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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_________________________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_________________________
`
`SAMSUNG BIOEPIS CO., LTD.,
`Petitioner,
`
`v.
`
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner.
`_________________________
`
`Case IPR2023-00884
`
`U.S. Patent No. 11,253,572
`_________________________
`
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 11,253,572
`
`
`
`RESPONSIVE DECLARATION OF DR. EDWARD CHAUM
`
`
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`Samsung Bioepis Exhibit 1092
`Page 1
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`TABLE OF CONTENTS
`INTRODUCTION .......................................................................................... 1
`I.
`BACKGROUND AND QUALIFICATIONS ................................................ 2
`II.
`INFORMATION RELIED UPON ................................................................. 2
`III.
`IV. RESPONSE TO DR. STEWART & UPDATED SUMMARY OF
`OPINIONS ...................................................................................................... 3
`A. A POSA Would Have Considered It Obvious That Some
`Patients Would Achieve and Maintain to Week 52 the Recited
`Gains Based on Pre-November 2010 Art ............................................. 3
`B. A POSA Would Have Considered It Obvious That Some DME
`Patients Would Achieve The Recited Gains Within 24 Weeks
`Based On Pre-November 2010 Art .................................................... 12
`
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`ii
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`TABLE OF EXHIBITS
`
`1003
`1004
`
`1005
`
`Exhibit Description
`1001 U.S. Patent No. 11,253,572
`1002
`Expert Declaration of Dr. Edward Chaum in Support of Petition for Inter
`Partes Review of Patent No. 11,253,572, dated April 27, 2023 (“Chaum
`Decl.”)
`Edward Chaum Curriculum Vitae
`Institution Decision in Apotex Inc. v. Regeneron Pharmaceuticals, Inc.,
`IPR2022-01524. (“Apotex ’572 ID”)
`Press Release, “Enrollment Completed in Regeneron and Bayer
`Healthcare Phase 3 Studies of VEGF Trap-Eye in Neovascular Age-
`Related Macular Degeneration (Wet AMD) (September 14, 2009),”
`available
`at: https://newsroom.regeneron.com/news-releases/news-
`release-details/enrollment-completed-regeneron-and-bayer-healthcare-
`phase-3 (“2009 Press Release”)
`Press Release, “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),” Exhibit 99.1
`to Regeneron 8-K filed on December 20, 2010, available at:
`https://yahoo.brand.edgar-
`online.com/displayfilinginfo.aspx?FilingID=7617341-6436-
`23571&type=sect&TabIndex=2&companyid=5036&ppu=%252fdef%
`E2%80%A6 (“December 2010 Press Release”)
`Press Release, “Bayer and Regeneron Report Positive Top-Line Results
`of Two Phase 3 Studies with VEGF Trap-Eye in Wet Age-related
`Macular Degeneration,” Exhibit 99.1 to Regeneron 8-K filed on
`November 22, 2010,
`available
`at: https://yahoo.brand.edgar-
`online.com/displayfilinginfo.aspx?FilingID=7572010-8611-
`26486&type=sect&TabIndex=2&companyid=5036&ppu=%252fdef%
`E2%80%A6 (“November 2010 Press Release”)
`1008 Apotex Petition for IPR filed
`in Apotex Inc. v. Regeneron
`Pharmaceuticals, Inc., IPR2022-01524 (Paper 1) (“Apotex Petition”)
`
`1006
`
`1007
`
`-iii-
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`Page 3
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`
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`1011
`
`1012
`
`
`
`Exhibit Description
`1009 Dixon JA, Oliver SC, Olson JL, Mandava N. VEGF Trap-Eye for the
`treatment of neovascular age-related macular degeneration. Expert Opin
`Investig Drugs. 2009;18(10):1573-1580. (“Dixon”)
`1010 Major JC et al., “DA VINCI: DME and VEGF Trap-Eye: INvestigation
`of Clinical Impact: Phase 2 Study in Patients With Diabetic Macular
`Edema (DME), ARVO Annual Meeting Abstract (April 2010), Vol. 51,
`Issue
`13,
`available
`at:
`https://iovs.arvojournals.org/article.aspx?articleid=2375028
`(“2010
`ARVO Abstract”)
`Final Written Decision in Mylan Pharmaceuticals Inc. v. Regeneron
`Pharmaceuticals, Inc., IPR2021-00881 (Paper 94) (“’338 FWD”)
`Institution Decision in Mylan Pharmaceuticals Inc. v. Regeneron
`Pharmaceuticals, Inc., IPR2022-01225 (Paper 21) (“’681 ID”)
`Institution Decision in Mylan Pharmaceuticals Inc. v. Regeneron
`Pharmaceuticals, Inc., IPR2022-01226 (Paper 22) (“’601 ID”)
`1014 Certified Prosecution History of U.S. Patent No. 11,253,572 (“’572
`patent PH)
`1015 Adis R&D Profile, Aflibercept: AVE 0005, AVE 005, AVE0005, VEGF
`Trap - Regeneron, VEGF Trap (R1R2), VEGF Trap-Eye. Drugs R D.
`2008;9(4):261-269. (“Adis”)
`1016 Hecht, “Opthalmic Preparations,” Remington: The Science and Practice
`of Pharmacy, Volume II, 19th edition, Chapter 89 (1995). (“Hecht”)
`1017 WO 2006/047325 Al (“Shams”)
`1018
`Elman MJ, et al., Randomized trial evaluating ranibizumab plus prompt
`or deferred laser or triamcinolone plus prompt laser for diabetic macular
`edema. Ophthalmology. 2010 Jun;117(6):1064-1077.e35. (“Elman
`2010”)
`Elman MJ, et al., Randomized trial evaluating ranibizumab plus prompt
`or deferred laser or triamcinolone plus prompt laser for diabetic macular
`edema. Ophthalmology. 2010 Jun;117(6):1064-1077.e35, published
`April 28 2010, available at https://www.aaojournal.org/article/S0161-
`6420(10)00243-5/fulltext (“Elman AAO Website)
`
`1013
`
`1019
`
`iv
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`
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`Exhibit Description
`1020 Authenticating Affidavit and the July 13, 2010 Web Archive of the
`CATT
`Patient
`Eligibility
`Criteria,
`available
`at
`https://web.archive.org/web/20100713035617/http://www.med.upenn.e
`du/cpob/studies/documents/CATTEligibilityCriteria_000.pdf, attached
`as Exhibit B (“CATT Study”).
`1021 Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked,
`sham-controlled trial of ranibizumab for neovascular age-related
`macular degeneration: PIER Study year 1. Am J Ophthalmol.
`2008;145(2):239-248. (“PIER Study”).
`1022 Comparison of Age-related Macular Degeneration Treatments Trials:
`Lucentis-Avastin
`Trial
`(NCT00593450),
`available
`at:
`https://clinicaltrials.gov/ct2/show/NCT00593450 (“NCT-450”)
`1023 Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked,
`sham-controlled trial of ranibizumab for neovascular age-related
`macular degeneration: PIER Study year 1. Am J Ophthalmol.
`2008;145(2):239-248, published December 3, 2007, available at
`https://www.ajo.com/article/S0002-9394(07)00881-1/fulltext
`(“PIER
`AJO Website”)
`1024 History of Changes for Study: A Study of rhuFab V2 (Ranibizumab) in
`Subjects With Subfoveal Choroidal Neovascularization Secondary to
`Age-Related Macular Degeneration (AMD) (NCT00090623), available
`at:
`https://clinicaltrials.gov/ct2/history/NCT00090623?V_1=View#StudyP
`ageTop. (“NCT-623”)
`at:
`available
`Background,
`1025 ClinicalTrials.gov
`https://clinicaltrials.gov/ct2/about-site/background (“ClinicalTrials.gov
`Background”)
`1026 ClinicalTrials.gov About the Results Database, available at:
`https://clinicaltrials.gov/ct2/about-site/results
`
` (“ClinicalTrials.gov
`About the Results Database”)
`Press Release, “Regeneron Reports Positive Phase 1 Data for the VEGF
`TRAP in Age-Related Macular Degeneration,” Exhibit 99(a) to
`Regeneron
`8-K
`filed
`on May
`2,
`2006,
`available
`at:
`https://yahoo.brand.edgar-
`
`1027
`
`v
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`
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`1029
`
`Exhibit Description
`online.com/displayfilinginfo.aspx?FilingID=4380124-5423-
`15279&type=sect&TabIndex=2&companyid=5036&ppu=%252fdef%
`E2%80%A6
`(“May 2006 Press Release”)
`1028 Nguyen QD et al. A phase I study of intravitreal vascular endothelial
`growth factor trap-eye in patients with neovascular age-related macular
`degeneration. Ophthalmology. 2009 Nov;116(11):2141-8.e1. (“Nguyen
`2009”)
`Press Release, “Bayer and Regeneron Dose First Patient in Second Phase
`3 Study for VEGF Trap-Eye in Wet Age-Related Macular Degeneration”
`published
`on
`May
`8,
`2008,
`available
`at:
`https://investor.regeneron.com/node/10561/pdf
` (“May 2008 Press
`Release”).
`1030 Do DV et al., “Results of a Phase I Study of Intravitreal VEGF Trap in
`Subjects With Diabetic Macular Edema: The CLEAR-IT DME Study,”
`ARVO Annual Meeting Abstract (May 2007), Vol. 48, Issue 3, available
`at: https://iovs.arvojournals.org/article.aspx?articleid=2384099 (“2007
`ARVO Abstract”).
`1031 Do DV et al., The DA VINCI Study: phase 2 primary results of VEGF
`Trap-Eye in patients with diabetic macular edema. Ophthalmology. 2011
`Sep;118(9):1819-26 (published online on May 5, 2011). (“Do 2011”)
`1032 Randolph and Jones, “Surfactant-Protein Interactions,” Rational Design
`of Stable Protein Formulations, edited by Carpenter and Manning, vol.
`13, 2002 (“Randolph”)
`Fraser et al., Journal of Clinical Endocrinology and Metabolism,
`February 2005, 90(2):1114-1122 (“Fraser”)
`Lucentis ® Original Approved Labeling (2006), available at:
`https://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/125156s000
`0_Lucentis_Prntlbl.pdf
`1035 Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker
`with potent antitumor effects. Proc Natl Acad Sci U S A.
`2002;99(17):11393-11398. (“Holash”)
`
`1033
`
`1034
`
`vi
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`
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`Exhibit Description
`1036 Rudge JS, Thurston G, Davis S, et al. VEGF trap as a novel
`antiangiogenic treatment currently in clinical trials for cancer and eye
`diseases, and VelociGene- based discovery of the next generation of
`angiogenesis targets. Cold Spring Harb Symp Quant Biol. 2005;70:411-
`418 (“Rudge 2005”)
`1037 Gomez-Manzano C, Holash J, Fueyo J, et al. VEGF Trap induces
`antiglioma effect at different stages of disease. Neuro Oncol.
`2008;10(6):940-945. (“Gomez-Manzano”)
`1038 Heier JS, et al., Intravitreal aflibercept (VEGF trap-eye) in wet age-
`related macular degeneration. Ophthalmology. 2012;119(12):2537-
`2548. (“Heier 2012”)
`1039 Heier JS, et al., CLEAR-IT 2 Investigators. 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. Ophthalmology. 2011
`Jun;118(6):1098-106. (“Heier 2011”)
`Pai A, El Shafei MM, Mohammed OA, Al Hashimi M., Current concepts
`in intravitreal drug therapy for diabetic retinopathy. Saudi J Ophthalmol.
`2010 Oct;24(4):143-9. (“Pai 2010”).
`1041 U.S. Patent App. Pub. US 2007/0190058A1 (“Shams US App. Pub.”)
`1042 U.S. Patent No. 9,254,338 (“’338 patent”)
`1043 WO 2012/097019A1 (“Yancopoulos PCT Application”)
`1044 U.S. Dep’t Health & Human Servs., Nat’l Inst. Health, Nat’l Eye Inst.,
`“Diabetic Retinopathy: What You Should Know (Sept. 2015),” available
`at:
`https://www.nei.nih.gov/sites/default/files/health-
`pdfs/Diabetic_Retinopathy_What_You_Should_Know.pdf
`DR”).
`1045 U.S. Dep’t Health & Human Servs., Nat’l Inst. Health, Nat’l Eye Inst.,
`“Age-Related Macular Degeneration: What You Should Know (Sept.
`2015),”
`available
`at:
`https://www.nei.nih.gov/sites/default/files/healthpdfs/WYSK_AMD_E
`nglish_Sept2015_PRINT.pdf (“NIH AMD”)
`
`(“NIH
`
`1040
`
`vii
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`
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`1048
`
`Exhibit Description
`1046 Halpern MT, Schmier JK, Covert D, Venkataraman K. Resource
`utilization and costs of age-related macular degeneration. Health Care
`Financ Rev. 2006;27(3):37-47. (“Halpern 2006”).
`1047 Rudge JS, Holash J, Hylton D, et al. VEGF Trap complex formation
`measures production rates of VEGF, providing a biomarker for
`predicting efficacious angiogenic blockade. Proc Natl Acad Sci U S A.
`2007;104(47):18363-18370. (“Rudge 2007”)
`Li E, Donati S, Lindsley KB, Krzystolik MG, Virgili G. Treatment
`regimens for administration of anti-vascular endothelial growth factor
`agents for neovascular age-related macular degeneration. Cochrane
`Database Syst Rev. 2020;5(5):CD012208. (“Li 2020”)
`1049 Brown DM, Michels M, Kaiser PK, et al. Ranibizumab versus
`verteporfin photodynamic therapy for neovascular age-related macular
`degeneration: Two-year results of the ANCHOR study. Ophthalmology.
`2009;116(1):57-65.e5. (“Brown 2009”)
`1050 Martin DF, Maguire MG, Fine SL, Ying GS, Jaffe GJ, Grunwald JE, et
`al, Comparison of Age-Related Macular Degeneration Treatments Trial
`(CATT) Research Group. Ranibizumab and bevacizumab for treatment
`of neovascular age-related macular degeneration: two-year results.
`Ophthalmology 2012; 119(7):1388-98 (“Martin”)
`1051 Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ,
`Wordsworth S, et al, Inhibition of VEGF in Age-related choroidal
`Neovascularization (IVAN) Study Investigators. Ranibizumab versus
`bevacizumab to treat neovascular age-related macular degeneration:
`one-year findings from the IVAN randomized trial. Ophthalmology
`2012; 119(7):1399-411 (“Chakravarthy 2012”)
`1052 Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY,
`et al. Ranibizumab for neovascular age-related macular degeneration.
`New England Journal of Medicine 2006; 355(14):1419-31 (“Rosenfeld
`2006”)
`1053 Heimann, H. (2007). Chapter 5 Intravitreal Injections: Techniques and
`Sequelae. In: Holz, F.G., Spaide, R.F. (eds) Medical Retina. Essentials
`in Ophthalmology. Springer, Berlin, Heidelberg. (“Heimann 2007”)
`
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`
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`1056
`
`Exhibit Description
`1054
`Jager RD, Aiello LP, Patel SC, Cunningham ET Jr. Risks of intravitreous
`injection: a comprehensive review. Retina. 2004;24(5):676-698. (“Jager
`2004”)
`1055 Certified Prosecution History of U.S. Patent No. 10,130,681 B2 (“’681
`patent PH”)
`Pilot Study of Intravitreal Injection of Ranibizumab for Macular
`Telangiectasia With Neovascularization (NCT00685854) (May 24,
`2008),
`available
`at:
`https://clinicaltrials.gov/ct2/history/NCT00685854?V_1=View#StudyP
`ageTop (“MACTEL Study”)
`1057 Authenticating Affidavit and the November 7, 2008 Web Archive of
`Ranibizumab Injections to Treat Macular Telangiectasia Without New
`Blood Vessel Growth (NCT00685854), available at
`https://web.archive.org/web/20081107014243/https://clinicaltrials.gov/
`ct2/show/NCT00685854, attached as Exhibit A (“MACTEL Study
`Wayback Machine”)
`available
`Machine,
`Wayback
`1058 Using
`the
`https://help.archive.org/help/using-the-wayback-machine/
`Eylea Label 2011 available at:
`https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125387lbl.
`pdf
`1060 Glenn J. Jaffe, Paul Ashton, P. Andrew Pearson, Intraocular Drug
`Delivery (2006) (“Jaffe”).
`Steps for a Safe Intravitreal Injection Technique (2009), available at:
`https://www.retinalphysician.com/issues/2009/july-aug/steps-for-a-
`safe-intravitreal-injection-technique
`1062 Mylan’s Emergency Motion to Modify Scheduling Order and For
`Emergency Status Conference filed in Regeneron Pharmaceuticals, Inc.
`v. Mylan Pharmaceuticals Inc., Case No. 1:22-cv-00061-TSK, Northern
`District of West Virginia. (Dkt. 415) (“Mylan April 10 Motion”)
`1063 April 19, 2023 Claim Construction Order entered in Regeneron
`Pharmaceuticals, Inc. v. Mylan Pharmaceuticals Inc., Case No. 1:22-cv-
`
`at:
`
`1059
`
`1061
`
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`
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`Exhibit Description
`00061-TSK, Northern District of West Virginia. (Dkt. 427) (“Mylan
`Litigation CC Order”)
`1064 U.S. Patent No. 7,531,173 (“’173 patent”)
`1065 U.S. Patent App. No 13/940.370 (July 12, 2013)
`1066 U.S. Patent App. No 13/940.370 (July 12, 2013)
`1067 Declaration of Zachariah Summers in Support of Motion for Admission
`Pro Hac Vice
`1068 Declaration of Elliot Choi in Support of Motion for Admission Pro Hac
`Vice
`Email Correspondence Between Petitioner Samsung Bioepis and Third
`Party Mylan Pharmaceuticals, Inc. Regarding Discovery
`Email Correspondence Between Petitioner Samsung Bioepis and Patent
`Owner Regeneron Regarding Discovery
`Transcript of Bench Trial (June 12, 2023) in Regeneron Pharms., Inc. v.
`Mylan Pharms. Inc., No. 22-cv-00061-TSK (N.D.W. Va. January 31,
`2024) (ECF No. 558)
`Transcript of Bench Trial (June 20, 2023) in Regeneron Pharms., Inc. v.
`Mylan Pharms. Inc., No. 22-cv-00061-TSK (N.D.W. Va. January 31,
`2024) (ECF No. 564)
`Transcript of Bench Trial (June 21, 2023) in Regeneron Pharms., Inc. v.
`Mylan Pharms. Inc., No. 22-cv-00061-TSK (N.D.W. Va. January 31,
`2024) (ECF No. 566)
`Partial Transcript of Yancopoulos Deposition in Regeneron Pharms.,
`Inc. v. Mylan Pharms. Inc., No. 22-cv-00061-TSK (N.D.W. Va. January
`31, 2024) (ECF No. 624) (REDACTED)
`Transcript of Karen Chu Deposition in Regeneron Pharms., Inc. v.
`Mylan Pharms. Inc., No. 22-cv-00061-TSK (N.D.W. Va. January 31,
`2024) (ECF No. 432-12)
`1076 Deposition Transcript of Michael W. Stewart, M.D. (May 30, 2024) in
`IPR2023-00884
`
`1075
`
`x
`
`1069
`
`1070
`
`1071
`
`1072
`
`1073
`
`1074
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`
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`Exhibit Description
`1077
`Stewart MW, Rosenfeld PJ. Predicted biological activity of intravitreal
`VEGF Trap. Br J Ophthalmol. 2008 May;92(5):667-8.
`1078 Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, Sy
`JP, Schneider S; ANCHOR Study Group. Ranibizumab versus
`verteporfin for neovascular age-related macular degeneration. N Engl J
`Med. 2006 Oct 5;355(14):1432-44. (“ANCHOR Study”)
`1079 Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY,
`et al. Ranibizumab for neovascular age-related macular degeneration.
`New England Journal of Medicine 2006; 355(14):1419-31 (“MARINA
`Study”)
`1087 Nguyen QD, Tatlipinar S, Shah SM, Haller JA, Quinlan E, Sung J,
`Zimmer-Galler I, Do DV, Campochiaro PA. Vascular endothelial
`growth factor is a critical stimulus for diabetic macular edema. Am J
`Ophthalmol. 2006 Dec;142(6):961-9.
`
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`
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`I.
`
`INTRODUCTION
`
`I have been retained by the law firm Quinn Emanuel Urquhart &
`
`Sullivan on behalf of Samsung Bioepis Co., Ltd., (hereinafter, “Petitioner”) to
`
`provide expert opinions concerning antagonists of Vascular Endothelial Growth
`
`Factor (“VEGF”) used as intravitreal injection for the treatment of angiogenic
`
`disorders such as age related macular degeneration, diabetic retinopathy, diabetic
`
`macular edema, central retinal vein occlusion (CRVO), branch retinal vein occlusion,
`
`and corneal neovascularization.
`
`
`
`In my prior declaration in this matter, I was asked to provide my
`
`opinions related to U.S. Patent No. 11,253,572 (“the ’572 patent”) (Ex. 1001) and
`
`the scientific and technical knowledge regarding the subject matter of the ’572 patent
`
`before January 2011.
`
`
`
`I understand from counsel that Regeneron Pharmaceuticals, Inc.
`
`(“Patent Owner” or “Regeneron”) alleges that references with publication dates after
`
`mid-November should not be considered prior art. In particular, I understand that
`
`Regeneron alleges that the 2010 ARVO Abstract (Ex.1010), the December 2010 PR
`
`(Ex.1006), and the November 2010 PR (Ex.1007) are not prior art.
`
`
`
`I understand Dr. Stewart provided a report assuming this is true, and I
`
`have also been asked to assume for the purposes of my report that this is true, and to
`
`1
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`provide an updated summary of my opinions in response to his report.
`
`
`
`I understand that if the 2010 ARVO and the December 2010 and
`
`November 2010 PRs are not prior art, they cannot properly be considered in the
`
`obviousness analysis or form the basis of an anticipation challenge. As set out further
`
`below, however, I confirm that my ultimate opinions regarding the obviousness of
`
`the claims of the ’572 patent do not change even if references with publication dates
`
`after mid-November 2010 are not considered.
`
`II. BACKGROUND AND QUALIFICATIONS
`
`I set forth my background and qualifications in my prior declaration,
`
`which I incorporate into this section.
`
`III.
`
`INFORMATION RELIED UPON
`
`The opinions I provide in this proceeding are based on my general
`
`knowledge gained as a result of my education and experience as an ophthalmologist.
`
`In my prior declaration, I set forth the initial set of materials I considered in forming
`
`my opinions, which I incorporate into this section.
`
`
`
`I have further reviewed and considered, among other things, additional
`
`records developed throughout this proceeding, including certain materials submitted
`
`by Patent Owner in support of its position and associated exhibits and declarations
`
`thereto.
`
`2
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`
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`The full list of information, in addition to my professional, academic
`
`and clinical experience and the materials submitted by Patent Owner, that I have
`
`relied upon in forming my opinions for this report is set forth throughout the
`
`declaration and in the Table of Exhibits.
`
` Where my conclusions are based on certain assumptions that I have
`
`adopted, I have stated such assumptions in this declaration.
`
`IV. RESPONSE TO DR. STEWART & UPDATED SUMMARY OF
`OPINIONS
`A. A POSA Would Have Considered It Obvious That Some Patients
`Would Achieve and Maintain to Week 52 the Recited Gains Based
`on Pre-November 2010 Art
`I understand that Dr. Stewart does not contest that a prior art dosing
`
`
`
`regimen for treating AMD patients, consisting of three monthly loading doses of 2.0
`
`mg aflibercept, followed by 8-week maintenance dosing was in the prior art well
`
`before 2010, as reflected in Dixon. I confirm that based on the pre-November 2010
`
`art—specifically Dixon and the 2006 PR—a POSA would have reasonably
`
`concluded that some patients treated with that regimen would achieve and maintain
`
`the gains recited in the patent claims—i.e. 8-9 letter gains—including to week 52.
`
`
`
`I understand that Dr. Stewart contends that the data available as of 2010
`
`was not sufficient to predict the results of the VIEW clinical trials that used the
`
`relevant dosing regimen. Ex. 2065, ¶¶75-95. Whether the data could predict the
`
`result of a clinical trial, however, does not resolve for me the question of whether a
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`POSA would find it obvious that “a patient” (as recited in the ’572 patent claims)
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`would achieve and maintain the relevant gains.
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` Contrary to Dr. Stewart’s opinion, given the volume and type of data
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`regarding aflibercept available to a POSA as of 2010—as reflected in Dixon’s
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`excellent summary and the 2006 PR—a POSA could make reasonable conclusions
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`about whether some patients treated with the relevant VIEW dosing regimen would
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`achieve and maintain the sorts of gains that had already become standard with anti-
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`VEGF agents without a full clinical trial.
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`In particular, as of November 2010, aflibercept had been extensively
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`studied. Regeneron had completed Phase I and II aflibercept trials, the details of
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`which were summarized by Dixon and further reported in detail in the art at the time.
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`Ex.1009; Ex.1027; Ex.2047.
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` First, as Dixon reports, Regeneron had completed by 2010 a Phase I
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`AMD trial, the results of which were reported in the 2006 PR. In that trial, a single
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`2 mg or 4 mg dose in AMD patients produced a “mean improvement in BCVA []
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`13.5 letters, with three of six patients gaining 15 or more letters” at six weeks.
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`Ex.1027, 2; Ex.1009, 1575.
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`I understand that Dr. Stewart criticized this data for failing to separate
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`out the results from the 2 mg and 4 mg groups. Ex.2065, ¶84. However, I understand
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`that Regeneron itself reported the two dosing groups together, which would have
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`indicated to a POSA that there was not a significant difference in the gains between
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`the groups. Ex.1027, 2; Ex.1028. In fact, consistent with this understanding, POSAs
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`understood the CLEAR-IT-2 data discussed below to show a negligible difference
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`in efficacy between the 2 mg and 4 mg groups.
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` Second, Dixon also describes the Phase II CLEAR-IT-2 results, which
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`confirmed that the initial gains from 2 mg aflibercept could be sustained to at least
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`52 weeks in AMD patients with far less than monthly loading dosing.
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`I understand that Dr. Stewart states that a POSA would not have
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`expected that the extended dosing regimen would succeed based on Dixon because
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`there was “limited information about the CLEAR-IT-2 Phase II clinical trial.”
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`Ex.2065, ¶87. However, a POSA would have been aware, if they were curious about
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`the strength of the numbers reported in Dixon, that more detail was available in the
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`art. For instance, Dixon references a 2008 presentation given at Retina Society
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`Annual Scientific Meeting in describing the CLEAR-IT 2 trial results. Ex.1009,
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`1576, 1579 (Reference 45). A POSA would have been aware of the details of the
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`CLEAR-IT 2 trial results.
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`In fact, although it appears Dr. Stewart did not consider it, I understand
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`Regeneron submitted that presentation as Ex. 2047 with its Patent Owner
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`Preliminary Response, and described it as “VEGF Trap-Eye in Wet AMD - CLEAR-
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`IT 2: Summary of One-Year Key Results, Presented at 2008 Retina Society Meeting,
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`Scottsdale, Arizona (Sep. 28, 2008).”
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` Ex. 2047 provides the data that Dr. Stewart calls out as missing,
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`including results within 24 weeks, how many subjects were in the 2.0 mg dose group
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`discussed in Dixon, and significant information regarding the timing of the doses
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`given.
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` Specifically, as reported in Ex. 2047 and Dixon, the Phase II CLEAR-
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`IT-2 investigated several aflibercept dosing regimens, with fixed loading doses (0.5,
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`2, or 4 mg) in the first 12 weeks on a quarterly or monthly regimen, followed by an
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`assessment based PRN period until the 1-year mark. A summary of the investigated
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`dosing arms is provided below:
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`Ex.2047, 6 (2q4 corresponds to a dosing arm with monthly loading doses through
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`12 weeks + PRN using 2 mg aflibercept; 2q12 corresponds a dosing arm with
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`quarterly loading doses through 12 weeks + PRN using 2 mg aflibercept).
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` As reported, in the monthly loading dosing arm (2q4), the patients
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`received four 2 mg monthly loading doses, but on average only ~5.6 doses over 52
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`weeks, with some patients requiring zero injections after the first four doses.
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`Ex.1009, 1576; Ex.2047, 12-13. Further, the average time to first re-injection was
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`over 85 days (approximately three months) for all cohorts. Ex.2047, 12-13. The data
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`also shows that retinal thickness and visual acuity substantially improved with three
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`monthly loading doses of 2 mg aflibercept. See, id., 17-18. And in the quarterly
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`loading dosing arm (2q12), patients received even fewer doses over 52 weeks (~4.5
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`doses), yet 29% of them still achieved gains of 15 or more letters, confirming the
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`durability of aflibercept’s efficacy over time. Id., 19. A summary of the visual acuity
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`results of the CLEAR-IT-2 trial at week 52 is provided below.
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`Ex.2047, 19.
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` Overall, based on these results, a POSA would have understood that a
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`patient receiving three loading doses and five 8-week doses (8 in total) as recited
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`would be more likely to sustain the gains because they would receive at least two
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`more doses than in CLEAR-IT-2 whether measured as a mean or median. Ex.2047,
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`6, 12, 18-19. This is further reinforced by the fact that the CLEAR-IT-2 dosing arms
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`achieved these results with fewer loading doses and fewer doses during the
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`maintenance period than the recited dosing regimen. Id.
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` This is consistent with Dr. Stewart’s acknowledgement that the
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`CLEAR-IT-2 data demonstrated to POSAs that aflibercept maintained its effect for
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`at least 8-week intervals, and confirmed the feasibility of an extended dosing for
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`aflibercept. Ex.1076, 78:23-81:16. Specifically, the results reported that “[a]t 12
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`weeks VEGF Trap-Eye [aflibercept]…[m]aintained effect on visual acuity with a
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`single dose to 8 weeks” equivalent to the clinical effect two monthly doses (at time
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`zero and four weeks) produced at 8 weeks. Id.; Ex.2047, 17. Consistent with this
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`understanding, Dr. Stewart published an article in 2008 suggesting that aflibercept
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`would maintain biological efficacy for 10-12 weeks and would be capable of less
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`frequent dosing. Ex.1077; Ex.1076, 58:1-63:4, 149:5-151:16.
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` Additionally, in my opinion, the CLEAR-IT 2 data further confirmed
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`that there was no particular benefit to using 4 mg over 2 mg dose of aflibercept, at
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`least for some patients. As shown above, the quarterly dosing arm with 4 mg of
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`aflibercept achieved the lowest percentage of patients with 15+ letter gains. Ex.2047,
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`19. In contrast, the 2 mg quarterly dosing arm and the monthly dosing arms had the
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`highest percentage of patients achieving these gains. Id. In fact, as shown below,
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`the 2 mg dosing arms generally had higher gains than the 4 mg dosing arm through
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`52 weeks.
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`Ex. 2047, 17.
` Based on those results, a POSA would have found it obvious and
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`expected that the 2 mg dose of aflibercept would have similar or better outcomes
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`than the 4 mg dose at least for some patients.
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` The reported CLEAR-IT-2 data
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`therefore reflects a POSA’s
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`understanding that it was obvious for some patients to achieve and maintain gains
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`through 52 weeks on an extended dosing schedule as described in the prior art.
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`Although I do not think the details of the CLEAR-IT-2 data in Ex. 2047 would have
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`been necessary to reach that conclusion, it was available to confirm the strength of
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`the numbers reported in Dixon.
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` Based on the Phase I and Phase II trial data, POSAs also understood
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`that Regeneron was moving forward with the VIEW 1 regimen in a Phase III trial
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`with the secondary endpoint of the VIEW 1/2 study for AMD was the “proportion
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`of patients who gained at least 15 letters of vision at week 52” as measured by
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`ETDRS. Ex.1009, 1573, 1576-1578; Ex.1005, 1.
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` Though a POSA would not necessarily conclude the Phase III trial
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`would hit this endpoint (though to my knowledge there was no significant
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`information suggesting it would not), based on the clinical results discussed above,
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`a POSA would have understood at least some patients would hit the endpoint.
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`I understand that Dr. Stewart focuses on the fact that POSAs would
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`have been aware of other drugs that failed Phase III trials. Ex. 2065, ¶137. I agree
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`this is true, but simply because a prior clinical trial failed to meet prespecified
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`statistical endpoints for the treated cohort as a whole, that does not mean some
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`patients did not receive a substantial benefit. The more salient fact informing my
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`opinion, when asking whether some patients would get a gain, is that in all of the
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`major ranibizumab trials (ANCHOR, MARINA, and PIER), at least 10% of patients
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`sustained gains of 15+ letters (the secondary endpoint). Ex.1078, 1432, 1437 (Fig.
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`1.B); Ex.1079, 1425 (Fig. 1.D) ; Ex.1021, 243 (Fig. 2). In the PIER study involving
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`three loading doses followed by every 12-week dosing, for instance, which Dr.
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`Stewart characterizes as a “failed” study, 13% of patients achieved and sustained
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`15+ letter gains through week 52. Ex.1021, 243 (Fig. 2). In view of a POSA’s
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`understanding that aflibercept was “the most promising anti-VEGF investigational
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`drug” that “may have longer duration of effect in the eye” than other anti-VEGF
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`drugs at the time, a POSA would have expected that aflibercept would produce a
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`comparable or better outcomes than those shown in these prior clinical trials, at least
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`for some patients.
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`
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`I understand that Dr. Stewart also suggests that a POSA would not have
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`believed that results from a protocol of four loading doses or two loading doses
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`would have predicted anything about the results of a protocol with three loading
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`doses. In my opinion, this ignores that the loading doses in CLEAR-IT-2 bracketed
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`the number of Dixon’s loading doses, as shown below:
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` Specifically, the 2q4 dosing arm in the CLEAR-IT-2 trial required four
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`loading doses whereas 2q12 required two loading doses by the 12 week mark. Both
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`of these dosing arms achieved 15+ letter gains in 29% of patients by 52 weeks. Ex.
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`2047, 19. Therefore, it would have been obvious to a POSA that the differences in
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`the loading doses (three versus two or four) would not prevent at least some patients
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`from achieving 15+ letter gains by week 52, given the results reported for the two
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`groups bracketing the 3 loading doses achieved substantial visual acuity gains over
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`15 letters.
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`In my opinion, this expectation was further confirmed by Regeneron’s
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`de