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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`CELLTRION, INC.,
`Petitioner,
`
`v.
`
`REGENERON PHARMACEUTICALS, INC.,
`Patent Owner.
`
`IPR2024-00260
`U.S. Patent No. 11,253,572
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 11,253,572
`
`

`

`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
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`Page
`
`IV.
`
`
`INTRODUCTION ....................................................................................... 11
`I.
`II. MANDATORY NOTICES PURSUANT TO 37 C.F.R. § 42.8(A)(1) ....... 16
`A.
`Real Party-In-Interest (37 C.F.R. § 42.8(b)(1)) ................................ 16
`B.
`Related Matters (37 C.F.R. § 42.8(b)(2)) .......................................... 16
`C.
`Lead and Backup Counsel (37 C.F.R. § 42.8(b)(3)-(4) ..................... 20
`D.
`Service Information (37 C.F.R. § 42.8(b)(4)) ................................... 21
`E.
`Payment of Fees (37 C.F.R. §§ 42.103 and 42.15(a)) ....................... 21
`III. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a); 37 C.F.R. ............. 21
`§§ 42.101(a)-(c)) ......................................................................................... 21
`IDENTIFICATION OF CHALLENGE AND RELIEF REQUESTED...... 21
`A.
`Identification of Challenge (37 C.F.R. § 42.104(b)) ......................... 22
`B.
`Grounds of Challenge (37 C.F.R. § 42.204(b)(2)) ............................ 22
`THE ’572 PATENT .................................................................................... 24
`A. Overview ........................................................................................... 24
`B.
`Priority Date ...................................................................................... 25
`C.
`The Challenged Claims ..................................................................... 25
`D.
`Prosecution History ........................................................................... 27
`E.
`Level of Ordinary Skill in the Art ..................................................... 27
`VI. CONSTRUCTION OF THE CHALLENGED CLAIMS ........................... 28
`A.
`“A method of treating…” .................................................................. 28
`B.
`Exclusion Criteria ............................................................................. 29
`VII. SCOPE AND CONTENT OF THE PRIOR ART ....................................... 30
`A.
`The 2009 Press Release .................................................................... 31
`B.
`The November 2010 Press Release ................................................... 31
`C.
`The December 2010 Press Release ................................................... 32
`D. Dixon ................................................................................................ 32
`
`V.
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`i
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`B.
`
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`Hecht ................................................................................................. 34
`E.
`
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`
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`Shams ................................................................................................ 34
`F.
`Elman 2010 ....................................................................................... 34
`G.
`CATT and PIER Studies ................................................................... 35
`H.
`Prior Art Regarding Aflibercept Efficacy ......................................... 37
`I.
`VIII. DETAILED GROUNDS FOR INVALIDITY ............................................ 39
`A. Ground I: Claims 15 and 24 Are Anticipated by Each of the 2009
`Press Release and December 2010 Press Release ............................ 39
`Ground II: Claims 1-5, 8-11, 16-17, and 20-21 (Generic/DME
`Results Claims) Are Anticipated by the December 2010 Press
`Release .............................................................................................. 42
` 1. Claims 1 and 16 ................................................................................ 42
` 2. Claim 2 .............................................................................................. 43
` 3. Claims 3, 8, 10, 17, and 21 and Claims 4, 9, and 20 ......................... 44
` 4. Claims 5 and 11 ................................................................................ 45
`C.
`Ground III: Claims 26-30 (AMD Results Claims) Are Anticipated
`by the November 2010 Press Release .............................................. 45
` 1. Claims 26-28 ..................................................................................... 45
` 2. Claims 29-30 ..................................................................................... 48
`D. Ground IV: Claims 1-5, 8-11, and 26-30 (Generic/AMD Results
`Claims) Are Rendered Obvious by Dixon Alone or In View of the
`2006 Press Release ........................................................................... 49
` 1. Claim 1 .............................................................................................. 50
` 2. Claim 2 .............................................................................................. 51
` 3. Claims 3-4 and 8-10 .......................................................................... 52
` 4. Claims 5 and 11 ................................................................................ 53
` 5. Claims 26-28 ..................................................................................... 53
` 6. Claims 29-30 ..................................................................................... 55
`E.
`Ground V: Claims 16-17, and 20-21 Are Rendered Obvious by the
`2009 Press Release Alone or in View of the 2007 ARVO Abstract,
`Dixon and/or the 2010 ARVO Abstract (collectively “Ground V
`References”) ...................................................................................... 56
`
`ii
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`F.
`
`I.
`
`
`Ground VI: Claims 6-7 and 12-13 Are Rendered Obvious by Each
`
`
`
`
`of Dixon in View of Hecht, Dixon in View of the 2006 Press Release
`
`
`
`and Hecht, and the December 2010 Press Release in View of Hecht
` .......................................................................................................... 59
`G. Ground VII: Claims 18-19 and 22-23 Are Rendered Obvious by
`Each of the December 2010 Press Release in View of Hecht, and the
`2009 Press Release in View of the Ground V References and Hecht
` .......................................................................................................... 61
`H. Ground VIII: Claim 14 Is Rendered Obvious by Each of Dixon and
`the December 2010 Press Release Alone or In View of the CATT
`Study and/or PIER Study ................................................................. 61
`Ground IX: Claim 25 is Rendered Obvious by the 2009 Press
`Release Alone or in View of Shams or Elman 2010 ........................ 62
`Grounds X and XI ............................................................................. 66
`J.
` 1. The “Results Limitations” in the Results Claims Are Not Entitled
`to Patentable Weight ......................................................................... 66
` 2. Ground X: Claims 1-5, 8-11, and 26-30 are Anticipated by Dixon
`Because the “Results Limitations” Lack Patentable Weight ........... 70
` 3. Ground XI: Claims 1-5, 8-11, 16-17, and 20-21 are Anticipated by
`the 2009 Press Release Because the “Results Limitations” Lack
`Patentable Weight ............................................................................. 71
`There Are No Secondary Considerations .......................................... 71
`K.
`IX. DISCRETIONARY DENIAL IS UNWARRANTED ................................ 72
`A.
`The Becton Dickinson Factors Do Not Favor Denial Under 35
`U.S.C. § 325(d) ................................................................................. 72
` 1. Becton Dickinson Factors (a), (b), and (d) ........................................ 73
` 2. Becton Dickinson Factors (c), (e), and (f) ......................................... 74
`B.
`The General Plastic Factors Do Not Support Denial Under 35
`U.S.C. § 314(a) ................................................................................. 75
`The Fintiv Factors Do Not Support Denial Under 35 U.S.C. § 314(a)
` .......................................................................................................... 77
`CONCLUSION ........................................................................................... 78
`
`C.
`
`
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`X.
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`iii
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`

`

`
`Exhibit Description
`1001 U.S. Patent No. 11,253,572
`1002
`Expert Declaration of Dr. Christine Kay in Support of Petition for Inter
`Partes Review of Patent No. 11,253,572 (“Kay Decl.”)
`1003 Dr. Christine Kay Curriculum Vitae
`1004
`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”)
`
`
`
`
`
`
`
`
`
`
`1005
`
`1006
`
`1007
`
`
`
`
`
`
`TABLE OF EXHIBITS
`
`
`
`
`
`
`
`
`
`
`iv
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`(“2010
`
`
`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
`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)
`
`
`
`
`
`
`
`1011
`
`1012
`
`1013
`
`1019
`
`v
`
`

`

`
`
`
`
`
`
`
`
`1020
`
`
`
`
`
`
`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”)
`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”)
`Press Release, “Regeneron Reports Positive Phase 1 Data for the VEGF
`TRAP in Age-Related Macular Degeneration,” Exhibit 99(a) to
`Regeneron 8K-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
`
`1027
`
`vi
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`(“May 2008 Press
`
`
`Exhibit Description
`
`
`
`(“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
`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”)
`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”)
`
`
`
`
`
`
`
`1029
`
`1033
`
`1034
`
`
`
`vii
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`1040
`
`
`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”)
`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”)
`
`viii
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`Exhibit Description
`
`
`
`Li E, Donati S, Lindsley KB, Krzystolik MG, Virgili G. Treatment
`1048
`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”)
`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:
`
`
`
`
`
`
`
`1054
`
`1056
`
`ix
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`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/
`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-
`00061-TSK, Northern District of West Virginia. (Dkt. 427) (“Mylan
`Litigation CC Order”)
`1064 U.S. Patent No. 7,531,173 (“’173 patent”)
`
`
`
`
`
`
`
`1059
`
`1061
`
`
`
`x
`
`

`

`
`
`I.
`
`
`
`
`
`
`INTRODUCTION
`
`
`
`Celltrion, Inc. (“Petitioner”) petitions for inter partes review (“IPR”) under
`
`
`
`
`
`
`
`
`
`35 U.S.C. §§ 311-319 and 37 C.F.R. §§ 42 et seq., seeking cancellation of claims 1-
`
`30 (the “Challenged Claims”) of U.S. Patent No. 11,253,572 (“’572 patent”)
`
`(Ex.1001), assigned to Patent Owner, Regeneron Pharmaceuticals, Inc.
`
`The Challenged Claims are directed to treating angiogenic eye disorders,
`
`including diabetic macular edema (“DME”) and age-related macular degeneration
`
`(“AMD”), by administering aflibercept via a number of initial monthly loading
`
`doses, followed by maintenance doses administered every two months.
`
`One subset of the Challenged Claims—claims 15-25—is directed to a dosing
`
`regimen for DME with two or more monthly loading doses followed by maintenance
`
`doses administered every two months (the “DME Claims”). Those claims were not
`
`challenged in Apotex’s prior ’572 IPR Petition (IPR2002-01524 (“Apotex
`
`Petition”)), which addressed the non-DME claims of the ’572 patent. Ex.1008.
`
`Unlike the other ’572 claims previously addressed by the Patent Trial and
`
`Appeal Board (“Board”), independent claim 15 and dependent claim 24 recite only
`
`DME dosing regimens and nothing more. They do not contain what the Board
`
`previously referred to as a “results limitation”—i.e. maintaining or gaining visual
`
`acuity. Ex.1004, 15. Instead, claim 15 recites treating DME by administering a
`
`single initial dose of aflibercept, followed by “one or more” monthly secondary
`
`
`
`11
`
`

`

`
`
`
`
`
`
`
`doses (the “loading” phase), and then maintenance doses every two months. Claim
`
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`24 depends from claim 15 and recites that “only two secondary doses” are
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`administered, meaning only three monthly doses are given before 8-week dosing.
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`Thus, claims 15 and 24 are anticipated by any aflibercept DME prior art
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`disclosing three monthly loading doses followed by 8-week maintenance dosing. A
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`Regeneron press release from September 14, 2009 (“2009 Press Release”) discloses
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`exactly that. It describes administering 2 mg aflibercept to treat DME using a dosing
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`regimen of three monthly loading doses that include an initial and two “secondary”
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`doses, followed by maintenance doses at 8-week intervals. Ex.1005. Another press
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`release from December 20, 2010 (“December 2010 Press Release”) discloses the
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`same DME regimen. Ex.1006. Thus, as shown in Ground I, each of the 2009 Press
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`Release and December 2010 Press Release anticipates claims 15 and 24.
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`A second subset of Challenged Claims—1-5, 8-11, 16-17, 20-21, and 26-30—
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`recite a loading/maintenance regimen for generic angiogenic eye disorders, DME,
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`or AMD, and also include certain “results limitations” reciting either a general result
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`within a specific time frame (e.g., “wherein the patient achieves a gain in visual
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`acuity within 52 [or 24] weeks”) or a specific visual acuity gain (e.g., “wherein the
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`patient gains at least 7 [or 8 or 9] letters” in the standard ETDRS letter score for
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`visual acuity, or wherein the regimen is “as effective” as ranibizumab). These claims
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`are collectively referred to as the “Results Claims” herein.
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`Results Claims 1-5, 8-11, 16-17, and 20-21 recite treating either a generic
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`angiogenic eye disorder or DME specifically (the “Generic Results Claims”/“DME
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`Results Claims”). As shown in Ground II, the December 2010 Press Release
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`anticipates the Generic/DME Results Claims. The December 2010 Press Release
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`discloses the same dosing regimens for DME as the 2009 Press Release, but further
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`reports the visual acuity results from DME clinical trials in which these regimens
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`were applied. The December 2010 Press Release explicitly discloses that DME
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`patients both achieved the results recited within the recited 24 or 52 week time
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`frames, and that they achieved the specific visual acuity gains recited (e.g., a gain of
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`at least 7, 8, or 9 letters).
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`Similarly, Results Claims 26-30 recite a method for treating AMD via a
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`loading/maintenance regimen (the “AMD Results Claims”), and further recite that
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`the method is “as effective” as monthly ranibizumab at week 52. As shown in
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`Ground III, the AMD Results Claims are anticipated by a November 22, 2010 Press
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`Release (“November 2010 Press Release”), which discloses the same dosing
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`regimen as the other press releases, but for treatment of AMD. Ex.1007. That Press
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`Release further explicitly discloses the ranibizumab comparison results recited by
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`the claim. Id.
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`The Results Claims are also rendered obvious by the 2009 Press Release or
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`separately by Dixon’s disclosure of the claimed dosing regimen for AMD. Notably,
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`in the Apotex Petition, Apotex argued that the “results limitations” only were
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`inherent or not entitled to patentable weight based on Dixon—an argument the Board
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`rejected; Apotex did not argue that they were obvious. Ex.1008, 12. It would have
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`been obvious to a POSA, however, that at least some patients, when treated via the
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`recited dosing regimens disclosed in the prior art, would achieve the recited 7-9 letter
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`gains, which were modest compared to known gains for aflibercept. For instance, it
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`was known that a single 2 mg dose of aflibercept produced 15 letter gains for some
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`patients within the first six weeks of treatment. And Dixon reports that AMD
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`patients who received four initial monthly doses, followed by PRN dosing resulting
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`in only an average of 1.6 additional injections through 52 weeks (for a total of 5.6
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`doses in a year on average), achieved a mean of 9 letter gains, with 29% gaining at
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`least 15 letters by 52 weeks. Ex.1009, Dixon, 1576.
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`Importantly, the Results Claims do not require every patient to achieve the
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`recited gain. Instead, the claims are directed to methods for treating “a patient,” and
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`thus a POSA only need find it obvious that some patients would achieve the recited
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`gains. See, Ex.1001, claims 1, 15, 26, and 29. It would have been obvious to a
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`POSA that at least some AMD patients would have achieved the lower 7-9 letter
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`gains claimed in the AMD Results Claims using three initial monthly doses followed
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`by 8-week maintenance dosing (instead of four monthly doses followed by less
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`frequent PRN dosing). Three initial doses followed by 8-week dosing would result
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`14
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`in eight overall doses during the 52 week period—two more doses than had been
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`shown to produce 15 letter gains in almost 1 in 3 patients.
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`Similarly, as to the DME Results Claims, POSAs knew that a single initial 4
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`mg dose of aflibercept had produced a 9 letter gain by 4 weeks (Ex.1009, 1575) and
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`that the DME clinical trials described in the 2009 Press Release had achieved a mean
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`gain of “+8.5 to +11.4 letter[s]” within 24 weeks (Ex.1010, 2010 ARVO Abstract,
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`1).
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`Thus, as shown in Grounds IV and V, Dixon and the 2009 Press Release, in
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`combination with references reporting aflibercept efficacy for AMD and DME,
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`render obvious the Generic/AMD and DME Results Claims respectively.
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`Petitioner also presents Grounds VI-IX addressing various dependent claims,
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`as further set out below. Finally, in Grounds X and XI, Petitioner addresses
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`anticipation of the Results Claims on the basis that the “results limitations” are not
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`entitled to patentable weight and are thus anticipated by the dosing regimens
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`disclosed in the September 2009 Press Release and Dixon.
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`Discretionary denial is not appropriate here. None of the references cited in
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`Petitioner’s grounds were substantively discussed during prosecution. While
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`Apotex previously filed a petition against the ’572 patent against AMD claims
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`including results limitations, Apotex did not challenge any of the DME claims—
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`including anticipated claims 15 and 24, which do not contain a “results limitation”—
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`and Apotex did not rely on the 2009 and 2010 Press Releases as part of its grounds.
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`See, Ex.1008. Moreover, Apotex did not present obviousness arguments as to the
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`Results Claims, including as to Dixon. Id. The only overlap in Petitioner’s grounds
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`and Apotex’s is as to minor dependent limitations and as to Grounds X and XI.
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`The Board should institute an inter partes review of the Challenged Claims
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`and find those claims unpatentable on the grounds presented herein.
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`II. MANDATORY NOTICES PURSUANT TO 37 C.F.R. § 42.8(A)(1)
`A. Real Party-In-Interest (37 C.F.R. § 42.8(b)(1))
`The real party-in-interest for Petitioner is Celltrion Inc., Celltrion Healthcare
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`Co. Ltd. And Celltrion Healthcare U.S.A., Inc., are the real parties-interest.
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`B. Related Matters (37 C.F.R. § 42.8(b)(2))
`As noted above, Apotex filed an IPR Petition on September 9, 2022 asserting
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`five grounds for invalidating the non-DME claims of the ’572 patent, all of which
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`recite “results limitations.” Ex.1008 (“Apotex Petition”). Grounds 1-4 of Apotex’s
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`petition were based on anticipation: (1) anticipation of claims 1-5, 8-11, 14, and 26-
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`30 based on Dixon; (2) anticipation of claims 1-5, 8-11, 14, and 26-30 based on a
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`May 8, 2008 Regeneron Press Release; (3) anticipation of claims 1-5, 8-11, 14, and
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`26-30 based on NCT-795 (i.e., VIEW 1 ClinicalTrials.gov entry); and (4)
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`anticipation of claims 1-5, 8-11, 14, and 26-30 based on NCT-377 (i.e., VIEW 2
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`ClinicalTrials.gov entry). Ex.1008, 12.
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`With respect to the “results limitations” in these claims, Apotex argued that
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`they (1) were not entitled to patentable weight (id., 17-20); or (2) were inherently
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`anticipated by practice of the claimed method (id., 35-68). Notably, Apotex did not
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`rely on obviousness to address the visual acuity limitations in any of the claims.
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`Apotex only asserted obviousness for claims 6, 7, 12, and 13 in its Ground 5.
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`For those claims, Apotex relied on any of the above anticipatory references in view
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`of Hecht. Ex.1008, 12. Apotex’s obviousness argument in Ground 5 was solely
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`directed to the “isotonic solution” limitation in dependent claims 6 and 12 and the
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`“nonionic surfactant” limitation in dependent claims 7 and 13—not the “results
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`limitations.” Ex.1008, 68-71.
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`In its Institution Decision, the Board determined that the “results limitations”
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`were entitled to patentable weight. Ex.1004 (“Apotex ’572 ID”), 14-18. The Board
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`then went on to determine that the prior art did not inherently disclose the “results
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`limitations” for at least two reasons: (1) less than all of the patients in the VIEW 1/2
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`trials achieved the claimed visual acuity limitations; and (2) the patient population
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`reported in the prior art as achieving the recited gains was not the same as that
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`described in the ’572 patent. Id, 30-36. It therefore denied institution. Id.
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`The ’572 patent is in the sa