UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`REGENERON PHARMACEUTICALS, INC.,
`Petitioner,
`
`v.
`
`NOVARTIS PHARMA AG,
`NOVARTIS TECHNOLOGY LLC,
`NOVARTIS PHARMACEUTICALS CORPORATION,
`Patent Owner.
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`
`Case No. IPR2020-01317
`U.S. Patent No. 9,220,631
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`
`
`
`PETITION FOR INTER PARTES REVIEW
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`

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`IPR2020-01317
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`V.
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`TABLE OF CONTENTS
`INTRODUCTION ........................................................................................... 1 
`I.
`II. MANDATORY NOTICES ............................................................................. 4 
`A.
`Real Party-in-Interest ............................................................................ 4 
`B.
`Related Matters ...................................................................................... 4 
`C.
`Lead and Back-up Counsel and Service Information ........................... 4 
`III. GROUNDS FOR STANDING ........................................................................ 5 
`IV. OVERVIEW OF THE TECHNOLOGY AT ISSUE ...................................... 5 
`A.
`Pre-filled Syringes ................................................................................. 5 
`B.
`Siliconization of Syringe Barrels .......................................................... 7 
`C.
`Sterilization of Drug Products and Container Systems ....................... 10 
`D.
`Particulate Content .............................................................................. 13 
`THE ’631 PATENT ....................................................................................... 13 
`A.
`The Challenged Claims ....................................................................... 14 
`B.
`The Specification ................................................................................. 16 
`1.
`Siliconization Methods and Alleged Surprising Results .......... 16 
`2.
`Terminal Sterilization ............................................................... 19 
`3.
`Particulate Content .................................................................... 19 
`The Prosecution History ...................................................................... 20 
`C.
`STATUTORY GROUNDS FOR THE CHALLENGES .............................. 22 
`VI.
`VII. LEVEL OF ORDINARY SKILL IN THE ART ........................................... 26 
`VIII. CLAIM CONSTRUCTION .......................................................................... 27 
`A.
`“Stopper Break Loose Force” ............................................................. 27 
`B.
`“Stopper Slide Force” .......................................................................... 28 
`C.
`“Terminally sterilized” ........................................................................ 28 
`IDENTIFICATION OF HOW THE CHALLENGED CLAIMS ARE
`UNPATENTABLE ........................................................................................ 29 
`A.
`Ground 1: Sigg in view of Boulange .................................................. 29 
`
`IX.
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`IPR2020-01317
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`1.
`2.
`3.
`
`Overview of Sigg ...................................................................... 30 
`Overview of Boulange .............................................................. 32 
`Motivation to Combine and Reasonable Expectation of
`Success ...................................................................................... 37 
`Claim 1 ...................................................................................... 43 
`4.
`Claims 2, 3, 5-9, 14, 16-22 and 24 ............................................ 49 
`5.
`Claim 15 .................................................................................... 57 
`6.
`Ground 2: Sigg in view of Boulange and Fries .................................. 59 
`B.
`Ground 3: Sigg in view of Boulange and Furfine .............................. 61 
`C.
`Ground 4: Sigg in view of Boulange and Macugen Label ............... 63 
`D.
`Ground 5: Sigg in view of Boulange and Dixon ................................ 65 
`E.
`CONCLUSION .............................................................................................. 67 
`
`X.
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`IPR2020-01317
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`PETITIONER’S EXHIBIT LIST
`
`Ex. 1001 U.S. Patent No. 9,220,631 (“the ’631 Patent”)
`
`Ex. 1002 Prosecution File History of U.S. Patent No. 9,220,631
`
`Ex. 1003 Declaration of Horst Koller under 37 C.F.R. § 1.68.
`
`Ex. 1004 Curriculum Vitae of Horst Koller
`
`Ex. 1005 Declaration of James Agalloco under 37 C.F.R. § 1.68.
`
`Ex. 1006 Curriculum Vitae of James Agalloco
`
`Ex. 1007 PCT Patent Publication No. WO 2011/006877 to Sigg et al. (“Sigg”)
`
`Ex. 1008 PCT Patent Publication No. WO 2009/030976 to Boulange et al.
`(“Boulange”)
`
`Ex. 1009 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 (“Macugen® Label”)
`
`Ex. 1010 Certified English Translation of Bruno Reuter and Claudia Petersen.
`“Die Silikonisierung von Spritzen: Trends, Methoden,
`Analyseverfahren,” TechnoPharm 2, Nr. 4 (2012): 238-244.
`(“Reuter”)
`
`Ex. 1011 Bhavnesh D. Shah & Bhupendra G. Prajapati, Pre-Filled Syringes: A
`New Concept, PHARMA BIO WORLD 51 (2009) (“Shah”)
`
`Ex. 1012 Arno Fries, Drug Delivery of Sensitive Biopharmaceuticals With
`Prefilled Syringes, 9(5) DRUG DELIVERY TECH. 22 (2009) (“Fries”)
`
`Ex. 1013 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”)
`
`Ex. 1014 U.S. Patent Publication No. 2012/0091026 to Chacornac et al.
`(“Chacornac”)
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`Ex. 1015 Sandeep Nema & John D. Ludwig, Pharmaceutical Dosage Forms:
`Parenteral Medications, Volume 1: Formulation and Packaging (3rd
`ed. 2010) (“Nema Vol. 1”)
`
`Ex. 1016 Sandeep Nema & John D. Ludwig, Pharmaceutical Dosage Forms:
`Parenteral Medications, Volume 2: Facility Design, Sterilization and
`Processing (3rd ed. 2010) (“Nema Vol. 2”)
`
`Ex. 1017 PCT Patent Publication No. WO 2007/035621 to Scypinski et al.
`(“Scypinski”)
`
`Ex. 1018 U.S. Patent Publication No. 2003/0003014 to Metzner et al.
`(“Metzner”)
`
`Ex. 1019 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. 1021 PCT Patent Publication No. WO 2007/149334 to Furfine et al.
`(“Furfine”)
`
`Ex. 1022 Michael W. Stewart et al., Fresh From the Pipeline Aflibercept, 11
`NAT. REV. DRUG DISCOV. 269 (2012) (“Stewart”)
`
`Ex. 1023 U.S. Patent No. 7,060,269 to Baca et al. (“Baca”)
`
`Ex. 1024 Prosecution File History of U.S. Patent No. 7,060,269
`
`Ex. 1025 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”)
`
`Ex. 1026 U.S. Patent No. 7,404,278 to Wittland et al. (“Wittland”)
`
`Ex. 1027 U.S. Food and Drug Administration, Lucentis® Highlights of the
`Prescribing Information, (June 2010) (“Lucentis® Label”)
`
`Ex. 1028 International Organization for Standardization, ISO 11040-4 Prefilled
`Syringes – Part 4: Glass Barrels for Injectables (2nd ed. 2007) (“ISO
`11040-4”)
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`Ex. 1029 PCT Patent Publication No. WO 2008/077155 to Lam et al. (“Lam”)
`
`Ex. 1030 James A. Dixon, et al. "VEGF Trap-Eye for the treatment of
`neovascular age-related macular degeneration." Expert opinion on
`investigational drugs 18.10 (2009): 1573-1580. (“Dixon”)
`
`Ex. 1031 Declaration of Dr. Szilard Kiss under 37 C.F.R. § 1.68.
`
`Ex. 1032 Curriculum Vitae of Dr. Szilard Kiss
`
`Ex. 1033 Declaration of James L. Mullins, Ph.D.
`
`Ex. 1034 Dow Corning® 365 35% Dimethicone NF Emulsion – Frequently
`Asked Questions (2002) (“DC365 FAQ”)
`
`Ex. 1035 European Patent Application No. 12174860 to Novartis AG
`
`Ex. 1036 U.S. Food and Drug Administration, Guidance for Industry: Sterile
`Drug Products Produced by Aseptic Processing—Current Good
`Manufacturing Practice (September 2004)
`
`Ex. 1037 Affidavit of Internet Archive Office Manager
`
`Ex. 1038 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/
`
`Ex. 1039 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/
`
`Ex. 1040 U.S. Food and Drug Administration, Eylea® Highlights of the
`Prescribing Information, (November 2011) (“Eylea label”)
`Ex. 1041 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
`Ex. 1042 International Standard ISO-7864, Sterile hypodermic needles for
`single use, ISO 7864:1993(E) (“ISO-7864”)
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`Ex. 1043 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”)
`Ex. 1044 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”)_
`Ex. 1045 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”)
`Ex. 1046 Pamela Carter, et al. The lowdown on low temperature sterilization
`for packaged devices, Healthcare Purchasing News, July 2008, 42-45.
`(“Carter”)
`Ex. 1047 U.S. Patent Publication No. 2005/0182370 to Hato (“Hato”)
`
`Ex. 1048 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”)
`Ex. 1049 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”)_
`Ex. 1050 K. Kereluk, et al. Microbiological Aspects of Ethylene Oxide
`Sterilization: I. Experimental Apparatus & Methods, Applied
`Microbiology 1970, 19(1):146-151. (“Kereluk”)
`Ex. 1051 Carl Hultman, et al. The Physical Chemistry of Decontamination with
`Gaseous Hydrogen Peroxide, Pharmaceutical Engineering,
`January/February 2007, 27(1):1-6 (“Hultman”)
`Ex. 1052 John R. Gillis & Gregg Mosley, Validation of Pharmaceutical
`Processes, Chapter 16 – Validation of Ethylene Oxide Sterilization
`Processes (2011), pp.241-262.
`Ex. 1053 FDA Pesticide Analytical Manual Vol. 1, Chapter 6 - HPLC,
`available at
`https://www.fda.gov/downloads/Food/FoodScienceResearch/
`ucm113651.pdf
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`Ex. 1054 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 )
`Ex. 1055 J.S. Penn, et al. Vascular Endothelial Growth Factor in Eye Disease,
`Prog. Retin Eye Res., July 2008, 27(4):331-371. (“Penn2008”)
`Ex. 1056 U.S. Food and Drug Administration, Trivaris ® Highlights of the
`Prescribing Information, (May 2008) (“Trivaris label”)
`Ex. 1057 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
`Ex. 1058 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”)
`Ex. 1059 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”)
`Ex. 1060 Curriculum Vitae of James L. Mullins, Ph.D.
`
`Ex. 1061 DUPONT™ TYVEK® COMPLIANCE TO ISO 11607-1:2006
`(2011)
`Ex. 1062 Center for Drug Evaluation and Research, Application Number: 21-
`756, Approved Labeling, Macugen® (pegaptanib sodium injection)
`(December 17, 2004)
`Ex. 1063 Evangelos S. Gragoudas et al., Pegaptanib for Neovascular Age-
`Related Macular Degeneration, New England Journal of Medicine
`2004; 351:2805-16, with Supplementary Appendix.
`Ex. 1064 Bruno Reuter and Claudia Petersen. “Die Silikonisierung von
`Spritzen: Trends, Methoden, Analyseverfahren,” TechnoPharm 2, Nr.
`4 (2012): 238-244. (Untranslated German version.)
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`IPR2020-01317
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`Pursuant to 35 U.S.C. § 312 and 37 C.F.R. § 42.100, Regeneron
`
`Pharmaceuticals, Inc. (“Petitioner”) respectfully requests inter partes review of
`
`claims 1-26 of U.S. Patent No. 9,220,631 (“the ’631 Patent”).
`
`I.
`
`INTRODUCTION
`The claims of the ’631 Patent are directed to a terminally sterilized, low-
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`volume (0.5–1 mL) volume pre-filled glass syringe for intravitreal injection that
`
`includes 1-100 μg of silicone oil on the syringe barrel and has stopper break loose
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`and slide forces that are less than 11 N or 5 N. The claims also require that the
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`syringe contains a vascular endothelial growth factor (“VEGF”) antagonist solution
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`that meets requirements set forth in the prior art U.S. Pharmacopeia (“USP”),
`
`Chapter <789>, Particulate Matter in Ophthalmic Solutions (i.e., fewer than 2
`
`particles per mL that are ≥ 50 µm, fewer than 50 particles per mL that are ≥ 10 µm,
`
`and/or fewer than 5 particles per mL that are ≥ 25 µm). These claims were allowed
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`only because the prior art of record during prosecution did not include prior art
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`patents and publications that disclose (i) terminal sterilization of low-volume pre-
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`filled glass syringes containing a VEGF-antagonist solution, and (ii) glass syringes
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`made with a process known as “baked-on siliconization,” which utilizes levels of
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`silicone oil below 100 µg, and results in break loose and slide forces below 11 N
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`and 5 N as claimed in the ’631 Patent.
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`During prosecution of the ’631 Patent, the claims were repeatedly rejected
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`IPR2020-01317
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`by the Examiner as being obvious and were allowed only after Patent Owner
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`amended the claims to require that the pre-filled syringe be “terminally sterilized.”
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`However, the prior art of record did not include WO 2011/006877 (“Sigg”) (Ex.
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`1007). Sigg unquestionably discloses terminal sterilization of a low-volume pre-
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`filled glass syringe containing a VEGF-antagonist solution. Ex. 1007 at 7:21-8:7,
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`9:11-10:16, 20:10-25.
`
`
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`This Petition also introduces prior art that contradict the statements made
`
`during prosecution by the applicants that they were the “first” to show that reduced
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`levels of silicone oil can be used in a pre-filled syringe while still retaining typical
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`break loose and slide forces. Ex. 1002.1276 (“The applicants have shown for the
`
`first time that you can reduce the silicone levels to far below previous standards
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`and still obtain a usable syringe…This flies in the face of conventional wisdom.”).
`
`For example, WO 2009/030976 (“Boulange”) (Ex. 1008) discloses glass syringes
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`made using a well-known process referred to as baked-on siliconization. This
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`process, which was not invented by the applicants and is disclosed in numerous
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`prior art references, involves the use of lower levels of silicone oil (~40 µg for 1
`
`mL syringe) in comparison to sprayed-on silicone without baking (~500 µg for 1
`
`mL syringe), and results in stopper break loose and slide forces of less than 11 N
`
`and 5 N – exactly as claimed in the ’631 Patent. Ex. 1008 at 6:10-29, 13:8-15,
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`14:14-15:21, 21:1-22:8. The Examiner therefore did not have key prior art (e.g.,
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`IPR2020-01317
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`Sigg and Boulange) demonstrating the obviousness of the claims of the ’631 Patent
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`during prosecution.
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`The motivation to combine the baked-on siliconized syringe disclosed in
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`Boulange with the terminally sterilized pre-filled syringe in Sigg is
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`straightforward. The prior art is replete with teachings that reducing the amount of
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`silicone oil in a pre-filled syringe is beneficial to avoid unwanted reactions
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`between the silicone oil and the therapeutic drug contained in the syringe.
`
`Boulange itself discloses that “with the medical device of the invention, it is
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`possible to decrease the total amount of lubricant, for example silicone oil, that is
`
`necessary in such a medical device” and “[i]n consequence, the medical device of
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`the invention allows to limit the risk of interaction between…silicone oil, and the
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`therapeutic molecules potentially stored in the container of the medical device.”
`
`Ex. 1008 at 6:23-29. This Petition demonstrates that the combination of Sigg with
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`Boulange would have been obvious to a POSITA as the application of a known
`
`technique (baked-on siliconization) to a known device (terminally sterilized pre-
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`filled syringe) that yields a predictable result (lower the amount of silicone oil
`
`while retaining typical break loose and slide forces).
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`For the reasons set forth in detail below, Petitioner respectfully requests that
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`IPR2020-01317
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`the Board institute inter partes review of claims 1-26 of the ’631 Patent and cancel
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`these claims as unpatentable pursuant to 35 U.S.C. § 103.
`
`II. MANDATORY NOTICES
`A. Real Party-in-Interest
`The real party-in-interest is Regeneron Pharmaceuticals, Inc.
`
`
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`B. Related Matters
`On June 19, 2020, Novartis Pharma AG, Novartis Pharmaceuticals
`
`
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`Corporation, and Novartis Technology LLC filed a complaint at the U.S.
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`International Trade Commission alleging that Petitioner infringes claims 1-6 and
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`11-26 of the ’631 Patent, and that a domestic industry exists with respect to claims
`
`1-10 and 14-26 of the ’631 Patent. On the same day, Novartis Pharma AG,
`
`Novartis Pharmaceuticals Corporation, and Novartis Technology LLC filed a
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`complaint in the United States District Court for the Northern District of New York
`
`alleging that Petitioner infringes at least claim 1 of the ’631 Patent.
`
`C. Lead and Back-up Counsel and Service Information
`Elizabeth S. Weiswasser (lead counsel)
`Brian E. Ferguson (backup counsel)
`Reg. No. 55,721
`Reg. No. 36,801
`Anish R. Desai (backup counsel)
`Christopher Pepe (backup counsel)
`Reg. No. 73,760
`Reg. No. 73,851
`Natalie Kennedy (backup counsel)
`WEIL GOTSHAL & MANGES, LLP
`Reg. No. 68,511
`2001 M Street NW, Suite 600
`Andrew Gesior (backup counsel)
`Washington, DC 20036
`Reg. No. 76,588
`T: 202-682-7000
`WEIL GOTSHAL & MANGES LLP
`F: 202-857-0940
`
`
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`IPR2020-01317
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`767 Fifth Avenue
`New York, NY 10153
`T: 212-310-8000
`F: 212-310-8007
`
`Petitioner consents to service by electronic mail at the following email
`
`address: Regeneron.IPR.Service@weil.com.
`
`III. GROUNDS FOR STANDING
`
`Petitioner certifies that the ’631 Patent is available for inter partes review
`
`and that Petitioner is not barred or estopped from requesting inter partes review
`
`challenging the patent claims on the grounds identified in this Petition.
`
`IV. OVERVIEW OF THE TECHNOLOGY AT ISSUE
`
`The below sections provide an overview of pre-filled syringes, siliconization
`
`of syringe barrels, sterilization of drug products and container systems, and the
`
`USP particulate content requirements for ophthalmic solutions. The content of the
`
`sub-sections below is based on patents and publications that are prior art to the
`
`’631 Patent.
`
`A.
`
`Pre-filled Syringes
`
`A pre-filled syringe is packaged and sold with a drug formulation already
`
`loaded into the syringe. Ex. 1003, ¶¶ 34-35. This provides several well-known
`
`advantages over vials, including less overfill, accurate dosing, quicker preparation
`
`and administration, product differentiation, potential for increased sales, and
`
`practitioner convenience. Id. ¶ 39. A typical pre-filled syringe includes several
`
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`basic components: a glass or plastic barrel, a stopper, a plunger rod, and a needle,
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`as illustrated below. Id. ¶¶ 36-38.
`
`Ex. 1011.002
`
`
`
`
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`Syringes have been sold for decades in standardized sizes prescribed by the
`
`International Organization for Standardization (ISO). Ex. 1003, ¶ 41. Three
`
`common standardized glass syringe sizes for small volume applications are the 0.5
`
`mL, the 1 mL long, and the 1 mL short/standard syringe, whose dimensions are
`
`presented in the table below. Id. Syringe needle sizes have also been standardized,
`
`and are referred to by their “gauge,” which denotes a set of standardized
`
`dimensions for each needle. Id. ¶ 42. A higher gauge number indicates a finer
`
`needle. Id.
`
`Nominal Volume Barrel Inner Diameter Barrel Length
`0.5 mL
`4.65 mm
`47.6 mm
`1 mL (long)
`6.35 mm
`54 mm
`1 mL (short)
`8.65 mm
`35.7 mm
`
`Ex. 1028.008
`
`Pre-filled syringes may be used to administer VEGF-antagonists, which are
`
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`
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`compounds that inhibit the expression of VEGF, a protein within the human body
`
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`whose overexpression contributes to diseases including cancer and vascular
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`IPR2020-01317
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`diseases of the eye. Ex. 1003, ¶¶ 32-33; Ex. 1031, ¶¶ 22-28. VEGF-antagonists
`
`are administered intravitreally1 to treat certain eye diseases, including “the
`
`neovascular (wet) form of age-related macular degeneration (AMD), a leading
`
`cause of blindness.” Ex. 1009.002. Several VEGF-antagonists were known and
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`commercially available before the earliest priority date of the ’631 Patent,
`
`including ranibizumab (Lucentis®), aflibercept (Eylea®), and pegaptanib
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`(Macugen®). Ex. 1031, ¶ 23. At least Macugen® had been commercially
`
`available as a pre-filled glass syringe for intravitreal administration several years
`
`before 2012. Ex. 1009.001, .008-.009; Ex. 1031, ¶¶ 25-27. The use of a low
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`volume, pre-filled glass syringe with a fine gauge needle for intravitreal injection
`
`of a VEGF-antagonist solution was known in the prior art before the earliest
`
`priority date of the ’631 Patent. Ex. 1003, ¶¶ 43; Ex. 1031, ¶¶ 25-28.
`
`B.
`Siliconization of Syringe Barrels
`To ensure proper delivery of an injectable pharmaceutical by way of a pre-
`
`filled syringe, the stopper must move through the barrel to expel the solution. This
`
`requires a certain force to start movement of the stopper from the resting position
`
`
`1 An intravitreal injection is an injection into the space in the back of the eye called
`
`the vitreous cavity. Ex. 1031, ¶ 23.
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`(called break loose or activation force), and a certain force to keep the stopper
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`IPR2020-01317
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`moving through the barrel (called gliding or slide force). Ex. 1003, ¶¶ 44-50.
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`These forces should preferably be minimized to ensure smooth and safe
`
`administration, particularly in pre-filled syringes for intravitreal applications. Id.
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`It was well-known that applying silicone oil to the glass syringe barrel provides an
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`interface between the stopper and the glass to reduce the break loose and slide
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`force, which allows for a smooth transition.2 Id. ¶¶ 51-54. Two known methods
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`for applying silicone oil to a syringe barrel are discussed below.
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`One known method of applying silicone oil to a syringe barrel involves
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`spraying silicone oil onto the barrel without further processing, which is known as
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`“spray-on” or “oily” siliconization. Ex. 1003, ¶¶ 55-59. While oily siliconization
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`produces desirable break loose and slide forces, a relatively large amount of
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`silicone oil is needed, which can have undesirable effects. See, e.g., Ex. 1012.006
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`(“[e]ven though silicone oil is inert toward most drug products, interactions with
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`sensitive biopharmaceuticals have been observed…includ[ing] aggregation,
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`deformation, and inactivation of native protein structures.”); Ex. 1015.330. This is
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`especially relevant in protein or biologic drugs administered into the eye because
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`2 The characteristics of the stopper also play a role in reducing break loose and
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`slide forces. Ex. 1003, ¶¶ 69-75.
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`the presence of silicone oil droplets can cause an increase in intraocular pressure,
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`aggregation or denaturation of the protein or biologic, and vision issues including
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`floaters in the eye. Ex. 1013.004; Ex. 1025.011; Ex. 1003, ¶¶ 57-59. Thus,
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`syringe manufacturers developed a process called “baked-on siliconization” that
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`minimizes interaction between silicone oil and the drug product contained in the
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`pre-filled syringe.
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`Baked-on siliconization was disclosed in the prior art years before the
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`earliest claimed priority filing date of the ’631 Patent. Ex. 1003, ¶¶ 60-68. It
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`requires less silicone oil and better maintains the integrity of a layer of silicone oil
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`in the syringe barrel, thereby minimizing the amount of free silicone that can
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`interact with the drug product. Id. Importantly, the baked-on method substantially
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`reduces the amount of silicone oil on the syringe barrel without impacting the
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`stopper break loose or slide forces. See, e.g., Ex. 1044.008 (“baked-on syringes,
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`which approximately contain ten-fold less free silicone oil, showed no deleterious
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`impact on product quality and no increase in subvisible particles formation”); Ex.
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`1008 at 21:1-5 (Table 7 disclosing low break loose and slide forces for a baked-on
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`pre-filled syringe including 4 µg/cm2 silicone on the syringe barrel as compared to
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`50 µg/cm2 silicone for spray-on syringe); see also Ex. 1003, ¶¶ 60-68.
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`The figure below from a 2005 publication illustrates how the break-loose
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`and slide forces for a baked-on syringe compare with that of an “oily” (non-baked)
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`syringe. The baked-on syringe and the oily syringe have the same break loose and
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`slide forces initially, thus showing that the reduced amount of silicone oil used in a
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`baked-on syringe does not affect usability. Id. ¶ 65. The baked-on syringe
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`provides the additional benefit that the break loose force does not increase as much
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`during storage as compared to the oily syringe. Id. The 2005 publication also
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`notes that the concentration of silicone oil in the baked-on syringe is reduced. Ex.
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`1013.004.
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`Ex. 1013.004 (annotations in orange)
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`
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`C.
`Sterilization of Drug Products and Container Systems
`It is well-known that many medical grade products should be sterile prior to
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`
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`being used by a practitioner to avoid infection or other risks for patients. Ex. 1005,
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`¶ 25; Ex. 1003, ¶ 76. Regulatory agencies, such as the FDA and EMA all require
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`ophthalmic products, such as a pre-filled syringe for intravitreal application, to be
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`sterile. Id. The FDA, in its guidance on aseptic filling, indicates that “terminal
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`sterilization” is required when possible. Ex. 1005, ¶ 26. In this context, which as
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`explained below is different from what is described in the ’631 Patent, “terminal
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`sterilization” typically refers to a process in which the drug and its container (i.e.,
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`syringe) are sterilized together in a single process. Ex. 1005, ¶¶ 26-27; Ex. 1003, ¶
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`79. This type of one-step terminal sterilization, available for drugs that are not
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`heat sensitive, can be accomplished by heating (for example, in an autoclave) with
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`steam to sterilize both the syringe and the drug product contained with the syringe.
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`Ex. 1005, ¶ 26. Sterilization processes that do not use high temperatures were also
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`well-known, such as sterilization using ethylene oxide (“EtO”) and vaporized
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`hydrogen peroxide (H2O2) (“VHP”). Ex. 1005, ¶¶ 28-34; Ex. 1003, ¶¶ 78-86.
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`
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`For sensitive drugs such as biologics, it was well known that the drug itself
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`often cannot withstand the heat and pressure used in typical sterilization processes,
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`such as autoclaving, and also should not come into contact with sterilizing agents,
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`such as EtO and VHP, which may denature the protein or negatively affect the
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`sensitive formulation. Ex. 1005, ¶ 28; Ex. 1003, ¶ 77. Thus, for pre-filled syringes
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`containing biologics, the prior art discloses that (i) the drug formulation is
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`sterilized separately, for example by filtering, (ii) the sterile drug formulation is
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`aseptically filled into the syringe; and (iii) the outer surface of the syringe is
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`sterilized using cold sterilization gases such as EtO or VHP, while contact between
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`the sterilizing gases and the drug formulation in the syringe is avoided. Ex. 1005,
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`¶¶ 30-34; Ex. 1003, ¶¶ 79-86. The “terminal sterilization” discussed and claimed
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`in the ’631 Patent refers to this type of known sterilization process where the outer
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`surface of the syringe is sterilized, and contact between the sterilizing agent and
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`the drug product in the syringe is avoided. Ex. 1001 at 1:17-37, 9:49-10:22.
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`
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`More specifically, it was known in the art that the outer surface of a pre-
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`filled syringe containing sensitive therapeutics (e.g., VEGF antagonists) can be
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`sterilized using EtO or VHP, including when the pre-filled syringe is in secondary
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`packaging (e.g., blister pack). Ex. 1005, ¶¶ 33-36; Ex. 1003, ¶¶ 81-88. WO
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`2008/077155 (“Lam”), which was published in June 2008, discloses filling a
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`syringe with sterile VEGF-antagonist ranibizumab (Lucentis®) formulation, and
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`performing EtO sterilization of the outer surface of such syringe. Ex. 1029 at 2:1-
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`33, 3:17-19, 7:19-26, 12:10-11, 13:10-15. In addition, Sigg, which was published
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`in January 2011, discloses aseptic filling of the syringe with a sterile drug
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`formulation, such as ranibizumab, and performing VHP sterilization of the outer
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`surface of the pre-filled syringe. Ex. 1007 at 1:5-8, 9:11-26, 12:15-28.
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`Neither of these references, which disclose terminal sterilization of a pre-
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`filled glass syringe containing a VEGF-antagonist, were of record during
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`prosecution of the ’631 Patent.
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`D.
`Particulate Content
`Particulate matter is to be avoided when administering injectable and/or
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`ophthalmic pharmaceutical solutions. Ex. 1016.144 (“Certain ophthalmic products
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`must meet compendial visible and subvisible particulate guidelines, as defined in
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`USP Chapter <789>”); see also Ex. 1003, ¶¶ 89-91. According to USP Chapter
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`<789> (“USP789”) (Ex. 1019), which went into effect on May 1, 2011, and is
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`recognized by FDA, ophthalmic solutions, including those that are injectable, are
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`required to contain, as measured by light obscuration and microscopic tests, fewer
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`than 50 particles per mL that are ≥ 10 µm, fewer than 5 particles per mL that are ≥
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`25 µm, and fewer than 2 particles per mL that are ≥ 50 µm. Ex. 1019.003-004; Ex.
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`1003, ¶¶ 89-91.
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`Ex. 1016.144
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`
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`V. THE ’631 PATENT
`The U.S. application resulting in the ’631 Patent was filed on January 25,
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`2013, and identifies multiple foreign priority applications, the earliest of which was
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`filed on July 3, 2012.3 Ex. 1002.226. Petitioner contends that the references
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`asserted in Grounds 1-5 qualify as prior art even assuming that the ’631 Patent is
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`entitled to a priority filing date of July 3, 2012. However, Petitioner reserves the
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`right to contest that the ’631 Patent is entitled to an earlier filing date because, for
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`example, the July 3, 2012 foreign application does not provide adequate written
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`description support for the claims of the ’631 Patent.
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`A. The Challenged Claims
`This petition challenges all of the claims of the ’631 Patent. Independent
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`claim 1 of the ’631 Patent is reproduced below:
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`1. A pre-filled, terminally sterilized syringe for intravitreal injection,
`the syringe comprising a glass body forming a barrel, a stopper and a
`plunger and containing an ophthalmic solution whic