`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
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`__________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`__________
`
`
`REGENERON PHARMACEUTICALS, INC.,
`Petitioner
`
`v.
`
`NOVARTIS PHARMA AG,
`NOVARTIS TECHNOLOGY LLC,
`NOVARTIS PHARMACEUTICALS CORPORATION,
`Patent Owners
`
`__________
`
`
`IPR2021-00816
`U.S. Patent 9,220,631
`
`__________
`
`PATENT OWNERS’ SURREPLY TO PETITIONER’S REPLY
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`
`
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`REDACTED VERSION
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`

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`TABLE OF CONTENTS
`
`I.
`
`II.
`
`Introduction .................................................................................................. 1
`
`Petitioner Has Not Proven Motivation to Combine Boulange’s
`Syringes with Sigg or Lam .......................................................................... 2
`
`A.
`
`B.
`
`C.
`
`A POSA Would Not Use a Parylene-C Coated Stopper With a
`VEGF-Antagonist .............................................................................. 2
`
`A POSA Would Not Use a Syringe Known to Have
`Inconsistent, Rising Forces ............................................................... 5
`
`Becton Dickinson (“BD”) Prefilled Syringes
` ............................................................. 6
`
`D.
`
`Boulange Teaches Aseptic Filling..................................................... 6
`
`III.
`
`Petitioner Has Not Proven Reasonable Expectation of Success ................. 7
`
`A.
`
`B.
`
`C.
`
`Terminally Sterilizing a PFS Without Degrading the VEGF-
`Antagonist Was Unpredictable .......................................................... 7
`
`Novartis’s
`
` .................................. 9
`
`The Prior Art Did Not Disclose Macugen PFS Being
`Terminally Sterilized .......................................................................10
`
`D.
`
`Petitioner
`
` ....................................................................................11
`
`IV.
`
`Petitioner Has Not Proven that Certain Dependent Claims Are
`Unpatentable ..............................................................................................13
`
`A.
`
`B.
`
`Claim 21 ..........................................................................................13
`
`Claims 24-26 ...................................................................................17
`
`V.
`
`Secondary Considerations Expose Petitioner’s Arguments as
`Hindsight-Driven .......................................................................................18
`
`A.
`
`Failure of Others ..............................................................................18
`
`1.
`
`2.
`
`3.
`
`Genentech ..............................................................................18
`
`Macugen PFS ........................................................................19
`Regeneron .............................................................................20
`
`Commercial Success........................................................................20
`
`Long-Felt Need ................................................................................24
`
`Skepticism .......................................................................................25
`
`B.
`
`C.
`
`D.
`
`i
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`REDACTED VERSION
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`

`

`E.
`
`Licensing .........................................................................................26
`
`VI. Conclusion .................................................................................................27
`
`ii
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`REDACTED VERSION
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`

`

`I.
`
`Introduction
`
`IPR2021-00816
`U.S. Patent 9,220,631
`
`The pre-filled syringes (“PFS”) claimed in the ’631 patent are a complex
`
`combination of elements that work together to solve the long-felt need for a safe,
`
`low silicone oil, terminally sterilized PFS for intravitreal injection of a VEGF-
`
`antagonist. Instead of looking at the invention as a whole, Petitioner attempts to
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`meet its burden by reducing the invention to its component parts and arguing
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`motivation and reasonable expectation of success of individual claim elements.
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`Even that effort fails.
`
`Petitioner has not rebutted the evidence that, as of the priority date, major
`
`pharmaceutical companies had tried and failed to make a PFS having the claimed
`
`characteristics. That objective evidence–demonstrating that making the claimed
`
`syringe was a difficult and unpredictable task–undermines Petitioner’s simplistic
`
`arguments and exposes them as hindsight. This is especially true for the inventions
`
`of claims 21 and 24-26. The evidence, including admissions by Petitioner’s expert,
`
`shows that a person of ordinary skill in the art (“POSA”) would not have had a
`
`reasonable expectation of being able to terminally sterilize the claimed PFS to a
`
`sterility assurance level (“SAL”) of 10-6 without unacceptably degrading the
`
`VEGF-antagonist active ingredient. Similarly, the evidence shows that a POSA
`
`would not have been motivated to use the Boulange syringes in a PFS to treat
`
`patients. Accordingly, the Board should confirm the patentability of the claims.
`
`REDACTED VERSION
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`

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`IPR2021-00816
`U.S. Patent 9,220,631
`
`II.
`
`Petitioner Has Not Proven Motivation to Combine Boulange’s Syringes
`with Sigg or Lam
`
`A.
`
`A POSA Would Not Use a Parylene-C Coated Stopper With a
`VEGF-Antagonist
`
`Petitioner’s argument that a POSA would have been motivated to combine
`
`Boulange’s Syringe B1 with Sigg or Lam rests on Mr. Koller’s opinion that a
`
`POSA would have used Parylene-C in a PFS for intravitreal injection of a VEGF-
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`antagonist. (Petition, 35; see also, Ex. 1103, ¶172.) As demonstrated in the Patent
`
`Owner Response (“POR”), however, Mr. Koller is not qualified to provide that
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`opinion and failed to address the relevant prior art. (POR, 10.) Petitioner has
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`therefore not met its burden on this issue. Petitioner’s belated attempt to rectify the
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`shortcomings in its prima facie case with the declaration of toxicologist Dr. Cohen
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`(Ex. 1108) fails.
`
`First, Dr. Cohen admits the prior art cited in the POR (Exs. 2030-2031)
`
`teaches that proteins adsorb to Parylene-C. (Ex. 1108.015, ¶30.) He argues a
`
`POSA would nevertheless not be deterred from using Parylene-C in a VEGF-
`
`antagonist-filled PFS because the references “encourage” its use “in medical
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`applications.” (Petitioner’s Reply to Patent Owner’s Response (“Reply”), 5; Ex.
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`1108.0014, ¶ 29.) As Dr. Cohen conceded, however, the known “medical
`
`applications” of Parylene-C were for implantable devices, and there was no
`
`2
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`REDACTED VERSION
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`

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`IPR2021-00816
`U.S. Patent 9,220,631
`
`teaching that Parylene-C could be used in a PFS, or other container, used to store
`
`protein drugs. (See e.g., Ex. 2340.019, 68:6-18; 69:9-70:2.) Boulange itself makes
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`no mention of using its syringes to administer protein drugs.
`
`The limited use of Parylene-C with implantable devices would not motivate
`
`a POSA to use it in a PFS filled with a VEGF-antagonist protein drug for
`
`intravitreal injection. (Ex. 2202.0031, ¶54; .0034, ¶59.) As Dr. Dillberger
`
`explained, a POSA would understand that protein adsorption would be desirable
`
`for an implantable device, but would be dangerous for a PFS for intravitreal
`
`injection of a VEGF-antagonist. (Ex. 2202.0039, n.2; see also Ex. 1015.241
`
`(“[Protein] adsorption can significantly impact a protein drug’s potency, stability
`
`and safety.”)) Dr. Cohen did not challenge Dr. Dillberger’s opinion. The use of
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`Parylene-C in the implantable “biomedical applications” of the prior art would
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`therefore deter, not encourage, a POSA from using it in a pharmaceutical
`
`application with a VEGF-antagonist. (Ex. 2202.0031, ¶54; .0034, ¶59.)
`
`Petitioner’s assertion that “the prior art teaches that Parylene-C has
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`comparable properties to silicone oil” (Reply, 5) is simply incorrect. The only
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`prior art cited for this point is Chang (Ex. 2030), but Chang makes no mention of
`
`silicone oil. It compares Parylene-C to a cured (i.e., solid) material called PDMS,
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`which Dr. Cohen confirmed is not silicone oil. (Ex. 2340.0029, 112:13-21.)
`
`
`
`3
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`REDACTED VERSION
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`

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`IPR2021-00816
`U.S. Patent 9,220,631
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`Second, Petitioner makes a new argument that a POSA would not worry
`
`about the Parylene-C on Boulange’s stopper because it would not contact the
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`VEGF-antagonist drug. (Reply, 6.) This argument is contrary to the teachings of
`
`Boulange, Mr. Koller’s prior testimony, and prior art cited in the Petition. As seen
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`below, Figure 2 of Boulange shows Parylene-C (8) coating the whole stopper (3).
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`(Ex.1008.001; .011, ll. 11-35; .012, ll. 8-35; .013, ll. 3-16.)
`
`
`Consistent with Figure 2, Boulange describes depositing Parylene-C over the
`
`
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`“entire accessible developed surface . . . completely (with no discontinuity).” (Ex
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`1008.005, ll. 7-13; see also .003, ll. 27-31.)
`
`Moreover, while Mr. Koller now contends that a POSA would apply the
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`Parylene-C coating to only part of the stopper and cover the rest with Fluorotec
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`(Ex. 1105.019, ¶29), he said the opposite at his earlier deposition:
`
`Q. Regardless of whether the FluroTec is just on the tip or it's on the sides,
`when you do the plasma deposition of the parylene C, you're going to
`cover the whole thing up, right?
`
`
`
`4
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`REDACTED VERSION
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`

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`IPR2021-00816
`U.S. Patent 9,220,631
`
`A. Right.
`
`Q. So the FluroTec won't have any effect on the stop -- the function of that
`stopper, right?
`
`A. Right.
`
`(Ex. 2189.0025, 95:21-96:2.) His current opinion is also inconsistent with
`
`Wolgemuth, a reference he himself cites, which teaches that the method of
`
`applying Parylene-C to an object coats “all surfaces” and “penetrates into every
`
`crevice.” (Ex. 1003.111-112, ¶175; Ex. 1072.003-004.)
`
`B.
`
`A POSA Would Not Use a Syringe Known to Have Inconsistent,
`Rising Forces
`
`As demonstrated in the POR, the description of Syringe C in Table 5 as
`
`“markedly inferior” qualifies as a teach away under Federal Circuit law. (POR, 4,
`
`14, 17.) Petitioner fails to distinguish, or even address, Patent Owner’s cases.
`
`Additional information in Boulange would further deter a POSA from using the
`
`syringe for intravitreal injection.
`
`Petitioner’s argument that a POSA would use Syringe C because its break
`
`loose forces remain within the claimed range over one month of aging misses the
`
`point. Even though the forces remain under 11N, they almost double over that
`
`period. A POSA would be concerned those inconsistent forces would continue to
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`rise, making the syringe unsuitable for intravitreal use. (Ex. 2204.0036, ¶72,
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`5
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`REDACTED VERSION
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`

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`IPR2021-00816
`U.S. Patent 9,220,631
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`.0052, ¶98, .0066, ¶131; Ex. 2001.00101, ¶¶145-149.)
`
`Petitioner’s argument that a POSA would use a siliconized stopper is also
`
`inconsistent with its argument (made for the first time on Reply) that a POSA
`
`would be concerned about all sources of silicone oil in a PFS, including on the
`
`stopper. (Reply, 25.) If Petitioner is correct, a POSA would not be motivated to
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`use stopper C because it would simply be replacing silicone oil on the barrel with
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`silicone oil on the stopper.
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`C. Becton Dickinson (“BD”) Prefilled Syringes Were
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`
`Petitioner argues a POSA would have looked to Boulange because it was
`
`assigned to BD, “a world leader in pre-filled syringe design, including for
`
`intravitreal injection.” (Pet. 33, cited IPR2021-0816, Paper 13, Institution
`
`Decision, 4.) The testimony of BD’s representative, Mr. Moyer,
`
`
`
`
`
`
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`104:6-105:6.) Consistent with that fact, Boulange makes no mention of the
`
` (Ex. 2346.027,
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`syringes being used for intravitreal administration.
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`D. Boulange Teaches Aseptic Filling
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`Petitioner does not dispute that Boulange makes no mention of “terminal
`
`sterilization,” yet argues that it cannot teach “aseptic filling” because those words
`6
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`REDACTED VERSION
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`

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`IPR2021-00816
`U.S. Patent 9,220,631
`
`do not appear in the reference. (Reply, 8 n.5.) Boulange discloses, however, the
`
`syringe components are sterilized before the syringe is filled with the active. (Ex.
`
`1008.006, 10-11 (“Over time, that is to say as soon as the medical device has been
`
`filled with the medical product ….”)) Terminal sterilization, on the other hand,
`
`takes place after the syringe is filled. (Ex. 1003.051, ¶ 81.) A POSA would be
`
`very familiar with aseptic filling, which is an alternative to terminal sterilization.
`
`As Mr. Agalloco testified, more of his clients use aseptic processing than terminal
`
`sterilization for drugs and medical products. (Ex. 2339.016-17, 60:4-7; 60:16-
`
`61:22.) There would therefore be no motivation for a POSA to combine Boulange
`
`with a reference that teaches terminal sterilization, and any suggestion to do so
`
`relies on impermissible hindsight.
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`III. Petitioner Has Not Proven Reasonable Expectation of Success
`
`A. Terminally Sterilizing a PFS Without Degrading the VEGF-
`Antagonist Was Unpredictable
`
`While Petitioner and Mr. Koller attempt to paint terminal sterilization using
`
`VHP and EtO as routine, Petitioner referred to it internally as
`
`
`
`”. (Ex. 2341.0016-17, 60:16-63:3; see also for context Ex.
`
`2344.001.) And Mr. Agalloco testified that it was “universally acknowledged” to
`
`be “the most difficult of all pharmaceutical production activities to execute.” (Ex.
`
`2339.015, 55:6-20.) Petitioner’s argument therefore rests on a false premise, and
`7
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`
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`REDACTED VERSION
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`

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`IPR2021-00816
`U.S. Patent 9,220,631
`
`the lack of disclosure of how to achieve terminal sterilization in this specific case–
`
`a PFS for intravitreal injection of a VEGF-antagonist–would be a significant
`
`obstacle for a POSA.
`
`Petitioner argues a POSA would reasonably expect Boulange’s syringes to
`
`withstand terminal sterilization because Boulange “provides teachings regarding
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`gas tightness” and “discloses a siliconized stopper.” (Reply, 8.) Boulange’s
`
`discussion of gas tightness, however, is aspirational. Boulange provides no syringe
`
`design and contains no teaching as to how to achieve sufficient “gas tightness” to
`
`terminally sterilize a syringe without degrading the protein contained within. (Ex.
`
`2347.0012-13, 247:4-12, 276:3-10.) Moreover, as Mr. Agalloco testified, EtO and
`
`VHP can absorb into the rubber stopper of a PFS and leach into the drug over time.
`
`(Ex. 2339.005, 14:18-15:16.) There is nothing in Boulange addressing how to
`
`prevent sterilizing gas from reaching the VEGF-antagonist through that
`
`mechanism.
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`Petitioner also attempts to minimize the problem of stopper movement
`
`caused by sterilization by asserting that Sigg’s VHP method could be done at
`
`ambient pressure rather than under vacuum. (Reply, 9.) But Mr. Agalloco testified
`
`that as of 2012 the VHP method POSAs knew was performed under vacuum, and
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`that, in any event, a vacuum would be used at the end of the process to remove
`
`
`
`8
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`REDACTED VERSION
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`

`

`IPR2021-00816
`U.S. Patent 9,220,631
`
`residual gases. (Ex. 2339.0009-10, 32:2-11; 32:16-33:3; .012, 41:10-18.)
`
`Finally, Petitioner argues Patent Owner’s position that a VEGF-antagonist-
`
`filled PFS must be specially designed to withstand terminal sterilization cannot be
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`correct because the ’631 patent does not provide sufficient disclosure of such a
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`PFS. (Reply, 9) Petitioner is incorrect. The ’631 patent identifies the problem and
`
`provides extensive disclosure of a PFS that solves it. (See, e.g., Ex. 1001.004,
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`1:14-43; .004-.005, 2:33-3:61; .008, 9:49-10:22; .008-.009, 10:47-12:20; .003,
`
`Figs. 1-5.) In any event, whether the ’631 patent’s disclosure is sufficient is not a
`
`subject for this IPR. The question here is whether Petitioner has proven a POSA
`
`would have had a reasonable expectation of success in achieving terminal
`
`sterilization of Boulange’s syringe if it contained a VEGF-antagonist solution. It
`
`has not.
`
`B.
`
`Novartis’s
`
` Dr. Sigg’s declaration is supported by contemporaneous
`
`documents, and Mr. Agalloco agreed to that at deposition. (See, e.g., Ex. 2339.23,
`
`86:11-18; .024. 92:10-15; Ex. 2206.0014, ¶¶39-40.) Petitioner nevertheless claims
`
`that Dr. Sigg’s testimony on this issue is “not credible,” pointing to a PTO
`
`declaration that Dr. Sigg submitted in March 2013 during prosecution of the Sigg
`
`9
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`REDACTED VERSION
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`

`

`IPR2021-00816
`U.S. Patent 9,220,631
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`application. (Reply, 12, citing Ex. 1252.209-.222.) That declaration, however, is
`
`completely consistent with Dr. Sigg’s testimony that
`
`explained in his declaration,
`
` As Dr. Sigg
`
`
`
`
`
`
`
`1 (Ex. 2206.0015-16, ¶¶42-48; Ex. 1213.090-91, ¶90:6-
`
`91:5.)
`
`C. The Prior Art Did Not Disclose Macugen PFS Being Terminally
`Sterilized
`
`Macugen PFS is not a printed publication so there is nothing “false” about
`
`asserting it is not prior art for purposes of this IPR. (Reply, 14.) The Macugen
`
`label, the only printed publication that Petitioner cites, does not mention terminal
`
`sterilization, and Mr. Agalloco testified he is unaware of any prior art disclosure on
`
`that point. (Ex. 1009.008-009; Ex. 2189.086, 86:18-87:3.) Petitioner attempts to
`
`support its argument with non-public FDA documents,
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`
`
`
`
`
`1 Petitioner takes advantage of the fact that Dr. Sigg is not a native English speaker
`to unfairly accuse him of being “misleading” in his declaration. (Reply, 12-13 fn.
`6.)
`
`
` (Ex. 1213.076-80, 76:20-80:17.)
`10
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`REDACTED VERSION
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`IPR2021-00816
`U.S. Patent 9,220,631
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`2 (Ex. 1220.091.)
`
`Even if Macugen was terminally sterilized, Petitioner has not cited any
`
`evidence indicating how long it took for the process to be developed. Macugen
`
`PFS
`
`
`
`
`
` This is far from proof that terminal sterilization “was
`
`within the level of ordinary skill in the art.” (Reply, 14) If anything, it shows that
`
`it took a tremendous amount of experimentation to get
`
` to work
`
`(assuming that it did).
`
`D.
`
`Petitioner
`
`
`Petitioner’s claim that “
`
`
`
` (Reply, 26) does not
`
`survive scrutiny, and in fact evidences the difficulty of terminally sterilizing a PFS
`
`containing a VEGF-antagonist. The declaration of its employee Dr. Graham
`
`
`2 Mr. Koller cites to Novartis internal documents that
`
`
`
`
`
`
`
`. (See, e.g.,
`Ex. 1105.077, ¶¶146, 147, 151-152; Ex. 2347.034, 359:14-360:7; .035, 364:10-14.)
`11
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`REDACTED VERSION
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`IPR2021-00816
`U.S. Patent 9,220,631
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` (Ex. 2341.007, 21:6-22:4; .010, 34:10-22; 35:19-36:5; Ex. 2342.013,
`
`.017, .018, .021–22.)
`
`
`
`
`
`
`
`
`
`
`
` (Ex. 2341.011, 37:17-38:3; Ex. 2343.002.)
`
`(Ex. 1002.015-16, ¶ 33.)
`
` (Ex. 2341.017, 61:8-62:9.)
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`
`
`
`
`
`
`
`
`Dr. Graham omitted additional evidence showing that
`
`
`
` (Ex. 2341.012, 41:16-57:7;
`
`see also Ex. 2349.0001; Ex. 2350.0003; Ex. 2351; Ex. 2352.0002.) And in August
`
`2017, an email from a Regeneron executive to the company’s CEO acknowledged
`
`that “
`
`
`
`
`
`” (Ex. 2341.015, 60:16-63:3; see also Ex. 2344.0001.) If anything,
`
`Regeneron’s struggles show that it would have taken a POSA extensive
`
`
`
`12
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`REDACTED VERSION
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`IPR2021-00816
`U.S. Patent 9,220,631
`
`experimentation to be able to terminally sterilize a PFS containing a VEGF-
`
`antagonist.
`
`IV. Petitioner Has Not Proven that Certain Dependent Claims Are
`Unpatentable
`
`A. Claim 21
`
`Neither Sigg nor Lam discloses an SAL of 10-6 for their VHP and EtO
`
`processes. As Dr. Miller explained, Mr. Koller’s opinion that the “6-log
`
`reduction” in Lam corresponds to an SAL of 10-6 was scientifically erroneous, and
`
`Mr. Agalloco agreed that a 6-log reduction is not a disclosure of an SAL of 10-6.
`
`(Ex. 2203.0038, ¶¶ 89, 90; Ex. 2339, 117:10-14.) As this error makes clear, Mr.
`
`Koller was unqualified to opine on the obviousness of terminal sterilization in
`
`general and Claim 21 in particular, and Petitioner has therefore failed to meet its
`
`burden of proof.3
`
`With respect to Sigg, Mr. Agalloco admitted that the only disclosure of
`
`achieving an SAL of 10-6 was for the beta radiation method of Example 2, and the
`
`only claim to a process achieving an SAL of 10-6 was for beta radiation. (Ex.
`
`2339.025, 94:21-97:19.)
`
`
`3 Petitioner was apparently aware Mr. Koller’s opinions would be insufficient, as
`in its previous IPRs on the ’631 patent, it submitted Mr. Agalloco’s declaration
`together with its Petition rather than in Reply. See IPR2020-01317, Ex. 1005;
`IPR2020-01318, Ex. 1005; IPR2020-01320, Ex. 1005.
`13
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`REDACTED VERSION
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`

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`IPR2021-00816
`U.S. Patent 9,220,631
`
`Petitioner has also not proven that a POSA would have reasonably expected
`
`to achieve an SAL of 10-6 when terminally sterilizing a PFS containing a VEGF-
`
`antagonist. The only evidentiary support in the Petition was Mr. Koller’s opinion
`
`that doing so would have been a matter of “routine optimization.” (Ex. 1003.152-
`
`153.) But, as set forth above, Mr. Koller’s opinions on what would have been
`
`“routine” lack credibility. (POR, 35-36.) Mr. Agalloco’s testimony demonstrates,
`
`on the contrary, the art was unpredictable.4
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`“Terminal sterilization” requires not only sterilizing the outside of the PFS,
`
`but also “minimizing contact between the drug product within the pre-filled
`
`syringe and sterilizing agent” so that the process “does not ‘cause unacceptable
`
`modification of the ophthalmic solution.’” (Institution Decision at 34 (quoting Ex.
`
`1001, 10:5-7.) Far from being “routine,” Mr. Agalloco testified that achieving an
`
`SAL of 10-6 without unacceptably degrading the drug product can require
`
`“extensive experimentation” and that “it’s all circumstance dependent.” (Ex.
`
`2339.030, 113:11-114:9.)
`
`
`4 Petitioner claims Patent Owner’s position that it would take more than routine
`experimentation to achieve an SAL of 10-6 “cannot be reconciled with the ’631
`patent.” (Reply, 20.) As discussed supra at 8, however, the ’631 patent contains
`detailed disclosure of a PFS that permits reaching an SAL of 10-6, and regardless,
`the sufficiency of the ’631 patent’s disclosure is not a subject for this IPR.
`14
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`REDACTED VERSION
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`IPR2021-00816
`U.S. Patent 9,220,631
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`Mr. Agalloco agreed that sometimes an SAL of 10-6 cannot be achieved even
`
`with extensive experimentation, and a less stringent SAL must be used. (Ex.
`
`2339.019, 71:20-72:3.) As Mr. Agalloco explained, “duration of the process, the
`
`concentration of the agent, the temperatures involved, the humidity . . . alone or in
`
`combination could result in your inability to achieve the 10-6 and allow you to
`
`defer to something less.” (Id., 72:10-16.) Indeed, the industry guidelines
`
`recognize that sometimes a terminal sterilization process cannot be designed that
`
`will “achieve an SAL of 10-6 without adversely affecting the essential safety and
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`function” of the product. (Ex. 2187.0015.)
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`While Mr. Agalloco opined in his declaration that “[d]etermining the SAL of
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`a sterilization process would be routine and well within the ordinary skill of a
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`POSITA prior to 2012” (Ex. 1100.014), he explained at deposition that this opinion
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`related only to the ability of a POSA to perform a sterilization process and
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`determine the resulting SAL, not to whether the sterilization process would achieve
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`an SAL of 10-6 without degrading the drug product. (Ex. 2339.020, 76:6-12.) Dr.
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`Miller’s testimony that methods of sterilizing a PFS to an SAL of 10-6 were known
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`(cited at Reply, 16) similarly speaks to the sterilization methods themselves, not to
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`whether a POSA would reasonably expect to achieve an SAL of 10-6 without
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`unacceptably degrading a VEGF-antagonist drug product using those methods.
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`(See, e.g., Ex. 2203.0021-24, ¶¶49-55; .0040, ¶94.)
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`Petitioner’s argument that Lam teaches achieving higher log reductions by
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`increasing sterilization time would not help a POSA. (Reply, 20-21.) As Mr.
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`Agalloco testified, a POSA would know that increasing the sterilization time can
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`degrade the active ingredient. (Ex. 2339.021, 77:2-7.) As shown in Lam Table 2,
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`the syringes of Runs 4 and 5 (the runs reported to achieve a 6-log reduction) were
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`never tested for loss of potency, so a POSA would have no idea what would
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`happen to the VEGF-antagonist if the sterilization times were doubled. (Ex.
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`2203.0033, ¶78.)
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` The difficulty of achieving an SAL of 10-6 without unacceptably modifying
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`the VEGF-antagonist is demonstrated by Genentech’s
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` (Ex. 2339.0029, 109:20-110:5.)
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`While Petitioner asserts Genentech
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` (Ex. 2203.0022-24, ¶¶51-55; .0031, ¶¶73-74;
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`.0035-.0038, ¶¶83-88; .0040, ¶94.) Petitioner has failed to meet its burden on
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`Claim 21.
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`B.
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` Claims 24-26
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`A POSA would be even less motivated to use Boulange’s syringes for
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`claims 24-26, which are methods of treating patients. An ophthalmologist would
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`not want to use a PFS for intravitreal injection of a VEGF-antagonist if it contained
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`Parylene-C, which was known to interact with proteins and had not been approved
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`by the FDA for such use. (Ex. 2345.017, 17:9-20; see also Ex. 2204.0016, ¶33;
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`.0066, ¶134; Ex. 2202.003, ¶¶53-59.) As Dr. Kiss opines, an ophthalmologist
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`would expect the stopper coatings on a PFS “had been specifically approved for
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`intravitreal injection.” (Ex. 1106.009, ¶11.) Dr. Kiss’s reluctance to treat his
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`patients with Avastin PFS, a VEGF-antagonist sold “in a variety of syringes” not
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`“specifically approved for intravitreal injection” (id.; Ex. 2345.004) exemplifies
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`that fact.
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`An ophthalmologist would similarly not be motivated to use a PFS that had
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`inconsistent forces because it could damage a patient’s eye. Dr. Kiss agreed “that
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`a PFS for intravitreal injection should have suitable forces to enable a physician to
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`administer the injection.” (Ex. 1106.011, ¶ 14.) As Dr. Kiss testified, he wants a
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`PFS with forces that he “do[esn’t] have to think about.” (Ex. 2345.018, 18:15-
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`19:8.) This is consistent with Mr. Koller’s opinion that the break loose effect is
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`potentially dangerous to a patient because “the user cannot detect the problem until
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`the point of administration when they try to depress the plunger,” at which point
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`the needle has already penetrated the patient’s eye. (Ex. 1003.035, ¶ 59 (quoting
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`Ex. 1013.004).) Petitioner therefore has failed to meet its burden on claims 24-26.
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`V.
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`Secondary Considerations Expose Petitioner’s Arguments as Hindsight-
`Driven
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`A.
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`Failure of Others
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`1.
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`Genentech
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`The evidence does not support Petitioner’s claim that Genentech
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` (Reply, 26.) It establishes instead Genentech
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`(Ex. 2203.0022-24, ¶¶51-55; .0035-.0038, ¶¶83-88; .0040, ¶94.) None of the
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`documents Mr. Agalloco cites attribute Genentech’s
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` Rather, they explain that
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` As Mr. Agalloco conceded,
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`
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`
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`20:11.) Based on Mr. Agalloco’s testimony, the degradation Genentech
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`18
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` (Ex. 2339.006, 18:18-
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`.
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`Mr. Agalloco’s opinion also ignores Genentech’s own findings on the issue.
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`As Dr. Miller testified, Genentech concluded
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`
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` (Ex. 1210.132-135, 132:16-135:3; .150, 150:6-154:2; Ex. 2115.008)
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` (Id.)
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` (Id.)
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` Finally, Petitioner’s argument does not apply to claim 21, as Petitioner does
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`not contend Genentech
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`2. Macugen PFS
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`While Petitioner characterizes Macugen as a “success,” it was a failure in
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`terms of the inventions of the ’631 patent. It is undisputed Macugen
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` (Ex. 2189.0047 84:19-22.) Even though there
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`
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`was strong motivation to do so, as Petitioner repeatedly argues (see, e.g., Pet. 31;
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`Reply, 7), Pfizer never lowered the amount of silicone oil on the syringe.
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`Petitioner’s claim this was due to Macugen’s declining sales (Reply, 26) is pure
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`conjecture.
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`Finally, Petitioner has not contended Macugen PFS achieved an SAL of 10-6,
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`so its argument does not apply to claim 21.
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`3.
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`Regeneron
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` As set forth above at 11, the evidence demonstrates that as of 2012
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`Regeneron had failed to successfully terminally sterilize Eylea PFS so in fact
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`demonstrates the failure of others.
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`B. Commercial Success
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`Regeneron’s expert admits
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`
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`(Ex. 2348.0007, 24:6-8; .0011, 37:21-38:6, .0011, 40:10-18.) Dr. Kiss agreed
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`physicians prefer PFS over vial presentations, and he testified that he switched all
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`his patients from Lucentis vial to Lucentis PFS when it came on the market. (See,
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`e.g., Ex. 1106.021-23; Ex. 2344.026, 26:4-19.)
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`Petitioner insists this real world evidence should be ignored because
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`Lucentis PFS is not coextensive with the ’631 claims. That assertion is misplaced
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`because Lucentis PFS is “essentially the claimed invention,” (see POR, 49-54; Ex.
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`2201.00150, ¶287) and a nexus should therefore be presumed. Fox Factory, Inc. v.
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`SRAM, LLC, 944 F.3d 1366, 1374 (Fed. Cir. 2019).
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`Petitioner’s argument that the commercial success of Lucentis PFS is due to
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`unclaimed features is meritless. Among the purported “unclaimed features” are
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`Lucentis PFS’s tip cap, plunger rod and stopper. But these are not additional
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`unclaimed elements. As Dr. Koller opined, they are standard components of any
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`PFS (Ex. 1003.061, ¶93), and are therefore encompassed within, and are one
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`embodiment of, the PFS of the claims. Nor is baked on siliconization an
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`unclaimed feature as Petitioner contends. It is simply the prior art method of
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`applying lower amounts of silicone oil.
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`Fox Factory, Inc. v. SRAM, LLC, 944 F.3d 1366 (Fed. Cir. 2019), cited by
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`Petitioner, does not lead to a different result. In that case, the Court illustrated the
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`situation where commercial success is not coextensive with the claimed invention
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`with the example of sales of an automobile being used to support the
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`nonobviousness of a claim to brake pads. (Reply, 22.) Unlike the brake pads,
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`Lucentis PFS is an embodiment of the claims but is not a component of a larger
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`product to which commercial success can be attributed.
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`
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` Thus, nexus
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`should be presumed.
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`Petitioner’s remaining arguments on nexus are little more than legally
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`flawed hand-waving. First, Petitioner suggests that physicians’ rapid and
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`overwhelming adoption of Lucentis PFS over the vial is due to “features that were
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`known in the art” – like improved convenience – and thus do not enjoy a nexus to
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`the ’631 patent claims. As discussed in the POR, this argument is legally incorrect
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`as it fails to consider the invention as a whole – in this case, a terminally sterilized
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`PFS containing a VEGF-antagonist with low break-loose forces and less than 100
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`µg (or 50 µg) of silicone oil. The improved convenience physicians enjoy with
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`Lucentis PFS would not have been possible without the claimed invention, which
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`addressed the unique difficulties posed by a PFS for intravitreal injection of a
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`VEGF-antagonist.
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`While Petitioner acknowledges the Federal Circuit law that a patentee “need
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`not sell every conceivable embodiment of the claims in order to rely upon evidence
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`of commercial success” (citing In re Kao, 639 F.3d 1057, 1069 (Fed. Cir. 2011)), it
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`proceeds to ignore that precedent and argue that Novartis bears the burden of
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`proving the commercial success of every embodiment of the claims. (Reply, 23.)
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`In re Greenfield, 571 F.2d 1185, 1189 (C.C.P.A. 1978), cited by Petitioner, is
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`inapplicable as it concerned the entirely different question of what showing needs
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`to be made to establish unexpected results.
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`Petitioner’s suggestion that
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`
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`
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` (Ex.
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`2347.0020, 303:6-18.)
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`Finally, Petitioner faults Novartis for not setting forth evidence “linking any
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`commercial success to the specific claimed features” of the ’631 patent. (Reply,
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`24.) First, this ignores that Novartis is entitled to a presumption of nexus because
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`Lucentis PFS is coextensive with the ’631 patent claims. Second, Novartis has
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`demonstrated – through Mr. Malackowski’s declaration, which relied on
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`contemporaneous records from Novartis and Roche – that
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`
`
`
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` (Ex. 2205.0026, ¶¶ 39-44.) Regeneron’s expert
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`conceded that she had not done her own analysis of this issue and that
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`23
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`REDACTED