UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner
`
`
`
`Case IPR2021-00881
`Patent 9,254,338 B2
`
`
`
`PETITIONER’S SECOND OBJECTIONS TO
`ADMISSIBILITY OF EVIDENCE SUBMITTED BY PATENT OWNER
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner
`
`
`
`Case IPR2021-00881
`Patent 9,254,338 B2
`
`
`
`PETITIONER’S SECOND OBJECTIONS TO
`ADMISSIBILITY OF EVIDENCE SUBMITTED BY PATENT OWNER
`
`
`
`
`Case No. IPR2021-00881
`
`Pursuant to 37 C.F.R. § 42.64(b), Petitioner Mylan Pharmaceuticals Inc.
`
`(“Petitioner”), hereby objects as follows to the admissibility of evidence filed by
`
`Patent Owner Regeneron Pharmaceuticals, Inc. (“Regeneron” or “Patent Owner”),
`
`in conjunction with the Patent Owner Response, filed February 11, 2022.
`
`In this paper, a reference to “FRE” means the Federal Rules of Evidence, a
`
`reference to “CFR” means the Code of Federal Regulations, and “’338 patent”
`
`means U.S. Patent No. 9,254,338. All objections under FRE 802 (hearsay) apply to
`
`the extent Patent Owner relies on the exhibits identified in connection with that
`
`objection for the truth of the matter asserted therein.
`
`Exhibit descriptions provided in this table are Patent Owner’s exhibit list and
`
`are used for identification purposes only. The use of the description does not indicate
`
`that Petitioner agrees with the descriptions or characterizations of the documents.
`
`Objection Key:
`
`A:
`B:
`
`FRE 802 (hearsay)
`FRE 901 (lacking authentication)
`
`C:
`
`D:
`
`E:
`
`FRE 402 (relevance) the document is not relevant to any issue in this
`IPR proceeding because the purported date of the document is after the
`filing date of the ’338 patent or the prior art status is not clear
`
`FRE 402 (relevance) to the extent the document is relied upon for
`secondary considerations of nonobviousness, there is no nexus to the
`claimed compositions and methods
`
`FRE 403 (confusing, waste of time) the document is not relevant to any
`issue in this IPR proceeding because the purported date of the document
`is after the filing date of the ’338 patent or the prior art status is not clear
`
`F:
`
`FRE 403 (confusing, waste of time) to the extent the document is relied
`
`
`
`Case No. IPR2021-00881
`
`upon for secondary considerations of nonobviousness, there is no nexus
`to the claimed compositions and methods
`
`FRE 702 (improper expert testimony) expert testimony that relies on the
`document is not based on sufficient facts or data and/or is not the product
`of reliable principles and methods
`
`FRE 703 (bases of expert opinion) expert testimony that relies on the
`document is unreliable because the document is not of a type
`reasonably relied upon by experts in the field
`
`FRE 106 (completeness) the document is incomplete and includes only
`a select portion of a larger document that in fairness should be
`considered along with this document
`
`FRE 701/702 (improper expert testimony) improper expert testimony by
`a lay witness
`
`FRE 1001-1003 (best evidence)
`
`FRE 403, 901 (improper compilation)
`
`FRE 403 (cumulative)
`
`FRE 402 (relevance) the document is not relevant to any issue in the
`IPR proceeding
`FRE 403 (confusing, waste of time) the document is not relevant to
`any issue in the IPR proceeding
`
`No exhibit filed
`Expert testimony fails to identify with particularity the underlying
`facts or data on which the opinion is based violating 37 C.F.R.
`§ 42.65(a)
`FRE 602 (lack of personal knowledge)
`FRE 702/703 to the extent that the expert declarant relies on an exhibit
`objected to under grounds G and H, the testimony is (i) not based on
`sufficient facts or data and/or is not the product of reliable principles
`and methods and/or is (ii) is unreliable because the exhibit is not of a
`type reasonably relied upon by experts in the field
`FRE 1006 (improper summary)
`FRE 105 (limited purpose) to the extent that any portion of this exhibit
`may be deemed admissible, such admissibility should be for a limited
`purpose
`FRE 705 and/or 37 C.F.R. § 42.65 the exhibit includes expert
`testimony that does not disclose the underlying facts or data
`
`G:
`
`H:
`
`I:
`
`J:
`
`K:
`
`L:
`
`M:
`
`N:
`
`O:
`
`P:
`Q:
`
`R:
`S:
`
`T:
`U:
`
`V:
`
`
`
`2
`
`
`
`Case No. IPR2021-00881
`
`Ex. No.
`
`Description
`
`Objections
`
`2048 Expert Declaration of Dr. Lucian V. Del Priore,
`M.D., Ph.D. - CONFIDENTIAL MATERIAL -
`SUBJECT TO PROTECTIVE ORDER
`
`A, C, D, E, F, G, H,
`J, M, N, O, Q, R, S,
`T, U
`
`2049 Expert Declaration of Dr. Alexander M. Klibanov,
`Ph.D. - CONFIDENTIAL MATERIAL -
`SUBJECT TO PROTECTIVE ORDER
`
`A, C, D, E, F, G, H,
`J, M, N, O, Q, R, S,
`T, U
`
`2050 Expert Declaration of David M. Brown, M.D.
`
`(including at least ¶¶150-181 for Patent Owner’s
`failure to comply with 37 CFR § 42.6(a)(3))
`
`2051 Expert Declaration of Dr. Diana V. Do, M.D.
`
`(including at least ¶¶98-170 for Patent Owner’s
`failure to comply with 37 CFR § 42.6(a)(3))
`
`2052 Expert Declaration of Richard Manning, Ph.D. -
`CONFIDENTIAL MATERIAL - SUBJECT TO
`PROTECTIVE ORDER
`
`(including at least ¶¶29-42, 48-117 for Patent
`Owner’s failure to comply with 37 CFR §
`42.6(a)(3))
`
`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/NCT0079441
`7?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/NCT0114861
`5?A=1&B=1
`
`C, D, E, F, G, J, N,
`O, and S,
`
`A, H, M, Q, R, T, U
`
`C, D, E, F, G, J, N,
`O, and S,
`
`A, H, M, Q, R, T, U
`
`C, D, E, F, G, J, N,
`O, Q, R and S,
`
`A, H, M, Q, R, T, U
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`3
`
`
`
`Case No. IPR2021-00881
`
`Ex. No.
`
`Description
`
`Objections
`
`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)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2056 Kim et al., A Brief History of Anti-VEGF for the
`Treatment of Ocular Angiogenesis, 181 THE
`AMERICAN JOURNAL OF PATHOLOGY 376
`(2012)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2057 Ramazi et al., Post-translational modifications in
`proteins: resources, tools and prediction methods,
`2021 DATABASE 1 (2021)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2058 Bork et al., Increasing the Sialylation of
`Therapeutic Glycoproteins: The Potential of the
`Sialic Acid Biosynthetic Pathway, 98 J. PHARM.
`SCI. 3499 (2009)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2059 Regeneron Sample Analysis Report: PK06005-9-
`SA-01V1 (2006) (“Koehler-Stec Report”) -
`CONFIDENTIAL MATERIAL - SUBJECT TO
`PROTECTIVE ORDER
`
`A, B, C, D, E, F, G,
`H, M, N, O, Q, R,
`S, U
`
`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)
`
`4
`
`A, B, C, D, E, F, G,
`H, I, M, N, O, Q, R,
`S, T, U
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`
`
`Case No. IPR2021-00881
`
`Ex. No.
`
`Description
`
`Objections
`
`2062 Nieto et al., Ocular silicon distribution and
`clearance following intravitreal injection of
`porous silicon microparticles, 116 EXP EYE
`RES. 161 (2013)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2063 Fernández-Ferreiro et al., Preclinical PET Study
`of Intravitreal Injections, 58 INVEST
`OPHTHALMOL. VIS SCI. 2843 (2017)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2064 Shen et al., Clearance of Intravitreal
`Voriconazole, 48 INVEST. OPHTHALMOLOGY
`& VISUAL SCI. 2240 (2007)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`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)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2067 Hirokawa et al., Tau Proteins: The Molecular
`Structure and Mode of Binding on Microtubules,
`107 J. CELL BIOL. 1449 (1988)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2068 Prangé et al., Exploring Hydrophobic Sites in
`Proteins with Xenon or Krypton, 30 PROTEINS:
`STRUCTURE, FUNCTION, AND GENETICS
`61 (1998)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`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)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2070 Demarest et al., Optimization of the Antibody CH3
`Domain by Residue Frequency Analysis of IgG
`Sequences, 335 J. MOL. BIOL. 41 (2004)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`5
`
`
`
`Case No. IPR2021-00881
`
`Ex. No.
`
`Description
`
`Objections
`
`2071 Kuhlmann et al., Lessons Learned from
`Biosimilar Epoetins and Insulins, 10 BRITISH J.
`DIABETES VASC. DISEASE 90 (2010)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`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
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2073 Zaltrap non-comparability issue: Regeneron
`Sanofi Analytical Investigation Workshop (March
`14, 2014) – CONFIDENTIAL MATERIAL -
`SUBJECT TO PROTECTIVE ORDER
`
`A, B, C, D, E, F, G,
`H, M, N, O, Q, R,
`S, U
`
`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/NCT0051928
`5?V_1
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`6
`
`
`
`Case No. IPR2021-00881
`
`Ex. No.
`
`Description
`
`Objections
`
`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/NCT0064412
`4?A=1&B=1
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`2080 Heier, VEGF Trap-Eye for Exudative AMD,
`RETINAL PHYSICIAN, Apr. 2009 (“Heier
`Retinal Physician 2009”)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2081 Curriculum Vitae of Dr. Dr. Lucian V. Del Priore,
`M.D., Ph.D.
`
`A, B, C, D, E, F, G,
`H, I, M, N, O, T
`
`2082 Curriculum Vitae of Dr. Alexander M. Klibanov,
`Ph.D.
`
`A, B, C, D, E, F, G,
`H, I, M, N, O, T
`
`2083 Curriculum Vitae of Dr. David Mark Brown,
`M.D.
`
`A, B, C, D, E, F, G,
`H, I, M, N, O, T
`
`2084 Anthony P. Adamis, Ocular Angiogenesis:
`Vascular Endothelial Growth Factor and Other
`Factors, in Retinal Pharmacotherapy 23 (Quan
`Dong Nguyen et al. eds., 2010)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`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)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`7
`
`
`
`Case No. IPR2021-00881
`
`Ex. No.
`
`Description
`
`Objections
`
`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)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`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)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2089 Daniele Cruz, PIER Data Suggest a Need for
`Tailored Injection Schedule, Ocular Surgery
`News, (Sept. 1, 2006),
`https://www.healio.com/news/ophthalmology/201
`20331/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/sep
`tember-2006/retinal-physician-symposium-
`covers-broad-range-of
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`2091 CDER Approved Labeling for BLA Application
`125156 (Lucentis®) (2006)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`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)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`8
`
`
`
`Case No. IPR2021-00881
`
`Ex. No.
`
`Description
`
`Objections
`
`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)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2095
`
`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)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2096 Clinical Study Agreement Between Vitreoretinal
`Consultants and Regeneron Pharmaceuticals, Inc.
`(July 31, 2007) – CONFIDENTIAL MATERIAL
`- SUBJECT TO PROTECTIVE ORDER
`
`A, B, C, D, E, F, G,
`H, M, N, O, Q, R,
`S, U
`
`2097 FDA, Non-Inferiority Clinical Trials to Establish
`Effectiveness: Guidance for Industry (Nov. 2016)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2098 CDER, Statistical Review for Application
`Number 125387 (Nov. 18, 2011)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2099 FDA, 22 Case Studies Where Phase 2 and Phase 3
`Trials Had Divergent Results (Jan. 2017)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2100
`
`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)
`
`2101 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.
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`9
`
`
`
`Case No. IPR2021-00881
`
`Ex. No.
`
`Description
`
`Objections
`
`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.
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2103 Ongoing Treatment for Patients with Neovascular
`AMD, Retinal Physician (Oct. 1, 2007),
`https://www.retinalphysician.com/issues/2007/oct
`ober-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/oct
`ober-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
`
`2106
`
`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/jul
`y-aug/lucentis-after-1-year
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`10
`
`
`
`Case No. IPR2021-00881
`
`Ex. No.
`
`Description
`
`Objections
`
`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
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`2108 FDA, Guidance for Industry: Expedited Programs
`for Serious Conditions—Drugs and Biologics
`(May 2014),
`https://www.fda.gov/media/86377/download
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2109 Macugen for Proliferative Diabetic Retinopathy
`Study With Extended Dosing (M-PDRS ED),
`ClinicalTrials.gov,
`https://clinicaltrials.gov/ct2/show/NCT01486771
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`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)
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`11
`
`
`
`Case No. IPR2021-00881
`
`Ex. No.
`
`Description
`
`Objections
`
`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)
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`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)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`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
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`2116 Press Release, Regeneron Announces FDA
`Approval of Eylea® (Aflibercept) Injection for the
`Treatment of Wet Age-Related Macular
`Degeneration (Nov. 18, 2011)
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`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
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`12
`
`
`
`Case No. IPR2021-00881
`
`Ex. No.
`
`Description
`
`Objections
`
`2119 Rosenfeld PJ, Brown DM, et al., Ranibizumab for
`neovascular age- related macular degeneration,
`N Engl J Med. 2006;355(14):1419-31
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`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/genent
`ech-inc-submitsbiologics-license-application-for-
`fda-review-of-lucentis-tm-in- wetage- related-
`macular-degeneration-/
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`2121 Genentech News Release, FDA Approves
`Lucentis for the Treatment of Wet Age-Related
`Macular Degeneration, (June 30, 2006)
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`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/NCT0047
`3330
`
`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
`
`13
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`
`
`Case No. IPR2021-00881
`
`Ex. No.
`
`Description
`
`Objections
`
`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
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`2128 VGFT-OD-0605 (VIEW 1 Trial) Protocol
`Signature Page- CONFIDENTIAL MATERIAL -
`SUBJECT TO PROTECTIVE ORDER
`
`A, B, C, D, E, F, G,
`H, I, M, N, O, Q, R,
`S, U
`
`2129 Transcript of Deposition of Mary Gerritsen, Ph.D.
`(January 14, 2022)
`
`Petitioner refers to
`the objections made
`during the
`deposition of Dr.
`Gerritsen, which are
`incorporated herein
`by reference.
`
`14
`
`
`
`Ex. No.
`
`Description
`
`Objections
`
`Case No. IPR2021-00881
`
`2130 Transcript of Deposition of Thomas Albini, M.D.
`(January 20, 2022)
`
`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
`
`Petitioner refers to
`the objections made
`during the
`deposition of Dr.
`Albini, which are
`incorporated herein
`by reference.
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2132 Exhibit 14 to Deposition of Thomas Albini, M.D.
`(January 20, 2022)
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`Petitioner further
`refers to the
`objections made
`during the
`deposition of Dr.
`Albini, which are
`incorporated herein
`by reference.
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`2133 Regeneron, Earnings Call Transcript, 2/13/2012
`
`2134 Regeneron, Earnings Call Transcript, 4/26/2012
`
`2135 Regeneron, Earnings Call Transcript, 7/25/2012
`
`2136 Regeneron, Eylea Marketing Material, c. 2013
`
`15
`
`
`
`Case No. IPR2021-00881
`
`Ex. No.
`
`Description
`
`Objections
`
`2137 Regeneron, Eylea Marketing Material, 11/2013
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`2138 Regeneron, “Physician ATU: Wave 2,” 2/2013 -
`CONFIDENTIAL MATERIAL - SUBJECT TO
`PROTECTIVE ORDER
`
`A, B, C, D, E, F, G,
`H, M, N, O, Q, R,
`S, T, U
`
`2139 Regeneron, “For the Treatment of Wet Age-
`Related Macular Degeneration,” c. 2012
`
`A, B, C, D, E, F, G,
`H, M, N, O, T, U
`
`2140 Regeneron, “Physician ATU: Wave 5,” 11/2013 -
`CONFIDENTIAL MATERIAL - SUBJECT TO
`PROTECTIVE ORDER
`
`A, B, C, D, E, F, G,
`H, M, N, O, Q, R,
`S, T, U
`
`2141 American Academy of Ophthalmology Website,
`Anti-VEGF Treatments,
`https://www.aao.org/eye-health/drugs/anti-vegf-
`treatments (accessed 11/8/2021)
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`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
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`2144 American Academy of Ophthalmology Website,
`Retinal Vasculitis,
`https://eyewiki.aao.org/Retinal_Vasculitis
`(accessed 1/13/2022)
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`2145 American Academy of Ophthalmology Website,
`What is Avastin, https://www.aao.org/eye-
`health/drugs/avastin (accessed 11/9/2021)
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`16
`
`
`
`Case No. IPR2021-00881
`
`Ex. No.
`
`Description
`
`Objections
`
`2146 American Academy of Ophthalmology Website,
`What is Eylea, https://www.aao.org/eye-
`health/drugs/what-is-eylea (accessed 11/9/2021)
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`2147 American Academy of Ophthalmology Website,
`What is Lucentis, https://www.aao.org/eye-
`health/drugs/lucentis (accessed 11/9/2021)
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`2148 American Society of Retina Specialists Website,
`About Us. https://www.asrs.org/about (accessed
`12/6/2021)
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`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)
`
`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)
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`17
`
`
`
`Case No. IPR2021-00881
`
`Ex. No.
`
`Description
`
`Objections
`
`2153 Amgen Website, Fusion Protein,
`https://www.amgen.com/stories/2018/08/the-
`shape-of-drugs-to-come/fusion-protein (accessed
`1/7/2022)
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`2154 American Speech-Language-Hearing Association
`Website, Calculating Medicare Fee Schedule
`Rates,
`https://www.asha.org/practice/reimbursement/me
`dicare/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
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2156 Drugs@FDA, Avastin Label, c. 2004, available
`at:
`https://www.accessdata.fda.gov/drugsatfda_docs/l
`abel/2004/125085lbl.pdf
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2157 BasePair Biotechnologies Website, What is an
`Aptamer? – Aptamers and SELEX,
`https://www.basepairbio.com/what-is-an-aptamer/
`(accessed 12/30/2021)
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`2158 Bausch and Lomb Website, Visudyne,
`https://www.bauschretinarx.com/visudyne/ecp/ab
`out/ (accessed 12/2/2021)
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`2159 Bausch and Lomb Website, Help Your Patients
`Obtain Access to Visudyne,
`https://www.bauschretinarx.com/visudyne/ecp/ord
`ering/ (accessed 1/12/2022)
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`2160 Bausch Health Companies, Form 10-K, 2020.
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`18
`
`
`
`Case No. IPR2021-00881
`
`Ex. No.
`
`Description
`
`Objections
`
`2161 Drugs@FDA, Beovu Label, 10/2019, available at:
`https://www.accessdata.fda.gov/drugsatfda_docs/l
`abel/2019/761125s000lbl.pdf
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2162 Drugs@FDA, Beovu Label, 6/2020, available at:
`https://www.accessdata.fda.gov/drugsatfda_docs/l
`abel/2020/761125s00 4lbl.pdf
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2163 Regeneron, “Physician ATU: Wave 4,” 8/6/2013 -
`CONFIDENTIAL MATERIAL - SUBJECT TO
`PROTECTIVE ORDER
`
`A, B, C, D, E, F, G,
`H, M, N, O, Q, R,
`S, U
`
`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=5
`0&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_informati
`on/vision_loss.htm
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`19
`
`
`
`Case No. IPR2021-00881
`
`Ex. No.
`
`Description
`
`Objections
`
`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)
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2169 Regeneron, “Eylea Sample Disbursement 2013 to
`2021,” c. 2021 - CONFIDENTIAL MATERIAL -
`SUBJECT TO PROTECTIVE ORDER
`
`A, B, C, D, E, F, G,
`H, I, M, N, O, Q, R,
`S, T, U
`
`2170 Regeneron, “US Eylea P&L LTD,” 12/2021 -
`CONFIDENTIAL MATERIAL - SUBJECT TO
`PROTECTIVE ORDER
`
`A, B, C, D, E, F, G,
`H, I, M, N, O, Q, R,
`S, T, U
`
`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)
`
`A, B, C, D, E, F, G,
`H, M, N, O, U
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`20
`
`
`
`Case No. IPR2021-00881
`
`Ex. No.
`
`Description
`
`Objections
`
`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=&keywordType=starts&areaId=all
`&docType=6,3,5,1,F,P&contractOption=all&hcpc
`sOption=code&hcpcsStartCode=J0178&hcpcsEn
`dCode=J0178&sortBy=title&bc=1
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2176 Regeneron, “Q4 2020 Performance Update Wet
`AMD, DME, MEfRVO & DR w/out DME,”
`1/29/2021 - CONFIDENTIAL MATERIAL -
`SUBJECT TO PROTECTIVE ORDER
`
`A, B, C, D, E, F, G,
`H, M, N, O, Q, R,
`S, T, U
`
`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
`
`A, C, D, E, F, G, H,
`M, N, O, U
`
`2178 Donohue, Julie, Ernst R. Berndt (2004), “Effect of
`Direct-to-Consumer Advertising on Medi
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