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
`
`____________
`
`Case IPR2021-008801
`Patent No. 9,669,069 B2
`____________
`
`PATENT OWNER’S SUR-REPLY
`
`1 IPR2022-00257 and IPR2022-00301 have been joined with this proceeding.
`
`

`

`TABLE OF CONTENTS
`INTRODUCTION ........................................................................................... 1
`I.
`THE POSA ...................................................................................................... 2
`II.
`III. CLAIM CONSTRUCTION ............................................................................ 4
`IV. GROUNDS 1-4: 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 ........................ 5
`A.
`Petitioner Improperly Uses Inherency to Backfill an Incomplete
`Description of VEGF Trap-Eye in the Prior Art ................................... 6
`1.
`Petitioner’s Cases Do Not Support Its Use of Inherency ........... 8
`2.
`VEGF Trap-Eye’s Sequence Was Not Publicly Accessible ..... 10
`Petitioner Has Failed to Show That the Sequences of VEGF Trap-
`Eye Are Necessarily Present in the Ground 1-4 References ............... 11
`1.
`The “Same Molecular Structure” Does Not Necessarily
`Mean the Same Sequence ......................................................... 12
`The POSA Would Understand That “VEGF Trap-Eye”
`Could Encompass a Genus of Proteins ..................................... 13
`Inconsistent Reporting of Molecular Weight Sows Doubt,
`Not Clarity ................................................................................. 16
`PO Did Not Characterize VEGF Trap-Eye and Aflibercept
`as the Same Agent ..................................................................... 16
`GROUND 4: PETITIONER FAILS TO ESTABLISH THAT
`CLAIMS 1 AND 8-12 ARE UNPATENTABLE BASED ON
`DIXON’S DISCLOSURE OF THE VIEW DOSING REGIMEN ............... 17
`
`V.
`
`B.
`
`2.
`
`3.
`
`4.
`
`–i–
`
`

`

`B.
`
`B.
`
`A.
`
`Petitioner Fails to Establish That Dixon’s Disclosure of VIEW
`Anticipates the Claimed PRN Dosing Regimen ................................. 18
`1.
`Fixed Q8 Dosing Does Not Equal PRN Dosing ....................... 18
`2.
`Dixon’s Disclosure of the 2-Year Regimen of VIEW’s 2Q8
`Arm Does Not Include Tertiary PRN Dosing ........................... 19
`Petitioner Fails to Establish That Dixon’s Disclosure of VIEW
`Renders Obvious the Claimed PRN Dosing Regimen ........................ 20
`1.
`Petitioner’s Assertion That “No Motivation to Combine Is
`Necessary” Is Wrong ................................................................ 21
`Petitioner Fails to Demonstrate Motivation to Substitute
`PRN Dosing for VIEW’s Q8 Fixed Dosing.............................. 21
`Petitioner Improperly Conflates PO’s Motivation with That
`of the POSA .............................................................................. 24
`VI. GROUND 5: PETITIONER FAILS TO ESTABLISH THAT ANY
`CHALLENGED CLAIM IS RENDERED OBVIOUS BY HEIER-
`2009 IN VIEW OF MITCHELL OR DIXON ............................................... 25
`A.
`Heier-2009 in View of Mitchell or Dixon Does Not Render
`Claims 1 and 8-12 Obvious ................................................................. 25
`Claim 8 Is Not Obvious Because the POSA Would Not Have
`Been Motivated to Drop from Four to Three Loading Doses
`Based on CLEAR-IT-2 Data ............................................................... 26
`1.
`Based on the Results of CLEAR-IT-2, the POSA Would
`Not Have Been Motivated to Drop a Fourth Loading Dose
`from a Dosing Regimen with VEGF Trap-Eye ........................ 26
`Petitioner’s Argument That Loading Doses Are
`Inconsequential Flouts the Limitations of Claim 8 ................... 28
`Petitioner’s Evidence of Generalized Motivation to Reduce
`Injection Frequency Is Directed at Chronic Dosing, Not
`Loading Doses ........................................................................... 29
`
`2.
`
`3.
`
`2.
`
`3.
`
`–ii–
`
`

`

`4.
`
`Prior Art Use of Three Loading Doses with Ranibizumab
`Does Not Provide a Motivation to Reduce Loading Doses ...... 31
`Dixon Would Not Have Motivated the POSA to Drop a
`Fourth Loading Dose from CLEAR-IT-2 ................................. 33
`VII. CONCLUSION .............................................................................................. 36
`
`5.
`
`–iii–
`
`

`

`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`Abbott Laby’s v. Geneva Pharms., Inc.,
`182 F.3d 1315 (Fed. Cir. 1999) ............................................................................ 8
`Abbott Lab’ys v. Sandoz, Inc.,
`566 F.3d 1282 (Fed. Cir. 2009) ............................................................................ 6
`Amgen, Inc v. Alexion Pharma.,
`IPR2019-00741, Paper 15 (P.T.A.B. Aug. 30, 2019) ................................. 7, 8, 10
`AstraZeneca LP v. Apotex, Inc.,
`633 F.3d 1042 (Fed. Cir. 2010) .......................................................................... 17
`In re Baxter Travenol Labs.,
`952 F.2d 388 (Fed. Cir. 1991) .............................................................................. 8
`Bayer Cropscience LP v. Syngenta Ltd.,
`IPR2017-01332, Paper 15 (P.T.A.B. Apr. 2, 2018) ....................................passim
`Bettcher Indus., Inc. v. Bunzl USA, Inc.,
`661 F.3d 629 (Fed. Cir. 2011) ................................................................ 5-6, 9, 11
`Celltrion, Inc. v. Genentech, Inc.,
`IPR2016-01667, Paper No. 15 (P.T.A.B. Mar. 2, 2017) (reh’g
`denied) ................................................................................................................. 11
`In re Donohue,
`766 F.2d 531 (Fed. Cir. 1985) ........................................................................ 9, 10
`Endo Pharms. Sols. Inc. v. CustoPharm Inc.,
`894 F.3d 1374 (Fed. Cir. 2018) .................................................................... 6, 7, 8
`Environmental Designs, Ltd. v. Union Oil Co.,
`713 F.2d 693 (Fed. Cir. 1983) .............................................................................. 4
`In re Fulton,
`391 F.3d 1195 (Fed. Cir. 2004) .................................................................... 27, 28
`
`–iv–
`
`

`

`Hoffer v. Microsoft Corp.,
`405 F.3d 1326, 1329-30 (Fed. Cir. 2005) ............................................................. 5
`Hospira, Inc. v. Fresenius Kabi USA, LLC,
`946 F.3d 1322 (Fed. Cir. 2020) ............................................................................ 8
`Intel. Corp. v. Tela Innovations, Inc.,
`2021 WL 886443 (P.T.A.B. Mar. 9, 2021) ........................................................ 21
`Intelligent Bio-Sys, Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) ......................................................... 19-20, 27-28
`LinkedIn Corp. v. eBuddy Tech. B.V.,
`IPR2022-00176, Paper 13 (P.T.A.B. May 17, 2022) ........................................... 3
`Monsanto Tech. LLC v. E.I. DuPont de Nemours & Co.,
`878 F.3d 1336 (Fed. Cir. 2018) ............................................................................ 8
`Net MoneyIN, Inc. v. VeriSign, Inc.,
`545 F.3d 1359 (Fed. Cir. 2008) .......................................................................... 20
`Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co.,
`868 F.3d 1013 (Fed. Cir. 2017) ............................................................................ 4
`In re Oelrich,
`666 F.2d 578 (C.C.P.A 1981) ............................................................................. 17
`In re Omeprazole Patent Litig.,
`483 F.3d 1364 (Fed. Cir. 2007) ............................................................................ 8
`Pfizer, Inc. v. Ranbaxy Lab’y Ltd.,
`457 F.3d 1284 (Fed. Cir. 2006) .......................................................................... 28
`Rosco, Inc. v. Mirror Lite Co.,
`304 F.3d 1373 (Fed. Cir. 2002) ...................................................................... 5, 16
`Schering Corp. v. Amgen Inc.,
`222 F.3d 1347 (Fed. Cir. 2000) .......................................................................... 11
`Schering Corp. v. Geneva Pharms.,
`339 F.3d 1373 (Fed. Cir. 2003) ............................................................................ 8
`
`–v–
`
`

`

`Scripps Clinic & Rsch. Found. v. Genentech, Inc.,
`927 F.2d 1565 (Fed. Cir. 1991) ............................................................................ 6
`Standard Oil Co. v. American Cyanamid Co.,
`774 F.2d 448 (Fed. Cir. 1985) ............................................................................ 24
`In re Stepan Co.,
`868 F.3d 1342 (Fed. Cir. 2017) .......................................................................... 21
`Sundance, Inc. v. DeMonte Fabricating Ltd.,
`505 F.3d 1356 (Fed. Cir. 2008) ............................................................................ 3
`Toro Co. v. Deere & Co.,
`355 F.3d 1313 (Fed. Cir. 2004) ............................................................................ 8
`TQ Delta, LLC v. CISCO Sys., Inc.,
`942 F.3d 1352 (Fed. Cir. 2019) .......................................................................... 30
`Unigene Lab’ys, Inc. v. Apotex, Inc.,
`655 F.3d 1352 (Fed. Cir. 2011) .......................................................................... 33
`Ex Parte Urban Weber,
`2021 WL 4319420 (P.T.A.B. Sept. 21, 2021) ...................................................... 8
`In re Vogel,
`422 F.2d 438 (C.C.P.A. 1970) ............................................................................ 28
`Statutes
`35 U.S.C. § 101 ........................................................................................................ 28
`35 U.S.C. § 102(b) ..................................................................................................... 9
`35 U.S.C. § 103 ........................................................................................................ 24
`35 U.S.C. § 112 ........................................................................................................ 28
`35 U.S.C. § 311 ........................................................................................................ 19
`Other Authorities
`37 C.F.R. §10.23(c)(18) ..................................................................................... 18-19
`37 C.F.R. §42.23(b) ..........................................................................................passim
`
`–vi–
`
`

`

`37 C.F.R. §1.56 ........................................................................................................ 18
`37 CLELR. 81.56 oe eeeeeecseececesscesecseecseesneeseessecsesensessessesseeceessneessesaecaeeesessesserseeees 18
`FED. R. EVID. 702 ....................................................................................................... 3
`FED. R. EVID. 702 ...........ccccccccssssecccccccsccccccesssccccccesssccccccscessssescessccsesssesessseesesssessnesssess 3
`
`–vii–
`—Vii-—
`
`

`

`TABLE OF EXHIBITS
`
`Description
`
`Ex. No.
`Exhibit Number Unused
`2001
`Exhibit Number Unused
`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)
`
`2008
`
`2014
`
`–viii–
`
`

`

`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
`
`–ix–
`
`

`

`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, 2030
`
`–x–
`
`

`

`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
`Exhibit Number Unused
`2051
`Exhibit Number Unused
`2052
`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)
`2058 Bork et al., Increasing the Sialylation of Therapeutic Glycoproteins:
`The Potential of the Sialic Acid Biosynthetic Pathway, 98 J. PHARM. SCI.
`3499 (2009)
`
`–xi–
`
`

`

`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)
`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
`
`–xii–
`
`

`

`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)
`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)
`
`–xiii–
`
`

`

`2088
`
`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)
`2099 FDA, 22 Case Studies Where Phase 2 and Phase 3 Trials Had Divergent
`Results (Jan. 2017)
`
`2095
`
`–xiv–
`
`

`

`2100
`
`2101
`
`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
`
`2106
`
`–xv–
`
`

`

`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
`
`–xvi–
`
`

`

`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)
`Supplemental Declaration of Doris Weber
`
`2129
`2130
`2131
`
`–xvii–
`
`

`

`2032-
`2286
`2287
`2288
`
`Intentionally Omitted
`
`Transcript of Deposition of Thomas Albini, M.D. (June 22, 2022)
`Transcript of Deposition of Mary Gerritsen, Ph.D. (June 17, 2022)
`
`–xviii–
`
`

`

`I.
`
`INTRODUCTION
`It is undisputed that the amino acid sequence of “VEGF Trap-Eye” was not
`
`disclosed in the prior art. Rather, Petitioner contends that “VEGF Trap-Eye” was
`
`synonymous with “VEGF Trap,” “VEGF TrapR1R2” and “aflibercept” and,
`
`consequently, the POSA would have known that “VEGF Trap-Eye” possessed the
`
`same amino acid sequence as aflibercept. But the record demonstrates that the art
`
`disclosed multiple amino acid sequences as “VEGF Trap” and “VEGF TrapR1R2”
`
`and that some of those sequences did not meet the recited sequence limitations of
`
`the Challenged Claims.
`
`Unable to connect-the-dots between “VEGF Trap-Eye” and the recited
`
`sequences in the prior art, on Reply, Petitioner tries to: (1) use inherency