`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`_________________________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_________________________
`
`SAMSUNG BIOEPIS CO., LTD., CELLTRION, INC.,
`and BIOCON BIOLOGICS INC.,
`Petitioners,
`
`v.
`
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner.
`_________________________
`
`Case IPR2023-008841
`
`U.S. Patent No. 11,253,572
`_________________________
`
`
`PETITIONER’S REPLY TO
`PATENT OWNER’S RESPONSE
`
`
`1 IPR2024-00260 and IPR2024-00298 are joined with IPR2023-00884.
`
`
`
`

`

`
`
`I.
`
`II.
`
`III.
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`Page
`
`INTRODUCTION ...............................................................................................................1
`
`THE CHALLENGED CLAIMS ARE OBVIOUS ..............................................................4
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Grounds IV, VI, VIII: Dixon/2006 PR and Generic/AMD Results Claims ............5
`
`Grounds V, VII, and IX: 2009 PR/DME Claims ...................................................14
`
`PO Is Not Entitled To An Earlier Priority: Grounds II-III.....................................18
`
`The Results Limitations Lack Patentable Weight: Grounds X and XI ..................23
`
`No Secondary Considerations ................................................................................25
`
`CONCLUSION ..................................................................................................................26
`
`
`
`
`
`i
`
`

`

`
`
`TABLE OF AUTHORITIES
`
`Cases
`
`Page
`
`Apator Miitors ApS v. Kamstrup A/S,
`887 F.3d 1293 (Fed. Cir. 2018) ..........................................................................22
`
`Dynamic Drinkware, LLC v. Nat’l Graphics, Inc.,
` 324 F.3d 1308 (Fed. Cir. 2003) ........................................................................... 19
`
`Fox Factory, Inc. v. SRAM, LLC,
`944 F.3d 1366 (Fed. Cir. 2019) ............................................................................25
`
`Genentech, Inc. v. Chiron Corp.,
`220 F.3d 1345 (Fed. Cir. 2000) ..........................................................................19
`
`Janssen Pharmaceuticals, Inc. v. Teva Pharmaceuticals, USA, Inc.,
` 324 F.3d 1308 (Fed. Cir. 2003) .................................................................... 3, 4, 7
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ..........................................................................................2, 7
`
`Los Angeles Biomedical Research Institute v. Eli Lilly & Co.,
`849 F.3d 1049 (Fed. Cir. 2017) ..........................................................................24
`
`Sensio, Inc. v. Select Brands, Inc.,
`IPR2013-00580, Paper 31 (PTAB Feb. 9, 2015) ................................................19
`
`Sonos, Inc. v. Implicit, LLC,
`No. IPR2018-00767, 2019 WL 4419356, (P.T.A.B. Sept. 16, 2019) ................19
`
`
`
`
`
`
`
`
`
`
`
`
`
`ii
`
`

`

`
`
`
`
`TABLE OF EXHIBITS
`
`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.”)
`
`1003
`
`Edward Chaum Curriculum Vitae
`
`1004
`
`1005
`
`1006
`
`1007
`
`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”)
`
`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”)
`
`iii
`
`

`

`
`
`
`
`Exhibit Description
`
`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”)
`
`1011
`
`1012
`
`1013
`
`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
`
`1019
`
`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)
`
`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
`
`iv
`
`

`

`
`
`
`
`Exhibit Description
`
`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”)
`
`1025 ClinicalTrials.gov Background, available at:
`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”)
`
`1027
`
`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-
`online.com/displayfilinginfo.aspx?FilingID=4380124-5423-
`15279&type=sect&TabIndex=2&companyid=5036&ppu=%252fdef%
`E2%80%A6 (“May 2006 Press Release”)
`
`v
`
`

`

`
`
`
`
`Exhibit Description
`
`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”)
`
`1029
`
`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”)
`
`1033
`
`1034
`
`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”)
`
`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”)
`
`vi
`
`

`

`
`
`
`
`Exhibit Description
`
`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”)
`
`1040
`
`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 (“NIH
`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”)
`
`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”)
`
`vii
`
`

`

`
`
`
`
`Exhibit Description
`
`1048
`
`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”)
`
`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”)
`
`1056
`
`Pilot Study of Intravitreal Injection of Ranibizumab for Macular
`Telangiectasia With Neovascularization (NCT00685854) (May 24,
`2008), available at:
`
`viii
`
`

`

`
`
`
`
`Exhibit Description
`
`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”)
`
`1058 Using the Wayback Machine, available at:
`https://help.archive.org/help/using-the-wayback-machine/
`
`1059
`
`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”).
`
`1061
`
`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-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
`
`ix
`
`

`

`
`
`
`
`Exhibit Description
`
`1068 Declaration of Elliot Choi in Support of Motion for Admission Pro
`Hac Vice
`
`1069
`
`1070
`
`1071
`
`1072
`
`1073
`
`1074
`
`1075
`
`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
`
`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”)
`
`x
`
`

`

`
`
`
`
`Exhibit Description
`
`1080 Deposition Transcript of George D. Yancopoulos, M.D., Ph.D. (April
`12, 2024) in IPR2023-00884
`
`1081
`
`Samsung Bioepis Petition for IPR filed in Samsung Bioepis Co., Ltd. v.
`Regeneron Pharmaceuticals, Inc., PTAB-IPR2023-00739 (Paper 1)
`(“Samsung 601 Petition”)
`
`1082 Deposition Transcript of Karen Chu (April 11, 2024)
`
`1083 RGN-EYLEA-MYLAN-00526220 - RGN-EYLEA-MYLAN-
`00526223
`
`1084 Deposition Transcript of Richard Manning, Ph.D. (March 27, 2024) in
`in Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc.,
`PTAB-IPR2023-00739 and -00884
`
`1085 Deposition Transcript of Michael W. Stewart, M.D. (March 29, 2024)
`in Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc.,
`PTAB-IPR2023-00739
`
`1086 Memorandum Opinion and Order Following Bench Trial,
`Regeneron Pharms., Inc. v. Mylan Pharms. Inc., No. 22-cv-00061-TSK
`(N.D.W. Va. January 31, 2024) (ECF No. 692) (REDACTED)
`
`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
`
`1088
`
`Institution Decision issued in Samsung Bioepis Co., Ltd. v. Regeneron
`Pharmaceuticals, Inc., PTAB-IPR2023-00739 (Paper 9) (“’601 IPR
`ID”)
`
`1089 Declaration of Michael W. Stewart, M.D. submitted as Exhibit 2027 in
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc., PTAB-
`IPR2023-00739 (“Stewart ’601 IPR Decl.”)
`
`1090
`
`Patent Owner Response submitted as Exhibit 2027 in Samsung Bioepis
`Co., Ltd. v. Regeneron Pharmaceuticals, Inc., PTAB-IPR2023-00739
`(“’601 IPR POR”)
`
`1091 RGN-EYLEA-MYLAN-00631182
`
`1092 Responsive Expert Declaration of Dr. Edward Chaum, dated June 10,
`2024 (“Chaum Resp. Decl.”)
`
`xi
`
`

`

`
`
`I.
`
`INTRODUCTION
`
`Samsung Bioepis Co., Ltd. (“Petitioner”) seeks cancellation of claims 1-30
`
`(the “Challenged Claims”) of U.S. Patent No. 11,253,572 (“’572 patent”) (Ex.1001),
`
`assigned to Patent Owner (“PO”).
`
`One subset of the Challenged Claims—claims 1-14 and 26-30—recite a
`
`dosing regimen for angiogenic eye disorders, along with general or specific visual
`
`acuity gains. Grounds IV, VI, VIII are based on Dixon as a primary reference and
`
`are directed to those claims. They are addressed in Section II.A below.
`
`A second subset of the Challenged Claims—claims 15-25—are directed to a
`
`dosing regimen for DME specifically. Some of these claims recite visual acuity
`
`results or a specified number of doses. Grounds I, V, VII, and IX are all based on
`
`the 2009 Press Release (“PR”) as a primary reference, and address claims 15-25.
`
`They are addressed in Section II.B below.2
`
`
`2 Consistent with the Board’s instruction to simplify its presentation,
`
`Petitioner notes the Board need not consider the references that PO contends are not
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`prior art (i.e., ARVO 2010 and the November/December 2010 PRs) in order to find
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`all Challenged Claims obvious, as set out in connection with Grounds I and IV-IX
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`below. Thus Petitioner has omitted discussion of them from those Grounds. Should
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`Case IPR2023-00884 – Petitioner’s Reply
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`With the exception of a single claim (claim 25, directed to five loading doses),
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`there is no dispute that the prior art discloses the dosing regimens recited in both
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`claim subsets—the core of the alleged inventions—or that there was motivation to
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`adopt them to treat AMD and DME.3 Furthermore, as the prior art shows, anti-VEGF
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`agents, and aflibercept in particular, had already produced visual acuity gains in
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`patients far superior to the modest gains recited in the claims. Indeed, while the
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`Challenged Claims recite a maximum gain of 9 letters for a patient at 52 weeks,
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`aflibercept had already been shown to produce gains of 15+ letters through 52 weeks.
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`These 15+ letter gains were achieved with treatment that included substantially
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`fewer doses through 52 weeks—both loading and maintenance—than a patient
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`would receive in the prior art regimens on which Petitioner relies.
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`The premise of PO’s response is that, allegedly, “none of those references
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`reliably indicate the outcome of the planned Phase III trials.” POR, 39. But that is
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`not the relevant question. “What matters is the objective reach of the claim.” KSR
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`Int’l Co. v. Teleflex Inc., 550 U.S. 398, 420 (2007). Here, the objective reach of the
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`claims do not require an entire patient population to achieve the recited gain on
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`the Board reject PO’s attempt to antedate, those references could be considered as
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`further confirming the Challenged Claims’ obviousness.
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`3 PO does not contest Ground I (claims 15 and 24). POR, fn. 5.
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`2
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`Case IPR2023-00884 – Petitioner’s Reply
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`average. They are directed to methods for treating “a patient.” “Nothing in the claims
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`requires that the regimen be used for—let alone be ideal for—the patient population
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`generally or a certain percentage of
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`the patient population.” Janssen
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`Pharmaceuticals, Inc. v. Teva Pharmaceuticals, USA, Inc., 97 F.4th 915, 926 (Fed.
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`Cir. 2024). Thus, “[g]iven the scope of the claims here, it [is] important… to
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`recognize the distinction and focus… on single patient administration.” Id.
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`Given the low hurdle set by the recited gains and the extraordinary and
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`sustained effect on angiogenic diseases that anti-VEGF agents, including aflibercept,
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`were already having on individual patients, a POSA would have reasonably
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`concluded that at least some patients would achieve the recited gains. That is
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`sufficient to resolve Grounds I and IV-IX, covering all Challenged Claims.
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`Because the Board should find the claims invalid as obvious, it need not reach
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`the remaining anticipation grounds (Grounds II-III), set out in Section II.C. These
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`grounds turn solely on Petitioner’s attempt to antedate. But should the Board reach
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`them, it should find PO failed to make the fundamental showing necessary to
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`antedate the art—that Dr. Yancopoulos was the first person to conceive of the dosing
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`regimen used in these trials. Nor did PO show that the work done by Bayer and PO
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`and reported in the prior art was on Dr. Yancopoulos’s “behalf,” as PO alleges.
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`Accordingly, the claims are invalid on these additional grounds as well.
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`3
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`Case IPR2023-00884 – Petitioner’s Reply
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`Finally, as set out in Section II.D, Petitioner requests that the Board reconsider
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`its decision to give patentable weight to the claimed efficacy limitations, and thus
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`find unpatentability under Grounds X and XI.
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`II. THE CHALLENGED CLAIMS ARE OBVIOUS
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`In response to the Petition, rather than taking on the disclosures of the prior
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`art, PO sets out a strawman test—whether individual data points in the references,
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`taken alone, were predictive of the ultimate Phase III trial results. PO’s response thus
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`runs “afoul of KSR’s basic mandate in a number of ways” by “failing to consider
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`the interrelated teachings of multiple references, the background knowledge
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`possessed by a person having ordinary skill in the art, or the inferences and creative
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`steps that a person of ordinary skill in the art would employ.” Janssen, 97 F.4th at
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`931 (cleaned up). But as the Board already correctly found, a POSA would “have
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`looked across the breadth of clinical trials” in the prior art to “identify the results of
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`administering 2 mg of aflibercept in the manner claimed in the ’572 patent.” ID, 55-
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`56. That analysis shows the claims are obvious, as set out below.
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`4
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`Case IPR2023-00884 – Petitioner’s Reply
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`A. Grounds IV, VI, VIII: Dixon/2006 PR and Generic/AMD Results
`Claims4
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`Claims 1-5, 8-11, and 26-30 are directed to methods of treating a patient with
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`an angiogenic disorder or AMD using monthly loading doses/8-week maintenance
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`doses, with additional limitations directed to particular visual acuity gains within or
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`at certain timepoints. PO does not dispute that Dixon discloses a dosing regimen that
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`meets the requirements of the claims challenged in these Grounds. The parties’ only
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`significant dispute is whether Dixon in view of the 2006 PR renders the “results
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`limitations” of claims 1-5, 8-11, and 26-30 obvious. It does. Ex.1092, ¶¶11-33.
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`1.
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`Ground IV
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`(a) Claims 1-5 and 8-11
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`Claims 1-5, 8-11, and 26-30 are rendered obvious by Dixon in view of the
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`2006 PR. The narrowest of claims 1-5 and 8-11 require that “the patient gains at
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`least 9 letters” within 24 weeks or 52 weeks. Ex.1001, 23:15-27, 32-44.
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`A 9-letter gain within 24 or 52 weeks was obvious. Dixon describes (1) the
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`Phase I trial, the results of which showed that a single 2mg or 4mg dose in AMD
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`4 The only issue of claim construction raised by PO (at 3-4) is that the
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`Challenged Claims allegedly recite a “fixed” or “predetermined” regimen. The
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`Board should reject this argument for the reasons stated in the ’601 Institution
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`Decision. See, e.g., Ex.1088, 39-42.
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`5
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`Case IPR2023-00884 – Petitioner’s Reply
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`patients produced a mean gain of 13.5 letters; and (2) the CLEAR-IT-2 trial, which
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`showed AMD patients maintained a mean gain of 9 letters by 52 weeks, with 29%
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`gaining 15+ letters. Ex.1009, 1576; see also Ex.1002, ¶173. As PO’s expert
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`testified, POSAs understood that the majority of patients achieve their gains in the
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`first 24 weeks (Ex.1089, 71:16-72:5), and the underlying CLEAR-IT-2 data shows
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`these gains were in fact made within the first 24 weeks (Ex.2047, 16-17), consistent
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`with that testimony.
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`PO challenges this conclusion not by taking on the disclosures of the prior art
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`as a whole, but by picking at individual data points in the reported clinical trial
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`results to suggest that, in its words (at 39), “none of those references reliably indicate
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`the outcome of the planned Phase III trials.” But that is not the test, and PO’s
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`arguments ignore the context of the art and a POSA’s knowledge.
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`For instance, PO argues (at 39-40) that a POSA would ignore the Phase I data
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`because it reports combined results for the 2mg and 4mg groups. But PO itself
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`reported the results together, indicating there was not a significant difference in the
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`gains between the groups such that reporting needed to be separate. Ex.1027, 2;
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`Ex.1092, ¶¶11-16.
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`Similarly, PO (at 42) complains that Dixon’s CLEAR-IT-2 data is incomplete
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`as to details like granular sample size, and thus cannot be used to predict the Phase
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`III trial results. But PO itself submitted a presentation it acknowledges was presented
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`6
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`Case IPR2023-00884 – Petitioner’s Reply
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`in 2008 and contained the complete CLEAR-IT-2 data (see Ex.2047; POPR, vii) —
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`clearly material that would have been part of “the background knowledge possessed
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`by a person having ordinary skill in the art.” Janssen, 97 F.4th at 931; KSR, 550 U.S.
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`at 418; Ex.2047; Ex.1092, ¶¶17-19. Regardless, a POSA would not need such detail
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`to conclude the claims were obvious, because what is required is not a definitive
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`prediction that the Phase III trials would succeed across a particular patient
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`population—just that the regimen would produce the modest recited gains in at least
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`some patients. Ex.1092, ¶¶11-33.
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`PO further argues (43) that a POSA would not have drawn conclusions based
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`on the Phase II trial data because “the POSA would have known that Phase III trials
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`regularly fail.” This is a strawman. A POSA would understand that even though
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`Phase III trials might fail to hit their endpoints, individual patients within those trials
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`would still receive substantial benefits consistent with the endpoint. Ex.1092, ¶30.
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`Finally, PO’s attempt to reframe Petitioner’s ground as “a disguised inherency
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`argument” is baseless. PO argues (47-50) that the Board misapplied Mustek and
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`Unwired Planet in the ID because Petitioner does not “point[] to any actual
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`disclosure of the claimed result in the prior art.” That is false. Petitioner points to
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`existing results in the art and explains why a POSA would reasonably conclude that
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`they would be produced by the prior art dosing regimens. The Board properly
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`recognized this distinction. ID, 56-57.
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`7
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`Case IPR2023-00884 – Petitioner’s Reply
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`(b) Claims 26-30
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`Claims 26-30 are rendered obvious by Dixon in view of the 2006 PR. Claims
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`26-30 recite the claimed method is “as effective in [achieving a gain in or
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`maintaining visual acuity]” as monthly administration of 0.5 mg ranibizumab “at 52
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`weeks.” Ex.1001, 24:26-25:5. PO’s expert acknowledged that a 8-9 letter gain
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`sustained to 52 weeks is sufficient to meet these limitations. Ex.1076, 14:13-16:12.
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`A POSA would have reasonably concluded that a three-loading dose/8-week
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`maintenance regimen would sustain such a gain to 52 weeks for at least some
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`patients. This is not a case where the recited gains were unknown. Indeed, Dixon
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`reports that CLEAR-IT-2 “study data… demonstrated stabilization of [patient’s]
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`vision that was similar to previous studies of ranibizumab at 1 year,” including the
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`ANCHOR and MARINA trials that studied monthly administration of 0.5 mg
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`ranibizumab. Ex.1009, 1576-77. In fact, the CLEAR-IT-2 data showed that
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`substantially higher gains of 15+ letters could be produced with fewer loading and
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`maintenance doses, and further confirmed that 8-week interval dosing would be
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`successful at maintaining gains. Ex.1092, ¶¶20-24.
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`Specifically, as reported in Dixon, nearly 30% of patients achieved gains of
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`15+ letters at 52 weeks, including for the arms that that received only two loading
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`doses (2q12) and those who received four (2q4). Ex.1009, 1576; Ex.1002, ¶¶180-
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`181; Ex.2047, 19. Moreover, this CLEAR-IT-2 result was achieved in patients who
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`8
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`Case IPR2023-00884 – Petitioner’s Reply
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`received both fewer loading doses and fewer doses during the maintenance period
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`than patients on a three-loading dose/8-week maintenance regimen. Ex.1092, ¶¶20-
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`24.
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`In addition, PO’s expert further acknowledged that POSAs understood that
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`the CLEAR-IT-2 trial discussed in Dixon demonstrated that aflibercept maintained
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`its effect for at least 8-week intervals (Ex.1076, 78:23-81:16)—the longest intervals
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`between doses in the