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 Owners
`
`__________
`
`
`Case IPR2021-00816
`Patent No. 9,220,631
`
`__________
`
`
`NOVARTIS PHARMA AG, NOVARTIS TECHNOLOGY LLC, AND
`NOVARTIS PHARMACEUTICALS CORPORATION’S
`PATENT OWNER RESPONSE
`
`
`
`
`
`
`

`

`
`
`
`
`TABLE OF CONTENTS
`Introduction ...................................................................................................... 1
`Person of Ordinary Skill in the Art .................................................................. 6
` The Claims of the ’631 Patent Are Entitled to Priority to July 3, 2012,
`and an Invention Date of October 2011 .......................................................... 7
` Ground 1: Petitioner Has Failed to Meet Its Burden of Proving The
`Challenged Claims Obvious Over Sigg Combined with Boulange ................ 8
` A POSA Would Not Have Been Motivated to Combine Sigg
`and Boulange to Arrive at the Claimed Invention ................................ 9
`A POSA Would Not Have Been Motivated to Use
`
`Boulange Syringe B1 Because of its Parylene-C Coating ........10
`A POSA Would Not Have Been Motivated to Use
`Boulange Syringe C Because of Its Force Profile ....................13
`A POSA Would Not Have Been Motivated to Use a
`Solution Having No More than Two Particles Greater
`than 50 µm in Diameter per mL ................................................18
`A POSA Would Not Have Had a Reasonable Expectation of
`Success in Combining Sigg and Boulange ..........................................20
`A POSA Would Not Have Reasonably Expected
`
`Boulange’s Syringes to be Compatible with VHP ...................20
`Sigg’s VHP Method Is Not Enabled ...................................................25
`Certain Dependent Claims are Separately Patentable over Sigg
`and Boulange .......................................................................................32
`Claim 14 ....................................................................................32
`
`Claim 17 ....................................................................................33
`
`Claim 21 ....................................................................................35
`
`Claim 22 ....................................................................................39
`
`Claim 24 ....................................................................................39
`
` Ground 2: Petitioner has Failed to Meet Its Burden of Proving The
`Challenged Claims Obvious Over Lam Combined with Boulange ..............41
`
`
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` A POSA Would Not Have Been Motivated to Combine Lam
`with Boulange to Arrive at the Claimed Inventions and Would
`Not Have Had a Reasonable Expectation of Success .........................42
`Lam’s Method of ETO Terminal Sterilization Is Not Enabled ...........43
`Certain Dependent Claims are Separately Patentable Over Lam
`and Boulange .......................................................................................44
`Claim 21 ....................................................................................44
`
`Claims 14, 22 and 24–26 ..........................................................46
`
` Objective Indicia of Nonobviousness Strongly Support the
`Patentability of the Claims ............................................................................46
`Record Evidence Shows a Clear Nexus Between Lucentis PFS
`and Certain Claims of the ’631 Patent ................................................49
`A Presumption of Nexus Applies on the Facts Here ................50
`
`The Evidence Proves Nexus Independent of Any
`
`Presumption ..............................................................................54
`Lucentis PFS Has Enjoyed Significant Commercial Success .............55
`Long-Felt but Unmet Need .................................................................56
`Failure of Others ..................................................................................58
`
`Skepticism ...........................................................................................59
`
`Licensing .............................................................................................60
`
` Conclusion .....................................................................................................60
`
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`
`ii
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`

`

`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`3M Co. v. Evergreen Adhesives, Inc.,
`860 F. App’x 724 (Fed. Cir. 2021) ..................................................................... 32
`ALZA Corp. v. Andrx Pharm., LLC,
`603 F.3d 935 (Fed. Cir. 2010) ................................................................ 27, 31, 44
`Amgen, Inc. v. Hoechst Marion Roussel, Inc.,
`457 F.3d 1293 (Fed. Cir. 2006) .......................................................................... 30
`Arctic Cat Inc. v. Bombardier Recreational Prods. Inc.,
`876 F.3d 1350 (Fed. Cir. 2017) .......................................................................... 15
`AstraZeneca AB v. Mylan Pharm. Inc.,
`19 F.4th 1325 (Fed. Cir. 2021) ........................................................................... 16
`ATD Corp. v. Lydall, Inc.,
`159 F.3d 534 (Fed. Cir. 1998) ............................................................................ 18
`Crocs, Inc. v. Int’l Trade Comm’n,
`598 F.3d 1294 (Fed. Cir. 2010) .................................................................... 17, 54
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .............................................................. 49, 58, 59
`Demaco Corp. v. F. Von Langsdorff Licensing Ltd.,
`851 F.2d 1387 (Fed. Cir. 1988) .......................................................................... 53
`Elan Pharms. v. Mayo Found.,
`346 F.3d 1051 (Fed. Cir. 2010) .......................................................................... 31
`Enzo Biochem, Inc. v. Calgene, Inc.,
`188 F.3d 1362 (Fed. Cir. 1999) .................................................................... 27, 44
`Fidelity Nat’l Info. Serv., Inc. v. Datatreasury Corp.,
`IPR2014-00491, Paper No. 9 (August 13, 2014) ................................................. 7
`
`iii
`
`

`

`Fox Factory, Inc. v. SRAM, LLC,
`944 F.3d 1366 (Fed. Cir. 2019) .............................................................. 50, 52, 53
`Henny Penny Corp. v. Frymaster LLC,
`938 F.3d 1324 (Fed. Cir. 2019) .......................................................................... 49
`In re Huai-Hung Kao,
`639 F.3d 1057 (2011) .......................................................................................... 54
`Impax Lab'ys Inc. v. Lannett Holdings Inc.,
`893 F.3d 1372 (Fed. Cir. 2018) .......................................................................... 60
`Indivior Inc. v. Dr. Reddy’s Labs.,
`930 F.3d 1325 (Fed. Cir. 2019) ............................................................................ 6
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) .......................................................................... 31
`Liebel-Flarsheim Co. v. Medrad, Inc.,
`481 F.3d 1371 (Fed. Cir. 2007) .......................................................................... 44
`Lupin Ltd. v. Pozen Inc.,
`IPR2015-01775, Paper No. 15 (Mar. 1, 2016) ..................................................... 7
`Millennium Pharms., Inc. v. Sandoz Inc.,
`862 F.3d 1356 (Fed. Cir. 2017) .......................................................................... 47
`In re Mouttet,
`686 F.3d 1322 (Fed. Cir. 2012) .......................................................................... 16
`Ormco Corp. v. Align Tech., Inc.,
`498 F.3d 1307 (Fed. Cir. 2007) .................................................................... 27, 44
`Ortho-McNeil Pharm., Inc. v. Mylan Lab’ys, Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .......................................................................... 47
`Polaris Indus., Inc. v. Arctic Cat, Inc.,
`882 F.3d 1056 (Fed. Cir. 2018) .......................................................................... 50
`Power Integrations, Inc. v. Fairchild Semiconductor Int’l, Inc.,
`711 F.3d 1348 (Fed. Cir. 2013) .......................................................................... 47
`
`
`
`iv
`
`

`

`Raytheon Techs. Corp. v. General Elec. Co.,
`993 F.3d 1374 (Fed. Cir. 2021) .................................................................... 25, 30
`In re Stepan,
`868 F.3d 1342 (Fed. Cir. 2017) .......................................................................... 32
`In re Stepan,
`868 F.3d at 137 ................................................................................................... 33
`Stratoflex, Inc. v. Aeroquip Corp.,
`713 F.2d 1530 (Fed. Cir. 1983) .......................................................................... 47
`WBIP, LLC v. Kohler Co.,
`829 F.3d 1317 (Fed. Cir. 2016) .................................................................... 46, 54
`Other Authorities
`37 C.F.R. § 42.6(a)(3) .............................................................................................. 32
`37 C.F.R. § 42.24 ....................................................................................................... 1
`
`
`
`v
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`
`
`INTRODUCTION
`Petitioner has not met its burden of proving that the challenged claims of US
`
`Patent No. 9,220,631 (the “’631 patent”) are unpatentable over either Sigg or Lam
`
`combined with Boulange. The ’631 patent achieves a unique combination of
`
`desirable characteristics for a prefilled syringe (“PFS”) in an area beset with
`
`complex design problems that had bedeviled sophisticated pharmaceutical
`
`companies for years.
`
`Design of the PFS for intravitreal injection of vascular endothelial growth
`
`factor (“VEGF”) antagonists claimed in the ’631 patent would have presented a
`
`person of ordinary skill in the art (“POSA”) with unique, complicated and
`
`intertwined challenges not encountered with ordinary syringes used for
`
`subcutaneous injection. The eye is a small, closed system that is uniquely
`
`susceptible to infection and damage. (Ex. 2204 ¶ 61 (Dec. of Andrew Calman).)
`
`To prevent injury, a physician must administer an injection into the eye in a single
`
`smooth motion with consistent, low forces. (Ex. 2019.002; Ex. 2204 ¶¶ 67, 70, 99;
`
`Ex. 2257 at 17:14–21 (Szilard Kiss Dep. Tr.).) The risk of harm to the eye is
`
`increased with injections of VEGF-antagonists, because such drugs are
`
`administered on a regular basis throughout a patient’s life. (Ex. 2204 ¶ 91.)
`
`As of 2012, it was conventional wisdom that achieving sufficiently low and
`
`predictable forces required lubricating a PFS with high amounts of silicone oil—
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`far above the amounts claimed in the patent. (Ex. 2201 ¶¶ 19-24.) Using high
`
`amounts of silicone oil had downsides, as silicone oil in a terminally sterilized PFS
`
`can leach into the drug product and end up in the eye after injection. (Ex. 2001 ¶
`
`42) Nevertheless, a POSA would have understood that minimizing silicone oil
`
`could not come at the expense of achieving low break loose forces or risking the
`
`introduction of potentially harmful substances into the syringe. (Ex. 2001 ¶ 107;
`
`Ex. 2204 ¶ 82, 89, 96.) Accordingly, as of 2012, it was understood that the
`
`preferred silicone amount for a syringe containing a biologic like a VEGF-
`
`antagonist was high—200 to 500 µg. Ex. 2201¶ 22. Indeed, the only PFS for
`
`intravitreal injection of a VEGF-antagonist on the market as of the priority date
`
`(Macugen PFS) contained
`
` of silicone oil. (See Ex. 2201 ¶ 112; Ex.
`
`2022.0011; Ex. 2189 at 42:21–43:10; 184:19-22.)
`
`Moreover, a POSA would have understood that VEGF-antagonists are much
`
`more sensitive and susceptible to damage than small molecule drugs, including
`
`from exposure to the sterilizing gases ethylene oxide (“EtO”) and vaporized
`
`hydrogen peroxide (“VHP”). (See Ex. 2202 (Dec. of John Dillberger) ¶¶ 39, 44–
`
`46; Ex. 1015.240-246.) Prior to the ʼ631 patent, and despite the concerted efforts
`
`of major pharmaceutical companies, no one had been able to develop a PFS for
`
`intravitreal administration of a VEGF-antagonist that (1) contained less than 100
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`µg of silicone oil, (2) had low enough forces for intravitreal use, and (3) could be
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`terminally sterilized using sterilizing gases without damaging the drug product.
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`Against this backdrop, Petitioner’s assertion that it would have been
`
`“routine” to make a PFS containing a VEGF-antagonist as claimed in the ʼ631
`
`patent is pure hindsight. At the relevant time, a POSA would have considered the
`
`prospect of combining Sigg or Lam with Boulange as plagued by unpredictability.
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`The terminal sterilization methods discussed in Sigg and Lam are performed under
`
`pressure extremes, including vacuum, heightening the risk that sterilizing gas could
`
`enter the syringe and contaminate the drug product and/or adsorbing (i.e., sticking)
`
`onto syringe components and leach into the drug product. (Ex. 2202 ¶ 45; Ex.
`
`2001¶ 49; Ex. 2104.007.) The vacuum conditions can also cause the stopper to
`
`move within the syringe, which can undermine the sterilization process and
`
`damage the drug product by shielding portions of the barrel that need to be
`
`sterilized while exposing the drug product to portions of the barrel that had been
`
`sterile. (Ex. 2001¶ 49.) Sigg recognizes these challenges by teaching that “very
`
`few” syringes are capable of withstanding his VHP process, but Sigg fails to
`
`identify any workable syringe. Lam likewise fails to provide any description of a
`
`syringe design that could withstand its EtO process.
`
`Petitioner’s arguments about Boulange are equally flawed. Boulange is a
`
`reference directed to the use of Parylene-C—a substance that, as of the priority
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`date, had never been used in a PFS for intravitreal injection, and which a POSA
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`would have expected to be incompatible with a VEGF-antagonist. (Ex. 2202 ¶ 55)
`
`Petitioner attempts to skip over this flaw by pointing to a comparator syringe tested
`
`by Boulange that was not coated with Parylene-C. But a POSA would have been
`
`similarly unmotivated to use that syringe based on its force profile, which showed
`
`a near doubling of break loose force in just a month, and on Boulange’s
`
`characterization of it as “markedly inferior” and not “acceptable for a medical
`
`device.” Ex. 1008 at 19:6–7, 21:4–5.
`
`Nor would a POSA have reasonably expected a combination of Boulange
`
`with either Sigg or Lam to succeed. There is no disclosure in Boulange that its
`
`syringes could be terminally sterilized, let alone with sterilizing gases. The only
`
`sterilization process mentioned in Boulange is “ionizing radiation,” which a POSA
`
`would have understood is part of an aseptic filling process—an alternative to
`
`terminal sterilization. (Ex. 2201 ¶ 65, 129-133; Ex. 1008 at 4:3–5.)
`
`Not only do Petitioner’s hindsight-driven arguments on motivation and
`
`reasonable expectation of success fail, but the extensive objective evidence
`
`confirms that the inventions of the ʼ631 patent would have been nonobvious to a
`
`POSA. As Petitioner effectively acknowledges in its motivation arguments (Pet.
`
`31-33.), there was a long-felt need for a PFS within the claims of the ʼ631 patent,
`
`but no such syringe had been commercialized as of the priority date. Yet despite
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`the market demand, and the efforts by sophisticated pharmaceutical companies to
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`attack the problem, no company had been able to commercialize a PFS for
`
`intravitreal injection of a VEGF-antagonist that could be terminally sterilized using
`
`EtO or VHP and operate with low, consistent injection forces with the low
`
`amounts of silicone oil claimed here. Indeed, the record establishes that Genentech
`
`tried and failed to develop a terminally sterilized PFS containing a VEGF-
`
`antagonist sterilized using EtO. Instead, Genentech had to license the ʼ631 patent
`
`to commercialize a Lucentis PFS– a product that embodies the ʼ631 patent claims
`
`and has been a huge commercial success.
`
`Finally, Petitioner pays little attention to the dependent claims, but, as
`
`explained in detail below, several are separately patentable over Boulange
`
`combined with either Sigg or Lam. For example, claim 21 requires the use of EtO
`
`or VHP to achieve a sterility assurance level (“SAL”) of 10-6. Neither Sigg nor
`
`Lam discloses this limitation, and, as discussed below, the record shows that it
`
`could not be achieved at the time using either Sigg’s or Lam’s sterilization
`
`methods.
`
`For all these reasons, and those discussed below, Petitioner has not met its
`
`burden of proving that any of the challenged claims are unpatentable.
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`PERSON OF ORDINARY SKILL IN THE ART
`Patent Owner disagrees with the split definition of POSA proposed by
`
`Petitioner, which presumes that a POSA would have had sufficient expertise to
`
`single-handedly develop a PFS, or a method of treatment using a PFS, as claimed
`
`in the ʼ631 patent. To the contrary, a POSA designing a PFS or method of
`
`treatment using a PFS would have worked in collaboration with others having
`
`complementary skills and experience. (Ex. 2201 ¶ 15; Ex. 2202 ¶ 10; Ex. 2203 ¶
`
`26-27; Ex. 2204 ¶ 38; see also Indivior Inc. v. Dr. Reddy’s Labs., 930 F.3d 1325,
`
`1343 (Fed. Cir. 2019) (POSA found to be a member of a team).) Accordingly,
`
`Patent Owner proposes the following definition for all claims:
`
`A POSA would have had an advanced degree (i.e., an M.S., a Ph.D., or
`
`equivalent) in mechanical engineering, biomedical engineering, materials science,
`
`chemistry, chemical engineering, or a related field, and at least 2–3 years of
`
`professional experience, including in the design of a PFS and/or the development
`
`of ophthalmologic drug products or drug delivery devices. Such a person would
`
`have been a member of a product development team and would have drawn upon
`
`not only his or her own skills, but also the specialized skills of team members in
`
`complementary fields including ophthalmology, microbiology and toxicology.
`
`(Ex. 2201 ¶ 16.)
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`Under either party’s proposed POSA definition, however, the challenged
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`claims of the ʼ631 patent would not have been obvious.
`
` THE CLAIMS OF THE ’631 PATENT ARE ENTITLED TO
`PRIORITY TO JULY 3, 2012, AND AN INVENTION DATE OF
`OCTOBER 2011
`The ’631 patent claims priority to several applications, the earliest of which
`
`was filed on July 3, 2012. (Ex. 2001 ¶ 28.) Although Mr. Koller alleges that the
`
`claims are only entitled to priority to a subsequent application, filed October 23,
`
`2012, he nevertheless “considered the state of the art as of and shortly before July
`
`3, 2012” in addressing obviousness. (Ex. 1003 ¶20.) As Petitioner does not
`
`contest that the challenged claims are entitled to priority to the July 3, 2012
`
`application, that is the applicable priority date. See Lupin Ltd. v. Pozen Inc.,
`
`IPR2015-01775, Paper No. 15, at 10–11 (Mar. 1, 2016) (petitioner must raise the
`
`issue of priority in the Petition); Fidelity Nat’l Info. Serv., Inc. v. Datatreasury
`
`Corp., IPR2014-00491, Paper No. 9 (August 13, 2014).
`
`Furthermore, the inventors of the ’631 patent had conceived of their
`
`invention at least as of October 2011 and worked diligently to reduce the invention
`
`to practice through the October 23, 2012 filing of European Patent Application No.
`
`EP 12189649 (“EP ’649”) (Ex. 2023), and the January 25, 2013 filing of U.S.
`
`Patent Application No. 13/750,352 (“the ’352 Application”), each of which evinces
`
`a constructive reduction to practice of the claimed inventions. (See Ex. 2002 ¶¶6–
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`19 (Declaration of Marie Picci); Exs. 2062–2088 (corroborating evidence of
`
`conception date); Ex. 2001 ¶¶193–211 (demonstrating constructive reduction to
`
`practice in EP ’649 and the ’352 Application).
`
` GROUND 1: PETITIONER HAS FAILED TO MEET ITS BURDEN
`OF PROVING THE CHALLENGED CLAIMS OBVIOUS OVER
`SIGG COMBINED WITH BOULANGE
`Petitioner argues that claim 1 of the ’631 patent is obvious over a
`
`combination of Boulange and Sigg. Although Boulange discloses several syringe
`
`configurations, the only two that Petitioner identifies for its combination with Sigg
`
`are the syringe with stopper B1 in Table 7 (“Syringe B1”) and the syringe with
`
`stopper C in Table 5 (“Syringe C”). (IPR2021-0816, Paper 1, Petition for Inter
`
`Partes Review (Apr. 16, 2021) (“Pet.”) 37–39.) For all the following reasons,
`
`discussed in detail below, Petitioner has failed to meet its burden:
`
`• A POSA would not have been motivated to combine Sigg with Boulange
`
`− A POSA would not have been motivated to use Boulange Syringe
`
`B1 in a PFS for intravitreal administration of a VEGF-antagonist
`
`because Syringe B1 contains Parylene-C.
`
`− A POSA would not have been motivated to use Boulange Syringe
`
`C in a PFS for intravitreal administration of a VEG-F antagonist
`
`because Syringe C has inconsistent forces that increase over time.
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`− A POSA would not have been motivated to use a VEGF-antagonist
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`solution having no more than two particles greater than 50 µm in
`
`diameter per ml because USP 789 does not require it.
`
`• A POSA would not have reasonably expected Boulange’s syringes to be
`
`compatible with Sigg’s VHP process, because there is no indication they
`
`are designed to withstand the vacuum and extreme pressure conditions of
`
`VHP sterilization.
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`• Sigg’s VHP method is not enabled because, even with knowledge of the
`
`prior art, a POSA would need to undertake undue experimentation to
`
`successfully practice the method.
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`• Secondary considerations strongly support the nonobviousness of claim.
`
` A POSA Would Not Have Been Motivated to Combine Sigg and
`Boulange to Arrive at the Claimed Invention
`Petitioner argues that a POSA would have been motivated to combine Sigg
`
`with the two specific syringes in Boulange (Syringe B1 or Syringe C) in order “to
`
`minimize the amount of silicone oil in Sigg’s terminally sterilized pre-filled
`
`syringe.” (Pet. 31.) A POSA would have understood, however, that the desire to
`
`minimize silicone oil would have had to be balanced with more pressing concerns,
`
`such as ensuring that (1) the PFS had sufficiently low break loose forces that
`
`remained consistent over time; (2) the VEGF-antagonist did not degrade; and (3)
`
`potentially toxic substances were not introduced into the patient’s eye via the
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`syringe. A POSA would not have been motivated to risk any of these important
`
`parameters just to chase lower silicone oil amounts. As set forth below,
`
`Petitioner’s argument is steeped in hindsight as it ignores the many reasons why a
`
`POSA would not have wanted to combine Sigg with Boulange and is steeped in
`
`hindsight.
`
`
`
`A POSA Would Not Have Been Motivated to Use
`Boulange Syringe B1 Because of its Parylene-C Coating
`Petitioner argues that a POSA would have been motivated to combine Sigg
`
`with Syringe B1, which contains Parylene-C on its stopper. Based on the
`
`preliminary record at Institution, the Board found that “Petitioner has sufficiently
`
`shown that a POSITA would have understood that Parylene C would be
`
`compatible with a terminally sterilized syringe comprising a VEGF-antagonist.”
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`IPR2021-0816, Paper 13, Institution Decision (Oct. 26, 2021) (“Inst. Dec.”) 67.
`
`That record consisted largely of Mr. Koller’s opinions. But Mr. Koller is not a
`
`toxicologist, and his views do not reflect the motivations of a POSA with a
`
`sufficient understanding of toxicology or input from a toxicologist. Patent
`
`Owner’s expert Dr. Dillberger is a toxicologist who spent years in the industry on
`
`drug product development teams looking at these precise types of issues. As Dr.
`
`Dillinger explains, the known properties of Parylene-C would have dissuaded a
`
`POSA from using it in a terminally sterilized PFS containing a VEGF-antagonist.
`
`Ex. 2202 ¶¶ 66–68.
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` Mr. Koller’s Motivation Does Not Look at the Prior
`Art as a Whole
`As an initial matter, Mr. Koller cites no prior art aside from Boulange that
`
`discusses using Parylene-C in a PFS. While Mr. Koller quotes an October 2012
`
`non-prior art article authored by the manufacturer of Parylene-C for the proposition
`
`that Parylene-C was “widely applied” to pre-filled syringes (Ex. 1003 ¶175), the
`
`statement in the article referred to syringes broadly; it did not identify any PFS
`
`actually containing Parylene-C, let alone one terminally sterilized for intravitreal
`
`injection (see Ex. 1072.003).
`
`Moreover, Mr. Koller lacks credible support for his opinion that “Parylene C
`
`was known to be chemically inert and would not react with drug formulations.”
`
`Ex. 1003 ¶177 (cited in Inst. Dec. 50). The only evidence he cites is the statement
`
`in Boulange that “the medical device of the invention” limited the risk of silicone
`
`oil interacting with “the therapeutic molecules potentially stored in the container.”
`
`Ex. 1003 ¶177 (quoting Ex. 1008 at 6:26–29). But that statement said nothing
`
`about either Parylene-C or about VEGF-antagonists, as Boulange’s experiments
`
`were all performed on syringes filled with water. (Ex. 1008 at 14:19–21.)
`
`These evidentiary gaps are significant, because a POSA would not have
`
`assumed that Parylene-C was compatible with a VEGF-antagonist merely based on
`
`Mr. Koller’s assertopm that “[i]t would make little sense” for Boulange to address
`
`the problem with silicone oil by “proposing the use of a coating (Parylene-C) that
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`would negatively interact with a drug product.” (Ex. 1003 ¶177.) A POSA would
`
`have known from the prior art that Parylene-C could indeed cause negative
`
`interactions with a VEGF-antagonist. (Ex. 2202 ¶¶ 66–69.)
`
`
`
`Dr. Dillberger Identifies the Paralyene-C
`Considerations Relevant to a POSA
`A POSA would have known that a major concern in developing biologic
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`drugs like VEGF-antagonists is their tendency to adsorb, or stick, to surfaces.
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`Adsorption can cause biologics to aggregate and degrade, resulting in a reduction,
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`or even total loss, of biological activity. (Ex. 2202 ¶¶ 44–46; Ex. 2175.116.)
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`Biologics are far more prone to degradation and aggregation than small molecule
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`therapeutics. (Ex. 2202 ¶¶ 44–46.) Based on the prior art, a POSA would have
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`expected that VEGF-antagonists would adsorb to Parylene-C, and that the presence
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`of Parylene-C in a PFS would lead to aggregation and degradation of the drug
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`product. (Ex. 2202 ¶¶ 44–46, 66–67). Accordingly, even if a POSA would have
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`inferred from Boulange that Parylene-C might be compatible with some drug
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`products, the POSA would not have expected it to be compatible with VEGF-
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`antagonists, and therefore would not have been motivated to use Parylene-C in a
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`PFS that was intended for their administration. (Ex. 2202 ¶¶ 54, 58–59, 69–71.)
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`Moreover, and critically, aggregation is the same problem that had been
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`observed with silicone oil. (Ex. 2202 ¶ 20.) A POSA would not have been
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`motivated to exchange concerns about silicone oil for the same concerns about an
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`untried alternative like Parylene-C. (Ex. 2202 ¶¶ 51, 58–59, 65.) That is
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`especially true because a POSA would have understood that Parylene-C could
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`introduce a several additional problems. For example, unlike silicone oil,
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`Parylene-C would have been considered an untested PFS component, and, as such,
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`would have required additional testing to ensure its safety and compatibility with
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`the syringe system. (Ex. 2202 ¶ 65; Ex. 2189 at 169:6–174:6.) The results of such
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`testing would have been unpredictable, at best. (Ex. 2202 ¶ 59.) In fact, a POSA
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`would have understood that Parylene-C would likely leach cytotoxic components,
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`which would present serious safety concerns for a PFS used for injections into the
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`eye. (Ex. 2202 ¶ 68.)
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`*****
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`In short, Mr. Koller’s opinion requires ignoring everything in the prior art
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`about Parylene-C other than Boulange, evidencing his hindsight approach. Based
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`on the prior art as a whole, a POSA would have had no motivation to employ a
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`syringe with a Parylene-C stopper in a terminally sterilized PFS intended for
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`intravitreal injection of a VEGF-antagonist.
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`A POSA Would Not Have Been Motivated to Use
`Boulange Syringe C Because of Its Force Profile
`Petitioner also argues that a POSA would have been motivated to combine
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`Sigg with Boulange Syringe C, despite Boulange’s explicit disparaging statements
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`about the syringe and the data showing its forces to be inconsistent and increasing
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`with time. Contrary to Mr. Koller’s arguments, Boulange’s disclosure would have
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`discouraged a POSA from using Syringe C.
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`As discussed above, a POSA would have known that a PFS for intravitreal
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`injection must maintain consistent, low break loose forces over time to avoid
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`injuring a patient’s eye. (Ex. 2204 ¶ 67, 70, 99.) Boulange itself emphasizes that
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`forces must “be maintained over time, even after prolonged storage.” Ex.
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`1008.006. As can be seen in the excerpt of Table 5 below, while the break loose
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`force for Syringe C was initially 4.7 N, it nearly doubled to 8.4 N within just one
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`month of accelerated storage, which simulated three months of actual storage time.
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`(Ex. 1008.021.) Based on its force profile, Boulange characterizes Syringe C as
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`“markedly inferior” and not “acceptable for a medical device.” (Ex. 1008 at 19:7,
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`21:4–5.) Confronted with these descriptions, even Mr. Koller had to concede at his
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`deposition that the statements in Boulange were “[n]ot very motivat[ing].” (Ex.
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`2189 at 147:13–148:4.) His attempts to nonetheless minimize the discouragement
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`from Boulange are flawed. Mr. Koller insists that the Boulange’s statement about
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`acceptability for a medical device was limited to Table 7, where the stopper of
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`Syringe C did not include any silicone oil; he contends that a POSA would have
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`recognized that if the stopper had been coated with silicone oil, as in Table 5, the
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`forces would have been acceptable. (Ex. 1003 ¶181.) But this opinion is
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`undermined by Boulange itself, which discloses that the break loose forces for
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`Syringe C in Table 7 and Table 5 were essentially identical, showing that that the
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`statement of discouragement logically applied to both. (Ex. 2001 ¶ 89-90).
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`Given the data in Table 5 and Boulange’s explicit statements, a POSA would
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`not have been motivated to use Syringe C in combination with Sigg. A POSA
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`would have known that even if the forces were “acceptable” at T0 and T1, as Mr.
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`Koller argues (Ex. 1003 ¶179), Syringe C could not be used for a PFS for
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`intravitreal injections because the forces are inconsistent over time and may
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`continue to rise over the shelf life of the PFS. (Ex. 2204 ¶ 72; Ex. 2201 ¶ 43-44.)
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`In fact, Mr. Koller himself emphasizes the importance of avoiding the “break loose
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`effect,” where break loose force increases over time, especially in a syringe for
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`intravitreal use. (Ex. 1003 ¶59 (quoting Ex. 1013.004).) As the Federal Circuit
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`has held, “[e]vidence suggesting reasons to combine cannot be viewed in a vacuum
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`apart from evidence suggesting reasons not to combine.” Arctic Cat Inc. v.
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`Bombardier Recreational Prods. Inc., 876 F.3d 1350, 1363 (Fed. Cir. 2017)
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`(affirming district court judgment of nonobviousness).
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`Considered as a whole, Boulange teaches away from Syringe C. As the
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`Federal Circuit recently reaffirmed, a reference teaches away when a POSA
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`“would be discouraged from following the path set out in the reference.”
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`AstraZeneca AB v. Mylan Pharm. Inc., 19 F.4th 1325, 1337 (Fed. Cir. 2021)
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`(affirming a judgment of nonobviousness based in part on a reference teaching
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`away). A “reference that properly teaches away can preclude a determinatio