`
`
`Regeneron’s Initial Invalidity Contentions
`in Inv. No. 337-TA-1207
`
`
`Exhibit A: Invalidity of U.S. Patent
`No. 9,220,631 Under 35 U.S.C. §§ 102-103
`
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`Novartis Exhibit 2003.001
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`Regeneron contends that each of the references set forth below, either alone or in
`
`combination with other prior art, invalidates the claims of the 631 Patent under 35 U.S.C. §§
`
`102-103:
`
`Prior Art Reference
`
`A. Fries, Drug Delivery of Sensitive
`Biopharmaceuticals with Prefilled Syringes,
`Drug Delivery Technology, Vol. 9, No. 5
`(May 2009) ("Fries")
`Bruno Reuter and Claudia Petersen. “Die
`Silikonisierung von Spritzen: Trends,
`Methoden, Analyseverfahren,”
`TechnoPharm 2, Nr. 4 (2012): 238-244.
`(“Reuter”)
`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”)
`Carl Hultman, et al. The Physical Chemistry
`of Decontamination with Gaseous Hydrogen
`Peroxide, Pharmaceutical Engineering,
`January/February 2007, 27(1):1-6
`(“Hultman”)
`Dow Corning® 365 35% Dimethicone NF
`Emulsion – Frequently Asked Questions
`(2002) (“DC365 FAQ”)
`European Patent Application No. EP2371406
`to Hioki et al. (“Hioki”)
`Macugen PFS: see e.g., Internet Archive
`WayBack Machine, March 7, 2011 Record
`of Drugs.com, Macugen Prescribing
`Information, available at
`https://web.archive.org/web/2011030706523
`8/http://www.drugs.com:80/pro/macugen.ht
`ml (“Macugen® Label”)
`
`Date of Publication or
`Other Prior Art Date
`2009
`
`Statutory Provision
`of Prior Art1
`102(b)
`
`2012
`
`102(a)
`
`December 2011
`
`102(a); 102(b)
`
`2007
`
`2002
`
`2011
`
`2011
`
`102(b)
`
`102(b)
`
`102(a); 102(b);
`102(e)
`102(a); 102(b)
`
`
`1 In light of Novartis’ failure to provide any basis to support its effective filing date and
`conception contentions with respect to the 631 Patent, Regeneron reserves the right to identify
`different statutory provisions under which each reference qualifies as prior art.
`
`
`
`2
`
`Novartis Exhibit 2003.002
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`Prior Art Reference
`
`John R. Gillis & Gregg Mosley, Validation
`of Pharmaceutical Processes, Chapter 16 –
`Validation of Ethylene Oxide Sterilization
`Processes (2011), pp.241-262. (“Gillis”)
`K. Kereluk, et al. Microbiological Aspects of
`Ethylene Oxide Sterilization: I. Experimental
`Apparatus & Methods, Applied
`Microbiology 1970, 19(1):146-151.
`(“Kereluk”)
`Pamela Carter, et al. The lowdown on low
`temperature sterilization for packaged
`devices, Healthcare Purchasing News, July
`2008, 42-45. (“Carter”)
`PCT Patent Publication No. WO
`2007/035621 to Scypinski et al.
`(“Scypinski”)
`PCT Patent Publication No. WO
`2007/149334 to Furfine et al. (“Furfine”)
`PCT Patent Publication No. WO
`2008/077155 to Lam et al. (“Lam”)
`PCT Patent Publication No. WO
`2009/030976 to Boulange et al.
`(“Boulange”)
`PCT Patent Publication No. WO
`2011/006877 to Sigg et al. (“Sigg”)
`PCT Patent Publication No. WO
`2011/159975 to D’Souza et al. (“D’Souza”)
`PCT Patent Publication No.
`WO1994/013328 to Hagen (“Hagen”)
`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”)
`Sandeep Nema & John D. Ludwig,
`Pharmaceutical Dosage Forms: Parenteral
`Medications, Volume 3: (3rd ed. 2010)
`(“Nema Vol. 3”)
`U.S. Patent Application No. 2007/0253984
`to Khandke et al. (“Khandke”)
`
`
`
`Date of Publication or
`Other Prior Art Date
`2011
`
`Statutory Provision
`of Prior Art1
`102(a); 102(b)
`
`1970
`
`2008
`
`2007
`
`2007
`
`2008
`
`2009
`
`2011
`
`December 2011
`
`1994
`
`2010
`
`2010
`
`2010
`
`2007
`
`3
`
`102(b)
`
`102(b)
`
`102(b)
`
`102(b)
`
`102(b)
`
`102(b)
`
`102(b)
`
`102(a); 102(b);
`102(e)
`102(b)
`
`102(b)
`
`102(b)
`
`102(b)
`
`102(b)
`
`Novartis Exhibit 2003.003
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`Prior Art Reference
`
`U.S. Patent Publication No. 2012/0091026 to
`Chacornac et al. (“Chacornac”)
`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”)
`U.S. Food and Drug Administration, Eylea®
`Highlights of the Prescribing Information
`(Nov. 2011) (“the Eylea® Label”)
`U.S. Food and Drug Administration,
`Lucentis® Highlights of the Prescribing
`Information, (June 2010) (“the Lucentis®
`Label”)
`U.S. Patent No. 6,790,410 to Metzner et al.
`(“Metzner”)
`United States Patent No 8,221,353 to
`Cormier et al. (“Cormier”)
`United States Patent No. 7,404,278 to
`Wittland et al. (“Wittland”)
`United States Patent Publication No.
`2007/0190058 to Sharms (“Sharms”)
`William Leventon, “Medical Device
`Sterilization: What Manufacturers Need to
`Know” (MDDI online, Sept. 1, 2002),
`available at
`https://www.mddionline.com/medical-
`devicesterilization-what-manufacturers-
`need-know (“Leventon”)
`Bhavnesh Shah, “Pre-filled Syringes: A New
`Concept,” Pharma Bio World (August 2009)
`(“Shah”)
`EYLEA Vial
`
`EYLEA PFS
`
`U.S. Food and Drug Administration,
`Lucentis® Highlights of the
`Prescribing Information, (June 2010)
`(“Lucentis® Label”)
`
`Date of Publication or
`Other Prior Art Date
`April 19, 2012
`
`Statutory Provision
`of Prior Art1
`102(a); 102(e)
`
`2007
`
`102(b)
`
`November 2011
`
`102(a); 102(b)
`
`June 2010
`
`102(b)
`
`2004
`
`July 17, 2012
`
`2008
`
`2007
`
`2002
`
`102(b)
`
`102(a); 102(b);
`102(e)
`102(b)
`
`102(b)
`
`102(b)
`
`2009
`
`102(b)
`
`On sale no later than
`November 21, 2011
`See Exhibits C1 and C2
`for conception and
`reduction to practice
`dates
`June 2010
`
`102(a); 102(b)
`
`102(g)
`
`102(b)
`
`
`
`4
`
`Novartis Exhibit 2003.004
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`Prior Art Reference
`
`Vetter Syringes
`Dr. Thomas Schoenknecht, “Pre-Filled
`Syringes: Why New Developments are
`Important to Injectable Delivery Today,”
`Prefilled Syringes: Innovations that meet the
`growing demand (2005) (“Schoenknecht”)
`Advait Badkar, “Development of
`Biotechnology Products in Pre-filled
`Syringes: Technical Considerations and
`Approaches,” AAPS PharmSciTech, Vol. 12
`No. 2 (June 2011) (“Badkar”)
`U.S. Pharmacopeia, USP 789, Particulate
`Matter in Ophthalmic
`Solutions, USP 34 NF 29 (2011) (“USP
`789”)
`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”)
`
`Date of Publication or
`Other Prior Art Date
`
`
`2005
`
`Statutory Provision
`of Prior Art1
`102(f)
`102(b)
`
`June 2011
`
`102(b)
`
`2011
`
`2009
`
`102(b)
`
`102(b)
`
`Each of the prior art references identified in Exhibits A1-A13, B1-B3, and C1-C2 of
`
`
`
`Regeneron’s initial invalidity contentions either anticipates one or more of the claims of the 631
`
`Patent and/or renders obvious one or more of the claims of the 631 Patent when viewed in
`
`combination with other prior art references. Regeneron reserves the right to contend that each of
`
`the anticipatory references renders the claims obvious either in view of the reference alone or in
`
`combination with other references. The identification of any patent or patent application should
`
`be deemed an identification of any counterpart patent, application, or associated product; the
`
`identification of any article or publication should be deemed a disclosure of any substantially
`
`similar article if published in some other form, or of any patent or patent application whole, as
`
`understood by a POSITA. For example, a reference to a figure should be deemed to refer to the
`
`text describing the figure and vice versa.
`
`
`
`5
`
`Novartis Exhibit 2003.005
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`In addition to the anticipatory references described in these invalidity contentions, the
`
`claims of the 631 Patent are invalid based on obviousness under 35 U.S.C. § 103. In general, a
`
`claimed invention is unpatentable if the differences between it and the prior art “are such that the
`
`subject matter as a whole would have been obvious at the time the invention was made to a
`
`person having ordinary skill in the art.” 35 U.S.C. § 103(a); Graham v. John Deere Co., 383 U.S.
`
`1, 13-14 (1966).
`
`Each prior art reference described in Exhibits A1-A13, B1-B3, and C1-C2, either alone or
`
`in combination with other prior art, renders the claims of the 631 Patent invalid as obvious. In
`
`particular, each prior art reference may be combined with (1) information known to persons
`
`skilled in the art at the time of the alleged invention, (2) any of the other anticipatory prior art
`
`references, and/or (3) any of the additional prior art identified herein and in the charts attached
`
`hereto. Specific combinations of prior art, by way of example, are provided in Exhibits A1-A13,
`
`B1-B3, and C1-C2. In addition, Regeneron incorporates by reference each and every prior art
`
`reference of record in the prosecution of the 631 Patent, including the statements made therein by
`
`the applicant, as well as the prior art discussed in the specification. Regeneron also incorporates
`
`by reference the Petitions for Inter Partes Review filed by Regeneron against the 631 Patent in
`
`IPR2020-01317 and IPR2020-01318, including the prior art references and grounds of invalidity
`
`set forth therein.
`
`In view of the Supreme Court’s KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127
`
`S.Ct. 1727, 1739 (2007) (“KSR”) decision, the USPTO issued a set of Examination Guidelines.
`
`See Examination Guidelines for Determining Obviousness Under 35 U.S.C. § 103 in view of the
`
`Supreme Court Decision in KSR International Co. v. Teleflex Inc., 72 Fed. Reg. 57, 526 (Oct. 10,
`
`2007). Those rationales include:
`
`
`
`6
`
`Novartis Exhibit 2003.006
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`• Combining prior art elements according to known methods to yield predictable
`
`results;
`
`• Simple substitution of one known element for another to obtain predictable
`
`results;
`
`• Use of a known technique to improve similar devices (methods, or products) in
`
`the same way;
`
`• Applying a known technique to a known device (method, or product) ready for
`
`improvement to yield predictable results;
`
`• “Obvious to try” – choosing from a finite number of identified, predictable
`
`solutions, with a reasonable expectation of success;
`
`• Known work in one field of endeavor may prompt variations of it for use in either
`
`the same field or a different one based on design incentives or other market forces
`
`if the variations would have been predictable to one of ordinary skill in the art;
`
`• Some teaching, suggestion, or motivation in the prior art that would have led one
`
`of ordinary skill to modify the prior art reference or to combine prior art reference
`
`teachings to arrive at the claimed invention.
`
`Id. at 57, 529. These rationales are consistent with the Supreme Court’s emphasis in KSR that
`
`“the results of ordinary innovation” from the perspective of a person of ordinary skill are not
`
`patentable, and further that “[a] person of ordinary skill is also a person of ordinary creativity,
`
`not an automaton.” KSR, 550 U.S. at 421. Regeneron contends that one or more of these
`
`rationales apply in considering the obviousness of the claims of the 631 Patent.
`
`
`
`As the Supreme Court emphasized in KSR, issued patent claims may be determined to be
`
`invalid as obvious even without a teaching, suggestion, or motivation to combine particular
`
`
`
`7
`
`Novartis Exhibit 2003.007
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`references. Id. at 419 (“The obviousness analysis cannot be confined by a formalistic conception
`
`of the words teaching, suggestion, and motivation, or by overemphasis on the importance of
`
`published articles and the explicit content of issued patents.”). Nevertheless, a person of skill in
`
`the art would have been motivated to combine each of the identified references with the others
`
`identified with respect to the claims of the 631 Patent. Regeneron contends that one of ordinary
`
`skill in the art, at the time the alleged inventions of the 631 Patent were made, would have been
`
`motivated to combine the references disclosed herein in such a way to reach the alleged
`
`inventions. The teaching, suggestion, or motivation to combine these references, although not
`
`required, is found, explicitly or implicitly, in one or more of at least the following: the
`
`knowledge or common sense of one of ordinary skill in the art; the prior art references
`
`themselves and/or the prior art as a whole, including interrelated teachings of multiple prior art
`
`references; the common fields of technology of the references; the subject matter acknowledged
`
`as prior art in the 631 Patent; the nature of the problem to be solved and the existence of similar
`
`improvements in similar applications; design incentives and other market forces, including the
`
`advantages of creating a superior and more desirable product and the effects of demands known
`
`to the design community or present in the marketplace; the ability to implement the alleged
`
`invention as a predictable variation of the prior art; improvements in similar devices; any needs
`
`or problems known in the fields addressed by the 631 Patent; the teachings in the references
`
`directed to solving the problems that the 631 Patent allegedly directed to solving; and the number
`
`of identified, predictable solutions to the problems addressed by these patents. In addition, the
`
`simultaneous (and/or prior) inventions described above (and elsewhere in these contentions) are
`
`evidence that motivation to combine the concepts described in the various prior art references
`
`did, in fact, exist, and they were, in fact, combined.
`
`
`
`8
`
`Novartis Exhibit 2003.008
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`These references identify and address many of the same technical issues and suggest
`
`similar solutions to those issues. Moreover, many of these references cross-reference and discuss
`
`one another, further illustrating the close technical relationship among this group of references.
`
`Accordingly, the teachings of the individual prior art references and alleged inventions,
`
`combined with the industry knowledge of a person of ordinary skill in the art at the time of the
`
`alleged invention of the 631 Patent, would render obvious the claims of the 631 Patent for at
`
`least the reasons described herein and in the incorporated exhibits. A person of ordinary skill at
`
`the time of the alleged inventions had reason to combine or modify one or more of the listed
`
`references in light of the knowledge of a person of ordinary skill in the art at the time of the
`
`alleged invention and information in the prior art cited herein. Thus, these references would
`
`logically have been combined pursuant to 35 U.S.C. § 103, and there was abundant motivation to
`
`combine such references at the time of the purported inventions of the 631 Patent.
`
`The prior art references set forth in Exhibits A1-A13, B1-B3, and C1-C2 clearly
`
`demonstrate that each of the limitations of the claims of the 631 Patent was known in the art. A
`
`person of ordinary skill would have been motivated to combine these known elements to arrive
`
`at claims 1-26 of the 631 at least for the reasons set forth in Regeneron’s Petitions for inter
`
`partes review in IPR2020-01317 and -01318, which are herein incorporated by reference. By
`
`way of example only, a person of ordinary skill would have been motivated to administer a
`
`known VEGF antagonist, such as those described and claimed in the 631 Patent, using a small
`
`volume glass pre-filled syringe because it was known that (1) only a small amount of drug
`
`product is injected into the eye; (2) glass is impermeable to gas and/or vapors that may be used
`
`as a sterilizing agent, which could otherwise harm a sensitive drug product; and (3) pre-filled
`
`syringes have numerous advantages, such as ease of use, reduced waste, reduced risk of
`
`
`
`9
`
`Novartis Exhibit 2003.009
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`contamination, elimination of dosing errors, and increase in drug supply. See e.g., IPR2020-
`
`01317 at Ex.1011.002; Ex. 1007 at 1:13-17, 21:10-25; Ex. 1015.329; Ex. 1021 at [0059], [0061];
`
`Ex. 1015.036; Ex. 1062.009; Ex. 1047.002 (Fig. 3); Ex. 2021 at 2:7-11; Ex. 1029 at 3:19. In
`
`addition, a person of ordinary skill would have been motivated to use a known process, such as
`
`baked-on siliconization, to apply an amount of silicone oil to the syringe barrel within the ranges
`
`set forth in the claims of the 631 Patent to achieve low operational forces (i.e., break loose and
`
`slide forces), which allows the prefilled syringe containing the VEGF antagonist solution to meet
`
`the requirements of USP789. See e.g., IPR2020-01317 at Ex. 1015.065, .330, .358; Ex.
`
`1012.006; Ex. 1014 at [0026]; Ex. 1008 at Table 7; Ex. 1012.006-007; Ex.1044.008; Ex.
`
`1011.004; Ex. 1044. 006-.007; Ex. 1013. 004; Ex. 1017 at 10: 14-11: 13; Ex. 1019.005-.006.
`
`Moreover, a person of ordinary skill would have been motivated to terminally sterilize a pre-
`
`filled syringe comprising a VEGF antagonist because the FDA requires all ophthalmic products
`
`to be sterile, including pre-filled syringes for intravitreal injection. See, e.g., 21 C.F.R. § 200.50
`
`(a)(l). A person of ordinary skill would have been motivated to use terminal sterilization as
`
`claimed in the 631 Patent to sterilize a pre-filled syringe comprising a VEGF antagonist because
`
`it was known in the art that such drug products were sensitive to certain types of sterilization
`
`processes, and that terminal sterilization would not impact the stability of the drug product. Ex.
`
`1007 at 2:15-17, 3:8-16, 7:29-8:2; Ex. 1029 at 1: 18-25; Ex. 1046.001-.002; Ex. 1015.260-.261;
`
`Ex. 1029 at 13:9-16:8. Moreover, a person of ordinary skill would have known and been
`
`motivated to achieve the sterilization residue content and sterility assurance levels claimed in the
`
`631 Patent to assure that the clinician is not exposed to the sterilizing agent while also ensuring
`
`that all products are sterile. See e.g., Ex. 1007 at 7:8-13, 10:5-6.
`
`
`
`10
`
`Novartis Exhibit 2003.010
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`Furthermore, a person of ordinary skill in the art at the time of the alleged invention
`
`would have had a reasonable expectation of success when combining the listed references and
`
`the known elements because the proposed combinations would have been well within the level of
`
`ordinary skill in the art. Indeed, the proposed combinations would have been merely the
`
`application of a known technique or component with a known system in the same field of
`
`endeavor. And, when combined, each element merely performs the same predictable functions as
`
`it does separately without significantly altering or hindering the functions performed by the other
`
`elements. As set forth in Regeneron’s Petition for inter partes review in IPR2020-01317 and -
`
`01318, it was known in the art before the 631 Patent to administer a VEGF antagonist using a
`
`small volume glass syringe. Moreover, processes for terminally sterilizing pre-filled syringes
`
`and methods for applying silicone oil in the quantities required by the claims to achieve the
`
`operational forces required by the claims were also well-known in the art. See e.g., IPR2020-
`
`01317, Ex. 1007; Ex. 1008; Ex. 1009; Ex. 1010; Ex. 1015; Ex. 1018; Ex. 1019; Ex. 1028; Ex.
`
`1029. That the 631 Patent fails to describe any new process for terminally sterilizing or applying
`
`silicone oil to the barrel of a pre-filled syringe confirms that a person of ordinary skill would
`
`have had a reasonable expectation of success in combining the known elements to arrive at the
`
`claimed invention.
`
`Furthermore, there are no secondary indicia of non-obviousness that support a finding
`
`that any claim of the 631 Patent is valid. Regeneron reserves the right to rebut any evidence of
`
`secondary indicia of non-obviousness that Novartis relies on. Regeneron may rely upon a subset
`
`of the references or all of the listed references depending upon the claim construction and further
`
`investigation. Regeneron’s contentions that the references described in these invalidity
`
`contentions, in various combinations, render the claims of the 631 Patent obvious under 35
`
`
`
`11
`
`Novartis Exhibit 2003.011
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`U.S.C. § 103 are in no way an admission or suggestion that each reference does not
`
`independently anticipate the claims of the 631 Patent under 35 U.S.C. § 102. Furthermore, the
`
`specific combinations described in these contentions are not intended to be exhaustive, as there
`
`are many possible combinations of these references, and it is not practical, particularly at this
`
`early stage before further factual investigation and claim construction proceedings, to identify
`
`and list all potentially relevant combinations.
`
`In addition to the specific disclosures in the prior art of all the limitations of the 631
`
`Patent claims, the limitations set forth below would have been obvious to a person of ordinary
`
`skill as a matter of routine optimization and/or as a result effective variable. In re Applied
`
`Materials, Inc., 692 F.3d 1289, 1295-97 (Fed. Cir. 2012) (“A recognition in the prior art that a
`
`property is affected by the variable is sufficient to find the variable result-effective.”); see also In
`
`re Boesch, 617 F.2d 272, 276 (CCPA 1980) (“[D]iscovery of an optimum value of a result
`
`effective variable…is ordinarily within the skill of the art.”); In re Aller, 220 F.2d 454, 456
`
`(“[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to
`
`discover the optimum or workable ranges by routine experimentation.”) (CCPA 1955).
`
`•
`
`•
`
`•
`
`•
`
`the syringe barrel comprises from about 1 μg to 100 ug silicone oil (claim 1)
`
`the VEGF antagonist solution comprises no more than 2 particles >50 μm in diameter
`
`per ml (claim 1)
`
`the syringe has a stopper break loose force of less than about 11N (claim 1)
`
`the syringe barrel has an internal coating of silicone oil that has an average thickness of
`
`about 450 nm or less (claim 2)
`
`•
`
`the syringe barrel has an internal coating of from about 3 μg to about 100 ug silicone oil
`
`(claim 3)
`
`
`
`12
`
`Novartis Exhibit 2003.012
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`•
`
`•
`
`•
`
`the VEGF antagonist solution further comprises one or more of (i) no more than 5
`
`particles ≧25 μm in diameter per ml, and (ii) no more than 50 particles ≧10 μm in
`
`diameter per ml (claim 5)
`
`the VEGF antagonist solution meets USP789 (claim 6)
`
`the VEGF antagonist solution further comprises one or more of (i) no more than 5
`
`particles ≧25 μm in diameter per ml, and (ii) no more than 50 particles ≧10 μm in
`
`diameter per ml (claim 10)
`
`•
`
`the syringe has a stopper break loose force of less than about 5N, and wherein the
`
`syringe has a stopper slide force of less than about 5N (claim 14)
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`the syringe has a stopper slide force of less than about 11N (claim 16)
`
`•
`
`•
`
`the outer surface of the syringe has ≦1 ppm EtO or H2O2 residue (claim 18)
`blister pack is ≦0.1 mg (claim 19)
`• ≦5% of the VEGF antagonist is alkylated (claim 20)
`
`•
`
`the total EtO or H2O2 residue found on the outside of the syringe and inside of the
`
`• a Sterility Assurance Level of at least 10−6 (claim 21)
`
`•
`
`the syringe barrel has an internal coating of from about 1-50 μg silicone oil (claim 22)
`
`For example, a person of ordinary skill would have motivated to design a pre-filled
`
`syringe that minimizes the particulate content in the drug solution because it was well-known in
`
`the art that particulate matter is to be avoided when administering injectable and/or ophthalmic
`
`pharmaceutical solutions. See e.g., IPR2020-01317, Ex. 1016.144 (“Certain ophthalmic products
`
`must meet compendial visible and subvisible particulate guidelines, as defined in USP Chapter
`
`<789>”). In particular, according to USP Chapter <789> (“USP789”) (IPR2020-01317, Ex.
`
`1019), which went into effect on May 1, 2011, and is recognized by FDA, ophthalmic solutions,
`
`
`
`13
`
`Novartis Exhibit 2003.013
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`including those that are injectable, are required to contain, as measured by light obscuration and
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`microscopic tests, fewer than 50 particles per mL that are ≥ 10 µm, fewer than 5 particles per mL
`
`that are ≥ 25 µm, and fewer than 2 particles per mL that are ≥ 50 µm. IPR2020-01317, Ex.
`
`1019.003-004.
`
`IPR2020-01317, Ex. 1016.144
`
`
`
`Thus, there was a clear motivation in the art to design a pre-filled syringe that meets the
`
`particulate content limitations of claims 1, 5, 6, and 10.
`
`
`
`Similarly, a person of ordinary skill would have had a clear motivation to optimize both
`
`the silicone oil content on the syringe and the operational forces (i.e., break loose and slide
`
`forces). For example, it was well-known in the art that silicone oil can interact with drug
`
`product, such that it was desirable to minimize the amount of free silicone that can interact with
`
`drug product. IPR2020-01317, Ex. 1015.330. Similarly, it was known in the art that it was
`
`desirable to minimize the break loose and glide force of a pre-filled syringe to ensure smooth
`
`operation and precision for safe injection. IPR2020-01317, Ex. 1015.035, .358 (explaining that
`
`break loose and slide forces must be maintained at an acceptably low level to ensure smooth
`
`operation); see also IPR2020-01317, Ex. 1012.007.
`
`
`
`Moreover, a person of ordinary skill would have also had a clear motivation to optimize
`
`the sterilization parameters required by the claims of the 631 Patent, including the amount of
`
`sterilization residue, sterility assurance level, and percent alkylation. For example, a person of
`
`ordinary skill would have been motivated to minimize the sterilization residue to protect the drug
`14
`
`
`
`Novartis Exhibit 2003.014
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`product within the syringe and the end-user from the sterilizing agent. See IPR2020-01317, Ex.
`
`1007 at 13:3-8, 13:24-26. Similarly, a person of ordinary skill would have been motivated to
`
`achieve a sterility level of 10-6 because that was known to be the preferred sterility level in the art
`
`for healthcare products. IPR2020-01317, Ex. 1007 at 7:10-13. Finally, a person of ordinary skill
`
`also would have been motivated to minimize the percent alkylation of the VEGF antagonist,
`
`which corresponds to the stability of the drug product. IPR2020-01317, Ex. 1007 at 2:10-13.
`
`
`
`For these and other reasons set forth in Exhibits A1-A13, B1-B3, and C1-C2, every claim
`
`of the 631 Patent would have been obvious to a person of ordinary skill in the art.
`
`
`
`
`
`
`
`
`
`15
`
`Novartis Exhibit 2003.015
`Regeneron v. Novartis, IPR2020-01318
`
`