)
`Deposition Transcript of Doris Weber (May 13, 2022) (“Weber Dep.
`Tr.”)
`Richard Manning Deposition Transcript (May 4, 2022) (“Manning
`Dep. Tr.”) CONFIDENTIAL MATERIAL - SUBJECT TO
`PROTECTIVE ORDER
`Manning Dep. Ex. 6, Highlights of Prescribing Information for Eylea
`(Revised: 6/2021) (“Manning Dep. Ex. 6, Eylea Label 06.2021”)
`Manning Dep. Ex. 7, Regeneron, Representative Regeneron U.S.
`Product Related Patents, EYLEA® (aflibercept) Injection,
`(https://www.regeneron.com/downloads/us-patent-products.pdf)
`(updated January 2022) (“Manning Dep. Ex. 7, Eylea Patent List”)
`Complaint, United States v. Regeneron Pharms., Inc., No. 1:20-cv-
`11217-FDS (D. Mass. June 24, 2020), ECF Nos. 1 – 1-39 (“2020-06-
`24 Complaint”)
`Angelika Batta et al., Trends in FDA Drug Approvals Over Last 2
`Decades: An Observational Study, 9 J. FAMILY MEDICINE &
`PRIMARY CARE 105 (2020) (“Batta”)
`Eylea® Label, Highlights of Prescribing Information for Eylea
`(Revised: 5/2016) (“Eylea Label 05.2016”))
`U.S. Patent No. 7,608,261 (“’261 patent”)
`U.S. Patent No. 7,972,598 (“’598 patent”)
`U.S. Patent No. 8,029,791 (“’791 patent”)
`U.S. Patent No. 8,092,803 (“’803 patent”)
`
`15
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`
`Exhibit
`1161
`1162
`1163
`1164
`1165
`
`1166
`
`1167
`
`1168
`
`1169
`
`1170
`
`1171
`
`1172
`
`1173
`
`1174
`
`
`
`Description
`U.S. Patent No. 8,343,737 (“’737patent”)
`U.S. Patent No. 8,647,842 (“’842 patent”)
`U.S. Patent No. 10,464,992 (“’992 patent”)
`U.S. Patent No. 11,066,458 (“’458 patent”)
`U.S. Patent No. 11,084,865 (“’865 patent”)
`FDA, PURPLE BOOK DATABASE OF LICENSED BIOLOGICAL PRODUCTS,
`https://purplebooksearch.fda.gov/patent-list (last visited May 13,
`2022) (“Purple Book List”)
`United Healthcare, Ophthalmologic Policy: VEGF Inhibitors,
`effective January 1, 2022 (“United Healthcare Ophthalmologic
`Policy, VEGF”)
`BCBS Florida, Vascular Endothelial Growth Factor Inhibitors for
`Ocular Neovascularization, revised April 1, 2022 (“BCBS Florida
`VEGF”)
`EYLEA® FDA SUMMARY REVIEW
`https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/125387O
`rig1s000SumR.pdf (last visited May 20, 2022) (“Eylea Summary
`Review”)
`GOOD DAYS, https://www.mygooddays.org/ (last visited May 18,
`2022) (“mygoodays.org CDF”)
`REGENERON PHARMACEUTICALS, INC., EYLEA, https://eylea.us/ (last
`visited May 18, 2022) (“Official EYLEA (aflibercept) Injection
`Website”)
`BIOSPACE, Bayer HealthCare AG and Regeneron Pharmaceuticals,
`Inc. to Collaborate on VEGF Trap for the Treatment Of Eye
`Diseases; Regeneron Retains U.S. Commercialization Rights,
`Receives $75 Million Upfront, and Eligible for up to $245 Million of
`Milestone Payments (Oct. 19, 2006),
`https://www.biospace.com/article/releases/bayer-healthcare-ag-and-
`regeneron-pharmaceuticals-inc-to-collaborate-on-vegf-trap-for-the-
`treatment-of-eye-diseases-b-regeneron-b-retains-u-s-c/ (“Bayer and
`Regeneron to Collaborate on VEGF Trap”)
`Complaint, Horizon Healthcare Servs., Inc. v. Regeneron Pharms.,
`Inc., No. 1:22-cv-10493-FDS (D. Mass. April 4, 2022), ECF Nos. 1
`– 1-18 (“Complaint, Horizon v Regeneron, 2022-04”)
`Publication of OIG Special Fraud Alerts, 59 Fed. Reg. 242 (Dec. 19,
`1994), available at https://oig.hhs.gov/documents/physicians-
`
`16
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`
`Exhibit
`
`1175
`
`1176
`
`1177
`
`1178
`
`1179
`
`1180
`
`Description
`resources/980/121994.pdf (“oig.hhs.gov Publication of OIG Special
`Fraud Alerts”)
`Zachary D. Miller, Taking Advantage of the New Purple Book Patent
`Requirements for Biologics (Apr. 26, 2021),
`https://www.morganlewis.com/pubs/2021/04/taking-advantage-of-
`the-new-purple-book-patent-requirements-for-biologics
`(“MorganLewis - New Purple Book Patent Requirements”)
`Hajir Dadgostar et al., Evaluation of Injection Frequency and
`Visual Acuity Outcomes for Ranibizumab Monotherapy in Exudative
`Age-related Macular Degeneration, 116 OPHTHALMOLOGY 1740
`(2009) (“Dadgostar”)
`Declaration of Robert V. Cerwinski in Support of Motion for Pro
`Hac Vice Admission
`Declaration of Aviv A. Zalcenstein in Support of Motion for Pro
`Hac Vice Admission
`Declaration of Brigid M. Morris in Support of Motion for Pro Hac
`Vice Admission
`Petitioner’s Demonstratives for Oral Argument
`(DEMONSTRATIVE EXHIBIT – NOT EVIDENCE)
`
`17
`
`
`
`
`
`

`

`CERTIFICATE OF SERVICE
`The undersigned hereby certifies that a true and correct copy of the foregoing
`
`