UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`REGENERON PHARMACEUTICALS, INC.,
`Petitioner,
`
`v.
`
`NOVARTIS PHARMA AG,
`NOVARTIS TECHNOLOGY LLC,
`NOVARTIS PHARMACEUTICALS CORPORATION,
`Patent Owner.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`PETITION FOR INTER PARTES REVIEW
`
`OF
`
`U.S. PATENT NO. 9,220,631
`
`
`
`
`

`

`
`
`
`TABLE OF CONTENTS
`INTRODUCTION ........................................................................................... 1
`I.
`II. MANDATORY NOTICES ............................................................................. 1
`A.
`Real Party-in-Interest ............................................................................ 1
`B.
`Related Matters ...................................................................................... 1
`C.
`Lead and Back-up Counsel and Service Information ........................... 3
`III. GROUNDS FOR STANDING ........................................................................ 3
`IV.
`35 U.S.C. §§ 314(a), 325(d) ............................................................................ 3
`V.
`TECHNOLOGY BACKGROUND ............................................................... 11
`A.
`Pre-filled Syringes for Intravitreal Injection ....................................... 11
`B.
`Syringe Barrel Siliconization .............................................................. 12
`C.
`Sterilization of Pre-Filled Syringes ..................................................... 15
`D.
`Particulate Content .............................................................................. 16
`VI. THE ’631 PATENT ....................................................................................... 17
`A.
`The Challenged Claims ....................................................................... 17
`B.
`The Specification ................................................................................. 18
`1.
`Siliconization Methods and Alleged Surprising Results .......... 18
`2.
`Terminal Sterilization ............................................................... 18
`3.
`Particulate Content .................................................................... 19
`The Prosecution History ...................................................................... 19
`C.
`VII. STATUTORY GROUNDS FOR THE CHALLENGES .............................. 21
`VIII. LEVEL OF ORDINARY SKILL IN THE ART ........................................... 24
`IX. CLAIM CONSTRUCTION .......................................................................... 24
`A.
`“Stopper Break Loose Force” ............................................................. 24
`B.
`“Stopper Slide Force” .......................................................................... 25
`C.
`“Terminally sterilized” ........................................................................ 25
`D.
`“About”................................................................................................ 25
`
`ii
`
`

`

`
`
`
`X.
`
`IDENTIFICATION OF HOW THE CHALLENGED CLAIMS ARE
`UNPATENTABLE ........................................................................................ 26
`A. Ground 1: Sigg in view of Boulange .................................................. 26
`1.
`Overview of Sigg ...................................................................... 26
`2.
`Overview of Boulange .............................................................. 27
`3. Motivation to Combine and Reasonable Expectation of
`Success ...................................................................................... 31
`Claim 1 ...................................................................................... 40
`4.
`Claims 2, 3, 5-9, 14, 16-22 and 24 ............................................ 47
`5.
`Claim 15 .................................................................................... 54
`6.
`B. Ground 2: Lam in view of Boulange ................................................... 55
`1.
`Overview of Lam ...................................................................... 56
`2.
`Claim 1 ...................................................................................... 56
`3.
`Claims 2, 3, 5-9, 14-22, and 24 ................................................. 59
`C. Grounds 3 and 4: Sigg or Lam in view of Boulange and Fries .......... 65
`D. Grounds 5 and 6: Sigg or Lam in view of Boulange and Furfine ...... 67
`Grounds 7 and 8: Sigg or Lam in view of Boulange and 2008
`E.
`Macugen Label .................................................................................... 68
`Grounds 9 and 10: Sigg or Lam in view of Boulange and
`Dixon ................................................................................................... 70
`XI. SECONDARY CONSIDERATIONS ........................................................... 71
`XII. CONCLUSION .............................................................................................. 74
`
`
`F.
`
`
`
`
`
`
`
`iii
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`

`

`
`
`
`
`
`PETITIONER’S EXHIBIT LIST
`
`U.S. Patent No. 9,220,631 (“the ’631 Patent”)
`
`Prosecution File History of U.S. Patent No. 9,220,631
`
`Declaration of Horst Koller under 37 C.F.R. § 1.68.
`
`Curriculum Vitae of Horst Koller
`
`ITC Investigation No. 337-TA-1207, Staff’s Pre-Hearing Brief (public
`version)
`
`ITC Investigation No. 337-TA-1207, Complainant’s Unopposed
`Motion to Terminate
`
`Ex.
`1001
`
`Ex.
`1002
`
`Ex.
`1003
`
`Ex.
`1004
`
`Ex.
`1005
`
`Ex.
`1006
`
`Ex.
`1007 PCT Patent Publication No. WO 2011/006877 to Sigg et al. (“Sigg”)
`Ex.
`PCT Patent Publication No. WO 2009/030976 to Boulange et al.
`1008
`(“Boulange”)
`
`Ex.
`1009
`
`Ex.
`1010
`
`Ex.
`1011
`
`Ex.
`1012
`
`Internet Archive WayBack Machine, March 7, 2011 Record of
`Drugs.com, Macugen Prescribing Information, available at
`https://web.archive.org/web/20110307065238/http://www.drugs.com:
`80/pro/macugen.html (“2008 Macugen Label”)
`
`ITC Investigation No. 337-TA-1207, Initial Determination Terminating
`the Investigation
`
`Bhavnesh D. Shah & Bhupendra G. Prajapati, Pre-Filled Syringes: A
`New Concept, PHARMA BIO WORLD 51 (2009) (“Shah”)
`
`Arno Fries, Drug Delivery of Sensitive Biopharmaceuticals With
`Prefilled Syringes, 9(5) DRUG DELIVERY TECH. 22 (2009) (“Fries”)
`
`iv
`
`

`

`
`
`
`
`
`Ex.
`1013
`
`Ex.
`1014
`
`Ex.
`1015
`
`Ex.
`1016
`
`Ex.
`1017
`
`Ex.
`1018
`
`Ex.
`1019
`
`Thomas Schoenknecht, Prefilled Syringes: Why New Developments Are
`Important In Injectable Delivery Today, in PREFILLED SYRINGES
`INNOVATIONS THAT MEET THE GROWING DEMAND (OnDrugDelivery
`2005) (“Schoenknecht”)
`
`U.S. Patent Publication No. 2012/0091026 to Chacornac et al.
`(“Chacornac”)
`
`Sandeep Nema & John D. Ludwig, Pharmaceutical Dosage Forms:
`Parenteral Medications, Volume 1: Formulation and Packaging (3rd
`ed. 2010) (“Nema Vol. 1”)
`
`Sandeep Nema & John D. Ludwig, Pharmaceutical Dosage Forms:
`Parenteral Medications, Volume 2: Facility Design, Sterilization and
`Processing (3rd ed. 2010) (“Nema Vol. 2”)
`
`PCT Patent Publication No. WO 2007/035621 to Scypinski et al.
`(“Scypinski”)
`
`U.S. Patent Publication No. 2003/0003014 to Metzner et al.
`(“Metzner”)
`
`U.S. Pharmacopeia, USP 789, Particulate Matter in Ophthalmic
`Solutions, USP 34 NF 29 (2011)
`
`Ex.
`1020 U.S. Patent Publication No. 2011/276005 to Hioki et al. (“Hioki”)
`Ex.
`PCT Patent Publication No. WO 2007/149334 to Furfine et al.
`1021
`(“Furfine”)
`
`Ex.
`1022
`
`Ex.
`1023
`
`Ex.
`1024
`
`Michael W. Stewart et al., Fresh From the Pipeline Aflibercept, 11
`NAT. REV. DRUG DISCOV. 269 (2012) (“Stewart”)
`U.S. Patent No. 7,060,269 to Baca et al. (“Baca”)
`
`Gerald McDonnel and Denver Russell, Antiseptics and Disinfectants:
`Activities, Action, and Resistance, Clinical Microbiology Review, (Jan.
`1999) (“McDonnel”).
`
`v
`
`

`

`
`
`
`
`
`Ex.
`1025
`
`Ex.
`1026
`
`Ex.
`1027
`
`Ex.
`1028
`
`Lu Liu et al., Silicone Oil Microdroplets and Protein Aggregates in
`Repackaged Bevacizumab and Ranibizumab: Effects of Long-term
`Storage and Product Mishandling, 52(2) INVESTIGATIVE
`OPHTHALMOLOGY & VISUAL SCIENCE 1023 (2011) (“Liu”)
`
`U.S. Patent No. 7,404,278 to Wittland et al. (“Wittland”)
`
`U.S. Food and Drug Administration, Lucentis® Highlights of the
`Prescribing Information, (June 2010) (“Lucentis Label”)
`
`International Organization for Standardization, ISO 11040-4 Prefilled
`Syringes – Part 4: Glass Barrels for Injectables (2nd ed. 2007) (“ISO
`11040-4”)
`
`Ex.
`1029 PCT Patent Publication No. WO 2008/077155 to Lam et al. (“Lam”)
`Ex.
`James A. Dixon, et al. "VEGF Trap-Eye for the treatment of
`1030
`neovascular age-related macular degeneration." Expert opinion on
`investigational drugs 18.10 (2009): 1573-1580. (“Dixon”)
`
`Ex.
`1031
`
`Ex.
`1032
`
`Ex.
`1033
`
`Ex.
`1034
`
`Ex.
`1035
`
`Ex.
`1036
`
`Declaration of Dr. Szilard Kiss under 37 C.F.R. § 1.68.
`
`Curriculum Vitae of Dr. Szilard Kiss
`
`Declaration of James L. Mullins, Ph.D.
`
`Dow Corning® 365 35% Dimethicone NF Emulsion – Frequently
`Asked Questions (2002) (“DC365 FAQ”)
`
`European Patent Application No. 12174860 to Novartis AG
`
`U.S. Food and Drug Administration, Guidance for Industry: Sterile
`Drug Products Produced by Aseptic Processing—Current Good
`Manufacturing Practice (September 2004)
`
`vi
`
`

`

`Ex.
`1037
`
`Ex.
`1038
`
`Ex.
`1039
`
`Ex.
`1040
`
`Ex.
`1041
`
`Ex.
`1042
`
`Ex.
`1043
`
`Ex.
`1044
`
`Ex.
`1045
`
`Ex.
`1046
`
`Ex.
`1047
`
`
`
`
`
`
`Affidavit of Internet Archive Office Manager
`
`Internet Archive WayBack Machine, March 8, 2011 Record of
`Drugs.com, Welcome to Drugs.com, available at
`https://web.archive.org/web/20110308203650/http://www.drugs.com:
`80/
`
`Internet Archive WayBack Machine, February 25, 2011 Record of
`Drugs.com, FDA Professional Drug Information, available at
`https://web.archive.org/web/20110225193929/http://www.drugs.com:
`80/pro/
`
`U.S. Food and Drug Administration, Eylea® Highlights of the
`Prescribing Information, (November 2011) (“Eylea label”)
`
`U.S. Food and Drug Administration, Guidance for Industry: Container
`Closure Systems for Packaging Human and Biologics – Chemistry,
`Manufacturing, and Controls Documentation (May 1999), available at
`https://www.fda.gov/downloads/drugs/guidances/ucm070551.pdf
`International Standard ISO-7864, Sterile hypodermic needles for single
`use, ISO 7864:1993(E) (“ISO-7864”)
`
`International Standard ISO-9626, Stainless steel needle tubing for the
`manufacture of medical devices – Amendment 1, ISO
`9626:1991/Amd.1:2001(E) (“ISO-9626”)
`Advait Badkar, et al. Development of Biotechnology Products in Pre-
`filled Syringes: Technical Considerations and Approaches, American
`Association of Pharmaceutical Sciences, June 2011, 12(2): 564-572
`(“Badkar”)
`William Leventon, “Medical Device Sterilization: What Manufacturers
`Need to Know” (MDDI online, Sept. 1, 2002), available at
`https://www.mddionline.com/medical-device-sterilization-what-
`manufacturers-need-know (“Leventon”)
`Pamela Carter, et al. The lowdown on low temperature sterilization for
`packaged devices, Healthcare Purchasing News, July 2008, 42-45.
`(“Carter”)
`U.S. Patent Publication No. 2005/0182370 to Hato (“Hato”)
`
`vii
`
`

`

`
`
`
`
`
`Ex.
`1048
`
`Ex.
`1049
`
`Ex.
`1050
`
`Ex.
`1051
`
`Ex.
`1052
`
`Ex.
`1053
`
`Ex.
`1054
`
`Ex.
`1055
`
`Ex.
`1056
`
`Ex.
`1057
`
`U.S. Department of Labor, Occupational Safety & Health
`Administration, Ethylene Oxide (EtO): Understanding OSHA’s
`Exposure monitoring Requirements, 2007 OSHA3325-01N (2007),
`available at https://www.osha.gov/Publications/ethylene_oxide.html
`(“OSHA Guidelines”)
`Bryon Lambert, et al. Radiation and Ethylene Oxide Terminal
`Sterilization Experiences with Drug Eluting Stent Products, American
`Association of Pharmaceutical Sciences, December 2011, 12(4):1116-
`1126 (“Lambert”)
`IPR2020-1317, Paper No. 10, Patent Owner’s Preliminary Response
`
`IPR2020-1317, Paper No. 14, Patent Owner’s Sur-Reply
`
`
`John R. Gillis & Gregg Mosley, Validation of Pharmaceutical
`Processes, Chapter 16 – Validation of Ethylene Oxide Sterilization
`Processes (2011), pp.241-262 (“Gillis”)
`FDA Pesticide Analytical Manual Vol. 1, Chapter 6 - HPLC, available
`at
`https://www.fda.gov/downloads/Food/FoodScienceResearch/
`ucm113651.pdf
`Kim, Leo & D’Amore, Patricia, ASIP Centennial Commentary – A
`Brief History of Anti-VEGF for the Treatment of Ocular Angiogenesis,
`The American Journal of Pathology, August 2012 182(2):376-379,
`available at (note: published online July 2, 2012
`https://ajp.amjpathol.org/article/S0002-9440(12)00442-7/fulltext )
`J.S. Penn, et al. Vascular Endothelial Growth Factor in Eye Disease,
`Prog. Retin Eye Res., July 2008, 27(4):331-371. (“Penn2008”)
`
`U.S. Food and Drug Administration, Trivaris ® Highlights of the
`Prescribing Information, (May 2008) (“Trivaris label”)
`
`Internet Archive WayBack Machine, May 17, 2011 Record of U.S.
`Pharmacopeia, Understanding USP–NF, available at
`https://web.archive.org/web/20110517215303/http://www.usp.org/
`USPNF/understandingUSPNF.html
`
`viii
`
`

`

`Ex.
`1058
`
`Ex.
`1059
`
`Ex.
`1060
`
`Ex.
`1061
`
`Ex.
`1062
`
`Ex.
`1063
`
`Ex.
`1064
`
`Ex.
`1065
`
`Ex.
`1066
`
`Ex.
`1067
`
`Ex.
`1068
`
`
`
`
`
`
`Christine I. Falkner-Radler, et al. Needle Size in Intravitreal Injections-
`Preliminary Results of a Randomized Clinical Trial, AVRO Annual
`Meeting Abstract, March 2012, 54(884), available at
`https://iovs.arvojournals.org/article.aspx?articleid=2350271 (“ARVO
`abstract”)
`Carsten H. Meyer, et al. Steps for a Safe Intravitreal Injection
`Technique – A look at how European and American approaches
`compare, Retinal Physician (July 1, 2009), available at
`https://www.retinalphysician.com/issues/2009/july-aug/steps-for-a-
`safe-intravitreal-injection-technique (“Meyer”)
`Curriculum Vitae of James L. Mullins, Ph.D.
`
`DUPONT™ TYVEK® COMPLIANCE TO ISO 11607-1:2006 (2011)
`
`Center for Drug Evaluation and Research, Application Number: 21-
`756, Approved Labeling, Macugen® (pegaptanib sodium injection)
`(December 17, 2004) (“2004 Macugen Label”)
`Evangelos S. Gragoudas, et al. Pegaptanib for Neovascular Age-
`Related Macular Degeneration, New England Journal of Medicine
`2004; 351:2805-16, with Supplementary Appendix.
`IPR2020-1317, Paper No. 15, Institution Decision
`
`Anita M. Leys, et al. Neovascular Growth Following Photodynamic
`Therapy for Choroidal Hemangioma and Neovascular Regression after
`Intravitreous Injection of Triamcinolone, Retina 2006; 26(6):693-7,
`available at https://pubmed.ncbi.nlm.nih.gov/16829815/ (“Leys”)
`Australian Government, Department of Health and Ageing, Australian
`Public Assessment Report for Aflibercept, (July 2012)
`
`Sophie J. Bakri and Noha S. Ekdawi, Intravitreal Silicone Oil Droplets
`after Intravitreal Drug Injections, Retina 2008; 20:996-1001, available
`at https://pubmed.ncbi.nlm.nih.gov/18698303/ (“Bakri”)
`Jared S. Bee, et al. Effects of Surfaces and Leachables on the Stability
`of Biopharmaceuticals, Journal of Pharmaceutical Science (Oct. 2011),
`available at https://pubmed.ncbi.nlm.nih.gov/21523787/ (“Bee”)
`
`ix
`
`

`

`Ex.
`1069
`
`Ex.
`1070
`
`Ex.
`1071
`
`Ex.
`1072
`
`Ex.
`1073
`
`Ex.
`1074
`
`Ex.
`1075
`
`Ex.
`1076
`
`Ex.
`1077
`
`Ex.
`1078
`
`Ex.
`1079
`
`Ex.
`1080
`
`
`
`
`
`
`Michael Colucciello, Prefilled Syringe Delivery of Intravitreal Anti-
`VEGF Medications: Advantages for Patients and Physicians, Retinal
`Physician (Mar. 1, 2019), available at
`https://www.retinalphysician.com/issues/2019/march-2019/prefilled-
`syringe-delivery-of-intravitreal-anti-ve (“Colucciello”)
`Declaration of Juergen Sigg (“Sigg Declaration”)
`
`Department of Health & Human Services, Macugen Approval Letter
`(Dec. 18, 2004)
`
`Lonny Wolgemuth, Challenges with Prefilled Syringes: The Parylene
`Solution, ONdrugDelivery (Oct. 2012), available at
`https://ondrugdelivery.com/wp-content/uploads/2018/11/Oct2012.pdf
`Therese M. Sassalos, Prefilled Syringes for Intravitreal Drug Delivery,
`Clinical Ophthalmology 2019:13 701-706, available at
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485318/
`SCS Coating Systems, SCS Parylene Properties (2007), available at
`https://www.physics.rutgers.edu/~podzorov/parylene%20properties.pdf
`(“SCS”)
`Lonny Wolgemuth, Assessing the Effects of Sterilization Methods on
`Parylene Coating, Medical Device & Diagnostic Industry, (Aug. 2002)
`
`David E. Overcashier, et al. Technical Considerations in the
`Development of Pre-filled Syringes for Protein Products, Am. Pharm.
`Rev. 2006;9(7): 77-83 (“Overcashier”)
`SDNY 20-5502 Docket
`
`Federal Court Statistics
`
`Novartis Letter to NDNY Court
`
`Mehmet S. Kocabora, et al. Intravitreal Silicone Oil Droplets
`Following Pegaptanib Injection, Acta Ophthalmologica 2010, available
`at https://onlinelibrary.wiley.com/doi/full/10.1111/j.1755-
`3768.2008.01336.x (“Kocabora”)
`
`x
`
`

`

`
`
`
`
`
`Ex.
`1081
`
`Ex.
`1082
`
`Ex.
`1083
`
`Ex.
`1084
`
`Ex.
`1085
`
`Ex.
`1086
`
`Macugen Label (2008)
`
`U.S. Pharmacopeia, USP 789, Particulate Matter in Ophthalmic
`Solutions, USP 32 NF 27 (2009)
`
`Novartis NDNY Complaint
`
`Novartis Letter to SDNY Court
`
`ITC Investigation No. 337-TA-1207, Statement on the Public Interest
`by Proposed Respondent Regeneron Pharmaceuticals, Inc.
`
`ITC Investigation No. 337-TA-1207, Statement on the Public Interest
`by Szilard Kiss
`
`Ex.
`1087
`
`Nitin Rathore, et al. Variability in Syringe Components and its Impact
`on Functionality of Delivery Systems, PDA Journal of Pharmaceutical
`Science and Technology 2011, 65 468-480 (“Rathore”)
`Ex.
`1088 PCT Patent Publication No. WO 2007/084765 to Deschatelets et al.
`Ex.
`PCT Patent Publication No. WO 97/44068 to Tack et al.
`1089
`
`xi
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`

`

`
`
`
`I.
`
`
`INTRODUCTION
`U.S. Patent No. 9,220,631 (“the ’631 Patent”) is directed to a terminally
`
`sterilized, pre-filled glass syringe for intravitreal injection that includes a VEGF-
`
`antagonist solution, a syringe barrel comprising about 1-100 μg, 3-100 μg, or 1-50
`
`μg of silicone oil, and stopper break loose and slide forces less than 11 N or 5 N.
`
`The claims are rendered obvious by (i) Sigg (Ex. 1007) or Lam (Ex. 1029), which
`
`disclose terminally sterilized pre-filled syringes containing a VEGF-antagonist; in
`
`combination with (ii) Boulange (Ex. 1008), which discloses “baked-on” syringes
`
`with < 50 µg of silicone oil and break loose and slide forces < 5N. The motivation
`
`to combine Sigg or Lam with Boulange is straightforward. The prior art discloses
`
`that reducing the amount of silicone oil in a pre-filled syringe minimizes unwanted
`
`interactions between the silicone oil and drug product, and also that reducing
`
`silicone oil decreases the risk of injecting silicone oil into a patient’s eye.
`
`
`
`Petitioner respectfully requests that the Board institute inter partes review of
`
`claims 1-26 of the ’631 Patent and cancel these claims as unpatentable.
`
`II. MANDATORY NOTICES
`A. Real Party-in-Interest
`The real party-in-interest is Regeneron Pharmaceuticals, Inc. (“Regeneron”).
`
`
`
`B. Related Matters
`On June 19, 2020, Novartis Pharma AG, Novartis Pharmaceuticals
`
`
`
`Corporation, and Novartis Technology LLC (collectively, “Novartis”) filed a
`
`1
`
`

`

`
`
`
`complaint at the International Trade Commission (“ITC”) alleging that Regeneron
`
`infringes claims 1-6 and 11-26 of the ’631 Patent, and that a domestic industry
`
`exists with respect to certain claims. On April 8, 2021, Novartis filed a motion to
`
`terminate the ITC Investigation on the basis of withdrawal of the complaint. On
`
`April 8, 2021, the Administrative Law Judge issued an initial determination
`
`terminating the ITC Investigation.
`
`
`
`On June 19, 2020, Novartis filed a complaint in the United States District
`
`Court for the Northern District of New York (N.D.N.Y. 1:20-cv-00690-TJM-CFH)
`
`alleging that Petitioner infringes at least claim 1 of the ’631 Patent. That case was
`
`stayed pursuant to 28 U.S.C. § 1659 on July 30, 2020.
`
`
`
`On July 16, 2020, Regeneron filed IPR2020-01317 and IPR2020-01318
`
`challenging claims 1-26 of the ’631 Patent. On December 2, 2020, Regeneron
`
`filed a motion to terminate IPR2020-01318 and the Board issued a determination
`
`terminating the proceeding on December 7, 2020. On January 15, 2021, the Board
`
`exercised its discretion under 35 U.S.C. § 314(a) and denied institution of
`
`IPR2020-01317 based on the co-pending ITC Investigation.
`
`
`
`On July 17, 2020, Regeneron filed a complaint in the United States District
`
`Court for the Southern District of New York against Novartis and Vetter Pharma
`
`International GmbH (“Vetter”) (S.D.N.Y. 1:20-cv-00502-AJN) seeking judgment
`
`that (i) Novartis’s and Vetter’s conduct violates Section 1 of the Sherman Act, 15
`
`
`
`2
`
`

`

`
`
`
`U.S.C. § 1; (ii) Novartis’s conduct violates Section 2 of the Sherman Act, 15
`
`U.S.C. § 2; and (iii) the ’631 Patent be declared unenforceable.
`
`C. Lead and Back-up Counsel and Service Information
`Lead Counsel:
`Backup Counsel:
`Elizabeth S. Weiswasser
`Brian E. Ferguson
`Reg. No. 55,721
`Reg. No. 36,801
`Backup Counsel:
`Christopher Pepe
`Anish R. Desai
`Reg. No. 73,851
`Reg. No. 73,760
`WEIL GOTSHAL & MANGES, LLP
`Natalie Kennedy
`2001 M Street NW, Suite 600
`Reg. No. 68,511
`Washington, DC 20036
`Andrew Gesior
`T: 202-682-7000
`Reg. No. 76,588
`
`WEIL GOTSHAL & MANGES LLP
`767 Fifth Avenue
`New York, NY 10153
`T: 212-310-8000
`
`
`Petitioner consents to service by electronic mail at:
`
`
`
`
`Regeneron.IPR.Service@weil.com.
`
`III. GROUNDS FOR STANDING
`
`Petitioner certifies that the ’631 Patent is available for IPR, and that
`
`Petitioner is not barred or estopped from requesting IPR.
`
`IV. 35 U.S.C. §§ 314(a), 325(d)
`
`The Board should decline any request to discretionarily deny institution of
`
`this IPR under 35 U.S.C. §§ 314(a) or 325(d). The history between Novartis and
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`3
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`Regeneron concerning the ʼ631 Patent compels the conclusion that institution is
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`appropriate and warranted.
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`A. Denial Pursuant to § 314(a) Is Not Appropriate
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`As explained in Section II.B, less than one month after Novartis filed its
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`complaint in the ITC, Regeneron filed IPR2020-1317 and IPR2020-1318. In its
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`POPRs, Novartis asserted that the Board should deny institution under § 314(a)
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`and § 325(d). As to § 314(a), Novartis was unequivocal – the IPR should not be
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`instituted because the ITC Action “will be tried approximately nine months, and
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`decided approximately six months, before any potential final written decision….”
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`Ex. 1050.012.1 According to Novartis, based on the Investigation, “all the Fintiv
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`factors weigh heavily against institution.” Id. Novartis urged the Board to deny
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`institution to avoid “engag[ing] in the inefficiencies, duplication of efforts and
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`potential for inconsistent decisions….” Id. at .012-013.
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`Regeneron filed a response to Novartis’s §§ 314(a), 325(d) arguments.
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`Novartis filed a sur-reply, repeating its position that the ITC “will produce a final
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`determination before the Board’s [FWD].” Ex. 1051.010. Novartis also
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`characterized Regeneron’s argument that the ITC defers to the Board’s expertise as
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`“irrelevant” because “the ITC’s final determination will come months before a
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`[FWD].” Id. at .012 (second emphasis in original); see id. (relying on the April 19,
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`1 All emphasis added unless noted otherwise.
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`4
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`2021 ITC hearing date and November 29, 2021 final ITC determination deadline);
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`id. at .014-015 (emphasizing that the ALJ told the parties that “this case is going to
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`go to trial”).
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`The Board denied institution based solely on Novartis’s § 314(a) arguments.
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`Ex. 1064.002. Specifically, the Board relied on Novartis’s assertion that the ITC
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`trial is the “key date for consideration” of Fintiv Factor 2 (id. at 14) and “agree[d]
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`with [Novartis] that the advanced stage of the ITC investigation weighs in its
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`favor….” Id. at .015. See also id. at .023 (“The outcome of the ITC Investigation
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`will be known months before we could reach a final determination.”).
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`The ITC Investigation proceeded. On March 26, 2021, the ITC Staff, an
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`independent arm of the government tasked with representing the public interest in
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`ITC investigations, submitted its pretrial brief. In a 200-page analysis of the facts
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`and evidence adduced by the parties, the Staff agreed that “the asserted claims [of
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`the ʼ631 Patent] are invalid.” Ex. 1005.013. Relevant to this Petition, the Staff
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`agreed that “the claimed invention of the ʼ631 patent would have been obvious
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`over the asserted combinations,” which included Sigg in view of Boulange and
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`Lam in view of Boulange. Ex. 1005.044-045. Thus, the Staff agreed that there as
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`clear and convincing evidence of obviousness. Id. at .025; see id. at .057-081
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`(Sigg in view of Boulange); id. at .089-094 (Lam in view of Boulange).
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`5
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`On April 8, 2021, Novartis filed a motion to terminate the ITC Investigation
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`by withdrawing its complaint—12 days before the start of trial—which the ALJ
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`granted. Ex. 1006; Ex. 1010. Novartis then asked the Court in the NDNY case to
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`lift the stay and proceed there. Ex. 1079. Accordingly, there is no longer an ITC
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`Investigation, while the NDNY case is stayed with no schedule set.
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`1.
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`The Fintiv Factors
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`Factor One: The NDNY case is currently stayed. Moreover, Regeneron has
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`not yet answered the complaint in the NDNY, and Regeneron intends to ask the
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`Court to maintain the stay pending the outcome of this IPR. No schedule or trial
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`date has been set and the most recent data from the NDNY shows that the time to
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`trial in civil cases is 40 months. Ex. 1078.002. With respect to the SDNY case, the
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`enforceability – not invalidity – of the ʼ631 Patent is at issue. Unenforceability and
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`invalidity are separate legal defenses. Smith Int’l, Inc. v. Hughes Tool Co., 759
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`F.2d 1572, 1578 (Fed. Cir. 1985). Regardless, there is currently a pending motion
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`by Novartis to transfer the SDNY case to the NDNY and no trial date has been set
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`by the SDNY. Ex. 1077. This factor favors institution.
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`Factor Two: There is no trial date in the NDNY (or SDNY), and even
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`assuming the NDNY case does not remain stayed, the typical time to trial is 40
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`months. Thus, the trial in NDNY will likely not occur for up to two years after a
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`FWD in this proceeding. This factor favors institution.
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`6
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`Factor Three: There has been no investment by the parties or Court in the
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`NDNY case, and the SDNY case has been limited to motion practice, and re-
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`production of documents produced during the ITC investigation. Moreover, no
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`Markman hearing will be scheduled in the SDNY case. This factor favors
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`institution.
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`Factor Four: There will be no overlap of issues. Should the Board institute
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`this IPR and find the ʼ631 Patent claims invalid, the NDNY case will not proceed
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`as to infringement and invalidity. Moreover, if this IPR is instituted, the estoppel
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`provisions of 35 U.S.C. § 315(e) will apply. Similarly, the obviousness grounds in
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`this Petition will not be decided in the SDNY case, as the issue of inequitable
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`conduct does not involve Lam or Boulange. This factor favors institution.
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`Factor Five: Regeneron and Novartis are the same parties in the NDNY
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`case and in this proceeding.
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`Factor Six: Significant “other circumstances” exist that weigh heavily in
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`favor of institution. First, as detailed in Section IV.A, Novartis repeatedly told the
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`Board in the 1317 IPR that the ITC would issue a final determination addressing
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`the validity of the ʼ631 Patent. The Board relied on Novartis’s representations in
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`denying institution. But when faced with the Staff’s position that there is clear and
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`convincing evidence that the ʼ631 Patent claims are invalid as obvious based on the
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`Sigg/Boulange and Lam/Boulange combinations, Novartis fled from the ITC
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`Investigation.2
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`The Board should not countenance such gamesmanship. Novartis used the
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`ITC Investigation to convince the Board to deny institution of the 1317 IPR, then
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`terminated the ITC Investigation before any determination of invalidity. Novartis
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`now wants to proceed with the NDNY case. General principles of fairness and
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`2
`Novartis may argue that it withdrew the ITC complaint because of concerns
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`that the Staff raised that the remedy Novartis sought— exclusion of Regeneron’s
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`flagship product from the U.S. market—would harm the public interest. That
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`argument is not credible in light of the Staff’s findings that the ʼ631 Patent claims
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`are invalid under both §§ 102(f) and 103. Tellingly, Novartis has stated that it will
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`continue to “vigorously prosecute” the ʼ631 Patent against Regeneron. Ex.
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`1084.003. Further, the NDNY complaint seeks preliminary and permanent
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`injunctive relief, and includes the statement that “[t]he public interest would not be
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`disserved by injunctive relief.” Ex. 1082.006. Novartis has also been aware of the
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`adverse impact its requested relief would have on the public interest since July 7,
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`2020, when Regeneron and others filed public interest statements in the ITC. Ex.
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`1084, Ex. 1085. Yet, Novartis moved forward in the ITC for months without
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`concern for the public interest.
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`8
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`equity dictate that Novartis should not be allowed to hit “reset” and proceed in the
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`NDNY case while avoiding a trial in this IPR proceeding. Put simply, the Board
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`should stop the gamesmanship and allow institution.
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`Second, the merits of Regeneron’s petition are objectively strong. The ITC
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`Staff already agreed that Regeneron put forward clear and convincing evidence
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`that the ʼ631 Patent claims are obvious based on the Sigg/Boulange and
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`Lam/Boulange combinations. That is more than enough to meet the threshold
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`“reasonable likelihood” standard for institution. 35 U.S.C. § 314.
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`Accordingly, the Fintiv factors overwhelmingly support institution, and the
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`Board should reject any argument by Novartis under § 314(a).
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`B. Denial Pursuant to § 325(d) Is Not Appropriate
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`In the 1317 and 1318 IPRs, Novartis argued that the Board should deny
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`institution under § 325(d) because Sigg, Lam, and Boulange are allegedly
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`“cumulative” of art before the Examiner. That argument should be rejected if
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`Novartis makes it again. See Becton, Dickinson and Co. v. B. Braun Melsungen
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`AG, IPR2017-01586, Paper 8 (PTAB Dec. 15, 2017).
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`First, there is no dispute that Sigg, Lam, and Boulange were not before the
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`examiner during prosecution. This alone supports the Board not exercising its
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`discretion to deny institution. Oticon Medical AB v. Cochlear Ltd., IPR2019-
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`00975, Paper 15 at 19-20 (PTAB Oct. 19, 2019) (precedential). Second, the ITC
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`Staff extensively examined Sigg, Lam, and Boulange, and confirmed that there
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`was clear and convincing evidence that the Sigg/Boulange and Lam/Boulange
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`combinations rendered the claims obvious. The Staff’s conclusion confirms that
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`Sigg, Lam, and Boulange are not merely cumulative of the art considered during
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`prosecution.
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`Third, there was no art before the Examiner that disclosed terminal
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`sterilization of a pre-filled syringe with a VEGF-antagonist—the very subject
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`matter that Sigg and Lam disclose. Ex. 1003, ¶¶ 116-117. The ʼ631 Patent
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`discloses that existing techniques – ethylene oxide and hydrogen peroxide – may
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`be used, but fails to acknowledge that they had been used on pre-filled syringes
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`containing a VEGF-antagonist. Ex. 1001 at 9:49-54. The Examiner allowed the
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`claims only after Novartis amended them to add that the pre-filled syringe was
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`“terminally sterilized.” The Examiner, however, did not have Sigg or Lam before
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`her, which is particularly egregious given that Sigg is assigned to Novartis and has
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`the same first named inventor as the ’631 Patent.
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`As to Boulange, it clearly discloses a baked-on syringe with the claimed
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`silicone oil ranges, and break loose and slide forces. There was no single reference
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`before the Examiner that disclosed a syringe that met both the silicone oil and
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`force limitations of the challenged claims. Ex. 1003, ¶ 118.
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`10
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`Sigg, Lam and Boulange are not cumulative. Accordingly, there is no basis
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`to deny institution under § 325(d).
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`V. TECHNOLOGY BACKGROUND
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`The technology overview set forth below is based on prior art to the ’631
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`Patent. See also Ex. 1003, ¶¶ 33-92.
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`A.
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`Pre-filled Syringes for Intravitreal Injection
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`A pre-filled syringe is packaged with a drug formulation already filled, and
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`provides advantages of less overfill, accurate dosing, and quicker administration.
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`Ex. 1003, ¶¶ 36-41. A typical pre-filled syringe includes several basic
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`components: a glass or plast