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 IPR2021-008811
`Patent No. 9,254,338 B2
`____________
`
`PATENT OWNER’S UPDATED EXHIBIT LIST
`
`1 IPR2022-00258 and IPR2022-00298 have been joined with this proceeding.
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`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)
`–1–
`
`2014
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`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
`
`–2–
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`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
`
`–3–
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`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)
`
`–4–
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`

`Case IPR2021-00881
`Patent 9,254,338 B2
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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)
`
`–5–
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`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`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)
`
`–6–
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`

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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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`
`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
`–8–
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`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
`
`–9–
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`Case IPR2021-00881
`Patent 9,254,338 B2
`
`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
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`Case IPR2021-00881
`Patent 9,254,338 B2
`
`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/agerelated-macular-degeneration (accessed 12/30/2021)
`
`–11–
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`2150 American Society of Retina Specialists Website, Branch Retinal Vein
`Occlusion, https://www.asrs.org/patients/retinal-diseases/24/branch-
`retinal-vein-occlusion (accessed 12/30/2021)
`2151 American Society of Retina Specialists Website, Central Retinal Vein
`Occlusion, https://www.asrs.org/patients/retinal-diseases/22/central-
`retinal-vein-occlusion (accessed 12/30/2021)
`2152 American Society of Retina Specialists Website, Diabetic Retinopathy,
`https://www.asrs.org/patients/retinal-diseases/3/diabetic-retinopathy
`(accessed 12/30/2021)
`2153 Amgen Website, Fusion Protein,
`https://www.amgen.com/stories/2018/08/the-shape-of-drugs-to-
`come/fusion-protein (accessed 1/7/2022)
`2154 American Speech-Language-Hearing Association Website, Calculating
`Medicare Fee Schedule Rates,
`https://www.asha.org/practice/reimbursement/medicare/calculating-
`medicare-fee-schedule-rates/ (accessed 11/22/2021)
`2155 U.S. Department of Health and Human Services (ASPE), “Medicare
`Part B Reimbursement of Prescription Drugs,” 6/2014, available at:
`https://aspe.hhs.gov/sites/default/files/private/pdf/106966/ib_mprpd.pdf
`2156 Drugs@FDA, Avastin Label, c. 2004, available at:
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/125085lbl.p
`df
`2157 BasePair Biotechnologies Website, What is an Aptamer? – Aptamers
`and SELEX, https://www.basepairbio.com/what-is-an-aptamer/
`(accessed 12/30/2021)
`2158 Bausch and Lomb Website, Visudyne,
`https://www.bauschretinarx.com/visudyne/ecp/about/ (accessed
`12/2/2021)
`2159 Bausch and Lomb Website, Help Your Patients Obtain Access to
`Visudyne, https://www.bauschretinarx.com/visudyne/ecp/ordering/
`(accessed 1/12/2022)
`Bausch Health Companies, Form 10-K, 2020.
`2160
`2161 Drugs@FDA, Beovu Label, 10/2019, available at:
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761125s00
`0lbl.pdf
`2162 Drugs@FDA, Beovu Label, 6/2020, available at:
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761125s00
`4lbl.pdf
`
`–12–
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`2163 Regeneron, “Physician ATU: Wave 4,” 8/6/2013 - CONFIDENTIAL
`MATERIAL - SUBJECT TO PROTECTIVE ORDER
`2164 Bright Focus Foundation Website, Age-Related Macular Degeneration:
`Facts & Figures, https://www.brightfocus.org/macular/article/age-
`related-macular-facts-figures (accessed 11/5/2021)
`2165 USC-Brookings, “Medicare Payment for Physician-Administered (Part
`B) Drugs: The Interim Final Rule and a Better Way Forward,” available
`at: https://www.brookings.edu/blog/usc-brookings-schaeffer-on-health-
`policy/2021/02/10/medicare-payment-for-physician-administered-part-
`b-drugs/
`2166 Calculator.net, “Sample Size Calculator,”
`https://www.calculator.net/sample-size-
`calculator.html?type=2&cl2=95&ss2=200&pc2=50&ps2=3000&x=
`68&y=18#findci (accessed 1/25/2022)
`2167 Centers for Disease Control and Prevention, “Vision Loss: A Public
`Health Problem,” 6/12/2020,
`https://www.cdc.gov/visionhealth/basic_information/vision_loss.htm
`2168 Centers for Medicare & Medicaid Services Website, Medicare
`Physician & Other Practitioners - by Provider and Service,
`https://data.cms.gov/provider-summary-by-type-of-service/medicare-
`physician-other-practitioners/medicare-physician-other-practitioners-by-
`provider-and-service (accessed 11/19/2021)
`2169 Regeneron, "Eylea Sample Disbursement 2013 to 2021," c. 2021 -
`CONFIDENTIAL MATERIAL - SUBJECT TO PROTECTIVE
`ORDER
`2170 Regeneron, "US Eylea P&L LTD," 12/2021 - CONFIDENTIAL
`MATERIAL - SUBJECT TO PROTECTIVE ORDER
`2171 CloudResearch Website, “Determining Sample Size: How Many Survey
`Participants Do You Need?”
`https://www.cloudresearch.com/resources/guides/statistical-
`significance/determine-sample-size/ (accessed 1/25/2022)
`2172 Centers for Medicare & Medicare Services Website, 2021 ASP Drug
`Pricing Files, https://www.cms.gov/medicare/medicare-part-b-drug-
`average-sales-price/2021-asp-drug-pricing-files (accessed 11/22/2021)
`2173 Centers for Medicare & Medicare Services Website, Medicare Part B
`Drug Average Sales Price, https://www.cms.gov/Medicare/Medicare-
`Fee-for-Service-Part-B-Drugs/McrPartBDrugAvgSalesPrice (accessed
`12/8/2021)
`
`–13–
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`2174 Centers for Medicare & Medicaid Services Website, Physician Fee
`Schedule, https://www.cms.gov/Medicare/Medicare-Fee-for-Service-
`Payment/PhysicianFeeSched (accessed 11/22/2021)
`2175 CMS.gov Medicare Coverage Database, “Billing and Coding:
`Aflibercept (Eylea),” 4/22/2021, available at:
`https://www.cms.gov/medicare-coverage-
`database/view/article.aspx?articleid=53387&ver=28&keyword=&keyw
`ordType=starts&areaId=all&docType=6,3,5,1,F,P&contractOption=all
`&hcpcsOption=code&hcpcsStartCode=J0178&hcpcsEndCode=J0178&
`sortBy=title&bc=1
`2176 Regeneron, “Q4 2020 Performance Update Wet AMD, DME, MEfRVO
`& DR w/out DME,” 1/29/2021 - CONFIDENTIAL MATERIAL -
`SUBJECT TO PROTECTIVE ORDER
`2177 Donohue, Julie et al. (2007), “A Decade of Direct-to-Consumer
`Advertising of Prescription Drugs,” The New England Journal of
`Medicine 35(7): 673–681
`2178 Donohue, Julie, Ernst R. Berndt (2004), “Effect of Direct-to-Consumer
`Advertising on Medication Choice: The Case of Antidepressants,”
`Journal of Public Policy & Marketing 23(2): 115–127
`2179 Dreyfuss, Juliana L., Ricardo J. Giordano, Gaio V. Regatieri (2015),
`“Ocular Angiogenesis,” Journal of Ophthalmology 2015
`2180 Miller & Zois, LLC, “Novartis Looking to Repurpose its Dangerous
`Beovu Drug,” 11/28/2020,
`https://www.drugrecalllawyerblog.com/novartis-repurpose-beovu.html
`2181 Drugs.com Website, Eylea FDA Approval History,
`https://www.drugs.com/history/eylea.html (accessed 11/16/2021)
`2182 Elyasi, Niki and Houman David Hemmati (2021), “Diabetic Macular
`Edema: Diagnosis and Management,” EyeNet Magazine, May 2021: 35-
`37
`2183 Eye Care Surgery Center Website, Macular Degeneration,
`https://www.eyecaresurgerycenterbr.com/diabetes-retina/macular-
`degeneration/ (accessed 11/18/2021)
`2184 EyeGuru.org Website, Intravitreal Injection Standard Dosing Table,
`https://eyeguru.org/blog/intravitreal-injection-dosing/ (accessed
`12/6/2021)
`2185 Drugs@FDA, Eylea Label, 11/2011, available at:
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125387lbl.p
`df
`
`–14–
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`2186 Drugs@FDA, Eylea Label, 9/2012, available at
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125387s00
`4lbl.pdf
`2187 Drugs@FDA, Eylea Label, 10/2014, available at:
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125387s04
`3lbl.pdf
`2188 Drugs@FDA, Eylea Label, 5/2019, available at:
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125387s06
`1lbl.pdf
`2189 Drugs@FDA, Eylea Label, 3/2021, available at:
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125387s06
`9lbl.pdf
`2190 Eylea Website, Wet AMD: Dosing Flexibility,
`https://hcp.eylea.us/about/wet-amd-dosing/ (accessed 1/5/2022)
`2191 FDA, "Macugen Drug Approval Package Page," 3/23/2005,
`https://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-
`756_Macugen.cfm
`2192 FiercePharma, “Beovu, Novartis,” 10/25/2021,
`https://www.fiercepharma.com/special-report/beovu-novartis-top-10-
`drug-launch-disasters
`2193 FiercePharma, “Novartis’ Hot New Eye Drug Beovu Tied to Potential
`Vision Loss: Experts,” 2/24/2020,
`https://www.fiercepharma.com/pharma/retinal-society-flags-serious-
`side-effect-for-novartis-beovu
`2194 FiercePharma, “The Top 20 Drugs by Worldwide sales in 2020,”
`5/3/2021, https://www.fiercepharma.com/special-report/top-20-drugs-
`by-2020-sales
`2195 FocusVision, “Survey Sample Size: How Much Do I Need?” 4/11/2019,
`https://www.focusvision.com/blog/survey-sample-size-how-much-do-i-
`need/
`2196 Gagnon, Marc-Andre and Joel Lexchin (2008), “The Cost of Pushing
`Pills: A New Estimate of Pharmaceutical Promotion Expenditures in the
`United States,” PLoS Med 5(1): 29–33
`2197 Regeneron, “Physician ATU – Benchmark Wave,” 9/15/2011 -
`CONFIDENTIAL MATERIAL - SUBJECT TO PROTECTIVE
`ORDER
`
`–15–
`
`

`

`Case IPR2021-00881
`Patent 9,254,338 B2
`
`2198 GEN, “FDA Green-Lights Genentech’s Lucentis for Macular Edema
`following Retinal Vein Occlusion, 6/23/2010,
`https://www.genengnews.com/news/fda-green-lights-genentechs-
`lucentis-for-macular-edema-following-retinal-vein-occlusion/
`2199 Genentech Press Release, “FDA Approves Lucentis for the Treatment of
`Wet Age-Related Macular Degeneration,” 6/30/2006,
`https://www.roche.com/dam/jcr:4ca7683d-1513-4e46-bd43-
`23faa0232507/en/irp060703.pdf
`2200 Regeneron, “U.S. Eylea Historical Brand P&L,” 5/2021 -
`CONFIDENTIAL MATERIAL - SUBJECT TO PROTECTIVE
`ORDER
`2201 Guha, Rahul, Jian Li, and Andrea L. Scott (2009), “The Economics of
`Commercial Success in Pharmaceutical Patent Litigation,” Landslide
`1(5)
`2202 HCPCS Codes Website, HCPCS Codes, https://hcpcs.codes/ (accessed
`1/6/2022)
`2203 Healio, “Access to Retina Providers Shows No Geographic Bias in
`U.S.,” 3/12/2019, available at: