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
`
`__________
`
`
`SUPPLEMENTAL DECLARATION OF KARL R. LEINSING, PE, IN
`SUPPORT OF NOVARTIS’S
`PATENT OWNER RESPONSE
`
`
`
`
`
`
`Novartis Exhibit 2201.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`IL
`
`III.
`
`IV.
`
`V.
`
`A.
`
`B.
`
`A.
`
`B.
`
`Introduction......................................................................................................1
`Summary Of Opinions In My Initial Declaration ...........................................1
`Summary Of Additional Opinions Presented..................................................2
`Legal Principles ...............................................................................................4
`Enablement............................................................................................4
`Secondary Considerations of Non-Obviousness...................................4
`Person of Ordinary Skill in the Art .......................................................5
`C.
`Further Analysis of Petitioner’s Obviousness Arguments ..............................7
`The Prior Art, Including Boulange, Shows That a POSA Would
`Not Have Expected Syringes With Less Than 100 μg of Total
`Silicone Oil to Be Suitable for Intravitreal Injection ............................7
`A POSA Would Not Have Been Motivated to Combine
`Boulange with Sigg or Lam and Would Not Have Had a
`Reasonable Expectation of Success in Doing So................................16
`A POSA Would Not Have Been Motivated to Use
`Parylene C in a PFS Filled with a VEGF-Antagonist...............17
`A POSA Would Not Have Been Motivated to Use the
`Non-Parylene C Syringes Disclosed in Boulange ....................22
`A POSA Would Not Have Been Motivated to Combine
`Sigg’s VHP Method with Syringes From Boulange.................31
`A POSA Would Not Have Been Motivated to Use Lam’s
`EtO Method With Syringes From Boulange ............................44
`A POSA Would Not Have Been Motivated to Make a
`VEGF-Antagonist Solution Having No More Than 2
`Particles Greater Than 50 μm in Diameter per Milliliter .........53
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`ii
`
`Novartis Exhibit 2201.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`C.
`
`D.
`
`E.
`
`6.
`
`1.
`
`2.
`3.
`
`1.
`2.
`3.
`4.
`
`A POSA Would Not Have Had a Reasonable Expectation
`of Success in Combining Boulange with Sigg or Lam.............56
`Sigg Does Not Enable Terminal Sterilization of a PFS While
`Minimizing Contact between the Drug Product and the
`Sterilizing Agent..................................................................................62
`Novartis’s unsuccessful attempts to implement Sigg’s
`VHP process..............................................................................64
`Genentech’s unsuccessful efforts..............................................72
`Neither a POSA’s General Knowledge nor Other
`References Cited by Mr. Koller Would Have Enabled a
`POSA to Practice Sigg’s Method on a Syringe from
`Boulange ...................................................................................73
`Lam Does Not Enable Terminal Sterilization of a PFS While
`Minimizing Contact between the Drug Product and the
`Sterilizing Agent..................................................................................91
`Genentech’s Failure to Develop a Lucentis PFS
`Demonstrates that Lam is Not Enabled ....................................91
`Additional Reasons Why Claims 17, 21, and 24–26 Are Non-
`obvious ................................................................................................94
`Dependent Claim 14 Would Not Have Been Obvious .............94
`Dependent Claim 17 Would Not Have Been Obvious .............96
`Dependent Claim 21 Would Not Have Been Obvious .............98
`Dependent Claims 24–26 Would Not Have Been
`Obvious ...................................................................................100
`Failure Of Others .........................................................................................102
`Genentech Tried and Failed to Develop a Lucentis® PFS ...............102
`A.
`Genentech’s Lucentis® PFS Product Embodies and is Co-Extensive
`with At Least Claims 1–10 and 14–23 Of The ’631 Patent .......................107
`Claim 1 ..............................................................................................109
`pre-filled, terminally sterilized syringe for intravitreal
`injection...................................................................................110
`
`VI.
`
`VII.
`
`A.
`
`1.
`
`iii
`
`Novartis Exhibit 2201.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`5.
`
`6.
`
`7.
`
`B.
`
`2.
`
`3.
`
`4.
`
`the syringe comprising a glass body forming a barrel, a
`stopper and a plunger and .......................................................112
`[the syringe] containing an ophthalmic solution which
`comprises a VEGF-antagonist, wherein .................................114
`(a) the syringe has a nominal maximum fill volume of
`between about 0.5 mL and about 1 mL, .................................116
`(b) the syringe barrel comprises from about 1 μg to 100
`ug silicone oil,.........................................................................117
`(c) the VEGF-antagonist solution comprises no more
`than 2 particles > 50 μm in diameter per mL..........................118
`wherein the syringe has a stopper break loose force of
`less than about 11N.................................................................120
`Dependent Claims .............................................................................121
`Claim 2....................................................................................121
`Claim 3....................................................................................123
`Claim 4....................................................................................123
`Claim 5....................................................................................124
`Claim 6....................................................................................126
`Claim 7....................................................................................128
`Claim 8....................................................................................129
`Claim 9....................................................................................130
`Claim 10..................................................................................131
`Claim 14..................................................................................133
`Claim 15..................................................................................134
`Claim 16..................................................................................135
`Claim 17..................................................................................136
`Claim 18..................................................................................138
`Claim 19..................................................................................139
`Claim 20..................................................................................141
`Claim 21..................................................................................142
`
`1.
`2.
`3.
`4.
`5.
`6.
`7.
`8.
`9.
`10.
`11.
`12.
`13.
`14.
`15.
`16.
`17.
`
`iv
`
`Novartis Exhibit 2201.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Claim 22..................................................................................143
`18.
`Claim 23..................................................................................144
`19.
`Declaration...................................................................................................147
`
`VIII.
`
`v
`
`Novartis Exhibit 2201.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`I.
`
`INTRODUCTION
`1.
`I am the same Karl Leinsing who submitted a declaration on July 28,
`
`2021 (“Initial Declaration”) on behalf of Novartis Pharma AG, Novartis
`
`Technology LLC, and Novartis Pharmaceuticals Corp. (collectively, “Patent
`
`Owner” or “Novartis”) in support of their Patent Owner Preliminary Response. I
`
`maintain the opinions set forth in my Initial Declaration and incorporate them by
`
`reference here. This supplemental declaration provides further opinions, consistent
`
`with those I provided in my Initial Declaration.
`
`2.
`
`I understand that Regeneron Pharmaceuticals, Inc. (“Petitioner” or
`
`“Regeneron”) initiated these proceedings by filing a Petition seeking cancellation
`
`of all claims of U.S. Patent No. 9,220,631 (“the ’631 patent”).
`
`3.
`
`The subject of this declaration is the validity of the ’631 patent. This
`
`declaration is the result of my review and analysis of the petitions, declarations,
`
`and prior art submitted by the Petitioner in the above referenced IPR proceeding,
`
`and the Board’s Institution Decision, as well as additional materials identified
`
`herein.
`
`II.
`
`SUMMARY OF OPINIONS IN MY INITIAL DECLARATION
`4.
`Based on my knowledge, experience and the reviewed materials, it is
`
`my opinion that the ’631 patent is not obvious over the prior art cited by the
`
`Petitioner in IPR2021-00816 for at least the following reasons:
`
`1
`
`Novartis Exhibit 2201.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`(cid:120) A person of skill in the art (“POSA”) would not have been motivated to
`
`combine the references relied upon by Petitioner to arrive at the claimed
`
`invention as claimed in Claims 1–26.
`
`(cid:120) A POSA would not have reasonably expected to successfully combine the
`
`references relied upon by Petitioner to arrive at the claimed invention.
`
`(cid:120) The prior art relied upon by the Petitioner would not have enabled a POSA
`
`to make or use the claimed invention.
`
`(cid:120) Secondary considerations support the non-obviousness of the ’631 patent.
`
`5.
`
`European application No. EP 12189649 and U.S. Application No.
`
`13/750,352 demonstrate a constructive reduction to practice of the claimed
`
`invention no later than October 23, 2012, and January 25, 2013, respectively.
`
`III.
`
`SUMMARY OF ADDITIONAL OPINIONS PRESENTED
`6.
`As set forth in detail below, in addition to the opinions contained in
`
`my Initial Report, it is my opinion that the ’631 patent is not obvious over the
`
`prior art cited by the Petitioner in IPR2021-00816 for at least the following
`
`reasons:
`
`(cid:120) Neither Sigg nor Lam enables terminal sterilization of a PFS while
`
`minimizing contact between the drug product and the sterilizing agent.
`
`(cid:120) Other prior art cited by Petitioner and Mr. Koller would not have taught a
`
`POSA the information missing from Sigg and Lam (i.e. how to design a
`
`2
`
`Novartis Exhibit 2201.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`suitable syringe) to enable the POSA to make the invention of the ’631
`
`patent.
`
`(cid:120) A POSA would not have expected syringes with less than 100 μg of total
`
`silicone oil to be suitable for intravitreal injection.
`
`(cid:120) A POSA would not have been motivated to use Parylene C or the non-
`
`Parylene C syringes disclosed in Boulange in a PFS filled with a VEGF-
`
`antagonist for intravitreal injection.
`
`(cid:120) A POSA would not have been motivated to combine Sigg’s VHP method or
`
`Lam’s EtO method with syringes from Boulange.
`
`(cid:120) A POSA would not have had a reasonable expectation of success in
`
`combining Boulange with Sigg or Lam.
`
`(cid:120) At least dependent claims 14, 17, 21, and 24–26 are non-obvious for
`
`additional reasons beyond those applicable to claim 1.
`
`7.
`
`Genentech tried and failed to make a PFS filled with the VEGF-
`
`Antagonist Lucentis®
`
`8.
`
`The Lucentis® PFS marketed in the United States by Genentech
`
`embodies claims 1-10 and 14–23 of the ’631 patent and is coextensive with the
`
`claims.
`
`3
`
`Novartis Exhibit 2201.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`I V .
`
`LEGAL PRINCIPLES
`9.
`In formulating my opinions and conclusions in this proceeding, I have
`
`been provided by counsel for Patent Owner with an understanding of the prevailing
`
`principles of U.S. patent law that govern the issues of patent validity.
`
`10.
`
`In addition to the legal principles outlined in my Initial Declaration, I
`
`have been provided with an understanding of the legal principles of enablement
`
`and secondary considerations of non-obviousness, as outlined below.
`
`A.
`11.
`
`Enablement
`I understand that, to render a claim obvious, the prior art taken as a
`
`whole must enable a person of ordinary skill in the art (“POSA”) to make and use
`
`the claimed invention.
`
`12.
`
`I understand that enablement requires that the identified references
`
`must collectively teach a POSA how to make and use the claimed invention
`
`without undue experimentation.
`
`B.
`13.
`
`Secondary Considerations of Non-Obviousness
`I understand that real-world evidence (also referred to as secondary
`
`considerations) is a necessary part of an obviousness analysis, and that such
`
`evidence can demonstrate non-obviousness. Some secondary considerations that
`
`may be considered in such an analysis include, but are not limited to, failure of
`
`others to arrive at the invention, commercial success of the patented invention,
`
`industry praise, teaching away in the art, long-felt need, skepticism of others
`4
`
`Novartis Exhibit 2201.009
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`toward the invention, and the taking of licenses under the patent by others. These
`
`factors are relevant only if there is a connection, or nexus, between the factor and
`
`the merits of the invention covered by the patent claim. I have been informed that
`
`nexus may be rebuttably presumed if the product tied to the secondary
`
`consideration embodies and is coextensive with the claimed invention. I have been
`
`informed that coextensiveness does not require perfect correspondence between the
`
`claims and the product, so long as the product is essentially the claimed invention
`
`and does not contain substantial unclaimed features that are responsible for the
`
`secondary consideration (e.g., commercial success).
`
`C.
`14.
`
`Person of Ordinary Skill in the Art
`I understand that whether the claims of a Patent are obvious is
`
`evaluated from the perspective of POSA to which the patent pertains as of the
`
`priority date of the Patent. I understand that the POSA is a hypothetical person,
`
`and that in determining the level of skill such a person would have, I may consider
`
`the following factors: (1) the type of problems encountered in the art; (2) the prior
`
`art solutions to those problems; (3) the rapidity with which innovations are made;
`
`(4) the sophistication of the technology; and (5) the educational level of active
`
`workers in the field.
`
`15.
`
`As discussed in my Initial Declaration, I understand that Petitioner
`
`has proposed a definition of a POSA for the ’631 patent. See Ex. 2001 ¶ 61. For
`
`5
`
`Novartis Exhibit 2201.0010
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`purposes of my Initial Declaration, I did not offer a proposed POSA definition, and
`
`simply applied Petitioner’s definition. Id. ¶ 62. However, Petitioner’s definition
`
`does not reflect the reality of medical device development as of the priority date,
`
`which generally involves collaborative work between persons of ordinary skill in
`
`the art and others with complementary skills and experience. For example, in my
`
`experience developing medical devices, I have routinely consulted with healthcare
`
`providers (e.g., physicians), toxicologists, and microbiologists who specialize in
`
`sterilization of medical devices and pharmaceutical products.
`
`16. Therefore, in my opinion a POSA for all claims of the ’631 patent
`
`would have had an advanced degree (i.e., an M.S., a Ph.D., or equivalent), and at
`
`least 2–3 years of professional experience, in mechanical engineering, biomedical
`
`engineering, materials science, chemistry, chemical engineering, or a related field,
`
`including experience with 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.
`
`17. The distinction between this definition of a POSA and Petitioner’s
`
`does not impact my opinions set forth in my Initial Declaration, and my opinions
`
`set forth here would not change if the Board adopted Petitioner’s POSA definition.
`
`6
`
`Novartis Exhibit 2201.0011
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`18.
`
`The opinions I provide herein are provided from the perspective of a
`
`POSA as of July 3, 2012, which as explained in my Initial Declaration, I
`
`understand is the date of the earliest application to which the ’631 patent claims
`
`priority, and the date relied upon by Petitioner and their expert, Mr. Koller, in
`
`arguing obviousness. Ex. 2001 ¶ 28; IPR2021-0816, Paper 1, Petition for Inter
`
`Partes Review (Apr. 16, 2021) (“Pet.”) at 24; Ex. 1003 ¶ 10. My opinion would
`
`not change were the relevant date October 23, 2012, the date to which Mr. Koller
`
`admits the ’631 can claim priority. Ex. 1003 ¶ 95.
`
`FURTHER ANALYSIS OF PETITIONER’S OBVIOUSNESS
`ARGUMENTS
`The Prior Art, Including Boulange, Shows That a POSA Would
`Not Have Expected Syringes With Less Than 100 μg of Total
`Silicone Oil to Be Suitable for Intravitreal Injection
`Petitioner and Mr. Koller rely on Boulange for disclosure of syringes
`
`19.
`
`with less than 100 μg of silicone oil. However, a POSA would not have
`
`understood Boulange, or the prior art as a whole, as teaching that syringes with this
`
`amount of silicone oil could be used for intravitreal injections. As explained in
`
`more detail below, syringes in the prior art were generally lubricated with silicone
`
`oil in amounts well in excess of 100 μg. And contrary to Mr. Koller’s opinion, the
`
`prior art concerning baked-on silicone oil does not teach that baked on silicone oil
`
`uses less total silicone oil (as the ’631 patent claims), only less free silicone oil,
`
`i.e., silicone oil that is not tightly bonded to the glass surface. Mr. Koller thus cites
`
`7
`
`Novartis Exhibit 2201.0012
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`Boulange for disclosure of syringes lubricated with less than 100 μg of silicone oil.
`
`See, e.g., Ex. 1003 ¶ 64. But Boulange goes against the overall weight of the prior
`
`art with respect to the amount of silicone oil that a POSA would have thought
`
`would be necessary for a well-functioning syringe. And Boulange itself—which
`
`concludes that use of Parylene C as a novel syringe coating is necessary in order to
`
`use amounts of silicone oil in the claimed range in order to have acceptable syringe
`
`forces—reflects skepticism that a POSA would have had with syringes that had
`
`amounts of silicone oil in the claimed ranges for intravitreal injection. In other
`
`words, a POSA would have believed that more than 100 μg of silicone oil would
`
`be required to achieve acceptable forces unless a product like Parylene C was also
`
`applied.
`
`20. Prior art that addresses siliconization of syringes identifies silicone oil
`
`amounts that are well in excess of the claimed amounts. It was generally
`
`understood that more silicone oil provided better lubrication, i.e., increasing the
`
`amount of silicone oil on a syringe would lead to reduced syringe forces. See, e.g.,
`
`Ex. 2021, Reuter 2013 at .002 (the “obvious solution” to inadequate lubrication
`
`resulting in “the forces in the injection process… be[ing] too high” is “to increase
`
`the amount of silicone oil used”). A POSA would have understood that there were
`
`disadvantages of using excessive silicone oil, but that a trade-off would thus be
`
`needed between providing sufficient lubrication and avoiding problems associated
`
`8
`
`Novartis Exhibit 2201.0013
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`with having too much silicone oil. In general, the prior art suggested amounts of
`
`silicone oil that were far greater than those claimed in the ’631 patent. Because of
`
`the safety risks of high or inconsistent plunger forces, a POSA would not have
`
`traded inferior mechanical function for reduced silicone oil in a PFS for intravitreal
`
`injection.
`
`21. For example, Badkar, a 2011 article by Pfizer scientists about
`
`“Development of Biotechnology Products in Pre-filled Syringes” reports that a
`
`“survey of leading PFS manufactures resulted in our finding that the typical
`
`[silicone oil] levels reported vary between 0.5 and 1 mg silicone per syringe,” i.e.,
`
`500 to 1,000 μg. Ex. 1044, Badkar 2011 at .007. Reuter 2013, an article about
`
`syringe siliconization by the Director of Product Development at the syringe
`
`manufacturer Gerresheimer Bunde, reports the results of a study showing that in a
`
`1 mL syringe, “the quantity of silicone oil per syringe could be reduced by 40%”—
`
`from 800 μg to 500 μg—“without any impairment of the system’s functional
`
`properties.” See Ex. 2021.003. Reuter 2013 further states that “[i]nadequate
`
`siliconisation of the syringe barrel… can cause slip-stick effects that impair the
`
`syringe’s function,” and that “[t] obvious solution is to increase the amount of
`
`silicone oil used to achieve a homogenous coating.” Ex. 2021.002. Sacha, a 2010
`
`article entitled “Practical fundamentals of glass, rubber, and plastic sterile
`
`packaging systems” by authors from the Research and Development department at
`
`9
`
`Novartis Exhibit 2201.0014
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`Baxter BioPharma Solutions, states that among the “[p]re-filled syringe options,”
`
`silicone level “[v]aries, 0.6–1.0 mg per 1 mL syringe,” i.e., 600–1,000 μg per
`
`syringe. Ex. 2035, Sacha 2010 at .005. Fries, an article entitled “Drug Delivery of
`
`Sensitive Biopharmaceuticals With Prefilled Syringes” by the Head of Sales, USA
`
`Syringes and Director, Product Management Syringes at Gerresheimer Bunde,
`
`states that “[i]n established manufacturing processes on the lines of syringe
`
`suppliers, biopharmaceutical companies, and CMOs, syringes are oily siliconized
`
`by spraying 0.4- to 1.0-mg silicone oil (e.g., Dow Corning 360, Medical Fluid) into
`
`the barrels.” Ex. 1012, Fries 2009 at .006.
`
`22.
`
`In another example, scientists in the Pharmaceutical Processing and
`
`Technology Development department at Genentech reported the results of the
`
`development and optimization of a syringe siliconization process. See Ex. 2022,
`
`Chan 2012. In this report, the Genentech scientists worked to optimize the
`
`siliconization of syringes using spray-on oily siliconization with two different
`
`siliconization apparatuses. They varied siliconization parameters to apply various
`
`amounts of silicone oil and tested the impact of the different silicone oil
`
`applications on silicone oil distribution and syringe function, including by
`
`measuring glide forces. Ex. 2022.003–.014. Chan determined that “[t]here is a
`
`clear trend that, regardless of the spraying condition, the higher the amount of
`
`coated silicone, the easier the syringe passes the glide force test.” Ex. 2022.011.
`
`10
`
`Novartis Exhibit 2201.0015
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`By optimizing the siliconization conditions and in view of need to avoid “a high
`
`amount of silicone” for biopharmaceutical products, Chan further determined that
`
`“[t]he preferred silicone amount for the 1 mL long syringe is in the range of 0.2 to
`
`0.5 mg per syringe.” Id. Syringes with less than 100 μg of silicone oil were
`
`deemed “under-coated.” Ex. 2022.007.
`
`23. Genentech is a world leader in biotechnology and the developer of
`
`Lucentis. It is notable that, even as late as 2012, these Genentech scientists—
`
`despite acknowledging concerns about using high amounts of silicone oil with
`
`biopharmaceutical products—were still focused on spray-on siliconization rather
`
`than baked-on and had determined that the optimal amount of silicone oil was 2 to
`
`5-fold more than the top of the range claimed by the ’631 patent.
`
`24. The disclosures of these prior art references concerning silicone oil
`
`levels used in prior art syringes are consistent with
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`11
`
`Novartis Exhibit 2201.0016
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`
`
`
`
`, four-fold above the limit
`
`claimed in the ’631 patent.
`
`25.
`
`In view of the clear teachings of the prior art that even well-optimized
`
`syringes contained silicone oil well in excess of 100 μg, Mr. Koller opines that
`
`“[i]t was…well known prior to 2012 that the baked-on siliconization process
`
`requires only about one-tenth the amount of silicone oil as oily siliconization to
`
`achieve the same break loose and glide force.” Ex. 1003 ¶ 64. But the prior art
`
`that Mr. Koller cites does not support his assertion that baked-on siliconization
`
`allows use of less total silicone oil, but rather focuses on benefits of baked-on
`
`siliconization that include reduction of free silicone oil—the silicone oil that is not
`
`fixed to the glass surface—which is distinct from total silicone oil. Shah explains:
`
`“Baking-on the silicone involves heating the silicone-coated syringe to a specific
`
`temperature for an appropriate time which results in longer chains that are more
`
`12
`
`Novartis Exhibit 2201.0017
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`closely adhered to the surfaces they coat. Thus the concentration of silicone in the
`
`syringe and its chemical reactivity are both reduced and the product’s stability is
`
`increased.” Ex. 1011, Shah 2009 at .006. Indeed, Mr. Koller acknowledges the
`
`distinction between total silicone and free silicone oil. In his discussion of baked-
`
`on siliconization, he asserts that baked-on siliconization allows use of less silicone
`
`oil (Ex. 1003 ¶ 64), and that “[a]nother benefit” is that it “reduces the amount of
`
`‘residual’ or ‘free’ silicone oil, which refers to the quantity of silicone oil that is
`
`not affixed to the inner surfaces of the syringe barrel and thus could dislodge from
`
`the surface and enter the drug formulation.” Ex. 1003 ¶ 65.
`
`26. Other references similarly make clear that “free” silicone oil—not
`
`total—was understood in the prior art to be reduced as a result of baked-on
`
`siliconization (emphasis added unless noted):
`
`(cid:120) Badkar states that the baking process results in “longer chains of Si that are
`
`more closely adhered to the surfaces they coat, thus resulting in a reduced
`
`concentration of free silicone in these syringes and lower chemical
`
`reactivity.” Ex. 1044.003. Also, “sprayed-on syringes contained higher
`
`residual-free silicone compared to baked-on silicone syringes.” Ex.
`
`1044.004. Furthermore, despite testing and directly comparing syringes
`
`with both spray-on and baked-on silicone oil (see Ex. 1044.003), Badkar
`
`reports that syringes from “leading PFS manufactures” had silicone oil
`
`13
`
`Novartis Exhibit 2201.0018
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`levels that “vary between 0.5 and 1 mg silicone per syringe,” without
`
`distinguishing between spray-on and baked-on syringes (Ex. 1044.007).
`
`(cid:120) Fries explains that baked-on siliconization was “developed to lower the
`
`level of free (non-bound) silicone oil in prefilled syringes.” Ex. 1012.006.
`
`(cid:120) Schoeknecht states that “[b]aking-on the silicone… results in longer chains
`
`[of silicone oil] that are more closely adhered to the surfaces they coat. Thus
`
`the concentration of silicone in the syringe… [is] reduced.” Ex. 1013,
`
`Schoeknecht 2005 at .004.
`
`(cid:120) Overcashier states that after siliconization, “[s]yringes subsequently may be
`
`heated, resulting in so-call ‘baked silicone’ in an effort to reduce silicone
`
`mobility and interaction with the drug product.” Ex. 1076, Overcashier
`
`2006, at .003.
`
`(cid:120) The Nema textbook (Nema Vol. 1) states that “[r]ecent developments to
`
`minimize free silicone include baking silicone at high heat onto the glass
`
`barrels, thereby minimizing the amount of free silicone that can interact with
`
`drug product.” Ex. 1015.330.
`
`(cid:120) Sacha states that “[s]ilicone coatings, typically silicone emulsions, are
`
`sometimes applied (‘baked’) to the inner surfaces of vials to produce a
`
`hydrophobic surface.” Ex. 2035.0010. In Table 1, “Pre-filled syringe
`
`options,” Sacha identifies as “Silicone application” options “Silicone oil or
`
`14
`
`Novartis Exhibit 2201.0019
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`silicone emulsion, Applied at syringe manufacturer, Applied at finished
`
`product manufacturer.” Ex. 2035.005. For “silicone level,” it identifies
`
`“Varies, 0.6-1.0 mg per 1 mL syringe.” Id. Lower levels for syringes using
`
`baked-on emulsion are not identified.
`
`The prior art references thus do not suggest that baked-on siliconization generally
`
`allows a reduction in total silicone oil.1 And a POSA would not have known
`
`merely from the use of baked-on silicone oil in any particular context how much
`
`silicone oil was used.
`
`
`
`1 The only reference besides Boulange that Mr. Koller cites for his assertion that it
`
`was “well known prior to 2012 that the baked-on siliconization process requires
`
`only about one-tenth the amount of silicone oil as oily siliconization to achieve the
`
`same break loose and glide force” is Chacornac (Ex. 1014). See Ex. 1003 ¶ 64. I
`
`understand that Chacornac is not prior art because it was filed on October 17, 2011
`
`and published on April 19, 2012, after the inventors had conceived of their
`
`invention as of October 2011. Id. And, as discussed below, the data in Boulange
`
`does not support Mr. Koller’s contention. On the contrary, it shows that using
`
`baked-on silicone oil with one-tenth the amount results in higher break loose and
`
`glide force.
`
`15
`
`Novartis Exhibit 2201.0020
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`27.
`
`It is also notable that the primary reference that Mr. Koller and
`
`Petitioner rely on for the use of low silicone oil levels—Boulange—is a patent
`
`application that proposes use of a novel stopper coating in conjunction with baked-
`
`on silicone oil. Indeed, the need for Parylene C in order to allow reduction of
`
`silicone oil is the main premise of Boulange, and Boulange says that the baked-on
`
`silicone oil with reduced total amounts alone is unsuitable. Ex. 1008 at 21:4–21:5.
`
`This further demonstrates that it was not accepted in the prior art that the silicone
`
`oil levels in Boulange that Mr. Koller relies on were able to provide acceptable
`
`syringes—particularly in syringe for delicate procedures like intravitreal injection.
`
`If less than 100 μg of baked-on silicone oil was understood to be a sufficient
`
`amount for syringes to have acceptable forces, there would have been no reason for
`
`Boulange and Becton Dickinson to attempt to develop Parylene C as a new stopper
`
`coating.
`
`B.
`
`A POSA Would Not Have Been Motivated to Combine Boulange
`with Sigg or Lam and Would Not Have Had a Reasonable
`Expectation of Success in Doing So
`28. As discussed in my Initial Declaration, a POSA would not have been
`
`motivated to combine Boulange with Sigg or Lam (Ex. 2001 ¶¶ 106–49, 166–71),
`
`and also would not have had a reasonable expectation of success in doing so (Ex.
`
`2001 ¶¶ 150–65, 172–74). First, as discussed in my Initial Declaration (Ex. 2001
`
`¶¶ 175–85) and in more detail below (at §§ V.C and V.D), the prior art (including
`
`16
`
`Novartis Exhibit 2201.0021
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Sigg and Lam) would not have enabled a POSA to use the sterilization methods
`
`discussed in Sigg and Lam to terminally sterilize a syringe that both has the
`
`characteristics of Boulange’s syringes and is filled with a VEGF-antagonist. A
`
`POSA would have recognized the gaps in the prior art disclosures and as a result
`
`neither would have been motivated to fill Boulange’s syringes with a VEGF-
`
`antagonist and then attempt to sterilize them using Sigg or Lam’s methods, nor
`
`would have expected to succeed in the endeavor.
`
`29.
`
`Second, Boulange’s substantial shortcomings are inconsistent with
`
`both a motivation to combine Boulange with Sigg or Lam and a reasonable
`
`expectation of success in doing so. Because of the deficiencies associated with
`
`syringes disclosed in Boulange—both with and without Parylene C—a POSA
`
`would not have selected any of Boulange’s syringes to attempt to make a PFS
`
`filled with a VEGF-antagonist that is te