`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`MYLAN PHARMACEUTICALS INC., CELLTRION, INC.,
`and APOTEX, INC.,
`Petitioners
`
`v.
`
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner
`
`____________
`
`Case IPR2021-008811
`Patent No. 9,254,338 B2
`____________
`
`PATENT OWNER’S SUR-REPLY
`
`1 IPR2022-00258 and IPR2022-00298 have been joined with this proceeding.
`
`
`
`B.
`
`Table of Contents
`TABLE OF EXHIBITS ........................................................................................... iii
`I.
`INTRODUCTION ........................................................................................... 1
`II.
`THE POSA ...................................................................................................... 1
`III. CLAIM CONSTRUCTION ............................................................................ 2
`A.
`Petitioner Fails to Address the Consequences of a Limiting
`Preamble ................................................................................................ 2
`Treatment Requires a High Level of Efficacy ...................................... 3
`1.
`The Intrinsic Record Supports A High Level of Efficacy .......... 4
`2.
`A High Level of Efficacy Is Not Uncertain Across
`Angiogenic Eye Disorders .......................................................... 9
`“Initial Dose,” Secondary Dose(s)” and Tertiary Dose(s)” ................ 12
`C.
`IV. GROUNDS 1, 3-5: PETITIONER FAILS TO DEMONSTRATE
`THAT “VEGF TRAP-EYE” WAS KNOWN IN THE ART TO
`CORRESPOND TO SEQ ID NO:1 AND/OR SEQ ID NO:2 ...................... 14
`A.
`Petitioner Improperly Uses Inherency to Backfill an Incomplete
`Description of VEGF Trap-Eye in the Prior Art ................................. 14
`1.
`Petitioner’s Cases Do Not Support Its Use of Inherency ......... 16
`2.
`VEGF Trap-Eye’s Sequence Was Not Publicly Accessible ..... 18
`Petitioner Has Failed to Show That the Sequences of VEGF Trap-
`Eye Are Necessarily Present in the Ground 1, 3-5 References ........... 19
`1.
`The “Same Molecular Structure” Does Not Necessarily
`Mean the Same Sequence ......................................................... 20
`The POSA Would Understand That “VEGF Trap-Eye”
`Could Encompass a Genus of Proteins ..................................... 21
`
`B.
`
`2.
`
`–i–
`
`
`
`3.
`
`4.
`
`V.
`
`Inconsistent Reporting of Molecular Weight Sows Doubt,
`Not Clarity ................................................................................. 24
`PO Did Not Characterize VEGF Trap-Eye and Aflibercept
`as the Same Agent ..................................................................... 24
`GROUND 2: ADIS DOES NOT ANTICIPATE THE
`CHALLENGED CLAIMS ............................................................................ 25
`VI. GROUND 1-5: PETITIONER FAILS TO ESTABLISH THAT ITS
`REFERENCES DISCLOSE A “METHOD FOR TREATING” .................. 26
`A.
`Knowledge of the “VEGF Trap-Eye” Amino Acid Sequence Will
`Not Necessarily Result in Treatment .................................................. 26
`Administration of “VEGF Trap-Eye” Using the Disclosed Dosing
`Regimen Will Not Necessarily Result in Treatment ........................... 28
`Petitioner’s References Do Not Disclose a Recognized Utility .......... 28
`C.
`VII. GROUND 6: PETITIONER FAILS TO DEMONSTRATE THAT
`ANY CHALLENGED CLAIM IS OBVIOUS BASED ON DIXON
`ALONE OR IN COMBINATION WITH DIX OR THE ’758
`PATENT ........................................................................................................ 30
`VIII. OBJECTIVE EVIDENCE CONFIRMS THE
`NON-OBVIOUSNESS OF THE CLAIMED DOSING REGIMEN ............ 33
`A.
`Petitioner Ignores the Failure of Others and That Eylea
`Unexpectedly Satisfied a Long-Felt Need .......................................... 33
`Eylea Is a Commercial Success ........................................................... 34
`B.
`IX. CONCLUSION .............................................................................................. 37
`
`B.
`
`–ii–
`
`
`
`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Abbott Lab’ys v. Geneva Pharms., Inc.,
`182 F.3d 1315 (Fed. Cir. 1999) .......................................................................... 17
`Amgen, Inc. v. Alexion Pharms.,
`IPR2019-00741, Paper 15 (PTAB Aug. 30, 2019) ................................. 15, 16, 18
`AstraZeneca LP v. Apotex, Inc.,
`633 F.3d 1042 (Fed. Cir. 2010) .......................................................................... 25
`Atlanta Attachment Co. v. Leggett & Platt, Inc.,
`516 F.3d 1361 (Fed. Cir. 2008) .......................................................................... 29
`Bayer Cropscience LP v. Syngenta Ltd.,
`IPR2017-01332, Paper 15 (PTAB Apr. 2, 2018) ........................................passim
`Bettcher Indus., Inc. v. Bunzl USA, Inc.,
`661 F.3d 629 (Fed. Cir. 2011) ................................................................ 14, 17, 19
`Boehringer Ingelheim Vetmedica, Inc. v. Schering-Plough Corp.,
`320 F.3d 1339 (Fed. Cir. 2003) .......................................................................... 32
`Budde v. Harley-Davidson, Inc.,
`250 F.3d 1369 (Fed. Cir. 2001) ............................................................................ 9
`Celltrion, Inc. v. Genentech, Inc.,
`IPR2016-01667, Paper 15 (PTAB Mar. 2, 2017) (Franklin, J.)
`(reh’g denied) ...................................................................................................... 20
`Chemours Co. FC, LLC v. Daikin Indus., Ltd.,
`4 F.4th 1370 (Fed. Cir. 2021) ............................................................................. 33
`Concordia Pharms., Inc. v. Method Pharms., LLC,
`No. 3:14-cv-00016-GEC, D.I. 219 (W.D. Va. Apr. 13, 2016) ........................... 35
`Cont’l Can Co. USA, Inc. v. Monsanto Co.,
`948 F.2d 1264 (Fed. Cir. 1991) .......................................................................... 35
`
`–iii–
`
`
`
`Crocs, Inc. v. Int’l Trade Comm’n,
`598 F.3d 1294 (Fed. Cir. 2010) .......................................................................... 35
`Endo Pharms. Sols., Inc. v. CustoPharm Inc.,
`894 F.3d 1374 (Fed. Cir. 2018) .................................................................... 15, 16
`Ex Parte Urban Weber,
`2021 WL 4319420 (PTAB Sept. 21, 2021) ........................................................ 17
`Gilead Scis., Inc. v. U.S.,
`IPR2019-01455, Paper 16 (PTAB Feb. 5, 2020) ................................................ 28
`Helsinn Healthcare S.A. v. Dr. Reddy’s Lab’ys, Ltd.,
`No. 14-4274 (SRC), 2018 WL 623642 (D.N.J. Jan. 30, 2018) .......................... 29
`Hoffmann-La Roche Inc. v. Apotex Inc.,
`748 F.3d 1326 (Fed. Cir. 2014) .......................................................................... 34
`In re Baxter Travenol Labs.,
`952 F.2d 388 (Fed. Cir. 1991) ............................................................................ 17
`In re Donohue,
`766 F.2d 531 (Fed. Cir. 1985) ...................................................................... 17, 18
`In re Oelrich,
`666 F.2d 578 (C.C.P.A. 1981) ...................................................................... 25, 27
`In re Omeprazole Pat. Litig.,
`483 F.3d 1364 (Fed. Cir. 2007) .......................................................................... 16
`Janssen Pharms., Inc. v. Teva Pharms. USA, Inc.,
`2021 WL 5323737 (D.N.J. Nov. 16, 2021) .................................................. 36, 37
`Multiform Dessicants, Inc. v. Medzam, Ltd.,
`133 F.3d 1473 (Fed. Cir. 1998) ........................................................................ 8, 9
`Nature Simulation Sys. Inc. v. Autodesk, Inc.,
`23 F.4th 1334 (Fed. Cir. 2022) ..................................................................... 10, 12
`Nevro Corp. v. Bos. Sci. Corp.,
`955 F.3d 35 (Fed. Cir. 2020) .............................................................................. 13
`
`–iv–
`
`
`
`Oticon Med. AB v. Cochlear Bone Anchored Sols. AB,
`IPR2017-01018, Paper 52 (PTAB Aug. 21, 2018) ............................................. 10
`Pfaff v. Wells Elecs., Inc.,
`525 U.S. 55 (1998) .............................................................................................. 29
`Pharmacylics LLC v. Alvogen Pine Brook LLC,
`556 F. Supp. 3d 377 (D. Del. 2021).................................................................... 35
`Rapoport v. Dement,
`254 F.3d 1053 (Fed. Cir. 2001) .................................................................... 27, 28
`Rosco, Inc. v. Mirror Lite Co.,
`304 F.3d 1373 (Fed. Cir. 2002) .................................................................... 14, 24
`Schering Corp. v. Amgen Inc.,
`222 F.3d 1347 (Fed. Cir. 2000) ...................................................................... 3, 19
`Schering Corp. v. Geneva Pharms., Inc.,
`339 F.3d 1373 (Fed. Cir. 2003) .......................................................................... 16
`Scripps Clinic & Rsch. Found. v. Genentech, Inc.,
`927 F.2d 1565 (Fed. Cir. 1991), overruled on other grounds ............................ 14
`Teva Pharms. USA, Inc. v. Corcept Therapeutics, Inc.,
`PGR2019-00048, Paper 51 (PTAB Nov. 18, 2020) ........................................... 33
`Therasense, Inc. v. Becton, Dickinson & Co.,
`593 F.3d 1325 (Fed. Cir. 2010) .......................................................................... 26
`Toro Co. v. Deere & Co.,
`355 F.3d 1313 (Fed. Cir. 2004) .......................................................................... 16
`Statutes
`35 U.S.C. § 102(b) ................................................................................................... 17
`35 U.S.C. § 271(e)(1) ............................................................................................... 36
`Other Authorities
`37 C.F.R. § 42.23(b) ................................................................................................ 18
`
`–v–
`
`
`
`TABLE OF EXHIBITS
`
`2008
`
`Description
`Ex. No.
`Expert Declaration of Dr. Diana V. Do, M.D.
`2001
`Curriculum Vitae of Dr. Diana Do
`2002
`Lucentis (ranibzumab injection) label, revised June 2010
`2003
`2004 Ex. (a)(1)(a) to Tender Offer Statement to Momenta, filed with SEC on
`September 2, 2020
`2005 Press Release, Johnson & Johnson, Johnson & Johnson to Acquire
`Momenta Pharmaceuticals, Inc., Expanding Janssen’s Leadership in
`Novel Treatments for Autoimmune Diseases, dated August 19, 2020
`2006 Press Release, Johnson & Johnson, Johnson & Johnson Completes
`Acquisition of Momenta Pharmaceuticals, Inc, dated October 1, 2020
`2007 Press Release, THOMAS REUTERS INTEGRITY “VEGF Trap-Eye
`final phase II results in age-related macular degeneration presented at
`2008 Retina Society Meeting” (September 2008)
`Information from ClinicalTrials.gov archive on the VIEW 2 study
`(NCT00637377) “VEGF Trap-Eye: Investigation of Efficacy and Safety
`in Wet AMD (VIEW 2)” versions available and updated on 17 March
`2008.
`2009 U.S. Patent App. No. 2006/0058234
`2010
`Excerpts from J.M. Berg et al., Biochemistry (5th Ed. 2002)
`2011 M.W. Stewart & P.J. Rosenfeld, Predicted Biological Activity of
`Intravitreal VEGF Trap¸ Br. J. Opthamol 92:667-68 (2008)
`2012 P. Iacono et al., Antivascular Endothelial Growth Factor in Diabetic
`Retinopathy, Dev. Opthamol. 46:39-53 (2010)
`2013 D.V. Do et al., An Exploratory Study of the Safety, Tolerability and
`Bioactivity of a Single Intravitreal Injection of Vascular Endothelial
`Growth Factor Trap-Eye in Patients With Diabetic Macular Oedema,
`Br. J. Opthamol 93:144-49 (2009)
`J.W. Moroney et al., Aflibercept in Epithelial Ovarian Carcinoma,
`Future Oncol 5(5):591-600 (2009)
`2015 U.S. Patent Publication 2010/0160233 A1 to Bissery et al., published
`June 24, 2010
`2016 T. Hachiya et al., Increase in respiratory cost at high growth
`temperature is attributed to high protein turnover cost in Petunia x
`hybrida petals, Plant, Cell, and Environment, 30:1269-1283 (2007)
`–vi–
`
`2014
`
`
`
`2018
`
`2017 M. Piques et al., Ribosome and transcript copy numbers, polysome
`occupancy and enzyme dynamics in Arabidoposis, Molecular Systems
`Biology 5: Article number 314 (2009)
`Jaffe et al., Differential Response to Anti-VEGF Regimens in Age-
`Related Macular Degeneration Patients with Early Persistent Retinal
`Fluid, Ophthalmology 2016;123:1856-1864 (2016)
`Eylea (aflibercept) Injection label, revised May 2016
`2019
`2020 A Study Investigating the Safety and Efficacy of Lampalizumab
`Intravitreal Injections in Participants With Geographic Atrophy
`Secondary to Age-Related Macular Degeneration (SPECTRI),
`NCT02247531, ClinicalTrials.gov (August 2, 2021),
`https://clinicaltrials.gov/ct2/show/NCT02247531?term=lampalizumab&
`phase=2&draw=2&rank=2
`2021 A Study Investigating the Efficacy and Safety of Lampalizumab
`Intravitreal Injections in Participants With Geographic Atrophy
`Secondary to Age-Related Macular Degeneration (CHROMA),
`NCT02247479, ClinicalTrials.gov (August 2, 2021),
`https://clinicaltrials.gov/ct2/show/NCT02247479?term=lampalizumab&
`phase=2&draw=2&rank=3
`2022 Efficacy and Safety Trial of Conbercept Intravitreal Injection for
`Neovascular AMD(PANDA-2), NCT03630952, ClinicalTrials.gov
`(August 2, 2021),
`https://clinicaltrials.gov/ct2/show/NCT03630952?term=NCT03630952
`&draw=2&rank=1
`2023 Efficacy and Safety Trial of Conbercept Intravitreal Injection for
`Neovascular AMD(PANDA-1), NCT03577899, ClinicalTrials.gov
`(August 2, 2021),
`https://clinicaltrials.gov/ct2/show/NCT03577899?term=NCT03577899
`&draw=2&rank=1
`2024 A Phase 3 Safety and Efficacy Study of Fovista® (E10030)
`Intravitreous Administration in Combination With Lucentis® Compared
`to Lucentis® Monotherapy, NCT01944839, ClinicalTrials.gov (August
`2, 2021),
`https://clinicaltrials.gov/ct2/show/NCT01944839?term=fovista&phase=
`2&draw=2&rank=1
`
`–vii–
`
`
`
`2025 A Phase 3 Safety and Efficacy Study of Fovista® (E10030)
`Intravitreous Administration in Combination With Lucentis® Compared
`to Lucentis® Monotherapy, ClinicalTrials.gov (August 2, 2021),
`https://clinicaltrials.gov/ct2/show/NCT01940900?term=fovista&phase=
`2&draw=2&rank=2
`2026 S. Elvidge, Opthotech’s Fovista crashes out in wet AMD,
`BIOPHARMADIVE (Aug. 14, 2017), available at,
`https://www.biopharmadive.com/news/opthotech-fovista-phase-3-
`failure-setback-novartis/449248/
`2027 X. Li et al., Safety and Efficacy of Conbercept in Neovascular Age-
`Related Macular Degeneration: Results from a 12-Month Randomized
`Phase 2 Study: AURORA Study, Ophthalmology 2014:121:1740-1747
`(2014)
`2028 Regeneron Pharmaceuticals Inc., “VEGF Trap-Eye CLEAR-IT 2 Final
`Primary Endpoint Results” presented at the 2007 Retina Society
`Conference in Boston, Massachusetts (September 30, 2007)
`2029 Bhisitkul, Robert B. and Stewart, Jay M., Alternative anti-VEGF
`treatment regimens in exudative age-related macular degeneration,
`Expert Rev. Ophthalmol., Vol. 5, No. 6 (2010).
`2030 Park, Young Gun et al., New Approach to Anti-VEGF Agents for Age-
`Related Macular Degeneration, Journal of Ophthalmology (2012).
`2031 Spaide, Richard, Ranibizumab According to Need: A Treatment for Age-
`related Macular Degeneration, American Journal of Ophthalmology
`(April 2007)
`2032 Boyer, David S., A Phase IIIb Study to Evaluate the Safety of
`Ranibizumab in Subjects with Neovascular Age-related Macular
`Degeneration, Ophthalmology, Vol. 116, No. 9 (Sept. 2009)
`Lucentis (ranibzumab injection) label, revised March 2018
`2033
`2034 U.S. Patent No. 7,303,746
`2035 U.S. Patent No. 7,521,049
`2036 U.S. Patent No. 7,303,747
`2037 U.S. Patent No. 7,306,799
`2038 Macugen (pegaptanib sodium injection) label submitted with NDA 21-
`756
`2039 Press Release, Regeneron, Regeneron Reports Fourth Quarter and Full
`Year 2012 Financial and Operating Results, dated February 14, 2013
`2040 Press Release, Regeneron, Regeneron Reports Fourth Quarter and Full
`Year 2019 Financial and Operating Results, dated February 6, 2020
`
`–viii–
`
`
`
`2042
`
`2041 Press Release, Regeneron, Regeneron and Bayer Report Positive Results
`for VEGF Trap-Eye in Phase 3 Study in Central Retinal Vein Occlusion
`(CRVO) and in Phase 2 Study in Diabetic Macular Edema (DME),
`dated December 20, 2010
`J.P. Levine et al., Macular Hemorrhage in Neovascular Age-related
`Macular Degeneration After Stabilization With Antiangiogenic Therapy,
`Retina 29(8):1074-79 (2009)
`2043 Press Release, Thomson Reuters Links Discovery and Literature
`Citation Databases, dated January 4, 2010
`2044 Declaration of Victoria Reines
`2045 Declaration of Daniel Reisner
`2046 Declaration of Matthew M. Wilk
`2047 Declaration of Jeremy Cobb
`2048 Expert Declaration of Dr. Lucian V. Del Priore, M.D., Ph.D. -
`CONFIDENTIAL MATERIAL - SUBJECT TO PROTECTIVE
`ORDER
`2049 Expert Declaration of Dr. Alexander M. Klibanov, Ph.D. -
`CONFIDENTIAL MATERIAL - SUBJECT TO PROTECTIVE
`ORDER
`Expert Declaration of David M. Brown, M.D.
`2050
`Expert Declaration of Dr. Diana V. Do, M.D.
`2051
`2052 Expert Declaration of Richard Manning, Ph.D. - CONFIDENTIAL
`MATERIAL - SUBJECT TO PROTECTIVE ORDER
`2053 A Study of Aflibercept Administered in Combination With Pemetrexed
`and Cisplatin in Patients With Advanced Carcinoma, NCT00794417,
`ClinicalTrials.gov (Posted Nov. 20, 2008),
`https://clinicaltrials.gov/ct2/history/NCT00794417?A=1&B=1
`2054 A Study of Intravenous Aflibercept With Docetaxel in Chinese Patients
`With Solid Tumors, NCT01148615, ClinicalTrials.gov (Posted Jun. 22,
`2010), https://clinicaltrials.gov/ct2/history/NCT01148615?A=1&B=1
`2055 Ferrara et al., Development of ranibizumab, an anti-vascular endothelial
`growth factor antigen binding fragment, as therapy for neovascular
`age-related macular degeneration. 26 RETINA 859 (2006)
`2056 Kim et al., A Brief History of Anti-VEGF for the Treatment of Ocular
`Angiogenesis, 181 THE AMERICAN JOURNAL OF PATHOLOGY 376 (2012)
`2057 Ramazi et al., Post-translational modifications in proteins: resources,
`tools and prediction methods, 2021 DATABASE 1 (2021)
`
`–ix–
`
`
`
`2058 Bork et al., Increasing the Sialylation of Therapeutic Glycoproteins:
`The Potential of the Sialic Acid Biosynthetic Pathway, 98 J. PHARM. SCI.
`3499 (2009)
`2059 Regeneron Sample Analysis Report: PK06005-9-SA-01V1 (2006)
`(“Koehler-Stec Report”) - CONFIDENTIAL MATERIAL - SUBJECT
`TO PROTECTIVE ORDER
`2060 Regeneron Pharmaceuticals Protocol VGFT-OD-0605, Table
`14.2.3/2a - Summary of Proportion of Vision Loss from Baseline to
`Week 96, Last Observations Carried Forward (Full Analysis Set)
`(“VGFT-OD-0605 Analysis Summary”) - CONFIDENTIAL
`MATERIAL - SUBJECT TO PROTECTIVE ORDER
`2061 Kim et al., Eyes that Do Not Meet the Eligibility Criteria of Clinical
`Trials on Age-Related Macular Degeneration: Proportions of the Real-
`World Patient Population and Reasons for Exclusion, 2021 JOURNAL OF
`OPHTHALMOLOGY1 (2021)
`2062 Nieto et al., Ocular silicon distribution and clearance following
`intravitreal injection of porous silicon microparticles, 116 EXP EYE RES.
`161 (2013)
`2063 Fernández-Ferreiro et al., Preclinical PET Study of Intravitreal
`Injections, 58 INVEST OPHTHALMOL. VIS SCI. 2843 (2017)
`2064 Shen et al., Clearance of Intravitreal Voriconazole, 48 INVEST.
`OPHTHALMOLOGY & VISUAL SCI. 2240 (2007)
`2065 Cabo et al., The Clearance of Intravitreal Gentamicin, 92 AMERICAN J.
`OPHTHALMOLOGY 59 (1981)
`2066 Pflugfelder et al., Intravitreal Vancomycin: Retinal Toxicity, Clearance,
`and Interaction with Gentamicin, 105 ARCH. OPHTHALMOL. 831 (1987)
`2067 Hirokawa et al., Tau Proteins: The Molecular Structure and Mode of
`Binding on Microtubules, 107 J. CELL BIOL. 1449 (1988)
`2068 Prangé et al., Exploring Hydrophobic Sites in Proteins with Xenon or
`Krypton, 30 PROTEINS: STRUCTURE, FUNCTION, AND GENETICS 61 (1998)
`2069 Kleiger et al., The 1.7 Å Crystal Structure of BOI: A Study of How Two
`Dissimilar Amino Acid Sequences Can Adopt the Same Fold, 299 J.
`MOL. BIOL. 1019 (2000)
`2070 Demarest et al., Optimization of the Antibody CH3 Domain by Residue
`Frequency Analysis of IgG Sequences, 335 J. MOL. BIOL. 41 (2004)
`2071 Kuhlmann et al., Lessons Learned from Biosimilar Epoetins and
`Insulins, 10 BRITISH J. DIABETES VASC. DISEASE 90 (2010)
`
`–x–
`
`
`
`2072 Murphy et al., Protein Folding, Misfolding, Stability and Aggregation:
`An Overview, in MISBEHAVING PROTEINS - PROTEIN (MIS)FOLDING,
`AGGREGATION, AND STABILITY; Murphy et al., Eds., Springer, New
`York, 2006
`2073 Zaltrap non-comparability issue: Regeneron Sanofi Analytical
`Investigation Workshop (March 14, 2014) - CONFIDENTIAL
`MATERIAL - SUBJECT TO PROTECTIVE ORDER
`2074 Solá et al., Effects of Glycosylation on the Stability of Protein
`Pharmaceuticals, 98 J. PHARM. SCI. 1223 (2009)
`Eylea® Approval Letter (November 18, 2011)
`2075
`2076 Cantu et al., Thioesterases: A New Perspective Based on Their Primary
`and Tertiary Structures, 19 PROTEIN SCIENCE 1281 (2010)
`2077 Chen et al., Carboxylic ester hydrolases: Classification and database
`derived from their primary, secondary, and tertiary structures, 25
`PROTEIN SCIENCE 1942 (2016)
`2078 Aflibercept in Combination With Docetaxel in Metastatic Androgen
`Independent Prostate Cancer (VENICE), NCT00519285,
`ClinicalTrials.gov (Posted Aug. 22, 2007),
`https://clinicaltrials.gov/ct2/history/NCT00519285?V_1
`2079 Aflibercept and Standard Chemotherapy (R-CHOP) in First Line of Non
`Hodgkin B-Cell Lymphoma, NCT00644124, ClinicalTrials.gov (Posted
`Mar. 26, 2008),
`https://clinicaltrials.gov/ct2/history/NCT00644124?A=1&B=1
`2080 Heier, VEGF Trap-Eye for Exudative AMD, RETINAL PHYSICIAN, Apr.
`2009 (“Heier Retinal Physician 2009”)
`Curriculum Vitae of Dr. Dr. Lucian V. Del Priore, M.D., Ph.D.
`2081
`Curriculum Vitae of Dr. Alexander M. Klibanov, Ph.D.
`2082
`Curriculum Vitae of Dr. David Mark Brown, M.D.
`2083
`2084 Anthony P. Adamis, Ocular Angiogenesis: Vascular Endothelial
`Growth Factor and Other Factors, in Retinal Pharmacotherapy 23
`(Quan Dong Nguyen et al. eds., 2010)
`2085 David M. Brown et al., Ranibizumab Versus Verteporfin Photodymanic
`Therapy for Neovascular Age-Related Macular Degeneration: Two-
`Year Results of the ANCHOR Study, 116 Ophthalmology 57 (2009)
`2086 Carl D. Regillo, David M. Brown et al., Randomized, Double-masked,
`Sham-controlled Trial of Ranibizumab for Neovascular Age-related
`Macular Degeneration: PIER Study Year 1, 145 Am. J. Ophthalmology
`239 (2008)
`
`–xi–
`
`
`
`2088
`
`2087 Prema Abraham et al., Randomized, Double-Masked, Sham-Controlled
`Trial of Ranibizumab for Neovascular Age-Related Macular
`Degeneration: PIER Study Year 2, 150 Am. J. Ophthalmology 315
`(2010)
`Irene Barbazetto et al., Dosing Regimen and the Frequency of Macular
`Hemorrhages in Neovascular Age-Related Macular Degeneration
`Treated with Ranibizumab, 30 Retina 1376 (2010)
`2089 Daniele Cruz, PIER Data Suggest a Need for Tailored Injection
`Schedule, Ocular Surgery News, (Sept. 1, 2006),
`https://www.healio.com/news/ophthalmology/20120331/pier-data-
`suggest-a-need-for-tailored-injection-schedule
`2090 Retinal Physician Symposium Covers Broad Range of Topics, Retinal
`Physician (Sept. 1, 2006),
`https://www.retinalphysician.com/issues/2006/september-2006/retinal-
`physician-symposium-covers-broad-range-of
`2091 CDER Approved Labeling for BLA Application 125156 (Lucentis®)
`(2006)
`2092 Ursula Schmidt-Erfurth et al., Efficacy and Safety of Monthly Versus
`Quarterly Ranibizumab Treatment in Neovascular Age-related Macular
`Degeneration: The EXCITE Study, 118 Ophthalmology 831 (2011)
`2093 Ron Margolis & K. Bailey Freund, Hemorrhagic Recurrence of
`Neovascular Age-Related Macular Degeneration Not Predicted by
`Spectral Domain Optical Coherence Tomography, 4 Retinal Cases &
`Brief Rep. 1 (2010)
`2094 David M. Brown et al., Primary Endpoint Results of a Phase II Study of
`Vascular Endothelial Growth Factor Trap-Eye in Wet Age-related
`Macular Degeneration, 118 Ophthalmology 1089 (2011)
`Jeff Heier, David M. Brown et al., The 1-year Results of CLEAR-IT 2, a
`Phase 2 Study of Vascular Endothelial Growth Factor Trap-Eye Dosed
`As-needed After 12-week Fixed Dosing, 118 Ophthalmology 1099
`(2011)
`2096 Clinical Study Agreement Between Vitreoretinal Consultants and
`Regeneron Pharmaceuticals, Inc. (July 31, 2007) - CONFIDENTIAL
`MATERIAL - SUBJECT TO PROTECTIVE ORDER
`2097 FDA, Non-Inferiority Clinical Trials to Establish Effectiveness:
`Guidance for Industry (Nov. 2016)
`2098 CDER, Statistical Review for Application Number 125387 (Nov. 18,
`2011)
`
`2095
`
`–xii–
`
`
`
`2101
`
`2106
`
`2100
`
`2099 FDA, 22 Case Studies Where Phase 2 and Phase 3 Trials Had Divergent
`Results (Jan. 2017)
`Jeffrey S. Heier & FOCUS Study Group, Abstract: Intravitreal
`Ranibizumab (Lucentis™) with Verteporfin Photodynamic Therapy for
`Neovascular Age-Related Macular Degeneration: Year One Results,
`Am. Soc’y Retina Specialists Ann. Meeting 94 (2005)
`Safety and Efficacy of Repeated Intravitreal Administration of Vascular
`Endothelial Growth Factor (VEGF) Trap in Patients With Wet Age-
`Related Macular Degeneration (AMD), ClinicalTrials.gov,
`https://clinicaltrials.gov/ct2/show/NCT00320788.
`2102 Wells, John A., et al. (2015), "Aflibercept, Bevacizumab, or
`Ranibizumab for Diabetic Macular Edema," The New England Journal
`of Medicine 372(13): 1193–1203.
`2103 Ongoing Treatment for Patients with Neovascular AMD, Retinal
`Physician (Oct. 1, 2007),
`https://www.retinalphysician.com/issues/2007/october-2007/ongoing-
`treatment-for-patients-with-neovascular-am
`2104 Andrew E. Mathis, Fine-Tuning Your Anti-VEGF Injection Protocols:
`The Second Article in Our Series Recapping Research and Analysis
`Presented at Our Annual Meeting, Retinal Physician (Oct. 1, 2009),
`https://www.retinalphysician.com/issues/2009/october-2009/fine-
`tuning-your-anti-vegf-injection-protocols
`2105 Scott W. Cousins, Controversies in the Long-term Management of
`Neovascular AMD: The Role of Imaging in Clinical Decision Making,
`Retinal Physician (Jan. 1, 2010),
`https://www.retinalphysician.com/issues/2010/jan-feb/controversies-in-
`the-long-term-management-of-neova
`Jerry Helzner, Lucentis After 1 Year: Doctors Praise This Practice-
`transforming Therapy—But Find Drawbacks, Retinal Physician (July 1,
`2007), https://www.retinalphysician.com/issues/2007/july-aug/lucentis-
`after-1-year
`2107 Press Release, Regeneron Announces FDA Approval of Eylea®
`(Aflibercept) Injection for the Treatment of Wet Age-Related Macular
`Degeneration (Nov. 18, 2011), available at
`https://www.fiercebiotech.com/biotech/regeneron-announces-fda-
`approval-of-eylea™-aflibercept-injection-for-treatment-of-wet-age
`2108 FDA, Guidance for Industry: Expedited Programs for Serious
`Conditions—Drugs and Biologics (May 2014),
`https://www.fda.gov/media/86377/download
`–xiii–
`
`
`
`2109 Macugen for Proliferative Diabetic Retinopathy Study With Extended
`Dosing (M-PDRS ED), ClinicalTrials.gov,
`https://clinicaltrials.gov/ct2/show/NCT01486771
`2110 Ron P. Gallemore & David Nguyen, When Anti-VEGF Treatment Fails:
`Retina Specialists Are Charting New Territory and Learning How to
`Spot and React to Failed Anti-VEGF Therapy, Rev. Ophthalmology
`(Mar. 20, 2008)
`2111 Press Release, Kanghong Pharmaceutical, Announcement of Chengdu
`Kanghong Pharmaceutical Group Co., Ltd. on Stopping the Global
`Multi-center Clinical Trial of Conbercept Ophthalmic Injection,
`http://epaper.zqrb.cn/html/2021-04/10/content_716426.htm?div=-1
`(original)
`2112 Press Release, Kanghong Pharmaceutical, Announcement of Chengdu
`Kanghong Pharmaceutical Group Co., Ltd. on Stopping the Global
`Multi-center Clinical Trial of Conbercept Ophthalmic Injection,
`http://epaper.zqrb.cn/html/2021-04/10/content_716426.htm?div=-1
`(English translation)
`2113 Michael Thomas et al., Comparative Effectiveness of Aflibercept for the
`Treatment of Patients with Neovascular Age-related Macular
`Degeneration, 7 Clinical Ophthalmology 495 (2013)
`2114 Matthew Ohr & Peter K. Kaiser, Aflibercept in Wet Age-related
`Macular Degeneration: A Perspective Review, 3 Therapeutic Advances
`Chronic Disease 153 (2012)
`2115 FDA Approves Eylea for Wet Age-Related Macular Degeneration,
`Drugs.com, (Nov. 18, 2011), https://www.drugs.com/newdrugs/fda-
`approves-eylea-wet-age-related-macular-degeneration-2955.html
`2116 Press Release, Regeneron Announces FDA Approval of Eylea®
`(Aflibercept) Injection for the Treatment of Wet Age-Related Macular
`Degeneration (Nov. 18, 2011)
`2117 Macugen Approval Letter (December 17, 2004)
`2118 Brown DM, et al., Ranibizumab versus verteporfin for neovascular age-
`related macular degeneration, N Engl J Med. 2006;355(14):1432-44
`2119 Rosenfeld PJ, Brown DM, et al., Ranibizumab for neovascular age-
`related macular degeneration, N Engl J Med. 2006;355(14):1419-31
`
`–xiv–
`
`
`
`2120 Press Release, Genentech, Inc. Submits Biologics License Application
`For FDA Review Of Lucentis(TM) In Wet Age-Related Macular
`Degeneration (Dec. 30, 2005), available at
`https://www.biospace.com/article/releases/genentech-inc-
`submitsbiologics-license-application-for-fda-review-of-lucentis-tm-in-
`wetage- related-macular-degeneration-/
`2121 Genentech News Release, FDA Approves Lucentis for the Treatment of
`Wet Age-Related Macular Degeneration, (June 30, 2006)
`2122 A Study of Ranibizumab Injection in Subjects With Clinically
`Significant Macular Edema (ME) With Center Involvement Secondary
`to Diabetes Mellitus (RISE), NCT00473330, ClinicalTrials.gov
`(December 22, 2021),
`https://www.clinicaltrials.gov/ct2/show/NCT00473330
`2123 A Study of Ranibizumab Injection in Subjects With Clinically
`Significant Macular Edema (ME) With Center Involvement Secondary
`to Diabetes Mellitus (RIDE), NCT00473382 ClinicalTrials.gov
`(December 22, 2021), https://clinicaltrials.gov/ct2/show/NCT00473382
`2124 A Study of the Efficacy and Safety of Ranibizumab Injection in Patients
`With Macular Edema Secondary to Branch Retinal Vein Occlusion
`(BRAVO), NCT00486018 (December 22, 2021),
`https://clinicaltrials.gov/ct2/show/NCT00486018
`2125 A Study of the Efficacy and Safety of Ranibizumab Injection in Patients
`With Macular Edema Secondary to Central Retinal Vein Occlusion
`(CRUISE), NCT00485836 (December 22, 2021),
`https://clinicaltrials.gov/ct2/show/NCT00485836
`2126 Vascular Endothelial Growth Factor (VEGF) Trap-Eye: Investigation of
`Efficacy and Safety in Central Retinal Vein Occlusion (CRVO),
`NCT00943072 (December 22, 2021),
`https://clinicaltrials.gov/ct2/show/NCT00943072
`2127 Vascular Endothelial Growth Factor (VEGF) Trap-Eye: Investigation of
`Efficacy and Safety in Central Retinal Vein Occlusion (CRVO)
`(GALILEO), NCT01012973 (December 22, 2021),
`https://clinicaltrials.gov/ct2/show/NCT01012973
`2128 VGFT-OD-0605 (VIEW 1 Trial) Protocol Signature Page-
`CONFIDENTIAL MATERIAL - SUBJECT TO PROTECTIVE
`ORDER
`Transcript of Deposition of Mary Gerritsen, Ph.D. (January 14, 2022)
`Transcript of Deposition of Thomas Albini, M.D. (January 20, 2022)
`
`2129
`2130
`
`–xv–
`
`
`
`2131 Brown DM, et al., Intravitreal Aflibercept Injection for Macular Edema
`Secondary to Central Retinal Vein Occlusion: 1-Year Results from the
`Phase 3 COPERNICUS Study, Am J Ophthalmol 2013;155:329-437
`Exhibit 14 to Deposition of Thomas Albini, M.D. (January 20, 2022)
`2132
`Regeneron, Earnings Call Transcript, 2/13/2012
`2133
`Regeneron, Earnings Call Transcript, 4/26/2012
`2134
`Regeneron, Earnings Call Transcript, 7/25/2012
`2135
`Regeneron, Eylea Marketing Material, c. 2013
`2136
`Regeneron, Eylea Marketing Material, 11/2013
`2137
`2138 Regeneron, “Physician ATU: Wave 2,” 2/2013 - CONFIDENTIAL
`MATERIAL - SUBJECT TO PROTECTIVE ORDER
`2139 Regeneron, “For the Treatment of Wet Age-Related Macular
`Degeneration,” c. 2012
`2140 Regeneron, “Physician ATU: Wave 5,” 11/2013 - CONFIDENTIAL
`MATERIAL - SUBJECT TO PROTECTIVE ORDER
`2141 American Academy of Ophthalmology Website, Anti-VEGF
`Treatments, https://www.aao.org/eye-health/drugs/anti-vegf-treatments
`(accessed 11/8/2021)
`2142 American Academy of Ophthalmology, “Bevacizumab,” 11/2/2021,
`https://eyewiki.aao.org/Bevacizumab
`2143 American Academy of Ophthalmology, “Ophthalmology
`Subspecialists,” 6/6/2016, https://www.aao.org/eye-health/tips-
`prevention/ophthalmology-subspecialists
`2144 American Academy of Ophthalmology Website, Retinal Vasculitis,
`https://eyewiki.aao.org/Retinal_Vasculitis (accessed 1/13/2022)
`2145 American Academy of Ophthalmology Website, What is Avastin,
`https://www.aao.org/eye-health/drugs/avastin (accessed 11/9/2021)
`2146 American Academy of Ophthalmology Website, What is Eylea,
`https://www.aao.org/eye-health/drugs/what-is-eylea (accessed
`11/9/2021)
`2147 American Academy of Ophthalmology Website, What is Lucentis,
`https://www.aao.org/eye-health/drugs/lucentis (accessed 11/9/2021)
`2148 American Society of Retina Specialists Website, About Us.
`https://www.asrs.org/about (accessed 12/6/2021)
`2149 American Society of Retina Specialists Website, Age-Related Macular
`Degeneration, https://www.asrs.org/patients/retinal-
`diseases/2/agerela