`
`
`
`
`
`
`
`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 RESPONSE
`
`
`
`
`1 IPR2022-00257 and IPR2022-00301 have been joined with this proceeding.
`
`
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`

`

`
`
`TABLE OF CONTENTS
`
`
`
`Page No.
`TABLE OF AUTHORITIES ................................................................................ iii 
`TABLE OF EXHIBITS .......................................................................................... vi 
`I. 
`INTRODUCTION ......................................................................................... 1 
`II. 
`THE STATE OF THE ART ......................................................................... 3 
`III.  THE ’069 PATENT ........................................................................................ 6 
`IV.  CLAIM CONSTRUCTION .......................................................................... 7 
`V.  GROUNDS 1-4: PETITIONER FAILS TO DEMONSTRATE
`THAT “VEGF TRAP-EYE” WAS KNOWN TO
`CORRESPOND TO SEQ ID NO:1 OR SEQ ID NO:2 .............................. 9 
`A. 
`Petitioner’s Grounds 1-4 References Do Not Expressly
`Disclose the Amino Acid or Nucleic Acid Sequence of VEGF
`Trap-Eye ............................................................................................. 10 
`Petitioner’s Grounds 1-4 References Do Not Inherently
`Disclose the Amino Acid or Nucleic Acid Sequence of VEGF
`Trap-Eye ............................................................................................. 11 
`1. 
`Dixon Does Not Disclose That VEGF Trap-Eye Shares
`the Same Amino Acid Sequence of Aflibercept ................... 13 
`The POSA Would Have Had Reason to Doubt That
`VEGF Trap-Eye Corresponded to Only Aflibercept .......... 15 
`VI.  GROUND 4: PETITIONER FAILS TO ESTABLISH THAT
`CLAIMS 1 AND 8-12 ARE UNPATENTABLE BASED ON
`DIXON’S DISCLOSURE OF THE VIEW DOSING REGIMEN ......... 22 
`
`B. 
`
`2. 
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`–i–
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`

`

`
`
`A. 
`
`B. 
`
`Petitioner Fails to Establish That the 8-Week Dosing Arm of
`the VIEW Clinical Trial Anticipates the Claimed PRN Dosing
`Regimen (All Challenged Claims) .................................................... 22 
`Petitioner Fails to Establish That the 8-Week Dosing Arm of
`the VIEW Clinical Trial Renders Obvious the Claimed PRN
`Dosing Regimen (All Challenged Claims) ....................................... 25 
`VII.  GROUND 5: PETITIONER FAILS TO ESTABLISH THAT
`ANY CHALLENGED CLAIM IS RENDERED OBVIOUS BY
`HEIER-2009 IN VIEW OF MITCHELL OR DIXON ............................ 28 
`A.  Heier-2009 in View of Mitchell or Dixon Does Not Render
`Obvious Claims 1 and 8-12 ............................................................... 29 
`Claim 8 Is Nonobvious for the Additional Reason That the
`POSA Would Not Have Been Motivated to Decrease the
`Number of Loading Doses from Four to Three Based on the
`CLEAR-IT 2 Data ............................................................................. 30 
`1. 
`Ranibizumab Dosing Regimens as Reported in Mitchell .... 34 
`2. 
`Prospective View Dosing Regimens as Reported in
`Dixon......................................................................................... 41 
`VIII.  CONCLUSION ............................................................................................ 43 
`
`
`
`B. 
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`–ii–
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`

`

`TABLE OF AUTHORITIES
`
`
`
` Page(s)
`
`Cases
`Advanced Display Sys., Inc. v. Kent State Univ.,
`212 F.3d 1272 (Fed. Cir. 2000) .......................................................................... 23
`Amgen, Inc. v. Alexion Pharms.,
`IPR2019-00741, Paper 15, 20 (PTAB Aug. 30, 2019) ................................. 12, 13
`AstraZeneca AB v. Aurobindo Pharma Ltd.,
`232 F. Supp. 3d 636 (D. Del. 2017) .................................................................... 28
`AstraZeneca LP v. Apotex, Inc.,
`633 F.3d 1042 (Fed. Cir. 2010) .......................................................................... 22
`Belden Inc. v. Berk–Tek LLC,
`805 F.3d 1064 (Fed. Cir. 2015) .......................................................................... 33
`Bettcher Indus., Inc. v. Bunzl USA, Inc.,
`661 F3d 629 (Fed. Cir. 2011) ............................................................................. 11
`Cheese Sys., Inc. v. Tetra Pak Cheese & Powder Sys.,
`725 F.3d 1341 (Fed. Cir. 2013) .......................................................................... 42
`Continental Can Co. USA v. Monsanto,
`948 F.2d 1264 (Fed. Cir. 1991) .......................................................................... 11
`Endo Pharms. Sols., Inc. v. Custopharm Inc.,
`894 F.3d 1374 (Fed. Cir. 2018) ........................................................ 12, 13, 21, 22
`Henny Penny Corp. v. Frymaster LLC,
`938 F.3d 1324 (Fed. Cir. 2019) .................................................................... 28, 43
`Impax Lab’ys. Inc. v. Lannett Holdings Inc.,
`893 F.3d 1372 (Fed. Cir. 2018) .................................................................... 33, 36
`Innogenics, N.V. v. Abbott Labs.,
`512 F.3d 1363 (Fed. Cir. 2008) .......................................................................... 33
`
`
`
`
`
`
`–iii–
`
`

`

`
`
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) .................................................................... 26, 43
`Kinetic Concepts, Inc. v. Smith & Nephew, Inc.,
`688 F.3d 1342 (Fed. Cir. 2012) .......................................................................... 33
`King Pharms., Inc. v. Eon Labs, Inc.,
`616 F.3d 1267 (Fed. Cir. 2010) .......................................................................... 10
`KSR Int’l Co. v. Teleflex, Inc.,
`550 U.S. 398 (2007) ............................................................................................ 33
`Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co.,
`868 F.3d 1013 (Fed. Cir. 2017) ........................................................................ 8, 9
`In re NTP, Inc.,
`654 F.3d 1279 (Fed. Cir. 2011) .......................................................................... 42
`In re Oelrich,
`666 F.2d 578 (C.C.P.A. 1981) ................................................................ 11, 21, 22
`Pers. Web Techs., LLC v. Apple, Inc.,
`848 F.3d 987 (Fed. Cir. 2017) ............................................................................ 33
`Rexnord Indus., LLC v. Kappos,
`705 F.3d 1347 (Fed. Cir. 2013) .......................................................................... 11
`Rosco, Inc. v. Mirror Lite Co.,
`304 F.3d 1373 (Fed. Cir. 2002) .......................................................................... 12
`Samsung Elecs. Co. v. Elm 3DS Innovations, LLC,
`925 F.3d 1373 (Fed. Cir. 2019) ............................................................................ 8
`Sanofi Aventis U.S., LLC v. Dr. Reddy’s Lab’ys, Inc.,
`933 F.3d 1367 (Fed. Cir. 2019) .......................................................................... 42
`Schering Corp. v. Amgen Inc.,
`222 F.3d 1347 (Fed. Cir. 2000) .......................................................................... 18
`Verdegaal Bros. v. Union Oil Co. of Cal.,
`814 F.2d 628 (Fed. Cir. 1987) ............................................................................ 23
`
`
`
`
`
`
`–iv–
`
`

`

`
`
`Statutes
`35 U.S.C. § 314(a) ............................................................................................. 26, 43
`Other Authorities
`21 CFR §§ 601.50, 601.51 ....................................................................................... 10
`
`
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`–v–
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`

`
`
`TABLE OF EXHIBITS
`
`Description
`
`2008
`
`Ex. No.
`2001 Exhibit Number Unused
`2002 Exhibit Number Unused
`2003 Lucentis (ranibzumab injection) label, revised June 2010
`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)
`2019 Eylea (aflibercept) Injection label, revised May 2016
`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)
`2033 Lucentis (ranibzumab injection) label, revised March 2018
`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
`
`–viii–
`
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`
`
`
`
`

`

`
`
`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
`2050 Expert Declaration of David M. Brown, M.D.
`2051 Exhibit Number Unused
`2052 Exhibit Number Unused
`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)
`
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`–ix–
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`

`
`
`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)
`
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`

`
`
`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)
`2075 Eylea® Approval Letter (November 18, 2011)
`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”)
`2081 Curriculum Vitae of Dr. Dr. Lucian V. Del Priore, M.D., Ph.D.
`2082 Curriculum Vitae of Dr. Alexander M. Klibanov, Ph.D.
`2083 Curriculum Vitae of Dr. David Mark Brown, M.D.
`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–
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`

`

`
`
`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
`
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`

`
`
`2100
`
`2101
`
`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–
`
`2106
`
`
`
`
`
`
`

`

`
`
`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
`2129 Transcript of Deposition of Mary Gerritsen, Ph.D. (January 14, 2022)
`2130 Transcript of Deposition of Thomas Albini, M.D. (January 20, 2022)
`
`–xv–
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`
`
`

`

`
`
`Patent Owner Regeneron Pharmaceuticals, Inc. (“Patent Owner” or
`
`“Regeneron”) respectfully submits that Petitioner Mylan Pharmaceuticals Inc.
`
`(“Petitioner” or “Mylan”) has not carried its burden of demonstrating by a
`
`preponderance of the evidence that Claims 1 and 8-12 (“the Challenged Claims”)
`
`of U.S. Patent No. 9,669,069 (“the ’069 Patent,” Ex.1001) are unpatentable.
`
`I.
`
`INTRODUCTION
`Petitioner, who is developing a biosimilar of EYLEA® for the treatment of
`
`angiogenic eye disorders, filed this challenge to try to invalidate Regeneron’s ’069
`
`Patent, which covers an alternate approved dosing regimen for EYLEA.
`
`Before the development of EYLEA, ranibizumab (Lucentis®) or off-label
`
`bevacizumab (Avastin®) were the standard-of-care for treatment of angiogenic eye
`
`disorders. While both ranibizumab and bevacizumab provided highly effective
`
`treatment, the great burden of monthly eye injections and office visits led to
`
`extensive efforts in the art to decrease injection frequency and physician monitoring.
`
`Ex.1018, 2537, 2545. However, fixed quarterly or “as needed” (pro re nata) dosing
`
`regimens without monthly monitoring visits were not effective at maintaining
`
`vision. Ex.1018, 2537; Ex.1001, 1:55-59.
`
`Regeneron sought to develop a therapy that would finally improve and
`
`maintain visual acuity with extended time between injections. The ’069 Patent
`
`discloses and claims the administration of a sequence-limited VEGF antagonist
`
`using a dosing regimen that includes a single initial dose of the VEGF antagonist,
`
`
`
`
`
`–1–
`
`

`

`
`
`followed by one or more secondary doses of the VEGF antagonist, followed by one
`
`or more tertiary doses of the VEGF antagonist, where the tertiary doses are
`
`“administered on an as-needed/pro re nata (PRN) basis, based on visual and/or
`
`anatomical outcomes as assessed by a physician or other qualified medical
`
`professional.”
`
`Petitioner’s anticipation challenges fail because its cited references do not
`
`expressly or inherently disclose the recited amino acid or nucleic acid sequences of
`
`the Challenged Claims. Because the art contained only an inconsistent and
`
`incomplete description of “VEGF Trap-Eye,” the recited sequence information is
`
`not inherent in Petitioner’s Grounds and cannot demonstrate anticipation of the
`
`Challenged Claims.
`
`Petitioner’s Ground 4 anticipation challenge fails for the additional reason
`
`that Dixon does not disclose the dosing regimen recited in Claim 8.
`
`Finally, Petitioner’s Ground 5 obviousness challenges fail both because the
`
`person of ordinary skill in the art (the “POSA”) would not have had a reason to
`
`modify Regeneron’s Phase 2 dosing regimen by omitting a monthly loading dose;
`
`to the contrary, the results from Regeneron’s Phase 2 trial, as well as the art taken
`
`as a whole, would have discouraged the POSA from doing so. Moreover, the POSA
`
`would not have been motivated to modify a fixed 8-week tertiary dosing regimen
`
`to become a PRN tertiary dosing regimen, as required by each of the Challenged
`
`Claims.
`
`
`
`
`
`–2–
`
`

`

`
`
`Thus, Patent Owner respectfully requests that the Board affirm the validity
`
`of the Challenged Claims of the ’069 Patent.
`
`II. THE STATE OF THE ART
`Angiogenic eye disorders, such as neovascular age-related macular
`
`degeneration (“wet AMD” or “wAMD”), diabetic macular edema (“DME”) and
`
`macular edema following retinal vein occlusion (“RVO”), are characterized by
`
`abnormal growth or permeability of blood vessels in the retina and elevated ocular
`
`levels of VEGF. Ex.2050 (Brown Decl.), ¶¶26-28. Early treatments for wAMD,
`
`such as laser ablation and photodynamic therapy (“PDT”), only slowed eventual
`
`vision loss. Id., ¶27. By the early 2000’s, scientists and clinicians began to
`
`investigate anti-VEGF agents to treat angiogenic eye disorders. Macugen® was the
`
`first anti-VEGF agent approved for treatment of angiogenic eye disorders,
`
`specifically wAMD,